Lung Cancer [2 ed.] 9781935864103

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SECOND EDITION SITE-SPECIFIC CANCER SERIES

Lung Cancer Edited by Nancy G. Houlihan, RN, MA, AOCN , and Leslie B. Tyson, MS, APRN, BC, OCN® ®

Oncology Nursing Society Pittsburgh, Pennsylvania

ONS Publications Department Executive Director, Professional Practice and Programs: Elizabeth M. Wertz Evans, RN, MPM, CPHQ, CPHIMS, FACMPE Publisher and Director of Publications: Barbara Sigler, RN, MNEd Managing Editor: Lisa M. George, BA Technical Content Editor: Angela D. Klimaszewski, RN, MSN Staff Editor II: Amy Nicoletti, BA Copy Editor: Laura Pinchot, BA Graphic Designer: Dany Sjoen Copyright © 2012 by the Oncology Nursing Society. All rights reserved. No part of the material protected by this copyright may be reproduced or utilized in any form, electronic or mechanical, including photocopying, recording, or by an information storage and retrieval system, without written permission from the copyright owner. For information, write to the Oncology Nursing Society, 125 Enterprise Drive, Pittsburgh, PA 15275-1214, or visit www.ons.org/publications. Library of Congress Cataloging-in-Publication Data Lung cancer / edited by Nancy G. Houlihan and Leslie B. Tyson. -- 2nd ed. p. ; cm. -- (Site-specific cancer series) Includes bibliographical references and index. ISBN 978-1-935864-10-3 (alk. paper) I. Houlihan, Nancy G. II. Tyson, Leslie B. III. Oncology Nursing Society. IV. Series: Site-specific cancer series. [DNLM: 1. Lung Neoplasms--nursing. WY 156] LC-classification not assigned 616.99’424--dc23 2011029072

Publisher’s Note This book is published by the Oncology Nursing Society (ONS). ONS neither represents nor guarantees that the practices described herein will, if followed, ensure safe and effective patient care. The recommendations contained in this book reflect ONS’s judgment regarding the state of general knowledge and practice in the field as of the date of publication. The recommendations may not be appropriate for use in all circumstances. Those who use this book should make their own determinations regarding specific safe and appropriate patient-care practices, taking into account the personnel, equipment, and practices available at the hospital or other facility at which they are located. The editors and publisher cannot be held responsible for any liability incurred as a consequence from the use or application of any of the contents of this book. Figures and tables are used as examples only. They are not meant to be all-inclusive, nor do they represent endorsement of any particular institution by ONS. Mention of specific products and opinions related to those products do not indicate or imply endorsement by ONS. Web sites mentioned are provided for information only; the hosts are responsible for their own content and availability. Unless otherwise indicated, dollar amounts reflect U.S. dollars. ONS publications are originally published in English. Publishers wishing to translate ONS publications must contact ONS about licensing arrangements. ONS publications cannot be translated without obtaining written permission from ONS. (Individual tables and figures that are reprinted or adapted require additional permission from the original source.) Because translations from English may not always be accurate or precise, ONS disclaims any responsibility for inaccuracies in words or meaning that may occur as a result of the translation. Readers relying on precise information should check the original English version. Printed in the United States of America

Oncology Nursing Society Integrity • Innovation • Stewardship • Advocacy • Excellence • Inclusiveness

Contributors

Editors Nancy G. Houlihan, RN, MA, AOCN® Nurse Leader Memorial Sloan-Kettering Cancer Center New York, New York Chapter 1. Overview

Leslie B. Tyson, MS, APRN, BC, OCN® Nurse Practitioner Thoracic Oncology Service Memorial Sloan-Kettering Cancer Center New York, New York Chapter 5. Clinical Presentation and Diagnostic Evaluation; Chapter 7. Paraneoplastic Syndromes; Chapter 9. Non-Small Cell Lung Cancer

Authors Lynn A. Adams, RN, MS, ANP-BC, AOCN® Nurse Practitioner, Coordinator Memorial Sloan-Kettering Regional Network Commack, New York Chapter 8. Small Cell Lung Cancer

Wendye M. DiSalvo, DNP, NP-C, AOCN® Senior Clinical Oncology Coordinator Genentech Lebanon, New Hampshire Chapter 4. Tobacco Control

Christine D. Berg, MD Chief, Early Detection Research Group Division of Cancer Prevention National Cancer Institute National Institutes of Health U.S. Department of Health and Human Services Bethesda, Maryland Chapter 3. Prevention and Control

Pamela K. Ginex, EdD, RN, OCN® Assistant Professor Lehman College City University of New York New York, New York Nurse Researcher Memorial Sloan-Kettering Cancer Center New York, New York Chapter 6. Oncologic Urgencies and Emergencies; Chapter 7. Paraneoplastic Syndromes; Chapter 9. NonSmall Cell Lung Cancer

Jayne M. Camporeale, MS, OCN®, ANP Assistant Clinical Professor Radiation Oncology University of North Carolina Hospitals Chapel Hill, North Carolina Chapter 10. Symptom Management

Margaret Joyce, PhD, RN, AOCN®, APRN-BC Assistant Professor School of Nursing University of Medicine and Dentistry of New Jersey Newark, New Jersey Chapter 10. Symptom Management iii

LUNG CANCER, SECOND EDITION

Anne Martin, PhD, LCSW Clinical Supervisor/Program Manager Department of Social Work Memorial Sloan-Kettering Cancer Center New York, New York Chapter 11. Psychosocial Concerns

Diane E. Paolilli, RN, MSN, AOCN® Nurse Leader Memorial Sloan-Kettering Cancer Center New York, New York Chapter 1. Overview Judith J. Smith, MSN, RN, AOCN® Nurse Consultant Lung and Upper Aerodigestive Cancer Research Group Division of Cancer Prevention National Cancer Institute National Institutes of Health U.S. Department of Health and Human Services Bethesda, Maryland Chapter 3. Prevention and Control

Susan Martin, RN, DNSc, AOCN® Senior Oncology Clinical Coordinator Genentech BioOncology Long Beach, New York Chapter 2. Biology of Lung Cancer Tamsin J. Mulrooney, FNP, PhD Clinical Trainer Genentech BioOncology Benicia, California Chapter 2. Biology of Lung Cancer

Disclosure Editors and authors of books and guidelines provided by the Oncology Nursing Society are expected to disclose to the readers any significant financial interest or other relationships with the manufacturer(s) of any commercial products. A vested interest may be considered to exist if a contributor is affiliated with or has a financial interest in commercial organizations that may have a direct or indirect interest in the subject matter. A “financial interest” may include, but is not limited to, being a shareholder in the organization; being an employee of the commercial organization; serving on an organization’s speakers bureau; or receiving research from the organization. An “affiliation” may be holding a position on an advisory board or some other role of benefit to the commercial organization. Vested interest statements appear in the front matter for each publication. Contributors are expected to disclose any unlabeled or investigational use of products discussed in their content. This information is acknowledged solely for the information of the readers. The contributors provided the following disclosure and vested interest information: Leslie B. Tyson, MS, APRN, BC, OCN®: Pfizer, consultant; Oncology Nursing Society, honoraria Lynn A. Adams, RN, MS, ANP-BC, AOCN®: Letters & Sciences, honoraria Wendye M. DiSalvo, DNP, NP-C, AOCN®: Genentech, employment and stock ownership

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Contents

Preface......................................................................................... vii

Summary................................................................................. 55 References.............................................................................. 55

Chapter 1. Overview.................................................................... 1 Introduction.............................................................................. 1 Histologic Classification........................................................... 2 Staging of Lung Cancer ........................................................... 3 Prognostic Factors..................................................................... 3 Pathogenesis ............................................................................ 3 Summary................................................................................... 4 References................................................................................ 4

Chapter 6. Oncologic Urgencies and Emergencies................. 59 Introduction............................................................................ 59 Superior Vena Cava Syndrome............................................... 59 Pericardial Effusion and Cardiac Tamponade......................... 61 Pleural Effusion...................................................................... 63 Malignant Spinal Cord Compression..................................... 65 Summary................................................................................. 67 References.............................................................................. 68

Chapter 2. Biology of Lung Cancer............................................ 5 Introduction.............................................................................. 5 Normal Cellular Behavior........................................................ 5 Malignant Cellular Behavior.................................................... 7 Molecular Pathogenesis of Lung Cancer................................ 10 Specific Abnormalities Found in Lung Cancer....................... 12 Summary................................................................................. 18 References.............................................................................. 18

Chapter 7. Paraneoplastic Syndromes..................................... 71 Introduction............................................................................ 71 Endocrine Paraneoplastic Syndromes.................................... 71 Paraneoplastic Neurologic Disorders..................................... 76 Hematologic: Trousseau Syndrome........................................ 78 Musculoskeletal: Clubbing and Hypertrophic Pulmonary Osteoarthropathy............................................................... 81 Summary................................................................................. 83 References.............................................................................. 83

Chapter 3. Prevention and Control.......................................... 21 Introduction............................................................................ 21 Lung Cancer Risk Factors....................................................... 21 Lung Cancer Prevention Strategies......................................... 26 Lung Cancer Screening.......................................................... 28 Summary ................................................................................ 31 References.............................................................................. 32

Chapter 8. Small Cell Lung Cancer......................................... 87 Introduction............................................................................ 87 Molecular and Genetic Characteristics................................... 88 Staging.................................................................................... 89 Treatment ............................................................................... 90 Recurrent Disease .................................................................. 94 Older Patients ........................................................................ 95 Future Directions.................................................................... 96 Summary................................................................................. 96 References.............................................................................. 96

Chapter 4. Tobacco Control...................................................... 37 Introduction............................................................................ 37 History.................................................................................... 37 Nursing................................................................................... 38 Tobacco Dependence.............................................................. 39 Pathophysiology of Nicotine Addiction.................................. 39 Tobacco Dependence Treatment ............................................ 40 Summary................................................................................. 44 References.............................................................................. 44

Chapter 9. Non-Small Cell Lung Cancer................................. 99 Introduction............................................................................ 99 Presentation of Non-Small Cell Lung Cancer........................ 99 Histologic Subtypes.............................................................. 100 Staging.................................................................................. 101 Treatment.............................................................................. 101 Performance Status............................................................... 122 Summary............................................................................... 122 References............................................................................ 122

Chapter 5. Clinical Presentation and Diagnostic Evaluation................................................................................ 47 Introduction............................................................................ 47 Clinical Presentation............................................................... 47 Diagnostic Tests...................................................................... 50 v

LUNG CANCER, SECOND EDITION

Chapter 10. Symptom Management....................................... 131 Introduction.......................................................................... 131 Cough................................................................................... 131 Hemoptysis........................................................................... 133 Dyspnea................................................................................ 135 Fatigue.................................................................................. 139 Pain....................................................................................... 142 Specific Treatment-Related Side Effects: Radiation Pneumonitis..................................................................... 144 Summary............................................................................... 147 References............................................................................ 147

Chapter 11. Psychosocial Concerns........................................ 153 Introduction.......................................................................... 153 Aging and Illness.................................................................. 153 Psychological and Social Issues of the Older Patient With Lung Cancer.................................................................... 153 Treatment Interventions........................................................ 155 Caregiver Issues.................................................................... 155 Summary............................................................................... 157 References............................................................................ 157 Index.......................................................................................... 161

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Preface

The revision of this book chronicles the incredible changes that have occurred in lung cancer in just five years. Evidence now suggests that computed tomography screening in high-risk individuals can improve survival, and for the first time, we have hope for earlier diagnosis. Advances in diagnostic testing with positron-emission tomography have improved staging, leading to more individualized plans of care. Minimally invasive surgeries and enhanced radiation techniques can preserve normal lung tissue while achieving optimal outcomes. Molecular strategies are now part of a standard treatment approach and are under evaluation for prognostic and predictive applications. Finally, a new international staging system that incorporates clinical, pathologic, and molecular parameters has been launched and will serve as a foundation for future research in lung cancer. Each chapter of this book has been updated to incorporate these and other changes in lung cancer prevention, detection, and overall management. One can only wonder what will happen in the next five years, as lung cancer genome sequencing provides us with an even greater understanding of this complex disease.

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CHAPTER 1

Overview Nancy G. Houlihan, RN, MA, AOCN®, and Diane E. Paolilli, RN, MSN, AOCN®

Introduction

Lung cancer was thought to be a disease of older men until the last half of the 20th century, when incidence in women rose sharply. Women now represent almost half of all new cases, with 2011 estimates of 115,060 for men versus 106,070 for women (Siegel et al., 2011). In addition, lung cancer surpassed breast cancer in 1987 as the leading cause of cancer-related deaths in women and currently accounts for more deaths than breast and all gynecologic cancers (e.g., ovarian, vulvar, vaginal, uterine) combined, as well as breast and colorectal cancer, the other leading causes of death, combined. Lung cancer is expected to account for 26% of all female cancer deaths in 2011 (Siegel et al., 2011) (see Table 1-1). Most lung cancers are attributed to tobacco exposure. At least 79% of lung cancer cases in women are related to smoking. Although smoking rates have declined since the 1960s, the current prevalence of smoking among U.S. women is still high—estimated at 22%—and mortality from lung cancer in women rose 600% from 1930 to 1997 as a result of smoking prevalence (U.S. Department of Health and Human Services, 2001). Whether the association between smoking and lung cancer is stronger for women than men is unclear. Many epidemiologic studies have provided evidence that women are more susceptible than men to the adverse effects of

Lung cancer is one of the most commonly occurring cancers in the United States, with an estimated 221,130 new cases developing in 2011. Cancers of the breast and prostate occur slightly more frequently, with estimates of 232,620 and 240,890 cases, respectively. Lung cancer is associated with the highest cancer-related mortality, with an estimated 156,940 deaths occurring in 2011. This far outweighs deaths from breast (39,970) and prostate (33,720) cancers (Siegel, Ward, Brawley, & Jemal, 2011). The five-year survival for lung cancer is approximately 15%. Treatment of early-stage disease can produce cures, with the five-year survival for treated stage I lung cancers as high as 70%. Unfortunately, less than 15% of lung cancers are localized at the time of diagnosis. Most lung cancers are diagnosed in advanced stages, and five-year survival in patients with locally advanced and metastatic disease is less than 10% (Siegel et al., 2011). Late diagnosis is attributed to multiple factors. Until recently, there has not been a proven method for screening or early detection in high-risk individuals, and no guidelines currently exist. Although most patients present with symptoms, symptoms such as cough and exertional dyspnea often are subtle and attributed to chronic symptoms of smoking. These topics will be explored further in this publication. According to data from the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program (2010), the age-adjusted rate for lung cancer for all race and sex groups combined has risen sharply since 1950. From 1969 to 1991, the overall incidence almost doubled, with rates diminishing over the last decade. Lung cancer rates for African American and White men peaked and began to decrease around 1984. Although incidence for women of both races continues to rise, the overall incidence rate for the general public is decreasing. The lag in this trend is attributed to the historical difference in cigarette smoking between men and women, which peaked in women 20 years later than in men (Siegel et al., 2011).

Table 1-1. Estimated Leading Cancer Incidence and Mortality by Sex, 2011 Sex

Cancer Type

Male

Female

Incidence

Mortality

Prostate

29%

11%

Lung

14%

28%

Colorectal

9%

8%

Breast

28%

15%

Lung

14%

26%

Colorectal

10%

9%

Note. Based on information from Siegel et al., 2011.

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tobacco smoke as a result of molecular influences, hormones, and genetics (O’Keefe & Patel, 2008). These findings will be discussed in Chapter 3. The magnitude of the effect of smoking on lung cancer risk may not differ between the genders, but smoking appears to have an impact on the type of lung cancer that develops in each gender. Female smokers have a greater risk of developing small cell lung cancer than male smokers. Also, women are more likely than men to develop adenocarcinoma, and the bronchoalveolar carcinoma subtype of adenocarcinoma is two to four times more common in women (Patel, 2005). The inclusion of women in lung cancer screening and treatment trials has not been adequate in the past. Active recruitment of women for trials with specific reference to gender is needed to investigate this phenomenon further. African American men experience higher lung cancer incidence and mortality rates than all other male racial groupings, including Whites, Asian Americans/Pacific Islanders, American Indians/Alaska Natives, and Hispanics/ Latinos. Incidence and death rates are similar between White and African American women with significantly lower incidence and mortality in the other female ethnic groups (Siegel et al., 2011).

Table 1-2. Histologic Groups of Lung Cancers Category

Histologic Groups

Non-small cell lung cancer

Adenocarcinoma Large cell carcinoma Squamous cell carcinoma

Small cell lung cancer

Combined small cell carcinoma

Sarcomatoid carcinoma Carcinoid Note. Based on information from Franklin et al., 2010; Travis et al., 2004.

be related to changes in tobacco use (Govindan et al., 2006). SCC can be detected by cytologic examination of exfoliated cells in its earliest form, carcinoma in situ, where stratified squamous epithelium is replaced with malignant squamous cells. Unchecked, the tumor eventually invades and obstructs the bronchial lumen. SCC tends to be slow growing and can take years to develop from a carcinoma in situ to a clinically evident tumor (Franklin et al., 2010). Adenocarcinoma is the most common form of lung cancer in North America, accounting for almost 40% of all lung cancers (Franklin et al., 2010). It presents as a peripheral tumor, arising from the alveolar surface epithelium or the bronchial mucosal glands. Tumors also can arise from areas of previous infections or scars. Adenocarcinoma tumors are mucin producing and form glands. Other than very early stage tumors, adenocarcinoma appears to have a worse prognosis than SCC. Bronchoalveolar carcinoma is a subclassification of adenocarcinoma that appears to have distinct clinical and pathologic properties (Franklin et al., 2010). Bronchoalveolar carcinoma and its properties will be described more extensively later in this book. Large cell lung carcinoma is the least common of all NSCLC tumors, representing about 10% of all lung tumors (Franklin et al., 2010). As diagnostic techniques have improved, tumors originally thought to be large cell lung carcinomas have been more appropriately diagnosed as poorly differentiated adenocarcinomas or SCCs.

Histologic Classification The World Health Organization (WHO) classification of lung cancer includes four major histologic types: squamous cell carcinoma, adenocarcinoma, small cell lung carcinoma, and large cell carcinoma (Travis, Brambilla, Müller-Hermelink, & Harris, 2004). These classes are further subdivided, and other less common lung tumors also exist, such as sarcomatoid carcinoma and carcinoid. For clinical purposes, the histologic classes are grouped into two main categories of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC includes a category called combined small cell carcinoma. NSCLC includes squamous cell carcinoma (SCC), large cell carcinoma, and adenocarcinoma (Franklin, Noguchi, & Gonzalez, 2010) (see Table 1-2).

Non-Small Cell Lung Cancer

Small Cell Lung Cancer

Approximately 75%–80% of all lung cancers in the United States are NSCLCs (Franklin et al., 2010). Although the subtypes may differ in incidence according to sex, race, and age, they are grouped because of similarities in course and response to treatment. SCC arises most frequently in the proximal segmental bronchi and is associated with squamous metaplasia. Tumors are composed of sheets of epithelial cells, which may be poorly or well differentiated. At one time, SCC was the most frequently occurring lung cancer in North America, but its incidence is decreasing and has been surpassed by adenocarcinoma for reasons that are thought to

SCLC is less common than NSCLC, representing about 13% of all lung cancer cases per year in the United States (Govindan et al., 2006). A slow decline has occurred over the past 30 years as a result of changing patterns in cigarette smoking. The WHO classification of SCLC includes a variant known as combined small cell carcinoma, which is defined as a small cell carcinoma with a component of any histologic subtype of NSCLC. SCLC is a neuroendocrine tumor that routinely occurs in the central airways. Among the subtypes of lung cancer, the highest association between the extent of 2

CHAPTER 1. OVERVIEW

tobacco exposure and risk occurs in SCLC and SCC (Franklin et al., 2010). Although SCLC officially is staged according to the International System for Staging Lung Cancer, a more common clinical staging introduced by the Veterans Administration Lung Cancer Study Group generally is used. SCLC is staged as either limited or extensive disease. Nearly one-third of patients present with limited-stage disease, which is defined as disease that is confined to one hemithorax, without pericardial or pleural effusion, and encompassed in a single radiotherapy port. Extensive is the term applied to all other presentations of the disease. SCLC is an aggressive disease, and limited-stage disease is more curable than extensive-stage disease. Prior to the use of chemotherapy, patients diagnosed with limited-stage disease survived about three months. Survival rates have improved modestly but significantly with current therapies. Median survival with chemotherapy is 10–14 months with a five-year survival of 10% (Huang, Shepherd, & Kelly, 2010). SCLC exhibits a high degree of neuroendocrine differentiation with expression of a wide variety of neuropeptides and neuropeptide receptors. Several of these neuropeptides have mitogenic potential and have been shown to be mediators of SCLC proliferation.

and provide precise anatomic definitions for all lymph node stations, now grouped as zones. Implementation of the IASLC lymph node map is intended to provide the basis for research and to resolve the controversies related to nodal status that currently affect patient care and clinical trials (Edge et al., 2010; Rusch et al., 2009).

Prognostic Factors Clinical stage is the most important prognostic indicator for lung cancer survival. The size and location of the tumor at the time of diagnosis is tied directly to the ability to achieve cure. Other factors have been known to affect survival. Male gender and age older than 60 years have been found to adversely affect survival. Numerous studies have shown that women generally survive longer than men (Patel, 2005). Tumor expression of mucin, seen in adenocarcinoma, has been identified as an adverse factor in early-stage disease because mucin may facilitate formation of metastases. In those with advanced stages at diagnosis, poor performance status, weight loss, and elevated serum lactate dehydrogenase have been associated with poor outcomes (Wozniak & Gadgeel, 2010). Advances in molecular testing have produced a variety of novel and potentially useful prognostic factors. The connection between activated oncogenes and loss of tumor suppressor gene function offers targets for determining prognostic outcomes. These targets include the significance of the presence of epidermal growth factor receptors on lung cancer cells, neuroendocrine markers, blood group antigens, and genetic markers such as K-ras mutations, TP53 mutations, bcl-2 expression, Fas expression, and angiogenic indicators, to name a few (Miller, 2008).

Staging of Lung Cancer Staging is a major indicator of prognosis and treatment for lung cancer. The purpose of clinical stage classification is to facilitate the accurate, concise description of the extent of disease in a way that can be communicated and replicated (the tumor, node, metastasis [TNM] classification) and to facilitate comparison of differing therapeutic approaches by combining patients with certain common attributes (TNM subsets) into groups or stages with generally similar prognoses and treatment options. Four stages of lung cancer have been identified depending on the presentation at diagnosis, and treatment is prescribed accordingly. The primary tumor is subdivided into four categories (T1–T4) and reflects size, site, and local involvement. Lymph node spread is subdivided into bronchopulmonary (N1), ipsilateral mediastinal (N2), and contralateral or supraclavicular disease (N3). Metastatic spread is either absent (M0) or present (M1) (Edge et al., 2010; Rusch et al., 2009). The American Joint Committee on Cancer and the International Union Against Cancer adopted the International System for Staging Lung Cancer in 1986 as a means of unifying variations in definitions and providing consistent meaning and interpretation among clinicians and scientists throughout the world. The system was revised in 1996 to improve the rules for TNM subsets and incorporate a new schema for regional lymph node mapping. In 2009, the International Association for the Study of Lung Cancer (IASLC) proposed revisions to the lymph node maps to reconcile differences in nomenclature

Pathogenesis Lung cancer arises from malignant changes to the epithelial cells in the lung. As a protective layer, the epithelium is continually damaged, shed, and replaced. Cellular abnormalities occur as the epithelium is chronically exposed to irritating inhaled substances. Exposure of the cell results in various combined genetic mutations that contribute to malignant transformation, taking a normal cell through the morphologic evolution of hyperplasia; metaplasia; mild, moderate, and severe dysplasia; carcinoma in situ; and invasive carcinoma (Schottenfeld, 2010). It is not known whether all epithelial cells are susceptible to malignant transformation or only a subset of cells. Lung cancer is a heterogeneous disease, and its cause reflects changes in cells with potential for differentiation (squamous versus adenomatous) and molecular changes. Multiple oncogenes, tumor suppressor genes, signaling pathways, and other cellular processes contribute to lung cancer pathogenesis (Larsen, Spinola, 3

LUNG CANCER, SECOND EDITION

Gazdar, & Minna, 2010). In addition, an inherited variability in genes that activate and detoxify carcinogens may contribute to a genetic susceptibility to developing lung cancer (Amos & Bailey-Wilson, 2010). The biologic influences on lung cancer development are discussed throughout this book. Chapter 2 describes in greater detail the molecular mechanisms of lung cancer. The chapters on each major cell type include discussion of the specific genetic mutations involved in their pathogenesis and the related treatment targets.

Huang, C.H., Shepherd, F.A., & Kelly, K. (2010). Chemotherapy for small cell lung cancer. In H.I. Pass, D.P. Carbone, D.H. Johnson, J.D. Minna, G.V. Scagliotti, & A.T. Turrisi III (Eds.), Principles and practice of lung cancer (4th ed., pp. 847–866). Philadelphia, PA: Lippincott Williams & Wilkins. Larsen, J.E., Spinola, M., Gazdar, A.F., & Minna, J.D. (2010). An overview of the molecular biology of lung cancer. In H.I. Pass, D.P. Carbone, D.H. Johnson, J.D. Minna, G.V. Scagliotti, & A.T. Turrisi III (Eds.), Principles and practice of lung cancer (4th ed., pp. 60–73). Philadelphia, PA: Lippincott Williams & Wilkins. Miller, V.A. (2008). EGFR mutations and EGFR tyrosine kinase inhibition in non-small cell lung cancer. Seminars in Oncology Nursing, 24, 27–33. doi:10.1016/j.soncn.2007.11.009 National Cancer Institute Surveillance, Epidemiology, and End Results Program. (2010). Incidence: Lung and bronchus cancer. Retrieved from http://www.seer.cancer.gov/statfacts/html/lungb. html O’Keefe, P., & Patel, J. (2008). Women and lung cancer. Seminars in Oncology Nursing, 24, 3–8. doi:10.1016/j.soncn.2007 .11.014 Patel, J.D. (2005). Lung cancer in women. Journal of Clinical Oncology, 23, 3212–3218. doi:10.1200/JCO.2005.11.486 Rusch, V.W., Asamura, H., Watanabe, M.D., Giroux, D.J., RamiPorta, R., Goldstraw, P., & Members of the IASLC Staging Committee. (2009). The IASLC Lung Cancer Staging Project: A proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. Journal of Thoracic Oncology, 4, 568–577. doi:10.1097/ JTO.0b013e3181a0d82e Schottenfeld, D. (2010). The etiology and epidemiology of lung cancer. In H.I. Pass, D.P. Carbone, D.H. Johnson, J.D. Minna, G.V. Scagliotti, & A.T. Turrisi III (Eds.), Principles and practice of lung cancer (4th ed., pp. 1–22). Philadelphia, PA: Lippincott Williams & Wilkins. Siegel, R., Ward, E., Brawley, O., & Jemal, A. (2011). Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA: A Cancer Journal for Clinicians, 61, 212–236. doi:10.3322/caac.20121 Travis, W.D., Brambilla, E., Müller-Hermelink, H.K., & Harris, C.C. (Eds.). (2004). World Health Organization classification of tumours: Pathology and genetics of tumours of the lung, pleura, thymus and heart (Vol. 10). Lyon, France: IARC Press. U.S. Department of Health and Human Services. (2001). Women and smoking: A report of the surgeon general. Retrieved from http://www.cdc.gov/tobacco/data_statistics/sgr/2001/index .htm Wozniak, A., & Gadgeel, S.M. (2010). Clinical presentation of nonsmall cell carcinoma of the lung. In H.I. Pass, D.P. Carbone, D.H. Johnson, J.D. Minna, G.V. Scagliotti, & A.T. Turrisi III (Eds.), Principles and practice of lung cancer (4th ed., pp. 327–339). Philadelphia, PA: Lippincott Williams & Wilkins.

Summary As our knowledge of the pathologic and molecular features has evolved, lung cancer can now be thought of as a heterogeneous disease. Identification of specific genetic activity has led to more customized therapeutic interventions that interfere with tumor initiation, progression, and metastasis and can be matched to individual disease presentations and mutational analysis. The following chapter on the lung cancer biology provides an in-depth review of the current genetic properties of lung cancer and a basis for a greater understanding of the evolving direction of treatment.

References Amos, C.I., & Bailey-Wilson, J.E. (2010). Genetic susceptibility to lung cancer. In H.I. Pass, D.P. Carbone, D.H. Johnson, J.D. Minna, G.V. Scagliotti, & A.T. Turrisi III (Eds.), Principles and practice of lung cancer (4th ed., pp. 47–56). Philadelphia, PA: Lippincott Williams & Wilkins. Edge, S.B., Byrd, D.R., Compton, C.C., Fritz, A.G., Greene, F.L., & Trotti, A., III. (Eds.). (2010). AJCC cancer staging manual (7th ed.). New York, NY: Springer. Franklin, W.A., Noguchi, M., & Gonzalez, A. (2010). Molecular and cellular pathology of lung cancer. In H.I. Pass, D.P. Carbone, D.H. Johnson, J.D. Minna, G.V. Scagliotti, & A.T. Turrisi III (Eds.), Principles and practice of lung cancer (4th ed., pp. 287–324). Philadelphia, PA: Lippincott Williams & Wilkins. Govindan, R., Page, N., Morgensztern, D., Read, W., Tierney, R., Vlahiotis, A., … Piccirillo, J. (2006). Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: Analysis of the Surveillence, Epidemiologic, and End Results database. Journal of Clinical Oncology, 24, 4539–4544. doi:10.1200/JCO.2005.04.4859

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CHAPTER 2

Biology of Lung Cancer Susan Martin, RN, DNSc, AOCN®, and Tamsin J. Mulrooney, FNP, PhD

Introduction

encourage cellular proliferation (proto-oncogenes) and those that suppress cellular division (tumor suppressor genes) (Merkle & Loescher, 2005). In addition to growth regulation genes, the dividing cell has the ability to identify mutations in cellular DNA sequencing and then repair the damaged sequence by activation of DNA repair genes. If this damage is unable to be repaired, the cell is destroyed (apoptosis) (Merkle & Loescher, 2005). Numerous regulatory processes must take place to encourage cellular proliferation. The first signaling mechanism is growth factor dependence. Cell division is driven by the presence of tissue-specific survival and growth factors. The epidermal growth factor is an example of a mitogenic or growth factor that, when present, drives proliferation and activation of cell cycle division. In contrast, transforming growth factor-beta (TGF-b) inhibits cell growth (Merkle & Loescher, 2005). Cell proliferation requires cellular anchorage to the extracellular matrix by way of integrins, which are transmembrane proteins responsible for adhesion of the cell to the extracellular matrix or basement membrane. This connection is required to prevent apoptosis. In addition, contact with like cells inhibits both cellular movement and replication; thus, the number of times a cell may divide is restricted. Human cells are limited to approximately 40–70 divisions before they cease division and enter senescence (Blasco & Khan, 2006; Pelengaris & Khan, 2006b). The ability to recruit an oxygen supply and nutrition is vital for cell survival. As cell numbers increase, the requirement for oxygen increases. If the demand for oxygen outgrows the supply, growth is further limited. Lastly, similar to pro-proliferative mitogenic signals that drive cell growth, proapoptotic or programmed cellular death signals are initiated under stress. Sensors monitor the extracellular and intracellular environment to identify conditions for apoptosis. Tumor necrosis factor-alpha (TNF-α), tumor suppressor genes

Cancer has been identified as a genetic disease since the early 1900s. This past decade has especially experienced an explosion of information regarding human genetics and our understanding of the genetic basis of cancer (Pelengaris & Khan, 2006b). With advances in molecular technologies, insight has been gained into the molecular pathology of lung cancer development. This new knowledge has changed the treatment landscape (Fong, Sekido, Gazdar, & Minna, 2003). It is important to understand the molecular variations in lung cancer biology and how these variations affect the development and discovery of early detection techniques, risk assessment, and new therapeutic agents (Fong et al., 2003). The purpose of this chapter is to review specific molecular alterations and carcinogenesis in lung cancer. The first section will focus on the differences between normal and malignant cellular behavior with particular emphasis on the functions that cancer cells possess that normal cells do not. Then the development of lung cancer will be discussed, including the molecular mechanisms that enable a cancer cell to function abnormally: oncogenes, tumor suppressor genes, growth factors and receptors, and intracellular pathways. Finally, biomarkers in lung cancer, as well as common testing methods for evaluating these biomarkers, will be presented.

Normal Cellular Behavior Normally, cellular behavior, especially replication and division, is highly regulated and regimented. Replication takes place under strict conditions, such as when tissue growth or cellular death is needed (Pelengaris & Khan, 2006a). Division is controlled by a balance of two types of genes: those that

The authors would like to acknowledge Nancy G. Houlihan, RN, MA, AOCN®, for her contribution to this chapter that remains unchanged from the first edition of this book.

5

LUNG CANCER, SECOND EDITION

such as tumor protein 53 (known as TP53), and the c-MYC signaling pathway are responsible for initiation of apoptosis (Blasco & Khan, 2006; Hanahan & Weinberg, 2000). An integral component of normal cellular development is the chain of activities that include the cell life cycle and its regulatory mechanisms. In the adult, most cells are quiescent, or resting, in a period called gap 0 (noted as G0 on Figure 2-1), which is external to cell division. The cell cycle is composed of four stages. Gap 1 (G1) is a period of cell growth that includes protein synthesis. Synthesis (S) is where DNA replication of every chromosome occurs. In gap 2 (G2), the cell continues growth and maintenance of genomic stability by repairing damaged DNA and halting the proliferation of damaged cells. Finally, the mitosis phase (M) is where a cell divides into two identical cells (Pelengaris & Khan, 2006b). When activated by mitogens, which are gatekeeper growth factors, resting cells initiate division. The process of activation occurs when mitogens in the extracellular environment attach to correlating receptors on the surface of the cell. Once attached, cytoplasmic protein signaling pathways in the intracellular space, such as the myelocytomatosis oncogene (c-MYC) and the rat sarcoma gene family (RAS), are innervated and signal the nucleus to drive cell replication. The movement through the cell cycle is highly regulated and

dependent on a group of proteins called cyclins as well as cyclin-dependent kinases (CDKs). When paired with their corresponding CDKs, cyclins drive each phase of the cell cycle. The cyclin-CDK complexes phosphorylate, or activate, target proteins, including the retinoblastoma protein (pRB) (Pecorino, 2008). To maintain regulatory balance, two classes of cyclin-dependent kinase inhibitors (CDKIs) negatively regulate cyclin-CDK complexes. As a cell enters early G1, cyclin D, together with its corresponding CDKs, CDKs 4/6, initiates phosphorylation and inactivates the tumor suppressor gene protein pRB. The pRB controls and restricts the point at which a cell commits to DNA replication. The inactivated pRB disassociates from an important S phase gene transcription factor (E2F), thus permitting progression through G1 and preparation for DNA synthesis. A restriction checkpoint late in G1 prevents premature entry into the S phase. In the presence of DNA damage, TGF-b, contact inhibition, decreased proliferate potential, signal pathway stress, or growth factor withdrawal, CDKIs (p27Kip1, p15Ink4b, p16Ink4a, p21Cip1) and the tumor suppressor gene TP53 are activated, which blocks cell progression (Massagué, 2004; Pelengaris & Khan, 2006a). As a cell enters the S phase with continued E2F transcription activity, the cyclin E/CDK2 and cyclin A/CDK2 complexes promote DNA duplication. In the S phase, CDK2 recruits DNA helicases, enzymes that are important in the separation of the DNA helix strands. Furthermore, the recruitment of DNA polymerase initiates synthesis of new DNA strands using the preexisting DNA strands as a template (Pelengaris & Khan, 2006a). After DNA synthesis, a cell enters G2. This phase is the checkpoint period that monitors for DNA mutations and corrects any damage. Similar to G1, the G2 restriction point activates the CDKI, p21, and tumor suppressor gene TP53, thus restricting movement into mitosis in the presence of incomplete DNA replication or double strand breaks (Massagué, 2004). A second G2 checkpoint driven by topoisomerase II is responsible for detangling DNA strands after synthesis (Pecorino, 2008). Cellular division occurs in the M phase. This phase is relatively short, lasting approximately one hour. M phase activity progresses under the direction of promoting cyclin B/CDK1 and cyclin A/CDK1, which are responsible for initiating spindle formation. This phase is characterized by four stages, including prophase, metaphase, anaphase, and telophase. The presence of chromosomes and the formation of mitotic checkpoint proteins occur in prophase. Alignment of chromosomes and assembly of microtubules that form the mitotic spindles occur in the metaphase of cell division. In anaphase, the mitotic spindles and chromatid separate. In the final stage, telophase, chromosomes accumulate at their respective poles, and cytokinesis (separation into two separate cells) occurs (Pecorino, 2008). One last checkpoint occurs in the M phase; the spindle assembly checkpoint ensures

Figure 2-1. Cell Cycle

cdks

cdks

cdks Note. Figure courtesy of Genentech USA BioOncology. Used with permission.

6

CHAPTER 2. BIOLOGY OF LUNG CANCER

for accurate chromosomal separation during mitosis and genetically identical nuclei.

tumor suppressor gene must be altered for the gene function to cease. When one copy is abnormal, the normal copy often can continue to function in the tumor suppressor role. However, sometimes only one mutation can halt tumor suppressor function; this is known as haploinsufficiency. The tumor suppressor function can also cease when one copy of the gene is deleted and the other copy is mutated (Modrek et al., 2009). It is now known that multiple tumor suppressor genes can be inactivated in lung cancer. These include the TP53, RB, and p16 genes (Campling & el-Deiry, 2003). When tumor suppressor genes are inactive, the abnormalities in a cell multiply. This abnormal cell and its daughter cells continue to divide uncontrollably (see Figure 2-2) (Roussel, 2006).

Malignant Cellular Behavior The many mechanisms involved in the life cycle of a cell reveal the overall complexity of cell function. Abnormalities or mutations in oncogenes can result in a gain of function whereby growth signals become hyperactive and lead to malignant cell development, proliferation, and evasion of apoptosis. Loss of function of tumor suppressor genes results in uncontrolled cellular division without a mechanism to halt abnormal growth. The next section of this chapter will review the role of oncogenes, tumor suppressor genes, growth factors, and signaling pathways that allow lung cancer cells to continue to grow, proliferate, evade apoptosis, and metastasize.

The Signaling Process Signaling pathways are important mechanisms in the proliferation, differentiation, and survival of cancer cells. A basic overview of the signaling process is found in Figure 2-3. Growth factors or ligands are found in the extracellular domain of the cell. They bind to the growth factor receptors, which span the cytoplasmic membrane. The growth factor receptors are the protein products of genes found in the nucleus. The binding sites of the growth factor receptors are on the extracellular domains (see Figure 2-3). Once this binding takes place, the receptors are activated and the signaling process can occur. Molecules bind to the activated growth factor receptor in the intracellular domain and transmit signals from the exterior of the cell through many different pathways to the organelles within the cell, including the nucleus and the mitochondria. In the nucleus, the signals cause the induction of transcription factors, which initiate transcription of specific genes (Yarden & Shilo, 2007).

Oncogenes Proto-oncogenes are normal genes that promote growth and development of cells. When proto-oncogenes become dysregulated as a result of cellular damage–causing protein alterations and overexpression, they are known as oncogenes. Only one of two copies of a specific pair of proto-oncogenes found in a cell need a mutation for an oncogene to become activated, dominant, and capable of stimulating tumor development (Pelengaris & Khan, 2006c). Oncogenes can be classified into four subgroups that identify their function and the function of the proteins that they encode: transcription factors, growth factors, receptors, and signal transducers. The oncogenes/oncogene products that play an important role in the development of lung cancer include epidermal growth factor receptor (EGFR), insulin-like growth factor-1 (IGF-1), mesenchymal-epithelial transition factor (c-Met), K-ras, and c-MYC (Poulsen, Poulsen, & Pappot, 2008). These will be reviewed in greater detail later in the chapter. The properties of these oncogenes can be related to an increase in copy number, an overexpression of the protein that is encoded by the oncogene, or from a fusion gene.

Cancer Cell Biology A small number of molecular, biochemical, and cellular alterations are responsible for the transformation of normal human cells into malignant cells. Hanahan and Weinberg (2000) proposed six essential alterations that are noted in most malignant cells (see Figure 2-4): self-sufficiency in growth signaling, insensitivity to growth inhibition signaling, evasion of apoptosis, evasion of senescence, sustainable angiogenesis, and invasion and metastasis. It is hypothesized that these essential alterations are vital in the transformation of lung tissue into cancer (Fong et al., 2003). As previously discussed, quiescent cells are dependent on mitogenic growth factors (proto-oncogenes) to initiate proliferation. Tumor cells have the ability to generate their own growth factor, thus reducing dependence on normal extracellular signaling. Mutated proto-oncogenes (oncogenes) may produce abnormal quantities of growth factor and aberrant signaling. Furthermore, the cell surface growth receptors may be dysregulated, causing overexpression of the receptor and hyperstimulation of cellular signaling pathways.

Tumor Suppressor Genes Of the 30,000 genes found in humans, only 30 have been identified as tumor suppressor genes. Tumor suppressor genes and their products play an important role in ensuring that a cell remains normal before it divides, after monitoring for abnormalities in the G1 and G2 phases of the cell cycle and repairing any DNA damage before proceeding to the next phase (Roussel, 2006). If the damage is irreparable, tumor suppressor genes can induce apoptosis or stop the cell from proliferating. The impact of altered tumor suppressor genes can occur in various permutations. In some situations, both copies of a 7

LUNG CANCER, SECOND EDITION

Figure 2-2. Tumor Suppressor Gene

Note. Figure courtesy of Genentech USA BioOncology. Used with permission.

Mutations in the cell receptor structure can activate growth signaling without the presence of growth factors (Hanahan & Weinberg, 2000). Several growth factors and their respective receptors are abnormally expressed in lung cancer, causing autocrine and paracrine stimulation loops (Fong et al., 2003). The ERBB family of tyrosine kinase growth factor receptors is important in the pathogenesis of non-small cell lung cancer (NSCLC). The EGFR (also sometimes called HER1) and HER2 receptor significantly influence NSCLC pathogenesis. In small cell lung cancer (SCLC), the c-Kit tyrosine kinase receptor signaling pathway is dysregulated and activates an autocrine response mechanism in approximately 70% of tumors (Felip & Baselga, 2005; Krystal, Hines, & Organ, 1996). The process of apoptosis or programmed cell death is crucial to the maintenance of tissue homeostasis. Cancer cells have developed mechanisms to evade apoptosis. The two main pathways for apoptosis are intrinsic (inside the cell) and extrinsic (outside the cell). Death receptors are found on the cell surface and possess extracellular, transmembrane, and intracellular domains. The extrinsic pathway of apoptosis is activated on the outside of the cell where ligands of the TNF family activate the death receptors in the extracellular domain.

Once the death receptors are activated, a series of signals occur to induce apoptosis. Enzymes called initiator caspases (i.e., caspase-2, -8, -9) will cleave and cause effector or executioner caspases (i.e., caspase-3, -6, -7) to induce proteolysis, which is the breakdown of the cell (Viktorsson & Lewensohn, 2007). The intrinsic pathway of apoptosis occurs as a result of changes in the mitochondria of cells. The mitochondrion in a normal state does not have high permeability. Mitochondrial outer membrane permeability (MOMP) is increased when apoptotic signals are present, allowing the mitochondria to release cytochrome-c and other proteins from inside to outside of the mitochondria into the cell. The proteins will activate the caspases necessary for apoptosis to occur. The B cell lymphoma 2 (BCL2) family of proteins is one of the factors that control MOMP. These proteins can both promote (BAK and BAX) and inhibit (BCL-XL and BCL2) apoptosis depending on the ratio found in the cell. This ratio is tightly regulated to allow for a balance in normal cell growth and death. Resistance to apoptosis in cancer may occur due to imbalances in these BCL2 proteins. Loss or mutation of the TP53 tumor suppressor gene can also prevent apoptosis from occurring, as TP53 is also a regulator of MOMP. TP53, when functioning normally, can block antiapoptosis proteins such as 8

CHAPTER 2. BIOLOGY OF LUNG CANCER

Figure 2-3. Disposition of Signaling Elements

Note. Figure courtesy of Genentech USA BioOncology. Used with permission.

BCL2 and stimulate proapoptosis proteins like BAX so that apoptosis can occur. Additionally, IGF-1 activates prosurvival signaling complexes that block the process of apoptosis (Hanahan & Weinberg, 2000). SCLCs have been shown to have a loss of certain caspases as well as a decrease in death receptor expression. This will decrease the ability of these SCLC cells to undergo apoptosis (Viktorsson & Lewensohn, 2007). BCL2, which can prevent apoptosis, is overexpressed in 75%–85% of SCLC (see Figure 2-5) (Fong et al., 2003). Another hallmark of cancer is the potential for limitless cell replication. Mammalian cells carry the capacity to limit intrinsic multiplication programming and the number of cellular divisions (Hanahan & Weinberg, 2000). Normally cells undergo 40–60 cellular division cycles, after which they stop division and enter permanent growth arrest called senescence (Hanahan & Weinberg, 2000; Pecorino, 2008; Pelengaris & Khan, 2006b). The length of the cell’s telomeres may partly regulate the process of senescence. Telomeres are the end portions of chromosomes that protect the chromosome and act as a replication potential counter (Pecorino, 2008). As cells divide, a small portion of the telomere is lost. Once the telomere shortens to a critical level, the cell ceases replication and enters senescence (Pelengaris & Khan, 2006b). The maintenance of telomeric activity is noted in virtually all

malignant cells (Shay & Bacchetti, 1997). In normal cells, telomerase, the enzyme responsible for telomere maintenance, lacks activity. However, upregulation or reactivation of telomerase occurs in more than 90% of tumor cells (Sun, Schiller, Spinola, & Minna, 2007). This activation permits limitless replication capacity. Telomerase activity is noted in preneoplastic cells of the bronchial epithelium and bronchial lavage specimens (Fong et al., 2003; Yashima et al., 1997). Vascular supply is crucial for cell function and survival. Almost all cells need to be within 100 mm of a capillary to survive (Hanahan & Weinberg, 2000). The process of angiogenesis, new blood vessel development, is normally highly regulated, occurring only during periods of tissue repair and regeneration. Vascular endothelial cells provide oxygen and nutrients and may provide growth factor signaling that effects cell survival and growth (Pelengaris & Khan, 2006b). Angiogenesis is a balancing act of more than two dozen pro­ angiogenesis factors and the same amount of antiangiogenesis proteins. Proangiogenic factors, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF1, FGF-2), stimulate vessel production. Other oncogenic signaling pathways, C-MYC and RAS, may be associated with angiogenic activation in response to hypoxia. Conversely, angiogenic suppression signals such as thrombospondin-1 9

LUNG CANCER, SECOND EDITION

receptors mediate cell-to-extracellular matrix interactions and intracellular signaling (Pecorino, 2008). When altered, this receptor enables mobility of tumor cells by modifying the distribution of the integrin receptors on the cell membrane or by binding with proinvasion receptors. Invasion into surrounding tissue requires the activation of specif ic proteases, enzymes that degrade proteins. These proteases corrode through the extracellular matrix and stroma and invade the surrounding tissue. Once this occurs, intravasation, tumor cell penetration into a blood or lymphatic vessel, permits the tumor to migrate to distant sites via the bloodstream either as single cells or in clusters. At the site of metastasis, the cell extravasates from the blood or lymphatic vessel by attaching to the side of the vessel, passing through the basement membrane, and migrating into the stroma (Pecorino, 2008). Metastatic colonization occurs resulting in tumor vascularization and new tumor growth. Reduced expression of invasion-tumor suppressor gene collapsing response mediator protein 1 (known as CRMP1) in lung cancer has been associated with advanced disease, lymphatic metastasis, and invasion (see Figure 2-6) (Fong et al., 2003; Shih et al., 2001).

Figure 2-4. Molecular Basis of Cancer

Mutation inactivates suppressor gene

Benign tumor cells grow only locally and cannot spread by invasion or metastasis

Cells proliferate Mutation inactivates DNA repair genes

Malignant cells invade neighboring tissue, enter blood vessels, and metastasize to different sites

Proto-oncogenes mutate to oncogenes More mutations, more genetic instability, and metastasis

Note. Figure courtesy of Genentech USA BioOncology. Used with permission.

Molecular Pathogenesis of Lung Cancer Greater knowledge of the molecular pathogenesis of lung cancer has evolved with significant impact over the past decade. Lung carcinogenesis is a multistage process of genetic and molecular changes that usually occur over several decades (Hahn & Weinberg, 2002; Wistuba & Gazdar, 2008). Several pathways are associated with the development of NSCLC and SCLC. Generally, lung cancer occurs after specific molecular changes arise in the lung epithelium. The molecular pathogenesis of adenocarcinoma has been identified as having two distinct pathways related to smoking versus nonsmoking history (Wistuba & Gazdar, 2008). In smoking-related adenocarcinoma, aberrations in the short arm (p) of chromosomes 3 and 9 are noted early in the epithelial tissue changes (Qian & Massion, 2008; Wistuba & Gazdar, 2008). Additionally, mutations in DNA repair genes that cause microsatellite instability and inflammatory signaling, specifically signaling cyclooxygenase-2 (COX2), are noted early in the carcinogenic process. Telomerase dysregulation with subsequent inactivation of TP53/ Rb initiates cellular proliferation, which progresses to a preneoplastic atypical adenomatous hyperplasia (AAH). Other molecular dysregulation has been identif ied in AAH including K-ras mutation; loss of heterozygosity in tuberous sclerosis complex (TSC) regions of chromosome 9q TSC1 and 16p TSC2 that may be responsible for tumor suppressor gene activity; loss of STK11 LKB1 responsible for tumor suppressor functioning; and finally, mutations and/or overexpression of TP53, cyclin D1, and survivin,

and integrin suppress blood vessel production (Hanahan & Weinberg, 2000). Abnormal blood vessel growth is noted in tissue where metabolic demand has increased or decreased blood flow. Typically, the metabolic demand is increased and tissue oxygenation is decreased in cancers. This environment is believed to be a primary regulator for angiogenesis (Shima & Ruhrberg, 2006). As solid tumor growth approaches 1–2 mm3, the tumor demands blood vessel growth. Alterations in angiogenesis are noted in lung cancer. Overexpression of specific VEGF subtypes correlates with tumor angiogenesis, postoperative relapse time, and survival (Fong et al., 2003). Part of this dysregulation in lung cancer may be related to the mutation of TP53 tumor suppression functioning. Finally, malignant tissue has the ability to invade and metastasize. The process of metastasis is complex and not well understood. The metastatic process involves several steps including migration, intravasation, transport, extravasation, and colonization (Pecorino, 2008). Normally, cells are bound molecularly to surrounding cells. Several proteins, including the immunoglobulin family of cell adhesion molecules and cadherins, are important mediators of cell-to-cell recognition interaction (Hanahan & Weinberg, 2000; Pecorino, 2008). The E-cadherin gene, under normal functioning, acts as a tumor suppressor to secure cellular adhesion and suppress tumor cell metastasis. Alterations in integrin receptor functioning are required for the cell to break free. Integrin 10

CHAPTER 2. BIOLOGY OF LUNG CANCER

Figure 2-5. Apoptosis

Note. Figure courtesy of Genentech USA BioOncology. Used with permission.

an antiapoptosis protein—all of which play a role in cellular survival. With mounting mutations and cellular dysregulation, bronchoalveolar and invasive carcinoma may ensue (Wistuba & Gazdar, 2008) (see Figure 2-6). Although 80% of lung cancers are smoking related, incidence of adenocarcinoma is rising among never-smokers (Scagliotti, Longo, & Novello, 2009). The mechanism of nonsmoking-related adenocarcinoma pathogenesis is not completely understood; however, mutations in the EGFR in normal epithelium tissue seem to be associated with nonsmoking status (Scagliotti et al., 2009; Sun, Schiller, & Gazdar, 2007; Wistuba & Gazdar, 2008). Furthermore, TP53 mutation is noted less often in nonsmokers (Sun, Schiller, & Gadzar, 2007). Similar to smoking-related adenocarcinoma, molecular abnormalities in the epithelium are noted in squamous cell carcinoma. The lung epithelium undergoes genetic alterations in chromosomes 3 and 9, microsatellite instability occurs,

and COX-2 amplification causes inflammatory signaling. Telomerase dysfunction with associated cellular proliferation ensues with development of hyperplasia followed by activation of the angiogenesis process. Squamous metaplastic and dysplastic changes result that reveal continued genetic aberrations including methylation of tumor suppressor genes p16, RAR-b, H-Cad, and DAPK (Sato, Shames, Gazdar, & Minna, 2007). Further changes are noted with EGFR overexpression and alterations in chromosomes 3, 5, 8, and 13. Finally, inactivation of TP53 is associated with development of invasive carcinoma (Wistuba & Gazdar, 2008). Unlike with NSCLC, premalignant and dysplastic changes are rarely noted in small cell carcinogenesis, suggesting that SCLC develops from histologically normal epithelium. Furthermore, distinct molecular changes, such as autocrine growth signaling, oncogenes, and tumor suppressor genes, are implicated in the pathogenesis of SCLC. Aberrations in chromosome 3, particularly deletions in the short arm, 11

LUNG CANCER, SECOND EDITION

Figure 2-6. Cell Migration and Metastasis

Note. Figure courtesy of Genentech USA BioOncology. Used with permission.

Specific Abnormalities Found in Lung Cancer

are noted in up to 95% of SCLC (Graziano et al., 1991). In comparison to NSCLC, point mutations in the tumor suppressor genes TP53 and RB are noted in greater frequency in SCLC (Sher, Dy, & Adjei, 2008). The pattern of the frequency of protein and signaling pathway overexpression differs as well between NSCLC and SCLC. The signaling pathways in SCLC that activate proliferation, antiapoptosis, angiogenesis, and metastasis include BCL2, c-KIT, and c-MYC (Sekido, Fong, & Minna, 2003; Sher et al., 2008). Furthermore, overexpression of the neuropeptides and polypeptides, gastrinreleasing polypeptides, stem cell factor, and IGF, activates an autocrine growth signaling, as well as upregulation of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (commonly known as AKT1) pathway responsible for apoptosis and chemotherapy resistance (Sher et al., 2008).

Many mechanisms lead to lung cancer development and growth. The next section of this chapter will describe the role of specific oncogenes, tumor suppressor genes, and signaling pathways that lead to survival of tumors.

Oncogene Abnormalities K-ras Ras genes are proto-oncogenes that encode ras proteins. These ras proteins regulate cell survival, motility, differentiation, and proliferation of cells (Aviel-Ronen, Blackhall, Shepherd, & Tsao, 2006). The ras genes and proteins are so named because they were initially identified 12

CHAPTER 2. BIOLOGY OF LUNG CANCER

in rat sarcomas. The three ras genes are H-ras, N-ras, and K-ras. The ras gene of particular importance in lung cancer is the K-ras gene, named for its discoverer, Kirsten (Riely, Marks, & Pao, 2009). Of the ras mutations, K-ras accounts for approximately 90% of those associated with lung cancer. In lung cancer, 97% of the K-ras mutations are found on codons 12 or 13 (Riely et al., 2009). K-ras mutations are found in approximately 10%–30% of adenocarcinomas but are rarely found in SCLC or in NSCLC of squamous histology (Herbst, Heymach, & Lippman, 2008). The signaling process involving K-ras occurs by activation of external receptor tyrosine kinases, such as EGFR and platelet-derived growth factor receptor, that in turn trigger the activation of many ras-dependent signaling pathways in the cell, such as the mitogen-activated protein kinase (MAPK) and PI3K pathways. The transmembrane receptor tyrosine kinases dimerize and become activated. Growth factor receptor-bound protein-2 (GRB2) attaches to the intracellular domain of the receptor tyrosine kinase. GRB2 binds with the son of sevenless homolog 1 (SOS1), which is a ras-specific guanine nucleotide exchange factor. K-ras protein is bound to guanosine diphosphate (GDP) when in an inactive state. SOS1 promotes GDP exchange for guanosine triphosphate (GTP), activating K-ras and various ras-dependent pathways (Molina & Adjei, 2006). Increased numbers of K-ras gene copies have been found in NSCLC tumors with activating mutations, where the ras protein becomes switched on in an active state (i.e., bound to GTP) leading to heightened activation of ras pathways and cell proliferation and survival. Wild-type ras proteins seem to cycle between being active (i.e., bound to GTP) and inactive (i.e., bound to GDP). Therefore, they are not always in an active state (Modrek et al., 2009). K-ras mutations are often associated with earlier phases in lung cancer development. People with cigarette and asbestos exposure tend to have more K-ras mutations; Asians tend to have a lower rate of K-ras mutations compared with Caucasians (Aviel-Ronen et al., 2006). K-ras mutations appear to be negatively associated with EGFR mutations, meaning that mutations in both K-ras and EGFR simultaneously are rare. Research on the association of K-ras with a poor prognosis or prediction of treatment response in lung cancer has been contradictory (Aviel-Ronen et al., 2006). At present, no approved therapy directly targets K-ras, but K-ras remains a target of interest in the research of cancer therapy (Adjei, 2008).

cell functions, such as proliferation and cell adhesion (Kim & Salgia, 2009). Amplification of the c-Met oncogene leads to overexpression of the receptor, and a surplus of the hepatocyte growth factor ligand increases activation of the c-Met receptor. These mechanisms enable uncontrolled cancer cell proliferation and increase cell motility and metastasis. c-Met overexpression has been found in lung cancer in approximately 67% of adenocarcinomas, 60% of carcinoid tumors, 25% of SCLC, 57% of large cell cancers, and 57% of squamous cell carcinomas (Herbst et al., 2008).

Tumor Suppressor Gene Abnormalities The TP53 tumor suppressor gene, located on chromosome 17p, is responsible for controlling intracellular transcription factors. The TP53 gene is often dysregulated in lung cancers by either deletion or mutation (Campling & el-Deiry, 2003). Estimates of TP53 mutations found in lung cancer range from 60%–70% of NSCLC with squamous histology, 50%–70% of adenocarcinomas of the lung, and approximately 75% of SCLC (Herbst et al., 2008). Most TP53 mutations in lung cancer are sporadic and thus not inherited. Normal cells usually have low levels of TP53. However, levels of TP53 will rise in the nucleus if DNA damage caused by stresses on the cell occurs or if oncogenes are hyperactive. In the presence of cellular abnormalities, normally functioning TP53 will either stop the cell cycle and repair damaged DNA to allow the cell cycle to proceed, or it will destroy the cell by activating apoptosis, halting cellular proliferation or preventing angiogenesis. When TP53 levels are low or not functioning properly, the reverse can occur: the cell cycle can continue despite abnormal DNA, apoptosis will not occur, and potentially the process of angiogenesis will be activated. At times the levels of TP53 can be high, but because it is not functioning properly, cancer can continue to develop (Roussel, 2006). Several mechanisms are believed to lead to TP53 inactivity. Missense mutations (when a single nucleotide is changed, creating a codon that codes for an amino acid that is different than what is supposed to occur in the genetic sequence) can inhibit tumor suppressor gene function, resulting in TP53 that does not work properly. MDM2 (mouse double minute 2) is an oncogene that can be overexpressed in lung cancer and can nullify or degrade the function of TP53. The theory is that an abnormality in just one TP53 allele can cease tumor suppressor function (Roussel, 2006). TP53 mutations are associated with smoking in SCLC as well as NSCLC of squamous histology. In adenocarcinomas, the relationship between TP53 mutations is present but not as strong as the aforementioned lung cancer types. It appears that TP53 mutations are associated with a poor prognosis in NSCLC. TP53 mutations are also associated with a poor response to radiation or chemotherapy in NSCLC but not in SCLC (Campling & el-Deiry, 2003).

Mesenchymal Epithelial Transition Factor c-Met is a proto-oncogene located on chromosome 7q21–q31 that encodes for the transmembrane c-Met receptor. As with many transmembrane receptors, c-Met has a ligand (hepatocyte growth factor) that activates the receptor and triggers pathways leading to the nucleus. These particular cellular pathways trigger the regulation of many 13

LUNG CANCER, SECOND EDITION

LKB1 is the kinase product of the gene LKB1 (sometimes called STK11). Through interactions with TP53 and CDC42 (a protein involved with the progression of the cell cycle), LKB1 acts as a tumor suppressor by activating kinase pathways that regulate cell metabolism and homeostasis as well as suppress abnormal growth and proliferation (Marignani, 2005). When there is a loss of function of LKB1, cells can grow uncontrollably in adverse conditions, such as when there is a lack of energy supply. In lung cancer, it is thought that LKB1 has a role in the development of premalignant lesions (Herbst et al., 2008). In one study of 144 NSCLC specimens, LKB1 mutations were found in 34% of adenocarcinomas and 19% of squamous cell carcinomas (Ji et al., 2007). LKB1 mutations in lung cancer are associated with a positive smoking history and with K-ras mutations but are rarely found in SCLC, Asian patients with lung cancer, or in patients with EGFR mutations (Herbst et al., 2008).

High levels of IGF-2 have been found in both SCLC and NSCLC and are associated with a poor prognosis. Overexpression of IGF-1R can be found in both SCLC and NSCLC. A decrease in the amount of IGFBP3 can increase the amount of IGF-1 and IGF-2 ligands and may indirectly increase the risk of lung cancer. This is commonly found in NSCLC (Velcheti & Govindan, 2006). Ras/Raf/MAPK Pathway The Ras/Raf/MAPK pathway is an important signal transduction pathway in normal cells. It is also an important pathway in the growth and progression of lung cancer (Herbst et al., 2008). Amplif ication of the K-ras gene results in hyperactivation of the Ras/Raf/MAPK signaling pathway. The most common transmembrane receptors that are associated with this pathway are EGFR and plateletderived growth factor receptor. Once these receptors are activated, the signaling process can begin. As described earlier, ras is found in the intracellular domain close to the cell membrane. In K-ras mutations, ras is generally found in its active form (GTP-bound as opposed to inactive/GDPbound) and can signal independent of external growth factor receptor activation. Active ras will then activate one of the members of the raf family of kinases—Raf-1, A-Ras, and B-raf. Phosphorylation of raf in turn allows for activation of MAPK (MAPK is sometimes referred to as MEK). When MAPK phosphorylates, it can activate extracellular-regulated kinase-1 and extracellular-regulated kinase-2, which are the next targets in the pathway. From here, the signaling pathway continues, leading to survival and proliferation of the cell. MAPK also allows for crosstalk between multiple signaling pathways (Molina & Adjei, 2006). Research on therapeutic targets for treatment in this pathway is evolving. Strategies for treatment may include inhibiting the expression of the ras protein, blocking signals with other mechanisms that interact with ras, targeting the K-ras oncogene, or inhibiting the targets that are downstream from ras, such as Raf and MAPK (Molina & Adjei, 2006).

Abnormalities in Signaling Pathways Insulin-Like Growth Factor Pathway The IGF pathway can increase cell proliferation and decrease apoptosis. Similar to other pathways, this is a complicated process where ligands activate cell membrane receptors, which in turn activate downstream intracellular signaling pathways to the nucleus. IGF-1 and IGF-2 are ligands produced in the liver and peripheral tissues. The IGF-1 and IGF-2 ligands are regulated by a group of six high-affinity IGF binding proteins (IGFBP1–IGFBP6) and their proteases. IGFBP3 is the most active of these proteins, binding to about 70%–80% of IGF-1 (Dziadziuszko, Camidge, & Hirsch, 2008). Matrix metalloproteinases secreted by tumors can increase the amount of IGFBP3, which can then increase the availability for IGF-1 and IGF-2 to bind with receptors. IGFBP3 on its own can have an antiproliferative and proapoptotic effect on the cell independent of IGF ligand activity (Velcheti & Govindan, 2006). The two main transmembrane receptors in this pathway are insulin-like growth factor receptor-1 (IGF-1R) and insulinlike growth factor receptor-2 (IGF-2R). The IGF-1 ligand binds more readily to the IGF-1R. The IGF-2 ligand binds to a broader range of receptors, increasing the impact on cell processes (Dziadziuszko et al., 2008). IGF-1R, once activated by a ligand, has signal transduction abilities as it activates the PI3K pathway in the intracellular domain. The PI3K pathway promotes cell proliferation and inhibits apoptosis. This pathway will be discussed in greater detail later in this chapter. IGF-2R does not have an active tyrosine kinase domain and thus does not have the ability to start an intracellular signal transduction pathway. Because of the ability of IGF-2R to bind with IGF-2, it can internalize and degrade this ligand, making it less available to bind with other receptors (Velcheti & Govindan, 2006).

Phosphatidylinositol 3-Kinase/Protein Kinase B (PI3K/AKT) The PI3K/AKT signaling pathway is important in cellular survival and proliferation in lung cancer (Blasco & Khan, 2006). These kinase receptors are dysregulated in cancers secondary to mutations and amplifications of the PIK3CA gene location on chromosome 3 (Yamamoto et al., 2008). The PI3K survival mechanism involves the downstream activation of AKT by lipids produced by PI3K that bind to AKT. This allows AKT to target proteins involved in cell death, including members of the BCL2 family and caspase-9, protecting cells from apoptosis (Solomon & Pearson, 2009). This pathway is an important downstream signaling pathway for many cellular mechanisms and is activated early in lung cancer development, specifically in the squamous histology subtype (Herbst et al., 2008) (see Figure 2-7). 14

CHAPTER 2. BIOLOGY OF LUNG CANCER

Epidermal Growth Factor Receptor Pathway EGFR (also known as HER1) is a member of the HER family of receptors that include HER2, HER3, and HER4. These receptors have an extracellular domain, a transmembrane domain, and an intracellular domain. The normal function of the HER family of receptors is to regulate growth and survival of a cell. EGFR has a number of ligands, including epidermal growth factor (EGF), TGF-α, amphiregulin, betacellulin, heparin-binding EGF, and epiregulin (Yarden & Shilo, 2007). HER family receptors bind to other receptors in the HER family to elicit intracellular signaling in a process called dimerization. EGFR, HER3, and HER4 need a ligand to become activated so that dimerization can take place. Binding of an HER family receptor to itself (e.g., EGFR binding to EGFR) is called homodimerization; binding of an HER family member to a different HER family receptor (e.g., EGFR binding to HER2) is called heterodimerization. Within the

HER family of receptors, this creates 10 possible receptordimer combinations. Different dimers recruit signaling molecules of specific pathways that result in specific cellular responses (Yarden & Shilo, 2007). The activation and phosphorylation of the intracellular or tyrosine kinase domain provides docking sites for multiple signaling molecules. Once a dimerized pair is activated, a specific pathway is activated. There is a binding pocket on the intracellular domain of the EGFR receptor, where adenosine triphosphate binds and allows for phosphorylation to occur. These chains of phosphates are the building blocks of the signal transduction pathway. Once the pathway reaches the nucleus of the cell, it allows for transcription of specific genes. The cell then responds with proliferation, differentiation, survival, or death (apoptosis) (Yarden & Shilo, 2007). One of the critical EGFR-dependent signaling pathways is the Ras signaling pathway. A second pathway, involving

Figure 2-7. Signal Transduction Pathways

Note. Figure courtesy of Genentech USA BioOncology. Used with permission.

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PI3K/AKT, is also associated with EGFR signaling. These pathways are important regulators of proliferation and antiapoptotic and prosurvival signals. Note that while EGFR homodimers may signal through the Ras/Raf/MAPK pathway, leading to cell proliferation, EGFR/HER3 heterodimers signal through the PI3K/AKT pathway, leading to the generation of cell survival signals. EGFR mutations cause increased activation of downstream pathways, preferentially activating the antiapoptotic pathways, such as PI3K/AKT, while having less effect on cellular proliferation through the K-ras signaling pathway (Herbst et al., 2008). EGFR is rarely abnormal in SCLC but is often abnormal in NSCLC. Kinase domain mutations are rare in NSCLC of squamous histology but occur in approximately 10%–40% of adenocarcinomas (Herbst et al., 2008). This abnormality is often associated with females, Asians, and nonsmokers. About 80% of these kinase domain mutations occur because of inframe deletions in exon 19 (an exon is a DNA sequence that contains information that is transcribed into messenger RNA) or an L858R mutation in exon 21 (Herbst et al., 2008). Two kinds of EGFR mutations, deletions and the point mutation L858R, have been demonstrated to increase receptor activity when compared with that of the wild-type receptor. These mutations cause repositioning of critical amino acids around the adenosine triphosphate binding cleft. This leads to EGFR constitutive activation, meaning that the receptor is active without the need for ligand binding. EGFR amplification abnormalities are again rare in SCLC but are found in 30% of squamous cell carcinomas and 15% of adenocarcinomas. Variant III mutations are rare in adenocarcinoma and SCLC but occur in about 5% of squamous cell carcinomas (Herbst et al., 2008). These variant III mutations result in a truncated extracellular domain of the EGFR.

researchers found that microRNA patterns differed between the two histologies, with let-7 family members inactivated in squamous cell and predictive of poor survival outcomes (Landi et al., 2010). MicroRNA is currently being evaluated in research studies for its predictive and prognostic potential, which may bring the treatment of lung cancer one step closer to a more personalized approach. Anaplastic Lymphoma Kinase Fusion Gene Fusion of the anaplastic lymphoma kinase (ALK) gene with another gene has been identified in approximately 7% of NSCLC, mostly of adenocarcinoma histology (Herbst et al., 2008). The most common fusion is between the ALK gene and the EML4 gene, resulting in the EML4-ALK fusion gene. The fusion can occur at different exon positions on the gene but will generally result in a gain of oncogenic function. The fusion gene can encode for a protein that has oncogenic activity such as constitutive dimerization, autophosphorylation, and activation of the ALK kinase despite the absence of a ligand. These ALK fusion rearrangements can be identified in fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reactions (Solomon, Varella-Garcia, & Camidge, 2009). Chemokines Chemokines are cytokines that can play a role in the ability of a cancer to grow, proliferate, metastasize, and develop a blood supply. The term chemokine is derived from “chemotactic cytokine.” Chemokines can be classed among four groups: CXC, CC, C, and CX3C. Chemokines act as ligands (noted with an “L” as in CXCL12) to chemokine receptors (noted with an “R” as in CXCR2) found as transmembrane receptors on the surfaces of a variety of cells (Arenberg, 2006). The CXC chemokines can be broken into two groups: those that promote angiogenesis (noted by “ELR”) and those that inhibit it. ELR-CXC chemokines can be found not only in lung cancer cells but also in the normal cells found in close proximity to the tumor such as macrophages, lymphocytes, endothelial cells, and fibroblasts (Balkwill, 2004). ELR-CXC chemokines are released from both tumor cells and those normal cells noted previously and attach to CXCR2 on the endothelial cells of surrounding vasculature. This is one of the many processes that can induce angiogenesis in tumors (Arenberg, 2006). CXCR4 is a chemokine receptor found in more than 20 different types of cancer cells, including NSCLC (Balkwill, 2004). CXCR4 plays an important role in metastases. The preferential ligand for CXCR4 is CXCL12. Circulating NSCLC cells that express CXCR4 tend to travel to where the CXCL12 ligand is found: lymph nodes, liver, adrenals, and bone. This is one hypothesis as to why lung cancer tends to metastasize to these particular sites of the body (Arenberg, 2006).

Other Mechanisms of Importance in Lung Cancer MicroRNA It has been long established that lung cancers differ significantly by histology. Over time, treatment plans for patients with lung cancer have been specifically designed to the histologic subtype. Ongoing research into the lung cancer’s cellular biology has led to discoveries that further differentiate lung cancers. One area of research has been evaluating microRNA expression in lung cancer tumors. Landi et al. (2010) described microRNA as noncoding RNA that are involved in many developmental systems of a cell. Evaluations of microRNA reveal that at times they can act as tumor suppressor genes or oncogenes. In lung cancer, the let-7 family of microRNA has been of particular interest because they act as tumor suppressor genes by stopping cell proliferation. The let-7 family can also regulate the RAS oncogene. In a sample of adenocarcinomas and squamous cell carcinomas, 16

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Future treatments for cancer may include targeting individual chemokines or the ligand-receptor pairs that aid in the survival of the cancer cells, such as the CXCR4/CXCL12 pair. In addition, because chemokine levels may be higher in those affected by cancer, they may one day be used as markers for disease or as prognostic indicators (Arenberg, 2006).

prognostic factors are predictive, and not all predictive factors are prognostic. The five biomarkers discussed in the most recent version of the National Comprehensive Cancer Network (NCCN) guidelines for NSCLC are EGFR, K-ras, echinoderm microtubule-associated protein-like 4/anaplastic lymphoma kinase (EML4-ALK), excision repair cross-complementation group 1 (ERCC1), and ribonucleotide reductase messenger 1 (RRM1) (NCCN, 2011). EML4-ALK is a fusion oncogene that occurs as a result of an abnormality found in the short arm of chromosome 2p. The resulting protein encoded from this fusion is EML4-ALK. The EML4 portion of the protein is found in the extracellular domain and is fused to the anaplastic lymphoma kinase (ALK) portion of the protein, found as a tyrosine kinase in the intracellular domain. The EML4 portion of the protein constitutively dimerizes, leading to increased oncogenic activity by the intracellular ALK. This mutation is rare, occurring in approximately 2%–7% of patients with NSCLC. Most patients with this abnormality tend to be younger, light or nonsmokers with adenocarcinoma. EML4-ALK appears to be mutually exclusive with EGFR mutations (Kwak et al., 2010). ERCC1 is a part of the nucleotide excision repair pathway and functions by repairing DNA strands and removing platinum adducts. From a prognostic standpoint, study results have been mixed, with both a better and a worse prognosis occurring with high levels of ERCC1 (Coate, John, Tsao, & Shepherd, 2009). However, it is generally thought that high levels of ERCC1 are indicative of a better prognosis, regardless of whether the patient has received therapy (NCCN, 2011). As a predictive biomarker, higher ERCC1 levels predict poor response to platinum-based therapy (Coate et al., 2009). RRM1 is an important component of ribonucleotide reductase, which assists with DNA synthesis and repair. RRM1 can activate PTEN, a tumor suppressor gene that helps regulate the rate of cellular division. High levels of RRM1 are prognostic of improved survival in patients with lung cancer regardless of therapy and are believed to be predictive of poor response to platinum-based (Coate et al., 2009) and gemcitabinebased (NCCN, 2011) therapies. EGFR and K-ras have been described previously in this chapter. Three methods are commonly used to test for these biomarkers, with more testing methodologies in development. The f irst assesses the level of expression of receptors on the surface of the cell. This is generally done by immunohistochemistry (IHC) studies whereby an antibody is attached to an enzyme that is used to recognize the cell surface protein of interest. The staining that occurs is then graded on a scale of 0–3+, with 0 being negative and 3+ being strongly positive for the presence of the receptor. IHC is available in most pathology departments and is a commonly used method for testing (Coate et al., 2009). The second assessment evaluates the number of gene copies in the cell. This is generally performed by either FISH or chromogenic in situ hybridization (CISH). In FISH, signals from a fluorescent

The Cancer Stem Cell Hypothesis The discovery of cancer stem cells in hematopoietic malignancies and solid tumors such as breast cancer has established another potential hypothesis for tumorigenesis. The cancer stem cell hypothesis purports that a small number of cells within a tumor preserve the ability of self-renewal and differentiation properties. It is hypothesized that cancers arise secondary to oncogenic mutations transforming the stem cell (Sullivan, Minna, & Shay, 2010). These transformed stem cells may account for tumor heterogeneity because they constitute a subpopulation within the tumor. Most importantly, these cells retain proliferative capacity and signaling noted in embryogenesis, whereas the majority of tumor cells have limited replication properties. The process of self-renewal is accomplished by activation and dysregulation of key signaling pathways normally expressed during embryogenic development, including Hedgehog (Hh), COX-2, telomerase inhibition, WNT, and Notch signaling (Rudin & Minna, 2009; Sullivan et al., 2010). During normal lung development, the Hh pathway is activated to promote growth and differentiation of trachea and lung tissue. Mutations in this signaling process may result in abnormal lung development. During lung regeneration after injury, activated Hh signaling is noted in the area of repair and in pulmonary neuroendocrine stem cells. This pathway may be significant in the pathogenesis of SCLC. The Notch signaling pathway is generally involved in cellular determination, organogenesis, and tissue homeostasis. In lung development, the Notch pathway appears to be required for determining lung epithelial cell placement, either proximal or distal, and preservation of the stem cell undifferentiated state. The WNT signaling pathway normally regulates cellular differentiation. This group of pathways may be overexpressed in NSCLC and play a role in blocking apoptotic signaling (Tennis, Van Scoyk, & Winn, 2007). Biomarkers The role of biomarkers in lung cancer continues to evolve. Analyzing these specific molecular markers may help determine the aggressiveness of a lung cancer and whether a patient will benefit from a particular therapy. Biomarkers can be predictive or prognostic. Prognostic factors relate to the prognosis or outcome the patient will have, whereas predictive factors can predict the likelihood of response to a particular treatment. For example, some evidence shows that K-ras mutations may be associated with a poor prognosis (prognostic) and poor response to many commonly used therapies (predictive) (Aviel-Ronen et al., 2006). Not all 17

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tag on a DNA probe are used to identify specific gene sequences by fluorescence microscopy. FISH can be used to detect gene amplification, chromosome translocations, and chromosome number (Thomas & Steward, 2006). Increases in the copy number of a gene can correspond to an increase of its encoded protein. CISH allows detection of gene amplification, chromosome translocations, and chromosome number by using enzymatic reactions under the light microscope. It is less expensive than FISH. DNA sequencing is used to detect changes in the DNA coding sequence. Mutations are detected by sequencing cellular DNA that is amplified by polymerase chain reaction from tumor sections.

Thorax, 58, 892–900. Retrieved from http://thorax.bmj.com/ content/58/10/892.long Graziano, S.L., Pfeifer, A.M., Testa, J.R., Mark, G.E., Johnson, B.E., Hallinan, E.J., … Brauch, H. (1991). Involvement of the RAF-1 locus, at band 3p25, in the 3p deletion of small-cell lung cancer. Genes, Chromosomes and Cancer, 3, 283–293. Hahn, W.C., & Weinberg, R.A. (2002). Rules for making human tumor cells. New England Journal of Medicine, 347, 1593–1603. doi:10.1056/NEJMra021902 Hanahan, D., & Weinberg, R.A. (2000). The hallmarks of cancer. Cell, 100, 57–70. doi:10.1016/S0092-8674(00)81683-9 Herbst, R.S., Heymach, J.V., & Lippman, S.M. (2008). Lung cancer. New England Journal of Medicine, 359, 1367–1380. doi:10.1056/ NEJMra0802714 Ji, H., Ramsey, M.R., Hayes, D.N., Fan, C., McNamara, K., Kozlowski, P., … Wong, K.K. (2007). LKB1 modulates lung cancer differentiation and metastases. Nature, 448, 807–810. doi:10.1038/nature06030 Kim, E.S., & Salgia, R. (2009). MET pathway as a therapeutic target. Journal of Thoracic Oncology, 4, 444–447. doi:10.1097/ JTO.0b013e31819d6f91 Krystal, G.W., Hines, S.J., & Organ, C.P. (1996). Autocrine growth of small cell lung cancer mediated by coexpression of c-kit and stem cell factor. Cancer Research, 56, 370–376. Kwak, E.L., Bang, Y.J., Camidge, D.R., Shaw, A.T., Solomon, B., Maki, R.G., … Iafrate, A.J. (2010). Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. New England Journal of Medicine, 363, 1693–1703. doi:10.1056/NEJMoa1006448 Landi, M.T., Zhao, Y., Rotunno, M., Koshiol, J., Liu, H., Bergen, A.W., … Wang, E. (2010). MicroRNA expression differentiates histology and predicts survival of lung cancer. Clinical Cancer Research, 16, 430–441. doi:10.1158/10780432.CCR-09-1736 Marignani, P.A. (2005). LKB1, the multitasking tumor suppressor kinase. Journal of Clinical Pathology, 58, 15–19. doi:10.1136/ jcp.2003.015255 Massagué, J. (2004). G1 cycle—cycle control and cancer. Nature, 432, 298–306. doi:10.1038/nature03094 Merkle, C.J., & Loescher, L.J. (2005). Biology of cancer. In C.H. Yarbro, M.H. Frogge, & M. Goodman (Eds.), Cancer nursing: Principles and practice (6th ed., pp. 3–25). Sudbury, MA: Jones and Bartlett. Modrek, B., Ge, L., Pandita, A., Lin, E., Mohan, S., Yue, P., … Cavet, G. (2009). Oncogenic activating mutations are associated with local copy gain. Molecular Cancer Research, 7, 1244–1252. doi:10.1158/1541-7786.MCR-08-0532 Molina, J.R., & Adjei, A.A. (2006). The Ras/Raf/MAPK pathway. Journal of Thoracic Oncology, 1, 7–9. National Comprehensive Cancer Network. (2011). NCCN Clinical Practice Guidelines in Oncology: Non-small cell lung cancer [v.3.2011]. Retrieved from http://www.nccn.org/professionals/ physician_gls/PDF/nscl.pdf Pecorino, L. (2008). Molecular biology of cancer: Mechanisms, targets, and therapeutics (2nd ed.). New York, NY: Oxford University Press. Pelengaris, S., & Khan, M. (2006a). DNA replication and the cell cycle. In S. Pelengaris & M. Khan (Eds.), The molecular biology of cancer (pp. 88–119). Malden, MA: Blackwell. Pelengaris, S., & Khan, M. (2006b). Introduction. In S. Pelengaris & M. Khan (Eds.), The molecular biology of cancer (pp. 1–34). Malden, MA: Blackwell. Pelengaris, S., & Khan, M. (2006c). Regulation of growth: Growth factors, receptors, and signaling pathways. In S. Pelengaris & M. Khan (Eds.), The molecular biology of cancer (pp. 120–157). Malden, MA: Blackwell.

Summary The developments and knowledge regarding the molecular nature of cancer pathogenesis and specifically lung cancer have provided a new direction for research. Additionally, the advances in signaling pathway knowledge have provided new ground for treatment options with regard to lung cancer pathology. Our newfound knowledge is being incorporated into the treatment continuum of prevention, early detection, prognostic forecasting, and therapeutic treatments. Advances in science will direct the future for the next generation of actual and potential patients with lung cancer.

References Adjei, A.A. (2008). K-ras as a target for lung cancer therapy. Journal of Thoracic Oncology, 3(6, Suppl. 2), S160–S163. doi:10.1097/ JTO.0b013e318174dbf9 Arenberg, D. (2006). Chemokines in the biology of lung cancer. Journal of Thoracic Oncology, 1, 287–288. Aviel-Ronen, S., Blackhall, F.H., Shepherd, F.A., & Tsao, M.S. (2006). K-ras mutations in non-small-cell lung carcinoma: A review. Clinical Lung Cancer, 8, 30–38. Balkwill, F. (2004). Cancer and the chemokine network. Nature Reviews Cancer, 4, 540–550. doi:10.1038/nrc1388 Blasco, M., & Khan, M. (2006). Telomeres and senescence. In S. Pelengaris & M. Khan (Eds.), The molecular biology of cancer (pp. 279–296). Malden, MA: Blackwell. Campling, B.G., & el-Deiry, W.S. (2003). Clinical implications of TP53 mutations in lung cancer. Methods in Molecular Medicine, 75, 53–77. Coate, L.E., John, T., Tsao, M.-S., & Shepherd, F.A. (2009). Molecular predictive and prognostic markers in non-small-cell lung cancer. Lancet Oncology, 10, 1001–1010. doi:10.1016/ S1470-2045(09)70155-X Dziadziuszko, R., Camidge, D.R., & Hirsch, F.R. (2008). The insulinlike growth factor pathway in lung cancer. Journal of Thoracic Oncology, 3, 815–818. doi:10.1097/JTO.0b013e31818180f5 Felip, E., & Baselga, J. (2005). Receptor tyrosine kinase abnormalities in lung cancer. In H.I. Pass, D.P. Carbone, D.H. Johnson, J.D. Minna, & A.T. Turrisi III (Eds.), Lung cancer: Principles and practice (3rd ed., pp. 147–159). Philadelphia, PA: Lippincott Williams & Wilkins. Fong, K.M., Sekido, Y., Gazdar, A.F., & Minna, J.D. (2003). Lung cancer 9: Molecular biology of lung cancer: Clinical implications. 18

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Poulsen, T.T., Poulsen, H.S., & Pappot, H. (2008). Molecular biology of lung cancer. In H. Hansen (Ed.), Textbook of lung cancer (2nd ed., pp. 20–34). London, United Kingdom: Informa Healthcare. Qian, J., & Massion, P.P. (2008). Role of chromosome 3q amplification in lung cancer. Journal of Thoracic Oncology, 3, 212–215. doi:10.1097/JTO.0b013e3181663544 Riely, G.J., Marks, J., & Pao, W. (2009). KRAS mutations in nonsmall cell lung cancer. Proceedings of the American Thoracic Society, 6, 201–205. doi:10.1513/pats.200809-107LC Roussel, M. (2006). Tumor suppressor genes. In S. Pelengaris & M. Khan (Eds.), The molecular biology of cancer (pp. 219–250). Malden, MA: Blackwell. Rudin, C., & Minna, J. (2009). Cancer stem cells. Journal of Thoracic Oncology, 4(11, Suppl. 3), S1079–S1081. doi:10.1097/01. JTO.0000361758.17413.7c Sato, M., Shames, D.S., Gazdar, A.F., & Minna, J.D. (2007). A translational view of the molecular pathogenesis of lung cancer. Journal of Thoracic Oncology, 2, 327–343. doi:10.1097/01. JTO.0000263718.69320.4c Scagliotti, G.V., Longo, M., & Novello, S. (2009). Nonsmall cell lung cancer in never smokers. Current Opinion in Oncology, 21, 99–104. doi:10.1097/CCO.0b013e328321049e Sekido, Y., Fong, K.M., & Minna, J.D. (2003). Molecular genetics of lung cancer. Annual Review of Medicine, 54, 73–87. doi:10.1146/ annurev.med.54.101601.152202 Shay, J.W., & Bacchetti, B. (1997). A survey of telomerase activity in human cancer. European Journal of Cancer, 33, 787–791. Sher, T., Dy, G.K., & Adjei, A.A. (2008). Small cell lung cancer. Mayo Clinic Proceedings, 83, 355–367. doi:10.4065/83.3.355 Shih, J.Y., Yang, S.C., Hong, T.M., Yuan, A., Chen, J.J., Yu, C.J., … Yang, P.C. (2001). Collapsin response mediator protein-1 and the invasion and metastasis of cancer cells. Journal of the National Cancer Institute, 93, 1392–1400. doi:10.1093/jnci/93.18.1392 Shima, D., & Ruhrberg, C. (2006). Angiogenesis. In S. Pelengaris & M. Khan (Eds.), The molecular biology of cancer (pp. 411–423). Malden, MA: Blackwell. Solomon, B., & Pearson, R.B. (2009). Class IA phosphatidylinositol 3-kinase signaling in non-small cell lung cancer. Journal of Thoracic Oncology, 4, 787–791. doi:10.1097/JTO.0b013e3181a74dba

Solomon, B., Varella-Garcia, M., & Camidge, D.R. (2009). ALK gene rearrangements: A new therapeutic target in a molecularly defined subset of non-small cell lung cancer. Journal of Thoracic Oncology, 4, 1450–1454. doi:10.1097/JTO.0b013e3181c4dedb Sullivan, J.P., Minna, J., & Shay, J.W. (2010). Evidence for selfrenewing lung cancer stem cells and their implications in tumor initiation, progression, and targeted therapy. Cancer Metastasis Reviews, 29, 61–72. doi:10.1007/s10555-010-9216-5 Sun, S., Schiller, J.H., & Gazdar, A.F. (2007). Lung cancer in never smokers—A different disease. Nature Reviews Cancer, 7, 779–790. doi:10.1038/nrc2190 Sun, S., Schiller, J.H., Spinola, M., & Minna, J.D. (2007). New molecularly targeted therapies for lung cancer. Journal of Clinical Investigation, 117, 2740–2750. doi:10.1172/JCI31809 Tennis, M., Van Scoyk, M.V., & Winn, R.A. (2007). Role of the wnt signaling pathway and lung cancer. Journal of Thoracic Oncology, 2, 889–892. doi:10.1097/JTO.0b013e318153fdb1 Thomas, A., & Steward, W. (2006). Diagnosis of cancer. In S. Pelengaris & M. Khan (Eds.), The molecular biology of cancer (pp. 424–443). Malden, MA: Blackwell. Velcheti, V., & Govindan, R. (2006). Insulin-like growth factor and lung cancer. Journal of Thoracic Oncology, 1, 607–610. Viktorsson, K., & Lewensohn, R. (2007). Apoptotic signaling pathways in lung cancer. Journal of Thoracic Oncology, 2, 175–179. doi:10.1097/JTO.0b013e318031cd78 Wistuba, I.I., & Gazdar, A.F. (2008). Molecular biology of preneoplastic lesions of the lung. In J. Roth, J.D. Cox, & W.K. Hong (Eds.), Lung cancer (3rd ed., pp. 84–97). Malden, MA: Blackwell. Yamamoto, H., Shigematsu, H., Normura, M., Lockwood, W.W., Sato, M., Okumura, N., … Gazdar, A.F. (2008). PIK3CA mutations and copy number gains in human lung cancers. Cancer Research, 68, 6913–6921. doi:10.1158/0008-5472.CAN-07-5084 Yarden, Y., & Shilo, B.-Z. (2007). SnapShot: EGFR signaling pathway. Cell, 131, 1018e1–1018e2. doi:10.1016/j.cell.2007.11.013 Yashima, K., Litzky, L.A., Kaiser, L., Rogers, T., Lam, S., Wistuba, I.I., … Gazdar, A.F. (1997). Telomerase expression in respiratory epithelium during the multistage pathogenesis of lung carcinoma. Cancer Research, 57, 2373–2377. Retrieved from http://cancerres. aacrjournals.org/content/57/12/2373.long

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Prevention and Control Judith J. Smith, MSN, RN, AOCN®, and Christine D. Berg, MD

Introduction

Kleihues, 2003). Studies conducted in the 1950s established a clear correlation between smoking and lung cancer (Doll & Hill, 1950, 1956; Hammond & Horn, 1954; Wynder & Graham, 1950). Since that time, numerous epidemiologic and experimental studies have consistently validated evidence of the causal relationship. Cigarette consumption rose dramatically in the U.S. population during the first half of the 20th century, peaking in the early 1960s. Prevalence rates began to decrease after publication of the first Surgeon General’s Report on Smoking in 1964, which reported the definitive linkage between tobacco use and lung cancer (U.S. Department of Health, Education, and Welfare, 1964). In fact, smoking prevalence rates have decreased from 42% to 20% among adults since that time (ACS, 2011; Fiore & Baker, 2009). Figure 3-1 compares the trend in cigarette consumption and corresponding lung cancer mortality rates for men and women over the past century. The lag time from peak consumption rate to peak mortality rates reflects the lengthy period, 20–30 years, over which lung cancer typically develops and the slow decrease in risk following smoking cessation (Kamangar, Dores, & Anderson, 2006; Keith, 2009; Peto et al., 2000). Although the downward trend in cigarette consumption has led to steadily decreasing lung cancer death rates for men since the late 1980s, rates for women have only recently begun to plateau after rising consistently for many years (ACS, 2011). This difference is attributed to historical smoking patterns, with smoking prevalence among women peaking 20 years later than prevalence among men (Alberg, Brock, & Samet, 2005). In addition to lung cancer, smoking is associated with at least 14 other malignancies, among which are cancers of the oropharynx, esophagus, and bladder (ACS, 2011). Moreover, smoking is responsible for increased risk of cardiovascular disease, respiratory diseases, reproductive and perinatal conditions, and a host of other health problems and illnesses (Giovino, 2007; Hecht et al., 2009; Keith, 2009). Despite such overwhelming evidence, approximately 20% of the U.S. adult population continues to smoke, greatly increasing their risk

The high incidence and mortality rates for lung cancer worldwide, coupled with an overall five-year survival rate of less than 15% (Keith, 2009), place lung cancer as a predominant global health threat. Lung cancer is the leading cause of cancer mortality in the United States, exceeding the combined total death rate for breast, prostate, and colorectal cancers. Approximately 221,130 new cases of lung cancer were diagnosed in 2011, and an estimated 156,940 lung cancer– related deaths occurred (American Cancer Society [ACS], 2011). Tobacco use is well established as the primary cause of lung cancer, accounting for nearly 90% of all cases. Other modifiable lifestyle risk factors, such as diet and nutrition, physical activity, and obesity, may also be associated with increased risk, although the evidence is much less compelling (Hecht, Kassie, & Hatsukami, 2009). Environmental factors and genetic susceptibility also play a role in increased lung cancer risk. Despite major advances in cancer therapeutics and technology, the overall five-year survival rate for lung cancer has not appreciably improved over the past three decades (Hecht et al., 2009; Kadara et al., 2009; Keith, 2009; Kelloff et al., 2006). Without more effective treatment options, the focus has shifted toward prevention and early detection strategies to control this deadly disease. Emerging evidence from the National Lung Screening Trial, a recently concluded study, shows that screening with low-dose computed tomography (LDCT) may lower lung cancer mortality. This chapter will review lung cancer risk factors; prevention and early detection strategies, including LDCT; and historical and current clinical trials.

Lung Cancer Risk Factors Tobacco Tobacco use is the primary cause of lung cancer worldwide, accounting for 17.8% of all cancer deaths annually (Stewart & 21

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Figure 3-1. U.S. Cigarette Consumption and Death Rates

Rights were not granted to include this figure in electronic media. Please refer to the original source.

*Age-adjusted to 2000 U.S. standard population. Source: Death rates: U.S. Mortality Data, 1960–2005, U.S. Mortality Volumes, 1930–1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006. Cigarette consumption: U.S. Department of Agriculture, 1900–2007. Note. From Cancer Statistics 2009, by the American Cancer Society, 2009. Retrieved from http://www.cancer.org/acs/groups/content/@nho/documents/ document/cancerstatistic2009slidesrevpp.ppt. Copyright 2009 by the American Cancer Society. Reprinted by the permission of the American Cancer Society, Inc. from www.cancer.org. All rights reserved.

States and other developed countries are currently diagnosed in former smokers (Gray et al., 2007; Sato, Shames, Gazdar, & Minna, 2007). Clearly, the greatest benefit from smoking cessation is for smokers who quit earlier in life (Khan, Afaq, & Mukhtar, 2010); however, even for individuals older than 60 years, lung cancer risk can substantially decrease after smoking cessation (Peto et al., 2000). The percentage of risk reduction following cessation depends upon the age at which an individual started to smoke, number of cigarettes smoked, length of years smoked, and depth of inhalation (Coyle, 2009; U.S. Department of Health and Human Services [DHHS], 2004). Cigarette smoke has been identified as a known human carcinogen (U.S. DHHS, Public Health Service, National Toxicology Program, 2005), containing at least 20 credible pulmonary carcinogenic components (Hecht et al., 2009). Carcinogens are present in tobacco smoke in both gas and particulate (tar) components. Exposure to these constituents triggers a cascade of genetic and epigenetic events that

for developing lung cancer when compared to individuals with no smoking history (Gray et al., 2007; Sun, Schiller, & Gazdar, 2007; Thun et al., 2008). Current smokers account for more than 46 million adults and are defined as individuals currently smoking or those who had quit smoking within the past 12 months. These individuals are 20–40 times more likely to develop lung cancer than never-smokers (Peto et al., 2000). Never-smokers are defined as individuals with a lifetime exposure of less than 100 cigarettes (Sun et al., 2007) and account for approximately 25,000 lung cancer deaths annually (Carbone, 2009; Goldstraw et al., 2007). Former smokers are individuals with a smoking history of exposure to more than 100 cigarettes and cessation of longer than 12 months. Former smokers account for approximately 45 million Americans. Although smoking cessation is a first-line cancer prevention strategy, it is important to note that the risk level for former smokers declines slowly over time but never returns to that of individuals who have never smoked (Keith, 2009; Peto et al., 2000; Schottenfeld, 2010). Moreover, more than half of all lung cancers in the United

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occur throughout lung cancer development (Besaratinia & Pfeifer, 2008). Certain smoke carcinogens are capable of forming DNA adducts, giving rise to genetic mutations (Simon, 2007) at distinctive locations along the DNA sequence. Epigenetic changes also occur in the lung in response to exposure to tobacco carcinogens (Stidley et al., 2010). Such modifications do not alter the primary DNA sequence; yet, these epigenetic changes control gene expression, for example, silencing of cancer-relevant genes by means of promoter methylation. Less is known about specific inflammatory agents of tobacco smoke, but proinflammatory changes are frequently found in smokers’ lungs. Moreover, inflammation is closely associated with tumor promotion (Lee et al., 2008; Smith, Perfetti, & King, 2006). Chronic obstructive pulmonary disease (COPD) has been linked to inflammation and is an independent risk factor for lung cancer, as discussed later (Kim, Rogers, & Criner, 2007; Turner, Chen, Krewski, Calle, & Thun, 2007). Although nicotine, a psychoactive component of tobacco, appears to play a major role in tobacco dependence, its carcinogenic properties have yet to be determined but may play a role in carcinogenesis by functioning as tumor promoters (Le Foll & Goldberg, 2009; West et al., 2003). The average success rate for cessation programs is less than 5% annually, although 70% of smokers attempt to quit during the same time frame (Hecht et al., 2009). A common cessation approach is the consumption of cigarettes with lower tar levels. Individuals choosing to reduce the tar component tend to maintain nicotine levels in the bloodstream by increasing cigarette consumption, increasing the depth of smoke inhalation, or holding smoke in the lungs for longer periods. Consistent with the theory of compensatory smoking, recent studies demonstrated no difference in risk levels between individuals smoking medium-tar filter, low-tar filter, and very low-tar cigarettes (Ginsberg, 2005).

approximately 3,000 lung cancer deaths each year and an additional 35,000 deaths related to cardiovascular and other diseases among nonsmokers (Giovino, 2007; U.S. DHHS, 2006). A number of states have enacted smoke-free laws, protecting nonsmoking individuals from the harmful effects of tobacco smoke in public spaces. Children of smoking parents frequently are not protected from continual exposure to SHS in the home. Infants and young children are especially vulnerable to the health risks associated with SHS, such as upper and lower respiratory infections, acute and chronic ear disease, long-term effects on lung function, low birth weight, and sudden infant death syndrome (Giovino, 2007; Marano, Schober, Brody, & Zhang, 2009). Children routinely exposed to SHS in their home environment are at twice the risk for emergency department visits for respiratory-related illness and three times more likely to require hospitalization for such illnesses (Hill & Liang, 2008). A recent study compared lung cancer risk between individuals exposed to SHS in the earlier part of life (0–25 years old) and those exposed after age 25 (Asomaning et al., 2008). After adjusting for active cigarette smoking, the study found that the risk was greater for individuals exposed to SHS prior to age 25, at a time when the lungs are still developing. Sadly, an estimated 40% of children younger than five years old reside in homes where SHS is present, despite widespread recognition that it is a preventable health hazard (Gergen, Fowler, Maurer, Davis, & Overpeck, 1998; Jarvie & Malone, 2008).

Diet and Nutrition In the early 1980s, Doll and Peto estimated that 30%–35% of all cancer deaths in the United States were associated with diet and nutrition (Anand et al., 2008; Doll & Peto, 1981). In 2009, the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) conducted a cumulative review of evidence-based studies, finding similar results (WCRF/AICR, 2009). Figure 3-2 presents findings from WCRF/AICR, which advocates eating a well-balanced diet rather than taking dietary supplements outside of clinical trials (WCRF/AICR, 2009). Researchers conducted numerous epidemiologic studies to explore the associations between diet and nutrition and lung cancer. Over the years, many of these studies have reported an inverse relationship between diets high in carotenoid-rich fruits and vegetables and lung cancer incidence. Several randomized controlled trials (RCTs) were conducted in the 1970s to evaluate this relationship in a definitive setting. Findings from the RCTs did not support findings from the epidemiologic studies. In fact, RCT results indicated that beta-carotene was not beneficial and caused harm in some cases (discussed later under Chemoprevention). Since that time, numerous epidemiologic studies have continued to find a protective effect from diets high in fruits and vegetables and decreased lung cancer risk (Khan et al., 2010; Kubik et al., 2008).

Sidestream Smoke No level of tobacco smoke exposure is safe for humans (Centers for Disease Control and Prevention [CDC], 2008b; Coyle, 2009; Giovino, 2007; U.S. DHHS, 2006; U.S. DHHS, Public Health Service, National Toxicology Program, 2005). Toxic chemical compounds are present not only in mainstream smoke (smoke inhaled directly from a cigarette), but also in sidestream smoke, commonly known as secondhand smoke (SHS), which is a combination of expired mainstream smoke and smoke from the tip of a burning cigarette. Philip Morris Tobacco Company’s unpublished toxicology research reported evidence that freshly inhaled SHS is four times more toxic per gram of total particulate matter than mainstream smoke (Schick & Glantz, 2005; Wakeham, 1961). In 2006, the U.S. surgeon general’s report, The Health Consequences of Involuntary Exposure to Tobacco Smoke (U.S. DHHS, 2006), reported on the detrimental effects of SHS, which causes 23

LUNG CANCER, SECOND EDITION

weekly physical activity and smoking history. Researchers defined physical activity as an energy expenditure lasting 20 minutes or longer and causing an increase in respiration or heart rate or causing perspiration. Researchers categorized the participants into five groups according to physical activity: 0 (inactive), less than 1, 1–2, 3–4, and 5 or more times per week. The researchers also labeled the participants as neversmokers, former smokers, or current smokers, as well as according to history of smoking intensity and number of years since quitting, if applicable. Results found that an increase in physical activity was associated with a 22% decrease in the risk of total lung carcinoma, even when controlled for known risk factors such as tobacco use (Leitzmann et al., 2009). Moreover, physically active participants in this study typically had other associated healthy lifestyle behaviors (e.g., decreased tobacco use, lower body mass index, healthy diet, decreased consumption of red meat). Although this study confirmed the majority of previous reports that physical activity is inversely related to risk of lung cancer, studies to further evaluate the relationship are under way.

Figure 3-2. World Cancer Research Fund/American Institute for Cancer Research General Dietary Recommendations • • • • • • • • •

Maintain lean body weight. Be physically active for at least 30 minutes every day. Avoid sugary drinks. Limit consumption of energy-dense foods. Eat an increased variety of vegetables, fruits, whole grains, and legumes such as beans. Limit consumption of red meats (such as beef, pork, and lamb), and avoid processed meats. Limit alcoholic drinks to two a day for men and one a day for women. Limit consumption of salty foods and foods processed with salt. Do not use supplements to protect against cancer outside a clinical trial.

Note. Based on information from World Cancer Research Fund & American Institute for Cancer Research, 2009.

Physical Activity

Environmental and Occupational Exposures

Many epidemiologic studies have indicated an inverse relationship between physical activity and the development of a number of malignancies, including lung cancer. In 2005, a meta-analysis evaluated the relationship between leisure-time physical activity and lung cancer (Tardon et al., 2005). The analysis evaluated nine observational studies from 1966 to 2003 and concluded that higher levels of leisure-time physical activity were protective against lung cancer for both men and women at moderate and high activity levels when compared to their sedentary counterparts. Analysis suggests several biologic mechanisms that may account for the inverse relationship. • Physical activity may affect growth factors associated with risk. • Physical activity lowers insulin, glucose, and triglycerides and raises high-density lipoprotein (or HDL) cholesterol, which may be associated with decreased risk. • Physical activity may affect the immune system by increasing the number and activity of macrophages, natural killer cells, and lymphokine-activated killer cells and their regulated cytokines and by increasing mitogen-induced lymphocyte proliferation rates. In 1995, the National Institutes of Health (NIH) and AARP (formerly known as the American Association of Retired Persons) initiated a large cohort study, the NIH-AARP Diet and Health Study, to evaluate relationships between diet and cancer (Leitzmann et al., 2009). A subanalysis of the study evaluated the effects of smoking on the relationship of physical activity and lung cancer. The study end point for this analysis was primary lung cancer incidence. The NIH-AARP study collected baseline information per mailed questionnaires from 501,148 men and women aged 50–71 years in the United States. Respondents answered questions regarding

The International Agency for Research on Cancer has identified more than 415 environmental and occupational agents as causal or putative factors of a variety of malignancies, including lung cancer (Clapp, Jacobs, & Loechler, 2008). The National Toxicology Program and the National Institute for Occupational Safety and Health have identified radon as a “known human carcinogen” (CDC, 2010; U.S. DHHS, Public Health Service, National Toxicology Program, 2005). The U.S. Environmental Protection Agency (EPA) has gone further, identifying radon as the leading cause of lung cancer among nonsmokers in the United States, accounting for 2,900 lung cancer deaths each year (U.S. EPA, 2009). In fact, after tobacco exposure, radon is the second most common cause of lung cancer in the United States. Radon-222 is an inert, colorless, odorless, radioactive gas found in rock and soil formed by the natural breakdown of uranium-238 (ACS, 2009b). Radon infiltrates residential dwellings and other buildings by seeping from rock and soil through structural foundations into living and working spaces. As radon decomposes, radioactive alpha particles (polonium-214 and polonium-218) are emitted and then inhaled and are capable of causing genetic alterations that may accumulate, thereby contributing to carcinogenesis of the lung (Simon, 2007). Activities to mitigate increased levels of radon in homes and other buildings focus on preventing seepage of gas into living spaces by sealing areas of possible entry (e.g., cracks in the foundation or crawl spaces) or by using natural or mechanical ventilation techniques (opening windows, installing ventilation pumps or fans) (Rahman & Tracy, 2009). Opening windows and air vents to outside air can reduce radon concentrations by up to 90% (Rahman & Tracy, 2009). 24

CHAPTER 3. PREVENTION AND CONTROL

Chemical and physical agents associated with occupational exposures contribute an estimated 5%–15% of lung cancer cases annually worldwide and may act synergistically with tobacco smoke (Schottenfeld, 2010). Occupational agents generally associated with lung cancer include asbestos (a primary cause of mesothelioma), bis(chloromethyl)ether, chromium, inorganic arsenic, polycyclic aromatic compounds, vinyl chloride, and nickel (Schottenfeld, 2010; Simon, 2007). Other probable carcinogenic contributors to lung cancer include cadmium, beryllium, acetaldehyde, silica, synthetic fibers, and welding fumes (Schottenfeld, 2010). Exposure to occupational carcinogens can be controlled only when levels of the carcinogenic agents are measured in the workplace and subsequent action plans are implemented to reduce or eliminate exposure. Frequently, such protective plans are initiated following legislation to control or eliminate the agent. Asbestos provides a good example. Asbestos was prominent in the manufacturing, construction, and mining industries through much of the 20th century. A strong association between asbestos and malignant mesothelioma was established many years ago (CDC, 2009). In 1971, the Occupational Safety and Health Administration (OSHA) established permissible exposure limits (PELs) to control asbestos in the workplace (CDC, 2009), and in 1999, the EPA banned its use (U.S. EPA, 1999). Despite these actions, approximately 1.3 million construction workers continue to be exposed to asbestos from imported sources or from exposure during rehabilitation or demolition of older asbestos-containing buildings. In fact, air samples collected in the construction industry exceeded the PEL by 20% in 2009 (CDC, 2009). Rigorous oversight of industrial materials and practices associated with carcinogenic exposure, as well as strict enforcement of federal regulations, is the only way to reduce occupational risk that may lead to lung cancer.

over eight years, the study identified 1,979 cases of lung cancer overall. Smoking prevalence was highest among African Americans (28.5%) and Native Hawaiians (20.1%) and lowest among Japanese Americans (15.5%) and Whites (15.9%) (Haiman et al., 2006). For both genders, Whites were the heaviest smokers, while African Americans and Latinos smoked the fewest cigarettes per day. Risk level was modified by the number of cigarettes smoked per day. Among participants who smoked 10 cigarettes or fewer per day, Whites had a 55% lower risk of lung cancer than African Americans, and among those who smoked 11–20 cigarettes per day, Whites had a 43% lower risk (Haiman et al., 2006). For Hispanics and Japanese Americans, the percentages were lower still. However, once smoking rates reached 30 cigarettes per day or more, the risk difference was minimal. Analysis ruled out differences in diet, occupation, and level of education as underlying factors to explain the risk disparities. Other ongoing epidemiologic studies are continuing to address potential interactions of SES and lung cancer risk.

Inflammation Lung cancer and COPD are leading causes of morbidity and mortality worldwide (Punturieri, Szabo, Croxton, Shapiro, & Dubinett, 2009). COPD is a collection of slowly progressive pulmonary diseases characterized by airflow obstruction that interferes with respiration. Tobacco smoke is a known risk factor for inflammatory pulmonary diseases, accounting for up to 75% of COPD deaths (CDC, 2008a). A large body of evidence suggests that smoking-induced pulmonary inflammation may play an important role in carcinogenesis (Smith, Perfetti, et al., 2006). COPD and emphysema are identified frequently in individuals with lung cancer (CDC, 2008a). Whether the association between pulmonary inflammation and lung cancer is attributable to shared genetic susceptibility factors, to facilitation of tumor initiation and promotion by inflammatory processes, or to both is not clear (Dubey & Powell, 2008). One mechanism of action supporting a relationship between COPD and lung cancer suggests that increased secretion of inflammatory mediators and proteolytic enzymes may damage DNA and lead to increases in cell proliferation rates (Smith, Perfetti, et al., 2006).

Socioeconomic Factors Socioeconomic status (SES), including income, education, gender, race, and ethnicity, is known to have an overall effect on healthcare access, opportunities, and outcomes. Findings from numerous epidemiologic studies show a disproportional distribution of smoking prevalence and lung cancer incidence among groups associated with low SES (Haiman et al., 2006; Hegewald & Crapo, 2007; Laaksonen, Rahkonen, Karvonen, & Lahelma, 2005; Sidorchuk et al., 2009). A meta-analysis of 64 studies evaluated associations between SES and lung cancer incidence. Analysis showed a significant increase in lung cancer risk among individuals with low SES across educational (61%), occupational (48%), and income-based (37%) indicators (Sidorchuk et al., 2009). A recent study evaluated the risk of smoking-related lung cancer among African American, Native Hawaiian, Japanese American, Latino, and White groups (Haiman et al., 2006). Conducted prospectively among 183,813 men and women

Genetic Susceptibility Despite high incidence and mortality rates for lung cancer, still only 10%–15% of all smokers develop the disease (Dubey & Powell, 2008; Schwartz, 2006). Moreover, lung cancer mortality rates for never-smokers and individuals with a minimal smoking history are as high as 15,000 deaths per year (Freedman, Leitzmann, Hollenbeck, Schatzkin, & Abnet, 2008; Thun et al., 2008). Data suggest that among these nonsmoking factors, a major component of susceptibility to lung cancer is genetically determined (Sato et al., 2007). 25

LUNG CANCER, SECOND EDITION

Tobacco smoke and genetic susceptibility act synergistically to influence carcinogenesis (Herbst, Heymach, & Lippman, 2008). Over the past 40 years, epidemiologic studies have consistently demonstrated a familial aggregation for lung cancer, even after adjusting for family smoking patterns (Schwartz, Prysak, Bock, & Cote, 2007). Such studies indicate a twofold increased risk for developing lung cancer in individuals with a family history of the disease (Sato et al., 2007). Clinicians should consider family smoking history as a valuable marker to assist in identifying high-risk individuals for participation in chemoprevention and screening clinical trials (Schwartz & Ruckdeschel, 2006).

phenotypic abnormalities, contributing to the global process of carcinogenesis. Internal and external factors, such as tobacco exposure and genetic susceptibility, influence these genetic and epigenetic modifications. Chemoprevention involves the use of natural or synthetic chemical compounds to interrupt or reverse the development of phenotypic, genetic, and epigenetic changes associated with the carcinogenic process (Greenwald, 1984; Lippman, Spitz, Trizna, Benner, & Hong, 1994; Sporn, 1991; Sporn, Dunlop, Newton, & Smith, 1976). The actual chemopreventive interventions may be nutritional supplements or pharmacologic agents that are chemically well defined and administered at predetermined dosages on specific administration schedules in pill, liquid, inhalant, or topical forms. Thus far, only three agents have received approval from the U.S. Food and Drug Administration (FDA) for standard use in cancer risk management. Tamoxifen and raloxifene, selective estrogen receptor modulators (known as SERMs), are approved for use in high-risk women to lower their risk of invasive breast cancer (raloxifene is approved for postmenopausal women only) (Fisher et al., 1998; Wickerham et al., 2009). Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is indicated for reduction of colorectal adenomas in highrisk individuals with familial adenomatous polyposis (Steinbach et al., 2000). The FDA has not approved any agent for reduction of lung cancer risk at this time; thus, all lung cancer chemoprevention agents are administered within the context of chemopreventive clinical trials. Chemoprevention trials are often classified as primary, secondary, or tertiary prevention, depending on the target population (Gasent Blesa, Esteban Gonzalez, & Alberola Candel, 2008; Zell & Meyskens, 2008). Primary chemoprevention refers to medical intervention in individuals from the general population who have no evidence of disease but are at significant increased risk. For example, relatively healthy cancer-free smokers and former smokers are ideal candidates for primary chemoprevention trials. Secondary chemoprevention trials target individuals with identified premalignant lesions, for example, bronchial dysplasia. Trials in this category allow researchers to evaluate the efficacy of an agent by comparing affected tissue before and after the intervention. The purpose of tertiary chemoprevention is to prevent the occurrence of second primary tumors in individuals previously treated with curative intent. Tertiary chemoprevention is of major importance because individuals successfully resected for lung cancer remain at significantly elevated risk for developing new lung cancers. Development of second primaries in this group can be as high as 1%–2% per year (Gray et al., 2007; Keith, 2009). Potential chemopreventive agents are identified through epidemiologic, laboratory, and preclinical research. Once identified, a candidate agent progresses through a series

Lung Cancer Prevention Strategies The overall five-year survival rate for lung cancer is less than 15% (ACS, 2009a; Keith, 2009). The one-year survival rate is 42% (Lee, Walser, & Dubinett, 2009). Such disappointing survival statistics are in large part due to the advanced stage at which the majority of lung cancers are diagnosed. Even so, resected clinical stage I disease is associated with a less than 50% survival rate (Carbone, 2009; Ginsberg, 2005; Goldstraw et al., 2007). Furthermore, only 15% of lung cancers are discovered at an early stage (Keith, 2009). With such a dismal outlook for patients with cancer, the cancer prevention research community has focused its attention on the development of effective medical interventions and screening strategies to prevent disease incidence and mortality.

Chemoprevention Lung cancer develops over a lengthy period during which lung tissue transforms from healthy cells to invasive malignancy through a multistep process called carcinogenesis (Hong & Lippman, 1995; Lippman, Benner, & Hong, 1994; Smith, Dunne, & Greenwald, 2011; Sporn, 1991). The steps, or phases, of the carcinogenic process are identified as initiation, promotion, and progression. Initiation occurs rapidly with exposure to carcinogens, such as those found in tobacco smoke, and irreversibly alters the genotype of a stem cell. The second phase, promotion, typically extends over a prolonged period, up to 30 years or more (Keith, 2009). During this time with continued carcinogenic exposure, the stem cell develops phenotypic characteristics typical of malignant disease (e.g., cell disorganization, proliferation, morphologic changes). The hallmark of this phase of carcinogenesis is reversibility. The prolonged period over which this phase occurs provides an opportunity to intervene with the purpose of lowering cancer risk by stopping, slowing, or reversing the carcinogenic process. The final phase, progression, refers to the complete transformation of a genetically altered cell to invasive malignancy and is irreversible. Genetic and epigenetic changes accumulate during these phases and manifest as progressive 26

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of phase I, II, and III clinical trials, similar to the process for evaluating chemotherapy agents. Table 3-1 presents a comparison of the key differences between prevention and treatment clinical trials. Although large numbers of agents are evaluated in early-phase trials (phases I–II) for safety and efficacy, few progress to large-scale phase III trials designed to evaluate cancer incidence as the primary end point. By nature, phase III trials require large numbers of participants (hundreds to thousands), take many years to complete, and are extremely costly. To make the trials more manageable, chemoprevention trials target only high-risk individuals (e.g., smokers or former smokers) in order to reach statistical significance with smaller numbers of participants because an increased number of cancer events are anticipated in this group. Chemoprevention clinical trials are currently evaluating agents that affect the carcinogenic process by blocking tumor initiation and preventing activation of carcinogens, enhancing detoxification systems, or preventing carcinogens from reaching their target sites. Other agents inhibit tumor progression through antiproliferative effects. Early-phase chemoprevention studies use biomarkers as intermediate end points, also called surrogate end points, to function as predictors, or surrogates, for cancer incidence. Biomarkers may consist of grossly visible lesions (e.g., oral leukoplakia), histologic markers (e.g., bronchial dysplasia), biochemical markers in the target tissue (e.g., enzyme activity), or genetic abnormalities (e.g., DNA aneuploidy, oncogene activation/tumor suppression, or gene inhibition) (Smith et al., 2011).

Ideally, candidate agents show promise in laboratory, preclinical, and epidemiologic research settings prior to entering human studies. In the early 1990s, two large phase III chemoprevention trials did not follow the traditional progression for potential agents. The Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC) and the BetaCarotene and Retinol Efficacy Trial (CARET) were based on strong epidemiologic data indicating a protective effect from fruits and vegetables high in beta-carotene against lung cancer risk. Results from basic research suggested beta-carotene may be a reasonable agent based on its antioxidant behavior (Burton & Ingold, 1984). The ATBC was a double-blind, placebo-controlled, primary prevention trial that used a factorial design. The study randomized 29,133 Finnish male smokers who were 50–69 years old to receive alpha-tocopherol alone, beta-carotene alone, alpha-tocopherol plus beta-carotene, or a placebo daily for an average of six years (ATBC Cancer Prevention Study Group, 1994). Rather than reducing risk, results showed that study groups receiving beta-carotene experienced a statistically significant increase (18%) in lung cancer incidence. Specifically, this increase in lung cancer incidence was observed among current smokers. CARET, also a double-blind, placebo-controlled trial, randomized 18,314 male and female smokers, former smokers, and workers exposed to asbestos (Omenn et al., 1996). In this two-arm trial, participants received a combination of beta-carotene plus retinol or a placebo for an average of four years. Results showed a statistically significant increase in lung cancer incidence (28%) and mortality (17%) in the intervention group (Omenn et al., 1996). In a comparison of smokers and former smokers, increased incidence rates were limited to current smokers in this study. Thus, results from both studies were not only negative, but showed a harmful effect of beta-carotene in the subpopulation of smokers. Although the studies were based on strong epidemiologic evidence and plausible suggestive findings in laboratories, data from animal models had not been available at the time the studies were initiated. Subsequent preclinical studies showed that beta-carotene supplementation promoted lung carcinogenesis in animal models in the presence of tobacco smoke (Wang et al., 1999). The surprising results from ATBC and CARET highlight the critical importance of using multiple lines of evidence as a basis for agent selection in cancer prevention trials (Szabo, 2008). A third RCT, the Physicians Health Study (Hennekens et al., 1996), was conducted simultaneously and included a component to evaluate the effects of beta-carotene on any type of malignant neoplasm except nonmelanoma skin cancer. This study randomized 22,071 male physicians (current and former smokers) to receive beta-carotene or a placebo on alternate days for an average of 12 years. Unlike ATBC and CARET, results of this study showed no statistically significant effect on lung cancer incidence and no indication of benefit or harm to smokers.

Table 3-1. Comparison of Prevention and Intervention Trials Chemoprevention Trials

Chemotherapy Trials

Agents

Minimal toxicity profile required; potentially long-term administration

Moderate to high toxicity profile tolerated; relatively short-term administration

Biomarkers

Intermediate/surrogate end point biomarkers; early detection biomarkers; cancer risk biomarkers

Cancer eradication, cancer control, cancer palliation

Cohorts

High-risk populations; individuals without cancer but with current premalignant lesions or previously treated malignancies

Individuals with cancer

Variables

Note. Based on information from Szabo, 2008.

27

LUNG CANCER, SECOND EDITION

A number of lung cancer chemoprevention clinical trials are currently under way, primarily phase I and II trials. The arachidonic pathway presents an avenue of interest for lung cancer chemoprevention. Arachidonic acid is metabolized to prostaglandins and prostacyclins via the COX pathway, and they have been implicated in carcinogenesis (Gray et al., 2007). Researchers are evaluating nonsteroidal antiinflammatory drugs, such as celecoxib and sulindac, alone and in combination with other agents to determine their role in lung cancer chemoprevention. These drugs exhibit multiple mechanisms of action, including antiangiogenesis, antiproliferation, antioxidation, induction of apoptosis, and modulation of the immune system (Omenn, 2007). Leukotrienes, which are end products of the lipoxygenase (LOX) pathway, also exhibit procarcinogenic effects in lung cancer. Zileuton, a 5-leukotriene inhibitor, is being assessed for its impact on the multiple cellular responses to LOX metabolites. Antioxidants, such as green tea polyphenols and broccoli sprout extract, contain phytochemicals (chemical compounds occurring naturally in plants) that have shown protective effects in cancer chemoprevention by blocking bioactivation of some carcinogens. Epidermal growth factor receptor inhibitors (e.g., erlotinib) and corticosteroids (e.g., budesonide) are also being investigated as potential chemopreventive agents for lung cancer prevention. Of necessity, all early-phase trials include the evaluation of surrogate end point biomarkers because these trials are not large enough or long enough to achieve statistical significance with regard to clinical end points.

Services Task Force, 2004). These major organizations will be reviewing emerging data from NLST and associated information to determine if guidelines are reasonable. Principles established by Wilson and Jungner (1968) still guide the decision-making processes for evaluating cancer screening tests. First, the disease must be an important public health issue with significantly increased incidence and mortality rates in the target population. Additionally, sufficient knowledge must exist with regard to the natural history of the disease, an effective treatment option must be available, and evidence must have demonstrated that early intervention can effectively decrease mortality rates. Ideally, screening tests should be easily accessible to the target population, inexpensive to administer, and cost-effective. Common metrics used to evaluate screening tests for effectiveness include (a) sensitivity—individuals with cancer have a positive test; (b) specificity—individuals without cancer have a negative test; (c) positive predictive value—individuals with a positive test in fact have cancer; and (d) negative predictive value—individuals with a negative test in fact do not have cancer. A number of nonrandomized studies and RCTs have been conducted over the past several decades to determine the effectiveness of various lung cancer screening modalities. Although nonrandomized screening studies provide valuable information about screening tests and techniques, RCTs are considered the gold standard for evaluating screening efficacy. Positive results from RCTs are necessary to make a persuasive case for recommending screening for high-risk populations. Until recently, results from large phase III screening RCTs were disappointing. Initial results from the NLST indicate there is reason for optimism that lung cancer screening will be an effective tool for reducing lung cancer mortality rates in high-risk individuals. Early RCTs were conducted in the 1970s to evaluate the effectiveness of screening for lung cancer using chest x-ray and sputum cytology: the Mayo Lung Project, Johns Hopkins Lung Project, and Memorial Sloan-Kettering Cancer Center (MSKCC) Lung Study. A similar study was conducted concurrently in Czechoslovakia. The Mayo Lung Project randomized 10,933 male smokers to receive annual chest x-ray plus sputum cytology every four months for six years or to a control group advised, but not required, to obtain the two tests annually (Fontana et al., 1986). Studies conducted at Johns Hopkins and MSKCC randomized 10,387 and 10,040 male smokers respectively to two groups, an intervention group receiving annual chest x-ray plus sputum cytology at four-month intervals or to a control group receiving annual chest x-ray only (Frost et al., 1984; Melamed et al., 1984). All three trials failed to show a significant decrease in lung cancer mortality in the intervention groups. In 2000, an extended follow-up of the Mayo Lung Project continued to support results from the initial analysis, finding no mortality benefit in the screened group (Marcus et al., 2000). In 2009,

Lung Cancer Screening Cancer screening is the testing of relatively healthy asymptomatic individuals for a target disease (Black, 2007; Tanner & Silvestri, 2010). The goal of cancer screening is to decrease cancer mortality rates by identifying preclinical forms of the target disease, thereby preventing, interrupting, or delaying disease progression through early detection. For a number of cancers, early detection equates to a more effective response to treatment and an increased potential for cure. Recent results from the National Lung Screening Trial (NLST), a large National Cancer Institute (NCI)-sponsored randomized screening study, indicated that this is also true for lung cancer (as discussed later). However, unlike other common cancers (e.g., breast, colon, prostate), lung cancer does not yet have an established set of screening guidelines. Also, no major organization (e.g., U.S. Preventive Services Task Force, American College of Physicians, Society of Thoracic Radiology, ACS) has endorsed lung cancer screening for standard practice at this time (Aberle, Gamsu, Henschke, Naidich, & Swensen, 2001; Bach, Silvestri, Hanger, & Jett, 2007; Smith, Cokkinides, & Eyre, 2006; U.S. Preventive 28

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sputum cytology data from the MSKCC Lung Study and the Johns Hopkins Lung Project were reanalyzed to determine if a modest benefit from cytology screening was not detected in previous analyses because of inadequate statistical power (Doria-Rose et al., 2009). Again, reanalysis was unable to demonstrate a statistically significant lung cancer mortality benefit associated with sputum cytology screening. The Czechoslovakian study was initiated in 1976 and evaluated participants with semiannual screening by chest x-ray and sputum cytology (Kubik & Polak, 1986). The study randomized 6,364 male smokers (40–64 years old). After a 15-year follow-up analysis, results supported those from the two U.S. studies. No evidence suggested that screening for lung cancer using chest x-ray plus sputum cytology reduced mortality rates. This study and the three studies conducted in the United States found that screening with chest x-ray and sputum cytology identified more pulmonary malignancies than in unscreened groups and improved survival rates, but failed to show a reduction in lung cancer mortality (Midthun & Jett, 2008). More recently, NCI sponsored the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) to determine if screening could effectively lower mortality rates for cancers of the prostate, lung, colon and rectum, and ovary. These cancers combined account for approximately 45% of U.S. cancer deaths annually (ACS, 2011). The lung cancer component of PLCO consisted of a chest x-ray at study entry and then annually for three years (Prorok et al., 2000). The PLCO accrued participants between 1993 and 2001, randomizing 155,000 males and females to an intervention group receiving screening chest x-ray or to a control group receiving routine care as advised by their healthcare providers. Participants will be followed through 2015. Results for the lung cancer screening component of the PLCO are currently under analysis and expected soon. Table 3-2 describes clinical trial characteristics and results (where available) for lung cancer screening trials focusing on chest x-ray and/or sputum. Excluding pending PLCO results, none of the studies reported evidence that screening for lung cancer with chest x-ray plus sputum cytology decreases lung cancer mortality. A nonrandomized screening study conducted in the United States in the late 1990s, the Early Lung Cancer Action Project (ELCAP), was designed to evaluate baseline and annual repeat screening using LDCT in individuals at high risk for developing lung cancer. The study screened 1,000 asymptomatic high-risk individuals. Noncalcified lung nodules were detected in 23% (233) individuals undergoing LDCT, whereas 7% (68) were detected by means of chest x-ray. Malignant nodules were found in 2.7% (27) by LDCT and 0.7% (7) by chest x-ray. The five-year survival rate for individuals with LDCT-identified malignancies was reported to be as high as 60%–80% (Henschke, 2000). A large multicenter, international, nonrandomized follow-up study, the

International ELCAP (I-ELCAP), screened 31,567 individuals with LDCT in the early 2000s. Lung cancer was diagnosed in 484 patients (1.5%), and 412 (85%) were found to have stage I disease. In the study publication, an increase of up to 88% in the 10-year survival rate for stage I malignancies was reported (Henschke et al., 2006). However, less than 20% of the subjects were observed for more than five years, with a median follow-up of only 40 months. Follow-up for other screened subjects in the study (those not diagnosed with stage I lung cancer) was not reported; thus, the study lacks the ability to estimate a mortality rate for the entire population (Tanner & Silvestri, 2010). Although both ELCAP and I-ELCAP clearly demonstrated that LDCT is highly sensitive and capable of detecting pulmonary nodules at a much higher rate than standard chest x-ray in asymptomatic individuals, it must be stressed that not all lung nodules detected by LDCT are malignant, and in fact, many are benign. Thus, the benefits of lung cancer screening must be carefully weighed against potential harms, which, in addition to false positives and the subsequent risks associated with related diagnostics and treatment, may also include side effects from radiation exposure, patient anxiety, and increased morbidity without decreased mortality from lung cancer (Tanner & Silvestri, 2010). In 2002, the American College of Radiology Imaging Network and the Lung Screening Study Group initiated the NLST in order to reach a conclusion about the usefulness of LDCT for lung cancer screening. The study is an NCIsponsored RCT designed to compare lung cancer mortality between a high-risk cohort screened with LDCT and a control group screened using standard chest x-ray (NLST Research Team, 2010). In less than two years, the NLST recruited 53,464 current or former smokers with a history of 30 or more pack-years (1 pack-year equals 1 pack of cigarettes per day for 1 year) and who were 55–74 years old at more than 30 study sites (Aberle et al., 2010). Subjects were screened annually for three years. NCI released the initial study results from this important study in a press conference on November 4, 2010. Researchers stopped the study early and released the results when the independent Data and Safety Monitoring Board concluded that a 20.3% reduction in lung cancer mortality occurred among trial participants screened with LDCT. A more detailed analysis of the results will be forthcoming. Table 3-3 describes additional RCTs evaluating LDCT.

Biomarkers and Other Lung Cancer Screening Modalities In addition to ongoing chemoprevention and screening clinical trials, other modalities are being evaluated for lung cancer prevention and control. An essential component of cancer prevention research includes the development and validation of biomarkers of risk prediction and early detection. Biomarkers are physical entities that can be 29

LUNG CANCER, SECOND EDITION

Table 3-2. Lung Cancer Screening Trials: Chest X-Ray With or Without Sputum Cytology Number of Subjects

Cancer Cases Detected (Prevalence + Incidence)

Lung Cancer Mortality (Per 1,000 Person-Years)

Chest x-ray plus sputum cytology every four months for six years

4,618

297

4.4

Advice for usual care— annual chest x-ray and sputum cytology

4,593

160

3.9 (20-year follow-up)

Chest x-ray and sputum cytology every four months

5,226

233

3.4

Chest x-ray annually

5,161

242

3.8 (5–8-year follow-up)

Memorial SloanKettering Cancer Center Lung Cancer Screening Program, 1974

Chest x-ray and sputum cytology every four months

4,968

176

2.7

Chest x-ray annually

5,072

178

2.7 (5–8-year follow-up)

Czechoslovakia, 1975

Chest x-ray and sputum cytology every six months for three years

3,172

127

7.8

Chest x-ray and sputum cytology at baseline and end of third year

3,174

82

6.8 (15-year follow-up)

Smokers: chest x-ray at baseline and annually for three years. Neversmokers: chest x-ray at baseline and annually every two years.

77,469

Results pending

Results pending

Usual care

77,468

Lung Cancer Screening Trial Mayo Lung Project, 1971

Johns Hopkins Lung Project, 1973

Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, 1993

Intervention

measured and used to indicate a biologic process, disease process, or response to an agent. The actual material of which biomarkers are made varies from histologic sections, to cytologic smears, to specific types of molecules (DNA/ genes, RNA/proteins, and metabolites). The protracted period of lung carcinogenesis enables monitoring of the premalignant stage, disease progression, and response to intervention with chemopreventive agents. This monitoring is implemented by means of biomarkers, including accumulating genetic alterations in progressively malignant tissue. Biomarkers being evaluated in current studies are found in breath, serum, sputum, and premalignant tissues. Several sensing techniques, such as gas chromatography, mass spectrometry, and colorimetric sensor arrays, are being evaluated to determine if these technologies are effective in

References Flehinger et al., 1993; Fontana et al., 1984, 1986; Marcus et al., 2000; Woolner et al., 1981

Berlin et al., 1984; Frost et al., 1984; Levin et al., 1982

Flehinger et al., 1984; Martini, 1986; Melamed et al., 1984

Kubik et al., 1990, 2000; Kubik & Polak, 1986

Gohagan et al., 2000

detecting volatile organic compounds (VOCs) in the exhaled breath of patients with lung cancer. Metabolic changes in genetically abnormal cells can alter the production and processing of VOCs found in exhaled breath. A number of small studies have shown encouraging results and may prove to be an inexpensive and noninvasive early detection tool for lung cancer in the future (Mazzone et al., 2007; Peng et al., 2009). Autofluorescence bronchoscopy (AFB) employs the use of blue light rather than white light during bronchoscopy. When blue light (wavelength 380–460 nm) illuminates abnormal mucosa, fluorescence is induced and premalignant lesions (e.g., bronchial dysplasia) are more readily identified than with standard white light. Also referred to as laser-induced fluorescence endoscopy (LIFE), a number of research centers 30

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Table 3-3. Helical Computed Tomography Lung Cancer Screening: Randomized Controlled Trials Total Subjects in Intervention Group

Total Subjects in Control Group

National Lung Screening Trial

26,314

26,049

LDCT versus chest x-ray

Smokers and former smokers

National Lung Screening Trial Research Team, 2010

NELSON

7,915

7,907

LDCT versus control

Smokers and nonsmokers; more than 30 pack-years

Xu et al., 2006

DANTE

1,276

1,196

Chest x-ray and sputum cytology at baseline; LDCT versus annual examination

Smokers; more than 20 pack-years

Infante et al., 2008

330

291

LDCT versus chest x-ray for 3 years

Smokers and former smokers

Blanchon et al., 2007

Lung Screening Feasibility Study

1,600

1,658

LDCT versus chest x-ray

Smokers

Gohagan et al., 2005

ITALUNG

1,613

1,593

LDCT annually for 4 years versus no screening

Smokers and former smokers; more than 20 pack-years

Lopes Pegna et al., 2009

Study

DepiScan

Design

Study Population

Reference

DANTE—Detection and Screening of Early Lung Cancer by Novel Imaging Technology and Molecular Essays; LDCT—low-dose computed tomography; NELSON—Nederlands-Leuvens Longkanker Screenings Onderzoek

are evaluating AFB in combination with sputum cytology and LDCT (Lam et al., 2009). Optical coherence tomography (OCT) is an imaging technology designed to visualize structures below the bronchial surface during bronchoscopy. OCT is able to obtain high-resolution cross-sectional microscopic images of tissue, potentially enabling optical biopsy to substitute for conventional excisional biopsy (Tsuboi et al., 2005). The technology is similar in principle to ultrasound but uses infrared light rather than sound waves. Data from early studies demonstrated that it is possible to distinguish dysplastic and carcinoma in situ lesions from lower-grade lesions (Coxson, 2008; Vestbo et al., 2008). Studies are ongoing to evaluate this non-biopsy optical imaging method to study the effect of chemopreventive interventions.

Tobacco use is the primary cause of lung cancer, both from direct inhalation for smokers and by secondary smoke in the environment for nonsmokers. Smoking cessation is the best prevention strategy, though often unsuccessful because of the addictive properties of nicotine, which may also be a tumor promoter. Socioeconomic factors are important in planning smoking cessation strategies because cigarette smoking is more prevalent in lower socioeconomic classes. Other environmental factors are associated with lung cancer, many of which appear to act synergistically with tobacco smoke. One of these is natural radon gas, which can accumulate in homes without adequate ventilation. Others include industrial chemicals, including asbestos. These are largely preventable through adequate ventilation and industrial scrubbing before these chemicals reach the environment. Diet and nutrition may also play a role in prevention of lung cancer. Epidemiologic evidence shows that a diet rich in carotenoids is associated with a decreased incidence of lung cancer, but controlled clinical trials have failed to confirm this and, in fact, have suggested that the opposite is true for smokers, at least in the form of pure beta-carotene. It is possible that some combination of naturally occurring compounds in a high-carotene diet will be responsible for the epidemiologic evidence that is not reproduced in controlled studies with a single compound. Moderate physical activity appears to have a beneficial effect on preventing lung cancer. This may be

Summary Lung cancer is the leading preventable cause of cancer mortality in the United States today. Incidence and mortality rates associated with lung cancer have not changed over the past several decades despite increased understanding of the carcinogenic process, advances in therapeutic interventions, improved imaging technology, and a better understanding of the associations between modifiable lifestyle behaviors and lung cancer. 31

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due to an effect on growth factors, reduction of low-density lipoprotein (or LDL) cholesterol levels, and increasing activity of the immune system. Controlled clinical trials have not been conducted to evaluate this effect. With more than 45 million current adult smokers in the United States and an equal number of former smokers (Peto et al., 2000), a pressing need exists for effective interventions for these high-risk groups. Accumulating knowledge about molecular changes that occur throughout the carcinogenic process continue to guide chemopreventive agent development and biomarker discovery. Although no chemopreventive agent has been discovered to decrease lung cancer risk to date, research is under way in phase I and II clinical trials to evaluate a number of targeted agents for safety and efficacy. At the same time, biomarkers of risk and early detection are being evaluated in these studies and are essential to the success of lung cancer prevention and control strategies. Early efforts in lung cancer screening using chest x-ray and sputum cytology were found to be unsuccessful in decreasing lung cancer mortality rates. Over the past decade, newer imaging technology, specifically LDCT, was introduced in single-arm nonrandomized studies and was reported to be successful in identifying early-stage disease. A major NCIsponsored screening RCT, the NLST, was designed to compare lung cancer mortality between a high-risk cohort screened with LDCT and a control group screened with standard chest x-ray. Recently, the trial was stopped early and results from this important study were released, indicating a 20.3% decrease in mortality for the intervention group. A broader analysis with more detailed results is forthcoming. Further analyses on the extensive data from this definitive trial will be used to propose clinical guidelines and policy recommendations for lung cancer screening. Results from this definitive screening trial will likely have major implications for public health policy and practice.

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CHAPTER 4

Tobacco Control Wendye M. DiSalvo, DNP, NP-C, AOCN®

Introduction

belong to the Mayan Indians of Mexico (Jacobs, 1997). The Native Americans grew tobacco for religious and medical purposes. Tobacco was the first cash crop in North America and was the main source of money for settlers in Jamestown, Virginia, in 1612. By the 1800s, tobacco was chewed or smoked with an average use of 40 cigarettes a year (Jacobs, 1997). Commercially produced cigarettes were available by the end of the Civil War. With the invention of the cigarettemaking machine, which produced 120,000 cigarettes a day, smoking became widespread in 1881. The ability to mass produce and package cigarettes came to fruition with the founding of the First American Tobacco Company, and by the 1900s, several more tobacco companies were established. With the advent of World Wars I and II, soldiers were given free cigarettes, and as women gained independence, their rate of smoking increased. By 1944, more than 300 billion cigarettes a year were being manufactured (Jacobs, 1997). In 1954, the British Medical Journal published an article written by Sir Richard Doll describing a close link between smoking and lung cancer (Doll & Hill, 1952). In 1962, the now famous U.S. surgeon general’s report warned the public about the health hazards related to smoking and indicated that tar and nicotine caused lung cancer (Davies, Houlihan, & Joyce, 2004). A year later, the U.S. Congress passed the Cigarette Labeling and Advertising Act, which made it mandatory to place a warning label on each pack stating “Cigarettes may be hazardous to your health” (Jacobs, 1997). In 1972, the public was warned about the dangers of SHS in the U.S. surgeon general’s report and advertising was banned from television and radio (Jacobs, 1997; Steinfeld, 1972). The classification of environmental tobacco smoke as a class A carcinogen occurred during this period and provided an important health warning (Davies et al., 2004). By the 1980s, the tobacco companies had come out with new brands of cigarettes with lower amounts of

Significant costs to society and individuals are associated with tobacco use. Smoking-related healthcare costs are an estimated $96 billion, and lost productivity costs approximately $97 billion per year (Fiore et al., 2008). Despite the poor outcomes associated with tobacco use, healthcare providers often fall short in recognizing and treating the addiction (Fiore et al., 2008). More than 435,000 deaths related to tobacco use occur each year in the United States. Furthermore, 30%, or 80,000, of all cancer deaths in the United States are related to tobacco use, and 87% of all lung cancers are caused by tobacco use (Ostroff & Dhingra, 2007). Individuals who are exposed to secondhand smoke (SHS) also are at risk. People who are exposed to SHS have an estimated 25% increased risk of lung cancer than people who are not exposed to SHS (World Health Organization [WHO], 2008). Other mortality related to tobacco use includes atherosclerotic cardiovascular disease, chronic obstructive pulmonary disease, and cancers of the aerodigestive tract. Although tobacco use is still a huge health threat, significant progress has occurred during the last half-century. Today, there are more former smokers than current smokers; tobacco use is now labeled a chronic disease rather than a habit; and numerous effective treatments exist and have known efficacy for treating tobacco addiction (Fiore et al., 2008). Despite the progress and all of the warnings on tobacco products, individuals continue to use them, which illustrates the highly addictive properties of nicotine.

History Drawings showing tobacco use dating back to the first century AD were discovered on cave walls and thought to

The author would like to acknowledge Marianne Davies, RN, MSN, ACNP, OCN®, Nancy G. Houlihan, RN, MA, AOCN®, and Margaret Joyce, PhD, RN, AOCN®, APRN-BC, for their contributions to this chapter that remain unchanged from the first edition of this book.

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tar and nicotine and improved filters to keep their customers buying and to help reduce fear. The early 1980s were called the “tar wars” because tobacco companies competed aggressively to make more than 100 brands of low-tar and “ultra” low-tar cigarettes. Each company made and sold many different brands of cigarettes, promoting their safety (Jacobs, 1997). In 1998, the attorneys general of 46 states and the four largest tobacco companies entered into the Tobacco Master Settlement Agreement (National Association of Attorneys General, 1998). The states settled their Medicaid lawsuits against the tobacco industry for recovery of their tobaccorelated healthcare costs by agreeing to receive $206 billion over 25 years. In exchange, the 46 states could not file further lawsuits against the tobacco companies, although the settlement did not preclude individuals from suing (Wilson, 1999). Since the original settlement, the states have spent just 3.2% of $6.5 billion of their tobacco-generated revenue on tobacco prevention and cessation programs (Campaign for Tobacco-Free Kids, 2008). The Robert Wood Johnson Foundation, the American Cancer Society Cancer Action Network, the Campaign for Tobacco-Free Kids, the American Lung Association, and the American Heart Association released A Decade of Broken Promises: The 1998 State Tobacco Settlement Ten Years Later (Lindblom, 2008). This report was an important warning related to tobacco and legislation. The report made clear that the United States will tragically miss an opportunity to win one of the most important public health victories if Congress and the states are unable to demonstrate the political determination to implement proven action plans for tobacco cessation. Although surveys have demonstrated a significant decline in smoking rates during the past 10 years, these rates have begun to slow. From 1997 to 2007, smoking rates declined by 45% among high school students and by 20% among adults. Alarmingly, 20% of high school students and 19.8% of adults are still current smokers. Tobacco use remains the nation’s leading cause of preventable death, taking the lives of more than 400,000 people and costing approximately $100 billion in healthcare expenditures yearly (Saad, 2008). Several significant and encouraging developments have occurred in tobacco control. On February 4, 2009, Congress enacted and President Obama signed into law a 62-cent increase in the federal cigarette tax, taking the tax to $1.01 per pack (Lee, 2009). More than four decades after the U.S. surgeon general warned the public about the health hazards related to smoking, President Obama signed the Family Smoking Prevention and Tobacco Control Act, which gave the U.S. Food and Drug Administration (FDA) unprecedented powers to regulate tobacco. The FDA will now be able to prohibit cigarette advertising, specifically that targeting children, and ban flavored cigarettes and labels such as “low tar” and “light” (Lee, 2009). Although meaningful and comprehensive reforms are taking place in the United States, tobacco control needs to be

elevated as a public health priority, as smoking contributes to health disparities among African Americans, Native Americans, the poor, and individuals with lower educational attainment (Yang & Novotny, 2009). As the U.S. market for tobacco products decreases, the tobacco industry is looking outside the United States for sales. More than one billion people are smokers worldwide, and more than five million tobacco-related deaths occur yearly. If the trend continues, more than eight million people will sustain tobacco-related mortality annually by 2030. Eighty percent of those individuals will reside in developing countries (WHO, 2003). Initiatives to address the global smoking concern are growing. In 2006, Michael R. Bloomberg funded part of a global initiative to reduce tobacco use in low- and middle-income countries through the use of grants to develop and deliver high-impact, evidence-based tobacco-control interventions (Henning, 2008). The first international, legally binding treaty, the WHO Framework Convention on Tobacco Control, was initiated in 2003 to address this issue and has been ratified by more than 168 countries (WHO, 2003). The treaty calls for a wide range of restrictions on tobacco advertising, promotion, smuggling, and misleading tobacco descriptors. The treaty also addresses tobacco treatment, usage of pictorial health warnings, and protection from SHS (WHO, 2003). Three global progress reports have been published to monitor implementation of the Convention report. Although variation and gaps exist in implementation of all policy measures, the five-year implementation report demonstrates a positive trend in global progress with more than half the Convention articles having high implementation rates (WHO, 2010).

Nursing Nurses are in a powerful position to facilitate change. They need to be aware of existing tobacco-control policies and how those policies influence tobacco cessation resources and quit rates (Bialous, 2006). Nursing encompasses one of the largest groups of health professionals and is well known by the public. Most individuals in our society personally know a nurse, and nurses usually are regarded as honest and ethical. Thus, nurses are in a prime position to be formidable crusaders in the arena of tobacco cessation (Malone, 2006). The barriers for nursing interventions include lack of support for nurses addicted to tobacco and the absence of tobacco cessation strategies in nursing curricula and integration of those strategies into nursing practice. Overcoming these barriers is crucial for nurses to assume an active role in cessation efforts (Schultz, 2002). In 2003, nursing leaders in education founded the Nurses for Tobacco Control Coalition (NTCC), whose purpose is to provide a comprehensive Web site for tobacco control. This 38

CHAPTER 4. TOBACCO CONTROL

Tobacco Dependence

site provides tools and resources for nurses to intervene with tobacco users. Acquisition of tobacco cessation knowledge helps nurses to facilitate the promotion of system changes for comprehensive access to cessation treatments and better policies to prevent and treat tobacco use. Public polices related to tobacco control can be created at the local, state, and national levels either in the form of legislation or regulations. In January 2004, healthcare professionals, including several nursing organizations, convened in Switzerland under the auspices of WHO to approve the Code of Practice on Tobacco Control for Health Professional Organizations. The code is a comprehensive policy statement focusing on facilitating healthcare professionals’ involvement in tobacco control, including their own cessation needs. The policy calls for professionals to utilize tobacco cessation interventions with their individual patients and the community at large and to integrate cessation strategies in practice as a standard of care (Bialous, 2006). In 2006, University of California, Los Angeles, School of Nursing professor Linda Sarna launched the Tobacco Free Nurses campaign (Tobacco Free Nurses, 2006). The organization’s Web site provides help for tobacco-addicted nurses and resources for nurses to help individuals quit and to facilitate tobacco control in the agenda of nursing organizations. A review of the literature showed that nurses can deliver effective evidence-based tobacco cessation interventions (Rice & Stead, 2008). Nurses have numerous opportunities to deliver the interventions: in the community, in hospitals, and in outpatient settings. Nurses can have an important voice in facilitating and leading effective tobaccocontrol policies (Sarna & Bialous, 2005; Sarna, Bialous, Barbeau, & McLellan, 2006). A paucity of tobacco-related research articles are published in nursing journals. Significant gaps in knowledge exist regarding effective tobacco cessation interventions with certain target groups and how nursing professionals can facilitate the acquisition of scientific knowledge. Areas that will benefit from nursing research include underserved populations, low socioeconomic populations, individuals with mental illness, and women (Sarna & Bialous, 2006). Professional organizations such as the Oncology Nursing Society, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network are advocates of tobacco cessation in patients with cancer, and these organizations recommend the assessment of smoking status in clinical trials involving these patients. Oncology nurses are in a unique position to facilitate tobacco cessation. In their practices, they witness the significant health consequences of tobacco use. In the past, a fatalistic attitude existed concerning tobacco cessation interventions for patients with cancer. As healthcare professionals’ attitudes shift to visualize patients with cancer as survivors, interventions aimed at cessation need to be a priority (Ostroff & Dhingra, 2007).

The use of nicotine in the form of tobacco products is associated with stimulation, pleasure, and stress and anxiety reduction. Tobacco may improve concentration, reaction time, and performance ability (Hurt, Ebert, Hays, & McFadden, 2009). With the absence of the substance, smokers may experience withdrawal symptoms that include irritability, depressed mood, anxiety, strained relationships with family and friends, increase in appetite, insomnia, and craving for tobacco. High concentrations of nicotine reach the central nervous system within seconds of the first puff. The positive reinforcement or reward found with tobacco use is a result of nicotine binding with the α4b2 nicotine acetylcholine receptor, which signals the release of dopamine in the brain’s reward center (Hurt et al., 2009). Just one cigarette leads to a substantial level of saturation of these receptors, and three cigarettes fully occupy these receptors for as long as three hours (Hurt et al., 2009). Nicotine addiction has a predictable recurring pattern of wanting-craving-needing the substance. Smokers lose autonomy over using tobacco products, which explains why it is so hard for users to quit. Individuals are free to use tobacco products when they have a desire but are not free to quit whenever they want to stop because wanting-cravingneeding makes it a difficult and unpleasant experience. Smokers engage in tobacco use that is elective and tobacco use that is compulsory. The longer an individual uses tobacco products, the more cigarettes become compulsive, and fewer cigarettes are elective (DiFranza, 2008). The use of nicotine sustains tobacco addiction, which in turn leads to significant sequelae including heart disease, lung disease, cancer of the aerodigestive tract, and increased susceptibility to infectious diseases (Hurt et al., 2009).

Pathophysiology of Nicotine Addiction Nicotine is a lipid-soluble alkaloid found mainly in tobacco plants. Although nicotine can be commercially synthesized, nearly all nicotine is obtained from tobacco plants, including the nicotine used in nicotine replacement therapy (NRT). Nicotine easily crosses the blood-brain barrier and the placenta. Upon inhaling tobacco smoke from a cigarette, nicotine is distilled and carried in smoke particles into the lung, where it is absorbed quickly into the pulmonary venous circulation. Nicotine then enters the arterial system and reaches the brain, where it diffuses and binds to nicotinic cholinergic receptors. In the brain, the receptors are mainly composed of alpha-4 subunits. Stimulation of the receptors results in the release of neurotransmitters. Nicotine causes the release of dopamine in the mesolimbic area, the corpus striatum, and the frontal cortex of the brain. The primary areas of importance are the dopaminergic neurons in the ventral 39

LUNG CANCER, SECOND EDITION

tegmental area and the release of dopamine from the nucleus accumbens. This pathway is linked to the drug-induced reward system in the brain (Hurt et al., 2009). Other neurotransmitters are mediated by nicotine, including norepinephrine, acetylcholine, serotonin, gammaaminobutyric acid, glutamate, and other endorphins (Benowitz, 2009). Increased concentrations of the α4b2 nicotinic acetylcholine receptor exist in the mesolimbic dopamine system (pleasure) and the locus coeruleus (cognitive function). The upregulation of these receptors is crucial for the development of tolerance and dependence on nicotine (Balfour, 1991; Hurt et al., 2009). The number of receptors is increased as a result of repeated exposures to high nicotine concentrations. Nicotine withdrawal is associated with deficient dopamine release and reduced reward. This is an essential component of addiction and a significant barrier to abstinence. The presence of a withdrawal state can result in an individual relapsing. The locus coeruleus is a densely compacted region of cells that pulse, just like a heartbeat. This pulsing activity determines the firing rate of noradrenergic (norepinephrine) neurons with projections to different brain areas and the autonomic nervous system. A correlation exists between how fast the locus coeruleus pulses and noradrenergic firing. This results in increased feelings of anxiety and restlessness, which signify nicotine withdrawal. Other symptoms of withdrawal and barriers to quitting include depressed mood, insomnia, irritability, difficulty concentrating, decreased heart rate, increased appetite, and weight gain. Tobacco users become habituated to associate the satisfying effects of tobacco use with their individual triggers such as coffee, alcohol, meals, and driving (Rigotti, 2002).

8,700 articles from 1975 to 2008 (Fiore et al., 2008). The guidelines emphasize that tobacco use is a chronic medical disorder where counseling, problem-solving and coping strategies, social support, and pharmacotherapy are essential in facilitating a person to quit. The 10 key findings are summarized in Figure 4-1. Each of the guidelines was based on a meta-analysis of research studies and provides healthcare professionals with evidence-based information. Important developments have occurred since the original guidelines were published: increased insurance coverage of tobacco treatment interventions, increased utilization and effectiveness of telephone quit lines, and the Joint Commission’s requirement that hospitals provide tobacco treatment interventions for hospitalized tobacco users who have experienced a myocardial infarction, congestive heart failure, or pneumonia (Hurt et al., 2009). When asked, approximately 70% of U.S. smokers say they want to quit, and more than 40% of smokers have made at least one quit attempt in the past year. Abstinence from tobacco products for a year is considered a quit, and only 5%–7% of users are able to sustain a quit (Fiore et al., 2008). It is imperative that healthcare providers use the five A’s algorithm developed by the U.S. Public Health Service guidelines for the elements of brief counseling: ask about smoking status, advise the smoker to quit, assess readiness to quit, assist the individual’s quit attempt, and arrange for follow-up visits (Fiore et al., 2008).

Figure 4-1. Smoking Cessation Clinical Practice Guideline Findings • Tobacco addiction is a chronic condition that often requires multiple interventions and repeated quit attempts. • It is imperative that healthcare providers and healthcare delivery systems consistently identify and document tobacco use, and every tobacco user should be treated. • Every tobacco user willing to make a quit attempt should be encouraged to use counseling and medication recommended in the guideline. • Healthcare providers should offer the recommended brief effective interventions listed in the guideline. • Treatment intensity increases the effectiveness of individual, group, and telephone counseling. • Clinicians should utilize the medications approved in treating tobacco dependence: bupropion, nicotine replacement therapy, and varenicline. Combinations of these medications can be used in treatment. • Counseling and medications are effective as single agents but have increased efficacy when used in combination. • Telephone quit line counseling is effective and reaches a broad and diverse population. • Motivational treatments as described in the guideline should be employed if the tobacco user is unwilling to make a quit attempt.

Tobacco Dependence Treatment The sequelae of tobacco use account for serious illness in 8.6 million Americans per year. Because of this significant morbidity and mortality, treatment of tobacco addiction is paramount (WHO, 2008). Although the link between smoking and lung cancer is well known, the benefits of stopping smoking after a diagnosis of lung cancer are not as well recognized. Cessation of tobacco use has been associated with improved tolerance to treatment, improved survival, and a decreased risk of developing a secondary cancer (Gritz, 2006). Smoking cessation practice guidelines have been developed for the delivery of succinct recommendations and evidence-based interventions. A panel of 37 experts in tobacco cessation first published the U.S. Department of Health and Human Services (DHHS) clinical practice guidelines for treating tobacco use and dependence. These guidelines were updated in 2000 and again in 2008. The guidelines are based on an extensive literature review of

Note. Based on information from Fiore et al., 2008.

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Research on tobacco cessation counseling has generally examined intensive counseling strategies that consist of repeated office visits and phone calls with a trained specialist, which have proved effective in increasing long-term abstinence (Ranney, Melvin, Lux, McClain, & Lohr, 2006). Minimal or brief interventions lasting less than 3 minutes in duration can also positively affect tobacco cessation rates, and interventions lasting more than 10 minutes are nearly twice as effective as brief advice. Multimodality cessation interventions in which healthcare providers strongly advise cessation, offer pharmacotherapy and support, and provide referral for more intense cessation counseling can increase quit rates by twofold (Fiore et al., 2008). The optimum strategy is to refer the tobacco user to a tobacco treatment specialist who is trained in cessation strategies and behavioral counseling.

et al., 2008). For those individuals unwilling to make a quit attempt, the use of motivational interviewing (MI) may move them toward quitting. MI is an intervention that is directive and focused on patient-centered counseling. The goal is to uncover any ambivalence about using tobacco by exploring the person’s feelings, beliefs, ideas, and values about tobacco use. Four general principles are the foundation for MI: expression of empathy, development of discrepancy, rolling with resistance, and support of self-efficacy (Rollnick & Miller, 1995). With the use of MI techniques, the content should reflect the five Rs: relevance, risks, rewards, roadblocks, and repetition. Research implies that the five Rs facilitate future quit attempts (Fiore et al., 2008). Several other approaches to counseling include in-person, telephone, and Web-based methods and clinician counseling. Counseling is most effective when cognitive-behavioral techniques are used, including self-monitoring rate, changing brands to decrease nicotine intake (known as brand fading), and setting a quit date. In-person counseling is characterized by weekly visits that start before the quit date and continue for several months after cessation has been achieved. Group programs are offered by voluntary health programs and commercial programs and are characteristically a lectureformat strategy for tapering use, exploring coping skills, and preventing relapse for the tobacco user (Ranney et al., 2006). One issue with these programs is that the timing of the visits or group meetings may not be convenient. Telephone counseling is an acceptable alternative. Tobacco users can take advantage of these free services in the United States by calling 800-QUIT-NOW (800-784-8669). Clinician counseling occurs in the office practice setting or in an inpatient hospital setting. Advice combined with brief counseling by a clinician significantly improves the chances of success (Stead, Bergson, & Lancaster, 2008).

Behavioral Approaches Prochaska and DiClemente (1994) developed a transtheoretical model/stages-of-change model based on their extensive research on adult smoking cessation. The theory proposed that health-related behavior change evolves through five stages of change. The theory can be employed to assess tobacco users’ motivation for cessation as well as to guide interventions (Prochaska, Redding, & Evers, 1997). The five stages are precontemplation, contemplation, preparation, action, and maintenance. Although 90% of tobacco users verbalize the need for cessation, only 20% are ready to quit in the next six months (Velicer et al., 1995). Once the stage of change is identified, appropriate interventions can be employed. The characteristic described in the precontemplation phase is the lack of interest in quitting in the next six months. Effective interventions include inserting doubt about the benefits of smoking, assessment of the tobacco user’s reasons for continued smoking, and his or her fears about withdrawal. In the contemplation stage, the individual is considering quitting in the next two to six months. Enhancing the motivation to quit through discussing the reasons to change and enhancing self-efficacy is the appropriate intervention in this stage. The preparation phase is described as preparing to quit in the next 30 days. For most tobacco users, this is not the first attempt at quitting; therefore, the intervention focuses on enabling the tobacco user to sustain a quit. In the action phase, the tobacco user has been abstinent for the past six months. Identifying barriers to maintaining the quit and enabling the individual to develop effective coping strategies are appropriate interventions. In the last stage of change, maintenance, the tobacco user has not used tobacco for more than six months. Identifying potential situations where a slip could occur is an appropriate intervention (Abrams et al., 2003). A lack of information about the harmful effects of tobacco and the benefits of quitting, a lack of financial resources, previous failed quit attempts, and fear of withdrawal may negatively affect an individual in making a quit attempt (Fiore

Pharmacotherapy As tobacco use is both a learned behavior and a physical addiction to nicotine, the combination of counseling and pharmacotherapy is synergistic. The 2008 DHHS guidelines recommend that pharmacotherapy be offered to all smokers who are making a quit attempt unless medically contraindicated. The most rapid delivery of nicotine to the central nervous system is the cigarette, which contributes to the dependency-producing properties of tobacco. It is important that the individual making the quit attempt stays as comfortable as possible in order to facilitate the quit (Fiore et al., 2008). The first-line FDA-approved medications used for tobacco cessation treatment include three categories of NRT, bupropion, and varenicline, which can be used alone or in combination (Fiore et al., 2008). The five types of nicotine products are the patch (three strengths), inhaler, gum (two strengths), lozenges (two strengths), and nasal spray. The patch, gum, and lozenges 41

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are over-the-counter medications. The other two products are available by prescription. By using nicotine replacement products, the tobacco user is able to alleviate withdrawal while breaking the behavior of smoking. These medications along with dose, duration of therapy, adverse events, and special notes are found in Table 4-1. Tobacco users who do not tolerate the side effects of one medication should be offered a lower dose or an alternative agent. Tobacco users who experience severe withdrawal should have their dose of medication increased or be placed on a combination of medications, such as two forms of NRT. NRT can be combined with bupropion. At this time, no efficacy data are available on combining varenicline with bupropion or NRT. Patients who fail combined-modality therapy will need increased behavioral counseling and support (Fiore et al., 2008).

One novel agent not found in Table 4-1 is the nicotine vaccine, which enables the body to generate specific antinicotine antibodies. When the person smokes, the antibody binds to nicotine in the bloodstream and forms a large antibody complex that is too large to cross the blood-brain barrier. Thus, nicotine does not reach the receptors in the brain, which, in theory, decreases the reinforcing effect of smoking. Three are in the final stages of clinical evaluation, and approval is expected in the near future. Despite the significant therapeutic potential of these vaccines, they do not target the nonpharmacologic factors of tobacco dependence and for maximal effectiveness will require combination with behavioral interventions that motivate abstinence from tobacco use (Escobar-Chávez, Domínguez-Delgado, & Rodríguez-Cruz, 2011).

Table 4-1. Pharmacotherapy for Tobacco Addiction Recommended Products

Dose

Duration

Adverse Events

Special Notes

First-Line Treatment Nicotine patch Over the counter (OTC)

21 mg/24 hours 14 mg/24 hours 7 mg/24 hours

4 weeks 2 weeks 2 weeks

Local skin reaction—Usually mild. Treat by rotating site and applying 1% hydrocortisone cream. Insomnia/vivid dreams—Apply patch on waking in the morning. May remove at bedtime.

Most smokers start with the 21 mg patch, but if smoking less than 10 cigarettes a day, they may start with a 14 mg patch. Pregnant smokers should be encouraged to quit without medication. Nicotine is U.S. Food and Drug Administration pregnancy category D for all products. Nicotine replacement therapy must be used with caution in the presence of cardiovascular disease.

Nicotine gum OTC

2 mg per piece (less than 25 cigarettes a day) 4 mg per piece (25 or more cigarettes a day)

Use one piece at least every 1–2 hours for 6 weeks up to 12 weeks. The maximum dose is 24 pieces a day.

Oral irritation Hiccups Dyspepsia Jaw ache

The gum should be chewed slowly until a flavor emerges, then it should be parked between the cheek and gum for ultimate absorption (park and chew). Acidic fluids (coffee, juices, and soft drinks) interfere with nicotine absorption. Avoid these beverages for 15 minutes prior to and during chewing.

Nicotine lozenge OTC

2 mg per piece for individuals who smoke their first cigarette more than 30 minutes after waking 4 mg per piece for individuals who smoke their first cigarette within 30 minutes

Allow to dissolve in the mouth rather than chewing or swallowing. Use at least 9 pieces per day in the first 6 weeks and use for up to 12 weeks with no more than 20 pieces per day.

Nausea Hiccups Heartburn

Acidic fluids (coffee, juices, and soft drinks) interfere with nicotine absorption. Avoid these beverages for 15 minutes prior to and during usage.

(Continued on next page)

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Table 4-1. Pharmacotherapy for Tobacco Addiction (Continued) Recommended Products

Dose

Duration

Adverse Events

Special Notes

Nicotine inhaler Prescription

Each cartridge contains a total of 4 mg nicotine over 80 inhalations.

6–16 cartridges a day for up to 6 months Tapering is recommended during the last 3 months.

Local irritation in the mouth or throat Coughing Rhinitis

Acidic fluids (coffee, juices, and soft drinks) interfere with nicotine absorption. Avoid these beverages for 15 minutes prior to and during the inhalation.

Nicotine spray Prescription

Each dose of the spray consists of one 0.5 mg to each nostril

Recommended dose is 8 doses a day with a maximum limit of 40 doses per day (5 doses/hour). Duration of therapy is 3–6 months.

Nasal irritation may be moderate to severe in the first 2 days. Nasal congestion Transient changes in sense of smell or taste

Nicotine spray has the highest potential for addiction.

Bupropion Prescription

Start 1–2 weeks before the quit date. Individuals start with 150 mg daily for 3 days and then twice daily for 7–12 weeks.

May be used for up to 6 months after the quit date.

Hypertension Insomnia Dry mouth Contraindicated in individuals with history of seizures, eating disorders, or history of using a monoamine oxidase inhibitor (MAOI) in the past 14 days

Alcohol only in moderation

Varenicline Prescription

One week prior to the quit date, an upward titration from 0.5 mg once a day for 3 days, to 0.5 mg twice daily for 4 days to 1 mg twice daily

Patients are instructed to quit smoking on the eighth day after starting varenicline and continue the drug for up to 6 months.

Depression Suicidal ideation Neurocognitive changes Insomnia Nightmares Nausea

Black box warning includes depressed mood, agitation, neurocognitive effects, changes in behavior, and suicidal ideation. Class C agent in pregnancy Use cautiously in individuals with creatinine clearance less than 30 ml/minute or patients who are on dialysis. Patients should use caution when driving or operating heavy equipment.

Second-Line Medications Clonidine Prescription only

Typically dose is 0.10 mg twice daily orally or 0.10 mg/day transdermal

3–10 weeks

Dry mouth Drowsiness Dizziness Sedation Constipation Hypotension Rebound hypertension

Class C agent in pregnancy Patients should use caution when driving and operating heavy equipment.

Nortriptyline Prescription only

Start at 25 mg/day. May be slowly titrated to 75–100 mg/day. Start 10–28 days before quit date.

6–12 months of therapy

Sedation Dry mouth Blurred vision Urinary retention Light-headedness Shaky hands

Class D agent in pregnancy Patients should use caution when driving and operating heavy equipment. Use caution in patients with cardiovascular disease, and do not coadminister with MAOIs. Overdose may be fatal.

Note. Based on information from Fiore et al., 2008.

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Summary

Lee, C.E. (2009, June 22). President Obama signs tobacco legislation. Retrieved from http://www.politico.com/news/stories/0609/24029 .html Lindblom, E. (2008, November 11). A decade of broken promises: The 1998 State Tobacco Settlement ten years later. Retrieved from http://www.rwjf.org/files/research/2008118ctfk2008report .pdf Malone, R.E. (2006). Nursing’s involvement in tobacco control: Historical perspective and vision for the future. Nursing Research, 55(Suppl. 4), S51–S57. National Association of Attorneys General. (1998). Master settlement agreement. Retrieved from http://www.naag.org/backpages/naag/ tobacco/msa/msa-pdf/MSA%20with%20Sig%20Pages%20 and%20Exhibits.pdf Ostroff, J.S., & Dhingra, L.K. (2007). Smoking cessation and cancer survivors. In M. Feuerstein (Ed.), Handbook of cancer survivorship (pp. 303–322). New York, NY: Springer. Prochaska, J.O., & DiClemente, C.C. (1994). The transtheoretical approach: Crossing traditional boundaries of therapy. Malabar, FL: Krieger. Prochaska, J.O., Redding, C.A., & Evers, K.E. (1997). The transtheoretical model and stages of change. In K. Glanz, F.M. Lewis, & B.K. Rimer (Eds.), Health behavior and health education: Theory, research, and practice (2nd ed., pp. 60–84). San Francisco, CA: Jossey-Bass. Ranney, L., Melvin, C., Lux, L., McClain, E., & Lohr, K.N. (2006). Systematic review: Smoking cessation intervention strategies for adults and adults in special populations. Annals of Internal Medicine, 145, 845–856. Rice, V.H., & Stead, L.F. (2008). Nursing interventions for smoking cessation. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD001188. doi:10.1002/14651858.CD001188.pub3 Rigotti, N.A. (2002). Clinical practice: Treatment and tobacco use and dependence. New England Journal of Medicine, 346, 506–512. doi:10.1056/NEJMcp012279 Rollnick, S., & Miller, W.R. (1995). What is motivational interviewing? Behavioral and Cognitive Psychotherapy, 23, 325–334. doi:10.1017/S135246580001643X Saad, L. (2008, July 24). U.S. smoking rates still coming down: About one in five American adults now smoke. Retrieved from http://www.gallup.com/poll/109048/US-Smoking-Rate-Still -Coming-Down.aspx Sarna, L., & Bialous, S. (2005). Tobacco control in the 21st century: A critical issue for the nursing profession. Research and Theory for Nursing Practice, 19, 15–24. Sarna, L., Bialous, S., Barbeau, E., & McLellan, D. (2006). Strategies to implement tobacco control policy and advocacy initiates. Critical Care Nursing Clinics of North America, 18, 113–122. doi:10.1016/j.ccell.2005.11.002 Sarna, L., & Bialous, S.A. (2006). Strategic directions for nursing research in tobacco dependence. Nursing Research, 55(Suppl. 4), S1–S9. Schultz, A.S. (2002). Nursing and tobacco reduction: A review of the literature. International Journal of Nursing Studies, 40, 571–586. doi:10.1016/S0020-7489(03)00038-5 Stead, L.F., Bergson, G., & Lancaster, T. (2008). Physician advice for smoking cessation. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD000165. doi:10.1002/14651858. CD000165.pub3 Steinfeld, J.L. (1972). The health consequences of smoking—A report of the surgeon general: 1972. Retrieved from http://profiles.nlm. nih.gov/NN/B/B/P/M/_/nnbbpm.pdf Tobacco Free Nurses. (2006). UCLA nursing school professor launches national campaign to help nurses quit smoking [Press release]. Retrieved from http://tobaccofreenurses.org

Tobacco use is the leading preventable cause of death worldwide. Effective tobacco control and cessation interventions can significantly reduce morbidity and mortality from the use of tobacco products. Tobacco users need to be managed with behavioral support, pharmacotherapy, and long-term follow-up. Patients with cancer are no exception and will benefit by quitting tobacco use. Nurses, including oncology nurses, are in a unique and powerful position to counsel patients to quit and advocate for tobacco-control legislation and nursing research.

References Abrams, D.B., Niaura, R., Brown, R.A., Emmons, K.M., Goldstien, M.G., & Monti, P.M. (2003). In D.H. Barlow (Ed.), The tobacco dependence treatment handbook (pp. 1–26). New York, NY: Guilford Press. Balfour, D.J. (1991). The influence of stress on psychopharmacological responses to nicotine. British Journal of Addiction, 86, 489–493. Benowitz, N.L. (2009). Pharmacology of nicotine: Addiction, smoking-induced disease, and therapeutics. Annual Review of Pharmacology and Toxicology, 49, 57–71. doi:10.1146/annurev. pharmtox.48.113006.094742 Bialous, S.A. (2006). Tobacco use cessation within the context of tobacco control policy: Opportunities for research. Nursing Research, 55(Suppl. 4), S58–S63. Campaign for Tobacco-Free Kids. (2008). On 10th anniversary of 1998 tobacco settlement, report finds most states fail to adequately fund tobacco prevention programs. Retrieved from http://www.tobaccofreekids.org/Script/DisplayPressRelease. php3?Display=1111 Davies, M., Houlihan, N.G., & Joyce, M. (2004). Lung cancer control. In N.G. Houlihan (Ed.), Site-specific cancer series: Lung cancer (pp. 17–34). Pittsburgh, PA: Oncology Nursing Society. DiFranza, J.R. (2008). Hooked from the first cigarette. Scientific American, 298, 82–87. Doll, R., & Hill, A.B. (1952). A study of the aetiology of carcinoma of the lung. BMJ, 2, 1271–1286. Retrieved from http://www.ncbi. nlm.nih.gov/pmc/articles/PMC2022425/?tool=pubmed Escobar-Chávez, J.J., Domínguez-Delgado, C.L., & Rodríguez-Cruz, I.M. (2011). Targeting nicotine addiction: The possibility of a therapeutic vaccine. Drug Design, Development and Therapy, 5, 211–224. doi:10.2147/DDDT.S10033 Fiore, M.C., Jaen, C.R., Baker, T.B., Bailey, W.C., Benowitz, W.C., Curry, S.J., … Wewers, M.E. (2008, May). Clinical practice guidelines— Treating tobacco use and dependence: 2008 update. Retrieved from http://www.surgeongeneral.gov/tobacco/treating_tobacco_use08.pdf Gritz, E. (2006). Smoking and smoking cessation in cancer patients. British Journal of Addiction, 86, 549–554. Henning, K.J. (2008). Bloomberg initiative to reduce tobacco use: Highlights and lessons learned [PowerPoint presentation]. Retrieved from http://www.powershow.com/view/1d26d-YmJhY/Bloomberg_ Initiative_to_Reduce_Tobacco_Use_flash_ppt_presentation Hurt, R.D., Ebert, J.O., Hays, J.T., & McFadden, D.D. (2009). Treating tobacco dependence in a medical setting. CA: A Cancer Journal for Clinicians, 59, 314–326. doi:10.3322/caac.20031 Jacobs, M. (1997). From the first to the last ash: The history, economics and hazards of tobacco. Retrieved from http:// healthliteracy.worlded.org/docs/tobacco/Unit1/2history_of.html 44

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Velicer, W.F., Fava, J.L., Prochaska, J.O., Abrams, D.B., Emmons, K.M., & Pierce, J.P. (1995). Distribution of smokers by stage in three representative samples. Preventive Medicine, 24, 401–411. doi:10.1006/pmed.1995.1065 Wilson, J.J. (1999, March). Summary of the Attorney General Master Settlement Agreement. National Conference of State Legislators. Retrieved from http://academic.udayton.edu/health/syllabi/ tobacco/summary.htm World Health Organization. (2003). The WHO framework convention on tobacco control. Retrieved from http://whqlibdoc.who.int/ publications/2003/9241591013.pdf

World Health Organization. (2008, April 1). Are the number of cancer cases increasing or decreasing in the world? Retrieved from http:// www.who.int/features/qa/15/en/ World Health Organization. (2010). 2010 global progress report on the implementation of the WHO Framework Convention on Tobacco Control. Retrieved from http://www.who.int/fctc/ reporting/progress_report_final.pdf Yang, J.S., & Novotny, T.E. (2009). Policy coherence in US tobacco Control: Beyond FDA regulation. PLoS Medicine, 6(5), e1000079. doi:10.1371/journal.pmed.1000079

45

CHAPTER 5

Clinical Presentation and Diagnostic Evaluation Leslie B. Tyson, MS, APRN, BC, OCN®

Introduction

2003). Once signs and symptoms develop, the malignancy usually is advanced and resection may not be possible. Signs and symptoms are categorized as those from local-regional effects of tumor, extrathoracic spread of tumor, or systemic symptoms. See Table 5-1 for the clinical manifestations of lung cancer.

Lung cancer is not only a prevalent disease but a lethal one; an estimated 156,940 men and women died from the disease in 2011 (Siegel, Ward, Brawley, & Jemal, 2011). Because of this, clinicians must be aware of the different clinical presentations of lung cancer, including oncologic emergencies and paraneoplastic syndromes, and astute in the assessment of patients with potential or suspected lung cancer. The clinical presentation of lung cancer varies widely. Approximately 5%–10% of patients with lung tumors are asymptomatic, and the cancer is found incidentally on routine examination (e.g., chest x-ray performed for unrelated preoperative testing) (Wozniak & Gadgeel, 2010). Others may present with symptoms related to local or distant effects of the lung cancer that have been present for varying amounts of time. Signs and symptoms of oncologic emergencies and paraneoplastic syndromes prompt others to see their physicians or go to the emergency department. The first part of this chapter will focus on the clinical presentations of lung cancer, including signs and symptoms of oncologic emergencies and paraneoplastic syndromes. The second part of this chapter will provide a summary of the diagnostic tests used to determine the presence of lung cancer.

Table 5-1. Clinical Manifestations Associated With Lung Cancer Category

Clinical Presentation Lung cancer may be present for several years before symptoms develop. Typically, lung cancer has a delayed presentation; signs and symptoms of lung cancer develop once the tumor is large enough to interfere with normal lung function or when the tumor has spread to distant areas and causes problems, such as pain from bone metastases. Signs and symptoms of lung cancer depend on the area of involvement. More than 90% of patients are estimated to have symptoms at presentation (Beckles, Spiro, Colice, & Rudd,

Signs and Symptoms

Local-regional manifestations

Cough Dyspnea Hemoptysis Wheezing Chest pain or discomfort Lymphadenopathy Hoarseness Pneumonia Pancoast syndrome Pleural effusion Pericardial effusion Superior vena cava syndrome

Manifestations of extrathoracic involvement

Headache Central nervous system disturbances Gastrointestinal disturbances Bone pain Hepatomegaly

Systemic symptoms

Weakness Fatigue Anorexia Cachexia Weight loss Anemia Symptoms associated with paraneoplastic syndromes

Note. From “Lung Cancers” (p. 1308), by R.J. Ingle in C.H. Yarbro, M.H. Frogge, M. Goodman, and S.L. Groenwald (Eds.), Cancer Nursing: Principles and Practice (5th ed.), 2000, Sudbury, MA: Jones and Bartlett. Copyright 2000 by Jones and Bartlett. Adapted with permission.

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Local-Regional Effects of Tumor

type of wheeze that is caused by partial obstruction of the larynx or trachea. It primarily occurs on inspiration and tends to be loud and gasping in character (Merck Manuals Online Edition, n.d.). It is a medical emergency requiring prompt recognition and treatment (Wozniak & Gadgeel, 2010). Chest pain is another common presenting symptom, estimated to occur in 30%–45% of patients at diagnosis (Wozniak & Gadgeel, 2010). This pain can have several etiologies, including primary tumor that extends into the chest cavity, pleural metastases, and tumors that invade the brachial plexus nerves. Chest pain that involves the pleural cavity can indicate either tumor or pulmonary embolism (EabySandy, 2011). In others, the pain may be inexplicable (Wozniak & Gadgeel, 2010). Established methods of pain control should be used in these patients regardless of the pain etiology. Hoarseness is caused by tumor impingement or invasion of the left recurrent laryngeal nerve and is the result of locally advanced disease. The laryngeal nerves supply the vocal cords and allow humans to perform three basic functions: swallowing (by sealing the trachea), breathing (by opening the cords over the airway), and speaking (Krishna & Rosen, 2008). Anatomically, the left recurrent laryngeal nerve passes through the aortic arch. Hoarseness is caused by lymphadenopathy in the anterior mediastinum or aortopulmonary window that invades or impinges the recurrent laryngeal nerve. In patients with lung cancer, the left recurrent laryngeal nerve most often is damaged because of its anatomic location. Paralysis or poor function of the left recurrent laryngeal nerve from tumor can result in aspiration and poor cough reflex. These patients need to be carefully evaluated if pulmonary dysfunction (i.e., poor cough reflex, aspiration, and dysphagia) is suspected. Hoarseness indicates locally advanced disease, and surgery is usually not an option for these patients (Wozniak & Gadgeel, 2010). Permanent damage to the recurrent laryngeal nerve from the tumor cannot be corrected with systemic treatment, even if the tumor responds. In patients with pulmonary dysfunction, the current treatment of choice is open medialization of the vocal cord (Krishna & Rosen, 2008). This can be achieved by one of two surgical procedures: injection augmentation (IA) or laryngeal framework surgery, also known as type I thyroplasty (Krishna & Rosen, 2008). IA can be performed in the outpatient setting with local anesthesia and light sedation. This procedure uses one of several substances (Gelfoam®, collagen, autologous fat, or Radiesse® Voice Gel). Gelfoam and collagen provide a temporary solution, whereas Radiesse and autologous fat are permanent solutions (Krishna & Rosen, 2008). Laryngeal framework surgery (medialization laryngoplasty) involves inserting a Gore-Tex or Silastic implant in a pocket created near the vocal fold (Krishna & Rosen, 2008). This procedure is a permanent solution. The purpose of either procedure is to move the vocal cord to the midline, thereby promoting proper or near-proper functioning of the vocal cords. Dysphagia and paralysis of the phrenic nerve are the result of locally advanced disease. Dysphagia can occur in patients

Cough is the most common presenting symptom and occurs in 8%–75% or more of all patients diagnosed with lung cancer (Baldwin, 2003; Eaby-Sandy, 2011; Spiro, Gould, & Colice, 2007). Cough is more common in patients who have centrally located tumors or in those with pleural effusions. In patients who are current smokers, subtle changes may occur in the cough. For many, the cough initially is attributed to smoking. In others, it may be attributed to an upper respiratory tract infection, and one or more courses of empiric antibiotics are prescribed before additional testing is performed. A new or worsening cough or cough lasting more than seven days in a patient with a significant smoking history should indicate the need for a chest radiograph. Patients who present with signs or symptoms of pneumonia (e.g., cough, fever, pleuritic chest pain) should have a chest radiograph regardless of smoking history. Dyspnea is the second most common symptom of lung cancer, occurring in an estimated 3%–60% of patients (Knop, 2005). Dyspnea has many causes in patients with lung cancer. It may be related to underlying lung disease, such as chronic obstructive pulmonary disease, asthma, or cardiac disease. In patients with centrally located tumors or disease in hilar lymph nodes, dyspnea is usually the result of partial or complete bronchial obstruction. With airway obstruction, atelectasis can occur, which also can contribute to dyspnea. Dyspnea may be caused by pleural effusion as a direct result of tumor, lymphangitic or alveolar spread of tumor, pneumonia, or pulmonary embolus (Wozniak & Gadgeel, 2010). In patients with peripheral tumors, dyspnea may or may not be present. Bronchorrhea is the abnormally abundant production of mucous secretions produced by coughing. It often is associated with mucinous bronchoalveolar carcinoma of the lung (Takao et al., 2010). Hemoptysis is defined as blood that is coughed up; it may be mixed with sputum. In 6%–35% of patients, hemoptysis is present at diagnosis (Knop, 2005). It usually occurs in patients who have centrally located tumors as a result of tumor-invading blood vessels or tumor necrosis. The amount of blood varies from small streaks or tinges of blood mixed with sputum to massive amounts of frank, red blood. Massive hemoptysis is rare but can occur when a major pulmonary vessel is invaded by tumor; this is often fatal. Hemoptysis can occur in patients with chronic bronchitis, infections such as pneumonia or tuberculosis, and congestive heart failure. It often is attributed to bronchitis, and antibiotics are prescribed. Recurrent or persistent hemoptysis requires further evaluation. Wheezing, a whistling or sighing sound, also occurs in patients with lung cancer and is the presenting symptom in some instances. Wheezing is the result of the vibration of a narrowed airway as air passes through it. In patients with lung cancer, wheezing often is caused by a lesion in the main stem bronchi. The wheezing is localized and may be associated with a cough. This should be differentiated from generalized wheezing, which usually is caused by bronchospasm (e.g., asthma). Stridor is a 48

CHAPTER 5. CLINICAL PRESENTATION AND DIAGNOSTIC EVALUATION

with bulky mediastinal adenopathy, which causes pressure on the esophagus (Knop, 2005). Paralysis of the phrenic nerve (likely from aortopulmonary window lymphadenopathy) most commonly results in elevation of the left hemidiaphragm and dyspnea. These signs and symptoms are not common in patients with lung cancer (Schrump, Giaccone, Kelsey, & Marks, 2008). Non-small cell lung cancer (NSCLC) tumors in the superior sulcus, located in the apex of the lung, are also known as Pancoast tumors, named after the radiologist who first described them (Pancoast, 1932). Pancoast syndrome is the result of nerve (brachial plexus), chest wall, and rib involvement by tumor located in the apex of the lung. Because of this location, nearly all patients are symptomatic at the time of diagnosis. Tumor signs and symptoms occur on the same side as the lung lesion. Classically, patients present with shoulder pain, usually located at the medial (paraspinal) aspect of the scapula (Shen, Meyers, Larner, & Jones, 2007; Steliga, Patel, & Vaporciyan, 2010). As the tumor enlarges, patients typically have arm pain and headache and can develop Horner syndrome. Horner syndrome is the result of paralysis of the superior cervical sympathetic nerve, which causes miosis, ptosis, and anhidrosis (Baldwin, 2003). Horner syndrome is usually a manifestation of late disease and implies involvement of the nerves of or alongside the vertebral column (Steliga et al., 2010). Lymphangitic spread of tumor throughout the lung parenchyma is characterized by increasing dyspnea, cough, and hypoxia. Radiographically, it is associated with an enlarging infiltrate (Wozniak & Gadgeel, 2010). Specifically, lymphangitic spread refers to a tumor that grows along or is spread through the lymphatic channels. In the lung, it often mimics interstitial lung disease, such as idiopathic pulmonary fibrosis, infection, or radiation pneumonitis, and as a result, often is difficult to diagnose (Wozniak & Gadgeel, 2010). Chest radiographs have been reported to be normal in up to 50% of patients with biopsyproven disease (Goldsmith, Kostakoglu, Somrov, & Palestro, 2004). High-resolution computed tomography (CT) scan often is required to support the diagnosis (Goldsmith et al., 2004). Firm diagnosis is made pathologically through bronchoscopy with bronchoalveolar lavage or open lung biopsy (Wozniak & Gadgeel, 2010). In patients who are unable to tolerate these procedures, empiric use of high-dose corticosteroids and antibiotics is recommended and may provide some relief of symptoms (Wozniak & Gadgeel, 2010). Lymphangitic spread of tumor is an ominous sign that often leads to rapid decline (Wozniak & Gadgeel, 2010). Local-regional effects of the tumor also can cause pleural effusion, pericardial effusion, and superior vena cava syndrome (see Table 5-1). These are addressed in detail in Chapter 6.

on the organ or system affected. Extrathoracic effects can include central nervous system symptoms, gastrointestinal symptoms, and pain. Eaby-Sandy (2011) reported that the brain is a common site for metastases. In an autopsy study, 54% of patients with NSCLC and 80% of patients with small cell lung cancer (SCLC) had brain metastases (Eaby-Sandy, 2011). Approximately 10% of patients with lung cancer have presenting symptoms of brain metastases (Eaby-Sandy, 2011). Signs and symptoms depend on the location of the tumor and the degree of accompanying swelling or bleeding. With increased intracranial pressure, patients may experience headache, nausea, and vomiting. Additionally, patients may experience changes in personality or level of consciousness. Focal weakness and seizures also can occur in patients with central nervous system metastases. Gastrointestinal symptoms can be caused by local effects of the tumor or systemic effects, such as anorexia. Hepatic metastases, which are common in patients with lung cancer, can cause nausea, vomiting, jaundice, and pain. However, most patients with hepatic metastases are asymptomatic. Gastrointestinal obstruction can occur as a direct result of metastatic disease, but this is uncommon (Eaby-Sandy, 2011). Adrenal metastases usually are asymptomatic, including in patients with bilateral adrenal disease. Even bilateral adrenal metastases rarely result in adrenal insufficiency (Wozniak & Gadgeel, 2010). Although rare, large adrenal metastatic tumors can cause flank pain. Pain is a common symptom in patients with lung cancer, and it can have many causes. Pain caused by bone metastases is a common symptom, as bone metastases are frequently present in patients with lung cancer (Eaby-Sandy, 2011). Management of bone metastases often requires aggressive treatment with analgesics. Although pain from bone metastases can improve with systemic treatment, radiation therapy often is needed when chemotherapy fails to control pain or when a weightbearing bone is affected (Wozniak & Gadgeel, 2010). The use of zoledronic acid has also been shown to benefit patients with NSCLC and bone metastases (Rosen et al., 2004). Back pain with neurologic symptoms such as weakness, sensory loss, and autonomic dysfunction is indicative of spinal cord compression. In some patients, this may be the initial manifestation of lung cancer. Spinal cord compression is addressed in more detail in Chapter 6.

Systemic Symptoms Systemic symptoms may or may not be present on initial evaluation of the patient with lung cancer. The incidence of systemic symptoms is similar in both NSCLC and SCLC. The etiology of the symptoms is not well understood (Knop, 2005). Systemic symptoms such as fatigue, weight loss, and anemia are often the result of the cancer. Additionally, paraneoplastic syndromes may be responsible for systemic symptoms.

Extrathoracic Spread of Tumor Extrathoracic effects of tumor occur when the cancer spreads beyond the lungs. Signs and symptoms depend 49

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Oncologic Urgencies and Emergencies and Paraneoplastic Syndromes

Table 5-3. Paraneoplastic Syndromes Associated With Lung Cancer

The initial manifestation of disease in patients with NSCLC and SCLC can include signs and symptoms of oncologic emergencies and paraneoplastic syndromes. As a result, clinicians must be familiar with the different emergent situations and paraneoplastic syndromes. In patients with lung cancer, examples of oncologic urgencies and emergencies include superior vena cava syndrome, cardiac tamponade, pleural or pericardial effusion, and malignant spinal cord compression (Cope, 2005; Flaherty, 2005; Kaplow, 2005; Moore, 2005). Paraneoplastic syndromes are the result of remote effects of the tumor and are not related to metastatic spread. They can cause a variety of systemic symptoms in patients with lung cancer. Overall, paraneoplastic syndromes in cancer are rare, but they are seen in 10%–20% of patients with lung cancer (Wozniak & Gadgeel, 2010). Some paraneoplastic syndromes characteristically are seen in patients with SCLC (e.g., Lambert-Eaton myasthenic syndrome), whereas others are more prevalent in those with NSCLC (e.g., hypertrophic osteoarthropathy). The hypercoagulable state is seen in patients with either type of lung cancer. Examples of paraneoplastic syndromes seen in either NSCLC or SCLC include humoral hypercalcemia of malignancy, ectopic adrenocorticotropic hormone syndrome, syndrome of inappropriate antidiuretic hormone (SIADH), Lambert-Eaton myasthenic syndrome, neurologic paraneoplastic syndromes, Trousseau syndrome, clubbing, and hypertrophic pulmonary osteoarthropathy (Wozniak & Gadgeel, 2010). Tables 5-2 and 5-3 outline the most common oncologic urgencies and emergencies and paraneoplastic syndromes, as well as the most common presenting signs and Table 5-2. Oncologic Emergencies Associated With Lung Cancer Oncologic Urgency or Emergency

Dyspnea; head fullness; chest pain; facial, neck, and arm swelling; stridor; and positive distension of superficial veins of chest, neck, and upper arms

Cardiac effusion and tamponade (Kaplow, 2005)

Dyspnea, cough, anxiety, jugular vein distension, tachycardia, pulsus paradoxus, and substernal chest pain

Pleural effusion (Cope, 2005)

Dyspnea, dry cough, pleuritic chest pain, dullness on chest percussion, and tracheal deviation

Malignant spinal cord compression (Flaherty, 2005)

Radicular or band-like back pain, neurologic symptoms, motor and sensory weakness, and autonomic dysfunction

Selected Signs and Symptoms

Humoral hypercalcemia of malignancy (Armstrong, 2005)

Nausea, fatigue, lethargy, constipation, altered mental status, and dehydration

Ectopic adrenocorticotropic hormone syndrome (Armstrong, 2005)

Proximal muscle weakness, hypokalemia, metabolic alkalosis, and glucose intolerance

Syndrome of inappropriate antidiuretic hormone (Keenan, 2005)

Fatigue, headache, weakness, muscle cramps, nausea, vomiting, lethargy, and loss of deep tendon reflexes

Lambert-Eaton myasthenic syndrome (Armstrong, 2005)

Proximal muscle weakness, muscle fatigue with exercise, constipation, and postural hypotension

Paraneoplastic cerebellar degeneration (Armstrong, 2005)

Multifocal neurologic disease including severe ataxia, dysarthria, dysphagia, diplopia, and sensory neuropathy

Trousseau syndrome (Armstrong, 2005)

Deep vein thrombosis: Asymmetrical limb edema, pain, and redness Pulmonary embolism: Acute dyspnea, pleuritic chest pain, and cough

Hypertrophic pulmonary osteoarthropathy, clubbing (Armstrong, 2005)

Symmetrical joint pain, joint effusions, joint swelling and erythema Characteristic appearance of fingers and toes

Paraneoplastic syndromes are clinically apparent in up to 10% of patients with lung cancer. a

symptoms. More information regarding oncologic urgencies and emergencies and paraneoplastic syndromes can be found in Chapters 6 and 7.

Selected Signs and Symptoms

Superior vena cava syndrome (Moore, 2005)

Paraneoplastic Syndromea

Diagnostic Tests History and Physical Examination Findings on patient history and physical examination in many cases will guide diagnostic testing. Additionally, a careful history and physical examination may prevent unnecessary surgery (Lau & Harpole, 2000). If symptoms suggest metastatic disease, additional testing can confirm 50

CHAPTER 5. CLINICAL PRESENTATION AND DIAGNOSTIC EVALUATION

this and thus avoid surgery. Table 5-4 outlines the clinical and laboratory findings that suggest metastatic disease (Spiro et al., 2007). The initial part of the patient history will include the chief complaint (the reason the patient sought medical care). The main symptoms should be fully explored and described in terms of location, quality, severity, timing, aggravating and alleviating factors, and other associated factors (Bickley, 2008). Past history may reveal hospitalization or treatment for pneumonia or other respiratory illnesses. A thorough tobacco history should be elicited, including type and amount of tobacco smoked per day and duration of smoking history. Additionally, the history should include exposure to passive smoking or other known carcinogens (e.g., radon). Family history may reveal other family members who have been diagnosed with lung cancer. The remainder of the patient history should focus on a review of systems, including the presence of constitutional symptoms such as fatigue, weight change, weakness, and fever. Physical examination may or may not reveal abnormal findings. Inspection of the head and neck may show nasal flaring if shortness of breath, or possibly cyanosis, is present. Palpation of the neck may reveal enlarged cervical or supraclavicular lymph nodes. The supraclavicular fossa is the most common site of palpable lymph nodes (Spiro et al.,

2007). If superior vena cava obstruction is present, swelling of the face and neck may be observed. Additionally, redness or flushing of the face (plethora) may be present. Inspection of the chest may reveal use of accessory muscles (retraction and bulging) if the patient is having difficulty breathing. The presence of prominent vascular markings on the chest wall should raise suspicion for superior vena cava syndrome or a blood clot. Swelling of the extremities may be present with thrombosis. Digital clubbing may be noted on examination of the hands and feet. A thorough examination of the chest should include palpation, percussion, and auscultation. Findings indicative of the need for further evaluation include signs of pleural effusion (e.g., decreased breath sounds, dullness on percussion, egophony), pericardial effusion (i.e., muffled heart sounds), wheezing, stridor, or elevation of the hemidiaphragm (i.e., phrenic nerve paralysis). A screening neurologic examination, including assessment of cranial nerves, will determine the presence of focal weakness, other signs suggestive of central nervous system metastases, or findings consistent with Horner syndrome.

Noninvasive Diagnostic Testing In addition to the history and physical examination, diagnostic testing for patients with suspected lung cancer consists of laboratory testing, radiography, and sampling of tissue or fluid to determine definitive diagnosis and cell type. The results of these tests will determine tumor type, help to determine clinical stage, and assist the clinician in developing an individual treatment plan. Radiographic findings, in addition to symptom assessment, can even lead to a presumptive differentiation between SCLC and NSCLC (Rivera & Mehta, 2007). SCLC is more likely to present as a hilar or centrally located mass and may be associated with a paraneoplastic syndrome (Rivera & Mehta, 2007). Additionally, the results of these tests can help clinicians to estimate individual prognoses. Laboratory testing most often includes an assessment of the hematologic and metabolic systems. A complete blood count and comprehensive metabolic profile, including electrolytes, liver enzymes, and renal function tests, are usually the initial laboratory tests performed. Abnormal results may provide clues about metastatic disease. Anemia may represent a paraneoplastic syndrome or the presence of chronic disease. An elevation in serum calcium or alkaline phosphatase may be indicative of bone metastasis, whereas abnormalities in electrolytes may occur in patients with SIADH. At present, no blood tests (e.g., serum markers) are available to diagnose patients with lung cancer (Lau & Harpole, 2000). In fact, the results of these laboratory tests may be completely normal despite the presence of lung cancer. Often the first radiographic test to be performed is the chest x-ray (Spiro et al., 2007). Both posterior-anterior and lateral views should be obtained. Chest x-ray can reveal the

Table 5-4. Clinical Findings Suggesting Metastatic Disease Testing

Finding

Symptoms elicited in history

Constitutional: Weight loss (more than 10 lb) Musculoskeletal: Focal skeletal pain Neurologic: Headaches, syncope, seizures, extremity weakness, recent change in mental status

Signs found on physical examination

Lymphadenopathy (greater than 1 cm) Hoarseness, superior vena cava syndrome Bone tenderness Hepatomegaly (greater than 13 cm span) Focal neurologic signs, papilledema Soft tissue mass

Routine laboratory tests

Hematocrit (less than 40% in men and 35% in women) Elevated alkaline phosphatase, GGT, SGOT, and calcium levels

GGT—gamma-glutamyl transferase; SGOT—serum glutamic-oxaloacetic transaminase Note. From “Initial Evaluation of the Patient With Lung Cancer: Symptoms, Signs, Laboratory Tests, and Paraneoplastic Syndromes: ACCP EvidenceBased Clinical Practice Guidelines (2nd Edition),” by S.G. Spiro, M.K. Gould, and G.L. Colice, 2007, Chest, 132(Suppl. 3), p. 154S. doi:10.1378/ chest.07-1358. Copyright 2007 by the American College of Chest Physicians. Adapted with permission.

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primary tumor as well as the presence of pleural or pericardial effusions. In general, malignant lesions may be differentiated from benign lesions on chest radiograph. Characteristics suggestive of malignant lesions include size greater than 3 cm, irregular or spiculated border, distortion of surrounding vascular markings, and thick, irregular-walled cavitary lesions (Lau & Harpole, 2000). Benign lesions also may share some of these characteristics; any lesion with the aforementioned characteristics should be considered malignant until proved otherwise (Lau & Harpole, 2000). If an earlier chest radiograph is available, it should be used for comparative purposes. Pericardial effusion may present as an enlarged cardiac silhouette on chest film; pleural effusion is suspected with blunting of the costophrenic angle. Additionally, elevation of a hemidiaphragm can be detected on chest radiograph, which may indicate phrenic nerve involvement. A chest CT scan usually is the next diagnostic test obtained. The addition of IV contrast helps to differentiate lymph nodes from vessels and aids in determining the extent of the primary tumor, invasion of other structures, and bony involvement (Quint, Bogot, & Rankin, 2010). Because the liver and adrenals are common metastatic sites for lung cancer, all CT scans of the chest should routinely include the upper abdomen to identify lesions in these areas. CT scan is not the most reliable method of determining mediastinal lymph node involvement from tumor. Malignancy is suspected if the transverse diameter of the lymph node is larger than 1 cm; however, mediastinal lymph nodes may be enlarged from inflammation, infection, and reactive hyperplasia (Quint et al., 2010). Conversely, small lymph nodes (smaller than 1 cm) may also contain foci of malignant cells. Positron-emission tomography (PET) is recognized as a valuable imaging modality in lung cancer staging (Stroobants, 2008). PET is a noninvasive imaging technique that can provide additional information to conventional radiographs and CT and magnetic resonance imaging (MRI) scans. PET scans provide functional tumor information, whereas CT scans provide anatomic information. The combination of both anatomic and functional information provided by these imaging modalities has achieved a higher level of accuracy in the evaluation and reevaluation of lung cancer than was previously possible (MacManus & Hicks, 2003). In the preoperative setting, the most accurate imaging test for staging mediastinal lymph nodes is PET (Freudenberg, Rosenbaum, Beyer, Bockisch, & Antoch, 2007). With an abnormal PET scan, biopsy of mediastinal lymph nodes should be performed prior to surgery when possible (Silvestri, Tanoue, Margolis, Barker, & Detterbeck, 2003). 18F-fluoro-2-deoxy-D-glucose (FDG), a glucose analog, is the preferred radiopharmaceutical agent in imaging tumors because tumor cells have increased glucose metabolism and thus readily absorb FDG (Reed et al., 2003; Stroobants, 2008). The amount of FDG uptake in tumor cells has been shown to correlate with both tumor aggressiveness and tumor growth rates (Duhaylongsod et al.,

1995). PET scans provide quantitative information regarding the amount of glucose used in selected tissue (Goldsmith & Kostakoglu, 2000). Increased glucose metabolism will appear as a “hot spot” on the scan. These hot spots can be measured as a standard uptake value (SUV) or standard uptake ratio (SUR). A lesion is considered to be abnormal if the SUV is more than 2.5 (Silvestri et al., 2003). Non-neoplastic conditions, such as inflammation, infection, and granulomatous diseases, also can appear as hot spots on PET scans. Thus, a positive PET scan does not always imply malignant disease; tissue will need to be obtained to determine malignancy. Additionally, tumors with low metabolic activity, such as carcinoid or bronchoalveolar tumors, may appear as false-negative PET scans (Goldsmith & Kostakoglu, 2000). Whole body PET scanning can be valuable in the detection of metastatic disease and can be accomplished with no additional radiation exposure (Stroobants, 2008). Patients are required to fast prior to undergoing PET scan because increased serum glucose levels may interfere with FDG uptake by the tumor. Similarly, this can be a concern in patients with diabetes who have elevated serum glucose levels. Although some researchers have not found this to be a major problem in patients with lung cancer, others suggest that for more meaningful imaging, serum glucose levels should not exceed 250–300 mg/dl (Goldsmith & Kostakoglu, 2000; Lowe & Naunheim, 1998). FDG-PET scanning is not recommended for detection of brain metastases because of high uptake of FDG by normal brain tissue. Medicare and most private insurers reimburse for FDG-PET for the diagnosis, staging, and restaging of NSCLC (Bietendorf, 2004). FDG-PET is also used in the evaluation of patients with SCLC. As valuable as CT and FDG-PET imaging are in the staging of patients with lung cancer, each test has some limitations as noted previously. Integrated PET-CT scanners are available that can image the body in about 30 minutes and provide both anatomic and functional tumor information (Stroobants, 2008). Multiple studies have demonstrated superiority of integrated PET-CT images and have led to more accurate staging of NSCLC as compared to either modality used alone (Aquino, Asmuth, Alpert, Halpern, & Fischman, 2003; Cerfolio, Bryant, Winokur, Ohja, & Bartolucci, 2004; Fischer et al., 2009; Halpern et al., 2005; Lardinois et al., 2003). The National Comprehensive Cancer Network (NCCN, 2011) recommends PET-CT imaging as part of the pretreatment evaluation (stages I–IV) of NSCLC. Furthermore, the NCCN guidelines recommend that positive findings on PET-CT need pathologic or radiologic confirmation. PET-CT is an exciting newer imaging modality that is useful in the pretreatment evaluation of NSCLC and may become more widely used in the evaluation of patients given chemotherapy or radiotherapy as more information from clinical trials becomes available. MRI is an imaging technique that does not use ionizing radiation. MRI of the chest is not routinely used in the staging 52

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or diagnosis of lung cancer for several reasons: it does not offer significantly more information than chest CT; it is a longer test, typically taking 30–45 minutes to produce images; and it is affected by respiratory motion, which creates motion artifact on the images (Quint et al., 2010). In some specific circumstances, MRI does provide more information than chest CT. MRI is helpful in evaluation of a lung mass that may be invading either a vertebral body or the spinal canal. MRI is considered to be the gold standard for diagnosis of metastatic disease to the spinal cord (Sun & Nemecek, 2010). MRI is better at imaging soft tissues than CT scan, and it offers multiplanar capability (Silvestri et al., 2007). Additionally, MRI is superior at determining whether a tumor has invaded vessels (Quint et al., 2010). MRI is more beneficial than CT in patients with superior sulcus tumors in which chest wall invasion, brachial plexus invasion, and subclavian vessel and vertebral body involvement exist (Quint et al., 2010; Silvestri et al., 2007). Heelan et al. (1989) found that MRI was accurate 94% of the time (compared with 63% with chest CT) in evaluating superior sulcus tumors that have invaded other structures. In patients suspected of having brain metastases, either modality can be used. At initial staging in patients with NSCLC, routine use of these tests is not recommended in patients with no symptoms suggestive of brain metastases, as asymptomatic brain metastases are observed in only 0%–10% of patients (Rivera & Mehta, 2007). NCCN guidelines do not recommend routine use of brain MRI in asymptomatic patients but do recommend MRI if aggressive treatment is being recommended for those with stages II–IV disease (NCCN, 2011). In contrast, evaluation of the head with MRI or CT is recommended in patients with SCLC, who commonly present with brain metastases (Simon & Turrisi, 2007). Patients with bone metastases usually are symptomatic and may have laboratory abnormalities (elevated serum alkaline phosphatase or calcium). In patients with these findings, further testing may include bone radiograph, radionuclide bone scan, MRI, or PET scan (Silvestri et al., 2007). Sputum cytology is a noninvasive method of diagnosing lung cancer. Clinical trials have found that sputum cytology is more likely to diagnose patients who have centrally located tumors than those who have peripheral tumors (Rivera & Mehta, 2007; Schreiber & McCrory, 2003). Additionally, studies have found that sputum cytology is more likely to diagnose lung cancer when three or more sputum cytology specimens per patient are produced and the samples are of adequate material (Bocking, Biesterfeld, Chatelain, GienGerlach, & Esser, 1992). Diagnostic sensitivity has been shown to be high in patients who provide multiple specimens (Saqi & Vazquez, 2010). Patients with squamous cell lung cancers, tumors larger than 2.4 cm, and bloody sputum are more likely to have positive diagnosis by sputum cytology (Risse, van’t Hof, & Vooijs, 1987). Because lung cancer diagnosis by sputum cytology depends on the quality of

the specimen, patients must be given specific instructions. The best samples are those that are collected first thing in the morning. Instruct the patient to rinse the mouth with water and then cough deeply and expectorate a sample into a collecting jar.

Invasive Diagnostic Testing Invasive testing, when feasible, is always recommended as the next step in the diagnosis of patients with suspected lung cancer. Invasive testing provides cytologic or histologic material that is valuable in determining disease treatment and prognosis. Approximately 30%–50% of patients diagnosed with lung cancer have mediastinal lymph node involvement at the time of diagnosis (Toloza, Harpole, Detterbeck, & McCrory, 2003; Wallace, Fritscher-Ravens, & Savides, 2003). In the absence of distant metastatic disease, determination of mediastinal lymph node status is crucial because those with stage IIIA disease are potentially curable with surgery, but those with stage IIIB disease are not. Multiple procedures are available to assess the primary tumor and mediastinal lymph nodes. Transthoracic needle aspiration (TTNA) taken through the chest wall, transbronchial needle aspiration (TBNA) at the time of bronchoscopy, and intraoperative needle aspiration at the time of mediastinoscopy are techniques that provide highly reliable samples with little discomfort or complications for patients. TTNA is more likely to yield a diagnosis in patients who have peripheral lesions that cannot be reached by bronchoscopy (Rivera & Mehta, 2007). TTNA is technically easier in patients with peripheral lesions; studies show that lesions greater than 1.5 cm resulted in a trend toward higher diagnostic yield (94%) as compared to lesions smaller than 1.5 cm (78%) (Schreiber & McCrory, 2003). Very often, CT scanning, ultrasound, or fluoroscopy is used to help localize lesions at the time of aspiration. CT localization in an interventional radiology setting is used more often than the other modalities. The use of CT-guided TTNA has allowed for biopsy of lesions as small as 0.5 cm (Schreiber & McCrory, 2003). Fine needles (22–25 gauge) for aspiration provide samples for cytology. Use of fine needles is known as fine needle aspiration (FNA). FNA commonly is used to aspirate palpable lymph nodes, such as supraclavicular or cervical lymph nodes. Bronchoscopy with or without TBNA and bronchoalveolar lavage (BAL) also are used in diagnosing and staging lung cancer. Bronchoscopy is valuable in the diagnosis and staging of lung cancer (El-Bayoumi & Silvestri, 2008). Flexible bronchoscopy is most useful in patients with centrally located tumors (Rivera & Mehta, 2007). Bronchoscopy allows for direct visualization of endobronchial abnormalities and direct sampling by brushing or washing of the abnormalities to yield a cytologic diagnosis. Endobronchial biopsy (using forceps) 53

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can provide histologic samples. Additionally, TBNA can be performed through the bronchoscope to sample lymph nodes in the mediastinum and peribronchial areas. It is one method for sampling submucosal disease and is useful in accessing lymph nodes in the anterior mediastinum (El-Bayoumi & Silvestri, 2008; Mazzone, Jain, Arroliga, & Matthay, 2002). The disadvantages of this procedure are that it is a “blind” procedure and only a few lymph node stations are accessible with this approach (Toloza et al., 2003). Bronchoscopy with TBNA is primarily performed in the outpatient setting with IV sedation; general anesthesia may also be used. Overall, this is a safe procedure with a low rate of complications. Complications include pneumothorax and bleeding, but these are rare (Mazzone et al., 2002). BAL involves the instillation of fluid into the distal bronchial tree during bronchoscopy. Fluid is then suctioned out and examined under a microscope; this fluid may contain cancer cells. This technology has changed little in the past three decades (Dooms et al., 2010). In addition to bronchoscopy, endobronchial ultrasound and endoscopic ultrasound are used for the diagnosis and staging of lung cancer. Endobronchial ultrasound with TBNA (EBUS + TBNA) is a newer technique used to assess mediastinal lymph nodes and to help distinguish stage IIIA from IIIB disease or whether the tumor is operable or inoperable. This procedure is performed at the time of bronchoscopy. An ultrasonic bronchoscope is inserted through an endotracheal tube and guided to a suspected area of metastatic disease. A steel needle is then introduced through the biopsy channel of the endoscope, and biopsies are obtained by passing the needle through the wall of the trachea or bronchus. An ultrasound of this area is conducted with the instrument immediately prior to the biopsy to facilitate correct placement of the needle (Krasnik, Vilmann, Larsen, & Jacobsen, 2003). Multiple lymph node stations are accessible through this technique, including paratracheal, subcarinal, hilar, and contralateral hilar nodes. Lymph node stations not accessible are the aortopulmonary window, paraesophageal, and the inferior pulmonary ligament (Adams, Shah, Edmonds, & Lim, 2009). Histology and cytology samples can be obtained with this procedure (Nakajima et al., 2007). EBUS + TBNA can be performed in the outpatient setting using conscious sedation or can be performed with general anesthesia if needed. Endoscopic ultrasound with needle aspiration (EUS + NA) is performed at the time of esophageal endoscopy. This procedure was initially used in the diagnosis and staging of gastrointestinal tumors. Because mediastinal lymph node stations are adjacent to the esophagus, this procedure has become useful in the staging and diagnosis of lung cancer. Lymph node stations accessible to EUS + NA include nodes lateral to the trachea, posterior aortopulmonary window nodes, and nodes along the inferior mediastinum adjacent to the esophagus (Wallace et al., 2003). Similar to EBUS + TBNA, a needle catheter is inserted through the endoscope.

Needle biopsies are obtained by passing the needle through the esophagus to biopsy suspicious mediastinal lymph nodes. This procedure is performed with ultrasound guidance, which provides a qualitative assessment of the lymph nodes being sampled and may aid in the selection of lymph nodes to be sampled (Toloza et al., 2003). Krasnik et al. (2003) postulated that the complementary nature of the two minimally invasive endoscopic procedures may eliminate the need for the more invasive procedures to stage the mediastinum. Mediastinoscopy is an invasive method used to evaluate the mediastinum in patients with lung cancer; it is considered to be the gold standard for evaluation of mediastinal lymph nodes (Detterbeck, DeCamp, Kohman, & Silvestri, 2003). This procedure is performed with the patient under general anesthesia in the operating room. Patients usually are discharged from the hospital the same day as the procedure, if stable. Mediastinoscopy is performed by making a small incision at the suprasternal notch. The mediastinoscope then is passed alongside the trachea, allowing biopsy of mediastinal lymph nodes. The sensitivity of this procedure in documenting cancer is 80%–85% (Detterbeck, Jantz, Wallace, Vansteenkiste, & Silvestri, 2007). Most mediastinal lymph nodes can be sampled with this procedure. Routinely, one node from five lymph node stations should be sampled. Lymph nodes not accessible with mediastinoscopy include posterior subcarinal, inferior mediastinal, aortopulmonary window, and anterior mediastinal nodes (Detterbeck et al., 2007). Aortopulmonary lymph nodes can be assessed using the Chamberlain procedure, also known as an anterior mediastinotomy (Detterbeck, 2010). The Chamberlain procedure involves making a small incision in the second or third intercostal space just to the left of the sternum. When used in addition to mediastinoscopy, the sensitivity of this procedure is estimated at 87% (Detterbeck et al., 2003). Newer techniques of video-assisted mediastinal lymphadenectomy (known as VAMLA) and transcervical extended mediastinal lymphadenectomy (known as TEMLA) are also used in staging the mediastinum (Detterbeck, 2010). Thoracoscopy (also known as video-assisted thoracic surgery [VATS]) can be used to assess lymph nodes not accessible by mediastinoscopy (Detterbeck et al., 2007). This procedure provides access to the hemithorax (one side of the mediastinum), like thoracotomy, but is less invasive (Deterbeck et al., 2007; Mentzer, DeCamp, Harpole, & Sugarbaker, 1995). As a result, VATS is especially useful with older patients or those with comorbid problems (Mentzer et al., 1995). Through a left-sided VATS, the aortopulmonary window lymph nodes can be sampled. VATS provides the ability to assess chest wall lesions and other lung parenchymal abnormalities (Mentzer et al., 1995). Additionally, VATS can assess pleural effusions. Thoracotomy usually is reserved for patients with a high probability of lung cancer but for whom other diagnostic measures have failed to provide a diagnosis. Excisional or Tru-Cut (a disposable needle used for collecting sample 54

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specimen) biopsies are performed for tissue diagnosis. If a lung cancer diagnosis is made by thoracotomy, staging of the mediastinum with lymph node sampling should be performed at the same time. Accurate diagnosis and staging of lung cancer is paramount. Once a tissue diagnosis is made, accurate staging will help to determine the treatment plan and also can make an estimate of the prognosis. Staging separates patients who are surgical candidates from those who are candidates for chemotherapy, radiation, or a combination of therapies. Staging is more complicated in patients with NSCLC; for these patients, surgery may be an option depending on disease stage. Staging for SCLC is not as complicated because this disease usually is not considered to be operable. Staging for both types of lung cancer is addressed in Chapters 8 and 9.

laboratory tests, and paraneoplastic syndromes. Chest, 123(Suppl. 1), 97S–104S. doi:10.1378/chest.123.1_suppl.97S Bickley, L.S. (2008). Interviewing and the health history. In L.S. Bickley (Ed.), Bates’ guide to physical examination and history taking (10th ed., pp. 1–33). Philadelphia, PA: Lippincott Williams & Wilkins. Bietendorf, J. (2004). FDG PET reimbursement. Journal of Nuclear Medicine Technology, 32, 33–38. Retrieved from http://tech. snmjournals.org/content/32/1/33.long Bocking, A., Biesterfeld, S., Chatelain, R., Gien-Gerlach, G., & Esser, E. (1992). Diagnosis of bronchial carcinoma on sections of paraffin-embedded sputum: Sensitivity and specificity of an alternative to routine cytology. Acta Cytologica, 36, 37–47. Cerfolio, R.J., Bryant, A.S., Winokur, T.S., Ohja, B., & Bartolucci, A.A. (2004). Repeat FDG-PET after neoadjuvant therapy is a predictor of pathologic response in patients with non-small cell lung cancer. Annals of Thoracic Surgery, 78, 1903–1909. doi:10.1016/j.athoracsur.2004.06.102 Cope, D.G. (2005). Malignant effusions and edema. In C.H. Yarbro, M.H. Frogge, & M. Goodman (Eds.), Cancer nursing: Principles and practice (6th ed., pp. 825–840). Sudbury, MA: Jones and Bartlett. Detterbeck, F.C. (2010). Surgical evaluation of the mediastinum. In H.I. Pass, D.P. Carbone, D.H. Johnson, J.D. Minna, G.V. Scagliotti, & A.T. Turrisi III (Eds.), Principles and practice of lung cancer (4th ed., pp. 426–435). Philadelphia, PA: Lippincott Williams & Wilkins. Detterbeck, F.C., DeCamp, M.M., Jr., Kohman, L.J., & Silvestri, G.A. (2003). Lung cancer—Invasive staging: The guidelines. Chest, 123(Suppl. 1), 167S–175S. doi:10.1378/chest.124.1suppl.167S Detterbeck, F.C., Jantz, M.A., Wallace, M., Vansteenkiste, J., & Silvestri, G.A. (2007). Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest, 132(Suppl. 3), 202s–220s. doi:10.1378/chest.07-1362 Dooms, C., Seijo, L., Gasparini, S., Trisolini, R., Ninane, V., & Tourney, K.G. (2010). Diagnostic bronchoscopy: State of the art. European Respiratory Review, 19, 229–236. doi:10.1183/09059180.00005710 Duhaylongsod, F.G., Lowe, V.J., Patz, E.F., Vaughn, A.L., Coleman, R.E., & Wolfe, W.G. (1995). Lung tumor growth correlates with glucose metabolism measured by fluoride-18 fluorodeoxyglucose positron emission tomography. Annals of Thoracic Surgery, 60, 1348–1352. doi:10.1016/0003-4975(95)00754-9 Eaby-Sandy, B. (2011). Lung cancer. In C.H. Yarbro, D. Wujcik, & B.H. Gobel (Eds.), Cancer nursing: Principles and practice (7th ed., pp. 1424–1457). Sudbury, MA: Jones and Bartlett. El-Bayoumi, E., & Silvestri, G.A. (2008). Bronchoscopy for the diagnosis and staging of lung cancer. Seminars in Respiratory and Critical Care Medicine, 29, 261–270. doi:10.1055/s-2008-1076746 Fischer, B., Lassen, U., Mortensen, J., Larsen, S., Loft, A., Bertelsen, A., … Højgaard, L. (2009). Preoperative staging of lung cancer with combined PET-CT. New England Journal of Medicine, 361, 32–39. doi:10.1056/NEJMoa0900043 Flaherty, A.M. (2005). Spinal cord compression. In C.H. Yarbro, M.H. Frogge, & M. Goodman (Eds.), Cancer nursing: Principles and practice (6th ed., pp. 910–924). Sudbury, MA: Jones and Bartlett. Freudenberg, L.S., Rosenbaum, S.J., Beyer, T., Bockisch, A., & Antoch, G. (2007). PET versus PET/CT dual-modality imaging in evaluation of lung cancer. Radiologic Clinics of North America, 45, 639–644. doi:10.1016/j.rcl.2007.05.003 Goldsmith, S.J., & Kostakoglu, L. (2000). Nuclear medicine imaging of lung cancer. Radiologic Clinics of North America, 38, 511–524. Goldsmith, S.J., Kostakoglu, L.A., Somrov, S., & Palestro, C.J. (2004). Radionuclide imaging of thoracic malignancies. Thoracic Surgery Clinics, 14, 95–112. doi:10.1016/S1547-4127(04)00034-9

Summary Clinicians must be alert to the different clinical presentations suggestive of lung cancer. A careful history and physical examination will often provide the first clues to the problem. The more unusual presentations, such as those who present with a paraneoplastic syndrome (hypertrophic pulmonary osteoarthropathy) or an emergent situation such as spinal cord compression, should prompt clinicians to suspect and investigate malignancy in the differential diagnosis. Following the physical examination, if malignancy is suspected, noninvasive testing should be initiated, including laboratory and radiographic testing as described in this chapter. At this time, the only way to determine a definitive diagnosis of lung cancer is through a cytologic or histologic sample. These samples are obtained through one of the invasive methods noted. Newer techniques such as EBUS and EUS with needle biopsy are less invasive procedures that have the potential to provide a definitive diagnosis of lung cancer.

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clinical practice guidelines (2nd edition). Chest, 132(Suppl. 3), 149S–160S. doi:10.1378/chest.07-1358 Steliga, M., Patel, A., & Vaporciyan, A. (2010). Management of stage II non–small cell lung cancer and Pancoast tumors. In H.I. Pass, D.P. Carbone, D.H. Johnson, J.D. Minna, G.V. Scagliotti, & A.T. Turrisi III (Eds.), Principles and practice of lung cancer (4th ed., pp. 474–489). Philadelphia, PA: Lippincott Williams & Wilkins. Stroobants, S.G. (2008). Nuclear imaging of the lung. In G.A. Patterson, J.D. Cooper, J. Deslauriers, A.E.M.R. Lerut, J.D. Luketich, & T.W. Rice (Eds.), Pearson’s thoracic and esophageal surgery (3rd ed., pp. 429–443). Philadelphia, PA: Elsevier Churchill Livingstone. Sun, H., & Nemecek, A.N. (2010). Optimal management of malignant epidural spinal cord compression. Hematology/Oncology Clinics of North America, 24, 537–551. doi:10.1016/j.hoc.2010.03.011 Takao, M.T., Takihiro, T., Suzuki, H., Shimamoto, A., Murashima, S., Taguchi, O., & Shimpo, H. (2010). Resection of mucinous

lung adenocarcinoma presenting with intractable bronchorrhea. Journal of Thoracic Oncology, 5, 576–578. doi:10.1097/ JTO.0b013e3181d3ccdf Toloza, E.M., Harpole, L., Detterbeck, F., & McCrory, D.C. (2003). Invasive staging of non-small cell lung cancer. A review of the current evidence. Chest, 123(Suppl. 1), 157S–166S. doi:10.1378/ chest.123.1_suppl.157S Wallace, M.B., Fritscher-Ravens, A., & Savides, T.J. (2003). Endoscopic ultrasound for the staging of non-small cell lung cancer. Endoscopy, 35, 606–610. doi:10.1055/s-2003-40216 Wozniak, A.J., & Gadgeel, S.M. (2010). Clinical presentation of non-small cell carcinoma of the lung. In H.I. Pass, D.P. Carbone, D.H. Johnson, J.D. Minna, G.V. Scagliotti, & A.T. Turrisi III (Eds.), Principles and practice of lung cancer (4th ed., pp. 327–340). Philadelphia, PA: Lippincott Williams & Wilkins.

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CHAPTER 6

Oncologic Urgencies and Emergencies Pamela K. Ginex, EdD, RN, OCN®

Introduction

cancer (Brumbaugh, 2011). Each year, an estimated 15,000 people develop SVCS in the United States. Small cell lung cancer (SCLC) is the most frequent histology for SVCS, and squamous cell lung cancer is the second most common histology (Brumbaugh, 2011). Both of these tumor types are more commonly central in location as opposed to other types of lung cancer, which tend to grow in peripheral areas of the lungs. SVCS is still an uncommon complication in lung cancer, with only 3%–10% of all patients developing the syndrome. Non-Hodgkin lymphoma is the second most common cause of SVCS (Brumbaugh, 2011).

Initial manifestations of non-small cell lung cancer (NSCLC) can include signs and symptoms of oncologic emergencies. Because of this, clinicians must be familiar with the different emergent situations. In patients with lung cancer, oncologic urgencies and emergencies include superior vena cava syndrome (SVCS), cardiac tamponade, pleural effusion, and malignant spinal cord compression. This chapter will review the pathophysiology, presenting signs and symptoms, and treatment of these conditions.

Pathophysiology

Superior Vena Cava Syndrome

The superior vena cava is located in the right side of the chest in the anterior mediastinum, making it more vulnerable to compression or invasion from a mass in the right side of the chest. It is surrounded by rigid structures, including the sternum and vertebrae, trachea, right bronchus, aorta, pulmonary artery, and lymph nodes (right hilar, right paratracheal, and subcarinal groups). The superior vena cava is the vessel that is responsible for drainage of venous blood from the head, neck, upper extremities, and upper thorax to the heart. The vessel is thin walled and carries low pressure. Obstruction of the superior vena cava results in diminished venous return to the right atrium and, accordingly, an increase in venous pressure behind the obstruction (Mack & Becker, 2008). The increase in venous pressure leads to venous stasis in the head, neck, upper arms, and upper chest with subsequent engorgement of the superficial vessels in the area. If occlusion occurs gradually, then collateral circulation can develop, which may lead to relief of some of the obstructive symptoms (Mack & Becker, 2008). In patients with acute onset of SVCS, the cause is usually complete obstruction from

SVCS is caused by an obstruction of the superior vena cava from tumor, thrombosis, radiation fibrosis, or infection. When Hunter first described this syndrome in the mid-1700s, it most commonly was caused by infection from syphilis-induced aortic aneurysm or fibrosis from tuberculosis (Haapoja & Blendowski, 1999). With the development of antibiotics and the successful treatment of infections, the most common cause of SVCS today is malignancy. SVCS usually is caused by external compression on the vessel by tumor or enlargement of mediastinal lymph nodes from tumor. Less commonly, it can be caused by invasion of the superior vena cava by tumor and thrombus within the vessel. Iatrogenic SVCS is caused by a clot associated with a central venous catheter, implanted venous access port, or pacemaker. Although many still consider SVCS an oncologic emergency, most symptoms develop gradually. Malignancy has been cited as the cause in 70%–80% (Brumbaugh, 2011) or as many as 97% (Mack & Becker, 2008) of all cases of SVCS, and 52%–81% of those cases are a result of lung

The author would like to acknowledge Leslie B. Tyson, MS, APRN, BC, OCN®, for her contribution to this chapter that remains unchanged from the first edition of this book.

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thrombus, whereas a more gradual onset of symptoms usually is caused by extrinsic compression of the vessel from tumor or enlarged lymph nodes (Haapoja & Blendowski, 1999). SVCS is rarely life threatening, and most patients have symptoms for at least a week. A definitive diagnosis should be made prior to treatment because treatments differ depending on the cause.

material administration is contraindicated (Brumbaugh, 2011). Diagnostic tests must be performed on patients without a diagnosis, as emergent radiation therapy before diagnosis can interfere with diagnosis and further treatment. Diagnostic tests include mediastinoscopy, sputum cytology, bronchoscopy, or fine-needle biopsy to obtain pathology for diagnosis. Initially, an increased risk of hemorrhage during diagnostic procedures in patients with SVCS was theorized; however, Ahmann (1984) demonstrated that this risk was small and without life-threatening complications. In situations that are not life threatening, diagnosis should be made for all patients to ensure appropriate treatment.

Signs and Symptoms Signs and symptoms of SVCS depend on how rapidly the obstruction develops, the degree of obstruction, and the presence or absence of collateral circulation (Haapoja & Blendowski, 1999). Dyspnea is the most common presenting symptom, occurring in more than 60% of patients (Yahalom, 2008). The next most common symptom is facial swelling or head fullness, which has been reported in 50% of patients (Keeley, 2007). Patients report cough, arm swelling, facial redness (plethora), dysphagia, and chest pain. Physical examination may reveal distension of the superficial veins of the upper chest and arms; facial, periorbital, neck, and arm swelling; plethora; mental status changes; and lethargy. Some patients report that symptoms worsen on bending forward, stooping, or lying down (Yahalom, 2008).

Treatment In general, treatment depends on the underlying problem. Patients with SVCS caused by thrombus from implanted venous access devices are treated with anticoagulants and antithrombolytics. Antithrombolytics are used to lyse the thrombus, whereas anticoagulants (heparin and warfarin) are used to prevent further clot formation and progression. A catheter-related thrombus occasionally results in removal of the catheter. In patients with tumor-induced SVCS, conservative management with steroids and diuretics often is used in patients with minimal symptoms or in those who are acutely ill and unable to tolerate more aggressive therapy. The use of both steroids and diuretics is controversial because of the absence of clinical trials showing efficacy (Luce, 2005). Theoretically, steroids are used to decrease inflammation, although inflammation is usually not associated with SVCS. Steroids may be useful in situations in which respiratory distress is present or to decrease edema associated with radiation therapy (Haapoja & Blendowski, 1999; Nickloes, Mack, Kallab, & Dunlap, 2010). Diuretics and steroids are used in emergency management of SVCS; however, the condition rarely presents in an acute, life-threatening manner (Beeson, 2010). Initial treatment of SCLC includes chemotherapy or radiation. These tumors are generally sensitive and have been shown to respond with similar frequency (greater than 90%) to both modalities in an analysis of 50 patients (Yahalom, 2008). Resolution or reduction of symptoms usually occurs within 7–14 days of treatment (Brumbaugh, 2011; Mack & Becker, 2008). Combination treatment with chemotherapy and radiation therapy may be used, but the incidence of toxicity is greater with combined modalities. Effective chemotherapy regimens include etoposide and cisplatin or cyclophosphamide, doxorubicin, and vincristine. Extreme care must be used when administering chemotherapy to patients with SVCS. Because of swelling and venous stasis from SVCS, some practitioners recommend not using the involved upper extremities because local accumulation and

Assessment and Diagnosis In addition to notation of signs and symptoms, clinicians must assess for relevant past medical history, which would include history of cancer. Diagnostic tests include chest x-ray, computed tomography (CT) scan, magnetic resonance imaging (MRI), and contrast venography. The initial diagnostic test usually is a chest radiograph. Chest x-ray may demonstrate mediastinal widening or right hilar mass. More than 60% of patients who have SVCS have mediastinal widening (Wan & Bezjak, 2009). Right-sided pleural effusion from venous hypertension and obstruction of thoracic lymph also may be present (Sitton, 2000). Chest CT with contrast or thoracic MRI will provide more information regarding the thoracic anatomy. CT scan is 100% accurate in determining whether the cause of SVCS is mass or thrombus (Haapoja & Blendowski, 1999). It also can determine if a mass is present, the size and position of the mass, and the extent of collateral circulation. Additionally, these tests can determine the degree of obstruction of the superior vena cava. Contrast venography can be performed to locate the area and degree of occlusion of the superior vena cava in patients who are candidates for stent placement or surgery (Haapoja & Blendowski, 1999; Sitton, 2000). Disadvantages of this procedure are that it is invasive and requires the use of contrast material. Contrast-enhanced CT can provide similar information. Magnetic resonance venography is a noninvasive diagnostic tool that can be used when contrast 60

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poor absorption of drug and vein irritation may occur; a central line through the femoral vein may be required (Brumbaugh, 2011). Radiation and chemotherapy also are used to treat SVCS associated with NSCLC. Radiation usually is the initial treatment because NSCLC generally is not recognized to be a chemosensitive tumor (Brumbaugh, 2011; Yahalom, 2008). Radiation is effective in providing relief in approximately three-quarters of SVCS due to SCLC and two-thirds of SVCS due to NSCLC (Rowell & Gleeson, 2002). Response is usually seen in one to two weeks and may occur as early as three days after initiation of therapy. Careful assessment is needed during treatment to monitor for side effects and response. If symptoms worsen, alternative interventions should be considered. Chemotherapy is often the initial treatment for SVCS from SCLC and lymphoma because of the chemotherapy sensitivity of these tumors. Chemotherapy can relieve symptoms in up to 80% of patients with non-Hodgkin lymphoma and 77% of patients with SCLC (Perez-Soler et al., 1984; Rowell & Gleeson, 2002). Similar to radiation therapy, responses can be seen in one to two weeks. In general, NSCLC is not as sensitive to treatment as SCLC. Although SVCS is not considered to be a poor prognostic sign in patients with SCLC, it usually is a poor prognostic sign in NSCLC (six months for patients with NSCLC and SVCS versus nine months for patients with NSCLC alone) (Mack & Becker, 2008; Yahalom, 2008). Overall prognosis in patients with SVCS depends on many factors, including the underlying disease and stage of disease, previous treatment, the responsiveness of the tumor to the chemotherapy or radiation, and the patient’s performance status. If histologic diagnosis cannot be determined and the status of the patient is deteriorating, radiation therapy has traditionally been the recommended treatment (Yahalom, 2008). Different fractionation schedules have been investigated, but no current data support one scheme over another. Symptoms due to venous congestion usually decrease within three to four days, and maximum relief can occur three weeks after treatment (Brumbaugh, 2011). Intravascular stent placement is an option in patients with SVCS. The stents are placed by an interventional radiologist. Three types of stents commonly are used: the Wallstent®, the Gianturco Z-Stent®, and the Palmaz® stent. The Wallstent is the most commonly used of the three (Yahalom, 2008). No prospective randomized trials support the use of one stent over another (Schindler & Vogelzang, 1999). Success rates are reported to be in the range of 68%–100% (Brumbaugh, 2011). Symptom improvement is immediate for some, with most patients experiencing symptom improvement within 48 hours. Peripheral edema and headache usually improve within a few days (Brumbaugh, 2011). The immediate symptom relief makes this procedure a viable alternative to radiation, especially in emergency and palliative situations (Yahalom,

2008). No consensus has been reached regarding the use of anticoagulants in patients with stents (Wan & Bezjak, 2009). Suggested approaches include use of low-dose warfarin, antiplatelet agents, or full anticoagulation agents (Brumbaugh, 2011).

Conclusions Overall, SVCS is an uncommon complication in patients with malignancy. It is most often seen in patients with SCLC, NSCLC with squamous cell histology, or non-Hodgkin lymphoma. For most patients, symptoms are present for one or more weeks, and SVCS rarely presents as a lifethreatening complication. Healthcare providers must be aware of the signs and symptoms of SVCS so that treatment can be initiated before complete obstruction occurs. Chemotherapy and radiation are the most commonly employed treatments; however, stent placement represents a new option for some.

Pericardial Effusion and Cardiac Tamponade Pericardial effusion is an abnormal increase in fluid within the pericardial sac. It can lead to cardiac tamponade, in which the heart is compromised from increased pericardial pressure. Cardiac tamponade is a medical emergency and is most commonly caused by malignant disease (Beauchamp, 1998; Knoop & Willenberg, 1999). The malignancies most often associated with pericardial effusion and tamponade are lung and breast cancers (Knoop & Willenberg, 1999). Other malignancies that can cause effusion include malignant mesothelioma, leukemia, and lymphoma. The incidence of pericardial effusion is highest in patients with lung cancer, and it has been reported to occur in 36.5%–80% of patients (Cope, 2011; Shelton, 2006). In one retrospective study, cardiac tamponade was the initial presentation of NSCLC in 30% of patients (Wang et al., 2000). For most patients, cardiac tamponade is a late manifestation of metastatic disease, and long-term survival for these patients is limited (Ewer, Durand, Swafford, & Yusuf, 2002). Cough and dyspnea are common symptoms and often are attributed to the patient’s underlying malignancy, especially in those with thoracic malignancies.

Pathophysiology In healthy people, the pericardial sac contains 15–50 ml of fluid, which provides lubrication. Pericardial effusion is an abnormally large accumulation of fluid within the pericardial sac. The amount of fluid can range from as little as 200 ml to as much as 1,800 ml (Beauchamp, 1998). Effusions can be caused by metastatic disease, pericarditis from radiation therapy, or increased capillary permeability caused by highdose chemotherapy or biotherapy (Shelton, 2006). Metastatic disease or direct tumor extension may block venous or 61

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lymphatic drainage, leading to increased fluid around the heart (Knoop & Willenberg, 1999). Other causes include infection, hemorrhage, and myocardial infarction. Additionally, some reports have documented the development of tamponade following improper placement of central venous catheters (Knoop & Willenberg, 1999). Development of tamponade depends on the compliance of the pericardium and the rate and amount of fluid accumulation (Kaplow, 2011). The body can compensate if fluid accumulates slowly; however, compensatory mechanisms fail if fluid accumulates quickly. Cardiac tamponade results when the heart is compromised from this increased pericardial pressure and can no longer function normally. Specifically, pressure is exerted on all four chambers of the heart, resulting in decreased cardiac output and stroke volume, increased intracardiac pressure, and decreased ventricular diastolic filling (Beauchamp, 1998). As a result of decreased cardiac output, the body compensates with adrenergic stimulation, which leads to tachycardia and peripheral vasoconstriction (Knoop & Willenberg, 1999). Cardiovascular collapse can ensue when the body is no longer able to compensate for the increased intrapericardial volume and pressure.

with a sphygmomanometer. Normally on inspiration systolic pressure drops 10 mm Hg. With pulsus paradoxus, the drop in systolic pressure is greater than 10 mm Hg and is accompanied by diminution or disappearance of pulse (Knoop & Willenberg, 1999). Paradoxical pulse is a classic finding in cardiac tamponade but may occur in patients with other lung disease, such as chronic obstructive pulmonary disease (Ewer et al., 2002). It is not diagnostic of effusion and tamponade.

Assessment and Diagnosis The gold standard for diagnosis of cardiac tamponade is the two-dimensional echocardiogram. This test is noninvasive and specific and may be done at the bedside if needed. It also is useful in determining hemodynamic stability of the heart (Ewer et al., 2002). Common findings on echocardiography include right atrial compression, diastolic collapse of the right ventricle, and cardiac “rocking” (Ewer et al., 2002). The right side of the heart is more likely to be affected by the pressure of pericardial fluid because it contains less muscle than the left side of the heart (Beauchamp, 1998). Echocardiography is useful in patients who require pericardiocentesis or placement of a drainage catheter. Other tests include chest x-ray, CT, and electrocardiogram. Chest x-ray may reveal an enlarged heart or the classic “water-bottle cardiac silhouette” and a widened mediastinum (Kaplow, 2011). CT is not the test of choice because it is both time consuming and no more accurate than echocardiogram. The main advantage of chest CT is that it can detect very small amounts of pericardial fluid and help to identify the type of effusion or masses (Kaplow, 2011). Electrocardiogram is not diagnostic but may support the diagnosis if low-voltage QRS complexes and electrical alternans are seen. Additionally, one may see elevated ST segments and nonspecific T wave changes (Camp-Sorrell, 2008). Pericardial fluid should be analyzed to help confirm the diagnosis of malignant effusion. In patients with malignant effusions, the fluid can be sanguineous or serosanguineous and have an increased lactic dehydrogenase (LDH) (CampSorrell, 2008). A recent retrospective study demonstrated that serous pericardial effusions are as likely to be associated with malignancy as bloody effusions (Chiu, Atar, & Siegel, 2001). Fluid should be analyzed for the presence of malignant cells, although in patients with NSCLC with cardiac tamponade, the most likely cause of effusion is the cancer, whether or not malignant cells are present in the fluid (Wang et al., 2000).

Signs and Symptoms The development of signs and symptoms of cardiac tamponade depends on the rate at which fluid accumulates within the pericardial space and the patient’s baseline cardiac function. In general, if fluid accumulates slowly, patients may be asymptomatic or have vague symptoms. In contrast, if fluid accumulates rapidly, patients may quickly decompensate and become critically ill. Patients with compromised cardiac function from comorbid conditions are likely to experience increased symptoms earlier in the course. With slow accumulation of pericardial fluid, patients may experience mild symptoms, such as fatigue, mild dyspnea, orthopnea, and cough. Dyspnea and cough are the most common symptoms in patients with pericardial effusion (Wozniak & Gadgeel, 2010). Patients also may experience vague retrosternal chest pain and palpitations (Knoop & Willenberg, 1999). Chest pain usually is more severe when the patient is in the supine position (Camp-Sorrell, 2008). As the fluid increases within the pericardial sac, symptoms become more pronounced and include worsening dyspnea and cough, peripheral edema, and, less likely, low-grade fever. Patients may have anxiety or become restless and confused (Kaplow, 2011). Physical examination may be normal or abnormal and depends on the amount of fluid and how rapidly fluid accumulates within the pericardial sac. Signs of tachycardia, muffled heart sound, hypotension, jugular venous distension, and edema may be present. Paradoxical pulse (pulsus paradoxus) and narrowed pulse pressure also are common findings on examination. Pulsus paradoxus is best determined

Treatment The initial goal of treatment in tamponade is fluid removal. Several methods are used to treat pericardial effusion and tamponade. Patient considerations to determine the best method for fluid removal include the initial presenting symptoms, the diagnosis and stage of disease, the tumor’s 62

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chemosensitivity, prognosis, patient age, physical condition, and hemodynamic stability (Kaplow, 2011). Goals of care should include restoration of cardiac function, prevention of fluid reaccumulation, maintaining filling pressures, and prevention of complications (Kaplow, 2011). Overall, the best way to control or prevent cardiac tamponade is to control the tumor. Pericardiocentesis is indicated in patients who have life-threatening tamponade and are unable to undergo surgery. This procedure can be performed at the bedside with cardiac monitoring (Kaplow, 2011; Shelton, 2006). A pericardial catheter often is left in place to drain the remaining fluid. The catheter is removed when the total 24-hour drainage is 50–100 ml (Shelton, 2000). The disadvantage to this procedure is that fluid will reaccumulate in most patients unless a more definitive procedure is performed. Pericardiocentesis with intrapericardial sclerosis is a more definitive procedure for prevention of recurrent effusions. In this procedure, fluid is drained as previously described. When the drainage is less than 50–100 ml in a 24-hour period, a sclerosing agent is instilled within the pericardial sac. Instillation of the agent creates an inflammatory response within the pericardial sac, which eventually leads to obliteration of the pericardial space, thus preventing reaccumulation of fluid. Commonly used sclerosing agents include doxycycline, bleomycin, and cisplatin (Kaplow, 2011). Immunotherapy agents such as interleukin-2 have also been used (Kaplow, 2011). The use of the radioisotope of iodine known as 125I and the monoclonal antibody HMF-G2 is currently under investigation as a sclerosing technique (Kaplow, 2011). A retrospective study examining 93 patients with malignant pericardial effusion demonstrated that patients who had drainage of pericardial effusion and sclerosis had lower morbidity, mortality, and recurrence rates compared to those who had drainage alone (Maher, Shephard, & Todd, 1996). In another retrospective study, pericardiocentesis with intrapericardial sclerosis was as effective as open surgical drainage for malignant pericardial effusions (Girardi, Ginsberg, & Burt, 1997). Additionally, the costs associated with surgery far exceeded those of pericardiocentesis with sclerosis. One disadvantage to pericardial sclerosis is that it can be a painful procedure and generally requires the use of narcotic analgesics, depending on the agent used. Additionally, some agents will cause a febrile reaction. Thiotepa has been recommended as the best compromise for sclerosing agents, as it generally does not cause pain or a febrile reaction and is less costly than other agents (Martinoni et al., 2000). Surgical management involves either formation of a pericardial window or a pericardiectomy. Both procedures are performed in the operating room with general anesthesia; although, in selected cases, pericardial window may be performed with local anesthesia and IV sedation (Moores et al., 1995). In general, both procedures should only be performed in those who are expected to have a longer survival (Beauchamp, 1998). Formation of a pericardial window involves removal

of a section of pericardium and insertion of mesh, which allows fluid to drain into the surrounding tissue (Shelton, 2006). Pericardiectomy involves removing or stripping of the pericardial membrane. This procedure rarely is performed because other options are readily available (Shelton, 2006).

Conclusions Cardiac tamponade is a life-threatening complication seen in patients with pericardial effusion. The majority of patients with tamponade are those with a diagnosis of bronchogenic cancer. Prompt recognition and treatment (evacuation of pericardial fluid) are required to prevent hemodynamic collapse and possible death. Healthcare providers should be aware of this complication. Several treatment options are available, and the best option takes into account the patient’s physical health, prognosis, and diagnosis.

Pleural Effusion Pleural effusion, an excess accumulation of fluid within the pleural space, is a common complication of cancer. Approximately one-half of all patients with lung cancer experience this, and lung and breast cancers are the most common causes of malignant pleural effusion (Donington, 2010; Neragi-Miandoab, 2006). Malignant pleural effusion caused by lung cancer may be the initial presentation in those patients. Symptoms depend on the amount of fluid present and the rate at which the fluid accumulates. Patients with small effusions may be relatively asymptomatic, whereas those with large amounts of fluid may have severe symptoms. Although rare, pleural effusions become emergent when a large amount of fluid is present and an associated opacification of the hemithorax with mediastinal shift exists, which can lead to hemodynamic compromise.

Pathophysiology The pleural surface is made up of a single layer of mesothelial cells that line the lungs (visceral pleura), chest wall, diaphragm, and mediastinum (parietal pleura) (Erasmus, Goodman, & Patz, 2000). The space between the parietal and visceral layers (the pleural space) normally contains 10–20 ml of fluid. However, over a 24-hour period, as much as 100–200 ml of fluid may pass through this space (Mayo, 1999). This fluid acts as a lubricant during respiration. Fluid within the pleural space is regulated by five processes: capillary permeability, oncotic pressure, hydrostatic pressure, negative intrapleural pressure, and lymphatic drainage. One or more of these processes is disrupted in patients with lung cancer, which results in the accumulation of abnormal amounts of fluid within the pleural space. Alteration of lymphatic drainage from the pleural space is usually the cause of pleural effusions 63

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with malignancy (Donington, 2010). Accumulation of large amounts of fluid within the pleural space can lead to restriction of lung function and affect the patient’s ability to breathe. Pleural effusions are classified as transudates or exudates. Characteristically, exudates in people older than 60 years old most commonly are caused by malignancy (Erasmus et al., 2000). Exudates usually are caused by local problems that have an effect on the formation and absorption of pleural fluid, such as malignancy, pneumonia, or tuberculosis (Hayes, 2001). An exudate generally contains white blood cells, red blood cells, and protein, resulting in fluid that appears to be cloudy or serosanguineous. Alternatively, if the exudate is caused by infection, it will have a purulent appearance (empyema). Transudates result from systemic problems, such as cirrhosis or left-ventricular failure. They are essentially devoid of plasma proteins and white cells and thus are watery or straw colored (Hayes, 2001).

definitively determine effusion, atelectasis, or pleural-based tumor (Baciewicz, 2000). CT can help to determine loculated effusions, mediastinal adenopathy, and tumors. CT is an important test, especially if pleural effusion is the presenting sign of malignancy. However, this test will not determine the etiology of the effusion. Thoracentesis with examination of the pleural fluid is often the next step in determining the cause of the pleural effusion. This test will help to determine whether the cause is cancer-related. Typically, malignant pleural fluid will appear grossly bloody and as an exudate. Not all bloody effusions are malignant. Malignant effusions usually are characterized as exudates, and 90%–97% of malignant effusions are exudates (Donington, 2010). Characteristics of an exudate based on Light’s criteria include pleural-to-serum protein ratio greater than 0.5, total protein greater than 3 g/dl, pleural LDH-toserum ratio greater than 0.6, and pleural fluid LDH level 67% or higher than upper limits of normal (Donington, 2010). Very often, the effusion has a leukocyte count of 1,000–10,000. In general, the white cells are mostly lymphocytes; however, if the predominant cell type is a neutrophil, inflammation should be considered (Baciewicz, 2000). Fluid also needs to be examined for cytology because 50% of malignant pleural effusions will demonstrate positive cytology (Cope, 2011). Occasionally, a malignant effusion will present as a transudate; this can happen early in the malignant process and usually is related to mediastinal adenopathy with impaired lymphatic drainage (Baciewicz, 2000).

Signs and Symptoms The severity of symptoms is related to the amount of pleural fluid and the rate at which the fluid accumulates. Most patients (96%) with malignant pleural effusion have shortness of breath; other symptoms include dry cough and pleuritic chest pain (Donington, 2010). As the amount of pleural fluid increases, patients also may experience orthopnea. With involvement of the diaphragmatic parietal pleura, ipsilateral shoulder pain or discomfort may exist (Baciewicz, 2000). In patients with lung cancer, these symptoms are common as a result of the underlying disease; they can be exacerbated by the development of a malignant pleural effusion. Therefore, not all symptoms may be relieved with treatment of the pleural effusion. Most signs found on physical examination are attributable to fluid in the pleural space that separates the air-filled lung from the chest wall. Signs include dullness to percussion over the fluid and decreased or absent tactile fremitus on palpation. With a large effusion with mediastinal shift, the trachea may be deviated to the opposite side (away from the effusion).

Treatment Patients with small asymptomatic malignant effusions usually do not require local treatment. Depending on the tumor type, the effusions may resolve with systemic treatment of the tumor. In patients who are symptomatic and have a larger effusion, goals of treatment include fluid removal for both symptom control and diagnosis. Thoracentesis often may be the first procedure, especially if a diagnosis needs to be established. Thoracentesis also is effective for short-term control of symptoms associated with pleural effusion, but repeated thoracentesis may lead to risk of infection. Loculated effusion and recurrence is frequent (Neragi-Miandoab, 2006). Pleurodesis offers a more definitive outcome and should be considered unless the prognosis is poor and the patient is too ill to tolerate the procedure. This procedure is performed under local anesthesia. Pleurodesis involves placement of a chest tube (tube thoracoscopy) to drain the effusion. When this is accomplished, a sclerosing agent is instilled through the chest tube into the pleural space. The agent causes irritation of the pleural cavity, which leads to an inflammatory reaction. This inflammatory reaction causes the parietal and visceral pleura to adhere, thus eliminating the pleural space and preventing fluid reaccumulation. Three factors contribute to

Assessment and Diagnosis When pleural effusion is suspected, usually the first test to be performed is a chest radiograph with posterior-anterior and lateral views. If fluid is evident on the radiograph (seen as blunting of the costophrenic angle), a lateral decubitus film should be performed. As little as 175 ml of fluid may be detected on an upright chest film, and smaller amounts may be seen on the lateral decubitus view (Baciewicz, 2000). A lateral decubitus film will determine if the fluid is free flowing or loculated. This is important because it will help to determine treatment. With large pleural effusions, chest film may demonstrate complete opacification of the hemithorax and mediastinal shift. Often, chest CT is performed to 64

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successful pleurodesis: the pleural space must be completely drained of fluid, the lung needs to reexpand, and the sclerosing agent must be adequately distributed (Stretton, Edmonds, & Marriman, 1999). Alternatively, in patients who need a diagnosis, videoassisted thoracoscopy (VATS) may be used. At the time of VATS, a chest tube is placed and sclerosis can be performed at the conclusion of the procedure (Donington, 2010). This is a surgical procedure and requires general anesthesia. Over the years, many different agents have been used for sclerosis. Most commonly, bleomycin and sterilized talc are used (Cope, 2011). Talc is considered to be the agent of first choice because success rates have been reported at 71%–96% (Cope, 2011). It is inexpensive and offers no risk of the systemic side effects associated with bleomycin. Complications of talc pleurodesis include respiratory distress syndrome and pneumonitis. Pain and fever also may occur with pleural sclerosis. However, bleomycin is the only sclerosing agent that also processes an antitumor benefit (Cope, 2011). Pleuroperitoneal shunting is the recommended procedure in recurrent effusions or in patients who have nonexpansion of the lung (trapped-lung syndrome) (Baciewicz, 2000; Stretton et al., 1999). A pleuroperitoneal shunt can be placed using local anesthesia (Stretton et al., 1999). Patients must be able to operate the shunt by pressing the pump at least 400 times each day (Cope, 2011). Disadvantages include shunt malfunction and clotting of the device. Placement of an indwelling pleural catheter with intermittent drainage is another treatment approach for patients with recurrent malignant pleural effusions. The catheter can be placed at the bedside or in the outpatient setting under local anesthesia. The catheter has a one-way valve, allowing outflow of pleural fluid but preventing air and fluid from entering the catheter (Taubert, 2001). Pleural fluid usually is drained every one to two days. Mechanical pleurodesis occurs in many patients because the catheter acts as an irritant in the pleural cavity and drains the pleural cavity dry, essentially the same process as with chemical pleurodesis (Taubert, 2001). This procedure offers a great advantage to many patients and caregivers. It allows the patient to be at home with symptom control maintained by draining the fluid every one or two days. This is especially important because the life expectancy in patients with recurrent malignant pleural effusion is limited. The Pleurex® pleural catheter is a type of small-bore silicone tube placed for longterm drainage of malignant pleural effusions (Brubacher & Gobel, 2003). The manufacturer provides special kits containing vacuum bottles and dressing supplies. Spontaneous pleurodesis has been reported to occur in some cases with the catheter alone (Brubacher & Gobel, 2003). This catheter is used primarily in patients with symptomatic, recurrent pleural effusions, those in whom pleurodesis has failed, and those unable to tolerate more invasive procedures. Pleurectomy is another option for managing effusions. This is a surgical procedure that must be performed in the

operating room under general anesthesia. In this procedure, a thoracotomy is performed and the parietal pleura removed, causing a mechanical pleurodesis (Taubert, 2001). This procedure is reserved for patients with recurrent malignant pleural effusions who have a good performance status and life expectancy.

Conclusions Malignant pleural effusion is a common complication in patients with lung cancer. Pleural effusions may be the initial presentation or may occur later in the course of the disease. In rare cases, when a large effusion is present, pleural effusion may present as an emergent situation, with opacification of the hemithorax, mediastinal shift, and hemodynamic compromise. In this case, immediate removal of fluid is required. For most patients, goals of treatment include palliation of symptoms and maintenance of quality of life. Small effusions in patients who are not symptomatic may not require intervention. In some, systemic treatment of the tumor may lead to resolution of the effusion. Larger effusions and patients who are symptomatic require intervention by one of the procedures outlined herein. In this case, the goals of treatment are obliteration of the pleural space and palliation of symptoms.

Malignant Spinal Cord Compression Spinal cord compression occurs in approximately 5%–14% of patients with cancer. In a study of 1,000 patients with spinal cord compression, lung cancer was second to breast cancer as the most common type of diagnosis (Kwok, Patchell, & Regine, 2010). Other causes of malignant spinal cord compression include prostate cancer and multiple myeloma. In the majority of cases, spinal cord compression is a later manifestation of malignancy; however, it is estimated to be the initial manifestation of malignancy in 8%–35% of cases (Labovich, 1994; Schiff, O’Neill, & Suman, 1997). Spinal cord compression is a true neurologic emergency. Successful outcomes depend on early recognition of the signs and symptoms of spinal cord compression and early intervention. Without prompt diagnosis and intervention, patients may become irreversibly paralyzed and experience sensory loss and sphincter incontinence. In patients with a loss of function at the diagnosis of spinal cord compression, treatment is not likely to reverse damage (Baehring, 2008).

Pathophysiology The spinal cord, a portion of the central nervous system, is protected by the vertebral column. It consists of nervous tissue that connects the brain and the body (Sunderland, 1994). The spinal column extends from the brain to the first two lumbar vertebrae (Flaherty, 2011; Sunderland, 1994). 65

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Below this, extending through the remaining vertebral column (lumbar, sacral, and coccygeal areas) is the cauda equina (a collection of nerve roots) (Flaherty, 2011; Flounders & Ott, 2003). The spinal cord and brain are protected by three membranes (the meninges), the dura mater, the arachnoid membrane, and the pia mater (Flaherty, 2011). The dura mater is the outermost layer closest to the vertebrae and skull; the pia mater lies closest to the brain and spinal cord. The arachnoid membrane lies in between the dura and pia mater. The epidural or extradural space lies between the vertebrae or skull and the meninges (Flaherty, 2011). Between the dura mater and the arachnoid membrane is the subdural space. The subarachnoid space lies beneath the arachnoid membrane (Sunderland, 1994). Malignant spinal cord compression most commonly is caused by metastatic disease rather than from a primary tumor of the spinal cord or spinal canal (Flounders & Ott, 2003). Three different types of spinal cord metastases exist: intramedullary, leptomeningeal, and epidural, referring to the location of metastatic disease (Flaherty, 2011). Metastasis to the epidural space is the most common type of spinal cord metastatic disease (Flaherty, 2011). Metastatic disease is rare in the intramedullary and leptomeningeal sites. Most metastatic disease (70%) occurs in the thoracic area of the spinal column (Grandt, 2006). Metastatic spread to the epidural space occurs through three mechanisms: “hematogenous spread, direct tumor extension, and direct metastatic deposits of tumor cells” (Bucholtz, 1999, p. 152). Metastatic disease causes 95% of spinal cord compressions; the remaining cases occur because of primary tumors in the vertebral column (Grandt, 2006). In this case, metastatic growth of tumor within the vertebra leads to subsequent destruction of bone. Direct tumor extension usually occurs in patients with non-Hodgkin lymphoma. Direct metastatic deposits of tumor cells are seen in patients with leukemia (Bucholtz, 1999). Neurologic abnormalities result from interruption of the vascular supply to the spinal cord by tumor or bone destruction, direct compression of the spinal cord, vertebral collapse secondary to pathologic bone destruction, and dislocation of vertebral bodies (Flounders & Ott, 2003). Cellular injury to nerve tissue occurs from pressure on the spinal cord exerted by the tumor (Flounders & Ott, 2003). Cellular injury is mediated by the following mechanisms: vasogenic edema; cytokines, including prostaglandin, interleukin-1, and interleukin-6, which cause demyelination and nerve tissue injury; serotonin and glutamine, which cause tissue damage; and cytotoxic edema, which causes irreversible paraplegia (Bucholtz, 1999).

(Sun & Nemecek, 2010). Pain is either localized or radicular in nature. Local pain occurs at or near the site of the tumor and characteristically tends to be constant, dull, and aching (Flounders & Ott, 2003). Radicular pain results from irritation of the nerve root by compression from tumor. It is shooting and burning in nature and can be exacerbated by coughing or movement. Constrictive-band-like pain is caused by compression of thoracic vertebrae, whereas involvement of cervical or lumbosacral vertebrae tends to cause pain in a limb (Flaherty, 2011). The pain associated with compression of thoracic vertebrae usually is bilateral, whereas pain associated with compression of cervical or a lumbosacral vertebra is usually unilateral (Flaherty, 2011). Pain radiating to the buttocks indicates compression at the sacral level (Weinstein, 2007). In older adults with lung cancer, back pain is a common problem and may be caused by degenerative or disc disease. Consequently, these patients often minimize back pain, attributing it to arthritis or injury. Characteristically, pain from spinal cord compression is worse on lying down, whereas pain from degenerative disease usually is relieved by this measure. Therefore, any patient who reports worsening of pain when lying down should be evaluated for spinal cord compression (Manzullo, Rhines, & Forman, 2002). In patients with epidural spinal cord compression, neurologic symptoms tend to progress from pain to motor weakness, sensory loss, motor loss, and autonomic dysfunction (Flounders & Ott, 2003). Motor weakness often is described as heaviness or stiffness in the limbs, which may cause difficulty in walking. Sensory loss is characterized by numbness, tingling, and the inability to determine temperature. Sensory changes are detected in nearly half of patients at presentation (Weinstein, 2007). Late manifestations of motor and sensory loss include autonomic dysfunction, such as loss of sphincter control, loss of coordination, and ataxia (Flounders & Ott, 2003). Some patients may have significant epidural compression with no neurologic signs or symptoms (Weinstein, 2001). Physical examination in a patient with suspected epidural spinal cord compression may not be revealing. The examination should focus on the neurologic and musculoskeletal systems (Bucholtz, 1999). It should include gentle percussion and palpation over the spine, which may reveal tenderness at the level of tumor involvement. Findings on neurologic examination will depend on the degree of spinal cord compromise. Neurologic examination may reveal sensory deficits below the level of disease. Motor deficits include weakness and hyperreflexia. Autonomic dysfunction should be suspected in those with decreased rectal tone or a distended bladder.

Signs and Symptoms

Assessment and Diagnosis

Signs and symptoms of spinal cord compression depend on the site of vertebral metastases and the amount of tumor invasion. Back pain is the initial presenting symptom in nearly all patients, followed by motor and sensory deficits

Radiographic assessment may include plain x-rays of the spine, bone scan, myelogram CT scan, and MRI. Plain films are often the first examination to be performed and may demonstrate a mass or a lytic or blastic lesion within the vertebrae. For 66

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this to be evident on plain film, significant bone change from tumor must occur; therefore, a normal examination does not rule out epidural metastases (Cherny, 2007; Weinstein, 2007). Additionally, the spinal cord and nerve roots are not visualized on plain films; therefore, CT, MRI, or myelogram must be performed (Novelline, 1997). When plain films are negative, a bone scan can be performed to detect possible bone disease. Bone scan has several disadvantages, however. It does not differentiate degenerative disease from metastatic disease, and it does not offer visualization of the spinal cord and nerve roots. When available, contrast-enhanced MRI is the gold standard to diagnose epidural spinal cord compression (Sun & Nemecek, 2010). This test is safe and noninvasive, and the entire spine can be imaged easily. The spinal cord and nerve roots are visualized on MRI. Additionally, paraspinal masses are visible (Sitton, 1998), and MRI can distinguish between vertebral, extradural, intradural, extramedullary, and intramedullary lesions (PetersonRivera & Watters, 1997). Leptomeningeal disease also can be more easily detected on MRI with use of gadolinium (Flaherty, 2011). If MRI is not available or the test is contraindicated (e.g., presence of pacemaker), CT myelogram should be performed. An advantage to myelogram is that a sample of cerebrospinal fluid can be obtained for analysis. CT myelography also allows the neural elements to be visualized. CT myelography is an invasive test that requires a lumbar puncture and injection of a contrast agent (Novelline, 1997; Peterson-Rivera & Watters, 1997). Patients who are claustrophobic should be referred to an open MRI facility or given a sedative prior to a traditional MRI examination (Flaherty, 2011).

Medical management includes the use of corticosteroids, pain control, and radiation therapy. Corticosteroids often are the first intervention and are used regardless of the choice of definitive treatment (Sitton, 1998). They are used to decrease edema and inflammation and to help with pain control (Flounders & Ott, 2003). Additionally, neurologic deficits may improve with the use of corticosteroids. However, many believe that high-dose corticosteroids, such as dexamethasone bolus IV followed by 96 mg/day given orally, tapered quickly over a few weeks, are superior to the lower-dose regimens (Kwok et al., 2010). Other studies have shown that lower-dose regimens are as effective and cause fewer steroid-related side effects (Heimdal, Hirschberg, Slettebo, Watne, & Nome, 1992; Vecht et al., 1989). Radiation therapy is the treatment of choice for spinal cord compression, and response rates have ranged from 40%–80% (Bucholtz, 1999; Sullivan, 1996). Because the success of radiation therapy depends on the radiosensitivity of the tumor, it has varying effects in NSCLC, which is not considered particularly radiosensitive (Sullivan, 1996). Radiation therapy is believed to be more effective in patients with SCLC because SCLC is believed to be more radiosensitive; however, this has not been proved (Sullivan, 1996). The optimum fractionation schedule for the treatment of malignant spinal cord compression has not yet been determined (Rades, Karstens, & Alberti, 2002). The most common dosage range of radiation is 20–40 Gy given in 5–20 fractions over 2–4 weeks (Flaherty, 2011). However, most courses are given in 10–15 fractions (Sun & Nemecek, 2010). The radiation field usually covers the area of spinal cord compression as well as one to two vertebral bodies above and below the area of compression (Flounders & Ott, 2003). Normal tissue is spared from the radiation as much as possible. Response to radiation therapy is measured as decrease in tumor mass, pain control, and preservation of function. In general, radiation therapy is well tolerated. The most common side effects include fatigue and skin changes.

Treatment For the majority of patients with lung cancer, epidural spinal cord compression is managed medically, and treatment is palliative in nature. The goals of treatment are preservation or restoration of neurologic function, pain control, and control of the tumor. Prompt intervention is required to prevent continued deterioration of the patient’s functional status. The majority of patients who were ambulatory before treatment remain so, but only about 10% of patients who were paraplegic before treatment will regain some function with treatment (Peterson-Rivera & Watters, 1997). Historically, surgical intervention was reserved for those with spinal instability, compression from bone fragments in the canal, radioresistant primary (worsening disease on or after radiotherapy), and significant pain (Flaherty, 2011). However, MRI and new stabilizing techniques have created more options for patients with spinal compression (Flaherty, 2011). In patients with lung cancer, surgical intervention should be considered on a case-by-case basis in patients with a good performance status and in whom the benefits outweigh the risks. Morbidity from surgical intervention has been estimated to be as high as 48%, and this type of surgery carries approximately a 6% mortality rate (Flaherty, 2011).

Conclusions Malignant epidural spinal cord compression is a true oncologic emergency that is seen in patients with lung cancer. For some patients, spinal cord compression may be the initial presentation of lung cancer. Outcome, including preservation of neurologic function, depends on prompt recognition and treatment. Early intervention using corticosteroids when spinal cord compression is suspected or diagnosed, followed by radiation therapy, most commonly is used in this group of patients.

Summary Oncologic emergencies are complications arising from the cancer itself and include SVCS, cardiac tamponade, pleural 67

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effusion, and malignant spinal cord compression. These conditions are often seen in patients with lung cancer. Prompt evaluation and diagnosis are critical. Treatment includes supportive measures in addition to treatment of the primary tumor. With prompt multidisciplinary treatment, many patients can return to their previous level of functioning. Thus, it is important for healthcare professionals to be aware of these common oncologic emergencies.

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Stretton, F., Edmonds, P., & Marrinan, M. (1999). Malignant pleural effusions. European Journal of Palliative Care, 6, 5–9. Sullivan, F. (1996). Palliative radiotherapy for lung cancer. In H.L. Pass, J.B. Mitchell, D.H. Johnson, & A.T. Turrisi (Eds.), Lung cancer: Principles and practice (pp. 775–789). Philadelphia, PA: Lippincott Williams & Wilkins. Sun, H., & Nemecek, A.N. (2010). Optimal management of malignant epidural spinal cord compression. Hematology/Oncology Clinics of North America, 24, 537–551. doi:10.1016/j.hoc.2010.03 .011 Sunderland, P.M. (1994). Structure and function of the nervous system. In K.L. McCance & S.E. Huether (Eds.), Pathophysiology: The biologic basis for disease in adults and children (pp. 397–436). St. Louis, MO: Mosby. Taubert, J. (2001). Management of malignant pleural effusion. Nursing Clinics of North America, 36, 665–683. Vecht, C.J., Haaxma-Reiche, H., van Putten, W.L., deVisser, M., Vries, E.P., & Twijnstra, A. (1989). Initial bolus of conventional versus high-dose dexamethasone in metastatic spinal cord compression. Neurology, 39, 1255–1257. Wan, J.F., & Bezjak, A. (2009). Superior vena cava syndrome. Emergency Medicine Clinics of North America, 27, 243–255. doi:10.1016/j.emc.2009.01.003 Wang, P.C., Yang, K.Y., Chao, J.Y., Liu, J.M., Perng, R.P., & Yen, S.H. (2000). Prognostic role of pericardial fluid cytology in cardiac tamponade associated with non-small cell lung cancer. Chest, 118, 744–749. Weinstein, S.M. (2001). Spinal cord compression. In A.M. Berger, R.K. Portenoy, & D.E. Weissman (Eds.), Principles and practice of supportive oncology: Updates 4 (pp. 1–16). Philadelphia, PA: Lippincott Williams & Wilkins. Weinstein, S.M. (2007). Management of spinal cord and cauda equina compression. In A.M. Berger, J.L. Shuster Jr., & J.H. Von Roenn (Eds.), Principles and practice of palliative care and supportive oncology (3rd ed., pp. 415–424). Philadelphia, PA: Lippincott Williams & Wilkins. Wozniak, A.J., & Gadgeel, S.M. (2010). Clinical presentation of non-small cell carcinoma of the lung. In H.I. Pass, D.P. Carbone, D.H. Johnson, J.D. Minna, G.V. Scagliotti, & A.T. Turrisi III (Eds.), Principles and practice of lung cancer (4th ed., pp. 327–340). Philadelphia, PA: Lippincott Williams & Wilkins. Yahalom, J. (2008). Oncologic emergencies: Superior vena cava syndrome. In V.T. DeVita Jr., T.S. Lawrence, & S.A. Rosenberg (Eds.), Cancer: Principles and practice of oncology (8th ed., pp. 2427–2434). Philadelphia, PA: Lippincott Williams & Wilkins.

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CHAPTER 7

Paraneoplastic Syndromes Leslie B. Tyson, MS, APRN, BC, OCN®, and Pamela K. Ginex, EdD, RN, OCN®

Introduction

Humoral Hypercalcemia of Malignancy

Paraneoplastic syndromes are the result of remote clinical effects of cancer and are not directly related to the primary tumor or metastatic deposits. Overall, paraneoplastic syndromes are rare, occurring in 10%–20% of patients with cancer (3%–5% of patients with small cell lung cancer [SCLC]), and are the result of substances (e.g., hormones, growth factors, cytokines, antibodies) secreted by the primary tumor or its metastases (Mayden, 2011). These substances have an effect on multiple systems of the body, including the endocrine, neurologic, hematologic, and musculoskeletal systems (Mayden, 2011). Paraneoplastic syndromes can occur with any cancer, but they occur more frequently in patients with lung carcinoma, particularly SCLC (Mayden, 2011). They may precede a lung cancer diagnosis and often lead clinicians to suspect and look for an undiagnosed cancer. This section will review the most common paraneoplastic syndromes seen in patients with lung cancer. They will be reviewed according to the systems that are affected. Anemia of malignancy and anorexia-cachexia syndrome will not be covered.

Hypercalcemia is def ined as an abnormal elevation in serum calcium. The normal range of serum calcium (depending on local laboratory normal values) is 8–10.8 mg/dl. In adults, hypercalcemia is present when the serum calcium level exceeds 10.8 mg/dl (Yeh & Berenson, 2007). In the general population, the primary cause of hypercalcemia is hyperparathyroidism. These patients are usually asymptomatic, and the diagnosis is made with an elevated serum parathyroid hormone (PTH) level. Patients with hypercalcemia caused by a malignant process are usually symptomatic and have low serum parathyroid hormone levels (Stewart, 2005). In patients with malignant disease, hypercalcemia most commonly is found with breast, lung, and genitourinary (kidney) cancers, multiple myeloma, and lymphomas. Overall, hypercalcemia is estimated to occur in 10%–20% of those with cancer (Kaplan, 2011). Regarding lung cancer, it is most often seen with SCLC and is rare with squamous cell histologies (Kaplan, 2011). Most patients have skeletal metastases; however, hypercalcemia can occur in those who do not have bone metastases. Patients with hypercalcemia in the setting of a malignancy generally have a poor prognosis (Horwitz, 2011). The control of hypercalcemia usually depends on control of the malignant process. New insights into the pathophysiology and new developments in the treatment of hypercalcemia have occurred and may improve the prognosis of those with this disorder. Calcium is the major cation involved in the structure of bone and teeth. Calcium’s other functions include the maintenance of normal clotting functions, muscle contractility, transmission of nerve impulses, and maintenance of normal cellular membrane permeability (Baird-Powell, 2006). Most calcium (99%) is found in bone as hydroxyapatite, where it is responsible for bone rigidity (Baird-Powell, 2006). The remaining 1% is found in the extracellular fluid, where half is bound to plasma protein (albumin) (Baird-Powell, 2006) and half is in the ionized free form and is responsible for

Endocrine Paraneoplastic Syndromes The most common and best understood of the paraneoplastic syndromes are those of the endocrine system. According to Armstrong (2005), these syndromes are diagnosed with concomitant hormone excess and malignancy and elevated hormone levels in the blood or urine. Improvement in the syndrome will occur with effective treatment (Armstrong, 2005). Endocrine paraneoplastic syndromes seen in patients with lung cancer include humoral hypercalcemia of malignancy, ectopic adrenocorticotropic hormone (ACTH) syndrome (also known as Cushing syndrome), and syndrome of inappropriate antidiuretic hormone (SIADH) (Armstrong, 2005). 71

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maintaining the most important of the calcium physiologic functions (Baird-Powell, 2006). Maintenance of normal calcium levels occurs through bone remodeling, renal calcium reabsorption, and gastrointestinal absorption. Hormonal factors also play a role in calcium regulation. The three hormones responsible for extracellular calcium regulation are PTH, calcitonin, and vitamin D (BairdPowell, 2006).

Table 7-1. Signs and Symptoms of Hypercalcemia of Malignancy System

Pathogenesis In healthy people, bone maintenance is a continuous process of bone resorption and bone formation. Osteoblasts and other factors are involved in bone formation, whereas osteoclasts and other factors are involved in bone resorption. Cells involved in establishing bone metastases include osteoclasts, osteoblasts, cancer cells, and mineralized bone matrix (Lipton et al., 2009). One indication of metastatic bone lesions is an increase in bone resorption by osteoclasts (Lipton et al., 2009). Increased bone resorption results in a release of calcium from bone, leading to hypercalcemia. Hypercalcemia in malignancy can be one of two types: humoral hypercalcemia of malignancy or osteolytic hypercalcemia (Yeh & Berenson, 2007). Both act to disrupt calcium balance by producing hormones, growth factors, and cytokines that interfere with normal calcium regulation. Humoral hypercalcemia occurs more often than osteolytic hypercalcemia (Yeh & Berenson, 2007). The cause of local osteolytic hypercalcemia is osteoclastic bone resorption that results in the release of large amounts of calcium from destroyed areas of bone (Keenan & Wickham, 2005; Yeh & Berenson, 2007). Breast cancer most often causes hypercalcemia by this mechanism (Horwitz, 2011). Humoral hypercalcemia is the result of tumor production of PTH-related protein (PTHrP), which mimics PTH (Horwitz, 2011; Stewart, 2005). PTHrP and other cytokines and factors stimulate osteoblasts to produce receptor activator of nuclear factor kappa B ligand (RANKL) (Fornier, 2010). RANKL contributes to bone destruction by promoting the survival and proliferation of osteoclasts (Yeh & Berenson, 2007). The increased osteoclastic activity causes bone destruction and the subsequent release of calcium and other growth factors, which in turn stimulate tumor growth, creating a continuous cycle (Yeh & Berenson, 2007).

Signs and Symptoms

Neurologic

Hyporeflexia Confusion Restlessness Somnolence Stupor Coma

Cardiovascular

Bradycardia Electrocardiographic abnormalities Heart block Cardiac arrest

Gastrointestinal tract

Anorexia Nausea and vomiting Constipation

Renal

Polyuria and nocturia Polydipsia Dehydration

Systemic

Fatigue Weakness Lethargy

Note. Based on information from Baird-Powell, 2006; Keenan & Wickham, 2005.

anorexia. Additionally, increased calcium in the extracellular fluid results in interference of the kidney’s ability to reabsorb sodium. This leads to sodium and water loss from polyuria, which further exacerbates dehydration (Keenan & Wickham, 2005). Diagnosis As mentioned previously, elevated levels of serum calcium are diagnostic of the problem. Serum calcium levels must be adjusted if albumin levels are low. When albumin levels are low, the corrected serum calcium is the measurement most often used to diagnose hypercalcemia. This is done by obtaining serum calcium and albumin levels. Keenan and Wickham (2005) provided three formulas for adjusting serum calcium. One method for correcting serum calcium is calculated by adjusting the calcium level for every gram of albumin (see Figure 7-1); this results in a rough estimate of the serum calcium but is still considered to be a useful tool (Keenan & Wickham, 2005). Measurement of the serum level of ionized calcium should be considered if there is doubt about the validity of the measurement of total calcium (Stewart, 2005). If the corrected calcium levels are between 10.5–12 mg/dl, mild hypercalcemia exists. If they are between 12–13.5 mg/dl, moderate hypercalcemia exists. Hypercalcemia is considered severe when levels exceed 14 mg/dl and life threatening when

Signs and Symptoms Signs and symptoms of malignancy-generated hypercalcemia are seen in Table 7-1. The frequency and degree of symptoms are related to the rate at which hypercalcemia develops. Hypercalcemia that develops slowly has fewer symptoms than when serum calcium levels rise acutely. Acute rises in serum calcium may cause dramatic changes in mental status. Other symptoms are vague and include nausea, vomiting, anorexia, constipation, and fatigue. Many patients become dehydrated from the nausea, vomiting, and 72

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levels exceed 16 mg/dl (Keenan & Wickham, 2005). Other important blood tests include assessment of renal function and measurement of PTH to rule out hyperparathyroidism. Assessment of patient history and symptoms, medication history, and physical examination are important considerations in patients with hypercalcemia. History should focus on the type and extent of cancer as well as treatment and response to treatment. Most cases of hypercalcemia are seen in patients with advanced cancer that is not responding to treatment. Assessment of symptoms (as seen in Table 7-1) and their duration will give clues about the onset of hypercalcemia. Medication history is important, as some medications (e.g., thiazide diuretics, lithium) can exacerbate hypercalcemia. Additionally, assessment of mental status and gastrointestinal symptoms is more difficult in patients using narcotics for pain control. Physical examination should be thorough and focus on changes in mental status, extent of dehydration, bowel motility, muscle strength and tone, deep tendon reflexes (delayed in hypercalcemia), and heart rate and rhythm (bradycardia and dysrhythmia in hypercalcemia).

binding to bone cell matrix, prevention of osteoclast precursor differentiation, and promotion of proapoptotic effects on tumor cells (Keenan & Wickham, 2005). Use of bisphosphonates may also reduce the risk of other skeletal complications (Horwitz, 2011). The bisphosphonates most often used in practice are pamidronate and zoledronic acid. Zoledronic acid is usually preferred over pamidronate because the administration time is short. The U.S. Food and Drug Administration (FDA) approved zoledronic acid in 2002, and it has been shown to be more effective than pamidronate (Yeh & Berenson, 2007). To date, zoledronic acid is most often used in the treatment of hypercalcemia of malignancy (Body, 2011; Yeh & Berenson, 2007). Zoledronic acid is a heterocyclic nitrogen-containing bisphosphonate and a potent inhibitor of bone resorption (Keenan & Wickham, 2005). It is given intravenously over 15 minutes, making it convenient to administer. The effects of zoledronic acid occur within 24–48 hours, and calcium levels are often maintained for four to six weeks following treatment. The dose is 4 mg but needs to be adjusted for declining renal function as measured by creatinine clearance. Zoledronic acid is also used to prevent skeletal complications, including hypercalcemia, bone pain, and fracture from solid tumors (Body, 2011). Side effects include fever, flu-like symptoms, hypocalcemia, hypophosphatemia, decreased appetite, nausea, and vomiting. Nephrotoxicity associated with bisphosphonates is both dose and infusion time dependent (Coleman, 2011). As a result, it is important to monitor renal function, hydration status, and observe recommended infusion times in patients receiving bisphosphonates. Other agents that may be used to treat hypercalcemia include calcitonin, glucocorticoids, and gallium nitrate, but these are used less often (Shane & Berenson, 2011). Denosumab is a monoclonal antibody that the FDA approved in 2010 for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Skeletalrelated events include fracture, skeletal instability or loss of skeletal integrity, spinal cord compression, need for surgery or radiation therapy for symptomatic bone metastases, and hypercalcemia (Coleman, 2011). It is also approved for the treatment of osteoporosis. The mechanism of action is osteoclast inhibition by targeting RANKL (Coleman, 2011). Denosumab is given as a subcutaneous injection every four weeks. The most common side effects are fatigue, hypophosphatemia, and nausea. Severe hypocalcemia can occur; as such, this needs to be corrected before administering denosumab. Concurrent administration of calcium and vitamin D can be used to prevent or treat hypocalcemia. Osteonecrosis of the jaw (ONJ) is a complication that is seen with high-potency bisphosphonates; it is seen in patients treated with zoledronic acid and denosumab. This complication is seen more often in those given zoledronic acid when compared to pamidronate (Coleman, 2011). Task forces for the American Association of Oral and Maxillofacial

Treatment Treatment is aimed at the underlying disease and immediate management of the hypercalcemia. General supportive measures include discontinuation of calcium supplements or medicines that can lead to hypercalcemia as noted previously. Many patients develop hypophosphatemia, which can impede treatment of hypercalcemia. Therefore, phosphorus needs to be replaced with neutral phosphorus (Stewart, 2005). Immediate measures include rehydration, use of bisphosphonates, or the new RANKL inhibitor denosumab. Ultimately, long-term control of hypercalcemia depends on control of the cancer. The degree of hypercalcemia determines whether patients can be managed in an ambulatory setting or must be admitted to the hospital. IV fluids with isotonic saline are given initially to restore hydration and promote urinary excretion of calcium. Diuretics may be used to enhance calcium excretion, but these have a limited effect (Yeh & Berenson, 2007). Monitoring of renal function and electrolytes is important during rehydration. These measures alone do little to control significant hypercalcemia; therefore, many patients are treated with bisphosphonates. Bisphosphonates work by inhibiting osteoclasts, which results in inhibition of tumor cell

Figure 7-1. Formula for Determining Corrected Serum Calcium 1. Subtract the albumin level from 4.0. 2. Multiply the difference by 0.8. 3. If the result is a negative number, subtract it from the serum calcium; if it is positive, add it to the calcium. Note. Based on information from Keenan & Wickham, 2005.

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Diagnosis Diagnosis is based on the aforementioned f indings and through the use of laboratory studies. The lowdose dexamethasone suppression test involves giving dexamethasone at bedtime, followed by serum measurement of cortisol levels in the morning. In patients with ectopic production of ACTH, cortisol levels will not be suppressed by dexamethasone (O’Shaughnessy & Jochen, 2007). However, the high-dose dexamethasone suppression test will suppress ACTH in patients with pituitary tumors (Chernecky & Berger, 2008; Masters, 2010). A more reliable test is done by obtaining a serum sample for ACTH level and a 24-hour urine collection for free cortisol. A 24-hour urine collection for free cortisol will demonstrate elevated urinary free cortisol levels (Chernecky & Berger, 2008). Serum ACTH levels in excess of 100 ng/L in conjunction with elevated serum cortisol levels (greater than 29 mcg/dl) are diagnostic of Cushing syndrome (Pelosof & Gerber, 2010).

Surgeons and the American Society for Bone and Mineral Research have developed working definitions of ONJ. They are, respectively: “current or previous treatment with a bisphosphonate; exposed, necrotic bone in the maxillofacial region that has persisted for more than 8 weeks; and no history of radiation therapy to the jaws” (Advisory Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws, 2007, p. 370) and “the presence of exposed bone in the maxillofacial region that does not heal within eight weeks after identification by a healthcare provider” (Khosla et al., 2007, p. 1479). The pathophysiology is not clear but is likely multifactorial; poor dental hygiene, poorly fitting dentures, periodontal disease, and tooth extraction or dental manipulation may also contribute to ONJ (Berenson, 2011). Treatment is conservative and includes debridement of the affected area, antibiotics, and mouth rinses (Berenson, 2011). Hypercalcemia is the most common metabolic disorder in patients with cancer and is seen in moderate frequency in patients with squamous cell lung cancer. Healthcare providers must be aware of patients who are at greatest risk for hypercalcemia and the most common signs and symptoms so that therapy can be initiated early. Treatment response of the underlying malignancy will provide the longest period of normocalcemia. Bisphosphonates can provide symptom relief and prevent hypercalcemia from worsening. Additionally, they can be administered in the outpatient setting.

Treatment For patients with ectopic production of ACTH, treatment is aimed at management of the primary tumor. Control of the tumor should lead to control of this paraneoplastic syndrome. Frequently, one of the first signs of tumor recurrence is reemergence of this syndrome. Drug therapy often is used in the treatment of Cushing syndrome. The most commonly used agent is ketoconazole. Ketoconazole has a rapid onset of action and inhibits corticosteroid production (Mayden, 2011). Common doses range from 400–1,200 mg/day (Mayden, 2011). Ketoconazole can be used in conjunction with combination chemotherapy in those with SCLC. Liver enzymes must be monitored closely, and patients must be evaluated for significant adrenal suppression that can occur from ketoconazole (Mayden, 2011). Other medications used in the treatment of ectopic ACTH production include metyrapone, aminoglutethimide, and octreotide. The latter most often is used in the management of ACTH-secreting bronchial carcinoid tumors (Mayden, 2011).

Ectopic Adrenocorticotropic Hormone Syndrome Incidence and Pathogenesis Ectopic ACTH syndrome (Cushing syndrome) is most commonly associated with SCLC, but other types of neoplasms can prompt this disease as well (Boyiadzis, Lieberman, Geskin, & Foon, 2008). SCLC represents about 50% of the cases, but only 2%–10% of these patients are diagnosed with a significant form of the disease (Mayden, 2011). Cushing syndrome also is seen in patients with benign pituitary tumors or hyperplasia. When the cancer produces large amounts of biologically active ACTH, the ACTH then stimulates the adrenal glands to produce excessive amounts of corticosteroids, which leads to the development of Cushing syndrome (Mayden, 2011).

Syndrome of Inappropriate Antidiuretic Hormone Incidence and Pathogenesis SIADH is a paraneoplastic syndrome characterized by abnormal production of arginine vasopressin (AVP), formerly known as antidiuretic hormone (ADH), which results in water retention and hyponatremia. Ectopic production of AVP is the most common cause of increased AVP levels. This most often occurs in patients with cancer, particularly SCLC, but it can be seen in patients with infections, such as pneumonia or tuberculosis, and with central nervous system disorders (e.g., trauma, infection, cerebral vascular accident), as well as those taking drugs that potentiate AVP (e.g., diuretics, vincristine, cyclophosphamide) (Ezzone, 2006). SCLC is the cause of SIADH in 75% of cases (Boyiadzis et al., 2008).

Signs and Symptoms The symptoms of paraneoplastic ACTH syndrome include proximal muscle weakness, hypokalemia, metabolic alkalosis, glucose intolerance, and hypertension. Steroid psychosis, personality changes, or depression can occur as a result of high cortisol levels (Jameson & Johnson, 2008). The more commonly associated signs and symptoms of increased ACTH production, such as moon face, buffalo hump, and hyperpigmentation of the skin, are late effects that may appear in patients with lung cancer depending on the patient’s life expectancy (Mayden, 2011). 74

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This syndrome can be seen in 3%–15% of patients who are diagnosed with SCLC (Boyiadzis et al., 2008). Hyponatremia is classified according to the patient’s fluid volume status as hypovolemic, hypervolemic, or euvolemic (Patel & Balk, 2007). Congestive heart failure, cirrhosis of the liver, and nephrotic syndrome are causes of hypervolemic hyponatremia. Hypovolemic hyponatremia is often caused by diuretic use, nausea, vomiting, diarrhea, and febrile illnesses. SIADH is a common cause of euvolemic hyponatremia (Patel & Balk, 2007). In SIADH, cancer cells create, store, and release excessive amounts of AVP, leading to a syndrome often referred to as water intoxication (Keenan, 2005). Patients with SIADH from malignancy have an increase in free water in the extracellular fluid with plasma hyposmolality, dilutional hyponatremia, and urine osmolality that exceeds plasma osmolality (Keenan, 2005; Patel &Balk, 2007). There is increased urinary sodium excretion with normal intake of water and salt (Patel & Balk, 2007). Water is moved from the extracellular to the intracellular space by an osmotic gradient, resulting in intracellular edema (Keenan, 2005). As a result, peripheral edema is absent and renal, adrenal, and thyroid function is normal, all characteristic of SIADH (Keenan, 2005; Patel & Balk, 2007).

Figure 7-2. Criteria for Diagnosis of Syndrome of Inappropriate Antidiuretic Hormone • • • • •

Serum sodium less than 130 mEq/L (hyponatremia) Plasma osmolality less than 275 mOsm/L (hyposmolality) Urine osmolality greater than plasma osmolality Euvolemia Normal thyroid, renal, and adrenal function

Note. Based on information from Keenan, 2005; Patel & Balk, 2007.

Treatment In patients with cancer-induced SIADH, treatment is aimed at correcting hyponatremia and reducing symptoms. For patients with SCLC, systemic chemotherapy, fluid restriction, and medications often are needed. SCLC usually is responsive to combination chemotherapy and will result in correction of the hyponatremia. Often, the first sign of progression of disease is a recurrence of SIADH. In patients with mild hyponatremia who are asymptomatic or have few symptoms, systemic chemotherapy and subsequent control of the tumor may lead to resolution of symptoms. Patients may or may not require restriction of fluid to 500–1,000 ml/day. Oral salt tablets are often used in addition to fluid restriction. In those with moderate hyponatremia, IV fluid administration with diuretics and electrolyte replacement may be required. Isotonic saline (0.9%) is used in most mild to moderate cases (Ezzone, 2006). Hypertonic saline (0.3%) is reserved for patients with severe hyponatremia. Guidelines direct the amount of sodium replacement needed to prevent serious neurologic problems; in general, sodium replacement should not exceed 0.5–1 mEq/L per hour until normalization or near normalization of sodium levels and resolution of symptoms occur (Ezzone, 2006). This is followed by additional sodium replacement of 12–15 mEq/L in 24 hours (Ezzone, 2006). Overly rapid correction of sodium can lead to osmotic demyelination syndrome (central pontine myelinosis), which is characterized by progressive extremity weakness and other neurologic symptoms (Ezzone, 2006; Vaidya et al., 2010). Drug therapy consists of the use of loop diuretics and demeclocycline. Furosemide commonly is used with IV fluid administration and is helpful in the management of fluid overload. In patients with chronic hyponatremia or in those who have difficulty maintaining water restriction, demeclocycline is used. Demeclocycline is a tetracycline derivative that inhibits the kidney’s response to antidiuretic hormone, thus leading to diuresis (Keenan, 2011). Dosages usually range from 600–1,200 mg/day (Ezzone, 2006; Keenan, 2011). Renal function should be monitored carefully, as demeclocycline is nephrotoxic, and patients need to be aware of photosensitivity and nausea (Keenan, 2011). Conivaptan and tolvaptan are vasopressin receptor antagonists that are available in the United States and are used in the treatment of hyponatremia from SIADH of any cause (Pelosof & Gerber, 2010).

Signs and Symptoms Hyponatremia exists when serum sodium levels are below 135 mEq/L. Signs and symptoms result from water excess and depend on the degree of hyponatremia and the rate at which it occurs. Generally, hyponatremia is graded as mild, moderate, or severe. Patients with mild hyponatremia may be asymptomatic or have vague symptoms that include tiredness, headache, weakness, muscle cramps, or decreased appetite. Those with moderate hyponatremia may experience confusion or personality changes; gastrointestinal symptoms of nausea, vomiting, or diarrhea; decreased urine output; increased thirst; lethargy; or loss of deep-tendon reflexes. Severe hyponatremia (less than 120 mEq/L) can cause symptoms that include seizure activity and coma; this constitutes a medical emergency (Adrogué, 2005; Vaidya, Ho, & Freda, 2010). Patients with SIADH do not have edema, but weight gain is seen because of the excess water. This usually only occurs when levels drop acutely. In patients with chronic low serum sodium levels, clinical manifestations are less common. Diagnosis Diagnostic criteria are well established and include both laboratory and physical findings. An absolute diagnosis of SIADH is based on five criteria, which are shown in Figure 7-2. Other laboratory findings include low to normal blood urea nitrogen, serum creatinine, uric acid, and phosphate levels. Additionally, serum ADH levels may be increased (Ezzone, 2006). Findings on physical examination reveal the absence of edema, weight gain, loss or decreases in deep tendon reflexes, and changes in levels of consciousness. 75

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In summary, SIADH is a common paraneoplastic syndrome in patients with SCLC. Most often, the hyponatremia normalizes with systemic treatment of the tumor. For many patients, the hyponatremia is chronic in nature and rarely presents as an emergency.

axon from the extracellular fluid. Once in the axon, calcium stimulates the release of acetylcholine. Acetylcholine is a neurotransmitter that is released by voltage-gated calcium channels (VGCCs), which are located in the presynaptic nerve terminal. Acetylcholine then crosses the synaptic cleft and binds with the postsynaptic receptors on the muscle cell, as described earlier, and a muscle contraction occurs (Fagerlund & Eriksson, 2009). Anything that interferes with this process will cause muscular weakness. The pathogenesis of LEMS is the result of antibodies directed against VGCCs (Darnell & Posner, 2006; Titulaer et al., 2011). Studies have found that in patients with LEMS, the tumor produces IgG antibodies against the calcium channels and the autoantibodies block the VGCCs in the presynaptic terminal, thus preventing or decreasing the amount of acetylcholine release (Mayden, 2011). The result is muscular weakness. The specific type of calcium-channel antibody is the P/Q-type; this type was found to be the most potent inhibitor of calcium influx and, in one study, was found in the serum of all patients diagnosed with LEMS and concurrent cancer (Darnell & Posner, 2006; Titulaer et al., 2011). Of all the paraneoplastic neurologic syndromes, LEMS provides the best evidence to support an autoimmune hypothesis for paraneoplastic neurologic disorders (Darnell & Posner, 2006). This has been demonstrated by the transfer of serum IgG from patients with the disease to animals, which reproduces the disorder; this meets the criteria for antibody-mediated autoimmune disease (Darnell & Posner, 2006). Symptoms also have improved in patients in whom VGCC antibodies are removed from the serum (Posner & Dalmau, 1997).

Paraneoplastic Neurologic Disorders Paraneoplastic neurologic disorders are rare and can involve any portion of the nervous system, from a single site as seen with Lambert-Eaton myasthenic syndrome (LEMS) and acetylcholine at the neuromuscular junction, or they can affect the nervous system diffusely as seen with paraneoplastic encephalomyelitis (Armstrong, 2005; Darnell & Posner, 2006). Overall, paraneoplastic neurologic disorders affect 10%–20% of patients with lung carcinomas (Wozniak & Gadgeel, 2010). In many cases, they are present for months to years before the cancer is diagnosed and can even direct the oncology workup. In contrast to other paraneoplastic syndromes, neurologic disorders are believed to be the result of autoimmune dysfunction, whereby the tumor ectopically produces proteins that the immune system identifies as foreign, resulting in an autoimmune reaction (Mayden, 2011). In some instances, the presence of a paraneoplastic neurologic syndrome slows tumor growth or is associated with spontaneous tumor regressions, suggesting that the immune system also can attack the tumor (Armstrong, 2005). The most common neurologic syndromes associated with SCLC are LEMS and syndromes associated with the anti-Hu antibody.

Signs and Symptoms The hallmark symptoms in patients with LEMS are proximal muscle weakness and muscle fatigue with exercise. Muscle weakness is always symmetrical. Most often, the patient will complain of difficulty arising from a chair or climbing stairs. The muscle weakness often is more pronounced at the end of the day. Usually, the lower extremities and pelvic girdle are first affected, with upper extremity weakness occurring to a lesser extent (Armstrong, 2005; Weinberg, 2011). Additionally, patients report muscle stiffness and myalgias (Weinberg, 2011). Autonomic symptoms may be present and include dry mouth, constipation, impotence, and postural hypotension (Weinberg, 2011). Dry mouth is the most common autonomic symptom, and erectile dysfunction has been seen in up to 45% of men with LEMS (Weinberg, 2011). On physical examination, patients will exhibit signs of proximal muscle weakness and loss or decrease in deeptendon reflexes. An increase in muscle strength and a return of deep-tendon reflexes following maximal muscle contraction is a classic finding in LEMS (Weinberg, 2011). Additionally, cranial nerves may be involved. This condition is generally

Lambert-Eaton Myasthenic Syndrome Incidence and Pathogenesis LEMS most commonly is seen in patients with SCLC; overall, it occurs in 3% of all patients with this diagnosis (Payne et al., 2010). This syndrome may be present for two to five years before an SCLC diagnosis is made, and up to 70% of patients with the syndrome will be diagnosed with cancer, almost always SCLC (Payne et al., 2010; Titulaer et al., 2011). LEMS also may be seen in patients without an underlying malignancy in which the cause is not known (Darnell & Posner, 2006). LEMS is a paraneoplastic disease that affects the transmission of nerve impulses at the neuromuscular junction. In healthy individuals, transmission of a nerve impulse at the neuromuscular junction occurs with the release of a presynaptic neurotransmitter across the synaptic cleft and the binding of the neurotransmitter at the postsynaptic receptors on the muscle cell (Fagerlund & Eriksson, 2009). For a nerve impulse to be transmitted from one cell to another, several processes need to occur. First, the nerve impulse stimulates calcium to enter the 76

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mild and includes symptoms of ptosis, diplopia, and dysarthria (Weinberg, 2011).

the diagnosis of cancer by months to sometimes years. A diagnosis of LEMS should prompt a search for cancer. In patients who have a prolonged period from the diagnosis of LEMS and SCLC, anti-VGCC antibodies are believed to play a role in controlling tumor growth, or these patients may have a slower growing, well-differentiated cancer rather than a poorly differentiated SCLC, which usually is a highly malignant, rapidly growing tumor (Newsom-Davis, 1998).

Diagnosis The diagnosis of LEMS is accomplished largely by ruling out a similar neurologic disorder, myasthenia gravis (Mayden, 2011). The diagnosis is supported by clinical findings, blood studies, and electrodiagnostic studies. In addition to proximal muscle weakness described earlier, patients with LEMS exhibit an improvement in muscle strength following brief but vigorous muscle activity (Weinberg, 2011). The serum of patients with LEMS does not contain anti-acetylcholine receptor antibodies, whereas the presence of these antibodies is diagnostic in patients with myasthenia gravis. Additionally, 90% of patients with LEMS have demonstrated the presence of serum anti-P/Q-type VGCC antibodies (Newsom-Davis, 1998; Weinberg, 2011). Finally, postexercise compound muscle action potential is increased by 100% compared with baseline evaluation on electrodiagnostic studies (Weinberg, 2011).

Paraneoplastic Cerebellar Degeneration Paraneoplastic cerebellar degeneration (PCD) is a rare paraneoplastic syndrome that can occur with any type of cancer, most commonly SCLC, breast and gynecologic cancers, and Hodgkin lymphoma (Dalmau & Rosenfeld, 2011). Of the paraneoplastic neurologic disorders, PCD is the best described and most easily recognized. Other antibodies (e.g., anti-Yo) also are known to cause this condition (Mayden, 2011). As seen in patients with LEMS, PCD often predates the cancer diagnosis. The anti-Hu antibody and other autoantibodies (e.g., antiYo, anti-Ri, anti-Ma, anti-Ta) are associated with several underlying cancers and neurologic syndromes (Dalmau & Rosenfeld, 2011). The anti-Hu antibody is common in patients with SCLC. One study, which evaluated 50 patients with PCD and anti-Hu antibody, found that patients with SCLC were more likely to have multifocal disease and have severe neurologic disability compared to other patient groups (Shams’ili et al., 2003).

Treatment Treatment is twofold; it is aimed at treating the underlying tumor and suppressing the immune system. The use of chemotherapy for the treatment of SCLC has resulted in an improvement of LEMS symptoms in those whose cancers respond to treatment (Chalk, Murray, NewsomDavis, O’Neill, & Spiro, 1990). However, irreversible nerve damage from cancer treatment may limit improvement in others. If symptoms do not respond with the treatment of the tumor, other measures may be helpful. This can involve suppression of the immune response with medications such as corticosteroids and azathioprine or a combination of both. Other agents that promote release of acetylcholine from the nerve terminal are sometimes useful, but their side effects may outweigh their benefits (Struthers, 1994). The agents in use are guanidine hydrochloride and 3,4-diaminopyridine (DAP). Generally, 3,4-DAP is beneficial for most patients. Side effects include perioral and distal paresthesia. Central excitation and seizures can occur with overdosage and sometimes are seen with recommended doses (Newsom-Davis, 1998). Usually, 3,4-DAP is the first choice for treatment because it is considered safer than guanidine. Guanidine should be considered if 3,4-DAP is unavailable because it can be very effective in reducing symptoms associated with LEMS. However, it should be used with caution because side effects can be serious and can include bone marrow suppression, renal failure, and atrial fibrillation (Newsom-Davis, 1998). In patients who do not respond to either guanidine or 3,4-DAP, prednisolone with or without azathioprine is usually helpful (Newsom-Davis, 1998). Additionally, plasma exchange or treatment with IV immunoglobulin also may be effective (Dalmau & Posner, 1997). LEMS is a neurologic paraneoplastic syndrome often seen in patients with SCLC. Symptoms frequently precede

Incidence and Pathogenesis Overall, neurologic paraneoplastic syndromes are rare. Mayden (2011) reported that only 300 incidents of PCD have been reported in the literature. PCD was first described by Brain and Wilkinson in 1965 and was classified as “a clinicopathologic concept characterized by the subacute onset of cerebellar dysfunction (gait difficulty and limb ataxia), sometimes associated with dysarthria, dysphagia, nystagmus, mental changes, and muscular and sensory deficits” (Mason et al., 1997, p. 1280). The most common pathologic finding is the absence of cerebellar Purkinje cells (Mason et al., 1997). Additionally, some patients have inflammatory infiltrates within the cerebellum and other areas of the neurologic system (Mason et al., 1997). The cerebellum is responsible for the coordinated action of skeletal muscles and voluntary muscular movement. With loss or dysfunction of cerebellar Purkinje cells, patients may have signs of ataxia, dysarthria, nystagmus, or loss of reflexes (Mayden, 2011). Signs and Symptoms As in patients with LEMS, signs and symptoms of PCD often predate the diagnosis of SCLC. However, this syndrome can occur at any time during the illness. The symptoms may appear acutely over a few days or over a longer period of time 77

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(Zumsteg & Casperson, 1998). Often, patients appear to be very ill and have severe ataxia, dysarthria, dysphagia, and difficulty speaking (Zumsteg & Casperson, 1998). In a study examining the serum of 57 patients with SCLC and presenting symptoms of PCD, Mason and colleagues (1997) found high anti-Hu antibody titers in 25 (44%) patients. Compared with those who had low anti-Hu antibody titers or those who were anti-Hu antibody negative, those who had high titers tended to be women, have multifocal neurologic disease, and be severely disabled (Dalmau & Rosenfeld, 2011; Mason et al., 1997).

Rutherford, 1996; Masters, 2010; Mayden, 2011; Wozniak & Gadgeel, 2010). This section will focus on Trousseau syndrome, which can be problematic in patients with lung cancer, causing deep vein thrombosis (DVT) and pulmonary emboli. Trousseau syndrome (or malignancy-related hypercoagulability) is one of several paraneoplastic conditions of the hematopoietic system. It is the earliest paraneoplastic syndrome described, and it demonstrates the association of thrombosis with malignancy (Staszewski, 1997). Trousseau syndrome initially referred to a pattern of migratory superficial thrombophlebitis in which superficial veins of the chest and arms are usually affected (Bauer, 2010). The designation has expanded to include other coagulation abnormalities in people with cancer, including idiopathic deep vein thrombosis, disseminated intravascular coagulation, nonbacterial thrombotic endocarditis, thrombotic microangiopathy, and arterial thrombosis (Bauer, 2010).

Diagnosis and Treatment Cerebellar dysfunction is more likely to be the result of metastatic disease (intracranial or leptomeningeal metastases) or other neurologic problems (e.g., Wernicke encephalopathy) rather than PCD (Zumsteg & Casperson, 1998). These disorders must be considered as part of the differential diagnosis. History, physical examination, and tests such as magnetic resonance imaging (MRI) can help to rule out other neurologic problems or metastatic disease. Treatment is twofold, with the goals of controlling tumor and improving or stabilizing neurologic deficits with immune therapy. Although improvement in neurologic symptoms has been noted in some patients with treatment of the tumor, in general, the course of PCD is independent of the tumor (Dalmau & Posner, 1997). Often, the result is irreversible neurologic damage that will not improve with treatment. Unlike patients with LEMS, immune suppression with corticosteroids, plasma exchange IV immunoglobulin, corticosteroids, rituximab, and cytoxan have been helpful in individual patients, but studies have not shown them to be helpful for most. Rare spontaneous improvement has been seen in some (Dalmau & Rosenfeld, 2011). PCD is a rare and often devastating paraneoplastic syndrome. It is seen most often in patients with SCLC and occasionally in patients with other tumors. Successful treatment of the tumor usually does not result in improvement in neurologic symptoms. PCD is especially difficult to treat when associated with SCLC or the presence of the anti-Hu antibody (Dalmau & Rosenfeld, 2011). Those with advanced age are more likely to die earlier; patients can die from neurologic disease or progression of SCLC (Dalmau & Rosenfeld, 2011).

Incidence and Pathogenesis Trousseau syndrome often is the first manifestation of cancer. The initial description of Trousseau syndrome was in patients with gastrointestinal tumors whose diagnosis was preceded by thrombophlebitis (Bauer, 2011a, 2011b; Shannon & Ng, 2002). It is seen in patients with mucinproducing tumors, such as adenocarcinoma of the lung or gastrointestinal tract. A study by Blom, Osanto, and Rosendaal (2004) demonstrated that the risk of venous thrombosis was significantly higher in mucin-producing adenocarcinomas of the lung compared to those with squamous cell carcinoma. However, non-mucin-producing tumors are also associated with the hypercoagulable state (Bauer, 2011a, 2011b). Postmortem studies have documented multiple emboli in patients with advanced cancer (Bauer, 2010; Naschitz, Yeshurun, & Lev, 1993). The hypercoagulable state in patients with cancer is well known, but the pathogenesis is not completely understood. Virchow triad still provides the basis for the pathogenesis of thromboembolic disease. Virchow triad describes a process of endothelial injury, venous stasis or alterations in normal blood flow, and alterations in coagulability (hypercoagulability) (Welch & Bonner, 2010). Patients with cancer and thromboembolic disease develop an alteration in the clotting pathway, caused either directly or indirectly by the tumor cells (Mayden, 2011). Cancer cells are known to activate the extrinsic clotting pathway and affect clotting factors, such as factor VII and X (Armstrong, 2005). These alterations can then initiate the clotting cascade, causing the formation of thromboses. Varki (2007) proposed another explanation of the mechanisms involved in the development of Trousseau syndrome (see Figure 7-3). Mechanisms include elevated tissue factor (TF) levels from oncogenes (EGFR, K-Ras, MET), which are believed to directly affect hypercoagulability,

Hematologic: Trousseau Syndrome Hematologic paraneoplastic syndromes can involve any of the corpuscular elements of the blood or hemostatic system (Staszewski, 1997). These syndromes include disorders of the platelets (thrombocytopenia, thrombocytosis), leukocytes (leukocytosis, neutropenia), and erythrocytes (erythrocytosis, anemia of malignancy) (Staszewski, 1997). Anemia of malignancy is considered to be the most common of the hematologic paraneoplastic syndromes. Information regarding this syndrome is available elsewhere (Frenkel, Bick, & 78

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Figure 7-3. Multiple Mechanisms in Trousseau Syndrome

There are multiple overlapping and interacting mechanisms that can explain the increased incidence of thrombosis in patients with malignancies. In Trousseau syndrome, hypercoagulability manifests even before the diagnosis of the tumor and is probably the result of products arising from the tumor itself. The most common malignancies associated with this syndrome are carcinomas (cancers of epithelial origin) that are often, but not always, mucin producing. This cartoon depicts a mucin-producing carcinoma arising in a hollow organ, which secretes mucins with altered glycans inappropriately into the bloodstream. Although the bulk of these mucins are probably rapidly cleared by the liver, a small fraction are resistant to clearance and can interact with P- and L-selectins, inducing the formation of platelet-rich microthrombi by multiple pathways. Exposure of tissue factor (TF)–rich tumor cell surfaces to the bloodstream or the release of TF-rich microvesicles by the tumor is presumed to induce fibrin formation and platelet aggregation by thrombin production. There is some evidence for a cysteine proteinase secreted by carcinoma cells that can directly activate factor X to generate thrombin. Although interactions of platelet and endothelial P-selectin with P-selectin glycoprotein ligand-1 (PSGL-1) on monocytes may further contribute to these reactions, the exact mechanism by which mucins eventually generate thrombin and fibrin production is unknown. Hypoxic conditions within the tumor, the expression of the MET oncogene, or both might also enhance production of procoagulant factors such as TF and plasminogen activator inhibitor-1 (PAI-1), and tumor-derived inflammatory cytokines may serve to activate endothelial and platelet adhesion molecules. Various combinations of these mechanisms can help explain the unusual, migratory, and exaggerated thrombotic phenomena of Trousseau’s syndrome. As indicated in the figure, heparin has potential salutary effects on many of the relevant processes. This may explain why heparin preparations of various kinds are the preferred agent for the management of Trousseau syndrome.

Note. From “Trousseau’s Syndrome: Multiple Definitions and Multiple Mechanisms,” by A. Varki, 2007, Blood, 110, p. 1725. doi:10.1182/blood-2006-10-053736. Copyright 2007 by the American Society of Hematology. Reprinted with permission.

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Diagnosis

activation of factor X by cysteine protease (CP), and oncogene activation of the hypercoagulable state (MET, PAI-1, COX-2) (Varki, 2007). Comorbid conditions and treatments that coexist in the patient with cancer play a role in the development of thromboembolic disease. A history of cardiac disease may predispose a patient for thromboses because of venous stasis. Immobility from pain or fatigue or following surgery contributes to the problem. Indwelling venous access devices are known to increase the risk of upper extremity venous thromboses. Additionally, treatment with chemotherapy, hormonal therapy, and radiation therapy may increase the risk for venous thromboses.

A DVT diagnosis is made based on clinical examination and radiographic studies. Laboratory studies are not diagnostic of thromboses, but they may be helpful in certain circumstances. Antithrombin III, proteins S and C, and antiphospholipid antibodies may be obtained in patients with recurrent disease and in those without other risk factors (Story, 2006). Elevated D-dimer levels (greater than 500 ng/ml) usually are seen with acute thrombosis. However, elevated D-dimer levels are nonspecific. They may be elevated in other disorders such as sepsis, trauma, pneumonia, and malignancy (Shannon & Ng, 2002). More recently, Carrier, Lee, Bates, Anderson, and Wells (2008) pooled data from three prospective studies that utilized clinical predictive models and D-dimer testing to assess the probability that a patient would have venous thromboembolism. Their study included 200 patients with cancer. Results demonstrated that D-dimer testing was of limited value in patients with cancer because many have a high prevalence of D-dimer levels (Carrier et al., 2008). Thus, imaging remains the testing of choice in patients with cancer (Streiff, 2009). Doppler ultrasound is the test most commonly used to diagnose venous thromboembolism in patients with cancer (Streiff, 2009). This test is used for both upper and lower extremities. Doppler ultrasound is a noninvasive test that uses ultrasound to measure venous patency by showing the movement of red blood cells through a vein (Story, 2006). The accuracy of this test’s results depends on the operator, but with a skilled technician, sensitivity and specificity are 95% (Story, 2006). Often, this is the test of choice because it is noninvasive and inexpensive. When venous thromboembolism is suspected to involve intrathoracic or intra-abdominal vessels, computed tomography (CT) or magnetic resonance venography is the test of choice (Streiff, 2009). Spiral CT and CT pulmonary angiography are often used in the diagnosis of pulmonary embolism; pulmonary angiography is considered to be the gold standard for the diagnosis of pulmonary embolism (Camp-Sorrell, 2006; Streiff, 2009). Both tests provide rapid results and will also determine an alternative nonthrombotic explanation of patient symptoms, such as external compression of the vessel by a tumor. Both tests involve the use of contrast material and are contraindicated in those with contrast allergy or poor renal function (Camp-Sorrell, 2006). For those with a contraindication to contrast material, a ventilation perfusion scan (V/Q scan) can be performed. For many years, V/Q scanning was considered to be the test of choice for the diagnosis of pulmonary embolism. However, results of the majority of V/Q scans are deemed indeterminate and do not rule out pulmonary embolus (Anderson et al., 2007; Shannon & Ng, 2002). This is common in patients with lung cancer, who may have other abnormalities in addition to a tumor in the lung. Additional testing may include electrocardiogram,

Signs and Symptoms Symptoms of DVT include pain and swelling of the affected extremity. In extremity DVT, the swelling is usually unilateral. Edema from other causes is usually symmetrical. Early in the course, mild pain may occur in the affected area without swelling, or the patient may be asymptomatic. Redness usually is seen in patients with superficial thrombophlebitis. With thrombosis associated with venous access devices, the swelling and pain usually are on the side of the implanted device. A thrombus in the superior vena cava (SVC) can cause swelling of the face and neck (SVC syndrome). Pulmonary embolus classically causes acute-onset shortness of breath and chest pain, but some people are asymptomatic. Early on, chest pain may resemble angina, but later in the course, this evolves to pleuritic chest pain. Pleuritic chest pain, dyspnea, cough, and anxiety are seen with pulmonary embolus. Massive pulmonary embolus may result in death. Signs on physical examination usually are indicative of the location of the thrombus. Patients with a lower-extremity DVT often will have swelling in the calf, ankle, or foot. Palpation of the calf may reveal a cord, and pain may be identified. Dorsiflexion of the foot with subsequent pain in the calf is known as Homan’s sign. However, physical examination as the sole modality for diagnosis is only accurate in 50% of patients (Story, 2006). In those with an upper-extremity DVT or SVC clot, swelling in the face, neck, or affected arm may be present. Additionally, examination may reveal the presence of prominent superficial vessels on the arm or chest wall. In patients with a pulmonary embolus, physical examination can be unremarkable or it may reveal tachypnea or tachycardia. Crackles or wheezing may be heard on auscultation of the lungs. Dyspnea, syncope, and cyanosis usually are indicative of a massive pulmonary embolus. Oxygen saturation (via pulse oximeter) may be abnormal. Fever and other nonspecific signs may be present (Camp-Sorrell, 2006). On cardiac examination, a gallop may be heard, or the pulmonary component of the second heart sound may be more prominent. In those with a pulmonary embolus, clinicians must look for signs and symptoms of a lower-extremity DVT. 80

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echocardiogram, and arterial blood gasses (Camp-Sorrell, 2006).

is contraindicated, a filter may be placed in the inferior vena cava. In patients with a proximal DVT, the risk for pulmonary embolus is increased. A filter in the inferior vena cava may prevent migration of thrombus to the pulmonary vasculature. Placement of a filter in a patient with cancer and a hypercoagulable state may prevent pulmonary emboli, but it does not prevent other incidents of thrombotic events.

Treatment Patient management will focus on the treatment of DVT and patients with pulmonary embolus who are stable. Treatment of massive pulmonary embolus, the unstable patient with pulmonary embolus, and use of thrombolytic therapy are beyond the scope of this chapter, and information is available elsewhere (Shannon & Ng, 2002). In patients with lung cancer (or any cancer) and DVT or pulmonary embolism, continued anticoagulation (low-molecular-weight heparin [LMWH] for three to five months, then warfarin thereafter) is recommended indefinitely or until the cancer is resolved (Story, 2006). Heparins, either unfractionated or low molecular weight, are the preferred treatment for the management of Trousseau syndrome (Varki, 2007). LMWHs (e.g., enoxaparin, tinzaparin) are FDA approved for outpatient management of patients with DVT and for inpatient treatment of those with pulmonary embolus. The doses of LMWHs are based on the patient’s body weight. They have been found to have better bioavailability, a longer half-life, and more predictable anticoagulant activity, and they do not require laboratory monitoring (Koopman et al., 1996). Studies have documented the efficacy and safety of LMWHs administered subcutaneously when compared with continuous-infusion heparin for treatment of venous thromboses in hospitalized patients (Lensing, Prins, Davidson, & Hirsh, 1995; Prandoni et al., 1992). Koopman and colleagues (1996) randomly assigned patients with proximal DVT to receive either standard IV heparin in the hospital or subcutaneous fixed-dose LMWH on an outpatient basis. Results of the study demonstrated that subcutaneous LMWH was as safe and effective as standard heparin, and 75% of patients treated with LMWH were able to be treated on an outpatient basis (Koopman et al., 1996). Quality-of-life assessments were made in this study, and results showed that patients treated with LMWH had less impairment of physical activity and social functioning (Koopman et al., 1996). Some clinicians continue to use oral anticoagulation with warfarin. If warfarin is used to accomplish long-term anticoagulation, patients are started on it on the first day after diagnosis. Simultaneous administration of warfarin and LMWH is required because development of adequate anticoagulation takes several days on warfarin alone. Measurement of the international normalized ratio (INR) provides laboratory monitoring of warfarin. Administration of LMWH is recommended for at least five days in addition to warfarin. Once the patient is therapeutic on warfarin (INR 2.0–3.0), the LMWH is stopped. Close, regular monitoring of warfarin is required to maintain therapeutic anticoagulation, as many different foods and medicines can affect the activity of warfarin. In patients in whom anticoagulation

Musculoskeletal: Clubbing and Hypertrophic Pulmonary Osteoarthropathy

Clubbing and hypertrophic pulmonary osteoarthropathy (HPOA) are considered to be paraneoplastic syndromes of the musculoskeletal system. These conditions often coexist, but they can occur separately. HPOA (also known as hypertrophic osteoarthropathy [HOA]) is a syndrome characterized by clubbing of the fingers and toes, arthritis/arthralgia, and periostosis of the long bones (Marino, Harigopalan, & Bangar, 2011; Nguyen & Hojjati, 2011). Depending on the source, HPOA and HOA are considered to be the same syndrome; others differentiate the syndrome as having a pulmonary etiology (HPOA) or nonpulmonary etiology (HOA) (Ito et al., 2010). Some nonmalignant conditions (e.g., diffuse inflammatory lung disease and bronchiectasis) can cause HPOA, but the most common cause of acute-onset HPOA is lung cancer (Marino et al., 2011; Yazici, 2011). Nonpulmonary (HOA) causes include cirrhosis, inflammatory bowel disease, and endocarditis (Marino et al., 2011).

Incidence and Pathogenesis This syndrome was first identified in the late 1800s (Marino et al., 2011). HPOA is most often seen in those with adenocarcinoma of the lung, compared with other types of lung cancer (Yazici, 2011). A recent study by Ito and colleagues in Japan examined the results of bone scintigraphy in 2,625 patients with lung cancer (Ito et al., 2010). HPOA was documented in 19 patients (0.7%). In their study, the majority of patients (n = 10) had adenocarcinoma, were male (n = 17), and were current or heavy former smokers (n = 18). In an earlier prospective study in which 111 patients with lung cancer and clubbing were studied, results demonstrated that the majority of patients were women with non-small cell lung cancer (Sridhar, Lobo, & Altman, 1998). HPOA pathogenesis is not completely understood. Clubbing appears as a raised nail bed with widening of the distal end of the fingers or toes. This swelling of the nail bed is thought to be caused by increased collagen deposits, inflammation with edema, and an increase in capillary formation (Marino et al., 2011). Periostosis of the long bones is thought to be caused by subperiosteal bone matrix deposits followed by calcification (Marino et al., 2011). Normal bone structure is interrupted by dysregulated osteoclastic and 81

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osteoblastic activity (Marino et al., 2011). Pain may be present on palpation of the affected bones and effusions may be seen in large joints, causing some to be diagnosed with arthritis (Yazici, 2011). Multiple mechanisms have been implicated in HPOA pathogenesis. One theory suggests that circulating factors such as signaling molecules and growth factors normally inactivated by the lungs now bypass the lungs and enter the systemic vasculature (Marino et al., 2011; Nguyen & Hojjati, 2011). These factors include bradykinin, vascular endothelial growth factor, platelet-derived growth factor, and dying platelets (Marino et al., 2011). It is suggested that these circulating factors are responsible for the signs and symptoms of HPOA (Marino et al., 2011; Yazici, 2011).

• • • •

Loss of the normal 15° angle between the nail and the cuticle Accentuated convexity of the nail Development of a clubbed appearance at the fingertips Development of a shiny or glossy change with longitudinal striations of the nail. Patients with HPOA experience significant, usually symmetrical, pain in the wrists, ankles, feet, knees, and lower legs (Armstrong, 2005). Joint effusions also may develop (Yazici, 2011). Pain can be disabling and can occur on palpation of the affected bone (Nguyen & Hojjati, 2011). Very often, these symptoms predate the diagnosis of cancer and often are initially mistaken for rheumatoid arthritis.

Diagnosis

Signs and Symptoms

Clubbing is diagnosed by findings on physical examination. No imaging studies demonstrate the abnormalities associated with clubbing. HPOA is diagnosed by signs and symptoms and presence of a cancer diagnosis. Additionally, bone scan will demonstrate increased metabolic activity, and radiographs of the long bones will demonstrate symmetrical uptake of contrast in the long bones (Ito et al., 2010).

The early stages of clubbing may be difficult to detect, as the signs are subtle; later stages are easier to recognize. Clubbing most often is symmetrical and generally is graded according to five criteria on physical examination (see Figure 7-4) including (Altman & Tenenbaum, 1997) • Fluctuation and softening of the nail bed (feels spongy to touch)

Figure 7-4. Normal and Abnormal Nails

Note. From Health Assessment in Nursing Practice (2nd ed., p. 168), by J. Grimes and E. Burns, 1987, Sudbury, MA: Jones and Bartlett. Copyright 1987 by Jones and Bartlett. Reprinted with permission.

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Treatment

Altman, R.D., & Tenenbaum, J. (1997). Hypertrophic osteoarthropathy. In W.N. Kelley & E.D. Harris (Eds.), Textbook of rheumatology (5th ed., pp. 1514–1520). Philadelphia, PA: Saunders. Anderson, D.R., Kahn, S.R., Rodger, M.A., Kovacs, M.J., Morris, T., Hirsch, A., … Wells, P.S. (2007). Angiography vs. ventilationperfusion lung scanning in patients with suspected pulmonary embolism. JAMA, 298, 2743–2753. doi:10.1001/jama.298.23.2743 Angel-Moreno Moroto, A., Martinez-Quintana, E., SuarezCastellano, L., & Perez-Arellano, J. (2005). Painful hypertrophic osteoarthropathy successfully treated with octreotide. The pathogenetic role of vascular endothelial growth factor (VEGF). Rheumatology, 44, 1326–1327. doi:10.1093/rheumatology/keh720 Armstrong, T.S. (2005). Paraneoplastic syndromes. In C.H. Yarbro, M.H. Frogge, & M. Goodman (Eds.), Cancer nursing: Principles and practice (6th ed., pp. 808–824). Sudbury, MA: Jones and Bartlett. Baird-Powell, S. (2006). Hypocalcemia/hypercalcemia. In D. CampSorrell & R.A. Hawkins (Eds.), Clinical manual for the oncology advanced practice nurse (2nd ed., pp. 1019–1029). Pittsburgh, PA: Oncology Nursing Society. Bauer, K.A. (2010). Duration of anticoagulation: Applying the guidelines and beyond. Hematology: American Society of Hematology Education Program Book, 2010, 210–215. doi:10.1182/asheducation-2010.1.210 Bauer, K.A. (2011a). Hypercoagulable disorders associated with malignancy. Retrieved from http://www.uptodate.com Bauer, K.A. (2011b). Pathogenesis of the hypercoagulable state associated with malignancy. Retrieved from http://www.uptodate. com Berenson, J.R., Rosen, L.S., Howell, A., Porter, L., Coleman, R.E., Morley, W., … Seaman, J.J. (2001). Zoledronic acid reduces skeletalrelated events in patients with osteolytic metastases. Cancer, 91, 1191–1200. doi:10.1002/1097-0142(20010401)91:73.0.CO;2-0 Blom, J.W., Osanto, S., & Rosendaal, F.R. (2004). The risk of a venous thrombotic event in lung cancer patients: Higher risk for adenocarcinoma than squamous cell carcinoma. Journal of Thrombosis and Haemostasis, 2, 1760–1765. doi:10.1111/j.1538 -7836.2004.00928.x Body, J.J. (2011). New developments for treatment and prevention of bone metastases. Current Opinion in Oncology, 23. Advance online publication. doi:10.1097/CCO.0b013e328347918b Boyiadzis, M., Lieberman, F.S., Geskin, L.J., & Foon, K.A. (2008). Paraneoplastic syndromes. In V.T. DeVita Jr., T.S. Lawrence, & S.A. Rosenberg (Eds.), Cancer: Principles and practice of oncology (8th ed., pp. 2343–2362). Philadelphia, PA: Lippincott Williams & Wilkins. Camp-Sorrell, D. (2006). Pulmonary embolism. In D. Camp-Sorrell & R.A. Hawkins (Eds.), Clinical manual for the oncology advanced practice nurse (2nd ed., pp. 219–223). Pittsburgh, PA: Oncology Nursing Society. Carrier, M., Lee, A.Y., Bates, S.M., Anderson, D.R., & Wells, P.S. (2008). Accuracy and usefulness of a clinical predictor rule and D-dimer testing in excluding deep vein thrombosis in cancer patients. Thrombosis Research, 123, 177–183. doi:10.1016/j. thromres.2008.05.002 Chalk, C.H., Murray, N.M., Newsom-Davis, J., O’Neill, J.H., & Spiro, S.G. (1990). Response of the Lambert-Eaton myasthenic syndrome to treatment of associated small-cell lung carcinoma. Neurology, 40, 1552–1556. Chernecky, C.C., & Berger, B.J. (2008). Laboratory tests and diagnostic procedures (5th ed.). St. Louis, MO: Elsevier Saunders. Coleman, R. (2011). Bisphosphonates and other osteoclast inhibitors in patients with metastatic cancer. Retrieved from http://www. uptodate.com

Treatment is aimed at control of symptoms and management of the cancer. Clubbing usually is asymptomatic and may resolve over many months with control of the tumor. For many with HPOA, the symptoms will abate with control of the lung tumor with chemotherapy or radiation (Ito et al., 2010). Symptoms have been known to resolve following resection of non-small cell lung cancer (Ito et al., 2010; Nguyen & Hojjati, 2011). Nonsteroidal anti-inflammatory agents, corticosteroids, and analgesics are used either alone or in combination to treat the arthralgia associated with HPOA. Bisphosphonates (e.g., pamidronate, zoledronic acid) have also been useful in treating refractory HPOA (King & Nelson, 2008; Slobodin et al., 2009; Yao, Altman, & Brahn, 2009). Two papers demonstrated significant pain relief with octreotide in patients with HPOA who had failed other conventional pain treatment modalities (Angel-Moreno Moroto, Martinez-Quintana, Suarez-Castellano, & Perez-Arellano, 2005; Johnson, Spiller, & Faull, 1997). Continued evaluation of octreotide is needed before it can be recommended in patients with HPOA. HPOA is a paraneoplastic syndrome of the musculoskeletal system that often predates a cancer diagnosis. It is characterized by a constellation of signs and symptoms that include clubbing of the fingers and toes, pain in the distal long bones and associated joints, and periostitis, which can be demonstrated radiographically. The pain associated with HPOA can be debilitating. Control of the tumor with radiation, chemotherapy, or surgery usually results in improvement or resolution of symptoms. Symptomatic improvement also can be obtained with conventional pain control methods.

Summary Multiple paraneoplastic syndromes exist. This chapter reviewed selected syndromes that can occur in patients with lung cancer and other malignancies. Overall, these syndromes are rare, although many clinicians are familiar with hypercalcemia of malignancy and SIADH. Paraneoplastic syndromes can often be the first manifestation of malignancy. Therefore, it is important that nurses be alert to the different presentations of these syndromes.

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Dalmau, J.O., & Posner, J.B. (1997). Paraneoplastic syndromes affecting the nervous system. Seminars in Oncology, 24, 318–328. Dalmau, J., & Rosenfeld, M.R. (2011). Paraneoplastic cerebellar degeneration. Retrieved from http://www.uptodate.com Darnell, R.B., & Posner, J.B. (2006). Paraneoplastic syndromes affecting the nervous system. Seminars in Oncology, 33, 270–298. doi:10.1053/j.seminoncol.2006.03.008 Ezzone, S.A. (2006). Syndrome of inappropriate antidiuretic hormone. In D. Camp-Sorrell & R.A. Hawkins (Eds.), Clinical manual for the oncology advanced practice nurse (2nd ed., pp. 685–690). Pittsburgh, PA: Oncology Nursing Society. Fagerlund, M.J., & Eriksson, L.I. (2009). Current concepts in neuromuscular transmission. British Journal of Anaesthesia, 103, 108–114. doi:10.1093/bja/aep150 Fornier, N.M. (2010). Denosumab: Second chapter in controlling bone metastases or a new book? Journal of Clinical Oncology, 28, 5127–5131. doi:10.1200/JCO.2010.31.0128 Frenkel, E.P., Bick, R.L., & Rutherford, C.J. (1996). Anemia of malignancy. Hematology/Oncology Clinics of North America, 10, 861–871. Horwitz, M.J. (2011). Hypercalcemia of malignancy. Retrieved from http://www.uptodate.com Ito, T., Goto, K., Yoh, K., Niho, S., Ohmatsu, H., Kubota, K., … Nishiwaki, Y. (2010). Hypertrophic pulmonary osteoarthropathy as a paraneoplastic manifestation of lung cancer. Journal of Thoracic Oncology, 5, 976–980. doi:10.1097/JTO.0b013e3181dc1f3c Jameson, J.L., & Johnson, B.E. (2008). Paraneoplastic syndromes: Endocrinologic/hematologic. In A.S. Fauci, E. Braunwald, D.L. Kasper, S.L. Hauser, D.L. Longo, J.L. Jameson, & J. Loscalzo (Eds.), Harrison’s principles of internal medicine (17th ed., pp. 617–622). New York, NY: McGraw-Hill Medical. Johnson, S.A., Spiller, P.A., & Faull, C.M. (1997). Treatment of resistant pain in hypertrophic pulmonary osteoarthropathy with subcutaneous octreotide. Thorax, 52, 298–299. doi:10.1136/ thx.52.3.298 Kaplan, M. (2011). Hypercalcemia of malignancy. In C.H. Yarbro, D. Wujcik, & B.H. Gobel (Eds.), Cancer nursing: Principles and practice (7th ed., pp. 939–963). Sudbury, MA: Jones and Bartlett. Keenan, A.K.M. (2005). Syndrome of inappropriate antidiuretic hormone. In C.H. Yarbro, M.H. Frogge, & M. Goodman (Eds.), Cancer nursing: Principles and practice (6th ed., pp. 940–945). Sudbury, MA: Jones and Bartlett. Keenan, A.M. (2011). Syndrome of inappropriate antidiuretic hormone. In C.H. Yarbro, D. Wujcik, & B.H. Gobel (Eds.), Cancer nursing: Principles and practice (7th ed., pp. 1005–1013). Sudbury, MA: Jones and Bartlett. Keenan, A.K.M., & Wickham, R.S. (2005). Hypercalcemia. In C.H. Yarbro, M.H. Frogge, & M. Goodman (Eds.), Cancer nursing: Principles and practice (6th ed., pp. 791–807). Sudbury, MA: Jones and Bartlett. Khosla, S., Burr, D., Cauley, J., Dempster, D.W., Ebeling, P.R., Felsenberg, D., … Shane, E. (2007). Bisphosphonate-associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research. Journal of Bone and Mineral Research, 22, 1479–1491. doi:10.1359/JBMR.0707ONJ King, M.M., & Nelson, D.A. (2008). Hypertrophic osteoarthropathy effectively treated with zoledronic acid. Clinical Lung Cancer, 9, 179–182. doi:10.3816/CLC.2008.n.027 Koopman, M.M., Prandoni, P., Piovella, F., Ockelford, P.A., Brandjes, D.P.M., van der Meer, J., … Prins, M.H. (1996). Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. New England Journal of Medicine, 334, 682–687. doi:10.1056/ NEJM199603143341102

Lensing, A.W.A., Prins, M.H., Davidson, B.L., & Hirsh, J. (1995). Treatment of deep venous thrombosis with low-molecular-weight heparins: A meta-analysis. Archives of Internal Medicine, 155, 601–607. Lipton, A., Uzzo, R., Amato, R.J., Ellis, G.K., Hakimian, B., Roodman, G.D., & Smith M.R. (2009). The science and practice of bone health in oncology. Journal of the National Comprehensive Cancer Network, 7(Suppl. 7), S1–S27. Marino, W.D., Harigopalan, J.A., & Bangar, M. (2011). A 49-yearold smoker with a lung mass and diffuse bone pain. Chest, 139, 460–463. doi:10.1378/chest.10-1674 Mason, W.P., Graus, F., Lang, B., Honnorat, J., Delattre, J.Y., Valldeoriola, F., … Dalmau, J. (1997). Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome. Brain, 120, 1279–1300. Retrieved from http://brain.oxfordjournals.org/content/120/8/1279.long Masters, G.A. (2010). Clinical presentation of small cell lung cancer. In H.I. Pass, D.P. Carbone, D.H. Johnson, J.D. Minna, G.V. Scagliotti, & A.T. Turrisi III (Eds.), Principles and practice of lung cancer (4th ed., pp. 341–351). Philadelphia, PA: Lippincott Williams & Wilkins. Mayden, K.D. (2011). Paraneoplastic syndromes. In C.H. Yarbro, D. Wujcik, & B.H. Gobel (Eds.), Cancer nursing: Principles and practice (7th ed., pp. 845–862). Sudbury, MA: Jones and Bartlett. Naschitz, J.E., Yeshurun, D., & Lev, L.M. (1993). Thromboembolism in cancer: Changing trends. Cancer, 71, 1384–1390. Newsom-Davis, J. (1998). A treatment algorithm for LambertEaton myasthenic syndrome. Annals of the New York Academy of Sciences, 841, 817–822. doi:10.1111/j.1749-6632.1998.tb11023.x Nguyen, S., & Hojjati, M. (2011). Review of current therapies for secondary hypertrophic pulmonary osteoarthropathy. Clinical Rheumatology, 30, 7–13. doi:10.1007/s10067-010-1563-7 O’Shaughnessy, I.M., & Jochen, A.L. (2007). Metabolic disorders in the cancer patient. In A.M. Berger, J.L. Shuster, & J.H. von Roenn (Eds.), Principles and practice of palliative care and supportive oncology (3rd ed., pp. 392–400). Philadelphia, PA: Lippincott Williams & Wilkins. Patel, G.P., & Balk, R.A. (2007). Recognition and treatment of hyponatremia in acutely ill hospitalized patients. Clinical Therapeutics, 29, 211–229. doi:10.1016/j.clinthera.2007.02.004 Payne, M., Bradbury, P., Lang, B., Vincent, A., Han, C., NewsomDavis, J., & Talbot, D. (2010). Prospective study into the incidence of Lambert Eaton myasthenic syndrome in small cell lung cancer. Journal of Thoracic Oncology, 5, 34–38. doi:10.1097/ JTO.0b013e3181c3f4f1 Pelosof, L.C., & Gerber, D.E. (2010). Paraneoplastic syndromes: An approach to diagnosis and treatment. Mayo Clinic Proceedings, 85, 838–854. doi:10.4065/mcp.2010.0099 Posner, J.B., & Dalmau, J.O. (1997). Paraneoplastic syndromes affecting the central nervous system. Annual Reviews of Medicine, 48, 157–166. doi:10.1146/annurev.med.48.1.157 Prandoni, P., Lensing, A.W.A., Buller, H.R., Carta, M., Cogo, A., Vigo, M., … ten Cate, J.W. (1992). Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet, 339, 441–445. doi:10.1016/0140-6736(92)91054-C Shams’ili, S., Grefkens, J., deLeeuw, S., Hooijkus, H., van der Hold, B., van den Bent, M., … Smitt, P.S. (2003). Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: Analysis of 50 patients. Brain, 126(Pt. 6), 1409–1418. doi:10.1093/ brain/awg133 Shane, E., & Berenson, J.R. (2011). Treatment of hypercalcemia. Retrieved from http://www.uptodate.com Shannon, V.R., & Ng, A. (2002). Noninfectious pulmonary emergencies. In S.-C.J. Yeung & C.P. Escalante (Eds.), Holland84

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Frei oncologic emergencies (pp. 191–248). Hamilton, Ontario, Canada: BC Decker. Slobodin, G., Rosner, I., Feld, J., Rimar, D., Rozenbaum, M., Boulman, N., & Odeh, M. (2009). Pamidronate treatment in rheumatology practice: A comprehensive review. Clinical Rheumatology, 28, 1359–1364. doi:10.1007/s10067-009-1256-2 Sridhar, K.S., Lobo, C.F., & Altman, R.D. (1998). Digital clubbing and lung cancer. Chest, 114, 1535–1537. doi:10.1378/ chest.114.6.1535 Staszewski, H. (1997). Hematological paraneoplastic syndromes. Seminars in Oncology, 24, 329–333. Stewart, A.F. (2005). Clinical practice: Hypercalcemia associated with cancer. New England Journal of Medicine, 352, 373–379. doi:10.1056/NEJMcp042806 Story, K.T. (2006). Deep venous thrombosis. In D. Camp-Sorrell & R.A. Hawkins (Eds.), Clinical manual for the oncology advanced practice nurse (2nd ed., pp. 281–290). Pittsburgh, PA: Oncology Nursing Society. Streiff, M.B. (2009). Diagnosis and initial treatment of venous thromboembolism in patients with cancer. Journal of Clinical Oncology, 27, 4889–4894. doi:10.1200/JCO.2009.23.5788 Struthers, C.S. (1994). Lambert-Eaton myasthenic syndrome in small cell lung cancer: Nursing implications. Oncology Nursing Forum, 21, 677–683. Titulaer, M.J., Maddison, P., Sont, J.K., Wirtz, P.W., Hilton-Jones, D., Klooster, R., … Verschuuren, J.J. (2011). Clinical Dutch-English Lambert-Eaton myasthenic syndrome (LEMS) tumor association prediction score accurately predicts small-cell lung cancer in the LEMS. Journal of Clinical Oncology, 29, 902–908. doi:10.1200/ JCO.2010.32.0440

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Small Cell Lung Cancer Lynn A. Adams, RN, MS, ANP-BC, AOCN®

Introduction

Patients typically experience cough and dyspnea secondary to the presence of a large hilar mass and bulky mediastinal lymphadenopathy. Superior vena cava syndrome is common. It is usually caused by invasion of the vena cava, extrinsic compression by the tumor, or intraluminal thrombosis. SCLC predominates as the cause of superior vena cava syndrome, followed by squamous cell carcinoma of the lung (Lu et al., 2010). Approximately 60% of patients with SCLC present with metastatic disease at diagnosis. The most common sites of distant metastases are the central nervous system, bones, liver, and adrenal glands (Lu et al., 2010). Presenting symptoms may be clearly attributable to the metastatic site (e.g., bone pain, right upper quadrant pain, headache). Patients may also present with nonspecific symptoms such as nausea, anorexia, weight loss, debility, anemia, and mental status changes. SCLC is associated with a number of endocrine and neurologic paraneoplastic syndromes, including syndrome of inappropriate antidiuretic hormone (SIADH) and Cushing syndrome. The paraneoplastic syndromes associated with SCLC differ from those observed in NSCLC. According to Krug, Kris, Rosenzweig, and Travis (2008), hypertrophic pulmonary osteoarthropathy and hypercalcemia are rarely seen in patients with SCLC. In contrast, the vast majority of patients with lung cancer and SIADH, Cushing syndrome, or neurologic paraneoplastic syndromes have SCLC. SCLC cells can produce adrenocorticotropic hormone, which causes Cushing syndrome, and vasopressin, which causes hyponatremia of malignancy. Neurologic paraneoplastic syndromes include Lambert-Eaton myasthenic syndrome (LEMS), encephalomyelitis, and sensory neuropathy. They often precede the diagnosis of a malignancy and do not improve with successful systemic treatment. LEMS presents with proximal leg weakness that improves with use and

Small cell lung cancer (SCLC) has unique biologic characteristics that distinguish it from the other major forms of lung cancer, which are collectively categorized as nonsmall cell lung cancer (NSCLC). The unique properties of SCLC include rapid cell growth and a tendency to be widely disseminated at the time of diagnosis. If untreated, SCLC has the most aggressive clinical course of any type of pulmonary tumor, with a median survival from diagnosis of two to four months (National Cancer Institute [NCI], 2011). SCLC is highly sensitive to initial chemotherapy and radiation. Although current therapy has a significant impact on the natural history of SCLC, long-term disease-free survival is rare.

Prevalence and Presentation The incidence of SCLC is declining. According to the NCI Surveillance, Epidemiology, and End Results (SEER) database, the proportion of SCLC among all lung cancers in the United States declined from 17.26% in 1986 to 12.95% in 2002 (Govindan et al., 2006). Most SCLC tumors are centrally located and present as a perihilar mass. SCLCs are typically situated in a peribronchial location and infiltrate the bronchial submucosal and peribronchial tissue. These tumors tend to disseminate early and widely, and extensive lymph node metastases are common. The tumors are typically large masses with extensive necrosis. Approximately 5% of SCLCs present as peripheral small lesions (Lu et al., 2010). Presenting symptoms in patients with SCLC can be divided into four categories: (a) those due to local tumor growth and intrathoracic spread, (b) those due to distant metastases, (c) nonspecific systemic symptoms, and (d) paraneoplastic syndromes.

The author would like to acknowledge Margaret Joyce, PhD, RN, AOCN®, APRN-BC, for her contribution to this chapter that remains unchanged from the first edition of this book.

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is caused by antibodies directed against the voltage-gated calcium channels (National Comprehensive Cancer Network [NCCN], 2011).

neuroendocrine cells. SCLC, which has a poor prognosis, is at one end of the spectrum. At the other extreme end of the spectrum is bronchial carcinoid, which has an excellent prognosis after surgical excision. Between these extremes is well-differentiated neuroendocrine carcinoma of the lung. Like SCLC, it occurs primarily in cigarette smokers; however, it metastasizes less frequently and has a more favorable prognosis (NCI, 2011). The current classification of subtypes of SCLC is (a) small cell carcinoma and (b) combined small cell cancer (when typical SCLC elements are mixed with at least 10% of neoplastic squamous or glandular components) (NCI, 2011). Although the diagnosis of small cell carcinoma rests primarily on morphologic assessment, immunocytochemistry plays a role. Virtually all SCLCs are immunoreactive for keratin, epithelial membrane antigen, and thyroid transcription factor-1 (often referred to as TTF1). Most SCLCs also stain positively for markers of neuroendocrine differentiation enolase, neural cell adhesion molecule, and synaptophysin. However, these markers alone cannot be used to distinguish SCLC from NSCLC because approximately 10% of NSCLC will be immunoreactive for at least one of these neuroendocrine markers (NCCN, 2011).

Relationship to Smoking Cigarette smoking is a very strong risk factor for the development of SCLC. According to Govindan et al. (2006), more than 90% of patients with SCLC are current or past smokers. The risk is related to the duration and intensity of the smoking; the incidence rate parallels smoking patterns. The decreased incidence of SCLC may be explained by the decrease in the percentage of smokers in the population. Cigarette consumption reached a peak in the 1960s but began to decline following the surgeon general’s report (Bayne-Jones et al., 1964) linking cigarette smoking to cancer and the ban on tobacco advertising on television. In 1965, 50% of men smoked; that number had decreased to 21% in 2005 (Krug et al., 2008). This was a much greater proportional reduction than for women, who decreased from a rate of 32% to 18% in the same time frame. Because of these past smoking patterns, SCLC was initially more prominent among men. However, as smoking became more prevalent in women, so did the incidence of SCLC. In 1973, 72.37% of patients with SCLC were men (Govindan et al., 2006). In 2002, the ratio of men to women diagnosed with SCLC was 1 to 1 (Govindan et al., 2006). Over the next few decades, the overall incidence of lung cancer should continue to decline in the United States. Increases in cigarette smoking were reported among adolescents and on college campuses, where 40% of students define themselves as active smokers (Patterson, Lerman, Kaufmann, Neuner, & Audrain-McGovern, 2004). If this increase in the popularity of cigarette smoking does not change, the decline in the incidence of lung cancer will halt and eventually reverse. Most of the carcinogens in tobacco smoke are present in the tar. Since 1954, the tar and nicotine yields in cigarettes have decreased as a result of industry change to (a) the use of efficient filter tips, (b) the use of highly porous cigarette paper, and (c) changes in the composition of the tobacco blend (Govindan et al., 2006). Smokers of cigarettes with low nicotine delivery tend to smoke more intensely in an adaptation to achieve a desired physiologic response to nicotine. Filtered cigarettes also lead to decreased size of aerosols. Cigarettes without filters and high tar and nicotine levels cause higher deposition of particles in the bifurcation zone in the tracheobronchial tree. Filtered cigarettes with lower tar and nicotine levels cause more deposition of particles in the smaller airways and alveoli. This distribution is more typical of adenocarcinoma than squamous cell carcinoma or SCLC (Govindan et al., 2006).

Molecular and Genetic Characteristics Carcinogenesis occurs over time in a multistep process. Approximately 10–20 genetic mutations occur by the time a lung cancer becomes clinically evident (Kobzik, 1999). Initiation occurs when carcinogens cause genetic damage. If DNA damage is not repaired and the cell divides, the daughter cells inherit the abnormal DNA and are called initiated cells. Tumor promotion occurs with excessive proliferation of the initiated cell. Cigarette smoke contains chemicals that are both initiators and promoters. Progression is the final step of tumor invasion and metastasis. Current therapies used in lung cancer management have had limited impact on survival. Lung cancer biology has become an area of intense research in an effort to find new and innovative therapies. Each stage of carcinogenesis may involve various oncogenes, tumor suppressor genes (TSGs), growth factors, and growth factor receptors (Ross, 2003; Works & Gallucci, 1996). The technology of molecular biology has allowed for the identification of gene families implicated in lung carcinogenesis, including proto-oncogenes and TSGs.

Proto-Oncogenes A proto-oncogene is a gene in a normal cell that influences the control of cellular proliferation and differentiation. Growth factors, growth factor receptors, signal transduction proteins, and nuclear regulatory proteins are proto-oncogenes (Ross, 2003). Mutations or amplifications of proto-oncogenes cause

Cell Types SCLC is considered a neuroendocrine carcinoma, which represents a spectrum of disease that arises from basal 88

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Tumor Progression

them to act as oncogenes. Oncogenes are capable of inducing one or more characteristics of cancer cells. One type of protooncogene that has attracted much attention is the tyrosine kinase proto-oncogenes. Of this group, the ERBB family is more common in NSCLC and is the target of a number of new therapies. KIT proto-oncogene, another tyrosine kinase receptor is found in many SCLCs. A number of other mutated genes have been identified in NSCLC and SCLC. They are discussed in greater detail in Chapter 2.

The MYC family of oncogenes may be involved in lung cancer progression. The MYC family activates downstream genes that regulate cell division. Amplified MYC genes overexpress nuclear regulatory proteins, which stimulate other growth regulatory genes. The cell divides continually, becoming immortal. This family of genes includes MYC, MYCN, and MYCL. MYC is frequently active in both NSCLC and SCLC, with MYCN and MYCL usually occurring only in SCLC. In SCLC, MYC amplification is associated with decreased survival (Ross, 2003). Considerable information exists about the molecular abnormalities involved in the pathogenesis of SCLC. Both common and distinct genetic pathways exist in the major subtypes of lung cancer (SCLC and NSCLC) that are consistent with markedly biologic and clinical features. New strategies for detection, prevention, and treatment are being developed based on an understanding of the basic underlying molecular genetic abnormalities.

Tumor Suppressor Genes TSGs normally inhibit cellular proliferation. When mutated or deleted, TSGs promote the development of cancer (Works & Gallucci, 1996). TP-53, retinoblastoma gene (Rb), and p16 are TSGs that can be inactivated in lung cancer (Ross, 2003). Many of the proto-oncogene and TSG changes are present in both major lung cancer subtypes (SCLC and NSCLC), although certain mutations have small cell specificity.

Tumor Initiation

Staging

Chromosome 3p is believed to contain a TSG, which when lost as a result of damage from tobacco smoke, allows malignant transformation to occur. Deletion of the short arm of chromosome 3p occurs in more than 90% of SCLCs and more than 80% of NSCLCs (Ross, 2003; Works & Gallucci, 1996). Other TSGs involved in lung cancer include TP53 and the Rb gene. The Rb gene encodes a nuclear regulatory protein, which acts as a “brake” on cell proliferation. Point mutations or deletions of this gene lead to uncontrolled cell division. Rb mutations are noted in 90% of SCLCs (Ross, 2003).

Accurate clinical staging is important to assess prognosis and determine treatment. It also is critical for entry into clinical trials that evaluate outcomes based on comparable patient populations. Fewer than 10% of patients, only those with disease confined to the lung, are candidates for thoracotomy (Krug et al., 2008). The usual tumor, node, metastasis (TNM) staging classification is not used for SCLC because most patients (90%) with SCLC have locally advanced or systemic metastases at the time of diagnosis (Krug et al., 2008). Pathologic nodal assessment is not required because surgery is not a primary approach in SCLC management. Patients commonly have radiologic evidence of hilar or mediastinal node involvement at initial presentation. For this reason, the Veterans Administration Lung Cancer Study Group (VALCSG) developed a simple two-stage system based on the anatomic extent of disease (NCI, 2011). This system classifies patients with limited disease (LD) when the tumor is confined to one hemithorax and its regional (ipsilateral hilar and mediastinal) lymph nodes, versus extensive disease (ED) with metastasis in the contralateral chest or distant sites. Since this staging system was developed, the LD classification has been refined to identify those who are not candidates for chemotherapy and radiation with curative intent. The initial VALCSG system defined limited stage as disease confined to one hemithorax including local extension, whereas the International Association for the Study of Lung Cancer (IASLC) allowed contralateral mediastinal and supraclavicular lymph node involvement as well as pleural effusion (NCI, 2011). Other publications, however, included only patients with extension to ipsilateral mediastinal and

Tumor Promotion Gastrin-releasing peptide (GRP) or bombesin is a growth factor for normal bronchial epithelium. Chronic proliferation of bronchial epithelium from prolonged exposure to cigarette smoke produces excessive GRP. SCLC cells synthesize and secrete GRP. GRP serves as an autocrine growth factor that stimulates their proliferation. Small cell carcinoma cell lines express a high-affinity, saturable-binding receptor for bombesin or GRP (Lu et al., 2010). TP53, a TSG, normally prevents genetically damaged cells from replicating. If cell damage repair is unsuccessful in the G1 phase of replication, TP53 triggers apoptosis, or cell death. Cells with inactivated TP53 (through deletion or point mutation) contribute to cancer promotion by replicating damaged DNA and passing the abnormality on to many more cells. Multiple studies have demonstrated abnormal TP53 expression in 40%– 70% of SCLCs. TP53 mutations are associated with tobacco smoke carcinogens (Ross, 2003). Mutation or deletion of the TP53 gene is the most common genetic abnormality in human cancer (Works & Gallucci, 1996). 89

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Prognostic Factors

supraclavicular nodes (Stupp, Monnerat, Turrisi, Perry, & Leyvraz, 2004). In essence, LD SCLC is localized disease that can easily be encompassed within an acceptable or tolerable radiation port. ED means that the tumor is too widespread to be included within the definition of limited-stage disease. Pericardial or bilateral parenchymal involvement are considered signs of ED because the radiation therapy (RT) portal required to encompass this bulk of tumor would be too large and associated with significant risk of unacceptable toxicity (Lu et al., 2010). Patients with contralateral pleural effusions should be included in the ED category. Any evidence of distant disease or disease outside of the thorax is considered ED. Common distant sites of metastasis are the adrenal glands, bone, liver, bone marrow, and brain. Chemotherapy is the mainstay of treatment for SCLC. Combination therapy (i.e., chemotherapy with concurrent RT) is employed in LD SCLC to augment primary control. Thus, accurate clinical staging (LD or ED) is important in SCLC to determine when adding RT to chemotherapy is necessary. Areas of controversy remain within this simple LD/ED staging system. Patients with pleural effusion have been both included and excluded from the LD group. Analyses of two large cooperative group databases, which included in total more than 4,000 patients, showed that the survival of individuals with an isolated effusion was similar to that of patients with ED. Patients with a malignant effusion are appropriate to exclude from combined modality therapy because hemithoracic radiotherapy to encompass the entire pleura is impractical (Krug et al., 2008).

Many prognostic factors have been evaluated in SCLC. Clinically, the most important are performance status, weight loss, and extent of disease (Stupp et al., 2004). In addition to being a strong and reproducible predictive and prognostic factor, poor performance status can also identify patients at higher risk for treatment-related complications. Elevation of serum LDH is found in 33%–57% of all patients with SCLC and up to 85% of patients with extensive-stage disease, and is considered an indicator of poor prognosis (Krug et al., 2008). Certain metastatic sites such as the liver, brain, bone marrow, and bone, as well as the total number of metastatic sites involved, have been found to be of prognostic significance for patients with ED (Krug et al., 2008). In patients with LD, good performance status (Eastern Cooperative Oncology Group [ECOG] 0–2), female gender, age younger than 70 years, normal LDH, and stage I disease are associated with a more favorable prognosis. For patients with extensive-stage disease, normal LDH and a single metastatic site are favorable prognostic factors (NCCN, 2011). Although other serum markers have been proposed to have prognostic significance, including neuron-specific enolase, chromogranin, c-kit, and precursors of GRP, none have been strong and reliable enough to warrant general use (Krug et al., 2008).

Treatment

Staging Procedures

Historical Perspective

The goal of staging procedures is to determine whether patients with SCLC have LD or ED. Initial workup includes a complete history and physical, contrast-enhanced computed tomography (CT) of the chest, and blood tests that include a complete blood count and biochemistry such as electrolyte levels (including calcium), renal and liver function tests, alkaline phosphatase level, and lactic dehydrogenase (LDH) level. Staging tests are applied to define extrathoracic sites of disease and include CT of the upper abdomen (to evaluate the liver and adrenals), and gadolinium-enhanced magnetic resonance imaging (preferred) or CT of the brain, and a radionuclide bone scan. Demonstration of one extrathoracic site of involvement is sufficient to complete the staging evaluation; hence, bone marrow aspiration and biopsies now are performed infrequently. Positron-emission tomography scan has become a valuable tool in the staging of lung cancer and allows the identification of occult advanced or distant disease in NSCLC and SCLC. With improved staging, patients with previously limited-stage disease may be upstaged, thereby avoiding unnecessary and more strenuous combined-modality therapy (Stupp et al., 2004).

Because of SCLC’s rapid growth rate and propensity to develop metastases early in the course of the disease, results from studies in the 1960s for surgery and radiation therapy alone were dismal. Surgical reports from before the 1970s found only one or two patients alive at five years. This led the Medical Research Council of Great Britain to prospectively randomize patients to surgical resection or RT. The median survival of patients in the surgery and RT arms was 199 and 300 days, respectively. At five years, one and three patients were alive in the surgery and RT arms, respectively. At 10 years, there were no surgical survivors. Researchers concluded that RT was preferable to surgery but that neither of the treatment modalities was effective. The investigators suggested that other modalities, such as chemotherapy or various combination therapies, might be more successful (Shepherd, 1996). Preoperative radiation was investigated next; again, it yielded no long-term survivors. Patients were dying of systemic metastases, which suggested that no treatment with local therapy would lead to long-term survival without primary systemic chemotherapy. 90

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Extensive-Stage Disease

In 1958, VALCSG conducted randomized studies testing alkylating agents in bronchogenic carcinoma and found that three courses of cyclophosphamide more than doubled the median survival compared with a placebo-treated control group in disseminated SCLC (Green, Humphrey, Close, & Patno, 1969). In the 1970s, the Medical Research Council Lung Working Party (1979) showed that a combination of cyclophosphamide and lomustine improved survival compared to radiation alone in patients with LD. This initiated the chemotherapy era for treatment of SCLC and, hence, the quest for the most efficacious chemotherapy agent or agents. Today, oncology practitioners acknowledge SCLC as a remarkably chemosensitive disease, and systemic chemotherapy is considered the cornerstone or primary treatment modality for both stages of SCLC.

Despite many active agents, SCLC rarely is treated with single agents largely because complete remissions are relatively infrequent and remission durations tend to be brief with single agents. Combination chemotherapy has been proven superior to single agents. A number of regimens currently used will produce overall response rates of 50%–80% and complete response rates of 0%–30% in patients with ED (NCI, 2011). The most commonly used initial combination chemotherapy regimen is EP (NCCN, 2011). In a meta-analysis of 19 trials published between 1981 and 1999, a significant survival advantage was shown for patients receiving platinum-based chemotherapy (Pujol, Carestia, & Daures, 2000). Cisplatin is associated with significant toxicity and requires IV hydration, which can be problematic in patients with cardiovascular disease. Carboplatin is dosed according to renal function. In clinical practice, clinicians often substitute carboplatin for cisplatin in combination with etoposide. Brahmer and Ettinger (1998) concluded that the combination of carboplatin and etoposide resulted in comparable efficacy, had less nonhematologic toxicity, and was easier to administer than cisplatin plus etoposide. The Hellenic Oncology Group compared the two regimens in a prospective trial, which included patients with both limited and extensive SCLC (Kosmidis et al.,1994). The median survival time was comparable and not statistically different. However, the sample size of this study was inadequate to confirm equivalent efficacy. The combination of cisplatin and etoposide remains the gold standard for treatment, although carboplatin plus etoposide is an acceptable alternative for patients unable to tolerate cisplatin. A phase III trial conducted in Japan compared the EP regimen to a combination of cisplatin and irinotecan (Noda et al., 2002). A statistically significant benefit was found in the group of patients randomized to the cisplatin plus irinotecan arm compared with the group of patients randomized to the EP arm (median survival time 12.8 months versus 9.4 months respectively [p = 0.002]). Severe or life-threatening myelosuppression was more frequent in the EP group. Severe or life-threatening diarrhea was more frequent in the irinotecan plus cisplatin group. However, two subsequent large phase III trials performed in the United States comparing irinotecan plus cisplatin to EP did not demonstrate a significant difference in the response rate or overall survival between the two regimens (Hanna et al., 2006; Natale et al., 2008). A number of strategies have been evaluated in an effort to improve upon the outcomes that have been achieved with standard chemotherapy (NCCN, 2011): • In an attempt to overcome drug resistance, regimens have been developed that allow as many chemotherapy agents as possible to have exposure to the tumor during initial treatment. This is accomplished by administering chemo-

Identification of Active Chemotherapy Agents An evaluation of the available agents revealed that anthracyclines, vinca alkaloids, and certain alkylating agents had response rates of up to 50% with less activity noted for the antimetabolites (Krug et al., 2008). In the 1980s, the epipodophyllotoxins (etoposide and teniposide) and the platinum analogs (cisplatin and later carboplatin) were introduced. Their activity ranged from 40%–60% in previously untreated patients. Since that time, numerous other chemotherapy agents have demonstrated activity in SCLC, but aside from the camptothecins (topotecan and irinotecan), the drugs identified in the 1970s and 1980s remain the backbone of current therapy (Krug et al., 2008). Combination Regimens After activity of cyclophosphamide was established in SCLC, multidrug combinations were developed and tested. Livingston and colleagues (1978) developed the cyclophosphamide, doxorubicin, and vincristine (CAV) regimen and reported on 358 patients who received this combination followed sequentially by thoracic and brain irradiation. In patients with ED, the complete response rate was 14%, overall response rate was 57%, and median survival was 26 weeks. In patients with LD, the complete response rate was 41%, overall response rate was 75%, and median survival was 52 weeks (Livingston et al., 1978). At that time, CAV became the standard first-line chemotherapy regimen. With the introduction of cisplatin in the treatment of SCLC, etoposide and cisplatin (EP) was studied as a salvage regimen. The combination demonstrated response rates of more than 50% in patients with recurrent disease and 86% in previously untreated patients. This combination proved to be superior in terms of efficacy and toxicity and supplanted CAV and other alkylating agent/anthracycline combination regimens in the limited-stage setting (Sundstrom et al., 2002). 91

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therapy in an alternating or sequential schedule. However, randomized trials have not yielded superior results over upfront treatment with EP. • A role for higher-dose therapy for patients with SCLC has not been established. Higher response rates and modestly improved median survival rates have been observed in patients receiving high doses compared to conventional doses of the same agents. However, randomized trials have not consistently shown an increase in response rate or survival. • Adding additional agents (i.e., paclitaxel, ifosfamide or cyclophosphamide plus an anthracycline) to the standard two-drug regimen has not provided a survival advantage but has added toxicity. • The optimal duration of chemotherapy has not been clearly defined. The administration of maintenance chemotherapy beyond four to six cycles offers no proven survival benefit and is associated with a greater risk of cumulative toxicity.

and fractionation of therapy. Descriptions of these individual RT issues follow.

Chemotherapy and Radiotherapy Sequencing and Timing The combination of etoposide and cisplatin has offered marked improvements in safety and efficacy of concurrent chemotherapy and radiation compared with earlier trials that used alkylating agents and doxorubicin. Concurrent combined-modality therapy has demonstrated a survival advantage compared with a sequential plan, in which RT is administered after chemotherapy, or a “sandwich,” in which chemotherapy is administered initially, is interrupted during RT, and is reinstated thereafter (Erridge & Murray, 2003; NCCN, 2011; Simon & Wagner, 2003). Optimizing radiation in conjunction with chemotherapy is an important issue because small cell carcinoma is very radiosensitive. Murray and colleagues (1993) studied the timing of radiation in a randomized controlled trial with chemotherapy given concurrently, with RT commencing early on week 3 or later on week 15. A statistically significant advantage was found in progression-free survival and overall survival for the earlier RT application. Early RT was associated with improved local and systemic control and a survival advantage. Patients in the late (week 15) RT arm had a higher risk of brain metastasis (p = 0.0006) (Murray et al., 1993). In one meta-analysis, the best results were seen with thoracic RT beginning three to five weeks from the start of chemotherapy (Murray & Coldman, 1995). As radiation was further delayed, the benefit decreased and survival approached that seen with chemotherapy alone (Simon & Wagner, 2003). Delayed chemoradiation usually is associated with a longterm survival rate of approximately 10%, which differs little from the 9% rate of chemotherapy alone. Long-term survival for early concurrent platinum and etoposide plus thoracic radiation consistently exceeds 20% at five years. This should be considered the minimum standard at this time for limitedstage SCLC (Erridge & Murray, 2003).

Limited-Stage Disease Limited-stage SCLC is disease confined to one hemithorax within a single radiation port. At the time of diagnosis, approximately 30% of patients with small cell carcinoma have LD (NCI, 2011). The addition of thoracic RT to chemotherapy has improved survival for patients with limited-stage disease. Two meta-analyses of randomized trials compared chemotherapy alone with chemotherapy combined with thoracic RT to evaluate the hypothesis that thoracic radiation contributes to a moderate increase in overall survival in LD SCLC. Warde and Payne (1992) showed a small but significant improvement in two-year survival and a major improvement in tumor control in the thorax in patients receiving thoracic radiation therapy. However, this was achieved at the cost of a small increase in treatment-related mortality. Pignon and colleagues (1992) reported a meta-analysis that collected individual data on patients enrolled in 13 randomized trials before December 1988. They found that the relative risk of death in the combined-therapy group as compared with the chemotherapy group was 0.86, which corresponded to a 14% reduction in the risk of death with combined therapy. The benefit in terms of overall survival at three years (± standard deviation) was 5.4% (±1.4%). A subgroup analysis showed a significant trend (p = 0.01) toward a larger proportional effect on survival in favor of the combined-therapy group among younger patients (younger than 55) compared with older patients. Pignon’s group (1992) was unable to evaluate the nonlethal toxicity of treatment because information about toxicity was heterogeneous. These two meta-analyses shifted the debate from whether to employ thoracic RT to how to best integrate it with chemotherapy (Simon & Wagner, 2003). Controversies in chest RT include the sequencing and timing of chemotherapy and RT (concurrent versus sequential and early versus late), the volume of the radiation port (original tumor versus shrinking field as the tumor responds), and dose

Radiation Target Volumes SCLC often presents with bulky mediastinal lymphadenopathy and with a mixture of tumor mass and atelectasis in the lung parenchyma. This requires a large area of tissue to be irradiated, which is known as the radiation target volume. The three main potential toxicities of thoracic RT are esophagitis, pneumonitis, and radiation myelopathy. For both the esophagus and the lungs, the risk of toxicity depends not only on dose, but also on the volume of tissue irradiated (Erridge & Murray, 2003); hence, oncologists have attempted to define the minimal appropriate target volume and dose. The idea of using either a shrinking volume technique or a reduced volume, treating just gross disease, is appealing to minimize toxicity. 92

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These approaches have not been compared in a randomized trial to more “standard” therapy. One Southwest Oncology Group randomized clinical trial examined the issue of radiation volume (Kies et al., 1987). Patients in this study, who had achieved a partial or stable response after four cycles of chemotherapy, were randomized to RT with one of two arms of tumor volume. One arm included treatment portals based on the tumor volume before induction chemotherapy, and the other arm was based on the reduced volume post-induction chemotherapy. No appreciable differences were detected in either overall survival or recurrence patterns between the two arms (Kies et al., 1987), suggesting that if RT is started after several cycles of chemotherapy, the postchemotherapy target volume can be employed. The North American Intergroup trial studied the concept of using limited elective radiation with no intentional radiation to normal-appearing lymph nodes in the contralateral hilum or supraclavicular nodes, except with bulky adenopathy (Turrisi, Glover, & Mason, 1988). This trial produced the best five-year survival rate reported by a cooperative group (Simon & Wagner, 2003).

chemotherapy is preferable to sequential therapy in patients with good performance status (ECOG 0–2). The radiation target volumes should be defined on the CT scan obtained at the time of RT planning. However, the prechemotherapy CT scan should be reviewed to include the originally involved lymph node regions in the treatment field (NCCN, 2011). Although improvements have been made in the treatment of both stages of SCLC with chemotherapy and radiation, the overall outcome remains disappointing with only a small percentage of patients achieving long-term survival. Investigation of newer agents and combination agents continues. Given the strong association of SCLC and smoking, primary prevention through tobacco abstinence and cessation remains paramount. Prophylactic Cranial Irradiation Brain metastases are common in SCLC. Patients whose cancer can be controlled outside of their brain have a high risk (more than 50%) of developing central nervous system (CNS) metastases (NCCN, 2011). The majority of these patients relapse only in their brains. Most chemotherapeutic agents do not readily cross the blood-brain barrier. CNS metastases are associated with significant morbidity and are frequently the cause of death in these patients. Overt metastatic disease to the brain, although often responding temporarily to radiation, is rarely, if ever, cured. Prophylactic cranial irradiation (PCI) evolves from the hypothesis that moderate doses of radiation given to patients without detectable CNS involvement might eradicate occult metastases, improve CNS control, and prolong survival (NCCN, 2011). The Prophylactic Cranial Irradiation Overview Collaborative Group (Auperin et al., 1999) performed a meta-analysis on individual data from 987 patients with SCLC in complete remission from seven trials that compared PCI with no PCI. The main end point was survival. The findings showed that PCI significantly decreased the cumulative incidence of brain metastases by about 50% and improved overall survival at three years (15.3% in the control group compared with 20.7% in the treated group) (Auperin et al., 1999). Higher RT doses (30–36 Gy using 2 Gy fractions) tended to have better results than 20 Gy doses, but this was not a randomized comparison, and the effect on survival did not differ significantly according to dose. Auperin and colleagues (1999) concluded that PCI improves both overall survival and disease-free survival among patients with SCLC who achieve complete remission. Although the number of patients in this meta-analysis with ED was small, the observed benefit was similar in both patients with LD and patients with ED. A recent randomized trial assessed PCI versus no PCI in 286 patients with ED SCLC who had responded to initial chemotherapy (Slotman et al., 2007). PCI decreased symptomatic brain metastases (14.6% versus 40.4%) and increased one-year survival (27.1% versus 13.3%) when compared with controls.

Radiation Dose and Fractionation Because SCLC is a rapidly proliferating tumor, researchers hypothesized that it may be more responsive to thoracic radiation given twice daily rather than once daily. The theory was that the cells exposed to multiple daily fractions would have little ability to repair sublethal damage (Erridge & Murray, 2003). Giving two fractions per day, with a modest reduction in fraction size from the usual 1.8–2 Gy to 1.5 Gy, accelerates treatment. Two prospective trials compared this approach to conventional daily fractionation. Turrisi et al. (1999) showed a modest survival advantage in favor of twice daily RT given over three weeks, compared to oncedaily RT given over five weeks (26% versus 16% at five years [p = 0.04]). Esophagitis increased with twice-daily treatment. Bonner et al. (1999) compared twice-daily to daily fractionation but with a different regimen. In both arms of this study, RT was administered with the fourth and fifth cycles of chemotherapy. The twice-daily irradiation dose was 48 Gy in 32 fractionations with a 2.5-week break after the initial 24 Gy. The once-daily thoracic radiation was 50.4 Gy in 28 fractions. This trial demonstrated no differences in local control or survival (Bonner et al., 1999). A criticism of the trial was that, unlike the Turrisi trial, the rest interval resulted in no overall acceleration of the radiation course (Simon & Wagner, 2003). The NCCN Guidelines™ (2011) recommend that for limited-stage disease, radiation should be delivered concurrently with chemotherapy at a dosage of 1.5 Gy twice daily to a total dose of 45 Gy or 2 Gy once daily to at least 60–70 Gy. Patients selected for combined-modality treatment that incorporates RT administered twice a day must have excellent performance status and good baseline pulmonary function. Concurrent 93

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An earlier nonrandomized study of long-term survivors treated with PCI suggested that patients may have a higher incidence of CNS impairment. The patients reported difficulty with memory, gait, and coordination (Johnson, 1999). However, data from more recent prospective trials (Arriagada et al., 1995; Komaki et al., 1995) found cognitive dysfunction in more than 90% of patients with SCLC before they underwent PCI. This dysfunction did not appear to worsen in any patients on completion of therapy or at two-year follow-up. This baseline impairment may in fact be related to the underlying malignancy. Ahles and colleagues (1998) showed neurocognitive deterioration after PCI in which the PCI was administered concomitantly with chemotherapy. Brain irradiation is believed to disrupt the blood-brain barrier so that chemotherapy given concomitantly or following PCI seems to enhance the toxicity of irradiation (Vines, Le Pechoux, & Arriagada, 2003). Slotman et al. (2007) evaluated quality-of-life end points such as acute side effects, global health status, hair loss, fatigue, role functioning, and cognitive and emotional function. Acute side effects included headache, nausea, vomiting, fatigue, lethargy, CNS dysfunction, and hair loss. Cranial irradiation was generally well tolerated, and side effects did not significantly affect the patients’ self-assessment of their global health status (Slotman et al., 2007). A balanced discussion between the patient and physician disclosing therapy benefit and potential adverse effects is necessary before making the decision to administer PCI. Evidence currently suggests that PCI is effective in decreasing the rate of brain metastasis in patients with limited-stage SCLC who achieve a complete response to therapy. This translates into an overall survival advantage. No demonstrable neurologic functional impairment secondary to PCI has been found when neuropsychological evaluations are conducted prospectively. Data do not lend support to the idea that PCI is associated with significant neurotoxicity. The NCCN Guidelines (2011) recommend PCI for patients with either LD or ED who attain a complete or partial response. PCI is not recommended for patients with poor performance status (ECOG 3–4) or impaired mental function. The recommended dose is 25 Gy in 10 fractions or 30 Gy in 10–15 fractions. PCI should not be given concurrently with systemic chemotherapy because of the increased risk of neurotoxicity (NCCN, 2011).

remained from the surgery arm. With the introduction of multidrug chemotherapy and combination therapies in limited-stage SCLC, many considered surgical treatment in this disease inappropriate. However, the most favorable subset of patients with T1N0 tumors identified either at the time of surgery or on postoperative pathologic examination showed long-term survival. This very limited disease (VLD) is rare and diagnosed in fewer than 5% of patients (NCCN, 2011). Patients with SCLC that is determined to be clinical stage I after a complete staging evaluation, including a mediastinoscopy to rule out occult nodal metastasis, may undergo surgical resection. Patients who undergo complete resection (ideally a lobectomy with mediastinal node dissection or sampling) should be treated with postoperative chemotherapy. If nodal disease is found at surgery, concurrent chemotherapy and postoperative mediastinal RT is recommended (NCCN, 2011). A large, prospective randomized trial failed to prove any added value for surgery after induction chemotherapy in the treatment of LD SCLC (Lad et al., 1994). All patients in this study received five cycles of induction chemotherapy with CAV. Patients who achieved a partial or complete response were randomized to surgery or no surgery. Both arms then received chest irradiation and PCI. Median survival times for the nonsurgical and surgical arms were 18.6 and 15.4 months, respectively (p = 0.78) (Lad et al., 1994). Thus, this study failed to demonstrate any survival advantage for the addition of surgery to standard chemotherapy and RT. This study is criticized because it included patients with LD SCLC but few patients with VLD. Szczesny, Szczesna, Shepherd, and Ginsberg (2003) concluded that results of retrospective analyses and prospective nonrandomized trials suggest that in a highly select subgroup of patients with VLD SCLC, the addition of surgery to standard treatment results in cure for some patients.

Recurrent Disease Although patients typically respond to first-line treatment with systemic chemotherapy, most patients eventually relapse with a very poor prognosis. When previously treated patients relapse, their median survival is four to five months (NCCN, 2011). Two predictors of response to salvage or second-line therapy in patients with SCLC are response to initial therapy and the time from initial therapy to relapse. Patients who relapse less than three months after first-line therapy commonly are called refractory (also called resistant) and response to second-line therapy is poor (10% or less) (NCCN, 2011). Patients who respond to initial therapy and relapse more than three months following treatment are called sensitive. These patients have the greatest benefit from second-line therapy. Expected response rates to additional chemotherapy are approximately 25% (NCCN, 2011). In patients with an initial complete response of six months or

Surgery in Limited-Stage Small Cell Lung Cancer Surgery for SCLC was abandoned after the British Medical Research Council published the results of their trial that compared primary RT to surgery in 144 patients with potentially resectable SCLC with a 10-year follow-up (Simon & Wagner, 2003). The overall survival was superior for patients in the radiation arm, and no long-term survivors 94

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more of progression-free survival (a late relapse), retreatment with the original therapy can be considered. In the case of local or isolated recurrence, local treatment should be considered; however, cumulative toxicities may prove problematic. A second-line regimen can be offered to patients who relapse early pending performance status, comorbidities, and sites of progression. In phase II trials, active agents in relapsed disease include docetaxel, oral etoposide, gemcitabine, ifosfamide, irinotecan, paclitaxel, topotecan, and vinorelbine. Response rates vary depending on whether the disease is sensitive or resistant. In a multicenter randomized trial, von Pawel and colleagues (1999) evaluated second-line treatment in SCLC with either CAV or topotecan. No significant differences were found in response rates or survival (25 weeks for topotecan and 24.7 weeks for CAV) between the two arms, but palliation of four of eight common lung cancer symptoms (dyspnea, anorexia, hoarseness, and fatigue) was improved in the topotecan group (von Pawel et al., 1999). Further randomized studies compared the IV versus oral routes of administration of topotecan (von Pawel et al., 2001). Initial results suggested no difference in efficacy and less severe neutropenia with the oral drug. At relapse, all salvage therapy is palliative. Topotecan reasonably can be recommended for “sensitive” relapsed SCLC in the absence of an appropriate clinical trial (Glisson, 2003). However, topotecan is associated with significant myelosuppressive toxicity and a logistically difficult administration schedule. Inclusion in a phase I clinical trial certainly is a treatment of choice. The rationale for this approach includes the limited curability of SCLC with currently available therapy and the low probability of false-negative results if the agent is truly active against SCLC. Alternatively, for some patients, symptom palliation and quality of life through supportive care are the more important factors in the design of a treatment plan than prolonged survival. Some patients with intrinsic endobronchial obstructing lesions or extrinsic compression caused by tumor have achieved palliation of symptoms with endobronchial laser therapy and brachytherapy. In patients with malignant airway obstruction, expandable metal stents can be inserted under anesthesia via a bronchoscope, which may result in improvement in symptoms and pulmonary function. Patients with symptomatic bone or CNS recurrences can benefit from RT if it has not been used previously (NCI, 2011).

Maione, Rossi, & Schild, 2007). Despite the fact that lung cancer in the older individual is more common, older adults are often excluded from participation in clinical trials. As a result, they receive treatment that is untested or inadequate. Older patients with cancer may present with physiologic and medical challenges that make treatment selection difficult. Aging is associated with changes in functional status, organ function, and drug pharmacokinetics. Specifically, bone marrow reserve, drug clearance, and lean body mass are decreased. Currently, the standard treatment for limited-stage SCLC consists of four to six cycles of platinum-based chemotherapy combined with thoracic radiation. Concurrent chemoradiation is superior to sequential and yields higher survival rates. This is followed by PCI in patients who obtain a complete response. The main issues regarding the feasibility of this approach in the older adults are the safety of concurrent chemoradiation, using standard platinum-based regimens, and the proper role of PCI in these patients. In the meta-analysis by Pignon et al. (1992), thoracic RT improved survival. However, this effect was not observed in patients 70 years of age and older. In a number of trials, including the Intergroup Trial 0096 and the NCCTG analysis of Protocol 89-20-52, younger patients fared better than older patients in terms of survival and toxicity rates. However, fiveyear survival rates in older patients were still respectable, suggesting cure is possible despite substantial toxicity rates (Gridelli et al., 2007). In terms of PCI, the meta-analysis of Auperin and colleagues (1999) showed that the increase in survival of 5.4% at three years was not influenced by age. However, a greater degree of hesitation should be used in older patients, particularly those with poor performance status or baseline neurocognitive problems (Gridelli et al., 2007). A comparison trial with oral etoposide monotherapy versus CAV as palliative therapy in patients with poor performance status was stopped early because the etoposide was found to be inferior to standard multidrug therapy with more grade 2 or worse hematologic toxicity (Girling, 1996). Souhami et al. (1997) also compared oral etoposide with IV and alternating CAV and platinum/etoposide regimens in patients with extensive SCLC. Overall and progression-free survival was worse in the oral etoposide arm (Souhami et al., 1997). With the exception of acute nausea and vomiting associated with the IV arm, all aspects of symptom control and quality of life were the same or worse in the oral etoposide group. Study closure was recommended, and the conclusion was that oral etoposide should not be used as first-line therapy in SCLC. This “gentler chemotherapy” is inferior to optimal combination chemotherapy. Patients with poor functional status or poor prognostic factors may benefit from either an abbreviated treatment plan (two cycles of CAV with thoracic irradiation) or CAV and etoposide in reduced doses (Murray et al., 1998; Westeel et al.,

Older Patients Lung cancer incidence increases with age. Sixty-six percent of patients with lung cancer are 65 or older. In the past decade, the incidence and mortality from lung cancer have decreased among those individuals aged 50 years and younger but have increased in those 70 years of age and older (Gridelli, Langer, 95

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References

1998). Both of these studies were associated with acceptable toxicity and have potential for useful palliation, but these treatments need to be investigated further. Performance status and comorbid health status usually guide decisions regarding therapy for SCLC. If both parameters are acceptable, the recommendation is to treat with full-dose platinum standard chemotherapy and RT if indicated. More myelosuppression can be expected in older patients, especially with etoposide, and greater ancillary support may be required (NCCN, 2011; Simon & Wagner, 2003). Older adults are at risk for under­ treatment with poor survival and excessive toxicity from standard therapy. Investigators should be encouraged to expand eligibility criteria to include older adults in clinical trials. In addition, more randomized phase III clinical trials are needed to define standards of care for older adults.

Ahles, T., Silberfarb, P., Herndon, J., II, Maurer, L., Kornblith, A., Aisner, J.L., … Holland, J. (1998). Psychologic and neuropsychologic functioning of patients with limited small-cell lung cancer treated with chemotherapy and radiation therapy with or without warfarin: A study by the Cancer and Leukemia Group B. Journal of Clinical Oncology, 16, 1954–1960. Arriagada, R., LeChevalier, T., Borie, F., Riviere, A.C., Chomy, P., Monnet, I., … Benhamou, S. (1995). Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Journal of the National Cancer Institute, 87, 183–190. doi:10.1093/jnci/87.3.183 Auperin, A., Arriagada, R., Pignon, J., LePechoux, C., Gregor, A., Stephens, R., … Aisner, J. (1999). Prophylactic cranial irradiation for patients with small cell lung cancer in complete remission. New England Journal of Medicine, 341, 476–484. doi:10.1056/ NEJM199908123410703 Bayne-Jones, S., Burdette, W.J., Cochran, W.G., Farber, E., Fieser, L.F., Furth, J., … Seevers, M.H. (1964). Smoking and health: Report of the Advisory Committee to the Surgeon General of the Public Health Service. Retrieved from http://profiles.nlm.nih.gov/ NN/B/B/M/Q/_/nnbbmq.pdf Bonner, J.A., Sloan, J.A., Shanahan, T.G., Brooks, B.J., Marks, R.S., Krook, J.E., … Jett, J.R. (1999). Phase III comparison of twice-daily split-course irradiation versus once-daily irradiation for patients with limited stage small cell lung cancer. Journal of Clinical Oncology, 17, 2681–2691. Retrieved from http://jco. ascopubs.org/content/17/9/2681.full.pdf+html Brahmer, J.R., & Ettinger, D.S. (1998). Carboplatin in the treatment of small cell lung cancer. Oncologist, 3, 143–154. Retrieved from http://theoncologist.alphamedpress.org/cgi/content/full/3/3/143 Erridge, S., & Murray, N. (2003). Thoracic radiotherapy for limitedstage small cell lung cancer: Issues of timing, volumes, dose and fractionation. Seminars in Oncology, 30, 26–37. doi:10.1053/ sonc.2003.50017 Girling, D. (1996). Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small cell lung cancer: A stopped multicenter randomized trial. Medical Research Council Lung Cancer Working Party. Lancet, 348, 563–566. doi:10.1016/ S0140-6736(96)02005-3 Glisson, B. (2003). Recurrent small cell lung cancer: Update. Seminars in Oncology, 30, 72–78. doi:10.1053/sonc.2003 .50014 Govindan, R., Page, N., Morgensztern, D., Read, W., Tierney, R., Vlahiotis, A., … Piccirillo, J. (2006). Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: Analysis of the Surveillance, Epidemiologic, and End Results database. Journal of Clinical Oncology, 24, 4539–4544. doi:10.1200/JCO.2005.04.4859 Green, R., Humphrey, E., Close, H., & Patno, H. (1969). Alkylating agents in bronchogenic carcinoma. American Journal of Medicine, 46, 516–525. doi:10.1026/0002-9343(69)90071-1 Gridelli, C., Langer, C., Maione, P., Rossi, A., & Schild, S.E. (2007). Lung cancer in the elderly. Journal of Clinical Oncology, 25, 1898–1907. doi:10.1200/JCO.2006.10.3085 Hanna, N., Bunn, P.A., Jr., Langer, C., Einhorn, L., Guthrie, T., Jr., Beck, T., … Sandler, A. (2006). Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. Journal of Clinical Oncology, 24, 2038–2043. doi:10.1200/ JCO.2005.04.8595 Johnson, B.E., Ihde, D.C., Matthews, M.J., Bunn, P.A., Zabell, A., Makuch, R.W., … Minna, J.D. (1986). Non-small cell lung cancer.

Future Directions Despite recent advances, the outcome of patients with SCLC has improved minimally over the past 30 years. The paucity of effective therapeutic agents has prompted exploration of targeted and novel agents that may be more effective than existing treatment strategies. New combinations are being explored. The introduction of effective targeted agents for SCLC has lagged behind those used for NSCLC. The classes of targeted agents undergoing testing in SCLC include antiangiogenic agents (bevacizumab and thalidomide) and vascular endothelial growth factor receptor inhibitors (e.g., sorafenib, sunitinib, vandetanib). The tyrosine and Src kinase inhibitors are being evaluated in phase I and II trials. The other pathways undergoing evaluation for the development of pharmacologic agents include inhibitors of bcl-2 and sonic hedgehog signaling. Investigators are hopeful that these trials will provide new effective agents for the treatment of SCLC (Johnson, Rudin, & Salgia, 2008).

Summary Current treatment options have undoubtedly had an impact on survival in SCLC during the past three decades. However, SCLC remains a formidable clinical problem. Despite improvements, the majority of patients with this cancer will die from the disease. Participation in clinical trials should be strongly encouraged. If a person is fortunate to be a longterm (greater than two years) survivor of SCLC, the risk for development of a second smoking-related malignancy, most notably NSCLC, is significant (Johnson et al., 1986). Prevention is paramount in this malignancy. An effective worldwide public health effort to stop smoking initiation in children and to promote smoking cessation in current smokers is a critical intervention. The elimination of cigarette smoking would virtually eliminate SCLC. 96

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Major cause of late mortality in patients with small cell lung cancer. American Journal of Medicine, 80, 1103–1110. Johnson, B.E., Rudin, C.M., & Salgia, R. (2008). Novel and targeted agents for small cell lung cancer. In ASCO 2008 educational book (pp. 363–367). Alexandria, VA: American Society of Clinical Oncology. Johnson, D. (1999). Management of small cell lung cancer. Current state of the art. Chest, 116(Suppl. 6), 525S–530S. Kies, M.S., Mira, J.G., Crowley, J.J., Chen, T.T., Pazdur, R., Grozea, P.N., … Livingston, R.B. (1987). Multimodal therapy for limited small-cell lung cancer: A randomized study of induction combination chemotherapy with or without thoracic radiation in complete responders; and with wide-field versus reduced-field radiation in partial responders: A Southwest Oncology Group study. Journal of Clinical Oncology, 5, 592–600. Kobzik, L. (1999). The lung. In R. Cotran, V. Kumar, & T. Collins (Eds.), Pathologic basis of disease (6th ed., pp. 697–755). Philadelphia, PA: Saunders. Komaki, R., Meyers, C.A., Shin, D.M., Garden, A.S., Byrne, K.N., Nickens, J.A., & Cox, J.D. (1995). Evaluation of cognitive function in patients with limited small cell lung cancer prior to and shortly following prophylactic cranial irradiation. International Journal of Radiation Oncology, Biology, Physics, 33, 179–182. Kosmidis, P.A., Samantas, E., Fountzilas, G., Pavlidis, N., Apostolopoulou, F., & Skarlos, D. (1994). Cisplatin/etoposide versus carboplatin/etoposide chemotherapy and irradiation in small cell lung cancer: A randomized phase III study. Hellenic Cooperative Oncology Group for Lung Cancer Trials. Seminars in Oncology, 21(3, Suppl. 6), 23–30. Krug, L.M., Kris, M.G., Rosenzweig, K., & Travis, W.D. (2008). Small cell and other neuroendocrine tumors of the lung. In V.T. DeVita Jr., T.S. Lawrence, & S.A. Rosenberg (Eds.), Cancer: Principles and practice of oncology (8th ed., pp. 946–971). Philadephia, PA: Lippincott Williams & Wilkins. Lad, T., Piantadosi, S., Thomas, P., Payne, D., Ruckdeschel, J., & Giaccone, G. (1994). A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy. Chest, 106(Suppl. 6), 320S–323S. doi:10.1378/chest.106.6_ Supplement.320S. Livingston, R.B., Moore, T.N., Heilbrun, L., Bottomley, R., Lehane, D., Rivkin, S., & Thigpen, T. (1978). Small-cell carcinoma of the lung: Combined chemotherapy and radiation. A Southwest Oncology Group Study. Annals of Internal Medicine, 88, 194–199. Lu, C., Onn, A., Vaporcuyan, A., Chang, J., Glisson, B., Komaki, R., … Herbst, R. (2010). Cancer of the thorax. In J. Holland & E. Frei III (Eds.), Cancer medicine (8th ed., pp. 999–1044). Shelton, CT: Peoples Medical Publishing House. Medical Research Council Lung Working Party. (1979). Radiotherapy alone or with chemotherapy in the treatment of small-cell carcinoma of the lung. British Journal of Cancer, 40, 1–10. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC2009951/?tool=pubmed Murray, N., & Coldman, A. (1995). The relationship between thoracic irradiation timing and long term survival in combined modality therapy of limited stage small cell lung cancer (LSCLC) [Abstract]. Proceedings of the American Society of Clinical Oncology, 14, 360. Murray, N., Coy, P., Pater, J.L., Hodson, I., Arnold, A., Zee, B.C., … Dixon, P. (1993). Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology, 11, 336–344. Murray, N., Grafton, C., Shah, A., Gelmon, K., Kostashuk, E., Brown, E., … Page, R. (1998). Abbreviated treatment for elderly, infirm, or noncompliant patients with limited-stage small-cell lung cancer.

Journal of Clinical Oncology, 16, 3323–3328. Retrieved from http://jco.ascopubs.org/content/16/10/3323.long Natale, R., Lara, P., Chansky, K., Crowley, J., Jett, J., Carleton, J., … Gandara, D.G. (2008). S0124: A randomized phase III trial comparing irinotecan/cisplatin (IP) with etoposide/cisplatin (EP) in patients with previously untreated extensive small cell lung cancer (E-SCLC) [Abstract]. Journal of Clinical Oncology, 26, 7512. National Cancer Institute. (2011, February). Small cell lung cancer treatment (PDQ ®). Retrieved from http://www.cancer.gov/ cancertopics/pdq/treatment/small-cell-lung/healthprofessional National Comprehensive Cancer Network. (2011). NCCN Clinical Practice Guidelines in Oncology: Small cell lung cancer [v.2.2011]. Retrieved from http://www.nccn.org/professionals/ physician_gls/pdf/sclc.pdf Noda, K., Nishiwaki, Y., Kawahara, M., Negoro, S., Suguria, T., Yokoyama, A., … Saijo, N. (2002). Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small cell lung cancer. New England Journal of Medicine, 346, 85–91. doi:10.1056/NEJMoa003034 Patterson, F., Lerman, C., Kaufmann, V.G., Neuner, G.A., & Audrain-McGovern, J. (2004). Cigarette smoking practices among American college students: Review and future directions. Journal of American College Health, 52, 203–210. doi:10.3200/ JACH.52.5.203-212 Pignon, J., Arriagada, R., Ihde, D., Johnson, D.H., Perry, M., Shouhami, R., … Wagner, H. (1992). A meta-analysis of thoracic radiotherapy for small cell lung cancer. New England Journal of Medicine, 327, 1618–1624. Retrieved from http://www.nejm.org/ doi/full/10.1056/NEJM199212033272302#t=articleTop Pujol, J., Carestia, L., & Daures, J. (2000). Is there a case for cisplatin in the treatment of small-cell lung cancer? A meta-analysis of randomized trials of a cisplatin-containing regimen versus a regimen without this alkylating agent. British Journal of Cancer, 83, 8–15. doi:10.1054/bjoc.2000.1164 Ross, J. (2003). Biology of lung cancer. In M. Haas (Ed.), Contemporary issues in lung cancer: A nursing perspective (2nd ed., pp. 11–23). Sudbury, MA: Jones and Bartlett. Shepherd, F. (1996). Role of surgery in the management of small cell lung cancer. In J. Aisner, R. Arriagada, M. Green, N. Martini, & M. Perry (Eds.), Comprehensive textbook of thoracic oncology (pp. 439–455). Philadelphia, PA: Williams & Wilkins. Simon, G., & Wagner, H. (2003). Small cell lung cancer. Chest, 123(Suppl. 1), 259S–271S. Slotman, B., Faivre-Finn, C., Kramer, G., Rankin, E., Snee, M., Hatton, M., … Senjan, S. (2007). Prophylactic cranial irradiation in extensive small-cell lung cancer. New England Journal of Medicine, 357, 664–672. doi:10.1378.chest.123.1_suppl.259S Souhami, R.L., Spiro, S.G., Rudd, R.M., Ruiz de Elvira, M.C., James, L.E., Gower, N.H., … Harper, P. (1997). Five-day oral etoposide treatment for advanced small cell lung cancer: Randomized comparison with intravenous chemotherapy. Journal of the National Cancer Institute, 89, 577–580. Stupp, R., Monnerat, C., Turrisi, A., III, Perry, M., & Leyvraz, S. (2004). Small cell lung cancer: State of the art and future perspectives. Lung Cancer, 45, 105–117. doi:10.1016/j. lungcan.2003.12.006 Sundstrom, S., Bremnes, R.M., Kaasa, S., Aasabo, U., Hatlevoll, R., Dahle, R., … Aamdel, S. (2002). Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: Results from a randomized phase III trial with 5 years’ follow-up. Journal of Clinical Oncology, 20, 4665–4672. doi:10.1200/JCO.2002.12.111 Szczesny, T., Szczesna, A., Shepherd, F., & Ginsberg, R. (2003). Surgical treatment of small cell lung cancer. Seminars in Oncology, 30, 47–56. doi:10.1053/sonc.2003.50016 97

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Turrisi, A.T., III, Glover, D.J., & Mason, B.A. (1988). A preliminary report: Concurrent twice-daily radiotherapy plus platinumetoposide chemotherapy for limited small cell lung cancer. International Journal of Radiation Oncology, Biology, Physics, 15, 183–187. doi:10.1016/0360-301(88)90364-1 Turrisi, A.T., III, Kim, K., Blum, R., Sause, W.T., Komaki, R.E., Wagner, H., … Johnson, D.H. (1999). Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. New England Journal of Medicine, 340, 265–271. doi:10.1056/ NEJM199901283400403 Vines, E., Le Pechoux, C., & Arriagada, R. (2003). Prophylactic cranial radiation in small cell lung cancer. Seminars in Oncology, 30, 38–46. doi:10.1053/sonc.2003.50013b von Pawel, J., Gatzemeier, U., Pujol, J.L., Moreau, L., Bildat, S., Ranson, M., … Ross, G. (2001). Phase II comparator study of oral versus intravenous topotecan in patients with sensitive small cell

lung cancer. Journal of Clinical Oncology, 19, 1743–1749. Retrieved from http://jco.ascopubs.org/content/19/6/1743.full.pdf+html von Pawel, J., Schiller, J.H., Shepherd, F.A., Fields, S.Z., Kleisbauer, J.P., Chrysson, N.G., … Gralla, R. (1999). Topotecan versus cylophosphamide, doxorubicin, and vincristine for the treatment of recurrent small cell lung cancer. Journal of Clinical Oncology, 17, 658–667. Retrieved from http://jco.ascopubs.org/content/17/2/658. long Warde, P., & Payne, D. (1992). Does thoracic irradiation improve survival and local control in limited-stage small cell carcinoma of the lung? A meta-analysis. Journal of Clinical Oncology, 10, 890–895. Westeel, V., Murray, N., Gelmon, K., Shah, A., Sheehan, F., McKenzie, M., … Page, R. (1998). New combination of the old drugs for elderly patients with small-cell lung cancer: A phase II study of the PAVE regimen. Journal of Clinical Oncology, 16, 1940–1947. Works, C., & Gallucci, B. (1996). Biology of lung cancer. Seminars in Oncology Nursing, 12, 276–284.

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CHAPTER 9

Non-Small Cell Lung Cancer Leslie B. Tyson, MS, APRN, BC, OCN®, and Pamela K. Ginex, EdD, RN, OCN®

Introduction

be involved and include lymphatic channels, nerves, alveolar tissue, and pulmonary vasculature (Knop, 2005). Metastatic disease results from progression of the tumor in the same way and most frequently involves bone, liver, adrenal glands, pericardium, and brain. Overall, paraneoplastic syndromes occur in 10% of patients with lung cancer (Beckles, Spiro, Colice, & Rudd, 2003). Paraneoplastic syndromes seen in patients with NSCLC are humoral hypercalcemia of malignancy and hypertrophic pulmonary osteoarthropathy (HPOA) (Knop, 2005). Approximately 12.5%–35% of patients with squamous cell lung cancer, a subtype of NSCLC, develop hypercalcemia at some point in their illness (Kaplan, 2011). Eighty-eight percent of all patients diagnosed with HPOA have adenocarcinoma or large cell lung cancer, both of which are subtypes of NSCLC (Mayden, 2011). The hypercoagulable state is seen in those with either type of lung cancer (Mayden, 2011). For more information on paraneoplastic syndromes in patients with lung cancer, see Chapter 7. Studies have identified clinical, histopathologic, and molecular factors that affect prognosis and predict treatment in patients with NSCLC. Despite this, the tumor, node, metastasis (TNM) stage of disease at diagnosis remains the most important determinant of survival at this time (Chansky et al., 2009; Edge et al., 2010). Patients who are diagnosed with a lower stage (i.e., stage I) of disease at the outset have the best chance for cure (Knop, 2005; Smythe, 2003). Survival advantages for a specific histologic subtype of NSCLC (i.e., adenocarcinoma, squamous cell carcinoma, large cell carcinoma) have not been supported in the literature. Results of clinical studies examining the impact of specific subtypes have been mixed (Padilla et al., 2002). A more recent study by Chansky et al. (2009) supported a survival advantage for males with squamous cell carcinoma compared to the other cell types. This survival advantage does not exist for females. Weight loss and poor performance status (PS) most often are correlated with poor survival in patients with NSCLC,

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers (Edge et al., 2010) and is the leading cause of cancer death in the United States (Herbst, Heymach, & Lippman, 2008). At five years or more after diagnosis, it is estimated that only 15% of patients with lung cancer remain alive (Edge et al., 2010; National Cancer Institute [NCI] Surveillance, Epidemiology, and End Results Program, 2010). Although these statistics are grim, the past decade has brought positive changes in the treatment and outcomes for some with NSCLC. This chapter will review the revised staging for NSCLC as well as treatment strategies for each stage of disease. New since the original publication is a section on adjuvant chemotherapy in resected NSCLC, the importance of histology, and the use of molecular markers in the determination of treatment for patients with NSCLC.

Presentation of Non-Small Cell Lung Cancer Characteristic signs and symptoms of lung cancer have been discussed previously (see Chapter 5). Lung cancer is broadly classified into two groups: small cell and non-small cell. Prognosis, staging, and treatment of each type are different, thus making the determination of cell type of utmost importance. In general, small cell lung cancer (SCLC) differs from NSCLC in several respects. SCLC usually is centrally located, is thought to be more aggressive (therefore, more likely to be metastatic at diagnosis), and more often is associated with paraneoplastic syndromes. In contrast, NSCLC can present as a peripheral tumor, or it can be centrally located. NSCLC tumors can grow within the lung parenchyma or the bronchial wall. Tumors can grow in and around the bronchial lumen, at times causing complete obstruction of the bronchus. Progression of the tumor is by lymphatic invasion or direct extension to the chest wall or diaphragm (Knop, 2005). Other pulmonary structures can 99

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despite the stage of disease at diagnosis (Harpole, Herndon, Young, Wolfe, & Sabiston, 1995). In a study examining 289 patients with stage I NSCLC, 189 patients had no symptoms at diagnosis and 100 were symptomatic; the five-year survival rates were 74% and 41%, respectively (Harpole et al., 1995). In particular, cough, hemoptysis, and chest pain were predictive of shorter survival (Harpole et al., 1995). Other factors that confer poor prognosis include male gender, elevated serum lactate dehydrogenase (LDH), and bone or liver metastases (Knop, 2005). Studies have found that histology (e.g., squamous cell versus adenocarcinoma) and molecular markers have an impact on outcomes and that they influence the treatment of patients with NSCLC (Edge et al., 2010). These markers include, but are not limited to, the epidermal growth factor receptor mutation, the fusion gene EML4-ALK, Kirsten-rous avian sarcoma (K-ras) mutation, and determination of ERCC1 level (Garcia, Riely, Nafa, & Ladanyi, 2008; Jackman et al., 2009; Olaussen et al., 2006; Riely, Marks, & Pao, 2009; Shaw et al., 2009).

molecular biologists gathered to address the recent advances in adenocarcinoma of the lung (Travis et al., 2011). The outcome of this meeting was a new classification of adenocarcinoma of the lung that provides uniform terminology and diagnostic criteria for lung cancer experts worldwide. An important change in the new classification was the elimination of BAC and mixed subtype adenocarcinoma (Travis et al., 2011). The group proposed that for those with advanced disease, NSCLC should be further differentiated as adenocarcinoma or squamous cell carcinoma (SCC) where possible and to reduce the use of the term NSCLC, not otherwise specified. This difference in histology has important treatment implications for those with advanced adenocarcinoma of the lung (Travis et al., 2011): • Patients whose tumors test positive for epidermal growth factor receptor (EGFR) mutations would likely benefit from treatment with EGFR tyrosine kinase inhibitors. • Adenocarcinoma histology is associated with improved outcomes in those given pemetrexed, compared to those with SCC. • Life-threatening hemorrhage is associated with SCC and bevacizumab; therefore, this complication could be avoided with the differentiation of adenocarcinoma and SCC. At this time, the reclassification of adenocarcinoma will not be incorporated into the current TNM staging; however, it will be incorporated at the next revision of TNM staging. Complete details for the reclassification of adenocarcinoma of the lung can be found in the paper by Travis et al. (2011). Approximately 30%–35% of all lung cancers are SCC (Eaby-Sandy, 2011). These carcinomas tend to occur more often in smokers and have a dose-response relationship with tobacco use. The majority of squamous cell tumors present as central tumors, commonly arising in the proximal bronchi and other central structures (Eaby-Sandy, 2011). Rarely, these tumors present in the periphery of the lung (Schrump, Giaccone, Kelsey, & Marks, 2008). Cavitation and necrosis is seen in approximately 10% of those with SCC (Eaby-Sandy, 2011). Histologically, intercellular bridging, squamous pearl formation, and individual cell keratinization are characteristics of these tumors (Knop, 2005). They are slow-growing tumors; the transformation from carcinoma in situ to invasive carcinoma can be as long as three to four years (Schrump et al., 2008).The cells are shed easily, and if expectorated, diagnosis can be made by sputum cytology. Hypercalcemia is most commonly seen in those with SCC (Wozniak & Gadgeel, 2010). Large cell carcinoma is the least common of the subtypes, occurring in 15% of patients (Eaby-Sandy, 2011). Large cell carcinoma is a diagnosis of exclusion; it is a poorly differentiated tumor that does not have features of either SCC or adenocarcinoma (Eaby-Sandy, 2011). Tumors are often in peripheral locations of the lung (Knop, 2005). The prognosis with large cell tumors is similar to that of adenocarcinoma. Large cell tumors that exhibit necrosis carry a poor prognosis (Schrump et al., 2008).

Histologic Subtypes As mentioned previously, approximately 85% of all lung cancers are classified as NSCLCs (Edge et al., 2010). NSCLC has three major histologic subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. This section will discuss the three major subtypes as well as bronchoalveolar carcinoma (BAC), a subtype of adenocarcinoma. These cell types have multiple subclassifications, according to the World Health Organization (Travis, Brambilla, MüellerHermelink, & Harris, 2004). Adenocarcinoma is the most common type of lung cancer worldwide and accounts for nearly half of all lung cancers (Curado et al., 2007). Although it is seen in patients with a history of tobacco use, it also is the most common cell type seen in nonsmokers and women (Knop, 2005). Poorly differentiated adenocarcinomas are associated with higher rates of metastases, even in those with stage I and II disease (Franklin, Noguchi, & Gonzalez, 2010). BAC is an uncommon subtype of adenocarcinoma that occurs in about 3% of all patients with lung cancer (Travis et al., 2000). The incidence of this tumor is also on the rise, largely because of the increases seen in adenocarcinoma (Ebright et al., 2002). BAC typically presents in younger patients, women, and nonsmokers (Ebright et al., 2002). It appears to arise from type 2 pneumocytes and grows along alveolar septa by lepidic (“scale-like”) growth (Travis, Linder, & Mackay, 2000). Compared to other NSCLCs, BAC has a decreased frequency of lymph node and extrathoracic metastases, and patients have a better prognosis when compared to those with nonBAC adenocarcinomas (Ebright et al., 2002). In 2011, an international group of pathologists, oncologists, pulmonologists, radiologists, thoracic surgeons, and 100

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Staging

The staging of tumors is a dynamic process that evolves as information and technology advance. It is important in lung cancer to note the use of biologic and molecular markers including B-cell lymphoma 2 (known as Bcl-2), thyroid transcription factor 1, cyclooxygenase 2 (known as COX-2), EGFR overexpression, EGFR mutation, ras, Ki67, human epidermal growth factor receptor 2 (known as ERBB2), vascular endothelial growth factor (VEGF), microvascular density, TP53, and aneuploidy for predicting prognosis in NSCLC (Edge et al., 2010). Although none of these is currently used to stage lung cancer on a regular basis, some, such as EGFR and K-ras, are used to identify the best treatment option for specific patients (Edge et al., 2010). Although the five-year survival rate for patients with clinical stage IA is 61%, the five-year survival rate drops off significantly in patients with stage IB and more extensive stages. The five-year survival rate is less than 1% in patients with stage IV disease. These dismal statistics are driving research efforts, including molecular biology of lung cancer, early diagnosis, and all aspects of treatment in patients at risk for and with a diagnosis of lung cancer.

The importance of the International Staging System for Lung Cancer cannot be overemphasized. This system provides a common language worldwide for clinicians who care for patients with lung cancer. This system was revised in 1996 and again in 2010, and the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer adopted the revisions (Edge et al., 2010; Goldstraw et al., 2007). The most recent staging system was the result of the International Association for the Study of Lung Cancer (IASLC) Lung Cancer Staging Project. This project was started in 1998 to bring together large databases available worldwide to form wellvalidated recommendations for staging lung cancer. Changes in clinical staging evolved over time with the routine use of methods such as computed tomography (CT) and positronemission tomography (PET) and necessitated a revised staging system (Edge et al., 2010; Goldstraw et al., 2007). The TNM classification has changed in the new system. See Figure 9-1 for TNM descriptors. Because the majority of patients are not surgical candidates, most patients are clinically staged, designated cTNM. Those with surgical pathologic staging are designated pTNM. Note that the TNM descriptors do not change regardless of whether the patient is clinically or pathologically staged. The classification system has eight stage subsets. However, to be consistent with other solid tumor AJCC staging, four stage groupings of disease still exist (stage I–IV). As a result, both NSCLC and SCLC patients can be classified into one of the four stage groups; these are also known as prognostic groups because the overall survival rate for patients in each group is different (Edge et al., 2010). Changes in the 2010 lung cancer staging guidelines include additional cutoffs for tumor size with tumors greater than 7 cm moving from T2 to T3, and pleural effusions have been reclassified as an M descriptor. In addition, there were some changes to certain stage categories. Table 9-1 outlines stage grouping by TNM subsets. For graphic examples of T, N, and M stages, see Figures 9-2 through 9-7. Stage IV patients have any T, any N, and M1 disease. Regional lymph nodes potentially involved by lung cancers extend from the diaphragm to the supraclavicular lymph nodes and have been described in two different mappings (site locations of specific lymph nodes); one by Naruke, which is used in Japan, and one by Mountain-Dresler, which was used in North America and Europe (Edge et al., 2010). A new lymph node map was proposed in 2007 by the IASLC. Based on the Japanese and Mountain-Dresler maps and reports in the literature, the IASLC map provides more detailed descriptions of the borders of the lymph node stations in the lungs (Edge et al., 2010; Goldstraw et al., 2007; Rusch et al., 2009). AJCC noted that “the IASLC lymph node map is now the recommended means of describing regional lymph node involvement for lung cancers” (Edge et al., 2010, pp. 254–255). Lymph node mapping and definitions are seen in Table 9-2.

Treatment Treatment decisions for patients with NSCLC are determined by disease stage, although these are not absolute indicators because other patient characteristics and the presence of comorbid disease must be considered as well. In general, treatment for lung cancer includes surgery, radiation, chemotherapy, and targeted biotherapy. Depending on the stage of disease, multimodality treatment with two or more combinations may be recommended. As research into treatments of the various stages of disease continues, recommendations will be revised.

Surgery Surgical intervention is considered to be the gold standard in treatment for patients with stage I and II disease, and complete resection is nearly always possible (Ginsberg & Port, 2000; Joyce & Houlihan, 2001). Five-year survival rates for patients with clinical stage IB, IIA, and IIB tumors are 43%, 36%, and 25%, respectively (Goldstraw et al., 2007). Stage IIIA (T3 N1) tumors are potentially operable, with a five-year survival rate of 19% (Goldstraw et al., 2007). For patients with stage II disease, adjuvant chemotherapy is recommended, and for patients who are medically inoperable or who refuse surgery, radiation therapy is a treatment option (Scott, Howington, Feigenberg, Movsas, & Pisters, 2007). Staging and Surgery Approximately 20% of all patients with a lung cancer diagnosis present with stage I or II disease (Scott, Howington, & Movsas, 2003; Smythe, 2003). In patients who are able to 101

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Figure 9-1. Tumor, Node, Metastasis (TNM) Descriptors Primary Tumor (T) TX

Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)*

T1a

Tumor 2 cm or less in greatest dimension

T1b

Tumor more than 2 cm but 3 cm or less in greatest dimension

T2

Tumor more than 3 cm but 7 cm or less or tumor with any of the following features (T2 tumors with these features are classified T2a if 5 cm or less); Involves main bronchus, 2 cm or more distal to the carina; Invades visceral pleura (PL1 or PL2); Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

T2a

Tumor more than 3 cm but 5 cm or less in greatest dimension

T2b

Tumor more than 5 cm but 7 cm or less in greatest dimension

T3

Tumor more than 7 cm or one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumor in the main bronchus (less than 2 cm distal to the carina* but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe

T4

Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, separate tumor nodule(s) in a different ipsilateral lobe

*The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus is also classified as T1a. Regional Lymph Nodes (N) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastases

N1

Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension

N2

Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)

N3

Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)

Distant Metastasis (M) M0

No distant metastasis

M1

Distant metastasis

M1a

Separate tumor nodule(s) in a contralateral lobe tumor with pleural nodules or malignant pleural (or pericardial) effusion*

M1b

Distant metastasis

*Most pleural (and pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple cytopathologic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient should be classified as M0. Note. Based on information from Goldstraw et al., 2007. Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Handbook, Seventh Edition, 2010, pp. 315–317, published by Springer Science and Business Media LLC, www.springer.com.

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tolerate surgery, the recommended procedure is lobectomy or pneumonectomy (Smythe, 2003). In those who are unable to tolerate extensive procedures, lesser procedures, such as wedge or bronchopulmonary resections, are recommended (Smythe, 2003). As noted, clinical trials are being conducted to investigate the use of adjuvant and neoadjuvant treatment in patients with stage IB or higher disease. Recently, it has been recommended that patients with stage IB–IIIA at the time of surgery receive adjuvant chemotherapy to reduce the risk of distant recurrence (Yoshino, 2009). However, patients who are found to have positive surgical margins should receive either surgical re-resection of margins or radiotherapy for local control (Smythe, 2003). Stage II disease is seen in only 5% of patients diagnosed with NSCLC overall and comprises the subsets seen in Table 9-1 (Scott

Figure 9-2. Diagram, T1a and T1b T1a

T

N

M

Occult carcinoma

TX

N0

M0

Stage 0

Tis

N0

M0

Stage IA

T1a T1b

N0 N0

M0 M0

Stage IB

T2a

N0

M0

Stage IIA

T2b T1a T1b T2a

N0 N1 N1 N1

M0 M0 M0 M0

Stage IIB

T2b T3

N1 N0

M0 M0

Stage IIIA

T1a T1b T2a T2b T3 T3 T4 N1

N2 N2 N2 N2 N1 N2 N0 N1

M0 M0 M0 M0 M0 M0 M0 M0

T1a T1b T2a T2b T3 T4 T4

N3 N3 N3 N3 N3 N2 N3

M0 M0 M0 M0 M0 M0 M0

Any T Any T

Any N Any N

M1a M1b

Stage IIIB

Stage IV

Tumour > 2 cm, ≤ 3 cm

Tumour ≤ 2 cm

Superficial spreading tumour of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus

Table 9-1. Anatomic Stage/Prognostic Groups Stage

T1b

Tumour ≤ 2 cm; any associated bronchoscopic invasion should not extend proximal to the lobar bronchus

Tumour > 2 cm, ≤ 3 cm; any associated bronchoscopic invasion should not extend proximal to the lobar bronchus

Note. Reprinted with permission courtesy of the International Association for the Study of Lung Cancer. Copyright 2008 Aletta Ann Frazier, MD.

Figure 9-3. Diagram, T2a and T2b T2a

T2b

Tumour: > 3 cm, ≤ 5 cm Tumour ≤ 5 cm, invasion of the visceral pleura Tumour involves main bronchus 2 cm or more distal to carina

Associated atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

Tumour: > 5 cm, ≤ 7 cm (or without other T2 descriptors)

Note: any associated pleural effusion should be shown on multiple microscopical examinations to be negative for tumour; it should be non-bloody and not an exudate, and clinical judgement should dictate that the effusion is not related to the tumour.

Note. Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Handbook, Seventh Edition, 2010, pp. 317–318, published by Springer Science and Business Media LLC, www.springer .com.

Note. Reprinted with permission courtesy of the International Association for the Study of Lung Cancer. Copyright 2008 Aletta Ann Frazier, MD.

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Figure 9-4. Diagram, T3 T3

Tumour > 7 cm

Figure 9-5. Diagram, T4 T4

Chest wall invasion, including Pancoast tumours without invasion of vertebral body or spinal canal, encasement of the subclavian vessels, or unequivocal involvement of the superior branches of the brachial plexus (C8 or above)

Tumour invades trachea and/or SVC or other great vessel

Invasion of parietal pleura over the mediastinum

Phrenic nerve or parietal pericardium invasion

Tumour invades aorta and/or recurrent laryngeal nerve

Tumour involves carina

Additional tumour nodule(s) in the lobe of the primary

Tumour invades adjacent vertebral body

Diaphragmatic invasion

Tumour invades esophagus, mediastinum and/or heart

Tumour in the main bronchus less than 2 cms for the carina (without involvement of the carina) and/or associated atelectasis or obstructive pneumonitis of the entire lung

Pancoast tumours with invasion of one or more of the following structures: • vertebral body or spinal canal • brachial plexus (C8 or above) • subclavian vessels

Tumour accompanied by ipsilateral nodules, different lobe

Note: any associated pleural effusion should be shown on multiple microscopical examinations to be negative for tumour; it should be non-bloody and not an exudate, and clinical judgement should dictate that the effusion is not related to the tumour.

Note. Reprinted with permission courtesy of the International Association for the Study of Lung Cancer. Copyright 2008 Aletta Ann Frazier, MD.

Note. Reprinted with permission courtesy of the International Association for the Study of Lung Cancer. Copyright 2008 Aletta Ann Frazier, MD.

et al., 2003). Stage II is divided into the subsets of IIA and IIB. As noted earlier, the five-year survival rates following resection are poor for both groups. Complete surgical resection is recommended in this group of patients, even in those with N1 disease (Scott et al., 2003). Adjuvant chemotherapy is currently recommended for patients with pathologic stage IB–IIIA disease (Yoshino, 2009). Clinical trials using adjuvant radiotherapy have demonstrated mixed results in improving survival (Scott et al., 2003). However, guidelines recommend radiation therapy for the improvement of local control (Scott et al., 2003). For patients with T3 disease and an incomplete resection, radiation therapy may improve survival (Scott et al., 2003). Stage III disease is divided into A and B subsets. In general, patients with stage IIIB are considered unresectable, as complete excision of all disease is not possible except in rare, carefully selected patients (Jett, Scott, Rivera, & Sause, 2003; Joyce & Houlihan, 2001). The standard of care for the majority of patients in this group is combined-modality treatment

with chemotherapy and radiotherapy (Jett et al., 2003). Surgery for stage IIIA disease is deemed technically possible (except for those with unresectable bulky N2 disease), but fiveyear survival rates in this group of patients are poor with this modality alone. Stage IIIA patients represent a heterogeneous group (in terms of treatment and prognosis), and some advocate the use of four subsets when making treatment decisions (Robinson, Wagner, & Ruckdeschel, 2003). The treatment of stage IIIA disease has been the subject of many clinical trials employing multimodality treatments. However, because of the variability of this stage, the optimal treatment strategies have not yet been defined (Robinson et al., 2003; Yoshino, 2009). Several trials have demonstrated five-year survival benefit with multimodal treatment compared to surgery or radiation therapy alone in patients with stage IIIA disease. These trials were reviewed in a meta-analysis published by the Non-Small Cell Lung Cancer Collaborative Group (1995). The recent American College of Chest Physicians (ACCP) guide104

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lines recommended that selected patients with completely resected stage IIIA disease receive radiation therapy because it has been shown to reduce local recurrence (Robinson et al., 2003). Radiation therapy does not improve overall survival in this population (Robinson et al., 2003). In patients with potentially resectable disease, multimodal therapy is better than surgery alone but, when possible, should be carried out in a clinical trial setting. Adjuvant and neoadjuvant trials of multimodal therapy are ongoing, and the future recommendations regarding stage IIIA may change (Robinson et al., 2003). Survival in the majority of patients with stage IV disease is not improved by surgery. In selected cases of patients with solitary brain, adrenal, or lung metastases and an otherwise resectable lung primary, surgery may be recommended for both the primary tumor and the metastatic site (Martini, 1993; Pearson, 1994). Improved survival and quality of life have been observed in these patients (Pearson, 1994). The recent ACCP guidelines support this approach (Detterbeck, Jones, Kernstine, & Naunheim, 2003).

should follow several basic guidelines to optimize complete resection and TNM staging. These guidelines, which Ginsberg and Port (2000, p. 685) advocated, are as follows. • The tumor and its draining intrapulmonary lymphatic tributaries should be resected in their entirety whenever possible. • The tumor should be completely excised without spilling or traversing it. • The surgeon should resect en bloc any structure invaded by tumor in order to achieve negative margins. • A complete ipsilateral mediastinal lymph node dissection or sampling should be performed in all patients. Pneumonectomy was first performed in 1933 in a patient with bronchogenic carcinoma. The procedure became the standard treatment for patients with resectable lung cancer in the 1940s (Waters, 2002). Pneumonectomy involves resection of the entire lung. Today, this procedure is limited to patients in whom a total resection (including negative margins) cannot be obtained with lobectomy. This includes tumors that involve the proximal bronchus, several lobes of the lung, the hilum, or the lymph nodes (Eaby-Sandy, 2011). This procedure is classified as simple or radical. Simple pneumonectomy involves removal of the lung with stapling of the bronchus. Radical pneumonectomy also includes removal of the

Surgical Procedures As noted earlier, surgical resection is the treatment of choice for early-stage lung cancers. Surgical oncologists

Figure 9-6. Diagram, N0, N1 and N2 N0

No regional lymph node metastases

N1

N2

Metastasis in ipsilateral intrapulmonary/peribronchial/hilar lymph node(s), including nodal involvement by direct extension

Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s), including ‘skip’ metastasis without N1 involvement

Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) associated with N1 disease

Note. Reprinted with permission courtesy of the International Association for the Study of Lung Cancer. Copyright 2008 Aletta Ann Frazier, MD.

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mediastinal lymph nodes. To prevent mediastinal shift, the remaining pneumonectomy space is allowed to fill naturally with fluid. Mortality following pneumonectomy is twice that of lobectomy, estimated at 6%; right-sided pneumonectomy is much more risky, with a 23.9% mortality rate (Eaby-Sandy, 2011; Quinn, 2003). Lobectomy was first performed in 1912 but did not become routine until the 1950s, following a report of long-term survival in a patient with a peripheral tumor (Martini & Ginsberg, 2002). Lobectomy is the complete resection of a lobe of the lung. Lobectomy with lymph node sampling of hilar and mediastinal nodes is the procedure of choice in patients with stage I NSCLC, in whom the cancer is confined to a single lobe (Ginsberg & Port, 2000). One or two chest tubes are placed following lobectomy; this practice varies from surgeon to surgeon (Martini & Ginsberg, 2002). The lobe is excised from the remaining lung, and, eventually, the remaining lung tissue expands to fill the space (Ingle, 2000). The mortality associated with lobectomy is approximately 3% (Ingle, 2000). Bilobectomy, a more extensive procedure, may need to be performed when the tumor crosses a major fissure or if more than one lobe is involved (Martini & Ginsberg, 2002). Empyema and bronchopleural fistula are more common in patients with bilobectomy involving the middle and lower lobes of the lung (Martini & Ginsberg, 2002). Limited resections include segmentectomy and wedge resection. Segmental resection first was performed in 1939 and initially was performed for the surgical management of patients with tuberculosis and bronchiectasis (Fell & Kirby, 2002). It is defined as the excision of one or more bronchopulmonary segments of a lobe (Fell & Kirby, 2002). Because of the anatomy of segmental lymphatic drainage, most or all of the lymphatic drainage is resected during segmentectomy (Ginsberg & Port, 2000). Another procedure, the wedge resection, is a nonanatomic operation (Quinn, 2003). This procedure generally is reserved for patients who are unable to tolerate greater resections because of poor pulmonary reserve or comorbid conditions. It also is used for removal of small peripheral tumors. The 2003 ACCP guidelines recommend lobectomy over lesser resections, as clinical trials have demonstrated higher local recurrence rates in patients with wedge or segmental resections compared with those having greater resections (Smythe, 2003). The first true sleeve resection with bronchoplastic reconstruction was performed in 1955 (Tsuchiya, 2002). Today, this procedure is performed when tumor is protruding from the main bronchus (Quinn, 2003). If tumor is confined to the bronchus, the involved area can be removed and the remaining bronchus can be reattached, thereby preserving unaffected lung tissue (Ingle, 2000). This procedure also can be performed in conjunction with lobectomy, often eliminating the need for pneumonectomy (Quinn, 2003). At the time of surgery, lymph node sampling must be performed for adequate nodal staging. To date, no evidence-based

Figure 9-7. Diagram, M1a and M1b M1a

Primary tumour

Contralateral pulmonary nodule(s)

Malignant pericardial effusion/nodule(s) Malignant pleural effusion/nodules(s) Distant metastases:

M1b

Brain

Distant nodal metastases (those beyond the regional nodes)

Bone

Liver

Adrenal

Note. Reprinted with permission courtesy of the International Association for the Study of Lung Cancer. Copyright 2008 Aletta Ann Frazier, MD.

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Table 9-2. Lymph Node Map Definitions Nodal Station

Anatomic Landmarks

N2 nodes—All N2 nodes lie within the mediastinal pleural envelope. 1 Highest mediastinal nodes

Nodes lying above a horizontal line at the upper rim of the brachiocephalic (left innominate) vein where it ascends to the left, crossing in front of the trachea at its midline

2 Upper paratracheal nodes

Nodes lying above a horizontal line drawn tangential to the upper margin of the aortic arch and below the inferior boundary of No. 1 nodes

3 Prevascular and retrotracheal nodes

Prevascular and retrotracheal nodes may be designated 3A and 3P; midline nodes are considered to be ipsilateral

4 Lower paratracheal nodes

The lower paratracheal nodes on the right lie to the right of the midline of the trachea between a horizontal line drawn tangential to the upper margin of the aortic arch and a line extending across the right main bronchus at the upper margin of the upper lobe bronchus, and contained within the mediastinal pleural envelope; the lower paratracheal nodes on the left lie to the left of the midline of the trachea between a horizontal line drawn tangential to the upper margin of the aortic arch and a line extending across the left main bronchus at the level of the upper margin of the left upper lobe bronchus, medial to the ligamentum arteriosum and contained within the mediastinal pleural envelope. Researchers may wish to designate the lower paratracheal nodes as No. 4s (superior) and No. 4i (inferior) subsets for study purposes; the No. 4s nodes may be defined by a horizontal line extending across the trachea and drawn tangential to the cephalic border of the azygos vein; the No. 4i nodes may be defined by the lower boundary of No. 4s and the lower boundary of No. 4, as described above.

5 Subaortic (aortopulmonary window)

Subaortic nodes are lateral to the ligamentum arteriosum or the aorta or left pulmonary artery and proximal to the first branch of the left pulmonary artery and lie within the mediastinal pleural envelope

6 Para-aortic nodes (ascending aorta or phrenic)

Nodes lying anterior and lateral to the ascending aorta and the aortic arch or the innominate artery, beneath a line tangential to the upper margin of the aortic arch

7 Subcarinal nodes

Nodes lying caudal to the carina of the trachea, but not associated with the lower lobe bronchi or arteries within the lung

8 Paraesophageal nodes (below carina)

Nodes lying adjacent to the wall of the esophagus and to the right or left of the midline, excluding subcarinal nodes

9 Pulmonary ligament nodes

Nodes lying within the pulmonary ligament, including those in the posterior wall and lower part of the inferior pulmonary vein

N1 nodes—All N1 nodes lie distal to the mediastinal pleural reflection and within the visceral pleura. 10 Hilar nodes

The proximal lobar nodes, distal to the mediastinal pleural reflection and the nodes adjacent to the bronchus intermedius on the right; radiographically, the hilar shadow may be created by enlargement of both hilar and interlobar nodes

11 Interlobar nodes

Nodes lying between the lobar bronchi

12 Lobar nodes

Nodes adjacent to the distal lobar bronchi

13 Segmental nodes

Nodes adjacent to the segmental bronchi

14 Subsegmental nodes

Nodes around the subsegmental bronchi

Note. From the IASLC Staging Handbook in Thoracic Oncology (p.64), by P. Goldstraw (Ed.), 2009, Orange Park, FL: Editorial Rx Press. Copyright 2009 by International Association for the Study of Lung Cancer. Reprinted with permission.

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consensus has been reached to guide surgeons as to how many lymph nodes constitute an adequate sample for staging lung cancers (Edge et al., 2010). However, according to the AJCC, “adequate N staging is generally considered to include sampling or dissection of lymph nodes from stations 2R, 4R, 10R, and 11R for right-sided tumors, and stations 5, 6, 7, 10L, and 11L for left-sided tumors” (Edge et al., 2010, p. 255). If a tumor is in a lower lobe, station 9 lymph nodes should also be evaluated. Accurate lymph node staging is especially important in early-stage lung cancers. Patients whose nodal status is determined by clinical methods have been shown to have decreased survival compared to those with pathologically staged lymph nodes (Haigentz & Keller, 2002). Controversy exists as to the most accurate way to sample lymph nodes to determine involvement by tumor (Ginsberg & Port, 2000). In general, lymph node sampling is performed in one of three ways: lymph node “sampling” refers to the removal of abnormal lymph nodes; “systematic sampling” refers to routine sampling of lymph nodes at different nodal stations; and “complete mediastinal lymph node dissection” refers to the removal of all lymph node tissue at levels specified by the surgeon (Haigentz & Keller, 2002). Two clinical trials have compared systematic sampling with complete mediastinal lymph node dissection (Keller, Adak, Wagner, & Johnson, 2000; Wu, Huang, Wang, Yang, & Ou, 2002). In the first trial, Keller et al. (2000) demonstrated that complete mediastinal lymph node dissection identified significantly more N2 lymph nodes, and this group had improved survival. Wu et al. (2002) found that complete mediastinal lymph node dissection was associated with significant improvements in survival. The patients in the Wu et al. (2002) trial were followed for up to 10 years following surgery. Investigators are examining the technique of sentinel lymph node sampling in an effort to eliminate systematic dissection (Liptay et al., 2000; Little, DeHoyos, Kirgan, Arcomano, & Murray, 1999). Both lymph node dissection and lymph node sampling provide staging information that is critical to treatment decisions. The evidence is insufficient to support one technique over the other (Scott et al., 2007). Minimally invasive surgery, including video-assisted thoracoscopic surgery (VATS), may be used for lung resection in selected circumstances. VATS is used for both diagnostic and therapeutic purposes. Potential advantages of VATS over conventional surgery include decreased postoperative pain, better preservation of pulmonary function, and earlier return to normal activities (Yim, 2002). A distinct disadvantage for VATS is the inability to perform adequate mediastinal lymph node sampling (Yim, 2002). Very often, VATS is used in patients who are unable to tolerate a thoracotomy or who have poor pulmonary reserve. Recent research has found that VATS and conventional resection were equivalent in terms of longterm survival and that VATS is an appropriate procedure for select patients with early-stage NSCLC (Farjah et al., 2009; Yan, Black, Bannon, & McCaughan, 2009).

Nursing care of patients prior to and following lung resection is complex. The patient’s physical status largely determines post-resection complications. Common complications following lung resection are pain, atelectasis, dyspnea, and cough (Eaby-Sandy, 2011). Cardiopulmonary side effects, such as atrial fibrillation and postoperative heart failure, are also potentially serious complications after surgery. Beta-blockers are often prescribed for several months after the procedure (Eaby-Sandy, 2011). Most postoperative pulmonary complications are related directly to chronic obstructive pulmonary disease (COPD). The focus of nursing care on the patient undergoing thoracic surgery should begin at the time the patient is being evaluated for resection and continue through the postoperative and ambulatory period. Preoperative improvement in pulmonary function in patients with COPD may improve outcomes following resection. Patients with obstructive disease may benefit from a preoperative regimen using inhalers, antibiotics, and breathing exercises (e.g., incentive spirometer, cough and deep breathing exercises). Preoperative evaluation of all patients should include respiratory function and extremity range of motion so that appropriate instruction can occur. Instruction should include diaphragmatic breathing exercises and range-of-motion exercises, which can be performed in the initial postoperative period. The exercise program should be initiated prior to surgery (see Figure 9-8). In those who are current or recent smokers, the importance of smoking cessation cannot be overemphasized. Patients must be assessed carefully for smoking history and understand the importance of becoming tobacco free. The initial postoperative period presents many challenges, including, but not limited to, prevention of post-thoracotomy pain, promotion of pulmonary toilet, prevention of infection, and early recognition of cardiac arrhythmias. Adequate pain control must be assessed frequently, and medication should be adjusted as needed. With successful pain control, pulmonary exercises and coughing, as well as pulmonary toilet, will be easier to perform. Range-of-motion exercises and early ambulation are promoted to prevent venous stasis and decrease the risk of thromboembolic disease. Continuous assessment for incisional infection or other pulmonary infection should be performed. Early recognition of infection and judicious pulmonary toilet may prevent more serious complications. Following hospital discharge, respiratory function and smoking status must be assessed. Patients must be aware that optimal respiratory function will not be immediate. Continuation of the exercise program may help to restore optimal respiratory function. If needed, patients may be referred to a pulmonary rehabilitation program. Smoking cessation efforts and encouraging patients to remain tobacco free are also important during this period.

Radiation Therapy Radiation therapy for NSCLC has been used since the 1950s. Since the early days, much research has been done to 108

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Figure 9-8. Preoperative Exercise Program This program includes breathing, flexibility, and strengthening exercises to improve your overall physical performance before surgery. It is most important to be in the best physical shape prior to surgery so you can take deep breaths, cough, and get out of bed after surgery. Breathing and Arm Exercise Sitting or standing position Place arms out at shoulder level; parallel to floor. Breathe in and raise arms above head, palms facing each other, and hold for two seconds. Breathe out through pursed lips as you lower your arms to shoulder level; arms are parallel to floor. Repeat 10 times. Open and Close Chest Sitting or standing position Place arms out at shoulder level, parallel to floor with palms facing forward. Breathe out through pursed lips as you move your arms to front of body, palms facing each other. Breathe in as you open arms and stretch arms back, squeezing shoulder blades together. Repeat 10 times. Sniffles (Aerobic Diaphragm Breathing Exercise) Sitting or standing position The diaphragm is the largest and primary muscle for breathing. Breathe in through the nose and breathe out through pursed lips. Close mouth. Breathe in and out of the nose as quickly as you can. Repeat for 15–30 seconds (start slow and increase speed in and out of nose). The goal is to be able to continue the exercise for 60 seconds. All breathing exercises should be done four times a day. Walking Regimen Walk one mile a day in less than 20 minutes. Stair climbing—Climb up two to four flights of stairs twice a day. (Breathe out as you step up on each step.) Your heart rate will increase; this is normal. If it takes you longer than five minutes to feel normal, then next time go a little slower. Always try to reach your goal of one mile a day and four flights of steps. The power of your breath is breathing out. Chair Squat Sit in the middle of the chair seat, feet hip-width apart. Heels should be two inches from the legs of the chair. Breathe in through the nose. Breathe out as you stand, squeezing your buttocks, and raise arms overhead. Lower arms and sit down. Breathe in through the nose. Breathe out and stand, squeezing buttocks, and raise arms overhead. Sit down. Repeat 10 times. Rest 20 seconds. Repeat 10 times. • Do not have your knees extend over your toes. • Your heart rate will increase; this is normal. Leg Exercises to Improve Strength Sitting position Sit in the middle of the chair, lift chest, push shoulders down, and tighten abdominal muscles to protect your back. Lift leg off chair, tightening muscles on top of thigh, then breathe out as you extend leg straight and hold for three seconds. Lower leg. Repeat 10 times. Rest 20 seconds. Repeat 10 times. Shoulder Press Sitting position with back supported by a chair (No weights or 2-, 3-, or 4-pound dumbbells) This exercise strengthens the arms, shoulders, and upper back. Make a fist with each hand or use a 2-, 3-, or 4-pound dumbbell in each hand at shoulder height. With palms facing forward, breathe out as you slowly lift upward until your arms are straight. Breathe in as you lower arms to shoulder level. Repeat 10 times. Rest 20 seconds. Repeat 10 times. Chest Fly Sitting position with back supported by chair Place fingertips on ears; your elbow is in alignment to shoulder. Breathe out as you move elbows forward (elbows do not have to touch). Breathe in through the nose as you open elbows, and push back to open the chest. This also can be done while holding a dumbbell in each hand. Repeat 10 times. Rest 20 seconds. Repeat 10 times. Biceps Curl Sitting with back supported by chair Make fists with your hands or hold a dumbbell in each. Arms are straight along your sides. Keep your elbows touching your body, close to your sides. Breathe out as you bend your elbows and slowly lift the weight to your shoulders. Lower the weight while slowly breathing in. Repeat 10 times. Rest 20 seconds. Repeat 10 times. (Continued on next page)

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Figure 9-8. Preoperative Exercise Program (Continued) Shoulder Rolls Sitting or standing position Place your arms straight along the side of your body with palms facing forward. Breathe in as you rotate your shoulders upward, then breathe out as you rotate your shoulders downward. Repeat 10 times. Breathing and Bending Forward Sitting position Breathe in as you raise arms overhead crossing wrists. Breathe out through pursed lips and bend forward; try to touch chest to thighs and lower arms to floor. Try to touch your fingers to floor. Always breathe out as you bend forward and never hold your breath. Raise your arms overhead as you breathe in. Repeat 10 times. Cough Technique Sitting or standing position Breathe in through the nose for a count of four. Hold your breath for two seconds. Breathe out through pursed lips for the count of eight. Repeat four times. On the fifth breath, breathe in through the nose, hold your breath for two seconds, then contract/tighten abdominal muscles and cough. Repeat two times, four times a day. Coughing is most important after lung surgery. Note. Courtesy of Donna Wilson, RN, MSN, RRT, Personal Trainer. Used with permission.

determine the optimum dose and fractionation schedule, as well as the integration of radiation therapy into multimodality treatment. Radiation therapy kills both cancer cells and normal cells. The effect of radiation therapy on normal tissue surrounding the tumor determines the maximal dose of radiation and the resulting toxicities. This effect is termed the therapeutic ratio (Haas, 2011). One dose of ionizing radiation will have the greatest effect, or cell kill, on both normal cells and cancer cells. The therapeutic ratio is accomplished by dividing the total dose of radiation into equal fractions or doses and giving it over a specified time period (Haas, 2011). Fractionating radiation doses accomplishes the goal of destroying cancer cells and reducing the probability of any remaining viable cells while maintaining the integrity of normal cells (Haas, 2011). In recent years, several innovations have been developed in the field of radiation therapy. The goals of these innovations are to improve outcomes and decrease side effects. Hyperfractionation is when the total daily dose of radiation is given in two divided doses. This method allows for delivery of a slightly overall higher dose over the same time or a shorter period with fewer side effects, including a reduction in late side effects (Jett et al., 2003). Results of clinical trials comparing hyperfractionated radiotherapy with standard radiation have been mixed (Edelman et al., 2008; Jett et al., 2003). Because of the mixed results of trials, it is still unknown whether this approach is superior to less aggressive therapy; therefore, hyperfractionation cannot be recommended over standard treatment. Continuous hyperfractionated accelerated radiotherapy (CHART) is delivered in up to three fractions per day (Hatton & Martin, 2010). The total dose delivered is greater than that for standard radiotherapy and with multiple smaller fractions so that normal cells receive less toxicity. Several studies

have shown advantages for patients receiving CHART compared to standard radiation therapy (Belani, 1993; De Ruysscher et al., 2008; Hazuka & Turrisi, 1993; Saunders et al., 1999). CHART is not widely used in practice, in part because of the difficulty of delivering treatment three times per day (Hatton & Martin, 2010; Jett et al., 2003). Proton beam therapy uses protons (as opposed to photons, which are used in standard radiotherapy) to kill cancer cells (Moore-Higgs, 2003). Because of the radiobiology of protons, radiation oncologists are able to deliver maximal doses of radiation to the tumor with significantly less toxicity to surrounding normal cells (Moore-Higgs, 2003). A study using proton-beam radiation therapy in early-stage lung cancer demonstrated safety with comparable local control and disease-free survival compared to conventional photon radiation therapy (Bush et al., 1999). As a result, higher doses of protonbeam therapy may be delivered to the tumor, leading to better control with reduced side effects (Bush et al., 1999). Presently, proton beam therapy is not widely available, and more research is needed before recommendations can be made. Three-dimensional conformal radiation therapy (3D-CRT) provides the prescribed dose of radiation to the configuration of the tumor but is able to deliver lower doses to the surrounding tissue. Treatment planning and dose delivery are based on computer-assisted programs. 3D-CRT offers enhanced precision in defining the tumor and reducing the effects of the radiation to the surrounding normal tissues. This type of treatment primarily has been used in patients with prostate cancer. It is being investigated for use in lung cancer and may be beneficial for select patients but is not widely used (Salama et al., in press). Two types of specialized 3D-CRT are being investigated for the treatment of lung cancer: intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy 110

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(SBRT). IMRT is a specialized form of 3D-CRT where radiation beams deliver more than two intensity levels for a single beam direction and a single source position (Velderman et al., 2008). A study of IMRT in lung cancer demonstrated a significantly lower incidence of toxicity for patients treated with IMRT than non-IMRT therapy (Velderman et al., 2008). Research is ongoing to evaluate IMRT in the treatment of lung cancer. SBRT is a specialized form of 3D-CRT that delivers high doses of radiation to small targets over a shorter course of therapy. SBRT is a hypofractionated delivery of radiation treatment where the total dose is delivered over a shorter time, often in one to five treatments (Smink & Schneider, 2008). SBRT is currently being investigated for the treatment of select patients with lung cancer. Brachytherapy is the placement of sealed radioactive sources in contact or close proximity to the target tissue. In patients with lung cancer, brachytherapy primarily is used in one of two ways: endobronchial or interstitial. Endobronchial brachytherapy is achieved by the bronchoscopic placement of a radioactive source beyond the distal margin of the tumor (Aumont-le Guilcher et al., 2011). Endobronchial brachytherapy has been shown to be an excellent method for palliation of symptoms, such as dyspnea, cough, or hemoptysis, from endobronchial lesions (Aumont-le Guilcher et al., 2011). Side effects are minimal, although bronchoesophageal fistula and hemoptysis have been reported (Aumont-le Guilcher et al., 2011; Speiser & Kresl, 2000). Interstitial brachytherapy involves the placement of radioactive seeds by needle to the target tissue. It is best used for local control of tumor following surgical resection when the margins are close or positive (Speiser & Kresl, 2000). Interstitial brachytherapy is not used as commonly as external beam radiotherapy because of a lack of expertise with the technique (Speiser & Kresl, 2000). At this time, interstitial brachytherapy has no proven lung cancer treatment role, either alone or in combination with surgery, external beam radiation therapy, or chemotherapy (Speiser & Kresl, 2000). High-dose-rate brachytherapy has been used to palliate symptoms of obstructive lung cancer, such as dyspnea, cough, and hemoptysis (Aumont-le Guilcher et al., 2011). Radiation therapy is used as primary treatment for medically inoperable stage I and II NSCLC, in patients with early-stage unresectable disease (either alone or combined with chemotherapy), as prophylactic treatment (e.g., for impending superior vena cava syndrome), or for palliative treatment (e.g., for painful bone metastases). Additionally, radiation therapy is used in the adjuvant setting for patients with early-stage lung cancer and positive resection margins (Smythe, 2003). In patients with NSCLC, standard treatment is delivered to the primary tumor as well as the regional lymphatic tissues. The standard dose is considered to be 50–65 Gy over a five- to six-week period. Management of side effects, specifically radiation pneumonitis, fibrosis, and esophagitis, is discussed in Chapter 10.

Studies examining the use of adjuvant or neoadjuvant radiation therapy in patients with early-stage lung cancer have not shown a survival benefit over surgery alone (Smythe, 2003). A meta-analysis reported that postoperative radiotherapy had a significant adverse effect on survival in patients with completely resected lung cancer and should not be used (PORT Meta-Analysis Trialists Group, 2005). The role of postoperative radiotherapy in patients with N2 disease is less clear and warrants further research (PORT Meta-Analysis Trialists Group, 2005). In patients with locally advanced cancer (stage III), standard radiation therapy has not achieved long-term control of disease. Several trials have compared radiation therapy alone with combination chemotherapy and radiation therapy treatment in patients with inoperable stage III disease. Both concurrent and sequential regimens have been used. Results of these trials have demonstrated improved survival and local control with the combination treatment (Curran, 2000; Johnson & Turrisi, 2000). Trials using cisplatin-based chemotherapy have shown an advantage (Sause et al., 2000). Combination radiation therapy and chemotherapy is the current standard for patients with unresectable stage III disease. In a phase III trial involving patients with regional advanced, unresectable NSCLC, patients were randomized to one of three arms: standard radiation, induction chemotherapy (cisplatinbased) followed by standard radiation, and hyperfractionated radiation (Sause et al., 2000). The purpose of the trial was to demonstrate that either hyperfractionated radiation or the combination of chemotherapy and radiation would improve survival in patients with regionally advanced lung cancer. The study did not confirm the benefit of hyperfractionated radiation; however, patients who received combination therapy had superior survival over the other groups (Sause et al., 2000). Palliative radiation therapy plays an important role in patients with advanced incurable NSCLC. Palliative radiation can improve symptoms and, in some cases, survival. Several factors must be considered in patients receiving palliative radiation therapy. These include the natural history of the disease, resources for treatment, likelihood of achieving meaningful benefit, and patient condition. Radiation therapy for malignant spinal cord compression and superior vena cava syndrome is discussed in Chapter 6. External beam whole brain radiation therapy (WBRT) is often used in patients with NSCLC who have metastatic disease to the brain. Prompt treatment often is required to prevent or minimize progressive neurologic deterioration. The use of steroids in conjunction with WBRT reduces swelling from tumor and neurologic symptoms. The steroids are tapered slowly after completion of the WBRT. Stereotactic radiosurgery can be used in selected patients with tumors that are 4 cm or smaller, with a maximum dimension of 3 cm or less considered to be ideal (Behrend, 2011). Bone metastases occur in 20%–40% of patients with lung cancer. The most common sites of metastases are ver111

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tebrae, pelvis, and femora. The skull and extremities are involved less often. Often, bone metastases cause pain, immobility, and pathologic fractures. Radiation therapy can improve pain and mobility and prevent pathologic fractures in these patients. Additionally, it has been shown to stop osteolytic bone destruction and promote reossification (Greenberg et al., 1972). Radiation therapy is an important treatment modality in the management of patients with nearly all stages of NSCLC. Clinical trials of newer methods such as 3D-CRT, IMRT (an advanced form of 3D-CRT), and proton beam therapy continue to refine and improve outcomes. Management of patients with NSCLC will improve as newer therapies develop.

jority of patients (49.3%) were given cisplatin at 100 mg/m2 in combination with etoposide for a total of three or four cycles (Arriagada et al., 2004). Other cisplatin combinations included vindesine, vinblastine, or vinorelbine. Overall survival at two years was 70.3% in those given chemotherapy versus 66.7% in those not given chemotherapy (Arriagada et al., 2004). Disease-free survival was significantly higher for those given chemotherapy versus the control group (p < 0.003). Results demonstrated an absolute five-year benefit in overall survival of 4.1% for those randomized to adjuvant chemotherapy (Arriagada et al., 2004). The authors concluded that the adjuvant chemotherapy offered similar benefits to those seen with adjuvant chemotherapy in other solid tumors. Arriagada and colleagues (2010) reported on an additional three-year follow-up of patients from their original trial. The significant survival benefit of adjuvant chemotherapy seen in the 2004 trial was no longer apparent after an additional three years of follow-up. The observed increase in noncancer-related deaths (from all causes) or the chemotherapy itself may have contributed to the reported 2009 results (Arriagada et al., 2010; Gettinger, 2010). A North American trial (JBR-10) examined the effects of adjuvant cisplatin plus vinorelbine versus observation in patients with resected stage IB or II disease (Winton et al., 2005). Four hundred eighty-two patients were randomized, 240 to observation and 242 to four cycles of chemotherapy. Results of this trial demonstrated a five-year survival rate of 69% for those given cisplatin plus vinorelbine versus 54% in those on the observation arm of the study disease (Winton et al., 2005). The survival advantage was greater in those with stage II disease. The most common side effect was grade 3 or 4 neutropenia seen in 73% of patients; two patients died as a result of treatment-related toxicity (Winton et al., 2005). The authors concluded that adjuvant chemotherapy should be offered to patients with completely resected stage IB and II NSCLC; it should be noted that those with stage II disease had the most benefit (Winton et al., 2005). Updated survival and a subsequent analysis of the data in those with stage IB disease (120 patients) revealed that those with larger tumors (greater than 4 cm) had more benefit with adjuvant chemotherapy than those with smaller tumors (Butts et al., 2010). Updated survival revealed that the median follow-up was 9.3 years (range 5.8–13.8 years). The updated results continue to demonstrate a significant survival advantage for adjuvant chemotherapy in early-stage resected NSCLC, particularly for those with stage II disease (Butts et al., 2010). The authors did not find evidence of unexpected late toxicity or an increase in second malignancies attributable to adjuvant chemotherapy. The Adjuvant Navelbine International Trialist Association (ANITA) conducted a trial of adjuvant chemotherapy in 840 patients with completely resected stage IB–IIIA disease (Douillard et al., 2006). The patients were randomized to receive vinorelbine plus cisplatin versus observation. This study was conducted in 14 European countries; 407 patients were

Chemotherapy for Non-Small Cell Lung Cancer Chemotherapy for NSCLC has been used widely for decades. Early treatments using alkylating agents, such as nitrogen mustard, were not very successful. Treatment outcomes improved with the second generation of platinum-based regimens. Researchers made greater progress with third-generation agents, including the taxanes (paclitaxel and docetaxel), vinorelbine, pemetrexed, gemcitabine, and irinotecan. Evidence-based guidelines are available to guide treatment decisions for those with NSCLC; these guidelines include the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer and the American Society of Clinical Oncology (ASCO) practice guidelines (Azzoli et al., 2009; NCCN, 2011). Adjuvant Chemotherapy Patients with completely resected early-stage disease are at risk for relapse and death despite surgery for NSCLC. Length of survival is related to stage of disease; those with resected stage I disease have a longer survival than those with resected stage II disease. Recurrence of disease often occurs as distant metastases (Scagliotti & Vokes, 2010). Despite early failures of adjuvant chemotherapy trials, recent randomized trials and a meta-analysis have shown a survival advantage for patients given cisplatin-based chemotherapy (Arriagada Bergman, Le Chevalier, Pignon, & Vansteenkiste, 2004, 2010; Douillard et al., 2006; Pignon et al., 2008; Winton et al., 2005). Adjuvant chemotherapy should now become routine practice for patients with resected early-stage NSCLC; the NCCN guidelines (2011) support this practice. One of the first trials was conducted by the International Adjuvant Lung Cancer Trial Collaborative Group (Arriagada et al., 2004). The purpose of this trial was to determine the effect of adjuvant chemotherapy versus no chemotherapy on overall survival in patients with completely resected early-stage NSCLC. To be eligible, patients had to have completely resected stage I–III NSCLC. In this trial, 1,867 patients were randomized to a cisplatin-based chemotherapy regimen or the control group, no chemotherapy. The ma112

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randomized to the chemotherapy arm and 433 to the observation arm. The overall five-year survival by stage and chemotherapy versus observation arms, respectively, follows: stage IB (62% versus 64%), stage II (52% versus 39%), and stage IIIA (42% versus 26%) (Douillard et al., 2006). The adverse effects of chemotherapy seen in this trial were similar to that seen in other trials with vinorelbine plus cisplatin. Overall survival for those given chemotherapy improved by 8.6% at five years and was 8.4% at seven years (Douillard et al., 2006). The benefit of chemotherapy was greater in those with stage II–IIIA disease. The Lung Adjuvant Cisplatin Evaluation (LACE) Collaborative Group recently published results of a meta-analysis examining cisplatin-based adjuvant chemotherapy (Pignon et al., 2008). The authors collected and pooled individual patient data (4,584 patients) from the five largest adjuvant trials conducted since the 1995 NSCLC meta-analysis. Results confirmed a significant benefit in overall survival and diseasefree survival favoring chemotherapy, with an absolute benefit of 4.2% at five years (Pignon et al., 2008). The results of this meta-analysis demonstrated that those with resected stage IA disease may not benefit from chemotherapy, but the benefit is clear for those with resected stage II and IIIA disease (Pignon et al., 2008). Strauss and colleagues (2008) reported the results of adjuvant carboplatin and paclitaxel versus observation for those with resected stage IB disease. The initial report of this trial in 2004 stated that adjuvant chemotherapy for stage IB disease improved overall survival and disease-free survival (Strauss et al., 2004). However, the more mature data reported in 2008 no longer supported the routine use of chemotherapy for stage IB disease, although a trend favored chemotherapy. An advantage for chemotherapy was noted in patients with large (4 cm or larger) tumors, and adjuvant chemotherapy could be recommended for this group (Strauss et al., 2008). Based on these results, adjuvant chemotherapy should be routinely recommended for those with resected stage II and III disease. This is supported by the 2011 NCCN guidelines. Cisplatin-based regimens should be offered to those who can tolerate it; generally four cycles of treatment are recommended. For those with comorbidities or those who are unable to tolerate cisplatin, carboplatin and paclitaxel may be given (NCCN, 2011).

to tolerate and many patients are not able to take all planned cycles of treatment (Burdett, Stewart, & Rydzewska, 2006; Pisters et al., 2000). Several phase II and III trials conducted from 2000 to 2006 demonstrated that chemotherapy before surgery is well tolerated and improves median and long-term survival (Abratt et al., 2006; Aerts et al., 2006; Betticher et al., 2003; Pisters et al., 2000). A more recent trial reported by Felip and colleagues (2010) enrolled 624 patients with stages I, II, or IIIA disease. Patients were randomized to neoadjuvant chemotherapy, adjuvant chemotherapy, or surgery alone. In both chemotherapy arms, patients were given carboplatin and paclitaxel for three cycles. Five-year disease-free survival in those with stage II and IIIA disease was 25%, 31%, and 37% for surgery, adjuvant, and neoadjuvant treatment, respectively (Felip et al., 2010). No survival advantage was indicated for either chemotherapy arm; however, it should be noted that 66% of those given adjuvant chemotherapy completed all three cycles of treatment, whereas 90% of those given neoadjuvant treatment completed all three planned cycles of treatment (Felip et al., 2010). Although these results are encouraging, more research is needed to further improve outcomes. First, the absolute benefit of adjuvant treatment for those with stage IB disease needs to be determined. More clinical trials are needed before neoadjuvant chemotherapy can be recommended as the standard of care. Second, more effective regimens with less toxicity need to be identified, as well as better identification of patients likely to benefit from adjuvant chemotherapy, and finally, treatment needs to be customized to the biology of the patient’s tumor (Gettinger, 2010; Pisters, 2005).

Treatment of Advanced Non-Small Cell Lung Cancer Advanced NSCLC includes patients with unresectable stage III disease and those with stage IV disease. Combinedmodality treatment with chemotherapy and radiotherapy is recommended for those with unresectable stage IIIA and IIIB disease (see the section on radiation therapy). Patients with stage IIIB disease who have a pleural or pericardial effusion and patients with stage IV disease are treated with palliative chemotherapy. Several practice guidelines, including those from ASCO, NCCN, and ACCP, recommend platinum-based chemotherapy in patients with a good PS (Azzoli et al., 2009; NCCN, 2011; Socinski, Morris, Masters, & Lilenbaum, 2003).

Neoadjuvant Chemotherapy Induction chemotherapy (neoadjuvant) is another treatment modality for those with stage I–IIIA disease. This method has not garnered as much attention as adjuvant treatment, and NCCN (2011) has not recommended this as a treatment modality. This alternative to adjuvant treatment has several advantages, including the potential to shrink the tumor and downstage the disease before surgery, gain early control of micrometastatic disease, and gain patient acceptance and compliance because chemotherapy after surgery is difficult

Chemotherapy Versus Best Supportive Care Multiple trials have definitively shown that chemotherapy plus best supportive care is superior to best supportive care alone in those with advanced NSCLC. In 1995, the NSCLC Collaborative Group published a meta-analysis, representing 9,387 patients, which demonstrated that platinum-based 113

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chemotherapy (carboplatin or cisplatin) improved survival over best supportive care in patients with advanced NSCLC (NSCLC Collaborative Group, 1995). Since that time, platinum-based chemotherapy has been the mainstay of treatment for this patient group. In 2008, the NSCLC Meta-Analyses Collaborative Group (the same group that published the 1995 meta-analysis) reported on the results of an additional 16 trials using more modern drugs and newer modes of administration (NSCLC Meta-Analyses Collaborative Group, 2008). All trials were randomized and compared either chemotherapy plus best supportive care versus best supportive care alone. Twelve trials were platinum based (carboplatin or cisplatin), and four trials were single-agent trials employing vinorelbine, etoposide, gemcitabine, or paclitaxel. Overall survival was highly statistically significant in favor of those given chemotherapy plus supportive care versus supportive care alone (p < 0.0001) (NSCLC Meta-Analyses Collaborative Group, 2008). PS was measured in 13 of the trials. Results demonstrated that those with a PS of 2 received benefit from treatment, although those with a PS of 0 or 1 derived more benefit from treatment (NSCLC Meta-Analyses Collaborative Group, 2008). In those given chemotherapy plus supportive care, no clear benefit was demonstrated for one chemotherapy regimen over another or single-agent chemotherapy compared with combination chemotherapy. Based on these results, the authors concluded that the treatment paradigm should not be changed in those with advanced NSCLC and that those who are well enough and want to receive chemotherapy should be offered treatment (NSCLC Meta-Analyses Collaborative Group, 2008). The majority of trials have measured the success of treatment by evaluating survival. Other trials had the end points of symptom control and quality of life. Cullen and colleagues (1999) and Spiro and colleagues (2004) each published an example of a trial with these end points. In both trials, patients were randomized to cisplatin-based chemotherapy versus best supportive care. The patients who received chemotherapy had reduced symptoms and improved quality of life when compared to those given best supportive care (Cullen et al., 1999; Spiro et al., 2004).

poor PS do not benefit from cytotoxic chemotherapy (Finkelstein, Ettinger, & Ruckdeschel, 1986; Socinski et al., 2003). Number of Agents and Platinum Versus Nonplatinum Regimens In the past 10 years, multiple published studies have addressed the questions of how many agents and if platinumbased chemotherapy produced better results than other agents. Some compared a platinum doublet (two-drug combination) to a nonplatinum single agent; others have compared a platinum three-drug combination (triplet) to a two-drug nonplatinum combination. In this same time period, results of several meta-analyses addressed the same questions. Results of four randomized controlled trials and one meta-analysis support the use of a two-drug combination when compared to single-agent treatment (Delbado et al., 2004; Georgoulias et al., 2004; Lilenbaum et al., 2005; Negoro et al., 2003; Sederholm et al., 2005). In addition, all of these trials contained a platinum comparator arm. In all four randomized trials, patients were previously untreated and were randomized to a two-drug platinum combination versus singleagent treatment. Overall survival was the primary end point of each study. More than 1,000 patients were randomized. Georgoulias et al. (2004) compared docetaxel plus cisplatin versus docetaxel alone. The primary end point of the study was overall survival. The overall response rate (complete response rate plus partial response rate) was 34.7% in those given the combination regimen versus 21% for those given docetaxel alone. The overall survival for docetaxel plus cisplatin and single-agent docetaxel was 10.5 months and 8 months, respectively. This result was not statistically significant. One-year survival was similar in both groups: 44% for those given the combination versus 43% for those given single-agent docetaxel (Georgoulias et al., 2004). As expected, toxicity was lower in patients given docetaxel alone. The authors demonstrated a higher response rate with the combination but no improvement in overall survival; for those who cannot tolerate cisplatin, docetaxel alone is a reasonable firstline alternative (Georgoulias et al., 2004). Another study, published in 2005 was conducted by the Cancer and Leukemia Group B (Lilenbaum et al., 2005). This study compared carboplatin plus paclitaxel versus paclitaxel alone. Overall response rate was statistically significant for those given carboplatin plus paclitaxel: 30% for the combination regimen and 17% for paclitaxel alone (p < 0.0001) (Lilenbaum et al., 2005). One-year survival was not significantly different between groups—37% for carboplatin plus paclitaxel, 32% for paclitaxel. Overall survival was not significantly different (Lilenbaum et al., 2005). Anemia, neutropenia, and thrombocytopenia were more frequent in the combination arm, as were nausea and vomiting. Negoro and associates (2003) compared irinotecan plus cisplatin versus irinotecan alone. The overall response rate was 43.7% for irinotecan plus cisplatin versus 20.5% for iri-

First-Line Chemotherapy In the past decade, multiple trials have been designed to answer the following questions. What is the best initial treatment? Are two cytotoxic drugs better than one; are three better than two? Is a platinum-containing regimen better than a nonplatinum regimen? Where do the newer targeted agents fit in with chemotherapy? Can older adults or those with a marginal PS be treated with cytotoxic chemotherapy? Current ASCO and NCCN guidelines recommend treatment for advanced NSCLC in those with a good PS (Eastern Cooperative Oncology Group [ECOG] PS 0–2) (Azzoli et al., 2009; NCCN, 2011). Studies have determined that patients with a 114

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notecan alone. Overall survival was not significantly different. Nausea and vomiting occurred more often in those given irinotecan plus cisplatin; grade 3 and 4 diarrhea was seen in 13.5% of patients (Negoro et al., 2003). Only one study demonstrated a significant difference in overall survival with a two-drug regimen versus a single agent. Sederholm and colleagues (2005) compared gemcitabine and carboplatin versus gemcitabine alone. The overall response rate was 29.6% for gemcitabine and carboplatin compared with 11.3% for gemcitabine alone. Overall survival and twoyear survival were significantly in favor of those given the two-drug combination (Sederholm et al., 2005). A significantly higher occurrence of grade 3 and 4 hematologic toxicity was reported in the gemcitabine and carboplatin arm. Two studies compared a three-drug platinum combination versus a two-drug nonplatinum regimen in the setting of advanced NSCLC (Alberola et al., 2003; Greco et al., 2007). Neither of these trials demonstrated a survival benefit in those given three drugs compared with a two-drug combination, but as expected, more side effects were seen with the threedrug regimen. Delbaldo and associates (2004) published the results of a meta-analysis. Eligible trials were those that compared the benefit of adding a drug to a single-agent regimen or a twodrug regimen in patients with advanced NSCLC. Those studies that compared a two-drug regimen versus one drug demonstrated a significant benefit in tumor response and one-year survival for the two-drug combinations (Delbaldo et al., 2004). The trials that compared three drugs versus two drugs showed a significant improvement in tumor response with three drugs, but no significant increase in overall survival (Delbaldo et al., 2004). Not unexpectedly, toxicity was more pronounced in combination regimens compared with those given single agent regimens. The results of this meta-analysis support the current approach of platinum-based doublet therapy for those with advanced NSCLC (Delbaldo et al., 2004). Several studies also addressed the question of which platinum combination is better, cisplatin or carboplatin (Ardizzoni et al., 2007; Hotta et al., 2004; Schiller et al., 2002; Soria & LeChevalier, 2002). Cisplatin is more difficult to administer than carboplatin; it requires IV hydration both before and after administration, thus requiring a much longer treatment period. Cisplatin has also been considered a more toxic regimen with prominent side effects of nephrotoxicity, neurotoxicity, and nausea and vomiting (Waxman, 2008). Nausea and vomiting no longer pose significant problems because of newer, more effective antiemetic regimens. Carboplatin is easier to administer; it causes less nausea and vomiting and almost no neurotoxicity or nephrotoxicity (Waxman, 2008). Hematologic toxicities such as thrombocytopenia are more common with carboplatin. Ardizzoni and associates (2007) reported the results of an individual patient data meta-analysis comparing cisplatinbased regimens with carboplatin-based regimens. The results demonstrated a better response rate and prolonged survival in

those given a cisplatin regimen (Ardizzoni et al., 2007). The cisplatin-based regimen was not associated with a higher incidence of severe side effects when compared to those given carboplatin. Many clinicians agree with Ardizzoni’s group that carboplatin is easier to administer than cisplatin and that the small benefit in response seen with cisplatin does not justify the preferential use of this agent. ASCO and NCCN guidelines support the use of platinumbased (cisplatin or carboplatin) chemotherapy regimens for the treatment of advanced NSCLC in those with a good PS and no contraindications to treatment. Based on the results of the published literature, the guidelines also support treatment with two cytotoxic agents versus three (Azzoli et al., 2009; NCCN, 2011). Targeted Agents and Chemotherapy Multiple authors agree that treatment with standard chemotherapy has reached a plateau in effectiveness against NSCLC and that newer agents with a different mechanism of action are needed to further improve upon response (Gridelli, Maione, Galetta, & Rossi, 2007; Wang, Reed, & Li, 2004). Targeted agents such as bevacizumab, cetuximab, erlotinib, and gefitinib fit this profile and are attractive in the treatment of NSCLC. Multiple other targeted agents exist and are in clinical trials, but these have been studied most. In general, they do not have overlapping toxicities (e.g., nausea, vomiting, neuropathy, neutropenia) when combined with cytotoxic agents; this makes them attractive for use in combination regimens. These agents have their own unique side effects that may require intervention, but when given as single agents, most people tolerate the side effects well. Bevacizumab is a recombinant humanized monoclonal antibody directed at VEGF. The VEGF-VEGF receptor pathway has been a focus of cancer research and drug development for many years (Gridelli, Maione, Rossi, & Di Marinis, 2007). Bevacizumab prevents VEGF from binding to its receptor, thereby delaying tumor growth and preventing metastasis. Bevacizumab was initially approved by the U.S. Food and Drug Administration (FDA) for the treatment of colorectal cancer in 2004. In 2006, the FDA approved bevacizumab as a first-line treatment for advanced NSCLC in combination with carboplatin and paclitaxel. The FDA based its decision on Sandler and associates’ (2006) published results of a phase III trial. In this trial, patients with advanced NSCLC were randomized to receive either bevacizumab with carboplatin and paclitaxel or carboplatin and paclitaxel alone as firstline treatment. The authors demonstrated a survival advantage for those given the three-drug combination with bevacizumab (Sandler et al., 2006). This was the first trial that demonstrated the benefits of adding targeted therapy to conventional chemotherapy versus chemotherapy alone in the treatment of advanced NSCLC. Since then, additional trials have demonstrated the benefits of adding bevacizumab to other chemotherapy combinations. 115

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A phase III trial by Reck and colleagues (2009) supported the use of bevacizumab in combination with cisplatin and gemcitabine. Patients with advanced NSCLC were entered into the trial. All patients were given cisplatin plus gemcitabine and were randomized to receive low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo. Treatment was given every 21 days until disease progression or for a maximum of six cycles. Progressionfree survival was the primary end point of the study and was significantly longer in those given either dose of bevacizumab (Reck et al., 2009). Objective response rate was significantly higher in patients given either dose of bevacizumab compared to placebo: 34.1% for low-dose bevacizumab, 30.4% for high-dose bevacizumab, and 20.1% for placebo (Reck et al., 2009). These two trials and others support the use of bevacizumab in combination with chemotherapy in the treatment of advanced NSCLC (Crinò et al., 2010; Johnson et al., 2004). Both NCCN and ASCO treatment guidelines recommend bevacizumab in combination with chemotherapy in selected patients with advanced NSCLC (Azzoli et al., 2009; NCCN, 2011). Side effects of bevacizumab are not insignificant. In the Sandler et al. (2006) study, the bevacizumab regimen was associated with more toxicity and a higher rate of death compared with paclitaxel and carboplatin alone. Grade 3–4 neutropenia, thrombosis/embolism, and hemorrhage were higher in those given therapy containing bevacizumab. A significantly higher incidence of hypertension, bleeding (pulmonary and gastrointestinal hemorrhage), neutropenia, febrile neutropenia, and thrombocytopenia was reported in patients who were given the three-drug combination. Treatment-related deaths were significantly higher in those given bevacizumab (15 deaths versus 2 deaths) (Sandler et al., 2006). Despite the higher incidence of toxicity, the authors continue to support the use of the bevacizumab regimen in carefully selected patients (Sandler et al., 2006). Of note, hypertension emerged as a marker of response in breast and pancreatic cancer. On further analysis of the Sandler et al. (2006) study, it was noted that those who developed hypertension with bevacizumab had statistically significant improvement in overall survival compared to those who did not (Friberg, Kasza, Vokes, & Kindler, 2005; Sandler et al., 2006; Schneider et al., 2008). ASCO guidelines specifically recommend adherence to the Sandler et al. (2006) study regarding patients who should not be offered bevacizumab-containing treatment. The recommendation is that patients with SCC of the lung, clinically significant hemoptysis, suboptimal organ function, poor PS (e.g., ECOG PS greater than 1), therapeutic anticoagulation, or clinically significant cardiovascular disease including uncontrolled hypertension should not be given bevacizumab. Research studies are ongoing in those with these clinical characteristics to examine the safety of bevacizumab. The EGFR pathway is another focus of research and drug development in the treatment of cancers, including lung can-

cer. Drugs that target this pathway interfere with tumor development by blocking the EGFR tyrosine kinase receptor, thereby inhibiting downstream signaling and the growth and proliferation of cancer. Erlotinib, gefitinib, and cetuximab are agents that target the EGFR pathway, but the FDA has yet to approve any of these for first-line treatment of NSCLC. However, multiple studies have used them in this setting. Current NCCN guidelines include both erlotinib and cetuximab as options for first-line treatment in those with advanced NSCLC (NCCN, 2011). In 2003, gefitinib was the first EGFR tyrosine kinase inhibitor that the FDA approved for use. Approval was granted based on the results of a study using gefitinib in the thirdline setting (Cohen et al., 2004). In 2004, the FDA restricted use of gefitinib to those patients who had received clinical benefit or those enrolled in clinical trials. This change occurred following the results of the Iressa® Survival Evaluation in Lung Cancer trial, which did not report a survival advantage for gefitinib compared with placebo (Thatcher et al., 2005). The FDA approved erlotinib for second- and third-line treatment of lung cancer in 2004 based on results of National Cancer Institute of Canada trial BR.21 (Miller et al., 2008; Shepherd et al., 2005). Phase III trials of erlotinib and gefitinib in combination with standard chemotherapy in the firstline setting were disappointing; none showed a survival advantage with the addition of erlotinib or gefitinib to standard platinum-based chemotherapy (Gatzemeier et al., 2007; Giaccone et al., 2004; Herbst et al., 2004, 2005). Further analysis of these trials and others revealed that subgroups of patients were more likely to benefit from EGFRtyrosine kinase inhibitor therapy. These subgroups included patients with the following characteristics: never-smokers or former light smokers, Asian ethnicity, women, and those with adenocarcinoma or a subset of adenocarcinoma histology— BAC (Herbst et al., 2004; Miller et al., 2004; Shepherd et al., 2005; Thatcher et al., 2005). In 2004, three investigators simultaneously published reports of those who had dramatic responses to gefitinib and who demonstrated the presence of genetic mutations in the EGFR gene (Lynch et al., 2004; Paez et al., 2004; Pao et al., 2004). The two most common mutations identified with response to gefitinib or erlotinib are the exon 19 deletion and the exon 21 point mutation (L858R) (Sharma, Bell, Settleman, & Haber, 2007). Multiple trials documented the correlation between clinical characteristics, the presence of EGFR mutations, and response to EGFR-tyrosine kinase inhibitor therapy (Han et al., 2005; Huang, Armstrong, Benavente, Chinnaiyan, & Harari, 2004; Kosaka et al., 2004; Paez et al., 2004; Pao et al., 2004; Riely et al., 2006). In 2006 and 2007, four trials examined the use of either gefitinib or erlotinib in patients with advanced NSCLC whose tumors tested positive for an EGFR mutation (Asahina et al., 2006; Inoue, Suzuki, et al., 2006; van Zandwijk et al., 2007; Yoshida et al., 2007). In all four trials, up to one-third of tumors tested positive for an EGFR mutation (24%–33%). Over116

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all response rate reported in three of the trials ranged from 75%–90.5% (Asahina et al., 2006; Inoue, Suzuki, et al., 2006; Yoshida et al., 2007). In the fourth trial, the mean progression-free survival was reported as 430 days (van Zandwijk et al., 2007). Another Japanese trial tested gefitinib in previously untreated individuals with poor PS and tumors that tested positive for EGFR mutation (Inoue et al., 2009). Thirty patients were enrolled; the overall response rate was 66%. Remarkably, an improvement in PS was observed in 68%; 22 individuals’ PS improved from 3 to less than 1 (Inoue et al., 2009). In the United States, Sequist and colleagues (2008) tested gefitinib in patients with advanced NSCLC and no prior chemotherapy. Ninety-eight people were entered, and 34 (35%) people had tumors that tested positive for EGFR mutation. Of those, 31 were given gefitinib on trial. The overall response rate was 55% with a median progression-free survival of 9.2 months (Sequist et al., 2008). In all trials, the most common side effects were mild and consisted of rash and diarrhea. Collectively, these trials support the use of first-line gefitinib or erlotinib in those with tumors that test positive for EGFR mutations. These trials were all single-arm studies and several questions remain, perhaps most importantly: Do patients with EGFR-mutated NSCLC have greater benefit from chemotherapy or EGFR-TKI therapy (Neal, & Sequist, 2010)? In the Iressa Pan-Asia Study (IPASS), Mok and associates (2009) published the first trial to compare standard chemotherapy with gefitinib in advanced NSCLC as a first-line treatment in select East Asian patients. Patients were selected if they had adenocarcinoma histology or were never-smokers or former light smokers. Participants were randomized to carboplatin and paclitaxel or single-agent gefitinib at 250 mg/day. EGFR mutation data were available for 437 participants, and 261 samples were positive for a mutation. The progressionfree survival at 12 months for all participants was 24.9% in those given gefitinib versus 6.7% in those given carboplatin and paclitaxel (Mok et al., 2009). The overall response rate was 43% versus 32.3% in those given gefitinib versus carboplatin and paclitaxel, respectively, regardless of EGFR mutation status (Mok et al., 2009). In patients whose tumors tested positive for EGFR mutation, the overall response rate was 71.2% for gefitinib and 47.3% for carboplatin and paclitaxel. Among all given gefitinib, the overall response rate was 71.2% in mutation-positive patients versus 1.1% in mutation-negative patients (Mok et al., 2009). Patients who were given gefitinib had improved quality of life compared to those given carboplatin and paclitaxel. Grade 3 and 4 adverse events were less common in those given gefitinib. Serious adverse events leading to death or hospitalization were similar between the two groups. The authors concluded that while progressionfree survival, objective response rate, and quality of life were improved in clinically selected patients given gefitinib, those with EGFR mutation–positive tumors benefited most (Mok et al., 2009). This was the first study to identify EGFR muta-

tion status as an important predictive marker of EGFR-tyrosine kinase inhibitor treatment. The North East Japan Study Group published their results of gefitinib compared with carboplatin and paclitaxel in patients with advanced NSCLC (Maemondo et al., 2010). Participants had to have previously untreated cancer and their tumors had to test positive for EGFR mutation. The trial was halted early after preplanned interim analysis of the first 200 participants demonstrated that progression-free survival was significantly longer in those randomized to gefitinib compared to chemotherapy, 10.8 months versus 5.4 months respectively (Maemondo et al., 2010). Progression-free survival at 12 and 24 months was 42.1% and 8.4% respectively for gefitinib and 3.2% and 0% for carboplatin and paclitaxel (Maemondo et al., 2010). Toxicity was milder in those treated with gefitinib. The authors concluded that selection of patients for EGFRtyrosine kinase inhibitor therapy should be based on mutation status (Maemondo et al., 2010). The results of the IPASS and the recently reported trial from the North East Japan Study Group confirm that in previously untreated patients with advanced NSCLC, the selection of treatment should be determined by EGFR mutation status whenever possible. These studies support the current NCCN guidelines for advanced NSCLC and have significantly contributed to the treatment of those with advanced disease. Hopefully, this information, combined with the knowledge gained in ongoing trials of NSCLC, will lead to improved treatment with a potential cure for this group of patients. Cetuximab is a monoclonal antibody that targets the EGFR pathway. It is not approved for the treatment of NSCLC; it is approved for the treatment of squamous cell head and neck cancer and for metastatic colorectal cancer. Clinical trials with this agent in combination with chemotherapy are ongoing in the treatment of NSCLC. Unlike the EGFR tyrosine kinase inhibitors in which response correlates with the presence of a biomarker (EGFR tumor mutation) and clinical characteristics, at this time, no such correlation exists with cetuximab and lung cancer. Two phase III studies using cetuximab in combination with standard chemotherapy have been reported. Pirker and colleagues (2009) conducted the First-Line Erbitux® in Lung Cancer (FLEX) trial in which patients were randomized to Erbitux (cetuximab), cisplatin, and vinorelbine, or cisplatin and vinorelbine without cetuximab. Overall survival was improved in those given the cetuximab regimen; median survival was 11.3 months for cetuximab and 10.1 months for those given chemotherapy alone (Pirker et al., 2009). This difference was small but significant. Those given cetuximab had a higher rate of grade 3 rash, severe diarrhea, and neutropenia. The authors examined patient characteristics (e.g., ethnicity, gender, smoking history) and response to treatment. The only correlation observed was between Caucasians and a trend toward improved efficacy with cetuximab (Pirker et al., 2009). The Bristol-Myers Squibb 099 trial was conducted to confirm results of the FLEX trial (Lynch et al., 2010). Patients 117

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were randomized to paclitaxel or taxane and cisplatin with or without cetuximab. Progression-free survival, the primary end point, was not significantly different between the groups. Overall response rate was significantly different in favor of cetuximab; overall survival was improved but not significantly with cetuximab (Lynch et al., 2010). In both studies it was noted that the appearance of early rash correlated with longer survival for those given cetuximab. Further study needs to be conducted to confirm this finding or to identify other clinical characteristics that predict response to cetuximab. See Figure 9-9, a suggested algorithm for first-line treatment in advanced NSCLC.

an EGFR mutation. Gefitinib was given at 250 mg daily. The overall response rate was 66% and the disease control rate was 90% (Inoue et al., 2009). Remarkable improvements in PS were seen, with 68% of patients who had a baseline PS of 3–4 improving to PS 1 (Inoue et al., 2009). The authors noted that this improvement in PS enabled participants to spend quality time at their end of life rather than being bedridden. Combination chemotherapy with a platinum combination can be considered for older patients with a good PS. The most notable trial to date was presented at the 2010 ASCO meeting. This was the first phase III randomized trial in older adults using a platinum doublet (Quoix et al., 2010). In this trial, 451 patients who were 70–89 years old with a PS of 0–2 were randomized to receive weekly paclitaxel with monthly carboplatin or weekly vinorelbine or gemcitabine. Overall survival was significantly improved for those given carboplatin and paclitaxel versus single-agent therapy—10.4 months versus 6.2, respectively (Quoix et al., 2010). Grade 3–4 hematologic toxicities were significantly higher in those given combination treatment, and no significant difference was reported in early deaths between the two arms of the study. Other phase II trials have demonstrated safety and efficacy in older patients (Inoue, Usui, et al., 2006; Pujol et al., 2006; Ramalingam et al., 2006; Sakakibara et al., 2010).

Age, Performance Status, and Chemotherapy Lung cancer is primarily a disease in older adults, with the majority of cases occurring in those older than 60 years old. Furthermore, an estimated one-third or more of cases occur in those older than 70 years old (Gridelli, Perrone, & Monfardini, 1997; Zalcman, Bergot, & Lechapt, 2010). Many clinicians assume that older adults are less likely to tolerate treatment because of the comorbid illnesses and declining organ function that occur as part of the aging process. Multiple studies have examined the use of single-agent and combination regimens in older adults for more than a decade; however, this population continues to be underrepresented in clinical trials (Pallis & Gridelli, 2010). Current NCCN guidelines note that chemotherapy may be given to older adults or other patients with PS 2. Treatment is not recommended in those with PS 3 or 4 (NCCN, 2011). ECOG PS is seen in Table 9-3. The Elderly Lung Cancer Vinorelbine Italian Study (known commonly as the ELVIS trial) was one of the earliest trials conducted in older adults (Gridelli, 2001). In this phase III trial, participants had to be 70 years or older with a PS of 0–2. Patients were randomized to vinorelbine or best supportive care. Results were reported in 161 patients. One-year survival for those given vinorelbine was 32% and was 14% in those receiving best supportive care (Gridelli, 2001). Vinorelbine was well tolerated; hematologic toxicities of neutropenia (grade 3–4) and anemia (grade 2–3) were seen in 10% and 16%, respectively (Gridelli, 2001). Overall, those given vinorelbine had better quality of life and fewer symptoms from lung cancer. Other studies have also demonstrated the benefits of singleagent therapy in older adults (Crinò et al., 2008; Gridelli et al., 2005; Kudoh et al., 2006; Lilenbaum et al., 2007). EGFR-tyrosine kinase inhibitor therapy with either gefitinib or erlotinib has been shown to be beneficial in both older adults and those with poor PS or compromised renal function (Cella et al., 2005; Gridelli, Maione, Galetta, et al., 2007; Inoue et al., 2009). Inoue and colleagues (2009) reported the results of a trial of gefitinib in patients with poor PS that included some older adult patients. Three treatment groups were studied: those 20–74 years old with PS 3–4, 75–79 years old with PS 2–4, and patients 80 years old and older with PS 1–4. All patients had to have a tumor that tested positive for

Maintenance Therapy in Advanced Non-Small Cell Lung Cancer Maintenance therapy is a new treatment modality in NSCLC. Maintenance chemotherapy as defined in NCI’s Dictionary of Cancer Terms is Treatment that is given to help keep cancer from coming back after it has disappeared following the initial therapy. It may include treatment with drugs, vaccines, or antibodies that kill cancer cells, and it may be given for a long time. (NCI, n.d.) Maintenance chemotherapy has long been used in hematologic malignancies. In NSCLC, patients were treated with a platinum-based regimen for a maximum of six cycles; this was often followed by a drug holiday. During this period, patients were monitored with expectant observation. Upon disease recurrence, second-line therapy was initiated. As many as 50% of patients go on to receive second-line treatment; some are not well enough to receive treatment, and others choose not to receive additional therapy (Schiller et al., 2002; Socinski et al., 2003). Despite maintenance chemotherapy, the majority will not be alive at one year (Jalal, Ademuyiwa, & Hanna, 2009). Maintenance therapy is a strategy that is being investigated to improve survival. Two different strategies have been used in maintenance therapy. One strategy involves the use of one or more of the chemotherapy agents that were used in the first line; the other strategy involves the introduction of a biologic agent, one that was not used in first-line treatment. 118

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Figure 9-9. Suggested Algorithm for First-Line Treatment in Advanced Non-Small Cell Lung Cancer

ECOG PS—Eastern Cooperative Oncology Group performance status; EGFR—epidermal growth factor receptor; NSCLC—non-small cell lung cancer; TKI— tyrosine kinase inhibitor Note. From “Recent Issues in First-Line Treatment of Advanced Non-Small Cell Lung Cancer: Results of an International Expert Panel Meeting of the Italian Association of Thoracic Oncology,” by C. Gridelli, A. Ardizzoni, J.Y. Douillard, N. Hanna, C. Manegold, F. Perrone, … F. de Marinis, 2010, Lung Cancer, 68, p. 328. Copyright 2010 by Elsevier. Reprinted with permission.

Pemetrexed was the first FDA-approved drug for maintenance chemotherapy. It is approved in the treatment of those with nonsquamous cell lung cancer. FDA approval came in 2009 following results of the randomized phase III study reported by Ciuleanu and colleagues (2009). Following treatment with platinum-based chemotherapy for stage IIIB or IV disease, those who did not have disease progression were randomized to receive pemetrexed or best supportive care to be given until progression. Pemetrexed was not given as firstline therapy. This was a randomized, double-blind study of 663 patients. The primary end points of the study were progression-free survival and overall survival. Median progression-free survival was four months in those given pemetrexed versus two months in those randomized to placebo (Ciuleanu et al., 2009). Median overall survival was also improved

in those given pemetrexed compared to placebo, 13.4 months versus 10.6 months, respectively. Grade 3–4 adverse events were significantly increased in those given pemetrexed. The authors concluded that pemetrexed was well tolerated and offers a new treatment option for those with nonsquamous NSCLC (Ciuleanu et al., 2009). Erlotinib, a biotherapy agent, was the second drug to be given FDA approval for use in the maintenance setting. The FDA granted approval in 2010 following the results of the Sequential Tarceva® in Unresectable NSCLC trial (known as the SATURN trial) (Cappuzzo et al., 2010). Patients were eligible following completion of four cycles of cisplatin-based chemotherapy without progression of disease. Participants were randomized to erlotinib 150 mg/day or oral placebo. EGFR immunohistochemistry was determined in all patients. Pro119

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3–4 hematologic toxicity was high in both trials. Pemetrexed is also approved for the second-line treatment of NSCLC. Pemetrexed treatment is always accompanied by treatment with folic acid and vitamin B12, which minimize hematologic and nonhematologic toxicities (Hanna et al., 2004). A phase III randomized trial comparing docetaxel with pemetrexed in second-line treatment of NSCLC was reported in 2004 (Hanna et al., 2004). Response rates were similar between the two arms, as were improvements in baseline symptoms from cancer. Hematologic toxicities were significantly higher in those given docetaxel. Two recent studies have noted that pemetrexed is more effective in adenocarcinoma and large cell carcinoma (Ciuleanu et al., 2009; Peterson et al., 2007). Erlotinib is approved for both second- and third-line treatment of NSCLC. Advantages for erlotinib include oral dosing as opposed to IV dosing, and a mild side effect profile for most. Approval in the second- and third-line setting came after published results from National Cancer Institute of Canada clinical trial BR.21 (Shepherd et al., 2005). Participants were randomized to erlotinib 150 mg/day or placebo following progression of disease after one or two prior chemotherapy regimens. Of the patients who received erlotinib, 8.9% responded to treatment compared to less than 1% in those given placebo, and 31% were alive at one year compared to 22% on placebo (Shepherd et al., 2005). These results are similar to those seen with second-line docetaxel. Those who received erlotinib had a decrease in cancer-related symptoms and an improved quality of life compared with placebo (Shepherd et al., 2005). When considering second- and third-line treatment in NSCLC, several factors must be considered. These include patient preference (oral versus IV administration), PS, comorbidities, patient characteristics, molecular characteristics, and tumor histology (Stinchcombe & Socinski, 2008). Clinical trials are ongoing in this area and include the use of vinflunine, cetuximab, and sunitinib (Bennouna et al., 2006; Hanna et al., 2006; Socinski et al., 2008).

Table 9-3. Eastern Cooperative Oncology Group (ECOG) Performance Status Grade

ECOG Description

0

Fully active, able to carry on all predisease performance without restriction

1

Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light house work, office work)

2

Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours.

3

Capable of only limited self-care, confined to bed or chair more than 50% of waking hours

4

Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.

5

Dead

Note. As published in “Toxicity and Response Criteria of the Eastern Cooperative Oncology Group,” by M.M. Oken, R.H. Creech, D.C. Tormey, J. Horton, T.E. Davis, E.T. McFadden, and P.P. Carbone, 1982, American Journal of Clinical Oncology, 5, pp. 649–655. The ECOG Performance Status is in the public domain and therefore available for public use. To duplicate the scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis, M.D., Group Chair. Retrieved from http://ecog.dfci.harvard.edu/general/perf_stat.html.

gression-free survival was significantly longer in those given erlotinib compared with placebo, regardless of EGFR immunohistochemistry status (Cappuzzo et al., 2010). Erlotinib was well tolerated, and mild skin rash and diarrhea were the most common side effects observed. Trials continue to examine the usefulness of different agents in the maintenance setting. Angiogenesis inhibitors and immunotherapy are also being investigated (Butts et al., 2005; Patel et al., 2009). Many questions remain unanswered, including the cost/benefit of maintenance treatment, improvement in quality of life, and who is most likely to derive benefit from maintenance therapy (Coate & Shepherd, 2010).

Personalized Lung Cancer Treatment: Histology and Biomarkers Cytotoxic chemotherapy has reached a plateau of response and survival in NSCLC. New strategies are needed to improve outcomes in those with this disease. Two such strategies, the determination of tumor histology and the identification of tumor biomarkers, have emerged as important considerations needed to direct patient therapy. This is a growing area of clinical research in NSCLC. Many trials have been published that support these two strategies. For many years, the treatment of NSCLC was the same for all cell types; adenocarcinoma, squamous cell, and large cell were treated identically because the medical community believed that they were the same disease. We now know that NSCLC is a heterogeneous disease (Onn & Herbst, 2005). NCCN and ASCO treatment guidelines now reflect this, and treatment recommendations are dif-

Second- and Third-Line Treatment Most patients with advanced NSCLC experience progression of disease following first-line treatment. Many of these patients remain well with good PS and choose to continue treatment with additional chemotherapy or biotherapy. Docetaxel, pemetrexed, and erlotinib are all recommended for second-line treatment. Current NCCN guidelines support the use of these agents in the second line (NCCN, 2011). Data from two phase III studies supported the use of docetaxel as second-line therapy in patients with advanced NSCLC (Fosella et al., 2000; Shepherd et al., 2000). The incidence of grade 120

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ferent according to NSCLC histologic classification (Azzoli et al., 2009; NCCN, 2011; Travis et al., 2011). In 2008, survival differences by histology were reported in a clinical trial for the first time. Scagliotti and colleagues (2008) conducted a randomized phase III trial comparing cisplatin and gemcitabine with cisplatin and pemetrexed in advanced NSCLC, with overall survival as the primary end point of the study. Treatment arms were balanced according to PS, gender, pathology (histology versus cytology), and stage of disease (IIIB versus IV). Results demonstrated that survival was significantly different according to histology (Scagliotti et al., 2008). Survival was significantly improved in those with adenocarcinoma and large cell carcinoma given cisplatin and pemetrexed compared to those with the same histology given cisplatin and gemcitabine (Scagliotti et al., 2008). The authors suggested that thymidylate synthase levels may play a role; high tumor levels of thymidylate synthase correlate with poor response to pemetrexed (Giovanetti et al., 2005). Another study in untreated patients demonstrated significantly higher thymidylate synthase levels in those with SCC compared to those with adenocarcinoma (Ceppi et al., 2006). In fact, the FDA limits the use of pemetrexed to those with nonsquamous NSCLC. Hirsch and associates (2008) published the results of a literature review examining the impact of histology in the treatment of advanced NSCLC. The literature search included phase II and III studies, retrospective analyses, and metaanalyses that reported prognostic or predictive effects of histology on clinical outcome. The authors identified 408 papers from 1982 to 2007. Conclusions from many papers were difficult to interpret because of study design and insufficient data. Thirty-two studies reported an association between outcome and histology: 14 of these reported that histology was prognostic and predictive of clinical outcomes in individuals treated with EGFR inhibitors, 11 reported a prognostic correlation between histology and clinical outcomes, and 7 papers suggested a correlation between histology and clinical outcomes with specific cytotoxic regimens (Hirsch et al., 2008). The results of this literature review support the importance of histology in guiding the selection of treatment options in those with NSCLC. Histology has also been an important safety factor when considering bevacizumab as part of the treatment regimen. In a randomized phase II trial, patients were given either carboplatin or paclitaxel alone or with low-dose (7.5 mg/kg) or high-dose (15 mg/kg) bevacizumab (Johnson et al., 2004). A life-threatening bleed occurred in six patients and was characterized as hemoptysis or hematemesis; four patients died as a result of the hemorrhage. Four of the six patients had squamous cell histology; the majority received the lower dose of bevacizumab. All six patients had tumors that were centrally located and close to major blood vessels, and five of the six had tumors that were cavitated or necrotic at baseline or it developed early in the treatment period. Bevacizumab is not

recommended for those who have squamous cell lung cancer, centrally located tumors, or tumors that are close to major blood vessels. EGFR and K-ras mutations have emerged as important biomarkers of response to EGFR tyrosine kinase inhibitors (Garcia et al., 2008; Jackman et al., 2009; Riely et al., 2009). Initial studies documented improved outcomes with gefitinib and erlotinib in those with the following clinical characteristics: adenocarcinomas and subtypes of adenocarcinoma (BAC and adenocarcinoma with BAC features), women, and neversmokers or former light smokers (Fukuoka et al., 2003; Herbst et al., 2005; Miller et al., 2004). In 2004, nearly simultaneously, three groups of investigators discovered somatic mutations in the tyrosine kinase domain of EGFR, which correlated with remarkable responses to gefitinib and erlotinib (Lynch et al., 2004; Paez et al., 2004; Pao et al., 2004). The four most common mutations occur in exons 18 to 21. EGFR mutations are found nearly exclusively in NSCLC and in approximately 30% of patients with adenocarcinoma (Lee et al., 2004; Miller, 2008). The typical response rate to EGFR-tyrosine kinase inhibitor therapy in those with EGFR mutations is in the range of 75%–80% (Riely et al., 2006). A large-scale screening study from Spain documented that EGFR mutations are more common in those with adenocarcinoma; mutations were also seen in those with BAC and large cell carcinomas, but to a lesser extent (Rosell et al., 2009). Of 2,105 patients, EGFR mutations were found in 350; those with mutations were considered for treatment with erlotinib as either first-, second-, or third-line therapy. In those given erlotinib, the complete and partial response rate was 70.6%, the median progression-free survival was 14 months, and the median overall survival was 27 months (Rosell et al., 2009). The authors concluded that large-scale screening is feasible and that screening for EGFR mutations should be conducted in women, never-smokers, and those with nonsquamous NSCLC (Rosell et al., 2009). K-ras is one of a family of ras genes that are believed to play a role in signal transduction pathways that affect cell growth, differentiation, and survival (Aggarwal, Somaiah, & Simon, 2010). Mutation of the K-ras gene leads to malignant transformation causing the development of lung cancer (Miller, 2008). K-ras is nearly always seen in patients with adenocarcinoma, and it is also seen in smokers and never-smokers. K-ras and EGFR mutations are mutually exclusive. Individuals whose tumors harbor K-ras mutations are resistant to EGFR-tyrosine kinase inhibitor therapy and do not benefit from adjuvant chemotherapy (Riely et al., 2009; Tsao et al., 2007; Winton et al., 2005). Moreover, seven studies confirmed that radiographic responses to erlotinib or gefitinib were seen only in those individuals with non-mutant K-ras (also known as wild-type Kras) tumors (Han et al., 2006; Hirsch et al., 2006, 2007; Jackman et al., 2007; Massarelli et al., 2007; Miller, 2008; Zhu et al., 2008). As a result of these studies, oncologists now request routine K-ras testing of tumors to determine who should be offered treatment with erlotinib or gefitinib (Riely et al., 2008). 121

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The excision repair cross-complementation group 1 (ERCC1) protein is associated with resistance to platinum drugs, including cisplatin, carboplatin, and oxaliplatin (de Laat, Jaspers, & Hoeijmakers, 1999; Martin, Hamilton, & Schilder, 2008; Rabik & Dolan, 2007). ERCC1 is involved in nucleotide excision repair (NER). Platinum compounds exert their effects by causing platinum DNA adducts, which lead to cell death. NER is involved in DNA damage repair (Rabik & Dolan, 2007). ERCC1 recognizes damage to DNA, including damage caused by platinum compounds. ERCC1 levels in tumors can now be reported, and clinical trials have evaluated ERCC1 levels to determine if they are useful as clinical or biologic predictors of benefit from platinum therapy. Olaussen and colleagues (2006) reported on the impact of ERCC1 expression in patients given cisplatin-based adjuvant chemotherapy. All patients had participated in the International Adjuvant Lung Cancer Trial Collaborative Group study (Arriagada et al., 2004). This trial was an adjuvant trial in which patients with resected NSCLC were randomized to treatment with cisplatin-based chemotherapy or observation. Tumor samples were tested for ERCC1 levels (positive or negative) to determine if they could be used to predict which patients would benefit from adjuvant chemotherapy. In patients randomized to chemotherapy, survival was significantly longer in those whose tumors tested negative for ERCC1. In contrast, ERCC1-positive tumors predicted longer survival in those randomized to observation. Other trials have also demonstrated that ERCC1negative tumors predicted better outcome in platinum-based treatment (Li et al., 2009; Lord et al., 2002; Zhou et al., 2004). ERCC1 tumor levels can help predict who will benefit from platinum-based chemotherapy and who can be spared the toxic effects of a treatment that is less likely to be effective. Echinoderm microtubule associated protein-like 4–anaplastic lymphoma receptor tyrosine kinase (EML4-ALK) is a fusion gene. The fusion of the two proteins (EML4 and ALK) is associated with potent oncogenic activity and is a new molecular target in NSCLC (Soda et al., 2007). Shaw and colleagues (2009) reported results on 141 patients whose tumors were screened for EML4-ALK. Patients were selected for screening if they had two of the following clinical characteristics: female gender, Asian, never-smoker or light smoker, or adenocarcinoma. These are the same clinical characteristics that are associated with EGFR mutations. Patients with metastatic disease were given treatment with erlotinib or gefitinib or platinum-based chemotherapy; treatment regimens, outcomes, and response rates were also examined. Nineteen tumors tested positive for the EML4-ALK rearrangement, and 31 tested positive for EGFR mutation (Shaw et al., 2009). Their findings demonstrated that patients whose tumors were likely to harbor this fusion gene were younger with a median age of 52, men, never-smokers or light smokers, and diagnosed with adenocarcinoma. Among patients who had a response to erlotinib or gefitinib, most had EGFR mutations; none had an EML4-ALK rearrangement (Shaw et al., 2009). The results of

this study add to the growing data that support the testing of tumors for biomarkers prior to treatment. ALK inhibitors are now being tested in clinical trials. The most tested agent to date is crizotinib (also known as PF02341066). One such trial reported remarkable results in patients with previously treated NSCLC and tumors that tested positive for EML4-ALK (Kwak et al., 2010). In this trial, 82 patients were evaluable for response, and 41% had three or more prior regimens of chemotherapy. The overall response rate was 57%, and the stable disease rate was 33% (Kwak et al., 2010). These are very exciting results in patients who have had prior treatment for NSCLC. Clinical trials are ongoing with this agent and others.

Performance Status PS has been identified as the most important prognostic factor in patients with NSCLC (Georgoulias et al., 2004; Socinski et al., 2003). The two most common scales used to identify PS were developed by Karnofsky (Karnofsky & Burchenal, 1949) and ECOG (Oken et al., 1982). Several trials have documented the impact of PS on survival. Two of the largest are those by Schiller et al. (2002) and Finkelsteinet al. (1986). The Finkelstein et al. (1986) trial is considered to be the landmark study (Socinski et al., 2003). In this study, which included nearly 900 patients, one-year survival for patients with PS level 0 was 36%, PS level 1 was 16%, and PS level 2 was 9%, a statistically significant difference (ECOG PS level 0 = normal, ECOG PS level 1 = fatigue without significant decrease in activity, ECOG PS level 2 = fatigue with significant impairment of daily activities or bed rest less than 50% of waking hours) (Finkelstein et al., 1986). Other prognostic variables included stage of disease, weight loss, and gender (women lived longer than men).

Summary NSCLC is a deadly disease worldwide and remains a difficult disease to treat. Major advances in the treatment and understanding of this disease have occurred in the past decade that have had an impact on outcomes. As summarized in this chapter, advancements have occurred with diagnostic techniques and all treatment modalities. Perhaps the biggest gains have occurred in our understanding of the disease itself, especially that NSCLC is a heterogeneous disease. Although many patients are benefiting from these advances, many more need to be helped.

References Abratt, R.P., Lee, J.S., Han, J.Y., Tsai, C.M., Boyer, M., Mok, T., … Lehnert, M. (2006). Phase II trial of gemcitabine-carboplatin-

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Strauss, G.M., Herndon, J., Maddaus, M.A., Johnstone, D.W., Johnson, E.A., Watson, D.M., … Green, M.R. (2004). Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non–small cell lung cancer (NSCLC): A report of Cancer and Leukemia Group B (CALGB) protocol 9633 [Abstract]. Journal of Clinical Oncology, 22, 7019. Strauss, G.M., Herndon, J.E., II, Maddaus, M.A., Johnstone, D.W., Johnson, E.A., Harpole, D.H., … Green, M.R. (2008). Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non–small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Group and North Central Cancer Treatment Group Study Groups. Journal of Clinical Oncology, 26, 5043–5051. doi:10.1200/ JCO.2008.16.4855 Thatcher, N., Chang, A., Purvish, P., Pereira, J.R., Ciuleanu, T., von Pawel, J., … Carroll, K. (2005). Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small cell lung cancer: Results from a randomized, placebo-controlled, multicenter study (Iressa Survival Evaluation in Lung Cancer). Lancet, 366, 1527–1537. doi:10.1016/S0140-6736(05)67625-8 Travis, W.D., Brambilla, E., Müeller-Hermelink, H.K., & Harris, C.C. (Eds.). (2004). World Health Organization classification of tumours: Pathology and genetics—Tumors of the lung, pleura, thymus, and heart. Lyon, France: IARC Press. Travis, W.D., Brambilla, E., Noguchi, M., Nicholson, A.G., Geisinger, K.R., Yatabe, Y., … Yankelewitz, D. (2011). International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. Journal of Thoracic Oncology, 6, 244–285. doi:10.1097/JTO.0b013e318206a221 Travis, W.D., Linder, J., & Mackay, B. (2000). Classification, histology, cytology, and electron microscopy. In H.L. Pass, J.B. Mitchell, D.H. Johnson, & A.T. Turrisi (Eds.), Lung cancer: Principles and practice (2nd ed., pp. 453–495). Philadelphia, PA: Lippincott Williams & Wilkins. Tsao, M.S., Aviel-Ronen, S., Ding, K., Lau, D., Liu, N., Sakurada, A., … Shepherd, F.A. (2007). Prognostic and predictive importance of p53 and ras for adjuvant chemotherapy in non small cell lung cancer. Journal of Clinical Oncology, 25, 5240–5247. doi:10.1200/JCO.2007.12.6953 Tsuchiya, R. (2002). Bronchoplastic techniques. In F.G. Pearson, J.D. Cooper, J. Deslauriers, R.J. Ginsberg, C.A. Hiebert, G.A. Patterson, & H.C. Urschel (Eds.), Thoracic surgery (2nd ed., pp. 1005– 1013). New York, NY: Churchill Livingstone. van Zandwijk, N., Mathy, A., Boerrigter, L., Ruijter, H., Tielen, I., de Jong, D., … Nederlof, P. (2007). EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: Retro and prospective observations in non-small cell lung cancer. Annals of Oncology, 18, 99–103. doi:10.1093/annonc/mdl323 Velderman, L., Madani, I., Hulstaert, F., De Meerleer, G., Mareel, M., & De Neve, W. (2008). Evidence behind use of intensity-modulated radiotherapy: A systematic review of comparative clinical studies. Lancet Oncology, 9, 367–375. doi:10.1016/S1470 -2045(08)70098-6 Wang, G., Reed, E., & Li, Q.Q. (2004). Molecular basis of cellular response to cisplatin chemotherapy in non-small cell lung cancer (Review). Oncology Reports, 12, 955–965. Waters, P.F. (2002). Surgical techniques pneumonectomy. In F.G. Pearson, J.D. Cooper, J. Deslauriers, R.J. Ginsberg, C.A. Hiebert, G.A. Patterson, & H.C. Urschel (Eds.), Thoracic surgery (2nd ed., pp. 974–981). New York, NY: Churchill Livingstone. Waxman, E.S. (2008). Advances in chemotherapy for non–small cell lung cancer. Seminars in Oncology Nursing, 24, 49–56. doi:10.1016/j.soncn.2007.11.012

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Winton, T., Livingston, R., Johnson, D., Rigas, J., Johnston, M., Butts, C., … Shepherd, F. (2005). Vinorelbine plus cisplatin vs. observation in resected non–small-cell lung cancer. New England Journal of Medicine, 352, 2589–2597. doi:10.1056/NEJMoa 043623 Wozniak, A.J., & Gadgeel, S.M. (2010). Clinical presentation of non small cell cancer of the lung. In H.L. Pass, D.P. Carbone, J.D. Minna, D.H. Johnson, G.V. Scagliotti, & A.T. Turrisi III (Eds.), Principles and practice of lung cancer (4th ed., pp. 327–340). Philadelphia, PA: Lippincott Williams & Wilkins. Wu, Y.L., Huang, Z.F., Wang, S.Y., Yang, X.N., & Ou, W. (2002). A randomized trial of systematic nodal dissection in resectable non-small cell lung cancer. Lung Cancer, 36, 1–6. doi:10.1016/ S0169-5002(01)00445-7 Yan, T.D., Black, D., Bannon, P.G., & McCaughan, B.C. (2009). Systematic review and meta-analysis of randomized and nonrandomized trials on safety and efficacy of video-assisted thoracic surgery lobectomy for early stage non small cell lung cancer. Journal of Clinical Oncology, 27, 2553–2562. doi:10.1200/ JCO.2008.18.2733 Yim, A.P.C. (2002). Video-assisted pulmonary resections. In F.G. Pearson, J.D. Cooper, J. Deslauriers, R.J. Ginsberg, C.A. Hiebert, G.A. Patterson, & H.C. Urschel (Eds.), Thoracic surgery (2nd ed., pp. 1073–1084). New York, NY: Churchill Livingstone.

Yoshida, K., Yatabe, Y., Park, J.Y., Shimizu, J., Horio, Y., Matsuo, K., … Hida, T. (2007). Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer. Journal of Thoracic Oncology, 2, 22–28. doi:10.1097/01243894 -200701000-00006 Yoshino, I. (2009). Current status and future direction of surgical treatment for non small cell lung cancer [Editorial]. Annals of Thoracic and Cardiovascular Surgery, 1, 1–3. Retrieved from http:// www.atcs.jp/pdf/2009_15_1/1.pdf Zalcman, G., Bergot, E., & Lechapt, E. (2010). Update on nonsmall cell lung cancer. European Respiratory Review, 19, 173– 185. doi:10.1183/09059180.00006610 Zhou, W., Gurubhagavatula, S., Liu, G., Park, S., Neuberg, D.S., Wain, J.C., … Christiani, D.C. (2004). Excision repair cross complementation group 1 polymorphism predicts overall survival in advanced non small cell lung cancer patients treated with platinum based chemotherapy. Clinical Cancer Research, 10, 4939– 4943. doi:10.1158/1078-0432.CCR-04-0247 Zhu, C.Q., de Cunha Santos, G., Ding, K., Sakurada, A., Cutz, J.C., Liu, N., … Tsao, M.-S. (2008). Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study, BR.21. Journal of Clinical Oncology, 26, 4268–4275. doi:10.1200/JCO.2007.14.8924

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C H A P T E R 10

Symptom Management Margaret Joyce, PhD, RN, AOCN®, APRN-BC, and Jayne M. Camporeale, MS, OCN®, ANP

Introduction

Cough

Managing the symptoms of the person with cancer is key to an overall positive outcome and maintenance of a satisfactory quality of life (QOL). Since the late 1980s, much research has gone into the development of supportive measures for the management of disease- and treatmentrelated symptoms. Oncology nurses have partnered with their colleagues in the search for evidence to better manage patient care. The result is a growing body of standards and guidelines for the supportive care of people with cancer. Comprehensive symptom management is critical for those with lung cancer. People with lung cancer experience more symptom distress than patients with other types of cancer (Cooley, 2000). Although therapy may diminish or relieve disease-related symptoms, treatment-related side effects or symptoms may result. The National Comprehensive Cancer Network (NCCN) clinical practice guidelines endorse that palliative care aimed to control symptoms be delivered concurrently with curative or life-prolonging therapies or as the main focus of care (NCCN, 2011e). This is the ideal symptom management approach in the care of patients with lung cancer. This chapter reviews and presents current evidence for appropriate interventions for the common physical symptoms in lung cancer, such as cough, hemoptysis, dyspnea, fatigue, and pain. Because thoracic radiation is a common treatment modality for those with lung cancer, specif ic thoracic radiation–induced side effects of pneumonitis, pharyngitis, and esophagitis also are presented. Chemotherapy-induced side effects common in many cancer populations are not included, as those symptoms are not unique to lung cancer therapy.

Persistent cough can be a most distressing symptom and detractor from QOL in people with lung cancer. Cough is the most common presenting symptom in lung cancer with a frequency ranging from 8%–75% (Beckles, Spiro, Colice, & Rudd, 2003). For people who are current or previous smokers, the new onset of cough, a change in the character of a preexisting cough, or the presence of hemoptysis should prompt consideration of cancer as the cause of the cough (Kvale, 2006). Chronic cough is defined as a cough that lasts longer than three weeks (Chung & Widdicombe, 2005). Under normal conditions, cough is a protective mechanism that allows people to clear secretions and inhaled particles from the airways; however, cough as the result of a disease process may become excessive and nonproductive with potentially harmful consequences (Canning, 2006). Complications of cough include musculoskeletal pain, rib fractures, hemoptysis, fatigue, and insomnia. The cough reflex consists of three phases. The first phase (inspiratory) occurs with deep inspiration. This is followed by closure of the glottis with a rapid increase in intrathoracic pressure, marking the second phase of the reflex. The final expiratory or explosive phase involves the opening of the glottis with a rapid release of pressure and expulsion of air or air and debris (Chung & Widdicombe, 2005). The high intrathoracic and intra-abdominal pressures generated by the cough mechanism underlie some of the adverse cardiovascular, gastrointestinal, genitourinary, neurologic, and musculoskeletal complications associated with cough (McCool, 2006). The cough reflex is initiated by stimulation of neural mucosal receptors located within the nasopharynx, larynx,

The authors would like to acknowledge Nancy G. Houlihan, RN, MA, AOCN®, Dana Inzeo, RN, MA, AOCN®, and Leslie B. Tyson, MS, ANP-C, OCN®, for their contributions to this chapter that remain unchanged from the first edition of this book.

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trachea, and bronchial tree (Tyson, 2006). The neural mucosal receptors are stimulated by mechanical or chemical irritants, resulting in transmission of impulses via cranial nerves IX and X to the cough center in the medulla. Once the cough center is stimulated, cough occurs from the forceful contraction of the diaphragm and other expiratory muscles in the chest (Tyson, 2006). Cough from lung cancer is more likely to occur in patients with tumors of the central airways, such as squamous cell carcinoma and small cell lung cancer. Tumors in the central airways can cause obstruction, either from intraluminal tumor growth or extraluminal compression of the airways, and this almost always leads to dyspnea and cough (Kvale, 2006). Adenocarcinoma usually presents as a peripheral lesion and therefore is less often associated with cough; however, tumor involvement of any part of the respiratory tract can cause cough. Other causes of cough in patients with lung cancer include recent upper respiratory tract infection, pleural or pericardial effusion, radiation pneumonitis, vocal cord paralysis, and aspiration. Causes of cough that are not related to cancer include rhinosinusitis (postnasal drip syndrome), asthma, gastroesophageal reflux disease (GERD), chronic bronchitis, exacerbation of chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), and medication, such as angiotensin-converting enzyme (ACE) inhibitors (Chung & Widdicombe, 2005; Pratter, 2006). Cough may be dry or associated with production of sputum. To treat cough adequately, the cause must be determined. A thorough history and physical examination will help to determine the cause. The cough history should include onset, duration, and precipitating factors; presence or absence of sputum production and the color and odor (if any) of sputum; and current medications. The history should include the presence or absence of any other illnesses or conditions that can cause cough (e.g., asthma, GERD), occupational or environmental exposure to irritants, and smoking history. Physical examination focuses primarily on the upper and lower respiratory tract. The oropharynx may reveal the presence of mucus, erythema, or a “cobblestone” appearance of the mucosa, which suggests postnasal drip (Chung & Widdicombe, 2005). Examination of the chest and lungs may reveal signs of pleural or pericardial effusion, pneumonia, or airway obstruction. When auscultating the lungs, listen for wheezing or other adventitious sounds and the presence or absence of breath sounds. The presence of stridor on inspiration suggests airway obstruction. Percussion of the chest may reveal areas of dullness, which can be associated with pneumonia or pleural effusion. Jugular venous distension, wet crackles at lung bases, and an S3 gallop suggest CHF. Observation of the respiratory rate, presence or absence of peripheral edema, and vital signs including temperature also is important. Diagnostic tests include evaluation of sputum, if present; radiologic tests, such as chest x-ray or computed tomography (CT); pulmonary function testing; and bronchoscopy.

As noted earlier, treatment of cough consists of treating the underlying cause. Treatment of postnasal drip includes antihistamines and intranasal steroids. A topical anticholinergic spray to the nose, such as ipratropium bromide to dry secretions may provide additional benefit (Chung & Widdicombe, 2005). Cough from postnasal drip should subside within days to weeks with the above treatment. Cough from GERD may respond to change in lifestyle and addition of H2-histamine receptor antagonists or proton pump inhibitors. Bronchodilators and corticosteroids may be helpful in the management of cough from COPD. If infection is suspected, a course of antibiotics is indicated. Cough from ACE inhibitors usually occurs within the first few weeks of treatment and resolves with discontinuation of the drug. If cough is caused by central airway obstruction from tumor, bronchoscopic therapies using a rigid bronchoscope or application of radiation brachytherapy may provide relief. The rigid bronchoscope can be used to examine the airways, place a stent to open an obstructed airway, and facilitate laser resection of an obstructing tumor (Kvale, 2006). These procedures usually are considered palliative for patients with lung cancer and may not entirely relieve cough. Cough from pleural effusion may be relieved by thoracentesis; however, pleural fluid often reaccumulates unless pleurodesis is performed. Intermittent drainage of pleural fluid through an indwelling pleural catheter is one approach for recurrent malignant effusions. Pharmacotherapy to promote comfort is the mainstay of treatment for people with cough from advanced bronchogenic carcinoma. When cough caused by tumor obstructing the trachea or main airway is the presenting symptom of lung cancer, treatment with chemotherapy or radiotherapy may lead to reduction in tumor and, therefore, reduction in cough. In these patients, return of cough often signals progression of disease. Pharmacologic management includes the use of nonopioid and opioid cough suppressants (see Table 101), bronchodilators, and corticosteroids. A commonly used nonopioid antitussive agent is dextromethorphan; it is available over the counter and comes in pill or liquid form. It often is available in combination with guaifenesin (e.g., Humibid DM®, Robitussin®), which is used as both an expectorant and antitussive. These agents are often of little value in patients with cough from advanced cancer. Benzonatate (Tessalon Perles®) has been shown to be helpful for some (Doona & Walsh, 1998). Benzonatate is a peripherally acting drug that is available by prescription. The recommended dose is 100–200 mg three times a day (Tyson, 2006). In patients in whom bronchospasm plays a role in cough, bronchodilator therapy using inhaled ipratropium (Atrovent®) has been shown to be helpful. To date, no studies have documented the role of corticosteroids in the management of cough from cancer. However, if cough is related to effects of radiation therapy (e.g., radiation pneumonitis), corticosteroids may be helpful (Kvale, Selecky, & Prakash, 2007). 132

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illness, and approximately 3% will die of massive hemoptysis (Kvale, Simoff, & Prakash, 2003). The severity of hemoptysis is determined by the amount of blood that is expectorated. Mild hemoptysis is less than 20 ml of blood in 24 hours (often described as blood-streaked sputum) and moderate hemoptysis is 20–60 ml in 24 hours (Camp-Sorrell, 2006). Patients who expectorate 100–600 ml of blood in 24 hours are considered to have massive hemoptysis (Kvale et al., 2003). Hemoptysis can be one of the most frightening and distressing symptoms associated with lung cancer. The lungs have a dual blood supply. The pulmonary circulation, a low-pressure system that supplies 95% of the blood to the lungs, contains both arteries and veins that supply mixed venous blood draining from all body tissues (Beers & Porter, 2006). This blood undergoes gas exchange and serves the function of oxygenation and elimination of carbon dioxide from the body (Levitzky, 2007). The other blood supply to the lungs is the bronchial system, a high-pressure system supplying 5% of the blood (mostly to the airways) and originating from the aorta (Beers & Porter, 2006). Blood in the respiratory tract can originate from either circulation system (i.e., bronchial arteries, pulmonary arteries, bronchial capillaries, or alveolar capillaries) (Camp-Sorrell, 2006). Although bleeding can occur at any level in either circulation system, hemoptysis most often occurs from the bronchial system (Beers & Porter, 2006). Hemoptysis has multiple noncancerous causes, including infection (e.g., pneumonia, lung abscess, tuberculosis), inflammation (e.g., bronchitis, bronchiectasis), pulmonary vascular disorders (e.g., pulmonary embolism, arteriovenous malformation, left ventricular dysfunction), and other causes such as coagulopathy, anticoagulant therapy, and foreign body (Wiese & Kvale, 2004). In patients with lung cancer, hemoptysis can occur as a result of tumor erosion of a blood vessel. A retrospective analysis at a tertiary referral hospital documented the diagnosis and severity of hemoptysis in 208 patients. Lung cancer was the cause of hemoptysis in 39 of the 208 patients evaluated. The most common primary lung cancer associated with hemoptysis in this review was small cell lung cancer (Hirshberg, Biran, Glazer, & Kramer, 1997). Squamous-type carcinoma was associated with pulmonary hemorrhage in six patients in a randomized cohort that received paclitaxel, carboplatin, and bevacizumab in a phase II study. Subsequently, patients with squamous cell lung tumors were excluded from the paclitaxel, carboplatin, and bevacizumab phase III study (Sandler et al., 2006). Current prescribing indication for bevacizumab in combination with carboplatin and paclitaxel chemotherapy is only in nonsquamous nonsmall cell lung cancer. The Avastin® (bevacizumab) package insert includes a boxed warning that severe or fatal hemorrhage including hemoptysis occurred up to fivefold more frequently in patients with squamous tumors who receive bevacizumab; thus, assessment for hemoptysis in patients receiving bevacizumab is an important clinical evaluation (Genentech, 2011).

Table 10-1. Examples of Oral Antitussives Drug

Dosage (Adults 12 Years and Older)

Codeine

10–20 mg PO every four to six hours (120 mg/24 hours); available in elixir

Dextromethorphan

10–20 mg PO every four to eight hours or 30 mg every eight hours (120 mg/24 hours); lozenges or elixir

Benzonatate

100 mg PO TID; do not chew

Guaifenesin

5–20 ml PO every four hours or tablets

Hydrocodone

5 ml PO every four to six hours

PO—per os (orally); TID—three times a day Note. From “Cough” (p. 151), by L.B. Tyson in D. Camp-Sorrell and R.A. Hawkins (Eds.), Clinical Manual for the Oncology Advanced Practice Nurse (2nd ed.), 2006, Pittsburgh, PA: Oncology Nursing Society. Copyright 2006 by the Oncology Nursing Society. Reprinted with permission.

Opioids currently are the best available treatment for intractable cough from lung cancer. The American College of Chest Physicians (ACCP) guidelines recommend the use of opioids in the management of chronic cough due to lung tumors (Kvale et al., 2007). The most commonly used opioid is codeine; it is a centrally acting agent. Codeine is available in both tablet and liquid form. Low doses (10–20 mg every four to six hours) are often sufficient for cough suppression (Tyson, 2006). Hydrocodone is available in tablet or liquid form and is a good alternative to codeine or in patients who cannot tolerate codeine. The lowest effective dose of opioids should be used, and caution is recommended with use of increasing doses, as respiratory depression and hypoventilation can occur. Constipation should be anticipated as an opioid-induced side effect that requires proactive prevention therapy. Pulmonary rehabilitation measures such as deep breathing exercises, effective coughing techniques, and pulmonary toilet with postural drainage can be taught and may relieve cough. Patients who smoke cigarettes should be advised regarding smoking cessation and available quit therapies. Air humidifiers may be helpful in the management of cough in a dry environment. Warm, humidified air decreases the viscosity of secretions, which also can be helpful for cough.

Hemoptysis Hemoptysis is the expectoration of blood that results from bleeding in the lower respiratory tract. The blood may or may not be mixed with sputum. Hemoptysis is the initial presenting symptom in an estimated 7%–10% of patients with lung cancer. Approximately 20% of patients with lung cancer experience it at some point during the course of the 133

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Hemoptysis usually is easily distinguished from hema­ temesis, bleeding from the stomach characterized by a darker, lower pH blood that may contain partially digested food (Camp-Sorrell, 2006; Lipchik, 2007). However, a key but difficult diagnostic task is distinguishing true hemoptysis from bleeding from the nasopharynx, larynx, or esophagus. This necessitates a careful history and a thorough endoscopic examination of the upper airway and upper gastrointestinal tract (Lipchik, 2007). The history should include the amount and color of the blood; the duration of the bleeding; the presence of clots; the relationship of bleeding to rest or activity; the presence of chest pain, cough, or dyspnea; prior history of heart and lung diseases; and history of cigarette smoking. Additionally, a careful medication history should be ascertained, as aspirin, nonsteroidal anti-inflammatory drugs, and anticoagulant medications all can cause bleeding. Diagnostic tests include laboratory examinations, chest x-ray, CT scan, and bronchoscopy. Laboratory tests should include a complete blood count to determine if anemia is present and to evaluate for thrombocytopenia. Coagulation tests include prothrombin time and partial thromboplastin time. Oxygenation should be measured. Chest x-ray may reveal pulmonary infiltrates, a cavitary lesion, or atelectasis, or it may be inconclusive. A CT scan or perfusion scan may reveal a source of bleeding, such as a pulmonary embolus or air bronchogram. Air bronchogram is a term to describe a condition in which the outline of an airway is made visible by changes in the surrounding tissue such as inflammatory edema. Air bronchograms suggest obstruction, bronchiectasis, and chronic bronchitis, all potential causes of hemoptysis. The most useful examination in patients who have hemoptysis is bronchoscopy. Bronchoscopy can reveal the source of bleeding and provide the physician with a means of intervention at the time of the procedure. Flexible fiberoptic bronchoscopy, which is an accessible bedside procedure, may be attempted first, but the rigid bronchoscope has an advantage, as the lumen is wide enough for suctioning of blood and debris, ventilation of the nonbleeding lung, and use of endoscopic procedures to control bleeding (Lipchik, 2007). Treatment of hemoptysis depends on the cause of bleeding and the severity or amount of expectorated blood. For most patients, hemoptysis stops spontaneously. In those with recurrent hemoptysis or those who expectorate larger amounts of blood, bronchoscopy usually is needed to identify and treat the site of bleeding. Multiple methods of local control to stop bleeding from endobronchial lesions are available, and all require an endoscopic procedure. Bronchial lavage with iced saline solution, bronchial instillation of topical epinephrine solution, or topical thrombin and fibrinogenthrombin solutions may be employed. Endotracheal insertion of a balloon to tamponade the bleeding site is a temporizing technique to control hemoptysis (Kvale et al., 2003; Lipchik, 2007).

Other management options for hemoptysis include electrocautery, argon plasma coagulation (APC), and neodymium-yttrium-aluminum-garnet (Nd:YAG) laser photocoagulation (Kvale et al., 2003, Lipchik, 2007). Electrocautery uses alternating electrical current to coagulate and vaporize bleeding endobronchial lesions (Lipchik, 2007). Disadvantages of electrocautery include thermal injury beyond the bleeding site. APC is a newer electrocautery modality that uses a catheter to introduce the current to tissue without need for direct contact. Nd:YAG laser is an older type of noncontact electrocautery, which has been shown to be helpful in controlling bleeding with a 60% response rate but requires specialized, expensive equipment (Kvale et al., 2003; Lipchik, 2007). Each procedure has its advantages and disadvantages. Bronchial artery embolization may also temporize the bleeding. This requires angiographic identification of the bleeding vessels and the injection of an agent (Gelfoam®, polyvinyl alcohol particles, and metallic coils) to selectively stop the blood flow (Lipchik, 2007). Photodynamic therapy (PDT) is another modality used in the palliative management of hemoptysis (Birn & Kosco, n.d.). PDT requires endoscopy; it uses lasers to activate light-sensitive pharmaceuticals to treat the lesion. PDT requires IV administration of Photofrin®, a photosensitive antineoplastic agent, 40–50 hours before the endoscopic procedure. A nonthermal laser light is used to activate the pharmaceutical agent. Approximately 24–72 hours later, another bronchoscopy is required to remove necrotic debris and perform another treatment if needed. The primary adverse effect of PDT is photosensitivity; sun exposure may cause potential skin and ocular damage (Lipchik, 2007). If an endobronchial lesion is visible and is determined not to be resectable or amenable to one of the aforementioned treatments, a course of external beam radiation therapy can be recommended (Kvale et al., 2003). In the palliative setting, therapy is delivered in the shortest time possible, with lower doses to achieve symptom control while minimizing side effects (Lipchik, 2007). Endobronchial brachytherapy is another alternative; although, paradoxically, brachytherapy for some tumor locations is associated with a risk of hemoptysis (Lipchik, 2007). Observation or conservative symptom management is preferred in patients with small amounts of hemoptysis (less than 20 ml/day) (Camp-Sorrell, 2006). Because infection is one cause of hemoptysis, a course of oral antibiotics should be considered (Camp-Sorrell, 2006). Additionally, cough suppression with an opioid (codeine) given around the clock will help to minimize irritation. For many patients, hemoptysis can be managed successfully with the aforementioned regimen on an outpatient basis. Although massive hemoptysis is rare, death from massive hemoptysis is estimated at 85% when it occurs (Lipchik, 2007). Surgical management usually is not an option because the majority of patients have advanced disease. Intervention, 134

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if undertaken, usually begins with endotracheal intubation to maintain an adequate airway and measures to prevent asphyxiation. Other emergency and supportive care measures are used, as well. Hospitalization is recommended; the patient should be placed in a lateral decubitus position with the bleeding side down and in the Trendelenburg position to prevent aspiration of blood into the opposite lung (Lipchik, 2007). Blood transfusions, oxygen supplementation, and antitussive agents may be used as needed. Placing dark red or maroon-colored towels near the nose or mouth to absorb blood oozing from either orifice is a homecare maneuver to decrease distress that would arise for family or visitors from seeing blood against white or light-colored sheets or bed linens. Overall, the prognosis is poor in patients with bronchogenic carcinoma and massive hemoptysis and, as noted, the majority do not survive.

In a survey of 120 outpatients with stages I–IV lung cancer, Smith and colleagues (2001) reported that 87% of study participants experienced dyspnea and patients with high dyspnea scores had lower QOL scores (p = 0.04). Dudgeon and associates (2001) evaluated 923 patients with cancer in the outpatient setting to assess dyspnea intensity and found that 46% of the patients had some shortness of breath. Only 4% of this study’s participants had a diagnosis of lung cancer, and, for that subgroup, 84% reported dyspnea. Muers and Round (1993) evaluated the presence and severity of dyspnea and other symptoms in a study of 289 patients with non-small cell lung cancer. Cough and breathlessness were the two most prevalent symptoms. Breathlessness of any grade was present in 216 patients (75%) distributed as severe breathlessness (8%), moderate breathlessness (33%), and mild breathlessness (34%) (Muers & Round, 1993). Furthermore, in a study of 157 outpatients with advanced lung cancer, Tanaka and colleagues (2002b) found that 55% of subjects reported “clinical dyspnea,” defined as dyspnea interfering with at least one of the following seven categories: work, walking, general activities, and sleep (which compose the physical domain), and mood, relationships, and enjoyment (which compose the psychological domain). Dyspnea interfered not only with the physical domain (52%) but also with the psychological domain (23%) (Tanaka et al., 2002b). Although this review is not exhaustive, it indicated that dyspnea is a prevalent symptom in patients with lung cancer and that it interferes with QOL and has an impact on both functional and emotional status.

Dyspnea Definition The term dyspnea generally is applied to the sensations that individuals with unpleasant or uncomfortable respiration experience. The American Thoracic Society (ATS, 1999), in a comprehensive consensus statement, defined dyspnea as a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity. The symptom derives from interactions among multiple physiologic, psychological, social, and environmental factors and may induce secondary physiologic and behavioral responses. This def inition stresses the subjective and multifactorial nature of the dyspnea experience.

Pathophysiology of Dyspnea A unifying theory is that dyspnea results from a disassociation or a mismatch between central respiratory motor activity and incoming information from receptors in the airways, lungs, and chest wall structures. In other words, a mismatch occurs between the motor command and the mechanical response, which produces a sensation of respiratory discomfort (ATS, 1999). ATS (1999) classified physiologic causes of dyspnea and alternative targets for treatment as • Heightened ventilatory demand, as demonstrated when the intensity of dyspnea increases with exertion or exercise. • Increased impedance or resistance to ventilation, as noted when the respiratory effort expended is out of proportion to the resulting level of ventilation. Asthma and COPD can narrow airways, thereby increasing resistance to ventilation. • Abnormalities of the respiratory muscles such as weakness or mechanical inefficiency. The pressure-generating capacity of the muscles is decreased, creating a disparity between the central respiratory drive and achieved ventilation. Malnutrition from cancer cachexia reduces both respiratory muscle strength and maximal voluntary ventilation. • Abnormal central perception of dyspnea caused from increased respiratory drive, as seen with blood gas abnormalities of hypoxia or hypercapnia.

Prevalence Dyspnea is a complex and distressing symptom. It can be a difficult clinical problem to manage. Dyspnea is aligned closely with a primal fear of death by suffocation, and, hence, it evokes a response that begs intervention from patients, caregivers, and health professionals. Ripamonti and Fusco (2002) reported that the prevalence of dyspnea in an advanced cancer population increases from 15%–55.5% at referral to palliative care service to 18%–79% during the last week of life. Although dyspnea is a frequent symptom in patients without demonstrable tumor in the lung, it is more common among patients with primary lung cancer or pulmonary metastases than among the general cancer population. The prevalence of dyspnea in patients diagnosed with lung cancer ranges from 55%–87% (Dudgeon, Kristjanson, Sloan, Lertzman, & Clement, 2001; Muers & Round, 1993; Smith et al., 2001; Tanaka, Akechi, Okuyama, Nishiwaki, & Uchitomi, 2002b). 135

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Similar to pain, dyspnea has an affective component. The stimulus intensity of “just noticeable difference” for shortness of breath may be the same among patients with similar lung pathology; however, the affective component can vary greatly and actually modulate the intensity of the symptom (CarrieriKohlman, Gormley, Douglas, Paul, & Stulbarg, 1996). Hence, the threshold perception of dyspnea varies widely with individuals and is related only moderately to the degree of pulmonary dysfunction. Frequently, a discrepancy is found between severity of disease and intensity of breathing discomfort (ATS, 1999). Cognitive variables that have been shown to modify dyspnea include anxiety, depression (Dudley, Martin, & Holmes, 1964; Gift, 1991; Smith et al., 2001), personality (Chetta et al., 1998), and the meaning of the symptom for the person (Cioffi, 1991).

Figure 10-1. Causes of Dyspnea in Patients With Cancer Dyspnea Directly Due to Cancer • Pulmonary parenchymal involvement (primary or metastatic) • Lymphangitic carcinomatosis • Intrinsic or extrinsic airway obstruction by tumor • Pleural tumor • Pleural effusion • Pericardial effusion • Ascites • Hepatomegaly • Phrenic nerve paralysis • Multiple tumor microemboli • Pulmonary leukostasis • Superior vena cava syndrome Dyspnea Indirectly Due to Cancer • Cachexia • Electrolyte abnormalities • Anemia • Pneumonia • Pulmonary aspiration • Pulmonary emboli • Neurologic paraneoplastic syndromes

Etiology of Dyspnea Dyspnea in lung cancer frequently has multiple etiologies. Possible causes of dyspnea in the general cancer population are listed in Figure 10-1. In addition to the effect of the primary lung tumor, a combination of other factors commonly contributes to dyspnea, depending on stage of disease. These include pleural effusion, anemia, cachexia, and underlying COPD. Many factors can converge to cause and contribute to the symptom of dyspnea.

Dyspnea Due to Cancer Treatment • Surgery • Radiation pneumonitis/fibrosis • Chemotherapy-induced pulmonary disease • Chemotherapy-induced cardiomyopathy • Radiation-induced pericardial disease

Assessment

Dyspnea Unrelated to Cancer • Chronic obstructive pulmonary disease • Asthma • Congestive heart failure • Interstitial lung disease • Pneumothorax • Anxiety • Chest wall deformity • Obesity • Neuromuscular disorders • Pulmonary vascular disease

Assessment of dyspnea is a nursing challenge, not only because of its multiple causes but also because of its subjective nature. One of the main problems is the variable intensity of dyspnea according to activity level and time of the day (Bruera & Ripamonti, 1998). Any assessment of dyspnea should attempt to differentiate the intensity or quality of the sensation and the emotional or behavioral response to the discomfort. Several standardized assessment tools and their psychometric properties exist to measure dyspnea. A description of tools that measure dyspnea can be accessed from Tables of Tools to Measure Oncology Nursing-Sensitive Patient Outcomes: Dyspnea (Joyce & Beck, 2005). Two useful tools that exist to measure dyspnea in the clinical setting are the visual analog scale and the numeric rating scale. A simple visual analog scale, which consists of a 100 mm line with anchors at each end to indicate the extremes of “not breathless at all” to “very breathless,” can be used. Scoring is accomplished by measuring the distance from the bottom of the scale (or left, if horizontally oriented) to the level indicated by the patient. A numeric rating scale for dyspnea asks patients to indicate on a scale from 0 (no shortness of breath) to 10 (worst possible shortness of breath) how much shortness of breath they currently are having or alternatively “during the past week” or “on average over the past few days.” The temporal aspect of the question for both the visual analog scale and numeric rating scale depends on the assessment parameter or the information needed to assess the dyspnea problem.

Note. From “Dyspnea in Cancer Patients: Prevalence and Associated Factors,” by D.J. Dudgeon, L. Kristjanson, J.A. Sloan, M. Lertzman, and K. Clement, 2001, Journal of Pain and Symptom Management, 21, p. 100. Copyright 2001 by Elsevier. Reprinted with permission.

The most common method to assess dyspnea in the clinical setting is self-report of the level of activity at which the patient has difficulty breathing. Common activities associated with dyspnea are climbing stairs or walking uphill, walking fast on level ground, and shortness of breath brought on by dressing or talking. Shortness of breath at rest or with no activity is most dire. One potential limitation of this assessment is that because the intensity of dyspnea depends on ambulation, mobility, or work performance, patients may reduce the exertion or rate of work performance and thereby minimize the reported intensity of the symptom. For example, a person may report 136

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the ability to climb a flight of stairs without reporting the need for frequent rest stops to reduce symptoms. An evaluation of dyspnea includes a complete history of the symptom, its temporal onset (acute or chronic), descriptors, precipitating and relieving events or activities, associated symptoms, and response to medication or behavioral changes (Ripamonti & Fusco, 2002). A dyspnea-focused physical examination includes complete vital signs (blood pressure, pulse, respiratory rate, and temperature) and observation of respiratory mechanics, such as pursed-lip breathing or the use of accessory muscles. Notice the presence of pallor (relative absence of oxyhemoglobin with its characteristic red color) or cyanosis at the fingertips, lips, and oral mucosa. Clubbing of the fingers and toes can be seen in patients with chronic hypoxia. Cardiac assessment includes auscultation of heart sounds, palpation of the central pulses, and observation of jugular venous distension. Lung auscultation is performed to evaluate for absent breath sounds or the presence of rales, rhonchi, wheezes, or a rub. Lung field percussion is performed to locate areas of dullness. Respiratory excursion and fremitus are assessed. Mental status signs of hypoxia include restlessness, anxiety, disorientation, and confusion (Myers & McGowan, 2006). Pertinent basic diagnostic testing includes pulse oximetry at rest and with activity, complete blood count, and chemistry panel. A chest radiograph may be indicated to evaluate for infiltrates, effusions, and pneumothorax as well as heart size and position. Pulmonary function tests that measure lung volumes and gas diffusion may be helpful to diagnose a reversible airway obstruction or hypoxemia, which can be improved with therapy. A ventilation-perfusion scan can be obtained if pulmonary embolus is suspected. The choice of appropriate diagnostic tests should be guided by the stage of disease, usefulness of the resultant information for therapeutic intervention, and the patient’s wishes. Considering the complex multidimensional nature of dyspnea, differentiating an acute and possibly reversible cause of dyspnea is important. Although dyspnea usually is a progressive complication of the lung cancer trajectory, some patients present with a sudden onset or acute exacerbation of shortness of breath. This could be considered a medical emergency depending on the presenting context and broad differential diagnosis possibilities.

palliative therapy to treat irreversible causes. The following therapy options are organized according to categorical causes of dyspnea: lung tumor, cancer therapy, indirect consequence of cancer diagnosis, and nonspecific palliative measures. Dyspnea Caused by Tumor If the lung tumor itself is causing shortness of breath, appropriate treatment with surgery, radiation, or chemotherapy will reduce symptoms. Even a minor response to oncologic therapy can improve dyspnea. Airway obstruction can be relieved with a tracheobronchial stent or laser ablation, or it can be palliated with either external beam radiotherapy or brachytherapy (Dudgeon, 2002). Malignant pleural effusions can compromise respiration in some circumstances. Thoracentesis aimed at removing pleural fluid is beneficial in relieving dyspnea if the lung reexpands. In most instances, the pleural fluid reaccumulates shortly after thoracentesis. If relief is obtained with initial removal of fluid, pleural drainage with a chest tube and instillation of a sclerosing agent, such as talc, can be an effective method to prevent reaccumulation of pleural fluid and associated shortness of breath. Alternatively, intermittent pleural fluid drainage is possible with the insertion of an indwelling pleural catheter (PleurX®) with a valve mechanism designed to prevent the reintroduction of air or fluid into the pleural space (CareFusion, 2011). With a catheter in place, pleural effusions can be drained by trained family members or caregivers. Lack of a caregiver or the funds to cover the cost of custom drainage kits (if not reimbursed by medical insurance) are potential barriers to this intervention (Brubacher & Gobel, 2003). Dyspnea Caused by Therapy Certain chemotherapy agents or chest radiation can cause either acute or chronic pneumonitis. Corticosteroids, usually prednisone, starting at 60–100 mg daily and tapered over days to weeks, are the mainstay of treatment for pneumonitis (Dudgeon, 2002). Occasionally, supportive oxygen and bronchodilators are required (Dudgeon, 2002). Certain chemotherapeutic agents, such as doxorubicin, can cause cardiomyopathy with a risk of CHF and shortness of breath. Conventional therapy for CHF and possibly a cardiology consultation are indicated.

Treatment of Dyspnea

Dyspnea as an Indirect Consequence of Cancer Many complications of chronic illness can occur that cause or contribute to dyspnea. Some common situations encountered in lung cancer are pneumonia and anemia. Pneumonia can be treated with adequate antibiotic therapy, which can lead to relief of dyspnea. If appropriate to the patient’s condition, anemia can be resolved with red cell transfusions or erythropoietin therapy. Short- and longterm benefits can be realized with improved function and comfort. Malnutrition, mineral and electrolyte deficiencies,

The therapeutic goals in treating dyspnea are to promote patient comfort, increase exercise tolerance, and promote physical and social well-being (Carrieri-Kohlman & JansonBjerklie, 1986). Modest alterations in a number of physiologic and psychological variables, as a result of a particular treatment, can culminate in a clinically meaningful reduction in symptoms (ATS, 1999). The optimal treatment of dyspnea is to treat reversible causes with specific therapies and to use nonspecific or 137

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and overall deconditioning also can contribute to dyspnea. Again, depending on the patient’s status, attempts to correct these circumstances may improve dyspnea control.

analyzed 18 double-blind, randomized, placebo-controlled trials of opioids for treatment of dyspnea secondary to any cause. Nine studies involved the use of oral or parenteral opioids, and nine involved nebulized opioids. This systematic review showed a statistically significant positive effect of oral and parenteral opioids on the sensation of breathlessness (p = 0.0008) (Jennings et al., 2002). The intermittent use of opioids (most frequently morphine) is recommended in a population of patients who already are receiving opioids chronically. The optimal dose has not been determined. Allard, Lamontagne, Bernard, and Tremblay (1999) evaluated 25% and 50% of a four-hourly opioid dose and found them equivalent in relieving dyspnea. Dyspnea reduction was relatively greater in patients with initially low and moderate dyspnea intensity. Allard’s group concluded that 25% of the four-hourly dose of an opioid may be sufficient to reduce dyspnea. The use of sustainedreleased morphine and slow-release morphine has not shown benefit compared to placebo in reducing breathlessness (Dudgeon, 2002; Ripamonti & Fusco, 2002). The addition of midazolam, a benzodiazepine, to morphine showed superior relief of breathlessness in one study that randomized patients to receive either morphine or midazolam subcutaneously around the clock with the alternate drug for breakthrough dyspnea in a population of patients with advanced cancer during the last week of life (Navigante, Cerchietti, Castro, Lutteral, & Cabalar, 2006). Although promising, further studies are needed to confirm the effectiveness of this intervention. Although the use of nebulized opioids to reduce dyspnea may be tempting because of local action on pulmonary receptors, a meta-analysis failed to show a positive effect of nebulized opioids on the sensation of breathlessness (Jennings et al., 2002). A synthesis of evidence about the use of nebulized opioids to treat dyspnea concluded that although scientific evidence is lacking to support the use, lower-level evidence notes a positive effect in individual clinical settings in patients such as those receiving systemic opioids or experiencing dyspnea at rest (Joyce, McSweeney, Carrieri-Kohlman, & Hawkins, 2004). Anxiolytics have the potential to relieve dyspnea by depressing hypoxic or hypercapnic respiratory responses as well as by altering the emotional response (ATS, 1999). However, clinical trials to determine the effectiveness of anxiolytics for the treatment of breathlessness have had conflicting results. In some patients, a trial of a benzodiazepine may be reasonable, particularly in those with morbid anxiety or respiratory panic attacks (ATS, 1999), but no evidence supports the routine use of long-term benzodiazepines to manage dyspnea (Bruera & Currow, 2009). Because cigarette smoking and secondhand cigarette smoke cause 85%–90% of lung cancer cases (NCCN, 2011d), a proportion of people with lung cancer may have untreated obstructive airway disease. These patients may benefit from

Nonspecific Treatments of Dyspnea Symptomatic management of dyspnea is based on three main elements: oxygen therapy, pharmacologic therapy, and general supportive measures and education. Usually a combination of these interventions is employed. Oxygen Therapy Patients who are hypoxemic on room air are quite likely to benefit from oxygen therapy (Bruera, deStoutz, VelascoLeiva, Schoeller, & Hanson, 1993). Most authorities currently recommend oxygen for patients with hypoxic dyspnea, even in the face of increasing hypercapnia, to achieve and maintain oxygen saturation greater than 88% (Dudgeon, 2002). However, the usefulness of palliative oxygen for management of patients with cancer who have nonhypoxic dyspnea is inconclusive. Palliative oxygen is the use of oxygen to relieve the sensation of dyspnea, not necessarily to correct hypoxemia. Studies did not demonstrate a significant difference in dyspnea scores between air and oxygen, and on average, patients improved symptomatically with both (Booth, Kelly, Cox, Adams, & Guz, 1996; Bruera et al., 2003; Phillip et al., 2006; Uronis, Currow, McCrory, Samsa, & Abernethy, 2008). Evidence indicates that oxygen does have beneficial effects in COPD and probably CHF, but patients with dyspnea from cancer most frequently have restrictive pulmonary failure and might not respond in the same way (Dalal, Palat, & Bruera, 2007). Airflow over the face and nasal mucosa during oxygen administration may itself ameliorate dyspnea through poorly understood mechanisms involving modulation of afferent information from cutaneous nerves (Dudgeon, 2002). In a similar way, the movement of cool air with a fan has been observed clinically to reduce dyspnea. This is a low-cost, low-risk intervention often initiated by patients asking to sit near a fan or open window. Stimulation of mechanoreceptors on the face or a decrease in temperature of the facial skin, both mediated through the trigeminal nerve, may alter afferent feedback to the brain and modify the perception of dyspnea (ATS, 1999). Pharmacologic Therapy Opioids have been explored as a means to relieve dyspnea presumably because of a known respiratory depressive effect or by altering perceptual sensitivity. Opioids may alleviate dyspnea by blunting perceptual responses so that for a given stimulus, the intensity of respiratory sensation is reduced (ATS, 1999). Strong evidence from a recent meta-analysis supports the use of oral and parenteral opioids to treat dyspnea. Jennings, Davies, Higgins, Gibbs, and Broadley (2002) 138

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simple bronchodilator therapy. Inhaled beta-2-adrenergic agonists (e.g., albuterol), inhaled anticholinergics, and sustained-release theophylline all have been shown to improve dyspnea in patients with stable COPD (Dudgeon, 2002).

precise pathophysiology of cancer-related fatigue is poorly understood. However, fatigue is thought to be multifactorial and several proposed mechanisms or etiologic factors (see Figure 10-2) have been identified (Mitchell, 2010; NCCN, 2011c). The impact of cancer-related fatigue on QOL cannot be minimized, as patients “become too tired to participate fully in the roles and activities that make life meaningful” (NCCN, 2011c, p. MS-1). Research has demonstrated the impact of fatigue, specifically in patients with lung cancer, as an isolated symptom or as part of a symptom cluster. One study showed that more than half (52%) of patients with advanced lung cancer reported a level of fatigue that interfered with the ability to perform at least one daily physical activity, such as walking or working, and that even fatigue rated low in severity (1–3 on a numerical 0–10 scale) still interfered with patients’ daily life activities (Tanaka, Akechi, Okuyama, Nishiwaki, & Uchitomi, 2002a). Light to moderate fatigue (mean score of 8, SD = 5.0, range = 0–20) was reported in a sample of 101 Taiwanese patients with lung cancer who were receiving chemotherapy (Lee, Tsai, Lai, & Tsai, 2008). Fatigue levels were reported as significantly higher (p = 0.03) in those receiving the third course of chemotherapy than those receiving a first course (Lee et al., 2008). Sarna and Brecht (1997) found that fatigue was among the most distressing and prevalent serious life disruptions among women with advanced lung cancer. Patients age 65 or older with advanced lung cancer reported fatigue more frequently during the first year after diagnosis than patients with breast cancer (Given, Given, Azzouz, Kozachik, & Stommel, 2001). Depression and

General Supportive Measures The effects of cognitive, emotional, and behavioral factors on the conscious awareness of the demand to breathe can modulate the perception of dyspnea. Interventions that may assist patients to cope with their dyspnea are breathing retraining, positioning, exercise training, and education about medication use (Carrieri-Kohlman & Janson-Bjerklie, 1986). Pulmonary rehabilitation uses a combination of techniques to decrease energy expenditure and maximize ventilation. The benefit of pursed-lip and diaphragmatic breathing retraining may be explained by the decrease in respiratory rate and the increase in tidal volume associated with their use. Positioning, such as leaning forward while sitting, may provide postural relief because of increased efficiency of the diaphragm. Patients themselves devise strategies to minimize energy expenditures. Relaxation training and similar techniques to reduce anxiety have been advocated and are clinically useful. The effectiveness of acupuncture as a nonpharmacologic intervention and cognitive-behavioral approach containing focused nursing interventions for dyspnea has not been established (DiSalvo, Joyce, Culkin, Tyson, & Mackay, 2009). This is a fertile area for nursing research. Nurses are in a unique position to educate patients about dyspnea coping strategies. Dyspnea is a complex symptom that requires thorough assessment and attention. Effectively managing dyspnea is a clinical challenge and usually requires a combined approach of various interventions. Evidence is scant about the efficacy of many interventions primarily because of the diff iculty of conducting research trials in patients with cancer who are experiencing dyspnea. Nonetheless, dyspnea is prevalent in lung cancer and can prompt many healthcare encounters.

Figure 10-2. Etiologic Factors for Cancer-Related Fatigue • • • • • • • • • • • • • •

Underlying disease Cancer treatment Anemia Hypothyroidism Adrenal insufficiency Hypogonadism Infection Malnutrition Depletion of vitamins B1, B6, and B12 Electrolyte disturbances (calcium, magnesium, phosphorus) Cardiopulmonary, hepatic, or renal dysfunction Deconditioning Generalized inflammation Side effects of medication that act on central nervous system (e.g., narcotics, anxiolytics, antiemetics) • Concurrent symptoms (e.g., pain, dyspnea) • Impaired sleep quality • Psychological distress (depression, anxiety)

Fatigue Cancer-related fatigue is def ined as “a distressing persistent, subjective sense of physical emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning” (NCCN, 2011c, p. FT-1). Fatigue is subjective and often experienced as “an extremely frustrating state of chronic energy depletion” (Cella, Peterman, Passik, Jacobsen, & Breitbart, 1998, p. 369). Fatigue is common in patients with cancer and is present in nearly all patients receiving treatment with cytotoxic chemotherapy, radiation therapy, bone marrow transplant, or biologic response modif iers (NCCN, 2011c). The

Note. From “Cancer-Related Fatigue” (p. 274), by S. Mitchell in C.G. Brown (Ed.), A Guide to Oncology Symptom Management, 2010, Pittsburgh, PA: Oncology Nursing Society. Copyright 2010 by the Oncology Nursing Society. Reprinted with permission.

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fatigue were reported as a significantly correlated symptom cluster with a negative relationship with QOL in a sample of 51 people diagnosed with lung cancer (Fox & Lyon, 2006). The symptom cluster of pain, fatigue, and insomnia was identified in an analysis of 80 patients newly diagnosed with lung cancer within 56 days of receiving chemotherapy (Hoffman, Given, von Eye, Gift, & Given, 2007). Evidence supports that fatigue is an important problem in people with lung cancer. “All patients should be screened for fatigue at their initial visit, at regular intervals during and following cancer treatment, and as clinically indicated” (NCCN, 2011c, p. FT2). Assessment of fatigue must reflect the multiple dimensions of this symptom or phenomena. The cornerstone of any thorough fatigue assessment is history, physical examination, and comprehensive review of the symptom. This includes reviewing the patient’s recent radiographic studies, laboratory values, current disease status, and type, duration, and response to treatment. Because fatigue is a highly subjective experience, patient self-report is essential. During self-report, healthcare providers must ask patients to characterize fatigue using terms such as decreased energy, muscular weakness, dysphoric mood, impaired cognitive functioning, or some combination of these. The onset and duration of the fatigue are important in helping to differentiate between an acute and chronic fatigue syndrome. Use of a fatigue measuring tool is helpful in quantifying the level of fatigue and as a benchmark for gauging success of the interventions. Simple one-dimensional scales can be used to measure fatigue in the clinical setting, such as a verbal rating scale of mild, moderate, or severe or a numeric rating scale of 0 (no fatigue) to 10 (worst fatigue). These scales typically measure fatigue severity or intensity. Multidimensional fatigue scales measure additional characteristics of fatigue, such as the physiologic or performance dimensions. Mitchell (2010) and Piper (2004) presented synthesized tables of instruments that measure cancer-related fatigue, including the dimensions of fatigue that each instrument evaluates. The choice of an instrument to measure fatigue should be driven by the information needed to address specific clinical or research questions.

lung cancer, with 80% of patients experiencing some degree of shortness of breath (Cooley, 2000). Difficult breathing combined with the emotional stress of coughing, shortness of breath, and the sight of bloody sputum strongly contribute to the fatigue syndrome (Kuo & Ma, 2002). Dyspnea and fatigue produce similar sensations, such as exercise intolerance, and are difficult symptoms to differentiate. Dyspnea interventions are discussed in the previous section. Pain syndromes specific to lung cancer vary according to the location of the lung tumor and sites of metastatic disease, with patients often experiencing pain in the chest wall, vertebrae, and brachial plexus (Silvestri, 2000). The experience of acute or chronic pain can contribute to fatigue because patients with pain can experience insomnia, depression, and exercise intolerance. Treatments prescribed to relieve pain and distress, especially narcotic analgesics and antianxiety drugs, are sedating. Effective agents found to control pain related to lung cancer are oral, transdermal, rectal, or parenteral opioids, as well as nonopioid analgesics (Paice & Fine, 2001). Long-acting preparations can reduce sedating effects, thereby reducing fatigue. Fatigue is often a presenting symptom of lung cancer, even before treatment begins. Fatigue has been reported to significantly increase during treatment with chemotherapy and radiation and persist for years after treatment ends (Fox & Lyon, 2006; Lee et al., 2008). Patterns of fatigue depend on the timing and treatment schedule for the chemotherapy regimen (e.g., every 21 days, weekly, continuous infusion). As the time between treatments increases, fatigue duration is shorter. In general, fatigue seems to peak four to five days after treatment, rise again around the nadir period, and decrease just prior to the next scheduled treatment. Radiation, another important and common treatment modality for lung cancer, can be associated with fatigue. The incidence is site specific, as most patients with lung cancer experience fatigue with radiation to the chest (93%) and pelvis (65%) (King, Nail, Kreamer, Strohl, & Johnson, 1985). Fatigue is reported to start three weeks after the initiation of treatment and last for up to three months post-treatment in about one-third of these patients. Because radiation treatments have a limited duration, fatigue does improve once treatment is completed. One of the initial presenting symptoms in lung cancer can be unexplained or unintentional weight loss (Brown, 2002). Cachexia is a syndrome characterized by anorexia, weakness, fatigue, weight loss, muscle wasting, impaired immune response, decreased motor ability, and mood disorder (Costa & Donaldson, 1980; Lindsey, 1986; Morrison, 1989). Effective intervention for the primary cancer can reduce cancer anorexia and feelings of fatigue. Corticosteroids and progestins (megestrol acetate) are recommended as appetite stimulants to manage anorexia in people with cancer (GrandaCameron & Lynch, 2010). Results from the European Cancer Anaemia Survey showed the overall incidence of anemia in patients with lung cancer

Assessment of Treatable Factors Contributing to Fatigue The goal of fatigue assessment is to uncover potential causative factors with an aim to treat each optimally as an initial approach to fatigue management. NCCN (2011c) cancer-related fatigue practice guidelines identify pain, emotional distress, sleep disturbance, anemia, nutrition, activity level, medication side effects (i.e., sedation), and other comorbidities as treatment targets. In the lung cancer population, dyspnea is identified as the symptom most closely associated with cancer-related fatigue. Dyspnea is one of the most common and distressing symptoms reported in advanced 140

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(N = 485) was 70.9%, with incidences of 79.6% for patients who received chemotherapy, 30.8% for those who received concomitant chemotherapy/radiotherapy, and 14.5% for those who received radiotherapy (Kosmidis & Krzakowski, 2005). Chemotherapy-induced anemia occurs as the result of the direct myelosuppressive effect of particular agents and as a secondary decrease in the production of erythropoietin related to renal impairment. Platinum-based chemotherapeutic agents (e.g., cisplatin, carbo­platin), which are common agents used in lung cancer chemotherapy, have a significant effect on the renal system with decreased erythropoietin production. Retrospective chart reviews have shown that patients with lung cancer receiving platinum-based chemotherapy require blood transfusions 30%–40% more than patients treated for other cancers that do not receive a platinum-based therapy (American Society of Clinical Oncology [ASCO], 1997; Wood & Hrushesky, 1995). Many of the other chemotherapy agents prescribed to treat lung cancer, including docetaxel, paclitaxel, gemcitabine, vinorelbine, and topotecan, have been proved to produce mild to moderate anemia (Groopman & Itri, 1999). In addition, patients with lung cancer have about a 33%–47% chance of developing severe anemia if they have been treated with radiation therapy, multiple regimens of chemotherapy, or chemotherapy and radiation concomitantly (Crinò et al., 1997). Fatigue, lethargy, and apathy are general constitutional symptoms of anemia (Miller, 2010). NCCN (2011b) includes fatigue as a subjective symptom of cancer- and chemotherapyinduced anemia. According to NCCN guidelines (2011b), recommended therapy for cancer-related anemia not attributed to myelosuppressive chemotherapy in patients with solid tumors such as lung cancer is transfusion with red blood cells per institutional guidelines. For people who receive myelosuppressive chemotherapy with curative intent and who experience anemia, transfusion with red blood cells also is the recommended therapy. For patients who are not being treated with curative intent and who experience myelosuppressive chemotherapyinduced anemia, treatment with erythropoietin-stimulating agents (ESAs) such as epoetin alfa or darbepoetin alfa may be appropriate therapy based on an evaluation of the risk and benefits of such therapy. NCCN guidelines (2011b) recommend that all patients who are dispensed or administered either drug be informed that ESAs have been found to shorten overall survival and/or time to progression in patients with non-small cell lung cancer when dosed to target hemoglobin 12 g/dl or higher. ESAs also have been associated with an increased risk of death in patients with cancer receiving radiotherapy or not receiving treatment with chemotherapy. Thus, the risk of ESA should be weighed against the possible or potential benefit of reduced fatigue. Depression can be common and persistent in patients with advanced-stage lung cancer. Depression was self-rated in 322 of 987 (33%) patients with inoperable lung cancer before

therapy and persisted in more than 50% of these patients (Hopwood & Stephens, 2000). The severity of depression is related directly to the severity of symptoms or functional limitations. Depression and symptom distress have been correlated closely with fatigue and compromised QOL (Newall, Sanson-Fisher, Girgis, & Ackland, 1999). However, a study by Visser and Smets (1998) did not support a cause-andeffect relationship between depression and fatigue. Rather, the study found that the two symptoms have a concurrent relationship, with both symptoms negatively affecting overall QOL. Effectively treating depression with antidepressants and counseling can improve sleep, cognition, treatment tolerance, fatigue, and overall QOL (Hopwood & Stephens, 2000). Fatigue can have an adverse effect on cognitive function in patients with cancer (National Cancer Institute [NCI], 2011). Careful assessment of mental status changes in patients with lung cancer is required to distinguish fatigue from diseaserelated changes such as central nervous system (CNS) metastases, paraneoplastic syndromes, electrolyte imbalances, or drug interactions. Interventions aimed at the potential contributing factors are the primary approach in treating fatigue. Beyond that, the NCCN guidelines (2011c) offer some general guidelines for fatigue management. Educating patients about fatigue and providing anticipatory guidance regarding the likelihood of experiencing fatigue can prepare them for the effect that treatment will have on their ability to perform usual activities. Patients must be informed that fatigue is an expected response from the cancer and treatment and is not a sign of treatment efficacy or disease progression. An important goal of educating patients and caregivers about fatigue is to promote self-care. Counseling on useful strategies for coping with fatigue should include energy conservation and distraction. Although maintaining a normal level of activity is important physically and emotionally, patients should be encouraged to prioritize activities, pace themselves according to their energy level, delegate more activities to others, and postpone any unnecessary activities or plan to do them when they experience peak energy levels. Distracting activities, such as games, reading, music, and socializing, have been shown to decrease fatigue, although the mechanism of action is unknown (NCCN, 2011c). Exercise or activity enhancement can be recommended as an effective intervention in preventing or treating fatigue based on several published guidelines (Mitchell, Beck, Hood, Moore, & Tanner, 2009; NCI, 2011; NCCN, 2011c). The benefit of exercise in fatigue management during and following treatment has not been investigated solely in people with lung cancer; studies in patients with breast cancer, prostate cancer, and mixed solid tumors and recipients of hematopoietic stem cell transplants support this recommendation. Although the usefulness of exercise in reducing cancer-related fatigue has been documented, patients with lung cancer may be unable to perform any level of exercise. These patients may benefit 141

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Pain

from a consult with a physical therapist for an appropriate exercise regimen or rehabilitation program. Before any exercise program is initiated, careful consideration must be given to the presence of bone metastasis, neutropenia, thrombocytopenia, anemia, anticoagulant therapy, fever, pain, or other complications from treatment (NCCN, 2011c). For those with lung cancer, evaluation of oxygen saturation levels before, during, and after exercise is recommended to assess for oxygen desaturation precipitated by exertion and the need for supplemental oxygen during activity. Patients with lung cancer who report fatigue should be offered counseling on stress management, anxiety, and depression because of the strong correlation between emotional distress and fatigue (NCCN, 2011c). Patients may benefit from referral for psychiatric intervention, support groups, or evaluation for mood-elevating medication. Attention-restoring therapy can be helpful for attentional fatigue, or a decreased capacity to concentrate. Restorative interventions, such as bird-watching or sitting outdoors, have been shown to improve concentration and problem-solving abilities in patients with cancer-related fatigue (Cimprich, 1992, 1993). Because people with cancer report significant sleep disturbances that could cause or exacerbate fatigue, measures to optimize sleep quality are likely to be effective in improving fatigue outcomes (Mitchell et al., 2009; NCCN, 2011c). Patients with sleep disturbances require direction on strategies to improve sleep quality. These include maintaining a consistent bedtime, limiting daytime napping, avoiding caffeine, and limiting stimulating activities prior to bedtime (Berger et al., 2002, 2003). The use of several pharmacologic agents that serve as psychostimulants have been considered as a treatment for fatigue, but insufficient data or data of inadequate quality (e.g., small sample size) render the effectiveness of this intervention as not established (Mitchell et al., 2009). Methylphenidate, dextroamphetamine, and modafinil can serve as CNS stimulants to enhance alertness and cognitive function or counter opioid-induced sedation (NCI, 2011). Preliminary evidence in two small uncontrolled studies suggests that a stimulating antidepressant, bupropion sustained-release, at a dose of 100–300 mg/day may improve cancer-related fatigue and depression outcomes (Mitchell et al., 2009). Many people with lung cancer have limited survival time after diagnosis. Fatigue is a prevalent symptom at end of life and thus, in this population, recommendations for fatigue symptom management usually focus on energy conservation such as maintaining balance between rest and activity, priority setting, and use of labor-saving devices (i.e., bedside commode, wheelchair). Pharmacologic interventions such as psychostimulant medications are an option in this population although effectiveness to relieve fatigue has not been established.

Pain is a prevalent symptom in lung cancer. The overall prevalence of pain in people with lung cancer as reported in one systematic review of lung cancer studies was 47% (Potter & Higginson, 2004). Portenoy and colleagues (1992) surveyed the prevalence of pain in ambulatory patients with lung or colon cancer and reported that more than 33% had more than one area of moderate pain over a four-week period and approximately 90% of the patients had pain more than 25% of the time. Almost 50% of patients with lung cancer experience pain in the last few days of life (McCarthy, Phillips, Zhong, Drews, & Lynn, 2000; Weiss, Emanuel, Fairclough, & Emanuel, 2001). Palliation of pain is essential for ensuring comfort at the end of life (Kvale et al., 2003; Weiss et al., 2001). Pain associated with lung cancer has variable presentations related to tumor location and underlying etiology. Silvestri and colleagues (2002) reported the three main causes of malignancy-related pain in lung cancer as skeletal metastases (34%), Pancoast tumor (31%), and chest wall disease (21%). Skeletal metastases usually present with localized pain. Metastases to the thoracic and lumbar spine are common pain sites reported by patients with lung cancer (Potter & Higginson, 2004). Bone pain can herald an oncologic emergency such as spinal cord compression or impending long bone fracture. A superior pulmonary sulcus tumor, also known as Pancoast tumor, is a primary lung tumor arising in the extreme apex of the lung. Pancoast lung tumors usually are associated with severe, unrelenting pain worsened by movement of the affected arm, and often develop months before diagnosis is made (Ginsberg, Payne, & Shamji, 1996). The tumor may involve or invade the lower trunk of the brachial plexus, the roots of the eighth cervical and first and second thoracic nerves, adjoining vertebral bodies of the upper thoracic spine, the upper thoracic sympathetic chain, the subclavian vessels, the adjacent ribs, and intercostal muscles. The characteristic clinical syndrome of pain in the shoulder and arm; sensorimotor loss along the ulnar nerve distribution that may include muscle wasting in the elbow, hand, or medial forearm; and Horner syndrome was described by Dr. Henry K. Pancoast in 1932 (Pancoast, 1932). Horner syndrome is characterized by ptosis (e.g., drooping of the upper eyelid), miosis (constriction of the pupil of the eye), hemianhidrosis (lack of sweating on one half of the face), and enophthalmos (recession of the eyeball within the orbit). Chest wall pain also is a common presentation in people with lung cancer. Often the thoracic tumor location can be correlated with the cause of the chest wall pain. Direct chest wall extension of tumor can cause radicular pain. Pleuritic pain can result from pleural invasion with or without effusion. Sternal pain or pressure can result from tumor or lymphadenopathy in the mediastinum. Nonspecific, 142

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noncardiac pain is noted as a result of tumor compression of surrounding structures. Chest wall pain can be treatment related such as post-thoracotomy pain or pain subsequent to pleural drainage and pleurodesis. It is important to correlate the pain symptom with the underlying disease, as this often leads to a specific treatment (i.e., radiotherapy, tailored pharmacologic agent) and could be of prognostic value concerning pain control. Despite increased knowledge about the use of opioid and nonopioid analgesics and alternative pain management techniques, healthcare providers continue to underaddress cancer pain and underprescribe pain medication. Barriers to prescribing maximum doses of pain medication include poor pain assessment and concerns over side effects (Von Roenn, Cleeland, Gonin, Hatfield, & Pandya, 1993). Providers without specialized oncology training tend to have a conservative view of cancer pain treatment and place a lower priority on pain management (Cleeland, Cleeland, Dar, & Rinehardt, 1986). “Inadequate treatment of cancer pain has profound negative effects on patients’ mood, functional status, and QOL. Therefore, assessment and aggressive management of cancer pain are priorities for all oncology nurses” (Miaskowski, 2010, p. 390). Effective pain management begins with a basic understanding of cancer-related pain. A comprehensive assessment is needed to classify the pain according to pathophysiology into two predominant mechanisms: nociceptive (further divided into somatic and visceral) or neuropathic in nature (NCCN, 2011a). Somatic pain, the type of pain experienced with bone metastases, usually is localized, caused by inflammation, and originates from peripheral and sensory efferent nerves. Visceral pain is more generalized, described as a deep ache, cramping, squeezing, or pressurelike pain. Visceral pain usually is caused by pressure on an organ by a tumor, such as a lung tumor stretching the thoracic viscera (NCCN, 2011a). Neuropathic pain results from pressure, injur y, inflammation, or damage to either peripheral or central nerves (NCCN, 2011a). This kind of pain can develop as a result of tumor compression or infiltration of peripheral or spinal cord nerves caused by surgery, radiation, or chemotherapy. Patients with lung cancer often present with both somatic and visceral pain; neuropathic pain occurs in about 15%–20% of this population (Weiss et al., 2001). Identifying the classification of the pain is essential for prescribing the most appropriate combination of pain management strategies. Patients with neuropathic pain generally report a burning, sharp, or shooting sensation that can radiate with a viselike quality and may be associated with sensory perception loss. Because of lung tumor location, patients can experience pain from pressure on the brachial plexus or from lumbosacral plexopathies. Pancoast tumors can cause brachial plexopathies in patients with lung cancer, and metastatic lung cancer to

the lumbosacral spine can cause nerve root compression presenting as a lumbosacral plexopathy. In addition, many patients with lung cancer report neuropathic pain at healed thoracotomy sites or thorax exit sites of previous chest drainage tubes. Tumor-related paraneoplastic syndromes and certain chemotherapies can cause peripheral neuropathy. Frequently used chemotherapeutic agents for lung cancer, such as the vinca alkaloids, platinums, and taxanes, can cause painful peripheral nerve injury or damage. Chemotherapy-related neuropathies usually present distally and bilaterally and are characterized by sensory complaints of numbness and paresthesia. Pain assessment also must incorporate the measurement of pain intensity. The most frequently used scale to quantify pain intensity is the 0–10 numeric rating scale with 0 being no pain and 10 being the worst pain. This 0–10 measure of pain severity is used in conjunction with questions about onset, duration, location, description of quality, aggravating and relieving factors, current and previous pharmacologic and nonpharmacologic therapies, and impact of pain on function (Miaskowski, 2010). Comprehensive pain assessment includes a thorough physical and neurologic examination. This approach allows healthcare providers to evaluate pain sites and identify potential associated physical or neurologic signs. In addition, the pain assessment includes review of all pertinent laboratory and radiologic data for potential pain etiology. The end goal of comprehensive assessment is to diagnose the etiology and pathophysiology (somatic, visceral, or neuropathic) and develop a pain treatment plan based on mutually developed goals and individualized to the patient (NCCN, 2011a). A most effective strategy for pain management is continuous assessment at every patient encounter. A trusting relationship between the patient and practitioner is critical for open, honest communication. Patients must feel that their complaints of pain are real and not just the result of inadequate coping (Arathuzik, 1991; Wolff, 1985). Once pain is treated, evaluation should focus on the success of the intervention and changes in the pain status and psychological well-being. Patients and caregivers must be educated about pain and how it affects all aspects of living. Healthcare providers must dispel myths of addiction and demonstrate how pain management is integral to the success and continuation of the treatment plan. Cancer-related pain management is a complex process that is most successful when viewed as a holistic treatment approach (Yeager, McGuire, & Sheidler, 2000). First, treatment must be focused on eradicating the underlying etiology. In patients with lung cancer, this involves treatment of the cancer with chemotherapy, radiation, or surgery. The next step is to use pharmacologic agents to change perceptions of pain (relieve the sensation of pain). Finally, psychological and emotional components of the pain syndrome must be addressed (Yeager et al., 2000). 143

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Because advanced-stage lung cancer is not curable, treatment eventually reaches the palliative phase. Studies have suggested that even in cases in which chemotherapy will not improve survival time, chemotherapy does have an effect on pain relief (Kvale et al., 2003). Supportive care for skeletal metastasis includes bisphosphonates that act by inhibiting the bone-resorption effects of osteoclasts. These agents, such as pamidronate and zoledronic acid, are infused monthly to strengthen the diseased bone, prevent idiopathic fracture, and promote pain relief. These drugs also are useful in treating hypercalcemia in patients with bone disease (McMenamin, 2011; Paice & Fine, 2001). Radiotherapy is an important treatment modality for pain relief in patients with lung cancer. Most commonly, it is used to treat painful bone metastases, epidural cord compressions, Pancoast tumors, and specific sites of disease causing severe pain (Jenis, Dunn, & An, 1999; Strohl & Hawkins, 2006; Tong, Gillick, & Hendrickson, 1982). Radiation to tumors that are compressing nerve roots, such as Pancoast tumors or epidural lesions, provides relief from the associated neuropathies. Patients with lung cancer who present with sudden onset of back pain radiating to the arms or legs, accompanied by weakness, sensory disturbance, or sphincter dysfunction, must be evaluated for spinal cord compression. Spinal cord compression is treated with corticosteroids and radiation therapy to the lesion (Jenis et al., 1999). Surgical intervention is indicated for intractable pain, spinal instability, or neurologic deterioration from vertebral collapse or failure of conservative treatment (Jenis et al., 1999). Cancer pain management should include both pharmacologic and nonpharmacologic interventions (Miaskowski, 2010). It behooves oncology nurses to become experts in optimal pain management by working with patients and caregivers to ensure initial pain assessment and appropriate intervention with reassessment and plan modification. Several clinical practice guidelines on the management of cancer pain have been published by consensus panels: American Pain Society (Miakowski et al., 2005), NCCN (2011a), and the Oncology Nursing Society (Aiello-Laws, Ameringer, Delzer, Peterson, & Reynolds, 2009). The recommendations contained within these documents are similar. Familiarity with these recommendations and consultation with other disciplines will give oncology nurses essential tools to provide optimal care to patients with lung cancer who report pain. Familiarity with alternate routes of analgesic administration will help to individualize pain management interventions according to patient need. Attention and monitoring for opioid side effects and proactively treating each issue are critical. Constipation tends to be the most distressing for patients with lung cancer. Constipation should be anticipated in patients beginning any opioid pain regimens and should be treated prophylactically. “Always initiate a bowel regimen (softener and laxative) when a patient is started on an opioid” (Aiello-Laws et al., 2009, p.

225). Every patient should be assessed for bowel function at every encounter and educated about increasing fluid and fiber intake. Bisanz et al. (2009) provided additional evidence-based recommendations to manage constipation in the Oncology Nursing Society Putting Evidence Into Practice resource. Although the primary treatment for cancer-related pain is pharmacologic, nonpharmacologic treatment strategies can augment pain control in patients with lung cancer. Complementary approaches, such as relaxation, massage, acupuncture, cognitive reframing, and distraction with humor and music, are designed to reduce the cognitive and affective components of pain (Miaskowski, 2010). These cognitivebehavioral strategies assist and guide patients in interpreting painful sensations (Miaskowski, 2010). The expected outcome for all cancer pain interventions is to reduce pain with minimal side effects and to improve the patient’s function. Further research and advancement in the treatment of lung cancer– related pain are critical. Research must focus on developing a better understanding of the mechanism of pain and providing greater support and acceptance of innovative methods for the treatment of cancer-related pain.

Specific Treatment-Related Side Effects: Radiation Pneumonitis Radiation pneumonitis is a misleading term that implies an infectious process (McDonald, Rubin, Phillips, & Marks, 1995). Instead, this syndrome of clinical, radiographic, and histologic findings reflects postirradiation lung injury. Radiation pneumonitis occurs in 5%–37% of treated patients depending on end point studied and is classified as either acute or late (Carver et al., 2007; Marks et al., 2003; Rodríguez & Padellano, 2007). Patients may be asymptomatic with radiographic findings or have clinical symptoms such as dry cough, fever, exertional dyspnea, cor pulmonale (right ventricular failure), and finally, death from respiratory failure (Marks et al., 2003; Robnett et al., 2000; Tucker et al., 2009). Pneumonitis usually does not appear until at least two to three months after radiotherapy when the damage is already present and cannot be reversed (Mehta, 2005). The desire to predict patients who are at risk for pneumonitis has driven the search for biochemical markers that will detect early pulmonary damage (Mehta, 2005). Current thinking implies that radiation pneumonitis and its long-term sequela—chronic pulmonary fibrosis—are likely the result of a cytokine cascade triggered by radiation itself (Mehta, 2005). The most radiosensitive subunit of the lung is the alveolar/ capillary complex. Radiation-induced lung injury is often described as diffuse alveolar damage. Radiation is directly toxic to parenchymal cells and initiates a cascade of molecular events that alter the cytokine milieu of the microenvironment, creating a self-sustaining cycle of inflammation and chronic oxidative stress. Replacement of normal lung parenchyma by 144

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fibrosis is the final outcome (Ghafoori, Marks, Vujaskovic, & Kelsey, 2008). In 1995, Rubin, Johnston, Williams, McDonald, and Finkelstein reported on a perpetual cascade of proinflammatory and profibrotic cytokines. The cytokines were released immediately after irradiation and persisted for weeks to months until fibrotic changes were seen in the lung septa (Rubin et al., 1995). These cytokines are thought to be key mediators of lung toxicity. Thus, many of them have been examined as potential early markers for radiation pneumonitis (Mehta, 2005). One study found that individuals who underwent thoracic irradiation had signif icantly higher levels of inflammatory cytokines interleukin-1 and interleukin-6 before, during, and after radiation. However, profibrotic cytokines such as basic fibroblast growth factor and transforming growth factor had little change (Chen et al., 2001; Mehta, 2005). In a prospective study of 30 patients receiving hyperfractionated (twice daily) treatment (150–160 cGy twice daily), serum levels of intercellular adhesion molecule-1 (slCAM-1) were checked before, midway, and after irradiation. Forty percent of the patients developed pneumonitis (Ishii & Kitamura, 1999). All study participants had elevated slCAM-1 levels before treatment compared to healthy adults; however, the slCAM-1 levels rose progressively during and after radiation in the pneumonitis group only. Although this information is valuable, ability to predict who will develop pneumonitis pretreatment still is not known (Ishii & Kitamura, 1999). Other potential markers for radiation pneumonitis have emerged, including pulmonary surfactant proteins A and D, and KL-6, a mucin-like glycoprotein, predictive of pneumonitis when one has a 1.5-fold increase in levels after conventional irradiation to the chest (Goto et al., 2001; Madani et al., 2007). Cytokeratin 19 expressed in bronchial epithelial cells has been studied, but it remains to be seen whether it is a reliable marker for pulmonary damage (Mehta, 2005). Transmembrane glycoprotein thrombomodulin (TM) is an endogenous anticoagulant that is released into the circulation during inflammation. In a prospective study of 17 patients with lung cancer who were treated with curative intent, one study found that patients who did not develop pneumonitis had lower plasma TM levels throughout treatment than patients who did develop pneumonitis (Hauer-Jensen, Kong, Fink, & Anscher, 1999). Thus, TM might serve as an early marker for pulmonary damage at a time when the radiotherapy plan can still be adjusted (Mehta, 2005). More likely, however, a combination of physical and chemical biomarkers will need to be identified before clinicians can predict which patients are most likely to develop this syndrome.

is at risk to develop radiation pneumonitis, the radiotherapy strategy likely influences risk (Mehta, 2005). Recently, a general trend toward lower reported rates of pneumonitis suggests that newer radiation techniques such as threedimensional conformal radiotherapy and intensity-modulated radiation therapy may be responsible. This implies that the major risk factor is the radiation dose administered to the normal lung tissue surrounding the tumor, which can be better adapted with these techniques (Mehta, 2005). Advanced age, reirradiation, and steroid withdrawal are thought to be exacerbating factors in the development of radiation pneumonitis (Gross, 1977). Studies examining smoking status as a risk factor have not been definitive, and pretreatment pulmonary function tests (PFTs) have not borne consistent results. In fact, many patients experience improvement in PFTs after radiotherapy, perhaps due to reduction in tumor size, and thus reduced lung obstruction (Mehta, 2005). Studies of treatment-related factors, such as radiation dose, dose per fraction, field size, and concurrent chemotherapy, offer conflicting results, but these factors seem to have contributing effects (Inoue et al., 2001; Robnett et al., 2000). Additionally, patients with tumors in the lower lobe of the lung are more likely to develop pneumonitis (Graham et al., 1999). In one retrospective analysis (Robnett, et al., 2000) aimed to predict patients at risk for radiation pneumonitis, 144 cases were reviewed from June 1992 to June 1998 for age, gender, performance status, histology (small cell versus non-small cell), stage (II/IIIA versus IIIB), pulmonary function, presence of weight loss, location of primary tumor, preradiation hemoglobin, radiation dose, initial field size, chemotherapy drugs, and timing of chemotherapy. The most significant predictor of severe radiation pneumonitis was Eastern Cooperative Oncology Group status 1 versus 0 (Robnett et al., 2000). Treatment-related factors such as dose and field size did not influence the risk of severe pneumonitis. This suggests that patients with compromised performance status due to tumor effects and/or other disease processes are more likely to develop radiation pneumonitis than individuals with better performance status (Robnett et al., 2000).

Acute Versus Late Pneumonitis Regional radiation-induced lung changes are seen in nearly all patients who receive radiation treatment to the thorax. Acute pneumonitis typically presents one to six months after treatment with cough, shortness of breath, and occasional fever (Marks et al., 2003). Radiographic findings are variable. No relationship exists between clinical symptoms and the extent of changes on radiograph or lung function parameters. Treatment with a steroid dose of 40–60 mg/day with a taper over several weeks is usually sufficient to provide relief (Marks et al., 2003). Although the use of steroids is the standard for managing radiation pneumonitis symptoms, studies have documented no significant difference in survival rate in

Risk Factors Many studies have investigated risk factors for radiation pneumonitis to identify high-risk groups. In determining who 145

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patients receiving corticosteroid therapy (Inoue et al., 2001). Antibiotics may be necessary in the presence of secondary infection. Oxygen, bronchodilators, and sedatives to control anxiety, dyspnea, and cough may be needed (Knopp, 1997). The late stage of pneumonitis is radiation-induced fibrosis. The chronic effects of radiotherapy start 6–12 months after treatment. Symptomatically, the patient experiences progressive chronic dyspnea associated with scarring of the previously irradiated lung. This can occur months to years after treatment (Marks et al., 2003). Treatment is aimed at symptom relief with steroids and oxygen if necessary. The clinical symptoms of radiation fibrosis are proportional to the extent of lung parenchyma involved with regard to the patient’s preexisting pulmonary reserve (Hernberg et al., 2002). Increases in lung density will usually stabilize by 12 months after radiation therapy (Ma et al., 2010).

frequently leads to dose-limiting toxicity. Addition of concurrent chemotherapy regimens may compound the complications. Studies using endoscopic examination of the esophagus have revealed that clinical symptoms often do not reflect the extent of mucosal damage (Suzuki, Kobayashi, & Kitamura, 1997). The incidence of severe acute esophagitis in patients treated for lung cancer with standard (once daily) radiation therapy alone is 1.3% (Werner-Wasik, 2005). Induction chemotherapy increases the risk of severe acute esophagitis slightly over that of standard radiation therpay alone. In contrast, a strong radiosensitizing effect of chemotherapy given concurrently with standard thoracic radiation is associated with an incidence of severe esophagitis of 14%–49% (Werner-Wasik, 2005). Zhang and colleagues (2009) reported significantly higher grade 2–3 esophagitis associated with lymph node status of N2/3. Esophagitis can lead to serious complications and greatly affect QOL by causing pain and inability to eat or drink. In addition, interruptions or delays in treatment schedules may be required, compromising the overall efficacy of treatment. Acute esophagitis may result in hospitalization, placement of a feeding tube, or IV feedings with steady supportive care (Werner-Wasik, 2005). Symptoms usually begin two to three weeks from the start of treatment but may occur sooner with concurrent chemotherapy. Symptoms may resolve during radiation or continue a few weeks after treatment. Patients with pharyngitis report fullness in the throat with difficulty swallowing, with or without soreness. Patients with esophagitis tend to have more severe symptoms as a result of inflammation and denudation of the surface epithelium of the esophagus (Knopp, 1997). Coarse foods and extreme food temperatures can further traumatize the mucosa. Patients may report epigastric discomfort, esophageal reflux, and pain on swallowing certain or all foods. Disruption of the normal mucosal barrier can lead to invasive fungal infections from Candida albicans, part of the normal gastrointestinal flora. Esophageal candidiasis has been reported to be associated with half the cases of radiation pneumonitis (Suzuki et al., 1997). Chronic esophagitis may occur as a result of a herpetic or fungal infection. Fungal infections require treatment with oral or IV antifungals. Esophageal stenosis or necrosis leading to fistula can occur several months after treatment, although rare and usually associated with prior surgery or tumor progression (Knopp, 1997). Measures to relieve symptoms include gargling with saline or a bland rinse such as a saline and sodium bicarbonate mixture before and after meals and taking liquid analgesics to control pain 30–60 minutes before meals. Any multiagent rinse for mucositis that contains alcohol should be avoided. Combinations or “cocktails” of local anesthetics, antacids, and antihistamines, often referred to as “magic mouthwash,” often are recommended in practice but little evidence is available to demonstrate the effectiveness of these rinses for mucositis

Pretreatment Measures Radiation planning will always take into account the surrounding area of the treatment field that will receive dose. Treatment cannot avoid some healthy surrounding tissue no matter how tight the radiation fields are. In an effort to spare normal tissue, cytoprotective agents may be used. Presently, however, the most effective free-radical scavenger for human use is amifostine, which was developed as a radioprotective agent in a classified nuclear warfare project. Following declassification, it was evaluated as a cytoprotective agent against toxicity of alkylating drugs and cisplatin. The active free thiol metabolite WR-1065 has been shown to prevent both radiation-induced cell death and mutagenesis while facilitating the repair of normal cells (Santini & Giles, 1999). The downside of amifostine is its short half-life in serum along with serious side effects that make it difficult and costly to administer (Colon et al., 2009). Preliminary clinical and preclinical evidence suggests that ACE inhibitors, carvedilol, pentoxifylline, melatonin, or gene therapy may also reduce radiation pneumonitis. Captopril, an ACE inhibitor, contains a thiol and has been proposed as a potential cytoprotective agent for radiation pneumonitis. The Radiation Therapy Oncology Group (RTOG) is investigating the agent as a treatment. Further studies are needed to confirm the efficacy and safety of these agents for prevention of radiation pneumonitis and to evaluate how radioprotective therapy influences tumor control, survival, QOL, and activities of daily living in patients with non-small cell lung cancer (Mehta, 2005).

Pharyngitis and Esophagitis The epithelial cells of the pharynx and esophagus are highly radiosensitive and are often in the field of the radiation treatment area. Radiation to the lungs and adjacent lymph nodes is associated with inflammation or ulceration of the mucosal lining of the pharynx and esophagus, which 146

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(Harris, Eilers, Cashavelly, Maxwell, & Harriman, 2009). An example of contents is equal parts of dyclonine 0.5%, Maalox®, and diphenhydramine powder. Another mixture used is Kaopectate®, diphenhydramine elixir, and viscous lidocaine. Patients are instructed to swallow 10 ml every 4–6 hours as needed but certainly 20–30 minutes before meals for a numbing effect (Knopp, 1997; Suzuki et al., 1997). A numbing effect on the esophageal phase of swallowing is desired, but a numbing effect on the mouth is of concern for potential injury (Harris et al., 2009). Liquid antacids alone (without a local anesthetic) before meals can provide comfort by coating the esophageal lining and can reduce additional ulceration from reflux (Suzuki et al., 1997). Dietary measures include a soft, bland diet with the addition of high-calorie snacks and supplements. Patients report that thicker, soft foods and fluids such as mashed potatoes and thick shakes are more tolerable than water or juices. It is also advisable to avoid irritants such as spicy or irritating foods, citrus, alcohol, and tobacco. Other tips include sitting upright for meals and remaining upright after meals for at least 15 minutes; drinking liquids through a straw to ease swallowing; eating slowly, chewing completely, and cutting foods into small pieces (Bruner, Haas, & Gosselin-Acomb, 2005). Medications may need to be changed to elixirs for easier swallowing. Rarely do patients require enteral feedings as is seen frequently with radiation therapy to the head and neck areas. Maintenance of fluid and nutritional status is key, and patients may require a nutrition referral during this period. IV fluid hydration may be necessary during highest acuity.

attributable to cancer of the lung (Salvo et al., 2009). Many lung cancers are found at an advanced stage, rendering the tumors inoperable and the treatment palliative (Salvo et al., 2009), even when delivered with a curative intent. Hence, a snapshot of lung cancer includes patients undergoing induction therapy prior to surgical resection and hoping for cure; those with advanced disease at diagnosis undergoing chemotherapy with the goal of living longer; those for whom available therapy- has been exhausted and who are receiving palliation only; and finally, the survivors who are living each day, coping with sequelae of illness and treatment and hoping for a disease-free life. Common symptoms associated with advanced lung cancer include cough, hemoptysis, and dyspnea, all of which can significantly debilitate and diminish QOL (Salvo et al., 2009). All patients require ongoing management of disease- and treatment-related needs with an emphasis on improving or maintaining their QOL. Although it is important to try to decrease side effects and find treatments that will provide less interference in life, we need to consider that QOL should be the end point when a cure is not attainable. Nursing interventions include direct care delivery; education about the illness and treatments to promote adaptation and safety related to self-care measures; support, counseling, and referral for psychosocial adjustment; management and palliation of symptoms; and coordination of end-of-life needs. As with all chronic diseases, education of patients and caregivers about available resources for services and support is an important component of assisting development of effective coping strategies.

Prevention

References

A phase III RTOG study of amifostine before radiation treatment did not reduce grade 3 or greater esophagitis per NCI criteria; however, patient self-assessment suggested a possible advantage to amifostine that should be explored with modified dosing and route strategies (Movsas et al., 2003). Amphotericin B was evaluated in small study by Wurstbauer, Merz, and Sedlmayer (2009) in Austria with 40 patients enrolled. Twenty patients were in the control group and 20 patients in the lozenge group. The amphotericin B lozenges were taken four times daily from day 8 of radiation until completion of therapy. In the control group, 14 patients developed grade 1 esophagitis, and 2 patients developed grade 2 esophagitis; in the lozenge group, only 5 patients developed a grade 1 esophagitis, thereby suggesting a benefit for patients receiving thoracic radiotherapy (Wurstbauer et al., 2009).

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Summary Nursing care of patients with lung cancer covers all aspects of treatment across the continuum of the disease. Approximately 27% of North American cancer deaths are 147

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Psychosocial Concerns Anne Martin, PhD, LCSW

Introduction

2008). They must cope with the combined assault of aging and illness, often experiencing physical losses of mobility, vision, hearing, mental acuity, and stamina, usually along with one or more comorbid medical problems (e.g., arthritis, hypertension, diabetes, kidney, cardiovascular disease). Personal losses, such as the death of a spouse, family member, or friend of a similar age, isolate older adults even more, often resulting in their dealing with illness alone. This sense of isolation is further exacerbated by retirement and geographic scattering of families. Thus, it is no surprise that even physically healthy older individuals experience a significant level of either clinical depression or, more often, symptoms of depression not severe enough to warrant a depression diagnosis (Lyness, 2004). Among older adults with serious acute or chronic illness, the frequency of depression (15%–25% or greater) often interferes with the ability to make treatment decisions and adhere to treatment regimens (Katon, Lin, & Kroenke, 2007; Katon & Sullivan, 1990; Katon et al., 2005; Katon & Unützer, 2006; Reynolds, Dew, Lenze, & Whyte, 2007). Patients of all ages struggle to cope with a diagnosis of cancer. Although older people are generally thought to cope better with illness and loss than younger individuals (Blank & Bellizzi, 2006; Blank, Bellizzi, Murphy, & Ryan, 2003; Eton & Lepore, 2002; Institute of Medicine, 2008; Zabora et al., 2001), the presence of physical aging–related problems, comorbid medical conditions, and their symptom burdens, can overwhelm older adults’ strong coping ability, leading to increased vulnerability to distress, anxiety, and depression (Blazer, 1994; Kurtz, Kurtz, Stommel, Given, & Given, 2001). These facts represent a compelling clinical need to develop psychosocial interventions tailored to fit the life stage and problems of older patients coping with aging and cancer.

Although lung cancer is a major cause of death in industrialized countries for both men and women, psychosocial research was limited in the past because metastatic disease is frequently found at the time of diagnosis and the limited survival time of these patients diminished the opportunity for psychosocial interventions (Bernard & Ganz, 1991; Zabora, BrintzenhofeSzoc, Curbow, Hooker, & Piantadosi, 2001). Poor performance status and rapid disease progression in many patients with lung cancer also inhibited studies that required patient attentiveness and cognitive effort. In addition, when lung cancer was predominantly a male diagnosis, men seemed more reluctant to participate in either psychosocial research or interventions (Addis & Mahalik, 2003; Blazina & Watkins, 1996; Möller-Leimkühler, 2002; Reevy & Maslach, 2001). But with increased numbers of both male and female patients as well as additional treatment options developed in the past 10 years, a concomitant focus has been on the specific psychosocial issues of patients with lung cancer and the treatment interventions that would be the most appropriate ways to address them. Because fewer than 3% of patients with lung cancer are younger than 45 years old, and the average age at diagnosis is 71 years old (American Cancer Society, 2009), this chapter will focus on the most common psychosocial issues of older patients and the variety of current treatment options.

Aging and Illness By 2030, one out of five Americans will be older than 65 years old (Rao & Cohen, 2004). Current collective healthcare resources are inadequate to meet the needs of this rapidly growing population, who represent high-volume users of healthcare services, particularly for medical conditions related to diabetes, heart disease, joint disease, and cancer. The greater need for mental health services can be anticipated among this large cohort of older, sometimes chronically ill patients (Institute of Medicine,

Psychological and Social Issues of the Older Patient With Lung Cancer Because of the late diagnosis of lung cancer in the context of comorbid aging issues, and at times, metastatic disease upon 153

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presentation, the patient is at risk for multiple psychosocial issues. Patients with lung cancer are faced with myriad challenges during the course of diagnosis and treatment. In addition to the physical manifestations of the disease such as pain, shortness of breath, and fatigue, psychological and practical issues must be addressed during each stage of the illness. The statistics on lung cancer survival superimpose a sense of immediacy to each of these stages. Specific interventions are needed to address the psychosocial characteristics of lung cancer such as demoralization, loneliness and isolation, depression, anxiety, shame and guilt, and the realization of one’s own mortality. Although social workers, psychologists, and psychiatrists are the primary providers in the provision of emotional care to the patient and family, nurses play a central role in both assessing patients’ psychosocial needs and, in some cases, providing the care themselves. The nurse, through education, support, and referral, plays a pivotal role in the psychosocial process at every point along the treatment continuum. For patients with lung cancer, particularly in the later stages of the disease, the collaboration of the multidisciplinary team is a primary factor in support of the patient/family system. As the saying goes, “it takes a village.”

all somatic symptoms are related to old age, reflecting the cultural negative attitudes of ageism (Weinberger, Roth, & Nelson, 2009). Most research on older adults has focused on depression, with less emphasis on anxiety and other problems of aging, though anxiety has been found to be generally correlated with depression. The presentation of depression in older people frequently appears as minor or subsyndromal depression with an estimated rate of 15%–25% in medically ill patients (Lyness, 2004). Older patients present with more somatic symptoms of depression than psychological, which compounds the likelihood of underdiagnosis and undertreatment (Morley, 2004; Yesavage et al., 1983). Anxiety disorders in late life have been overlooked more than depression as a cause of morbidity. Wolitzky-Taylor, Castriotta, Lenze, Stanley, and Craske (2010) estimated the prevalence of anxiety disorders can range from 3.2% to 14.2% because of the condition’s complex etiology. Moreover, some research points to anxiety as a particular problem for older people (Frazier, Waid, & Fincke, 2002). In addition, the onset of dementia may begin with symptoms of anxiety and depression (Henderson, 2000). Comorbid disorders such as major depression and generalized anxiety disorder significantly affect the ability to cope with physical losses and the limitations of older age and cancer treatment.

Loneliness and Isolation

Shame and Guilt

In both the geriatric and oncology literature, social isolation has been linked to an increased risk of mortality. The Nurses Health Study evaluated the impact of social support in 2,835 women with stage I–IV breast cancer. Socially isolated women had a 66% increased risk of all-cause mortality and a twofold increased risk of breast cancer–specific mortality, adjusted for covariates including stage of disease (Michael, Kawachi, Berkman, Holmes, & Colditz, 2000). Similar findings have been reported in the geriatric literature, demonstrating that an absence of social support is a predictor of poorer survival as well as greater psychological distress (Kornblith et al., 2003, 2006; Waxler-Morrison, Hislop, Mears, & Kan, 1991). Social support has been said to have a buffering effect for patients with cancer in that it protects the patient from the full impact of the stressors produced as a result of diagnosis (Cohen & Wills, 1985). Several studies have explored the association between social support and survival. One such study by Ell, Nishimoto, Mediansky, Mantell, and Hamovitch (1992) predicted differential rates of survival based on the type of cancer. However, in lung cancer, the only predictors for survival were stage of illness and role limitations. Social support was predictive of increased quality of life but had no effect on its length.

Although it seems to be a logical assumption that current or past smokers would experience more guilt and shame related to a diagnosis of lung cancer, the research has shown more nuanced results. One such study compared stage IV patients with non-small cell lung cancer (NSCLC), breast, or prostate cancer to determine the levels of guilt and shame related to previous smoking, with the assumption that NSCLC patients would have higher levels. The survey included tests of generalized guilt, shame, depression, and anxiety as well as guilt, shame, and embarrassment related to one’s cancer. Of the 172 participants in the study, patients with NSCLC had higher levels of perceived cancer-related stigma than patients with prostate cancer or breast cancer but not higher baseline levels of shame and guilt. A belief that one caused one’s own cancer is correlated with higher levels of guilt, shame, anxiety, and depression (LoConte, Else-Quest, Eickhoff, Hyde, & Schiller, 2008). These findings could be translated into an increased need for open communication among patients and their healthcare providers surrounding issues of cancer causation, guilt, shame, and other emotional disorders (LoConte et al., 2008).

Depression and Anxiety

Demoralization, Despair, and Existential Concerns

Older patients do not readily complain of mental symptoms, and physicians have a tendency to assume that

Older adults, especially those facing more urgent end-oflife issues, face a range of existential concerns, particularly 154

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demoralization (Jacobsen et al., 2006; Kissane et al., 2004). Jacobsen and colleagues (2006) relate demoralization to Erikson, Erikson, and Kivnick’s (1986) concept of despair in the final stage of life. It refers to a sense of regret over the life one has lived, as well as a feeling of hopelessness. Individuals who have achieved a sense of self, on the other hand, are more able to come to terms with the life that they have led, continue to feel connected to others, and experience a sense of meaning and coherence, as they face the approach of death. Kissane and colleagues (2004) described demoralization as existential despair, hopelessness, helplessness, and loss of meaning and purpose in life. They distinguished demoralization from depression as a sense of subjective failure to achieve life’s goals. Depression is characterized more by anhedonia (the loss of pleasure in living one’s life). In one prospective study, Jacobsen et al. (2006) conf irmed that these syndromes are distinct from each other and appear to be associated with the patient’s degree of inner peacefulness. Although these studies have come from patients receiving palliative care and those near the end of life, with about 14% of individuals describing themselves as “demoralized,” this construct may have applicability to older patients in active cancer treatment who are reporting high levels of distress (Breitbart, 2001; Chochinov, 2007).

of Viktor Frankl and uses a manualized therapy (a therapy approach that follows a set of prewritten suggestions or guidelines) to help patients with advanced cancer search for meaning. Chochinov (2007) is conducting a multinational study of dignity therapy to help patients cope with the end of life and leave a written legacy document for loved ones. This type of intervention facilitates patients’ ability to arrive at an integrated overview and understanding of their lives. Kissane and colleagues (2006) have developed a familyoriented therapy to facilitate a sense of meaning prior to a patient’s death. Two studies showed the efficacy of an interpersonal psychoeducational intervention on distress in largely older women with breast and lung cancer. In both studies, the intervention was delivered by telephone. Patients who received monthly telephone monitoring had significantly less anxiety, depression, and overall distress at six months (Gooen-Piels et al., 2007). Patients commented that the call between office visits meant that “someone cares,” highlighting the qualitative evidence of their social isolation (Donnelly et al., 2000; Gooen-Piels et al., 2007). A few interventions specifically tested on older patients with cancer have shown some promise. Lapid et al. (2007) provided a multidisciplinary therapy for 16 older patients with advanced cancer, five of whom had lung cancer. Those who completed the intervention had improved quality of life compared with patients who had been randomized to standard care. A review of the literature supports that psychoeducational interventions, including of the aforementioned components, assist in improving quality of life and depressive symptoms (Fawzy & Fawzy, 1998; Graves, 2003; Lepore, Helgeson, Eton, & Schulz, 2003; Penedo et al., 2006; Quesnel, Savard, Simard, Ivers, & Morin, 2003; Rehse & Pukrop, 2003) (see Table 11-1).

Treatment Interventions Despite the success of interventions for older patients with chronic illness and the desire for a nonmedication treatment, few psychotherapy or psychoeducational approaches have been specifically tested in older adults with cancer (Rao & Cohen, 2004). Several studies support group-based interventions to improve coping in patients with cancer of all ages. Individuals who share their cancer experience with others in the same situation are more likely to begin cognitive restructuring and to experience a sense of meaning (Lechner & Antoni, 2004; Penedo et al., 2006; Tedeschi & Calhoun, 1996). They also engage in cognitive coping skills such as reframing and processing of difficult events. Interventions that focus on anxiety reduction and provide helpful tools to assist further in the processing of painful past and present events have been found to be effective (Lechner & Antoni, 2004; Penedo et al., 2006; Tedeschi & Calhoun, 1996). A number of psychoeducational techniques have been tested in samples of older patients with cancer (Lander, Wilson, & Chochinov, 2000; Rao & Cohen, 2004). Supportive psychoeducational interventions and cognitive behavioral groups have specifically shown effectiveness (Lesczc, 1990, 1997; Rao & Cohen, 2004). Breitbart (2001) developed the meaning-centered psychoeducational intervention, which is based on the work

Caregiver Issues The caregiver of a loved one with lung cancer balances many conflicting feelings. Similar to the patient in the early stages of the illness, the caregiver struggles with the shock and fear of the life-threatening diagnosis. These feelings may be in direct conflict with other more antagonistic feelings, such as anger and blame from years of trying to intervene in the patient’s health issues along with fears of impending loss. The caregiver may also have feelings of anxiety and inadequacy about caring for the patient in the later stages of the disease. Some studies show a higher level of depressive symptoms in caregivers. In one such study, the authors sought to identify the personality correlates of depressive symptoms in 120 spouses of people with lung cancer. The results showed that neuroticism was directly associated with greater depressive symptoms and indirectly associated with less social support and greater caregiving burden. Interpersonal self-efficacy was indirectly 155

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every caregiver intervention has its limitations and may only assist in moderating the significant emotional impact of a life-threatening diagnosis. At times, the most that healthcare professionals can do is to provide reassurance that the multidisciplinary team will be available to the patient and family system throughout the treatment continuum by providing education, resources, and support appropriate to the stage of disease. Although this intervention may not seem substantial to the healthcare provider, for those facing the threat of impending loss, knowing that they will not be abandoned provides significant comfort during an extremely painful life process.

associated with the severity of depressive symptoms through both social support and caregiving burden (Kim, Duberstein, Sörensen, & Larson, 2005). These findings have implications for identifying spouses of individuals with lung cancer who are vulnerable to depression and could inform the design of programs to reduce depressive symptoms in the context of cancer caregiving. Depending on the caregiver’s needs, all of these issues can be addressed through individual, couple, or family counseling. For many caregivers, education and support groups may assist in providing the perspective of others who are struggling with the same issues. As with patient issues,

Table 11-1. Psychosocial Patient and Family Challenges and Clinical Interventions Throughout the Treatment Continuum Treatment Stage

Patient and Family Challenges

Psychosocial Clinical Interventions

Diagnosis

• Coping with the realization of one’s own mortality • Coping with the overwhelming emotions that accompany the diagnostic process • Making treatment decisions • Building a network of individuals and services that can provide emotional, practical, spiritual, and social supports throughout the disease and treatment process

• Validating emotional distress related to diagnosis • Helping the patient manage intense feelings of anxiety, fear, sadness, and helplessness • Facilitating integration of complex medical information • Providing orientation to the hospital system • Assisting the patient in managing disruption in family life and routines • Assisting with planning and medical decision making • Educating on practical assistance available (e.g., transportation, housing, financial, education) • Educating the patient and family about the psychosocial impact of cancer • Supporting and reinforcing information given by medical staff

Initiation of treatment

• Understanding the treatment plan • Moderating distressed mood • Preparing for the management of treatment side effects • Addressing concerns around body image, sexuality, and privacy • Reorganizing family roles for needed emotional support and practical assistance during treatment

• Facilitating communication with healthcare team • Teaching stress reduction techniques to manage anxiety regarding treatment side effects and postsurgical pain • Addressing concerns of body image, sexuality, and privacy • Mediating family issues such as role change and redistribution of responsibilities • Assisting the patient with changes in normative lifestyle and routines • Reducing stress, maximizing coping skills, and increasing the patient’s self-control through individual, couple, or family counseling; support groups; and community referrals • Encouraging mobilization of the patient’s preexisting support systems • Problem solving practical impediments to treatment compliance • Developing or facilitating appropriate discharge plan

Survivorship

• Recognizing and coping with fears of having less medical surveillance • Returning to work and personal situations predating the cancer diagnosis • Adapting to residual physical impairments and psychological stress • Readjusting expectations of support from family and friends

• Facilitating adjustment to living with uncertainty in the aftermath of cancer treatment • Providing individual, group, and couple counseling

(Continued on next page)

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Table 11-1. Psychosocial Patient and Family Challenges and Clinical Interventions Throughout the Treatment Continuum (Continued) Treatment Stage

Patient and Family Challenges

Psychosocial Clinical Interventions

Recurrence or advanced disease

• Regaining a life focus and time perspective appropriate to the changed prognosis • Processing information and developing communication with the medical team about the new stage of illness • Alleviating feelings of guilt, self-blame, failure, despair, and anger • Resolving practical problems related to the new or prolonged treatment schedule

• Assisting the patient in exploring medically indicated treatment options • Assisting the patient in identifying areas of control within the context of a changing prognosis • Beginning discussion of end-of-life planning (e.g., identifying a healthcare proxy, addressing dependent care issues) • Reinforcing options and availability of care in order to minimize anxiety related to fears of abandonment as illness progresses • Providing information regarding the availability of resources to help with physical symptoms, suffering, and existential distress

End of life

• Maintaining a meaningful quality of life • Developing coping strategies around deteriorating physical condition • Confronting existential or spiritual issues as appropriate to the patient/family system • Developing plan for surviving family members

• Assisting the patient and family in end-of-life decision making • Exploring homecare and inpatient options • Supporting effective decision making regarding advance directives and treatment cessation • Assisting the patient and family in expressing fears regarding separation and loss • Collaborating in developing a plan for pain and symptom management • Facilitating communication between the patient/family and the healthcare team • Engaging the patient and family in anticipatory grief work • Assisting family in making funeral arrangements as necessary • Providing information on relevant community resources

Bereavement

• Accepting the reality of the loss • Experiencing the pain of grief • Adjusting to familial and social roles as a result of the loss • Separating from the hospital support system • Withdrawing emotional energy over time from the deceased patient as a way of reinvesting in other people and activities

• Assisting family survivors with completion of these five tasks • Facilitating the family’s separation from the hospital system and encouraging reengagement with community life

Note. Based on information from Christ, 1993.

Summary

References

Although the challenges and psychosocial interventions for patients with lung cancer are similar to those of patients with other cancers, specific issues affect the severity of being diagnosed with this disease. Most patients with lung cancer are a particularly vulnerable population because of their age, medical comorbidities, advanced stage at diagnosis, and lower functional status due to the nature of the disease and the side effects of treatment. When other psychosocial issues are present, such as marital problems, a history of psychiatric disorders, financial difficulties, and ineffective coping styles, psychosocial intervention is not only an option but should be an integral part of the treatment process. The recent medical advances in extending patient survival time provide a new imperative for psychosocial providers to develop innovative interventions aimed at increasing the quality of life in this high-risk population.

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159

Index

The letter f after a page number indicates that relevant content appears in a figure; the letter t, in a table.

A ACE inhibitors, 146 acetylcholine, 76 action phase, of smoking cessation, 41 addiction, to nicotine, 39–42, 40f adenocarcinoma, 2, 10–11, 78, 81, 99–100, 121 Adjuvant Navelbine International Trialist Association (ANITA), 112–113 adrenal metastases, 49 air bronchogram, 134 alkylating agents, for SCLC, 91 Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC), 27 American College of Chest Physicians (ACCP) guidelines for cough treatment, 133 for NSCLC treatment, 104–105 American Joint Committee on Cancer (AJCC), 101 American Pain Society, 144 amifostine, 146–147 aminoglutethimide, 74 amphotericin B, 147 anaplastic lymphoma kinase (ALK) fusion gene, 16–17, 122 anemia, 78, 140–141. See also fatigue angiogenesis, 9–10 anorexia, 140 anterior mediastinotomy, 54 anthracyclines, for SCLC, 91 anticoagulants for DVT, 81

for superior vena cava syndrome, 60–61 antidiuretic hormone (ADH), 74 anti-Hu antibody, 77–78 antimetabolites, for SCLC, 91 antioxidants, 28 antithrombolytics, for superior vena cava syndrome, 60 anxiety, 154 anxiolytics, for dyspnea, 138 apoptosis, 5–6, 8–9, 11f arachidonic pathway, 28 arginine vasopressin (AVP), 74 argon plasma coagulation (APC), for hemoptysis, 134 asbestos, 25 atypical adenomatous hyperplasia (AAH), 10 autofluorescence bronchoscopy (AFB), 30–31 azathioprine, 77

bleomycin, 65 blood supply, for lungs, 133 bombesin, 89 bone maintenance, 72 bone metastasis, 49, 53, 73, 111–112, 144 bone pain, 49, 142 bone resorption, 72 bone scan, 67, 82 brachytherapy, 111, 132, 134 brain metastases, 49, 53, 93, 111 brand fading, 41 Bristol-Myers Squibb 099 trial, 117–118 bronchial carcinoid, 88 bronchoalveolar carcinoma (BAC), 2, 100 bronchoalveolar lavage (BAL), 53 bronchodilator therapy, 132, 138–139 bronchopulmonary resection, 103 bronchorrhea, 48 bronchoscopy, 30–31, 53–54, 132, 134 bupropion, for smoking cessation, 41, 43t

B back pain, 49, 66 behavioral approaches, to smoking cessation, 41 benzonatate, 132 Beta-Carotene and Retinol Efficacy Trial (CARET), 27 beta-carotene, as risk factor, 27 bevacizumab, 100, 115–116, 121, 133 bilobectomy, 106 biomarkers, 17–18, 29–31, 120–122, 145 bisphosphonates, 73, 83, 144 bleeding. See hemoptysis

C cachexia, 140 calcium, 71–72, 73f camptothecins, for SCLC, 91 cancer-related fatigue. See fatigue cancer stem cell hypothesis, 17 captopril, 146 carboplatin

161

for NSCLC, 113–115, 117– 118, 121–122, 133 for SCLC, 91 carcinogenesis, 7–12, 26, 88–89 carcinoid, 2t cardiac tamponade, 50t, 61–63 caregiver issues, 155–156 catheters, pleural, 65, 137 CAV chemotherapy regimen, for SCLC, 91, 95 celecoxib, 26, 28 cell cycle, 6, 6f cellular behavior malignant, 7–10, 8f–12f normal, 5–7, 6f cerebellar Purkinje cells, 77 cessation. See smoking cessation cetuximab, 115, 117 Chamberlain procedure, 54 chemokines, 16–17 chemoprevention, 26–28, 27t chemoprevention clinical trials, 27t chemotherapy adjuvant, 112–113 vs. best supportive care, 113–114, 118 combination regimens, 91–92, 114–115, 118 maintenance, 118–120 neoadjuvant, 113 for NSCLC, 112–120, 119f for pain management, 144 with radiation therapy, 90, 92–95, 111 for SCLC, 90–92 and superior vena cava syndrome, 60–61 and targeted agents, 115–118 chest CT scan, 52

INDEX

chest wall pain, 48, 142–143 chest x-ray, 28–29, 51–52, 60, 62, 64 chromogenic in situ hybridization (CISH), 17–18 chronic obstructive pulmonary disease (COPD), 23, 25, 108, 132 cigarette consumption, 21, 22f, 88. See also tobacco use Cigarette Labeling and Advertising Act, 37 cigarette smoke, 22–23, 88 cigarette tax, 38 cisplatin for NSCLC, 112, 114–118, 121–122 for SCLC, 91–92 c-Kit tyrosine kinase receptor signaling pathway, 8 clinical trials. See also specific trials on chemoprevention, 26–28, 27t on screening, 28–31, 30t–31t clonidine, for smoking cessation, 43t clubbing, 50t, 81–83, 82f c-MYC oncogene, 6–7 codeine, for cough, 133 Code of Practice on Tobacco Control for Health Professional Organizations, 39 cognitive-behavioral approaches, to smoking cessation, 41 cognitive function, 141 combined small cell carcinoma, 2–3 conivaptan, 75 constipation, with opioid use, 144 contemplation stage, of smoking cessation, 41 continuous hyperfractionated accelerated radiotherapy (CHART), 110 contrast venography, 60 corticosteroids chemoprevention with, 28 for cough, 132 for HPOA, 83 for Lambert-Eaton myasthenic syndrome, 77 for spinal cord compression, 67 cough, 48, 131–133 cough reflex, 131–132 cough suppressants, 132, 133t crizotinib, 122 CT myelogram, 67 CT pulmonary angiography, 80 CT scan, 52, 60, 62, 64, 66, 80, 90

Cushing syndrome, 50t, 74, 87 CXC chemokines, 16 CXCR4 chemokine receptor, 16 cyclin-dependent kinase inhibitors, 6 cyclin-dependent kinases (CDKs), 6 cyclins, 6 cyclooxygenase-2 (COX-2), 10, 11, 80, 101 cyclophosphamide, for SCLC, 91 Czechoslovakian study, 29, 30t

E-cadherin gene, 10 echocardiogram, 62 ectopic adrenocorticotropic hormone (ACTH) syndrome, 50t, 74, 87 EGFR receptors, 8 Elderly Lung Cancer Vinorelbine Italian Study (ELVIS trial), 118 electrocautery, for hemoptysis, 134 ELR-CXC chemokines, 16 EML4-ALK fusion gene, 16–17, 122 emotional distress, 141–142 emphysema, 25 endobronchial biopsy, 53–54 endobronchial brachytherapy, 111, 134 endobronchial ultrasound, with TBNA (EBUS + TBNA), 54 endocrine paraneoplastic syndromes, 71–76, 87 endoscopic ultrasound, with needle aspiration (EUS + NA), 54 energy conservation, 141–142 environmental exposures, as risk factor, 24–25 EP chemotherapy regimen, for SCLC, 91 epidermal growth factor, 5 epidermal growth factor receptors (EGFRs), 7, 15–16, 28, 100, 121 epipodophyllotoxins, for SCLC, 91 ERBB proto-oncogenes, 89 erlotinib, 115–121 erythropoietin-stimulating agents (ESAs), 141 esophagitis, from RT, 92–93, 146–147 etoposide for NSCLC, 112, 114 for SCLC, 91–92, 95 European Cancer Anaemia Survey, 140–141 exercise, 24 for fatigue management, 141–142 presurgical, 109f–110f extensive disease (ED), 89–92 extrathoracic tumor spread, 49 exudative pleural effusions, 64

D DANTE trial, 31t D-dimer testing, 80 deep vein thrombosis (DVT), 78, 80 demeclocycline, 75 demoralization, 155 denosumab, 73 dependence, on tobacco, 39–40, 40f, 40–42 DepiScan trial, 31t depression, 141, 154–155 despair, 155 dexamethasone supression tests, 74 dextromethorphan, for cough, 132 diagnosis/diagnostic testing invasive, 53–55 of lung cancer, 50–55 noninvasive, 51–53 of superior vena cava syndrome, 60 diet, as risk factor, 23, 24f dimerization, 15 distress, 141–142 diuretics for SIADH, 75 for superior vena cava syndrome, 60 division, of cells, 5 docetaxel for NSCLC, 112, 114, 120 for SCLC, 95 dopamine, released by nicotine, 39–40 Doppler ultrasound, for DVT diagnosis, 80 dose, of radiation therapy, 93 doxorubicin, for SCLC, 91 dysphagia, 48–49 dyspnea, 48, 135–139, 136f, 140

F Family Smoking Prevention and Tobacco Control Act, 38 fatigue, 76–77, 139f, 139–144 FDG-PET scanning, 52

E Early Lung Cancer Action Project (ELCAP), 29

162

fibroblast growth factor (FGF), 9 fine needle aspiration (FNA), 53 First-Line Erbitux in Lung Cancer (FLEX) trial, 117 five A’s algorithm, for smoking cessation, 40 five-year survival rates, 2, 21, 26, 100–101, 104 flexible bronchoscopy, 53 fluorescence in situ hybridization (FISH), 17–18 fractionation, of radiation therapy, 93, 110 fruits/vegetables, consumption of, 23 fungal infections, 146 furosemide, 75

G gastrin-releasing peptide (GRP), 89 gastroesophageal reflux disease (GERD), cough with, 132 gefitinib, 115–118, 121 gemcitabine for NSCLC, 112, 114, 116, 118, 121 for SCLC, 95 genetic risk factors, 25–26 global initiatives, for tobacco restriction, 38 growth factor receptor-bound protein-2 (GRB2), 13 guanidine, for Lambert-Eaton myasthenic syndrome, 77 guilt, 154

H haploinsufficiency, 7 Hedgehog (Hh) signaling pathway, 17 hematemesis, 134 hematologic paraneoplastic syndromes, 78–81 hemoptysis, 48, 131, 133–135 heparin, 81 heterodimerization, 15 high-dose-rate brachytherapy, 111 histologic classifications, 2t, 2–3, 88, 100, 120–122 hoarseness, 48 Homan’s sign, 80 homodimerization, 15 hopelessness, 155 Horner syndrome, 49 humoral hypercalcemia of malignancy, 50t, 71–74, 99 hydrocodone, for cough, 133

INDEX

hypercalcemia, 71–72, 73f, 99. See also humoral hypercalcemia of malignancy hyperfractionation, of RT, 110 hyperparathyroidism, 71 hypertrophic osteoarthropathy (HOA), 81–83 hypertrophic pulmonary osteoarthopathy (HPOA), 50t, 81–83, 99 hyponatremia, 75 hypophosphatemia, 73

I ifosfamide, for SCLC, 95 incidence, 1, 1t, 21, 87 initiation phase, of carcinogenesis, 26, 88–89 injection augmentation (IA), 48 insulin-like growth factor-1 (IGF-1), 7 insulin-like growth factor (IGF) pathway, 14 integrins/integrin receptors, 5, 10 intensity-modulated radiation therapy (IMRT), 110–111 International Adjuvant Lung Cancer Trial Collaborative Group, 112, 122 International Association for the Study of Lung Cancer (IASLC), 3, 89, 101 International ELCAP (I-ELCAP) study, 29 International Staging System for Lung Cancer, 3, 101 International Union Against Cancer, 101 interstitial brachytherapy, 111 intravasation, 10 Iressa Pan-Asia Study (IPASS), 117 Iressa Survival Evaluation in Lung Cancer trial, 116 irinotecan for NSCLC, 112, 114–115 for SCLC, 91, 95 isolation, 154 ITALUNG trial, 31t

J Johns Hopkins Lung Project, 28–29, 30t

K ketoconazole, 74 K-ras mutation, 7, 10, 12–13, 121

L

from NSCLC, 99, 102f, 106f from SCLC, 87 spinal cord, 66 metyrapone, 74 microRNA, 16 midazolam, for dyspnea, 138 mitochondrial outer membrane permeability (MOMP), 8 mitogen-activated protein kinase (MAPK) pathway, 13–14 mitogens, 6 mitosis, 6f, 6–7 molecular markers, for NSCLC, 100–101 morphine, for dyspnea, 138 mortality rates from lung cancer, 1, 1t, 21, 22f, 47 from lung surgeries, 106 from tobacco use, 37–38 motivational interviewing (MI), for smoking cessation, 41 mucositis, 146–147 muscular weakness, 76 musculoskeletal paraneoplastic syndromes, 81–83 mutations, 7–10, 10f. See also specific genes myasthenia gravis, 77 MYC oncogenes, 6–7, 89 myelocytomatosis oncogene (c-MYC), 6–7

laboratory testing, for diagnosis, 51–53 Lambert-Eaton myasthenic syndrome (LEMS), 50t, 76–79, 87 large cell carcinoma, 2, 99–100, 121 laryngeal framework surgery, 48 laser-induced fluorescence endoscopy (LIFE), 30–31 let-7 family of microRNA, 16 leukotrienes, 28 limited disease (LD), 89–90, 92, 94 lipoxygenase (LOX) pathway, 28 lobectomy, 103, 106 locus coeruleus, 40 lomustine, for SCLC, 91 loneliness, 154 low-dose computed tomography (LDCT), 21, 29, 31t low-molecular-weight heparin (LMWH), 81 Lung Adjuvant Cisplatin Evaluation (LACE) Collaborative Group, 113 Lung Screening Feasibility Study, 31t lymphangitic tumor spread, 49 lymph node mapping, 101, 107t lymph node sampling, during surgery, 106–107

N

M

National Comprehensive Cancer Network (NCCN) guidelines on biomarkers, 17 on chemotherapy, 112 on diagnostic testing, 52 on radiation therapy, 93–94 on symptom management, 131, 141 National Institutes of HealthAARP Diet and Health Study, 24 National Lung Screening Trial (NLST), 21, 28–29, 31t Nd:YAG laser photocoagulation, for hemoptysis, 134 negative predictive value, of screening tests, 28 NELSON trial, 31t neuroendocrine carcinomas, 88 neurologic paraneoplastic disorders, 76–78, 87 neuropathic pain, 143 neurotransmitters, 39–40, 76 nicotine, 23, 88 addiction to, 39–42, 40f nicotine replacement therapy (NRT), 39, 41–42

magnetic resonance imaging (MRI), 52–53, 60, 67, 80, 90 maintenance phase, of smoking cessation, 41 maintenance therapy, in advanced NSCLC, 118–120 malignant spinal cord compression, 49, 50t, 65–67, 144 massive hemoptysis, 134–135 Mayo Lung Project, 28, 30t mediastinoscopy, 54 Medical Research Council Lung Working Party, 91 Medical Research Council of Great Britain, 90, 94 Memorial Sloan-Kettering Cancer Center (MSKCC) Lung Study, 28–29, 30t mental status changes, 141 mesenchymal-epithelial transition factor (c-Met), 7, 13 mesothelioma, 25 metastases, 10, 12f adrenal, 49 bone, 49, 53, 73, 111–112 to brain, 49, 53, 93, 111

163

nicotine vaccine, 42 nociceptive pain, 143 non-small cell lung cancer (NSCLC), 2, 2t, 99 advanced, 113, 119f, 119–120 chemotherapy for, 112–120, 119f classification of, 100, 120–122 radiation therapy for, 108–112 recurrent, 120 signs/symptoms of, 99–100 staging of, 99–101, 102f surgical treatment for, 101–108 Non-Small Cell Lung Cancer Collaborative Group, 104 North American Intergroup trial, 93 North East Japan Study Group, 117 nortriptyline, for smoking cessation, 43t Notch signaling pathway, 17 Nurses for Tobacco Control Coalition (NTCC), 38–39 Nurses Health Study, 154 nursing care following lung resection, 108 tobacco cessation and, 38–39

O occupational exposures, as risk factors, 25 octreotide, 74, 83 older adults, 153 back pain in, 66 NSCLC in, 118 psychosocial concerns of, 153–155, 156t–157t SCLC in, 95–96 oncogenes, 6–7, 88–89 oncologic emergencies, 50, 50t, 59–67. See also specific conditions one-year survival rates, 26 opioids for cough, 133 for dyspnea, 138 for pain, 144 optical coherence tomography (OCT), 31 osteolytic hypercalcemia, 72 osteonecrosis of the jaw (ONJ), 73–74 oxaliplatin, 122 oxygen therapy, for dyspnea, 138

P PI3K/AKT signaling pathway, 14

INDEX

PI3K signaling pathway, 13–14 paclitaxel for NSCLC, 112–115, 117– 118, 121, 133 for SCLC, 95 pain, 142–144 assessment of, 143 back, 49, 66 bone, 49, 142 chest wall, 48, 142–143 fatigue from, 140 management of, 143 palliative chemotherapy, 95, 144 palliative radiation therapy, 111, 144 pamidronate, 73, 83, 144 Pancoast tumors, 49, 142, 144 paraneoplastic cerebellar degeneration, 50t, 77–78 paraneoplastic encephalomyelitis, 76, 87 paraneoplastic syndromes, 50, 50t. See also specific syndromes endocrine, 71–76 hematologic, 78–81 musculoskeletal, 81–83 neurologic, 76–78 with NSCLC, 99 with SCLC, 87 parathyroid hormone (PTH), 71 parietal pleura, 63 pathogenesis, of lung cancer, 3–4 patient history, 50–51, 51t pemetrexed, for NSCLC, 112, 119–121 performance status (PS), 99– 100, 114, 118, 120t, 122 pericardial effusion, 50t, 61–63 pericardial fluid, 62 pericardial window, 63 pericardiectomy, 63 pericardiocentesis, 63 periostosis of long bones, 81–83 peripheral neuropathy, 143 PET-CT scanning, 52 pharyngitis, from radiation therapy, 146–147 photodynamic therapy (PDT), for hemoptysis, 134 phrenic nerve paralysis, 48–49 physical activity, 24 for fatigue management, 141–142 presurgical, 109f–110f physical examination, 50–51, 51t Physicians Health Study, 27 phytochemicals, 28 platinum-based chemotherapy. See also carboplatin; cisplatin; oxaliplatin anemia from, 141 for NSCLC, 114–115, 118, 122

for SCLC, 91, 95 pleural catheters, 65, 137 pleural effusion, 50t, 63–65, 90, 132, 137 pleural fluid, 64 pleural space, 63 pleurectomy, 65 pleurodesis, 64–65 pleuroperitoneal shunting, 65 pneumonectomy, 103, 105–106 pneumonitis, from RT, 92, 137, 144–147 positive predictive value, of screening tests, 28 positron-emission tomography (PET), 52, 90 postnasal drip, cough from, 132 precontemplation phase, of smoking cessation, 41 predictive factors, 17 prednisolone, for Lambert-Eaton myasthenic syndrome, 77 preparation phase, of smoking cessation, 41 primary chemoprevention, 26 prognostic factors, 3, 17 for NSCLC, 103t for SCLC, 90 progression phase, of carcinogenesis, 26, 88–89 promotion phase, of carcinogenesis, 26, 88–89 prophylactic cranial irradiation (PCI), 93–95 Prophylactic Cranial Irradiation Overview Collaborative Group, 93 Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), 29, 30t proton beam therapy, 110 proto-oncogenes, 5, 7, 12–13, 88–89 psychosocial concerns, 153–155, 156t–157t psychotherapeutic interventions, 155 pulmonary angiography, 80 pulmonary emboli, 78 pulmonary rehabilitation, 139 pulsus paradoxus, 62

dosing/fractionation of, 93, 110 for NSCLC, 108–112 for pain management, 144 postoperative, 111 for SCLC, 90 sequencing/timing, 92 for spinal cord compression, 67 and superior vena cava syndrome, 60–61 target volumes, 92–93 toxicities of, 92 Radiation Therapy Oncology Group (RTOG), 146 radioprotective agents, 146–147 radon, 24 raloxifene, for prevention, 26 RANKL (receptor activator of nuclear factor kappa B ligand), 72–73 Ras/Raf/MAPK pathway, 14 rat sarcoma gene family (RAS), 6 receptor activator of nuclear factor kappa B ligand (RANKL), 72–73 recurrent disease, 94–95, 120 regional lymph nodes, and NSCLC, 101, 102f. See also TNM staging replication, of cells, 5, 9 retinoblastoma protein (pRB), 6, 89 reversibility, of carcinogenesis, 26 risk factors, 21–26

S salvage therapy, 94–95 sarcomatoid carcinoma, 2t sclerosing agents, 63, 65 screening, 28–31, 30t–31t secondary chemoprevention, 26 secondhand smoke (SHS), 23, 37 second-line chemotherapy regimens, 95, 120 segmentectomy, 106 selective COX-2 inhibitors, 26, 28 selective estrogen receptor modulators (SERMs), 26 senescence, 9 sensitivity, of screening tests, 28 sensory neuropathy, 87 Sequential Tarceva in Unresectable NSCLC (SATURN) trial, 119–120 shame, 154 shortness of breath. See dyspnea shunts, pleuroperitoneal, 65

R radiation myelopathy, 92 radiation pneumonitis, 92, 137, 144–147 radiation target volumes, 92–93 radiation therapy (RT) for bone metastases, 112 chemotherapy with, 90, 92–95, 111

164

signaling pathways, 6–8, 9f, 14–16, 15f signs and symptoms of cardiac tamponade, 62 of cerebellar degeneration, 77–78 of clubbing, 82, 82f of DVT, 80 of ectopic ACTH syndrome, 74 of hypercalcemia of malignancy, 72, 72t of Lambert-Eaton myasthenic syndrome, 76–77 of lung cancer, 47t, 47–50 of NSCLC, 99–100 of pleural effusion, 64 of SCLC, 87–88 of SIADH, 75 of spinal cord compression, 66 of superior vena cava syndrome, 60 sleep disturbances, 142. See also fatigue small cell lung cancer (SCLC), 2t, 2–3, 87 classification of, 88 extensive-stage treatment, 91–92 history of treatment, 90–91 limited-stage treatment, 92, 94 molecular/genetic characteristics, 88–89 prevalence of, 87 recurrent, 94–95 signs/symptoms of, 87–88, 132 staging of, 89–90 surgical treatment of, 94 smoking. See tobacco use smoking cessation, 22, 38–39, 40f, 40–42 approaches to, 41 barriers to, 39–41 pharmacotherapy for, 41–42, 42t–43t with surgery, 108 social support, for older patients, 154 socioeconomic status (SES), as risk factor, 25 sodium replacement therapy, 75 somatic pain, 143 specificity, of screening tests, 28 spinal cord, 65–66 spinal cord compression, 49, 50t, 65–67, 144 spinal cord metastases, 66 spiral CT, 80 sputum cytology, 28–29, 53 squamous cell carcinoma (SCC), 11, 59, 99–100, 121, 132–133

INDEX

stages-of-change model, for smoking cessation, 41 staging, 3 of NSCLC, 99–100, 102f, 105 of SCLC, 3, 89–90 and surgical treatment, 101–105 standard uptake ratio (SUR), 52 standard uptake value (SUV), 52 stent placement, for superior vena cava syndrome, 61 stereotactic body radiation therapy (SBRT), 110–111 stridor, 48 sulindac, chemoprevention with, 28 superior vena cava, 59–60 superior vena cava syndrome (SVCS), 50t, 59–61, 80 surgical treatment chemotherapy before, 113 exercise program for, 109f– 110f for hoarseness, 48 for NSCLC, 101–108 for pericardial effusion, 63 for pleural effusion, 64–65 for SCLC, 90, 94 for spinal cord compression, 67 survival rates, 2, 21, 26, 100– 101, 104 syndrome of inappropriate antidiuretic hormone (SIADH), 50t, 74–76, 75f, 87

T talc pleurodesis, 65 tamoxifen, for prevention, 26 targeted agents, for NSCLC, 115–118 tar, in cigarette smoke, 88 telomeres/telomerase, 9, 11 teniposide, for SCLC, 91

tertiary chemoprevention, 26 therapeutic ratio, of RT, 110 thiotepa, 63 thoracentesis, 64, 137 thoracoscopy, 54 thoracotomy, 54–55, 89 three-dimensional conformal radiation therapy (3DCRT), 110 3,4–DAP, for Lambert-Eaton myasthenic syndrome, 77 thromboembolic disease, 80 thrombophlebitis, 78 Tobacco Free Nurses campaign, 39 Tobacco Master Settlement Agreement, 38 tobacco use. See also nicotine; smoking cessation dependence on, 39–42, 40f history of, 37–38 prevalence of, 1–2, 38 as risk factor, 21–23, 22f and SCLC, 88 tolvaptan, 75 topotecan, for SCLC, 91, 95 TP53 mutation, 6–14, 89, 101 transbronchial needle aspiration (TBNA), 53–54 transcervical extended mediastinal lymphadenectomy (TEMLA), 54 transforming growth factor-beta, 5 transtheoretical model, for smoking cessation, 41 transthoracic needle aspiration (TTNA), 53 transudative pleural effusions, 64 Trousseau syndrome, 50t, 78–81, 79f tuberous sclerosis complex (TSC), 10 tube thoracoscopy, 64 tumor necrosis factor-alpha, 5–6 tumor, node, metastasis (TNM) staging, 3, 89, 99–101, 103f–106f

tumor protein 53, 6 tumor suppressor genes, 5–7, 8f, 89 two-dimensional echocardiogram, 62 type I thyroplasty, 48 tyrosine kinase proto-oncogenes, 89

U ultrasound, 54, 80 U.S. Department of Health and Human Services (DHHS) guidelines, for smoking cessation, 40, 40f, 41 U.S. Public Health Service guidelines, for smoking cessation, 40 U.S. Surgeon General’s report, on smoking, 37, 88

V varenicline, for smoking cessation, 41, 43t vascular endothelial growth factor (VEGF), 9, 101, 115 vasopressin receptor antagonists, 75 ventilation perfusion scan (V/Q scan), 80 very limited disease (VLD), 94 Veterans Administration Lung Cancer Study Group (VALCSG), 90 staging system, 89 video-assisted mediastinal lymphadenectomy (VALMA), 54 video-assisted thoracic surgery (VATS), 54, 65, 108 vinblastine, for NSCLC, 112 vinca alkaloids, for SCLC, 91

165

vincristine, for SCLC, 91 vindesine, for NSCLC, 112 vinorelbine for NSCLC, 112–114, 117–118 for SCLC, 95 Virchow triad, 78 visceral pain, 143 visceral pleura, 63 volatile organic compounds (VOCs), 30 voltage-gated calcium channels (VGCCs), 76

W Wallstent intravascular stent, 61 warfarin, 81 water intoxication, 75 wedge resection, 103, 106 weight loss, 140 wheezing, 48 whole brain radiation therapy (WBRT), 111 wild-type ras proteins, 13, 121 withdrawal, from nicotine addiction, 39–40 WNT signaling pathway, 17 women lung cancer in, 1t, 1–2 smoking rates for, 88 World Health Organization (WHO) Framework Convention on Tobacco Control, 38 histologic classifications, 2t, 2–3

Z zileuton, chemoprevention with, 28 zoledronic acid, 49, 73, 83, 144