Integrative oncology [Second edition] 9780199329724, 0199329729

Table of contents :
1. Why Integrative Oncology?
2. An Integrative Approach to Cancer Prevention
3. Molecular Targets of Botanicals Used for Chemoprevention
4. Research Methodology Challenges in Integrative Oncology
5. Diet and Cancer: Epidemiology and Prevention
6. Nutritional Interventions in Cancer
7. Botanical Medicine in Integrative Oncology: What is Known?
8. Cannabinoids and Cancer
9. Botanical-Drug Interactions in Oncology - What Is Known?
10. The Antioxidant Debate
11. Physical Activity and Cancer
12. Massage Therapy
13. Mind-Body Medicine in Integrative Cancer Care
14. Music and Expressive Arts Therapies
15. Energy Medicine and Cancer
16. The Role of Spirituality
17. Naturopathic Oncology
18. Traditional and Modern Chinese Medicine
19. Ayurveda and Yoga for Cancer Supportive Care
20. Anthroposophic Medicine, Integrative Oncology, and Mistletoe Therapy of Cancer
21. Integrative Medicine and Breast Cancer
22. Prostate Cancer: An Integrative Approach
23. Integrative Medicine in Colorectal Cancer: Role of Energy Balance as Treatment
24. Lung Cancer: An Integrative Approach
25. Integrative Therapies in Cancer Symptom Management
26. Alternative Therapies as Primary Treatments for Cancer
27. Communication Issues in Integrative Oncology
28. Tending the Spirit in Cancer
29. A Patient's Perspective

Citation preview

Integrative Oncology

Integrative Medicine Library Published And Forthcoming Volumes SERIES EDITOR

Andrew T. Weil, MD Donald I. Abrams and Andrew T. Weil: Integrative Oncology Timothy Culbert and Karen Olness: Integrative Pediatrics Daniel A. Monti and Bernard D. Beitman: Integrative Psychiatry Victoria Maizes and Tieraona Low Dog: Integrative Women’s Health Gerard Mullin: Integrative Gastroenterology Randy Horwitz and Daniel Muller: Integrative Rheumatology, Allergy, and Immunology Stephen DeVries and James Dalen: Integrative Cardiology Robert Norman, Philip Shenefelt, and Reena Rupani: Integrative Dermatology Myles Spar and George Munoz: Integrative Men’s Health Robert A. Bonakdar and Andrew W. Sukiennik: Integrative Pain Management Mary Jo Kreitzer and Mary Koithan, Integrative Nursing

Integrative Oncology SECOND EDITION

EDITED BY

Donald I. Abrams, MD Chief of Hematology-Oncology

San Francisco General Hospital Integrative Oncology

UCSF Osher Center for Integrative Medicine Professor of Clinical Medicine

University of California, San Francisco San Francisco, California

Andrew T. Weil, MD

Director of The Arizona Center for Integrative Medicine Lovell-Jones Professor of Integrative Rheumatology Clinical Professor of Medicine Professor of Public Health University of Arizona Tucson, Arizona

1

1 Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford New York Auckland  Cape Town  Dar es Salaam  Hong Kong  Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With offices in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam Oxford is a registered trademark of Oxford University Press in the UK and certain other countries. Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016

© Oxford University Press 2014 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by license, or under terms agreed with the appropriate reproduction rights organization. Inquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above. You must not circulate this work in any other form and you must impose this same condition on any acquirer. Library of Congress Cataloging-in-Publication Data Integrative oncology (Abrams) Integrative oncology / edited by Donald I. Abrams, Andrew T. Weil. — Second edition. p. ; cm. — (Integrative medicine library) Includes bibliographical references and index. ISBN 978–0–19–932972–4 (alk. paper) I.  Abrams, Donald I., editor of compilation.  II.  Weil, Andrew, editor of compilation.  III.  Title.  IV.  Series: Weil integrative medicine library. [DNLM: 1. Neoplasms—therapy.  2. Complementary Therapies.  3.  Integrative Medicine. QZ 266] RC254.5 616.99′406—dc23 2014000082 This material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the conditions described in this material is highly dependent on the individual circumstances. And, while this material is designed to offer accurate information with respect to the subject matter covered and to be current as of the time it was written, research and knowledge about medical and health issues is constantly evolving and dose schedules for medications are being revised continually, with new side effects recognized and accounted for regularly. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulation. The publisher and the authors make no representations or warranties to readers, express or implied, as to the accuracy or completeness of this material. Without limiting the foregoing, the publisher and the authors make no representations or warranties as to the accuracy or efficacy of the drug dosages mentioned in the material. The authors and the publisher do not accept, and expressly disclaim, any responsibility for any liability, loss or risk that may be claimed or incurred as a consequence of the use and/or application of any of the contents of this material. 1 3 5 7 9 8 6 4 2 Printed in the United States of America on acid-free paper

PREFACE TO THE SERIES

I

ntegrative medicine (IM) is healing-oriented medicine that takes account of the whole person (body, mind, spirit), as well as all aspects of lifestyle. It emphasizes the therapeutic relationship and makes use of all appropriate therapies, both conventional and complementary. IM is not synonymous with alternative medicine or with CAM (complementary and alternative medicine). It neither rejects conventional medicine nor accepts alternative treatments uncritically. Integrative medicine is a rapidly growing movement in North America. Consumer demand for it has increased steadily over the past decades. Now, as the conventional health-care system collapses because of out-of-control escalation of costs of high-tech medicine, medical institutions are finally taking IM seriously. The Consortium of Academic Health Centers for Integrative Medicine has 57 members; among them are many leading medical schools, whose deans and chancellors recognize the need to move medical education, research, and practice in this direction. A major reason for the acceptance of IM is awareness that it can lower health-care costs in two ways: (1) by shifting the focus of health care from disease management to health promotion through its attention to lifestyle and the innate healing potentials of the human organism; and (2) by bringing lower-cost treatments into the mainstream that can give outcomes as good as or better than those of pharmaceutical drugs and other conventional therapies. Practitioners are also increasingly drawn to IM because they recognize its potential to restore core values of medicine that have eroded in the era of profit-driven health care. Yet demand for clinicians trained to practice IM greatly exceeds supply. The Arizona Center for Integrative Medicine that I founded in 1994 has graduated more than 1000 physicians (and some nurse practitioners) from comprehensive fellowships, mostly in distributed learning formats. Many of them now direct IM programs at other institutions, some are training others, and some have authored leading textbooks in the field. The Center also trains medical students, pharmacists, and medical residents. v

vi  Preface to the Series

One of its major goals is to develop a core curriculum in IM that will become a required, accredited part of all residency training in all medical specialties. In the meantime, there is an immediate need to organize and make accessible to many more clinicians the basic principles of IM in practical application to common health conditions. It is hoped that the present series of volumes will help fulfill that need. Each volume will cover the relevance of IM to a particular specialty, and each will draw on the editorial expertise of a specialist who is fully trained in IM as well as the advice of senior experts who are open to, but not directly involved with, the IM movement. Each volume will also give detailed protocols for the management of conditions that respond well to integrative treatment and will discuss areas of controversy and uncertainty where further research is needed. Some physicians may find this information of use in meeting the needs of patients better. Some may use it to determine the best treatments for common conditions. Others may simply want to know more about CAM therapies their patients are using, if only to be able to discuss them intelligently and give advice about possible interactions between, say, conventional drugs and dietary supplements or botanical remedies. Promoters of IM have been criticized for advocating unscientific or even antiscientific theories and practices. The commitment of all editors involved in this project is to present the evidence base for integrative treatment strategies. Readers should note, however, that IM teaches practitioners to use a sliding scale of evidence in making therapeutic choices: the greater the potential of a treatment to cause harm, the stricter the standard of evidence it should be held to for efficacy. We may recommend therapies that do not yet have a solid evidence base for efficacy if their potential for harm is low. Examples are suggesting therapeutic massage for persons with advanced forms of cancer as a means of improving quality of life or teaching hypertensive patients breathing techniques to increase the tone of the parasympathetic nervous system. All authors have been charged with the task of citing the best available evidence for both safety and efficacy of therapies discussed. Although randomized controlled trials of specific interventions are helpful, what is most needed are outcome studies comparing integrative versus conventional management of common health problems, especially ones that absorb many of our health-care dollars. Because integrative protocols are complex—including, possibly, dietary change, dietary supplements, recommendations for physical activity and stress reduction, mind–body therapies, or use of a whole-system approach like Chinese medicine, in addition to selective use of conventional therapies—and because they are customized to address the problems of individual patients, studying them can be challenging. Nonetheless, it is outcomes data that we must have to evaluate the effectiveness

Preface to the Series  vii

and cost-effectiveness of IM relative to conventional medicine to advance the field and change reimbursement priorities that now fully cover costly conventional treatments but make it difficult for IM practitioners to get fair compensation for their time and effort. I am grateful to Oxford University Press for having the vision to suggest this series of volumes, which I believe will be seen as a milestone in the development of integrative medicine. I am more than pleased with the outstanding work that the editors and coeditors have done in their selection of content and authors. I have learned a great deal in the course of acting as series editor, not the least from reading chapters as they came in. I hope you find these volumes as stimulating and refreshing as I do. Andrew T. Weil Tucson, Arizona June 2008 Updated February 2014

PREFACE TO THE FIRST EDITION

I

ntegrative oncology can be defined as the rational, evidence-based combination of conventional therapy with complementary interventions into an individualized therapeutic regimen that addresses the whole person living with and beyond cancer—body, mind, and spirit. The number of cancer patients and survivors incorporating complementary modalities into their treatment programs is difficult to estimate precisely but seems to be large and on the increase. Many choose not to disclose their use of complementary therapies to conventional oncologists for fear of being ridiculed, abandoned, or asked to stop. Others recognize that their oncology team has neither the time nor the information to answer their often complex questions, so they remain silent. Although there is little we can do to encourage patients living with or beyond cancer to discuss their integration of complementary therapies, we hope that this book will greatly assist all who care for them to become more familiar with and comfortable discussing the most widely utilized modalities. This volume is targeted at health-care providers who seek an up-to-date, comprehensive, user-friendly source of information that will be relevant to the care of their cancer patients. We hope that it will quickly become the definitive resource in this emerging field. An outstanding group of renowned contributors has produced chapters discussing the latest information on the most widely used modalities employed in integrative oncology. We have attempted to provide a text that is as global and inclusive as possible. The presence of a chapter in the book does not necessarily indicate that we endorse a particular modality. Three chapters focus on the common cancers—breast, prostate, and colon—presenting rational integrative treatment plans that demonstrate how many of the individual modalities can be woven into a comprehensive therapeutic approach. We also include discussions on research challenges, communication issues, a patient perspective, and thoughts about the future of integrative oncology. We know that this comprehensive book will serve as a valuable resource for all who provide care for patients living with cancer and cancer survivors. We ix

x  Preface to the First Edition

hope that practitioners will be stimulated by these chapters to learn more and begin to incorporate some of these modalities into their own treatment plans. Providing patients with other tools in addition to surgery, radiation, cytotoxic chemotherapy, hormonal manipulation, and targeted therapies is indeed a challenge, but one well worth the effort. Making a bit more time to inquire about nutrition, exercise, the use of supplements, mind–body interventions, and spirituality shows that we care about the whole person living with cancer, not just their malignancy. Providing patients with the opportunity to integrate these interventions with their conventional cancer care goes a long way in increasing the sense of empowerment and control that so many have lost at the time of diagnosis. Until that day when chapters like these are included in standard oncology textbooks, this book should be of value to those on the front lines of cancer care and their patients. Donald I. Abrams

PREFACE TO THE SECOND EDITION

T

he first edition of Integrative Oncology has become a valuable asset in this rapidly evolving field. The text has proven useful to medical professionals as well as people living with and beyond cancer and to their caregivers. To date, the book has been translated into Japanese, Korean, and Indonesian, confirming international interest in the subject. More conventional oncology texts have added sections or chapters on complementary therapies, exposing an increasing number of health professionals to the concept of integrative cancer care. In the meantime, more research has been conducted and more evidence collected supporting the practices endorsed by integrative oncologists, which prompts the publication of our second edition. In addition to updates of the information presented in the first edition, this volume includes some new expert authors and additional chapters. Whereas one or two authors have written many of the available texts covering the topic, our text brings together the leading experts in the field, on the front lines of research and clinical care. They offer the latest evidence on the benefits of the various individual complementary modalities in the early chapters. Newly added is a discussion of music and expressive arts therapies and a chapter on naturopathic oncology. Demonstrating how these modalities can be integrated into a comprehensive treatment plan for specific patient populations, we now add a new chapter on the integrative approach to lung cancer to the existing discussions of breast, prostate, and colon cancers. As in the first edition, we have tried to be as global and inclusive as possible with the information we provide to allow the inquisitive provider or patient to understand the rationale for and latest information on the various complementary interventions available. The presence of a chapter in the book does not indicate that we endorse a particular modality. Some chapter authors present information or recommendations that may appear to conflict or contradict what others have said. Rather than edit out any such apparent inconsistencies, we appreciate that individuals practicing different modalities may have a variety of perceptions of the evidence they use to inform their discussions. This xi

xii  Preface to the Second Edition

allows the reader to know the perspectives of the thought leaders in particular fields. Reader-friendly highlights of the first edition—such as key concepts at the front of each chapter, boxed highlights, comprehensive tables and helpful figures—are retained here. The increased space in this softcover version allows us to provide the reader with a bibliography in each chapter, citing all the references provided. This should greatly facilitate retrieving information from source documents. Since the publication of the first edition, the field of integrative oncology has become more firmly established. Patient demand for complementary therapies to be integrated into their conventional cancer treatment plan continues. An increasing number of cancer centers offer programs in integrative oncology or complementary therapies in their clinics and even in some inpatient settings. The American Society for Clinical Oncology is including sessions in its programing and is publishing some of the seminal research in the field in its journals. The Society for Integrative Oncology has just held its 10th annual conference, and the Oncology Association of Naturopathic Physicians now also meets yearly. All this can only serve to offer our patients more options in their journey through cancer treatment to survivorship. Even for those who seek palliative care, integrative oncology provides much to complement the conventional approach. We hope that this updated, upgraded edition of Integrative Oncology will provide you with the latest information to enable you to provide or receive optimal cancer care. Donald I. Abrams Andrew T. Weil

CONTENTS

Contributors 1. Why Integrative Oncology?

xv 1

Andrew T. Weil

2. An Integrative Approach to Reducing the Risk of Cancer

13

3. Molecular Targets of Botanicals Used for Chemoprevention

52

4. Research Methodology Challenges in Integrative Oncology

85

5. Diet and Cancer: Epidemiology and Risk Reduction

96

Heather Greenlee

Muriel Cuendet, Andreas Nievergelt, and John M. Pezzuto Vinjar Magne Fønnebø Cynthia A. Thomson

6. Nutritional Interventions in Cancer

120

7. Botanical and Mycological Medicine in Integrative Oncology

160

8. Cannabinoids and Cancer

246

9. Botanical-Drug Interactions in Oncology—What Is Known?

285

10. The Antioxidant Debate

317

11. Physical Activity and Cancer

349

12. Massage Therapy

373

Keith I. Block and Charlotte Gyllenhaal Leanna J. Standish, Lise N. Alschuler, Morgan Weaver, and M. Nezami Donald I. Abrams and Manuel Guzman Alex Sparreboom and Sharyn D. Baker Elena J. Ladas and Kara M. Kelly Clare Stevinson, Matthew Hobbs, and Kerry S. Courneya Lisa W. Corbin

xiii

xiv Contents

13. Mind–Body Medicine in Integrative Cancer Care

389

14. Music and Expressive Arts Therapies

419

15. Energy Medicine and Cancer

434

16. The Role of Spirituality

487

17. Naturopathic Oncology

504

18. Traditional and Modern Chinese Medicine

516

19. Ayurveda and Yoga for Cancer Supportive Care

552

20. Anthroposophic Medicine, Integrative Oncology, and Mistletoe Therapy of Cancer

560

Martin L. Rossman and Dean Shrock Suzanne B. Hanser

Susan K. Lutgendorf, Elizabeth Mullen-Houser, and Emira Deumic Mary Jo Kreitzer and John E. Wagner Lise N. Alschuler and Leanna J. Standish Qing Cai Zhang Anand Dhruva

Peter Heusser and Gunver Sophia Kienle

21. Integrative Medicine and Breast Cancer

589

22. Prostate Cancer: An Integrative Approach

620

23. Integrative Medicine in Colorectal Cancer: Role of Energy Balance as Treatment

643

Debu Tripathy

Jillian Scambia, Annie Darves, and Aaron Katz

Jeffrey A. Meyerhardt

24. Integrative Medicine and Lung Cancer

661

25. Integrative Therapies in Cancer-Symptom Management

690

26. Alternative Therapies as Primary Treatments for Cancer

714

27. Communication Issues in Integrative Oncology

764

28. Tending the Spirit in Cancer

778

29. A Patient’s Perspective

786

Moshe Frenkel

Brian D. Lawenda

Stephen M. Sagar and Christina M. Garchinski Donald I. Abrams

Rachel Naomi Remen

Manuchehr Shirmohamadi

Index 803

CONTRIBUTORS

Lise N. Alschuler, ND, FABNO

Naturopathic Specialists, LLC Scottsdale, Arizona Sharyn D. Baker, PharmD, PhD

Department of Pharmaceutical Sciences St. Jude Children’s Research Hospital Memphis, Tennessee Keith I. Block, MD

Block Center for Integrative Cancer Treatment Skokie, Illinois Lisa W. Corbin, MD

Associate Professor of General Internal Medicine University of Colorado School of Medicine Medical Director of Integrative Medicine University of Colorado Hospital Aurora, Colorado Kerry S. Courneya, PhD

Director, Behavioral Medicine Laboratory Canada Research Chair in Physical Activity and Cancer University of Alberta Edmonton, Canada

Muriel Cuendet, PhD

Associate Professor of Pharmacognosy School of Pharmaceutical Sciences University of Geneva University of Lausanne Geneva, Switzerland Annie Darves, MS IV

Department of Urology Winthrop-University Hospital Mineola, New York Emira Deumic, BS

Carver College of Medicine University of Iowa Iowa City, Iowa Anand Dhruva, MD

Associate Professor of Medicine University of California, San Francisco San Francisco General Hospital San Francisco, California Vinjar Magne Fønnebø, MD, MSc, PhD

Department of Community Medicine University of Tromsø Tromsø, Norway

xv

xvi Contributors

Moshe Frenkel, MD

Clinical Associate Professor University of Texas Medical Branch Galveston, Texas Director of Integrative Oncology Service Institute of Oncology Meir Medical Center Kfar Saba, Israel Christina M. Garchinski, BA (hons. psych), BEd.

Brock University, St. Catharines, Ontario, Canada

Matthew Hobbs, MS

Fellow, School of Sport Leeds Metropolitan University Leeds, United Kingdom Aaron Katz, MD

Chairman of Urology Winthrop-University Hospital Mineola, New York Kara M. Kelly, MD

Department of Epidemiology Mailman School of Public Health Columbia University New York, New York

Professor of Pediatrics Division of Pediatric Hematology/ Oncology/Stem Cell Transplant Columbia University Medical Center Morgan Stanley Children’s Hospital of New York-Presbyterian New York, New York

Manuel Guzman, PhD

Gunver Sophia Kienle, MD

Heather Greenlee, ND, PhD

Professor of Biochemistry and Molecular Biology School of Biology Complutense University Madrid, Spain Charlotte Gyllenhaal, PhD

Block Center for Integrative Cancer Treatment Skokie, Illinois Suzanne B. Hanser, Ed.D, M.Mus.

Chair of Music Therapy Berklee College of Music Boston, Massachusetts

Peter Heusser, MD, MME

Chair of Theory of Medicine, Integrative, and Anthroposophic Medicine Witten/Herdecke University Herdecke, Germany

Senior Research Scientist Institute for Applied Epistemology and Medical Methodology Witten/Herdecke University Freiburg, Germany Mary Jo Kreitzer, PhD, RN, FAAN

Director of the Center for Spirituality and Healing Professor of Nursing University of Minnesota Minneapolis, Minnesota Elena J. Ladas, PhD, RD

Director of the Center for Comprehensive Wellness Division of Pediatric Hematology/ Oncology/Stem Cell Transplant Columbia University Columbia University Medical Center New York, New York

Contributors  xvii

Brian D. Lawenda, MD

Clinical Director of 21st Century Oncology Las Vegas, Nevada Adjunct Assistant Professor of Radiation Oncology Indiana University School of Medicine Indianapolis, Indiana Susan K. Lutgendorf, PhD

Professor of Psychology Professor of Urology, Obstetrics and Gynecology Departments of Psychology, Obstetrics and Gynecology, and Urology University of Iowa Holden Comprehensive Cancer Center Iowa City, Iowa Jeffrey A. Meyerhardt, MD

Associate Professor of Medicine Department of Medical Oncology Dana-Farber Cancer Institute Boston, Massachusettes Elizabeth Mullen-Houser, PhD

Counseling and Testing Center Department of Psychology University of Wisconsin-La Crosse La Crosse, Wisconsin M. Nezami, MD

Director Pacific Medical Center of Hope Fresno, California Andreas Nievergelt, PhD

Postdoctoral Research Associate School of Pharmaceutical Sciences University of Geneva University of Lausanne Geneva, Switzerland

John M. Pezzuto, PhD

Dean and Professor Daniel K. Inouye College of Pharmacy University of Hawaii at Hilo Hilo, Hawaii Rachel Naomi Remen, MD

Clinical Professor of Family and Community Medicine UCSF School of Medicine University of Califoria, San Francisco San Francisico, Calfornia Director of the Institute for the Study of Health and Illness at Commonweal Bolinas, California Martin L. Rossman, MD

Clinical Associate of Medicine University of California Medical Center, San Francisco Director of the Collaborative Medicine Center Greenbrae, California Stephen M. Sagar, BSc (Hons), MBBS, MRCP, FRCR, FRCPC

Professor of Oncology McMaster University Juravinski Cancer Centre Hamilton, Ontario Canada Jillian Scambia, DO

Fellow Department of Urology Winthrop-University Hospital Mineola, New York Manuchehr Shirmohamadi, PhD, PE

Adjunct Professor California State University San Francisco, California

xviii Contributors

Dean Shrock, PhD

Cynthia A. Thomson, PhD, RD, CSO

Alex Sparreboom, PhD

Debu Tripathy, MD

Leanna J. Standish, PhD, ND, LAc, FABNO

John E. Wagner, MD

Mind-Body Medicine Consultant Yachats, Oregon

Associate Faculty Member Department of Pharmaceutical Sciences St. Jude Children’s Research Hospital Memphis, Tennessee

Research Professor Naturopathic Medicine Bastyr University Kenmore, Washington Clinical Professor of Public Health University of Washington Seattle, Washington Clare Stevinson, PhD

Lecturer Department of Sport, Exercise, and Health Sciences Loughborough University Leicestershire, United Kingdom

Professor of Public Health University of Arizona Cancer Center Tucson, Arizona

Priscilla and Art Ulene Chair in Women’s Cancer Professor of Medicine Keck School of Medicine University of Southern California Los Angeles, California

Director of Hematology-Oncology and Blood and Marrow Transplantation Professor of Pediatrics University of Minnesota Minneapolis, Minnesota Morgan Weaver, BS

Research Coordinator Bastyr University Kenmore, Washington Qing Cai Zhang, MD

Founder, Zhang Clinic SinoMed Research Institute New York, New York

Integrative Oncology

1 Why Integrative Oncology? ANDREW T. WEIL

I

ntegrative medicine (IM) is an established movement in North America and China. It is a developing movement in parts of the Middle East and continental Europe, especially Scandinavia. I  am confident that it is the direction medicine and health care must take to address demands from patients, dissatisfaction of practitioners, and the worsening economics of health care worldwide. Many people consider IM and alternative medicine synonymous. This is not the case. Alternative medicine comprises all those therapies not taught in conventional (allopathic) medical schools, based on ideas that range from sensible and worth including in mainstream medicine to those that are foolish and a few that are dangerous (Weil, 1998). The term alternative medicine has recently been incorporated into a broader term, complementary and alternative medicine, or “CAM,” that is used by the federal government in the United States and other institutions; the National Institutes of Health has its National Center for CAM (NCCAM). Neither alternative nor complementary captures the essence of integrative medicine. The former suggests replacement of conventional therapies by others; the latter suggests adjunctive therapies, added as afterthoughts. IM does include ideas and practices currently beyond the scope of the conventional, but it neither rejects conventional therapies nor accepts alternative ones uncritically. And it emphasizes principles that may or may not be associated with CAM: • The Natural Healing Power of the Organism—IM assumes that the body has an innate capacity for healing, self-diagnosis, self-repair, regeneration, and adaptation to injury or loss. The primary goal of 1

2  Integrative Oncology

treatment should be to support, facilitate, and augment that innate capacity. • Whole Person Medicine—IM views patients as more than physical bodies. They are also mental/emotional beings, spiritual entities, and members of particular communities and societies. These other dimensions of human life are relevant to health and to the accurate diagnosis and effective treatment of disease. • The Importance of Lifestyle—Health and disease result from interactions between genes and all aspects of lifestyle, including diet, physical activity, rest and sleep, stress, the quality of relationships, work, and so forth. Lifestyle choices may influence disease risks more than genes and must be a focus of the medical history. Lifestyle medicine, which is one component of IM, gives physicians information and tools to enable them to prevent and treat disease more effectively. • The Critical Role of the Doctor–Patient Relationship—Throughout history, people have accorded the doctor–patient relationship special, even sacred, status. When a medically trained person sits with a patient and listens with full attention to his or her story, that alone can initiate healing before any treatment is offered. A great tragedy of contemporary medicine, especially in the United States, is that for profit, corporate systems have virtually destroyed this core aspect of practice. If practitioners have only a few minutes with each patient— the time limit set by the managed-care systems they work for—it is very unlikely they will be able to form the kind of therapeutic relationships that foster health and healing. Furthermore, this special form of human interaction has been the source of greatest emotional reward for the physician, and its disappearance in our time is a main reason for rising practitioner discontent. IM insists on the paramount importance of the therapeutic relationship and demands that health-care systems support and honor it (e.g., by reimbursing physicians for time spent with patients rather than number of patients seen). In essence, IM is conservative. It seeks to restore core values of the profession that have eroded in recent times. It honors such ancient precepts as Hippocrates’ injunctions on physicians to “first do no harm” and “to value the healing power of nature.” It is conservative in practice, favoring less invasive and drastic treatments over more invasive and drastic ones whenever possible, and it is fiscally conservative in relying less on expensive technology and more on simpler methods, as appropriate to the circumstances of illness. The IM movement in North America is gathering momentum. Fifty-seven leading medical schools in the United States and Canada have now joined

Why Integrative Oncology?  3

the Consortium of Academic Health Centers for Integrative Medicine (www. imconsortium.org), which seeks to advance the field on three fronts: education, research, and clinical practice. Textbooks of IM, written for clinicians, are appearing with increasing frequency (see, e.g., Audette & Bailey, 2008; Cohen Ruggie, & Micozzi, 2006; Kliger & Lee, 2004; Low Dog & Micozzi, 2004; Rakel, 2002, 2007, 2012). And demand for training in the field is growing steadily. To help answer that demand, I founded the Program in Integrative Medicine (now the Arizona Center for Integrative Medicine or AzCIM) at the University of Arizona in 1994 (www.integrativemedicine.arizona.edu) and continue to direct it. AzCIM’s focus has been the development of new educational models for training medical students, residents, physicians, nurse practitioners, pharmacists, and other health professionals. The Center has offered intensive fellowships to MDs and DOs, increasingly in distributed learning formats, mainly Internet based. The curriculum we have developed covers the philosophy of IM as well as broad subject areas currently slighted or omitted entirely from conventional medical education. These include nutritional medicine (e.g., designing an optimum diet for health and longevity; using dietary supplements appropriately; using dietary change as a primary therapeutic strategy, etc.), botanical medicine, mind-body medicine, manual medicine (such as osteopathic manipulative therapy), spirituality in health and illness, environmental medicine, and overviews of traditional systems of medicine (like Chinese medicine and Ayurveda) and CAM. Our teaching about traditional medicine and CAM is intended to convey the philosophies behind these approaches, the evidence base for them, their strengths and weaknesses, and their appropriateness or inappropriateness in specific health conditions. We also cover the training and credentialing of CAM practitioners and information on how to find and refer to competent ones when appropriate. Criticism of IM has mostly focused on perceived advocacy of ideas and practices not consistent with evidence-based medicine (EBM). Training at AzCIM requires fellows to assess the evidence base for all recommended treatments, including conventional ones. The Center also trains future researchers, many of whom are working on new research designs to investigate complex systems and new outcome measures to assess the effectiveness and cost-effectiveness of integrative treatment plans (as opposed to single interventions). We also teach practitioners to use a sliding scale of evidence in evaluating treatments: the greater the potential of an intervention to cause harm, the stricter the standard of evidence it should be held to for efficacy. It has never been my wish or that of AzCIM to see the field of IM evolve into a subspecialty of general medicine, family medicine, internal medicine, public health, or any other discipline. Rather, my colleagues and I consider training

4  Integrative Oncology

in IM to be foundational to the education and training of all physicians, as well as of nurses, pharmacists, and allied health professionals. Even a neurosurgeon or dermatologist should know the basics of nutrition and health, mind-body interactions, and botanical medicine. Every medical doctor should know the difference between an osteopathic physician and a chiropractor and have at least some sense of important traditional systems, like Chinese medicine and Ayurveda. Every medical professional should understand the influence of lifestyle on health. Nonetheless, board certification in IM will soon be available through a new American Board of Integrative Medicine, a sign of maturity of the field and a way to help patients identify practitioners properly trained in it. A present focus of AzCIM is development of a comprehensive curriculum of IM, consisting of several hundred hours of instruction that can be taught in a distributed learning format. Our goal is to have this become a required, accredited part of residency training in all medical specialties. AzCIM’s graduates now include more than a thousand physicians from many specialties, including growing numbers of oncologists. I am happy about this, because although the demand for integrative oncology is overwhelming, practitioners trained to provide it are very few. To cater to public demand, some leading cancer centers advertise that they offer integrative treatment, but I find the claims misleading. They offer selected CAM therapies, mostly the safest, least controversial ones, such as massage, stress reduction, and nutritional counseling but advise patients to shun botanical remedies that might ameliorate the toxic effects of chemotherapy and radiation as well as most dietary supplements, and they have no informed advice to give about more complex therapies, such as those from the Ayurvedic tradition of India. One chain of private cancer-treatment centers that builds its reputation on an “integrative” philosophy employs conventional oncologists untrained in IM while using doctors of naturopathy (NDs) to supervise CAM therapies as adjuncts. The first answer to “Why integrative oncology?” is that most patients with cancer want integrative care. The great majority—as many as 90% in some surveys—are using other therapies while receiving conventional treatment (Deng & Cassileth, 2005; Richardson, Sanders, Palmer, Greisinger, & Singletary, 2000). Most of those do not tell their oncologists what else they are doing, because they expect to be criticized, ridiculed, or told to stop. In any medical situation, whatever the disease, the physician in charge ought to know all therapies that the patients are using, both to be able to avoid adverse interactions and to be able to assess outcomes. An integrative oncologist can elicit this information and give patients sound advice about CAM therapies. Because nutrition, including the use of dietary supplements, is a core competency of IM education, integrative oncologists can answer some of the most

Why Integrative Oncology?  5

common and urgent questions of cancer patients starting chemotherapy and radiotherapy, such as, “Are there any foods I should or shouldn’t eat during treatment?” and “Can I continue to take my vitamins?” Here is a glaring example of the present paucity of training about nutrition and cancer:  The daughter of a woman undergoing chemotherapy for metastatic colon cancer consulted me in distress, because the medical oncologist told her mother to “eat only white foods” during the entire course of treatment. She wanted permission to encourage her mother to eat more wholesome meals. Numerous cancer patients tell me they are advised not to eat fruits and vegetables while receiving chemotherapy or radiotherapy, because the antioxidants in them would compromise the efficacy of those treatments. Countless others express dismay that their oncologists are unable to talk to them about best nutritional strategies for reducing risks of recurrence. “Just eat a balanced diet,” or “Whatever you feel like eating,” are common responses they get, leaving them frustrated and unsure about where to turn for better advice and information. If a patient undergoing cancer treatment asks a conventionally trained oncologist about the value of the Chinese herb astragalus (from the root of Astragalus membranceous) to protect the bone marrow and white cell populations from some of the toxicity of some chemotherapeutic agents or the use of Asian mushrooms like maitake (Grifola frondosa), enoki (Flammulina velutipes), or turkey tail (Trametes versicolor) to “boost immunity,” it is unlikely the physician will know anything about these natural products. The reflexive response will be, “Do not take anything other than what we give you,” again leaving patients frustrated and often angry about their doctors’ limited knowledge, hence the tendency to conceal the use of such products, which may have been recommended by friends, by books, by CAM providers, or by Internet sites. A  major component of patients’ frustration with these interactions is a strong sense of disempowerment and inability to have any partnership in shaping their medical destiny. Given the fact that so few integrative oncologists exist and that cancer patients in our part of the world have such difficulty putting together sound and safe integrative treatment plans, it is surprising to learn that their counterparts in China are much luckier. At least in large Chinese cities, most cancer patients who undergo surgery, chemotherapy, and radiotherapy also get Chinese herbal therapy to increase efficacy and reduce toxicity of the conventional treatments, as well as acupuncture, massage, energy work (such as Qigong), and dietary recommendations to support general health and manage symptoms (see Chapter 18, this volume). Of the various specialties of medicine, oncology has been much slower to embrace IM than most. Family medicine, pediatrics, and psychiatry are quite

6  Integrative Oncology

open to IM philosophy and training, and there is receptivity in internal medicine as well, especially from cardiologists. Integrative oncology seems so sensible and so needed. What are the sources of resistance that have slowed its development? One is surely the emotionalism that surrounds cancer—a frighteningly common, mysterious, and serious group of diseases. We can argue about whether the incidence of cancer is increasing or not, but most people I know feel that cancer now touches their lives more directly than it used to, affecting them, their immediate families, their friends, and neighbors. The possibility of developing cancer or having to care for or help someone who has it is very great. Moreover, conventional cancer treatments are also frightening, because they can be painful, debilitating, disfiguring, and not always as successful as those who perform them represent them to be. Many people have a strongly negative perception of chemotherapy and radiotherapy because of their obvious toxicity and known potential to cause mutations and malignant transformation. Progress in the diagnosis and management of cancer has been significant. A dramatic example is that it is now possible to envision the management of metastatic breast cancer as a chronic disease, much like AIDS, rather than as an inevitable and premature death sentence. (At the same time, the incidence of breast cancer is at an all-time high.) The prospect of individualized and targeted therapies is already being realized, with significant reduction in toxicity. Still, I and many others look forward to the advent of new and better treatments—gene therapy, immunotherapy, antiangiogenesis therapy—that will render many of our current strategies obsolete and reduce some of the emotionalism that now fuels the debate about other ways of managing cancer. Over the years I have looked at a number of alternative cancer treatments— those offered instead of surgery, chemotherapy, and radiotherapy. I have seen many patients who used them as primary therapies, others who tried them after recurrences or when they were terminal. I also served on a federal government advisory panel charged with evaluating alternative cancer treatments. Although I  have known individual patients who responded very well to one or another of these diverse therapies, none of them, in my experience, has produced reliably good outcomes in significant numbers of patients. Some of these therapies are based on utterly unsound ideas: that cancer is caused by infection with parasites or other germs that can be seen by developers of proprietary vaccines but not by mainstream microbiologists; that cancer results from nutritional deficiencies or excesses and can be cured by dietary change alone; and so forth. A  prominent and disturbing message from the alternative-cancer-treatment community is that a conspiracy of pharmaceutical companies and medical organizations profits handsomely from

Why Integrative Oncology?  7

conventional treatment and has suppressed effective natural and alternative therapies. I will also say that I have come across elements of alternative cancer treatments that seemed to me possibly useful and worthy of investigation. A broad example is the repertory of Chinese herbal remedies used along with chemotherapy and radiotherapy to increase their efficacy and reduce toxicity. A narrow one is the use of a topical extract of bloodroot (Sanguinaria canadensis) to provoke an immune reaction against and kill some skin cancers. (This was a part of the notorious Hoxsey therapy, developed by a Texas chiropractor in the mid-20th century; see www.drweil.com/drw/u/id/QAA361873). Practitioners of integrative oncology should be informed about alternative cancer treatments and able to answer patients’ questions about them factually. They should also encourage research on those that show any evidence of efficacy. No integrative oncologist would ever advise a patient to forego evidence-based treatment in favor of unproved therapy of unknown safety and efficacy. However, a major role for such a practitioner would be to help patients make difficult choices about standard therapeutic options. Often cancer patients must decide among different courses of treatment, such as whether to use chemotherapy after surgery or radiation, whether to submit to aggressive chemotherapy in the event of a recurrence, whether to try an experimental vaccine or stem-cell transplant. They must gamble—with their lives—on making the right choices. In most medical situations that involve serious disease, both doctors and patients are forced to deal with uncertainty. Rarely do we have all the information we need to make decisions that will guarantee desired outcomes. Instead we must use incomplete information to estimate probabilities and place the wisest bets we can. Ultimately, patients must take responsibility for this, but doctors can and should help them understand the possible therapeutic options and their probable consequences. Most of us, physicians and patients alike, have not been trained in the science of uncertainty and probability. There is such a science—gambling theory, a branch of mathematics—and I have long wanted to adapt it to a course on medical decision making. My intent is to include it in the comprehensive curriculum for IM in Residency under development at the University of Arizona. Most of our cancer treatments have significant risks as well as benefits. Patients must understand the risk/benefit ratio for any treatment offered, especially impact on quality of life versus quantity of life. If a patient opts to forego chemotherapy following surgical removal of a breast or lung tumor, choosing instead to make all the right lifestyle choices to reduce risk of recurrence and to use various herbs and dietary supplements as insurance, is this an informed and wise decision? It may be—if she has been able to estimate the probabilities

8  Integrative Oncology

of outcomes. She will be guessing in the midst of uncertainty, but if she can get and can understand the best available data on her particular type and stage of cancer and on the risks and benefits of the therapeutic options under consideration, she can bet wisely. As the provider and interpreter of medical information, the integrative oncologist is indispensable to this process. I cannot overstress the urgency of need for this service. Most cancer patients I know are desperately seeking the advice and counsel of oncologists who are well trained and credentialed; up-to-date with the science of cancer and its treatment; open-minded and nonjudgmental, who are interested in the influence of all aspects of lifestyle on health and illness; understand the interactions of mind and body; and have at least basic knowledge of botanical remedies, dietary supplements, and commonly used CAM therapies. Most often, patients (and their loved ones and friends) cannot find such practitioners. In addition, because IM puts so much emphasis on total lifestyle, it is in a better position than conventional medicine to offer true preventive care. Preventive medicine as a field has accomplished much, but it has focused narrowly on public-health measures like sanitation, eradication of insect vectors of disease, diagnostic screening, and immunization rather than on the choices people make about how to eat, get physical activity, play, and handle stress. Most of the chronic diseases that kill and disable people prematurely are diseases of lifestyle that could be avoided or postponed by making better choices and developing better habits of living. Because the treatment of cancer is difficult and costly, especially if it has spread from its primary site, risk reduction must be a high priority—not only by means of diagnostic screenings but primarily by counseling patients and educating society about the details of lifestyles associated with lower risk. In the case of the hormonally driven cancers, for example of the breast and prostate, we know a great deal about dietary and other influences that both raise and lower risk, but much of this information is not yet common knowledge; nor are there societal incentives to encourage people to change behavior. For example, the chemistry of the formation of carcinogens as animal tissue cooks is well known: the higher the temperature and the longer the time of cooking, the higher the dose of carcinogens in the meat (or poultry or fish) that comes to the table. We also have clinical data indicating that a preference for meat cooked “well done” is a significant risk factor for breast cancer in women (Steck et al., 2007). Most women I know, including some with family histories of breast cancer, are unaware of these facts; certainly, no physician has made them aware of the danger. There is good evidence that moderate, regular consumption of whole soy foods, beginning early in life, affects the development of the female breast in ways that make it resistant to malignant growth (Cabanes et  al., 2004).

Why Integrative Oncology?  9

I believe it also offers significant protection against prostate cancer in men. Integrative oncology should develop strategies for helping people, especially parents of young children, to access, understand, and implement this information. Conversely, there is growing evidence that the hormonal content of cow’s milk in North America (and products made from it) add to other hormonal pressures, both exogenous and endogenous, that increase the possibility of malignant growth in both the breast and the prostate. I refer to natural bovine hormones, not man-made ones. In our part of the world, dairy cows are maintained in almost continual states of pregnancy and lactation, an unnatural lifestyle that greatly increases levels of sex hormones in their milk (Rich-Edwards et al., 2007; see also www.news.harvard.edu/ gazette/2006/12.07/11-dairy.html). Yet in a revision of the U.S. government’s food pyramid, the medical community did not mount any counteroffensive, when, under pressure from the dairy industry, the Department of Agriculture increased the recommended daily servings of milk and milk products from two to three. Many similar situations exist where specialinterest groups affect public policy in ways that promote rather than safeguard against the development of cancer. Integrative oncologists could take the lead in improving them. A first generation of integrative oncologists will probably find themselves most in demand as consultants. These are the main areas in which their advisory role will be needed: • Helping patients with difficult decisions about conventional treatment options. • Helping patients put together integrative treatment plans that use dietary strategies, mind-body therapies, and selected CAM therapies during and after conventional cancer treatment. • Advising patients about possible risks and benefits of alternative cancer treatments. • Informing patients about strategies for increasing efficacy and reducing side effects of chemotherapy and radiotherapy. • Advising patients about nutritional and other lifestyle strategies for reducing risks of recurrence. • Teaching those at risk for cancer about lifestyle strategies for reducing risk. • Helping patients with incurable cancer to get the best palliative care, drawing on all therapeutic options. • Helping terminal patients and families with issues around death and dying.

10  Integrative Oncology

Recently, a 64-year-old man with newly diagnosed bile duct carcinoma consulted both of the editors of this volume for help in several of these areas. All the doctors involved with his case at a major academic health center agreed that a Whipple resection was indicated, but experts disagreed about follow-up treatment. Because this is a rare carcinoma, statistical evidence on outcomes is scant, and the conventional oncologists he talked with based their recommendations on experience with pancreatic cancer. He was strongly advised to do both a full course of radiotherapy followed by aggressive chemotherapy. The patient was educated, health conscious, and most interested in other opinions from experts with a broader perspective. The conventional oncologists could not answer his questions about the wisdom of using the dietary supplements he was taking or about foods he should or shouldn’t eat. They had nothing to say about physical activity, mental/emotional factors that might influence outcomes, or lifestyle factors that might have contributed to the development of his cancer or that might help his body contain any malignant tissue that might escape removal by surgery or destruction by radiation and chemotherapy. I put him in touch with a practitioner of modern Chinese medicine—an MD trained in China with experience in the Chinese style of integrative cancer treatment—who recommended herbal products both to slow the growth of any cancer left behind by surgery and to protect his bone marrow and other immunologically active tissues from damage by radiation and chemotherapeutic drugs. He decided not to discuss these products with the surgical or medical oncologists with whom he finally partnered. I also directed him to one of the few integrative oncologists in practice who happened to work in a nearby city. The patient had two meetings with him prior to surgery and was able to get answers to his questions about nutrition and dietary supplements during treatment. He was also given recommendations for some additional ones. The patient then had phone sessions with a hypnotherapist I referred him to in order to prepare for surgery, and he obtained from the therapist audio programs to use in the hospital. By the time he called Dr. Abrams for additional opinions, I felt he was in danger of getting too many points of view and too much information. I  suggested he use the nearby integrative oncologist as his primary advisor in matters that his other physicians could not address. Dr.  Abrams was able to put him in touch with a patient who had recently undergone a Whipple resection for pancreatic cancer and come through it very well. The two patients had a number of telephone conversations that proved very helpful, making the man facing surgery much more informed about what to expect and much more optimistic about recovery and outcome.

Why Integrative Oncology?  11

(In my own practice I have always tried to introduce patients with chronic diseases to others with the same or similar problems who have done well. There is no better way to convince a sick person that better health is possible. This may be especially important in people newly diagnosed with cancer.) The surgical procedure went well. There was no evidence of spread of the tumor beyond the primary site, but because one margin was not clean, there was consensus that a course of radiotherapy was indicated. The question of concurrent chemotherapy, however, produced disagreement among experts. The patient had a mostly smooth recovery; made sure he got good, healthful food; took the botanicals and dietary supplements; did his mind-body practice; and started walking every day as much as he could. His mental state was positive, but he wrestled with the decision about chemotherapy. His medical oncologist urged aggressive treatment, using cisplatin, but said she would be comfortable with giving a routine course of 5-FU, a much less toxic agent. Some of his consultants, including one surgical oncologist, advised against any chemotherapy, saying its benefits in bile duct carcinoma were negligible. After weighing all the opinions, he opted for 5-FU, and his integrative oncologist supported this choice, adjusting his dietary, herbal, and supplement regimen for the six-week course of concurrent radio- and chemotherapy. According to the physicians directly involved in these treatments, the patient came through them with less difficulty, fewer side effects, and a better response than any comparable patient they had treated. The patient believes his good response to be due to all that he is doing to support his general health and body defenses, all of which he learned from his research into integrative cancer treatment. He feels confident about his future and motivated to be diligent about protecting his health by attending to all areas of his life under his control. He expresses willingness to act as a resource for other persons with cancer trying to find the information he sought and also to assist in the development of the field of integrative oncology. I wrote earlier that the AzCIM is working toward the goal of making basic education in IM a required, accredited part of residency training in all specialties and subspecialties of medicine. When we achieve that, all clinicians, including oncologists, will have the perspective and information to practice IM. At that point, I also hope we will be able to drop the word integrative. This will just be good medicine, the kind that patients want, the kind that doctors find most rewarding to practice, the kind that produces the best outcomes. IM is not revolutionary, but it is radical in the literal sense of that word (from Latin radix: “root”) in that it aims to reconnect medicine to its roots, to restore its core values.

12  Integrative Oncology

Integrative oncology simply means doing the best we can to prevent and treat cancer and support those affected by it on all levels:  body, mind, and spirit. REFERENCES

Audette, J.  F.,  & Bailey, A. (2008). Integrative pain medicine. Totowa, New Jersey: Humana Press. Cabanes, A., Wang, M., Olivo, S., DeAssis, S., Gustafsson, J. A., Khan, G., & Hilakivi-Clarke L. (2004). Prepubertal estradiol and genistein exposures up-regulate BRCA1 mRNA and reduce mammary gland tumorigenesis. Carcinogenesis, 25(5), 741–748 Cohen, M. H., Ruggie, M., & Micozzi, M. S. (2006). The practice of integrative medicine: A legal and operational guide. New York: Springer. Deng, G., & Cassileth, B. (2005). To what extent do cancer patients use complementaryand alternative medicine? Nature Clinical Practice Oncology, 2, 496–497 Kligler, B., & Lee, R. A. (2004). Integrative medicine. New York: McGraw Hill. Low Dog, T., & Micozzi, M. (2004). Women’s health in complementary and integrative medicine: A clinical guide. Philadelphia: Churchill Livingstone. Rakel, D. (Ed.). (2002, 2007, 2012). Integrative medicine. Philadelphia: Saunders. Richardson, M. A., Sanders, T., Palmer, J. L., Greisinger, A., & Singletary, S. E. (2000). Complementary/Alternative medicine use in a comprehensive cancer center and the implications for oncology. Journal of Clinical Oncology, 18, 2505–2514. Rich-Edwards, J. W., Ganmaa, D., Pollak, M. N. Nakamoto, E. K., Kleinman, K. Tserendolgor, U., . . . Frazier, A. L. (2007). Milk consumption and the prepubertal somatotropic axis. Nutrition Journal [Electronic Resource], 6, 28. Steck, S. E., Gaudet, M. M., Eng, S. M., Britton, J. A., Teitelbaum, S. L., Neugut, A.  I. . . . Gammon, M.  D. (2007). Cooked meat risk of breast cancer— Lifetime versus recent dietary intake. Epidemiology, 18(3), 373–382. Weil, A. (1998). Health and healing: The philosophy of integrative medicine (rev. ed.). Boston: Houghton Mifflin.

2 An Integrative Approach to Reducing the Risk of Cancer HEATHER GREENLEE

Key Concepts An individual’s risk of developing cancer is determined in part by genetic predisposition and lifetime exposures. Information about these factors can be used to recommend an appropriate screening schedule. ■ Conventional approaches to cancer risk reduction include behavioral modifications (such as dietary changes and physical activity), biological agents (such as antioxidants, multivitamins, minerals, hormone modulators, and anti-inflammatory agents), surgery, and vaccinations. ■ Complementary and alternative medicine (CAM) approaches to cancer risk reduction include special diets, botanicals (for various properties including antioxidant, anti-inflammatory, immune modulating, hormone modulating, and adaptogenic effects, and the induction of biotransformation enzymes), vitamins and minerals, other dietary supplements, mind-body therapies, and energy therapies. ■ Non-Western systems of healing such as Chinese medicine, Ayurvedic medicine, Tibetan medicine, and Native American medicine offer their own perspectives on what causes cancer and what can be done to prevent cancer. ■ An integrative approach to cancer risk reduction encourages individuals to make healthy lifestyle choices, use appropriate cancer-screening technologies, and achieve and maintain a sense of wellness and balance. ■

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14  Integrative Oncology

Introduction Disease prevention is generally viewed as encompassing three levels: primary, secondary, and tertiary. The goal of primary prevention is to reduce the risk of developing the disease. Primary cancer prevention measures include healthy lifestyle behaviors (e.g., diet, physical activity, body size), use of chemopreventive agents, avoidance of exposure to environmental carcinogens, and surgical removal of susceptible organs (e.g., prophylactic mastectomy (Alberts & Hess, 2008)). Secondary prevention involves screening and early detection methods, used among asymptomatic individuals, to identify abnormal tissue changes or precancerous lesions before they become cancerous, or detect them at an early stage when treatment is most likely to lead to a cure (Alberts & Hess, 2008). Tertiary prevention, often referred to as cancer control, involves preventing existing cancer from spreading, preventing recurrence, preventing second primary cancers, and preventing other cancer-related complications. Tertiary prevention includes a variety of aspects of patient care, including interventions to improve quality as well as duration of life, adjuvant therapies, surgical intervention, and palliative care (Alberts & Hess, 2008). This chapter focuses on primary cancer prevention, also known as risk reduction. The chapter discusses what people without a cancer diagnosis can do to reduce the risk of developing cancer. Current conventional risk reduction approaches begin with risk assessment based on age, gender, genetics, personal and family medical history, occupational and lifestyle exposures. Appropriate interventions are recommended based on the determination of individual risk. Everyone can benefit from a healthful diet and physical activity. Individuals at higher-than-average risk may want to consider pharmacological chemoprevention, surgery to remove the susceptible organ, and vaccinations. Complementary and alternative medicine (CAM) approaches include biologic therapies and behavioral modifications such as dietary modifications, botanicals (herbs), vitamins and minerals, other dietary supplements, mind/body therapies, energy medicine, and non-Western systems of healing, most of which are not typically used as part of conventional medical practice. Complementary medicine refers to practices that are performed in conjunction with conventional treatments, while alternative medicine refers to practices used in lieu of standard treatments. Complementary and integrative medicine (CIM) is an emerging field, especially within cancer care, where CIM modalities with strong research showing their effectiveness are used alongside conventional medicine as a holistic approach to care (Hughes, 2001).

An Integrated Approach to Reducing the Risk of Cancer  15

Until recently, the mere concept of primary prevention of cancer was considered somewhat unconventional because there was little evidence to support the concept that carcinogenesis (Alberts & Hess, 2008) could be reversed or halted, or that people could change their habits to prevent cancer. However, in the past few decades, clinical trials have shown both that cancer can be prevented (or postponed) and that people can modify their diet or stop smoking to reduce their cancer risk. The tamoxifen trial proved that a drug could reduce the risk of developing breast cancer among women at higher than average risk (Fisher et al., 1998) and a low-fat diet was shown to reduce the likelihood of breast cancer recurrence (Chlebowski et al., 2006). The American Institute for Cancer Research (AICR) estimates that, by improving diet and physical activity as well as maintaining a healthy weight, one-third of cancer diagnoses can be prevented (American Institute for Cancer Research, 2013a). It is estimated that 11% to 70% of cases among 14 different cancers could be prevented using just these three strategies (American Institute for Cancer Research, 2013a). This body of literature proves the principle that cancer can be prevented and provides support for the concept that there is a continuum between reducing the risk of developing cancer and cancer treatment. The National Cancer Institute has a division devoted specifically to cancer prevention research, with research groups working to identify chemopreventive agents; test those agents in clinical trials; perform clinical trials for controlling symptoms and outcomes related to cancer; identify biomarkers that detect cancer early; evaluate the effectiveness of screening these biomarkers; examine the effects of diet on cancer risk reduction; and create statistical models to examine cancer risk (National Cancer Institute, 2013). Clearly, in 2014, cancer prevention research is a well-established field of study.

Prevention and Risk Some individuals without specific known risk factors for cancer are more focused on preventing cancer than on preventing other conditions, such as cardiovascular disease, for which their actual risk may be higher, or on maintaining their health and ability to enjoy life. The good news is that maintaining a heart-healthy lifestyle may also reduce the risk of cancer. For example, the impact of not smoking is greater on cardiovascular disease risk than on cancer risk. Cancer risk reduction trials are generally conducted among individuals who are known to be at higher-than-average risk of developing cancer. The higher the cancer risk among the study subjects, the less person time and cost are required to observe the effects of the intervention, if any, and the greater

16  Integrative Oncology

the justification for exposing subjects to an intervention that may have adverse side effects. The risk reduction associated with a preventive intervention may not compensate for its effects on quality of life or its economic costs. For example, among women with a strong family history of breast cancer, prophylactic mastectomy has been shown to reduce breast cancer risk by over 90% (Hartman et al., 1999; McDonald et al., 2001), and tamoxifen reduces risk by more than 35% (Fisher et al., 1998, 2005). However, relatively few women, even with very high risk, have taken advantage of these options. Some are looking to CIM for less invasive and gentler alternatives. However, many of the CIM strategies have not been tested in clinical trials. What is considered CIM can shift depending on when, if and how the specific modality is adapted into mainstream culture and medicine. Treatments that begin as alternative can become conventional, depending on research results and the ways in which both the therapy and the context for its use evolve. For example, green tea has been studied for its chemopreventive potential (Crowell, 2005). Historically in many Asian cultures, green tea was an infusion prepared and sipped during important social interactions and considered part of the good life. Now, it is being studied as a pill or capsule that is swallowed quickly to prevent a disease. In the end, what we want to know is not whether a therapy is considered CIM or conventional but whether it is effective at preventing cancer. This chapter discusses an integrated approach to cancer risk assessment and prevention therapeutics and provides an overview of conventional and CIM approaches commonly used in the United States.

Assessing Cancer Risk A person’s risk of developing cancer is based on several factors, including family medical history, genetic predisposition, and lifetime exposures. If a physician learns that a patient has a family history of cancer suggestive of genetic high risk, the patient may be referred to a genetic counselor that takes a detailed personal and family history and then makes a determination as to whether the individual should undergo DNA testing. Based on the risk assessment and possible genetic test results, individuals and their physicians can make joint decisions on what, if any, actions to take, including lifestyle modifications, increased screening, chemoprevention, and/or surgery (Ozanne, Klemp, & Esserman, 2006). The U.S. National Cancer Institute (NCI) has regularly updated websites that explain the concept of risk to the public (http:// www.cancer.gov/cancertopics/wyntk/cancer/page3) and describe what is

An Integrated Approach to Reducing the Risk of Cancer  17

currently known about cancer causes and risk factors (http://www.cancer.gov/ cancertopics/prevention-genetics-causes/causes). New technologies are being developed and tested to provide biological assessments of cancer risk, including genetic profiles that determine how the body metabolizes endogenous and exogenous substances, that is, metabolomics and proteomics; thermography that may detect areas of a breast that has increased metabolism; cytology sampling, such as ductal lavage and mammary aspiration for breast cancer; and blood-based biomarkers such as nuclear matrix proteins. The acceptance and uptake of new technologies for assessing cancer risk is generally based on results from clinical trial data, though there are no formal guidelines or governing bodies that regulate this area. Similarly, there are limited data demonstrating whether or not intervening in high-risk populations and/or individuals makes a difference in actual risk of developing cancer. This is an active area of investigation. Some clinicians and laboratories offer alternative laboratory tests and in-office procedures that provide nonvalidated assessments of cancer risk. These may include urine analyses, blood analyses, genetic analyses, energy scans, electromagnetic scans, etc. Many of these methods are based on epidemiological studies and/or theoretical assumptions, as opposed to clinical trials, and have not been validated as diagnostic of cancer risk. The tests are often co-marketed with neutraceutical products that will “correct” whatever imbalance is detected. Most of these tests and products have not been evaluated in risk reduction clinical trials and their claims should be carefully scrutinized.

Cancer Risk Reduction Modalities Both conventional and CAM therapeutic modalities for primary risk reduction involve lifestyle modifications, such as dietary changes, physical activity, behavioral modifications, and biological agents that may prevent or halt carcinogenesis. When considering any approach to cancer risk reduction, whether it be conventional, CIM, or integrative, it is important to determine the magnitude of expected benefit while accounting for safety, cost, and likelihood of adherence. Some prevention approaches are targeted to the population level, such as strengthening antismoking laws to prevent lung cancer. Other approaches are targeted to an individual, and have more predictably large effects, such as prophylactic mastectomy in a woman with a BRCA1 mutation. In addition, some cancer risk reduction strategies will also decrease the risk of other diseases, for example increasing physical activity also decreases risk of cardiovascular disease.

18  Integrative Oncology

It is important to acknowledge that it is often difficult to convince people to participate in cancer risk reduction interventions, whether conventional or CAM. Just because the conventional medical community espouses a conventional cancer prevention method, it is not necessarily widely used or widely accepted by the general population. One of the biggest barriers to cancer risk reduction is convincing people that it is possible and beneficial to make changes in their lives, for example quitting smoking. Sometimes, CIM approaches may be more appealing to individuals who are unwilling to tolerate some of the side effects of conventional therapies or who find that conventional therapies do not fit within their own personal or cultural system of beliefs and preferences. CONVENTIONAL CANCER RISK REDUCTION MODALITIES

Conventional recommendations on what people can do for cancer risk reduction are usually based upon epidemiological and clinical trial evidence. These include dietary modifications, physical activity, behavioral modifications, biological agents, surgery, and vaccinations. Some of these cancer prevention approaches are believed to be important and safe enough to disseminate via public health messages and to make changes in public health policy, particularly pertaining to smoking cessation. Public smoking restrictions and tobacco taxation have both resulted in decreased smoking rates, even among youths (Cokkinides, Bandi, Ward, Jemal, & Thun, 2006). In 2010, Congress approved legislation aimed at improving the nutrition of snacks sold in schools by limiting the amount of fat, sugar, and salt as well as requiring the snack to meet certain nutritional standards. This restriction on unhealthy school snacks will go into effect by the 2014 school year (Abutaleb, 2013; Strom, 2013). Grocery produce shoppers frequently see the “5 a day” message (Centers for Disease Control and Prevention, 2007), and the CDC is implementing 10 strategies to improve and promote fruit and vegetable consumption (Centers for Disease Control and Prevention, 2011). Another area of research and intervention is on the built-environment’s effect on health. The built environment encompasses many elements of a person’s neighborhood from green spaces, to walkability, to social networks, and these aspects have been linked to cancer risk factors such as nutrition and physical activity (Renaldo, Smith, & Hale, 2010). New urban planning efforts to change the built environment and employer incentives are beginning to promote increased opportunities for physical activity (Brennan Ramirez et  al., 2006). Employers such as SAS, Johnson  & Johnson, and Chevron encourage employees to improve physical activity and nutrition by offering

An Integrated Approach to Reducing the Risk of Cancer  19

wellness programs within the workplace environment that include access to fitness facilities, healthy eating options, and health related workshops (Berry & Mirabito, 2011).

Diet and Physical Activity The American Cancer Society has four main recommendations for reducing the risk of cancer that focus on diet and physical activity. Their recommendations include maintaining a healthy weight, staying physically active, eating healthy, and limiting alcohol consumption (Kushi et  al., 2012). See Table 2.1 for a cancer-site specific summary of risk factors and dietary and physical activity recommendations by the American Cancer Society (Kushi et  al., 2012). The American Institute of Cancer Research offers the following general diet and health guidelines based on the current evidence to date (American Institute for Cancer Research, 2007, 2013b): (a) maintain a healthy weight, (b)  be physically active, (c)  reduce consumption of sugary drinks and energy dense foods, (d)  choose a diet rich in a variety of plant-based foods and eat plenty of vegetables and fruits; (e) limit intake of red meats, (f) drink alcohol only in moderation, if at all; (g) select foods low in fat and salt, (h) do not use supplements to prevent cancer and (i) do not use tobacco in any form. Agencies such as The American Institute of Cancer Research do not currently recommend supplements due to the fact that there is no conclusive evidence to date regarding their effects on chemoprevention. As will be discussed in this chapter, the evidence base is growing, but research is still needed before making any definitive recommendation regarding supplement use. It is generally accepted that high intake of fruits and vegetables is beneficial for cancer risk reduction (Boeing et  al., 2012; Glade, 1997). The benefits are likely due to the high concentrations of antioxidants, other phytonutrients, and fiber (Glade, 1997). Cruciferous vegetables are one family of edible plants that may play a significant role in cancer risk reduction (Herr & Buchler, 2010; Park & Pezzuto, 2002). High intake of cruciferous vegetables, including broccoli, cauliflower, cabbage, kale, bok choy, Brussels sprouts, radish, and various mustards has been associated with decreased cancer risk. Crucifers have high content of glucosinolates and their hydrolysis products, isothiocyanates, protect against carcinogenesis. Crucifers also contain flavonoids, polyphenols, vitamins, fiber and pigments that may have anticancer activities. The most important chemoprevention mechanisms may be that crucifers inhibit phase I enzymes, for example, cytochrome P450s, which can activate carcinogen metabolites, and they induce phase II enzymes, for example, glutathione transferase enzymes,

Table 2.1.  Cancer Site-Specific Risk Factors and Recommendations to Reduce Risk Cancer Site

Risk Factors

Strategies to Reduce Risk Nutrition

Physical Activity

Body Size

Other

Breast

First menstrual period before age 12. Not giving birth, or first birth after age 30. Late age at menopause. Family history of breast cancer. Overweight or obese (among postmenopausal women). Weight gain during adulthood. Alcohol consumption, especially if low folate intake. Postmenopausal hormone replacement therapy.

Eat a diet high in vegetables and fruits. Greatly lowering fat intake. Avoid or limit intake of alcoholic beverages.

Engage in moderate to vigorous physical activity 45 to 60 minutes per week.

Avoid obesity. Reduce lifetime weight gain through the combination of limiting your calories and regular physical activity.

Limit the use of hormones, i.e., hormone replacement therapy.

Colorectal

Family history of colorectal cancer. Long-term tobacco use. Overweight or obese, especially obesity in men. Lack of exercise and poor nutrition. Diet high in processed and/or red meats. Diet low in vegetables. Excessive alcohol use.

Eat a diet high in vegetables and fruits. Limit intake of processed and red meats. Avoid excess alcohol. Vitamin D supplementation.

Moderate to vigorous physical activity.

Avoid obesity.

Finding and removing polyps through colorectal cancer screening.

Endometrium

Polycystic ovarian syndrome. Overweight or obese.

Kidney

Tobacco smoke. Overweight or obese.

Lung

Tobacco smoke. Chewing tobacco. Snuff. Radon exposure. High doses of beta-carotene and/ or Vitamin A. Increased risk among smokers.

Ovarian

Obesity. No firmly established nutritional risks.

Pancreatic

Adult-onset diabetes. Impaired glucose tolerance. Tobacco smoke. Obesity. Physical inactivity. Diets high in processed and red meats.

Eat a plant-based diet rich in vegetables, whole grains, and beans. Decrease consumption of red meat, saturated fat, and animal fat.

High physical activity.

Maintain healthful weight through diet and regular physical activity.

Avoid becoming overweight. Eat at least 5 servings of vegetables and fruits a day.

Avoid tobacco use. Avoid tobacco use or exposure Avoid radon exposure

Remain physically active.

Maintain a healthful weight.

Avoid tobacco use.

(continued)

Table 2.1.  Continued Cancer Site

Risk Factors

Strategies to Reduce Risk Nutrition

Prostate

Overweight and obese. High dairy intake. High calcium intake (primarily through supplements) increases risk for aggressive forms of prostate cancer.

Eat 5 or more servings of vegetables and fruits each day, especially tomatoes, cruciferous vegetables, soy, beans, and other legumes. Eat foods and supplements containing antioxidant. nutrients, such as beta-carotene, and lycopene

Stomach

Chronic stomach infections by bacterium Helicobacter pylori. High intake of salt-preserved foods.

Eat at least 5 servings of vegetables and fruits daily. Reduce salt-preserved food consumption.

Physical Activity

Vigorous exercise. Active lifestyle.

Body Size

Other

Maintain a healthy weight.

Maintain a healthy weight.

Eat fresh foods. Refrigerate foods.

Adapted from the American Cancer Society Prevention and Early Detection: The Complete Guide—Nutrition and Physical Activity (American Cancer Society, 2006). Alberts, D. S., Hess, L. (2008). Fundamentals of cancer prevention (2nd edn.). Berlin: Springer. National Cancer Institute. (2013). Scientific Scope, from http://prevention.cancer.gov/about/mission

An Integrated Approach to Reducing the Risk of Cancer  23

which enhance carcinogen detoxification (Herr  & Buchler, 2010; Park  & Pezzuto, 2002). Epidemiological data has also suggested that a low-fat diet can help reduce cancer risk (Glade, 1997); however, clinical trial data were lacking to support this and observational studies have shown conflicting evidence. The results from the Women’s Intervention Nutrition Study (WINS) study showed that a low-fat diet was associated with a decreased breast cancer recurrence rate (Chlebowski et al., 2006). The Women’s Health Initiative Dietary Modification trial showed that a low-fat diet reduced the risk for ovarian cancer in postmenopausal women, but did not reduce the risk for breast, colorectal, and endometrial cancers (Prentice et al., 2007). Also, the Woman’s Healthy Eating and Living (WHEL) study did not find a significant effect for a high fruit and vegetable and low fat diet on preventing breast cancer or reducing recurrence and mortality (Prentice et al., 2006; Pierce et al., 2007). Future clinical trials need to elucidate whether type of fats consumed contributes to cancer risk. It is generally accepted that maintaining a healthy body weight, which is defined as a body mass index (BMI) between 18 and 25 kg/m2, can help prevent cancer. The mechanism here has not been fully elucidated but it is hypothesized that some of the endogenous hormones produced with increased body fat increase cancer risk. Maintaining a healthy body weight is best achieved by eating a balanced diet and engaging in regular physical activity. There is also evidence to suggest that alcohol from light to heavy intake increases the risk of some cancers (Bagnardi et al., 2013; Glade, 1997).

Behavioral Modifications A number of behavioral modifications beyond dietary and physical activity have been associated with decreased cancer risk. These include preventing tobacco use, ceasing tobacco use, decreasing sun exposure, and decreasing use of exogenous hormone therapy. Tobacco use, including smoking and chewing tobacco, has been strongly associated with cancers of the lung, lower urinary tract, upper aero-digestive tract, pancreas, stomach, liver, kidney, and uterine cervix, and causing myeloid leukemia (Vineis et al., 2013). Despite the fact that decreasing tobacco consumption by preventing initiation and promoting cessation would lead to preventing the largest numbers of cancers, this has been difficult to achieve and smoking rates are growing globally (Kanavos, 2006; McCormack & Boffeta, 2011; Stewart & Coates, 2005). Regular sun exposure, especially at an early age, is associated with an increased risk of skin cancer. The regular use of sunblock and using sun-protective clothing has been associated with decreased risk of melanoma and nonmelanoma skin cancer (Saraiya et al., 2004). The population level decrease in breast cancer incidence reported in 2003 is possibly associated with the decreased use of hormone replacement

24  Integrative Oncology

therapy after the results from the Women’s Health Initiative were published in 2002 (Ravdin, Cronin, Howlander, Chlebowski, & Berry, 2006); however, this may also be due to a decrease in screening mammography (Gompel  & Plu-Bureau, 2010). See Table 2.1 for a summary of behavior modification recommendations provided by the American Cancer Society.

Biologically Based Agents Biological chemoprevention agents that can be taken in pill form are appealing because they are less laborious to administer and more easily standardized than lifestyle changes. Chemopreventive agents include vitamins, minerals, naturally occurring phytochemicals, and synthetic compounds. Currently, the most promising agents include biologicals that have antioxidant, hormone modulating, or anti-inflammatory properties. Botanical agents have been shown to affect numerous molecular targets for chemoprevention, including protein kinases, antiapoptotic proteins, apoptotic proteins, growth factor pathways, transcription factors, cell cycle proteins, cell adhesion molecules, metastases, DNA methylation and angiogenesis (Aggarwal & Shishodia, 2006). This is an active area of research involving pharmacological, biological, and nutritional interventions to prevent, reverse, or delay carcinogenesis. Currently, the only FDA approved agents for risk reduction are tamoxifen and raloxifene for breast risk reduction among high-risk women (Fisher et  al., 1998; Vogel et  al., 2006). However, the Division of Risk reduction of the U.S. National Cancer Institute is actively pursuing new and novel compounds for risk reduction. Some of these agents include NSAIDS, curcumin, indole-3-carbinol/DIM, deguelin, green tea (Polyphenon E), and isoflavones in soy, lycopene, and resveratrol (National Cancer Institute, 2013a). Many of these agents are used by CAM practitioners and some are discussed later under CIM therapies. antioxidants  Antioxidants

include compounds such as vitamin E (alpha-tocopherol), vitamin C (ascorbic acid), beta-carotene, selenium, and zinc. Many of these agents are found in foods and can also be taken as dietary supplements. Exogenous antioxidants ingested via foods or dietary supplements can quench procarcinogenic reactive oxygen species (ROS) and may halt carcinogenesis (Halliwell, 1996; Klaunig, Kamendulis  & Hocevar, 2010; Valko, Rhodes, Moncol, Izakovic,  & Mazur, 2006). Many different kinds of exposures contribute to the carcinogenesis stages of initiation, promotion, and progression. An accumulation of reactive oxygen species may cause DNA mutations and cellular damage, which some authors suggest initiates most

An Integrated Approach to Reducing the Risk of Cancer  25

of carcinogenesis (Klaunig et  al., 2010; Valko et  al., 2006). Reactive oxygen species can be byproducts of normal endogenous cellular metabolism; they may be produced during respiration, by neutrophils and macrophages during inflammation, or by mitochondria-catalyzed electron transport chain reactions (Cadenas, 1989; Klaunig et al., 2010; Valko et al., 2006). Reactive oxygen species can also be produced by exogenous exposures, including nitrogen oxide pollutants, smoking, pharmaceuticals, and radiation. Reactive oxygen species cause oxidative stress, which can induce cancer-causing DNA mutations, damage cellular structures including lipids and membranes, oxidize proteins, and alter signal transduction pathways that enhance cancer risk (Borek, 2004; Gutteridge, 1993; Klaunig et al., 2010;Valko et al., 2006). Though this is a promising area of research, clinical trials that have used exogenous antioxidants or free-radical scavengers (such as vitamin E, vitamin C, or beta-carotene) as chemopreventive agents have, on the whole, been markedly unsuccessful, and even harmful in some cases. Two trials testing beta-carotene as a chemopreventive agent in male smokers and asbestos workers at high risk of developing lung cancer, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) and Carotene and Retinol Efficacy Trial (CARET) studies, showed that high doses of synthetic beta-carotene actually increased risk of lung cancer (Albanes et al., 1995; Omenn et al., 1996). It is unclear how to extrapolate these results to people of average risk using natural forms of the vitamins in low, normal, or high doses. A meta-analysis found conflicting results when analyzing the effects of beta-carotene on different cancer sites, ranging from small protective effects to increased risk of mortality (Druesne-Pecollo et al., 2010). The U.S. Preventive Services Task Force concluded that beta-carotene supplementation is unlikely to provide important benefits and might cause harm in some groups (U.S. Preventive Services Task Force, 2003). A study of vitamin E supplementation for preventing second primary head and neck cancers showed that vitamin E supplementation was associated with increased risk of developing a second primary cancer (Bairati et al., 2005). In the Nutritional Prevention of Cancer Study, selenium supplementation did not decrease the incidence of basal cell or squamous cell skin cancer; however, secondary analyses suggested that selenium supplementation reduced the incidence and mortality of cancers in other sites, the most promising of which was reducing the risk of developing prostate cancer (Clark et al., 1996). Contrary to this hypothesis, the Selenoum and Vitamin E Cancer Prevention Trial (SELECT) trial, which was designed to test selenium and vitamin E supplementation for reducing the risk of prostate cancer, found no protective effect on cancer and a nonsignificant increase in risk (Lippman et  al., 2009). Similarly, another trial testing the cancer prevention effect of

26  Integrative Oncology

selenium in men with high-grade prostatic intraepithelial neoplasia found no significant protective effect (Marshall et al., 2011). multivitamin and mineral supplements  The benefit of and/or need for vita-

min and mineral supplementation is population dependent. Populations that are undernourished may have a need for supplementation to combat health outcomes due to vitamin deficiencies, and this supplementation may have added benefits against cancer in that specific population. Conversely, in overnourished groups, supplementation may have different effects, including being helpful, not effective, or harmful. A synthesis of randomized, controlled trials assessed the efficacy of multivitamin and supplement use for risk reduction (Huang et al., 2006). The authors concluded that the evidence is currently insufficient to prove the presence or absence of benefits. However, two trials did show an effect. In a poorly nourished population living in Linxian, China, the combined supplementation of beta-carotene, alpha-tocopherol, and selenium reduced gastric cancer incidence and mortality rates and reduced the overall mortality rate from cancer by 13–21% (Blot et al., 1993, 1995; Wang et al., 1994). In the French Supplementaion en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study, combined supplementation of vitamin E, beta-carotene, selenium, and zinc reduced the overall cancer rate by 31% in men, but not in women (Hercberg et al., 2004; Meyer et al., 2005). This protective effect of supplementation did not persist after the intervention was stopped, as seen in the 5-year follow-up period of the study (Hercberg et al., 2010). The different effects by gender are not understood. hormone modulators   Some cancers are hormone dependent, including

hormone-receptor positive breast cancer, ovarian cancer, and prostate cancer. Breast cancer prevention trials using selective estrogen receptor modulators (SERMs) to block estrogen receptors (Breast Risk reduction Trial (BCPT) and (Study of Tamoxifen and Raloxifene [STAR]) have been successful in decreasing breast cancer incidence in women at high breast cancer risk, though they had significant adverse effects including increased risks of endometrial cancer and osteoporosis (Fisher et al., 1998, 2005; Vogel et al., 2006, 2010). Though the Women’s Health Initiative study showed that estrogen plus progesterone therapy was protective against colon cancer, the increased risk of breast cancer and cardiovascular disease indicate that it is not an appropriate cancer risk reduction strategy (Anderson et al., 2004). In clinical trials, Exemestane, an aromatase inhibitor, reduced estrogen levels and significantly reduced breast cancer risk among postmenopausal women (Goss et  al., 2011). The Prostate Risk reduction Trial (PCPT) tested the effects of finasteride, a 5-alpha-reductase inhibitor, on prostate cancer incidence and found that, though it inhibited

An Integrated Approach to Reducing the Risk of Cancer  27

the formation of prostate cancer overall, it was associated with increased risk of sexual dysfunction and high-grade prostate cancer, although this finding is thought to be due to finasteride improving the detectability of high-grade cancer (Sarvis  & Thompson, 2008; Thompson et  al., 2003). The Reducation by Dutasteride of Prostate Cancer Events (REDUCE) trial, which tested the effects of dutasteride, a dual 5-alpha-reductase inhibitor, in men with an increased risk of developing prostate cancer found a 22.8% reduction in prostate cancer events among the intervention group (Andriole et  al., 2010). In men with high-grade prostatic intraepithelial neoplasia (PIN), the selective estrogen receptor modulator (SERM) toremifene decreased the incidence of prostate cancer (Price et al., 2006). Several epidemiological studies have shown a significant inverse relationship between serum vitamin-D levels and breast cancer risk (Crew, 2013). Vitamin D is involved in regulating bone metabolism. Vitamin D and its analogs have been receiving a considerable amount of attention for their possible antiproliferative roles in the prevention of cancer in many sites, including prostate, gastrointestinal, breast, endometrial, skin, and pancreatic cancers (Schwartz & Skinner, 2007). Clinical trials are underway to test these hypotheses. There are currently no data showing that increasing an individual’s vitamin D concentration has any effect on cancer outcomes. anti - inflammatory agents   Observational studies have shown that non-

steroidal anti-inflammatory drug (NSAID) use is associated with lower risk of breast and colon cancer occurrence (Sansbury et  al., 2005; Terry et  al., 2004). Two clinical trials of COX-2 inhibitors, rofecoxib and celecoxib, to prevent colorectal cancer in high-risk individuals showed that they were effective; however, these drugs simultaneously increased risk of cardiovascular disease (Arber et al., 2006; Bertagnolli et al., 2006; Bresalier et al., 2005). A  risk:  benefit analysis showed that in 1,000 patients with colonic adenomas, celecoxib use would prevent 1.6 colorectal cancers but would cause 12.7 cardiovascular-disease events (Psaty & Potter, 2006). Therefore, COX-2 inhibitors are not being recommended for cancer risk reduction. Aspirin has been found to be protective against colorectal, esophagus, stomach, lung, breast, and ovarian cancers in observational studies with potentially fewer risks than other NSAID drugs. In 2009, The International Conference on Risk reduction, suggested that further research should be conducted to elucidate the timing and dose necessary to recommend aspirin use for chemoprevention (Cuzick et  al., 2009). A  concern with aspirin is that it can increase the risk of gastrointestinal bleeding and, therefore, offset any chemopreventive benefit.

28  Integrative Oncology

Surgery If an individual is considered to be at high risk for developing a specific cancer, she may be offered the option of surgically removing the organ or tissue. Women at high breast or ovarian cancer risk may have prophylactic mastectomies or oophorectomies. This approach is not without consequence, such as disfigurement and inability to conceive, and is not acceptable to many women (Ackerman et al., 2006; Borgen et al., 1998). Individuals with familial adenomatous polyposis or longstanding ulcerative colitis may choose to have colectomies, but morbidity, mortality, and quality of life issues should be considered (Metzger & Schneider, 2001).

Vaccinations Viral infections are believed to be responsible for 15% of cancers globally (Frazer, Lowy, & Schiller, 2007), some of which are cervical, nasopharyngeal, liver, and blood cancers (Carillo-Infante, Abbadessa, Bagella, & Giordano, 2007). Therefore, vaccinations are actively being examined for risk reduction. The hepatitis B vaccine has been shown to be effective in preventing chronic hepatitis, which often progresses to liver cancer (Chang et al., 2005; Di Bisceglie, 2009). More recently, the human papilloma virus (HPV) vaccine was shown to be effective at preventing HPV infection and precancerous lesions, which can cause cervical cancer (Mao et al., 2006). The HPV vaccine is perhaps an unprecedented approach to risk reduction in that it may be given to all sexually active females, regardless of their risk of cervical cancer. The HPV vaccines have the potential to prevent approximately 70% of cervical cancer cases globally (Crosbie, Einstein, Franceschi, & Kitchener, 2013). The feasibility and acceptability of implementing these strategies on a populationwide basis is under debate, especially in children (Colgrove, 2006); however, the proof of principle has been established. CIM CANCER PREVENTION THERAPEUTICS

As stated earlier, some conventional therapies used for cancer treatment, such as tamoxifen, are applied to high-risk individuals for cancer risk reduction. Likewise, many of the CIM therapies discussed elsewhere in this book that are used for cancer treatment are also used by cancer-free individuals for risk reduction. The agents have varying levels of research evidence to support their use, and most of the evidence is from in vitro and animal studies, rather than clinical trials. Few clinical trials have been conducted on the use of CIM modalities for cancer risk reduction, thus the use of these agents is primarily based on theoretical and hypothesized mechanisms. CIM cancer risk

An Integrated Approach to Reducing the Risk of Cancer  29

reduction therapeutics are presented next, using two broad categories: those that are biological agents and those that are behavior based. BIOLOGICAL AGENTS

A wide variety of CIM biological agents have possible applications for cancer risk reduction. These include special diets, botanicals (also called herbs), vitamins, minerals, and other dietary supplements.

Special Diets To date, an abundance of data is available to suggest that people who have high intake of fruits and vegetables are less likely to develop cancer than those with low intake (Glade, 1997). The data are less clear regarding which specific vegetables should be consumed, during what phase of life, and for how long. Data on specific dietary patterns that are not considered CAM, such as the Mediterranean diet or eating a low-fat diet, suggest that eating in a specific pattern on a regular basis can have cancer-risk-reducing effects (Glade, 1997). One dietary pattern that is gaining in popularity and that may be on the cusp between conventional medicine and CAM is a “whole foods” diet. A whole foods diet is one that emphasizes eating foods, especially grains, fruits, and vegetables, which are as close to their natural form as possible in order to benefit from the phytonutrients and fiber present, while avoiding additives that are in processed foods. However, it appears that only a small number of individuals have the inclination or ability to fully adopt this way of eating and preparing foods. Other dietary patterns may be considered “CAM” because they are not followed by large numbers of individuals and are considered more out of the mainstream. These include vegan, raw foods, and macrobiotic diets. Vegan refers to not eating any animal products, usually for ethical and health reasons. A raw foods diet takes this one step further by eating a vegan diet and limiting the use of heat in order to preserve the naturally occurring plant enzymes and proteins and to prevent the formation of carcinogens that occurs with heating proteins and carbohydrates (Clement & Di Geronimo, 1998). A macrobiotic diet emphasizes locally grown, organically grown whole grain cereals, legumes, vegetables, fruit, seaweed, and fermented soy products, combined into meals according to the principle of balance between yin and yang properties (Kushi et al., 2001). Though the epidemiological and clinical trial literature is sparse, the data suggest that adopting diets that promote increased fruit and vegetable consumption leads to commensurate reduction in fat and calorie intake, both of which have separately been associated with decreased cancer risk (Glade, 1997; Link & Potter, 2004).

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A diet that restricts caloric intake, also known as a hypocaloric diet, is hypothesized to reduce the occurrence of chronic disease, including cancer (Mason, 2006). However most of this evidence is based on animal studies and recent human data suggest that short-term caloric restriction may increase the incidence of some cancers (Elias, Peeters, Grobbee, & van Noord, 2007). Some methods of producing and preparing food are hypothesized to prevent cancer due to reducing exposure to carcinogens. This includes eating organically grown food to avoid pesticides and not cooking with or storing food in plastics to avoid chemicals that may leach into food. However, conclusive studies supporting these claims have not been conducted.

Botanicals Many plants contain phytochemicals that have potential anticancer properties, including antioxidant, anti-inflammatory, immune modulation, modulation of detoxification enzymes, hormone modulation, and adaptogenic effects. Historically, these botanicals have often been used as foods, spices, and medicines (Lampe, 2003). Few of the agents have undergone phase III trials to demonstrate efficacy for risk reduction; therefore, the data are insufficient to derive specific recommendations on formulations, doses and duration of use. antioxidants  Most plants contain some form of antioxidants, typically

found in their pigments and/or chemical defensive agents that are used to deter predators. As stated earlier, antioxidants are hypothesized to be beneficial for cancer risk reduction because they may prevent the formation of free radicals, which can lead to DNA damage, and they may repair oxidative damage. Botanical compounds that have been identified, which contain particularly high levels of antioxidants include curcumin in turmeric (Curcuma longa; Aggarwal, Kumar, & Bharti, 2003), epigallocatechin-3-gallate (EGCG) in green tea (Camellia sinensis; Park & Pezzuto, 2002; Beltz, Bayer, Moss, & Simet, 2006), resveratrol in red grapes, peanuts, and berries (Delmas, Lancon, Colin, Jannin, & Latruffe,2006), silymarin in milk thistle (Silybum marianum; Aggarwal & Shishodia, 2006), 6-gingerol in ginger (Zingiber officinale; Park & Pezzuto, 2002; Shukla  & Singh, 2006), lycopene in tomatoes (Giovannucci, 2005; Park  & Pezzuto, 2002), and polyphenols in pomegranate juice (Gil, Tomas-Barberan, Hess-Pierce, Holcroft, & Kader, 2000). anti - inflammatory agents  As stated earlier, inflammatory agents in

the body, such as prostaglandins, are potentially carcinogenic. A number of botanical agents are known to have substantial anti-inflammatory effects by inhibiting cyclooxygenase (COX) or other parts of the inflammation pathway.

An Integrated Approach to Reducing the Risk of Cancer  31

Curcumin (Ireson et  al., 2001; Park  & Pezzuto, 2002; Plummer et  al., 1999; Ravindran, Prasad,  & Aggarwal, 2009)  and ginger (Ozaki, Kawahara,  & Harada, 1991; Park  & Pezzuto, 2001; Shukla  & Singh, 2006)  are two of the most potent anti-inflammatory botanical agents. Preliminary in vitro and case-report data suggest interesting anti-inflammatory effects of a combination herbal anti-inflammatory agent, Zyflamend, on prostate cancer cells and in men with high-grade PIN (without prostate cancer; Bemis, Capodice, Anastasiadis, Katz, & Buttyan, 2005; Rafailov, Cammack, Stone, & Katz, 2007). A phase I clinical trial was recently conducted to test Zyflamend’s safety in men with high-grade PIN and was found to have neither serious side effects nor adverse events (Capodice, Gorroochurn, Cammack,  & Eric, 2009). Clinical trials will need to test whether this compound is effective on prostate cancer outcomes. immune function modulators  A well-functioning immune system

is hypothesized to be beneficial for risk reduction because circulating immune cells can destroy nascent cancer cells. Some of the botanicals that have been identified for their effects on improving immune function include medicinal mushrooms, astragalus (Astragalus membranaceus), and ginseng (Panax ginseng). Several varieties of immune modulating mushrooms have been identified, including Reishi (Ganoderma lucidum), turkey tail (Trametes aka Coriolus versicolor), and maitake (Grifola frondosa; Pelley & Strickland, 2000). Astragalus, frequently used in Chinese medicine, is not as well studied but historically has been shown to improve immune function (Block & Mead, 2003). Panax ginseng has also demonstrated immune system enhancing effects (Block & Mead, 2003; Shin Kim, Yun, Morgan, & Vainio, 2000). biotransformation enzyme modulators  Biotransformation enzymes

modulate the effects of chemical carcinogens. Compounds in various botanical agents have been shown to induce or inhibit enzymes related to cancer risk. As discussed earlier, cruciferous vegetables can inhibit phase I enzymes and induce phase II enzymes. Indole-3-carbinol is a compound found in cruciferous vegetables. It has been shown to up-regulate hepatic enzyme systems that metabolize endogenous carcinogens. Early phase human trials have shown that it may have some applicability in lung, cervical, and breast cancer; however, liver toxicities may prevent its widespread use (Kim & Milner, 2005; Weng, Tsai, Kulp, 2008). Curcumin has been shown to inhibit phase I enzymes and induce phase II enzymes, such as glutathione-S-transferase (Sharma, Gescher, & Steward, 2005).

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hormone regulators   Given that some cancers are hormone dependent, for

example some forms of breast cancer, ovarian cancer, prostate and testicular cancer, botanicals that modulate endogenous hormone levels may be indicated for cancer risk reduction. There has been ongoing debate on the role of soy products in risk reduction. Isoflavones are found in leguminous plants, such as soy. The most active isoflavones are diaidzein and genistein, both of which have been shown to possess both estrogenic and anti-estrogenic activities. The current consensus is that there is insufficient evidence to recommend soy isoflavones as a risk reduction tactic and, therefore, soy should be eaten in moderation (Messina, McCaskill-Stevens, & Lampe, 2006). Animal and observational data suggest that green tea consumption may lower blood estrogen levels, thus lowering breast cancer risk, while limited data suggest that black tea may increase breast cancer risk (Wu & Yu, 2006; Yuan, Sun, & Butler, 2011). adaptogens   Adaptogens are botanicals used to stimulate the central ner-

vous system to decrease stress, decrease depression, eliminate fatigue, and enhance work performance. This may be of importance in psychoneuroimmunological models of cancer, which hypothesize that a positive neurological state leads to a well-functioning immune system. Botanicals used for this purpose include Panax ginseng, Siberian ginseng (Eleutherococcos senticosus), schisandra (Schisandra chinensis) and rhodiola (Rhodiola rosea; Davydov  & Krikorian, 2000; Kelly, 2001; Panossian  & Wagner, 2005; Shin et al., 2000). However, there is conflicting evidence whether Panax ginseng and rhodiola exert estrogenic effects, which would contraindicate their use in estrogen-dependent cancers (Albertsson & Seiving, 1996; Eagon et al., 2004; Liu et al., 2001). combination formulas  Historically, botanical preparations have been

used in combination in order to make use of synergistic properties between individual botanical agents. Traditional Chinese Medicine, Ayurvedic and Western botanical formulations operate on this principle. Two Western botanical formulations, Essiac tea and Hoxsey formula, have made claims to prevent and treat cancer. However, to date these claims have not been supported with scientific evidence (American Cancer Society, 1990; Boon & Wong, 2004; Ulbricht et al., 2009).

Vitamins and Minerals As discussed earlier, epidemiological studies suggest that vitamin and mineral intake can affect risk of developing specific cancers. Some people have

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interpreted this as evidence to support the use of mega-doses of these agents. Taking doses of antioxidants, vitamins, and minerals above that which is found in a standard multivitamin may be considered CAM. Orthomolecular medicine, coined by Linus Pauling, PhD, refers to the practice of preventing and treating disease by providing the body with optimal amounts of substances that are natural to the body, which often results in the use of high doses of natural compounds (Orthmolecular Medicine, 2006). Given the results from the ATBC and CARET trials discussed earlier, it is unclear how efficacious this high-dose approach may be. These studies were in high-risk populations and used high doses of synthetic forms of the vitamins. Coenzyme Q10 is a potent antioxidant but has limited clinical data to support its use specifically for cancer risk reduction (Shekelle et al., 2003).

Other Dietary Supplements Other dietary supplements have been proposed as possible cancer risk reduction therapies. Some of the more promising dietary supplements include melatonin, omega-3 fatty acids, probiotics, and prebiotics. Changes in circadian rhythm due to night-shift work or increased ambient light dysregulates melatonin levels. Melatonin supplementation is hypothesized to have oncostatic, cytotoxic, and antiproliferative effects (Grant, Melan, & Latimer, 2009; Jung & Ahmad, 2006). Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have several proposed mechanisms for lowering cancer risk. The most studied mechanism is inhibiting the formation of proinflammatory and procarcinogenic eicosanoids, such as prostaglandins (Moyad, 2005; Terry, Terry,  & Rohan, 2004). Some observational studies have shown that omega-3 fatty acids reduced the risk of colon, prostate, and breast cancers, yet the current epidemiological evidence is inconsistent (Gerber, 2012). Pro- and prebiotics may have chemopreventive roles in gastrointestinal cancer. Probiotics, such as Lactobacillus sp., are hypothesized to confer chemopreventive benefits in gastrointestinal cancers by deactivating procarcinogenic cellular components of microorganisms, inhibiting and/or inducing colonic enzymes, controlling growth of harmful bacteria, stimulating the immune system, and producing physiologically active anticancer metabolites (Commane, Hughes, Shortt,  & Rowland, 2005; Geier, Butler,  & Howarth, 2006; Kumar, Kumar, Nagpal, et  al., 2010; Wollowski, Rechkemmer,  & Pool-Zobel, 2001). Prebiotics are short-chain carbohydrates, such as undigested polysaccharides, resistant starches, and fiber enhance the formation of beneficial bacteria and of short-chain fatty acids, which can reduce oxidative stress and induce the

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chemopreventive enzyme glutathione transferase (Davis  & Milner, 2009; Geier et al., 2006; Wollowski et al., 2001). BEHAVIORAL APPROACHES

One of the most basic differences between conventional and integrative approaches to risk reduction is that an integrative medicine approach often encourages people to do things beyond ingesting biological agents in order to reduce risk of developing cancer. These activities can be referred to as “mind-body” and “energy” medicine. Similar to many of the biological agents, these are lacking clinical trials to demonstrate efficacy, and are based on theoretical and hypothesized mechanisms.

Mind-body Medicine Available evidence links stress, behavioral response patterns, and resultant neurohormonal and neurotransmitter changes to cancer development and progression (Antoni et al., 2006; Thaker & Sood, 2008). Collectively this work suggests that stress management may modify neuroendocrine deregulation and immunological functions that potentially have implications for tumor initiation and progression (Antoni et al., 2006; Thaker & Sood, 2008). Clinical and some observational studies indicate that stress (Antonova, Aronson,  & Mueller, 2011; Sloan et al., 2010), chronic depression (Cohen et al., 2012; Satin, Linden, & Phillips, 2009), social support (Lutgendorf et al., 2012), and other psychological factors may influence cancer onset, progression, and mortality (Antoni et al., 2006). This area of medicine is often called mind-body medicine, or psychoneuroimmunology. There are a wide variety of types of therapies that fall under the rubric of mind-body medicine (Antoni et al., 2006). Sensory therapies include aromatherapy, massage, touch therapy, music therapy, and creating a calm and/or beautiful space such as a room with a view or a healing garden. Cognitive therapies include meditation, Mindfulness-based Stress Reduction (MBSR), guided imagery, visualization, hypnosis, and humor therapy. Expressive therapies include writing, journaling, art therapy, support groups, individual counseling, and psychotherapy. Physical therapies include dancing, yoga, and tai chi. Though none of these approaches have been shown to reduce the risk of cancer per se, some of them have been shown to affect parameters associated with cancer development, such as improving immune function and decreasing circulating cortisol. It is of note that an early study showed that support groups increased survival in breast cancer patients (Spiegel, Bloom, Kraemer, & Gottheil, 1989). However, these results have not been replicated,

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and there is no evidence to date supporting the use of psychological interventions to prevent cancer (Sagar, 2006).

Other Systems of Healing and Health All cultures have systems to promote health and healing, many of which are highly developed and very different from the conventional medical model accepted in Western societies. The conventional medical model tends to be best at responding to and treating disease, and relatively ineffective at preventing disease. The goal of many of these other systems of healing is to promote health and wellness, thereby preventing disease. Some of these other systems include Traditional Chinese Medicine (TCM), Ayurvedic medicine, Tibetan medicine, and Native American medicine. Each of these is briefly discussed next. It is important to note that though each tradition is a rich, complete system unto itself, practitioners within each tradition may be diverse in terms of their interpretations, approaches, and therapeutics for preventing, diagnosing, and treating disease. The descriptions provided here are very basic. Even for clinicians practicing within the Western medical tradition, having a familiarity with other systems of healing and health may be a critical skill (Fadiman, 1997) . CHINESE MEDICINE

Traditional Chinese Medicine (TCM) is a medical system from China. TCM therapeutics aim to restore the body’s balance and harmony between the natural opposing forces of yin and yang and the five elements (wood, earth, air, fire, water). An imbalance among any of these forces can block qi, blood, or phlegm, which can result in disease, including cancer. Diagnostic techniques include tongue and pulse diagnosis. TCM therapeutic modalities include acupuncture, botanical formulations, qigong, tui na (massage), moxibustion, and dietary modification (Beinfeld  & Korngold, 1991). TCM was popularized in the United States in the 1970s after the fall of the “bamboo curtain” (Beinfeld & Korngold, 1991). Another form of Chinese medicine, Five Element acupuncture, focuses on the use of acupuncture to restore mental and spiritual balance (Moss, 1999). AYURVEDIC MEDICINE

Ayurvedic medicine, Ayurveda, or “the science of life,” comes from India. A central concept to Ayurveda is that the three doshas, or body constitutions,

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Kapha, Pitta, and Vata, need to be kept in balance in order to maintain health. An imbalance results in disease, including cancer. Causative factors for these imbalances include eating unhealthy foods, poor hygiene, bad lifestyle habits and environmental exposures which if left uncorrected lead to the accumulation of one or more doshas somewhere in the body (Singh, 2002). Diagnostic techniques involve tongue and pulse diagnosis. Ayurvedic therapeutic modalities include dietary modifications, botanical formulations, massage, precious substances, yoga, and spiritual practice (Lad, 2002). Ayurveda was popularized in the United States in the 1990s by Depak Chopra (Chopra, 1991). TIBETAN MEDICINE

Tibetan medicine comes from Tibet, and is based on Buddhist teachings. Here, the three humors—bile, phlegm, and wind—need to be kept in balance. Cancer is caused by an imbalance in one, two, or all three of the humors. In addition, cancer can arise due to contaminants that have been introduced into the atmosphere and the environment. Diagnostic techniques include examination of the tongue, pulse, and urine. Therapeutic modalities include diet therapy, botanical formulations, physical activity, precious metals, and meditation (Donden, 1986). NATIVE AMERICAN MEDICINE

Each indigenous tribe in the Americas has a unique healing tradition and there is not a definition that can describe a single Native American medicine (Larkey, Greenlee, & Mehl-Madrona, 2005). However, there are some common themes in these traditions. In Native American medicines, there is not a differentiation between medicine and religion. In order to heal, one must acknowledge an “Inner Healer.” Many tribes teach that spirit is indivisible from mind and body and that a healthy balance, harmony, and connection with spirit is vital for disease prevention (Larkey et al., 2005). Illness results when there is imbalance or disharmony and wellness occurs when balance is restored (Burhansstipanov & Hollow, 2001). Ceremony is intrinsic to creating and maintaining harmony. It is important to note that cancer can also be caused by disturbing the sacred nature of the land (Burhansstipanov & Hollow, 2001). Common to healing systems such as TCM, Ayurveda, Tibetan medicine, and Native American medicine is the recognition of a balance between an individual, their community, and their environment. Any disturbance in one of these areas can lead to disease, including cancer. Perhaps what we can learn from these systems of health and healing is that it behooves us to conceptualize

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a holistic approach to risk reduction, which incorporates body, mind, spirit, and environment.

A Vision for Future Clinical Services Currently, in the United States there are few truly integrated medical centers providing cancer risk reduction care. Some cancer centers are beginning to offer risk-assessment services, however they are limited to genetic screening and medical-history risk and do not have well developed programs on prevention tactics. Two main factors that have limited the widespread provision of these services include a lack of research on efficacy of many risk reduction approaches, and poor, if any, physician reimbursement for prevention care. In addition, patients are not reimbursed or rewarded for time and resources spent at being proactive about disease prevention. Unfortunately, all these factors may make it confusing for individuals using conventional or CAM modalities for general health maintenance and for risk reduction because they are without clear guidance. In the future, it is possible that people will be able to visit specialized clinics to receive comprehensive assessments of their personal risk of developing cancer. These risk assessments will take into account the results of screening tests, personal disease history, family disease history, genetic tests, prior environmental exposures, dietary history, exercise history, and socio-economic status. New tools will be available to assess stress, immune function, and genetic risk including an individual’s ability to metabolize various substances. Once this assessment is made, people will be offered and counseled on interventions to counter their risk, including pharmaceuticals, natural compounds, dietary changes, exercise programs, and mind/body interventions. The clinics will be staffed by people with varying areas of expertise, including genetics, medical oncology, radiation oncology, health psychology, nutrition, exercise, mind-body medicine, botanical medicine, and functional medicine.

Future Research Directions Each of the cancer prevention approaches described earlier would benefit from further investigation. Many of these approaches are promising, but few have enough evidence to promote large-scale implementation. The gold standard for determining whether a risk reduction approach is effective is to use cancer incidence as the endpoint in large, randomized, phase III studies. Because these trials are expensive and can be difficult to implement, early phase trials

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using intermediate or surrogate markers for predicting cancer occurrence may be warranted. These endpoints include clinical, histological, biochemical, and molecular biomarkers that can demonstrate responses to chemoprevention agents, behaviors, or healing modalities (Smith, Tully, & Padberg, 2005). These studies will need to carefully screen potentially therapeutic strategies to identify which have the most promise, which target populations will benefit the most, and what the appropriate endpoints will be. Most integrative medicine practitioners are trained to tailor their therapies to an individual. Increasingly, conventional medical practitioners and researchers are acknowledging the benefit of individualizing health care delivery. This approach will be especially beneficial in the area of cancer risk reduction where it may be difficult to implement and sustain preventive measures in large numbers of individuals. Assuming that additional effective cancer risk reduction modalities will be identified in the future, individuals will be asked to regularly ingest substances, change their behaviors, and/or receive vaccinations. It will be important to tailor these recommendations to an individual to make them as effective and as acceptable as possible.

Conclusion Cancer risk reduction is just one aspect of optimizing health. Average-risk individuals want to know what they can do to decrease their risk of developing any disease. Individuals at high cancer risk want to know their options for decreasing their specific cancer risk. Ideally, in the future people will have access to cancer prevention centers that offer an integrated team of clinicians to coordinate medical and lifestyle recommendations, with a focus on staying well, rather than on treating disease. Ideally, some of the CAM modalities that are proven efficacious for disease prevention and/or enhancing a sense of well-being will be offered at these centers. To be sustainable, this will need to be done in the context of a medical system that invests in prevention and pays and reimburses for prevention work. In the meantime, we can consider advocating lifestyle changes that may prevent cancer initiation and/or progression, while simultaneously helping individuals increase their sense of wellness. We can eat a diet rich in fruits, vegetables, and whole grains; stay physically active; maintain a BMI of less than 25; and keep stress at bay, possibly using one of the mind-body techniques described earlier. We can know our risk of developing cancer based on age, gender, family history, and exposures and be screened appropriately. Finally, we can live a full life, keeping in mind traditional systems of medicine that promote balance among body, mind, spirit, and environment.

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Acknowledgments The author would like to acknowledge and thank Ms. Laura Falci for her assistance with manuscript preparation. REFERENCES

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3 Molecular Targets of Botanicals Used for Chemoprevention MURIEL CUENDET, ANDREAS NIEVERGELT, AND JOHN M. PEZZUTO

KEY CONCEPTS The treatment of many diseases is dependent on natural products, and this is especially true for the treatment of cancer. ■ Chemoprevention is the use of synthetic or natural agents to inhibit, retard, or reverse carcinogenesis, or prevent the development of invasive cancer. ■ Dietary consumption of foods and herbal medicines is a convenient method of administrating potentially beneficial phytochemicals in a cost-effective manner. ■ Extracts of plant or marine organisms can be evaluated for potential chemopreventive activity using a battery of in vitro bioassays developed to monitor the alterations of targets involved in tumorigenesis at various stages. ■ Grapes, turmeric, ginger, soya, licorice, citrus, cruciferous vegetables, green tea, Allium vegetables, and tomatoes have shown cancer chemopreventive activities. ■ Only a few compounds have been approved by the U.S. Food and Drug Administration (FDA) for use as chemopreventive agents. ■

52

T

Molecular Targets of Botanicals Used for Chemoprevention  53

he treatment of many diseases is highly dependent on natural products, and this is especially true for the treatment of cancer (Cragg, Newman, & Snader, 1997; Pezzuto, 1997). Several potent drugs have been isolated from natural sources. The Vinca alkaloids isolated from the Madagascar periwinkle, Catharanthus roseus G. Don, comprise a group of about 130 terpenoid indole alkaloids (Svoboda & Barnes, 1964). Their clinical value was clearly identified as early as 1965 and this class of compounds has been used as anticancer agents for over 40 years and represents a true lead compound for drug development (Johnson, Armstrong, Gorman, & Burnett, 1963). Today, two natural compounds, vinblastine and vincristine, and three semisynthetic derivatives, vindesine, vinorelbine, and vinflunine, have been registered. The antineoplastic activity of the Vinca alkaloids is usually attributed to disruption of microtubules, resulting in dissolution of mitotic spindles and metaphase arrest in dividing cells (Bruchovsky, Owen, Becker, & Till, 1965; George, Journey, & Goldstein, 1965; Krishan, 1968; Lengsfeld, Schultze, & Maurer, 1981; Malawista, Sato, & Bensch, 1968). Over 60% of the approved drugs developed as anticancer or anti-infective agents are of natural origin.

In 1971, Wani, Taylor, Wall, Coggon, & McPhail (1971) discovered the highly potent anticancer agent paclitaxel, which occurs widely in plants of Taxus species. Paclitaxel and an analog, docetaxel, are very useful anticancer chemotherapeutic agents. Among antineoplastic drugs that interfere with microtubules, paclitaxel exhibits a specific mechanism of action (Kumar, 1981; Manfredi & Horwitz, 1984; Schiff, Fant, & Horwitz, 1979; Thompson, Wilson, & Purich, 1981). Paclitaxel promotes assembly of microtubules by shifting the equilibrium between soluble tubulin and microtubules toward assembly, reducing the critical concentration of tubulin required for assembly. The result is stabilization of microtubules, which is damaging to cells because of the perturbation in the dynamics of various microtubule-dependent cytoplasmic structures that are required for functions such as mitosis, maintenance of cellular morphology, shape changes, neurite formation, locomotion, and secretion (Baum et al., 1981; Letourneau & Ressler, 1984; Rowinsky, Donehower, Jones, & Tucker, 1988; Roytta, Laine, & Harkonen, 1987). Work on Taxus brevifolia leading to the discovery of paclitaxel (Taxol®) started in 1962; Taxol® did not reach the market until 1992.

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In the early 1960s, the discovery of camptothecin (CPT) by Wall and Wani as an anticancer drug added an entirely new dimension to the field of chemotherapy (Wall et al., 1966; Wall, 1998). Camptothecin was first isolated from the Chinese ornamental tree Camptotheca acuminata Decne, also known as the “tree of joy” and “tree of love.” Preliminary studies revealed a substantial antitumor activity in standard in vitro test systems as well as in mouse leukemia cells. Interest in CPT and analogs remained at a low ebb until 1985 when it was discovered that CPT, by a unique mechanism, inhibited the enzyme topoisomerase I (Hsiang, Hertzberg, Hecht, & Liu, 1985; Redinbo, Stewart, Kuhn, Champoux, & Hol, 1998; Staker et al., 2002). Topoisomerase I involves the transient single-strand cleavage of double-stranded DNA, followed by unwinding and relegation. These actions facilitate essential cellular processes such as DNA replication, recombination, and transcription (Gupta, Fujimori, & Pommier, 1995). Cancer, however, is considered the end stage of a chronic disease process characterized by abnormal cell and tissue differentiation (Sporn & Suh, 2000). This process of carcinogenesis eventually leads to the final outcome of invasive and metastatic cancer. Recent advances in defining cellular and molecular levels of carcinogenesis, along with a growing body of experimental, epidemiological, and clinical trial data, have led to the development of cancer chemoprevention, a relatively recent strategy in preventing cancer (Sporn, Dunlop, Newton, & Smith, 1976; Wattenberg, 1985). Cancer chemoprevention is defined as the use of synthetic or natural agents to inhibit, retard, or reverse carcinogenesis, or prevent the development of invasive cancer (Sporn et al., 1976; Wattenberg, 1985; Kelloff, Sigman, & Greenwald, 1999). Most human cancers seem to be potentially preventable because of controllable or removable causative exogenous factors, such as cigarette smoking, dietary factors, environmental and occupational chemicals, lifestyle and socioeconomic factors, radiation, and specific microorganisms (Greenwald, Kelloff, Burch-Whitman,  & Kramer, 1995). These exogenous factors offer the most likely opportunities for interventions targeted to primary prevention—that is, elimination of or avoiding exposure to these factors (Figure 3.1) (Surh, 1999). In addition, however, as a serious and practical approach to the control of cancer, cancer chemoprevention can play an integral role in the overall strategy geared toward reducing the incidence of cancer (Wattenberg, 1985; Sporn & Suh, 2000). Rational and successful implementation of chemopreventive strategies relies intrinsically on tests for efficacy and mechanistic assays, as well as availability of promising chemopreventive agents, reliable intermediate biomarkers, and appropriate clinical cohorts to discover safe and effective drugs for primary and secondary prevention of human cancers (Kelloff et al., 1996; Kelloff et al., 2006). Dietary consumption of foods and herbal medicines is a

Molecular Targets of Botanicals Used for Chemoprevention  55 Blocking agents Inhibitors of carcinogen formation

Initiation Normal cell

Suppressing agents

Promotion Initiated cell

Progression Benign tumor

Malignant tumor

Exogenous factors Cigarette smoking Dietary factors Chemicals Lifestyle Radiation Microorganisms

Figure 3.1.  Schematic representation of multistage (initiation, promotion, progression) carcinogenesis. Exogenous factors act as tumor initiators, tumor promoters, or as complete carcinogens. These exogenous factors offer opportunities for intervention targeted to primary prevention. In addition, chemopreventive agents can play an integral role in the overall strategy geared toward reducing the incidence of cancer.

convenient method of administrating potentially beneficial phytochemicals in a cost-effective manner.

Discovery of New Chemopreventive Agents from Natural Sources In 1991, we instituted a multidisciplinary project supported by NCI wherein plant and (more recently) marine organism materials procured from throughout the world are used for activity-guided fractionation schemes that yield novel and otherwise unpredictable chemical entities with cancer chemoprevention activities. The overall aspects of this program have been summarized previously (Jensen & Fenical, 1994; Pezzuto et al., 1999; Kinghorn et al., 1998). Crude nonpolar and polar extracts, prepared from each plant or marine organism obtained, are evaluated for their potential chemopreventive activity using a battery of short-term in vitro bioassays developed to monitor inhibition of tumorigenesis at various stages (Figure 3.1) (Pezzuto, Angerhofer, & Mehdi, 1998). For initiation, induction of NAD(P)H:quinone oxidoreductase 1 (QR1) activity (Song et al., 1999), and antioxidant activity (Chung et al., 1999) are

56  Integrative Oncology

assayed. For promotion, inhibition of activities such as cyclooxygenase (COX) (Cuendet & Pezzuto, 2000), tumor necrosis factor alpha (TNF-α)-induced nuclear factor-kappa B (NF-κB) activation, phospholipase A2 (PLA2), and phorbol ester-induced ornithine decarboxylase (ODC) (Gerhauser et al., 1997) is assayed. For progression, inhibition of aromatase activity (Jeong, Shin, Kim, & Pezzuto, 1999) and histone deacetylase (HDAC) activity, as well as induction of human leukemia cell differentiation (Mata-Greenwood et al., 2001) are assayed. Over 20,000 tests have been performed, and the number of plants or marine organisms characterized as “active” is in the range of 5% of the total. In general, these “active” plant or marine organism extracts are tested in a secondary model of greater physiological complexity, such as the mouse mammary organ culture (MMOC) model. In this assay, test materials are evaluated for their ability to inhibit 7,12-dimethylbenz(a)anthracene (DMBA)-induced preneoplastic lesions (Mehta, Hawthorne, & Steele, 1997). Active extracts in the secondary model are subjected to bioassay-guided fractionation using an in vitro system as a monitor to uncover their active principles. Active isolates are considered for evaluation in full-term animal studies, including the two-stage mouse skin model using DMBA as an initiator and 12-O-tetradecanoylphorbol13-acetate (TPA) as a promoter, and the rat mammary carcinogenesis model with N-methyl-N-nitrosourea or DMBA as a carcinogen (Jang et al., 1997; Udeani et al., 1997). Additional in vivo models are used as required. At present, isoliquiritigenin (QR1 inducer; Cuendet, Oteham, Moon, & Pezzuto, 2006), abyssinone II (aromatase inhibitor; Lee et al., 2001), zapotin (HL-60 cell differentiation; Mata-Greenwood et al., 2001), brusatol (HL-60 cell differentiation; Luyengi, Suh, Fong, Pezzuto, & Kinghorn, 1996), and resveratrol (Bhat & Pezzuto, 2002) are undergoing further investigation in animal studies as lead compounds. Clinical trials are anticipated in due course.

Phase II Enzyme Induction Carcinogenesis is a complex multistage process, yet the entire course can be initiated by a single event wherein an endogenous or exogenous agent damages a cellular macromolecule. Strategies for protecting cells from these initiating events include decreasing metabolic enzymes responsible for generating reactive species (phase I  enzymes) while increasing phase II enzymes that can deactivate radicals and electrophiles known to intercede in normal cellular processes. Important defenses against electrophile toxicity are provided in the family of phase II enzymes, such as glutathione S-transferase (GST) and QR1. Although phase I induction and functionalization of xenobiotics may be required for complete

Molecular Targets of Botanicals Used for Chemoprevention  57

detoxification by the subsequent action of phase II enzymes, phase I enzyme elevation may also be considered a potential cancer risk factor for activation of procarcinogens to reactive species (Yang, Smith, & Hong, 1994). Therefore, an agent that induces phase II enzymes selectively would theoretically appear to be a better protector than induction of both phase I and II enzymes. QR1 elevation with in vitro and in vivo systems has been shown to correlate with induction of other protective phase II enzymes and provides a reasonable biomarker for the potential chemoprotective effect of test agents against cancer initiation (Talalay, 1992). In searching for novel cancer chemopreventive agents, we have utilized a rapid, sensitive QR1 assay to identify potential detoxification enzyme inducers (Talalay, Fahey, Holtzclaw, Prestera, & Zhang, 1995). One of the most effective inducers of phase II enzymes is sulforaphane; high concentrations are found in broccoli sprouts and seeds.

Antioxidant Activity Since reactive oxygen species (ROS), mainly oxygen radicals, play an important role in carcinogenesis and are involved in both initiation and promotion, antioxidants present in consumable fruits, vegetables, and beverages have received considerable attention as cancer chemopreventive agents (Mukhtar, Katiyar, & Agarwal, 1994). Paradoxical as it may seem, various antioxidants such as flavonoids elicit their beneficial effects only after autoxidation and thereby generate hydrogen peroxide or oxidize glutathione (Erlank, Elmann, Kohen, & Kanner, 2011; Lambert & Elias, 2010). Notably, ROS are important second messengers and a central defense mechanism against bacteria and malignant cells. Many antioxidants can also function as pro-oxidants. Paradoxically, pro-oxidants can have beneficial effects too.

Several assay systems have been developed to discover potentially active compounds from synthetic and natural sources (Lee et al., 1998). It is important to note that a potential antioxidant lead must be evaluated in more than one antioxidant assay because of variability in the different test systems (Schlesier, Harwat, Bohm, & Bitsch, 2002). The presence of antioxidants in extracts has been assessed, for instance, by determining scavenging activity with stable DPPH free radicals (Fujita et al., 1988), inhibition of TPA-induced free radical

58  Integrative Oncology

formation with cultured HL-60 cells (Sharma, Stutzman, Kelloff,  & Steele, 1994), and inhibition of superoxide anion production in xanthine/xanthine oxidase systems (Sheu, Lai, & Chiang, 1998).

Anti-inflammatory Activities CYCLOOXYGENASE INHIBITION

Two COX isoforms, COX-1 and COX-2, are known. COX-1 is constitutively expressed in many tissues (O’Neill & Ford-Hutchinson, 1993; Simmons, Xie, Chipman, & Evett, 1991), and prostaglandins produced by COX-1 are thought to mediate “housekeeping” functions such as cytoprotection of the gastric mucosa, regulation of renal blood flow, and platelet aggregation (Merlie, Fagan, Mudd, & Needleman, 1988). In contrast to COX-1, the more recently discovered isoform COX-2 is not generally detected in most tissues (Jouzeau, Terlain, Abid, Nedelec, & Netter, 1997). However, COX-2 is an inducible enzyme that is expressed in response to pro-inflammatory agents, including cytokines, endotoxins, growth factors, tumor promoters, and mitogens (O’Banion, Winn,  & Young, 1992; Smith, Meade, & DeWitt, 1994). COX-2 is expressed in a few specialized tissues such as brain, testes, and macula densa of the kidney, in the apparent absence of any induction process. Considerable evidence has accumulated to suggest that COX-2 is important for tumorigenesis. COX-2 expression is markedly increased in colorectal adenocarcinomas, as well as in other solid organ tumors, such as breast, lung, and prostate (Eberhart et al., 1994; Prescott & Fitzpatrick, 2000). As a result, COX-2 inhibitors have the potential of inhibiting tumor development, and hence many experimental studies using cell lines and animal models have demonstrated an ability to prevent tumor proliferation. Moreover, after performing a randomized study for polyp chemoprevention in patients with familial adenomatous polyposis (FAP), which showed that treatment with the COX-2 selective inhibitor celecoxib significantly reduced the number of colorectal polyps, the U.S. Food and Drug Administration (FDA) quickly approved the clinical use of this drug for FAP patients (Steinbach et al., 2000). It is important to note, however, that some COX-2 inhibitors were subsequently reported to increase the risk of serious cardiovascular events, including heart attack and stroke (Bombardier et al., 2000). Due to such cardiovascular events, the approval of celecoxib for the treatment of FAP was withdrawn in 2012. Some of these side effects are caused by a shift in the balance not only between COX-1 and COX-2 derived prostaglandins (PGs) but also from PGs to other

Molecular Targets of Botanicals Used for Chemoprevention  59

eicosanoids (e.g., leukotrienes). Nevertheless, nonsteroidal anti-inflammatory drugs such as acetylsalicylic acid (aspirin) remain of great interest in cancer chemoprevention (Burn et al., 2011). Prostaglandins produced by COXs are represented by a large series of compounds that mainly enhance cancer development and progression, acting as carcinogens or tumor promoters with profound effects on carcinogenesis (Hong & Sporn, 1997). Thus, the ability to regulate the COX pathway provides a reasonable opportunity for cancer chemoprevention. The assay we use is based on measurement of PGE2 produced in the COX reaction via an enzyme immunoassay (Cuendet & Pezzuto, 2000). Selectivity of anti-inflammatory agents is important. Some may cause adverse side effects such as ulcers or cardiac problems.

NF-κB INHIBITION

NF-κB is a ubiquitous transcription factor that is activated in a variety of cellular survival settings (Pahl, 1999). NF-κB is maintained in the cytoplasm in an inactivated or resting state by the substance known as kappa B (IκB). Only after IκB is phosphorylated by IκB kinase (IKK), is NF-κB released and free to translocate to the nucleus where it can perform its function (Zandi & Karin, 1999). Upon activation, NF-κB has been shown to transcriptionally upregulate many genes, most of which encode proteins involved in cellular survival pathways and inflammation (Schwartz, Hernandez, & Evers, 1999). The signaling pathways with which these proteins interface are diverse, and many are directly involved in subverting apoptosis. A wide range of drugs and molecules that activate NF-κB in tumor cells have been identified, including cytokines such as TNF-α and interleukin 1β (IL-1β), lipopolysaccharide, cellular stress-like ultraviolet irradiation (Perkins, 2007), as well as chemotherapeutic agents (Das & White, 1997). The principle of the assay relies on the ability of natural products to inhibit the action of the aforementioned stimuli, which turn on a promoter, NF-κB, artificially constructed upstream of the luciferase gene. Once the promoter is triggered, it leads to transcription and eventually translation of the luciferase protein. Luciferase activity is easily measured using a luminometer. PHOSPHOLIPASES A2 INHIBITION

Phospholipases A2 are classified into five types: secreted PLA2 (sPLA2), cytosolic PLA2 (cPLA2), calcium-independent PLA2 (iPLA2), platelet-activating

60  Integrative Oncology

factor acetylhydrolases (PAF-AH, also known as lipoprotein-associated phospholipase A2 or Lp-PLA2), and lysosomal PLA2. Knowledge of the important roles of PLA2, besides lipid metabolism, has emerged only recently and our understanding of the role of these enzymes is still limited. PLA2 hydrolyze diacyl-phospholipids into lysophospholipids and free fatty acids, both important precursors for second messengers mainly in inflammation-related signaling. sPLA2 plays a central function in lipid digestion, iPLA2 in lipid metabolism and, as housekeeping functions, cell membrane bilayer remodeling and are involved in calcium signal transduction. sPLA2 and cPLA2 are furthermore involved in proliferation, maturation, and apoptosis and play crucial roles in acute and chronic inflammatory diseases by regulating maturation (iPLA2) and secretion (cPLA2) of IL-1β, a key cytokine in early inflammation. PLA2 inhibitors look promising as anti-inflammatory drugs due to their dual action on eicosanoids (with a different effect on arachidonic acid metabolite balance than nonsteroidal anti-inflammatory drugs) and on IL-1β. So far, only therapeutic proteins against IL-1β are approved for the treatment of severe autoimmune diseases such as rheumatoid arthritis. There is an acute need for “softer,” safer, and less expensive drugs also for the treatment of less severe diseases as well as prevention of inflammation-related cancers. One among several useful assays in PLA2 inhibitor screening is a mixed micelle-based enzymatic assay using a thio-phospholipid substrate. Enzymatic turnover is calculated after thioreactive fluorophore linkage (i.e., with monobromobimane) and HPLC separation coupled to a fluorescence detector (Nievergelt, Marazzi, Schoop, Altmann, & Gertsch, 2011).

Ornithine Decarboxylase Inhibition Ornithine decarboxylase (ODC) is the first and apparently the rate-limiting enzyme for the biosynthesis of polyamines in mammalian cells and is highly inducible by growth-promoting stimuli including growth factors, steroid hormones, cAMP-elevating agents, and tumor promoters (Coffino, 2001; Pena et al., 1993). A number of factors finely tune ODC activity, including the expression, stability, and transcription rate of ODC messenger RNA, as well as the stability and translation rate of the ODC enzyme, and also the posttranslational modification of the enzyme (van Daalen Wetters, Brabant, & Coffino, 1989). Furthermore, ODC has been shown to play a role in transformation (Hurta, 2000) and to correlate with metastatic potential (Hardin, Mader, & Hurta, 2002). Since ODC activity is essential for proliferation of normal cells, and, on the other hand, is overexpressed in various cancer cell lines, it is now recognized that inhibition of ODC, likely combined with a polyamine transport inhibitor (Aziz et al., 1996),

Molecular Targets of Botanicals Used for Chemoprevention  61

may be a good strategy for cancer chemoprevention and chemotherapy. To assess the inhibitory activity of extracts, we used TPA to induce ODC activity in T24 cells; enzymatic activity is measured by quantifying 14CO2 released from l-(1–14C)-ornithine (Lee & Pezzuto, 1999).

Aromatase Inhibition Estrogens are involved in the development of numerous hormone-related disorders, most notably carcinomas such as breast and endometrial cancers (Brodie & Njar, 1998). Estrogen deprivation is one strategy frequently used for treatment of hormone-dependent tumors. A  decrease in estrogen levels can be achieved by modulating some estrogen receptors with antiestrogens, also known as selective estrogen receptor modulators (SERMs), or by reducing estrogen production by inhibiting aromatase, the key enzyme in estrogen biosynthesis (Njar & Brodie, 1999). Aromatase is a reasonable target for inhibition since it is the final and rate-limiting step in estrone and estradiol biosynthesis (Hong  & Chen, 2006). As a member of the cytochrome P450 (CYP) superfamily, aromatase shares common features with other CYP enzymes. In this regard, the selectivity of aromatase inhibitors is an important issue because of the widespread presence of CYPs in mammals; nonselective inhibition could cause serious side effects. Aromatase inhibitors have been developed to treat breast cancer in postmenopausal women. Three aromatase inhibitors, anastrozole, letrozole, and exemestane have been approved by the FDA for use as chemopreventive agents in the adjuvant treatment of postmenopausal women with estrogen receptor-positive early breast cancer. To assess aromatase inhibition, a modified assay based on the fluorescence-based high-throughput screening system from BD Biosciences (San Jose, CA) is employed (Stresser et al., 2000).

Differentiation-Inducing Agents Differentiation-inducing agents have been shown to suppress cancer cell self-renewal selectively from normal stem cell renewal by inducing terminal differentiation followed by apoptosis. In addition, inducers of terminal differentiation, such as the retinoid and deltanoid (vitamin D3 derivatives) classes of compounds, have shown promising chemopreventive activities as suppressing agents that act during the promotion-progression stages of carcinogenesis (Kelloff et al., 1994). Although toxicity has hampered the development of these agents as primary chemopreventive agents, novel structural analogs with high affinity and selectivity for specific nuclear receptors have been developed

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(Hong & Sporn, 1997). The HL-60 cell line is a valuable tool for research on myeloid maturation at the cellular and molecular level (Collins, 1987). This cell line can be induced to differentiate into the granulocytic, monocytic/macrophagic, or eosinophilic pathways of cellular development.

Epigenetic Control Epigenetic control refers to modulation of gene expression without changing the genetic code. DNA methylation, RNA interference, and histone modifications (mainly acetylation and methylation) play a central role in heterochromatin formation and regulation of transcription and translation. Aberrant histone deacetylation has been recognized as a major epigenetic mechanism in cancer development and especially in leukemia (Ellis, Atadja, & Johnstone, 2009). Amplified histone deacetylases (HDAC) (mainly from class I) activity may cause functional gene silencing of DNA sequences coding for self-regulatory and/or pro-apoptotic proteins, whereas SIRT1 (sirtuin 1, a class III HDAC) activity has been demonstrated to induce stress resistance, apoptosis, and anti-inflammatory activities (Xie, Zhang, & Zhang, 2013). On the other hand, DNA hypomethylation, which has been associated with many cancers, causes the overexpression of cell survival proteins and oncogenes (Ehrlich, 2002). Several natural products have shown promising anticancer activities through epigenetic modulation, namely by inhibiting DNA methyltransferases (DNMT) and HDAC (Hardy & Tollefsbol, 2011). The best studied HDAC inhibitors are hydroxamates; the first one being approved by the FDA for the treatment of some lymphomas is vorinostat. However, their main application is cancer treatment and not prevention, because they exhibit a rather high toxicity and lack HDAC subtype specificity. New, more stable and also nonhydroxamate derivatives have been synthesized by various companies and research groups. Compounds of natural origin, such as romidepsin, often showed a better subtype specificity (Glaser, 2007; Bertrand, 2010). This justifies plants, marine organisms, fungi, and microorganisms as important sources of new chemical entities. HDAC inhibition can be measured in cells by using commercial colorimetric, fluorimetric, and luminescent assay kits (Wegener, Hildmann, & Schwienhorst, 2003).

Active Compounds Isolated from Edible Plants RESVERATROL

Resveratrol (trans-3,4´,5-trihydroxystilbene) is one of the phytoalexins produced in large amounts in grape skin in response to infection by Botrytis

Molecular Targets of Botanicals Used for Chemoprevention  63

cinerea. This production of resveratrol blocks the proliferation of the pathogen, thereby acting as a natural antibiotic. Numerous studies have reported interesting properties of resveratrol as a preventive agent against various pathologies such as vascular diseases, cancers, viral infection, or neurodegenerative processes. Several epidemiological studies have revealed that resveratrol is probably one of the main microcomponents of wine responsible for its health benefits. Resveratrol acts on the process of carcinogenesis by affecting the three phases—tumor initiation, promotion, and progression—and suppresses the final steps of carcinogenesis, that is, angiogenesis and metastasis. It is also able to activate apoptosis, to arrest the cell cycle, or to inhibit kinase pathways (Signorelli & Ghidoni, 2005; Delmas, Lancon, Colin, Jannin, & Latruffe, 2006; Pezzuto, 2006). Effects on cell-cycle regulation and apoptosis along with increased stress resistance may be explained by its modulatory activities on estrogen receptor (ER) isoforms and subsequent mitochondrial superoxide dismutase expression (Cos et al., 2003; Robb & Stuart, 2011; Signorelli & Ghidoni, 2005) (Table 3.1). Moreover, blood concentrations of resveratrol that can be achieved in vivo seem to be sufficient for an anti-invasive activity. Interestingly, low doses of resveratrol can sensitize to low doses of cytotoxic drugs and provide a strategy to enhance the efficacy of anticancer therapy in various human cancers. Nearly 5,000 manuscripts have appeared in the scientific literature describing the mode of action of resveratrol.

CURCUMIN AND PHENYLPROPANOIDS

The Zingiberaceae family comprises over 1,200 plant species from 53 genera, many of which are traditionally used as spices and medical plants such as turmeric, ginger, galangal, and cardamom. Mainly the rhizomes are a rich and diverse source of phenylpropanoid- and curcumin-related compounds showing a broad range of biological activities. The most studied diarylheptanoid is curcumin, the main yellow pigment in turmeric (Curcuma longa L.), whereas a broad chemical diversity has been isolated from plants of the genus Alpinia. Curcumin has emerged as one of the most powerful in vitro and in vivo chemopreventive and anticancer agents. This compound has been shown to exert anticarcinogenic effects in a diverse array of animal and cell-culture models. It can act as a chemopreventive agent in cancers of colon, stomach, and skin by suppressing colonic aberrant crypt foci formation and DNA adduct formation (Singh & Khar, 2006). Curcumin is a good antioxidant by itself and furthermore

Table 3.1.  Molecular Targets of Dietary Agents.* Plant Name:

Mechanisms

Molecular Targets

References

Active Constituents

Grapes (Vitis vinifera L.): Stilbenes (e.g., resveratrol)

Phase II & SOD expression ↑, ODC expression ↓ Kinase signaling ↓: MAPK & tyrosine kinases Nuclear factor signaling ↓: AP-1, EGR-1 & NF-κB Modulation of cell cycle regulatory proteins, survival & apoptosis

Inhibition of COX, ER & Keap1 Induction of SIRT1

(Gertz et al., 2012; Pezzuto, 2006; Signorelli & Ghidoni, 2005)

Turmeric (Curcuma longa L.): Curcumin

Antioxidant, Phase II expression ↑, ODC & VEGF expression ↓ Pleiotropic effects on cell signaling: AP-1, NF-κB, MAPK, p53 & STAT Induction of apoptosis

Inhibition of matrix metalloproteinases, DNMT, HAT, HDAC & Keap1

(Hasima & Aggarwal, 2012; Singh & Khar, 2006)

Ginger (Zingiber officinale Roscoe): Phenylpropanoids, diarylheptanoids, flavonoids, terpenoids

iNOS expression ↓, NO & cytokine production ↓, Phase II expression ↑ Intracellular signaling ↓: NF-κB & MAPK

Inhibition of COX, i/cPLA2 & Keap1 Partial activation of 5-HT1A R

(Chrubasik, Pittler, & Roufogalis, 2005; Nievergelt, Marazzi, Schoop, Altmann, & Gertsch, 2011)

Soybean (Glycine max L.): Isoflavones Licorice (Glycyrrhiza glabra L.): Chalcones

Antioxidant, anti-estrogenic, Phase II expression ↑

Activation of ER β Inhibition of Keap1

(Froyen & Steinberg, 2011; Yadav, Prasad, Sung, & Aggarwal, 2011)

Lemon (Citrus x limon): Flavonoids, coumarins, limonins, monoterpenes, ascorbic acid

Antioxidant, Phase II expression ↑, iNOS & COX expression ↓, NO & TNF-α production ↓ Modulation of drug metabolism

Inhibition of CYP1B1 & Keap1

(Benavente-Garcia & Castillo, 2008; Takemura, Itoh, Yamamoto, Sakakibara, & Shimoi, 2010)

Cruciferous vegetables (Brassica sp.): Isothiocyanates (e.g., sulforaphane), indole derivatives (e.g., indole-3-carbinol)

Phase I & II expression ↑ Modulation of intracellular signaling: AP-1↓↑, IKK/NF-κB ↓, MAPK ↓↑ Induction of cell cycle arrest and apoptosis via pro-oxidant activities: GSH ↓, ROS ↑

Activation of AhR Inhibition of CYP, HDAC & Keap1

(Keum, Jeong, & Kong, 2005)

Green tea (Camellia sinensis L.): Catechins (e.g., EGCG)

Anti-/pro-oxidant, expression of iNOS ↓, inhibition of DNA damage, Pleiotropic effects on cell signaling: AP-1, MAPK, NF-κB & protein kinases Modulation of cell cycle regulatory proteins & apoptosis

Inhibition of matrix metallo-proteinases, COX & DNMT

(Hou, Lambert, Chin, & Yang, 2004)

Allium vegetables (Allium sp.): Organosulfur compounds

Phase II expression ↑ ODC expression ↓ Nuclear factor signaling ↓: NF-κB Modulation of cell cycle regulatory proteins & induction of apoptosis

Inhibition of Keap1, CYP

(Robert, Mouille, Mayeur, Michaud, & Blachier, 2001; Singh et al., 1998)

Tomato (Solanum lycopersicum L.): Lycopene

Antioxidant Nuclear factor signaling ↓: NF-κB Modulation of cell cycle regulatory proteins & induction of apoptosis

(Bhuvaneswari & Nagini, 2005)

*Also see references (Aggarwal & Shishodia, 2006; Park & Pezzuto, 2002). 5-HT1A R, serotonin 1A receptor; AhR, arylhydrocarbon receptor; AP-1, activator protein 1; COX, cyclooxygenase; CYP, cytochrome P450; DNMT, DNA methyltransferases; EGCG, (–)-epigallocatechin-3 gallate; EGR-1, early growth response factor 1; ER, estrogen receptor; GSH, glutathione; HAT, histone acetyltransferases; HDAC, histone deacetylases; i/cPLA2, calcium-independent and cytosolic phospholipases A2; IKK, IκB kinase; iNOS, inducible nitric oxide synthase; Keap1, kelch-like ECH-associated protein 1; MAPK, mitogen-activated protein kinases; NF-κB, nuclear factor-kappa B; NO, nitric oxide; ODC, ornithine decarboxylase; ROS, reactive oxygen species; SIRT1, sirtuin 1; SOD, mitochondrial superoxide dismutase; STAT, signal transducer and activator of transcription; VEGF, vascular endothelial growth factor.

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induces QR1, GST, and other “antioxidant” enzymes. Also, curcumin has been shown to directly inhibit NF-κB, thereby suppressing proliferation and inducing apoptosis, and to possess antiangiogenic properties by down-regulating the expression of proangiogenic genes such as VEGF and decreasing migration and invasion of endothelial cells. In summary, curcumin interferes with several cell-signaling pathways involved in inflammation and carcinogenesis at various stages; this includes inhibition of growth-factor receptors, protein kinases, transcription factors, and cytokine expressions as reviewed in numerous articles (Table 3.1) (Esatbeyoglu et al., 2012; Grynkiewicz & Slifirski, 2012; Hasima & Aggarwal, 2012; Shehzad & Lee, 2013). Cell lines that are resistant to certain apoptotic inducers and radiation become susceptible to apoptosis when treated in conjunction with curcumin. Several other effects have been described in the literature mainly with in vitro assays (Kunnumakkara, Anand, & Aggarwal, 2008). Curcumin has some drawbacks, which are its high lipophilicity and hence poor absorption, and its extensive metabolism. This, the several in vitro effects reported, and the lack of published negative controls (e.g., targets or enzymes unaffected by curcumin) leave the true nature of the in vivo molecular target(s) somewhat unclear. Though no adverse effects are known to date and very high alimentary doses are tolerated, these drawbacks restrict its use to local applications, mainly gastrointestinal, because achievable plasma concentrations are around a thousand-fold below effective ones observed in most in vitro assays. Hence, related diarylheptanoids from other species are increasingly being investigated. The second most studied Zingiberaceae species is garden ginger (Zingiber officinale Roscoe). Besides the essential oil, the rhizome of this plant contains various phenylpropanoids with 6-gingerol as its main constituent. These compounds have proven antiemetic activity and much research on their anticancer and anti-inflammatory activities has been done. Ginger constituents have been reported to inhibit prostaglandin production, COX isoenzymes, inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production, cytokine release, as well as mitogen-activated protein kinases (MAPK) and NF-κB activation. Also, a selective partial agonistic activity on the 5-HT1A receptor has been demonstrated (Nievergelt, Huonker, Schoop, Altmann, & Gertsch, 2010). This receptor is not only involved in central neurotransmission but also expressed on immune cells and involved in immune system responses and inflammation. Additionally, 6-shogaol (the dehydration product of 6-gingerol) was shown to alkylate several proteins such as tubulin and kelch-like ECH-associated protein 1 (Keap1). Furthermore, a direct inhibition of iPLA2 and cPLA2, with a subsequent inhibition of IL-1β, but not sPLA2, was also found (Nievergelt et al., 2011). The dual effect on COX and PLA2

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drastically reduces prostaglandin production and alters free arachidonic acid concentrations. FLAVONOIDS

The flavonoid family is as diverse as their described effects. They have been claimed as dietary supplements to prevent diseases, promote health, and act as cancer chemopreventive agents. Their antioxidant capacity is the most widely studied activity. Here we will focus on a few selected flavonoids with well-defined molecular targets, such as soy isoflavones and chalcones found in licorice. Isoflavones, such as genistein and daidzein, as well as chalcones, such as liquiritigenin and isoliquiritigenin, act as selective ER β agonists, a receptor that predominates in normal mammary epithelium and mediates certain effects of antiestrogens (e.g., tamoxifen) (McCarty, 2006; Hong et al., 2011). This receptor has some overlapping as well as certain opposite activities to the better-known ER α (Zhao, Dahlman-Wright, & Gustafsson, 2008). The latter is mostly responsible for growth-promoting activity in estrogen-sensitive tumor cells. ER β binds primarily to the estrogen response element but also to the antioxidant response element (ARE) and induces the expression of phase II enzymes. Also, isolflavones have been found to augment the binding of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) to the ARE (Froyen & Steinberg, 2011) and chalcones to alkylate the Nrf2 inhibitor Keap1 (Eggler, Liu, Pezzuto, van Breemen, & Mesecar, 2005). Therefore, these flavonoids strongly increase the expression of phase II metabolizing enzymes by two different pathways merging at the ARE. Nrf2 is commonly regarded as the main nuclear factor binding to the ARE and is also induced by many other flavonoids. In contrast, ER β and to a lesser extent ER α, have only recently been recognized as converse transcriptional regulators at this promoter site (Montano, Jaiswal, & Katzenellenbogen, 1998). The dual effect on ER β and Keap1/Nrf2 may explain the potential breast cancer protective effect of isoflavones, chalcones, and probably other phytoestrogens. A recent meta-analysis correlated high isoflavone intake with a reduction of breast cancer, but mainly in postmenopausal Asian women (Xie et al., 2013). Besides Nrf2 and ER, the aryl hydrocarbon receptor (AhR) was found as a third transcription factor of phase II enzymes, but this nuclear factor also leads to the induction of phase I enzymes (e.g., CYPs). Among the many flavonoids reported as Nrf2 activators, several aglycones (e.g., apigenin, chrysin, flavone, flavanone, galangin, luteolin, and naringenin), and especially synthetic lipophilic derivatives (e.g., β-naphthoflavone and 4´-bromoflavone), have been found to be AhR ligands and thus less favorable dual phase I and II inducers.

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Some flavonoids are substrates and substrate inhibitors of various CYP isoforms. For example, flavonoids such as the methoxylated ones from lemon zest inhibit CYP1B1, the cytochrome best known to transform polycyclic aromatic compounds and estradiol into mutagens (Shimada et al., 2010; Takemura, Itoh, Yamamoto, Sakakibara, & Shimoi, 2010; Androutsopoulos, Papakyriakou, Vourloumis, & Spandidos, 2011); whether this is one of the molecular mechanism responsible for cancer preventive activities of citrus-fruit consumption remains an open question (Hakim, Harris, & Ritenbaugh, 2000; Li et al., 2010; Takemura, Sakakibara, Yamazaki, & Shimoi, 2013). Although daily intake of natural flavonoids is high and their observed in vivo toxicity negligible, their pharmaceutical use should be considered with care.

ISOTHIOCYANATES

Epidemiological evidence relating cancer risk reduction to the consumption of cruciferous vegetables such as broccoli, cauliflower, cabbage, kale, bok choy, Brussels sprouts, radish, wasabi, or various mustards has been summarized in several comprehensive reports (Cohen, Kristal, & Stanford, 2000; Lin et al., 1998; Michaud et al., 1999; Spitz et al., 2000; Zhang et al., 2000; Zhao et al., 2001). Highly significant cancer-risk reduction with increasing cruciferous vegetable intake was observed in cohorts that developed prostate (Cohen et al., 2000), breast, bladder (Michaud et al., 1999), and lung cancer (Spitz et al., 2000; Zhao et al., 2001), and non-Hodgkin lymphoma (Zhang et al., 2000). Potential mechanisms of chemoprevention by cruciferous plants appear to be the induction of phase II enzymes via alkylation of Keap1 (Eggler et al., 2005), inhibition of IKK-mediated NF-κB activation, modulation of MAPK signaling and AP-1 mediated gene expression, as well as HDAC inhibition (Keum, Jeong, & Kong, 2005; Rajendran et al., 2013) (Table 3.1). The active constituents of cruciferous vegetables are isothiocyanates, also known as mustard oils, and indole derivatives. They are generated by the enzyme myrosinase from stable glucosinolate precursors upon damage to the tissue. Isothiocyanates are fairly toxic toward many species, including microorganisms and insects, and thus protect the plants from herbivores. Some of these compounds are remarkably potent cancer chemopreventive agents, such as sulforaphane and phenethyl isothiocyanate components of broccoli and watercress, respectively (Hecht, 2000). Isothiocyanates are highly reactive, rather unstable, and heat-sensitive molecules often of volatile nature. Even though humans tolerate higher amounts of cruciferous vegetables than many other species, their reactivity should raise more concerns about selectivity, toxic, and mutagenic effects. Fortunately, the latter two seem to require

Molecular Targets of Botanicals Used for Chemoprevention  69

concentrations several magnitudes higher than commonly achieved plasma levels upon consumption (Fimognari, Turrini, Ferruzzi, Lenzi, & Hrelia, 2012). On the contrary, these concentrations are quite often in the range of those utilized with in vitro assays. Additionally, thiocyanate, one of the main terminal metabolites, is well known for its goitrogenic effect especially in cattle, but in other species as well (Bell, 1984). The American Cancer Society recommends five or more servings of cancer-fighting fruits and vegetables each day.

(–)-EPIGALLOCATECHIN-3-GALLATE

On a worldwide basis, the most popular chemopreventive drink is green tea. Green tea is the water extract of the unfermented dry leaves of Camellia sinensis L. (–)-Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea, is credited with the majority of health benefits associated with green tea consumption. The organ sites where tea or tea constituents are found to be effective include the skin, lung, oral cavity, esophagus, stomach, small intestine, colon, liver, prostate, and bladder. The mechanisms of carcinogenesis inhibition have also been investigated extensively, mostly in cell-culture systems, but no clear conclusion can be reached concerning the in vivo cancer-preventive mechanisms. Possible mechanisms include anti- and pro-oxidant activities, the inhibition of protein kinase and proteases, blockage of receptor-mediated functions and nuclear factor activation, as well as inhibition of DNA methyltransferases (DNMT) (Table 3.1) (Yang & Hong, 2013). These events may lead to cell-cycle regulation, growth inhibition, enhanced apoptosis, inhibition of angiogenesis, and inhibition of invasion and metastases (Hou, Lambert, Chin, & Yang, 2004). The possible complications of translating results obtained in cell culture studies to animals and humans may come from possible artifacts due to the autooxidation of EGCG in vitro (Lambert & Elias, 2010; Yang et al., 2006) as well as from its nonspecific interaction with proteins (Yang & Wang, 2011). Activities observed in cell culture with elevated concentrations of EGCG may not be relevant because of the limited systemic bioavailability and fast metabolism of EGCG (Lambert, Sang, & Yang, 2007; Lee et al., 2002; Renouf et al., 2010). ORGANOSULFUR COMPOUNDS

The large genus Allium includes onion, garlic, chive, leek, and shallot. Preclinical investigations demonstrate consistently that cancer

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chemoprevention by garlic and related sulfur compounds is clearly evident and appears to be independent of the organ site or the carcinogen employed (Knowles & Milner, 2001; Milner, 1996). The protection of tumor incidence by garlic may arise from several mechanisms, including blockage of N-nitroso compound formation, suppression of the bioactivation of several carcinogens, enhanced DNA repair, reduced cell proliferation, and/or induction of apoptosis (Milner, 2001). Also, some studies showed that ODC was inhibited, QR1 was induced, and various genes related to CYPs were inhibited (Dion, Agler, & Milner, 1997; Robert, Mouille, Mayeur, Michaud, & Blachier, 2001; Singh et al., 1998) (Table 3.1). Some organoselenium compounds are superior to the corresponding sulfur analogs in cancer prevention. Selenium-enriched garlic, selenium-enriched yeast, and selenium-enriched broccoli are more effective cancer chemopreventive agents in various animal models than regular garlic, yeast, and broccoli, respectively (Whanger, 2004). However, the active form or metabolite of selenium that is responsible for risk reduction in epidemiological studies remains unknown. The selenium content of plants is dependent on the amount of selenium in the soil. Most of our common foods, including garlic, contain a rather low level of selenium (Waegeneers, Thiry, De Temmerman, & Ruttens, 2013). LYCOPENE

Epidemiological studies have provided evidence that high consumption of tomatoes effectively lowers the risk of ROS-mediated diseases such as cardiovascular disease and cancer likely by improving the antioxidant capacity. Among many red plants and fruits, tomatoes are rich sources of lycopene, a fat soluble antioxidant carotenoid reported to be a stable and more potent singlet oxygen quenching agent compared to other antioxidants. In addition to its antioxidant properties, lycopene showed an array of biological effects including cardioprotective, anti-inflammatory, antimutagenic, and anticarcinogenic activities. The anticancer activity of lycopene has been demonstrated both with in vitro and in vivo tumor models. The mechanisms underlying the inhibitory effects of lycopene on carcinogenesis could involve ROS scavenging, interference with cell proliferation, inhibition of cell cycle progression, and modulation of signal transduction pathways (Bhuvaneswari & Nagini, 2005; Table 3.1). Consumption of pizza with red tomato sauce has been associated with reduced incidence of prostate cancer.

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Conclusions It is generally recognized that the lifetime probability for an individual to develop some form of cancer is in the range of 50–70%. In some of these cases, etiological factors are well established, such as overexposure to ultraviolet irradiation or cigarette smoking, making primary prevention the strategy of choice. Conversely, the etiology of major cancers, such as breast cancer and prostate cancer, remains largely unknown. In these situations, alternate methods of prevention are highly desirable. Similarly, in high-risk groups, such as individuals who have survived bouts with cancer, prevention strategies are of imminent importance. In many respects, dietary cancer chemoprevention seems an ideal approach. Problems associated with this approach are often low levels of active constituents in natural dietary materials (with the exception of turmeric, green tea, Allium sp., and several pungent tasting cruciferous vegetables), thermal and metabolic instability, or poor bioavailability. Hence, actual effectiveness may be questionable. Apart from a standard drug-development approach involving synthetic derivatization and lead optimization, selection of dietary components containing higher levels of chemopreventive agents may be one method to circumvent some of these problems, but bioengineering of edible plants and especially microorganisms (e.g., resveratrol production in yeast-based bioreactors) are more direct. Although a specific mechanism of action for chemopreventive agents with a single target affected would be desirable, it is generally not the case. Compounds presented earlier have shown a myriad of biological responses. The use of complex physiological systems and computer models would be the best hope to try to identify the most critical pathways (Francy-Guilford & Pezzuto, 2008). The line between cancer therapy and prevention is rather blurred. As shown in the few examples later, if a cancer chemotherapeutic agent is not toxic, it can be used for chemoprevention. In the past, the FDA has approved only a few purely synthetic compounds and no natural ones for use as chemopreventive agents. They included for some time the COX-2 specific inhibitor celecoxib to reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis, as an adjunct to usual care, which was withdrawn in 2012. Two SERMs, tamoxifen and raloxifene, as well as three aromatase inhibitors, anastrozole, letrozole, and exemestane, are also considered as cancer chemopreventive drugs for the adjuvant treatment of women with hormone receptor-positive early breast cancer (Wu, Patterson, & Hawk, 2011). More recently, finasteride has shown promise for the prevention of prostate cancer (Thompson et al., 2013). These are important breakthroughs. Nonetheless, a great deal of additional work is required. For example, dilemmas such as the near 100% probability of developing prostate cancer, given a sufficient lifespan, and the lack

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of effectiveness of agents such as tamoxifen against ER-negative breast cancer, need to be recognized. Thus, new cancer chemopreventive agents are still required, and plant materials are a promising source for the identification of lead compounds.

Acknowledgments The authors are grateful to the National Cancer Institute for support provided under the auspices of program project P01 CA48112 entitled “Natural Inhibitors of Carcinogenesis.” REFERENCES

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4 Research Methodology Challenges in Integrative Oncology VINJAR MAGNE FØNNEBØ

Key Concepts When researching complementary and alternative medicine (CAM) cancer researchers need to realize that patients are well aware of the limitations of CAM treatment with regard to prolonged overall survival and reduction of tumor size. ■ The difference in preresearch patient experience between conventional medicine and CAM precludes a direct replication of the conventional research approach to the CAM field. ■ Research in CAM and cancer should lead to results ensuring that the treatments patients seek are safe, document what packages of care are most beneficial, and double-check claims of efficacy of products and procedures that are intended for general and widespread use among cancer patients. ■

A

pproximately 50% of cancer patients in Western developed countries have used complementary and alternative medicine (CAM) in addition to their conventional treatment (Horneber et al., 2012; Molassiotis et al., 2005), in breast cancer patients the proportion is even higher (Kremser et al., 2008; Nagel, Hoyer, & Katenkamp, 2004; Navo et al., 2004). Researchers with experience from conventional medicine have been responsible for most of the research on CAM and cancer. It is therefore not surprising that the CAM research in cancer has followed the same methodology as that in conventional medicine. It has tested the specific efficacy of supposed active components of a therapy. The results from this research have 85

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generally shown little clinical trial evidence supporting CAM therapy components to be effective in cancer cure. The current widespread use of CAM by patients must, therefore, be based on patients having other treatment goals than cure, their mistrust in the available research, or their willingness to be misled by unwarranted claims. Patients’ reported reasons for seeking CAM seem to support the first option (Sirois, 2008; Verhoef, Balneaves, BNoon, & Vroegindewey, 2005). Given reasons include beliefs in complementary and/or holistic care, taking charge of the disease, dealing with cancer symptoms, dealing with side effects of conventional treatment, improving quality of life/well-being, strengthening the immune system, increasing energy, working with a supportive practitioner, and supplementing conventional cancer treatment. Patients seem to make these treatment choices on the basis of the qualities of the provider, desire for “individualized” treatments, and their perception of overall effectiveness rather than efficacy. This seems to indicate that patients are well aware of the limitations of CAM treatments with regard to reducing tumor size. Researchers, therefore, need to take this clinical reality into account when researching CAM and cancer.

Overall Research Strategy The practice of CAM is generally characterized by the absence of regulatory and financial gatekeepers. There is, therefore, a plethora of CAM approaches to treatment, including that for cancer. The outer limits of this treatment landscape are constantly changing, and large parts of the landscape are at any one time unknown to researchers. Substantial areas of CAM treatment are therefore unavailable for research attention. When planning or performing research on CAM and cancer, researchers, therefore, naturally limit their efforts to treatment approaches that are already in clinical use in one or more patient populations. Hence, research is initiated in areas where patients already have clinical experience. This differs somewhat from research in conventional oncology where researchers develop novel treatment approaches, exposing patients to these treatments only after extensive testing has been done through phase I–III clinical trials. This difference in preresearch patient experience between the two clinical areas precludes a direct replication of the conventional research approach to the CAM field. The real-world clinical practice necessitates a reorganization of existing research elements (Fønnebø et al. 2007) (Figure 4.1). This rearrangement is, however, not meant as a chronological sequence defining when specific research phases should occur but as a framework to

Research Methodology Challenges in Integrative Oncology  87 Screening of chemical substances

Biological mechanisms

Biological mechanisms

Component efficacy

Phase I trials

Comparative effectiveness

Phase II trials

Safety status

Phase III trials

Context, paradigms, philosophical understanding, and utilization

Clinical practice

Clinical practice

Figure 4.1.  Research strategies in drug trials and CAM (proposed). Phases that contrast the proposed phased research strategy in CAM (thick arrows) with that conventionally used in drug trials (thin arrows). Adapted from Fønnebø, V., Grimsgaard, S., Walach, H., Ritenbaugh, C., Norheim, A. J., MacPherson, H., . . . Aickin, M. (2007). Researching complementary and alternative treatments—the gatekeepers are not at home. BMC Medical Research Methodology [Electronic Resource], 7(1), 7.

guide CAM research. It illustrates the necessary building blocks required for a rigorous evidence base. The framework does not include novel methodological elements and is appropriate for any treatment approach that has developed in and from clinical practice, and whose specific treatment tools are unregulated. In conventional medicine this might include nursing, health psychology, counseling, and some aspects of general practice.

Understanding Treatment Choices of Cancer Patients The fundamental aspect in the aforementioned research strategy is understanding the processes and assumptions inherent in the specific CAM therapies, often using an inductive research approach. In light of the need for broad research in an early phase, data collection methods should record as much of patients’ background, philosophies, contexts, choices, and experiences as

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possible. This basic research phase has often been overlooked, and research ideas have therefore often been generated haphazardly on a case report basis. The inductive research approach can include several approaches, and the appropriate methodology for this phase of research is mostly qualitative, but observational quantitative methods can also contribute valuable insight. Researchers are often entering into territory totally unknown to them and need to explore and seek meaning and understanding of patient and practitioner behavior. I will give only two examples of international efforts to approach this field in a systematic way in order to develop research hypotheses that can be further tested in clinical trials.

Exceptional Case History Registration When cancer patients experience a clinical outcome after CAM treatment that differs markedly from what can be expected on the basis of conventional treatment alone, they can be classified as having an exceptional case history. Exceptional cancer-patient experiences of this kind have been collected and analyzed by several institutions worldwide (Launsø et al., 2006). This can be an important clue in understanding the processes that take place when patients seek CAM treatment for their cancer. Two principally slightly different approaches have been identified when doing these kinds of studies: 1. A review of CAM practitioners’ best cases: This approach is utilized by the National Cancer Institute (NCI) in the United States through their best-case series (BCS) methodology (NCI Best Cast Series Program, 2013); the study group Unconventional and Complementary Methods in Oncology at the Department of Internal Medicine, Oncology and Hematology at the Klinikum Nuernberg (UCMO) in Nuremberg, Germany (Buschel et  al., 1998); and investigators at Columbia University at New  York (Jacobson, 2005). 2. A review of patients’ own exceptional case histories: This approach is utilized by The National Research Center in Complementary and Alternative Medicine (NAFKAM), Tromsø, Norway, in establishing an Exceptional Case History Registry (Fønnebø, 2012); The Danish Multiple Sclerosis Society in Denmark; and Johanna Hök at Karolinska Institute, Stockholm, Sweden (Hök, Tishelman, Ploner, Forss, & Falkenberg, 2008). The Danish and Swedish groups collaborate with NAFKAM.

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In contrast to the NCI approach, NAFKAM collects both best and worst cases but follows procedures similar to those at NCI to evaluate the medical aspects of the reported exceptional case history. These international efforts need to be further developed and coordinated. A worldwide database of exceptional case histories in cancer treatment will, due to numbers, rapidly be able to generate patterns of care that can be further tested in clinical trials. This can be seen as a process similar to the basic research underlying the choice of chemical components to include in phase I clinical pharmaceutical trials in conventional medicine.

Cohort Study of Treatment Choices Cancer patients are seeking CAM as a treatment system. Research needs to be done to examine the outcomes of these treatments both in combination with and as an alternative to conventional care (Lewith, Thomas, & Fønnebø, 2006). Although a number of studies have been done internationally to monitor CAM use in cancer patients, they are mostly cross-sectional studies querying patients at one point in time. As mentioned earlier, there is extensive clinical experience indicating that treatment choices can change over the course of the disease duration. Few researchers have documented these changing patterns of CAM use (Corner et al., 2006; Ma, Carpenter, Sullivan-Halley, & Bernstein, 2011; Risberg, Lund, Wist, Kaasa, & Wilsgaard, 1998). It is therefore necessary to initiate large-scale cohort studies to follow and monitor patients’ treatment choices. It is important to understand what is chosen and why it is chosen, and relate this to the clinical course of the disease process. This type of study has not yet been performed among cancer patients.

Safety Conventional cancer treatment has potentially grave, sometimes lifethreatening, side effects. These are acceptable given the serious nature of the underlying treated disease. CAM treatments have, on the other hand, often been claimed to be without risk, but adverse effects in CAM are definitely more than occasional case reports (Norheim  & Fønnebø, 1996). Although adverse effects in CAM most likely are of a mild nature, little research has been done to investigate this carefully. Only the field of acupuncture has provided a thorough risk assessment not only pinpointing infections and pneumothorax as the most serious adverse effects but also identifying a number of minor

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adverse occurrences in connection with acupuncture treatment (MacPherson, Thomas, Walters, & Fitter, 2001). There is virtually no knowledge about adverse effects in other fields within CAM, and this lack of knowledge needs to be corrected. The methodology of choice can be largely copied from conventional medicine—individual reporting of adverse effect occurrences and monitoring of adverse events in clinical trials or observational studies. In the cancer field, an additional risk assessment needs to be done related to CAM treatments. Although CAM interventions in themselves are thought to carry little direct biological risk, denial of conventional treatment in favor of exclusive use of CAM is thought to be a serious threat to cancer patients. This denial of conventional treatment is sometimes done on recommendations from CAM treatment providers, and this makes it appropriate to classify it as a potential adverse effect. Cancer patients who deny conventional treatment have been reported to have a higher case-fatality rate, but the evidence is limited (Han, Johnson, & DelMelena, Glissmeyer, & Steinbock, 2011).

Comparative Effectiveness In conventional medicine, we take for granted that seeking advice from a health-care professional is a good way of dealing with diverse health problems. Research in conventional medicine therefore focuses on choosing the best tools for health professionals to use. These tools include drugs, diagnostic methods, and surgical procedures, and the research employed often results in recommendations of a one-size-fits-all therapeutic prescription. Research in conventional medicine may, however, have overlooked that the clinical effect of most therapies are overestimated when studied under optimal circumstances on susceptible, cooperative patients. The randomized controlled trial is, despite this, a useful method for making decisions about tools to include in the toolbox of conventional medicine. When studying effectiveness of CAM treatments, it is often useful to utilize the whole systems research (WSR) model developed by CAM researchers (Ritenbaugh, Verhoef, Fleishman, Boon,  & Leis, 2003; Verhoef et  al., 2005). Specific suggestions have been made regarding the application of this methodology to CAM research in cancer (Verhoef, Vanderheyden, & Fønnebø, 2006). This model can be applied to established whole systems such as Traditional Chinese Medicine (TCM), naturopathic medicine, homeopathy, and integrative medicine, as well as to individualized systems where patients design their own programs of care. If researchers limit their studies to an evaluation of

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the effectiveness of a single standardized component of cancer care (e.g., a support group) on a specific set of outcomes (e.g., disease progression, survival, or quality of life), the impact of individual and contextual factors and/or other treatments can be overlooked. Possible interaction effects can likewise be missed. This research, although perhaps internally valid, may lack external validity, because it does not reflect the real-world situations that cancer patients experience. Because patients are unique and differ in attitudes, beliefs, health status, and personalities, Sidani, Epstein, & Moritz (2003) recommend a minimal list of exclusion criteria when researching whole systems. Selection criteria that are too stringent result in a participant population that is not reflective of the real world, thus limiting the generalizability of results. Whole systems research often requires an expanded set of outcome measures, of which survival, conventional assessments of biomedical outcomes, and quality of life constitute parts. In addition, both global outcomes, which assess overall well-being, and individualized outcomes, which assess unique patient-centered outcomes for each research participant, are needed because treatment interventions are often intended to affect more than one outcome over a long period. Rychetnik, Frommer, Hawe, and Shiell (2002) suggest asking the following questions to determine whether appropriate outcomes have been selected: (a) Do the outcomes adequately address the questions asked by key stakeholders (e.g., patients, providers, policy makers)? (b) Do the chosen outcomes allow for both anticipated and unanticipated effects to be tracked? and (c) Has (cost) efficiency been addressed? Data analysis in WSR may require a shift from the norm in intervention research. Instead of attempting to determine the effect of an intervention for the average participant, it may be more appropriate to determine for which participants, presenting with which characteristics, an intervention is effective or not (Sidani et al., 2003). In general the goal of a WSR should be to determine how the participants, provider, context, and intervention factors interact to affect the process and outcomes of healing and ultimately to determine which interventions, given under what conditions or context, result in which outcomes for which patients. This resembles the principles involved in realist reviews (Rawson, Greenhalgh, Harvey,  & Walshe, 2005), which are seen as increasingly relevant also in medicine. This whole-systems approach to study the effectiveness of CAM treatment of cancer represents only preliminary suggestions. Whole systems research methods will need to be refined through a process that includes practical examples, reflection, and revision.

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Efficacy Efficacy is the area that has received most attention and research money to date. The methods of choice are generally double-blind randomized placebo-controlled trials. In CAM, the well-established documentation of acupuncture/acupressure stimulation of one acupuncture point in the treatment of chemotherapy-induced nausea/vomiting is an example of appropriate efficacy research (Ezzo et al., 2005). When testing dietary supplements, herbal medicine, or other standardized interventions intended for general use in cancer patients, this well-proven research method should of course be utilized, and there is no need to enter into a lengthy argumentation for its justification. It is, however, important to recognize that results from efficacy research cannot be used to document or disprove the effectiveness of a “whole system” treatment.

Conclusion With the widespread use of CAM among cancer patients, a stronger research effort is warranted. The increasing use is in itself a strong indication that patients experience the treatments they seek as useful. The challenge for researchers in this field is to contribute mainly in three areas: 1. Ensure that the treatments patients are seeking are safe. 2. Document what packages of care are most beneficial. 3. Double-check claims of efficacy of products and procedures that are intended for general and widespread use among cancer patients. Whether patients gain any benefit whatsoever from seeking CAM treatments is probably no longer of interest as a practical issue. REFERENCES

Buschel, G., Kaiser, G., Weiger, M., Weigang, K., Birkmann, J., & Gallmeier, W.  M. (1998). Bestfallanalysen zu 4 aktuellen unkonventionellen Behandlungsverfahren in der Onkologie. Forsch Komplementarmed, 5(Suppl. S1), 68–71. Corner, J., Yardley, J., Maher, E. J., Roffe, E., Young T., Maslin-Prothero, S., . . . Lewith, G. (2009). Patterns of complementary therapy (CAM) use among

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people undergoing cancer treatment. European Journal of Cancer Care, 18, 271–279. Ezzo, J., Vickers, A., Richardson, M. A., Allen, C., Dibble, S. L., Issell, B., . . . Zhang, G.   (2005). Acupuncture-point stimulation for chemotherapyinduced nausea and vomiting. Journal of Clinical Oncology, 23(28), 7188–7198. Fønnebø, V., Drageset, B. J., & Salamonsen, A. (2012). The NAFKAM international registry of exceptional courses of disease related to the use of complementary and alternative medicine. Global Advances in Health & Medicine, 1(1): 60–62. Fønnebø, V., Grimsgaard, S., Walach, H., Ritenbaugh, C., Norheim, A. J., MacPherson, H., . . . Aickin, M. (2007). Researching complementary and alternative treatments—the gatekeepers are not at home. BMC Medical Research Methodology [Electronic Resource], 7(1), 7. Han, E., Johnson, N., DelaMelena, T., Glissmeyer, M., & Steinbock, K. (2011). Alternative therapy used as primary treatment for breast cancer negatively impacts outcomes. Annals of Surgical Oncology, 18, 912–916. Hök, J., Tishelman, C., Ploner, A., Forss, A., & Falkenberg, T. (2008). Mapping patterns of complementary and alternative medicine use in cancer:  An explorative cross-sectional study of individuals with reported positive “exceptional” experiences. BMC Complementary and Alternative Medicine, 2008(8), 48. Horneber, M., Bueschel, G., Dennert, G., Less, D., Ritter, E., & Zwahlen, M. (2012). How many cancer patients use complementary and alternative medicine. A  systematic review and metaanalysis. Integrative Cancer Therapy, 11(3),187–203. Jacobson, J. S., Grann, V. R., Gnatt, M. A., Hibshoosh, H., Austin, J. H., Millar, W. S., . . . Neugut, A. I.  (2005). Cancer outcomes at the Hufeland (complementary/alternative medicine) klinik: A best-case series review. Integrative Cancer Therapies, 4(2), 156–167. Kremser, T., Evans, A., Moore, A., Luxford, K., Begbie, S., Bensoussan, A., . . . Zorbas, H. (2008). Use of complementary therapies by Australian women with breast cancer. Breast, 17(4), 387–394. Launsø, L., Drageset, B. J., Fønnebø, V., Jacobson, J. S., Haahr, N., White, J. D., . . . Egeland, E. (2006). Exceptional disease courses after the use of CAM: Selection, registration, medical assessment, and research—An international perspective. Journal of Alternative and Complementary Medicine (New York, NY), 12(7), 607–613. Lewith, G., Thomas, K.,  & Fønnebø, V. (2006). Whole systems research in cancer care—Report of meeting in Tromsø (Sommarøy), 14–16 September 2005. Complementary Therapies in Medicine, 14, 157–164.

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Ma, H., Carpenter, C. L., Sullivan-Halley, J., & Bernstein, L. (2011). The roles of herbal remedies in survival and quality of life among long-term breast cancer survivors—results of a prospective study. BMC Cancer, 11, 222. MacPherson, H., Thomas, K., Walters, S., & Fitter, M. (2001). The York acupuncture safety study:  Prospective survey of 34 000 treatments by traditional acupuncturists. British Medical Journal, 323(7311), 486–487. Molassiotis, A., Fernadez-Ortega, P., Pud, D., Ozden, G., Scott, J. A., Panteli, V., . . . Patiraki, E. (2005). Use of complementary and alternative medicine in cancer patients: A European survey. Annals of Oncology, 16(4), 655–663. Nagel, G., Hoyer, H.,  & Katenkamp, D. (2004). Use of complementary and alternative medicine by patients with breast cancer: Observations from a health-care survey. Support Care Cancer, 12(11), 789–796. Navo, M. A., Phan, J., Vaughan, C., Palmer, J. L., Michaud, L., Jones, K. L., . . . Smith, J. A. (2004). An assessment of the utilization of complementary and alternative medication in women with gynecologic or breast malignancies. Journal of Clinical Oncology, 22(4), 671–677. NCI Best Case Series Program. (2013). Internet Communication. Retrieved June 25, 2013, from http://cam.cancer.gov/best_case_intro.html. Norheim, A. J., & Fønnebø, V. (1996). Acupuncture adverse effects are more than occasional case reports. Complementary Therapies in Medicine, 4, 14–20. Pawson, R., Greenhalgh, T., Harvey, G., & Walshe, K. (2005). Realist review—a new method of systematic review designed for complex policy interventions. Journal of Health Services Research & Policy, 10 (Suppl 1), 21–34. Risberg, T., Lund, E., Wist, E., Kaasa, S., & Wilsgaard, T. (1998). Cancer patients use of nonproven therapy:  A  5-year follow-up study. Journal of Clinical Oncology, 16(1), 6–12. Ritenbaugh, C., Verhoef, M., Fleishman, S., Boon, H., & Leis, A. (2003). Whole systems research: A discipline for studying complementary and alternative medicine. Alternative Therapies in Health and Medicine, 9(4), 32–36. Rychetnik, L., Frommer, M., Hawe, P., & Shiell, A. (2002). Criteria for evaluating evidence on public health interventions. Journal of Epidemiology and Community Health, 56(2), 119–127. Sidani, S., Epstein, D.R., & Moritz, P. (2003). An alternative paradigm for clinical nursing research:  An exemplar. Research in Nursing  & Health, 26(3), 244–255. Sirois, F. M. (2008). Motivations for consulting complementary and alternative medicine practitioners: A comparison of consumers from 1997–8 and 2005. BMC Complementary and Alternative Medicine, 2008(8), 16. Verhoef, M.  J., Balneaves, L.  G., Boon, H.  S.,  & Vroegindewey, A. (2005). Reasons for and characteristics associated with complementary and

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alternative medicine use among adult cancer patients: A systematic review. Integrative Cancer Therapies, 4(4), 274–286. Verhoef, M.  J., Lewith, G., Ritenbaugh, C., Boon, H., Fleishman, S.,  & Leis, A. (2005). Complementary and alternative medicine whole systems research: Beyond identification of inadequacies of the RCT. Complementary Therapies in Medicine, 13(3), 206–212. Verhoef, M. J., Vanderheyden, L. C., & Fønnebø, V. (2006). A whole systems research approach to cancer care: Why do we need it and how do we get started? Integrative Cancer Therapies, 5, 287–292.

5 Diet and Cancer: Epidemiology and Risk Reduction CYNTHIA A. THOMSON

Key Concepts Cancer is a chronic disease that occurs through multiple insults to cells and tissue; therefore, it is most likely to be prevented by repeated exposures to sufficient, but not excess, amounts of cancer-preventive nutrients and bioactive food component consumed throughout the lifespan. ■ Cancer-preventive bioactive compounds are found predominantly in foods of plant origin and many have several biological activities associated with reduced cancer risk. ■ Diet  alters carcinogenesis through a variety of cellular and molecular pathways including immune modulation, modulation of growth factors/signals, methylation, apoptosis, antioxidation, and anti-inflammatory effects. ■ Specific dietary recommendations for risk reduction are available from the American Cancer Society and the American Institute for Cancer Research/World Cancer Research Fund. These recommendations reflect the need for significant behavioral change for most Americans and sufficient support for adopting healthier food choices should be provided. ■ Cancer will be diagnosed in 50% of males and over one-third of females in their lifetime; thus most Americans are “at-risk” for this disease and should be encouraged to adopt a cancer-preventive diet; select populations have even greater risk—cancer survivors, family members of cancer patients, smokers, obese individuals, those with high UV light or other environmental exposures and those with compromised immunity—these subgroups should be specifically targeted for cancer-risk-reduction education. ■

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hat one chooses to eat can have profound effects on his/her health, particularly when it comes to reducing the risk of cancer. In fact, food selections throughout the lifespan likely have relevance in terms of lifetime cancer risk. Cancer is a multistage, stepwise, and cumulative disease. It evolves from chronic damage to healthy cells and tissue in which both the localized tissue and the wider microenvironment demonstrate abnormalities ranging from genetic deletions, to p53 mutations, to cellular anoxia (Goldberg & Diamandis, 1993). The summative effects of multiple insults to tissue which escape repair by the immune system, over time, result in malignant transformations (Gatenby & Gawlinski, 2003). Diet and the constitutive nutrients and bioactive food components (BAFC) play a vital role in enhancing the host response against cancer. Further, diet is a modifiable cancer risk factor. Unlike age or genetic predisposition, dietary choices can be changed by the individual with the goal of reducing cancer risk. This chapter will provide an overview of the current recommendations for healthy eating associated with reduced cancer risk as well as practical information regarding how to implement healthy eating practices among patients. Strategies to reduce the risk for cancer are appropriate for the population at large, but likely have greater relevance in at-risk groups such as cancer survivors and family members of those diagnosed with cancer. Individualizing diet therapy to meet the individual needs of a given patient is critical to long-term adoption of healthy eating behaviors. In addition, changing eating behavior to promote health, does, for most Americans, propose significant challenges in terms of food knowledge, food purchasing, as well as food preparation. Support must be comprehensive, delivered incrementally and reinforce healthy choices to assure the long-term commitment to healthy eating.

Mechanisms of Anticancer Activity of Select Food Components Efforts to elucidate the anticarcinogenic activity of the diet in relation to cancer risk reduction have been challenging. At the most basic level, there has been significant cell culture and animal research describing pathway-specific, targeted activity(ties) of food. These include bioactivity in relation to inflammation and immune modulation (Gonzalez-Gallego, Garcia-Mediaville, Sanchez-Campos, & Tunon 2010; Valdes-Ramos & Benitez-Arciniega, 2007; Zheng, Viswanathan, Kesarwani,  & Mehrotra, 2012)  oxidative damage and histone deacetylation (Dashwood  & Ho, 2007; Su et  al., 2013), methylation (Milner, 2006), nuclear factor-kappa B (NF-κB) inhibition and apoptosis (Lee et  al., 2013), promotion of cellular differentiation (Ovesna, Vachalkova,  &

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Table 5.1.  Select Food Sources of Bioactive Food Components and Related Mechanisms of Cancer Risk Reduction. Food with Bioactive Components

Mechanisms of Cancer Risk Reduction

References

Avocado

Cell cycle arrest, apoptosis

Ding, Chin, Kinghorn, D’Ambrosio, 2007

Broccoli, broccoli sprouts (cruciferous vegetables

Histone deacetylation, hormone modulation, reduction in oxidative stress, carcinogen metabolism

Hayes et al., 2008

Berries

Reduce malignant transformation, reduction in oxidative stress

Duthie, 2007

Carotenoid-rich orange-yellow vegetables

Antioxidants, anti-inflammatory, cell differentiation

Tanaka, Shnimizu, & Moriwaki, 2012

Curcumin

Anti-inflammatory apoptosis, cell cycle arrest

Ferguson & Philpott, 2007; Surh & Chun, 2007

Garlic/ organosulfur compounds

Carcinogen detoxification, antimicrobial, DNA repair, cell cycle arrest

Moriarty, Naithani, & Surve, 2007

Grapes (resveratrol)

Reduce oxidative stress, anti-inflammatory

Jang et al., 1997

Green tea

Anti-inflammatory, reduce oxidative stress, inhibition of growth factor cell signaling

Butt & Sultan, 2009

Tomato products

Reduce oxidative stress, modulation of insulin growth factors

Riso et al., 2006

Horvathova, 2004), cell cycle control/apoptosis (Davis  & Milner, 2007; Meeran  & Katiyar, 2008), hormones/insulin resistance (Giovannucci et  al., 2010; Patterson et  al., 2013), inhibition of drug resistance in the therapeutic setting and gut microbiota. Table 5.1 lists several biological targets for food/ food components relevant to reducing cancer risk. Further, whole foods may act on a variety of molecular targets or biologically relevant pathways to reduce cancer risk while individual food components may have specific or broad anticancer effects. As an example, bioactives in cruciferous vegetables have been shown to reduce inflammatory response, repair oxidative damage, promote histone deacetylation, and upregulate estrogen receptor α, thus enhancing the antiestrogenic effects of tamoxifen (Hayes,

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Kelleher,  & Eggleston, 2008). Additionally, several diet-derived compounds may act on similar targets as is the example of tannins in apples, dietary nucleotides, fatty acids, and alkylamines (Percival, Bukowski, & Milner, 2008) all of which modulate T-cell activity. Others have broader effects such as omega-3 fatty acids in fatty fish, curcumin/turmeric and carotenoids in vegetables and fruits, which promote reductions in inflammation systematically (Leiherer et al., 2013). To optimize these biologically based cancer preventive functions of foods, it is imperative that individuals consume a varied diet that provides some regular, repetitive, and sufficient exposure (intake and bioavailability) to cancer-preventive compounds to reduce cancer risk. Diets that only occasionally provide protective compounds or that limit exposure to low “dosage” levels are likely insufficient to reduce risk. On the other hand, variety in intake of cancer-preventive foods will more likely result in consistent protective dietary effects that over time lower cancer risk. It is also important to understand that dietary factors can modify cancer risk both in terms of reducing risk and, in relation to some components, increasing risk (Figure 5.1). For example, rice and in particular brown rice, is frequently a source of inorganic arsenic a known human carcinogen (Bhattacharjee, Banerjee, & Giri, 2013), although a 2013 analysis of over 1,300 rice-based foods by the Food and Drug Administration suggested usual intake does not result in excess exposure.

Dietary Recommendations Periodically, most cancer-specific associations provide the public with updated guidelines with regards to healthy diet behaviors to reduce cancer risk. For the American Cancer Society (ACS) these guidelines were updated in 2012 and include the following recommendations for diet, physical activity, and weight control (ACS, 2012). •   Achieve and maintain a healthy weight throughout life. Be as lean as possible. Avoid excessive weight gain throughout life. Engage in physical activity, limiting high-calorie foods & beverages. • Adopt a physically active lifestyle. Adults should aim for a combination of 75–150 minutes per week of moderate to high intensity activity.

100  Integrative Oncology Diet-Cancer Associations Antioxidants, vitamin A, selenium, folate, polyphenols, carotenoids Omega 3 FAs, curcumin/turmeric, weight loss

DNA damage

Fat, Western diet, low folate, low vegetable-fruit

Inflammation

Fat, omega 6 FAs, obesity

Apoptosis Caloric restriction, insulin-lowering foods-fiber Phase I, II enzyme inducers-isothiocyanates

Cell proliferation Carcinogen/ exposure

Antioxidant-rich foods, vitamin E

Oxidative stress

Fiber, weight loss, sulfurophane, soy

Hormones

Vitamin A, omega 3 FAs, carotenoids polyphenols, isothiocyanates Omega 6 FAs, fat, excess intake, foods contributing to high insulin

Saccharin, nitrosoamines, heterocyclic amines, molds Iron, fat, omega 6 FAs, arachidonic acid Fat, obesity

Figure 5.1.  Mechanisms of cancer-related activity of food.

Children and adolescents should engage in at least 1 hour of moderate or vigorous activity daily, with vigorous intensity at least 3 days per week. Limit sedentary behavior. Doing some physical activity can have many health benefits. •  Eat a healthy diet, with an emphasis on plant sources. Choose food or beverages in amounts that help achieve and maintain a healthy weight. Eat at least 2.5 cups of vegetables and fruits every day. Choose whole grains in preference to processed (refined) grains. Limit consumption of processed and red meats. •  If you drink alcoholic beverages, limit consumption. Drink no more than 1 drink per day for women or 2 per day for men.

A “meeting of the minds” of leading researchers in risk reduction research across North America who openly discussed the available peer-reviewed evidence to develop behavior-specific recommendations for both diet and physical activity to reduce cancer risk developed the ACS recommendations. These recommendations are updated approximately every five years. A recent analysis suggested that women who adhere to the ACS guidelines have a 17% lower

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risk of being diagnosed with cancer and a 22% and 52% lower risk for breast and colorectal cancer, respectively (Thomson et al., 2014). Similar recommendations are published by the American Institute for Cancer Research and the World Cancer Research Fund (AICR/WCRF) and are supportive of the ACS recommendations (WCRF/AICR, 2007). Since 2008, the AICR/WCRF recommendations are continually updated in a Web-based format to reflect ongoing systematic literature reviews of the available scientific evidence. Much of the evidence presented in the 2007 report, Food, Nutrition, Physical Activity and the Prevention of Cancer: A Global Perspective, and which is updated online evolves from available epidemiological studies with greater weight given to randomized controlled intervention trials, followed by prospective cohort studies and lastly case-control study results. The recommendations state the following: • • • • • • • • •

Be as lean as possible within the normal range of body weight. Limit consumption of energy-dense foods; avoid sugary drinks. Eat mostly foods of plant origin. Limit intake of red meat and avoid processed meat. Limit alcoholic drinks. Limit consumption of salt; avoid moldy cereals or pulses. Aim to meet nutritional needs through diet alone. Mothers to breastfeed; children to be breastfed. Cancer survivors follow the recommendations for risk reduction.

The consistency of the recommendations in terms of the two organizations is clear. In fact, the current dietary recommendations to reduce cancer risk are consistent also with many of the recommendations for weight control, cardiovascular disease risk reduction, stroke prevention, and, to a large extent, diabetes control.

Expanding on Current Recommendations PLANT FOODS

The recommendation that a diet rich in plant foods will reduce cancer risk has remained a primary focus of risk reduction recommendations for the past several decades. This is despite what continues to be mixed epidemiological evidence to support this recommendation. One concern is that although case-control studies predominantly indicate a protective effect of plant foods,

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prospective cohort studies are less consistent in supporting statistically significant relationships. Unfortunately randomized controlled trials testing hypotheses using high plant diets versus usual diets have not been pursued due to the cost and required longevity of such trials to test these hypotheses. Further, evidence from case-control trials is largely suspect when it comes to cancer outcomes in that people diagnosed with cancer commonly associate their disease with less healthy dietary choices, and thus misreported “recall” of dietary intake and eating patterns before the cancer diagnosis is common. Prospective cohort studies avoid the recall bias associated with case-control studies, but may be inaccurate due to the overall difficulty in estimating true dietary intake. Table  5.2 provides a summary of select evidence from published meta-analyses by cancer site. As shown, inconsistencies in vegetable-fruit and cancer associations exist. One explanation for the inconsistencies may be the fact that total vegetable and fruit intake would include both those rich in cancer-protective BAFC and nutrients (berries, spinach, carrots, tomato, broccoli, etc.) as well as those with relatively low health-promoting compounds (iceberg lettuce, cucumber, corn) (Russo, 2007). Thus, the total vegetable and fruit exposure variable used to evaluate protective effects of a high vegetable/fruit diet may or may not reflect exposure to a cancer-preventive diet. Additionally, preparation methods can alter the bioavailability of select cancer-preventive bioactive compounds (heating of isothiocyanates in broccoli) or negate healthful effects (deep-fat frying of onions). Further, there is evidence, albeit limited, that co-consumption of a mixture of plant foods rich in BAFC results in a synergistic response, particularly in terms of antioxidant response (Liu, 2004). Generally the evidence suggests that diets higher in vegetables and fruit would reduce the risk of several cancers. Evidence suggests variety is also relevant to lowering cancer risk. In fact several specific foods have also been suggested to reduce the risk of select cancers, as detailed in Table  5.3. Of note, many analyses group vegetables and fruits together to evaluate associations and yet for individual constituents, vegetables dominant in terms of variety of constitutive cancer-preventive compounds. Evaluating the combined protective effects can “dilute” the overall risk reduction, alternatively vegetable intake alone may be insufficient in volume to meet thresholds for risk reduction. Importantly, fruit intake frequently includes fruit juices, which, when consumed in large amounts by individuals with insulin resistance, may contribute to higher circulating insulin and in turn higher cancer risk. Clinicians must, therefore, rely on the overall trends in associations to formulate recommendations for the individual patient. The currently available epidemiological evidence generally, albeit inconclusive, support the

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Table 5.2.  Select Epidemiological Meta-Analysis evaluating association between vegetable and fruit intake/Dietary Patterns high in fruits and vegetables and Cancer Risk. Epi Study

Liu et al, 2013

Sample Size

RR/OR (95% Confidenceinterval)

Clarifications

Bladder cancer 5772 cases from 10 studies

Cruciferous RR = 0.80 (0.69–0.92)

Reduced risk with case-control; not significant with cohort studies

Breast cancer 19,116 cases from 15 studies

Fruit/vegetables RR = 0.89 (0.80–0.99)

No protection with vegetable & fruit and fruit, but not vegetable alone

Magalhaes et al., 2012

Colorectal cancer cases

RR = 0.80 (0.70-0.90)

High fruit & vegetable meal pattern

Bandera, Kushi, Moore, Gifkins, & McCullough, 2007

Endometrial cancer 6352 cases, 16 case-control studies

Vegetables OR = 0.71 (0.55–0.91) Fruit OR = 0.90 (0.72–1.12)

Cruciferous vegetables OR = 0.85 (0.74–0.97)

Bertuccio et al., 2013

Gastric cancer 3,179 cases 8 studies

OR = 0.75 (0.63–0.90)

“Prudent/healthy” diet pattern

Edefonti et al., 2012

Oral cancer 2452 cases 5 case-control studies

OR = 0.76 (0.43–0.70)

“Antioxidants & fiber” diet pattern

recommendation that consuming a diet high in vegetables and other plant foods when prepared without excess dietary fat may reduce cancer risk. DIETARY FAT

Historically, dietary fat has been suggested to be associated with increased risk of several cancers, particularly solid tumors such as breast, colorectal, ovarian, gallbladder, and prostate cancers. However, as our understanding of the types of dietary fat has expanded, there is growing evidence that total fat may be a surrogate for other dietary factors that influence cancer risk more so than fat alone. Specifically, evidence that trans fats contribute to cancer risk was convincing enough (along with other deleterious effects on health, that is

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Table 5.3.  Studies Supporting a Reduced Risk for Site-specific Cancers in Relation to Intake of Select Vegetables and Fruit. Cancer Type

Specific Vegetable and Fruit

Bladder

Cruciferous vegetables (LiuMao, Lin, Zhou, & Xie, 2013)

Breast

Carotenoid-rich (Aune et al., 2012b)

Colorectal

Cruciferous vegetables (Kim & Park, 2009), folate-rich plant foods (Duthie 2011; Vargas & Thompson, 2012)

Gastric/ stomach

Antioxidant-rich plant foods (Williams, 2013)

Esophageal

Citrus and vegetables and fruit rich in vitamin C (De Stefani & Boffetta, 2005)

Lung

Carotenoid-rich (Neuhouser et al., 2003; Soerjomataram et al., 2010)

Prostate

Cruciferous vegetables (Liu, Mao, Cao, & Xie, 2012; Hori, Butler, & McLoughlin, 2011)

cardiovascular disease risk) to result in labeling regulation to reveal the trans fat content of foods on the label. In 2006, the results of the largest prospective randomized trial of dietary fat reduction in primary risk reduction were published (Prentice et al., 2006). The Women’s Health Initiative randomized trial of 48,835 postmenopausal women showed that a low fat diet, consisting of an average fat intake of 24.3% total energy (at year 1), for a period of 8.1 years did not demonstrate a significant reduction in breast and/or colorectal cancer as was hypothesized, HR = 0.91 (95% CI = 0.83–1.01). Of importance, among women who entered the study with a dietary pattern demonstrating fat intake within the highest quintile and who were able to achieve the greatest overall reduction in percent total energy intake as fat, breast cancer risk appeared to be significantly reduced. This suggests that small reductions in total fat intake after menopause are unlikely to reduce breast cancer risk in “healthy volunteers,” but targeting women who demonstrate high fat intake can be advantageous. In terms of colorectal cancer for which 480 cases occurred over 8.1 years, no significant protective effects of the low-fat diet were shown, HR = 1.08 (95% CI = 0.90–1.29) (Beresford et al., 2006). Yet, a later analysis of ovarian cancer risk showed a protective effect of adopting the low-fat diet (Prentice et al., 2007) with HR of 0.60 (95% CI = 0.38–0.96), an association that was not demonstrated for ovarian cancers diagnosed within 4 years of adopting the diet. These findings suggest that dietary efficacy in terms of reducing cancer risk is likely to require long-term changes in eating patterns and it is unlikely that shorter-term changes will appreciably modify risk. Red meat intake has been associated with increased colorectal cancer risk, an association that has been hypothesized to be a result of higher iron intake,

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a known oxidant, as well as greater saturated fat exposure. The evidence suggesting that high intake of red meat is associated with greater colorectal cancer risk is more consistent from earlier epidemiological studies (Giovannucci & Willett, 1994; Willett et al., 1990), with associations somewhat less significant in more recent studies (English et al., 2004; Tiemersma et al., 2004) possibly related to the greater availability of lean cuts of red meat in the food supply. The current recommendations, which consider dose-response, suggest that restriction in red meat intake is an appropriate behavior to reduce the risk for colorectal cancer. Evidence is suggestive of the relationship between processed meats and increased risk for cancer, particularly colorectal cancer (Alexander, Miller, Cushing, & Lowe, 2010). Processed meats include items such as bologna, hot dogs, cold cuts and bacon and are a more commonly consumed protein source for families with restricted food budgets. Recommending a reduction in processed meats, based on current evidence for cancer risk as well as association with other diet-related chronic diseases, such as cardiovascular disease and hypertension, is a prudent approach to improve health.

The Role of Body Weight in Reducing the Risk for Cancer Excess body weight and adiposity is associated with the risk of several cancers. Attaining and maintaining a healthy body weight is a central recommendation for reducing the risk of cancer, including the avoidance of adult weight gain. Overweight and obesity are thought to increase the overall risk for cancer by 14% to 20% (Calle, Rodriguez, Walker-Thurmond, & Thun, 2003) and overweight status plays an influential role in numerous cancers including postmenopausal breast, pancreatic, gallbladder, colorectal (males), ovary, cervical, endometrial, and esophageal cancers and multiple myeloma (AICR/WCRF, 2007). Some evidence suggests that being overweight contributes to a more advanced tumor type at the time of diagnosis or overall survival (Amling, 2004; Gilbert & Slingerland, 2012). Treatment of obesity is challenging, and ideally patient’s weight and waist circumference should be routinely assessed to provide for early identification of undesirable gains. That said, there is some evidence that diets high in nutrient density—including vegetables, fruit, and fiber intake—are associated with reduced caloric intake and thus help to promote weight control (Svendsen, Blomhoff, Holme, & Tonstad, 2007). Conversely, efforts to reduce energy density of the diet (e.g., dietary fat and beverages high in simple sugars) also promotes weight loss/control.

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Obesity may alter carcinogenesis through a variety of biological mechanisms including modulation of hormone levels, suppression of immune response, elevation in inflammatory cytokines, and growth factors (insulin, insulin-like growth factors (Gilbert & Slingerland, 2013; Hursting, 2007; Vucenik & Stains, 2012), and contributing to physical inactivity. Obese individuals also demonstrate higher levels of oxidative stress (Vincent, Innes, & Vincent, 2007) that can lead to cellular damage resulting in both localized and systemic inflammatory response. The current recommendations suggest that body mass index (BMI) should be maintained between 18.5 and 24.9  kg/m2. Although BMI represents one appropriate target, health-care providers should also consider setting goals for waist circumference, as abdominal fatness appears to be of particular concern in relation to cancer risk (NHLBI, 1998). Waist circumference goals (NHLBI, 1998) Males: ≤ 40 inches < 102 cm Females: ≤ 35 inches < 90 cm Body fat percentage goals (Gallagher et al., 2000) Males: 13%–23% Females: 25%–35%

In addition, it is imperative that health-care providers not only evaluate body weight at a specific point in time (individual provider visit), but also track trends in body weight over time, similar to the current practice of plotting growth curves in children or weight-gain patterns through pregnancy. In this way, small elevations in body weight in adult life can be identified early and strategies can be implemented to reduce body weight before the problem accelerates in magnitude. Health-care providers should also utilize dual X-ray absorptometry (DXA) scans to evaluate the individual’s percentage body fat and lean mass over time. These assessments can be safely included in annual patient evaluations and provide accurate and detailed information regarding body composition along with bone biomarker data. In relation to body weight, the average adult in the United States gains approximately 14 kg between the ages of 18 and 50 years. Critical life events contributing to undesirable weight gain include marriage, pregnancy and childbirth, entrance into the workforce, menopause, divorce, and significant changes in job responsibilities. Thus, patients who have experienced any of these life events should be targeted for health-promotion education. Further, body weight is tightly regulated in

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relation to diet and physical activity, making our ability to independently predict risk related to these factors difficult (Shin et al., 2009). A summary of the current diet–risk-reduction recommendations by cancer site is presented in Table 5.4.

New Initiatives Currently there are approximately 430 active research trials in the area of diet and risk reduction funded by the National Cancer Institute. Access to the trial descriptions is available at: http://www.cancer.gov/clinicaltrials. Table 5.5 lists several trial titles of relevance to clinicians, which are likely to produce important data regarding approaches to reduce cancer risk and enhance cancer control that will influence clinical practice in this area. The studies are listed by three subgroups—those that are specific to the study of a specific nutrient, followed by those investigating BAFC, and finally those addressing the area of body weight and cancer risk reduction. Several large clinical trials have been completed in diet and cancer and provide ongoing evidence for/against diet– cancer associations. These include, but are not limited to, the polyp prevention trial (low fat, high fiber, high fruit and vegetable, and polyp risk), the Women’s Health Initiative (low fat diet and risk for breast or colorectal cancers as well as other cancer outcomes), Linxian trials of China (a randomized controlled trial of vitamin/mineral supplements), Women’s Health Study (low-dose aspirin and vitamin E), selenium and Vitamin E in Prostate Cancer (SELECT), and the Women’s Healthy Eating and Living Study (WHEL) targeting a plant-based diet in women previously treated for breast cancer. The role of the gut microbiota in reducing cancer risk is gaining increasing attention. The gut microbiota is colonized with trillions of microorganisms, mostly bacteria that generally promote health, enhance immunity (Kamada, Seo, Chen,  & Nunez, 2013)  and support the gut-associated lymphoid tissue integrity and function. As such, the gut microbiota is particularly relevant to the role of diet in colon- and rectal-cancer risk (Zhu, Gao, Wu, & Qin, 2013), but may also alter risk of other obesity-related cancers (Russell, Duncan,  & Flint, 2013). Although the gut microbiome is relatively stable, it can be favorably modified by dietary exposures in particular foods rich in pre- and probiotics (Jirillo, Jirollo, & Magrone, 2012) (e.g., yogurts, fermented foods). Conversely, local inflammation that can be promoted by western diets and antibiotic use can lead to unfavorable gut microbiome that may promote cancer.

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Table 5.4.  Dietary Recommendations for Cancer Risk Reduction by Cancer Site. Cancer Site

Recommendation

Considerations

Breast

Avoid adult weight gain and abdominal fatness Avoid alcohol Breast feed

Even small unintentional increases in body weight should be addressed quickly and consistently Get active! Have body composition (fat) tested annually using dual X-ray absorptometry (DXA) Adequate folate intake reduces the detrimental effects of alcohol in terms of breast cancer risk Women should breast feed for a minimum of 6 months to reduce risk

Colorectal

Increase fiber intake to >25 grams/day Restrict intake of red meat and processed meat Avoid alcohol Avoid adult weight gain and abdominal fatness

Evidence from RCT does not support in terms of polyp prevention, but researchers/clinicians continue to support this recommendation based on multiple mechanisms for cancer risk reduction Lean cuts are likely less problematic; some menstruating females may need the iron provided by lean red meat Even small unintentional increases in body weight should be addressed quickly and consistently Get active!

Esophagus

Avoid alcohol Avoid excess body fat

Any amount is considered potentially harmful; drink green tea instead as it may reduce risk Even small unintentional increases in body weight should be addressed quickly and consistently Get active! Weight-bearing activity to promote increased lean mass in addition to weight control

Kidney

Avoid excess body fat

Even small unintentional increases in body weight should be addressed quickly and consistently Get active! Weight-bearing activity to promote increased lean mass in addition to weight control

Liver

Avoid aflatoxins Avoid alcohol

Any amount is considered potentially harmful; drink green tea instead as it may reduce risk

(continued)

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Table 5.4.  Continued Cancer Site

Recommendation

Considerations

Lung

Consume fruits and vegetables rich in carotenoids Avoid arsenic in drinking water

Eat a variety of colored fruits and vegetables— several servings daily—9+; avoid supplements of individual carotenoids Check local water supply; also avoid fish from arsenic-containing waters

Mouth/ oral

Avoid alcohol Consume vegetables and fruits rich in bioactive food compounds

Any amount is considered potentially harmful; drink green tea instead as it may reduce risk Eat a variety of colored fruits and vegetables— several servings daily—9+; avoid supplements of individual carotenoids

Ovary

Reduce dietary fat

Results from the Women’s Health Initiative trial suggest a diet low in fat 40 kg/m2) women had higher overall mortality than normal weight women. Overall mortality was similar in normal, overweight, obese and severely obese women. Only morbidly obese women were more likely to die of breast cancer. A U-shaped survival curve was thus noted for weight and mortality. A study in the Pooling Project, by Caan et al. (2012) on weight gain and loss also found a U-shaped curve. Women who maintained a stable weight in the first few years after diagnosis had the lowest overall mortality risk. Weight gains and losses of >10% body weight predicted increased risk of death, especially in Shanghai women. Normal weight women were most at risk for gaining weight after diagnosis, and also had the highest increase in overall mortality. A recommendation that women should not gain excessive weight after diagnosis is thus reasonable. Weight loss of over 10%, however, may be more problematic except in otherwise healthy women. Weight loss in women with comorbid conditions may represent involuntary loss rather than controlled efforts to lose weight. Losses in lean body mass related to comorbid conditions may be part of the problem if breast cancer patients are showing involuntary weight loss. Weight loss reduced overall survival rather than breast cancer survival; it particularly reduced cardiovascular disease survival, so monitoring weight-losing breast cancer patients for cardiovascular disease would be appropriate. Other studies have addressed the question of weight gain or loss in breast and other cancers. In a study by Inoue-Choi, Robien, and Lazovich (2013), older breast cancer survivors who adhered to a guideline to be as lean as possible without being underweight had significantly higher all-cause mortality, but no effect on breast cancer mortality. In the case of prostate cancer, weight gain increased recurrence risk after prostatectomy, though obesity did not (Joshu et al., 2011). Dietetic consults should be made available to patients concerned about both weight gain and weight loss. This is especially important with two studies

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raising concerns about leanness or excessive weight loss. If overweight or obese patients want to lose weight after diagnosis, lean body mass should be monitored using body composition analysis, and patients should perform strengthening exercises, especially if a loss greater than 10% is planned. If losses of lean body mass are found, diet should be adjusted and an exercise professional should be consulted. Continuing support in weight management should be made available to patients. A  pilot study of minority breast cancer patients observed that they were able to lose 3.3% of body weight in 6 months using a commercial diet and exercise program that emphasized lowering fat and calories and increasing vegetables; however, 6 months after the program, patients did regain some weight (Greenlee et al., 2013). The difficulty of maintaining weight loss is also observed in the clinic, and suggests the need for continuing support in this area.

Plant-Based Dietary Pattern Most integrative nutritional counseling has suggested that a plant-based dietary pattern is most healthful for cancer patients. In particular, diets rich in vegetables, fruits, whole grains and plant proteins are a major feature of such counseling, in addition to being recognized as preferable in dietary guidelines for both cancer survival and prevention, as well as for overall reduction of disease risks. As noted above, the dietary pattern studies have overwhelmingly supported beneficial outcomes with diets high in whole grains, vegetables and fruits, and increased risk with diets that emphasize refined carbohydrates and meats, especially processed meats. The literature on cancer risk suggests that vegetables and fruits contribute to risk reduction. A critical review on effects of vegetables and fruits on chronic diseases finds probable evidence that high consumption of vegetables and fruits reduces cancer risk, while noting possible evidence that vegetables and fruits may reduce body weight gain (Boeing et al., 2012). Counseling of patients to increase fruit and vegetable consumption has been shown to be effective in many studies, and has been delivered in several ways including in-person and telephone counseling. We will now discuss particular vegetables and fruits, as well as some concerns with these items. VEGETABLES AND FRUITS

Vegetables and fruits contribute to cancer outcomes in various ways. Vegetables in particular tend to have low caloric densities, due to their high contents of

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fiber and water. This makes them ideal components of lower-calorie diets. Several vegetables and fruits also have notable laboratory or human studies indicating anticancer activity. To maximize the nutritional value of vegetable and fruit consumption, these vegetable and fruit groups should be prioritized for cancer patients. Cruciferous vegetables (cabbage, broccoli, cauliflower, kale, brussels sprouts, bok choi and many others) are well known for cancer-preventive properties. Phytochemicals such as diindolylmethane, indole-3-carbinol and sulforaphane have a variety of anticancer impacts. Their specific effects after a cancer diagnosis have been explored less. The After Breast Cancer Pooling Project did not find an impact of cruciferous vegetables on mortality or recurrence (Nechuta et al., 2013). In prostate cancer patients, however, those who ate the most cruciferous vegetables had a 59% decreased risk of prostate cancer progression (Richman, Carroll, & Chan, 2012). Carotenoids are abundant in vegetables and fruits: carrots, squash, mango, cantaloupe and sweet potatoes are a few examples high in these phytochemicals. Plasma levels of carotenoids in patients with head and neck cancer at the end of radiotherapy were positively correlated with progression-free survival (Sakhi et al., 2010). Higher plasma levels of carotenoids have been linked to positive outcomes in breast cancer patients as well (Rock et  al., 2009). Tomatoes, a major source of the carotenoid lycopene, have been linked with better outcomes in prostate cancer patients; two studies with lycopene supplements have supported a lowering of PSA levels, although a prevention effect was not validated in a recent meta-analysis (Ilic  & Misso, 2012). Because of their many benefits for cancer patients, vegetable intakes ranging from 2.5 to 4 cups daily, depending on calories needed in the diet, have been suggested (Block, 2009; Rock et al., 2012). Several fruits are also showing promising anticancer activities. Randomized trials found that pomegranate juice or extract lengthened PSA doubling time (Paller et al., 2013). Blueberries inhibit oxidative damage and pro-inflammatory molecules (Johnson  & Arjmandi, 2013). Large doses of freeze-dried black raspberries improved plasma levels of GM-CSF and IL-8 as well as markers of cell proliferation and apoptosis in colorectal cancer patients (Mentor-Marcel et al., 2012). Two problems with fruit have been pointed out. The effect of grapefruit juice on drug metabolism is well known, and can be anticipated in patient counseling for drugs susceptible to this interaction. A  more recent topic of discussion has been the impact of fructose on health. Although most of the discussion of fructose has centered on the health impact of high-fructose corn syrup, proponents of some alternative diets recommend strict limitations on or elimination of fruit to avoid excess fructose; some sources even advocate

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substituting fructose with sucrose. In most cancers, fructose intake has not been shown to be correlated with cancer risk. Some studies of pancreatic cancer, however, link elevated fructose intake (although not sucrose or total carbohydrates) and risk of pancreatic cancer (Auneet al., 2012b). Most elevated fructose intake in the United States may result from drinks sweetened with high-fructose corn syrup, but full-strength fruit juice can also boost caloric intake without affecting satiety, leading to excess calorie consumption. Given the beneficial phytochemicals found in many fruits, it is not appropriate to eliminate fruit consumption to avoid fructose. Consumption of fruit juices should be limited, but whole fruits, together with their content of fiber, are appropriate. In addition, it is appropriate to consume fruits in lower quantities than vegetables since they are richer in calories. Fruit consumption from 1.5 to 2.5 cups daily, depending on calorie levels, has been recommended (Block, 2009; Rock et al., 2012). In addition, fructose has a lower glycemic index than glucose or sucrose. The glycemic index measures how much a particular food raises blood glucose levels, and is standardized at 100 for glucose. Reducing the overall glycemic load (the glycemic index of foods adjusted for total carbohydrate amounts in each food) in a daily diet is considered beneficial to blood glucose control. Because fructose has a much lower glycemic index than glucose (19 vs 100), limited amounts of fructose-containing fruits or natural sweeteners may be permitted. Highly refined sweeteners, such as high-fructose corn syrup (which contains nearly as much glucose as fructose) and sucrose (a disaccharide composed of glucose plus fructose), including sugar cane juice products, should be eliminated or severely limited. A variety of natural sweeteners is available, including noncaloric sweeteners such as stevia or lo han quo, as well as agave, which contains fructose and should be used in very limited amounts. WHOLE GRAINS

With the current interest in low-carbohydrate diets, even whole grains are being disparaged, despite long-standing epidemiological evidence of cancer risk reduction and improvement in glucose tolerance. In the concern to limit carbohydrate consumption, diet proponents may overlook the contributions of fiber, especially insoluble fiber, to controlling glycemia. For instance, in a prospective study of healthy participants, high whole grain consumption reduced risk of deteriorating glucose tolerance or development of diabetes (Wirström, Hilding, Gu, Östenson, & Björklund, 2013). Belle et al. (2011) found that high dietary fiber consumption was related to reduced breast cancer recurrence and

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mortality. Landberg et al. (2010) compared the use of rye whole grain and bran intake with refined wheat produces with added cellulose in a pilot study with prostate cancer patients. The grain products constituted 50% of caloric intake. The whole grain products reduced PSA levels and also lowered plasma insulin and C-peptide, used as a marker of insulin. Whole rye flour, as well as other whole grains, contains a variety of phytochemicals with anticancer activities. These include lignans, phenolic acids, flavonoids, tocopherols, phytosterols and unsaturated fatty acids (Rock et al., 2012). Whole grains also contribute to control of glycemia and insulin resistance, discussed further later. Increasing numbers of patients are being diagnosed with gluten intolerance or gluten sensitivity, and being placed on gluten-free diets. Others are adopting gluten-free diets without medical diagnoses. These diets are, of course, of importance in controlling celiac disease. Patients on gluten-free diets do not eat wheat, and may substitute a variety of refined grain products or sugar in their diets if they do not receive adequate dietary counseling. They can be directed to a number of other whole grains as substitutes. Brown rice, whole-grain cornmeal, millet, teff, buckwheat, amaranth and quinoa as well as legume flours such as chickpea flour can be substituted. Some, but not all oats are gluten-free. PLANT-BASED PROTEINS

Concern about the use of animal proteins, especially red meat and processed meat, is evident in integrative nutritional discussions of risk reduction, survivorship and overall disease risks. Studies of prevention of colorectal, prostate and stomach cancers emphasize the role of meat with a particular concern about red and processed meats (Rock et al., 2012). Potential impacts on survival are also evident in the literature. For instance, men with prostate cancer who had the highest intakes of saturated fat had a mortality rate three times higher than those whose diets were lowest in saturated fat (Meyer, Bairati, Shadmani, Fradet, & Moore, 1999). In a study of patients with nonmetastatic prostate cancer, Richman et al. (2013) found that fat from vegetable sources and polyunsaturated fat were associated with reduced all-cause mortality, whereas fat from animal sources and trans fat were associated with increased all-cause mortality. A review of dietary fat in breast cancer suggests that prediagnosis consumption of high levels of saturated fat predicts both higher breast cancer-specific and higher overall mortality. High monounsaturated fat (largely vegetable oils) consumed before and after diagnosis was also linked to increased breast cancer and overall mortality. Post-diagnostic intake of trans fats (which are based on vegetable oils) increased overall mortality. High omega-3 fats (such as fish oils) are suggestively related to lower overall

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mortality (Makarem, Chandran, Bandera, & Parekh, 2013). This review suggests that saturated fat-containing foods are not benign in breast cancer, although neither are monounsaturates. Given the widely cited beneficial effects of monounsaturated fat, some of this effect may be due to impact on weight gain. If patients are to avoid red and processed meats, alternative proteins become important. Possible alternatives that patients may ask about include poultry, grass-fed beef, eggs, dairy products and vegetable proteins. Along with egg yolks, beef and sausage, poultry is a common source of an omega-6 fatty acid, arachidonic acid, in the American diet (National Cancer Institute, 2010). High arachidonic acid consumption is not recommended for persons with inflammatory conditions, of which cancer is arguably one example. Grass-fed beef contains similar amounts of arachidonic acid to grain-fed beef, but also a higher amount of omega-3 fatty acids, improving its omega-6 to omega-3 ratio (1.53 for grass-fed vs 7.65 for grain-fed; Daley, Abbott, Doyle, Nader,  & Larson, 2010). Similar levels of saturated fat are present, although possibly less atherogenic than in grain-fed. Saturated fat might be decreased by eating lean cuts of meat, or removing fat. Eggs that contain higher amounts of omega-3 fatty acids are also available, and egg whites are excellent protein sources that do not contain arachidonic acid, saturated fats or cholesterol. Dairy, including whey protein supplementation, could be considered. There is some concern about insulin and IGF-1 stimulation with dairy proteins (see discussion later under cancer terrain factors), although similar concerns exist with other protein sources as well. The high calcium content of dairy foods may increase prostate cancer risk, but decrease colorectal cancer risk. Kroenke, Kwan, Sweeney, Castillo, and Caan (2013) report that high-fat dairy intake was significantly and positively related to higher breast cancer mortality as well as all-cause mortality; the relationship to recurrence was positive but not significant. Low-fat dairy was not significantly correlated to mortality. Some studies have suggested that milk, specifically lactose, increases risk of ovarian cancer, although studies are not consistent. Finally, vegetable proteins, including those from legumes as well as some nuts and seeds, offer a protein source that is diverse, adaptable, and contains a variety of helpful phytochemicals and constituents such as fiber, as well as carbohydrates. A  further benefit of protein from legumes, specifically the pulses such as lentils, dried split peas and chickpeas, is their effect on blood glucose. Questions have been raised, however about soyfoods, which are widely used throughout Asia but have begun to be used more recently in Western countries.

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SOYFOODS

The role of soy in breast cancer has been controversial. Aside from concerns about allergenicity and adverse effects on hypothyroid patients, a series of animal studies indicated that the phytoestrogenic properties of soy isoflavones might stimulate breast cancer (Helferich, Andrade, & Hoagland, 2008). However, a 2010 review (Messina, Abrams, & Hardy, 2010) pointed out a number of advances in human studies of soy and soy isoflavones that suggested that breast cancer patients might safely use soyfoods. Further support for this position has emerged more recently. For instance, soy isoflavone extracts taken for 10 months did not increase mammographic density in a randomized, placebo-controlled trial (Delmanto et al., 2013). A high-soy diet and a low-soy diet in a randomized crossover trial had no impact on estrogens in nipple aspirate fluid or serum (Maskarinec et al., 2011). Soy isoflavone extract did not change breast epithelial proliferation in a randomized trial, although it did increase Ki-67 in premenopausal but not postmenopausal subjects (Khan, Chatterton et al., 2012). In addition to laboratory data suggesting a general lack of harm for soy foods, the After Breast Cancer Pooling Project assessed intake of soy foods after women were diagnosed with breast cancer. They found that soy intake was associated with better survival (HR = 0.85) in breast cancer, both ER+ and ER-, and for both premenopausal and postmenopausal women (Chi et al., 2013). Soy intake was associated with lower recurrence rates (HR = 0.79) in ER+/PR+ and ER- women, and in postmenopausal women. Soy was unrelated to recurrence in premenopausal women, and unrelated to both recurrence and mortality in patients taking tamoxifen. An explanation of the different results of human versus animal studies is suggested by Setchell et al. (2011), who compared plasma levels of unconjugated (biologically active) genistein in humans and rodents fed different isoflavones or soy foods. They noted that genistein levels in rats and mice were 20–150 times higher than any observed in humans. Thus, the animal study results suggesting negative effects of soy phytoestrogens may not be applicable to soy effects in humans. Based on these observations, breast cancer patients who wish to use soy foods as part of their protein intake should have little concern in doing so, absent contraindications such as allergies. Due to the lower caloric content of most soyfoods relative to many animal proteins, they could even be encouraged to help with weight management. However, randomized trial data to indicate that soyfoods could actually treat breast cancer are lacking. Convincing data on the safety of soy isoflavone supplements in patients with ER+ tumors are also lacking, and until such studies are available, isoflavone supplements should not be recommended. Similar recommendations could be followed with other estrogen-sensitive cancers. The roles of soy

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in other cancers, such as prostate and colorectal, are not yet clear, due to contradictory results in the small trials that have been conducted, and to limited epidemiological data. Some studies do show soy protein increasing levels of IGF-1 (Teas et al., 2011), which is of concern in certain cancers; other proteins, including dairy protein, also increase IGF-1, so avoidance of dairy and excess protein intake in general is advisable. Otherwise, there is no obvious contraindication of soy use in other cancers.

Dietary Supplements It is widely recognized that obtaining nutrients from diets whenever possible is optimal: in their natural state, nutrients are accompanied by a variety of other compounds that are physiologically relevant for health. However, in the clinic, nutritional testing often shows that cancer patients, especially in advanced disease stages, have various nutritional deficiencies. If deficiencies are documented based on either biochemical testing (e.g., low plasma vitamin D) or clinically (e.g., low bone density), supplementation should be considered. In addition, supplements should be considered if nutrient intakes fall persistently below about two-thirds of recommended levels (Rock et al., 2012). One reason for reluctance of many researchers to recommend nutritional supplementation is the lack of efficacy demonstrated for antioxidant supplements in several large-scale trials of risk reduction (Goodman, Bostick, Kucuk, & Jones, 2011). Trials have covered several vitamins and minerals, and, while some efficacy in nutritionally deficient populations has been demonstrated, most trials have been negative, especially in populations that are already well-nourished. Some supplements have also been associated with potentially harmful effects. Integrative cancer practices typically use dietary supplements more frequently than would be countenanced in conventional treatment centers. In some cases, this is an attempt to use a vitamin or mineral pharmacologically for a specific purpose, such as the use of vitamin B6 for control of chemotherapy side effects. In other cases, supplements may be used preventatively in situations where deficiencies can be expected. For instance, numerous chemotherapy drugs deplete vitamins or minerals: in some instances, supplementation is standard even in conventional therapy. A few examples of nutrient depeletions by chemotherapy drugs are as follows; more are listed by Stargrove, Treasure, and McKee (2008): adriamycin—riboflavin; 5-fluorouracil—niacin and thiamin; cisplatin— magnesium, potassium, zinc. Intravenous magnesium supplementation is routinely used with cisplatin.

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In addition to nutrient depletion, other types of supplement-drug interactions are observed. Interactions with cytochrome P450 enzymes and interactions with supplements that reduce blood coagulation or interfere with surgical anesthesia are of particular importance and need to be taken into account clinically. Another consideration for dietary supplementation is that there are vitamins and minerals that are associated with promotion of particular cancers. Most multivitamin formulas do not take this into account, and thus include levels of these vitamins or minerals that may actually be inappropriate for cancer patients. For instance, dietary heme iron in red meat catalyzes oxidative damage and may be involved in initiating cancers (Tappel, 2007), suggesting that iron supplementation should be avoided in cancer (except in the case of iron-deficiency anemia). Copper is involved in multiple pathways of angiogenesis, suggesting that copper supplementation should be avoided (Brewer & Merajiver, 2002). Magnesium may play both promoting and inhibiting roles in cancer growth (Wolf et  al., 2007). Folic acid may promote some cancers (Smith, Kim, & Refsum, 2008). These reports suggest that these supplements should be reduced in or omitted from formulas for cancer patients, and that most commercial multivitamins are actually quite inappropriate for cancer patients. Many studies are available regarding use of dietary vitamin and mineral supplementation for cancer patients, including both cohort studies and clinical trials. Antioxidant vitamins have raised the most concerns, since prevention studies have been negative. Some cohort studies, however, have assessed consumption of these vitamins by cancer patients. While most cohort studies use multivariate analyses to separate effects of different variables, studies that track supplement use may entail some bias because of differential supplement use by differing subpopulations. For instance, users of multivitamins may have healthier lifestyles than non-users that could result in better survival. In a study of Iowa breast cancer patients, multivitamin use both before and after diagnosis was related to a nonsignificant reduction of recurrence and mortality, but only in those who had been treated with radiation or radiation and chemotherapy (Kwan et al., 2011). The women who used multivitamins both before and after diagnosis also ate more fruits and vegetables and were more physically active. The authors concluded that multivitamin use associated with good diet and exercise might be helpful for breast cancer patients whose disease was serious enough to merit postsurgical adjuvant radiation or chemotherapy. This would suggest that use of multivitamins combined with good health habits is helpful: poor health habits might counteract positive effects of supplements—a concern frequently pointed out by integrative practitioners.

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In the After Breast Cancer Pooling Project, which combines the data of four cohorts, vitamin supplement use was also assessed (Poole et  al., 2013). Vitamins C and E were associated with decreased risk of recurrence and death, respectively, but these correlations were attenuated when the authors adjusted supplement intake to take into account use of multiple supplements. None of the supplements reduced breast cancer-specific mortality, but use of antioxidant supplements (multivitamins, C or E) was associated with a 16% reduction in overall mortality. Vitamin D was associated with decreased recurrence in ER+, but not ER- tumors. The authors suggest that considering antioxidant supplements as a group may be more clinically relevant than analyzing individual vitamins. In other cancers, multivitamin use by colorectal cancer patients during and 6 months after chemotherapy was found not to be associated with recurrence or mortality, or grade 3 or higher chemotherapy toxicity (Ng et al., 2010). In prostate cancer, several smaller randomized trials tested use of a variety of vitamins, minerals and phytochemicals (Posadski et  al., 2013). No positive results were found for vitamin D or selenium, but two trials of a combination of antioxidants, phytochemicals and minerals significantly lowered PSA levels. Results indicating that a complex mixture was effective are consistent with an integrative approach that favors addressing many targets simultaneously, since cancer is not a disorder based on a single genetic defect, but on multiple aspects of disordered metabolism and genetic mutations. Vitamin D has been of substantial interest in cancer in the last several years. Several epidemiological studies have been completed, which are analyzed in a recent meta-analysis, including both studies on cancer mortality in general populations and survival in cancer patients (Pilz et al., 2013). There were no consistent associations in the general populations, but in cancer patients, those with higher 25-hydroxy vitamin D had decreased mortality, especially in the case of colorectal cancer patients. Some clinical trials of vitamin D relevant to cancer have been conducted, but there have been problems with experimental design, and we are not near to a consensus on optimal levels of supplementation or blood levels of serum vitamin D. Vitamin D supplementation along with calcium is usually recommended when patients are undergoing treatment with interventions that can promote bone loss, including aromatase inhibitors, surgical oophorectomy, or ovarian failure due to chemotherapy. However, in prostate cancer patients undergoing androgen deprivation therapy, with commonly recommended doses (500–1,000 mg calcium and 200–500 IU vitamin D), patients suffered bone loss (Datta & Schwartz, 2012). Given the epidemiological evidence, however, patients should be tested for vitamin D deficiency and supplemented to reach at least normal levels (30-100 ng/ml). Excessive supplementation could result in hypercalcemia,

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azotemia, anemia or other toxicities. Also related to calcium metabolism is the use of intravenous calcium and magnesium during oxaliplatin therapy to prevent neuropathy. After several smaller trials, a phase 3 trial in 353 colon cancer patients indicated that such infusions are not effective in preventing neuropathy (Loprinzi et al., 2014). B vitamins are of some importance in cancer as well. Supplementation with vitamin B12 and folate is advised before administration of pemetrexed and of pralatrexate to reduce toxicities. For lung cancer patients, at least, supplementation can begin a few days before treatment with pemetrexed commences, rather than waiting a week or more, with no difference in toxicity (Kim, Sun, Ahn, Ahn, & Park, 2013). Other than prior to these drugs, folic acid supplementation should be commenced with caution in cancer patients unless sub-optimal levels are demonstrated on blood tests. High doses of folic acid as well as inadequate doses are associated with increased cancer risk. There are indications of negative interactions of folic acid with chemotherapy drugs, and it should be used cautiously during chemotherapy administration (Goodman et al., 2011; Schrøder, Clausen, Ostergård, & Pressler, 1986). Vitamin B6 may be beneficial in reducing hand-foot syndrome and other dose-limiting toxicities during treatment with capecitabine or other chemotherapy drugs, and vitamin E, as well as glutamine and acetyl-l-carnitine, have been examined for prevention of neuropathy. However, results of trials are inconsistent.

The Cancer Terrain The internal biochemical environment of the body plays an integral role in determining the outcome of malignant disease. This influence is exerted in several ways, but primarily through the impact on the microenvironment surrounding the cells. This internal biochemical milieu has been referred to as the cancer terrain (Block, 2009). The terrain concept is similar to the “seed and soil” concept of cancer metastasis (Comen, 2012), but is generalized to the entire cancer process. There are several important dimensions or factors in the terrain concept, each of which impacts cancer growth, response and resistance to treatment, daily functioning in cancer patients and/or cancer complications. These factors are oxidation, inflammation, glycemia (the insulin-IGF axis), blood coagulation, immunity and stress chemistry. Each process is necessary to life, but is prone to becoming imbalanced in cancer. Restoring balanced functioning of the terrain factors is one way to address a variety of cancer problems. Restoring balance can be done medically and through use of supplements, but we will explore in this chapter chiefly the use of dietary interventions. Due to space limitations, we will emphasize oxidation, inflammation

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and glycemia, with comments on other terrain factors. It is clear that many cancer-related conditions depend on multiple terrain factors, such as cachexia, which is strongly linked to both oxidative stress and inflammation (Vaughan, Martin, & Lewandowski, 2013). OXIDATION

Fiaschi and Chiarugi (2012) review the action of oxidative stress in cancer. Although normal cells under oxidative stress undergo apoptosis or other cell death mechanisms, cancer cells exploit the proooxidative milieu and even generate reactive oxygen species (ROS) to further their activities. ROS have been linked to all the hallmarks of cancer. In established disease, ROS help cancers evade apoptosis, by activating NF-κB and other signaling molecules as well as promoting anoikis resistance. In metastasis, oxidative stress promotes matrix metalloproteinase secretion, cell motility and formation of invadopodia. ROS also support angiogenesis, inflammation and the Warburg effect. Other evidence also suggests the importance of oxidative stress in established disease. Oxidative stress, which is accentuated by androgen deprivation therapy, modulates cellular events including androgen receptor overexpression, activation, synthesis and mutation (Shiota, Yokomizo,  & Naito, 2012). This leads to prosurvival and anti-apoptotic effects on prostate cancer cells, and encourages treatment resistance. Antioxidant therapy might counteract these activities. Breast cancer patients receiving adjuvant chemotherapy who had higher levels of total antioxidant capacity in plasma and higher levels of the DNA repair enzyme KU86 had better survival and less recurrence (Vera-Ramirez et al., 2011). Hepatocellular carcinoma patients who have high serum levels of oxidative stress (derivatives of reactive oxygen metabolites assay) were more prone to recurrence after treatment (Suzuki et  al., 2013). Colorectal cancer patients with increased plasma levels of retinol and carotenoids had lower levels of overall mortality (Cooney et al., 2013). These studies suggest the need for an overall reduction in general oxidative stress throughout the disease course. On the other hand, there is evidence that elevated levels of intracellular antioxidant enzymes such as glutathione and related enzymes or manganese superoxide dismutase may reduce response to treatment in breast cancer (Woolston et  al., 2011; Yao et  al., 2010). These enzymes can be determined by genetic polymorphisms. These studies suggest that the endogenous antioxidants, which are present at high levels in cancer cells, and which protect them from their very high levels of intracellular ROS, are problematic during treatment. The negative effect of endogenous antioxidants may not, however,

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extend to antioxidant supplements given during treatment. Indeed, a systematic review of randomized clinical trials of antioxidants given during chemotherapy did not find any evidence that the antioxidants diminished treatment response or survival (Block et  al., 2007). Many antioxidants are known to behave as prooxidants when given at high concentrations (e.g., the prooxidant activity of intravenous vitamin C) or when they are placed in prooxidant environments, thus promoting apoptosis of cancer cells. This has been reported even for glutathione, an endogenous antioxidant, when applied extracellularly (Perego, Gatti, Crenini, DalBo, & Zunino, 2000). Khan, Zubair, Ullah, Ahmad, and Hadi (2012) discuss antioxidant polyphenols, which are well known for causing apoptosis and cytotoxicity in cancer cells, a function usually associated with prooxidants. However, these polyphenols are known to act as prooxidants when they are in the presence of copper. Since cancer cells often contain high amounts of copper, this could account for the well-known ability of antioxidant polyphenols to cause apoptosis and cytotoxicity in cancer cells. Questions have been raised about use of antioxidants during radiation as well. A large trial of beta-carotene and vitamin E supplements during radiation therapy for head and neck cancer observed excess recurrence and mortality risks with supplements, although supplemented patients had fewer side effects. Later analysis, however, showed that excess risks of recurrence and mortality were all among those patients who smoked tobacco during supplementation; smoking is known to have a negative interaction with high beta-carotene doses (Meyer, Bairati, Fortin, et al., 2007). Analysis of dietary intakes and plasma beta-carotene showed that patients who had higher dietary beta-carotene intake had lower incidence of adverse radiation effects, and those with higher plasma levels had lower rates of recurrence (Meyer, Bairati, Jobin, et al., 2007). An additional complication in this study was that the vitamin E intake was in the form of alpha tocopherol, which reduces the effects of other forms of natural vitamin E (a mixture of 8 tocopherols and tocotrienols; Wu et al., 2007). Regardless of effects during treatment, there seems to be an argument for maintaining high levels of antioxidants throughout much of the course of cancer. Rather than relying solely on a few antioxidant supplements, it is recommended that patients follow a diet that is rich in fruits and vegetables, as well as other antioxidant foods including olive oil and nuts, both rich in polyphenols (Zamora-Ros et al., 2013). Supplements containing multiple antioxidant phytochemicals and extracts at lower dosage levels may also be useful. Also important in promoting antioxidant capacity is the elimination or reduction of factors that promote oxidative stress, including overweight, excess polyunsaturated fat consumption, elevated arachidonic acid consumption (from meat) and excess iron consumption (Thomson et al., 2006).

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INFLAMMATION

Inflammation is recognized as promoting carcinogenesis, but also appears to be a marker for poor cancer outcomes. Inflammatory C-reactive protein (CRP) and interleukin-6 have been recognized as predicting increased mortality and recurrence in several cancers, including gastric, colorectal, renal, lung and breast (Kim et  al., 2009; Pierce et  al., 2009; Suzuki et  al., 2013; Wilop et  al., 2008; Yasuda et  al., 2012). Lung cancer patients with markers of systemic inflammation (elevated neutrophil-to-lymphocyte ratio) during bevacizumab treatment had shorter progression-free and overall survival (Botta et  al., 2013). Inflammation also affects daily functioning in cancer patients:  breast cancer patients with elevated CRP were significantly more likely to report fatigue (HR = 1.8; Alfano et al., 2012); patients with high consumption of n-6 fatty acids relative to n-3 fatty acids had higher CRP and more fatigue (HR = 2.6). Antiinflammatory dietary patterns can help to control inflammation. As in the study by Alfano et al. (2012), an excessive ratio of n-6 to n-3 fatty acids will raise inflammation, so this is a primary consideration in control of inflammation. Reducing intake of arachidonic acid found in meats is one consideration, as is reducing n-6 fatty acids in poultry, eggs (omega-3 enriched eggs are now available), and vegetable oils such as corn, soy, sunflower and safflower. Grains contain low amounts of n-6 fatty acids, but consumption of whole grains was associated with lower concentrations of CRP in premenopausal women (Gaskins et  al., 2010). Whole grains in this case may displace consumption of some animal sources of n-6 fatty acids. Much of the n-6 fatty acids in meat and poultry can be expected to come from corn that is commonly fed these animals in the United States, and grass-fed beef has higher n-3 fatty acid content than corn-fed beef (although it does retain significant levels of saturated fat). Additionally, subjects fed diets high in oat bran, rye bran and sugar beet fiber had reduced CRP and fibrinogen relative to those fed diets lower in these fiber sources (Johansson-Persson et al., 2014), so high-fiber foods may have a beneficial impact on inflammation as well as blood coagulation parameters. Women counseled to increase fruits and vegetables were found to have reductions in CRP (Lima et  al., 2010). Adherence to a Mediterranean-type diet was assessed in Spanish patients at high cardiovascular risk. Although overall adherence to the Mediterranean diet pattern was not associated with reduced inflammatory markers, high consumption of fruits, cereals, nuts and virgin olive oil was related to lower levels of various inflammatory markers (Salas-Salvadó et al., 2008). Numerous randomized trials on the effects of fish oils in cancer indicate its beneficial impact on inflammatory and clinical markers. The major fatty

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acids in fish oil that are responsible for anti-inflammatory effects are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Early trials of fish oil in cancer had produced variable results, but recent trials indicate a more substantive effect. Fish oil in doses of 2 grams (600 mg EPA+DHA) given to Brazilian colorectal cancer patients during chemotherapy resulted in stability of body mass index and weight, while non-supplemented patients saw reductions; the CRP/albumin ratio also had a clinically relevant reduction (Silva et al., 2012). Prostate cancer patients scheduled for prostatectomy received a low-fat diet with 5 grams fish oil for 4-6 weeks before surgery or a control Western diet. Supplemented patients had lower Ki-67 and when serum samples from these patients were applied to prostate cancer cells in vitro, proliferation was lower than for samples of the control patients (Aronson et al., 2011). Murphy et al. reported on fish oil supplementation (EPA dose 2.2-2.5 g/ day) in lung cancer patients undergoing chemotherapy versus control patients (Murphy, Mourtzakis et al., 2011a,b). Patients in the fish oil group maintained weight, while controls lost weight. About 69% of fish oil patients gained or maintained muscle mass, while only 29% of controls maintained muscle mass. Chemotherapy response rate and clinical benefit were also higher in the fish oil group, with a non-significant trend toward better 1-year survival in this group. Murphy comments that changes in design may account for better results in more recent trials, including beginning fish oil supplementation before patients are in an advanced state of cachexia (Murphy, Mourtzakis, & Mazurak, 2012). Fish oil also affects immunity. Oral fish oil reduced the immune suppression that resulted from simulated solar radiation in human subjects (Pilkington et  al., 2013). An immunonutrition formula containing fish oil, arginine and RNA and designed for use at the time of surgery has undergone extensive testing, especially in gastrointestinal cancers. A systematic review of randomized trials of the formula found that it reduced length of hospital stay, morbidity of postoperative infectious complications and also postoperative non-infectious complications compared with standard nutrition (Zhang, Gu, Guo, Li, & Cai, 2012). GLYCEMIA

Our awareness of the importance of proper balance in blood glucose and the insulin-IGF axis in cancer has grown over the past several years. Insulin is a known driver of cancer. It is often measured clinically as C-peptide, a byproduct of insulin synthesis that is more amenable to analysis than insulin. In a cohort of non-diabetic breast cancer patients, C-peptide was positively

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associated with both overall mortality and breast-cancer specific mortality (Irwin et  al., 2011). Pre-diagnosis levels of C-peptide were positively correlated with increased mortality in colorectal cancer patients (Wolpin et al., 2009). Prostate cancer patients who were overweight and who had high C-peptide had an elevated risk of prostate-cancer specific mortality (Ma et al., 2008). Colorectal cancer patients being treated with cetuximab plus irinotecan who had high BMI plus high fasting blood glucose had a time to progression that was over two months less than that of those who had normal BMI and blood glucose (Pantano et al., 2013). Elevated levels of IGF-1, in addition to below-normal levels, correlate with cancer mortality in older men (Svensson et al., 2012). Serum IGF-1 level in European women was found to be linked to higher intake of protein, although not energy, fat, or carbohydrate intake. A positive relationship with milk and cheese was observed, whereas vegetables and beta-carotene were inversely related (Norat et al., 2007). Another European study found that total protein, dairy protein and calcium intake were positively associated with serum IGF-1, and decreased IGFBP-2 (Crowe et  al., 2009). Specific proteins or calcium sources other than those from dairy were not correlated with IGF-1. Young et al. similarly found increased IGF-1 with increases in dairy and dairy protein in the diet (Young et  al., 2012). In a U.S.  population, however, total calcium intake had a modest inverse correlation with C-peptide, as did vitamin D (Wu, Willett, & Giovannucci, 2009). Notably, milk in the United States is fortified with vitamin D, and is thus a major vitamin D source for U.S. citizens, whereas milk in Europe and England is generally not fortified. Low vitamin D appears to be related to insulin resistance. Interventions for reducing insulin or IGF-1 are under study. Clearly, dietary control of insulin resistance and type 2 diabetes, including weight loss under supervision, is wise. A low glycemic-load diet reduced post-prandial responses of glucose and insulin, along with a modest reduction in IGF-1. A randomized trial of almonds compared with controls eating whole-wheat muffins found that almonds significantly reduced 24-hour urinary C-peptide relative to the controls. With the acknowledgment of the importance of insulin in cancer, an interest has emerged in the use of metformin as a medical strategy for lowering insulin and improving cancer outcomes. A trial of metformin in breast cancer patients undergoing neoadjuvant chemotherapy and surgery found that metformin reduced body weight, insulin and CRP. Ki-67 in tumor tissue decreased, and TUNEL staining for apoptosis increased relative to findings at initial biopsy (Niraula et al., 2012).

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Low Carbohydrate and Ketogenic Diets The substantial interest in low-carbohydrate diets for weight loss has a parallel in the investigation of low-carbohydrate and ketogenic diets for cancer. It is well-known that tumors use glucose at a high rate to support their growth: the use of labeled glucose for PET scans takes advantage of this phenomenon. It is not surprising that low-carbohydrate diets would thus be of interest in cancer control. Klement and Kammerer (2011) state the case for low-carbohydrate diets in cancer. Cancers differ from normal tissue in their constant need for high levels of glucose. Metabolic dysfunction is a hallmark of cancer cells, and as a consequence most tumor cells cannot use fat or ketones for metabolism when glucose levels are low, which normal cells can. High levels of glucose also raise insulin and IGF-1, and these promote cancer growth. Because of these observations, a number of studies in laboratory animals have been conducted that show efficacy of low-carbohydrate diets in shrinking tumors. Seyfried and Shelton (2010) expand this line of thinking with a discussion of the Warburg effect in cancer, and a report of a case of glioma controlled during the time that a patient subsisted on a ketogenic diet. The Warburg effect is the continued use of glycolysis in aerobic conditions by cancer cells. Glycolysis is a metabolic pathway that uses elevated levels of glucose and produces lactic acid. Glycolysis is only used by normal cells in anaerobic conditions; the presence of oxygen will suppress glycolysis. In cancer cells, however, glycolysis continues in oxygenated conditions. Because glycolysis is less efficient in producing energy than oxidative phosphorylation, used by normal cells, cancer cells need high levels of glucose to survive. Seyfried explains that the use of glycolysis by cancer cells arises because of damage to the mitochondria that renders them ineffective in performing normal glucose metabolism. Cells using glycolysis cannot metabolize ketones. Thus, a ketogenic diet, which dramatically lowers glucose levels, seems ideal to help eliminate tumors. Energy restriction can also reduce glucose levels: to achieve the levels of energy restriction seen in animal studies, humans would need to perform a water-only fast, or restrict calories to 500–600 kcal daily. This obviously will induce significant weight loss, which could be problematic in advanced cancer patients, and should only be done under supervision of an experienced clinician or specialist. A case of glioma controlled with the help of a ketogenic diet has been reported (Zuccoli et al., 2010). Normal brain cells are adapted to use ketones, but most gliomas are unable to use them. Interestingly, a ketogenic diet can be used to control seizures in childhood epilepsy and in other neurological disorders, and cases of childhood gliomas controlled with ketogenic diets have been reported. An adult glioma patient thus conducted short periods of water-only

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fasting and then was placed on a ketogenic diet consisting of Keto-Cal (a dietary product for the ketogenic diet) supplemented with medium chain triglycerides, proteins, vitamins and minerals, and 10 grams carbohydrates per day. The patient then underwent standard radiation plus temozolomide. After this the patient was shifted to a nonketogenic diet delivering only 600 kcal daily, which also maintained ketosis. Complete regression of the tumor was observed. The patient eventually lost 20% of body weight but was in good health. The patient then began to exceed the caloric limits, at which time the tumor recurred, and she was treated conventionally. The low-carbohdyrate and ketogenic diets thus possess interesting rationale and demonstrative case reports. A few small-scale human studies have been conducted with the diet. Fine et al. (2012), for example, gave patients with incurable cancers a diet with 35% fewer calories than normal, with 5% of calories from carbohydrates, resulting in ketosis and reduced insulin levels. Stable disease or partial response was observed in 5 of 10 patients. Some potentially relevant epidemiological data also exist. Trichopoulou, Psaltppoulou, Orfanos, Hsieh, and Trichopoulos (2007) developed an assessment method for low-carbohydrate, high-protein diets in a Greek population. The dietary pattern was related to increased overall mortality, and also to increases in cardiovascular and cancer mortality. In Sweden, Nilsson and colleagues (2012) assessed a low-carbohydrate, high protein dietary pattern, and found that it was not related to cancer mortality. The dietary pattern in these studies, however, does not necessarily correlate with the low-carbohydrate programs currently being explored in cancer. In general, epidemiological work directly addressing the low-carbohydrate pattern is uncommon. Diets low in glycemic index or glycemic load, or diets that lower insulin are related to low-carbohydrate diets and have been studied in relation to cancer risk. A meta-analysis of 10 studies found that elevated glycemic index, but not glycemic load, significantly increased breast cancer risk (HR = 1.08; Dong & Qin, 2011). A meta-analysis of 14 cohort studies of colorectal cancer found that there was no relationship of carbohydrates, glycemic index or glycemic load to occurrence of colorectal cancer (Aune et al., 2012a). Fung et al. (2012) attempted to analyze what dietary patterns promoted high or low insulin levels, as measured by C-peptide. The dietary pattern that contributed to elevated C-peptide was high in meat, fish and sweetened beverages, and low in coffee, dairy and whole grains. On the other hand, in another study dietary fructose and high glycemic foods contributed to high C-peptide, while high consumption of cereal fiber related to lower C-peptide (Wu et al., 2004). In studies of cancer patients, Belle et al. (2011) assessed dietary fiber, carbohydrates, glycemic index and glycemic load in breast cancer survivors, and

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found that of these, only dietary fiber was non-significantly related to lower risks of breast cancer mortality and recurrence. Breast cancer patients receiving targeted therapy treatment who had high fasting glucose were more likely to have disease progression on treatment (Barbaet  al., 2012). Kroenke et  al. (2013) and Pettersson et al. (2012) reported poor outcomes in breast and prostate cancer patients who ate high amounts of whole milk or dairy fat; prostate cancer patients who consumed the most whole milk were at twice the risk of progression of those who consumed the least, while those consuming low-fat dairy were at lower risk of progression. This would suggest that dairy fats be avoided as elements of low-carbohydrate diets. Related to low-carbohydrate and ketogenic diets is the use of fasting in cancer. Fasting is an ancient healing modality. Periodic fasting may be useful in cancer as a more manageable alternative to continual caloric restriction. It may also sensitize tumors to conventional treatment and protect normal tissues from side effects of these treatments. Short-term fasting protected mice from high-dose chemotherapy side effects better than 50% calorie restriction (Brandhorst, Wei, Hwang, Morgan, & Longo, 2013). However, clinical research on fasting in cancer patients is in its earliest stages. Research on low-carbohydrate diets is thus certainly in preliminary stages, with limited data to support it to date. Further, laboratory studies from by Michael Lisanti and his research group suggest that the importance of the Warburg effect may be modified by what they term the “reverse Warburg effect.” By dissecting different anatomical components of tumors, this group has demonstrated that different tumor compartments have strongly varying metabolism. In head and neck cancers, for example, Curry et al. (2013) found that the bulk of the tumor, which actually consists of nonproliferating epithelial cells, does indeed use glycolysis. These nonproliferating cells are poor in mitochondria, and export lactate and ketones. Similarly, the tumor stroma (fibrous tissue surrounding the tumor), which maintains an active communication with the tumor body, also functions with glycolysis, exporting lactate and ketones, and is poor in mitochondria, although these are actually nonmalignant cells. However, the actively growing compartment of the tumor, located between the stroma and nonproliferating cells, undergoes oxidative phosphorylation, and is rich in mitochondria. These cells are programmed to use fuels such as ketones and lactate. This compartment consists of basal epithelium that resembles stem cells. As a result of the intense proliferation of these cells, hydrogen peroxide is exported to the stroma and the nonproliferating cells. This causes oxidative stress in the other compartments, promoting mitochondrial dysfunction and the use of glycolysis, and continuing to increase the production of lactate and ketones, used by the proliferating cells. Of significant concern, high lactate and ketone concentrations were shown to

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promote stem-cell like gene expression in breast cancer (Martinez-Outschoorn et al., 2011). Lisanti’s group has documented similar compartmental metabolism in breast tumors, and they suggest the use of antioxidants to combat oxidative stress in the stroma, as well as use of metformin as a “mitochondrial poison” in treating cancers. The importance of ketone bodies to the actively growing or stem cell-like component of tumors raises questions as to the long-term suitability of ketogenic or low-carbohydrate diets, although, as the glioma case suggests, there may be some relevance to their use in reducing tumor bulk in brain cancers. Alternative cancer diets. Most “alternative” diets used by cancer patients follow rather closely the low-fat, plant-based pattern described above. However the diets are potentially problematic for cancer patients in certain situations and generally lack the quantitation of food intake necessary for optimal diet therapy. Five such diets are commonly used. Macrobiotic Diet. The macrobiotic diet is an adaptation of the traditional Japanese diet. It comprises 50% to 70% whole grains, 20% to 25% vegetables, 5% to 10% beans and sea vegetables, and 5% vegetable soups. Nuts, seeds, fruits, and fish are consumed occasionally, but red meat, dairy, and sugar are avoided. Macrobiotic counselors adapt the diet according to personal conditions, season, climate, and other factors. Difficulties can arise for patients with cachexia due to the low caloric density of this diet. Gerson Diet. Max Gerson developed this diet in the early 1900s. It emphasizes a vegetarian diet, raw vegetables, and fruit juices. Fasting and coffee enemas are included in the protocol, which can be very rigorous and sometimes difficult to follow. Monitoring for adequate protein intake in patients with cachexia is necessary, and the intake of fruit juice may compromise blood-sugar control. Kelly Diet (Metabolic types). Developed by dentist William Kelly, this diet is similar to the Gerson diet but includes more cooked foods and animal proteins, pancreatic enzymes, fasting, colonic irrigation, and coffee enemas. Diets are tailored to the type of cancer and aspects of the patient’s condition, classified as metabolic types. Diets high in vegetables and fruits are recommended for some cancers, but other cancers require high-meat diets, which are questionable on epidemiologic grounds. A variant used by Nicholas Gonzalez adds supplementation with micronutrients, amino acids, glandular substances, and digestive enzymes. The very large number of supplements can be problematic for some patients. Living Foods Diet. Ann Wigmore of the Hippocrates Institute developed a diet based on only raw foods, fermented vegetables, sprouted grains, and

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juices such as wheatgrass juice. Inadequate protein and n-3 fatty acid intakes have been raised as potential problems with long-term use of this diet.

Implementation of Nutritional Counseling at an Integrative Oncology Center The Block Center for Integrative Cancer Treatment, an independent community-based oncology center, serves a patient population with a high diversity of cancer types, generally concentrated in more advanced disease stages. Although we see numerous early stage patients, we also see a large portion of patients with recurrent or Stage IV disease at our outpatient chemotherapy unit, which provides chronomodulated (time-sensitive administration) chemotherapy and other specialized services. As is typical in many integrative centers, patients often seek out the center due to recurrent disease following multiple prior chemotherapies. With a high proportion of patients thus at increased risk for nutritional complications, the Center has developed a strong nutritional counseling protocol. Diet recommendations are individualized for cancer type, stage of disease, nutritional status at intake and underlying biochemical and metabolic predispositions of the patient. Additionally, molecular tissue profiling is available for both drug and nutritional formulations to target specific, relevant biomarkers. All nutritional counseling at the Center is provided by registered dietitians, and supervised by staff physicians. Nutritional counseling begins with traditional dietetic assessment of patients as to current intake (1- to 3-day food records and food frequency questionnaire); assessment of BMI, recent weight gain, or loss along with physical signs of cachexia; and discussion of potential nutritional risk factors such as overweight and obesity, current conventional treatments, or weight loss induced by cancer or cancer treatment. Body composition is also assessed. Specific recommendations for caloric intake are based on height and weight using the Harris-Benedict equation. These recommendations are modified based on the need to gain or lose weight depending on nutritional risk factors. The Center uses recognized nutritional standards for calculating grams of protein per kg body weight for patients with cachexia as well as patients of normal weight. The Center uses laboratory tests to determine aspects of nutritional risk that may dictate food choices and dietary supplement use. The cancer terrain, or internal biochemical environment of each patient, is assessed to determine the presence of imbalances in oxidation, inflammation, glycemia, blood coagulation, immunity or stress chemistry that could promote cancer progression or recurrence. Comprehensive, advanced laboratory tests used for these conditions include C-reactive protein, fibrinogen, blood sugar, and insulin

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levels, oxidized LDL, levels of specific phytochemicals such as tocopherols and carotenoids, CBC and natural killer cell cytotoxicity. In addition, whenever possible a variety of tumor markers are assessed in tumor tissue in addition to commonly reported markers. If assessing the biochemical environment indicates excessive inflammation, oxidation, or other abnormal values, specific food choice and supplement recommendations are made. If the tests indicate pathological levels of these factors, prescription drugs may be used to normalize these values. Patients who have low levels of phytochemicals are given recommendations for food choices (Mayland, Bennett. & Allan, 2005). If levels are particularly low and do not recover, specific dietary supplements (e.g., mixed tocopherols, mixed carotenoids, vitamin C) are advised. If tumor markers indicate that molecular target drugs (e.g., trastuzumab) will be useful, they are prescribed. However, if molecular targets that lack current drug recommendations are present, we determine and advise selected nutraceuticals that are supported by experimental or early clinical trial evidence. Food choices for patients are summarized in a series of seven recommendations, as follows: 1. Eat large amounts of vegetables and fruits, emphasizing diversity by using different plant families (e.g., crucifers, onions) and phytochemical content as shown in bright colors. 2. Consume plentiful whole grains and whole grain products. 3. Consume an adequate amount of calories and protein to maintain or attain healthy body weight, emphasizing proteins from legumes, soyfoods, fish, egg whites and n-3 rich whole eggs. 4. Limit total fat intake, shifting towards n-3 fats and monounsaturated fats. 5. Substitute milk, cheese, and ice cream with nondairy alternatives based on soy, rice, oat, almond, or related products, due to concerns with elevated IGF-1 levels. 6. To reduce sweet cravings, or for baking, use fruits and small amounts of less problematic sweeteners (e.g., stevia, barley malt, agave). 7. Drink adequate, healthful fluids including safe water, herb teas, green tea, and diluted fruit juice to maintain hydration.

Patients under the care of the center receive a full work-up and consultative supervision by one of the center’s treating physicians prior to dietetic consultation. Patients are given specific recommendations for quantifying the amounts of vegetables, fruits, grains, proteins, nuts and oils, and other foods, based on calculations of caloric totals and protein content. Specific foods are

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given ratings based on one to three stars, and patients are given lists of foods to emphasize and others to avoid. Dietitians instruct patients on portion sizes and practicalities such as shopping; a weekly discussion group is available to help patients with lifestyle change strategies. With patients who are overweight or suffering muscle loss due to cachexia, dietitians work with the staff physicians on countering underlying physiological imbalances and with our physical therapist on exercise recommendations. Dietitians provide ongoing nutritional consultation based on records submitted by patients. They also recommend supplements, with consultation by physicians as needed. Nutritional consultation with patients at the Block Center is begun immediately after initial medical evaluation and in consultation with medical staff. Since nutritional therapy is regarded as foundational to the entire integrative system, it is provided to every patient. Patients who are receiving their medical care at other centers may come to the Center for integrative care and may have nutritional consultations with the Block dietitians. Dietitians are commonly scheduled to meet with patients as they undergo chemotherapy treatments, along with other integrative practitioners, despite the administrative burden of scheduling multiple practitioner visits. Our study of a cohort of 90 metastatic breast cancer patients on the Center’s recommended diet  along with exercise and other integrative interventions, recorded an extended median survival time of 38 months, in comparison with survivals in the general range of 18-24 months in contemporaneous research trials and studies of other community clinic data (Block et al. 2009). Similar results in a small cohort of advanced prostate cancer patients are in preparation for publication. The policy of dietetic care for every patient certainly poses a logistic challenge. However, the potential benefits of nutrition as the foundation of integrative care are, as outlined in this paper, sufficiently powerful that every effort should be made to ensure that patients have constant access to nutritional care as their battle with cancer proceeds. Future studies should explore the application of whole foods regimens and supplements (where possible, whole food based) that are tailored to the specific needs of cancer patients, emphasizing the use of macronutrients, micronutrients, botanicals, and phytochemicals in restraining cancer growth and recurrence, improving treatment response and tolerance, and optimizing patients’ quality of life. REFERENCES

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7 Botanical and Mycological Medicine in Integrative Oncology LEANNA J. STANDISH, LISE N. ALSCHULER, MORGAN WEAVER, AND M. NEZAMI

Key Concepts Many of our best chemotherapy drugs originally came from plants (e.g., paclitaxel from the yew tree, vincristine, vinblastine, vinorelbine from the red periwinkle plant, camptothecin from the Chinese tree Camptotheca accuminata, podophyllin from mayapple). ■ It is likely that there are still antineoplastic and immunomodulatory plant and fungal medicines yet to be discovered. ■ The use of botanicals in oncology is based on the synergistic hypothesis—that combinations of well-selected active constituents from one or more botanical species will together have a synergistic anticancer effect. Some ancient Traditional Chinese Medicine (TCM) combination therapies have been shown to improve the response rates to chemotherapy in people with various cancers such as pancreatic and colon cancer. ■ Botanicals are used in naturopathic oncology in several ways:  to prevent cancer and metastasis in high-risk patients, to manage side effects of conventional cancer therapy, as adjuvants to improve efficacy and safety of chemotherapy agents, and as immunomodulators to prevent cancer relapse after treatment. ■ At this time, the botanicals and botanically derived compounds with the highest level of preclinical and clinical evidence as anticancer or immunomodulatory agents include:  Allium sativum (garlic), ■

160

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curcumin from Curcuma longa, Camellia sinensis (green tea), resveratrol from Polygonum cuspidatum, artemisinin from Artemisia annua, Viscum spp. (mistletoe), quercetin from various plants, bromelain (typically from pineapple), Silybum marianum (milk thistle), Astragalus membranaceous (astragalus), Withania somnifera (ashwagandha), and the medicinal mushrooms Trametes versicolor (turkey tail), Ganoderma lucidum (reishi), Lentinus edodes (shiitake), and Grifola frondosa (maitake). ■ As the use of natural products such as botanicals and mushrooms by cancer patients and their integrative health-care providers increases, there is a critical need for clinical research trials of single botanical agents as well as combination botanical treatments, in both the adjuvant setting and in prevention of tumor relapse after standard treatment.

P

lant medicines, or herbal therapies, often called phytomedicinals, are used by integrative health-care providers and self-prescribed by cancer patients to treat cancer. Botanical medicines are used in cancer chemoprevention, as adjunctive therapy to chemo- and radiotherapy to mitigate side effects, and in secondary prevention. There is evidence that specific phytomedicinal agents as well as whole herbal preparations can both harm and benefit cancer patients who are undergoing primary conventional cancer treatment. The integrative oncologist must be informed on drug–herb interactions and the growing body of literature regarding the potential benefits and risks of concurrent antioxidant therapy during radiation treatment (Lamson & Brignall, 1999; 2000a,b) as well as the growing body of literature showing improved outcomes from chemotherapy when specific herbal or fungal medicines are used (Chu, 2006; Novaes, Novaes & Valadares, 2011). Botanical medicines have been hypothesized to play a significant role in secondary chemoprevention in reducing risk of recurrence of disease locally or of metastases following primary conventional treatment. The clinical application of herbal therapies in secondary prevention is growing within the most progressive integrated oncology clinics. It is here that botanicals may have their greatest role. The search for natural products as potential anticancer agents dates back to Papyrus Ebers, an Egyptian physician who listed more than 700 drugs, mostly from plants, during the middle of the second millennium BC (Subbaraju &

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Golakaoti, 2005). In the 21st century, plant medicines are used by integrative health-care practitioners in six ways: • In primary prevention of cancer in patients at high risk for malignancy (anti-inflammatory via multiple pathways, pro-apoptosis actions and inhibition of proliferation pathways, antioxidants, and immunomodulators). • As phytopharmaceuticals with direct tumoricidal and apoptotic effects. • As adjuvants to improve the cytotoxic activity of cancer drugs. • As immunomodulators to enhance endogenous immunological tumoricidal activity. • To treat radiation-related reactions and fatigue. • To mitigate the hematological, neurologic, and gastrointestinal toxicities of U.S. Food and Drug Administration (FDA)-approved chemotherapy pharmaceuticals. • To improve survival and quality of life in survivorship. This chapter is written and designed for the clinician who seeks the current state of the preclinical and clinical science for botanical and mushroom therapy in cancer treatment, from diagnosis, through conventional primary treatment, in secondary prevention, survivorship and “wellness” care, in management of metastatic stage IV patients, and in palliative oncologic care.

Rationale for Botanical Oncology in the 21st Century The foundations and principles of botanical oncology are sound, but the science is far behind the theoretical uses of plant medicines in cancer patients. Evidence for even some of the most popular herbal medicines used by cancer patients has only been sketchy, often only in vitro evidence. Nevertheless, the long traditional uses of these herbs, many of which are available over the counter, indicates that some may be relatively harmless, some harmful as chemotherapy adjuvants, and some helpful, appearing to have a wide therapeutic window. In the last 60 years researchers have applied Western methods of science to botanical formulas of ancient Chinese and Ayurvedic medicine, as well as the indigenous plant medicines from ancient peoples all over the globe. We have been impressed time and again by the power of some of these plant medicines.

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If we, in the Western world, have not found effective plant medical treatments for cancer, it is, in our opinion, because we have not tried hard enough. From the indigenous Amazonian entheogenic plant medicine perspective, we lack a plant medicine cure for cancer because we have not listened to or learned from the plants. The concept of plant intelligence is just beginning to be explored by ethnopharmacologists. We anticipate an exciting future in the clinical study of indigenous plant medicines, including psychoactive plant medicines, used in traditional healing. We have much to learn from our plants and from indigenous peoples who know their plants.

Plants Are the Original Source of Many FDA-Approved Cytotoxic Chemotherapies Botanical medicines are the original source of some of our most powerful FDA-approved cytotoxic chemotherapy agents. In the West, drug-based chemotherapy is more than 70 years old. Natural products have been major molecular structural resources for drug discovery. Among the 520 new drugs approved in the United States between 1983 and 1994, 157 were natural products or derived from natural products, and more than 60% of antibacterials and anticancer drugs have originated from natural products (Zaidman, Yassin, Mahajna, & Wasser, 2005). There are now more than 100 FDA-approved anticancer agents. Many of our most powerful chemotherapy drugs are synthetic analogs of molecules first discovered in natural products, including bacteria, animals, and especially plants. For example, the microtubulin-disrupting taxane chemotherapy drugs (paclitaxel, docetaxel, albumin-bound paclitaxel) were developed from the Pacific Yew tree (Taxus brevifolia). Originally vincristine and vinblastine, chemotherapeutic agents with microtubulin-disrupting activity used in leukemias and lymphomas, were developed from the vinca alkaloids found in the pink or red periwinkle plant (Catharanthus roseus). Vinorelbine is another vinca alkaloid with anticancer activity used in several adenocarcinomas, including breast and ovarian cancer. The topoisomerase-targeting camptothecin (derived from an alkaloid produced by the Chinese tree Camptotheca acuminata) was identified by Western scientists as an antineoplastic agent in the 1960s. The mayapple (Podophyllum peltatum) is Minnesota’s native plant and has a long history of use in treating cancer by Native Americans. Podophyllin, the active constituent, is an alcohol extract of the roots and rhizomes of the tree. Inspired by mayapple’s traditional use and activity against warts, the NCI explored its potential as an anticancer drug in animal and human trials in the 1950s. However, because it was too toxic, clinical trials were abandoned. Later, in the 1960s, Sandoz Ltd. resumed

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research on podophyllotoxin, leading to the development of semisynthetic analogs that later became the FDA-approved drugs, teniposide and etoposide, that are widely used in treating non–small-cell lung carcinoma, lymphomas, and leukemias. Triterpenoid acids such as oleanolic and ursolic acid, which are common plants constituents, are known to have anti-inflammatory and antitumor activities. Attempts to synthesize new analogs have led to in vitro and in vivo studies, especially in ovarian cancer (Melichar et  al., 2004). β-Lapachol is a simple napthoquinone extracted from the bark of the lapacho tree, Tabebuia avellanedae, found in South America. It has a long history of ethnobotanical use in the Amazonian basin. However, the isolated compound β-lapachol showed unacceptable levels of toxicity, and further investigation was dropped by the NCI (Cragg & Newman, 2005). Many plant cytotoxic molecules have been abandoned for further development by the NCI because isolated single constituents have unacceptable toxicities. Unfortunately, but not surprisingly, the use of whole plants or combination plant constituents has not been pursued by mainstream oncology researchers. Even those who have pursued whole-plant botanical oncology research have been stymied by the absence of adequate taxonomic, chemical, and bioassay validation of the natural products used in research. Botanical oncology research can succeed only with knowledge-based consensus on the plants, the parts of plants, and the active constituents that should be studied and the bioassays that should be used to confirm activity. With leadership and support from the National Center for Complementary and Alternative Medicine (NCCAM) and the NIH Office of Dietary Supplements, this work is moving forward. Chemotherapy for many types of cancer relies on well-selected combinations of agents. Conventional combination chemotherapy utilizes multiple single molecular agents that have additive or synergistic activity. The most compelling rationale for combination chemotherapy is twofold: (1) tumor cell heterogeneity and its associated drug resistance, and (2) the success of combination chemotherapy in the clinic (Henderson et al., 2003). Primary treatment for breast cancer, ovarian cancer, colorectal cancer, pediatric lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin’s disease, and small and non– small-cell lung carcinomas involve two to seven agents (Frei  & Paul, 2003). Study medication development, quality assurance, and quality control in clinical research of natural products is far more complex than single molecule drug trials. Nevertheless, the potential of combination plant therapy in cancer treatment warrants the extra effort required to conduct high-quality clinical trials using complex plant mixtures.

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Botanicals in Oncologic Practice: Which Plants Show the Greatest Potential? The use of botanical and fungal medicines by integrative oncologists in the West is largely evidence based. The peer review literature is rich with in vitro studies of plant constituents investigating their cytotoxic, apoptotic, anti-inflammatory, gene stabilization, and antiangiogenic effects. Many herbs in common use also have supporting animal studies using murine models of specific tumor types. However, it was not until John Boik’s 2001 publication of Natural Compounds in Cancer Therapy (Boik, 2001) that integrative oncologists had an evidence-based systematized list of most promising botanicals. On the basis of in vitro, animal, and human data, Boik identified 21 higher fungi and vascular plants, and plant-derived compounds, on which significant anticancer data was available to warrant further clinical trials. They are listed here ranked by level of evidence from the highest to the lowest level:  Trametes versicolor, genistein and daidzein from Glycine max (soy), Panax ginseng (ginseng), bromelain from pineapple, Astragalus membranaceous (astragalus), quercetin from various plants, Eleutherococcus senticosus (Siberian ginseng), Camellia sinensis (green tea), boswellic acid from Boswellia serrata (boswellia), Ganoderma lucidum (reishi), Lentinus edodes (shiitake), curcumin from Curcuma longa (turmeric), Allium sativum (garlic), resveratrol typically from Polygonum cuspidatum (Japanese knotweed), flax seed, anthocyanins from  berries, hypericin from Hypericum perforatum John’s wort), parthenolide from Tanacetum (feverfew), Centella asiatica (gotu kola), Ruscus aculeatus (butcher’s broom), and Aesculus hippocastanum (horse chestnut). Many of these botanical therapies are prescribed by naturopathic physicians who specialize in the treatment of cancer patients (see Naturopathic Oncology chapter). The most commonly used botanical medicines for each cancer type are listed here: Breast cancer—turkey tail mushroom, maitake mushroom, artemisinin, resveratrol, garlic, quercetin, bromelain, curcumin, green tea, flax seeds, soy, 3,3’-diindolylmethane (DIM) and sulforaphane extracted from cruciferous vegetables Prostate cancer—garlic, green tea, soy, pomegranate, silymarin, curcumin, lycopene Lung cancer—turkey tail mushroom, astragalus, green tea, curcumin, silymarin, bromelain, ginseng, garlic, ginkgo, mistletoe Colorectal and gastric cancer—turkey tail mushroom, maitake mushroom, curcumin, garlic, astragalus, green tea, mushrooms, flax seeds, resveratrol, mistletoe (Viscum alba)

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Head and neck cancer—turkey tail mushroom, curcumin, green tea, Glioblastoma multiforme—resveratrol from grape seeds, bosellia, curcumin, aloe vera, curcumin, lycopene Melanoma—green tea, curcumin, flavonoids, mistletoe (Viscum alba) Ovarian cancer—turkey tail mushroom, ginkgo biloba, soy, green tea, curcumin Hepatocellular carcinoma—turkey tail mushroom, green tea, ginseng, mushroom derivative beta glucans, milk thistle Lymphoma—turkey tail mushroom, Lomatium isolatum, curcumin, green tea, flavonoids, astragalus Leukemia—turkey tail mushroom, green tea, astragalus, soy Multiple myeloma—plant enzymes, curcumin, green tea, astragalus, soy

Evidence for Botanical Therapies in Primary Treatment and Secondary Prevention of Cancer In this section we review the current state of the preclinical and clinical science for eight of the most commonly used botanicals in integrative oncology by naturopathic physicians who are board certified in naturopathic oncology. Mistletoe cancer treatment is widely used in Europe. A review of the literature on the use of alternative cancer therapies reports that mistletoe preparations are listed among 11 of the most commonly used CAM methods in Europe (Hauser, 1991). Please see Anthroposophical Medicine chapter for further details. GARLIC (ALLIUM SATIVUM)

Garlic and related vegetables of the Allium genus have an especially wide variety of beneficial effects on human health. Among the potential effects are prevention and amelioration of certain cancers. When garlic is cut or crushed, enzymes are activated to produce several organosulfur compounds, including the volatile substances that give garlic its odor. These sulfur-containing chemicals are implicated in the beneficial dietary effects of garlic. Although these volatile and unstable molecules are difficult to study, the understanding of their chemistry is far ahead of an understanding of their biology. In fact, very little is known about the mechanisms by which garlic constituents affect human cancer cells. Garlic extract induces apoptosis of several breast

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cancer cell lines, but not normal fibroblast cells (unpublished data Sivam and Standish). High consumption of fruits and vegetables is associated with decreased risk of cancer at many sites. Allium vegetables, particularly garlic (Allium sativum) have had an important dietary and medicinal role for centuries. Several lines of investigation have demonstrated anticancer effects of garlic (Lea, 1996). Epidemiologic studies have indicated decreased site-specific cancer incidence associated with fresh garlic consumption. For example, Steinmetz et al. conducted a large prospective cohort study of colorectal cancer among women in Iowa (Steinmetz, Kushi, Bostick, Folsom, & Potter, 1994). They analyzed intake of 15 vegetable and fruit groups and dietary fiber. The strongest inverse association found in the study was for garlic consumption with an adjusted relative risk of 0.68. A Swiss study reported a substantially greater protective effect (0.32) for colorectal cancer in the upper tertile of garlic consumption (Levi, Pasche, La Vecchia, Lucchini, & Franceschi, 1999). Studies in China and Italy have observed similar results for gastric and laryngeal cancer (Buiatti et  al., 1989; Cipriani, Buiatti,  & Palli, 1991; Zheng et al., 1992). Case–control studies of dietary factors have also shown inverse associations with breast and prostate carcinomas (Challier, Perarnau, & Viel, 1998; Key, Silcocks, Davey, Appleby, & Bishop, 1997). Table 7.1 lists the results for published epidemiological studies related to fresh garlic consumption. Several biologic activities have been identified for garlic extracts that may be relevant to cancer, including lipid-lowering effects, antiplatelet, immunomodulatory, and antioxidant properties (Agarwal, 1996). There are also reports of direct action of garlic extracts on tumor cells. Antiproliferative effects of garlic extract have been reported for human colon carcinoma, hepatoma, and leukemia cell lines at IC50 concentrations from 30 to 480 μg/mL (Siegers, Steffen, Röbke,  & Pentz, 1999). Various single components in fresh or aged garlic extracts, including diallylsulfenic acid (allicin), diallyl di- and tri-sulfides, ajoene, and S-allylcysteine, and S-allylmercaptocysteine have also been demonstrated to have antiproliferative, and in some cases, apoptotic effects on cancer cell lines (Anagnostou, & Steiner, 1997; Dirsch, Gerbes, & Vollmar, 1998; Pinto et al., 1997; Sakamoto, Lawson, & Milner, 1997; Scharfenberg, Ryll, Wagner & Wagner, 1994; Sigounas, Hooker, Sigounas, Hooker, Li, Anagnostou, & Steiner, 1997b; Sundaram & Milner, 1996; Zheng et al., 1997). Nonmalignant cells were reported to be less sensitive to these organosulfur compounds (Sakamoto et al., 1997). Several biochemical mechanisms have been proposed, including reduction in polyamine levels, oxidative stress, and activation of the transcription factor nuclear factor kappa-B (NF-κB) (Dirsch et al., 1998; Pinto et al., 1997). The organosulfur compounds of garlic are secondary metabolites and are responsible for the characteristic odor of crushed garlic (Lawson, 1996). The

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Table 7.1.  Epidemiological Studies on Cancer and Garlic Consumption.* Country

Reference

Cancer Type

Food

Cancer Association (Odds Ratio) †

Argentina

Iscovich et al., 1992

Colon

Garlic

0.2–0.4

China

Mei et al., 1982

Stomach

Raw garlic (20 g/day)

0.08‡

China

You et al., 1989

Stomach

Garlic (>4 g/day)

0.7

Garlic (0.3–4 g/day)

0.8

All Allium species (44–64 g/day)

0.5

China

Zheng et al., 1992

Larynx

Garlic

0.5–0.6

Italy

Buiatti et al., 1989

Stomach

Cooked garlic

0.4–0.6

Italy

Cipriani et al., 1991

Stomach

Garlic and onion

0.8

Iran

Cook-Mozafari et al., 1979

Esophagus, men

Raw garlic (≥1 serving/ month) Pickled garlic (ever)

1.1§ 0.6

Switzerland

Levi et al., 1993

Breast Endometrium

Garlic Garlic

0.6–0.7 0.6

USA

Steinmetz & Potter, 1994

Colon

Garlic (>1 serving/week)

0.7

Colon (distal)

Garlic (≥1 serving/week)

0.5

*Taken from Lawson, 1996 with the permission of the author. † Values below 1 indicate decreased risk of cancer. ‡Cancer incidence was only 8% of those consuming less than 1 g/day. § Not statistically significant, but all other studies are.

organosulfur compounds of intact garlic cloves contain mainly the amino acid cysteine, and include approximately equal amounts of S-alkylcysteine sulfoxides and α-glutamyl-S-alkylcysteines, the alkyl groups being strictly allyl, methyl, and trans-1-propenyl. When garlic cloves are crushed, chewed, or cut (or when dehydrated, powdered garlic is exposed to water), the vacuolar

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enzyme, alliinase or alliin lyase rapidly lyses the cytosolic cysteine sulfoxides (Lawson, 1996) to form sulfenic acids, which immediately condense to form the alkyl alkanethiosulfinates, the compounds that are responsible for the odor of fresh cut or crushed garlic. At room temperature, this process is complete in a few minutes. Aged garlic (Kyolic) contains S-allylcysteine and S-allylmercaptocysteine, both of which have demonstrated anticancer activity. A  study of 51 patients with precancerous adenomas seen on screening colonoscopy and removed surgically were randomized to garlic or placebo. Aged garlic significantly suppressed both the size and number of colon adenomas after 12 months of treatment (Tanaka et al., 2006). Aged garlic extract was shown to prevent decline in natural killer (NK) cell number and activity in patients with advanced colorectal, liver or pancreatic cancer (Ishikawa et al., 2006). Another garlic-derived organosulfur component called ajoene was shown to decrease basal cell carcinoma tumor size after topical application in 21 patients (Tilli et al., 2003). On the basis of in vitro experiments, the authors speculate that ajoene reduces basal cell carcinoma by inducing a mitochondrial-dependent apoptotic mechanism. Although no randomized human clinical trials of garlic for the treatment of cancer exist to date in the United States, research abroad continues. In a study of 1,424 lung cancer cases and 4,543 healthy controls, researchers found that ingestion of raw garlic twice per week or more was inversely associated with lung cancer in a dose-dependent manner (OR = .56) (Jin et al., 2013).

Garlic Summary Several garlic constituents have apoptotic and immune modulating activity with strong preclinical evidence. Sadly, as yet there have been no cancer clinical trials of garlic in the United States. There are several epidemiological studies that have demonstrated decreased risk of various cancers, such as gastric, prostate, endometrial, and multiple myeloma from garlic consumption. A phase I/II clinical trial of allicin in breast cancer is a high-priority study.

CURCUMA LONGA: CURCUMIN IN CANCER RISK REDUCTION AND THERAPY

Curcumin (diferuloylmethane) is a polyphenol derived from the rhizome of the plant curcuma longa, a member of the ginger (Zingiberaceae) family. Also known as turmeric, Indian yellow root or Indian saffron, curcuma longa is cultivated throughout Asia and used extensively as a culinary spice and is a principal ingredient in curry. Curcumin also has a long history of use as a botanical

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medicine in both traditional Chinese and Indian (Ayurvedic) medicines to treat a wide variety of conditions. Current research has focused on curcumin as an anti-inflammatory, anti-oxidant, hepatoprotective, antimicrobial, and anticarcinogenic agent. There is an impressive amount of peer-reviewed literature on curcumin. A  Pubmed search in 2013 yielded more than 5,850 articles on curcumin, over 2,100 of which are specifically related to its impact on carcinogenesis. Curcumin has been shown to exhibit multiple anticancer effects in a wide variety of cancer types. The mechanisms through which curcumin is believed to interfere with carcinogenesis are many. They include inhibition of inflammation via NF-kB inhibition, promotion of programmed cell death (apoptosis), interference with new blood vessel growth to tumors (angiogenesis), decreased activation of multiple kinase pathways with resultant decreased cellular proliferation, reduction in cancer cell motility and possibly synergistic effects with some chemotherapeutic agents and radiotherapy. Oral administration of curcumin in doses up to 8 to 10 g per day without dose-limiting toxicity further marks curcumin as a promising therapy for both the prevention and treatment of cancer (Aggarwal et al., 2005). A key mediator in all stages of carcinogenesis is the transcription factor NF-κB, which is involved in pro-inflammatory pathways at all stages of carcinogenesis, including initiation, promotion, and progression (Grivennikov & Karin, 2010). In experimental models, curcumin has been shown to block recruitment of leukocytes, a source of inflammatory cytokines linked to carcinogenesis via inhibition of NF-κB (Kumar, Dhawan, Hardegen, & Aggarwal, 1998). In colon cancer cell lines, Su and colleagues reported that curcumin decreased not only levels of NF-κB, but also levels of other inflammatory mediators, including COX-2 and matrix metalloproteinase (MMP)-2, at both protein and mRNA levels. Plummer and colleagues also found a reduction in COX-2 levels in tumor necrosis factor (TNF)-induced colon cancer cells by curcumin and traced this reduction to mediators in the NF κB pathway (Plummer et al., 1999). Animal studies have shown that curcumin is effective in reducing experimentally induced colitis via inhibition of NF-κB (Jian et al., 2005) and COX-2 (Zhang, Deng, Zheng, Xia, & Sheng, 2006). Curcumin has also been shown to suppress cyclin D1, COX-2 and MMP-9 as well as block the activation of NF-κB in lung cancer cells exposed to NF-κB activating free radicals from cigarette smoke (Shishodia, Potdar, Gairola, & Aggarwal, 2003). A study of curcumin in a mouse gastric cancer model showed that both a 2% curcumin diet and intraperitoneal curcumin injection significantly decreased tumor size and likelihood of tumor growth, as well as decreased myeloid-derived suppressor cells (an important component of tumor growth, angiogenesis, and suppression) and interleukin-6 levels in both serum and tumor tissues (Tu

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et al., 2012). In a prostate cancer model using human cell lines, Guo, Xu, Ye, Yu, and Hu (2013) found that curcumin worked by up-regulating the NF-κB inhibitor IκBα. DNA adducts, which form as a result of oxidative damage, can result in mutagenesis and can therefore promote carcinogenesis (Phillips, 2005). Curcumin has been shown to act as an antioxidant and reduce DNA adduct formation in experimental models. Animal studies have suggested that curcumin reduces DNA adduct formation in oral cancers and reduces the number, size and grade of oral lesions (Krishnaswamy, Goud, Sesikeran, Mukundan, & Krishna, 1998). Curcumin has been shown to induce apoptosis in a wide variety of cancer cell types by interacting with many of these ligands and receptors. Numerous studies have shown that curcumin promotes cell cycle arrest at the G(2) phase by increasing p53/BAX expression (Choudhuri, Pal, Das, & Sa, 2005; Liontas & Yeger, 2004; Shehzad et al., 2013; Shi et al., 2006), inhibiting NF-κB (Aggarwal, Takada, Singh, Myers, & Aggarwal, 2004; Han, Chung, Robertson, Ranjan, & Bondada, 1999; Li, Braiteh, & Kurzrock, 2005; Mukhopadhyay, Bueso-Ramos, Chatterjee, Pantazis, & Aggarwal, 2001; Zheng, Ekmekcioglu, Walch, Tang, & Grimm, 2004), altering Bcl2 and caspase expression (Mukhopadhyay et  al., 2001; Shi et  al., 2006; Woo et  al., 2003), down-regulating IAPs (Woo et  al., 2003) and other mechanisms. Through these mechanisms, curcumin has been shown to induce apoptosis in a wide variety of cancer cell lines, including breast (Choudhuri et al., 2005; Liu & Chen, 2013; Ramachandran & You, 1999), prostate (Mukhopadhyay et al., 2001; Nayak et al., 2010), ovarian (Shi et al., 2006), lung (Radhakrishna Pillai, Srivastava, Hassanein,  Chauhan,  & Carrier, 2004), pancreas (Li, Braiteh,  & Kurzrock, 2005), head and neck (Aggarwal et  al., 2004), melanoma (Zheng et al., 2004), renal (Woo et al., 2003), B cell lymphoma (Han et al., 1999; Das & Vinyak, 2012), acute myeloblastic leukemia (Mukherjee Nee Chakraborty et al., 2006), neuroblastoma (Liontas & Yeger, 2004), glioblastoma (Karmakar et al., 2006), gastric (Moragoda, Jaszewski, & Majumdar, 2001; Tu et al., 2012), endometrial (Hu & Kavanagh, 2003; Saydmohammed, Joseph, & Syed, 2010), and colon cancer (Jaiswal, Marlow, Gupta, & Narayan, 2002; Tu et al., 2011). In comparing the effects of anti-inflammatory medicines on apoptosis, Wei and colleagues found that curcumin induced a more potent apoptotic response than celecoxib, nifedipine, or sundilac in colon cancer cells with defects in mismatch repair (MMR) genes (Wei et al., 2004). Using animal models, researchers have demonstrated that curcumin interferes with angiogenesis via several mechanisms. Chen and colleagues (2011) found that curcumin effectively inhibited the growth of engrafted melanoma in mice by effecting a number of vasculogenic factors (including EphA2, PI3K, MMP-2 and MMP-9). Yoysungnoen and colleagues demonstrated reduced

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neovascularization in mice inoculated with hepatocellular carcinoma cells treated with curcumin and found that treated mice had significant reductions in COX-2 over-expression and decreased serum levels of VEGF (Yoysungnoen, Wirachwong, Bhattarakosol, Niimi, & Patumraj, 2006). Gururaj and colleagues also found that curcumin reduced neovascularization in two in vivo angiogenesis systems with concomitant reduction in pro-angiogenic gene expression (VEGF, angiopoietin-1 and 2)  (Gururaj, Belakavadi, Venkatesh,  Marmé,  & Salimath, 2002). Curcumin has also been reported to inhibit angiogenesis via the FGF and MMP signaling pathways (Mohan et  al., 2000)  and to inhibit endothelial sprout formation via lipoxygenase inhibition (Jankun et al., 2006). Integrative oncologists are increasingly using plasma VEGF levels in peripheral blood as a biomarker for anti-angiogenic therapies. Experimental and animal data support the hypothesis that curcumin inhibits the process of metastasis by reducing motility of cancer cells or their invasive potential. Reductions in the invasive capacity of curcumin-treated cancer cell lines have been demonstrated in colon (Su, Chen, Lin, Wu,  & Chung, 2006), liver (Ohashi, Tsuchiya, Koizumi,  Sakurai, Saiki, 2003), and prostate cancer (Hong, Ahn, Bae, Jeon,  & Choi, 2006). Suppression of transcription of several genes involved in invasion has also been observed in lung cancer cell lines, including suppression of MMP 14, cell adhesion molecules, integrins, and heat shock proteins (Chen et al., 2004). In prostate cancer cell lines, curcumin has been shown to arrest cell movements by altering microfilament organization and function (Holy, 2004). In animal models of prostate cancer, treatment with curcumin not only reduced tumor size in the primary site but was also found to decrease the number of metastatic nodules possibly through inhibition of MMPs (Hong et al., 2006). Ohashi and colleagues demonstrated that oral curcumin altered formation of actin stress fibers resulting in functional alterations in the organization of the cytoskeleton and suppression of intrahepatic metastasis (Ohashi et al., 2003). Though curcumin has a low bioavailability and is rapidly cleared from the body (Anand, Kunnumakkara, Newman, & Aggarwal, 2007), attempts to prolong its uptake and half-life, and bolster its bioavailability, have been met with increasing success. Novel delivery systems are currently being investigated in the field: Lan et al. (2005) tested a liposomal preparation of curcumin in human pancreatic cancer cells and showed suppression of NF-κB activity, suppressed tumor growth, and increased apoptosis of the target cells in vitro, whereas another group of researchers found that curcumin-bearing magnetic nanoparticles showed 2.5 fold serum bioavailability compared to regular curcumin in tumor-grafted mice (Yallapu et al., 2013).

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There are currently limited data on the effects of curcumin in combination with conventional chemotherapy and radiotherapy. However, initial reports suggest that this may be an area worthy of exploration. In the previously mentioned study by Yallapu et al., cisplatin-resistant ovarian cancer cells that had been pretreated with curcumin nanoparticles were significantly more vulnerable to both radiotherapy and chemotherapy with cisplatin. Experimental data supports a role for curcumin along with another polyphenol, quercetin, in sensitizing ovarian cancer cells to cisplatin-mediated killing, possibly through reduction in autologous IL-6 production and other mechanisms (Chan, Fong, Soprano, Holmes,  & Heverling, 2003). Curcumin has also demonstrated potential in cell culture in reducing resistance of cancer cells to chemotherapy by inhibiting drug efflux pumps such as multidrug resistance protein 1 (MRP1) (Chearwae et al., 2006). Aggarwal and colleagues found curcumin effective at interfering with the paclitaxel-induced expression of antiapoptotic, proliferative and metastatic proteins. Also in experimental models, researchers have found curcumin capable of decreasing postradiation colony counts significantly in models of squamous cell carcinoma, likely through its effects in cell cycle arrest at stages of the cell cycle in which radiotherapy is the most effective (Khafif et al., 2005). The bulk of the experimental data suggests that curcumin favorably affects several key processes in carcinogenesis including promotion of apoptosis and inhibition of inflammation, angiogenesis, cell motility and metastasis. Curcumin may therefore, be an effective medicine in both chemoprevention and treatment of many different types of cancer. Some clinical data have been generated to evaluate how well curcumin performs as an anticancer therapy in humans. A  phase I  dose-escalation study of curcumin in patients with advanced colorectal cancer found that curcumin and its metabolites are evident in serum and urine, suggesting bioavailability, at doses of 3.6 g per day with no dose limiting toxicities. Although abundant amounts of curcumin can be recovered from the feces at this dose and dosages as low as 450 mg daily, curcumin appears to have a short half-life with serum retention times of 37 minutes or less (Sharma et al., 2004), with an elimination half-life of 28.1 ± 5.6 and 44.5 ± 7.5 hours at considerable doses of 10 mg/kg IV and 500mg/kg oral, respectively (Yang, Tseng, Wang, & Tsai, 2007). Other investigators found no evidence of serum curcumin at levels up to 8 g daily, when tested 1 hour after administration, but did at levels up to 12 g with excellent tolerability and minimal side effects such as diarrhea, yellow stool, headache and rash (Lao et al., 2006). Owing to the rapid clearance of curcumin, it may be appropriate to test for serum curcumin and its metabolites within 30 minutes of oral administration.

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Curcumin has been evaluated in combination with quercetin (a bioflavonoid) in five patients with familial adenomatous polyposis (FAP), an autosomal dominant disorder notable for the development of hundreds of polyps and the greatly increased risk of developing colon cancer. After 6 months of treatment with curcumin 480 mg plus 20 mg of quercetin three times daily, all five patients had a decrease in both number (mean reduction 60.4%) and size of polyps (mean reduction 50.9%), and both findings were statistically significant (Cruz-Correa et al., 2006). It appears from the phase I studies that oral doses between 3.6 to 8 g daily are well tolerated and demonstrate serum bioavailability when accessed within 30 minutes after administration. Future investigation may benefit from using this dosage range, particularly for sites outside the gastrointestinal system. With a wealth of experimental, safety, and bioavailability data behind it, curcumin is clearly ready for clinical trials in a multitude of cancer types, and these investigations are beginning to get underway. Researchers at the University of Pennsylvania are currently conducting a Phase II study to evaluate the effects of curcumin on cellular proliferation, apoptosis, and COX-2 expression in patients with previously resected adenomatous polyps. The National Cancer Institute sponsored a Phase IIa trial evaluating the effects of curcumin on aberrant crypt foci in current smokers. It was found that 4g of oral curcumin per day, taken for 30 days showed a 40% decrease in the number of aberrant crypt foci, whereas no significant reduction was found in the 2g/ day group (Carroll et al., 2011). Investigators at MD Anderson Cancer Center conducted a Phase II trial evaluating the effects of curcumin on response rates and survival of patients with adenocarcinomas of the pancreas and a Phase I trial assessing safety and tolerability of curcumin in patients with multiple myeloma. Twenty-five patients with advanced pancreatic cancer received 8,000 mg of curcumin (Sabinsa Corp, Piscataway, NJ) by mouth daily for 2 months. Two patients had stable disease for over 6 months (8 and 10+ months) and one patient had a brief partial remission (73% reduction in tumor size) that lasted for 1 month. No toxicities were observed. At completion, tests showed a down-regulation of transcription factors (including NF-κB) as well as other growth-regulatory molecules including STAT3, COX-2, and growth factor receptors (Dhillon, 2006). There are several forms of curcumin available as dietary supplements that have demonstrated superior absorption and bioavailability compared to curcumin extract. Three forms with clinical evidence of superior absorption are Meriva®, a phospholipid-curcumin complex, BCM-95®, a sesquiterpene and curcuminoid complex and Theracurmin®, a small particle size of curcumin suspended in gum ghatti. These forms of curcumin have demonstrated clinical effects with smaller doses.

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Curcumin Summary Curcumin is emerging as a promising anticancer agent and may prove to be a powerful intervention in the chemoprevention and treatment of a wide variety of cancer types. The experimental data suggest that curcumin acts through a diverse array of mechanisms. Safe and well tolerated at doses up to 8 g daily, curcumin is clinical-trial ready. Phase I/II and III studies are needed to further evaluate safety; impact on appropriate surrogate biomarkers; efficacy of curcumin as a chemopreventive agent in patients with precancerous lesions and other high-risk groups; and as a treatment for those with established cancers, either alone or in combination with conventional therapies. Because bioavailability of curcuminoids after oral intake is low, intravenous liposomal and nanoparticle preparations of curcumin are already in use by integrative oncologists.

CAMELLIA SINENSIS

Green tea has been consumed throughout Asia since at least 3000 BC to promote longevity, improve mental functions, and prevent disease. Camellia sinsensis, the common tea plant, remains the most widely consumed hot beverage on the planet. Camellia sinensis is cultivated in Indonesia and China, India, Japan, and Sri Lanka. The plant grows to 15 meters and bears oblong-ovate, dark green, shiny leaves. Research on Camellia sinsensis over the past several decades has marked this plant as one of the most indicated and potent botanical chemopreventive and antineoplastic agents. Several clinical trials have been conducted, with promising results in areas such as prostate cancer (McLarty et al., 2009) and colorectal cancer (Stingl et al., 2011). The young shoots are picked and to make green tea, the young leaves are allowed to wilt and then rolled. This rolling exudes some of the cell sap, and the leaf structure is partly broken down. To make black tea, the leaves are then fermented to convert the polyphenols to phlobaphenes and for aromatic substances to be formed. The fermentation occurs as a result of the leaf enzymes, particularly polyphenol oxidase, on tannins and catechins. To make green tea, fermentation is omitted and, instead, the leaves are steamed (“roasting” in the Chinese method and “sweating” in the Japanese method), which inactivates the enzymes and thus preserves the polyphenols. Red tea (oolong) and yellow tea are partially fermented tea. The leaves are then dried by hot air. Green tea contains several compounds including polyphenols— catechins (30%–42% of the extractable solids) and gallocatechins (including epigallocatechin gallate); flavonols 5%–10%; theogallin 2%–3%; quinic acids

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2%; methylxanthines—caffeine 3%–5%, theophylline 0.02% theobromine 0.1%; theanine 4%–6%; carotenoids; trigalloylglucose; minerals 6%–8%, depending on soil content of aluminum and manganese. Green tea interferes with the majority of the steps of carcinogenesis (Lin, Liang,  & Lin-Shiau, 1999)  and metastasis. The multiple points of interference lend broad applicability to green tea as an agent of chemoprevention. These actions are summarized in Figure 7.1. Tea extract inhibits mutagens and carcinogens extracellularly and intracellularly. Green tea catechins, namely, epicatechin (EC), epicatechin-3-gallate (ECG), epigallocatechin-3-gallate (EGCG), and gallocatechin (GC) inhibit cytochrome P450-dependent metabolic activation of promutagens and induce detoxification of mutagens via induction of glutathione and other phase II enzymes. Additionally, these same catechins scavenge free radicals, thereby inhibiting free radical–induced oncogene mutations, or tumor initiation. The catechins EGCG and ECG increase DNA repair and support DNA replication of healthy cells while inhibiting the replication of neoplastic cells. Green tea catechins have been found to inhibit colonic aberrant crypt formation in rats, evidencing their genomic reparative actions (Franke et  al., 2002). Epigallocatechin gallate and EGCG induce apoptosis in a variety of ways. Ironically enough, one major apoptogenic mechanism is the induction of reactive oxygen species with high electron-transfer properties. Green tea catechins exert significant interference with promotion. This effect is, in part, due to EGC, EGCG, and GC inhibition of tumor necrosis factor (TNF)-α release from neoplastic cells (Fujiki et al., 2000). TNFα is an endogenous tumor promoter and a central mediator of cancer development. The ability to inhibit TNF-α release is considered to be one of the most important mechanisms of the antipromotion activity of green tea (Fujiki, 1999). Furthermore, green tea catechins and EGCG inhibit matrix enzymes (urokinase), thus inhibiting tumor invasion and metastasis (Kuroda & Hara, 1999). In addition, research also suggests that green tea alters MT1-MMP-mediated intracellular signaling, which is involved in the vascularization of tumors (Zgheib et al., 2013). The apoptogenic effect of green tea extracts and EGCG in particular has been demonstrated in a variety of studies. EGCG and ECG induce apoptosis by inhibition of telomerase (Kuroda & Hara, 1999) and via downregulation of cyclin D1 and cyclin-dependent kinase (bladder tumor cells) (Chen, Ye, & Koo, 2004). In vitro and in vivo models have elucidated the molecular targets of green tea polyphenols in prostate carcinoma cells. The experimental administration of epigallocatechin gallate (EGCG) from green tea to androgen-dependent and androgen-independent human prostate cancer cells (LNCaP, DU145, and PC-3 cells) results in apoptosis. EGCG inhibits 5α-reductase, thus inhibiting the conversion of testosterone to its activated form, dihydrotestosterone,

Botanical and Mycological Medicine in Integrative Oncology  177 Tumor inhibition by green tea polyphenols

Mutagens and Procarcinogens

Inhibition of cP450 enzymes

Induction of phase II enzymes Induction of phase II conjugation: detoxification of carcinogen

Carcinogen

Reduction of hydroxyl radicals and modulation of DNA repair

Oncogene formation and tumor initiation Induces apoptosis of initiated cells

Tumor promotion

Inhibition of mitotic signals

Tumor progression Inhibition of matrix enzymes

Tumor invasion and metastasis

Figure 7.1.  Chemoprevention by Camellia sinensis.

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resulting in decreased hyperplasia (Adhami, Ahmad,  & Mukhtar, 2003). Green tea polyphenols suppress a host of tumor-related growth factors and prostate-specific antigen (PSA). In a study of 26 men with prostate cancer, an oral dose of 1.3g/day of green tea polyphenols resulted in decreased levels of six biomarkers including PSA, hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), and all patients showed a decrease in liver function tests, supporting green tea’s reputation as a nontoxic herbal therapy (McLarty et al., 2009). Green tea has also demonstrated antipromotional and antimetastatic activities (Annabi et  al., 2002). Additionally, EGCG inhibits proteasome, which results in tumor-growth arrest. Green tea extract and EGCG also suppress mRNA protein expression, resulting in a significant decrease in vascular endothelial growth factor (VEGF) and associated angiogenesis and tumor growth (Zhang, Andreotti, et al., 2006). De Amicis and colleagues found that EGCG had an inhibitory effect on growth and motility in human thyroid cancer cell lines, as evinced by inhibition of numerous oncogenic proteins and transcription factors such as N-cadherin and α5-integrin, and promotion of certain antitumor factors. More broadly, the researchers noted EGCG’s effect on tumor cell adhesion and reorganization of the actin cytoskeleton, as well as a reduction in epithelial-to-mesenchymal transition of the cells. Several animal studies have confirmed the in vitro anticarcinogenic actions of green tea. The chemopreventative effects of green tea have been demonstrated in a rat model of bladder cancer. The growth of N-butyl-N(4-hydroxybutyl)-nitrosamine–induced bladder cancers was prevented in rats that were prefed with green tea leaves (Sato & Matsushima, 2003). The antitumorigenic effects of tea extracts have been demonstrated for prostate cancer in several animal models. One such study implanted athymic nude mice with androgen-sensitive human prostate carcinoma cells (CWR22Rnul) and then gave the mice water extracts of green tea polyphenols, black tea, EGCG, and theaflavins. All tea extracts, given at humanly achievable concentrations, caused significant inhibition of tumor growth, reduction in PSA, induction of apoptosis, and decreases in VEGF (Siddiqui et al., 2006). Inhibition of lung carcinoma has been shown in mice with experimentally induced lung tumors. Out of several concentrations of oral green tea solution, the highest concentration, 0.6%, significantly reduced the number of lung tumors, inhibited angiogenesis, and resulted in a higher apoptotic index (Liao et al., 2004). This concentration corresponds to approximately five cups of green tea for humans. The cancer chemopreventive actions of green tea have been demonstrated in epidemiological studies. A  1988 review of the epidemiological studies (Bushman, 1998) concluded that, in the majority of studies, green tea

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consumption was inversely correlated with pancreatic cancer, colorectal cancer, gastric cancer, and urinary bladder cancer. In these studies, consumption of at least 5 cups of green tea daily was required for a preventive effect to be noted. Epidemiological studies also suggest a chemopreventive effect of tea against prostate cancer in humans (Jain, Hislop, Howe, Burch, & Ghadirian, 1998). Other epidemiological studies clarify the chemopreventive potential of green tea and elucidate the importance of dosing. One such prospective study (Nagano, Kono, Preston, & Mabuchi, 2001) followed 58,540 people for 15 years. A self-administered questionnaire ascertained the consumption of green tea (never, once daily, 2–4 times daily, and 5 or more times daily). The incidence of solid cancers, hematopoietic cancers and cancers of all sites combined were noted. The study concluded that green tea consumption was unrelated to incidence of cancers under study. However, the authors of this study note that this study may not have evaluated a minimum effective dose. The maximum studied dose in this study was 5 cups daily, a dose below the concentration of green tea extract used in the majority of in vivo studies that demonstrate benefit—an amount equivalent to 10 cups of green tea per day in humans. To this point, another large prospective cohort study (Imai, Suga,  & Nakachi, 1997) followed Japanese individuals living in Japan who consumed 10 cups of green tea daily for 10 years. This study did show a chemopreventive effect. The study included 8,552 male and female participants, all of whom were above the age of 40. During the study, 153 men and 109 women died of cancer. Male participants who consumed over 10 cups of green tea daily survived 3.6 years longer than did their male counterparts who drank less than 3 cups daily. Female participants who consumed over 10 cups of green tea daily lived 7.8 years longer than did their female counterparts who drank less than 3 cups daily. In addition, the age at onset of cancer was 3.0 years later in men and 8.7 years later among women who drank over 10 cups of green tea daily than in those drinking less than 3 cups of green tea daily. The difference between men and women was explained by the higher tobacco use by men. Finally, in an extension of the same study, the researchers determined that women who drank over 10 cups of green tea daily showed a lower relative risk of cancers of the lung, colon, and liver. Although this quantity of green tea may seem to be high, it should be noted that the “cups” referred to in these studies are Japanese tea cups, which hold approximately 6 oz. of tea. Additionally, this quantity of tea appears to be well tolerated. In contrast with the favorable data trends regarding the chemoprevention properties of green tea against the development of most solid tumors, there appears to be no chemoprevention of gastric cancer. In a population-based, prospective cohort study in Japan, 26,311 volunteers completed a self-administered questionnaire that included questions about the frequency of consumption of

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green tea. During 199,748 person-years of follow-up (over a period of 8 years), Cox regression was used to estimate the relative risk of gastric cancer according to consumption of green tea and no association was found. The study controlled for co-variables, but did not assess for the impact of dose on the chemopreventive effect (Tsubono et al., 2001). Another study in China, composed of 1,514 upper gastric cancer patients and 1,514 matched controls, evaluated the effects of jasmine green tea, and also found no significant protective effect (Gao et al., 2009). Green tea has been studied for its secondary and tertiary chemoprevention effects in women with breast cancer. In a prospective cohort study (Nakachi et  al., 1998)  of 472 Japanese women with histologically confirmed invasive breast carcinomas (stage I, II and III), the subjects were assessed for axillary lymph node metastases and progesterone and estrogen receptor expression at the time of partial or total mastectomy. These women were then followed up for 7 years for recurrence in relation to green tea consumption. This study found that the premenopausal women who drank more than 5 cups of green tea daily had a lower mean number of metastasized lymph nodes. Subsequent to surgery, among the women with stage I and II breast cancer, green tea drinkers of greater than 5 cups daily experienced a 16.7% recurrence rate, whereas consumers of less than 4 cups per day experienced a 24.3% recurrence rate (P < 0.05). In addition, those who drank over 5 cups per day of green tea had a longer disease-free period by 3.6 years compared with those who drank fewer than 4 cups each day. Inoue et al. (2001) also looked at the impact of regular green tea consumption on the risk of breast cancer recurrence. This study was conducted over a 9-year period from 1990 to 1999. In 1990, 1160 new surgical cases of invasive breast cancer in female patients at a Japanese cancer center were enrolled in the study. These women were monitored for recurrence and daily green tea consumption over a 9-year period. The average age was 51.5 years. During 5,264 person-years of follow-up (average 4.5  years per subject), 133 subjects (12%) experienced recurrence. A 31% decrease in risk of recurrence, as measured by hazard ratio, adjusted for stage, was observed with consumption of three or more daily cups of green tea (HR = 0.69). This risk reduction was particularly statistically significant in stage I patients with an observed risk reduction of 57%. The risk reduction was present, but was less significant, in stage II and not present among patients with more advanced stages. Additional epidemiologic evidence is available to support the benefits of green tea as a chemopreventative agent in ovarian, oropharyngeal, colon, lung, prostate, and cancers of the hepatobiliary tree. No apparent chemoprotective effect, however, has been seen in gastric cancer.

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EGCG

↑ Apoptosis and cell cycle arrest ↓ Cancer cell proliferation ↓ Angiogenesis Antioxidant/pro-oxidant activities

↑ Chemo/radiotherapy anti-cancer effects ↑ Plasma and intracellular drug concentration ↑↓ Hormone receptor-related signaling pathways ↑↓ Chemo/radioresistance-related molecular pathways

Cancer prevention

↓ Inflammation

↑↓ Redox-regulated processes

Chemo/radiosensitization

Initiation, progression, metastasis

↓ Oxidative damage

↓ Cancer therapy side effects

Cancer therapy

Figure 7.2.  Role of EGCG in risk reduction and treatment. ↑, Increase; ↓, decrease; ↑↓, modulation. Lecumberri, E. et al. “Green tea polyphenol epigallocatechin-3-gallate (EGCG) as adjuvant in cancer therapy.” Clinical Nutrition. (2013) 32(6):894-903. Reprinted with permission from Elsevier.

Green tea may have synergistic actions with chemotherapeutic antineoplastic agents. Green tea extracts have been studied with doxorubicin (Adriamycin). Although there are no human trials, the preliminary in vitro and animal data are consistent with a beneficial relationship between these two agents. When doxorubicin was administered intraperitoneally to mice with implanted Ehrlich ascites carcinoma, a 25% reduction in tumor weight was observed. When mice ingested green tea during the time of doxorubicin administration, a decrease of 37% in tumor weight was observed. The ingestion of green tea enhanced the doxorubicin tumor inhibition by 2.5-fold. The tumors of the green tea-fed mice demonstrated an increase in doxorubicin concentration by 1.7-fold compared to the doxorubicin-alone group. Additionally, the doxorubicin concentrations in the heart and liver did not increase with ingestion of green tea; in fact the doxorubicin concentration in the heart was less than the doxorubicin-alone group (Sadzuka, Sugiyama, & Hirota, 1998). These results suggest that the addition of green tea to doxorubicin may intensify the antitumor action of doxorubicin while protecting healthy tissue against doxorubicin-induced toxicity.

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Concurrent green tea administration with cisplatin has also been shown to reduce nephrotoxicity biomarkers in rats (Sahin et al., 2010), whereas another study showed that EGCG helps maintain glomerular filtration rates in rats treated with cisplatin.

State of the Evidence: Green Tea The body of evidence clearly supports a role for green tea and its catechins in a risk reduction and treatment program. Green tea appears to be most effective in preventing cancer and has promise as a treatment in early stage cancers. The selectivity of the antineoplastic effect of green tea on malignant tissue combined with the protective and reparative effect on cardiac, renal, and myeloplastic cells is a powerful combination. The question that remains unanswered is optimal concentration and length of administration of green tea extracts in people with active malignancies.

Flavonoid Plant Compounds Flavonoid compounds are ubiquitous in the plant kingdom. Plants rely on flavonoids to survive the ultraviolet energy of the sun. Flavonoids protect plants by absorbing reactive oxygen species generated in the course of photosynthesis. Flavonoids are responsible for the colors of flowers and fruits and darker colored fruit skins and flower petals represent a high density of flavonoids. There are many types of flavonoids such as quercetin, hesperidin, and anthocyanidins (cyanidin, delphinidin, malvidin, pelargonidin, peonidin, and petunidin). Although not all flavonoids have been studied for their cancer chemoprevention or antineoplastic activities, there are a few flavonoids that are emerging as promising agents in this regard. Flavonoids, as a group of compounds interfere with inflammation and carcinogenesis in a variety of ways. Several flavonoids quench reactive oxygen species (Huang, Wu, & Yen, 2006). Ingested fruit juices concentrated in anthocyanin/polyphenol flavonoids exert significant anti-oxidative actions. An intervention study compared a red mixed-berry juice to a polyphenol-depleted juice (Weisel et al., 2006). After a 3-week run-in period, 18 male subjects consumed 700 mL juice, and 9 consumed control juice for 4 weeks, followed by a 3-week wash-out. During the intervention with polyphenol-rich juice, biomarkers of DNA oxidative damage decreased and reduced glutathione and glutathione status increased. These values returned to run-in levels in the subsequent wash-out phase. In addition to the reduction of oxidative damage, flavonoids enhance

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cellular detoxification and antioxidation enzymes via activation of Nrf-2. Other flavonoids suppress the pro-inflammatory and growth promoting gene expression mediated by NF-κB (Surh, Kundu, Na, & Lee, 2005). Flavonoids also interfere with signal transduction pathways, thereby reducing tumor initiation and promotion. Tyrosine kinases are key regulators of intracellular signaling and, when overexpressed or mutated, contribute to the development and progression of tumors. This makes the tyrosine kinase pathway and, in particular, its receptors, such as epidermal growth factor receptor (EGFR), excellent targets for antineoplastic effects. An example of this inhibition is ellagic acid, a polyphenol present in fruits and nuts. Ellagic acid inhibits VEGF receptors (Labrecque et al., 2005). Delphinidin, an anthocyandin flavonoid found in berries, red grapes, purple sweet potatoes, red cabbages, and other pigmented fruits and vegetables, interferes with signal transduction pathways. In vitro, low concentrations of delphinidin inhibit VEGF-induced tyrosine phosphorylation of VEGFR-2, leading to the inhibition of downstream signaling and VEGF-induced activation of ERK-1/2 signaling. In vivo, delphinidin is able to suppress basic FGF-induced vessel formation in the mouse Matrigel plug assay. This VEGF inhibition by delphinidin holds promise as a naturally occurring antiangiogenesis agent (Lamy et al., 2006). Another study (Wang et al., 2012) investigated the potential mechanisms of ellagic acid and its effect in the VEGFR-2 signaling pathway in breast cancer (both in vitro and in vivo), and proposed that ellagic acid may work by disabling the ATP-binding region of the VEGFR-2 kinase unit, crippling a complex chain of oncogenic reactions leading to breast cancer. The polyphenol bioflavonoids derived from pomegranates (Punica granatum) possess anticarcinogenic actions, albeit derived from a different mechanism. Pomegranate polyphenols interfere with estrogen biosynthesis from androstenedione and testosterone by inhibiting aromatase enzyme. Additionally, fermented pomegranate juice polyphenols exert significant inhibitory effects on 17-β-estradiol resulting in reduced proliferation especially of estrogen- dependent MCF-7 breast cancer cells (Kim et  al., 2002). Pomegranate polyphenols also suppress human prostate cancer cell growth (Albrecht et al., 2004).

Quercetin Is the Best-Studied Anticancer Polyphenol Quercetin, a bioflavonoid found in high concentrations in onions, has been demonstrated to interfere with signal transduction pathways in ovarian epithelial cancer cells in vitro (Nicosia, Bai, Cheng, Coppola,  & Kruk, 2003).

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Quercetin inhibits protein kinase and thus may reduce ovarian tumor cell growth, survival, and progression. Quercetin has also been shown to block EGFR-signaling pathway in MiaPaCa-2 human pancreatic cells (Lee et  al., 2002). This disruption results in significant growth inhibition of these cells and the induction of apoptosis. Quercetin has been evaluated in several clinical trials in humans for several conditions including cancer. Quercetin is a histone deacetylase inhibitor with chemotherapy sensitizing effects and estrogen receptor modulation in hormonal dependent tumors. Histone deacetylase inhibitors have been extensively studied in cancer (Bangert et al., 2012; Srivastava, Tang, Zhu, Meeker, & Shankar, 2011), including their effect on glycolysis (Wardell et  al., 2009). Quercetin shows promise as a treatment for diverse cancer types due to its genetic regulatory (lowering RAS and bcl-2) and epigenetic effects. It is also suggested that quercetin may reduce the risk of cancer. Quercetin interacts with a variety of cellular receptors. Mechanisms of anticancer activity suggested by Lamson & Brignall (2000a, b) include inhibition of cellular growth phase at G1 and G2 phases of the cell cycle, inhibition of tyrosine kinases to prevent uncontrolled proliferation, influencing estrogen receptors, and interacting with heat shock proteins to prevent proliferation. Relevant to both risk reduction and treatment, Li et  al. have shown that quercetin may interact with receptors like Raf and MEK that are involved in tumor proliferation. Interactions with other receptors are also suspected, mainly affecting expression of surface receptors and growth of cancerous cells. A second theoretical mechanism of cancer risk reduction is modification of signal transduction. Quercetin is reported to affect cell cycle regulation, cell death, inflammatory reactions and derivation of new blood supply. The anticancer activity of quercetin has been demonstrated in a variety of cell lines (Ruiz, Braune, Hölzlwimmer, Quintanilla-Fend, & Haller, 2007; Wachter et al., 2012; Yuan, Koh, Sun,  Lee,  & Yu, 2005). Quercetin has also been shown to lower the toxicity of chemotherapy drugs and increase their potential effect by lowering the tumor resistance (Kawahara et  al., 2009; Staedler, Idrizi, Kenzaoui, & Juillerat-Jeanneret, 2011). This also is a focus of interest in carcinogenesis as quercetin can affect the heat shock protein 27 involved in cancer stem cell growth (Hsu et al., 2011). Two animal studies have been conducted to assess quercetin’s ability to treat cancer. One study reported a 20% increase in lifespan after quercetin was injected peritoneally in mice inoculated with ascites tumor cells (Molnar et al., 1981). Another study inoculated mice with a human squamous cell carcinoma line showed selective inhibition of cancer growth when quercetin was injected

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intraperitoneally, with minimal effects on surrounding normal cells (Castillo et al., 1989). One epidemiological study by Nothlings et al. (2007) reported a total of 529 cases of exocrine pancreatic cancer that arose during an 8-year period, tracked through state cancer registries. Dietary quercetin intake was negatively correlated with pancreatic cancer among current smokers, showing a significantly decreased (0.55) relative risk between the highest and lowest quintiles of intake. In other studies oral quercetin has shown inferior effectiveness due to poor absorption (Gugler, Leschik, & Dengler, 1975). There is some human clinical research demonstrating quercetin’s ability to treat cancer. Ferry et al. conducted an open label, uncontrolled dose-finding clinical trial of quercetin as a cancer treatment in 1996. This phase I trial established a safe dosage for further studies. In this trial, increasing doses of up to 1,700 mg/m2 intravenous quercetin were administered weekly for 3 weeks to 50 patients who had cancer that was deemed no longer treatable by conventional methods (Ferry et  al., 1996). Patients with a variety of cancers were treated including large bowel, stomach, pancreas, ovarian, and melanoma. None of the patients achieved tumor suppression as defined by the radiological criteria of WHO, but two showed sustained decreases in serum tumor markers following quercetin therapy. In addition, tyrosine kinase levels were measured in 11 subjects, and a decrease in 9 was reported. The authors concluded that this study provides preliminary evidence suggesting quercetin’s ability to inhibit tyrosine kinase, and phase 2 studies should be undertaken (Ferry et al., 1996). The results of this study have been supported by several in vitro trials, in which quercetin caused suppression of tyrosine kinase expression in malignant and nonmalignant cells (Bernaudin et  al., 2002; Levy, Teuerstein, Marbach, Radian,  & Sharoni, 1984). Some integrative oncology centers are administering quercetin intravenously in stage IV cancer patients.

State of the Evidence: Flavonoids Data regarding the anticancer potential of flavonoids is encouraging. Flavonoids are potent antioxidants, appear to stimulate apoptosis, exert antiangiogenesis actions, and inhibit metastasis. These effects have been aptly demonstrated in vitro, especially in large epidemiological meta-analyses (Romagnolo & Selmin, 2012). Several critical questions remain unanswered, the most critical of which is to determine how much of the preclinical data translates into clinical effects.

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State of the Evidence: Quercetin Quercetin polyphenols have anticancer activity via multiple pathways including tyrosine kinase inhibition, histone deacetylase inhibitor inhibition with chemo sensitizing effects, and estrogen receptor modulation in hormonal-dependent tumors. Dietary use of quercetin is associated with reduced incidence of and death from several cancers. Some integrative oncology centers are administering quercetin intravenously in stage IV cancer patients.

Plant Enzyme Therapies Enzymes from plant sources have long played a role in traditional and complementary cancer therapy. Enzymes are believed to be both anti-inflammatory and catalytic to tumors. Bromelain is the most commonly used plant enzyme in cancer therapy. Bromelain is a water extract from pineapple stem that contains cysteine proteinases that have several purported therapeutic effects, including antimetastatic, antithrombotic (Eckert et al., 1999; Glaser & Hilberg, 2006), antiedematous, fibrolytic, and immunomodulatory actions. In vitro studies have shown that bromelain inhibits the metastatic invasion of glioma cells (Tysnes et  al., 2001), and alters cell adhesion cell surface molecules in leukocytes (Hale, Greer,  & Sempowski, 2002). Bromelain has been shown to stimulate both innate and adaptive aspects of immune function both in vitro to activate murine macrophages and NK cells (Engwerda, Andrew, Murphy, & Mynott, 2001)  and in murine in vivo experiments (Engwerda, Andrew, Ladhams,  & Mynott, 2001). Oral doses of bromelain reduced inflammatory cytokine release in rats injected intraperitoneally with lipopolysaccharide (Hou, Chen, Huang,  & Jeng, 2006). Bromelain inhibited growth of lung tumors in mice inoculated with tumor cells (Beuth  & Braun, 2005). Amini and colleagues (2013) tested bromelain in several human gastric cancer cell lines, and found that bromelain promoted cancer-cell apoptosis via the caspase system as well as extranuclear p53, and decreased cancer cell survival by inhibiting the Akt pathway and modulating various oncoproteins. Bromelain is routinely used in naturopathic oncology to prevent postradiation fibrosis and to reduce the risk of lymphedema. This practice is based on a small number of clinical studies in post-traumatic and postsurgical edema using Phlogenzym, a mucos proteolytic combination enzyme formula containing bromelain from a German pharmaceutical company (Kamenicek, Holan, & Franĕk, 2001). It is also used for prevention and treatment of post-operative

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ileus although this has only been demonstrated thus far in a rodent study (Wen et al., 2006). The use of bromelain in prevention of post-radiotherapy fibrosis is supported by a Ukranian paper (Hubarieva et al., 2000) reporting on the use of bromelain in preventing lymphogranulomatosis in cancer patients receiving radiation therapy. Doses are often expressed in terms of milk clotting units (MCU) or sometimes in simple milligram weights. Adult oral doses range from 400 to 4000 mg/day.

State of the Evidence: Bromelain Because bromelain has been shown to be generally safe in oral doses, integrative oncologists should feel comfortable prescribing it to cancer patients for short-term therapeutic trials for a variety of cancer-related conditions including postradiotherapy fibrosis, postsurgical edema, ileus, lymphedema, immunomodulation, and inflammatory bowel disorders.

SILYMARIN OFFICINALIS

Silymarin officinalis or milk thistle is an herb with significant experimental evidence as a general chemopreventive agent. European herbalists have used milk thistle for hundreds of years for the treatment of liver diseases, specifically alcoholic liver disease. Milk thistle contains a polyphenoloic flavonoid antioxidant, silymarin. Silymarin is composed of silybin, dehydrosilybin, silydianin, and silycristin. Of these, silybin has been most well studied. Silybinin inhibits the conversion of initiated cells to dormant tumor cells. This growth inhibition has been noted in human prostate, breast, and cervical carcinoma cells (Bhatia, Zhao, Wolf, & Agarwal, 1999). This effect is mediated via impairment of receptor and nonreceptor tyrosine kinase signaling pathways (Ahmad, Gali, Javed, & Agarwal, 1998) along with inhibition of TNF-α release and associated changes in cell cycle progression (Zi, Mukhtar, & Agarwal, 1997). This effect has been confirmed in vivo. In vitro and animal studies suggest that silymarin may exert significant chemopreventive effects against prostate, breast, oral, and hepatocellular cancers. Of concern, however, was the finding that in cell culture, treatment of human MCF-7 breast cancer cells with serum-achievable concentrations of silymarin in the rodent models stimulated their growth, in part through an estrogen-like activity. It would appear that the estrogenic activity of silibinin outweighs the antiproliferative actions in estrogen-dependent cancers. Using lung cancer as a model, several studies mentioned in Mateen, Raina, and Agarwal (2013) found that silibinin inhibits proliferation, angiogenesis

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and epigenetic-related events through a variety of mechanisms. Raina and colleagues (2013) found that silibinin induced oxidative stress in colorectal cancer cells while simultaneously dissipating mitochondrial potential and cytochrome c release, resulting in apoptosis. Furthermore, the researchers found that silibinin seemed to inhibit glucose uptake by the malignant cells, in effect starving them, as well as interfering with protein and phospholipid synthesis. Silybin, a constituent of Silybum marianum (milk thistle), has also been studied for its protective activity against cisplatin toxicity in an animal model of testicular cancer. In an in vitro study, silybin exerted a dose-dependent growth inhibitory effect on drug-resistant ovarian cancer cells. Additionally, silybin potentiated the cytotoxic effect of cisplatin on these cells (Scambia et al., 1996). Orally delivered silibinin suppresses human non–small-cell lung carcinoma A549 xenograft growth and enhances the therapeutic response of doxorubicin in athymic BALB/c nu/nu mice, while preventing doxorubicin-caused adverse health effects (Singh et al., 2004). Some integrative oncology centers are using silibinin intravenously in advanced cancer patients.

State of the Evidence: Milk Thistle The data on milk thistle as a chemopreventative agent is almost entirely preclinical. The preclinical data paints a convincing case for the apoptogenic, antiproliferative, and antiangiogenic actions of milk thistle extracts in a variety of cancers. Although the estrogenic characteristics of milk thistle flavonoids may preclude its use in breast carcinomas, there is great potential for milk thistle in other cancers. Of particular value is the indication of a synergistic effect of milk thistle extracts with various chemotherapy agents.

ASTRAGALUS MEMBRANACEUS

Astragalus membranaceus (astragalus) has been used in Chinese herbal medicine as a Qi tonic. In Chinese herbal medicine, Qi tonics are used to strengthen parenchymal tissue and bodily processes that are weak to help build defenses against disease. Tonic herbs tend to strengthen and penetrate deep into the body tissue and structures. Astragalus has been used in Chinese herbal medicine for wasting/thirsting syndrome, to stabilize the exterior to stop sweating, to promote urination and reduce edema, to promote healing, particularly in diabetic ulcerations, and to help rebuild Qi and blood postpartum, or after significant loss of blood.

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Astragalus has been widely studied for its immune-potentiating activity in the context of malignancy. One study looked at the effects of various fractions of astragalus on mononuclear cells derived from healthy normal donors and from colon-cancer patients using the local xenogeneic graft-versus-host reaction. The astragalus extracts exhibited remarkable immunopotentiating activity and one fraction was capable of fully correcting in vitro T-cell function deficiency (Chu, Wong, & Mavligit, 1988). In a randomized, phase II, double-blind clinical trial, 58 cancer patients with significant fatigue completed treatment with either intravenous placebo or astragalus extract PG2 (PhytoHealth Corp., Taiwan). The astragalus group received 500 mg of PG2 intravenously, three times weekly. At the end of the trial (split into two cycles: placebo or PG2 followed by PG2 for all patients), a significant response of at least 10% improvement in fatigue scores, with a majority of the PG2 group reporting >20% improvement, was found. Furthermore, a significant percentage of the placebo group who were nonresponders in the first cycle reported a significant reduction in fatigue during the second PG2 cycle. Of the different types of cancer, breast cancer patients were the most responsive to the treatment. Of the 10 patients treated with PG2 the first cycle, 7 noted significant improvement in fatigue symptoms, whereas the second-highest responders were head-and-neck-cancer patients (Chen et al., 2012). Another placebo-controlled study found a reduction in side effects of radiation (including CD8 and CD4/CD8 count increase) and improvement in subjective quality of life in 40 elderly patients with non-small cell lung cancer (Qin et al., 2009). Tolerance to cyclophosphamide can be limited by the immunosuppression that this drug may cause. Cyclophosphamide reduces leukocyte counts and suppresses both humoral and cellular immune responses. An aqueous extract of an isolated fraction from Astragalus membranaceus was given intravenously to rats for 8  days. The study rats that received astragalus in addition to the immunosuppressive cyclophosphamide experienced almost complete restoration of immune function as evidenced by their increasing ability to reject grafted human tissue (Chu, Lepo-Zuniga, Wong, LaPushin, & Mavligit, 1988). A meta-analysis of astragalus-based Chinese herbs and platinum-based chemotherapy for advanced non–small-cell lung cancer concluded that astragalus may increase the effectiveness of platinum-based chemotherapy (McCulloch et al., 2006). Thirty-four randomized studies representing 2,815 patients met the inclusion criteria of the study. Combined results from the meta-analysis demonstrate overall benefit. Twelve studies reported reduced risk of death at 12 months. Thirty studies reported improved tumor response. Performance status in most studies was stable or improved. Among the studies reporting median survival, none included confidence intervals or P values of variance. Therefore, a meta-analysis of median survival could not be done.

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Despite this, the authors of the analysis conclude that combining astragalus with platinum-based chemotherapy in the treatment of non–small-cell lung cancer may increase survival, tumor response, performance status, and reduce chemotherapy toxicity when compared to platinum-based chemotherapy alone.

State of the Evidence: Astragalus Astragalus has been used for immune stimulation for centuries and modern research is uncovering the nature of these effects. The strongest indication for astragalus in the context of oncology care is to help prevent the immunosuppression caused by chemotherapy agents. Additionally, there is some indication that astragalus may also potentiate the cytotoxic effects of certain chemotherapy agents and improve cancer-related fatigue.

WITHANIA SOMNIFERA (ASHWAGANDHA)

Withania somnifera (Ashwagandha) has historically been used as a strengthening or “tonifying” herb. One of the common names for W. somnifera is Indian ginseng. This name hints at its restorative properties. In fact, ashwagandha has historically been used in individuals who are debilitated and who suffer from nervous exhaustion, emaciation, and anemia. In these individuals, ashwagandha is helpful in convalescence after acute illness or stress, impotence, chronic disease with inflammation and bony degeneration, and as a general tonic, for hypertension and high cholesterol. One important characteristic of ashwagandha is that it exerts a sedative effect and thereby rests and restores the health of the nervous system and overall person. Ashwagandha has demonstrated immunostimulatory effects in chemotherapy-induced immunosuppression. Ashwagandha was fed to mice at a dose that corresponds to 4 to 6 g per day in humans. When ashwagandha was combined with cyclophosphamide, it prevented myelosuppression, resulted in a significant increase in hemoglobin concentration, red blood cell count, white blood cell count, platelet count, and body weight as compared with mice treated with cyclophosphamide only (Ziauddin, Phansalkar, Patki, Diwanay, & Patwardhan, 1996). Although this study does not rule out the possibility that ashwagandha could interfere with the activity of cyclophosphamide, the cytotoxic effects of cyclophosphamide on target tissues remained intact in the ashwagandha-treated mice. This suggests that the immunostimulatory actions of ashwagandha are the result of direct effects on the immune system.

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Withaferin A, a steroidal lactone found in ashwagandha, appears to have antineoplastic actions. An extract concentrated with withaferin A  had a growth inhibitory effect on Chinese hamster V79 cancer cells. The withaferin A induced a G2/M block in vitro at higher doses (Devi, Akagi, Ostapenko, Tanaka,  & Sugahara, 1996). The antitumor effect of Withania somnifera (ashwagandha) was also demonstrated against the mouse tumor Sarcoma 180 (Devi, Sharada, Solomon, & Kamath, 1992). Another study assessed the antiproliferative effects of ashwagandha on laryngeal carcinoma (Mathur et  al., 2006). These findings suggest that the withanolides in the roots of Withania somnifera possess cell cycle disruption by blocking the cell cycle in G1 phase of cell division and antiangiogenic activity by inhibiting VEGF, which may be a critical mediator for its anticancer action. Research indicates that withaferin A has the ability to induce apoptosis in cancer cells through a complex effect on tumor cells’ apoptosis suppression pathways (Hahm & Singh, 2012)  in normal and breast cancers. In addition, withaferin A  was found to restore the p53 tumor suppression pathway and down-regulate HPV oncogenes. For a detailed account of observed mechanisms of action see Munagala et al. (2011). Perhaps the most interesting indication for ashwagandha is to promote the tumor-kill effects of radiation therapy. Withania somnifera has been studied for its radiosensitizing properties. At least five studies in animals have confirmed a radiosensitizing effect of ashwagandha. Withaferin A  appeared to inhibit repair of radiation damage in tumor cells in a mouse model. Although this in vivo data is compelling, the applicability to human patients remains unstudied and not definitively known. One issue that makes the translation from the preclinical to clinical scenario difficult is that the ashwagandha extracts used in many of the in vivo studies were intraperitoneal injections. It is unknown how oral dosing of ashwagandha in humans compares to intraperitoneal administration in rodents. In addition, it is unclear whether the radiosensitizing effect is localized to tumor cells only, or whether normal cells in the radiation field would also experience increased radiation effects. Emerging clinical trials have shed some light on ashwaghanda treatment in human cancer patients. Biswal, Sulaiman, Ismail, Zakaria, & Musa (2012) found that in two groups of breast cancer patients (50 total), those receiving chemothereapy plus two grams of Withania somnifera extract orally per day had significantly less fatigue and higher quality of life according to standardized questionnaires, although no significant difference in 24-month survival was found (study 74% versus control 56% (p = 0.174), possibly due to small n and inclusion of late-stage breast cancer patients.

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State of the Evidence: Ashwagandha Ashwagandha has potential as a multipronged antineoplastic agent. The immunostimulatory, anticarcinogenic, and radiosensitizing actions of this plant give it a unique place in the herbal armamentarium against cancer. Although only limited human data exist, the evidence is encouraging.

Mycomedicinal Therapy in Oncology Although in a kingdom of their own and not strictly encompassed by “botanical medicine,” several species of higher fungi have been used traditionally as well as in modern times in the treatment of cancer. The most commonly used medicinal mushrooms are Trametes versicolor (Turkey Tail, formerly Coriolus or Polysporus versicolor), Ganoderma lucidum (Reishi), Lentinus edodes (Shiitake), Grifola frondosa (Maitake), and Schizophyllum commune. Mushrooms typically have not shown strong direct cytotoxic activity against tumor cells, but are rather used as immunomodulators. On the basis of what is known about the immunology of cancer, an effective immunomodulatory therapy could enhance innate immunity and tumor-specific adaptive immunity. Both of these immune response pathways are typically weakened due to tumor-induced immune suppression. Innate immune reactions that are typically suppressed in cancer states include NK cell tumoricidal activity, as well as maturation, recruitment, and activation of antigen-presenting cells (APCs), such as macrophages and dendritic cells. Tumor-induced immune suppression appears to often also lead to down-regulation of type I  inflammatory responses in APCs, which, on encounter with tumor antigens, activate T cells that are needed for effective antitumor responses (Chung, Chen, Chan, Tam, & Lin, 2004). Dendritic cell dysfunction has been shown to lead to immunosuppression in cancer states (Pinzon-Charry, Maxwell, & López, 2005), with a shift away from type I dendritic cell (DC1) and toward DC2 development (Rissoan et al., 1999). This shift is hypothesized to promote regulatory T cell activation (Treg) and recruitment into tumor sites, and suppress T helper 1 (TH1)-dependent, cytotoxic T lymphocyte (CTL) responses. Thus, agents that could correct these immune imbalances and restore lymphocyte homeostasis, enhance APC-mediated delivery of adequate stimulation of antitumor effector cells, and inhibit Treg activity either systemically or locally would serve as excellent candidates in immune-based cancer therapy (Whiteside, 2006; Yamaguchi  & Sakaguchi, 2006).

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Because of their broad immune activity, medicinal mushrooms are a rich potential source of immunoceuticals. Although other natural products from other plant species have known immunomodulatory activities (plant sterols, plant COX-2 inhibitors, thiol-containing allium vegetables), polysaccharides extracted from certain mushroom species have been the most thoroughly studied in preclinical and clinical studies. TRAMETES VERSICOLOR (YUN ZHI, TURKEY TAIL MUSHROOM)

More than 270 recognized species of mushrooms are known to have specific immunotherapeutic properties (Ooi & Liu, 2000). Of these, 50 nontoxic mushroom species have yielded potential immunoceuticals in animal models, and of these, six species have been studied in human cancers (Kidd, 2000). An extract from one of these medicinal mushroom species, Trametes versicolor, has been assessed in over 37 Phase I, II, and III randomized clinical trials in over 18,441 stomach, colorectal, esophageal, and breast cancer patients in Japan, Korea, and China. Trametes versicolor has a long history of medical use in Asia dating back hundreds of years in traditional Asian medicine. Trametes versicolor belongs to the more advanced Basidiomycetes class of fungi. It grows on tree trunks throughout the world in many diverse climates (Figure  7.3). In China it is called Yun Zhi or Cloud Fungus. According to Kidd (Kidd, 2000), the immunomodulatory activity of polysaccharide peptides in Trametes versicolor was discovered in 1965 in Japan by a chemical engineer who observed a case of cancer remission after ingesting Yun Zhi. Subsequent research revealed that there were two closely related proteoglycan constituents of Trametes versicolor with anticancer activity:  polysaccharide-krestin (PSK, or Krestin) and Polysaccharopeptide (PSP). PSK has been studied most extensively and is in wide clinical use as an adjunctive and adjuvant cancer therapy in Japan and China (Fisher & Yang, 2002; Kidd, 2000; Sun et al., 2012; Wasser, 2002). PSK was approved in 1977 as a cancer therapy by the Japanese National Health Registry and represents 25% of the total national costs of cancer care in Japan (Hobbs, 2004). The closely related PSP was first isolated in China in 1983. Adjunctive treatment with these Trametes versicolor polysaccharide-peptide fractions is a standard of oncologic care in mainstream modern Japanese and Chinese cancer management. However, although PSK and PSP have been extensively studied in Asia, there has only been one trial on the anticancer activity of the several distinct Trametes versicolor preparations now commercially available, despite their growing use in the United States. A phase I dose escalating trial

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Figure 7.3.  Trametes versicolor.

of Trametes versicolor freeze dried mycelium in women with breast cancer who had completed radiotherapy showed both safety up to 9 grams/day and immunological activity. Natural killer cell activity was dose-dependently enhanced in this small trial (Torkelson et al., 2012). Most of the clinical research has focused on the effects of the Trametes versicolor Japanese product PSK as adjuvant therapy on disease-free survival and overall survival rates. In a randomized study of 158 esophageal cancer patients, survival of the group receiving radiochemotherapy plus PSK (3,000 mg/day for 12 weeks) was significantly better than that of the group receiving radiochemotherapy alone (Ogoshi et al., 1995). Since 2005, the results of over a dozen PSK trials in colorectal cancer have been published (Ishibashi et  al., 2008; Kanazawa et al., 2005; Ohwada et al., 2006; Sadahiro et al., 2010; Shichinohe, 2011; Takahashi, Mai, & Nakazato, 2005; Torisu et al., 1990; Yoshino et al., 2005), including one meta-analysis in 1094 colorectal cancer patients (Sakamoto et al., 2006), all showing positive impact on clinical outcomes. Current investigations of the mechanisms of action of Trametes versicolor have led to the hypothesis that β-1,3-D-glucans are the main immunologically active constituents present in the polysaccharide-peptide fractions PSK and PSP. Previously published studies assessing the effects of PSK on cytokine responses after oral administration in vivo have shown that PSK can enhance TNF-α, IFN-γ, IL-2, IL-8 and IL-12 protein concentrations. Data from epidemiological studies of immune deficiency in African-American women diagnosed with breast cancer, immune studies of the effect of chemotherapy drugs and radiotherapy on immune status, and the Asian literature on the clinical benefit of polysaccharide immune therapy together suggest that immune function may play a key role in primary and secondary prevention of breast cancer.

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High-priority research areas for breast cancer immunotherapy include clinical trials of polysaccharide-peptide fractions (PSK and PSP) and Trametes versicolor biomass from which the polysaccharide fractions are extracted, in breast cancer patients. Two types of human trials are necessary to assess the potential for Trametes versicolor in integrative cancer therapy. Clinical trials are required to assess the safety and effectiveness of Trametes versicolor as a concurrent adjuvant therapy administered along with chemotherapy, radiotherapy, and Her2 neu monoclonal antibody therapy (Herceptin). In keeping with its potential role in secondary prevention as well as common use of Trametes versicolor in Asian oncology, clinical trials of Trametes versicolor immunotherapy after completion of standard cancer treatment are also needed. Breast cancer clinical trials currently rely on short-term surrogate markers of immune status such as natural killer cell activity toward the ultimate goal of improving breast cancer cure rates. Two PSK cancer trials in stage IV breast and prostate opened in the U.S.  funded by NIH-NCCAM funded Bastyr/University of Washington Oncomycology Research Center (Clinicaltrials.gov identifiers NCT00680667 and NCT01685489, respectively). GANODERMA LUCIDUM (REISHI)

Ganoderma lucidum is another polysaccharide-containing immunomodulatory polypore fungus. It has a long history of use in traditional Asian medicines. It is called Lingzhi in China and Reishi in Japan. Preclinical studies have established that the polysaccharide fractions of Ganoderma lucidum have diverse and potent immunomodulatory effects in vitro and in animal studies (Figure. 7.4). Ganoderma is purported to have activity in breast and prostate cancer and has been shown to inhibit prostate and breast cancer-cell migration. Sliva (2003) compared commercially available Ganoderma lucidum spore and mycelial powder products and compared their ability to inhibit cancer cell migration and effect on NF-κB in vitro. Some products had strong activity against breast and prostate cancer-cell lines and inhibited NF-κB, whereas others did not. Clinical evidence has been sparse until recently. Several clinical studies, mostly by research oncology groups in Asia and New Zealand, have been conducted on the effects of oral Ganoderma lucidum intake on immune parameters in advanced cancer patients. The studies have had mixed results that are difficult to interpret. Such inconsistencies may be due to the fact that the mycelia, fruiting body, and spores of the fungus may all have different

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Figure 7.4.  Ganoderma log.

biological properties; hence it is critical to know what part of the Ganoderma is being utilized. Hot water extraction is believed by most traditional practitioners to yield the immunomodulatory polysaccharides from within medicinal mushrooms such as Ganoderma lucidum and Tramets versicolor. Doses of Ganoderma lucidum used in clinical trials typically range from 1,500 mg/day to 5,600 mg/ day (1,800 mg three times/day) (Tang et al., 2005). Shing et al. (2008) found that a 6-month treatment (using 1.2-1.8 gm of Ganoderma per day) with Ganoderma augmented mitogen-induced lymphoproliferative responses in children with cancers. LENTINUS EDODES (SHIITAKE)

Lentinus edodes, called shiitake in Japanese and xiang gu or “fragrant mushroom in China, is the second most commonly cultivated edible mushroom worldwide (Chang, 1996). The shiitake is a large, umbrella-shaped mushroom that is dark brown and is prized both for its culinary and medicinal properties (Figure 7.5). It has been renowned as a food and medicine for thousands of years and is a major ingredient of Chinese cuisine (Hobbs, 2000). The shiitake mushroom contains components that have been shown to have many health and medicinal benefits. There are two preparations of Lentinus edodes with well-studied pharmacological effects:  Lentinus edodes mycelium (LEM), an extract from the powdered mycelia before the fruiting bodies develop and Lentinan, a highly purified, cell-wall constituent extracted from the fruiting bodies or mycelium (Hobbs, 2000). Lentinan was first isolated and studied in 1969 for its antitumor effects by Chihara and coworkers

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Figure 7.5.  Lentinus edodes.

of the National Cancer Institute of Japan (Chihara, Hamuro, Maeda, Arai, & Fukuoka, 1970). Numerous animal studies demonstrated antitumor effect by activating different immune responses in the host (Aoki, 1984; Aoki, Miyakoshi, Horikawa, & Usuda, 1981; Dennert & Tucker, 1973; Herberman & Nunn-Hargrove, 1981; Miyakoshi  & Aoki, 1984; Mayell, 2001; Miyakoshi, Aoki, & Mizukoshi, 1984; Nanba, Mori, Toyomasu, & Kuroda, 1987; Ng & Yap, 2002). Lentinan, a 1,3-β-glucan found in Lentinus edodes, has been found to activate macrophages, T lymphocytes, and other immune effector cells that modulate the release of cytokines (Chang, 1996; Hamuro  & Chihara, 1985). Clinical trials have been done on Lentinan in Japan although none have been placebo-controlled and double-blinded (Zaidman et  al., 2005). In Japan, Lentinan is often used to help support immune function in cancer patients during chemotherapy (Hobbs, 2000) and has been approved for clinical use there since the mid 1980s. It has been shown to increase overall survival of cancer patients (Oka, Yoshino, Hazama, Shimoda,  & Suzuki, 1992; Yoshino, Oka, Hazana, & Suzuki, 1989), especially those with gastric and colorectal carcinoma (Furue  & Kitoha, 1981; Hobbs, 2000; Taguchi et  al., 1985). A  recent open label study (n = 62) by deVere White et al., however, showed that shiitake mushroom extract alone was ineffective in the treatment of clinical prostate cancer (deVere White, Hackman, Soares, Beckett, & Sun, 2002). In human clinical studies shiitake extract has been given at an oral dose of 4 to 8 g/day. Other smaller studies used 9 g of dried mushrooms or 90 g of fresh mushrooms (Chang, 1996). Oral bioavailability of Lentinan is reportedly limited because of its molecular weight on the order of 400,000 to 1,000,000 daltons; although a superfine dispersed Lentinan powder has become recently available in Japan. A  clinical trial of the powder showed a reduction in the

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adverse effects of chemotherapy and improved quality of life scores in 71 patients receiving 15 mg of Lentinan once daily for 12 weeks (Hazama et al., 2009). Interestingly, this effect was linked to rates of Lentinin binding to peripheral blood monocytes in each patient. Lentinan seems to be safe when given to humans in the dosage range of 1 to 5 mg/day once or twice a week by intravenous injection (Hobbs, 2000). GRIFOLA FRONDOSA

Maitake is the Japanese name for the edible fungus Grifola frondosa, which is characterized by a large fruiting body and overlapping caps. In the United States and Canada it is known as hen of the woods and sheep’s head. It is a premier culinary mushroom with excellent taste and texture as well as a medicinal mushroom for health benefits. It is now being cultivated for food and use as a dietary supplement. It is estimated that commercial maitake production worldwide exceeds 40,000 tons (Mayell, 2001). In Japan, maitake has long been recognized as a tonic or adaptogen—a substance that balances bodily functions and enhances wellness, vitality, strength, and vigor (Figure  7.6) (Mayell, 2001). Numerous animal studies have confirmed that maitake has prominent beneficial effects on immune function and cancer inhibition (Adachi, Nanba, & Kuroda, 1987; Mayell, 2001). Enhancement of the immune system by activation of macrophages, T cells, and NK cells has been demonstrated in tumor-bearing mice (Adachi et al., 1987; Hishida, Nanba, & Kuroda, 1988; Kodama, Komuta, & Nanba, 2002; Kodama, Komuta, & Nanba, 2003; Mayell, 2001; Nanba, 1995; Nanba, 1997; Suzuki et al., 1985; Suzuki et al., 1989). In the early 1980s Japanese mycologist Hiroaki Nanba identified a D-fraction found in both the mycelia and the fruit body of the maitake. The D-fraction is a standardized form of isolated β-glucan polysaccharide compounds (β-1,6 glucan and β-1,3 glucan) and a more purified extract, the MD-fraction, have shown particular promise as immunomodulating agents, and as an adjunct to cancer, specifically colon, lung, stomach, liver, prostate and brain (Mayell, 2001; Nanba, 1995; Nanba, 1997). Human studies are limited; however, nonrandomized clinical studies using D-fraction and whole maitake reduced the size of lung, liver, and breast tumors (Kodama et al., 2002; Nanba, 1997). Maitake may also work in conjunction with chemotherapy to lessen its side effects, such as hair loss, pain, and nausea (Nanba, 1997). Maitake is an edible mushroom that can be eaten as food or made into tea. A typical dosage of dried maitake in capsule or tablet form is 3 to 7 g daily. Most of the published studies to date have been animal studies; therefore, it

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Figure 7.6.  Grifola frondosa.

is not known what doses may be safe or effective. Some references state that for disease prevention doses of 12 to 25 mg extract or 0.5 to 1 mg per kilogram daily should be taken in divided doses (Mayell, 2001). Because it has been used as a food in Japan for hundreds of years, in amounts up to several hundred grams per day, it is thought to be safe (Kidd, 2000). Little is known about the safety of maitake in pregnancy and breastfeeding, and, therefore, its use as a supplement in these settings cannot be recommended. In a phase I/II clinical trial of maitake, the oral dose was escalated from 0.1–10mg/kg in 34 postmenopausal breast cancer patients. No toxicity was shown, although blood counts of various immune biomarkers found a complex effect in which some immune functions were suppressed and other stimulated depending on dose. The researchers note that the study does not carry specific implications in cancer, but demonstrates a more complex effect than previously assumed, and that physicians may want to adjust dosage based on the desired immune effect (Deng et al., 2009). SCHIZOPHYLLUM COMMUNE

Schizophyllum commune is called Suehirotake by the Japanese. The common name is “split gill or split-fold.” Schizophyllum commune is one of the most common mushrooms in the world that grows on fallen trees in deciduous woodlands (Hobbs, 1995; Stamets, 2002). Schizophyllum is not generally available in North America or Europe for commercial trade. It is used primarily in Japan as an adjunctive antitumor polysaccharide with radiation therapy

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for cancer treatment and the commercial product (SPG, Sonifilan) is a pure β-glucan: β1–3, β1–6 D-glucan. Schizophyllum commune is similar to Lentinan in composition and biological activity, and its mechanism of immunomoduation and antitumor action appears to be quite similar (Smith, Rowan,  & Sullivan, 2003). In one study, researchers tested schizophyllum component SC3 (a hydrophobin) in mouse melanoma and sarcoma models, and found that while the IV treatment reduced the size and weight of only the melanoma during the 12-day treatment period, a strong antitumor effect was observed upon microscopic analysis revealed a 4.3-fold reduction in “vital mass” of the sarcoma (Akanbi et al., 2013). Mansour and colleagues (2012) treated mice with a tumor-inducing agent alone, with tamoxifen, with schizophyllum, or with both, and found that schizophyllum reduced DMBA-induced mammary tumors by 85%, as well as suppressed hepatic lesions.

Medicinal Mushrooms Summary Mushroom polysaccharides are known to stimulate both the innate and adaptive immune systems and activate natural killer cells, T-cells, B-Cells and macrophage-dependent immune system responses (Wasser 2002). The immunomodulating action of mushroom polysaccharides is especially valuable as a means of prophylaxis, prevention, and adjuvant treatment with chemotherapy. The potential use of medicinal mushrooms for disease prevention and treatment is an expanding target for research and development. Given the rich background of medicinal mushroom for health benefits and the recent interest in research on mushroom extracts, it seems feasible that mushroom therapy may play an increased role in disease prevention and immunotherapy for adjunctive cancer therapy. More Western-based clinical trials are needed to identify which mushroom extracts are most effective against specific tumors in their ability to elicit cellular response and demonstrate safety. The oncomycology field is moving toward individualized combinatorial mushroom extract immune therapy for cancer patients.

Commercially Available Combination Herbal Therapies Because botanical medicines have diverse mechanisms of action, including apoptotic, cytotoxic, autoantigenic, and immunomodulatory activities, both traditional and modern herbal cancer treatments involve multiple plants. Here we mention specific combination botanical products that have been evaluated

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in published peer-reviewed clinical studies. Two commonly used commercially available combination botanical products are Essiac, and Zyflamend®. Zick, Feng, Green, Olatunde, & Boon (2007) reported that women who used Essiac did not appear to have improved quality of life relative to nonusers in a retrospective cohort study of 510 Canadian women (Zick et al., 2007) (See Chapter 26). Zyflamend® has been studied in vitro, in animal experiments, and in Phase I  clinical trial in men with prostate intraepithelial neoplasia. Zyflamend® is an encapsulated combination botanical medicine consisting of 10 standardized herbal extracts in olive oil (rosemary, tumeric, ginger, holy basil, green tea, Hu zhang, Chinese goldthread, barberry, oregano, and Baical skullcap). These herbs are among the richest sources of naturally occurring and chemically diverse cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) inhibitor activity, both of which are up-regulated in many tumors. Zyflamend® has undergone preclinical and clinical evaluation. Bennani-Baiti, Bondar, Leaby, Fox, & Barnett (2006) at the Cleveland Clinic Brain Tumor Institute reported that Zyflamend® induced apoptosis in a human glioblastoma cell line and induced COX-2 and inhibited 5-LO expression while downregulating tubulin (Bennani-Bati et al., 2006). Newman et al. (2006) at MD Anderson Cancer Center reported that Zyflamend® inhibited progression of oral carcinogenesis using the DMBA-induced hamster cheek pouch model (Newman et al., 2006). Zyflamend® also has antiprostate cancer activity in in vitro and in vivo studies. Bemis, Capodice, Lee, Katz,  & Bultyan (2006) at Columbia University Medical Center treated human prostate cancer cells for 24 hours with 0.1 μL/mL Zyflamend® and observed a down-regulation of androgen receptors (Bemis et  al., 2006). The interim results of a Phase I  clinical trial of Zyflamend® in men with high-grade prostatic intraepithelial neoplasia (PIN) were reported at the November 2006 meeting of the Society for Integrative Oncology. Of 29 African American high-risk PIN patients enrolled, 50% had a decrease in serum PSA values and one patient had a biopsy proven reversal of PIN. A  similar phase I  study published in 2009 (Capodice et  al., 2009)  showed that 48% of subjects with high-risk PIN demonstrated a 25 to 50% decrease in prostate-specific antigen and as well as reduction in NF-κB after 18 months of 3 or more Zyflamend capsules daily,

Botanical Interactions in Chemotherapy and Radiotherapy Use of botanical therapy concurrent with chemo- and radiotherapy must be undertaken with caution. Many botanicals have hepatic effects that may have pharmacokinetic effects that alter plasma levels and half-lives of

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chemotherapeutic drugs. Some botanicals have antioxidant effects that could, in theory, affect the tumor cell killing ability of radiotherapy. Table 7.2 shows the predicted herb–chemotherapy drug interactions based on cytochrome P450 effects of a number of botanicals. Since many herbal medicines induce P450 enzymes, exogenous molecules, including chemotherapy drugs, are metabolized by the liver in a more efficient manner. This leads to reduced plasma levels of the drugs and thus lowers exposure of tumor cells to the chemotherapy. However, some botanicals have hepatic effects that would be predicted to increase the half-life of some chemotherapy agents. We can envision a future in integrative oncology in which selected botanicals will be administered concurrently with cytotoxic drugs to improve efficacy. In the meantime, in the absence of detailed information on drug–herb interaction, it is best to follow the motto, “When in doubt, leave it out.” Chemotherapy represents a relatively small portion of the cancer patient’s overall treatment plan. Co-administration of botanicals with chemotherapy drugs may risk reducing efficacy of chemotherapy, and thus, in the absence of data, it is best to suspend most herbal therapies during chemotherapy. There are notable exceptions, particularly those summarized in this chapter (see Table 7.2). Certain botanicals such as green tea, milk thistle, astragalus, and ashwaghanda are rarely contraindicated. Other botanicals such as curcumin, garlic, milk thistle, and ginseng are contraindicated with certain therapies, but well indicated with others.

Herbal Therapies Used to Mitigate Cancer Treatment Side Effects A chapter on botanical oncology would not be complete without a mention of herbal therapies in common use by naturopathic physicians who specialize in the cancer care. Many of these treatments have not undergone clinical trial for either safety or efficacy. Nevertheless, most of the treatments have a long history of safe use. The integrative oncologist can feel comfortable using these treatments as therapeutic trials with patients with the following cancer-treatment–related side effects. RADIATION DERMATITIS

Various therapies are recommended, though clinical evidence has shed light on some commonly used treatments. In a randomized, double-blind, placebo-controlled trial of 30 breast cancer patients undergoing radiation, Ryan and colleagues (2013) found that 6.0 g of oral curcumin daily (split into

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Table 7.2.  Selected Herbal Therapies for Co-administration with Chemotherapy. Chemotherapy Agent

Cisplatin

Enhances Tumoricidal Actions

Quercetin Curcumin

Cyclophosphamide

Reduces Toxicity

Trametes versicolor (and PSK) Silybum marianum (silybin) Ginkgo biloba Astragalus membranaceus, Withania somnifera, also Trametes versicolor

Docetaxel

Curcumin

5-FU (5-fluorouracil)

Ellagic acid

Mitomycin-C

Panax ginseng

Doxorubicin (Adriamycin) and Idarubicin

Green tea

Paclitaxel

Green tea

Tamoxifen

Green tea Panax quinquefolius

Fluorouracils Interleukin-2

Curcumin Green tea Astragalus membranaceus Panax ginseng

Green tea

–

Ichikawa et al., 1998; Sadzuka et al., 1998; Sugiyama & Sadzuka 1998; Fukaya & Kanno, 1999; Masuda, Suzui, & Weinstein, 2001; Sugiyama et al., 2001; Hrelia et al., 2004; Kim et al., 2004; Koo et al., 2004; Mei, Qian, Wei, & Liu, 2004; Du et al., 2006.

three doses daily during radiation therapy), reduced radiation dermatitis severity and moist desquamation in the subjects (28.6% versus 87.5% of site tissue in curcumin versus placebo, respectively). Aloe has not been shown to be effective, despite the fact that it is widely prescribed and used for radiation burns. A meta-analysis of 20 studies and 3,098 patients showed no significant effect of aloe vera in treating radiodermatitis (Zhang, Zhang & Shao, 2013). ANEMIA

Marrow Plus is an encapsulated traditional Chinese herbal formulation for blood deficiency. This formula has been used in treating chemotherapy and zidovudine–related anemia in HIV- positive patients. ®

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LEUKOPENIA

Astragalus has been shown to be helpful. The strongest indication for astragalus in the context of oncology care is to help prevent the immunosuppression caused by chemotherapy agents. Additionally, there is some indication that astragalus may also potentiate the cytotoxic effects of certain chemotherapy agents. NAUSEA AND VOMITING

Cannabis is a potent antiemetic and is available to cancer patients in several countries and in several American states (see Chapter 8). Ginger tea also seems helpful for some patients. One placebo-controlled trial showed that ginger capsules were useful in lowering postoperative nausea and vomiting in 80 women undergoing gynecologic laparoscopic surgery (Pongrojpaw, & Chiamchanya, 2003). More evidence on its mechanism of action was shown in Walstab et al.’s 2007 paper, which details ginger extract’s inhibition of gastric 5-HT3 receptor activation. However, a single clinical trial showed that ginger capsules in 48 gynecologic cancer patients receiving cisplatin treatment was not more effective than metoclopramide (Manusirivithaya et al., 2004). HAND-FOOT SYNDROME

Chlorophyll and calendula cream have been helpful for some patients (Kern, Schmidinger, Locker, Kopp, 2007), usually in combination with vitamin B6 therapy. INSOMNIA

Valerian has a long history of use as a sleep-promoting herb. Clinical trials are sparse and conflicting. Since valerian has been shown to have no effect on CYP3A4 or CYP2D6 activity in healthy humans (Donovan et al., 2004) it may be safe to use with cancer patients undergoing chemotherapy. However, most naturopathic physicians who specialize in cancer care will prescribe melatonin as a first-line sleep therapy because of cancer clinical trial evidence that concomitant oral melatonin in doses of 20 or 40 mg before bed improved chemotherapy outcomes (Seely et al., 2010). APTHOUS ULCERS, STOMATITIS, AND MUCOSITIS

Slippery elm tea can reduce pain on eating and swallowing.

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FATIGUE

Eleutherococcus senticosis (Siberian ginseng) is often prescribed by naturopathic physicians to treat radiotherapy-related fatigue. Barton and colleagues’ (2013) study found a significant benefit among a group of 364 patients diagnosed with cancer—especially among patients receiving active cancer treatment. DEPRESSION

St. John’s wort is contraindicated with concurrent use of many chemotherapy drugs, but may be useful for both depression and menopausal hot flashes that are common sequela to completion of conventional cancer treatment. MENOPAUSAL VASOMOTOR STABILITY

St. John’s wort and hesperidin are both worth trying in cancer patients. Use caution during chemotherapy as hypericin can alter hepatic metabolism of several chemotherapy drugs.

Botanical Medicine as Secondary Prevention Naturopathic physicians who specialize in oncology agree that botanical therapy plays a significant role in secondary prevention. Based on their safety and scientific evidence, most NDs include them in their core protocol for reducing the risk of cancer relapse in patients who have received primary conventional treatment (surgery, chemotherapy, radiation). The following botanicals are administered orally. Doses in common use are provided as well. Curcumin

3,000–9,000 mg/day

Camellia sinensis

1,000 mg bid

Quercetin

750 mg bid

Bromelain

750 mg bid

Garlic

3,200 mcg allicin bid

Silymarin officinalis

500 mg bid

Trametes versicolor

1,500 mg bid

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Conclusions, Future Directions, and Research Agenda Plant medicines may fill gaps in current oncology treatment and offer useful targeted immunomodulatory, anti-inflammatory, apoptotic, and antiangiogenic treatments. Botanical oncology is an emerging field and research is desperately needed. Perhaps the most important question to answer is whether a botanical exists with chemopreventive, immunomodulatory, anti-inflammatory, and antiangiogenic activity, effective in reducing the risk of cancer recurrence following conventional treatment with surgery, radiation and chemotherapy? High-priority studies include the following: • Prospective outcomes study of naturopathic oncology clinics where science-based botanical medicine is being applied. • Combination botanical oncology trials using active isolated molecular constituents from multiple plants that have anticancer activity utilizing multiple mechanisms. • Translational research from mechanism of action of anticancer botanicals to targeted botanical treatments. • Development of intravenous formulations of curcumin, EGCG, silibinin, and resveratrol. • Combination natural product whole-plant botanical oncology trials present methodological challenges that exceed those of conventional drug trials. These difficulties can, and must, be overcome. An approach to standardization of both the chemical constituents and the biological activity of herbal products across trials must be adopted. • Single-agent dose-escalating botanical trials in stage IV cancer patients. • Phase I clinical trials of botanical medicines used by traditional shamans in South America, Central America, and Africa, including entheogenic plant medicines, to treat cancer.

Acknowledgments Grateful acknowledgment to Bastyr library scientists Jane Saxton, MLS and Susan Banks, MLS. We thank Paul Stamets and Tom Volk for providing the mushroom photos. Paul Stamets is a well-known mycologist, author, and founder of Fungi Perfecti®

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a company specializing in gourmet and medicinal mushrooms-http://www. fungi.com. Tom Volk is professor of biology at the University of Wisconsin-La Crosse, WI, [email protected]. The authors wish to acknowledge Ann B. Ready, Carolyn Torkelson, Gowsala Sivam, and Cynthia Werner, the authors of the first edition of this chapter, for their contribution. REFERENCES

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8 Cannabinoids and Cancer DONALD I. ABRAMS AND MANUEL GUZMAN

Key Concepts Cannabis has been used in medicine for thousands of years prior to achieving its current status as an illicit substance ■ Cannabinoids, the active components of Cannabis sativa, mimic the effects of the endogenous cannabinoids (the so-called endocannabinoids), activating specific cannabinoid receptors, particularly CB1 found predominantly in the central nervous system and CB2 found in cells involved with immune function. ■ Delta-9-tetrahydrocannabinol, the main bioactive cannabinoid in the plant, has been available as a prescription medication approved for chemotherapy-induced nausea and vomiting and treatment of anorexia associated with the AIDS wasting syndrome. ■ In addition to treatment of nausea and anorexia, cannabinoids may be of benefit in the treatment of cancer-related pain, possibly in a synergistic fashion with opioid analgesics. ■ Cannabinoids have been shown to be of benefit in the treatment of HIV-related peripheral neuropathy suggesting that they may be worthy of study in patients with chemotherapy-related neuropathic symptoms. ■ Cannabinoids have a favorable drug safety profile, medical use predominantly limited by their psychoactive effects and their limited bioavailability. ■ There is no conclusive evidence that chronic cannabis use leads to the development of any malignancies; some preclinical studies actually suggest a protective effect. ■

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Cannabinoids inhibit tumor growth in laboratory animal models by modulation of key cell-signaling pathways, inducing direct growth arrest and tumor cell death, as well as by inhibiting tumor angiogenesis and metastasis. ■ Cannabinoids appear to be selective antitumor compounds because they kill tumor cells without affecting their nontransformed counterparts ■ More basic and clinical research is needed to ascertain not only the role of cannabinoids in palliative cancer care, but to delineate their role as potential anti-cancer agents with activity at a number of sites by way of multiple mechanisms of action. ■

Introduction Although long-recognized for its medicinal values and widely used by millions throughout the world, cannabis receives little attention in the standard literature because of its status as a controlled substance and classification in the United States as a Schedule I agent with a high potential for abuse and no known medical use. Data on the potential effectiveness of medicinal cannabis is difficult to find due to the limited numbers of clinical trials that have been conducted to date. As a botanical, cannabis shares those difficulties encountered in the study of plants that are grown in many climates and environments from diverse genetic strains and harvested under variable conditions. However, the potential benefits of medicinal cannabis have not been lost on a large number of people living with cancer, some of whom have been quite vocal in attributing their ability to complete their prescribed course of chemotherapy to the anti-emetic effects of inhaled cannabis. In the practice of integrative oncology, the provider is frequently faced with situations in which being able to recommend medicinal cannabis seems like the right thing to do (Adler & Colber, 2013; Bostwick, Reisfield, & Dupont, 2013). A growing body of preclinical evidence suggests that cannabis may not only be effective for symptom management, but may have a direct anti-tumor effect as well (Bowles, O’Bryant, Camidge,  & Jimeno, 2012). This chapter will be devoted to a review of the role of cannabinoids in cancer.

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Cannabis as Medicine: A Brief History The use of cannabis as medicine dates back nearly 3000  years (Abel, 1980; Booth, 2003; Joy, Watson, & Benson, 1999; Mack, Joy, 2001; NCI PDQ CAM). Employed widely on the Indian subcontinent, cannabis was introduced into Western medicine in the 1840’s by W. B. O’Shaughnessy, a surgeon who learned of its medicinal benefits first hand while working in the British East Indies Company. Promoted for reported analgesic, sedative, anti-inflammatory, antispasmodic and anticonvulsant properties, cannabis was said to be the treatment of choice for Queen Victoria’s dysmennorhea. In the early 1900s, medicines that were indicated for each of cannabis’s purported activities were introduced into the Western armamentarium making its use less widespread. Physicians in the United States were the main opponents to the introduction of the Marihuana Tax Act by the Treasury Department in 1937. The legislation was masterminded by Harry Anslinger, director of the Federal Bureau of Narcotics from its inception in 1931 until 1962, who testified in Congress that “Marijuana is the most violence-causing drug in the history of mankind.” The Act imposed a levy of one dollar an ounce for medicinal use and one hundred dollars an ounce for recreational use, which in 1937 dollars was a prohibitive cost. By using the Mexican name for the plant and associating it with nefarious South-of-the-Border activities, the proponents fooled many physicians. The Act was singly opposed by the American Medical Association who felt that objective evidence that cannabis was harmful was lacking and that its passage would impede further research into its medical utility. In 1942, cannabis was removed from the U.S. Pharmacopoeia. Mayor Fiorello LaGuardia of New York commissioned an investigation into the reality of the potential risks and benefits of cannabis that reported in 1944 that the substance was not associated with any increased risk of criminal activity, addiction or insanity as had been claimed. The LaGuardia Commission Report, as well as subsequent similar investigations that have been commissioned nearly every decade since, went largely ignored. In 1970 with the initiation of the Controlled Substances Act, marijuana was classified as a Schedule I  dug. Where both Schedule I  and Schedule II substances have a high potential for abuse, Schedule I drugs are distinguished by having no accepted medical use. Other Schedule I substances include heroin, LSD, mescaline, methylqualone and, most recently, gammahydroxybutyrate (GHB). In 1973, President Nixon’s investigation into the risks and benefits of marijuana, the Shafer Commission, concluded that it was a safe substance with no addictive potential that had medicinal benefits. Despite the fact that it was deemed to have no medical use, marijuana was distributed to patients by the

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United States government on a case by case basis by way of a Compassionate Use Investigational New Drug (IND) program established in 1978. In the late 1980s and early 1990s, many people living with human immunodeficiency virus-1 (HIV) developed a wasting syndrome as a preterminal event (Chan, Naton, Saravolatz, Crane,  & Osterberger, 1995). The wasting syndrome, characterized by anorexia, weight loss of greater than 10% body weight and frequently fever and diarrhea created hordes of cachectic individuals in search of any potential therapeutic intervention. Many turned to smoking cannabis (Abrams, 2000; Abrams, Child, Mitchell, 1995; Werner, 2011). Fearful that there might be a run on the Compassionate Use program, the Bush administration shut it down in 1992, the same year that dronabinol (delta-9-tetrahydrocannabinol [THC], Marinol®) was approved for treatment of anorexia associated with the AIDS wasting syndrome. Delta-9-THC is one of the approximately 100 cannabinoids found in the cannabis plant and is felt to be the main psychoactive component. Overall, the plant contains about 400 compounds derived from its secondary metabolism, many of which may contribute to its medicinal effect. Synthetic delta-9THC in sesame oil was first licensed and approved in 1986 for the treatment of chemotherapy-associated nausea and vomiting. Clinical trials done at the time determined that dronabinol was as effective, if not more so, than the available antiemetic agents (Sallen & Zinberg, 1975). The potent class of serotonin 5-HT3 receptor antagonists which have subsequently revolutionized the ability to administer emetogenic chemotherapy had not yet come to market. Dronabinol was investigated for its ability to stimulate weight gain in patients with the AIDS wasting syndrome in the late 1980’s. Results from a number of trials suggested that although patients reported an improvement in appetite, no statistically significant weight gain was appreciated (Beal et al., 1995; Gorter, Seefried,  & Volberding, 1992). In one trial evaluating megesterol acetate and dronabinol alone and together, the cannabinoid seemed to negate some of the weight increase seen in those only receiving the hormone (Timpone et al., 1997).

Cannabinoid Chemistry and Biologic Effects Cannabinoids are a group of 21 carbon terpenophenolic compounds produced uniquely by Cannabis sativa and Cannabis indica species (Figure 8.1) (Adams & Martin, 1996; Grothenherman & Russo, 2002). With the discovery of endogenous cannabinoids and to distinguish them from pharmaceutical compounds, the plant compounds may also be referred to as phytocannabinoids. Although delta-9-THC is the primary active ingredient in cannabis, there are

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a number of non-THC cannabinoids and noncannabinoid compounds that also have biologic activity. Cannabidiol (CBD), cannabinol, cannabichromene, cannabigerol, tetrahydrocannabivirin and delta-8-THC are just some of the additional cannabinoids that have been identified. It is postulated that the secondary compounds may enhance the beneficial effects of delta-9-THC, for example by modulating the THC-induced anxiety, anticholinergic or immunosuppressive effects, and may reduce the unwanted effects of delta-9-THC, for example by attenuating seizures, psychoses or motor discoordination. In addition, cannabis associated terpenoids and flavonoids may increase cerebral blood flow, enhance cortical activity, kill respiratory pathogens and provide anti-inflammatory activity (Russo, 2011). The neurobiology of the cannabinoids has only been identified within the past 25  years during which time an explosion of knowledge has occurred (Devane, Dysarc, Johnson, Melvin,  & Howlett, 1988; Devane et  al., 2002; Felder  & Glass, 1998; Katona  & Freund, 2012; Pertwee, 1997; Pertwee et  al, 2010). In the mid-1980s, researchers developed a potent cannabinoid agonist to be used in research investigations. In 1986 it was discovered that cannabinoids inhibited the accumulation of cyclic adenosine monophosphate (cAMP), suggesting the presence of a receptor-mediated mechanism. By attaching a radiolabel to the synthetic cannabinoid, the first cannabinoid receptor, CB1, was pharmacologically identified in the brain in 1988. The CB1 receptor is coupled to Gi proteins. Its engagement inhibits adenylyl cyclase and voltage-gated calcium channels, and stimulates rectifying potassium conductances and mitogen-activated protein kinase activity. By 1990, investigators had cloned the CB1 receptor, identified its DNA sequence and mapped its location in the brain, with the largest concentration being in the basal ganglia, cerebellum, hippocampus and cerebral cortex. Nowadays CB1 is known to be an ubiquitous protein that is present in basically all body tissues. In 1993 a second cannabinoid receptor, CB2, was identified outside the brain. Originally detected in macrophages and the marginal zone of the spleen, the highest concentration of CB2 receptors is located on the B lymphocytes and natural killer cells, suggesting a possible role in immunity. The existence of cannabinoid receptors has subsequently been demonstrated in most animal species, all the way down to invertebrates. Are these receptors present in the body solely to complex with ingested phytocannabinoids? The answer came in 1992 with the identification of a brain constituent that binds to the cannabinoid receptor. Named anandamide from the Sanskrit word for bliss, the first endocannabinoid had been discovered. Subsequently 2- arachidonoylglycerol (2-AG) has also been confirmed as part of the body’s endogenous cannabinoid system. These endocanabinoids function as neuromodulators. As the ligands for the 7-transmembrane domain cannabinoid

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Cannabinoids

Endogenous cannabinoids Arachidonic acid derivatives

OH

N

O

Anandamide (AEA) O

Cannabis

Endogenous

Synthetic

THC

AEA

Nabilone

OH O OH

2-Arachidonoylglycerol (2-AG)

CB

Figure 8.1.  Cannabinoids and their receptors. Cannabinoids are a group of 21 carbon terpenophenolic compounds produced by Cannabis species. The phytocannabinoids complex with two receptors, CB1 and CB2, to produce their physiologic effects.

receptors located in presynaptic nerve terminals, binding of the endocannabinoid leads to G-protein activation and the cascade of events transpires resulting in the opening of potassium channels which decreases cell firing and the closure of calcium channels which decreases neurotransmitter release (Figure 8.2). The functions of the endogenous cannabinoid system in the body are becoming more appreciated through advances in cannabinoid pharmacology (Miller & Devi, 2011; Pertwee, 2009). The identification of the cannabinoid receptors has led to a host of agonists and antagonists being synthesized. Utilizing these tools, investigators are discovering that the system is likely to be important in the modulation of pain and appetite, suckling in the newborn and the complexities of memory (Michael Pollen in The Botany of Desire gives a particularly entertaining description of the natural function of endocannabinoids in memory (2001)). In addition to being utilized to learn more about the natural function of the endocannabinoid system, a number of these cannabinoid receptor agonists and antagonists are being developed as potential pharmaceutical therapies. In the meantime, dronabinol, nabilone (Cesamet®, a synthetic cannabinoid) and cannabis are the currently available cannabinoid

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Cannabinoid receptors: G-protein coupling Cannabinoids

GIRK

CB1 Gi/o

AC

VSCC

cAMP

K+ MAPK

PKA

Control of cell function

Figure 8.2.  Signaling pathways coupled to the CB1 cannabinoid receptor. Cannabinoids exert their effects by binding to specific Gi protein-coupled receptors. The CB1 cannabinoid receptor signals to a number of different cellular pathways. These include, for example, (i)  inhibition of the adenylyl cyclase (AC)–cyclic AMP–protein kinase A (PKA) pathway; (ii) modulation of ion conductances, by inhibition of voltage-sensitive Ca2+ channels (VSCC) and activation of Gi protein-coupled inwardly rectifying K+ channels (GIRK); and (iii) activation of mitogen-activated protein kinase (MAPK) cascades. Other less established cannabinoid receptor effectors and the crosstalk among the different pathways have been omitted for simplification.

therapies in the United States. Levonantradol (Nantrodolum®) is a synthetic cannabinoid administered intramuscularly, not used as much clinically since the oral agents became available. Nabiximols (Sativex®), a whole plant extract delivered as an oro-mucosal spray with varying combinations of THC and cannabidiol, is available in Canada and some European countries and undergoing late phase testing in the US and other countries. Through the receptors described above, cannabis delivered by way of inhalation, orally or oro-mucosally can produce a host of biologic effects (Borgelt, Franson, Nussbaum, & Wang 2013). The 1999 Institute of Medicine report— Marijuana and Medicine: Assessing the Science Base—makes the following general conclusions about the biology of cannabis and cannabinoids (Joy et al., 1999)

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• Cannabinoids likely have a natural role in pain modulation, control of movement, and memory. • The natural role of cannabinoids in immune systems is likely multifaceted and remains unclear. • The brain develops tolerance to cannabinoids. • Animal research has demonstrated the potential for dependence, but this potential is observed under a narrower range of conditions than with benzodiazepines, opiates, cocaine, or nicotine. • Withdrawal symptoms can be observed in animals but appear mild compared with those of withdrawal from opiates or benzodiazepines.

Pharmacology of Cannabis When taken by mouth, there is a low (6–20%) and variable oral bioavailability (Adams & Martin, 1996; Agurell et al., 1986; Borgelt et al., 2013). Peak plasma concentrations occur after 1–6 hours and remain elevated with a terminal half-life of 20–30 hours. When consumed orally, delta-9-THC is initially metabolized in the liver to 11-OH-THC, also a potent psychoactive metabolite. On the other hand, when inhaled, the cannabinoids are rapidly absorbed into the bloodstream with a peak concentration in 2–10 minutes, which rapidly declines over the next 30 minutes. Thus, smoking achieves a higher peak concentration with a shorter duration of effect. Less of the psychoactive 11-OH-THC metabolite is formed. When nabiximols is taken oro-mucosally, no pharmacokinetic interactions seem to occur between its two major cannabinoid constituents, namely THC and CBD, and the pharmacokinetic properties of the THC present in nabiximols are similar to those of oral THC (Karschner, Darwin, Goodwin, Wright, & Huestis, 2011). Cannabinoids can interact with the hepatic cytochrome P450 enzyme system (Watanabe, Matsunaga, Yamamoto, Funae, & Yoshimura, 1995; Yamamoto, Watanabi, Narimatsu, & Yoshimura, 1995). CBD, for example, can inactivate CYP 3A4. After repeated doses, some of the cannabinoids may induce P450 isoforms. The effects are predominantly related to the CYP1A2, CYP2C and CYP3A isoforms. The potential for a cannabinoid interaction with cytochrome P450 and, hence, possibly metabolism of chemotherapeutic agents has led to a small amount of data on the possibility of botanical:drug interactions. In one study, 24 cancer patients were treated with intravenous irinotecan (600 mg, n = 12) or docetaxel (180 mg, n = 12), followed 3 weeks later by the same drugs concomitant with medicinal cannabis taken as an herbal tea for 15 consecutive days, starting 12  days before the second treatment (Engels et  al.,2007). The

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carefully conducted pharmacokinetic analyses showed that cannabis administration did not significantly influence exposure to and clearance of irinotecan or docetaxel.

Cannabinoids and Cancer Symptom Management ANTIEMETIC EFFECT

The nausea and vomiting related to cancer chemotherapy continues to be a significant clinical problem even in light of the newer agents that have been added to our armamentarium since the 1970s and 1980s when clinical trials of cannabinoids were first conducted (Sutton & Daeninck, 2006) In those days, phenothiazines and metoclopropramide were the main antiemetic agents used. Dronabinol, synthetic THC, and nabilone, a synthetic analog of THC, were both tested as novel oral agents in a number of controlled clinical trials. Nabilone was approved in Canada in 1982, but only recently became available in the United States. Dronabinol was approved as an antiemetic to be used in cancer chemotherapy in the United States in 1986. Numerous meta-analyses confirm the utility of these THC-related agents in the treatment of chemotherapy-induced nausea and vomiting. Tramer et al. (2001) conducted a systematic review of 30 randomized comparisons of cannabis with placebo or antiemetics from which dichotomous data on efficacy and harm were available. Oral nabilone, oral dronabinol, and intramuscular levonantradol were tested. No trials of smoked cannabis were included. There were 1,366 patients involved in the systematic review. Cannabinoids were found to be significantly more effective antiemetics than prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, or alizapride. In this analysis, the number needed to treat (NNT) for complete control of nausea was 6; the NNT for complete control of vomiting was 8.  Cannabinoids were not more effective in patients receiving very low or very high emetogenic chemotherapy. In crossover trials, patients preferred cannabinoids for future chemotherapy cycles. Tramer identified some “potentially beneficial side effects” that occurred more often with cannabinoids including the “high,” sedation or drowsiness, and euphoria. Less desirable side effects that occurred more frequently with cannabinoids included dizziness, dysphoria or depression, hallucinations, paranoia, and hypotension. A later analysis by Ben Amar reported that 15 controlled studies compared nabilone to placebo or available antiemetic drugs (Ben Amar, 2006). In 600 patients with a variety of malignant diagnoses, nabilone was found to

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be superior to prochlorperazine, domperidone and alizapride, with patients clearly favoring the nabilone for continuous use. Nabilone has also been shown to be moderately effective in managing the nausea and vomiting associated with radiation therapy and anesthesia after abdominal surgery (Robson, 2001; Tramer et  al., 2001; Walsh, Nelson,  & Mahmoud, 2003). In the same meta-analysis, Ben Amar reports that in 14 studies of dronabinol involving 681 patients, the cannabinoid antiemetic effect was equivalent or significantly greater than chlorpromazine and equivalent to metochlopramide, thiethylperazine and haloperidol. It is noted that the efficacy of the cannabinoids in these studies was sometimes outweighed by the adverse reactions and that none of the comparator antiemetics were of the serotonin receptor antagonist class that is the mainstay of treatment today. A small pilot, randomized, double-blind, placebo-controlled phase II trial was conducted to investigate the whole-plant cannabis-based medicine, nabiximols, added to standard antiemetics in the treatment of chemotherapy-induced nausea and vomiting (Duran et al., 2010). Seven patients were randomized to receive the mixture of delta-9-THC and CBD and 9 added placebo to their standard of care antiemetic regimen. Of the nabiximols recipients, 5 of the 7 compared to 2 of the 9 on placebo experienced a complete response with a mean daily dose of 4.8 sprays in both groups without serious adverse effects. Further larger studies of the potential of nabiximols as an antiemetic are warranted. There have been only three controlled trials evaluating the efficacy of smoked cannabis in chemotherapy-induced nausea and vomiting (Ben Amar, 2006). In two of the studies, the smoked cannabis was only made available after patients failed dronabinol. The third trial was a randomized, double-blind, placebo-controlled, cross-over trial involving 20 adults where both smoked cannabis and oral THC were evaluated. One-quarter of the patients reported a positive antiemetic response to the cannabinoid therapies. On direct questioning of the participants, 35% preferred the oral dronabinol, 20% preferred the smoked marijuana and 45% did not express a preference. Four participants receiving dronabinol alone experienced distorted time perception or hallucinations, which were also reported by two with smoked marijuana and one with both substances. Both dronabinol and nabilone are FDA-approved for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic therapy. Nabilone’s extended duration of action allows for twice-a- day dosing of one or two milligrams commencing 1 to 3 hours prior to receiving chemotherapy. A dose of 1 or 2 milligrams the night before administration of chemotherapy might also be useful. It is recommended to commence dronabinol at an initial dose of 5 mg/m2, also 1 to 3 hours prior to the administration of

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chemotherapy, then every 2 to 4 hours after chemotherapy, for a total of 4 to 6 doses/day. Should the 5 mg/m2 dose prove to be ineffective, and in the absence of significant side effects, the dose may be escalated by 2.5 mg/m2 increments to a maximum of 15 mg/m2 per dose. Nabilone, with fewer metabolites and a lower dose range, may be associated with fewer side effects. The need to dose one to three hours prior to chemotherapy is one factor that drives patients to prefer inhaled cannabis where the delivery and effect peak within minutes. Patients also prefer the ability to more tightly titrate the dose of cannabinoids they receive when inhaling compared to oral ingestion. The National Comprehensive Cancer Network antiemesis guidelines recommend cannabinoids among other therapies to consider as a breakthrough treatment for chemotherapy-induced nausea and vomiting (www.nccn.org). APPETITE STIMULATION

Anorexia, early satiety, weight loss, and cachexia are some of the most daunting symptom management challenges faced by the practicing oncologist. There are very few tools in the tool-box for addressing these concerns. Patients are not only disturbed by the disfigurement associated with wasting, but also by their inability to engage in the social interaction associated with breaking bread and partaking of a meal. For many, the hormonal manipulation with megestrol acetate (synthetically derived progesterone) may be contraindicated or the side effects undesirable. Two small controlled trials demonstrated that oral THC stimulates appetite and may slow weight loss in patients with advanced malignancies (Ben Amar, 2006) In a larger randomized, double-blind, parallel group study of 469 adults with advanced cancer and weight loss, patients received either 2.5 mg of oral THC twice daily, 800 mg of oral megestrol daily, or both. In the megestrol monotherapy group, appetite increased in 75% and weight in 11% compared to 49% and 3%, respectively, in the oral THC group. These differences were statistically significant. The combined therapy did not confer additional benefits. A smaller randomized placebo-controlled trial of dronabinol in cancer patients demonstrated enhanced chemosensory perception in the treatment group (Brisbois et  al., 2011). In the patients receiving cannabinoids, food was reported to taste better, appetite improved and the proportion of protein calories was increased compared to the placebo group. Many animal studies have previously demonstrated that THC and other cannabinoids have a stimulatory effect on appetite and increase food intake. It is felt that the endogenous cannabinoid system may serve as a regulator of feeding behavior. For example, anandamide in mice leads to a potent enhancement of appetite (Mechoulam, Berry, Avraham, DiMarzo, & Fride, 2006). It

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is felt that the CB1 receptors, present in the hypothalamus where food intake is controlled and in the mesolimbic reward system, may be involved in the motivational or reward aspects of eating. This led to the development of the pharmaceutical CB1 antagonist rimonabant (Acomplia ®), which was approved in Europe for the treatment of obesity on the basis of Phase III clinical trials where it was shown to induce a 4–5 kg mean weight loss with improved glycemic and lipid profiles (Christensen, Kristensen, Bartels, Bliddal, & Astrup, 2007). However, Acomplia® was never approved in the United States and was ultimately withdrawn from the European market because it was found to induce anxiety and depressive disorders that were deemed high risk, often leading to patient suicide. Anecdotal as well as clinical trial evidence also supports the appetitestimulating effect of inhaling cannabis. In classic trials conducted in the 1970s in healthy controls, it was found that, especially when smoked in a social/communal setting, cannabis inhalation led to an increase in caloric intake, predominantly in the form of between-meal snacks, mainly in the form of fatty and sweet foods. In cancer patients with anorexia as well as chemotherapy-induced nausea, it is worth noting that cannabis is the only antiemetic that also has orexigenic action. Although cannabis thus provides two potential benefits to the patient with cancer, the appetite-stimulation does not always reverse the cancer cachexia that is a function of energy wasting in addition to decreased food intake. ANALGESIA

Our understanding of the possible mechanisms of cannabinoid-induced analgesia has been greatly increased through study of the cannabinoid receptors, endocannabinoids and synthetic agonists and antagonists. The CB1 receptor is found in the central nervous system as well as in peripheral nerve terminals. Elevated levels of the CB1 receptor—like opioid receptors—are found in areas of the brain that modulate nociceptive processing (Fine  & Rosenfeld, 2013; Walker et  al., 1999). In contrast, CB2 receptors are located in peripheral tissue and are present at very low expression levels in the CNS. Of the endogenous cannabinoids identified, anandamide has high affinity for CB1 receptors, whereas 2-AG has affinity for both CB1 and CB2 receptors. With the development of receptor-selective antagonists (SR141716 for CB1 and SR144528 for CB2), additional information has been obtained regarding the roles of the receptors and endogenous cannabinoids in modulation of pain (Meng, Manning, Martin, & Fields, 1998; Walker, Huang, Strangman, Tsou, & Sanudo-Pena, 1999). Where the CB1 agonists exert analgesic activity in the

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CNS, both CB1 and CB2 agonists have peripheral analgesic actions (Calignano, LaRana, Giuffrida, & Piomelli. 1998; Fields & Meng, 1998). Cannabinoids may also contribute to pain modulation through an anti-inflammatory mechanism—a CB2 effect with cannabinoids acting on mast cell receptors to attenuate the release of inflammatory agents such as histamine and serotonin and on keratinocytes to enhance the release of analgesic opioids (Facci & Meng, 1998; Ibrahim et al, 2005; Richardson, Kilo, & Hargreaves, 1998). Cannabinoids are effective in animal models of both acute and persistent pain. The central analgesic mechanism differs from the opioids in that it cannot be blocked by opioid antagonists. The potential for additive analgesic effects with opioids as well as the potential for cannabinoids to reduce nausea and increase appetite make a strong case for the evaluation of marijuana as adjunctive therapy for patients on morphine (Elikottil, Gupta, & Gupta, 2009). Medical literature cites evidence of cannabinoids’ ability to reduce naturally occurring pain, but few human studies have been performed. Early studies of cannabinoids on experimental pain in human volunteers produced inconsistent results. In some cases, the administration of cannabinoids failed to produce observable analgesic effects; in others, cannabinoids resulted in an increase of pain sensitivity (hyperalgesia). Institute of Medicine reviewers noted that these studies suffered from poor design and methodological problems and dubbed their findings inconclusive (Joy et al., 1999). Encouraging clinical data on the effects of cannabinoids on chronic pain come from three studies of cancer pain. Cancer pain results from inflammation, mechanical invasion of bone or other pain-sensitive structure, or nerve injury. It is severe, persistent, and often resistant to treatment with opioids. Noyes and colleagues conducted two studies on the effects of oral THC on cancer pain. Both studies used standard single-dose analgesic study methodology and met the criteria for well-controlled clinical trials of analgesic efficacy. The first experiment measured both pain intensity and pain relief in a double-blind, placebo controlled study of 10 subjects (Noyes, Brunk, Baram, & Canter, 1975). Observers compared the effects of placebo and 5, 10, 15, and 20 mg doses of delta-9-THC over a 6-hour period. Researchers reported that 15 and 20 mg doses produced significant analgesia, as well as anti-emesis and appetite stimulation. Authors cautioned that some subjects reported unwanted side effects such as sedation and depersonalization at the 20 mg dose level. In a follow-up single-dose study of 36 subjects, Noyes et al. reported that 10 mg of THC produced analgesic effects over a seven-hour observation period comparable to 60 mg of codeine, and that 20 mg of THC induced effects equivalent to 120 mg of codeine (Noyes, Brunk, Avery,  & Canter, 1975)  Authors noted that respondents found higher doses of THC to be more sedative than

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codeine. However, in a separate publication, Noyes et al reported that patients administered THC had improved mood, sense of well-being, and less anxiety (Noyes & Baram, 1974). A study by Staquet and colleagues on the effects of a THC nitrogen analogue on cancer pain yielded similar results (Staquet, Gantt, & Machin, 1978). Authors found the THC analogue equivalent to 50 mg of codeine and superior to both placebo and 50 mg of secobarbital in subjects with mild, moderate and severe pain. A more recent study investigated the effects of whole-plant extract preparations in patients with intractable cancer pain (Johnson et al., 2010). One hundred seventy-seven patients experiencing inadequate analgesia despite chronic opioid use were randomized to receive the THC:CBD extract (N=60), the THC extract (N  =  58) or placebo (N  =  59) in a two-week, multicenter, double-blind trial. Pain relief was superior in the THC:CBD group with twice as many patients in the combination arm achieving a greater than 30% reduction in pain when compared to placebo. The THC alone group fared more or less the same as the placebo recipients. No change from baseline in median dose of opioids or need for breakthrough medications was seen.

NEUROPATHY

Cannabinoids have also been shown to be of potential benefit in an animal model of neuropathic pain (Herzberg, Eliav, Bennett,  & Kopin, 1997). Neuropathic pain is a troubling symptom in cancer patients, especially those treated with platinum-based chemotherapy or taxanes. A  painful sensory peripheral neuropathy is also commonly encountered in patients with HIV infection either as a consequence of HIV itself or antiretroviral drugs used in treatment of the infection. We completed a randomized, controlled trial of smoked cannabis compared to placebo in 50 subjects with HIV-related peripheral neuropathy (Abrams et al., 2007). Smoked cannabis reduced daily pain by 34% compared to 17% with placebo (p  =  0.03). Greater than 30% reduction in pain was reported by 52% in the cannabis group and by 24% in the placebo group (p  =  0.04). The first cannabis cigarette reduced chronic pain by a median of 72% compared to 15% with placebo (p  0 to < 1 joint-years of marijuana use had a 37% reduction in the risk of developing lung cancer compared to those who never smoked marijuana. Although this was the only cohort in which the reduction in lung cancer risk reached statistical significance, in the model, all levels of marijuana use (including ≥ 60 joint-years) had adjusted odds ratios less than 1.0. The authors report adjusted ORs 32  µmol/L are associated with inactivation of CYP3A4 function (Venkataramanan et  al., 2000). Therefore, the plasma concentrations of silybin at the manufacturer-recommended doses of milk thistle as applied in this study may be too low to affect the various disposition pathways of irinotecan. Overall, this suggests that milk thistle is unlikely to alter the pharmacokinetics of anticancer drugs that are predominantly eliminated by CYP3A and/or UGT1A. ST. JOHN’S WORT

St. John’s wort is composed of a very complex mixture of over two dozen compounds, including catechin-type tannins and condensed-type proanthocyanidins; flavonoids (mostly hyperoside, rutin, quercetin, and kaempferol); biflavonoids (e.g., biapigenin); phloroglutinol derivatives like hyperforin, phenolic acids, volatile oils and naphtodianthrones, including hypericin and pseudohypericin (Barnes, Anderson, & Phillipson, 2001).

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Hyperforin (St. John’s Wort component) H

ACD Anticancer Drug

ACD

Cytoplasm

H

Nucleus

PXR RXR

CYP1A2 CYP2B6 CYP2C9 UGT1A1 CYP2C19 UGT1A9 CYP3A4

Promoter Region

ABCB1 ABCC2

ABC transporters

OH

ACD

CYP

UGT GA

ACD

ACD

Figure 9.4.  Induction of cytochrome P450 (CYP) isozymes, UDP glucuronosyltransferase (UGT) isozymes, and ATP binding cassette (ABC) transporter proteins by the St. John’s wort constituent, hyperforin, through activation of the human pregnane X receptor (PXR; also known as Nr1i2). PXR binds to DNA via a pregnane response element as a heterodimer with the 9-cis retinoic acid receptor (RXR), and transduces phase I metabolism (e.g., hydroxylation), Phase II metabolism (e.g., glucuronic acid [GA] conjugation), and active, outward-directed transport of many commonly used anticancer drugs (ACD).

Various in vitro studies have shown that St. John’s wort is a potent inducer of CYP1A2 (Karyekar, Eddington,  & Dowling, 2002), CYP2B6 (Goodwin, Moore, Stoltz, McKee, & Kliewer, 2001), CYP2C9, CYP2C19 (Zou, Harkey, & Henderson, 2002), and CYP3A4 (Moore et  al., 2000; Wentworth, Agostini, Love, Schwabe, & Chatterjee, 2000), but not of CYP2D6 (Zhou et al., 2003), CYP3A5, CYP3A7, and CYP3A43 (Krusekopf, Roots, & Kleeberg, 2003). The inducing effects on CYP2B6 (Goodwin et al., 2001), CYP2C19 (Chen, Ferguson, Negishi, & Goldstein, 2003), and CYP3A4 (Bertilsson et al., 1998; Lehmann et al., 1998; Watkins et al., 2003) have been linked to hyperforin-induced ligand activation of a steroid- and xenobiotic-regulated transcription factor known as the pregnane X receptor (also known as PXR or NR1I2) (Figure 9.4). Using cDNA-expressed models, St. John’s wort extracts have also been reported to inhibit the activity of several enzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 through both competitive and noncompetitive actions (Budzinski, Foster, Vandenhoek, & Arnason, 2000; Foster et al., 2003; Obach, 2000).

302  Integrative Oncology

Animal studies using probe drugs have provided compelling evidence that St. John’s wort is also a potent modulator of CYP3A activity in vivo both in mice (Bray, Perry, Menkes,  & Rosengren, 2002; Cantoni, Rozio, Mangolini, Hauri, & Caccia, 2003) and rats (Durr et al., 2000). However, short-term treatment of St. John’s wort, hypericin, or hyperforin failed to induce CYP isoforms (Bray, Brennan, Perry, Menkes,  & Rosengren, 2002; Noldner  & Chatterjee, 2001). Human studies indicated that long-term (i.e. more than 2 weeks) administration of St. John’s wort significantly induced intestinal and hepatic CYP3A4 (Dresser, Schwarz, Wilkinson, & Kim, 2003; Durr et al., 2000; Gurley et al., 2002; Kerb, Bauser, Brockmoller, & Roots, 1997; Roby, Anderson, Kantor, Dryer, & Burstein, 2000; Wang et al., 2001), but did not alter CYP2C9 (Wang et  al., 2001), CYP1A2 (Gurley et  al., 2002; Wang et  al., 2001), or CYP2D6 (Gurley et  al., 2002; Markowitz et  al., 2000; Roby, Dryer,  & Burstein, 2001; Wang et al., 2001). As predicted from the animal experiments, induction of CYP3A4 by St. John’s wort is subject to the dosing regimen, and schedules involving administration of the herb for less than 8 days are unlikely to activate PXR (Ereshefsky, Gewertz, Francis Lam, Vega, & Ereshefsky, 1999; Markowitz et  al., 2000). The cited studies have also indicated that St. John’s wort contains both inhibitory and activating constituents for the CYP system, causing temporally distinguishable inhibition and induction depending on the dose, duration of administration, and the formulation and source of the botanical. LS-80 intestinal carcinoma cells exposed to St. John’s wort or hypericin have shown strong induction of ABCB1 in a dose-dependent fashion (Perloff, Von Moltke, Stormer, Shader, & Greenblatt, 2001). Similarly, the administration of St. John’s wort significantly increases the intestinal expression of ABCB1 in rats and humans (Durr et  al., 2000), as well as its expression in peripheral blood lymphocytes (Hennessy et al., 2002). Given the broad substrate specificity of this protein, these findings have been used to support the importance of ABCB1 in addition to CYP3A4 as a mechanism to reduce oral absorption of substrate drugs given combined with St. John’s wort. The mechanism for most of the interactions observed in subsequent clinical trials remains unclear, although for some agents induction of CYP3A4 (e.g., indinavir, midazolam, simvastatin), ABCB1 (e.g., digoxin, fexofenadine), or both (e.g., cyclosporin, tacrolimus) may explain their increased clearance. Nonetheless, although common molecular mechanisms may be involved, the quantitative aspects of CYP3A4 and ABCB1 induction are complex and depend on the particular drug and the relative contribution of both proteins to its absorption and disposition (Dresser et al., 2003). Another factor adding to the complexity is the recent finding that St. John’s wort produced significantly greater increases in CYP3A4 expression in females compared to males, which appeared to be unrelated to body mass index (Gurley et al., 2002).

Botanical-Drug Interactions in Oncology—What Is Known?  303

Although no differences have been noted in the extent of inducibility by St. John’s wort among six different ethnic groups (Xie et al., 2005), the effects of this botanical remain unpredictable, especially when based on in vitro or animal studies. For example, St. John’s wort did not alter the pharmacokinetics of the CYP3A4 substrate carbamazepine (Burstein et al., 2000), presumably because repeated intake of the drug already maximizes enzyme induction. More recently, it was shown that various transcription factors, including the pregnane X receptor, regulate constitutive expression of mouse Ugt1a1 and Ugt1a9 (Mackenzie et al., 2003), and human UGT isoforms (Xie et al., 2003). However, in a clinical study, St. John’s wort had no effect on the extent of glucuronidation of SN-38, the active metabolite of the anticancer drug irinotecan (Mathijssen, Verweij, de Bruijn, Loos, & Sparreboom, 2002), which is a known substrate for UGT1A1 and UGT1A9 (Hanioka et al., 2001). Regardless, the modulation of CYP3A4 activity and subsequently reduced exposure to SN-38 observed in the study with St. John’s wort administered to cancer patients receiving irinotecan is particularly worrisome bearing in mind that the degree of drug-induced myelo-suppression, and likely also the antitumor activity, was substantially reduced in the presence of the botanical (Mathijssen et al., 2002). Animal studies have further suggested that St. John’s wort may modulate irinotecan-induced toxicity by mechanisms that are unrelated to altered drug clearance (Hu et al., 2005; Hu et al., 2006). On the basis of in vitro data obtained in human hepatocyte cultures, increased docetaxel metabolism can also be expected in patients using St. John’s wort chronically (Komoroski et al., 2005). Because of the extensive reduction in the plasma levels of SN-38, patients should be advised to refrain from taking St. John’s wort to prevent undertreatment. The same advice could be given to patients that are going to be treated with imatinib. In two clinical trials, healthy subjects taking imatinib combined with St. John’s wort showed on average a 30% to 32% lower mean area under the curve (Frye, Fitzgerald, Lagattuta, Hruska, & Egorin, 2004; Smith et al., 2004). It should be noted that the main metabolite formed after metabolism of imatinib, an N-desmethylated piperazine derivative, has been shown to have anti-tumor activity comparable with that of imatinib. Since St. John’s wort had no substantial influence on the systemic exposure to this metabolite, the clinical implications of the reduced plasma levels of imatinib after St. John’s wort intake is, therefore, unclear and requires further investigation (Meijerman, Beijnen, & Schellens, 2006). Overall, however, the reported data suggest that interactions between St. John’s wort and most anticancer agents are likely to have clinical and toxicological implications (Table  9.4), and that rigorous testing for possible interactions is urgently needed.

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Table 9.4.  Suspected Interaction of St. John’s Wort with Anticancer Drugs Anticancer Drug

Main Proteins Involved in Drug Absorption and/or Elimination

Expected Effectof Chronic St. John’s Wort Coadministration

6-Mercaptopurine

Thiopurine methyltransferase, ABCC4

None

6-Thioguanine

N/a

None

Anastrazole

CYP2C9, CYP3A4

Decreased exposure

Arsenic trioxide

Non CYP methylation

None

Asparaginase

N/a

None

Axitinib

CYP3A4, CYP3A5

Decreased exposure

Bleomycin

N/a

None

Bosutinib

CYP3A4, ABCB1

Decreased exposure

Busulfan

CYP3A4

Decreased exposure

Cabozantinib

CYP3A4, CYP2C9

Decreased exposure

Capecitabine

Esterases, cytidine deaminase

None

Carboplatin

N/a

None

Chlorambucil

ABCC2

Decreased exposure

Cisplatin

OCT2

None

Crizotinib

CYP3A4, CYP3A5

Decreased exposure

Cyclophosphamide

CYB2B6, CYP2C9, CYP3A4

Decreased exposure

Cytarabine

Cytidine deaminase, ABCC4

None

Dabrafanib

CYP2C8, CYP3A4

Decreased exposure

Dacarbazine

CYP2E1

Decreased exposure

Dasatinib

CYP3A4, FMO3

Decreased exposure

Docetaxel

CYP3A4, CYP3A5, ABCB1

Decreased exposure

Doxorubicin

CYP3A4, CYP2D6, ABCB1

Decreased exposure

Epirubicin

CYP3A4

Decreased exposure

Erlotinib

CYP3A4, CYP1A2

Decreased exposure

Estramustine

N/a

None

Etoposide

CYP3A4, ABCB1, ABCC1, ABCC2

Decreased exposure

Exemestane

CYP3A4

Decreased exposure

Fluorouracil

Dihydropyrimidine dehydrogenase

None

Gefitinib

CYP3A4, ABCB1, ABCG2

Decreased exposure

Gemcitabine

Deaminases

None

Hydroxyurea

N/a

None

Ifosfamide

CYP2B6, CYP3A4

Decreased exposure

(continued)

Botanical-Drug Interactions in Oncology—What Is Known?  305

Table 9.4.  Continued Anticancer Drug

Main Proteins Involved in Drug Absorption and/or Elimination

Expected Effectof Chronic St. John’s Wort Coadministration

Imatinib

CYP2C9, CYP2C19, CYP3A4, ABCB1, ABCG2

Decreased exposure

Irinotecan

CYP3A4, CES2, UGT1A1, ABCC2, ABCG2

Decreased exposure

Ixabipelone

CYP3A4

Decreased exposure

Lapatinib

CYP3A4, CYP3A5, ABCB1, ABCG2

Decreased exposure

Letrozole

CYP2A6, CYP3A4

Decreased exposure

Melphalan

N/a

None

Mesna

N/a

None

Methotrexate

ABCC1, ABCC2, ABCC4, ABCG2

Decreased exposure

Mitomycin C

N/a

None

Mitoxantrone

ABCB1, ABCG2

Decreased exposure

Nilotinib

CYP3A4

Decreased exposure

Oxaliplatin

OCT2

None

Paclitaxel

CYP3A4, CYP2C8, ABCB1

Decreased exposure

Pazopanib

CYP3A4, CYP1A2, CYP2C8

Decreased exposure

Ponatinib

CYP3A4, CYp2C8, CYP2D6

Decreased exposure

Regorafenib

CYP3A4, UGT1A9

Decreased exposure

Ruxolitinib

CYP3A4

Decreased exposure

Sorafenib

CYP3A4, UGT1A9

Decreased exposure

Sunitinib

CYP3A4

Decreased exposure

Tamoxifen

CYP2B6, CYP3A4, CYP1A2, CYP2E1

Decreased exposure

Temozolomide

N/a

None

Teniposide

CYP3A4, ABCB1

Decreased exposure

Thiotepa

N/a

None

Topotecan

CYP3A4, ABCB1, ABCG2

Decreased exposure

Trametinib

Non-CYP deacetylation”

Unknown

Tretinoin

CYP2C8, CYP2C9, CYP3A4

Decreased exposure

Vandetanib

CYP3A4, FMO1, FMO3

Decreased exposure

Vemurafenib

CYP3A4, ABCB1

Decreased exposure

Vinblastine

CYP3A4, ABCB1

Decreased exposure

Vincristine

CYP3A4, CYP3A5, ABCB1

Decreased exposure

Vinorelbine

CYP3A4

Decreased exposure

N/a, information not available.

306  Integrative Oncology

St. John’s wort is currently the only top-selling botanical for which sufficient clinical data is available that warrants labeling a contraindication for its concurrent or concomitant use with prescription anticancer drugs.

Conclusions and Future Research In recent years, a wealth of evidence has been generated from in vitro and in vivo studies showing that many botanical preparations interact extensively with drug-metabolizing enzymes and drug transporters. Moreover, a number of clinically important pharmacokinetic interactions have now been recognized, although causal relationships have not always been established. Most of the observed interactions point to the botanicals affecting several isoforms of the CYP family, either through inhibition or induction. These enzymes have a crucial role in the elimination of various anticancer drugs, and concurrent use of at least some botanicals with chemotherapy is destined to have serious clinical and toxicological implications (Table 9.5). Therefore, rigorous testing Table 9.5.  Specific Botanicals to Discourage and Avoid during Chemotherapy. Botanical

Concurrent Chemotherapy/Condition (Suspected Effect)

Ephedra

Avoid with all cardiovascular chemotherapy (synergistic increase in blood pressure)

Ginkgo

Caution with camptothecins, cyclophosphamide, TK inhibitors, epipodophyllotoxins, taxanes, and Vinca alkaloids (CYP3A4 and CYP2C19 inhibition); discourage with alkylating agents, antitumor antibiotics, and platinum analogues (free-radical scavenging)

Ginseng

Discourage in patients with estrogen-receptor positive breast cancer and endometrial cancer (stimulation of tumor growth)

Green tea

Discourage with erlotinib and pazopanib (CYP1A2 induction)

Japanese arrowroot

Avoid with methotrexate (ABCC and OAT transporter inhibition)

St. John’s wort

Avoid with all concurrent chemotherapy (CYP2B6, CYP2C9, CYP2C19, CYP2E1, CYP3A4, and ABCB1 induction)

Valerian

Caution with tamoxifen (CYP2C9 inhibition), cyclophosphamide, and teniposide (CYP2C19 inhibition)

Kava-kava

Avoid in all patients with preexisting liver disease, with evidence of hepatic injury (herb-induced hepatotoxicity), and/or in combination with hepatotoxic chemotherapy; caution with camptothecins, cyclophosphamide, TK inhibitors, epipodophyllotoxins, taxanes, and Vinca alkaloids (CYP3A4 induction)

TK, tyrosine-kinase.

Botanical-Drug Interactions in Oncology—What Is Known?  307

for possible pharmacokinetic interactions of anticancer drugs with widely used botanicals is urgently required. An additional consideration for cancer chemotherapy is that botanical-mediated induction of various enzymes and transporters may also take place in tumor cells, and subsequently result in resistance to anthracyclines, epipodophyllotoxins, taxanes, and Vinca alkaloids (Broxterman, Lankelma, & Hoekman, 2003). Likewise, catalytic inhibition of topoisomerase IIα in tumor cells by some botanicals (Peebles, Baker, Kurz, Schneider, & Kroll, 2001) might diminish therapeutic responses to anthracyclines, dactinomycin, and etoposide (Mansky & Straus, 2002). Because of the high worldwide prevalence of herbal medicine use, physicians should include botanical supplement usage in their routine drug histories to have an opportunity to outline to individual patients which potential hazards should be taken into consideration (de Smet, 2002; Weiger et al., 2002). REFERENCES

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10 The Antioxidant Debate ELENA J. LADAS AND KARA M. KELLY

Key Concepts Patients with cancer are taking antioxidant supplements in combination with conventional chemotherapy and radiotherapy to enhance the anticancer activity and to reduce the side effects of conventional treatment. ■ Although some evidence suggests that antioxidants may be beneficial (e.g., enhancing survival, reducing toxicity), other evidence suggests that antioxidants may reduce the efficacy of cancer therapy. ■ Not all antioxidant supplements are equivalent; antioxidants counteract free radical activity through multiple mechanisms of action. ■ Not all chemotherapy agents rely on oxidative stress for anticancer activity, so the risk of interaction with antioxidant supplements is also dependent on the type of conventional chemotherapy thereby making uniform recommendations difficult. ■ Several studies have shown that plasma concentrations of antioxidants are depleted in individuals undergoing treatment for cancer; some studies suggest that this decrease may be associated with therapy-related toxicities. ■ The role of antioxidants for the treatment of cancer remains unclear. Most of the published studies have evaluated vitamin C and melatonin, with a few other studies examining single or combinations of antioxidants. Additionally, most of the available studies have been performed among individuals with advanced disease who have not responded to initial treatment. ■

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For symptom management, the efficacy of antioxidants as part of a supportive care regimen is limited; the results of these trials have been mixed. ■ The use of β-carotene and vitamin E supplements in conjunction with radiation therapy is contraindicated and should be avoided, especially among smokers. ■ For some antioxidants, the results from clinical trials appear to be encouraging; however, health-care providers should be cautious about recommending antioxidant supplements during chemotherapy until adequately powered clinical studies performed in homogenous patient populations are available to guide clinical practice. ■

Introduction The use of antioxidant supplements by patients during conventional cancer treatment is among one of the most controversial areas in oncology practice. Past estimates of antioxidant use by patients with cancer have varied considerably, with rates ranging from 13% to 87% depending on the survey, the type of cancer studied, and a variety of other individual and demographic factors (Block et  al., 2007; Branda, Naud, Brooks, Chen,  & Muss, 2004; Burstein, Gelber, Guadagnoli, & Weeks, 1999; Clemens, Waladkhani, Bublitz, Ehninger, & Gey, 1997; Greenlee et al., 2009; Kelly et al., 2000; Legha et al., 1982; Lesperance et al., 2002). Surveys have found that supplementation with antioxidants extends into survivorship with up to 81% of survivors reporting supplementation (Greenlee et al., 2009; Miller et al., 2008). Much of the controversy surrounding antioxidants and cancer therapy has arisen because certain classes of chemotherapy agents exert some of their anticancer effects by generating reactive oxygen species, or free radicals (Moss, 2006). These agents include the anthracyclines (e.g., doxorubicin), platinum-containing complexes (e.g., cisplatin, carboplatin), and alkylating agents (e.g., cyclophosphamide, ifosfamide), as well as radiation therapy. The theoretical concern is that antioxidants might somehow interfere with or counteract the activities of these anticancer agents. However, many chemotherapy agents have multiple mechanisms of action and do not necessarily rely on the generation of free radicals (Table 10.1). Data on interactions with the newer targeted agents for cancer is evolving. For example, vitamin C can inhibit the in vitro activity of bortezomib through

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Table 10.1.  Oxidative Stress and Chemotherapy. Class

High

Low

Insufficient Data

Examples

Anthracyclines

Doxorubicin, daunorubicin

Alkylating agents

Cyclophosphamide, ifosfamide, procarbazine, dacarbazine, melphalan

Platinum containing complexes

Cisplatin, carboplatin

Topoisomerase 1 inhibitors

Irinotecan

Topoisomerase 2 inhibitors

Etoposide

Proteosome inhibitors

Bortezomib

Purine/Pyrimidine analogues

6-Mercaptopurine, 6-thioguanine

Antimetabolites

Methotrexate, L-asparaginase

Monoclonal antibodies

Rituximab

Vinca alkaloids

Vincristine, vinblastine

Taxanes

Paclitaxel

Corticosteroids

Prednisone, dexamethasone

Antiangiogenic agents

Bevacizumab+

Tyrosine kinase inhibitors

Imatinib+, dasatinib+, nilotinib+

+ Preclinical data suggests that mechanism of action may in part be related to oxidative stress.

a direct binding between the hydroxyl group of the antioxidant agent and the boronic acid of the proteasome inhibitor (Fernandez et al., 2006; Llobet et al., 2008; Zou et al., 2006), thereby reducing the affinity of the proteasome inhibitor for the chymotrypsin-like subunit of the proteasome. Another study showed that plasma collected from donors taking a daily supplement of vitamin C reduced the proteasome inhibitor activity and cytotoxicity of bortezomib in vitro, and in a xenograft mouse model of multiple myeloma, the efficacy of bortezomib for inhibiting human multiple myeloma cell growth and prolonging host survival were reduced when mice received bortezomiband vitamin C supplements concurrently (Perrone et al., 2009). Free-radical-mediated damage to normal tissues often manifests as the side effects of chemotherapy, such as anthracycline-associated cardiomyopathy, or hearing loss or kidney failure that can be caused by platinum-based

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agents. Antioxidant supplementation may facilitate anticancer treatment by protecting normal tissues and allowing for higher doses of chemotherapy to be administered. Additionally, at certain concentrations, they might also be able to directly affect cancer cells through pro-oxidant effects. Many proponents for combining antioxidant supplements with conventional cancer therapy justify this approach because observational studies have identified the depletion of antioxidant levels during treatment with radiation and chemotherapy, particularly with the use of conditioning regimens prior to stem cell transplantation (Durken et al., 2000; Kennedy, Ladas, Rheingold, Blumberg, & Kelly, 2004; Kennedy et al., 2004). Chemotherapy agents vary in their risk for interaction with antioxidant supplements. Table 10.1 lists chemotherapy agents by association with the generation of oxidative stress, with “high oxidative stress” agents being at potentially increased risk for interaction with antioxidant supplements.

The use of accepted pharmaceutical protective agents that work through antioxidant mechanisms further supports the use of antioxidant supplements during chemotherapy. Mesna, for example, minimizes the risk of hemorrhagic cystitis by forming nontoxic compounds in the bladder with acrolein, 4-hydroxy-metabolites, and other urotoxic metabolites of oxazaphosphorines related to ifosfamide and cyclophosphamide metabolism. The thiol metabolite of amifostine is readily taken up by cells where it binds to and detoxifies reactive metabolites of platinum and alkylating agents as well as scavenges free radicals. Tumor cells are generally not protected because amifostine and metabolites are present in normal cells at 100-fold greater concentrations than in tumor cells (Creagan et al., 1979; Culy & Spencer, 2001; McEvoy, 2002; Moertel et  al., 1985). The use of these cytoprotective agents is based on the results of preclinical studies and evidence accumulated from clinical trials to date, which is still lacking for most antioxidant supplements. A limited number of clinical trials have investigated antioxidant supplementation for the treatment of specific cancers, or for the reduction in or prevention of common adverse effects associated with anticancer therapy. Several systematic reviews have evaluated the health advantages of using antioxidant supplements concomitantly with chemotherapy (Block et al., 2007; Greenlee et al., 2009; Ladas et al., 2004; Lawenda et al., 2008; Simone, Simone, Simone, & Simone, 2007), with each of the systematic reviews producing similar conclusions. Most clinical trials have been limited by heterogeneous patient populations, variation in the routes of antioxidant administration, or study designs

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that lacked appropriate blinding to randomization or adequate sample sizes with statistical power (Block et  al., 2007; Greenlee et  al., 2009; Ladas et  al., 2004; Lawenda et al., 2008). Moreover, one trial demonstrated the risk of supplementing with antioxidants during radiation treatment, thus highlighting the concern that antioxidants, although “natural” substances, may have deleterious effects on health outcomes (Bairati et al., 2005). This chapter provides an overview of the issues surrounding this very controversial topic, with a summary of the key clinical trial evidence that has been reported to date. CLASSES OF ANTIOXIDANTS

“Antioxidant” is a broad term that refers to a myriad of different compounds. Due to the disparity in the biological actions and targets of antioxidants, there is no simple paradigm for advising patients on their safe use during conventional chemotherapy and radiotherapy. Antioxidants function through a variety of mechanisms and each may belong to more than one functional category (Papas, 1999). There are two general categories of antioxidants: 1. Enzymatic antioxidants such as catalase, superoxide dismutase and glutathione peroxidase. 2. Nonenzymatic antioxidants, such as vitamin C, vitamin E, coenzyme Q10, melatonin and pycnogenol. Within these two broad categories, there are four functional subclasses: 1. Preventative agents that suppress the formation of free radicals. 2. Radical scavenging agents that inhibit chain initiation and/or propagation. 3. Repair and de novo enzymes that repair and reconstitute cell membranes. 4. Adaptation agents that generate appropriate antioxidant enzymes and transfer them to the site of action. The wide spectrum of activity of antioxidant compounds further complicates the counsel for patients on the safety of taking antioxidants in combination with conventional cancer therapy. Most nonenzymatic antioxidants compounds or their precursors are obtained orally, either through foods or dietary supplements. Although dietary intake of antioxidant-rich foods rich has been shown to elevate human plasma

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antioxidant levels, it is unlikely that intake from the typical 2,500 calorie American adult diet could effectively achieve the steady-state levels required to interact with the chemotherapy concentrations used in anticancer treatments. Although one study in children being treated for acute lymphoblastic leukemia found that an increased dietary intake of antioxidant nutrients was associated with reductions in chemotherapy-associated side effects (Kennedy et al., 2004), this observation has not been confirmed in larger studies. It is conceivable that the regular use of antioxidant supplements could achieve steady state levels that might interact with chemotherapy or radiation therapy. Nonetheless, the dose, duration, and particular type of antioxidant that might be able to create an interactive effect have not yet been established. The bioavailability of antioxidant compounds varies according to their source, route of administration, and form (Ratnam, Ankola, Bhardwaj, Sahana, & Kumar, 2006). Lycopene, for example, is more readily absorbed in cooked rather than raw form, and intravenous administration of vitamin C has a biological activity that differs from its oral form (Padayatty et al., 2006; Ratnam et al., 2006). Studies evaluating antioxidant supplementation during chemotherapy are further complicated by the individual variation in the genes that code for antioxidant enzymes as well as variation in the enzymes involved in the metabolism of chemotherapeutic agents, thus potentially impacting the effectiveness of the antioxidant. Individuals with limited or no activity in specific antioxidant genes, such as glutathione-S-transferase, may have decreased ability to exert anti-radical activity, which may impact the incidence of toxicity and influence treatment outcomes (Ambrosone et  al., 2005; Davies et  al., 2001). The overall antioxidant status of the patient will further impact their effectiveness. Children with acute lymphoblastic leukemia with a higher antioxidant status, measured by the oxygen radical absorbance assay, have been shown to experience fewer side effects associated with cancer therapy (Kennedy et al., 2004). The safety of antioxidant supplementation during chemotherapy and radiation therapy is likely to depend on the specificity of the antioxidant and the chemotherapy agent. The opinion that all antioxidants are contraindicated within the context of anti-cancer treatment is narrow and over-simplified.

ANTIOXIDANTS FOR THE TREATMENT OF CANCER

Although there is preclinical data supporting a possible role for antioxidant supplements as anticancer agents, the evidence from clinical trials remains quite limited. Multiple systematic reviews of studies have evaluated the effects of antioxidants during chemotherapy, with all of the reviews underscoring the

The Antioxidant Debate  323

need for additional studies with pre-defined outcomes in homogenous cancer populations (Block et al., 2007; Greenlee et al., 2009; Ladas et al., 2004; Lawenda et al., 2008).

Single Antioxidant Supplements Vitamin C, a strong reducing agent, functions as a metal chelator and cellular protector. Vitamin C was postulated to have an important role in the treatment of cancer, based upon the observations that vitamin C is involved in host resistance to cancer and that patients with cancer are often found to be depleted of vitamin C (Cameron & Pauling, 1974). Early studies investigating supplementation with vitamin C promoted the nutrient’s ability increase host resistance to cancer by stimulating immune function, increasing resistance to intercellular ground substance hydrolysis by hyalurindase elaborated by tumor cells, stabilizing the production of hormones, and by protecting the pituitary-adrenal axis from the effects of stress (Cameron, Pauling,  & Leibovitz, 1979; Wittes, 1985). Case studies of terminal stage cancer patients treated with a combination of high dose oral and intravenous vitamin C who demonstrated prolonged survival were reported (Cameron, 1991; Cameron & Pauling, 1976, 1978; Cameron et al., 1979). Two subsequent double-blind, randomized, placebo-controlled trials showed no survival advantage with high dose oral vitamin C supplementation as a treatment for cancer (Creagan et al., 1979; Moertel et al., 1985). Critics of this work suggested that doses were not adequate to sustain therapeutic concentrations of vitamin C and suboptimal administration (oral versus intravenous) (Koh et  al., 1998; Stephenson, Levin, Spector,  & Lis, 2013). A case study has reported a beneficial effect of intravenous administration of vitamin C on tumor control endorsing its intravenous administration over oral (Padayatty et  al., 2006). Three phase I  studies have been performed to identify the maximum tolerated dose of vitamin C (Hoffer et al., 2008; Monti et al., 2012; Stephenson et al., 2013). Stephenson et al. reported that intravenous vitamin C administered at 70–80 mg/m2 is tolerable and able to achieve therapeutic serum vitamin C concentrations. Doses above this do not provide further increases in vitamin C concentrations. Other phase I studies have evaluated intravenous vitamin C administered with chemotherapy (Held et al., 2013; Welsh et al., 2013). Phase I studies have been performed in adults with metastatic pancreatic cancer (Monti et al., 2012; Welsh et  al., 2013)  because prior studies have demonstrated that pancreatic cancer is sensitive to pharmacologic ascorbate both in vitro and in animal models (Chen et  al., 2008). Doses of intravenous vitamin C (15–125 grams,

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twice per week (Welsh et al., 2013); 50–100 grams, three times per week (Monti et al.) in combination with conventional therapy are well tolerated with some suggested efficacy of the treatment combinations. Additionally, several studies have investigated intravenous vitamin C in conjunction with chemotherapy for relapsed/refractory multiple myeloma. In a phase I study evaluating the feasibility of concomitant arsenic trioxide, ascorbic acid (1 gram/day), and bortezomib, four of 10 patients achieved clinical benefit, with one patient achieving a durable partial response (Held et al., 2013). A  phase I/II study investigating the safety and efficacy of arsenic trioxide, bortezomib, and intravenous ascorbic acid in 22 adults with relapsed or refractory multiple myeloma found that the regimen was tolerated with a suggestion of efficacy of the treatment regimen evidenced by an objective response rate in 27% of participants (Berenson et  al., 2006). One study reported on the use of intravenous ascorbic acid as part of a frontline treatment for multiple myeloma. In a single-arm, multicenter, phase II study examining the combination of bortezomib, intravenous vitamin C, and melphalan performed in 35 patients with newly diagnosed multiple myeloma, the combination was well-tolerated and disease control was achieved in 94% of the patients (Berenson et al., 2009). Melatonin is an endogenous hormone that is synthesized and secreted by the pineal gland from the amino acid tryptophan. Melatonin protects against oxidative stress through its ability to upregulate antioxidant enzymes such as superoxide dismutases, peroxidases, and enzymes of glutathione supply; to down-regulate pro-oxidant enzymes such as nitric oxide synthases and lipoxygenases; and also to govern some of the actions of quinone reductase 2 (Hardeland, 2005). In addition to its antioxidant effects, melatonin stimulates apoptosis, reduces tumor growth factors, decreases endothelial growth factor and exerts anti-inflammatory properties (Lissoni et al., 2002). At physiologically attainable concentrations, melatonin inhibits cancer cell division and with administration of higher oral doses (20–40 mg/day), melatonin is cytotoxic (Mahmoud, Sarhill, & Mazurczak, 2005). A systematic review has suggested that melatonin supplementation may improve survival in a number of solid tumors (Mills, Wu, Seely,  & Guyatt, 2005). Although the effects of melatonin on prolonging survival are intriguing, the studies demonstrating cancer survival were all conducted by the same research group and thus should be confirmed in larger phase III trials. Melatonin has also been studied as an adjunctive agent to chemotherapy. The addition of melatonin to interferon therapy in the treatment of 22 patients with progressive metastatic renal cell carcinoma was associated with remission in seven patients (three complete) and achievement of stable disease in nine others (Neri et  al., 1994). In conjunction with cisplatin and etoposide,

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melatonin has also been studied as a treatment for non-small–cell lung cancer (Lissoni, Chilelli, Villa, Cerizza, & Tancini, 2003). The addition of melatonin to irinotecan in 30 patients with metastatic colorectal cancer who were progressing on 5-fluorouracil therapy was well-tolerated and was associated with partial responses to treatment and the ability to decrease irinotecan dose by 50% without attenuating its efficacy (Cerea et  al., 2003). Melatonin has also been studied in combination with radiotherapy. In a randomized phase II trial, 126 patients with brain metastasis were assigned to radiation alone or radiation combined with melatonin (Berk et al., 2007). The addition of melatonin to the treatment did not increase survival. MIXTURES OF ANTIOXIDANT SUPPLEMENTS

The administration of antioxidant mixtures has been investigated in the treatment of several different cancer types, with largely insignificant results. For example: • A  randomized trial of chemotherapy alone or chemotherapy with antioxidants [vitamin C 6100 mg/day; dl-alpha-tocopherol 1050 mg/ day; and β-carotene 60mg/day] for treatment of 136 patients with stage IIIb and stage IV non-small– cell lung cancer observed no difference in tumor response rate or chemotherapy associated toxicities (Pathak et al., 2005). • A  case-control study investigating mega-doses of vitamins in 90 women with unilateral nonmetastatic breast cancer noted no improvements in disease-free survival in the supplemented group; in fact, the supplemented group had lower survival overall, albeit nonsignificantly (Lesperance et al., 2002). • In men with androgen insensitive prostate cancer, combination antioxidant treatment (750 mg of vitamin C, 200 mg selenium, 350 mg vitamin E, and 200 mg of coenzyme Q10) was not associated with significant effects on PSA levels (Hoenjet et al., 2005). • However, building on reports of prolonged remission in two women with advanced epithelial ovarian cancer supplementation with vitamin C (3,000–9,000 mg/day), vitamin E (1200 IU/day), β-carotene (25 mg/day), and vitamin A  (5,000–10,000 IU/day), (Drisko, Chapman, & Hunter, 2003b) a randomized controlled trial was initiated according to a publication in 2003. No subsequent reports confirming these initial observations have been published (Drisko, Chapman, & Hunter, 2003a).

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ANTIOXIDANTS FOR SUPPORTIVE CARE

Several trials have investigated the efficacy of antioxidants as supportive care agents in individuals receiving conventional anti-cancer therapy. Although many trials investigating the role of antioxidants as supportive care agents have been published, very few have been double-blind, randomized trials. Summarized below are the results from select studies of antioxidants for cancer-related toxicities, categorized by symptoms (Tables 10.2 and 10.3).

Cancer Related Cachexia and Weight Loss Cancer-related wasting, or cachexia is characterized by early satiety, weight loss, anemia, and asthenia (Langer, Hoffman,  & Ottery, 2001). A  variety of tumor-related factors and increased catabolism often incite cachexia, and its progression is associated with the depletion of intracellular glutathione (GSH) as well as increases in markers of oxidative stress. Supplementation with a GSH-repleting agent has been shown to be effective in treating cachexia associated with human immunodeficiency virus infection (Pacheo, Goldhart, Guilford, Kwyer,  & Kongshavn, 1997). Several studies have investigated the administration of intravenous GSH in adults with colon (Cascinu et al., 2002), ovarian (Colombo et al., 1995; Parnis et al., 1995; Smyth et al., 1997), gastric (Cascinu, Cordella, Del Ferro, Fronzoni,  & Catalano, 1995; Fujimoto et  al., 1983), and other cancers (Schmidinger et al., 2000), with results not supporting its efficacy in managing chemotherapy-related side effects or improving overall survival (Lawenda et al., 2008). Only one nonrandomized, pilot study in children with cancer at high risk for developing cachexia investigated the effects of an undenatured whey-protein derivative (a GSH precursor that is efficiently utilized by cells). Improvements in clinical status including weight gain and increased levels of reduced glutathione were observed; however, these results have not been confirmed in trials (Melnick et al., 2005). Several studies have evaluated the effect of melatonin on symptoms including poor appetite, fatigue, and depression in patients with cancer. Patients with metastatic solid tumors randomly assigned to supportive care plus melatonin for three months stabilized weight better and had lower levels of tumor necrosis factor α than patients receiving supportive care alone (Lissoni et al., 1996). However, in a double-blind, randomized controlled trial among 48 adults with advanced lung or gastrointestinal cancer, melatonin or placebo administered over a 28-day period was not associated with improvements in appetite, quality of life, or weight gain (Del Fabbro, Dev, Hui, Palmer, & Bruera, 2013). Two studies have investigated antioxidant combinations for cachexia-related symptoms. One case-control study examined the combination of selenium

Table 10.2.  Studies of Antioxidant Supplements for Supportive Care during Cancer Therapy in Adults. Author, Year

Antioxidant (Dose)

Indication

Type of Cancer

Outcome

Mantovani, 2006

α-Lipoic acid (300 mg) vitamin E (400mg) vitamin C (500 mg)

Cachexia

Advanced Cancer

­ Lean body mass, appetite, and body weight ↑ ↓ Proinflammatory cytokines and tumor necrosis factor ­Quality of life ↓ Fatigue

Iarussi, 1994

Coenzyme Q10 (200 mg)

Cardiotoxicity

Acute lymphoblastic leukemia Non-Hodgkin lymphoma

↑ % Left ventricular fractional shortening (p < 0.05; placebo; p < 0.002 intervention group) ↓ Septum wall thickening (control only, p < 0.01)

Okuma, 1984

Coenzyme Q10 (90 mg)

Cardiotoxicity

Various malignancies

Prolongation of QTc observed in controls compared to intervention group (p < 0.05)

Takimoto, 1982

Coenzyme Q10 (90 mg)

Cardiotoxicity

Various malignancies

­ In cardiothoracic ratio in controls ↑ compared to intervention (p < 0.01) No significant differences in pulse rates or QRS voltage

Lenzhofer, 1983

α-Tocopherol (200 mg)

Cardiotoxicity

Metastatic breast cancer

After 6 hrs of doxorubicin,↑ in PEPI:LVETI ratio in controls (p < 0.001) Doxorubicin distributed and eliminated faster in subjects (p < 0.05) In controls, correlation between change in PEPI:LVETI ratio and doxorubicin concentration (p < 0.001) (continued)

Table 10.2. Continued Author, Year

Antioxidant (Dose)

Indication

Type of Cancer

Outcome

Legha, 1982

α-Tocopherol (2 gm/m2)

Cardiotoxicity

Metastatic breast cancer

No significant findings

Wagdi, 1996

Vitamin C (1gram), vitamin E (600 mg)

Cardiotoxicity

Various malignancies

No significant findings

Weitzman, 1980

dl- α-Tocopherol (1800 IU)

Cardiotoxicity

Various malignancies

No significant findings

Argyriou, 2005

α-tocopherol (600 mg)

Neurotoxicity

Nonmyeloid malignancies

↓ Incidence of neurotoxicity (p = .019) ↓ Risk of developing neuropathy (RR=.34; CI=0.14-0.84)

Argyriou, 2006

dl-alpha tocopheryl acetate (600 mg)

Neurotoxicity

Solid malignancies

↓ Incidence of neurotoxicity (p = .03) ↓ Risk of developing neuropathy (RR=.3; CI=0.1–0.9)

Weijl, 2004

vitamin C (1000 mg), dl-atocopherol acetate (400 mg), and selenium (100 μg)

Cisplatin-induced ototoxicity and nephrotoxicity

Various malignancies

No significant findings

Sieja, 2004

selenium (50 μg), vitamin C (200 mg), vitamin E (36 mg), and β-carotene (15 mg)

Chemotherapyrelated toxicities

Ovarian cancer

­ neutrophil count and % after 12 wks in ↑ treatment group versus controls (p < 0.05) ↓ in severity of side-effects in treatment group vs. controls after 12 wks (p < 0.05)

Hu, 1997

Selenium (4000 μg)

Cisplatin-induced toxicities

Various malignancies

Leukocytes ↑ during treatment on Days 7 (p < 0.05), 10 (p < 0.05), and 14 (p < 0.05) ↓ need of blood transfusions and use of Granulocyte Colony Stimulating Factor due to leucopenia during treatment (p < 0.05, p 100 beats/min or 145 mmHg systolic and 95 mmHg diastolic. Resting blood pressure < 85 mmHg systolic. Irregular pulse. Swelling of ankles.

Caution if at risk of cardiac disease: recommend medically supervised exercise testing and training. If on blood pressure medication that controls heart rate, target heart rate may not be attainable; avoid overexertion. Lymphedema: wear compression garment on limb when exercising.

Pulmonary

Severe dyspnea. Cough, wheezing. Chest pain increased by deep breath.

Mild-to-moderate dyspnea: avoid maximal tests.

Neurological

Significant decline in cognitive status. Dizziness/lightheadedness. Disorientation. Blurred vision. Ataxia.

Mild cognitive changes: ensure that patient is able to understand and follow instructions. Poor balance/peripheral sensory neuropathy: use well-supported positions for exercise.

Source: Reprinted with permission from McNeely, M. L., Peddle, C., Parliament, M., & Courneya, K. S. (2006). Cancer rehabilitation: Recommendations for integrating exercise programming in the clinical practice setting. Current Cancer Therapy Reviews, 2, 351–360. Copyright 2006, Bentham Science Publishers Ltd.

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cardiovascular disease, osteoporosis), and particularly so for cancer survivors who may be at increased risk of further disease (Brown, Brauner, & Minnotte, 1993; Mahon, 1998; Penedo, Schneiderman, Dahn, & Gonzalez, 2004).

Summary The evidence that physical activity can help prevent cancer is convincing for colon cancer, and probable for postmenopausal breast cancer and endometrial cancer. However, the optimal type and volume has not been determined for reducing risk. Similarly, there is currently insufficient evidence to firmly establish if physical activity protects against other cancers. The emerging research on survival outcomes indicates that physical activity performed after diagnosis is associated with lower mortality among survivors of breast and colorectal cancer. The evidence base on rehabilitation is rapidly expanding and currently indicates positive effects on outcomes relating to physical functioning, fatigue, and quality of life, both during cancer therapy, and after treatment completion.

Acknowledgment Kerry S. Courneya is supported by the Canada Research Chairs Program. REFERENCES

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Penedo, F. J., Schneiderman, N., Dahn, J. R., & Gonzalez, J. S. (2004). Physical activity interventions in the elderly:  cancer and comorbidity. Cancer Investigation, 22, 51–67. Pescatello, L. S., Franklin, B. A., Fagard, R., Farquhar, W. B., Kelley, G. A., Ray, C. A., & American College of Sports Medicine. (2004). American College of Sports Medicine position stand. Exercise and hypertension. Medicine and Science in Sports and Exercise 36, 533–553. Renehan, A.  G., Tyson, M., Egger, M., Heller, R.  F.,  & Zwahlen, M. (2008). Body-mass index and incidence of cancer:  A  systematic review and meta-analysis of prospective observational studies. Lancet, 371, 569–578. Rundle, A. (2005). Molecular epidemiology of physical activity and cancer. Cancer Epidemiology, Biomarkers & Prevention, 14, 227–236. Schmitz, K.  H., Ahmed, R.  L., Hannan, P.  J.,  & Yee, D. (2005). Safety and efficacy of weight training in recent breast cancer survivors to alter body composition, insulin, and insulin-like growth factor axis proteins. Cancer Epidemiology and Biomarkers Prevention, 14, 1672–1680. Schmitz, K.  H., Courneya, K.  S., Matthews, C., Demark-Wahnefried, W., Galvão, D.  A., Pinto, B.  M., . . . American College of Sports Medicine. (2010). American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Medicine and Science in Sports and Exercise, 42, 1409–1426 Schmitz, K.  H., Ahmed, R.  L., Troxel, A.  B., Cheville, A., Lewis-Grant, L., Smith, R., . . . Chittams, J. (2010). Weight lifting for women at risk for breast cancer-related lymphedema: A randomized trial. Journal of the American Medical Association, 304, 2699–2705. Schmitz, K. H., Holtzman, J., Courneya, K. S., Mâsse, L.C., Duval, S., & Kane, R. (2005). Controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. Cancer Epidemiology, Biomarkers & Prevention, 14, 1588–1595. Schwartz, A.  L. (2000). Exercise and weight gain in breast cancer patients receiving chemotherapy. Cancer Practice, 8, 231–237. Segal, R., Reid, R. D., Courneya, K. S., Malone, S. C., Parliament, M. B., Scott, C. G., . . . Wells, G. A. (2003). Resistance exercise in men receiving androgen deprivation therapy for prostate cancer. Journal of Clinical Oncology, 21, 1653–1659. Singh, F, Newton, R. U., Galvão, D. A., Spry, N., & Baker, M. K. (2013). A systematic review of pre-surgical exercise intervention studies with cancer patients. Surgical Oncology, 22, 92–104. Speck, R. M., Courneya, K. S., Mässe, L. C., Duval, S., & Schmitz, K. H. (2010) An update of controlled physical activity trials in cancer survivors:  a

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12 Massage Therapy LISA W. CORBIN

Key Concepts Patients with cancer often suffer physical symptoms and psychological stress. Massage therapy, widely used by healthy people for relaxation, may have benefits for patients in all stages of cancer treatment. ■ The use of massage therapy, with specific precautions in certain situations, is safe for patients with cancer. ■ There are few large, well-designed trials of massage therapy for patients with cancer; however, the most robust research supports benefits for lymphedema and anxiety. ■ Though there is less substantial research to support other claims, massage is often suggested and may be helpful for improved postoperative wound healing, sleep, pain, fatigue, constipation, and improved immune function. ■ Physicians caring for patients with cancer should ask all patients about the use of massage, consider recommending massage for anxiety, distress, and lymphedema, and help guide the patient to a qualified massage therapist. ■

M

assage therapy, a complementary therapy known primarily for its use in relaxation, may benefit patients with cancer in additional ways. However, the use of massage techniques in patients with cancer requires special consideration. Although safe and efficacious for some 373

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patients, it may be harmful or ineffective in other situations. Risks can be minimized and benefits maximized when the clinician feels comfortable discussing massage with his or her patients. This chapter reviews and summarizes the literature on massage and cancer to provide the clinician with reliable information regarding the safe, appropriate use of massage therapy for patients with cancer, thus facilitating discussions with patients. Defined by the National Center for Complementary and Alternative Medicine (NCCAM), “massage therapy” is classified within the category of “manipulative and body-based therapies” as an “assortment of techniques involving manipulation of the soft tissues of the body through pressure and movement” (http://nccam.nih.gov/). There are many different styles of massage therapy (such as Swedish, Rolfing, deep tissue, and neuromuscular). A detailed comparison of techniques is not relevant to this text; instead, the clinician should work with a massage therapist skilled in treating patients with cancer and who can employ the techniques appropriate for the situation. Almost all cultures have developed massage therapy because it seems instinctual to rub and press an area of muscular pain. References date back at least as far as 1600 bc. Hippocrates mentioned massage (around 400 bc), and massage was used and referenced as a medical therapy until the focus of medical care shifted to the biological sciences in the early 20th century. In the 1970s, massage in the United States found renewed interest, especially for athletes. Over the past 25 years, the therapeutic uses of massage have broadened, and research has sought to investigate its physical, physiological, and psychological effects. Proposed theories abound to explain the mechanism of action of massage therapy. Few of these theories are well tested, however, and there is little to no correlation of bench research (such as the observation of an acute increase in natural killer cell number and activity following massage (Hernandez-Reif et  al., 2005; Zeitlin, Keller, Shiflett, Schleifer,  & Bartlett, 2000)) to clinical outcomes (such as improved disease-free survival for patients with cancer). Theories on mechanisms of action are summarized in Table 12.1 (Field, 1998; Moyer, Rounds, & Hannum, 2004). The lack of a thorough understanding of mechanism of action or clinical correlation should not necessarily dissuade the physician from recommending massage therapy, however, because these theories lend plausibility to the anecdotal reports and the small studies supporting efficacy discussed in a subsequent section. Ideally, the physician will have a candid discussion with his or her patient about the potential benefits and safety issues framed in the context of studies that support benefit. Patients with cancer may suffer physical symptoms and psychological stress. Physical symptoms such as pain or early satiety may be due to the location of the tumor; other symptoms, such as constipation or nausea, can result from the

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Table 12.1.  Theories of Mechanism of Action of Massage Therapy Theory

Explanation

Gate control theory of pain reduction

Massage therapy creates a physical stimulus; the brain has difficulty processing and perceiving competing stimuli, thus, other physical stimuli, such as pain, are less recognized.

Increasing parasympathetic activity

Massage therapy may shift the autonomic nervous system from the sympathetic (“fight or flight”) to parasympathetic (relaxation), with a subsequent reduction of stress hormones (such as cortisol), increased immune response, increased alertness, and general feelings of well-being.

Increasing serotonin and endorphins

Some studies have linked massage therapy with increases in these “feel-good” neurotransmitters.

Improved blood flow

Massage has been theorized to improve blood flow, thus helping to clear waste products (such as lactic acid, thus reducing muscle pain) or to promote wound healing.

Improved lymphatic circulation

Massage therapy may improve lymphatic circulation and is used to reduce lymphedema.

Interpersonal attention

Some theorize that the effects of massage therapy are due to the attention given to the patient by the therapist and less to the actual physical treatment.

medications used to treat these symptoms. Patients who have undergone cancer treatment may have related symptoms, such as postsurgical pain or lymphedema. The burden of psychological stress, anxiety, and depression in cancer patients cannot be overemphasized. Depression has been estimated to be four times as common in cancer patients as the general population. Anxiety may lead to patients overestimating the risks associated with treatments or worsen their perception of their physical symptoms. Because of undertreated psychological symptoms, patients with cancer may not follow through with treatment recommendations or may report a higher severity of physical symptoms. Massage therapy has been increasingly employed and investigated as a therapeutic intervention to reduce symptoms in cancer patients. Studies are typically small or poorly designed, however, making it difficult to draw firm conclusions (see Benefits of Massage Therapy section). Indeed, studies have shown that patients with cancer are increasingly drawn to massage therapy in an attempt to alleviate symptoms (Ashikaga, Bosompra, O’Brien,  & Nelson, 2002; Coss, McGrath,  & Caggiano, 1998; Lengacher et  al., 2002). Surveys have been conducted in a variety of settings. In a study published in 2000, 26% of 453 adult patients surveyed

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at MD Anderson Cancer Center acknowledged using massage therapy (Richardson, Sanders, Palmer, Greisinger,  & Singletary, 2000); in 2001, 20% of 100 patients seeking care at a private cancer center reported having received massage therapy (Bernstein & Grasso, 2001). 10.6 % of 153 radiation oncology patients in rural Minnesota were using massage therapy (Rausch et al., 2011). Survivors of childhood cancer also report using complementary therapies; a study of 197 survivors discovered that massage therapy was used by 57 respondents and was the most commonly used complementary therapy in adolescent and young-adult survivors (Ndao et al., 2013). Of 169 hospices, 60% responding to a survey published in 2004 reported that they offered integrative medicine services at their hospices, with massage therapy the most commonly offered service (available at 83% of the hospices offering complementary therapies) (Demmer, 2004). Despite the popularity and availability of massage therapy for patients with cancer, some patients and their family members remain unaware of the potential uses of massage as a therapy for symptom control. Over 20% of patients with cancer report using massage therapy as an adjunct to conventional care. Massage is the most commonly available complementary therapy in US hospices. Clinicians are aware that patients use integrative medicine therapies, including massage therapy, but often do not discuss it with patients (Bourgeault, 1996). It has been widely postulated that open discussion between physicians and patients about complementary therapies may result in an enhanced physician/patient relationship and encourage compliance with recommended treatments.

Safety of Massage Therapy Overall, therapeutic massage is widely considered to be safe, though adverse events have been reported. Healthy patients may experience an allergic reaction to the lubricants used, bruising, swelling of massaged muscles, or a temporary increase in muscular pain; absolute risk of these events is unknown. Pregnant women should avoid prolonged positioning on their back. Case reports have reported serious adverse events, including fractures and dislocations; internal hemorrhage, and hepatic hematoma (Trotter, 1999); dislodging of deep venous thrombosis and resultant embolism of the renal artery (Mikhail, Reidy, Taylor, & Scoble, 1997); and displacement of a ureteral stent (Kerr, 1997). A  review of cases reported in the literature and randomized controlled trials of massage therapy found that few reported adverse events (Ernst, 2003). Cancer patients may be at higher risk for these problems,

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Table 12.1.  Circumstances with Potential for Massage-Related Adverse Events. Situation

Potential Harm

Modification Necessary

Coagulation disorder (low platelet count, warfarin, heparin, or aspirin therapy)

Bleeding (ranging from minor bruising to internal hemorrhaging)

Lighter pressure and avoidance of deep tissue massage

Metastatic cancer in bones

Fracture

Knowledge of location of metastases and lighter pressure over those areas

Open wounds; radiation dermatitis

Increased pain, infection

Avoid massage directly over open or healing wounds or dermatitis

requiring modification of technique to avoid them. Table 12.2 shows specific situations often encountered with cancer patients, the potential harm of massage in these situations, and suggestions on ways to decrease risk. There has been no evidence that massage therapy can spread cancer, although direct pressure over a tumor is usually discouraged. There is no evidence that therapeutic massage can spread cancer.

Certainly, massage should never be advocated as a substitute for potentially curative oncological care. Health-care providers should also realize that although massage therapy can be safe for their patients with cancer, massage therapists may also be suggesting certain herbs or other complementary medicine therapies to their patients that may put the patient at risk.

Benefits of Massage Therapy Few studies have adequate numbers of patients to investigate efficacy of massage therapy for symptoms in cancer patients. A  meta-analysis (detailed in the next paragraph) found only eight randomized clinical trials, with a total of only 357 patients. Investigators have found large trials difficult to design and carry out; one report described unforeseen challenges including late-stage cancer patients being too ill to participate and health-care providers withholding referrals to the study because of a bias against having their patients possibly randomized to the non-massage-therapy control group (Westcombe et al., 2003).

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A meta-analysis by the Cochrane collaborative group reviewed randomized controlled trials published prior to May 2002 that investigated the use of massage to reduce symptoms in patients with cancer. Their search strategy yielded eight randomized controlled trials with a total of 357 patients. The authors noted that a reduction in anxiety (19% to 32% in four studies; 207 patients) was most commonly seen. Only three studies with a total of 117 patients measured pain; a decrease was noted in just one study. Criticisms of these studies included the small number of subjects enrolled and the use only of standardized massages that did not allow the therapist to direct the massage based on the patient’s specific situation. Similarly, only two studies (71 patients) demonstrated a reduction in nausea. Individual studies showed improvement in other common symptoms, such as sleep (Fellowes, Barnes, & Wilkinson, 2004). A few randomized controlled trials have been published since the meta-analysis. In the United Kingdom, Soden et  al. randomized 42 hospice patients with cancer to receive massage, massage plus aromatherapy, or no intervention over a 4-week period. They did not find any significant benefits for pain, anxiety, or quality of life, although statistically significant improvements in sleep were seen in both massage groups, and a reduction in depression was noted in the massage-only group. Patients with higher initial levels of psychological distress had more response to the massage interventions (Soden, Vincent, Craske, Lucas, & Ashley, 2004). Post-White et al. in 2003 randomized 230 cancer outpatients to receive a standardized massage, healing touch (an intervention whereby the practitioner is believed to modify a patient’s energy fields by motion of his or her hands near or gently on the patient), or the presence of a staff member in the room in a crossover design. Each intervention was given weekly for 45 minutes for 4  weeks. Physiological effects such as decreased heart rate and respirations were seen in all three groups; massage therapy lowered pain (with a reduction in the use of nonsteroidal anti-inflammatory medications also noted) and anxiety, and therapeutic touch also lowered anxiety (Post-White et al., 2003). The largest randomized trial on massage for symptom reduction in cancer patients to date was published by Kutner et al. in 2008. This NIH-funded multisite study enrolled 380 patients with advanced cancer (90% of whom were in hospice care) and pain (at least 4 on a 0–10 point pain scale) to either six 30-minute massage-therapy visits or six 30-minute visits of nonmoving touch (administered by a volunteer instructed to place his/her hands in predefined locations on the patient’s body for a total of 30 minutes) over a 2-week period. Participants received an average of 4.1 visits. The nonmoving touch control was chosen to control for the benefits of attention and simple touch. Pain was reduced over the course of the study to a similar extent in both groups; however, massage therapy showed a greater benefit in short-term pain control.

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Massage therapy was safe in this population, though patients with known coagulopathies or unstable spines were excluded (Kutner et al., 2008). A small study investigated the impact of massage for fatigue. Twenty breast cancer survivors reporting fatigue were randomized in a crossover fashion to receive massage or a control intervention. Improvement in mood scales and a decrease in fatigue was seen with massage but not with the control intervention. Interestingly the effect of massage was modulated by the attitude of the patient toward massage, with patients who stated that they expected massage to be beneficial finding it to be more beneficial than those who had less initial expectations of benefit (Fernandez-Lao et al., 2012). A large, retrospective, observational study of pre- and postmassage symptom scores of 1,290 in- and outpatients seen over a 3-year period at Memorial Sloan-Kettering Cancer Center (3,609 massages delivered) showed an average 50% reduction in symptoms (ranging from 21% improvement for nausea to 52% for anxiety) following massage. Follow-up surveys at 48 hours showed persistence of the benefit. Patients rated symptoms including pain, fatigue, anxiety, nausea, and depression on a 0 to 10 scale. For whatever symptom rated the highest on premassage assessment, improvement was 54%. Results were felt to be clinically significant and, although the study did not have a randomized design, it certainly supports the idea of massage’s utility in symptom control for patients with cancer (Cassileth & Vickers, 2004). Another small study of 39 patients from outpatient oncology practices in the UK randomized subjects to either aromatherapy massage or cognitive-behavioral-therapy sessions delivered up to 8 sessions weekly over 3  months. Both practices improved mood, depression, and anxiety (Serfaty, Wilkinson, Freeman, Mannix, & King, 2012). The feasibility of providing massage to pediatric oncology patients has also been investigated. In one trial, 23 children who were undergoing a hematopoietic cell transplant were offered combined massage—acupressure three times weekly during hospitalization; this group was compared to usual care. Parents were also trained to provide additional acupressure. Though in this small study none of the results achieved statistical significance, there was a trend toward benefits such as fewer days of mucositis; lower overall symptom burden; and having fewer moderate to severe symptoms of pain, nausea, and fatigue (Mehling et al., 2012). Massage, either given or received, also has been proposed to provide benefits for caregivers of patients with cancer. In the previously mentioned study of massage for childhood hematopoetic cell transplant patients, parents were also trained to apply acupressure massage to their children as needed. The effects on parents/caregivers of the children were also qualitatively explored. In addition to confirming benefits to their children, the caregivers reported

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feeling closer to their child and feeling more competent about their role in the child’s care (Ackerman et al., 2012). Studies investigating the provision of massage to reduce stress and increase relaxation in caregivers included a study of 42 spouses of patients with cancer randomly assigned to a trial group receiving a single 20-minute therapeutic back massage or to a control group. Mood assessed pre-intervention, immediately postintervention, and 20 minutes postintervention showed improvement postintervention in the massage group (Goodfellow, 2003). A  separate trial assigned 36 caregivers of patients undergoing autologous hematopoietic stem cell transplant to receive two 30-minute massage sessions (13 participants), two 30-minute healing-touch sessions (10 participants), or one 10-minute nurse visit (13 patients). Anxiety and depression as well as fatigue were significantly reduced in the massage group (Rexilius, Mundt, Eckson Megel,  & Agrawal, 2002). Massage therapy may also reduce stress and anxiety for caregivers of oncology patients.

A specific massage technique, “manual lymphatic drainage” (MLD), has been employed to decrease breast-cancer-related lymphedema and is commonly used in combination with support/compression garments, skin care, and exercise. Despite widespread use, MLD has not been rigorously studied. An exhaustive Cochrane collaboration search identified just two randomized studies (Preston, Seers, & Mortimer, 2008). A randomized crossover design study specifically examined this technique in 31 women with breast-cancer-related lymphedema and showed significantly reduced limb volume as well as symptoms such as pain and heaviness. Quality of life was positively affected and sleep improved (Williams, Vadgama, Franks,  & Mortimer, 2002). However, in a study of 42 women with mastectomy-related lymphedema comparing MLD along with compression garments versus compression garments alone, the addition of MLD did not offer additional improvement in lymphedema (Anderson, Hojris, Erlandsen, & Anderson, 2000). Abdominal massage has been advocated to reduce constipation; a review of trials of massage for chronic constipation in 1999 concluded that the numbers of patients studied was too small to make definitive statements on efficacy (Ernst, 1999). Massage has been promoted to improve immune function, but actual studies are small and inconclusive (Field et al., 2001). Massage therapy is also commonly advocated to cancer patients to help promote postoperative wound healing and reduce scar-tissue formation, and to help release metabolic

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waste by improving circulation. A  Medline search failed to locate any published trials demonstrating the efficacy of massage therapy for these indications for patients with cancer. However, a review found 9 trials of massage for reduction in scars; although the trials were small and very dissimilar in study design, in general they supported the use of massage to decrease scars, especially post operatively (Shin  & Bordeaux, 2012). Future well-designed trials may wish to explore massage therapy for these indications, and specifically in patients with cancer. Research on the benefits of massage therapy is ongoing. For the clinician who is interested in information on current clinical trials involving massage and cancer can be found by searching the NIH CRISP database (http://clinicaltrials.gov). As of October 2013, there were 2 open studies and 3 studies of unknown status investigating the effects of massage therapy on patients with cancer listed on this site. The focus of these studies is quite varied: One investigates caregiver massage on quality of life in pediatric oncology patients; the others explore the use of massage to improve operative outcomes in breast cancer patients and to explore the effects of massage on fatigue in patients with cancer. In summary, trials of massage therapy in cancer patients give the strongest evidence for its ability to decrease anxiety and distress. Massage may likely decrease pain but the number of patients studied is small; the efficacy of massage on other symptoms associated with cancer as well as on the number of medications used for symptom control also warrants more study. If massage therapy is indeed beneficial in cancer patients, perhaps more centers caring for patients with cancer will make massage therapy available.

Discussing the Use of Massage Therapy with Cancer Patients Cancer patients often use complementary medical therapies, including massage therapy, in conjunction with conventional treatment. Although massage is generally safe, cancer patients, particularly those undergoing active treatment, are at higher risk for complications. The clinician should note the presence of comorbid conditions that may put the patient at higher risk for complications, such as anticoagulant use, heart failure, deep venous thrombosis, cellulitis, the presence of catheters, pregnancy, or bone metastases. If the patient has any of these comorbidities, he or she should be advised to work with a therapist experienced in medical massage or cancer massage who will feel comfortable making the appropriate modifications in technique necessary to decrease risk. Secondarily, patients should be encouraged to consider the

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Table 12.3.  Finding a Qualified Massage Therapist Standard

Minimum qualifications

Preferred Qualifications (in Addition to the Minimum)

Education

500 hours Accredited school Experience working with cancer patients.

Advanced training in oncology massage

Licensure and certification

Licensed, if required by state (LMT or LMP). Certified, if no licensure required (CMT).

Certified by NCBTMB

Philosophy

View selves as extension of patient’s health-care team, not as a stand-alone therapy. Will communicate with other health-care providers. Aware that massage is not contraindicated in patients with cancer but that special considerations may be necessary.

use of massage therapy for adjunctive management of pain and anxiety. If a patient is interested in using massage therapy, the physician should help them find a qualified therapist (see Table 12.3 for further details). If the patient is uncomfortable or fearful of complementary therapies, referring the patient to meet with a knowledgeable integrative medicine consultant can reduce the barriers of fear that impede the use of CAM therapies, according to a 2010 study at MD Anderson (Frenkel et al., 2010). Not all areas have access to knowledgeable integrative medicine specialists; a good start to find such a provider is to look in an academic medical center, where more and more oncology programs are affiliated with integrative medicine programs. The Consortium for Academic Health Centers for Integrative Medicine has a listing of academic integrative medicine programs that may be helpful (www. imconsortium.org). Another resource is the Society for Integrative Oncology (www.integrativeonc.org), where one can find a list of academically oriented integrative oncology practices as well as continuing education events to further distribution of research about the use of massage and other integrative modalities in the care of patients with cancer. Philosophy and education of therapists is variable, with some massage therapists laboring under the mistaken belief that cancer is a contraindication for massage and others perhaps discouraging patients from receiving potentially curative conventional care or promoting potentially harmful therapies. Thus,

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finding a massage therapist experienced and comfortable with both cancer patients and the conventional care commonly used is paramount. Clinicians can help patients find a qualified massage therapist. Given that many cancer centers, hospitals, and hospices now have integrative medicine programs offering massage therapy, clinicians can ideally refer patients to seek treatment in these settings. If no such programs are available, the clinician should encourage the patient to interview potential therapists or should do so himself or herself to establish an ongoing consultant relationship for future referrals. When interviewing a potential massage therapist, ask about education and experience including licensing and certification. Consider only massage therapists who have a minimum of 500 hours of training. Massage therapy schools voluntarily meeting criteria set by the Commission on Massage Therapy Accreditation have achieved and maintained a level of quality, performance, and integrity that meets meaningful standards. A directory of accredited programs is available on the Commission’s website (www.comta.org/). Specialized programs for advanced training in massage care of the patient with cancer are also available; additional education and experience in working with cancer patients is a must. Specialized programs are not standardized, however. Overall, studies of massage in other conditions have suggested that the greatest benefits are seen with the most experienced massage therapists (Furlan, Brosseau, Imamura, & Irin, 2002). Not all states regulate massage therapists. A current list is available from the American Massage Therapy Association (http://www.amtamassage.org/about/ lawstate.html). If a therapist is licensed, the initials “LMT” (Licensed Massage Therapist) or “LMP” (Licensed Massage Practitioner) are used after the therapist’s name. In other nonlicensing states, a therapist should have “CMT” (Certified Massage Therapist) as a minimum qualification. Beyond this, the initials NCBTMB indicate that the therapist has voluntarily taken and passed an exam given by the National Certification Board of Therapeutic Massage and Bodywork. The right massage therapist will be knowledgeable about risks and benefits of massage in a cancer population and should be comfortable communicating with the referring physician on an ongoing basis. They should see themselves as an extension of the patient’s health-care team, not as a replacement. Some massage therapists may have experience with other complementary therapies and should agree to encourage the patient to discuss any suggestions on other therapies with their clinician. The cost of massage therapy visits is generally reasonable when compared with the cost of some medications and other conventional treatments for symptom control, but may be prohibitive for some patients because it is often

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not covered by insurance. There may be funds available for patients through charitable organizations, and these options should be explored. The cost of massage therapy will typically qualify for reimbursement through medical flexible spending accounts and usually will count toward medical expenses that can be itemized on federal taxes. Patients should be encouraged to verify this with their employer and/or tax accountant or attorney. A relatively new and intriguing area of research in massage therapy is exploring the idea of teaching caregivers to massage patients undergoing cancer treatment. If this approach can be shown to be feasible and effective in terms of reduced symptoms in cancer patients, it may present a much more cost-effective and convenient approach.

Summary and Conclusions Over 20% of patients with cancer use massage therapy, with most patients using massage and other complementary therapies along with conventional treatments. Though physicians increasingly recognize that patients use complementary therapies, many are reluctant to bring the subject up with their patients. Discussion of complementary therapies with patients may enhance the doctor–patient relationship, improve compliance with conventional treatments, and allow the physician to promote nonpharmacological approaches to symptom management. A nice general review of discussion of complementary and alternative medical therapies with cancer patients can be found in this text. Given what is known from research studies, massage should be promoted to cancer patients as a therapy to help reduce stress and anxiety, and should be considered for pain management. Though the ability of massage therapy to reduce symptoms other than these has not yet been conclusively demonstrated, the low likelihood of harm and studies leaning toward proving benefit for other symptoms makes massage therapy an attractive adjunct to conventional care. The American College of Chest Physicians reviewed the topic of complementary/alternative medicine use for lung cancer and recommended “In lung cancer patients whose anxiety or pain is not adequately controlled by usual care, addition of massage therapy performed by trained professionals is suggested as part of a multi-modality cancer supportive care program (Grade 2B)” (Deng et al., 2013). Massage should not be used as a substitute for conventional cancer care, and clinicians should recognize and discuss that massage practitioners may at times promote other potentially harmful unconventional therapies. Massage therapy should be accepted and condoned as a potentially beneficial

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intervention for symptomatic relief in patients with cancer, and it can be safely incorporated into their conventional care. GENERAL REFERENCES

National Cancer Institute (www.cancer.gov/cancerinfo/treatment/cam) American Massage Therapy Association (http://www.amtafoundation. org) Touch Research Institutes (http://www.miami.edu/touch-research/). National Center for Complementary and Alternative Medicine (http:// nccam.nih.gov/) REFERENCES

Ackerman, S. L., Anne Lown, E., Dvorak, C. C., Dunn, E. A., Abrams, D. I., Horn, B.  N., . . . Mehling, W.  E. (2012). Massage for children undergoing hematopoietic cell transplantation:  A  qualitative report. Evidence-Based Complementary & Alternative Medicine. Anderson, L., Hojris, I., Erlandsen, M.,  & Anderson, J. (2000). Treatment of breast-cancer related lymphedema with or without manual lymphatic drainage: A randomized study. Acta Oncologica, 39, 399–405. Ashikaga, T., Bosompra, K., O’Brien, P., & Nelson, L. (2002). Use of complementary and alternative medicine by breast cancer patients:  Prevalence, patterns and communication with physicians. Supportive Care Cancer, 10, 542–248. Bernstein, B. J., & Grasso, T. (2001). Prevalence of complementary and alternative medicine use in cancer patients. Oncology, 15, 1267–1272. Bourgeault, I. (1996). Physicians’ attitudes toward patients’ use of alternative cancer therapies. Canadian Medical Association Journal, 155, 1679–1685. Cassileth, B. R., & Vickers, A. J. (2004). Massage therapy for symptom control: Outcome study at a major cancer center. Journal of Pain and Symptom Management, 28, 244–249. Coss, R. A., McGrath, P., & Caggiano, V. (1998). Alternative care: patient choices for adjunct therapies within a cancer center. Cancer Practice, 6, 176–181. Demmer, C. (2004). A survey of complementary therapy services provided by hospices. Journal of Palliative Medicine, 7(4), 510–516. Deng, G. E., Rausch, S. M., Jones, L. W., Gulati, A., Kumar, N., Greenlee, H, . . .  Cassileth, B. R. (2013). Complementary therapies and integrative medicine in lung cancer. Chest, 143(5 Supplement).

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Ernst, E. (1999). Abdominal massage therapy for chronic constipation: A systematic review of controlled clinical trials. Forsch Komplementarmed, 6(3), 149–151. Ernst, E. (2003). Safety of massage therapy. Rheumatism, 42, 1101–1106. Fellowes, D., Barnes, K., & Wilkinson, S. (2004). Aromatherapy and massage for symptom relief in patients with cancer. Cochrane Database of Systematic Reviews (2), CD002287. Fernandez-Lao, C., Cantarero-Villanueva, I., Diaz-Rodriguez, L., Cuesta-Vargas, A.  I., Fernandez-Delas-Penas, C.,  & Arroyo-Morales, M. (2012). Attitudes towards massage modify effects of manual therapy in breast cancer survivors: A randomised clinical trial with crossover design. European Journal of Cancer Care, 21(2), 233–241. Field, T. M. (1998). Massage therapy effects. American Psychology, 53, 1270–1281. Field, T., Cullen, C., Diego, M., Hernandez-Reif, M., Sprinz, P., Beebe, K., . . . Bango-Sanchez, V. (2001). Leukemia immune changes following massage therapy. Journal of Bodywork and Movement Therapies, 5, 271–274. Frenkel, M., Cohen, L., Peterson, N., Palmer, J.  L., Swint, K.,  & Bruera, E. (2010). Integrative medicine consultation service in a comprehensive cancer center: Findings and outcomes. Integrative Cancer Therapy, 9, 276–283. Furlan, A. D., Brosseau, L., Imamura, M., & Irin, E. (2002). Massage for low back pain. Cochrane Database of Systematic Reviews (2), CD001929. Goodfellow, L. M. (2003). The effects of therapeutic back massage on psychophysiologic variables and immune function in spouses of patients with cancer. Nursing Research, 52(5), 318–328. Hernandez-Reif M, Field T, Ironson G, Beutler, J., Vera, Y., Hurley, J.,  & Fraser, M. (2005). Natural killer cells and lymphocytes increase in women with breast cancer following massage therapy. International Journal of Neuroscience, 115(4), 495–510. Kerr, H. D. (1997). Ureteral stent displacement associated with deep massage. WMJ, 96(12), 57–58. Kutner, J. S., Smith, M. C., Corbin, L., Hemphill, L., Benton, K., . . . Fairclough, D.  L. (2008). Massage therapy versus simple touch to improve pain and mood in patients with advanced cancer:  A  randomized trial. Annals of Internal Medicine, 149, 369–379. Lengacher, C. A., Bennett, M. P., Kip, K. E., Keller, R., LaVance, M. S., Smith, L. S., & Cox, C. E. (2002). Frequency of use of complementary and alternative medicine in women with breast cancer. Oncology Nursing Forum, 29, 1445–1452. Mehling, W. E., Lown, A. E., Dvorak, C. C., Cowan, M. J., Horn, B. N., . . . Hecht, F. M. (2012). Hematopoietic cell transplant and use of massage for improved symptom management:  Results from a pilot randomized control trial.

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Evidence-Based Complementary & Alternative Medicine. 2012;2012:450150. doi: 10.1155/2012/450150. Epub 2012 Feb 9. Mikhail, A., Reidy, J. F., Taylor, P. R., & Scoble, J. E. (1997). Renal artery embolization after back massage in a patient with aortic occlusion. Nephrology Dialysis Transplant, 12, 797–798. Moyer, C. A., Rounds, J., & Hannum, J. W. (2004). A meta-analysis of massage therapy research. Psychological Bulletin, 130(1), 3–18. Ndao, D. H., Ladas, E. J., Bao, Y, Cheng, B., Nees, S. N., Levine, J. M., & Kelly, K. M. (2013). Use of complementary and alternative medicine among children, adolescent, and young adult cancer survivors: A survey study. Journal of Pediatric Hematology and Oncology, 35, 281–288. Post-White, J., Kinney, M.  E., Savik, K., Gau, J.  B., Wilcox, C.,  & Lerner, I. (2003). Therapeutic massage and healing touch improve symptoms in cancer. Integrative Cancer Therapies, 2(4), 332–344. Rausch, S.  M., Winegardner, F., Kruk, K.  M., Phatak, V., Wahner-Roedler, D. L., Bauer, B., & Vincent, A. (2011). Complementary and alternative medicine: use and disclosure in radiation oncology community practice. Support Care Cancer, 19, 521–529. Rexilius, S. J., Mundt, C., Eckson Megel, M., & Agrawal, S. (2002). Therapeutic effects of massage therapy and handling touch on caregivers of patients undergoing autologous hematopoietic stem cell transplant. Oncology Nursing Forum Online, 29(3), E35–E44. Richardson, M. A., Sanders, T., Palmer, J. L., Greisinger, A., & Singletary S. E. (2000). Complementary/Alternative medicine use in a comprehensive cancer center and the implications for oncology. Journal of Clinical Oncology, 18(13), 2505–2514. Serfaty, M., Wilkinson, S., Freeman, C., Mannix, K., & King, M. (2012). The ToT study:  Helping with Touch or Talk (ToT):  A  pilot randomised controlled trial to examine the clinical effectiveness of aromatherapy massage versus cognitive behaviour therapy for emotional distress in patients in cancer/palliative care. Psycho-Oncology, 21(5), 563–569. Shin, T.  M.,  & Bordeaux, J.  S. (2012). The role of massage in scar management: A literature review. Dermatologic Surgery, 38(3), 414–23. Soden, K., Vincent, K., Craske, S., Lucas, C., & Ashley, S. (2004). A randomized controlled trial of aromatherapy massage in a hospice setting. Palliative Medicine, 18(2), 87–92. Trotter, J. F. (1999). Hepatic hematoma after deep tissue massage. New England Journal of Medicine, 341(26), 2019–2020. Westcombe, A. M., Gambles, M. A., Wilkinson, S. M., Barnes, K., Fellowes, D., Maher, E. J., . . . Ramirez, A. J. (2003). Learning the hard way! Setting up an

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RCT of aromatherapy massage for patients with advanced cancer. Palliative Medicine, 17(4), 300–307. Williams, A. F., Vadgama, A., Franks, P. J., & Mortimer, P. S. (2002). A randomized controlled crossover study of manual lymphatic drainage therapy in women with breast cancer-related lymphoedema. European Journal of Cancer Care, 11(4), 254–261. Zeitlin, D., Keller, S. E., Shiflett, S. C., Schleifer, S. J., & Bartlett J. A. (2000). Immunological effects of massage therapy during acute academic stress. Psychosomatic Medicine, 62(1), 83–84.

13 Mind–Body Medicine in Integrative Cancer Care MARTIN L. ROSSMAN AND DEAN SHROCK

Key Concepts A  serious cancer diagnosis carries unique psychological challenges. A  compassionate physician with an integrative perspective can be a key ally. ■ The ubiquity of the placebo effect suggests that every communication between a doctor and patient is a mind–body interaction that can have effects as potent as a scalpel or cytotoxic agent. Professionals need to be aware of the power of their communications and use them skillfully. ■ There are a wide range of mind–body approaches that allow professionals to help cancer patients, and allow patients to help themselves. They can be delivered as self-care tools, in groups, or in individual sessions. ■ The issue of whether mind–body approaches can influence survival is unresolved, but the evidence that mind–body approaches improve quality of life is consistent, abundant, and unequivocal. ■ Mind–body therapies can reduce anxiety and depression, temper adverse effects of cancer treatments, relieve pain, stimulate immune responses, and help people deal with a wide range of cancer-related stress including relationships, decision-making, planning for the future, dealing with loss, and, if necessary, coming to terms with end-of-life issues. ■ Mind–body approaches have minimal risk, significant benefits, low cost, and should be the standard of care with every cancer patient. ■

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Introduction A cancer diagnosis is one of the most common traumatic events faced in developed cultures. A serious cancer diagnosis carries with it a unique set of challenges for patients, their families, and health-care professionals. Patients newly diagnosed with cancer, and their support people, are frequently in shock, fearful, and emotionally regressed. During this difficult emotional time, they are called on to evaluate complex information and opinions that are often in conflict, and to make difficult treatment decisions, in an atmosphere of urgency. They can feel pressured to sort through an overwhelming amount of information, and may feel torn between conventional, complementary and alternative treatment advice. Finally, cancer patients often are asked to choose treatments that can have difficult, disfiguring, and sometimes life-threatening effects of their own, which make them difficult to choose, even when they offer potential benefits. For all these reasons, physicians with integrative perspectives can be critical allies in helping patients choose the optimal approach to their management and treatment.

The Mind–Body Effects of Physician–Patient Communications The National Institutes of Health (NIH) define mind–body therapies as interventions designed to facilitate the mind’s capacity to affect bodily function and symptoms. In actuality, all therapeutic encounters have a mind–body effect. This effect results from the patients’ hopes, beliefs, and expectations, and it can be potentiated or depotentiated by both physicians’ beliefs and the way that physicians communicate. Usually called the placebo effect, it is the most ubiquitous phenomenon in all of medicine. The fact that both the patients’ and physicians’ expectations impact treatment effects is the reason that we go to the immense trouble and expense to do double-blind studies. Although researchers want to eliminate the placebo effect, patients and clinicians want to maximize its benefit, and use it to therapeutic advantage.

The ubiquity of the placebo effect suggests that every communication between a doctor and patient can have consequences as potent as a scalpel

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or cytotoxic agent. Communications from doctor to patient can set the stage for a heroic response or a collapse into despair. Telling patients that they have cancer is not easy, but there are ways of communicating this news that tells the truth but leaves room for hope. Carl Simonton, MD, a radiation oncologist who pioneered in the mind–body treatment of cancer patients, uses the phrase, “This is a serious illness, and you may be able to do something about it.” Following this communication model can help prevent creating what can amount to an iatrogenic posttraumatic stress disorder. We have seen too many patients who say “I will never forget the look on my doctor’s face when he told me I have cancer.” Patients often have great trouble overcoming such memories and its discouraging effects, in spite of intensive counseling. If we could instill confidence and calmness as easily and powerfully as we can instill terror, we would be great physicians indeed. The best opportunity we have is when we first deliver the diagnosis, and we need to be mindful of what and how we are communicating.

Major Mind–Body Approaches Used in Cancer Care There are many different mind–body approaches that allow professionals to help cancer patients, and allow patients to help themselves. The most researched and frequently used are: relaxation training, guided and interactive guided imagery, meditation, hypnosis, biofeedback, and forms of group social support. Almost all mind–body techniques involve a combination of relaxation and imagery, which is why we think it is crucial for practitioners to familiarize themselves with these modalities. The most common form of imagery is worry, and cancer patients often spend far too much time focusing involuntarily on their fears and concerns, which is not only frightening but also exhausting. Teaching them more productive uses of their thoughts and imagination offers multiple benefits, which are detailed later in this chapter.

RELAXATION TECHNIQUES

Utilizing abdominal breathing, muscle relaxation, autogenic suggestions, and simple imagery are the most widely used, easily learned, and generally

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useful mind–body techniques. Because stress is such a common experience in cancer, reducing it through regular relaxation practice allows a patient to interrupt obsessive worry, regain some sense of control, and create periods of respite from the ongoing challenges of cancer and its treatment. GUIDED IMAGERY

Guided imagery includes a range of techniques from simple visualization and direct imagery-based suggestion to metaphor and story telling. Guided imagery is used to help teach psycho-physiologic relaxation, to relieve symptoms, to stimulate healing responses in the body, to access inner resources, and to help people tolerate procedures and treatments more easily. Mental imagery may include visual, auditory, olfactory, or other sensory modes of thinking. SOCIAL SUPPORT AND PSYCHOEDUCATIONAL GROUPS

Social support and psychoeducational groups consistently demonstrate improved quality of life for cancer patients, and they may contribute to better survival. Feeling listened to, cared for, supported, and learning how to live fully despite a cancer diagnosis are essential components of cancer care. Not everyone benefits from support groups, but almost everyone benefits from support, whether from professionals, family, friends, a spiritual community, or counseling.

Meditation Meditation involves concentrating the mind on either a neutral or meaningful focus: a word, image, external object, one’s breath, or whatever is occurring at the time. Meditation distracts the mind from worrisome imagery, tends to create a physiologically relaxed state, and helps develop peace of mind. There are many forms of meditation, including mindfulness, where one is fully present in the moment. Some forms are connected to particular religious belief systems, and others are nonsecular and compatible with any belief system. BIOFEEDBACK

Biofeedback uses sensitive physiologic monitors to display the reactions the body is having in response to thoughts and feelings. By being able to see, hear, or otherwise experience changes the body makes in response to mental contents, it is possible to gain control over physical functions normally out

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of conscious control. When people see how quickly and effectively the body responds to thoughts, it gives them confidence to use their mind to affect their bodies. HYPNOSIS

Hypnosis is a term used to describe a state of relaxed focused attention in which response to suggestions is enhanced. Although words are used to create suggestions, the most effective suggestions involve mental imagery. In actual practice, guided imagery and hypnosis often are indistinguishable, although people’s beliefs associated with each term can affect their responses. INTERACTIVE GUIDED IMAGERYSM

Interactive Guided Imagery (IGI) is a specific way of using imagery that is particularly effective in helping patients utilize their own inner resources. Patients are guided to work with their own personal imagery and insights about their illness and healing, to clarify any issues that may be involved, and to learn to use the mind to support their own healing. IGI principles can be used in self-care approaches, but often they are best facilitated by a trained health professional, especially where highly emotional issues are involved, as they often are with cancer. All these therapies have the potential to affect the psychological and treatment issues that arise in the diagnosis, treatment, and care of cancer patients and their families. Mind–body therapies can make a substantial impact by helping patients and families reduce anxiety and depression, manage their emotions, help in their decision making, reduce adverse effects of cancer treatments and procedures, manage pain, stimulate an immune response, deal with loss, plan for the future, support the will to live, and, if necessary, come to terms with end-of-life issues.

Evidence Supporting Mind–Body Approaches with Cancer Here we will review research that supports the use of mind–body approaches to address six important aspects of working with cancer patients: (1) the psychological and emotional aspects of being diagnosed with cancer; (2) coping

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with and reducing adverse effects of cancer treatments; (3) stimulating immunity, blood flow, and other healing responses; (4) reducing or relieving cancer related pain; (5) improving quality of life; and (6) influencing the progression or outcome of the diagnosis. Out of the 152 research articles cited, 60 of them have been added to this second edition. Although a few articles were simply overlooked in our original search, most of them are newly published, indicating that mind–body care in cancer is a vital and growing area of interest and benefit. EARLY PSYCHOLOGICAL AND EMOTIONAL ISSUES OF BEING DIAGNOSED WITH CANCER

Almost everyone responds to the diagnosis of cancer with a period of shock, numbness, and disbelief. Approximately 40–60% of cancer patients are significantly fearful and distressed following their diagnosis (Graves et al., 2007; Hegel et al., 2006), and these emotions can affect their ability to follow through with treatment plans. Depression is common, but often under-recognized by oncologists and nurses (Passik et al., 1998). There is so much evidence that mind–body interventions reduce or relieve anxiety and depression in cancer patients that we will quote only selected reviews and papers for the reader who wants to investigate this in more depth. Reviews of the literature and meta-analyses (Barsevick, Sweeney, Haney,  & Chung, 2002; Greer, 2002; Jacobsen  & Jim, 2008; Ott, Norris,  & Bauer-Wu, 2006) consistently conclude that psychosocial interventions, including relaxation, guided imagery, cognitive behavioral, psychoeducational, supportive— expressive group therapies, and mindfulness meditation reduce anxiety and depression and improve mood and quality of life in cancer patients. A recent study of 877 people being treated for cancer who received psychosocial support once again demonstrated decreased levels of distress, depression and anxiety over a one-year period (Carlson, Waller, Groff, Giese-Davis, & Bultz, 2013). Additional studies have demonstrated well-maintained reductions of cortisol after a cognitive-behavioral stress management group intervention in cancer patients during and just after treatment (Phillips et al., 2008). A randomized study by Schnur et al. (2008) concluded that brief presurgery hypnosis can be an effective means of controlling presurgical distress in women awaiting diagnostic breast cancer surgery. Cameron, Booth, Schlatter, Ziginskas, and Harman, (2006) and Burgess et al. (2005) recommend group emotional and social support to help patients manage their anxiety and depression in the first year following diagnosis.

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Families of cancer patients also experience many negative psychological symptoms as a result of diagnosis and treatment for cancer, and can benefit from psychosocial interventions (Teschendorf et  al., 2007). Birnie, Garland, and Carlson (2010) found that a mindfulness-based stress reduction program improved psychological functioning for both members of couples coping with this diagnosis. COPING WITH AND REDUCING ADVERSE EFFECTS OF CANCER TREATMENTS

Although medical treatments including surgery, chemotherapy, and radiation can be powerful weapons in fighting cancer, side effects including fatigue, pain, and nausea can be debilitating and even cause patients to forego or discontinue treatment. Randomized studies demonstrate that mind–body therapies can reduce or eliminate emotional and physical side effects of surgical, radiation, and chemotherapy treatments. Relaxation with guided imagery, self-hypnosis, and giving patients reassuring information prior to surgery have been shown to be highly effective in reducing anxiety before, during, and after surgery in both adults and children (Ashton et al., 2000; Bugbee et al., 2005; Calipel, Lucas-Polomeni, Wodey, & Ecoffey, 2005; Faymonville et al., 1995; Huth, Broome, & Good, 2004; Lang & Hamilton, 1994; Lang, Joyce, Spiegel, Hamilton, & Lee, 1996; Laurion & Fetzer, 2003; Ludwick-Rosenthal & Newfeld, 1993; McCaffrey & Taylor, 2005; Pellino et al., 2005). The same mind–body techniques can shorten surgical procedures (Butler et al., 2009; Lang et al., 2000; Tusek, Church, Strong, Grass, & Fazio, 1997) and significantly reduce pain and the need for pain medication post-operatively (Antall & Kresevec, 2004; Ashton et al., 2000; Disbrow, Bennett, & Owings, 1993; Faymonville et  al., 1995; Huth et  al., 2004; Lang et  al., 2000; Lang  & Hamilton, 1994; Lang et al., 1996; Manyande et al., 1995; Meurisse et al., 1999; Pellino et  al., 2005; Rensi, Peticca,  & Pescatori, 2000; Syrjala, Donaldson, Davis, Kippes, & Carr, 1995; Tusek et al., 1997; Weinstein & Au, 1991). Guided imagery and suggestion reduces the time it takes for patients’ bowels to return to normal functioning (Disbrow et  al., 1993; Tusek et  al., 1997), and shortens hospital stays (Cowan, Buffington, & Cowan, 2001; Disbrow et al., 1993; Meurisse et al., 1996; Rapkin Straubing, & Holroyd, 1991; Tusek et al., 1997). There also is evidence that these techniques can reduce blood loss (Enqvist, von Konow,  & Bystedt, 1995; Lucas, 1975; Meurisse et  al., 1996)  and speed wound healing (Holden-Lund, 1988; Jones, 1977).

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In a prospective, randomized, controlled trial Burgio et al. (2006) studied 125 prostate cancer patients after radical prostatectomy, and found that preoperative biofeedback hastened the recovery of urine control and decreased the severity of incontinence. Elkins et  al. (2008) reported that hypnosis reduced hot flashes in breast cancer survivors in a randomized study, and that it can have additional benefits, including reduced anxiety, depression, and improved sleep. A randomized clinical trial with 200 breast cancer surgery patients concluded that hypnosis controlled side effects of pain, nausea, fatigue, discomfort, emotional upset at time of discharge, and reduced institutional costs (Montgomery et  al., 2007). A  literature review by Kwekkeboom, Cherwin, Lee, and Wanta (2009) determined that mind– body interventions could improve a cluster of symptoms (pain-fatigue-sleep disturbance) with a single treatment strategy. A meta-analysis demonstrated the effectiveness of hypnosis for managing nausea and vomiting in cancer chemotherapy (Richardson et al., 2007). A review of evidence-based interventions to prevent, manage, and treat chemotherapy-induced nausea and vomiting recommended the use and effectiveness of guided imagery, progressive muscle relaxation, and psychoeducational support and information (Tipton et al., 2007). Several sources, including Blue Shield of California and Cedars Sinai Medical Center (Los Angeles), have reported that 88% of patients who used guided imagery tapes to prepare for surgery were very satisfied with them. It also reduced their average bill by nearly $800 (Fontana, 2000; Holden-Lund, 1988). As many as 25% of cancer patients have nausea and vomiting in anticipation of chemotherapy, an effect clearly mediated by expectations. Morrow and Morrell (1982) showed that systematic desensitization, (a behavioral treatment using relaxation and guided imagery,) had a significant anti-emetic effect in these patients. Vasterling, Jenkins, Tope, and Burish (1993) reported that both cognitive distraction and relaxation training reduced nausea and blood pressure in patients on chemotherapy. Burish and Jenkins (1992) found that biofeedback combined with relaxation training decreased nausea and anxiety during chemotherapy, and physiological arousal after chemotherapy. Given et al. (2004) reported that a cognitive-behavioral intervention, (which included self-care management, problem-solving, communication, and counseling and support) for 237 patients undergoing chemotherapy resulted in significantly lower levels of symptom severity for all symptoms measured. Molassiotis, Yung, Yam, Chan, and Mok (2002) concluded that progressive muscle relaxation training and guided imagery considerably decreased the duration of nausea, vomiting, and overall mood disturbance

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in a study of 71 chemotherapy—naive breast cancer patients. Eller (1999) found 46 studies that suggested the effectiveness of guided imagery in the management of stress, anxiety and depression, and for the reduction of blood pressure, pain and other side effects of chemotherapy. A clinical trial with 110 patients demonstrated that preparatory information, cognitive restructuring, relaxation and guided imagery significantly reduced nausea and fatigue seven days after autologous bone marrow/peripheral blood stem cell transplantation when the side effects of treatment are usually most severe (Gaston-Johansson et al., 2000). Yoo, Ahn, Kim, Kim, and Han (2005) assessed the effectiveness of progressive muscle relaxation training and guided imagery in a randomized study of 60 patients with breast cancer. The treatment group had a better quality of life with significantly less anxiety, depression, and hostility than the control group. They also had less anticipatory and post chemotherapy nausea and vomiting. Mundy, DuHamel, and Montgomery (2003) reviewed 67 studies of behavioral interventions for cancer treatment, and reported that they effectively control anticipatory nausea and vomiting from chemotherapy, can decrease levels of anxiety and distress associated with cancer diagnosis and treatments, and can help control cancer related pain. Methods involving relaxation training, systematic desensitization, and guided imagery have the greatest research support (Figueroa-Moseley et al., 2007). Mind–body therapies have been found to be an effective means for reducing fatigue from cancer treatments (Ganz  & Bower, 2007; Kangas, Bovbjerg,  & Montgomery, 2008; Mitchell  & Berger, 2006; Montgomery et al., 2009; Mustian et al., 2007), but one randomized study, while showing significantly improved functioning revealed only a trend in that direction. A  systematic review of mindfulness-based stress reduction interventions reported significant improvements in anxiety, depression, stress, sexual difficulties, physiological arousal and immune function across the cancer trajectory (Shennan, Payne, & Fenlon, 2011). Self-help interventions were found to reduce depression, fatigue, and nausea associated with radiation therapy for cancer (Badger, Braden,  & Mishel, 2001). In a randomized comparison study, women undergoing radiation therapy for breast cancer who learned muscular relaxation or relaxation and guided imagery from audiotapes had relief from depression, with the group utilizing imagery improving more than the relaxation group. The control group, where women were encouraged to talk about their feelings, had worsened depression during the same time (Bridge, Benson, & Petroni, 1988). Audiotapes were also found to be effective in improving self-care and increasing comfort in breast cancer patients undergoing radiation therapy (Hagopian, 1996; Kolcaba & Fox, 1999).

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STIMULATING IMMUNITY AND OTHER HEALING RESPONSES

In 1981 Ader and Cohen discovered that the immune system could be classically conditioned, which demonstrated the link between the central nervous and immune systems. Ader (1981) coined the term “psychoneuroimmunology” (PNI) to describe the field that examines the basis and phenomena of this relationship. From PNI research we now know that there is direct innervation to the thymus gland and lymph nodes, and that lymphocytes not only have receptor sites to all known neurotransmitters, they also produce neurotransmitters that can cause neurological and emotional symptoms. Thus, a biochemical mechanism has been established to explain how depression, anxiety, and related negative or positive emotional states can affect immunity., A significant down-regulation of immunity has been demonstrated frequently with stressful life events, grief, and depression, all of which commonly accompany a cancer diagnosis (Glaser & Kiecolt-Glaser, 2005). Bakke, Purtzer, and Newton (2002) concluded that hypnosis and guided imagery could enhance both psychological well-being and immune function in patients treated for stage I  or II breast cancer. Fawzy et  al. (1993) evaluated the immediate and long-term effects on immune function of a 6-week psycho-educational group with 61 patients with malignant melanoma. They reported reduction in levels of psychological distress, greater use of active coping methods, and significant increases in the percent of large granular lymphocytes and natural killer cells. Gruber et al. (1993) found that when patients with breast cancer used guided imagery to increase an immune response, they significantly increased numbers and aggressiveness of natural killer cells, an effect, which increased with time. Hall, Minness, and Olness (1993) found evidence of mind–body mediated influence on immunity in 18 of 24 studies they reviewed. More current studies confirm that relaxation training and guided imagery can affect a significant immune response, including NK cell activity and lymphocyte proliferation in patients undergoing cancer treatment (Antoni et al., 2009; Eremin et al., 2009; Fang et al., 2010; Hidderley & Holt, 2004; Kang et al., 2011; Lengacher et al., 2008; Wahbeh, Haywood, Kaufman, & Zwickey, 2009). In addition to having patients imagine an effective immune response, we also encourage patients to imagine cutting off blood supply to tumors, or to imagine turning off the gene switches that stimulate tumor growth. Biofeedback research has shown repeatedly that people can alter blood flow patterns, and suggestion has been shown to reduce bleeding during surgery (Enqvist et al., 1995; Lucas, 1975; Meurisse et al., 1996). Altered genetic transcription responses in wounds have been shown to be part of a stress response

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(Roy et al., 2005), and immune modulation is a result of up-regulation of cytokines due to effects on regulatory genes. Although there is no evidence yet that a patient can specifically reduce blood flow to tumors, or turn off oncogenes, these images serve as autosuggestions representing other potential mechanisms of resisting or overcoming cancer. As long as they are not substituted for more definitive or effective treatment, clinically we feel it is ethical and reasonable to encourage patients to imagine healing in a way that has meaning for them. REDUCING OR RELIEVING CANCER-RELATED PAIN

Pain is both a physical sensation and an emotional experience. It is one of the most common, burdensome, and feared symptoms experienced by patients with cancer (Sheinfeld et  al., 2012), and is often underreported, underdiagnosed, and undertreated (Levy, Chwistek, & Mehta, 2008). The prevalence of pain in patients with cancer has been reported to be between 50% and 70% during cancer treatment and 65% for those with advanced disease (Pujol  & Monti, 2007). The way a patient manages stress, tension, and emotions can amplify or reduce the suffering associated with their pain. Pharmacologic treatment of pain does not always meet patients’ needs and may produce difficult side effects. Research shows that mind–body interventions can reduce or relieve pain in cancer patients, whether from the disease itself or from side effects of treatments, and allows patients to participate in their own care (Cassileth, Trevisan, & Gubili, 2007; Porter & Keefe, 2011). The World Health Organization (WHO) recommends behavioral and psychosocial interventions as a standard of care in cancer pain treatment (Jadad  & Browman, 1995). The American Pain Society similarly recommends psychosocial interventions for pain management in cancer. A  meta-analysis concluded that psychosocial interventions should be systematically implemented as part of a multimodal approach for cancer pain management (Sheinfeld et al., 2012). Redd, Montgomery, and DuHamel (2001) reviewed 54 published studies of behavioral intervention methods in the control of aversive side effects of cancer treatments, and reported that hypnotic-like methods, involving relaxation, suggestion and distracting imagery, showed the greatest effects for pain management. Devine (2003) conducted a meta-analysis of the effect of psychoeducational interventions on pain in adults with cancer from 25 studies published between 1978-2001 and concluded that reasonably strong evidence exists for relaxation-based cognitive—behavioral interventions, education about analgesic usage, and supportive counseling.

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A randomized clinical trial with 124 women with metastatic breast cancer concluded that hypnosis is an effective treatment for pain (Butler et  al., 2009). Another randomized study with 201 cancer patients reported beneficial effects of hypnosis to reduce pain (Lang et al., 2008). Dalton, Keefe, Carlson, and Youngblood (2004) showed in a randomized study of 131 cancer patients that a cognitive behavioral therapy tailored to patient characteristics reduced pain and interference of pain with sleep, activities, walking, and relationships, and less confusion. Cutson (1998) reported that inclusion of nonpharmacologic treatments, including psychological, are important for effective management of cancer pain. Liossi, White, and Hatira (2006) and Richardson, Smith, McCall, and Pilkington (2006) both reported that hypnosis produced significant reductions in pain, anxiety, and distress in children with cancer undergoing lumbar punctures and other diagnostic and therapeutic procedures. Spiegel and Bloom (1983) showed that both group therapy and hypnosis reduced pain in a randomized study of 54 women with metastatic breast carcinoma. Both interventions reduced pain, and the combination worked better than each alone. Syrjala et al. (1995) also found that relaxation and imagery training reduced pain levels in a study with 94 cancer patients receiving bone marrow transplants. QUALITY OF LIFE Along with people newly diagnosed or in treatment for cancer, there are an increasing number of people living with a history of cancer. It is important to attend to the quality of life and health of both groups. Interestingly, the most common treatment goal of research examining psychosocial interventions for cancer patients has been to improve quality of life (Moyer, Sohl, Knapp-Oliver, & Schneider, 2009). Reviews and meta-analyses consistently report the benefits of psychosocial interventions across the course of the cancer trajectory (Stanton, 2006). This is highlighted by the 2007 landmark report entitled “Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs” from the Institute of Medicine of the National Academies of Science. It mandates that psychosocial aspects must be integrated into routine cancer care.

Patients should be screened at their initial visit for psychological needs, and survivors should have a treatment plan that includes attention to possible increased anxiety on completing treatment, development of posttraumatic stress symptoms, and mixed anxiety and depressive symptoms (Holland  &

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Weiss, 2008). A position paper by Surbone et al. (2010) similarly calls for a new paradigm of care that identifies and meets the psychosocial needs of cancer patients and survivors. The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Distress Management discusses the identification and treatment of psychosocial problems in patients with cancer to ensure that all patients with distress are recognized and treated (Holland et al., 2013). Many randomized studies and reviews support mind–body or psychosocial interventions to enhance the quality of life of cancer patients and their families. Mind–body techniques are generally pleasant, inexpensive, effective, free of adverse effects, and are a source of empowerment and self-regulation (Biegler, Chaoul, & Cohen, 2009; Clark et al., 2013; Daniels & Kissane, 2008; Lengacher et  al., 2009; León-Pizarro et  al., 2007; Montazeri, 2008; Monti, Sufian,  & Peterson, 2008; Nidich et  al., 2009; Penedo et  al., 2006; Smith, Richardso, Hoffman, & Pilkington, 2005; Wesa & Cassileth, 2009). A survey of 896 caregivers participated in the American Cancer Society Quality of Life Survey for Caregivers, and concluded that caregivers can benefit from interventions that enhance their ability to accept their situation and find meaning in their caregiving experience. This may improve their satisfaction with life and reduce their depressive symptoms (Kim, Schulz, & Carver, 2007). A related needs assessment of family caregivers of cancer survivors reported that interventions designed to help caregivers manage their own emotional distress as well as the survivors’ distress, can help them find meaning in the cancer caregiving experience and foster supportive familial relationships that will benefit the caregivers quality of life, not only during the time of diagnosis and treatment, but for years afterward (Kim, Kashy, Spillers, & Evans, 2010). Cancer survivors often suffer from fear of recurrence for years after their initial diagnosis. A  systematic review of quantitative studies concluded that interventions should be implemented to reduce this fear, which would improve quality of life as well as psychosocial well-being (Koch, Jansen, Brenner,  & Arndt, 2013). A randomized clinical trial with cervical cancer survivors also reported that interventions leading to enhanced quality of life could result in improved clinical outcome including survival (Nelson et al., 2008). INFLUENCING THE PROGRESSION OR OUTCOME OF THE DIAGNOSIS

A nonintervention study by Cassileth, Lusk, Miller, Brown, and Miller (1985) on patients with advanced metastatic disease showed no correlation at that

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time between psychosocial factors and survival. However, more recent studies suggest that there may be a survival advantage with psychosocial interventions. The strongest evidence is a randomized, prospective study conducted at UCLA by Fawzy et  al. (1993) of newly diagnosed melanoma patients participating in a six-week, 90-minute per week group that taught active behavioral coping skills, including relaxation, assertive communication, and emotional management. After six years there were one-third the number of deaths and half the number of recurrences in the treatment group, along with improved immune and psychological functioning. Survival benefit weakened at ten years but remained significant (Fawzy, Canada, & Fawzy, 2003). Küchler, Bestmann, Rappat, Henne-Bruns, and Wood-Dauphinee (2009) similarly reported improved survival after 10 years in patients with gastrointestinal cancers who received psychotherapeutic support and relaxation training while hospitalized for cancer surgery. Studies by Andersen et al. (2008), Richardson, Shelton, Krailo, and Levine (1990) and Shrock, Palmer, and Taylor (1999) showed a survival advantage for patients participating in supportive, educational program interventions. In a prospective, longitudinal study, Cunningham et al. (2000) concluded that there appears to be a strong association between longer survival and psychological factors related to the involvement of cancer patients in psychological self-help activities. Spiegel, Bloom, Kraemer, and Gotthei (1989) reported a positive effect on survival with cancer in a group intervention with metastatic breast cancer patients. However, a careful replication of this study by Goodwin et al. (2001) confirmed positive effects on psychological adjustment, mood, and pain perception, but did not demonstrate extended survival. A review of the literature by Goodwin in 2005 reported that there was good evidence that support groups could lead to improved psychological outcomes, but evidence of improved survival was not convincing. Phillips et al. (2008) similarly concluded that interventions for adverse psychosocial factors are warranted to improve quality of life, but could not be said to improve survival. A randomized control trial with 485 women with advanced breast cancer concluded that supportive-expressive group therapy did not prolong survival, although it did improve quality of life and protection against depression (Kissane et al., 2007). Although a randomized clinical trial with 227 breast cancer patients conducted by Andersen et al. (2008) concluded that a psycho-educational intervention improved survival and reduced rates of relapse (Andersen, Thornton, Shapiro, et al., 2010), Stefanek, Palmer, Thombs, and Coyne (2009) challenged their conclusion on methodological and statistical grounds and expressed

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concern that focus on survival detracted from the significance of the important psychosocial benefits. In response to this criticism, Kaufmann (2009) noted that a broad literature supports the importance of lifestyle, stress, and other psychosocial variables as independent risk factors for cancer and other diseases, and positive psychological well-being is associated with reduced mortality. He argued that the Andersen et  al. study is clinically meaningful despite its lack of statistical power, and that work and research must continue to delve into this aspect of mind–body interventions. In a major review of mind–body medicine in 2003, Astin et  al. concluded that the debate regarding whether mind–body therapies can influence survival among cancer patients remains unresolved (Astin, Shapiro, Eisenberg, & Forys, 2003). A more recent review by Spiegel (2011) posits that the very name psycho-oncology implies interaction between brain and body. This review of randomized mind–body intervention trials concluded that the stress of advancing cancer and management of it is associated with endocrine, immune, and autonomic dysfunction that has consequences for host resistance to cancer progression. Even at the end of life, helping patients face death, making informed decisions about level of care, and controlling pain and distress are not only humane but appear to be medically more effective than simply carrying on with intensive anti-cancer treatments alone (Spiegel, 2011; Temel et al., 2010). We agree with Astin, Spiegel, and Dreher (1997), who stated that cancer patients should not be denied programs that improve quality of life and well-being simply because there is uncertainty about whether such programs might also lengthen life spans. A  recent study by Giese-Davis et  al. (2011) found that a decrease in depression symptoms is associated with longer survival in patients with metastatic breast cancer. Since there are multiple studies showing that quality-of-life measures can predict survival, and since we know that psychosocial interventions improve quality of life, it is fully justified not only to intensify research into how psychological treatment can extend life for cancer patients, but to make such treatment widely available in clinical practice. We concur that there is a scientific and moral imperative to provide cancer patients with support and skills that build strength, hope, and psychological resilience. Mind–body interventions offer clear benefits in symptom reduction and quality of life, and may offer extended survival as well. Given the low cost, minimal risk, and significant benefit of such interventions, they should be standard of care in cancer treatment.

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Precautions and Contraindications to Using Mind–body Approaches Although mind–body approaches are very safe, especially when compared to most medical and surgical interventions for cancer, there are some precautions to be taken. First, mind–body techniques should not be offered as stand-alone treatment for any cancer, but they should be offered as ways that patients may be able to help themselves along with proper medical care. Second, patients with mental illness, especially with a history of psychosis or diffuse dissociative disorders may be at risk for being overwhelmed by emotional content, especially if explorative techniques are used. Patients who have difficulty distinguishing outer reality from inner experience, should work with health professionals who understand these issues and are well trained in both psychology and mind–body therapies. Third, our clinical experience has demonstrated that approximately 10–15% of patients have relaxation-induced anxiety and will become more anxious when asked to close their eyes, or as they begin to relax and do imagery work. Mild cases can respond to reassurance and patience, but more severe cases are best assisted by a qualified health professional. Fourth, if patients can help themselves by using mind–body approaches, it does not mean that they caused their disease by mind–body error or neglect. Mind–body approaches should offer patients an opportunity to participate in their efforts toward recovery or acceptance, and not be construed as “blaming the victim.” If these precautions are heeded, there is minimal risk and significant benefit to be had by providing mind–body training and support to people with cancer.

Mind–body Resources for Patients and Physicians Mind–body interventions often are taught and used as self-help tools, and resources for multimedia and audio teaching tools are listed in the following Resource Guide. Trained health professionals also are available to work with patients either in groups, classes, or individually, depending on the needs and willingness of the patient. Sources for referral are listed, also.

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RESOURCE GUIDE

Guided Imagery Self-Care Books and Tapes The Healing Mind www.thehealingmind.org Books and audio programs from Martin Rossman, MD (including book and CD home study program “Fighting Cancer from Within”), Jeanne Achterberg, PhD, Kenneth Pelletier, PhD, Rachel Remen, MD, Emmett Miller, MD, and more. Research reviews and professional community resources are listed.

Professional Training, Imagery Groups, and Referrals Academy for Guided Imagery Provides professional training and Certification in Interactive Guided Imagerysm and referrals to Certified practitioners. www.acadgi.com Center for MindBody Medicine Provides training and referrals to Cancer Guides who can help patients survey and navigate their options for treatment www.cmbm.org Simonton Cancer Center, Pacific Palisades, CA Week-long retreats for cancer patients and support people for self-healing www.simontoncenter.com Commonweal www.commonweal.org Week-long retreats for cancer patients and support people for self-healing BOOKS

Achterberg, J., Dossey, B.,  & Kolkmeier, L. (1994). Rituals of healing:  Using imagery for health and wellness. New York: Bantam Doubleday Dell. Barasch, M.  I. (1995). The healing path:  A  soul approach to illness New York: Penguin. Bolen, J. S. (1998). Close to the bone: Life-threatening illness and the search for meaning. New York: Touchstone Books.

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Chopra, D. (1995). Creating health:  How to wake up the body’s intelligence. Boston: Houghton Mifflin. Dossey, L. (1997) Reinventing medicine: Beyond mind-body to a new era of healing. New York: HarperOne. Dossey, L. (2005). Prayer is good medicine: How to reap the healing benefits of prayer. New York: HarperCollins. LeShan, L. (1999). Cancer as a turning point: A handbook for people with cancer, their families, and health professionals. New York: Plume. Miller, E.  E. (1997). Deep healing:  The essence of mind/body medicine. Hay House. Remen, R. N. (1997). Kitchen table wisdom: Stories that heal. New York: Riverhead Books. Rossi, E. (1993). The psychobiology of mind-body healing: New concepts of therapeutic hypnosis. New York: W.W. Norton. Rossman, M. L.(2003). Fighting cancer from within. New York: Owl Books. Rossman, M.,  & Kramer, H.  J. (2000). Guided imagery for self-healing. New World Library. Seigel, B. S. (1990). Peace, love and healing: Bodymind communication and the path to self-healing. New York: Harper Perennial Library Servan-Schreiber, D. (2009). Anticancer. New York: Viking Adult. Simonton, O.  C., Matthews-Simonton, S.,  & Creighton, J.  L. (1992). Getting well again. New York: Bantam Books. Weil, A., (1996). Spontaneous healing: How to discover and enhance your body’s natural ability to maintain and heal itself. New York: Ballantine Books. REFERENCES

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14 Music and Expressive Arts Therapies SUZANNE B. HANSER

Key Concepts The fields of art, dance/movement, drama, and music therapies are regulated by national organizations in the United States, with specific credentialing processes for qualified practitioners. Poetry therapy and expressive writing are considered expressive arts therapies, but their practitioners are not credentialed. ■ Music and expressive arts therapists apply heterogeneous interventions for people with cancer, including individual and group work, passive and active methods, and techniques based on multiple philosophical orientations. Clinical goals include psychological as well as physiological and spiritual outcomes. ■ Research meta-analyses reveal improvement in quality of life via expressive writing, art, dance/movement, and music therapies. Various protocols enhance social coping, mood, and general/physical health, and reduce anxiety, fatigue, depression, and distress. A Cochrane Review reports moderate impact of music therapy and music medicine interventions on pain. ■ Because these holistic approaches are also highly individualized and interactive, quantitative analyses of efficacy and generalization are limited. However, numerous qualitative investigations report highly significant and transformational experiences through the arts, poetry, and writing. ■

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Introduction Music, art, dance, movement, drama, poetry, expressive writing—these are the media of creative expression and joy. What do these art forms have to do with cancer? Everyone is capable of enjoying the arts in a multitude of ways, so it is not always apparent that these modes of expression are capable of becoming powerful forms of therapy for people living with cancer. Indeed, if one heeds the words of philosophers far and wide, art and music speak the language of the soul, surround humans in awe, and lift the spirit. Since ancient times, the arts have been used as therapy in cultures around the world—David soothing Saul with the lyre being a potent example—and their potentials as tools of healing are sometimes reported in mammoth proportions. Only recently have their precise methods become defined more clearly in scientific protocols and their outcomes assessed more scientifically in randomized controlled trials. When words and rational explanations fail, the arts emerge as safe media of communication, expression of unconscious thought, with metaphor and symbolic language as the grammar. When individuals encounter a diagnosis of cancer, they require a safe and open space to explore its meaning while they identify their needs for the journey to come. The expressive and creative arts can serve this function, while offering specific coping tools that call upon the person’s inner resources. Although these therapies are practiced around the world, the formal disciplines of art therapy, dance/movement therapy, music therapy, and drama therapy have evolved in the United States with the establishment of their respective professional organizations only within the last 65 years. Currently, each association sets guidelines for education and clinical training, certification, codes of ethics, standards of practice, and other professional responsibilities. Around the world, coalitions, international organizations, and countrywide professional organizations also offer standards and guidelines. Table  14.1 shows minimum and preferred qualifications for each of these arts therapists, as well as titles and websites of their professional associations. The National Association for Poetry Therapy offers resources and conferences, but no recognized curriculum or certification process (www.poetrytherapyorg). The National Coalition of Creative Arts Therapies Associations is an alliance and advocacy group for these therapies (www.nccata.org), and the International Expressive Arts Therapy Association adopts a multimodal, multicultural approach to the use of all arts in therapeutic settings (www. ieata.org).

Table 14.1.  Qualifications and Certification of Music and Expressive arts Therapists Professional Association

Website

Certification

Minimum Qualifications

Preferred Qualifications

Art Therapy

American Art Therapy Association— AATA

arttherapy.org

Registered Art Therapist (ATR), Board Certified AT (ATR-BC), Art Therapy Certified Supervisor (ATCS)

The Art Therapy Credentials Board (ATCB) grants registration (ATR) after reviewing documentation of completion of graduate education and postgraduate supervised experience.

The Registered Art Therapist (ATR) who successfully passes the written examination administered by the ATCB is qualified as Board Certified (ATR-BC), a credential requiring maintenance through continuing education.

Dance/ Movement Therapy

American Dance Therapy Association— ADTA

adta.org

Registered Dance/ Movement Therapist (R-DMT), Board Certified Dance/ Movement Therapist (BC-DMT)

The Registered Dance/ Movement Therapist (R-DMT) represents attainment of a basic level of competence, signifying both the first level of entry into the profession and the individual’s preparedness for employment as a dance/ movement therapist within a clinical and/or educational setting.

The Board Certified Dance/ Movement Therapist (BC-DMT) credential can be obtained after the R-DMT is awarded, with additional requirements and experience. BC-DMT is the advanced level of dance/movement therapy practice, signifying both the second level of competence for the profession and the individual’s preparedness to provide training and supervision in dance/movement therapy. (continued)

Table 14.1.  Continued Professional Association

Website

Certification

Minimum Qualifications

Preferred Qualifications

Music Therapy

American Music Therapy Association— AMTA

musictherapy. org

Board Certified Music Therapist (MT-BC)

Upon successful completion of the music therapy bachelor’s or master’s degree, an individual is eligible to sit for the national certification exam to obtain the credential Music Therapist-Board Certified (MT-BC) which is necessary for professional practice. The national exam is administered by the Certification Board for Music Therapists (CBMT).

Graduate programs in music therapy examine, with greater breadth and depth, issues relevant to the clinical, professional, and academic preparation of music therapists, usually in combination with established methods of research inquiry. Selected universities offer doctoral study in music therapy, some of which include coursework in music therapy in combination with doctoral study in related areas.

Drama Therapy

North American Drama Therapy Association— NADTA

nadta.org

Registered Drama Therapist (RDT), Board Certified Trainer (BCT)

The Registered Drama Therapist (RDT) holds a master’s level credential requiring coursework in psychology and drama therapy, experience in theater, supervised internship and work experience. RDTs are also board certified in the practice of drama therapy.

A Board Certified Trainer in drama therapy (BCT) is a Registered Drama Therapist (RDT) who has the responsibility of training, guiding and mentoring individuals who aspire to becoming RDTs. Any Registered Drama Therapist who meets the requirements set forth by the NADTA board can apply for the status of BCT.

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Music and Expressive Arts Therapies in Medicine Artists, musicians, writers, and other professionals and volunteers have made their presence known in integrative medical centers through such activities as entertaining staff, patients, and families, creating a healing environment, providing workshops on their art forms, and offering their talents to individual patients. The International Association for Music and Medicine values several medical applications of artistic endeavors, including “arts medicine, music performance, performance arts medicine, music psychology, medical humanities, ethnomusicology, music cognition, and music medicine” (www. iammonline.com). A useful distinction among music specialties is that music therapy refers to the “clinical and evidence-based use of music interventions to accomplish individualized goals within a therapeutic relationship by a credentialed professional who has completed an approved music therapy program” (www.musictherapy.org), whereas other uses of music in medical settings by nonmusic therapists are referred to as music medicine. A similar differentiation between other arts therapies and their respective arts medicine specialties is important to note in public education as well as research protocols.

Art Therapy in Cancer Care Art therapy explores the inner resources of individuals diagnosed with cancer, as they express themselves nonverbally through a variety of artistic media, and verbally analyze their art. These may be painted, drawn, sculpted, or demonstrated through any visual art form, with the emphasis being on the creative process, as opposed to the artistic product. Art therapists use this process, the artistic outcome, and their working relationship with the patient, to enhance quality of life, self-awareness, self-esteem, and symptom relief. They work individually or in groups to improve well-being by addressing a broad range of symptoms, including body image, social and sexual relationships, personal identity, fatigue, depression, and anxiety (www.arttherapy.org). One systematic review of the published literature identified 14 articles describing 12 research investigations of art therapy in adult oncology services, 7 of which were implemented by a qualified art therapist (Wood, Molassiotis, & Payne, 2011). Models of art therapy varied considerably. Many applied a psychodynamic approach, using art as projective media for evaluating underlying feelings and psychological issues. Two studies incorporated an “anthroposophical” framework to explore the natural and spiritual world through the

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inspiration of artistic expression (Steiner, 1995). Nine of the 14 studies were quantitative experiments; 3 of these were randomized controlled trials. Half of the research involved group art therapy interventions; duration of sessions ranged from a few minutes to 2.5 hours, over a period of 1 to 22 weeks. Most of the research participants were women. Large effect sizes were observed for social coping, anxiety, and quality of life, yet several studies failed to show significant improvement. General health, fatigue, distress, and depression outcomes were promising; however, effect sizes calculated for the three randomized trials were small to medium. In the five qualitative studies reviewed, one used thematic analyses of the art to reveal positive changes in feelings and existential/spiritual issues. Another two interviewed participants or examined their narratives, finding improvement in emotional stabilization, expression, growth, coping, communication, motivation, openness to discussing medical condition, general well-being, and quality of life. Participants also reported a sense of empowerment, a stronger sense of self, and deeper meaning to their lives as a function of the art therapy experiences. In an overview of painting and drawing as art therapy interventions in oncology, 17 articles published between 1999 and 2009 were examined (Geue et  al., 2010), many of which were also included in the 2011 review. These papers described 12 research studies, 5 of which were qualitative reports. A significant decrease in anxiety was reported from pre- to posttest in 6 of the 7 quantitative studies; 6 of the 7 also reported reductions in depression. The 3 quantitative investigations of quality of life all showed significant improvements. Summarization and cross-study comparisons of art therapy research are affected by the heterogeneity of approaches, philosophies, artistic media, and practitioner. The forms of art therapy included in the 2011 systematic review included the following: an anthroposophical approach, a museum/ gallery visit followed by individual studio work, creation of art using diverse media, a “creative journey” through explorations of color/shape and “visual poems,” 3 workshops on drawing, reflection, and creation of a book, open painting and watercolor group, development of a multimedia art project, a “body outline,” “mindfulness-based art therapy,” a semistructured experience including guided meditation and poetry, and a one-hour opportunity to create and discuss art, painting therapy with drawing analogs, body outline, and individual choice followed by a final image summarizing the work. Clearly, art therapy as one of the expressive arts, defies definition when it is the individual needs and experiences of the patient that guide the work.

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Dance/Movement Therapy in Cancer Care The American Dance Therapy Association defines dance/movement therapy as “the psychotherapeutic use of movement to further the emotional, cognitive, physical and social integration of the individual” (www.adta.org). Body movement is the core assessment and intervention for addressing expression, communication, and adaptation. Clinical outcomes rely heavily on the therapeutic relationship, as well as on the many creative techniques of dance and movement as therapy. Here again, the techniques and underlying philosophies may be as varied as the individual dance/movement therapists who do the work and their patients. Dance has been integrated into healing rituals of many cultures throughout the ages. From the Zar ritual in the Middle East to the American Indian sacred dances, to the !Kung trance in Africa, to the tarantella of South America, community rituals incorporate indigenous dances as forms of prayer and supplication, a way to balance physical and psychic energy, and a powerful magnet for the spirit. Some dance/movement therapists engage people in rediscovering these ancient practices, some use modern dance techniques, some develop unique improvisational methods, and others engage in body work and somatic psychotherapy that focus on the physical manifestations of illness and health. The choice of method may be based as much on the therapist’s training and background as on the therapeutic process that unfolds in each moment. Movement expresses the visceral nature of human identity, so the therapist uses the movements that emerge from therapy as a clue to understand underlying pathology versus well-being. Body-oriented psychotherapies call attention to the integration of mind and body through awareness of the body and its movement through space. The diversity of styles and approaches challenge the research process, as in art therapy, where there is no single protocol for oncology patients. There have been 18 randomized controlled trials (RCTs) measuring the impact of dance/movement therapy in general (Strassel et al., 2011). However, a Cochrane Review of physical and psychological outcomes of dance/movement therapy specifically for oncology patients identified only two randomized controlled trials. Both of these investigations concerned women who have breast cancer, with a total of 68 women enrolled (Bradt, Goodwill,  & Dileo, 2011). One used “Healing through Movement and Dance,” a method by Lebed-Davis aimed at restoring body symmetry and range of motion (Sandel et al., 2005). Results revealed positive changes in quality of life, as measured by the FACT-B. A single-group pre/posttest study of 77 women with cancer, conducted in Germany (Mannheim & Weis, 2005), supports this finding. The

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second RCT applied “authentic movement,” a technique involving movement through space with eyes closed and attention on inner experience, guided by a witness/facilitator (Dibbell-Hope, 2000). This intervention reduced fatigue, a symptom also ameliorated in a nonrandomized study of 12 women with breast cancer by Serlin, Frances, Vestevich, Bailey, and Lavaysse (1997).

Music Therapy and Music Medicine in Cancer Care Music therapy strategies are also diverse, encompassing modalities such as music-facilitated stress reduction, and guided imagery and meditation; active music performance, improvisation, singing, and songwriting; expressive music-making and creative approaches initiated by formal assessment or the current state of the patient. Interdisciplinary techniques draw upon the integration of evidence-based therapies. Examples include:  The Bonny Method of Guided Imagery and Music (BMGIM), improvisation-based methods, life review through music, psycho-spiritual music therapy, physio-acoustic therapy, musically supported counseling, and cognitive behavioral music therapy (Krout, 2004). Complete descriptions of referral criteria, music therapy assessments, interventions for each phase of the cancer journey, and evaluation methodologies can be found in Medical Music Therapy for Adults in Hospital Settings (Hanson-Abromeit & Colwell, 2010). Music therapy is not always expressive therapy. For example, one effective coping strategy for pain management focuses attention on the images, memories, and associations evoked by music, rather than requiring the patient to express the pain through music. Numerous clinical protocols have been designed for research and replication purposes, enhancing the ability to determine efficacy. However, the majority of RCTs reported in meta-analyses are music medicine interventions that involve passive listening to music without therapist contact or individualized attention. The literature on music interventions for individuals with cancer includes considerably more RCTs than other creative arts therapies. A Cochrane Review of the impact of music on physical and psychological symptoms of oncology patients included 30 trials with 1,891 research subjects (Bradt, Dileo, Grocke, & Magill, 2011). These studies involved a variety of music techniques, with 17 investigations of listening to recorded music, and 13 music therapy protocols. Of the music therapy studies, only five utilized an active, live music therapy methodology; one used clinical music improvisation, and the others applied passive music listening methods facilitated by a music therapist. Even though the form and format of the music interventions for the 30 studies varied widely, there

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were significant pooled effects on anxiety as measured by State-Trait Anxiety Inventory-State (STAI-S) scale (95% CI = 19.59 to –2.82, p = 0.009) and with other measurement instruments (95% CI = –0.97 to –0.26, p = 0.0007). Physical symptoms showed small differences as a function of musical involvement, including heart rate (95% CI = 6.50 to –1.06, p = 0.007) and breathing rate (95% CI –4.51 to –0.17, p  =  0.03). When one study was deleted due to a sensitivity analysis, significant differences in blood pressure were observed (95% CI: –10.80 to –1.10, p = 0.02 for SBP; 95% CI: –7.14 to –1.42, p = 0.003 for DBP). Quality of life (QOL) and mood were also positively affected (95% CI: 0.58 to 1.47, p = 0.00001 as pooled estimate for two studies of QOL; 95% CI: 0.03 to 0.81, p = 0.03 for mood). Results on a myriad of other variables, such as depression, fatigue, body image, oxygen saturation, immune function, spirituality, and communication, were inconclusive, principally due to small sample size for each single variable. There was moderate impact on pain when pooled results of 391 participants from six trials were analyzed (95% CI: –0.92 to –0.27, p = 0.0003). An additional study that examined reported pain scores supported this finding with significant differences between music therapy (mean change score = –0.44, SD = 2.55) compared with standard treatment (mean change score  =  0.45, SD  =  1.87). These results corroborate findings of another Cochrane Review on the effects of music on pain relief (Cepeda, Carr, Lau, & Alvarez, 2006). In this review of a variety of pain typologies including cancer pain, 51 studies with 3,663 participants revealed that exposure to music was effective in reducing reported pain, decreasing the amount of opioid analgesics required, and increasing the number of patients who expressed a minimum of 50% pain relief. Four trials showed that patients who listened to music were 70% more likely to report pain relief than control patients (95% CI: 1.21 to 2.37). At two hours postsurgery, patients listening to music required 18.4% less morphine than those who did not hear music (95% CI: –2.0 to –0.2); and in five reports, at 24 hours postsurgery, those listening to music required 15.4% less morphine than those not exposed to music (95% CI: –8.8 to –2.6). Although the impact was relatively small, these interventions were not music-therapy strategies designed to meet individual needs, background, and preferences, but rather consisted of very simple listening procedures, many of which failed to take account of individual music preferences. One study with radiation patients demonstrated a dosage effect, such that the more they listened to preferred music, the greater the impact on distress (Clark et al., 2006). Five randomized and quasi-randomized trials were reviewed in a Cochrane Review of music therapy in end-of-life care (Bradt & Dileo, 2010). With a total of 175 participants, these data were too limited to determine true impact on multiple variables; however, moderate benefit was observed for QOL (95% CI: 0.11 to 1.27, p = 0.02). In this setting, the feasibility of the RCT may be

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questionable because randomization is often not possible, and experimental control is difficult to achieve, so examination of other types of research informs a more comprehensive view of clinical outcomes. In the area of palliative care and hospice, qualitative research focuses primarily on the meaning of a patient’s personal experience, offering a more complete picture of the impact of creative arts and expressive therapies. In one review of music therapy research in oncology and palliative care, both objectivist and constructivist approaches were included (O’Callaghan, 2009). Objectivist research refers to hypothesis-driven, quantitative research performed under controlled conditions, whereas constructivist research is designed to uncover the quality of the person’s holistic experience and the meaning generated from that experience. The constructivist lens revealed 66 studies by music therapists as researchers and/or clinicians, demonstrating such outcomes as positive awareness, spirituality, emotional growth, sense of identity, and affirmation of aliveness; opportunities for creativity, enrichment, release, empowerment, balance, and meaning; and reduction of pre-occupation with adversity.

Other Expressive Arts in Cancer Care Drama therapy has been practiced in oncology; however, no RCTs of its outcomes were found in the published literature. Similar to other expressive therapies, drama therapy is based largely on constructivist principles, whereby the meaning of individual experience is the focal point for interventions. Psychodrama is one technique that has been applied extensively in psychotherapy and in innovative adaptations where patients re-create an experience, such as having cancer, through theatre or role-playing. They may spontaneously improvise or design scripts taken from their own histories, and then assess their performances, often developing insights about underlying feelings, use of psychological schemata, and current psychological status (Moreno, 1946). There have been a number of modern plays on themes of cancer, written by survivors, as a therapeutic expression of their perspectives on the cancer journey, for example, 1 A Minute (Gujral, 2010) and Sick (Kenny, 2010). Poetry, expressive writing, and journaling are methods used by individuals as means of communicating and processing the experience of cancer. The health benefits of these natural forms of personal expression are being studied, with poetry writing groups reportedly offering transformational benefits for individuals who have life-threatening illnesses (Rickett, Greive, & Gordon, 2011), although no RCTs could be located. Profound revelations are also evident in individual cases when people use metaphor and symbolic language to work through suffering, pain, and loss (Jones, 1997).

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Expressive writing is a form of narrative journaling that is autobiographic and expresses personal feelings, emotions, and insights related to something important to the person (Pennebaker, 1997). Often the paradigm involves writing about trauma, crisis, or the experience of illness, and opens the writer to examine underlying beliefs as well as confront previously buried emotions (Baikie & Wilhelm, 2005; Pennebaker & Seagal, 1999). A meta-analysis of 13 investigations of its impact on healthy people revealed significant outcomes in physical health, physiological and general health status, and psychological well-being (d = 0.47, p < 0.0001; Smyth, 1998). In a meta-analysis of nine studies involving people with psychiatric as well as physical disorders, expressive writing resulted in significant impact on physical health (d = 0.19, p < 0.05), but not psychological health (d = 0.07, p < 0.17; Frisina, Borod, & Lepore, 2004). One RCT with 90 women who were newly diagnosed with breast cancer asked them to exercise their choice of journaling by hand or via computer (Bauer-Wu et  al., 2007). Women who journaled showed less depression than those in the standard care control group (p < 0.02). A similar RCT with 120 early breast cancer survivors found enhanced quality of life (Craft, Davis, & Paulson, 2012; p < 0.001).

Conclusions Music and expressive arts provide safe and benign therapeutic interventions that can be implemented in groups and with individuals, in both clinical and more naturally occurring settings, such as home. Moreover, there is convincing evidence of enhanced symptom management and psychological/ physical well-being due to certain protocols in specific cancer populations. Yet the diversity of treatment methodologies subverts the process of amassing sufficient data to determine effect size and generalizability of findings. In these holistic approaches that emphasize the uniqueness of each individual’s interaction with artistic or expressive media and the therapist’s facilitation of unique creative moments, both objectivist and constructivist research methods contribute to efficacy determination. The vast individual differences inherent in subjective expression challenge the researcher to identify new ways of measuring outcomes. Interactive approaches based on meeting the patient in the moment are not conducive to standardized protocols, and metaphorical aspects of the work complicate definition. In addition, the spiritual and existential significance of the work is underrepresented in meta-analyses that seek to summarize and objectify clinical outcomes. With all these challenges, RCTs have revealed the positive impact of various music and expressive arts interventions on individuals who have cancer. Table 14.2 summarizes expected outcomes based on research meta-analyses.

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Table 14.2.  Selected Music and Expressive Therapies Protocols and Expected Outcomes Researched Cancer Protocols

Expected Outcomes

Art Therapy

Anthroposophical art therapy, museum + studio art, creative journey, visual poems, multimedia projects, body outline, mindfulness-based art therapy

⇑ quality of life, social coping, general health ⇓ fatigue, anxiety, distress, depression

Dance/ Movement Therapy

“Healing through Movement and Dance,” “Authentic Movement,” body work and body awareness techniques, somatic psychotherapy, use of modern dance techniques and improvisational movement

⇑ quality of life ⇓ fatigue

Music Therapy

Music-facilitated stress reduction, guided imagery and meditation, music performance, instrumental accompaniment, clinical improvisation, singing, songwriting, passive listening to music, music medicine interventions

⇑ quality of life, mood ⇓ anxiety, heart rate, respiration, and blood pressure, pain (reports + opioid use)

Drama Therapy

Psychodrama, re-creation of cancer journey, role-playing, improvisional and scripted theatre

No RCTs

Poetry Therapy

Poetry writing groups, analysis of metaphor and symbolic language in individual poems

No RCTs

Expressive Writing

Narrative journaling, writing about experience of illness

⇑ quality of life, physical health ⇓ depression

As shown, quality of life has been enhanced through the use of any of these therapeutic modalities, except drama and poetry therapy, where no RCTs have tested this effect. Social coping, mood and general/physical health have also shown improvement. Reductions in anxiety (both through psychological and physiological measurements), fatigue, depression, and distress may be observed as a function of various expressive approaches. Pain (both through verbal report and opioid use) has been managed through music therapy and music medicine interventions. Coupled with extensive qualitative accounts and individual case reports of substantive and transformative changes, music and the expressive arts therapies offer constructive, humanizing opportunities for communication, disclosure, working through, and insight into the cancer journey.

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GENERAL REFERENCES

American Art Therapy Association (www.arttherapy.org). American Dance Therapy Association (www.adta.org). American Music Therapy Association (www.musictherapy.org). International Association for Music and Medicine (www.iammonline.com). International Expressive Arts Therapy Association (www.ieata.org) National Coalition of Creative Arts Therapies Associations (www.nccata.org), National Association for Poetry Therapy (www.poetrytherapyorg). North American Drama Therapy Association (www.nadta.org). REFERENCES

Baikie, K. A., Wilhelm, K. (2005). Emotional and physical health benefits of expressive writing. Advances in Psychiatric Treatment, 11(5), 338–346. Bauer-Wu, S., Norris, R., Powell, M., Healey, M., Habin, K., Partridge, A., & Schapira, L. (2007). A web-based expressive writing intervention for young women with newly diagnosed breast cancer. Oncology Nursing Forum, 34(1), 202. Bradt, J.,  & Dileo, C. (2010). Music therapy for end-of-life care. Cochrane Database of Systematic Reviews (1), CD007169. Bradt, J., Dileo, C., Grocke, D.,  & Magill, L. (2011). Music interventions for improving psychological and physical outcomes in cancer patients. Cochrane Database of Systematic Reviews (8) CD006911. Bradt, J., Goodwill, S.  W.,  & Dileo, C. (2011). Dance/movement therapy for improving psychological and physical outcomes in cancer patients (Review). Cochrane Database of Systematic Reviews (10), CD00710. Cepeda, M. S., Carr, D. B., Lau, J., & Alvarez, H. (2006). Music and pain relief. Cochrane Database of Systematic Reviews 2006 (2), CD004843. Clark M, Isaacks-Downton, G., Wells, N., Redlin-Frazier, S., Eck, C., Hepworth, J. T., & Chakravarthy, B. (2006). Use of preferred music to reduce emotional distress and symptom activity during radiation therapy. Journal of Music Therapy, 43(3), 247–265. Craft, M. A., Davis, G. C., & Paulson, R M. (2012). Expressive writing in early breast cancer survivors. Journal of Advanced Nursing, 69(2), 305–315. Dibbell-Hope, S. (2000). The use of dance/movement therapy in psychological adaptation to breast cancer. Arts in Psychotherapy, 27(1), 51–68. Frisina, P. G., Borod, J. C., & Lepore, S. J. (2004). A meta-analysis of the effects of written emotional disclosure on the health outcomes of clinical populations. Journal of Nervous and Mental Disease, 192(9), 629–634.

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Geue, K., Goetze, H., Buttstaedt, M., Kleinert, E., Richter, D.,  & Singer, S. (2010). An overview of art therapy interventions for cancer patients and the results of research. Complementary therapies in medicine, 18, 160–170. Gujral, N. S. (2010). 1 a minute. Accessed at http://www.1aminute.com Hanson-Abromeit, D.,  & Colwell, C. (2010). Medical music therapy for adults in hospital settings. Silver Spring, MD:  American Music Therapy Association. Jones, A. (1997). Death, poetry, psychotherapy and clinical supervision (the contribution of psychodynamic psychotherapy to palliative care nursing). Journal of Advanced Nursing, 25, 238–244. Kenny, E. (2010). Sick. Accessed at http://shadylaneproductions.org/Sick/ Krout, R. E. (2004). A synerdisciplinary music therapy team approach for hospice and palliative care. Australian Journal of Music Therapy, 15, 33–45. Mannheim, E. G., & Weis, J. (2005). Dance therapy with cancer patients: Results of a pilot study. Musik, Tanz, und Kunsttherapie, 16(3), 121–128. Moreno, J. L. (1946). Psychodrama, first volume. New York: Beacon House. O’Callaghan, C. (2009). Objectivist and constructivist music therapy research in oncology and palliative care:  An overview and reflection. Music and Medicine, 1(1), 41–60. Pennebaker, J.  W. (1997). Opening Up:  The Healing Power of Expressing Emotions. New York: Guilford Press. Pennebaker, J. W., & Seagal, J. D. (1999). Forming a story: The health benefits of narrative. Journal of Clinical Psychology, 55(10), 1243–1254. Rickett, C., Greive, C.,  & Gordon, J. (2011). Something to hang my life on: The health benefits of writing poetry for people with serious illnesses. Australasian Psychiatry, 19(3), 265–268. Sandel, S. L., Judge, J. O., Landry, N., Earia, L., Ouellette, R., & Majczak, M. (2005). Dance and movement program improves quality-of-life measures in breast cancer survivors. Cancer Nursing, 28(4), 301–309. Serlin, I. A., Frances, B., Vestevich, K., Bailey, T., & Lavaysse, L. (1997). The effect of dance/movement therapy on women with breast cancer. Alternative Therapies in Health and Medicine, 3,103. Smyth, J. M. (1998). Written emotional expression. Effect sizes, outcome types, and moderating variables. Journal of Consulting and Clinical Psychology, 66, 174–184. Steiner, R. (1995). Anthroposophy in everyday life. Hudson, NY: Anthroposophic Press.

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Strassel, J. K., Cherkin, D. C., Steuten, L., Sherman, K. J., Hubertus, J. M., & Vrijhoef, J. M. (2011). A systematic review of the evidence for the effectiveness of dance therapy. Alternative therapies, 17(3), 50–59. Wood, M. J. M., Molassiotis, A., & Payne, S. (2011). What research evidence is there for the use of art therapy in the management of symptoms in adults with cancer? A systematic review. Psycho-Oncology, 20, 135–145.

15 Energy Medicine and Cancer SUSAN K. LUTGENDORF, ELIZABETH MULLEN-HOUSER, AND EMIRA DEUMIC

Key Concepts Energy medicine is a complementary modality whose practitioners purport to restore the flow of energy fields associated with the human body for symptom relief, disease prevention, and health restoration. ■ Experimental evidence of the health benefits of energy medicine is promising overall, although findings have been mixed, with many studies suffering from methodological weaknesses. ■ Preclinical trials suggest that energy medicine may enhance immunity and decrease growth and activity of cancer cells. ■ Clinical trials have reported evidence of improved mood, quality of life, immune parameters such as natural killer-cell activity, and normalized diurnal cortisol patterns; however, research is still sparse and replication is needed ■ Larger energy medicine clinical trials with strong methodology are needed to address both the effectiveness and mechanisms of action, as well as factors influencing replication of these effects. ■ The majority of patients using energy medicine do not automatically inform physicians about their use of complementary therapies. Medical practitioners are advised to ask their patients whether they are utilizing energy medicine treatments or other integrative medicine modalities. ■

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Use of Energy Medicine in Oncology Settings Integrative medicine therapies are reportedly used by 30% (Fouladbakhsh, Stommel, Given,  & Given, 2005; Markovic, Lenore, Natalie,  & Michael, 2006) to 76.64% (Anderson & Taylor, 2012) of cancer patients. Cancer patients using complementary therapies are more often female, undergoing surgery or chemotherapy, experiencing substantial symptoms (Fouladbakhsh et al., 2005), well educated, and with higher income (Alferi, Antoni, Kilbourn, & Carver, 2001, Fouladbakhsh & Stommel, 2010). Energy-based therapies are among the CAM therapies sought out by cancer patients (Fouladbakhsh et al., 2005; Hann et al., 2005; Markovic et al., 2006; Molassiotis et al., 2005; Sparber et al., 2000). Although there have been some successful clinical trials, the data is still sparse for establishing the efficacy, effectiveness, and putative mechanisms of these therapies. This chapter examines the use of energy therapies in oncology settings and the state of the evidence-based literature on preclinical and clinical findings. Although there is substantial literature on the effects of long-distance healing and prayer (Astin, Harkness, & Ernst, 2000; Benson et  al., 2006; Sicher, Targ, Moore,  & Smith, 1998), the focus of the present chapter is on energy therapies used at close proximity to the patient.

National Institutes of Health Definition and Assumptions of Energy Medicine According to the National Center for Complementary and Alternative Medicine (NCCAM), energy medicine deals with two types of energy fields—those that can be measured (called veritable) and those that have yet to be measured (called putative) (see Table 15.1 for a summary of NCCAM Classified Energy Therapies). Veritable energy fields include measurable vibrations such as sound, visible light, laser beams, and rays from the electromagnetic spectrum. Measurement of putative energy fields is more controversial. It has been proposed that energy emanating from healers may actually incorporate both types of energies. Energy therapies conceptualize the physical body as an energy field suffused with a “life force.” This life force is called different names according to the culture such as prana in Ayurvedic medicine and Qi in Traditional Chinese Medicine and is thought to flow through pathways such as meridians in the traditional Chinese system or nadis and chakras in the Ayurvedic system. Free flow of this “life force” through the body is thought to support health, whereas disturbances or

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blockages in the flow of this energy are thought to cause impaired function in organs and tissues, and ultimately illness. Potential illness is described as visible in the energy system before physical signs appear. Modulation of a patient’s energy field to recreate flow and balance is thought to relieve certain symptoms of illness, as well as to prevent emergence of illness (Mentgen & Bulbrook, 2002; NCCAM, 2004).

Table 15.1.  Brief Description of NCCAM Classified Energy Therapies Name

Description

External Qi Therapy (Qigong therapy) (Shannon, 2003)

• External Qi therapy is based on Qigong, 2,000-year-old Chinese mind–body exercises. Qi means breathing and vital energy, according to Traditional Chinese Medicine and Gong means power. • Intentional transfer of Qi-energy from one person to another person or organism. • Can be done in close proximity or from a distance. • There are many different types of Qigong traditions. • No formal organizational structures regulate the teaching and certification of practitioners. • Qigong can also be used as a system of exercises that a patient can do to strengthen flow of Qi within the body and decrease energy congestion.

Reiki (IARP, 2006; Miles & True, 2003)

• Created in Japan by Mikao Usui in the early 1900s. Reiki is purported to increase health by accessing universal life energy and connecting this with the body’s own innate healing abilities via hands-on healing. • Formalized Reiki training exists, in which a Reiki master transfers the healing ability to a student through a process called “attunement,” and formalized levels of training have been developed.

Johrei (Laidlaw et al., 2003; Taft et al., 2005)

• Founded in Japan by Mokichi Okada, this modality was brought to the United States in 1953. • It involves a nontouch transfer of life energy. Healing ability is thought to develop through a life of spiritual practice, not formal training. • Practitioners direct energy from their hands toward the recipient. The practitioner visualizes healing light entering their own body and directs it via an outstretched hand to the recipient in a spirit of goodwill.

Polarity Therapy (Wilson, 2007)

• Developed by Randolph Stone, D.C., D.O., N.D. in the 1940s. • Energy conduction through hands-on touch to resolve energy blocks and restore a smooth flow of energy. • Part of a larger health system including diet, exercises, and increased self-awareness.

(continued)

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Table 15.1.  Continued Name

Description

Therapeutic Touch (TT: Krieger, 1979; Mathúna, 2000)

• A system formalized by Dora Kunz and Dolores Krieger, R.N., Ph.D. in the 1970s, it is used in many health care settings. • TT utilizes nontouch energy transfer to restore balance and self-healing capacity. • Posits that living organisms have energy fields which interact with information from the environment. • Practices include centering, assessment, unruffling, modulation of energy, and closure. • Advanced practitioner status is achieved through a certification process.

Pranic Healing (Sui, 1999)

• Originating in China thousands of years ago, it was reformulated more recently by Master Choa Kok Sui, based in the Philippines. • Healers are said to manipulate patient ki by perceiving “auras” of color around the human body, and projecting corrective colors to the aura to bring a state of balance and health.

Healing Touch (Mentgen, 2001; Mentgen Bulbrook, 2002)

• Developed by Janet Mentgen, B.S.N., R.N., and Dorothea Hover-Kramer, Ed.D., R.N., in the 1980s, HT integrates indigenous healing techniques as well as techniques of many prominent healers. • HT uses gentle touch to restore harmony and balance the patient’s energy system to assist the patient to self-heal. • Practitioners place hands above and on the patient’s body to determine areas of energy imbalance, unblock energy, promote physical healing and emotional, mental, and spiritual balance. • Over 30 specific techniques are taught as part of this process. These include techniques that address specific problem areas (mind clearing, pain, and lymphatic drain) as well as specific pathologies (arthritis, back pain). • There is a standardized HT curriculum and formal certification offered through Healing Touch International and endorsed by the American Holistic Nurse’s Association.

VERITABLE ELECTROMAGNETIC FIELDS

Measurable (veritable) electromagnetic fields have had substantial use in medicine. Both static and pulsing electromagnetic fields have been used for the diagnosis and treatment of a variety of illnesses in current medical practice. For example, pulsed electromagnetic fields, using waves of approximately 15 Hz, have been shown to enhance healing of bone fractures, to stimulate bone formation, and are commonly utilized in medical practice (Fredericks,

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Nepola, Baker, Abbott,  & Simon, 2000; McLeod  & Rubin, 1992; Rubin, Donahue, Rubin, & McLeod, 1993). The effect of magnetic fields for treatment of cancer has been examined, though much of this work is still in preclinical stages. Pulsating magnetic fields have been shown to inhibit tumor growth in animal models (Salvatore  & Markov, 2004)  and to inhibit tumor angiogenesis (Markov, Williams, Cameron, Hardman, & Salvatore, 2004; Williams & Markov, 2001; Williams, Markov, Hardman, & Cameron, 2001). Some reports, however, have indicated that electromagnetic fields can enhance tumor growth (Hannan, Liang, Allison, & Searle, 1994; Watson, Parrish, & Rinehart, 1998). Electromagnetic fields have also been used to reverse resistance of tumor cells to chemotherapy and to enhance the effects of chemotherapy. These experiments have been successful in both in vitro and animal models and have the potential of ultimately decreasing the amount of chemotherapy required and providing alternative means of dealing with resistance to chemotherapy (Cadossi et al., 1991; Salvatore & Markov, 2004; Zucchini et al., 1991). Some phase I work has also established safety and minimal toxicity of static magnetic fields accompanying antineoplastic chemotherapy in humans (Salvatore, Harrington, & Kummet, 2003). MEASUREMENT AND PROPERTIES OF PUTATIVE ENERGY FIELDS

The concept of the presence of electromagnetic fields underlying the pattern and organization of biological systems has been a basic tenet of medical systems such as traditional Chinese medicine and ayurvedic medicine for centuries (NCCAM, 2004). Various attempts have been made to empirically validate these putative energy fields. From 1916 to the mid-1950s, Dr. Harold Saxton Burr, Professor of Anatomy at Yale University School of Medicine, made pioneering efforts in this field and devoted his career to mapping the energy fields of living organisms, publishing more than 93 scientific papers and several books. Burr proposed that electrodynamic fields, which he called “fields of life” or “L-fields,” were the organizing matrix of all living organisms and determined the relative state of health or illness of the organism. He developed a methodology of measuring and mapping these fields with standard voltmeters, and using this technology he demonstrated that changes in the electrical potential of the L-field preceded changes in the health of the organism (Burr, 1972). Burr’s voltmeter technology was extended to cancer populations in two publications that were reported in the mainstream journals American Journal of Obstetrics and Gynecology and Science in the late 1940s and early 1950s

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(Langman  & Burr, 1947, 1949). Burr was part of a team from Bellevue and New York University hospitals that measured voltage differences between the tip of the cervix and the ventral abdominal wall in 428 patients with gynecologic cancers and healthy controls. A reversal of these polarities was noted in almost 99% of patients as compared to the controls, a pattern subsequently replicated in 860 patients (Langman, 1972; Langman & Burr, 1947, 1949). The authors suggested that such electromagnetic patterns may allow for atypical cell growth in patients (Langman, 1972). Later in his life, Burr’s work received strong criticism, and this line of work does not appear to have been continued in cancer patients. More recently, Michael Levin and colleagues at Tufts University have been studying how transmembrane voltage gradient patterns regulate cellular properties. They have observed that all tissues contain endogenous bioelectric signals, which they define as patterns of resting potential. These bioelectric signals drive cellular cues that orchestrate patterns of cellular regeneration and wound healing. These scientists have now observed that a specific bioelectric membrane signature is present during tumor development, and suggest that changes in resting membrane potential may be utilized as a strategy for normalization of tumor cells (Chernet & Levin, 2013). To date, the putative role of electromagnetic patterns or fields in maintaining health has been poorly characterized. However, there is some documentation that the physiological processes of a living system such as plant growth, enzyme activation, or hemoglobin production can be positively influenced by nontouch influences thought to work by “exchange of energy” (Byrd, 1988; Grad, 1963, 1964; Grad, Cadoret,  & Paul, 1961; Krieger, 1972; Smith, 1972; Smith, 1973). Since these effects occurred without actual physical contact, they have been used to support the interpretation that these effects were induced by means of an energy transfer from the healer to the recipient. Effects of energy therapies are hypothesized to occur through alteration of “biomagnetic fields” (Chen & Liu, 2004; Kiang, Marotta, Wirkus, Wirkus, & Jonas, 2002; Oschman, 2000; Wirth, Brenlan, Levine,  & Rodriguez, 1993; Wirth  & Cram, 1993)  by practitioners of various energy therapies (Berden, Jerman, & Skarja, 1997; Grad, 1963, 1964; NCCAM, 2004; Zimmerman, 1990). In an experiment to determine the types of wavelengths that were emitted during biofield healing, a group at the University of Pennsylvania examined waves emanating from the hands of a Japanese “Ki-expert” (healer using Qi energy) and studied the effect on cellular mitochondria function. His treatment appeared to protect mitochondria from oxidative stress (discussed in more detail in the next section). Examination of materials that could block these effects suggested that the emitted energy involved a wavelength near the infrared spectrum, with a size of approximately 0.8–2.7 µm (Ohnishi, Ohnishi,

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Nishino, Tsurusaki, & Yamaguchi, 2005). Other studies have implicated γ radiation as being fundamental to energy therapy. Researchers from the University of Arizona have now found that reliable alterations in amplitude in the extra low frequency range can be detected to be emanating from hands of healers who were “running energy” (Connor, Schwartz, & Tau, 2006). An extremely sensitive magnetometer (device used to detect magnetic fields) known as the SQUID (superconducting quantum interference device) has been able to detect pulsing magnetic fields from the hands of Therapeutic Touch (TT) practitioners during treatments, as well as from the hands of practitioners of yoga, meditation, and Qigong (Benford, 2001). These fields were of extremely low frequency, from approximately 21 to 50 Hz, but interestingly, they were similar to the fields being tested for accelerating healing in tissues in various medical experiments (Benford, 2001). However, with a few exceptions (Berden et al., 1997), testing of the hypothesis of energy transfer has been largely absent (Quinn, 1989). For more detailed discussion of these concepts, refer to Hammerschlag and colleagues (2013) and Oschman (2000).

In Vitro Studies of Energy Medicine and Cancer In vitro studies have been used as experimental models to examine the effects of energy medicine without the placebo effect confounds seen in human trials. In vitro studies of biofield medicine have shown effects in decreasing growth and activity of cancer cells, although the findings have been mixed and often attempts at replication have not been successful. Many of these experiments have lacked proper controls and had problems in design. A number of well-designed studies are presented in the following paragraphs. Readers are also referred to Kevin Chen’s review of Qigong studies on cancer in China (Chen & Yeung, 2002). Table 15.2 provides a summary of preclinical trials. Ohnishi and colleagues reported that 5- to 10-minute treatments of cultured human liver carcinoma cells by a Japanese Ki-expert decreased cancer cell numbers by 30.3% at 5 minutes and by 40.6% at 10 minutes and also increased protein content/cell (Ohnishi et  al., 2005). RT-PCR analyses indicated that the mRNA expression for c-myc, a tumor stimulator gene, was decreased, whereas that for regucalcin, a suppressor of DNA synthesis, was increased. Levels of p53 did not change with the Ki-intervention. The authors suggest that the Ki-energy suppressed proliferation of these cells by influencing gene expression in the nucleus. Ki effects were blocked when either aluminum foil or black acrylic plates were placed between the healer and the cells but were not blocked by a clear plastic plate. As noted earlier, based on this differential

Table 15.2.  Summary of Preclinical Trials in Energy Medicine References

Treatment Modality

Type of Cancer/ Biological Marker

Method

Results

Bengston & Krinsley (2000). The effect of the “laying on of hands” on transplanted breast cancer in mice. Journal of Scientific Exploration, 14, 353–364.

Laying on of hands

Mice injected with mammary adenocarcinoma (H2712)

Experimental condition: • Mice treated by “skeptical” healers who have learned laying on of hands. Two control conditions: • Mice not treated but housed on-site. • Mice not treated and housed off-site. Four replications of experiment.

•E  xperimental mice: Tumors imploded and healed and mice lived a normal span and showed resistance to future carcinoma injection. •C  ontrol mice: On-site evidenced enhanced. remission and survival • Off-site died within predicted time frame (14 to 27 days). Investigators suggest belief in treatment not necessary for effectiveness.

Abe, Ichinomiya, Kanai, & Yamamoto (2012). Effect of a Japanese energy healing method known as Johrei on viability and proliferation of cultured cancer cells in vitro. The Journal of Alternative and Complementary Medicine, 18, 221–228.

Johrei

Cultured human cancer cells

• Human gastric carcinoma cells cultured and treated with Johrei for 3 or 4 days: twice daily for 15 minutes each at distance 15cm away. • Some control groups received no Johrei treatment; other control groups included volunteers with no Johrei experience standing by cultured cells. • Measures included cell viability, proliferation, and time-lapse microscropy.

• Johrei group had significantly higher viability loss compared to either control group. • Responsiveness to Johrei varied with different cancer cell types. • Gastric cancer cells treated with Johrei for 72 hours had significantly decreased proliferation rate compared to untreated cells. • Extent of cell death and/or number of dead cells was greater in Johrei group versus untreated cells. (continued)

Table 15.2.  Continued References

Chen et al. (2002). A preliminary study of the effect of external Qigong on lymphoma growth in mice. The Journal of Alternative and Complementary Medicine, 8, 615–621.

Treatment Modality

Qigong

Type of Cancer/ Biological Marker

Lymphoma

Method

Results

SJL/J mice: • Randomized, dual blind (research director, assistants and statistician were blinded to procedure; Qigong healer was not). 3 groups: • Treated with Qigong, sham treatment (not described) and no-treatment group. Study 1: • Qigong group receives treatment 10 minutes every other day for 5 sessions. • Mice injected with lymphoma cells 24 hours after first treatment. Study 2: • Qigong group receives treatment 10 minutes every day for 5 days.

Study 1: •D  ay 9 sacrifice: Qigong mice showed less tumor in lymph nodes but not spleen than other groups. •D  ay 11 sacrifice: Qigong group exhibited less tumor growth in lymph nodes and spleen than control but not sham group. Study 2: • No significant differences. Larger standard deviations than study 1. • Study differences may be due to greater handling stress of control mice in study 1.

Fukushima Kataoka, Hamada, & Matsumoto (2001). Evidence of Qi-gong energy and its biological effects on the enhancement of the phagocytic activity of the human polymorphonuclear leukocytes. The American Journal of Chinese Medicine, 29, 1–16.

Qigong

Human peripheral blood leukocytes

• External Qigong applied to saline solution (PBS) vs. no-treatment control. • Experimental condition of PBS was masked, and either treated or untreated PBS added to leukocyte suspensions and phagocytic activity measured for 10 trials. Subset of samples exposed to rotated microwave treatment and autoclave treatment. • Another subset of samples exposed first to unrotated microwave and then to pulsed laser treatments.

• Qi-treated samples demonstrated greater phagocytic activity. Rotated microwave but not autoclave treatments decreased this effect. • Unrotated microwave and laser irradiation produced similar effects as Qi-treatment.

Jhaveri et al. (2008)

Therapeutic Touch

Human Osteoblasts (HOB) and humanosteosarcoma cell lines (SaOs-2)

Experimental condition: • TT applied twice weekly for 10 minutes for 2 weeks Control Condition: • No TT treatment but identical lab conditions. Placebo control: • Hand movements by untrained individual counting backward from 1000.

• TT increased DNA synthesis, differentiation and mineralization in HOB cells compared to controls. • TT decreased differentiation and mineralization in SaOs-2 cells compared to controls. • Placebo-treated cultures did not differ from controls in proliferation or mineralization. (continued)

Table 15.2.  Continued References

Kiang et al. (2005). External bioenergy-induced increases in intracellular free calcium concentrations are mediated by Na+/Ca2+ exchanger and L-type calcium channel. Molecular and Cellular Biochemistry, 271, 51–59.

Treatment Modality

External bioenergy (EBE)

Type of Cancer/ Biological Marker

T cells

Method

Results

Experimental condition: • Bioenergy specialist emitted external bioenergy (EBE) toward tubes of cultured Jurkat T cells for 15 minutes. • Intracellular calcium (Ca2+) levels measured at baseline, for 4 minutes during treatment, and immediately post treatment. • In a subset of samples, EBE treatment applied at varying distances and/or time intervals. • In one experiment, untreated cells were placed in the site of previous EBE treatment for 15 minutes. • External calcium and sodium were depleted from some samples before EBE Sham condition: samples with no EBE treatment.

• EBE treatment increased intracellular free Ca2+ concentrations by 30% at 3 inches; sham treatment did not increase intracellular free Ca2+. • Distance from healer did not diminish results. • Number of treatments did not change results. • Intracellular free Ca2+ increases were seen in samples exposed to the site where EBE treatment had previously occurred, suggesting contextual effects. • EBE effects were not seen in samples depleted of external calcium and sodium. • Authors suggest that sodium/calcium exchange is a mechanism of EBE-related intracellular free Ca2+ increases.

Lee, Huh, Jang, et al. (2001). Effects of emitted Qi on in vitro natural killer cell cytotoxic activity. American Journal of Chinese Medicine, 29, 17–22.

Qi therapy

NK cell activity

• Blood collected from 6 healthy men and 5 healthy women • Each sample divided into one experimental and one control sample. • Experimental received various durations of Qi treatment between 30 and 300 seconds. Standard NK cytotoxicity assay performed.

• NK cell activity increased in the Qi treated cells only; no change in control cells.

Mager et al. (2007). Evaluating biofield treatment in a cell culture model of oxidative stress. EXPLORE: The Journal of Science and Healing, 3, 386–390.

Six practitioners including two Qigong, two Johrei and two “Biofield Healers,” using techniques similar to Qigong and Johrei

Cultured human brain cells

• Cultured human brain cells exposed to incrementally greater concentrations of hydrogen peroxide to stimulate cell death. Biofield practitioners delivered treatment for 30 minutes to four cell lines, one at a time. • Treatment applied before and after hydrogen peroxide application. • Nontreated cell cultures served as controls. Cell death quantified by computerized time-lapse microscopy. Samples blinded for outcome measures.

• Cell death did not differ significantly between cell lines in treatment and control conditions.

(continued)

Table 15.2.  Continued References

Treatment Modality

Type of Cancer/ Biological Marker

Method

Results

Ohnishi, Ohnishi, and Nishino (2006). Ki-energy (Life-energy) protects isolated rat liver mitochondria from oxidative injury. Evidence-Based Complementary and Alternative Medicine, 3, 475–482.

Ki-energy

mitochondria of rat liver

• Rat liver mitochondria exposed to 0, or 5 to 10 minutes of Ki-energy. • A portion of mitochondria then exposed to a 10-minute heat treatment (39oC).

• Ki-energy improved respiration ratios in nonheated mitochondria. • Lipid peroxidation reduced in the heattreated mitochondria when Ki was applied, suggesting Ki protected it from oxidative stress.

Ohnishi et al. (2005). Growth inhibition of cultured human liver carcinoma cells by Ki-energy (life energy): Scientific evidence for Ki-effects on cancer cells. Evidence Based Complementary and Alternative Medicine, 2, 387–393.

Ki-energy

Human cultured liver carcinoma cells, HepG2

• Cells either exposed to 0, 5, or 10 minutes of Ki-energy by a Japanese “Ki-expert” or handled by non-Ki expert for 5 or 10 minutes. • Blocking experiments were also done.

• Significant decrease in cell numbers and increase in protein content per cell seen in Ki condition. • In non-Ki handling condition, no changes seen. • Non-Ki handled cultures also had significantly less growth post treatment. • Covering cultures with aluminum foil, and acrylic, blocked changes induced by Ki-expert but polysterene did not block changes.

Rubik et al. (2006). In Vitro effect of Reiki treatment on bacterial cultures: Role of experimental context and practitioner well-being. The Journal of Alternative and Complementary Medicine, 12, 7–13.

Reiki

E. coli K12 cultures

•E  . coli samples heat-shocked, then each Reiki practitioner applied treatment to 5 samples. • For 2 samples, Reiki first applied to a patient with a sprained ankle (healing context), in 3 samples no prior healing was performed (nonhealing context). • Well-being self-report of Reiki practitioners assessed pre-post all sessions. • Outcome measure: E. coli growth.

Nonhealing context: • No difference between Reiki and controls. • In practitioners with diminished well-being E coli counts less than control. • Practitioners with high well-being, E coli counts higher than control. In healing context: • Reiki-treated cultures had more bacteria counts than controls, suggesting. augmenting effect of prior treatment. • Mood × treatment effect: In practitioners with poorer mood, E coli counts were less than controls.

Taft et al. (2005). Time-lapse analysis of potential cellular responsiveness to Johrei, a Japanese healing technique. BMC Complementary and Alternative Medicine, 5. Retrieved January 30, 2007, from http://www. biomedcentral. com/1472-6882/5/2

Johrei

Brain tumor cell line: glioblastoma multiforme

• Johrei treated cultures: treated for 4 hours each, with 2 healers assigned to each culture, alternating every half hour. • Time-lapse microscopy used to quantify tumor cell death, proliferation, and cellular emigration

• No evidence of response to Johrei treatment

(continued)

Table 15.2.  Continued References

Treatment Modality

Type of Cancer/ Biological Marker

Method

Results

Yan et al. (2006). External Qi of Yan Xin Qigong differentially regulates the Akt and extracellular signal-regulated kinase pathways and is cytotoxic to cancer cells but not normal cells. The International Journal of Biochemistry & Cell Biology, 38, 2102–2113.

Qigong

Pancreatic cancer cells (BxPC3)

• Cells treated with external Qi for 5 minutes, then harvested and analyzed 10 minutes post treatment. • Subset of cells received 3 5-minute treatments. • Subset of cells serum-starved 48 hours before treatment. • Fibroblast cells serum-starved 24 hours pre-treatment, then harvested at various times points post –treatment

• Qi treatment differentially regulated survival pathways in cancer versus normal cells. • Qi treatment of cancer cells inhibited cell growth mechanisms (Akt, epidermal growth factor, NF-κΒ), induced apoptosis and DNA fragmentation. • Prolonged treatment of cancer cells led to rapid cell lysis. • fibroblasts did not show cytotoxic effect.

Yan et al. (2008). External Qi of Yan Xin Qigong induces G2/M arrest and apoptosis of androgen-independent prostate cancer cells by inhibiting Akt and NF-jB pathways. Molecular Cellular Biochemistry, 310, 227–234.

External Qi

Androgenindependent prostate cancer (PC3) cells

• Cultured PC3 cells exposed to Qi treatment for 5 minute period then assessed for growth and apoptosis. • Methods included assays for electrophoresis mobility shift, DNA fragmentation, cell cycle, and Western Blot.

• Exposure to Qi treatment led to G2/M arrest associated with reduced cyclin B1 expression and apoptosis in PC3 cells. • Qi treatment inhibited Akt phos-phorylation, and NF-κΒ activation, and downregulated anti-apoptotic Bcl-2 and Bcl-xL expression. • Exposure to Qi treatment increased phosphorylation of Akt and Erk1/2 in human umbilical vein endothelial cells (HUVEC), and had no cytotoxic effect on either HUVEC or peripheral blood mononuclear cells.

Yan et al. (2010). External Qi of Yan Xin Qigong induces apoptosis and inhibits migration and invasion of estrogen-independent breast cancer cells through suppression of Akt/NF-κB signaling. Cellular Physiology and Biochemistry, 25, 263–270.

External Qi

Estrogenindependent breast cancer MDA-MB-231 cells

• Yan Xin External Qi Gong applied to breast cancer cells for 5 minute periods then assessed for growth, migration, invasion, apoptosis, and related molecular mechansims. • Methods included assays for cytotoxicity, clonogenics, migration and invasion, apoptosis and cell cycle, DNA fragmentation, electrophoresis mobility shift, and Western Blot.

• Qi treatment caused a time-dependent reduction in viability, blocked clonogenic growth, and induced apoptosis. • Blocked migration and invasion of MDA-MB-231 cells. • Inhibited constitutive and EGF-induced Akt phosphorylation. • Substantially repressed NF-κB activity, resulting in decreased expression of anti-apoptotic Bcl-2, Bcl-XL, XIAP and surviving proteins.

Yan et al. (2012). External Qi of Yan Xin Qigong induces cell death and gene expression alterations promoting apoptosis and inhibiting proliferation, migration and glucose metabolism in small-cell lung cancer cells. Molecular Cellular Biochemistry, 363, 245–255.

External Qi

Small-cell lung cancer (NCI-H82) cells

• Qi treatment cultures treated for 10 minutes sessions. Nontreatment cultures underwent sham-operated procedure. • Cultures assessed for cytotoxicity. • Methods included MIT cell viability assay, gene expression profiling, and flow cytometric cell death detection.

• Qi treatment caused potent cytotoxic effects toward NCI-H82 cells by inducing apoptosis. • Qi treatment altered expression of 39 genes of NCI-82 cells detected by gene expression profiling. • Qi treatment facilitated cancer cell apoptosis while repressing proliferation, metastasis, and glucose metabolism potentially through gene modulation.

(continued)

Table 15.2.  Continued References

Treatment Modality

Type of Cancer/ Biological Marker

Method

Results

Yan X et al. (2013). External Qi of Yan Xin Qigong inhibits activation of Akt, Erk1/2 and NF-ĸB and induces cell cycle arrest and apoptosis in colorectal cancer cells. Cell Physiology and Biochemistry, 31(1):113–122

External Qi

Colorectal cancer cells (HT-29)

Phosphorylation of Akt, Erk, and NF-kB and expression of proteins involved in regulation of cell cycle and apoptosis assessed by Western blot.

• Qi treatment decreased viability and blocked colony formation • Induced G1 cell cycle arrest by downregulating cyclin D1. • Induced apoptosis via downregulation of antiapoptotic proteins Bcl-xL, surviving, Mcl-1 and increased expression of pro-apoptotic proteins. • Inhibited activation of Akt, Erk1/2, and NF-κΒ. • Qi-treated PBS or plant extract induced apoptosis in these cells.

Yount, Solfvin, et al. (2004). In vitro test of external Qigong. BMC Complementary and Alternative Medicine, 4. Retrieved January 30, 2007, from http:// www.biomedcentral. com/1472–6882/4/5

Qigong—external

Normal brain cells

• Series of three studies (96 total experiments between these studies) involving 20-minute external Qigong treatment or no treatment. • Brain cells cultured and examined for colony-forming efficiency (CFE).

Study 1: • No significant difference in cell duplication between Qigong treated and control cells. Study 2: • Qigong-treated cells duplicate significantly more than control Study 3: • Cell duplication did not differ between Qigong treated and sham cells.

Yount et al. (2013). Evaluation of biofield treatment does and distance in a model of cancer cell death. The Journal of Alternative and Complementary Medicine, 19(2), 124–127.

Biofield Healing

Cultured human glioblastoma cancer cells

This chart includes several additional studies not contained in the text.

• Two separate studies assessed biofield treatment dosage and biofield treatment distance with three independent experiments within each. • Treatment dosage assessed from short distance (0.25m) in three experiments varying number of treatments. Three independent parallel mock treatments: • Treatment distance assessed in 3 expts. at.25, 25, and ~2000m using 2 biofield treatment. Three independent mock treatments also assessed. • Viability measured with spectrophotometric assay

• A negative relationship was found between biofield dose and cell viability. • No relationship was found between biofield distance and cell viability. • All mock treatments showed relatively stable viability ratios for both biofield dosage and distance. • Experimenters deemed results inconclusive due to inability to reproduce cellular response in experiment replication.

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blocking, the authors suggested that the emanated Ki-energy may be a form of electromagnetic wave in the spectrum of infrared radiation. Yan and colleagues have performed a series of studies involving a collaboration between the Chongqing Institute of Traditional Chinese Medicine in China and the Dana Farber Cancer Institute and Harvard Medical School. In an early publication (Yan et  al., 2006), this group treated BxPC3 pancreatic cancer cells with external Qigong for 5 minutes and examined effects on pathways relevant to survival, proliferation, and resistance to apoptosis. External Qi differentially regulated the survival pathways in cancer versus normal fibroblast cells. In the pancreatic cancer cells, inhibition of pathways critical to cell growth, including Akt, epidermal growth factor, and nuclear factor kappa-B (NF-κB), were observed. A 5-minute external Qi treatment also induced apoptosis and DNA fragmentation, and prolonged treatment caused rapid lysis of these cells. In marked contrast, external Qi treatment of normal fibroblasts did not have a cytotoxic effect and induced transient activation of pathways described earlier. These intriguing findings indicate that energy treatments may have differential effects on cancer cells as opposed to normal cells and that cytotoxic effects of Qi may be seen specifically in cancer cells. A second study by the same authors reported cytotoxic effects of external Qi in androgen-independent PC3 prostate cells. External Qi healing downregulated specific molecular pathways (including Akt and NF-κB) in cancer cells but not in normal cells (Yan et al., 2008). In a third study by this group, Yan and colleagues (2010) treated estrogen-independent breast cancer (MDA-MB-231) cells with external Qi healing for 5 minutes and examined effects on pathways relevant to growth, migration, invasion, and apoptosis. Qi healing significantly reduced viability, blocked clonogenic growth, induced apoptosis, and blocked migration and invasion by interfering with Akt/NF-κB signaling. Next, this group treated small-cell lung cancer cells with 5 minutes of external Qi healing (Yan et  al, 2012). These treatments altered gene expression of 39 genes, including upregulation of apoptotic and cell death-inducing proteins and downregulation of several key oncoproteins, all of which were confirmed by semiquantitiative RT-PCR and real-time qPCR. These findings indicate that external Qi healing exerted anticancer effects through modulating gene expression. A final study (Yan et  al., 2013)  found that external Qi healing inhibited cell signaling pathways (including Akt, Erk1/2, and NF-κB) necessary for cell proliferation and survival, and induced cell cycle arrest and apoptosis in colorectal cancer cells. Additionally, external Qi healing applied to either a plant extract or a phosphate buffered saline solution, which was then applied to these colorectal cells, also induced apoptosis. Taken together, this body of research demonstrates robust cytotoxic effects of external Qi healing on in

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pancreatic, prostate, breast, lung, and colorectal cancer cells. Furthermore, molecular pathways by which healing effects occur are elucidated. As these findings are all from one laboratory with one method of healing, it would be important to replicate these findings in other laboratories, and to determine if similar results could be observed with other healing modalities. Gronowicz’s group at the University of Connecticut (Jhaveri, Walsh, Wang, McCarthy,  & Gronowicz, 2008)  showed differential effects between the effects of Therapeutic Touch on healthy cells (human osteoblasts (HOB)) versus cancer cells (an osteosarcoma-derived cell line (SaOs-2)). Cells received Therapeutic Touch twice weekly for 10 minutes over the course of 2 weeks. Therapeutic Touch significantly increased mineralization in HOB cells and decreased mineralization in SaOs-2 cells as compared to no-treatment controls. Additionally, Therapeutic Touch induced an increase in mRNA expression for Type I collagen, bone sialoprotein, and alkaline phosphatase in HOB cells whereas these bone markers decreased in SaOs-2 cells. Two weeks of Therapeutic Touch treatment significantly increased DNA synthesis in HOB but not in SaOs-2 cells. These effects were not seen at 1 week. These findings highlight differential effects of Therapeutic Touch in healthy and cancer cells. Therapeutic Touch appears to increase DNA synthesis, differentiation, and mineralization in healthy human osteoblast cells, whereas differentiation and mineralization are decreased in bone cancer cells. Kiang and colleagues (2005) reported that a 15-minute treatment of Jurkat T cells by a biofield healer increased intracellular calcium by approximately 22%, an effect that lasted 2 hours. This outcome was indicative of improved cellular functioning because intracellular free calcium stimulates many key cellular functions such as metabolism, proliferation, gene expression, and movement. Interestingly, a blunted version of this effect (11% increase in calcium) was observed when cells were placed in an area in which the biofield experiments had previously been performed. This contextual effect disappeared after 24 hours. Externally applied bioenergy was also able to decrease cellular responses to heat stress, without induction of heat shock protein-72, which is known to be calcium dependent. In contrast to these successful demonstrations of cellular changes following applications of biofield energy, a considerable number of in vitro studies have shown no effects or variable effects of biofield energy treatments. Yount and colleagues performed three double-blinded studies to determine the ability of energy medicine practitioners and nonpractitioner controls to distinguish cancer cells from culture medium or sterile water. Participants performed at the level expected by chance in all studies (Yount, Smith et al., 2004). Yount and colleagues also observed a significant increase in the proliferation of cultured normal human brain cells following external Qigong treatment by

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practitioners under controlled conditions, but this effect was not seen in a replication study (Yount, Solfvin et al., 2004). These researchers also found that healing treatments by six highly experienced healers to normal brain cells that had been damaged by oxidative stress did not alter cell death rates as compared to normal control cells (Mager et al., 2007). A third set of experiments by Yount and colleagues (2013) assessed potential influence of biofield treatments on cultured glioblastoma (brain cancer) cells, along with effects of treatment dose and distance between the healer and the cells. Viability of treated cells was measured with respect to mock-treated samples using a spectrophotometric assay. In the dose-response experiment, there was a trend toward decreasing cell viability as the biofield dose increased (to 5 five-minute treatments). Findings were not able to be replicated; additionally no effect was seen in the distance experiments. Zachariae and colleagues conducted three controlled in vitro experiments with three different biofield healers with the goal of reducing the proliferation and viability of two cancer cell lines (an adherent human breast cancer cell line [MCF-7] and a nonadherent mouse B-lymphoid cell line [HB-94]). Five different doses of healing and control were used. No differences between treated and control cells were found on a number of markers of growth and viability (Zachariae et al., 2005). Taft and colleagues (2005) performed experiments in which Johrei treatment was delivered to human brain cancer cells (glioblastoma multiforme SF188GBM) by practitioners who participated in teams of two, alternating every half hour, for a total of 4 hours of treatment. Proliferation and cell death were documented by computerized time-lapse microscopy before, during, and after Johrei experiments and were compared to similar parameters of control cells observed under identical conditions. No differences were seen in cell death and proliferation rates of cultured human cancer cells. These findings, taken together, indicate that although there are some very strong positive in vitro studies with well-characterized molecular endpoints, there are multiple studies with negative or equivocal findings. Methodological differences between healers, healing techniques, and laboratories may offer clues to these findings.

Animal Models Preclinical models afford the ability to examine biofield effects on cancer cells within an animal model, but without placebo effects. There is some debate on how representative animal models of cancer are of the human setting. Chen and Yeung (2002) studied 30 mice injected intravenously with lymphoma cells

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that localize and aggressively grow into lymphoid tissues. Mice were treated with Qigong from a Qigong healer, with sham Qigong from an untrained individual, or were not provided any treatment. Qigong treatment significantly decreased the tumor growth in lymph nodes as compared to sham-treated or control mice; however, in a replication study, although the same pattern was seen, the results did not reach statistical significance, secondary to large variability in all groups in this study. Bengston and Krinsley (2000) reported an intriguing set of experiments in which skeptical individuals apprenticed in “techniques alleged to reproduce a healing effect” were the healers. Five experimental mice were injected with a mammary adenocarcinoma that usually causes death within 14 to 27 days and were then treated for an hour a day for 1 month. “Tumors developed a ‘blackened area’, then ulcerated, imploded, and closed, and the mice lived their normal lifespans.” The experiment was repeated three times and produced an overall cure rate of 88% in 33 experimental animals. Interestingly, control mice with adenocarcinoma that were given no healing experienced an enhanced rate of total remissions over the four experiments as well. In contrast, control mice with adenocarcinoma and no healing housed in another lab in another city died within the expected time frame. Although this experiment implies the possibility of (a) biofield healing of the experimental mice and (b) contextual transfer of the healing effect to the control mice, similar laboratory conditions may underlie the longer survival of the experimental and control mice as opposed to the distant mice—thus a replication of this type of experiment is necessary before any conclusions are drawn. In general, more in vivo studies would greatly help the understanding of mechanisms involved in effects of energy medicine in cancer.

Clinical Studies There have been several recent clinical trials on energy medicine in cancer, but much more research still needs to be done, and many of the existing studies have methodological weaknesses such as low sample size and statistical concerns. To a certain extent, this area of research has been hampered by inadequate funding, and thus opportunities for large scale trials and physiological outcome measures have been limited. There are several good reviews of energy modalities in noncancer settings (Jain & Mills, 2010; Wardell & Weymouth, 2004); thus, the findings presented here will be limited to cancer patients. Jain and colleagues (2012) at the University of California at San Diego examined the effectiveness of eight 1-hour sessions of biofield healing versus “mock” healing versus waitlist control in 76 fatigued breast cancer survivors

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(stages I–IIIa). The primary outcome measure was fatigue; secondary outcomes included assessments of diurnal cortisol variability, depression, and quality of life. Patient belief in the efficacy of treatment was examined as a covariate to determine effects of belief on outcomes. The mock healing was performed by “skeptical scientists” who had been trained to administer the identical hand placement protocol as the biofield practitioners but who were instructed to refrain from any intention of healing the patient. Instead, they were instructed to think about upcoming research studies and grants, thus providing a very conservative control for the effects of healing intention and energy. Seventy-five percent of patients, independent of group assignment, thought they received energy treatments. Fatigue was significantly diminished in patients receiving both biofield healing and mock healing as compared to controls; there was no difference in fatigue between these groups. Patients in the biofield healing groups showed a significantly more normalized pattern of diurnal cortisol variation than either of the two other groups; this finding is important because cortisol patterns have been shown to be related to fatigue and to survival in cancer patients. Belief did not impact fatigue or cortisol variability, but did impact patient assessment of quality of life, with greater quality of life reported by patients who believed they had received biofield healing. Strengths of this study included use of a mock healing control group as well as controlling for the effects of belief. Findings suggest that energy healing may be a promising treatment for cancer-related fatigue, although effects may be related to nonspecific factors including touch and rest (which were provided in the mock treatment condition) in addition to specific biofield treatments. Biological findings appeared to be independent of the nonspecific factors that were measured, suggesting that effects of the biofield intervention were not reducible to touch, rest, or belief. This study highlights the importance of examination of both specific and nonspecific factors in energy research. Lutgendorf and colleagues (2010) at the University of Iowa randomized 60 cervical cancer patients undergoing a standard 6-week course of chemotherapy and daily radiation treatment to Healing Touch, relaxation, or usual care in an NIH-funded protocol. Healing Touch and relaxation sessions (approximately 20 to 30 minutes) were given immediately following radiation 4 days a week (days on which the patient did not receive chemotherapy) either in the Clinical Research Center or in the Radiation suite. Rather than use mock healing, the relaxation group was designed to provide a credible active control group using an intervention that is known to reduce stress and enhance the immune response and to control for the provision of social support. Primary outcomes included measures of cellular immunity, distress, and side effects. Patient expectation was also assessed and did not differ among the three groups.

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The Healing Touch protocol, provided by nursing faculty who were certified Healing Touch practitioners, included 6 specific strategies designed to clear congested energy, remove toxins, support free flow of energy throughout the body, and promote mental calm and clarity. Both touch and nontouch techniques were used. (For more details see Hart, Freel, Haylock, & Lutgendorf, 2011.) The manualized relaxation protocol was delivered by a research assistant and was designed to promote deep relaxation. Healing Touch appeared to protect patients from the decrements in cellular immunity that occurred during radiation in the other groups. Specifically, patients in both the usual care and relaxation groups showed significant declines in natural killer cell cytotoxicity (NKCC) during the 6 weeks of active treatment, whereas patients in the Healing Touch group maintained their NKCC close to pretreatment levels with minimal decrease. As the decline in NKCC in the usual care group was 68% and that in the relaxation group was 44%, these findings are likely to be clinically significant. Additionally, patients receiving Healing Touch showed significant declines in depressive mood in contrast to the relaxation and usual care groups who did not show declines in depression. No differences between the groups were observed in quality of life, fatigue, red or white blood cell counts, days of treatment delay, or clinically rated radiation toxicities. Long-term implications of these findings are not known. The Lutgendorf et al. (2010) and Jain et al. (2012) studies show physiological effects from two different biofield treatments in two different cancer populations. Several interesting points are raised by the methodologies of these studies. Both investigations used intensive treatment: Lutgendorf et al. provided treatments 4 times weekly over 5 weeks whereas Jain and colleagues provided 8 sessions over 4 weeks. This raises the question of the dose of biofield treatment that might be necessary to observe changes in outcome variables. Patients in the community often receive treatments once weekly- without empirical validation of whether this is an effective dose. Dose response research would be important to help address this question. Post-White and colleagues (2003) prospectively studied 230 heterogeneous cancer patients (including breast, gynecological, gastrointestinal, hematological, lung, genitourinary, or other) at all stages during chemotherapy. Patients were divided into three groups: massage (MT), healing touch (HT), or “caring presence” (P). Patients received four weekly 45-minute sessions of their assigned intervention and four weekly 45-minute sessions of a standard care control, with the order of intervention or control randomized. Session 1 started prior to the next scheduled day of chemotherapy. Care providers for MT and HT were nurses credentialed in their modality. In comparison with standard care and presence, both MT and HT significantly reduced heart rate

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(approximately 7 bpm) systolic blood pressure, and self-rated pain within session. Over the 4-week intervention period, HT significantly reduced total distress and fatigue, whereas massage reduced total distress and anxiety. Patients receiving massage, but not those receiving HT, showed a decrease in medication use (nonsteroidal anti-inflammatory drugs) over the intervention period. There was no change in nausea in the intervention groups. Although there was a relatively high dropout rate (29%), likely due to the lengthy commitment to this study among sick patients (44% of whom had Stage III disease), findings of this study indicate that during the course of an HT session in cancer patients undergoing chemotherapy, HT induced relaxation as assessed by decreases in blood pressure, heart rate, and pain. Over time, patients receiving HT showed sustained decreases in distress and fatigue. This study was methodologically sound, had a good sample size, and used adequate statistics. Olson and colleagues (2003) compared pain, quality of life, and use of analgesic medications in 24 advanced-stage cancer patients with pain randomized to receive Reiki plus standard opioid management or standard opioid management alone. Following their first afternoon analgesic dose on days 1 and 4 of the study, participants either rested or received Reiki for 1.5 hours. Participants receiving Reiki reported less pain as measured by visual analog scales on days 1 and 4 following treatment. These patients also experienced significant drops in heart rate and diastolic blood pressure on day 1 and improved quality of life from days 1 to 7. There was no reduction in opioid use. The research assistant was present for both rest and Reiki, but because the patients in the Reiki arm had the additional presence of the Reiki practitioner, it is not known whether the pain reduction was due to the Reiki or due to nonspecific aspects of the treatment such as the mere presence of another person. Patients report that the effect of a Reiki treatment lasts approximately 2 to 3 days—thus ratings that include days 1 to 7 might well be subject to the bias of retrospective report. The trial ended prematurely when patients became unwilling to accept random assignment to the control condition. Cook and colleagues (2004) conducted a single-blind randomized clinical trial examining the effectiveness of Healing Touch versus mock Healing Touch among gynecological and breast cancer patients receiving radiation treatment for their cancers. Seventy-eight patients were randomized to receive six 30-minute weekly sessions of either Healing Touch or mock treatment, which commenced during the first third of their radiation treatment. Approximately 20% of patients dropped out of the study before completing, leaving a final sample of 62. The study had a number of methodological strengths, including the fact that patients were separated from providers by an opaque screen placed between their head and body so they could not determine whether they were receiving Healing Touch or mock treatment and thus were blind

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to condition. In the mock therapy group, providers walked around the lower portion of the massage table with their hands at their sides, performing mathematical calculations silently in their heads. A random subset of mock treatment and Healing Touch sessions were videotaped to ensure the integrity of the interventions. Providers had a standard level of Healing Touch certification and used a standard protocol, although the specific Healing Touch techniques used were not specified. At the end of the study, Healing Touch participants demonstrated higher overall quality of life and showed specific gains in mental health, emotional role functioning, and health transition. At the end of the study, the Healing Touch group also showed significantly better outcomes in physical functioning, pain, and vitality compared to the mock Healing Touch. The mock treatment group did not have increased overall quality of life but did show significant increases in physical role functioning and health transition. However, the experimental and control groups were not evaluated in the same statistical model over time due to power considerations. Thus, the inadequate statistics prevent drawing robust conclusions from this otherwise well-designed study. This study also brings to light some of the difficulties involved in selecting an adequate control group. For example, many Healing Touch practitioners use techniques involving points around the head (such as “mind clearing”) in their work with cancer patients. Such techniques are thought to be valuable for helping the patient develop a calm frame of mind and also for clarity of thought. A design involving Healing Touch treatments only below the neck to provide for an adequate control group may actually have blunted the efficacy of the Healing Touch treatments. On the other hand, developing an adequate control strategy is one of the most difficult challenges in clinical research with energy medicine. Roscoe and colleagues examined effects of polarity therapy in reducing fatigue induced by radiation therapy in a small study of 15 breast cancer patients who were randomized to receive 0, 1, or 2 polarity treatments during their radiation treatment. In the 10 patients who received a treatment, there was a decrease in fatigue and an increase in health-related quality of life as compared to the control patients. In addition, there was a dose-response effect, with the five patients who received two treatments having a more pronounced alleviation of symptoms than the two other groups. These preliminary findings in a small sample suggest a positive effect on fatigue in this group of patients and suggest the possibility of energy therapies on fatigue as a possible fruitful area of study in the future (Roscoe, Matteson, Mustian, Padmanaban, & Morrow, 2005). Qigong has been studied in cancer patients in two ways:  as an energy practice performed by the patient or as the external application of Qi from

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a practitioner. Practicing Qigong has been associated with improvements in quality of life and physiological markers in several studies. Many of these studies from China have been discussed in Chen’s review of the literature (Chen & Yeung, 2002) with the conclusion that the Qigong recipients had better survival rates or more improvement than controls. A recent study of Qigong practice at the University of Sydney in Australia randomized 81 heterogeneous cancer patients that had received or were receiving chemotherapy to either a 10-week medical Qigong program or a standard care control. The intervention consisted of a twice-weekly 10-week intervention with 30 minutes of daily home practice recommended as well. Participants were considered to have received the full intervention if they attended at least one session for 7 out of the 10 weeks. Sessions included 15 minutes of health discussion; 15 minutes of gentle stretching and postures designed to open “energy channels” and support circulation of energy; 15 minutes of seated postures, and 30 minutes of seated meditation, breathing, and visualization exercises. Participants completed a home practice diary. Outcome measures included self-reported cognitive difficulties, quality of life, and systemic inflammation as measured by serum C-reactive protein. Qigong participants had significantly better cognitive function and quality of life and lower levels of inflammation at the end of the study. Weaknesses of the investigation included the heterogeneity of diagnoses and treatment status. Although the absence of objective neuropsychological testing is one acknowledged weakness of the investigation, the authors correctly point out that there is generally a poor correlation between patient cognitive complaints and neuropsychological testing in this population, as patient deficits may be too subtle to be picked up by neuropsychological testing. The use of self-reported cognitive outcome measures for patients who were not blind to experimental condition also gives rise to the possible influence of expectation on outcome variables. However the fact that improvement in cognitive functioning was paralleled by decreases in C-reactive protein, and inflammatory processes are known to be a factor implicated in cancer-related cognitive difficulties lends additional credence to the findings. Because this was a multimodal investigation including discussion, breathing, meditation, and movement to support energy flow, it is not possible to know to what extent changes in movement of energy contributed to findings. Nevertheless, findings support positive effects of medical Qigong on cognitive function, quality of life, and inflammation in these cancer patients. As there are few if any interventions that are known to ameliorate post chemotherapy cognitive difficulties, these results are promising, and suggest the importance of future work to better understand these effects (Byeongsang, 2012). Three additional small-scale studies taught QiGong to healthy volunteers or assessed physiological parameters in long-term QiGong practitioners. In

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general, findings supported an improved cellular immune response and hormonal profile, which would be of relevance to cancer risk reduction and control (Jones, 2001; Li, Li, Garcia, Johnson, & Feng, 2005; Lee, Kim & Ryu, 2005). Although small sample size is a caution, these studies suggest the potential value of examining the effects of Qigong practice among cancer patients to see whether similar patterns can be reproduced. One intriguing case study of external Qigong has been published (Lee, Yang, Lee, & Moon, 2005) in which effects of external Qigong (Korean Chun Soo Energy Healing) were examined on cancer symptoms of a 35-year-old man with Stage IV lung cancer with metastases to the stomach, lung, and bone, and with complications such as diabetes and hypertension. He had received radiation and chemotherapy 6 months previously, and at the time of the study was receiving opioid medication (120 mg/day oxycodone) for pain but no other treatment. At the start of the study his Karnofsky Performance Status was 40, indicating that over the past month he was disabled and required special care and assistance. Over the course of 16 days, the patient received eight 20-minute Qi therapy sessions performed on alternate days at the hospital. At baseline, the patient reported that his pain was 8 on a 10 point scale. Following the first treatment, the patient discontinued oxycodone, and following the second treatment, his pain further decreased to 2 on a 10-point scale. For the 2 weeks of assessment following treatment, his pain increased slightly to 4 on a 10-point scale, still without medication. The patient, who reported moderately high levels of vomiting at the start of the study, reported no vomiting after the fifth Qi session, an improvement that was sustained throughout the follow-up. Dramatic improvements were reported for anorexia, fatigue, insomnia, and peace of mind, and were maintained through follow-up. His Karnofsky score improved to 70 after the fourth session (indicating that he was in bed less than 50% of the time and was able to care for self) and was maintained at the 2-week follow-up. This study suggests positive effects of intensive Qi treatments. Taken together, these studies suggest that energy healing may have clinically relevant effects on mood, fatigue, quality of life, cortisol, and immune parameters in cancer patients. This is a literature that definitely needs replication and explication of issues related to dose and timing. Small sample sizes and statistical considerations limit the generalizations that can be made from much of this data. The physiological changes and cognitive changes observed in individuals who practice Qigong also point to possibilities of patients increasing their own physical health without an energy medicine practitioner, although substantial replication and greater specificity is needed. Cancer patients use energy medicine for many indications, including dealing with the nausea and fatigue induced by cancer treatments, as well as the hope that energy treatments can prolong survival. To date, data that test the

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question of whether energy medicine retards tumor growth in cancer patients are not available. Well-controlled, adequately powered studies are critically needed to examine questions of whether energy medicine applications can support physiology and prolong survival in cancer patients. Several studies have examined potential psychophysiological mediators of changes induced by energy healing in healthy individuals. A subset of these is presented here to help clarify possible mechanisms that underlie the effects of energy medicine that may be investigated in clinical studies. Wardell and colleagues examined physiological effects before and after 30 minutes of Reiki in 23 healthy subjects. There was no control group in this study. During the session there were significant reductions in systolic blood pressure and anxiety accompanied by nonsignificant decreases in muscle tension as measured by electromyography and galvanic skin response and a nonsignificant increase in skin temperature. There was no significant change in salivary cortisol (Wardell & Engebretson, 2001). In a second study of 45 healthy individuals, measures of autonomic nervous system function were examined before, during, and after a 30-minute Reiki treatment by an experienced Reiki practitioner versus a rest-only control, versus a placebo Reiki treatment. Cardiac monitoring was done with instrumentation, which recorded all parameters continuously. Both Reiki and placebo Reiki groups had significant reduction in heart rate accompanied by increases in cardiac vagal tone and in cardiac sensitivity to baroreflex. This constellation suggests an increase in parasympathetic activity. Both of these groups also had significantly decreased respiration. Additionally, the Reiki group had significant decreases in diastolic blood pressure and mean blood pressure that were not seen in either the placebo or the control group. The drops in heart rate and diastolic blood pressure in the Reiki group were significantly different from these measures in the placebo group. There were no changes in any of these autonomic parameters in the control group. These findings suggest that Reiki may have some effect on the autonomic nervous system over and above a placebo control, although effects were limited to blood pressure changes (Mackay, Hansen, & McFarlane, 2004). These studies suggest possible directions for future examination of psychophysiological mediators of energy healing. Table 15.3 summarizes the results of selected published clinical trials in energy medicine.

Health Beliefs of Patients Using Energy Medicine Critical to the understanding of patients’ use of energy medicine is an appreciation of why patients choose to use complementary treatments

Table 15.3.  Summary of Clinical Trials in Energy Medicine References

Treatment Modality

Type of Cancer/ Biological Marker and Participant number

Method

Results

Aghabati et al. (2008). The effect of therapeutic touch on pain and fatigue of cancer patients undergoing chemotherapy. Evidence-Based Complementary and Alternative Medicine, 7(3), 375–381.

Therapeutic Touch (TT)

Various cancer types N = 90

• Participants randomly assigned to one of three conditions: experimental (TT), placebo (mimic TT), or control (routine care). • TT treatment and mimic treatment administered once per day for 5 days. • Pre- and postmeasures using the Visual Analog Scale for pain and the Rhoten Fatigue Scale for pain and fatigue.

• Self-reported results: pain and fatigue scores of TT group participants significantly reduced compared to both placebo and control groups.

Birocco et al. (2011). The effects of Reiki therapy on pain and anxiety in patients attending a day oncology and infusion services unit. American Journal of Hospice and Palliative Medicine, 29(4), 290–294.

Reiki

Patients with various cancer types and receiving chemotherapy (CT) N = 118

• Minimum of 4 treatments administered during CT infusion for 30 minutes each. • No control group. • Pain and anxiety measured post-treatment using Visual Analog Scale and description of physical feelings in specific sites during treatment e.g., warm/ cold, relaxation/stress, and well-being/ discomfort.

• Reiki sessions improved self-reported measures of well-being, relaxation, pain relief, sleep quality, and anxiety.

(continued)

Table 15.3.  Continued References

Treatment Modality

Type of Cancer/ Biological Marker and Participant number

Method

Results

Byeongsang et al. (2012). Effect of medical QiGong on cognitive function, quality of life, and a biomarker of inflammation in cancer patients: a randomized controlled trial. Supportive Care Cancer, 20, 1235–1242.

Medical Qigong

Heterogeneous cancer patients N = 81

• RCT: 10 weeks of 2 sessions of medical Qigong/week plus 30 mins home practice. • Control group was standard care. • Outcomes: cognitive function, QOL, CRP.

• Improved cognitive function and QOL, decreased inflammation in MQ group compared to standard care.

Catlin & Taylor-Ford (2011). Investigation of standard care versus sham Reiki placebo versus actual Reiki therapy to enhance comfort and well-being in a chemotherapy infusion center. Oncology Nursing Forum, 38(3), E212–E220.

Reiki

Chemotherapy patients N = 189

• Double-blind, randomized clinical controlled trial with 3 conditions: actual Reiki, sham Reiki placebo, or standard care. • Reiki and sham Reiki implemented for 20-minute sessions. • Pre- and posttreatment measures included demographics survey, self-report comfort scale, and the Well-Being Analog Scale.

• No differences between actual Reiki and sham Reiki placebo treatment; both treatments raised self-reported comfort and well-being levels between pre- and posttreatment measures. • No changes in standard care group over time. • Post-hoc hypothesis that RN support during treatment was the causal factor for increased comfort and well-being rather than energy treatments.

Cook et al. (2004). Healing Touch and quality of life in women receiving radiation treatment for cancer: A randomized controlled trial. Alternative Therapies, 10, 34–41.

HT

Gynecological or breast N = 62

• Patients received six 30-minute weekly sessions of either HT or mock treatment. • Quality of life measured pre and post treatment. • Attitude toward HT measured pretreatment. • Participants blind to condition.

• HT recipients had higher QOL outcomes on all subscales compared to mock HT. • Within group analyses: HT recipients reported significant gains in total, emotional, mental, and health transition QOL during treatment. • Mock treatment participants improved significantly on physical and health transition QOL.

Jain et al. (2012). Complementary medicine for fatigue and cortisol variability in breast cancer survivors. Cancer, 118(3), 777–787.

Biofield healing

Breast cancer/ diurnal cortisol variability (slope) N = 76

• Blind, randomized controlled trial in Stages I–IIIa fatigued breast cancer survivors. • Biofield therapy vs. mock healing vs. waitlist control used for 4 weeks for eight 1-hour sessions. • Primary outcome is fatigue • Secondary outcomes included diurnal cortisol variability/slope, depression, and quality of life (QOL).

• Cortisol slope significantly decreased for biofield healing versus both mock healing and control group. • Biofield healing and mock healing significantly decreased total fatigue. • Treatment belief predicted changes in QOL, but did not influence fatigue or cortisol slope. (continued)

Table 15.3.  Continued References

Treatment Modality

Type of Cancer/ Biological Marker and Participant number

Method

Results

Lee et al. (2005). Qi-training (Qigong) enhanced immune functions: What is the underlying mechanism? Journal of International Neuroscience, 115, 1099–1104.

Qigong training

Growth hormone (GH) and Superoxide free radical (O2−) metabolism by neutrophils N = 10

• 1 hr of Qigong training for older men. • Blood pre- and post-training; incubated with neutrophils from young subjects. • GH and O2− generation measured

• Post-training, significant increases in GH, O2− neutrophil production. • No increases in GH-depleted samples • Suggests that endogenous GH released during and after Qi training mediates neutrophil function.

Lee et al. (2005). Effects of Qi therapy (external Qigong) on symptoms of advanced cancer: A single case study. European Journal of Cancer Care, 14, 457–462.

Qigong therapy

Lung (metastatic) N = 1

• 6 days of preassessment, 8 treatment sessions on alternate days over 16 days, 2 week follow up. • Assessments: cancer symptoms using visual analog scale.

• Reductions in pain, vomiting, dyspnea, fatigue, anorexia, insomnia, and increases in daily activity and calmness both immediately and 2 weeks post Qi therapy.

Li et al. (2005). Genomic profiling of neutrophil transcripts in Asian Qigong practitioners: A pilot study in gene regulation by mind-body interface. Journal of Alternative and Complementary Medicine, 11, 29–39.

Qigong

Gene profiling in blood of healthy individuals N = 12

• Genetic profiling including phenotypic changes in gene expression compared in six Qigong practitioners and six healthy controls. • Neutrophils isolated from blood samples and assayed for gene expression, function and survival.

• Cells of Qigong practitioners demonstrated enhanced immunity, downregulation of cellular metabolism, more rapid response to inflammation, prolonged lifespan of normal neutrophils, accelerated death of inflammatory neutrophils, and enhanced phagocytosis compared to controls.

Lutgendorf et al. (2010). Preservation of immune function in cervical cancer patients during chemoradiation using a novel integrative approach. Brain, Behavior, and Immunity, 12(8), 1231–1240.

Healing Touch

Natural killer cell cytotoxicity (NKCC) N = 60

• Conditions: Healing Touch (HT), relaxation training (RT), usual care (UC). • 60 women (stages IB1 to IVA cervical cancer) were randomly assigned to HT, RT, or UC. • HT or RT administered 4 time per week immediately following pre-existing chemoradiation treatment. • Psychosocial and blood samples were assessed at baseline and weeks 4 and 6.

• HT patients had minimal decrease in (NKCC). • NKCC of RT and UC patients declined. • HT patients showed decline in total depression scores to non-depressed range compared to RT and UC. No differences between groups in QOL, fatigue, toxicity, or treatment delay. (continued)

Table 15.3.  Continued References

Treatment Modality

Type of Cancer/ Biological Marker and Participant number

Method

Results

MacKay et al. (2004). Autonomic nervous system changes during Reiki treatment: A preliminary study. Journal of Alternative and Complementary Medicine, 10, 1077–1081.

Reiki

Heart rate, cardiac vagal tone, blood pressure, cardiac sensitivity to baroreflex, breathing activity N = 45

• Conditions: Reiki, sham Reiki, rest-only control. • 15-minute rest period followed by 30-minute Reiki treatment and then 10-minute rest period.

• True and sham Reiki groups demonstrated greater decreases in heart rate, increase in vagal tone, and increase in cardiac sensitivity to baroreflex and decreased respiration compared with rest-control. • True Reiki had decreases in diastolic blood pressure and mean blood pressure compared with either placebo group.

Marcus et al. (2013) Symptomatic improvement reported after receiving Reiki at a cancer infusion center. American Journal of Hospice and Palliative Medicine, 30(2), 216–217.

Reiki

Various cancer types N = 145

• Survey administered to patients at university hospital receiving Reiki through volunteer services. • Self-report survey included items about changes in pain, mood, distress, sleep, and appetite. • No control group.

• Reiki rated as a positive experience with improvement in areas of relaxation, anxiety/worry, mood, sleep, pain, isolation/loneliness, attitude, and appetite. • Response unaffected by previous Reiki, massage, or other touch therapy exposure.

Olson et al. (2003). A phase II trial of Reiki for the management of pain in advanced cancer patients. Journal of Pain and Symptom Management, 26, 990–997.

Reiki

Advanced cancers, site not specified N = 24

• Participants completed a 1.5 hour treatment, rest or Reiki, on days 1 and 4. • Participants not blinded to condition. • Patients received opioid medication as usual. Edmonton Staging System for cancer pain administered on day 1. • Visual analog pain assessments pre and post treatment; and daily at mealtime. Participants recorded all opioid use.

• Reiki group reported less pain on days 1 and 4 and improved quality of life. • No differences in opioid use. • Trial ended prematurely when patients became unwilling to accept random assignment to control condition.

Post-White et al. (2003). Therapeutic massage and HT improve symptoms in cancer. Integrative Cancer Therapies, 2, 332–344.

HT vs. Therapeutic Massage vs. presence

Breast, gynecological, gastrointestinal, hematological, lung, genitourinary, or other; stages unstaged-IV N = 230

• Patients randomly assigned to one of three interventions: HT, Massage, or simple presence of a healer. • Patients received 4 weekly sessions of one intervention plus standard care control condition; within-subject order of condition randomly assigned. Outcome variables included: • Pre and postsession: heart rate, respiratory rate, blood pressure, nausea, and pain. • Days 1 and 4 of each intervention: anxiety, mood, fatigue, and satisfaction with care. • Day 4 of intervention condition: satisfaction with intervention. • Weekly: diaries of analgesic and antiemetic use.

• Pre-post intervention effects (within session over 4 weeks): • Greater reduction in pain, respiratory, and heart rate and blood pressure in both Massage and HT than in standard care control • Greater reduction in heart rate, systolic blood pressure, and pain in both HT and massage than in presence of healer. Change from week 1 to week 4: • Both Massage and HT reduced distress and anxiety more than standard care. • Overall satisfaction with care similar between groups. (continued)

Table 15.3.  Continued References

Treatment Modality

Type of Cancer/ Biological Marker and Participant number

Method

Results

Roscoe et al. (2005). Treatment of radio-therapy-induced fatigue through a nonpharma-cological approach. Integrative Cancer Therapies, 4, 8–13.

Polarity therapy

Breast cancer N = 15

• Women receiving radiation therapy randomized to either standard care or to either 1 or 2 sessions of polarity treatment. • In 2 session groups, treatments were separated by 1 week. • Fatigue and HR QOL assessed pretreatment and 3 days after each treatment.

• After the first week of treatment, both treatment groups reported less fatigue and greater QOL than standard care. • 2-session group reporting greatest adjustment, 1-session group reported greater adjustment than standard care. • Polarity therapy may reduce fatigue and increase health-related QOL in a dose-response manner in breast cancer patients undergoing radiation.

Wardell & Engebretson (2001). Biological correlates of Reiki Touch healing. Journal of Advanced Nursing, 33, 439–445.

Reiki

Salivary IgA, cortisol, systolic blood pressure, skin temperature, EMG N = 23

• 30 minutes of Reiki applied with pre and post measures of anxiety, salivary IgA, blood pressure, galvanic skin response, muscle tension, and skin temperature

• Significant: IgA rose, anxiety reduced, SBP drop in Reiki group. • No change in cortisol. • Insignificant trend toward increase in skin temp and decrease in EMG in Reiki group.

These charts include several additional papers not included in text.

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such as energy medicine. Several studies have indicated that patients most likely to use complementary medicine have health beliefs, indicating that cancer etiology involves external factors such as diet, stress, and environment (Gawler, 2001; Maskarinec, Gotay, Tatsumura, Shumay, & Kakai, 2001; Plant, 2002). In a study of Australian gynecologic cancer patients, specific health beliefs about cancer leading to the use of complementary therapies and energy therapies were assessed (Markovic et al., 2006). Patients who used complementary therapies did so for four major reasons: 1. Belief in alternative theories of cancer etiology (e.g., cancer was caused by stress, diet, environment, and energy imbalances). These patients sought integrative medicine therapies to minimize risks of cancer recurrence and were most likely to engage in changes in diet and life style, energy healing, or yoga. 2. Belief in the efficacy of complementary treatments to reduce the side effects of biomedical treatments. These patients predominantly used meditation, acupuncture, Reiki, or vitamins. 3. Belief in the efficacy of biomedical treatments combined with interest in maximizing their overall health. These patients tended to use exercise and diet as integrative therapies. 4. Exploratory users, some of whom turned to complementary therapies as a last resort after their cancer had spread or in the absence of effective biomedical treatments for their stage of cancer. Use of energy treatments in this group was low. Patients tend to have explanatory or “common sense” beliefs about the etiology, chronicity, and treatment of their illness (Leventhal, Nerenz, & Steele, 1984; Martin et al., 2004). These beliefs may or may not be consistent with the beliefs of their health-care providers. For example, we have reported that 46% of gynecologic cancer patients feel that their disease has been caused by stress, and 39% felt it was an act of God (Costanzo, Lutgendorf, Bradley, Rose,  & Anderson, 2005). Because common-sense beliefs of patients are critical factors in compliance with traditional medical care and in seeking out alternative care (Leventhal et al., 1984; Markovic et al., 2006), patients’ health beliefs should be addressed by practitioners.

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Recommendations for Physicians and Health Care Practitioners • Ask patients if they are using complementary therapies, including energy medicine. Usually only about 30% to 40% of patients tell their physician that they are using these treatments (Boon et al., 2000). • Find out what your patient thinks about the complementary therapies they are using. Is their use of energy medicine an experiment or is it fundamentally related to how the patient understands sickness and health? • Familiarize yourself with the emerging research on energy medicine to facilitate a supportive discussion based on evidence. • Find out whether your patient’s practitioner is certified, or what kind of training the practitioner has had.

Design Issues Specific methodology issues need to be considered in clinical studies examining energy medicine. Many of these have been outlined in a text edited by Jonas and Crawford (2003). What constitutes an adequate “dose” of a particular treatment, how often should it be repeated, how long do treatment effects last, and the adequate treatment length or intensity to produce the required dose have not been well characterized. Patients are treated weekly in most studies; however, anecdotal reports from the healers in our research indicate that daily treatment increases the ability of patients to “hold” the new energy patterns (Hart et al., 2011). In many studies with energy modalities, sessions have been short and/or time limited and limited in number, designs that may contribute to minimizing an intervention effect by not providing an adequate “dose” of treatment. In some Therapeutic Touch studies, patients have received single treatments for as short as 5 minutes, a time span thought by practitioners to be inadequate (Winstead-Fry & Kijek, 1999). Studies allowing the practitioner to individualize the biofield treatment so as to deliver an “adequate dose” of the treatment have shown greater effects (Winstead-Fry & Kijek, 1999). More treatment sessions have tended to produce stronger results (Turner, Clark, Gauthier,  & Williams, 1998). However, individual differences among healers exist, and the relative “dose” and application of energy derived from any particular healer may vary substantially from those of other healers (Connor et al., 2006). Furthermore, the state of well-being of the practitioner on a given day has been shown to have effects on the efficacy of healing in vitro (Rubik, Brooks, & Schwartz, 2006). This is an important variable in energy research, as well as clinically.

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For biofield treatments designed to reduce the side effects of radiation or chemotherapy, no clear understanding exists regarding how soon after chemotherapy or radiation therapy energy treatments should be given, so as to not interfere with the desired effects of the chemotherapy or radiation. In the Lutgendorf et  al. study (2010), the practitioners did not provide treatment within 24 hours of chemotherapy to allow the drugs to have an opportunity to work in the body before any toxic effects were “cleared” from the liver. This type of consideration is one that would be important to address in animal research to clarify the effects of biofield application on pharmacokinetics of chemotherapy. Based on recommendations from radiation oncologists, our group has used energy treatments immediately after radiation therapy. Assessment of expectancy or placebo effects has also been recommended. To address whether expectancy or belief in the treatment accounted for outcomes, several researchers have administered questions on the extent to which subjects believed in the logic or the efficacy of the treatments they were receiving (Gagne  & Toye, 1994; Turner et  al., 1998). Studies vary in the extent to which belief is associated with outcomes, and which outcomes are associated with beliefs (Jain et al., 2010; Turner et al., 1998). Demographics have also not correlated with outcomes (Spence & Olson, 1997). Recommendations for energy medicine research include (a)  treatments that are tailored to the patient and gauged as being adequate by the healer, (b) examining the number and frequency of treatments needed for effective outcomes, (c)  examining the effects over time when appropriate (e.g., with chronic illness), (d) using study designs in which the healer is not the investigator so that they are not attached to outcomes, (e) using patients with chronic illness rather than healthy individuals, and (f)  using experienced practitioners who can describe their practice (Astin et al., 2000; Winstead-Fry & Kijek, 1999). Several reviews suggested the need to compare energy therapies to other analgesic or relaxation techniques as a way of more adequately specifying mechanisms (Quinn  & Strelkauskas, 1993; Samarel, Fawcett, Davis,  & Ryan, 1998; Spence  & Olson, 1997). This field very much needs to move to understanding mechanisms, replication of effects, and conditions underlying failure to replicate. Clinical trials need to be larger, contain objective outcome markers (physician assessment, biomarkers), and have adequate randomization and control groups.

Future Research Although research is promising, there are more unanswered than answered questions in this field. There are multiple domains of cancer research that

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would be relevant for energy medicine research. These include effects of energy healing on presurgical preparation, postsurgical recovery (nausea and vomiting, removal of effects of anesthesia, pain reduction, wound healing), effectiveness of clearing undesired side effects of chemotherapy and radiation from the body, minimizing cognitive deficits from chemotherapy, minimizing fatigue and depression, minimizing radiation burns, increasing well-being, posttreatment health maintenance, and promotion of survival. Use of energy medicine, or energy-based practices such as Qigong, to promote health maintenance after a definitive treatment or after recurrence, for assistance with pain management and palliative care, or in bone marrow transplant also are important domains for future work. Understanding individual differences in response (personality, stage, or disease, belief in treatment) is also an important research question.

Possible Mechanisms of Action of Biofield Therapies for Cancer To date, the clinical outcome studies have not addressed whether energy medicine therapies can actually affect the course of disease. This is often the hope of cancer patients who use this modality. There are several possible mechanisms, both direct and indirect, by which effects on disease course might occur. The in vitro research, although not consistent, suggests that some types of energy therapies can directly impair the growth of cancer cells. There have been some very promising results, but replication has been difficult. Indirect mechanisms include induction of relaxation with subsequent downregulation of the neuroendocrine stress response that may have downstream effects on tumor growth and on the immune response. To the extent that energy therapies can provide social support, instill hope, and induce the relaxation response, they are likely to modulate the sympathetic nervous system and neuroendocrine stress responses. The findings of Jain and colleagues point to normalization of the diurnal cortisol pattern with biofield therapy; Post-White and colleagues (2003) indicate that Healing Touch was able to decrease autonomic activity in heterogeneous cancer patients. To the effect that biofield therapies can affect the neuroendocrine stress response, they may be able to alter tumor growth patterns. Stress hormones, particularly norepinephrine and epinephrine, are known to promote tumor growth by processes including increased tumor angiogenesis and invasiveness (Antoni et al., 2006; Lutgendorf, Sood, & Antoni, 2010; Thaker et al., 2006). Thus, to the extent that the neuroendocrine stress response can be blunted by energy therapies, critical cancer growth processes may be retarded. A  third

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possibility includes mechanisms not mediated by the neuroendocrine stress response, such as the possibility that energy therapy unblocks obstacles to free flow of energy within the patient. This allows for freer circulation of “life energy” through the patient, supporting greater resistance to disease, higher levels of energy, and fewer side effects of treatment by affecting multiple physiological systems. There may also be cellular receptors sensitive to energy dynamics. Any or all of these mechanisms could also work together. How are possible effects of energy healing understood? Bell and colleagues propose that models from complex systems and network science are necessary for understanding the types of effects noted here (Bell, Baldwin, & Schwartz, 2002). It has been suggested that conceptual frameworks based on Newtonian physics, molecular biology, and biochemistry are not adequate to address the phenomenology reported in energy healing (Liboff, 2004). This is particularly true of long-distance healing and spontaneous remissions. Rather, quantum physics, postquantum physics, and a model of the organism as an electromagnetic system are proposed as being integral to an understanding of the phenomenology of energy healing (Liboff, 2004; Tiller, 2002). Because Newtonian physics and the biomedical model are part of the “common sense” model of the laws of nature for most people, and particularly health-care practitioners, there has been substantial resistance to accepting an alternative. In a similar vein, 35  years ago, the concept that the mind could influence the immune system was seen as being outrageous. Robert Ader, Professor of Psychology at the University of Rochester and one of the early pioneers of the field of psychoneuroimmunology, stumbled upon findings demonstrating that the immune response could be conditioned (Ader, 1995). He was severely criticized for this work—but over the last 35 years, pathways of communication between the central nervous system and the immune system have been well characterized and central-nervous-system involvement in modulation of the immune response is now widely accepted (Ader, 2007). It was only after the data was replicated and physiological mechanisms delineated that a new understanding of the bi-directional communication between the brain and immune system emerged and became accepted. Similarly, an acceptance of energy medicine will require a paradigm shift by the public and the scientific community as well as continued research into the physics of the biofield and its use in therapy. Because understanding this field may involve the use of a novel scientific paradigm, there has been substantial resistance. The promising but equivocal data presented herein support the necessity for rigorous preclinical and clinical research to address some of the fundamental questions delineated in the preceding text. Energy medicine may present an important adjunct in cancer treatment; however, much more needs to be known.

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Acknowledgments Work on this chapter was partially supported by grants R21CA102515, R01CA104825, and R21AT0095801 from NIH to S.L. and the grant P20AT75601 from NIH (Karen Prestwood, P.I.) We are grateful to Gary Schwartz and Melinda Connor for helpful comments on the original edition of this chapter. This chapter is dedicated to the memory of Dr. Remi Cadoert, an early pioneer in biofield research who encouraged me in this work toward the end of his life. REFERENCES

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16 The Role of Spirituality MARY JO KREITZER AND JOHN E. WAGNER

Key Concepts Spirituality: Spirituality has been defined in a multitude of ways and is generally understood to be related to but distinct from religiosity. In the broadest sense, spirituality is focused on purpose as well as meaning and connectedness with self, others, and a higher power. Spirituality is recognized as an integral part of being human that is interconnected with health and well-being. ■ Spiritual Assessment: A spiritual assessment or screening can be conducted by a physician, nurse, spiritual care provider, or other health professional as a routine part of providing care. It is common for screening questions to be incorporated into standard health history interviews and forms. ■ Spiritual Issues: Grief, loss, pain, suffering, shock, denial, fear, hopelessness, spiritual distress, despair, isolation, and survivor guilt are examples of spiritual issues faced by patients with cancer and their families. These issues may differ in their occurrence and intensity at different phases along the cancer continuum, such as new diagnosis, periods of remission, recurrence, long-term survival, and/or at the end of life. ■ Spiritual Practices: Commonly used spiritual practices include prayer, meditation, journaling, labyrinth walking, and interacting with nature. ■

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Introduction In a book titled Close to the Bone, psychiatrist Jean Shinoda Bolen writes about the impact of a serious illness such as cancer in a person’s life. “A life threatening illness” she writes, “has the impact of a stone hitting the still surface of a lake, sending concentric rings of disturbance out, as feelings, thoughts and reactions radiate out from this center. It impacts relationships, it stirs the depths of others, and it potentially brings the patient and those who are affected ‘close to the bone’ ” (Bolen, 1996). A  diagnosis of cancer provokes a spiritual crisis in the lives of many patients and their families. Feelings of anger, grief, loss, despair, and hopelessness accompany questions such as “why me?,” “why now?” and “what is the meaning of this illness in my life?” It is also common for people facing a health-care crisis to note how the lives of people around them go on unchanged while their lives may be irrevocably changed. This chapter will explore the topic of spirituality through examining definitions of spirituality, the relationship between spirituality and health outcomes, ways to assess the spiritual needs of patients, commonly used spiritual interventions and practices, and the role of the health-care professional in meeting the spiritual needs of patients and their families. Throughout history, and across all cultures, spiritual beliefs and practices have been expressed in a myriad of ways. The word spirit comes from the Hebrew work “ruah,” which means wind, breath, or air, that which gives life (Golberg, 1998). Greeks viewed the spirit in opposition to the body and any material reality. In Chinese, spirit means “chi,” or “vital energy” (Chiu, 2000). The Latin, spiritus, means breath. Spirituality, in its broadest sense, is recognized as an integral part of being human that is interconnected with health and well-being. The healing professions of nursing and medicine, from their earliest beginnings, were grounded in spirituality. In ancient societies, the connection between spirituality and healing was so close that the roles of priest, shaman, and healer were one and the same. Hildegaard of Bingen, a 12th-century Christian mystic was well known for her use of herbs, art, music, and prayer. The first hospitals were founded by religious orders, and missionary movements across the centuries and continents have recognized the need for spiritual healing alongside physical healing. It was only since the time of the scientific revolution and the advent of dualism in the 17th century that a wall of separation divided the care of people into mutually exclusive and often antagonistic camps. Medicine was charged with caring for the body, and later the mind, whereas religion was left with care and feeding of the soul. Contemporary Western science, including the

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disciplines of medicine and nursing, have often dealt poorly with the spiritual side of human nature by ignoring it and viewing these needs as being beyond the scope of their professional practice. Over the past 20  years, there has been a growing interest in the topic of spirituality and its impact on health and well-being in both the lay press and professional literature. Consumers are demanding care that is holistic and attentive to the whole person—mind, body, and spirit. Clinicians are beginning to recognize the importance of both assessing and addressing spiritual needs of patients and their families, and researchers are establishing a link between spirituality, spiritual interventions, and health outcomes.

Defining Spirituality Spirituality is a multidimensional construct that has been defined in a multitude of ways and is generally understood to be related to but distinct from religiosity (Albaugh, 2003; Ameling  & Povilonis, 2001; Chiu, Emblen, VonHofwegen, Sawatzky, & Meyerhoff, 2004; Fry, 1998; Narayanasamy, 1999; Tanyi, 2002). Religious beliefs are associated with a particular faith tradition. Participation or commitment to a religion may involve adherence to certain beliefs (ideology), religious practices (prayer, sacraments, and rituals), religious proscriptions (dietary modifications or avoidance of tobacco, alcohol, and drugs) and participation in a religious community. Spirituality is understood to be a broader concept that includes many dimensions. Murray and Zentner (1989) define spirituality as a quality that goes beyond religious affiliation and that strives for inspiration, reverence, awe, meaning and purpose, even in those who do not believe in God. The spiritual dimension, they suggest, is in harmony with the universe, strives for answers about the infinite, and comes into focus when the person faces emotional stress, physical illness, or death. Spirituality has also been described as a process and sacred journey (Mische, 1982), the essence or life principle of a person (Colliton, 1981), an experience of the radical truth of things (Legere, 1984), and the propensity to make meaning (Reed, 1992). Waldfogel (1997) notes that the experiences of joy, love, forgiveness, and acceptance all depend on, and are manifestations of, optimal spiritual wellbeing. Cohen (1993) adds that spirituality involves finding deep meaning in everything, including illness and death and living life according to a set of values. Chiu et al. (2004) describe spirituality as a power, force, or energy that stimulates creativity, motivation, or a striving for inspiration. Christina Puchalski contends that “spirituality is the aspect of humanity that refers to the way individuals seek and express meaning and purpose and

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Box 16.1.  Characteristics of Spirituality Connectedness/relationships with self, others, Higher Power, nature Meaning and purpose in life Transcendence Love/compassion Wholeness Energy

the way they experience their connectedness to the moment, to self, to others, to nature, and to the significant or sacred” (Puchalski et al., 2009). According to Mario Beauregard and Denyse O’Leary, researchers and authors of The Spiritual Brain, “spirituality means any experience that is thought to bring the experiencer into contact with the divine (in other words, not just any experience that feels meaningful)” (Beauregard & O’Leary, 2009). The simplest and most straightforward definition is from Pargament (1997), who coined spirituality as the “search for the sacred.” Box 16.1 lists characteristics commonly associated with spirituality.

Relationship between Spirituality and Health Outcomes Spiritual and religious beliefs and practices are prevalent in contemporary American society. According to the Gallup Poll that has tracked U.S. religious beliefs for over 50 years, 91% of Americans believe in God (Gallup, 2011). As many as 97% of Americans pray, and 57% pray once or more daily (General Social Survey, 2008). In addition, 70% of patients ask for religious counseling and “surveys indicate that nearly 90% of patients with serious illness will engage in prayer for the alleviation of their suffering or disease” (Jonas  & Crawford. 2003) According to Puchalski, prayer is the second most common method of pain management (after oral pain medication), and the most common nondrug method of pain management (Puchalski, 2004). Over 40% of patients would also like their physicians to address religious or spiritual issues in the context of a medical visit (Williams & Meltzer, 2011). Interest in spiritual matters is not limited to a particular age group. In a national study conducted by the Higher Education Research Institute at the University of California, Los Angeles, CA (2005) of over 112,000 college freshmen, 74% of the students reported that they experience a connection with God

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or a higher power that transcends their personal self, four out of five indicated an “interest” in spirituality, and nearly two-thirds reported spirituality to be a source of joy in their lives. Studies of health professionals have also documented their perceptions of the importance of spiritual and religious beliefs and practices. Most physicians (56%) believe that spirituality and religion have an influence on health, but few (6%) believe that “hard” medical outcomes are changed. Rather, most physicians believed that spirituality and religion helps patients cope (76%), gives patients a positive state of mind (75%), and provides emotional and practical support via the religious community (55%) (Curlin, Sellergren, Lantos, & Chin, 2007). Eighty-seven percent of nurses reported the high importance of paying attention to patient’s spiritual needs (Strang, Strang, & Ternestedt, 2002), 71% felt they identified spiritual needs in their practice (McSherry, 1998), yet both groups felt they fell short in meeting those needs. When asked about their attitudes toward spirituality and healing, 94% of HMO executives indicated that they believe that personal prayer, meditation, or other spiritual and religious practices can speed or help the medical treatment of people who are ill (Yankelovich, 1997). The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) has added spiritual care to the criteria for accreditation (JCAHO, 2000). Hospitals are now required to establish guidelines for the documentation of assessments of spiritual beliefs and practices, pastoral care must be available for patients who request it, and hospitals must meet the spiritual needs of dying patients and their families. A number of studies report findings that suggest that spiritual and religious beliefs contribute to positive health benefits including stress reduction and an increased sense of well-being (Larson et al., 1992). A meta-analysis of 29 studies by McCullough, Hoyt, Larson, Koenig, and Thoreson (2000) revealed that the odds of survival were significantly greater for people who scored higher on measures of religious involvement than for people who scored lower, even after controlling for a variety of social and health-related variables. Although there is no evidence that religion or spirituality can impact cancer progression or mortality (Stefanek, McDonald,  & Hess, 2004), a substantial number of studies have found a link between spirituality and quality of life, adjustment and symptom management (Meraviglia, 2006; Yanez, et. al, 2009) . Spiritual well-being is significantly associated with the ability of cancer patients to enjoy life despite high levels of pain or fatigue (Brady, Peterman, Fitchett, Mo, & Cella, 1999). A study of 95 cancer patients diagnosed within the past 5 years found that spirituality was associated with less distress and better quality of life regardless of perceived life threat. (Laubmeier, Zakowski, & Bair, 2004). Existential well-being was found to have a strong negative correlation

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with depression (Nelson, Rosenfeld, Breitbart, & Galietta, 2002), whereas existential distress has been associated with loss of autonomy, lowered self-esteem, and a sense of hopelessness (Morita, Tsunoda, Inoue, & Chihara, 2000). In a longitudinal study of cancer pain and depression, spirituality and well-being were found to be inversely related to depression (O’Mahony et  al., 2005). Cancer survivors who draw on spiritual resources reported substantial personal growth related to the trauma associated with their diagnosis of cancer (Carpenter, Brockopp, & Andrykowski, 1999). Spiritual struggle, on the other hand, is associated with poorer quality of life and life satisfaction (Hills, Paice, Cameron, & Shott, 2005) and emotional adjustment (Manning-Walsh, 2005). Spiritual well-being has been found to be a contributor to overall quality of life at the end of life (Tang, Aaronson, & Forbes, 2004; Thomson, 2000).

Assessing Spirituality A spiritual assessment or screening can be conducted by a physician, nurse, spiritual care provider, or other health professional as a routine part of providing care. It is common for screening questions to be incorporated into standard health history interviews and forms. Box 16.2 provides an example of questions that may help to detect a spiritual need or issue. The FICA interview guide (Puchalski & Romer, 2000) is frequently used to obtain a spiritual history in clinical settings. FICA is an acronym that stands for: • • • •

What is your faith? How important is your faith? Are you part of a religious community? How would you like spiritual issues addressed in your care?

A tool called Hope, developed by Anadarajah, Long, & Smith (2001), taps into four similar domains. Examples of questions in the interview guide include the following: 1. H stands for sources of hope, meaning, comfort, strength, peace, love, and connection. • What do you hold onto in difficult times? • What sustains you and keeps you going? 2. O stands for organized religion. • Are you part of a spiritual or religious community? • What aspects of your religion are helpful or not so helpful to you?

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Box 16.2.  Spiritual Screening Questions What are your sources of hope, strength, comfort, and peace? Are you part of a religious or spiritual community? What spiritual practices do you find most helpful to you personally? Are there any specific practices or restrictions I should know about in providing your health care? Source: Leonard, B., & Carlson, D. (2013). Spirituality in Healthcare. www.csh. umn.edu/modules/index.html (accessed May 28, 2013).

3. P stands for personal spirituality and practices. • Do you have personal spiritual beliefs that are independent of your religion? • What spiritual practices do you find most helpful to you personally? 4. E stands for effects on medical care and end-of-life issues. • Has being sick affected your ability to do things that usually help you spiritually? Beyond these tools, there are a growing number of standardized measures developed to assess spiritual and religious beliefs and practices for the purpose of research and evaluation. The Spiritual Well-Being Scale (SWBS), developed by Paloutzian and Ellison (1982), measures both religious and existential well-being. Religious well-being refers to one’s relationship with God or some higher power and existential well-being refers to a sense of purpose in life and satisfaction with life. The Functional Assessment of Chronic Illness Therapy—Spiritual Well-Being (FACIT-Sp) tool (Brady et al., 1999; Peterman, Fitchett, Brady, Hernandez, & Cella, 2002) is part of the widely used Functional Assessment of Cancer Therapy (FACT) quality-of-life battery (Cella et  al., 1993). It taps into both traditional religiousness dimensions (faith factor) and spiritual dimensions (meaning and peace factor). The Brief Serenity Scale (Kreitzer, Gross, Waleekhachonloet, Reilly-Spong, & Byrd, 2009) focuses on a dimension of spirituality called serenity. Serenity is defined as being a spiritual experience of inner peace that is independent of external events.

Addressing Spiritual Issues Grief, loss, pain, suffering, shock, denial, fear, hopelessness, spiritual distress, despair, isolation, and survivor guilt are examples of spiritual issues faced by

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patients with cancer and their families. These issues may differ in their occurrence and intensity at different phases along the cancer continuum, such as new diagnosis, periods of remission, recurrence, long-term survival, and/or at the end of life. Being diagnosed with cancer brings the patient to a full and acute awareness of personal mortality and vulnerability. A heightened sense of one’s spirituality may accompany this awareness. Reed (1986) found that people diagnosed with cancer had significantly higher levels of religiousness than healthy matched controls and later found greater spiritual perspective among hospitalized terminally ill patients compared with other hospitalized patients (Reed, 1987). Johnston (1997) described more intense experiences of spirituality as death becomes more imminent and identified two fundamental end-of-life questions: “How shall I die?” and “How shall I live before I die?” Experiences of loss and change may manifest spiritually as a search for meaning, she writes, whereas isolation or loneliness may prompt efforts toward loving others and strengthening relationships. Feelings of guilt or shame may lead to a search for forgiveness and acceptance by others. Conducting a spiritual screening or assessment is only reasonable to do if members of the health-care team have awareness of spiritual issues and the capacity to provide spiritual care. Increasingly, health-care providers are discovering or rediscovering how core spirituality is to healing and the art of medicine and nursing. In Box 16.3, “Spirituality and the Art of Medicine,” Dr. John Wagner, a distinguished scientist and clinician who is the director of the Pediatric Bone Marrow Transplant program at the University of Minnesota and the scientific director of clinical research at the Stem Cell Institute, describes how his growing awareness of the importance of spirituality has led to profound changes in his practice and how he views his role as a clinician and healer. As health-care providers’ awareness of spirituality increases, common questions and concerns surface: “How should we intervene?” “What should we say?” and “What should we do?” In the foreword to the book Making Health Care Whole, Rachel Naomi Remen advises that “caring of the soul requires that we be fully present in situations we cannot control and patient as a genuine meaning and a direction unfold.” As Remen notes, this means seeing familiar things in new ways, listening rather than speaking, learning from patients rather than teaching them, and cultivating the capacity to be amazed (Puchalski, Ferrell, & Remen, 2010). The National Cancer Institute, in a document titled “Spirituality in Cancer Care” (NCI, 2006), identified intervention strategies that are appropriate to consider in addressing the spiritual concerns of patients. These interventions include the following: • Health-care provider may choose to explore the spiritual concerns of patients within the context of usual medical care.

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Box 16.3.  Spirituality and the Art of Medicine After 25 years of caring for the most sick, I have only recently come to understand the place of spirituality in allopathic medicine. Entirely focused on the science of various diseases in my quest to find potential cures for the incurable, I had given little more than a passing thought to the role spirituality played in the lives of my patients and their families. Of course, it was not so much a lack of empathy or caring but a lack of understanding of how spirituality impacts their day-to-day lives. Although I consider myself quite “connected” to these kids, I am all “business”—I diagnose the problem, find potential solutions to the problem, and go all out to conquer the problem— and I leave the “touchy-feely” stuff to others. Perhaps, it is the experience of taking care of dying children who cannot communicate so much in words but more by expression that led me down this path toward recognizing the spiritual side of medicine. Perhaps it was the child with a mutilating, deadly skin disorder whose hope, if an experimental therapy ever worked, was only to be able to wear tennis shoes or hold a baseball bat; or perhaps it was hearing the mother who prayed for her child’s death as a release for lifelong suffering. Perhaps it just comes with age or a freedom of unobstructed openness to new ideas. Whatever it was, I had an epiphany of sorts that made me wonder if I had neglected a whole dimension in the care of these children, their parents, and the people who surround them. Perhaps, the better doctor is someone who not only goes through the motions of listening to the lungs and heart with a stethoscope, evaluating the chest CT, skimming over a hundred different lab results, but who also sits down next to the patient, perhaps touching the hand, shoulder, or knee, and simply listens and feels. In fact, spirituality has always played a role in medicine—it is the art of medicine. The more the practitioner explores this side of medicine, the better doctor, nurse, social worker, pharmacist, or any other kind of provider you will become. Regardless of why I had this epiphany so far down the road of my career, it’s a lesson to share. When I first shared my new interest with the staff at our Center for Spirituality & Healing at the University, they simply listened and with open arms conveyed “welcome home.” John E. Wagner MD.

• Patients may be encouraged to seek assistance from their own clergy or spiritual-care provider. • A referral may be made to a chaplain or religious- or faith-based therapist. • A referral may be made to a support group that is known to address spiritual issues.

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To be effective in assessing and addressing the spiritual needs of patients, health-care providers need skills in the following areas: • Listening:  Careful listening enables the health-care provider to be alert for meanings, connections, and yearnings reflected in conversations. It is important to listen to both what is said as well as what is not said. Authenticity is critically important. Patients can sense when the listener is distracted or not really interested. • Seeing:  Observing the nonverbal messages that accompany the client’s spoken words may reveal thoughts and feelings that the client is unable to verbalize. • Presence: When we are truly present to another human being, we are intentionally choosing to be with another in a healing way. It requires more than just physical presence. In the western culture, there is a strong bias for action. Health-care providers too often feel that they are not effective unless they are doing something. Presence requires being, not doing. This may be especially challenging for providers during times of expressions of anger or anguish by patients and/or families during their cancer journeys. • Touching:  The healing power of touch, which can range from the informal touch provided in usual care to that accompanied by healing intentions, is well established. Healing and therapeutic touch have emerged from the discipline of nursing over the past 25  years and gained varying levels of acceptance by patients and providers. There is a more ancient tradition called “laying on of hands” that has been associated with many faith traditions and healing ministries for centuries. In addition to these skills, health-care providers also need information and ongoing education on commonly used spiritual practices. • Prayer:  There are many forms of prayer. Prayer may be offered in words, song, sighs, cries, gestures, or silence. Prayer may be individual or communal, public, or private. Prayers may be petitions, requests for healing, for peace, for safety, for acceptance, for strength to continue, as well as for courage. Prayer is a means of reaching out and connecting with a Higher Power. • Meditation:  Meditation is a self-directed practice for relaxing the body and calming the mind that has been used by people in many cultures since ancient times. Kabat-Zinn (2005) emphasizes that meditation is best thought of as a way of being rather than a collection of

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•

•

•

•

techniques. Mindfulness expands the capacity for awareness and for self-knowing. When a mindful state is cultivated, it frees people from routinized thought patterns, routinized senses, and routinized relationships and destructive mind states and emotions that accompany them. When people are able to escape from highly conditioned, reactive, and habitual thinking, they are able to respond in more effective and authentic ways. Music, art, and nature: The arts are powerful healing tools that can help people explore feelings, gain new insights and perspectives, and enhance other spiritual practices. For some, being in nature is a powerful spiritual experience. Journaling: Journaling is both a way to record experiences and way to get in touch with inner thoughts and feelings. People who journal on a regular basis often find it to be a way to measure progress in self-growth and attain a broader perspective on life and relationships. Walking a labyrinth: A labyrinth is a circuitous path that leads to a center. It is different from a maze that has twists, turns, and blind alleys. A labyrinth has only one way in to the center and one way out. When people walk the labyrinth, they may pray, meditate, listen to music, or just observe nature. People report that when they walk the labyrinth, they gain insight or perspective. For some people, walking the labyrinth is both an actual physical experience as well as a metaphor for life’s journey. Spiritual direction or counseling:  Spiritual directors or counselors accompany people on their spiritual journeys. They help people explore such spiritual issues as grief, loss, anger, and abandonment as well as life challenges. They may offer guidance in prayer, journaling, and reading of sacred texts. Spiritual directors may also help explore how God or the Divine is present and active in one’s life. Spiritual directors are listeners and companions. Like other forms of counseling, spiritual directors do not give answers but assist individuals in exploring questions, issues, and concerns in their lives. Spiritual directors are found at retreat centers and in private practice and may be employed by health-care institutions or faith communities.

A task force (Lo et al., 2002) of physicians and end-of-life specialists offers several guidelines for health-care providers as they respond to patients’ spiritual concerns. • Respect the patient’s views and follow the patient’s lead. It is not appropriate to impose one’s own beliefs and practices on the patient.

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• Identify common goals for care and health-care decisions. • Mobilize other resources of support for the patient, such as referring the patient to a chaplain or other spiritual care provider. Spirituality is also important for family members and impacts their ability to both cope with illness and deal with the potential of having a loved one die. As noted by Taylor (2006), patients with cancer and family caregivers have similar spiritual needs including being positive, loving others, finding meaning, and relating to God. Noting that families play a central role in a cancer patient’s diagnosis, treatment, and recovery, Marshall (2010) emphasizes the importance of family care and support and offers the following intervention strategies: • Help families manage a range of emotions and address expectant grief issues. • Help families tap into their strengths and sort out realistic versus unrealistic fears. • Explore with families how to take advantage of the time they have left. • Encourage families to include trusted members of the extended family or cultural and spiritual communities in their support system.

Summary Although the terms spirituality and religion are often used interchangeably, they hold different meanings in people’s lives and are expressed in a myriad of ways. Health-care providers need to remain mindful of these individualities, respect them, and factor them into care. There is a growing body of literature that has documented the relationships between spirituality, religious beliefs and practices, and health outcomes. Given this connection and the expectation that patients have that their spiritual needs should be addressed, health-care providers and hospitals are developing the competencies and capacities to respond to spiritual issues and concerns. Spirituality can no longer be ignored in the provision of holistic care. People whose lives have been touched by cancer either as a patient or as a family member commonly experience spiritual distress which may be expressed as grief, loss, pain, suffering, shock, denial, fear, hopelessness, despair, isolation, and survivor guilt. Spiritual interventions offered by health professionals or spiritual care providers may both address these issues and contribute to overall health and well-being. As noted by Puchalski and Ferrell, “spirituality helps give meaning to suffering and helps people find hope in the

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midst of despair. In the midst of suffering, a skilled, caring and compassionate health care professional can be an important anchor in which the patient can find solace and the strength to move through distress to peace and acceptance” (Puchalski et al., 2010).

REFERENCES

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17 Naturopathic Oncology LISE N. ALSCHULER AND LEANNA J. STANDISH

Key Concepts Applied in the realm of oncology, naturopathic medicine provides a scientifically sound and vital component to the holistic support of each person diagnosed with cancer—from prevention through treatment and into survivorship. ■ Naturopathic medicine is based on the core principle of the healing power of nature. This principle demands an acceptance of the body’s inherent ability to heal itself. ■ Although the knowledge base of naturopathic oncology has yet to be translated into practice guidelines per se, the general approach to prevention and treatment is consistent among naturopathic oncologists. ■ Outside of active treatment, naturopathic oncology offers a comprehensive, individualized program to reduce risk of cancer development, to minimize progression in those with established disease, and to reduce risk of recurrence for those who have successfully completed treatment ■ Epidemiological evidence shows that 15–25% of cancers are said to be linked to chronic infection or chronic inflammation, thereby making the assessment and treatment of chronic inflammation a cornerstone of naturopathic oncology. ■ An important area of naturopathic assessment and management is immunity in that the inflammatory process that often underlies malignancy is initiated and perpetuated by immunologic mediators. ■

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It is well established that insulin and insulin-like growth factor—1 (IGF-1) are direct growth factors for cancer cells and therapies targeted to correction of this metabolic imbalance are paramount. ■ The risk/benefit profile of physical activity is favorable, assuming that key safety issues are considered for each individual before initiating an exercise program. ■

Introduction Naturopathic medicine represents the convergence of global traditions of healing with modern scientific understanding. Naturopathic oncology is the application of the naturopathic approach to the disease of cancer. Naturopathic medicine offers a sophisticated integration of traditional healing philosophies with modern scientific understanding and research opportunities (Steel  & Adams, 2011). Applied in the realm of oncology, naturopathic medicine provides a scientifically sound and vital component to the holistic support of each person diagnosed with cancer—from prevention through treatment and into survivorship. The specialty of naturopathic oncology is at the forefront of this integration.

Principles of Naturopathic Medicine Naturopathic medicine is based on the core principle of the healing power of nature (Fleming & Gutknecht, 2010). This principle demands an acceptance of the body’s inherent ability to heal itself. This understanding, in turn, delineates the role of the naturopathic doctor as one to support this inherent healing process. Naturopathic doctors are trained to utilize a continuum of therapies to provide this support, with preference being given to those that are of natural origin. This principle determines lifestyle—namely diet, activity, sleep, emotional and spiritual wellness—as the platform of the naturopathic therapeutic approach. This approach is reinforced by the second principle of naturopathic medicine, to identify and treat the cause. Naturopathic practitioners seek to discover the underlying cause of disease and dysfunction in an attempt to correct the problem at its source. The core of dysfunction is often found in the lifestyle of the patient, thereby emphasizing the importance of a lifestyle-based approach to both prevention and treatment of disease.

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In recognition of the influence of lifestyle on disease, cancer included (Charvat et al., 2013), naturopathic medicine utilizes a third principle to guide the application of therapies, namely, treat the whole person. This principle guides the naturopathic physician to evaluate and incorporate a person’s personal health history, family history, their societal and cultural influences, as well internal biochemical, molecular, and genetic factors. The complexity of this analysis mirrors the inherent complexity of the human being, and, in turn, necessarily negates a reductionist approach. For this reason, naturopathic treatment typically includes systemic treatments such as diet, as well as targeted therapies such as specific nutrients, nutraceuticals, and botanicals. The application of these therapies is guided by the fourth principal of naturopathic medicine, first do no harm. This principal requires that the naturopathic physician constantly evaluate each therapeutic option from a cost-versus-benefit perspective. From this evaluation, it is often the case that the least harmful, and therefore, most indicated therapy, may actually be therapies with significant potential toxicity (chemotherapy and radiation for instance). Endorsement of these therapies is entirely consistent with naturopathic oncology when viewed from the perspective of the necessity of these therapies to remove the destructive expression of pathology, namely malignancy.

The fifth principal of naturopathic medicine is doctor as teacher. This underscores the belief that the therapeutic relationship is paramount to healing. A  naturopathic doctor seeks to establish a professional healing relationship with each patient. For this reason, naturopathic practitioners require time with their patients and typically offer longer consultations in order to develop this relationship, educate their patients about their state of health, and to explain the rationale for therapies (Heiligers, de Groot, Koster, & van Dulmen, 2010). The final principal of naturopathic medicine is prevention. Prevention is woven into every encounter as both rationale and desired outcome. Although most patients seek naturopathic medical care to treat disease, in the course of this treatment, the underlying aspects that lead to pathology are addressed as a way of preventing future detriment to health.

Practice of Naturopathic Medicine Naturopathic medicine is one of the fastest growing complementary health-care professions in the United States (Lafferty et al., 2006). Naturopathic medical

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postgraduate education includes basic medical sciences and conventional diagnostics as well as training in naturopathic therapeutic modalities. Naturopathic modalities include: therapeutic nutrition, botanical medicine, homeopathy, lifestyle counseling, classical Chinese medicine theory, hydrotherapy, naturopathic manipulative therapy, drug/herb/nutrient interactions, pharmacology, minor office procedures, and supervised outpatient clinical training.

After completing premedical training, naturopathic physicians attend a four-year graduate-level federally recognized naturopathic medical school. There are 7 naturopathic medical programs accredited by the Council on Naturopathic Medical Education (CNME), the sole accrediting agency for naturopathic medical education recognized by the U.S. Department of Education. The accredited naturopathic schools in North America are: Bastyr University, National College of Natural Medicine, Southwest College of Naturopathic Medicine, University of Bridgeport, National University of Health Sciences, Canadian College of Naturopathic Medicine, and Boucher Institute. Currently the following states license the practice of naturopathic medicine: Alaska, Arizona, California, Colorado, Connecticut, Hawaii, Idaho, Kansas, Maine, Maryland, Minnesota, Montana, New Hampshire, Oregon, South Dakota, Utah, Vermont, Washington. In addition, Puerto Rico, the Virgin Islands, the District of Columbia, and all provinces in Canada also license naturopathic doctors. Naturopathic doctors (NDs) typically practice in outpatient settings. The majority of naturopathic doctors provide comprehensive family medical care. In some states, naturopathic doctors serve as primary-care providers. Naturopathic doctors may also be found working alongside other provider types in hospitals and integrated clinics serving diverse patient populations (Brett, Brimhall, Healey, Pfeiffer, & Prenguber, 2013). In all cases, naturopathic doctors utilize both conventional and specialty assessment tools to provide diagnosis and treatment to their patients.

The Profession of Naturopathic Oncology In response to the growing need for expertise in natural and integrative oncology care, the Oncology Association of Naturopathic Physicians (OncANP) as well as the American Board of Naturopathic Oncology (ABNO) were

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established in 2004. The OncANP, a recognized affiliate organization by the American Association of Naturopathic Physicians (AANP), has, as its central tenet, the support and enhancement of naturopathic oncology. This commitment extends into several areas. The OncANP provides continued education opportunities for practicing naturopathic doctors, hosts a member forum, and supports practice development for its members. The OncANP companion organization, ABNO, administers a board certification process for naturopathic doctors. Naturopathic doctors who meet eligibility criteria may sit for a psychometrically validated board certification examination. Eligibility requirements to sit for this examination include completion of an oncology focused residency program in a CNME recognized institution or a minimum of 5 years of naturopathic practice that includes a minimum of 5,000 cumulative patient care hours with at least 50% oncology care. Of note, the requirements for board certification have become more stringent over time. Upon passing the naturopathic specialty examination, a naturopathic doctor becomes a Fellow of the American Board of Naturopathic Oncology (F.A.B.N.O.). Re-certification is required every 10 years. As of 2013, there were 85 Fellows of naturopathic oncology. A listing of all Fellows can be found on www.oncanp.org. Although the majority of naturopathic physicians provide care to people diagnosed with cancer in their practices, NDs with FABNO certification are recognized experts in the area of naturopathic oncology. Furthermore, Fellows of naturopathic oncology typically focus the majority or all of their practices on the care of people diagnosed with cancer. Naturopathic doctors with FABNO certification are found in hospitals, conventional clinics, integrated health-care clinics as well as in solo outpatient practices. Although the clinical practice of naturopathic oncology is cohesive, the field does not yet have practice guidelines. The cohesiveness derives from the shared knowledge base of naturopathic oncology. Naturopathic oncologists have demonstrated knowledge competency in various areas critical to the practice of naturopathic oncology: • Epidemiology, incidence, risk factors, pathogenesis, prevention, screening, signs and symptoms, diagnosis, staging and prognostic factors, conventional treatments and supportive care for individual cancer types. • Principles of naturopathic oncology, with emphasis on primary prevention, including chemoprevention with nutrients and botanical agents; active co-management strategies with conventional treatments; nutritional, homeopathic, and nutraceutical support with

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• • • •

•

emphasis on indications, contraindications, drug interactions, and mechanisms of action. Parenteral therapy with nutritional and botanical therapies such as intravenous ascorbic acid. Secondary prevention through detoxification, nutrition, immune support, targeted therapies, and exercise. Psychosocial support at all stages of cancer. Application of therapies that will improve the terrain, interrupt carcinogenesis, remove promoters, provide detoxification, support apoptosis, control up-regulated cell proliferation, enhance cell communication and stromal integrity, restore health and vitality, and promote prevention. Specific and commonly used naturopathic therapies such as: • Dietary changes including vegetable based diets, anti-inflammatory diets, low glycemic load diets, broth fasting and calorie restriction diets. • Dietary supplements such as, but not limited to: acetyl-L-carnitine, alpha lipoic acid, coenzyme Q10, essential fatty acids, glutathione, L-carnitine, individual and combination vitamins and minerals, L-glutamine, L-theanine, melatonin, and probiotics. • Botanical therapies such as, but not limited to:  Actea racemosa, Allium sativa, Astragalus membranaceous, bromelain, Camellia sinensis, Cordyceps sinensis, Curcuma longa, Magnolia officinalis, Trametes versicolor, Viscum album, and Withania somnifera. • Physical agent therapies such as, but not limited to: hyperthermia, constitutional hydrotherapy and acupuncture. • Selected antineoplastic therapies such as, but not limited to low-dose naltrexone, Viscum album, and intravenous therapies.

Thus, the knowledge base of naturopathic oncology is well defined. This knowledge base has yet to be translated into practice guidelines per se; however, the general approach to prevention and treatment is consistent among naturopathic oncologists.

The Role of Naturopathic Oncology The practice of naturopathic oncology is characterized by its approach to care. One may consider that there are three phases of the cancer experience, those being prediagnosis, active conventional treatment and the post-conventional care. Naturopathic oncology features prominently in each phase. There are

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several guiding principles of naturopathic oncology that underlie its approach in each phase of treatment. During active conventional treatment, naturopathic oncology places great emphasis on the safe application of nutritional and botanical agents (Hardy, 2008). Each intervention is assessed for possible drug/nutrient/herb interactions. This assessment precludes the use of certain botanical agents with certain chemotherapeutics as well as certain high-dose antioxidants with radiation therapy. On the other hand, in the absence of interactions, selected agents are utilized that have been studied to show synergistic effects with chemotherapeutics and radiation as well as some that can ameliorate adverse toxicities. The nutrient and botanical program is developed uniquely for each individual in order to take into account their health status, treatment regimen, toleration issues, and medication history. Naturopathic physicians are well familiarized with the highest quality dietary supplements and utilize this knowledge to further buttress the safety of their recommendations. Despite the fact that the FDA regulates the manufacture of dietary supplements, inconsistent enforcement combined with sporadic disregard of the regulations on the part of some manufacturers has led to a continuum of quality in the marketplace. People with cancer are particularly vulnerable to the dangers posed by inferior quality and contaminated supplements. Therefore, it is imperative that patients are recommended products that meet, and, in fact, exceed the manufacturing regulations. There are many professional brands of dietary supplements that fit this description and are relied upon by naturopathic oncologists. Outside of active treatment, naturopathic oncology offers a comprehensive, individualized program to reduce risk of cancer development, minimize progression in those with established disease and to reduce risk of recurrence for those who have successfully completed treatment.

In order to engineer the most effective treatment plan, NDs routinely assess their patients for many established, as well as emerging, risk factors. This assessment includes an evaluation of family and personal cancer history. This assessment also encompasses standard clinical and genetic screening tests. Additionally, naturopathic evaluation places significant focus on assessing the person’s overall health, with specific attention on areas considered to contribute to carcinogenesis. The rationale for this assessment stems from the acceptance of the role of various and specific physiological processes in carcinogenesis. Naturopathic oncology eschews the notion that carcinogenesis is solely the result of genetic mutations. Rather, naturopathic oncology

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acknowledges the role of physiology as a key collaborator in the oncologic process. The naturopathic oncology approach is epigenetically oriented.

Naturopathic Oncology Principles and Practice There are several systemic processes involved in carcinogenesis that are, therefore, continuously evaluated in the course of naturopathic oncology. Inflammation is considered to be a key predisposing factor to cancer development. The relationship between inflammation and cancer has been well established. Epidemiological evidence shows that 15–25% of cancers are said to be linked to chronic infection or chronic inflammation (Hussain & Harris, 2007). In particular, the extrinsic pathway of inflammation, characterized by up-regulated chemokines, cytokines, and prostaglandins, up-regulates proliferation, angiogenesis, invasiveness, and inhibits adaptive immunity (Mantovani, Allavena, Sica,  & Balkwill, 2008). Oncogenes are up-regulated in this cytokine/chemokine enriched environment. These oncogene products further contribute to the inflammatory environment and ultimately to aberrant cell behavior. The tumor microenvironment is fundamentally characterized by long-standing and systemic inflammation. Conversely, acute localized inflammation favors resolution of the tumor due to the lymphocytic infiltration; in fact, lack of immunoreactivity is a poor prognostic indicator. Thus, understanding the extent and duration of inflammation is an important aspect of whole person evaluation. For this reason, biomarkers of chronic inflammation are a hallmark of the naturopathic evaluation of cancer susceptibility and underlie naturopathic oncologic management.

Evaluation of inflammation includes blood testing for biomarkers of the inflammatory process, including C-reactive protein (CRP). C-reactive protein is elevated in association with increased risk of lung cancer (Kanoh, Abe, Masuda, & Akahoshi, 2013), prostate and breast cancer (Guo, Pan, Du, Ren,  & Xie, 2013), colorectal cancer (Toriola et  al., 2013), as well as other squamous cell cancers of the head and neck (Peter, Wittekindt, Finkensieper, Kiehntopf, & Guntinas-Lichius). High CRP in conjunction with low albumin (CRP/albumin, known as the Glasgow prognostic score) is also an important laboratory assessment. Another inflammatory biomarker often assessed, as a part of naturopathic prevention, is serum IL-6. Elevated serum IL-6 is associated with lymphoma (Seymour, Talpaz, Cabanillas, Wetzler,  & Kurzrock,

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1995), hepatocellular cancer (Ohishi et al., 2014), and metastatic breast cancer (Shostak  & Chariot, 2011). Additionally, other acute phase reactants associated with the presence of aggressive cancer are often measured in the blood to gauge the presence and degree of inflammation; these include vasoendothelial growth factor (VEGF), fibrinogen, TNFa, IL-1, and IL-8. An abnormal inflammatory profile indicates specific anti-inflammatory strategies. Many of these interventions directly inhibit NF-kB activation, whereas others target the secondary inflammatory interleukins and cytokines. These are inclusive of diet, dietary supplements and botanical approaches. This inflammatory process is initiated and perpetuated by immunologic mediators making immunity an important area of assessment (Coussens  & Werb, 2002). The majority of patients diagnosed with cancer have a lowered Th1:Th2 immune ratio, which suggests impaired type-1 immunity. T lymphocytes expressing CD4, also called helper T cells, are either Th1 or Th2 lymphocytes. The cytokines that each lymphocyte subset produces are known as Th1-type cytokines and Th2-type cytokines (Berger, 2000). In general, individuals diagnosed with cancer have an imbalance in their Th inflammatory responses that favors Th2 at the expense of Th1 (Lu et al., 2012). The roles of Th1 cell mediated immunity as well as innate natural killer cell directed immunity play a critical role in the immunological eradication of tumors. The presence of malignancy also increases T regulatory cells, which aggravate immunosuppression (Huang et al., 1995). Understanding the status of immunity through cell enumeration testing as well as cytokine profiles provides important insight into the type and degree of immune dysregulation. This, in turn, provides direction to the naturopathic oncologist for immune-directed natural therapies. Another key area of concern to the naturopathic oncologist is that of cancer cell metabolism and insulin resistance. It is well established that insulin and insulin-like growth factor-1 (IGF-1) are direct growth factors for cancer cells (You, Liu, Tang, Liao, & Fu, 2013). Elevated insulin and insulin resistance is correlated with increased risk of developing and dying from cancer. It is also well known that tumor cell metabolism is altered under the influence of persistent hyperglycemia away from oxidative phosphorylation and toward aerobic glycolysis. Under the combined conditions of insulin- and IGF-1-fueled cell proliferation, along with the oxidative stress from aerobic glycolysis, apoptosis is impaired. Thus, assessing the state of insulin resistance in a cancer patient creates an important area of potential therapeutic focus. This justifies various metabolic nutrient and botanical therapies as well as dietary strategies. A key area of emphasis in the naturopathic oncologic approach is a whole-person psycho-spiritual assessment. This provides valuable insight into coping mechanisms and further establishes an opportunity to better understand the significance of the stress response as a proliferative influence. The

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main stress hormone, cortisol, has been associated with poorer prognosis in a variety of cancers including renal cell cancer (Cohen et al., 2012), breast cancer (McGregor & Antoni, 2009), and ovarian (Diaz, Karlan, & Li, 2012) cancer. An understanding of a patient’s perception of stress and physiological expression of stress provides another arena of intervention. Naturopathic medicine has uniquely effective tools to normalize the stress response with a combination of stress-management-mindfulness techniques, hydrotherapy, adaptogenic herbs, and nutrient therapies. The future of naturopathic oncology depends to a great extent on its research agenda. Naturopathic research has been a robust activity within the naturopathic profession. Naturopathic oncology is complex algorithmic individualized medicine using multiple modalities and multiple agents. The complexity of naturopathic medicine does not lend itself easily to the single drug phase I, II, III randomized controlled trial model that is appropriate for single pharmaceutical agents. Solving complex methodological issues, naturopathic physicians have taken a lead role in integrative oncology research.

Naturopathic oncology driven research includes longitudinal observational studies of survival and recurrence rates in cancer patients who receive naturopathic oncology services and clinical trials of individual natural cancer therapies (e.g., Trametes versicolor). Naturopathic research has also focused on understanding the anticancer mechanisms of action of botanical and fungal medicines used to treat our patients. Naturopathic oncology experts are developing better ways to administer our best immunomodulatory and anticancer medicines intravenously. These treatments are being evaluated in naturopathic oncology clinics and reported at the annual meeting of the Oncology Association of Naturopathic Physicians. Our experience and knowledge base grows yearly. Naturopathic oncology is a scientifically sound and comprehensive adjunct to conventional treatment as well as a legitimate stand-alone approach in certain phases of cancer prevention and management. The naturopathic oncologist’s rational use of natural therapies is a key component of integrative oncology. REFERENCES

Berger, A. (2000). Th1 and Th2 responses:  What are they? British Medical Journal, 321, 424–425.

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Brett, J., Brimhall, J., Healey, D., Pfeifer, J., & Prenguber, M. (2013). Competencies for public health and interprofessional education in accreditation standards of complementary and alternative medicine disciplines. Explore (NY), 9(5), 314–320. Charvat, H., Sasazuki, S., Inoue, M., Iwasaki, M., Sawada, N., Shimazu, T., Yamaji, T., & Tsugane, S. (2013). Impact of five modifiable lifestyle habits on the probability of cancer occurrence in a Japanese population-based cohort: Results from the JPHC study. Preventive Medicine, pii: S0091–7435(13)00322-8. Cohen, L., Cole, S.  W., Sood, A.  K., Prinsloo, S., Kirschbaum, C., Arevalo, J.  M., . . . Pisters L. (2012). Depressive symptoms and cortisol rhythmicity predict survival in patients with renal cell carcinoma: Role of inflammatory signaling. PLoS One, 7(8), e42324. Coussens, L.  M.,  & Werb, Z. (2002). Inflammation and cancer. Nature, 420(6917), 860–867. Diaz, E. S., Karlan, B. Y., & Li, A. J. (2012). Impact of beta blockers on epithelial ovarian cancer survival. Gynecological Oncology, 127(2), 375–378. Fleming, S. A., & Gutknecht, N. C. (2010). Naturopathy and the primary care practice. Primary Care, 37(1), 119–136. Guo, Y.  Z., Pan, L., Du, C.  J., Ren, D.  Q.,  & Xie, X.  M. (2013). Association between C-reactive protein and risk of cancer:  A  meta-analysis of prospective cohort studies. Asian Pacific Journal of Cancer Prevention, 14(1), 243–248. Hardy, M. L. (2008). Dietary supplement use in cancer care: Help or harm. Hematology/Oncology Clinics of North America, 22(4), 581–617. Heiligers, P. J., de Groot, J., Koster. D., & van Dulmen, S. (2010). Diagnoses and visit length in complementary and mainstream medicine. BMC Complementary & Alternative Medicine, 10, 3. doi: 10.1186/1472-6882-10-3 Huang, M., Wang, J., Lee, P., Sharma, S., Mao, J. T., Meissner, H., . . . Dubinett, S. M. (1995). Human non-small cell lung cancer cells express a type 2 cytokine pattern. Cancer Research, 55(17), 3847–3853. Hussain, P.,  & Harris, C. (2007). Inflammation and cancer:  An ancient link with novel potentials. International Journal of Cancer, 121, 2373–2380. Kanoh, Y., Abe, T., Masuda, N.,  & Akahoshi, T. (2013). Progression of non-small cell lung cancer:  diagnostic and prognostic utility of matrix metalloproteinase-2, C-reactive protein and serum amyloid A. Oncology Reports, 29(2), 469–473. Lafferty, W.  E., Tyree, P.  T., Bellas, A.S., Watts, C.  A., Lind, B.  K., Sherman, K. J., . . . Grembowski, D. E. (2006). Insurance coverage and subsequent utilization of complementary and alternative medicine providers. American Journal of Managed Care, 12(7), 397–404.

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Lu, K., Feng, X., Deng, Q., Sheng, L., Liu, P., Xu, S., & Su, D. (2012). Prognostic role of serum cytokines in patients with nasopharyngeal carcinoma. Onkologie, 35(9), 494–498. Mantovani, A., Allavena, P., Sica, A.,  & Balkwill, F. (2008). Cancer-related inflammation. Nature, 454(7203), 436–444. McGregor, B.  A.,  & Antoni, M.  H. (2009). Psychological intervention and health outcomes among women treated for breast cancer: A review of stress pathways and biological mediators. Brain, Behavior, and Immunology, 23(2), 159–166. Ohishi, W., Cologne, J.  B., Fujiwara. S., Suzuki, G., Hayashi, T., Niwa, Y., . . . Chayama, K. (2014). Serum Interleukin-6 associated with hepatocellular carcinoma risk: A nested case-control study. International Journal of Cancer, 134(1), 154–163. Peter, F., Wittekindt, C., Finkensieper, M., Kiehntopf, M., & Guntinas-Lichius, O. (2013). Prognostic impact of pretherapeutic laboratory values in head and neck cancer patients. J Cancer Research  & Clinical Oncology, 139(1), 171–178. Seymour, J. F. Talpaz, M., Cabanillas, F., Wetzler, M., & Kurzrock, R. (1995). Serum interleukin-6 levels correlate with prognosis in diffuse large-cell lymphoma. Journal of Clinical Oncology, 13(3), 575–582. Shostak, K.,  & Chariot, A. (2011). NF-κB, stem cells and breast cancer:  The links get stronger. Breast Cancer Research, 13(4), 214. Steel, A., & Adams, J. (2011). Approaches to clinical decision-making: A qualitative study of naturopaths. Complementary Therapy in Clinical Practice, 17(2), 81–84. Toriola, A. T., Cheng, T. Y., Neuhouser, M. L. Wener, M. H., Zheng, Y., Brown E, . . . Ulrich, C. M. (2013). Biomarkers of inflammation are associated with colorectal cancer risk in women but are not suitable as early detection markers. International Journal of Cancer, 132(11), 2648–2658. You, L., Liu, C., Tang, H., Liao, Y.,  & Fu, S. (2013). Advances in targeting insulin-like growth factor signaling pathway in cancer treatment. Current Pharmaceutical Design, Aug 12 [Epub ahead of print].

18 Traditional and Modern Chinese Medicine QING CAI ZHANG

Key Concepts Cancer is seen in Chinese medicine (CM) as a local manifestation of a systemic disease. Therefore, CM treatment focuses on the local lesion and the whole-body as well. ■ The CM concept of cancer is a weakening of resistance in the body while the oncogenic factor grows. Therefore, eliminating the tumor occurs by way of strengthening the resistance, the immunity, as well as the antitumor intervention. ■ Through integrating with core western medicine (WM) oncotherapies, CM aims to support body functions, to regulate immunity; mitigate the side effects, attenuate toxicity, reverse drug-resistance, enhance the therapeutic effects of WM’s surgery, chemo, and radiation treatments; and prevent relapse and metastasis. ■ The goal of successful CM treatment is not just to eliminate cancer, but also to allow the patient to survive with quality of life while coexisting with a stabilized cancer. ■ Integrated CM and WM cancer care includes (a)  primary prevention to treat precancerous conditions to prevent cancer; (b)  Initial diagnosis, aggressive oncotherapies such as surgery, radiotherapy, and chemotherapy to dramatically reduce cancer load; (c)  promoting recovery following aggressive treatment; (d) additional rounds of treatment to treat minimal residual disease; and (e) secondary and/or tertiary prevention that is long-term consolidation treatment to prevent relapse and metastasis. CM works in every stage of cancer care. ■

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New CM cancer treatment strategies have been developed to suppress cancer growth, induce cancer cell differentiation, promote cancer cell apoptosis, anti-angiogenesis, and antimetastasis. ■ CM gives the cancer patient greater confidence and strength to combat illness by improving quality of life with effective treatments for symptoms and complications. CM now is one of the core cancer treatments in modern China. ■

T

he theory, practice, and medications of Traditional Chinese Medicine (TCM) and modern Chinese medicine (MCM) for oncology differ significantly from those of Western medicine (WM). Cancer in CM is seen as a local manifestation of a systemic disease. There are various stages in the disease course, involving multiple body systems. Accordingly, treatment is multiple-target regulation to restore general health and eliminate the cancer. In CM this is called “Fuzheng Quxie” (strengthening genuine Qi to eliminate pathogenic factors). A theoretical and practical system of treating cancer with CM has been well established. New treatments are also being developed as an ongoing process of integrating CM and WM. Integrative CM and WM oncology (ICWO) treatment has been practiced for more than five decades and has shown that CM has been an excellent complement to WM in cancer treatment (E. X. Yu et al., 1985). In the area of theoretical research, CM explores various anticancer strategies, such as blocking the cancer cell-growth cycle, inducing cancer-cell differentiation; promoting apoptosis; facilitating antiangiogenesis, reversing drug-resistance, sensitizing the cancer to the oncotherapies, antirelapse and -metastasis; as well as reducing risk of cancer development in the first place. When combined with core WM treatments, CM is effective at mitigating the side effects and enhancing the therapeutic effects of chemotherapy and radiotherapy. CM can also aid in the preparation for and recovery from surgery, adjustment to biological response moderation (BRM), shrinking and stabilizing tumors, and improving quality of life and long-term prognosis. While ICWO is getting encouraging clinical results, more foreign cancer patients came to China seeking ICWO. The international medical community started to show much more interest and more oncologists have traveled to China to observe and study ICWO. Some ICWO treatments have been accepted worldwide, such as the use of arsenic trioxide (As2O3) combined with all-trans retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia (APL), which was developed

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in the Shanghai Institute of Hematology, Samuel Waxman Cancer Research Foundation Lab of Rui-Jin Hospital of Jiaotong University of Shanghai, China (G. Q. Chen et al., 1997). In 2012, this work won the grand prize of the Seventh St. George Cancer Research Progress Award. It combined the TCM therapeutic arsenic agent with medication of the WM in the treatment of APL, greatly prolonging the survival of APL patients. The integrative therapy has increased five-year survival rate without relapse from 25% to 95%, and has become a standardized treatment for APL internationally, turning a virtually fatal disease into an almost curable disease (Shanghai Jiao-tong University, 2012). There was an international forum held in 2006 at the National Center for Complementary and Alternative Medicine of NIH to discuss Cancer Research and Chinese Medicine in Bethesda. After this conference, the National Cancer Institute (NCI) started a research project to study the molecular mechanism of immune regulatory effects of “Fuzheng” herbal treatment of cancer patients (J. Li, 2008). Some imminent cancer institutions have started to set up collaborative studies with Chinese institutions, such as the one between Fudan University Cancer Hospital of Shanghai, China and The University of Texas M. D. Anderson Cancer Center, which is a part of the International Center of TCM for Cancer (funded partially by the NCI). This collaborative group conducted a Pilot Study of the Effects of Huachansu in Patients with Hepatocellular Carcinoma (HCC), Non-Small Cell Lung Cancer (NSCLC), and/or Pancreatic Cancer (Meng et al., 2009). Shanghai TCM University and New York Sloan-Kettering Center for Cancer Research are studying Safety and Pharmacokinetics of Jin Fu Kang in Combination with Docetaxel for Patients w/NSCLC. The Xihuan Hospital of China Academy of Chinese Medicine in Beijing is collaborating with a Norwegian institute conducting an international multicenter study for improving the rate of radical cure of colorectal cancer with CM (H. S. Lin, 2008a,b). Through the international coordination, the rest of the world will become more familiar with ICWO and help cancer patients to get better clinical outcomes. This article is an introduction to the current integration of CM and WM in oncology as practiced and developed in China.

Overview of Integrative Chinese and Western Medicine Oncology Integrative Chinese and Western medicine oncology (ICWO) is the main method of modernizing TCM oncology so that CM and WM can practice in the same medical settings by the same doctors for the same patients. The modernization movement has also created new terminologies to interpret TCM

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concepts through the lenses of modern pathophysiology and phytopharmacology. ICWO uses TCM principles for malignant diseases as a guideline and combines WM knowledge—cancer pathophysiology, diagnosis, and pharmacology—to formulate treatment protocols (E. X.  Yu et  al., 1985). ICWO has been blending the best aspects of both medical systems and uses each system’s understanding of cancer and the health status of the individual patient to formulate a comprehensive treatment plan. The efficacy of ICWO has proven to be better than TCM or WM used alone, as will be discussed further later (R. C. Yu, 1988; R. C. Yu et al., 2005). From more than five decades of development, ICWO has established the following four basic precepts among Chinese oncologists: 1. Cancer is termed as “Zheng xu xie shi” (deficiency (xu) of Zheng (also called Zhengqi, which can be translated as genuine Qi denoting life activity and host resistance, i.e., immunity) and excess (shi) of Xie (also called Xieqi, which can be any pathogenic factor or pathological damage in a broad sense), a chronic weakening of the body’s resistance while malignant growth develops. The basic treatment strategy for cancer is “Fuzheng Quxie” (strengthening the body’s resistance to eliminate oncogenic factors). ICWO studies attempt to explain the nature of Zheng and Xie and the conflict between them (E. X.  Yu, 1993). Genuine Qi is responsible for the immune functions. When it becomes deficient, a favorable environment is created for cancer to occur. In Western terms, this is a deterioration of the immune surveillance function, which fails to discover cancerous mutations as they occur and suppress their growth. Genuine Qi is also damaged during the course of the core WM oncotherapies, so CM treatment emphasizes Fuzheng (supporting genuine Qi). Dr. Sun Yan of the Chinese Science Academy has been advocating Fuzheng treatment for many decades and has significantly improved the outcome of ICWO treatments (Y. Sun, 1995). 2. The disease course of cancer can be seen as a dynamic confrontation between genuine Qi and malignant growth. The course of treatment can be divided into five stages. a. Actively treating precancerous condition as primary cancer prevention. b. Initial diagnosis, when oncogenesis is the predominant concern, should be followed by aggressive treatments such as surgery, chemotherapy, and radiation therapy, as well as anticancer herbs to

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dramatically reduce cancer load. At the same time, CM is used to mitigate the toxicity of aggressive WM treatments and enhance their therapeutic effects. c. Recovery following aggressive treatments, after the cancer load has been greatly reduced. Treatment is focused on maximizing recovery of the digestive, hematopoietic, and immune functions. CM treatment is used to restore general health by rebuilding the Zhengqi. d. Additional rounds of anticancer treatment are used to treat minimal residual disease. e. Long-term recovery using supportive and noncytotoxic CM anticancer methods to prevent relapse and metastasis as secondary and/or tertiary prevention. CM has been used in every stage of the cancer treatment and now in China it becomes a core oncotherapy being used as common as surgery, chemo, and radiation. 3. ICWO protocol should be based on WM’s disease differentiation and CM’s syndrome differentiation, the latter of which rationally addresses the relationship between the local lesion and systemic health and also the individualization of treatment. In TCM, a syndrome is a diagnosis of the patient’s general health status, in which illness is seen as a result of functional imbalances caused by pathological changes in the context of the patient’s internal constitution. The combination of systemic CM and cancer-focused WM treatments yields better efficacy than either modality used alone. 4. The success of CM cancer treatment is not gauged by elimination of the cancer alone. Instead, if malignancy cannot be totally eradicated, the objective is to allow the patient to survive and maintain quality of life while coexisting with the stabilized cancer. The purpose of ICWO is to prolong life and improve the quality of life. Thus, if the patient’s condition can be stabilized, quality of life improved, and survival time prolonged while living with a chronically manageable cancer, the treatment efficacy should be considered to be better than if the cancer is reduced but the patient displays a diminished quality of life and a reduced life span. The objective is to transform cancer into a chronic manageable disease (R. C. Yu et al., 2005). With this thought in mind, the harmful over-treatment can be avoided. As one of the achievements of the integration of Chinese and western medicine, many herbal anticancer proprietary medicines have been developed and

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Table 18.1.  Comparison of CM, ICWO, and WM in Treating Late NSCLC Group

N

Ca Reduction

Ca Stability

Median Survival

Average Cost*

CM

99

4%

66.7%

292 days

18682.2

ICWO

103

26.2%

81.6%

355 days

36148.5

WM

92

14.1%

76.1%

236 days

28750.5

*Cost is in Chinese RMB yuan.

now are available in Chinese markets. There are 107 CM drugs for cancer care made from TCM herbs that have been approved by the Chinese Food and Drug Administration. Among them are 15 injections, 6 external usage, and 86 oral dosage forms. They can be classified into three categories: (1) anticancer drugs are used to reduce the size of the cancer; (2) adjunctive treatment drugs are used for enhancing the chemotherapy and radiation effects and mitigating their side effects and toxicities. They are also used for treating late stage cancer for improving symptoms, quality of life, and prolonging survival and regulating immunity; and (3) Drugs are used for complications caused by cancer and chemotherapies and radiotherapies, such as pain, and irradiative esophagitis, for example (G. X. Li, 2008). Clinically ICWO improved long-term survival in many cancers, such as stage III gastric cancer postsurgery, where 5-year survival increased from 20%–30% to 50%–60%; nasopharyngeal carcinoma postradiotherapy where 5-year survival increased from 20%–40% to 50%–60%; and lung cancer postradiotherapy where 3-year survival rate increased from 8.6% to 22.9% (D. Z. Zhang, Hao, & Cui, 2008). For example, Zhou et al. reported a multi-center randomized, controlled prospective study to compare CM, ICWO and WM treatments for middle and late stages of non-small cell lung cancer. The results are listed in Table 18.1 (Zhou, Lin, & Zhou, 2005). The conclusion of this study was that CM is an effective and economic treatment for middle and late stage non-small cell lung cancer and the ICWO had the best clinical outcome.

Integrating CM with Core Western Cancer Treatments Following a diagnosis of cancer, all possible methods should be used to eliminate cancer cells. The main WM methods are surgery, chemotherapy, radiotherapy, and biologic response modifiers, including targeted therapies. These treatments focus on the cancer lesion and can quickly reduce tumor

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load. CM offers supportive treatments to regulate body functions, to restore immunity, to mitigate the side effects of WM treatments, attenuate toxicity, reverse drug-resistance, and enhance the therapeutic effects of WM methods. CM can act synergistically sensitizing originally insensitive cancer cells to WM therapies to make patients more tolerant of WM treatments (E. X. Yu, 1992). With ICWO the rate of completion of the chemotherapy and radiation therapy compared to patients not receiving CM increased about 20%. Overall the toxicity on the gastrointestinal system, bone marrow, and local irradiative field are much less in ICWO treated patients, and the effectiveness (CR+PR) of chemotherapy and radiation increased 29.2% to 37.1%. All these differences were statistically significant. It confirmed that ICWO can mitigate side effects and enhance therapeutic effects of conventional cancer therapies (D. Z. Zhang et al., 2008).

Surgery and Chinese Medicine Surgery is the first choice in early- to mid-stage cancer, provided the cancer is localized and operable. Surgery, however, causes injury to the body and may promote metastasis and implantation to the surrounding tissues. Only those patients with lesions in situ or at the earliest stage can be cured by surgery alone. Surgery is often combined with chemotherapy, radiotherapy, and biologic response modifiers. In China, surgery is routinely combined with CM treatments. As a perioperative care, CM is used for three purposes: • Presurgery to prepare the patient by improving general health and the health of particular organs and systems, such as the liver and the cardiovascular system. • Immediately following surgery to promote recovery from surgical injury and anesthesia and to relieve postsurgery symptoms, such as low-grade fever and digestive disruptions, thereby preparing the patient for chemotherapy or radiotherapy. • Following recovery from surgery to restore general health and immunity to reduce the risk of recurrence and metastasis.

Both the direct effects of cancer and the trauma of anesthesia and surgery can suppress immune function. This, in turn, favors the escape of residual cancer cells from immune detection, increasing the possibility of recurrence and metastasis. CM treatment can help restore immune functions to reduce these risks (E. X. Yu, 1993).

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Chinese oncologists have been using Shengqi (ginseng and astragalus) injection and administration of the polysaccharide fraction of Zhuling mushroom (Polyporus umbellatus) preoperatively to promote postsurgical recovery and improve immunity. Presurgical use of anticancer herbal preparations such as 10% emulsion of Yadanzi (Fructus bruceae) strengthened immune reactions around the tumor as observed on pathology slides. Spleenqi- (digestive function-) supportive herbs are used after surgery to promote recovery from the procedure itself (Q. S. Yu et al., 2005). Immediately after surgery, CM treatment can help to promote recovery of the surgical injuries. Dong, Zhang, and Yu (2010) reported that combined treatment of Shenmai Injection (SMI) and enteral nutrition could regulate mood and sleep and reduce postoperative fatigue through improving nutritional status and immune function, thus speeding the recovery of patients. The CM treated patients showed better profile of mood status and Pittsburgh sleep quality index, less postoperative fatigue (p < 0.05), and also the levels of serum albumin and IgA were higher in CM treated group (p < 0.05). Shenmai injection is made from the active ingredients of Renshen (Panax ginseng) and Maidong (Ophiopogon japonicus) (Dong et al., 2010). C. Liang, Zhang, and Cai (2005) reported that early application of Sijunzi Decoction on the base of enteral nutritional therapy could lessen the degree of postoperational stress and inflammatory response, and enhance the immune function of the patients. The concentration of IgA, IgG, IgM, number of total lymphocyte, CD3, CD4, CD4/CD8, and serum IL-2 were obviously higher (p < 0.05), and levels of IL-6, TNF-a and CRP were significantly lower in the CM treated group than those in the control group (p < 0.05) (C. Liang et al., 2005). Q. Li. et al. (2005) reported the immune-cell activities of 67 patients with hepatocellular carcinoma (HCC) before and after surgery. Thirty patients were treated with CM herbal decoctions, consisting of the following substances: Danggui (Angelicae radix), Huangqi (Astragali radix), Baiying (Solanum lyratum), and Longguei (Solanum nigrum). Another 37 cases without herbal treatment acted as the control group. The presurgery levels of immune cell counts were similar in the two groups. Postsurgery levels of CD3+, CD4+, CD4+/ CD8+, B cells, and natural killer (NK) cells were lower compared with presurgery levels in both groups. However, the postsurgery levels of the CM-treated group were significantly better than that of the control group. Among these findings, the CD4+/CD8+ results are especially interesting. The stability of this ratio maintains normal immune function. The CM-treated group had significantly higher CD4+/CD8+ ratios compared with the control group. This may be related to the bone-marrow protective and immune regulatory effects of the

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Table 18.2.  Survival Time of Late-Stage Stomach Cancer Patients Treated with CM + Chemo and Chemo Alone Group

Survival Time

3 Years Survival Rate

5 Years Survival Rate

CM + Chemo

3.19 year

54.8%

34.4%

Chemo

1.12 year

17.6%

5.9%

p < 0.01.

herbal treatment. The immune-protective effects can help reduce the chance of postsurgery relapse and metastasis (Q. Li et al., 2005). Rao et al. (1994) reported that postsurgery CM treatment could improve the long-term survival of late-stage gastric cancer patients. In a study of 81 postsurgery stage III and IV gastric cancer patients, the CM herbal formula Shenxue Tang (hematopoiesis-promoting formula), combined with chemotherapy regimens (methotrexate, 5-fluorouracil, and vincristine and mitomycin, 5-fluorouracil, and cisplatin) extended survival compared to the control group. This was calculated according to the life-table method and demonstrated that the survival time for the CM-plus-chemotherapy group was 3.2  years compared to 1.1  years for the chemotherapy-only group. The results are shown in Table 18.2 (Rao et al., 1994). Postsurgery CM treatment can help to prevent cancer relapse and metastasis. L.  Xu et  al. (1997) reported the metastasis rates of two groups of postsurgery lung cancer patients using the CM formula Yifei kangai Yin (lung nourishing anticancer decoction). One group was treated with CM combined with chemotherapy, whereas the control group was treated with stand-alone chemotherapy. They found that the CM-treated group had a significantly lower metastasis rate (p < 0.01). In addition, the CM-treated group showed greater activity levels of NK cells, OKT3, and OKT4 (L. Xu et al., 1997). X. R.  Li et  al. (2001) reported similar results in a study of 58 postsurgery lung cancer patients. When the CM herbal formula Xiaoliuping (Tumor-resolving formula) was combined with chemotherapy, the metastasis rate was 12.5%, and the relapse rate was 25%. In comparison, the rates in the chemotherapy-alone group were 58.33% and 66.67, respectively (p  0.05

p < 0.05

p 0.05

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response (RR = 1.76; 95% CI, 1.23 to 2.53). Another herbal Ai Di Injection used in four studies (n  =  257) reportedly stabilized or improved Karnofsky performance status (RR = 1.28; 95%cl, 1.12 to 1.46). The authors concluded that the astragalus-based Chinese herbal medicine may increase effectiveness of platinum-based chemotherapy when combined with chemotherapy. These results require confirmation in rigorously controlled trials. Wu, Xu, and Wang, (2010) reported on Kangliu Zengxiao (KLZX) (antitumor enhancing efficacy) Decoction, formulated by Professor Z. Y. Xu of Shanghai TCM University. In a study of in patients with stage IIIa to IV non-small cell lung cancer, when KLZX was with chemotherapy with Navelbine (NVB) +Cisplatin (DDP) chemotherapy, the CM treated group had better effects in terms of improvement of symptoms, median survival time (15.62 months versus 11.27 months p < 0.05), Karnofsky score (p < 0.05), and body weight compared to chemotherapy alone. There were also benefits seen in strengthening immune functions, decreasing levels of tumor markers (CEA, VEGF, CYFRA21-1, p < 0.05) and alleviating hematopoietic and digestive adverse reactions (p < 0.05). The KLZX formula has clear toxicity-reduction and efficacy-enhancement effects compared to the chemotherapy regimen alone (J. Wu et al., 2010)

Chinese Medicine for Toxicities of Western Medicine Treatments The toxicity of chemotherapy drugs is one of the main factors limiting their usage and patient compliance. ICWO has developed toxin-mitigating and efficacy-enhancing treatments to deal with this issue. An analysis of the compliance to chemotherapy in 21,000 cancer patients in China was conducted in the 1990s. Among patients who received chemotherapy alone, the compliance rate was 50%–70% versus 70–90% in patients treated with ICWO (p < 0.05) (D. Z. Zhang et al., 2008). In WM, the toxic effects of chemotherapy on the gastrointestinal and immune systems can be treated with serotonin receptor antagonists and colony-stimulating factors; however, these treatments are costly. A. J. Xia et al. treated toxic side effects with the CM herbal formula Jiawei guizhi renshen tang (Modified Cinnamon and Ginseng Combination) and found that the patients’ white blood cells, platelets, T lymphocytes, and T-cell subsets after chemotherapy showed no significant change. The levels in the chemotherapy alone group, however, were significantly worse following chemotherapy. The CM-treated group also experienced less nausea and vomiting. The effects of the herbal treatment were similar to those of antiemetics and colony-stimulating factors

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in mitigating the side effects of chemotherapy, but at much less cost (A. J. Xia, et al, 2002). Cisplatin has been used extensively as a broad-spectrum anticancer drug. However, it is toxic to the kidneys and may cause kidney failure and even death. When cisplatin was used alone, kidney toxicity occurred in approximately 28% to 36% of patients (Williams & Hottendorf, 1985). In order to mitigate the toxic effects on the kidneys, large-volume intravenous hydration is used. This requires about 4,000 ml of fluids per day and is difficult for patients to tolerate. Even with hydration, about 10% to 20% of patients may still develop azotemia. J. H. Zheng et al. (1994) of Jiangxi Province Cancer Hospital designed the herbal formula of “spleen-nourishing, Qi-supporting, and diuresis-promoting” to treat kidney toxicity. The herbal treatment was more effective than hydration in mitigating cisplatin’s renal toxicity. It was observed that the 95 cases treated with cisplatin in the CM-treated group had much lower blood urea nitrogen (p < 0.05) and creatinine (p < 0.01) levels compared to the hydration group (J. H. Zheng et al., 1994). Also, the CM-treated group had much lower levels of beta-2-microglobulin, urine N-acetyl-β-D-glucosamidase, and urine proteins indicating that the glomerular filtration and reabsorption rates were protected. With CM treatment, only one-third of amount of intravenous fluid was required (J. H. Zheng et al., 1994).

Chinese Medicine for Reversal of Multidrug Resistance Multidrug resistance (MDR) means a cancer may be resistant to more than one drug. The resistance could be endogenous or acquired. It is the main cause of the failure of chemotherapy. For example, with chemotherapies MDR positive leukemia patients’ clinical CR rate is only 21.5% versus 66.6% of MDR negative patients. To reverse MDR is one of the key measures in improving the therapeutic effects of chemotherapy. Many Chinese herbal ingredients have been found to have MDR reversing effects. For example, tetrandrine, which is extracted from the Chinese herb Hanfangji (Stephania tetrandra Radix), has been found to be an effective MDR reverser. W.  L. Xu, Hou, and Cheng (1994) reported that at a concentration of 10 µmol/L, tetrandrine can enhance daunorubicin and vincristine’s effects on leukemia cells, and the effect is dose dependent. Peng and Tian found that at the same concentration, tetrandrine can completely reverse the MDR of MCF-7/Adr cells to Adriamycin. The mechanism underlying the reversing effect of tetrandrine is to increase the accumulation of anticancer drug

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inside the cancer cells. Other substances found to have MDR-reversing effects are:  Tetramethylpyrazine from Chuanxiong (Ligusticum chuanziong), which can reverse HL60/VCR cell’s MDR. PM1 and PM2 from Zhebeimu (Fritillaria thunbergii) also have MDR-reversing effects. Some other substances that have been studied for reversing MDR are epigallocatechin gallate, tetraarsenic tetraoxide (As4O4), berbamine, and arsenic trioxide (AS2O3) (Peng & Tian 1995). Reversing drug resistance has also been studied with CM herbal formulas. To study the effects of a multiherb recipe, a method called “herb recipe containing serum” is used. The serum is taken from an animal that has been treated with the herbal recipe and used in cell culture. W. K. Ma, Li, and Yao (2011) reported that Jiedu Huayu (removing toxin and blood stasis) Recipe containing serum could block the NF-kB signal pathway of leukemia K562/ A02 cells and reverse their drug resistance by influencing the expression of NF-kB-survivin genes. The effects were dose dependent. The Jiedu Huayu Recipe contains the following herbs:  Qingdai (Indigo Naturalis), Shancigu (Pseudobulbus cremastrae appendiculatae), Huzhang (Polygoni Cuspidati Rhizoma), Ezhu (Zedoariae Rhizoma), Chuanxiong (Ligusticum chuanziong), Danshen (Salviae Miltiorrhziae Radix), and Buguzhi (Fructus psoralae) (W. K. Ma et al., 2011). Cao, Yin, and Yang (2012) reported that curcumin could induce apoptosis of drug-resistant hepatocellular carcinoma Bel7402/5-FU cell line and showed favorable reversing effects on MDR of the hepatocellular carcinoma cells. Methyl thiazolyl tetrazolium assay showed that the differences in the inhibition ratio of Bel7402/5-FU cells by curcumin, 5-fluorouracil, and curcumin plus 5-fluorouracil were statistically significant. Curcumin could be a potential treatment for reversing MDR in hepatocellular carcinoma. It has also showed similar effects for other cancers, such as gastric cancer, lung cancer, and leukemia (Cao et al., 2012). Clinically, granules made from Zhebeimu (Fritillaria thunbergii) have been used in the treatment of drug-resistant refractory acute leukemia. Y.  Zhang et  al. (2006) reported that in a randomized controlled clinical study of 126 patients, the complete response and effectiveness rate of the 65 cases treated with compound Zhebeimu granules plus chemotherapy were 40% and 72.3% versus 24.6% and 52.5% in the control group of 61 cases treated with chemotherapy alone (p < 0.05).

Radiotherapy and Chinese Medicine Radiotherapy is a localized treatment used in 60% to 70% of cancer patients for such malignancies as nasopharyngeal cancer, pharyngeal cancer, lung cancer,

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esophageal cancer, cervical cancer, and lymphoma. It is also used as adjunctive treatment for other cancers. Systemically radiation side effects cause disruption of gastrointestinal functions, anemia, and bone marrow suppression, and locally radiation causes inflammation and fibrosis. The main roles of CM treatment for patients undergoing radiotherapy are to enhance the anticancer effects of radiation, reduce its side effects, restore general health, prevent relapse and metastasis, and treat complications. According to CM syndrome diagnosis, the radiation side effects are considered as “toxic fire,” which causes inflammation and Spleen (digestion functions) and blood deficiency. The corresponding CM treatment principle is to cool the heat and nourish the blood and Spleen. This treatment can also sensitize the cancer cells to the radiation. E. X. Yu et al. (1992) used a modified Sijunzi Decoction to sensitize hepatocellular carcinoma, which is generally not sensitive to radiation therapy. This formula was combined with radiotherapy in treating 228 cases of mid-stage hepatocellular carcinoma. The 5-year survival rate was 43%, and the median survival time was 53.4 months. In comparison, the 5-year survival rate for stand-alone radiotherapy was 14.5%, and the median survival was 11.1 months (P < 0.01). Symptomatically, the CM-treated group exhibited fewer side effects and better appetite, and some patients even gained body weight (E. X. Yu et al., 1992). Yuen et al. (2006) reported that in a controlled study of radiotherapy for nasopharyngeal cancer where 28 cases were treated with modified Qingyin Decoction combined with radiation and 26 cases with radiation alone. They found that although there was no effect on the primary tumor, metastatic lymph nodes responded better in the treatment group (p < 0.05). The compliance of the CM treated group was 96.4% versus 76.9% of the radiation alone group (p  0.5), but the radiation alone group was significantly worse (p < 0.05). The study showed that Qingyin decoction could not only improve the radiation efficacy but also reduce radiative side effects and complications (Yuen et al., 2006). Nasopharyngeal carcinoma patients treated by radiotherapy combined with CM formulas that “promote blood circulation and remove stasis (PBCRS)” required smaller doses of radiation than the control group. PBCRS treatment can improve the aerobic condition of the cancer and increase its sensitivity to radiation therapy. When the same dose of radiation was given, combined with CM, the cancer elimination rate was markedly higher than using radiotherapy alone (D. Z. Zhang, 1992).

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B. Y. Liang (2006) reported a controlled study of using an antifibrosis CM formula to prevent radiation complications in 148 cases of lung cancer. Seventy cases were in the radiation plus CM group and 78 received radiation alone. Both groups received the same radiation regimen. At the end of radiotherapy, the rates of radiation pneumonitis and radiation-induced lung fibrosis in CM treated group were 29.4% and 8.5%, versus 38.4% and 12.8% in control group (p  < 0.05). This study showed that CM antifibrosis formula has preventive effects on radiation injuries to the lung (B. Y. Liang, 2006). Y. Han (2005) reported a clinical study of CM “Spleen- invigorating and Kidney- reinforcing” herbal treatments for preventing blood toxic effects of radiation treatment for breast cancer. Sixty postsurgery breast cancer patients were divided into two groups: 30 in CM plus radiation group and other 30 in WM medicine plus radiation group. Both received the same radiation regimen, and the CM group used Ba Zheng Tang and Er Zhi Wan, whereas the WM treatment group took Leucogen and Batilol. The treatment course was 4 weeks. The protective effects of CM on blood toxicities were much better than the conventional medications (p < 0.01) (Y. Han, 2005). The Beijing Sino-Japan Friendship Hospital reported that when “constitution-supportive, heat-clearing, and toxin-resolving” herbs were combined with radiation for lung cancer the effectiveness rate was 70% versus 41% in a radiotherapy alone group (P < 0.05). In addition, adverse reactions to radiation were greatly reduced (D. Z. Zhang et al., 1998). In the radiation therapy of cervical cancer, combining CM fumigation and washing formula Xunxi No.1 as localized treatment lowered the HPV positive rate after the radiotherapy. The 5-year tumor-free survival rate was superior to that of the radiation only group. The pelvic lymph node metastasis rate was also significantly lower. The comparison of clinical outcome between the two groups was shown in Table 18.5.

Table 18.5.  Comparison of CM+Radiation and Radiation Alone in the Treatment of Cervical Cancer Group

N

3 Years Survival

5 Years survival

5 Years Pelvic Metastasis

CM+radiation

40

33 (82.5%)

26 (65%)

3 (7.5%)

Radiation alone

40

27 (67.5%)

17 (42.5%)

10 (25%)

χ2

2.400

4.073

3.860

p

>0.05