New Cancer Research Developments [1 ed.] 9781608765058, 9781606924471

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Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved.

Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved.

NEW CANCER RESEARCH DEVELOPMENTS

Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved.

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.

Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved.

NEW CANCER RESEARCH DEVELOPMENTS

THOMAS D. FORD

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EDITOR

Nova Biomedical Books New York

Copyright © 2009 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication.

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This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA New cancer research developments / editor, Thomas D. Ford. p. ; cm. Includes bibliographical references and index. ISBN 978-1-60876-505-8 (E-Book) 1. Cancer. 2. Breast--Cancer--Radiotherapy. 3. Carcinogenesis. 4. Cancer--Molecular aspects. I. Ford, Thomas D. [DNLM: 1. Neoplasms. 2. Biomedical Research. QZ 200 N5305 2009] RC262.N49 2009 616.99'44906--dc22 2009002418

Published by Nova Science Publishers, Inc.  New York

CONTENTS Preface Chapter I

Chapter II

Chapter III

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Chapter IV

vii Radiotherapy in Autologous Breast Reconstruction: Timing and Outcomes Namrata S. Anavekar and Warren M. Rozen Risk Analysis and Risk Management of Radiation Treatment for Breast and Other Cancers Robert C. Lee Cardiac Toxicity after Radiotherapy for Breast Cancer: Current Concepts of Associated Risk and Strategies of Dose Reduction Thomas Kuhnt, Martin Friese and Dirk Vordermark Intraoperative Radiotherapy in the Conventional Linear Accelerator Room for Early Breast Cancer Treatment Antonio Luiz Frasson, Felipe Pereira Zerwes, Aroldo Paiva Braga Filho, Fabiane Barbosa, Betina Vollbrecht and Janaina Viegas

1

19

79

91

Chapter V

Cancers in Persons with Intellectual Disability: Current Data Daniel Satgé, Bernard Azéma, Stéphane Culine and Annie J. Sasco

Chapter VI

The Role of the Cytokines in Udder Immunity Evaluation in Dairy Cows Angelo Peli and Domenico Britti

139

Interleukin-18 And Its Roles As Neuro-Immuno-Modulator in the Periphery and the Central Nervous System Shuei Sugama and Bruno Conti

165

Chapter VII

Chapter VIII

Role of Molecular Biology in Molecular Imaging Archana Mukherjee and Mathew L. Thakur

101

187

Contents

vi Chapter IX

Mutational Analysis of the Lung Cancer Genome – Era of High-Throughput Sequencing and Targeted Therapy Zhe Tang, Runlei Du, Shan Jiang and Patrick C. Ma

Chapter X

Mechanisms of Adrenocortical Growth and Tumorigenesis Matthias Haase, Holger S. Willenberg, Sven Schinner and Matthias Schott

255

Chapter XI

Mechanisms of B-Cell lymphomagenesis Takashi Kumagai

271

Chapter XII

Fibronectin – A Matrix Glycoprotein with Roles in Lung Carcinoma Cell Growth and Progression ShouWei Han, Jeffrey D. Ritzenthaler and Jesse Roman

293

ATP Binding Cassette Transporters in Resistance to Clinically Relevant Antitumor Agents Laura Gatti, Giovanni Luca Beretta and Paola Perego

317

Chapter XIII

Chapter XIV

Regulated Secretion of Chemokines from Endothelial Cells Inger Øynebråten and Guttorm Haraldsen

339

Chapter XV

Different Fates of In Vitro T Cell Activation: Methods and Pitfalls E. Valencic, E. Piscianz, M. Granzotto and A. Tommasini

361

Chapter XVI

Extraperitoneal Endoscopic Radical Prostatectomy: Techniques and Results Marcos Tobias-Machado, Eduardo S Starling, Fernando Korkes, Ricardo L Machado and Eric R. Wroclawski

Short Communication A: Cancer Biology: From Molecular Biology to Systems Biology James A. Marcum

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219

377

397

Short Communication B: Retinoblastoma Laura Schwartz

409

Index

413

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PREFACE Cancer is a group of different diseases (more than 100) characterized by uncontrolled growth and spread of abnormal cells. Cancer can arise in many sites and behave differently depending on its organ of origin. If a cancer spreads (metastasizes), the new tumor bears the same name as the original (primary) tumor. Significant progress has been made in recent years in the battle against cancer and in understanding its underlying biological mechanisms. This research progress has resulted in many experimental treatments and cures which establish hope for wide-spread cures. This book presents new research of importance to the field. Chapter I - Radiotherapy has become increasingly important as a component of breast cancer management. Recent randomized trials have demonstrated that radiotherapy delays and prevents local recurrence, as well as improving breast cancer mortality and overall survival. At the same time, breast reconstruction plays a significant role in the management of breast cancer, with significant psychosocial benefit to the patient. With each modality affecting the delivery of the other, the optimal timing for either radiotherapy or breast reconstruction are points of contention. While autologous breast reconstruction may have less radiation-associated complications compared to expander/implant reconstruction, the timing of radiotherapy in this setting is controversial. Some studies suggest that delay in administration of radiotherapy may reduce the chance of loco-regional disease control and impact on overall survival, while others have suggested no such effect. Similarly, some studies have demonstrated no effect on cosmetic outcome or complications with adjuvant radiotherapy, while others have shown increased rates of fat necrosis, infection, and poor cosmesis. The current paper comprises a thorough Medline literature review, performed with a focus on the oncological need for adjuvant or neoadjuvant radiotherapy and the effect of radiotherapy timing on breast reconstruction. We subsequently discuss our experience with radiotherapy in this setting, reviewing 181 cases of autologous breast reconstruction with the abdominal wall donor site. Length of operation, length of stay, operative complications and oncologic outcome were assessed. Immediate breast reconstruction does not impair the oncological safety of breast cancer management, with no increase in local recurrence rates, and no delays in the initiation of radiotherapy. There is some evidence for increased complications in the setting of adjuvant

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radiotherapy, but both the literature review and our experience did not show this to be statistically significant. Breast reconstruction is oncologically safe in both the immediate and delayed settings, but optimal conditions for reconstruction require consideration. Based on the evidence presented, recommendations for management are discussed. Chapter II - External beam radiation treatment for breast and other cancers can be highly effective, but is associated with a nontrivial risk of patient morbidity or mortality if improperly administered. This chapter describes a multifaceted research program designed to characterize, analyze, and manage risks in radiation treatment (RT) for cancer. The program was conducted from 2003 to 2006 at a large cancer treatment facility in Canada. This work represents the first time, to the author’s knowledge, that a holistic quantitative risk analysis and risk management framework has been applied in a health care scenario. The Introduction to this chapter describes the context and the framework itself. Subsequent sections summarize the following analyses: • •

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• •

An analysis of the impact on RT decisions of uncertainties associated with staging of breast cancer; Development and evaluation of an incident taxonomy and classification system for RT; A probabilistic fault tree analysis of a portion of the RT process; and, Introduction of an incident learning system (ILS) to a cancer treatment organization, and analysis of its impact.

In conclusion, the findings and impact of this research in the context of cancer treatment, and as relevant to health care in general, are discussed. Chapter III - Post-operative radiotherapy of the surgically treated breast or chest wall has successfully reduced locaregional recurrence rates with some improvement in long-term survival. Radiotherapy for left-sided breast cancer, however, has been linked to increased rates of cardiac events including myocardial infarction and sudden death. Own data show that with currently used 3D-conformal radiotherapy techniques (tangential beam technique vs. photon-electron technique), specific dose distributions in cardiac structures (coronary arteries, valves, large vessels) must be expected. Whereas favorable protection of most structures is observerd with tangential beam technique, the left coronary artery is frequently located in the mid- to high dose region even with this technique. Recent studies regarding the risk of cardiac toxicity suggest that the risk is moderate with adequate total doses of radiotherapy and adequate target volumes but severely increased with (now obsolete) treatment regimens. In an analysis of over 27,000 women treated with radiotherapy for breast cancer, the 15-year cardiac mortality rates for patients with left-sided vs. right-sided breast cancer were 13.1% vs. 10.2% (treatment period 1973-79), 9.4% vs. 8.7% (1980-1984) and 5.8% vs. 5.2% (1985-1989), respectively, also suggesting that cardiac risk is not significantly increased after modern radiotherapy for breast cancer. Cardiac morbidity, including ischemic heart disease, valvular dysfunction, arrhythmia and congestive heart failure, was also similar between left-sided and right-sided breast cancer patients treated with radiotherapy, at a mean follow-up of 9.5 years. Despite these encouraging data, there is some concern about long-term cardiac event risk after combination

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therapy with radiotherapy and potentially cardiotoxic chemotherapy (epirubicin) or molecular targeting agents (trastuzumab) and there is so far a lack of high-quality data with a sufficiently long follow-up (>15 years) regarding this issue. Pilot studies have shown that specific techniques of triggering the radiation beam to breathing phases, in particular to deep-inspiration breath hold, may reduce the dose-volume exposure of the heart in patients with unfavorable thoracic anatomy and thereby significantly reduce the estimated cardiac mortality. Functional imaging of the heart has recently received attention as a tool to study early changes after radiotherapy. In particular, prospective singlephoton emission computed tomography (SPECT) perfusion studies demonstrated the development of new perfusion defects in about 30 to 40% of patients with left-sided breast cancer in the first two years after radiotherapy, the probability of which was associated with the percentage of the heart volume exposed. An understanding of the long-term functional consequences of this finding requires further study. Chapter IV - Breast-conserving surgery is widely accepted form of treatment in patients with initial breast cancer [1,2]. To reduce the risk of local recurrence, conservative procedures necessitate post-surgical treatment with radiotherapy, which, in the majority of cases, is applied to the whole breast with the dosage varying from 50-66 Gy in 5-6 weeks, with or without a boost applied to the scar [3-6]. Most of the literature reports that postoperative radiotherapy considerably reduces the risk of local recurrence, but does not substantially influence survival [7-10]. Recent study findings show that local recurrence after breast-conserving surgery occurs mostly in the quadrant harbouring the primary carcinoma, suggesting that whole-breast radiotherapy may not always be necessary [11]. The rationale for the use of this segmental radiation therapy in place of whole-breast irradiation is based on the finding that approximately 85% of breast relapses occur in close proximity to the primary tumour bed [12]. Thus, the necessity of whole breast radiotherapy has been questioned, and several centres have evaluated the feasibility and efficacy of single tumour bed irradiation [11-14]. Interest in intraoperative radiation therapy for breast cancer has increased as the possible benefits of this technique for the patient have become apparent. Chapter V - The frequency of cancer in persons with intellectual disability (PWID) is globally similar to the one in the general population. However, the neoplasms are different: their distribution in various organs and tissues is peculiar, and sometimes they occur earlier. The group is not homogeneous, as each constitutional or acquired condition, genetic or nongenetic, displays its own tumor profile. The tumor profile of Down syndrome, with some neoplasms more represented and others less frequent, and the tumor profile of type 1 neurofibromatosis are the best known. Additionally, for the whole group, there is a probably enhanced risk for digestive tract tumors, as well as a reduced risk for ear, nose and throat tumors, respiratory tumors and skin tumors, most probably due to different exposure to known risk factors related to the conditions of life of these patients in institution or in the community. The diagnosis of neoplasm in PWID is sometimes made late, for example, the diagnosis of breast cancer. A specific follow-up should be performed taking into account the particular cancer risk of the syndromes. The available means of cancer surveillance and cancer screening recommended in the general population should be adapted. For instance, cervical

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screening may not be needed if there is no sexual activity, and prostate cancer screening is debatable given the low frequency of prostatic cancer in old men with intellectual disabilities. On the contrary, a particular surveillance is needed for digestive cancers, as well as for testicular cancer. Treatment is sometimes difficult due to the larger tumor volume and higher tumor stage in some patients, and also because of difficulties with communication between the patient and the oncologic team due to limited input of PWID. Additionally, biological particularities of some conditions sometimes necessitate modifying the procedures for anaesthesia, surgery, radiotherapy and chemotherapy. An adapted care model of PWID with cancer necessitates the use of a multidisciplinary approach, and a good knowledge of three fields: intellectual disability, somatic repercussion of genetic diseases (biological, pharmacological etc.), and oncology. This challenge is being effectively met in the treatment of cancer in Down syndrome, particularly for leukaemia. This should be extended to other frequently occurring conditions, such as Fragile X syndrome, 22q11 microdeletion syndrome, and neonatal causes. For such purpose we gathered and synthesised the available data on epidemiology, diagnosis and treatment of persons with intellectual disabilities having a neoplasia. Chapter VI - Mastitis are generally recognized as one of the most costly diseases for the dairy industry. The routine diagnostic tools (somatic cells count, bacteriological examination etc) are useful to identify diseased subjects and the causative agent but they give no information about the stage of the infection and the type of immune response. For this reason, the traditional laboratory methods for the diagnosis of mastitis are inadequate from an immunological point of view. In the last two decades, the interest of many researchers focused on the role of immunological mediators, such as the cytokines, in the mechanisms of defence against mastitis. Cytokines are small proteins involved in a variety of physiological/pathological processes and, in particular, these molecules are critical in the induction, modulation, and resolution of the inflammatory response. There are three main directories of research on the role of the cytokines in the evaluation of udder immunity in dairy cows: 1) cytokines as biomarkers to evaluate the immunological status of the animal or of the mammary gland; 2) cytokines in new strategies for immunotherapy; 3) cytokines as “natural adjutants” in developing efficacious vaccines against mastitis. The understanding of the changes in the cytokine profile in healthy and mastitic mammary gland could helpful to detect a pre-inflammatory status or a sub-clinical infection, to evaluate the immunological status of the udder, and to monitor the efficacy of a pharmacological treatment. Furthermore, the comprehension of the role of cytokines in connecting the immune system and the inflammatory cascade is crucial to set up new therapeutic strategies aimed: to inhibit the synthesis and the release of cell mediators; to stimulate the production of antiinflammatory cytokines; to remove the circulating inflammatory molecules; to block their binding to the cellular receptors or, finally, to inhibit the transduction signals. Moreover cytokines are promising targets for the manipulation of the udder’s immune system in order to reduce the susceptibility of the organ to clinical mastitis. In fact, the cytokine pattern evoked in the mammary gland influence the differentiation of T helper cells

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toward the Th1-type, which is involved in cell-mediated inflammatory reaction, or the Th2type which mediate the humoral immune response. The Th-1 response is considered a key mechanism to enhance mammary gland defences against invading bacteria, thus the possibility to polarize the Th-type response using recombinant cytokines has received considerable research attention. Chapter VII - Interleukin-18 (IL-18) is a polytrophic cytokine with pro-inflammatory action demonstrated or proposed to contribute to several pathologies. IL-18 has peculiar features suggesting that this cytokine may be a mediator of the communication between the nervous, the endocrine and the immune systems and may have a specific role in these systems. In this chapter we summarize the evidence showing that IL-18 can be synthesized in the periphery following stress or neurogenic stimulation, and in the CNS. We will discuss the findings and the implications for the CNS-dependent modulation of IL-18 with respect to its possible role as psycho-neuro-immuno-modulator. Finally the action and role of IL-18 in the CNS will be addressed. Focus will be given to the clinical implications of the neuron-immune modulatory action of IL-18 on atherosclerosis, ischemic heart diseases, type 2 diabetes mellitus as well as ischemia, Parkinson’s disease and multiple sclerosis. Chapter VIII - Recent progress in molecular biology has provided new insights into the molecular basis of diseases and molecular targets for diagnosis and therapy of human diseases. Molecular imaging is a research discipline aimed at development and testing of novel tools, reagents and methods to image specific molecular pathways in vivo that are key targets in disease process and appear much earlier than anatomical and physiological changes. The advancement in the field of imaging and therapy of diseases is mainly due to the vast information available from molecular biology research on new targets with specific ligands and methods to evaluate their application in in vitro and in vivo systems. Improvement in imaging modalities like single photon emission computed tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRI), computed tomography (CT) and optical imaging (OI) has also contributed in the progress of molecular imaging. First section of this chapter is focused on molecular imaging, different approaches adopted for development of molecular imaging agents and recent imaging modalities and their applications. Molecular biological techniques used in in-vitro diagnostics are being adapted to the special requirements of imaging diagnostics and high affinity imaging is achieved based upon receptor-ligand, antigen-antibody, transporter-substrate and enzyme–substrate interactions. Development of newer approaches based on reporter gene concept are solely dependent on molecular biology research tools. Small animal models of human diseases have become available after completion of human genome project. Noninvasive imaging of molecular, genetic and cellular processes in animal models complements established ex vivo molecular biological assays and imaging provides a new dimension to understanding of various diseases. Role of molecular biology research in molecular imaging is discussed in second section of this chapter. Development of imaging agents based on peptides and role of molecular biology methods in identification of their targets to development of labelled ligands and their evaluation in in-vitro and in-vivo systems is also discussed. Chapter concludes with the applications of molecular imaging in diagnostics, gene therapy and drug development. Advancements in biology and medicine is possible due to

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synergism between various new disciplines, especially molecular biology research has contributed significantly towards progress of molecular imaging. Chapter IX - Cancer is now known to be a genetic disease. Lung cancer remains a difficult disease to treat with cancer-specific mortality as high as 95%. Recent highthroughput mutational analyses of gene families in human lung cancer, among other malignancies identified a number of kinases that are mutated in the cancer genome. Advances in high-throughput mutational analysis, coupled with high-throughput inhibitor screening, have expedited the pace of novel target and drug discovery in lung cancer therapeutics. The success of the inhibitors, gefitinib and erlotinib, against epidermal growth factor receptor (EGFR, ERBB1) in lung cancer therapy was followed by enormous mutational findings in the KRAS and ERBB family kinases (EGFR, ERBB2, ERBB4) especially in correlating to clinical response. Nonetheless, it remains somewhat controversial whether mutational analysis of the target receptor a priori to EGFR inhibitor therapy is beneficial or necessary. Other criteria of response correlation such as gene copy number have also emerged. Moreover, emerging findings of other novel targets and their mutations such as MET have renewed the hope for developing further novel inhibitors to improve the outcome of the lethal cancer in the future. It is expected that our capacity in lung cancer genome-wide sequencing in high-throughput fashion would eventually bring forth tremendous understanding of the role of mutations and various signaling pathways in the initiation, maintenance and progression of lung cancer. Finally, the potential role of genetic susceptibility in lung cancer development can be elucidated by better understanding of the role of somatic versus germline mutations of the target genes such as EGFR and MET. Mutationally-targeted personalized lung cancer therapy based on tumor specific mutations will be a realistic goal in the near future. Chapter X - The clinical and biological appearance of adrenocortical tumors is not uniform. It varies from small inapparent masses without clinical significance to the highly aggressive phenotype of adrenocortical carcinoma and includes hormonally active tumors as well as tumors without hormone secretion. Although the exact mechanisms that lead to different tumor cell populations and their associated biological properties are not fully characterized, significant advances in the understanding of growth regulation and its determinants in adrenocortical cells as well as in the different tumor types have been made. These mechansims and factors that alter the character of a normal adrenocortical cell with regular function and change it into a phenotype with increased proliferation and survival are complex and involve the interaction of a multitude of molecular mechanisms at different cellular levels. Signals from the cellular outside (e.g. corticotropin (ACTH), other peptides derived from POMC, insulin-like growth factor-2, basic fibroblast growth factor, interleukin1 (IL-1)), their corresponding receptors (e.g. ACTH receptor (MC2R), IL-1 receptor), intracellular signals (e.g. cAMP pathway, mitogen-activated protein (MAP) kinases) and transcription factors (e.g. TP53, steroidogenic factor-1) are integrated in the process of adrenocortical growth regulation. On the one hand, some of these cellular elements have been associated with adrenocortical tumorigenesis in the context of hereditary tumor syndromes including TP53 (Li-Fraumeni syndrome), GNAS1alpha (McCune-Albright syndrome), IGF-2, H19, p57/kip2 (Beckwith-Wiedemann syndrome), PRKAR1A (Carney Complex), menin (Multiple

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Endocrine Neoplasia type 1) and different steroidogenic cytochrome P450 enzymes (congenital adrenal hyperplasia). On the other hand, such cellular elements may be altered in non-hereditary tumors. Aberrant ectopic expression or eutopic overexpression of G-protein-coupled hormone receptors or receptors for other peptides (e.g. interleukin-1) is also associated with adrenal tumorigenesis and hormone excess in a number of cases. Loss of heterozygosity of the MC2R was documented in a subset of adrenocortical carcinomas. Furthermore, recent studies have identified new molecular elements (e.g. wnt-signaling, CITED2) that are likely candidates involved in adrenocortical tumorigenesis. Thus, the protein kinase A and MAP kinase signaling cascades constitude important cellular elements that are frequently disturbed in tumor formation of the adrenal cortex. The knowledge of the molecular mechansims of adrenocortical growth control will help to identify potential targets for a specific diagnosis and therapy. There are studies that focus not only on the identification of but also on targeting illicit membrane receptors. Here we review the determinants of adrenocortical growth regulation, their mechanisms as well as their significance to adrenocortical tumorigenesis. Chapter XI - The transformation of normal B-cells to lymphomas is considered to result from a multistep process. An important step in this process is reciprocal chromosomal translocation involving immunoglobulin loci and another gene, which in turn, involves cmyc, bcl-2, bcl-6, cyclin D1, and MALT-1. These translocations dysregulate or overexpress the genes involved and are associated with the stimulation of proliferation, blocking apoptosis, and inhibition of differentiation. The process of somatic hypermutation also contributes to lymphoma pathogenesis by aberrantly targeting non-Ig genes involving bcl-6 and FAS. In addition, epigenetic changes such as DNA methylation and histone deacetylation cause frequent inactivation of tumor-suppressor genes in some lymphoma tissues. It is wellknown that these genetic changes contribute to the malignancy of B-cells; however, other factors also play an important role in B-cell lymphomagenesis. For example, viral infection such as EB virus is considered to be involved in lymphomagenesis. In several lymphomas, antigen activation of lymphoma cells through B-cell receptor (BCR) signals, sometimes by infectious agents, may contribute to lymphomagenesis. Furthermore, certain factors from the microenvironment, such as stimulatory signals from T-cells, follicular dendritic cells, and local cytokines, may be critical for tumor formation of B-cells. These multiple factors may offer new therapeutic strategies, other than chemotherapy, for treating B-cell lymphomas. Chapter XII - Tumor growth and invasion are not only the result of malignant transformation, but also depend on environmental influences from their surrounding stroma, local growth factors, and systemic hormones. In particular, the composition of the extracellular matrix (ECM) is believed to affect malignant behavior in vivo. Thus, recognition of ECM components by tumor cells through integrin signaling is considered an important aspect in cancer biology. Fibronectin, a high-molecular-weight ECM adhesive glycoprotein, is highly expressed in injured tissues and is believed to influence chronic organ function. In lung, fibronectin is believed to stimulate epithelial cell hyperplasia, influence inflammation, and promote proliferation and survival of tumor cells. This mitogenic agent is also produced by tumor cells thereby serving as an autocrine factor in cancer. Of note, injured tissues and tumor cells produce distinct fibronectin isoforms that are thought to play varying roles in

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carcinogenesis. In view of these considerations, it is not surprising that fibronectin and its receptors are being considered as targets for biomolecular intervention, both in the development of inhibitory molecules that block the interaction of fibronectin with integrins and other receptors, and in the generation of ligand-based targeted imaging and therapeutic strategies for tumors. This document reviews information that implicates fibronectin in regulation of lung carcinoma cell proliferation, progression and resistance to therapy, and summarizes how this new knowledge can drive lung cancer therapeutics. Chapter XIII - The development of resistance to antitumor drugs of different classes represents a relevant clinical problem. A major role has been recognized for drug efflux transporters among the mechanisms implicated in conferring resistance to a broad spectrum of structurally unrelated antitumor agents in tumor cells. Indeed, such a phenomenon, known as multidrug resistance (MDR), mainly results from activation of ATP binding-cassette (ABC) transporters which decrease active drug concentration in the cell by pumping the drug out. Until now, fifty different members of the human ABC transporters family have been identified. Among these, the best known are P-gp, MRPs and BCRP. An increased expression of the transporters is usually associated with the MDR phenotype, but several lines of evidences suggest that genetic polymorphisms could affect their function. In addition, recent studies suggest an involvement of ABC transporters in regulating the biology of stem cells. The precise definition of the substrate specificity and the characterization of the different members are expected to provide insights in the design of new drugs capable to overcome transporter-mediated MDR. The present review focuses on the pharmacological significance of some recently described efflux transporters such as those encoded by the ABCG2 and ABCC4 genes, with particular reference to their possible role in resistance to clinically relevant antitumor drugs and to perspectives in the development of useful modulators of their function. Chapter XIV - Circulating leukocytes interact with endothelial cells (ECs) via selectins until being activated by chemokines that enable the firm, integrin-mediated adhesion required for subsequent transmigration. We observed that the prototype chemokine IL-8 (CXCL8) localizes similar to P-selectin in the Weibel-Palade body (WPB) of vascular ECs, and that exposure to histamine or thrombin leads to exocytosis of IL-8 within minutes (i.e. regulated secretion) [1,2]. Subsequent studies allowed us to demonstrate that chemokines produced by the endothelium can be classified into three groups, i) those that are limited to constitutive secretion (IP-10 (CXCL10) and RANTES (CCL5)) [3], ii) those that are released by regulated secretion from a dense secretory granule, the WPB (IL-8 and eotaxin-3 (CCL26)) [1-3], and iii) those that are released by regulated secretion from small granules (GROα (CXCL1) and MCP-1 (CCL2)) [3,4]. These latter granules are more sensitive to modulators of protein kinase A and C compared to the WPB and represent a new compartment that might enable differential chemokine release from ECs in response to currently unknown extracellular cues [4]. Signals or domains that target chemokines to compartments of regulated secretion in ECs are currently unknown and sorting of RANTES to granules of T cells and platelets [5,6] but not to such compartments in ECs implies cell-type specific mechanisms. Taken together, the secretory pathway of ECs seems to harbour highly controlled mechanisms for chemokine secretion to the cell exterior which might be important to fine tune leukocyte extravasation. Moreover, our data imply that regulated secretion of

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chemokines from the endothelium is restricted to those that predominantly recruit leukocytes of the innate immune system. In this manner, regulated chemokine secretion might enhance rapid recruitment of leukocytes involved in the first line of defense to sites of inflammation. Chapter XV - Activation and proliferation of T lymphocytes can be obtained by different stimuli in vitro. This review will focus on stimuli and conditions associated with different fates of T cell activation. Moreover, we will discuss the risk that different methods used to analyze the phenotype and function of stimulated cells could generate troubles in comparing results among studies. Depending on the selection of cells to be activated, on the stimulus and on the environment, we can obtain the activation and/or proliferation of different T cells lineages (Th0, Th1, Th2, Th17, Treg). Each condition could be associated to the expression of different transcription factors and to the use of different signalling pathways. In general, in vitro activation leads to develop of a mixture of T cells, which could be divided by immunomagnetic sorting to be further characterized. Phenotypic, genomic and epigenetic studies can be used to better describe the fate of T cell activation and the stability of the lineage obtained. An integrated use of these methods is particularly important when cell manipulation procedures are intended to be translated in animal studies or even in clinical settings. Chapter XVI - Laparoscopic and robotic assisted radical prostatectomies are continuous developing techniques, with feasibility and reproducibility demonstrated worldwide. Low morbidity and excellent functional and oncological outcomes can be achieved, although learning curve without robotic assistance is longer. The majority of centers that employ this technique have preferred transperitoneal access. Few groups prefer endoscopic extra peritoneal route but this surgical access is currently receiving a higher acceptance. We herein review the improvements in our personal technique reporting current experience with endoscopic extra peritoneal radical prostatectomy (EEERP) as a first line therapy for localized prostate cancer. In a 5-year period 120 patients underwent 5 to 6-port EEERP at our center in Brazil. Nerve sparing procedure was applied in 85% of surgeries, with mean operative time of 180 minutes after the 40 initial cases, and mean blood loss of 210 mL (transfusion rate 2.2%). Peritoneum perforation occurred in 40% and no conversion to open surgery was required. Complications occurred in 12.5% of men and median hospital stay was 2 days. Mean return to normal activities was 4 weeks. Erection sufficient to penetration in previous potent patients occurred in 75% of men and 98% of men remained continent. Overall positive surgical margin occurred in 10% and after a mean 3.5-year follow-up 90% of men were free of PSA recurrence. EEERP can be performed with efficacy providing the benefits of both laparoscopy and a totally extra peritoneal approach. Severe complications related to learning curve (urinary and rectal fistula) seem to be less morbid in EEERP. Reduction of complication rate and better oncological and functional results can be achieved by surgeon experience, and robotic assistance might reduce the learning curve. An analysis of the literature shows equivalence between trans and extra peritoneal access in experienced hands. Reduced learning curve period favored robotic assisted surgery to introduce laparoscopic radical prostatectomy in USA. Costs, availability and training facilities are important issues related to acceptance of minimally invasive surgery in development countries.

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Short Communication A - With the initial completion of the human genome project in the early 2000s, molecular biology paved the way for the emergence of a systems or network biology approach to investigate the complexity of biological organisms and their associated diseases. The current high throughput techniques of genomics and proteomics, in particular, provide vast amounts of data about the dynamical states of a cell or tissue, whether normal or pathological. Biologists today employ systems biology computational analyses and models to gain insight into those data, especially for developing safe and effective therapeutics to diseases. In this commentary, the transition from molecular biology to systems biology, including complexity and chaos theories, is reconstructed in an introductory section, followed by a section in which the fundamental concepts of system biology, including holism, emergence, and robustness, are discussed. In the next section the molecular biology and organicism approaches to cancer biology are discussed, followed by application of the systems biology approach to the investigation and analysis of carcinogenesis. The challenges facing the systems or network biology approach are then discussed, followed by a brief conclusion on the challenges facing the application of systems biology to cancer biology. Short Communication B - The retinoblastoma diagnosis, prognosis and treatment are based to the ophthalmological and anatomopathological classifications. The option considered the first alternative treatment for cancer, generally, defines the evolution of the illness. The evaluation of long-term retinoblastoma survivors must be documented to obtain information about sequels, second cancer development and offspring.

In: New Cancer Research Developments Editor: Thomas D. Ford

ISBN: 978-1-60692-447-1 © 2009 Nova Science Publishers, Inc.

Chapter I

RADIOTHERAPY IN AUTOLOGOUS BREAST RECONSTRUCTION: TIMING AND OUTCOMES Namrata S. Anavekar and Warren M. Rozen∗ University of Melbourne, Victoria, Australia.

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ABSTRACT Radiotherapy has become increasingly important as a component of breast cancer management. Recent randomized trials have demonstrated that radiotherapy delays and prevents local recurrence, as well as improving breast cancer mortality and overall survival. At the same time, breast reconstruction plays a significant role in the management of breast cancer, with significant psychosocial benefit to the patient. With each modality affecting the delivery of the other, the optimal timing for either radiotherapy or breast reconstruction are points of contention. While autologous breast reconstruction may have less radiation-associated complications compared to expander/implant reconstruction, the timing of radiotherapy in this setting is controversial. Some studies suggest that delay in administration of radiotherapy may reduce the chance of loco-regional disease control and impact on overall survival, while others have suggested no such effect. Similarly, some studies have demonstrated no effect on cosmetic outcome or complications with adjuvant radiotherapy, while others have shown increased rates of fat necrosis, infection, and poor cosmesis. The current paper comprises a thorough Medline literature review, performed with a focus on the oncological need for adjuvant or neoadjuvant radiotherapy and the effect of radiotherapy timing on breast reconstruction. We subsequently discuss our experience ∗

Correspondence concerning this article should be addressed to: Dr Warren Matthew Rozen, Jack Brockhoff Reconstructive Plastic Surgery Research Unit, Department of Anatomy and Cell Biology, The University of Melbourne, Grattan St, Parkville, 3050, Victoria, Australia. Email: [email protected]; Phone: +61 411 456 644.

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Namrata S. Anavekar and Warren M. Rozen with radiotherapy in this setting, reviewing 181 cases of autologous breast reconstruction with the abdominal wall donor site. Length of operation, length of stay, operative complications and oncologic outcome were assessed. Immediate breast reconstruction does not impair the oncological safety of breast cancer management, with no increase in local recurrence rates, and no delays in the initiation of radiotherapy. There is some evidence for increased complications in the setting of adjuvant radiotherapy, but both the literature review and our experience did not show this to be statistically significant. Breast reconstruction is oncologically safe in both the immediate and delayed settings, but optimal conditions for reconstruction require consideration. Based on the evidence presented, recommendations for management are discussed.

INTRODUCTION Since the milestone randomized trials published in 1997 [1,2], radiotherapy has become an increasingly important component of breast cancer therapy. It has been clearly demonstrated to prevent or delay local recurrences [3-7], as well as improving breast cancer mortality and overall survival [1,2,8,9]. When contemplating autologous breast reconstruction, the timing of radiotherapy with its subsequent effects in these patients requires special consideration. The impact of radiotherapy on vessel selection, post-operative complications and oncologic and cosmetic outcomes will be explored. In addition, a review of experience within Australian centres will be presented.

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Indications and Delivery of Radiotherapy The purpose of radiotherapy is to eliminate residual subclinical disease, as well as minimize local recurrence rates. This is achieved via the delivery of external beam radiation. The indications for radiotherapy in the treatment of breast cancer are listed in Table 1 [10]. The majority of guidelines agree that radiation is beneficial in patients with tumors greater than 5cm, locally advanced (ie.T3-T4) disease or greater than 3 positive axillary lymph nodes. Significant discrepancy exists, however, regarding irradiating patients with tumors less than 5cm, 1-3 positive axillary nodes or in those receiving neoadjuvant/preoperative chemotherapy. Decision-making regarding the latter patients usually rests on the policies of the institution or treating team. Three anatomic regions are considered in determining the radiotherapy field: 1) the breast or chest wall, 2) the internal mammary lymph node region, and 3) the supraclavicular fossa and axilla. One, two or three of these areas may require irradiation depending on the clinical scenario. The target field for the intact breast, or the chest wall in a mastectomized patient, extends from the midline of the sternum to the mid-axillary line. The field is bounded superiorly by the base of the clavicular head. Inferiorly, the target volume extends 1cm below the inframammary fold in the intact breast, or 1cm below the contralateral inframammary fold in

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the chest wall of a postmastectomy patient. It should be remembered that the radiation field following mastectomy must include the mastectomy scar.

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Table 1. Summary of Postmastectomy Radiotherapy (PMRT) Guidelines [10] 1. Patients With Four or More Positive Axillary Lymph Nodes - PMRT is recommended 2. Patients With One to Three Positive Axillary Lymph Nodes - insufficient evidence to make recommendations regarding routine use of PMRT in patients with T1 or T2 tumors with one to three positive nodes. 3. Patients With T3 or Stage III Tumors - PMRT is recommended for patients with T3 tumors with positive axillary nodes and in patients with operable stage III tumors. 4. Patients Undergoing Preoperative Systemic Therapy - insufficient evidence to make recommendations or suggestions on whether all patients initially treated with preoperative systemic therapy should be given PMRT after surgery. 5. Modifications of These Guidelines for Special Patient Subgroups - insufficient evidence to make recommendations or suggestions for modifying the above guidelines based on other tumor-related, patient-related, or treatment-related factors. 6. Chest Wall Irradiation In patients given PMRT, we suggest that adequately treating the chest wall is mandatory. 7. Details of Chest Wall Irradiation - nsufficient evidence for the panel to recommend or suggest such aspects of chest wall irradiation as total dose, fraction size, the use of bolus, and the use of scar boosts. 8. Axillary Nodal Irradiation - suggest full axillary radiotherapy not be given routinely to patients undergoing complete or level I/II axillary dissection; - insufficient evidence to make suggestions or recommendations as to whether some patient subgroups might benefit from axillary irradiation. 9. Supraclavicular Nodal Irradiation for Patients With Four or More Positive Axillary Lymph Nodes - recommend a supraclavicular field should be irradiated. 10. Supraclavicular Nodal Irradiation for Patients With One to Three Positive Axillary Lymph Nodes - insufficient evidence to state whether a supraclavicular field should or should not be used. 11. Internal Mammary Nodal Irradiation - insufficient evidence to make recommendations on whether deliberate internal mammary nodal irradiation should or should not be used in any patient subgroup. 12. Sequencing of PMRT and Systemic Therapy - insufficient evidence to recommend the optimal sequencing of chemotherapy, tamoxifen, and PMRT. The panel does suggest, given the available evidence regarding toxicities, that doxorubicin not be administered concurrently with PMRT. 13. Integration of PMRT and Reconstructive Surgery - insufficient evidence to make recommendations or suggestions with regard to the integration of PMRT and reconstructive surgery. 14. Long-Term Toxicities - potential long-term risks of PMRT include lymphedema, brachial plexopathy, radiation pneumonitis, rib fractures, cardiac toxicity, and radiation induced second neoplasms. - in general, the risk of serious toxicity of PMRT (when performed using modern techniques) is low enough that such considerations should not limit its use when otherwise indicated. However, follow-up in patients treated with current radiotherapy techniques is insufficient to rule out the possibility of very late cardiac toxicities. 15. Toxicity Considerations for Special Patient Subgroups - insufficient evidence to recommend that PMRT should not be used for some subgroups of patients because of increased rates of toxicity (such as radiation carcinogenesis) compared with the rest of the population.

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Namrata S. Anavekar and Warren M. Rozen

Internal mammary lymph nodes lie superior to the pleura, lateral to the sternum, and follow the course of the corresponding vein and artery. Typically, the first three intercostal spaces, as opposed to lower spaces, are more likely to demonstrate disease involvement, hence these are usually included in the treatment field. This also minimizes cardiac toxicity, and hence long-term cardiac morbidity. The supraclavicular target volume is bounded by medially by the pedicles of the cervical spine. The lateral boundary is variable; if the entire axilla is being treated a wide target volume is involved, whereas if only the supraclavicular nodes and apex of axilla are irradiated a narrower target volume will be required. It should be noted that the apex of the axilla is always included in the supraclavicular field. The superior boundary is usually the upper border of the first rib, however some physicians may prefer to also include the skin of the supraclavicular fossa. It may be observed that the supraclavicular target volume lies directly superior to the breast or chest wall field, hence careful consideration must be given to mapping these areas to avoid overlap of treatment. Optimal dosing and fractionation of radiotherapy regimens is yet to be firmly established. Based on several randomized trials using standard 1.8-2.0 Gy fractions, an acceptable regimen may be 45-50 Gy whole breast radiotherapy over 5-5.5 weeks. A Canadian trial exploring breast irradiation regimens following lumpectomy lymph-node negative patients compared a schedule of 50 Gy in 25 fractions over 35 days versus 42.5 Gy in 16 fractions over 22 days. No difference was found in 5-year local recurrence rates, disease-free or overall survival, or cosmetic outcome [11]. Additionally, preliminary findings from the START (Standardization of Breast Radiotherapy) trials suggest that patients may be safely treated with a lower total dose with fewer fractions [12]. This trial compared administration of 50 Gy in 25 fractions, 41.6 Gy in 13 fractions of 3.2 Gy each, and 39 Gy in 13 fractions of 3 Gy each, all delivered over 5 weeks. Additional comparison was made to a commonly used hypofractionation dosing of 40 Gy in 15 fractions over 3 weeks. Significant findings were that of lower locoregional relapse with the hypofractionated regimen, and subjective superiority of the lower dose schedules when assessing for breast swelling, as judged by both the physician and patient. It is too early to comment on disease-free or overall survival at this stage. It should be noted that these trials were conducted in patients with completely excised, T1-3 N0-1 nonmetastatic breast cancer. In addition to whole breast radiotherapy, many treatment centres deliver radiotherapy boosts to the tumor bed in an intact breast [13]. Some may argue that this is of limited benefit based on the NSABP (National Surgical Adjuvant Breast and Bowel Project) which demonstrated no difference in local recurrence rates when delivering a boost among women with negative margins [14]. Further trials have suggested a role for radiotherapy boosts. A trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) demonstrated lower local recurrence rates, with subsequently lower numbers of salvage mastectomies among women with negative resection margins who had received radiotherapy boosts. Overall survival, however, was not affected by boost radiotherapy [15]. These findings have encouraged most centres to deliver boost therapy. This may be delivered via electrons, photons or an interstitial implant, with similar outcomes [16]. Typical electron boosts are in the order of 14 Gy, or up to 20 Gy in patients who have demonstrated focally positive margins following lumpectomy.

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Timing of Radiotherapy and Breast Reconstruction The timing of radiotherapy in the setting of breast reconstruction is controversial. Several studies have demonstrated that any delay in the administration of radiotherapy may reduce the chances of achieving locoregional disease control, as well as reducing overall survival [17-19]. Regardless of when irradiation is delivered, potential problems may be encountered, hence the choice between pre-reconstructive and post-reconstructive radiotherapy is difficult (Table 2). Radiotherapy prior to reconstruction will compromise the quality of skin and underlying tissue, hence there may be a higher incidence of postoperative complications, including fat necrosis, infection, and inferior cosmetic results, when compared to nonirradiated patients [20,21]. Post-reconstructive radiotherapy may distort anatomy, and necessitate further surgery. These issues require further discussion. Table 2. Considerations regarding radiotherapy and autologous breast reconstructions Advantage Immediate Tissues have been unaffected by radiation - improved tissue viability for healing - more pliable, aiding reconstruction Psychologically less stressful for patient Single anesthetic and single inpatient admission Delayed Any tissues severely damaged by radiotherapy may be discarded Staging of cancer has been finalized

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Final flap will be unaffected by adverse effects of radiotherapy, such as hyperpigmentation, induration and telangiectasia

Disadvantage Unpredictable cosmetic outcome, which may ultimately necessitate further surgery May impact delivery of radiotherapy

Choice of flaps may be limited (eg.latissimus dorsi cannot be used for large defects) Psychological distressing for patient whilst awaiting reconstruction Requirement of second anesthetic and additional hospital inpatient admission

Autologous breast reconstructions appear to have less radiation-associated complication rates as compared to expander/implant reconstructions [22-28]. In fact, following exposure to radiotherapy, the safest reconstructive outcome is generally with the use of autologous tissue [29]. This is largely due to the advantage of being able to replace irradiated tissue with healthy structures. Even among patients undergoing autologous latissimus dorsi (ALD) reconstructions, poorer outcomes are encountered among those receiving an implant. The timing of delivering radiotherapy in these patients is yet to be clarified. There is a distinct paucity of studies investigating optimal timing of radiotherapy in patients undergoing autologous breast reconstruction. There do not appear to be any published randomized

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control trials, and of the studies in the literature, the majority are single institutional with patient numbers being too small to form any conclusive recommendations (Table 3). Table 3. Studies comparing outcomes based on timing of radiotherapy in autologous breast reconstructions Study

Timing of radiotherapy Pre-op: n=14 Post-op: n= 16

Williams et al (retrospective review)

Details of flap & follow up TRAM Follow up=37mo TRAM Follow up=60 in delayed group, 36 in immediate group TRAM Follow up: mean=47.6

Rogers et al [41] (retrospective review)

DIEP Follow up: mean=19.9

Post-op: n = 30 No radiation: n = 30

Banic et al [45] (prospective multicentre study) Delay et al [46] (retrospective review)

TRAM Follow up: mean=19

Pre-op: n = 34 No radiation: n = 77

LD Follow up: mean=20

Pre-op: n= 60 No radiation: n= 40

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Chawla et al [22] (retrospective review) Tran et al [31] (retrospective chart review)

Pre-op: n=70 Post-op: n= 32

Pre-op: n=108 Post-op: n= 19

Findings No difference in complication rate or cosmetic outcome Higher incidence of late complications (eg. Fibrosis, contracture, poor cosmesis) with post-op irraditation

It is not the complication rate which is affected by timing of radiation, but rather the nature of the complication Higher incidence of flap related complications among patients who receive post-op radiotherapy, compared to no radiotherapy Similar complication rate amongst both patient groups

Previous radiotherapy was associated with higher incidence of complications

Impact of Radiotherapy on Operative Complications Few studies have assessed complication rates among radiotherapy patients undergoing autologous breast reconstructions. Watterson et al reviewed 556 patients who underwent a total of 729 pedicled transverse rectus abdominis myocutaneous (TRAM) flap reconstructions, 73 of which were in the delayed setting [30]. This review demonstrated a statistically significant increase in both flap necrosis and fat necrosis in patients with prior chest wall irradiation. Interestingly, these complications were decreased among patients undergoing bipedicled TRAM reconstructions, possibly owing to greater blood supply. In a 10year study, Tran et al [31] compared immediate free TRAM flap reconstruction followed by radiation therapy versus radiotherapy prior to reconstruction. The study

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population comprised 32 immediate and 70 delayed TRAM reconstructions. The incidence of late complications was found to be significantly elevated in the former group. In contrast, however, it has been demonstrated that it is not the complication rate that differs between immediate versus delayed reconstructions, but rather the nature of the complications [31]. In particular, it is the incidence of late complications such as fat necrosis, flap volume loss and flap contracture, that deter the use of immediate reconstructions in patients who require radiotherapy [31,32]. Early complications such as vessel thrombosis, partial flap loss and total flap loss have been repeatedly shown not to be influenced by prior irradiation [32-34]. Spear et al [35] examined the effect of radiotherapy among patients who had undergone pedicled TRAM flaps. The study population comprised 150 patients with a total of 171 pedicled reconstructions. Of these patients, 72 received radiotherapy (corresponding to 80 flap reconstructions). Although the use of radiotherapy was associated with an overall increase in flap complications, the timing of radiotherapy did not adversely affect the risk for flap or donor-site complications. In particular, irradiation was associated with elevated incidence of fat necrosis when compared to the non-irradiated group. Thus, radiotherapy undoubtedly increases post-operative complications in those undergoing autologous breast reconstruction. The timing of radiotherapy, however, does not seem to influence these outcomes.

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Impact of Radiotherapy on Oncologic Outcomes One of the concerns with immediate autologous reconstructions is the inability to detect early local recurrence, and hence the potential increased incidence of distant metastasis. Although there have been a handful of studies assessing the radiation effects on TRAM flaps, literature pertaining to the long-term oncologic outcomes of radiotherapy in these patients is extremely limited. One study, however, specifically investigated local recurrence rates and the incidence of distant metastasis in postmastectomy radiotherapy patients undergoing immediate TRAM flap reconstructions [34]. In this study comprising 191 postmastectomy radiotherapy patients, 82 underwent TRAM flap reconstruction, whereas 109 did not. Over a median follow up period of 40months, no significant difference was demonstrated between the TRAM flap and non-TRAM flap patients with regard to complication rates, locoregional recurrence or the incidence of distant metastasis. Thus, although oncologic outcomes do not appear to be adversely affected by performing an immediate reconstruction prior to irradiation, there is insufficient literature to substantiate this finding.

Impact of Reconstruction on Delivering Radiotherapy The impact of breast reconstructions in the planning and delivery of radiotherapy also requires consideration. As discussed earlier, radiotherapy fields may include one or more of chest wall, ipsilateral supraclavicular fossa and axillary region. It is desirable to minimize exposure to the heart and lung fields if possible. Schechter et al specifically investigated the

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influence of immediate breast reconstruction on postmastectomy radiation [36]. Their study was a retrospective review of 152 patients who received post-mastectomy radiotherapy over a 1-year period. They found that immediate reconstructions adversely affected the delivery of postmastectomy radiation by preventing adequate coverage of the chest wall internal mammary chain regions, as well as exposing the lung fields to an excessive amount of radiation. Hence, from the viewpoint of delivering radiotherapy, it is desirable to await reconstruction until after radiotherapy has been administered.

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Impact of Radiotherapy in Selecting Type of Autologous Reconstruction Aside from deciding when to administer radiation in patients undergoing autologous breast reconstructions, consideration must also be given to the type of reconstruction undertaken. First let us consider TRAM flap reconstructions; these may be pedicled or free. Pedicled TRAMs, when undertaken in irradiated tissue beds, have complication rates reported to be in the order of 25-33% [32,37]. Following irradiation, pedicled TRAMs have been associated with a higher incidence of skin and fat necrosis [38], flap failure [39] and major infection [20]. These complications are owing to radiation induced microangiopathic changes which compromise tissue healing. Although their study population only comprised 16 patients, Moran et al [40] demonstrated a lower complication rate with free TRAMs versus pedicled TRAMs in previously irradiated tissue beds. Other reconstructive options include the deep inferior epigastric perforator (DIEP) flap. Only one study appears to have examined radiation effects with DIEP flaps [41]. This study compared outcomes of 30 patients receiving radiotherapy following immediate DIEP reconstructions with that of 30 patients who did not receive post-reconstructive radiation. Those who received radiotherapy had a statistically significant increase in the incidence of structural changes to the breast. In particular fat necrosis (23% in irradiated group vs. 0% in control group), fibrosis/shrinkage (56.7% in irradiated group vs. 0%) and flap contracture (16.7% in irradiated group vs. 0% in control group). It is interesting to note that most cases of poor or delayed wound healing were encountered prior to irradiation. Alternatively, latissimus dorsi flaps may be employed. This reconstructive option is used less commonly, as implants are often combined with this procedure. Consequently, there is limited data in the impact of radiotherapy on these reconstructions. Past history of radiotherapy, however, does not necessarily contribute to increased rates of flap loss, although residual radiated tissue can predispose to infection and extrusion of the flap [37]. Given the limited literature, it is difficult to compare various methods of reconstruction and their ability to tolerate the adverse tissue effects of irradiation. It can be said, however that free TRAM reconstructions appear to do better than pedicled TRAM flaps.

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Impact of Radiotherapy on Vessel Selection Vessel selection is also of importance when presented with a previously irradiated field. Generally, thoracodorsal vessels are selected in the setting of immediate reconstruction and axillary dissection. This is owing to the good exposure of these vessels during axillary dissection, as well as their reliable anatomic course and appropriate calibre to match the deep inferior epigastric vessels. Although the internal mammary vessels are often preferred as recipient vessels in view of their impressive calibre, there is no evidence to suggest improved outcomes when this vessel is selected. Additionally, it should be noted that use of the internal mammary precludes its future use on that side for cardiac bypass grafting. Further disadvantages to the use of these vessels are the challenge of microsurgery in the setting of respiratory movements and the risk of pneumothoraces. Both internal mammary and thoracodorsal vessels may be affected by radiation delivered postmastectomy. Also, access to thoracodorsal vessels may be difficult when there is scarring from axillary dissection. Temple et al [42] specifically compared the use of internal mammary and thoracodorsal recipient vessels in patients undergoing delayed TRAM flaps following irradiation. Outcomes were largely found to be similar regardless of vessel choice. Internal mammary vessels were rejected in 20% of cases, whilst the thoracodorsal vessels were rejected in 26% of patients. Moran et al encountered a much lower rejection rate of thoracodorsal vessels (7%) [40], perhaps owing to their much smaller patient population of 16, compared to Temple’s 123 patients. Thus, vessel selection does not appear to be influenced by prior irradiation.

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Impact of Radiotherapy on Cosmetic Outcome The evaluation of aesthetic outcome is highly subjective. Perhaps the best way of assessing this outcome measure is the patient’s opinion. Halyard et al [43] reviewed 15 patients undergoing TRAM reconstructions who received post-operative radiotherapy. Thirteen patients (87%) were satisfied with the cosmetic outcome, rating it as good to excellent. Although not statistically significant, Spear et al’s study found that post-TRAM radiotherapy resulted in a uniformly decreased aesthetic outcome as assessed by blinded reviewers, when compared to pre-reconstruction radiotherapy [35]. Williams et al [20] and Tran et al [31] both performed studies which directly compared pre-reconstructive radiotherapy and post-reconstructive radiotherapy in patients undergoing TRAM flaps. Their studies both suggested a higher rate of adverse cosmetic outcomes when radiotherapy was administered after reconstruction. Rogers and Allen’s study of radiation effects on DIEP reconstructions similarly demonstrated poorer cosmetic outcomes with the use of radiotherapy [41]. In particular, symmetry, volume of superior pole and aesthetic proportions were deemed as being inferior as judged by a panel of blinded reviewers comprising plastic surgeons, plastic surgery residents, medical students, and lay people. The cosmetic outcome in patients receiving radiotherapy prior to DIEP reconstruction is yet to be assessed.

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Similarly, radiotherapy impacts the cosmetic outcome of autologous latissimus dorsi (ALD) reconstructions. McKeown et al [44] invited patients who had undergone ALD flaps between 1997 and 2000 to a research clinic. The study population comprised 13 patients who had pre-reconstruction radiotherapy and 11 patients who received post-reconstruction radiotherapy. At this clinic, cosmetic outcome was assessed by a panel of reviewers comprising surgeons, nurses and lay people. There was a trend toward better aesthetic outcomes in patients undergoing delayed reconstructions. In particular, volume and contour of the upper pole seemed to be most affected by delivering radiotherapy to the reconstructed breast. Despite this assessment by reviewers, patients were still highly satisfied with their results. Overall, it would seem that delaying reconstruction after completion of radiotherapy would optimize aesthetic outcomes.

Summary of the Literature Available literature appears to suggest that the primary benefits of delaying reconstruction until after irradiation is to enable safer delivery of radiotherapy and to improve cosmetic outcome. Although the use of radiotherapy influences vessel selection and postoperative complications, the timing of its delivery does not influence overall outcome. Similarly, oncologic outcomes are not altered by the timing of radiotherapy.

AN AUSTRALIAN PERSPECTIVE Given the equivocal opinions suggested in the literature regarding timing of radiotherapy in the setting of autologous breast reconstruction, we performed a retrospective review to clarify the impact of radiotherapy in these patients.

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Methods The study design was a cohort study of all women undergoing autologous breast reconstruction with an abdominal wall donor site free flap in eight metropolitan hospitals in Melbourne, Australia, between January 2004 and January 2007. This comprised 181 breast reconstructions in 152 consecutive female patients. There were 123 cases of unilateral breast reconstruction and 29 cases of bilateral breast reconstruction. Institutional ethics approval was obtained and all patients gave verbal and written informed consent. A minimum of 3 months follow-up was required and achieved for all patients. Patients were classified according to whether they had received preoperative radiotherapy, postoperative radiotherapy or no radiotherapy for breast cancer treatment, relative to the definitive reconstructive procedure. For these groups, 87 women did not receive any radiotherapy, 60 women received preoperative radiotherapy, and 5 women

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received postoperative radiotherapy. As the postoperative radiotherapy group comprised only 5 patients, this group was excluded from analysis. The outcome measures assessed comprised the length of operation, length of stay, major postoperative complications and breast cancer recurrence. Statistical Analysis For each of the two groups (no radiotherapy and preoperative radiotherapy), average figures were calculated for each of the outcome measures. For length of operation and complication rate, patients were sub-classified into whether they had undergone unilateral or bilateral breast reconstruction. Outcomes were analysed using the 2-sample t test. A p value of 0.05 was used to represent statistical significance.

Results The study comprised 181 breast reconstructions in 152 patients (123 unilateral cases and 29 bilateral cases). Of these patients, 87 did not undergo any adjuvant radiotherapy (of which 70 underwent unilateral breast reconstruction and 17 underwent bilateral reconstructions); 60 patients underwent preoperative radiotherapy (of which 50 were unilateral reconstructions and 10 were bilateral); and 5 patients underwent postoperative radiotherapy (of which 3 were unilateral and 2 were bilateral). Outcome Measures

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1) Length of Operation The total operating time, from first incision to cessation of anaesthetic, was compared for those that had undergone preoperative radiotherapy and those that had not. There was no statistical difference noted between groups, whether for unilateral or bilateral cases (see Table 4). Table 4. Mean operating time for patients undergoing unilateral or bilateral breast reconstruction, classified by whether they had undergone previous radiotherapy. Statistical significance assessed using the 2-sample t test No Radiotherapy Unilateral Bilateral

Mean Length of Operation (Minutes) Mean Length of Operation (Minutes)

332

Preoperative Radiotherapy 334

P value 0.85

581

599

0.65

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Namrata S. Anavekar and Warren M. Rozen

Table 5. Percentage of cases that resulted in major complications for patients undergoing unilateral or bilateral breast reconstruction, classified by whether they had undergone previous radiotherapy. Statistical significance assessed using the 2-sample t test No Radiotherapy Unilateral Bilateral

Major Complications (Percentage of Cases) Major Complications (Percentage of Cases)

37.1

Preoperative Radiotherapy 50.0

p value 0.17

52.9

50.0

0.89

2) Major Complications Early to medium term complications were assessed, comprising a review of all flaprelated complications (partial flap loss, total flap loss or fat necrosis), donor site complications (abdominal bulge, weakness or herniation), hematoma formation (breast or abdomen), seroma formation, re-operation rate, or others (for example, postoperative decline in haemoglobin requiring transfusion). These were compared for those that had undergone preoperative radiotherapy and those that had not (Table 5). Of note, there was a relatively high complication rate overall, which may be accounted for by the high reporting rate at our institutions. 3) Length of Hospital Stay The total length of hospital stay for each patient, from admission until discharge, was reviewed for all patients, comparing those patients undergoing preoperative radiotherapy with those who did not. There was no statistical difference between groups, with a mean of 8 days for both groups (range 4 – 21 days) (see Table 6).

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Table 6. Mean length of stay for patients undergoing breast reconstruction, classified by whether they had undergone previous radiotherapy. Statistical significance assessed using the 2-sample t test

Mean Length of Stay (Days)

No Radiotherapy 8.1

Preoperative Radiotherapy 7.9

P value 0.68

4) Breast Cancer Recurrence The recurrence of breast cancer was reviewed for all patients, comparing those patients undergoing preoperative radiotherapy with those who did not. There were only four cases of breast cancer recurrences amongst the 152 women. Three occurred in the group that had no radiotherapy (recurred in lung, vertebrae and ribs, respectively) and one recurred in the preoperative radiotherapy group (bone marrow). There were no recurrences in the postoperative radiotherapy group. The recurrence rates are shown in Table 7, with no statistical difference between groups (see Table 7).

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Table 7. Percentage of patients with a recurrence (any site) of breast cancer, classified by whether they had undergone previous radiotherapy. Statistical significance assessed using the 2-sample t test

Breast Cancer Recurrence (Percentage of Cases)

No Radiotherapy 3.4

Preoperative Radiotherapy 1.5

p value 0.45

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DISCUSSION After reviewing our experience with 181 breast reconstructions, it is evident that autologous breast reconstruction is safe in the setting of adjuvant or neoadjuvant radiotherapy. Although our study reviewed only a cohort that underwent breast reconstruction (and not those that did not), and as such did not compare to a control group, nor directly compared the impact of timing of radiotherapy on autologous breast reconstruction, the study does highlight several key issues. Firstly, from a surgical viewpoint, although a previously irradiated tissue bed may present difficulties in dissection and vessel selection, this did not result in an increase in operating time, nor length of hospital stay. Similarly, despite reports of higher complication rates among patients who have received prereconstruction radiotherapy [30,35], this did not appear to be the case in our study population, with no statistically significant difference observed. The oncologic outcomes of breast reconstruction have been a further point of discussion in the literature, as described previously. Although Huang et al’s study in 2006 [34] demonstrated no difference in rates of locoregional recurrence or distant metastases in irradiated patients undergoing immediate breast reconstruction when compared to those not undergoing reconstruction, there remain concerns regarding adverse oncologic outcomes in these patients. Our study could not adequately assess this, as we did not have a nonreconstructed group as a control. However, a review of the rates of any recurrence in our patients (minimum 3 month, maximum 3 year follow up) revealed an overall low recurrence rate (1.5 - 3.4% of patients). This is comparable to cohorts in the literature undergoing reconstruction or not, with or without radiotherapy, as discussed previously. Patients in our cohort who received radiotherapy (which implies later stage disease if radiotherapy is recommended, and hence higher risk of recurrence) had a recurrence rate of 3.4%, whereas those without radiotherapy (implying low risk) also had a low recurrence rate of 1.5%. These rates are comparable, with no statistical difference between them. Furthermore, given the small number of patients (only 4 patients overall), a valid comparison is not possible. In summary, our study population, all of whom underwent autologous breast reconstruction with an abdominal wall reconstructive flap, demonstrated no differences in length of operation, length of stay, major complications or oncologic outcome, between irradiated and non-irradiated patients. As such, a continued approach to the rational selection of patients for immediate breast reconstruction is a safe and viable option.

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CONCLUSION Radiotherapy has a well-established role in the management of breast cancer. Its effects on both superficial and deep tissues however, presents a reconstructive dilemma. There is a paucity of literature assessing the optimal timing of radiotherapy in the context of autologous breast reconstruction. Several factors need to be considered when timing radiation treatment and reconstruction, and these include oncologic outcomes, impact of radiotherapy on selecting an appropriate reconstructive option and post-operative outcomes, whether they be operative complications or aesthetic satisfaction. As such, there remains significant controversy in timing radiotherapy when reconstruction is planned. A review of the literature, in combination with our own findings, would suggest that immediate reconstruction is safe in most circumstances, particularly when high risk patients have been adequately grouped and selected for a delay in reconstruction. These high risk patients can then promptly undergo adjuvant therapies, and complete their reconstructive goals upon completion of radiation treatment. This would serve to ensure adequate oncologic treatment, enable safe delivery of radiotherapy and optimize cosmetic outcome. Each individual case should be discussed in the setting of a multi-disciplinary unit comprising the patient, the reconstructive surgeon, medical oncologist, radiation oncologist and the breast management team.

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Radiotherapy in Autologous Breast Reconstruction: Timing and Outcomes [8]

[9]

[10] [11]

[12] [13]

[14]

[15]

[16]

[17] [18]

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[19] [20] [21]

[22]

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Gebski.V, Lagleva.M, Keech.A, et al. Survival effects of postmastectomy adjuvant radiation therapy using biologically equivalent doses: a clinical perspective. J. Natl. Cancer Inst. 2006; 98(1): 26-38. Overgaard.M, Jensen.M.B, Overgaard.J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group 82c randomized trial. Lancet. 1999; 353(9165): 1641-8. Recht A, Edge SB, Solin LJ, et al. Postmastectomy radiotherapy: guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001; 19(5): 1539-1569. Whelan.T, MacKenzie.R, Julian.J, et al. Randomized trial of breast irradiation schedules after lumpectomy with lymph-node negative breast cancer. J. Natl. Cancer Inst. 2002; 94: 1143. Dewar.JA, et al. Hypofractionation for early breast cancer: First results of the UK standardization (START) trials (abstract). J. Clin. Oncol. 2007; 25: 7s. Pierce, LJ, Moughan, J, White, J, et al. 1998-1999 patterns of care study process survey of national practice patterns using breast-conserving surgery and radiotherapy in the management of stage I-II breast cancer. Int J Radiat Oncol Biol Phys 2005; 62:183. Fisher.B, Anderson.S, Redmond.CK, et al. Reanalysis and results after 12 years of follow up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N. Engl. J. Med.1995; 333(22):1456-61. Bartelink, H, Horiot, JC, Poortmans, PM, et al. Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol 2007; 25:3259. Frazier, RC, Kestin, LL, Kini, V, et al. Impact of boost technique on outcome in earlystage breast cancer patients treated with breast-conserving therapy. Am J Clin Oncol 2001; 24:26. Huang J, Barbera L, Brouwers M, et al. Does delay in starting treatment affect the outcomes of radiotherapy? A systematic review. J. Clin. Oncol. 2003; 21(3): 555-63. Hershman DL, Wang X, McBride R, et al. Delay in initiating adjuvant radiotherapy following breast conservation surgery and its impact on survival. Int. J. Radiat. Oncol. Biol. Phys. 2006; 65(5): 1353-60. Jobsen JJ, van der Palen J, Ong F, et al. Timing of radiotherapy and survival benefit in breast cancer. Breast Cancer Res. Treat. 2006; 99(3): 289-94. Williams JK, Bostwick J 3rd, Bried JT, et al. TRAM flap breast reconstruction after radiation treatment. Ann Surg. 1995; 221(6):756-64. Kroll SS, Coffey JA Jr, Winn RJ, Schusterman MA. A comparison of factors affecting aesthetic outcomes of TRAM flap breast reconstructions. Plast Reconstr Surg. 1995; 96(4): 860-4. Chawla A, Kachnic, L, Taghian, A, et al. Radiotherapy and breast reconstruction: complications and cosmesis with TRAM versus tissue expander/implant. Int J Radiat Oncol Biol Phys 2002; 54(2):520-6.

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[23] Spear, SL, Onyewu, C. Staged Breast Reconstruction with Saline-Filled Implants in the Irradiated Breast: Recent Trends and Therapeutic Implications. Plast Reconstr Surg 2000; 105(3):930-42. [24] Spear, SL, Majidian, A. Immediate breast reconstruction in two stages using textured, integrated-valve tissue expanders and breast implants: a retrospective review of 171 consecutive breast reconstructions from 1989 to 1996. Plast Reconstr Surg 1998; 101(1):53-63. [25] Contant, CM, van Geel, AN, van der, Holt B, et al. Morbidity of immediate breast reconstruction (IBR) after mastectomy by a subpectorally placed silicone prosthesis: the adverse effect of radiotherapy. Eur J Surg Oncol 2000; 26(4):344-50. [26] Krueger, EA, Wilkins, EG, Strawderman, M, et al. Complications and patient satisfaction following expander/implant breast reconstruction with and without radiotherapy. Int J Radiat Oncol Biol Phys 2001; 49(3):713-21. [27] Tallet, AV, Salem, N, Moutardier, V, et al. Radiotherapy and immediate two-stage breast reconstruction with a tissue expander and implant: Complications and esthetic results. Int J Radiat Oncol Biol Phys 2003; 57(1):136-42. [28] Ascherman, JA, Hanasono, MM, Newman, MI, Hughes, DB. Implant reconstruction in breast cancer patients treated with radiation therapy. Plast Reconstr Surg 2006; 117(2):359-65. [29] Disa JJ, Cordeiro PG, Heerdt AH, et al. skin-sparing mastectomy and immediate autologous tissue reconstruction after whole-breast irradiation. Plast Reconst Surg 1998; 102(5): 1502-7. [30] Watterson PA, Bostwick J 3rd, Hester TR Jr, Bried JT, Taylor GI. TRAM flap anatomy correlated with a 10-year clinical experience with 556 patients. Plast Reconstr Surg 1995; 95(7):1185-94. [31] Tran, NV, Chang, DW, Gupta, A, et al. Comparison of immediate and delayed free TRAM flap breast reconstruction in patients receiving postmastectomy radiation therapy. Plast Reconstr Surg 2001; 108(1):78-82. [32] Williams, JK, Carlson, GW, Bostwick J, 3rd, et al. The effects of radiation treatment after TRAM flap breast reconstruction. Plast Reconstr Surg 1997; 100(5):1153-60. [33] Anderson, PR, Hanlon, AL, McNeeley, SW, Freedman, GM. Low complication rates are achievable after postmastectomy breast reconstruction and radiation therapy. Int J Radiat Oncol Biol Phys 2004; 59(4):1080-7. [34] Huang, CJ, Hou, MF, Lin, SD, et al. Comparison of local recurrence and distant metastases between breast cancer patients after postmastectomy radiotherapy with and without immediate TRAM flap reconstruction. Plast Reconstr Surg 2006; 118(5):107986. [35] Spear SL, Ducic I, Low M, Cuoco F. The effect of radiation on pedicled TRAM flap breast reconstruction: outcomes and implications. Plast Reconstr Surg. 2005; 115(1): 84-95. [36] Schechter NR, Strom EA, Perkins GH, et al. Immediate breast reconstruction can impact postmastectomy irraditation. Am J Clin Oncol. 2005; 28(5): 485-94. [37] Kroll SS, Schusterman MA, Reece GP, et al. Breast reconstruction with myocutaneous flaps in previously irradiated patients. Plast Reconstr Surg. 1994; 93(3): 460-9.

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[38] Jones G, Nahai F. Management of complex wounds. Curr Probl Surg. 1998; 35(3): 179-270. [39] Hartrampf CR Jr, Bennett GK. Autogenous tissue reconstruction in the mastectomy patient: A critical review of 300 patients. Ann Surg. 1987; 205(5): 508-19. [40] Moran SL, Serletti JM, fox I. Immediate free TRAM reconstruction in lumpectomy and radiation failure patients. Plast Reconstr Surg. 2000; 106(7): 1527-31. [41] Rogers NE, Allen RJ. Radiation effects on breast reconstruction with the deep inferior epigastric perforator flap. Plast Reconstr Surg. 2002; 109(6):1919-24. [42] Temple CL, Strom EA, Youssef A, Langstein HN. Choice of recipient vessels in delayed TRAM flap breast reconstruction after radiotherapy. Plast Reconstr Surg. 2005; 115(1): 105-13. [43] Halyard MY, McCombs KE, Wong WW, Buchel EW, Pockaj BA, Vora SA, Gray RJ, Schild SE. Acute and chronic results of adjuvant radiotherapy after mastectomy and transverse rectus abdominis myocutanoeous (TRAM) flap reconstruction for breast cancer. Am J Clin Oncol. 2004; 27(4):389-94. [44] McKeown DJ, Hogg FJ, Brown IM, Walker MJ, Scott JR, Weiler-Mithoff EM. The timing of autologous latissimus dorsi breast reconstruction and effect of radiotherapy on outcome. J Plast Reconstr Aesthet Surg. 2007; doi:10.1016/j.bjps.2007.11.046 [45] Banic A, Boeckx W, Greulickx P, et al. Late results of breast reconstruction with free TRAM flaps: A prospective multicentric study. Plast Reconstr Surg. 1995; 95(7): 1195-204. [46] Delay E, Gounot N, Bouillot A, et al. Autologous latissimus dorsi reconstruction: A 3 year clinical experience with 100 patients. Plast Recontr Surg. 1998; 102(5): 1461-77.

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In: New Cancer Research Developments Editor: Thomas D. Ford

ISBN: 978-1-60692-447-1 © 2009 Nova Science Publishers, Inc.

Chapter II

RISK ANALYSIS AND RISK MANAGEMENT OF RADIATION TREATMENT FOR BREAST AND OTHER CANCERS Robert C. Lee1,2 1

University of New Mexico, USA; 2 University of Calgary, Canada.

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ABSTRACT External beam radiation treatment for breast and other cancers can be highly effective, but is associated with a nontrivial risk of patient morbidity or mortality if improperly administered. This chapter describes a multifaceted research program designed to characterize, analyze, and manage risks in radiation treatment (RT) for cancer. The program was conducted from 2003 to 2006 at a large cancer treatment facility in Canada. This work represents the first time, to the author’s knowledge, that a holistic quantitative risk analysis and risk management framework has been applied in a health care scenario. The Introduction to this chapter describes the context and the framework itself. Subsequent sections summarize the following analyses: An analysis of the impact on RT decisions of uncertainties associated with staging of breast cancer; Development and evaluation of an incident taxonomy and classification system for RT; A probabilistic fault tree analysis of a portion of the RT process; and, Introduction of an incident learning system (ILS) to a cancer treatment organization, and analysis of its impact. In conclusion, the findings and impact of this research in the context of cancer treatment, and as relevant to health care in general, are discussed.

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Robert C. Lee

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INTRODUCTION Cancer treatment of any kind is associated with risks as well as benefits to the patient. This is certainly the case with radiation treatment (RT). RT is the treatment of cancer with targeted high energy ionizing radiation, usually X-rays. Such radiation damages or destroys cancer cells in the area being treated, impeding division of the cells. Although radiation can damage both cancer cells and normal cells, the goal of properly administered treatment is to keep normal tissue damage at an acceptable level while at the same time damaging the cancer cells. Thus, there is both a dose (intensity and duration) component as well as a spatial component of an optimal treatment plan. In breast cancer patients, external beam RT is often given as an adjuvant treatment postsurgery to control recurrence. RT is most beneficial when the chosen technique is matched to the appropriate type, grade and stage of cancer. The stage of cancer, which indicates how far the cancer has progressed, is the most important factor in the choice of RT technique for breast cancer patients. Most breast cancer patients at the present time are treated with a 2field (2 beams) technique, 4-field (4 beams) technique or with palliative intent (i.e., for pain management). RT occurs in a complex environment that is subject to uncertainties and unintentional incidents, which in turn can compromise treatment outcomes and/or result in patient morbidity or mortality. In this chapter, “uncertainties” are defined as lack-of-knowledge regarding the true state of a system. For example, 3 pathologists may arrive at different conclusions regarding the state of progression (as represented by stage) of a tumor, based upon examination of a small section on a microscope slide. There is a true state of the tumor, and oncologists are reliant upon the pathologists to come to conclusions regarding this state based upon incomplete information and differing levels of skill and experience. Thus, there is a small but real probability that at least 1 pathologist, and perhaps all 3, will come to the wrong conclusion with regard to stage, and thus perhaps misinform treatment decisions. An “incident” is an unwanted or unexpected deviation from normal system behavior that causes, or has the potential to cause, an adverse event. An “adverse event” is an incident that occurs during the process of providing health care and results in a sub-optimal clinical outcome, including unintended injury or complication leading to disability, death or prolonged hospital stay for the patient. An “error” is the failure to complete a planned action as it was intended, or a situation in which an incorrect plan is used in an attempt to achieve a given aim. Errors often result in incidents. However, only a few incidents result in adverse events. Therefore, not all errors lead to adverse events; only a critical few errors lead to adverse events. Incidents can result from uncertainties, or they may be faults in the process of care. For example, a technician may enter a wrong value in the process of calibrating a treatment machine. If this incident is not “caught” by a quality control (QC) process, then it may compromise the treatment of one or many patients. The commissioning (testing in clinical settings) of technologies and treatment with RT are tightly monitored and regulated by national, provincial/state, and local agencies. A large amount of resources is expended at a typical cancer treatment center on QC and quality assurance (QA). Yet, despite great care to ensure accurate and precise administration of RT, there are notable reports of incidents in RT that have led to serious adverse events, including

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Risk Analysis and Risk Management of Radiation Treatment…

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patient death and disability [1,2]. Formal analysis of such systems is likely to be useful in understanding the systems and identifying influences that pose the greatest risk, yet few studies have been published in this area. There are a number of modeling methods used in potentially high-risk industries, such as the nuclear, aviation and chemical industries, to assess and manage risk [3-5]. Despite the successful application of such methods to complex systems, their application to health care systems and patient safety is comparatively rare. Most health care patient safety efforts focus on qualitative or semi-quantitative retroactive methodologies such as root-cause analysis [6] and proactive methodologies such as failure mode and effects analysis [7], as these are simple and can be applied to a wide variety of scenarios. While useful, these methods are not necessarily fully informative for more complex and technologically intensive systems, thus quantitative modeling methods such as probabilistic risk analysis are starting to be applied in some health care settings [8-12]. Modeling allows analysis of the system itself, thus providing insight into important variables, interactions, causal pathways, and other aspects of the system that may lead to incidents. A number of challenges, however, that analysts face in the transfer of engineering modeling methods to health care are noted in the literature [13,14]. First, most models are data intensive and health care information systems are typically designed to meet clinical requirements, not risk management needs. As a result, most clinical data lack the details that would be ideal for system modeling purposes. Second, each health care facility has a unique combination of service models, programs, and performance standards, which makes it difficult to develop generalizable models. Third, clinical procedures have to be flexible in order to accommodate different patients, which results in the interactions between the wide variety of doctors, nurses, therapists, pharmacists, physicists and other staff being quite complex. Finally, within the time line of any particular modeling project, it is not uncommon to encounter changes such as technology upgrades, which can substantially change the system to be modeled. However, despite the challenges faced, it is generally agreed that health care systems can and do benefit from rigorous modeling techniques [13,14]. The framework that was developed by the author and others to address RT patient safety is illustrated in Figure 1 [9,12,15,16]. The system that was evaluated was the Tom Baker Cancer Centre (TBCC), a large treatment and research center in Calgary, Alberta, Canada. The TBCC is part of the Alberta Cancer Board, a publicly funded provincial cancer agency. The process map that is the foundation of Figure 1 was developed in a collaborative and iterative fashion with clinical staff members who were expert in some part of the process. Similar to other cancer treatment facilities, there was no person or persons who were expert in all parts of the process; this would not be humanly possible. The safety of the system is therefore in large part reliant upon a degree of “trust” that the information or decisions produced by earlier parts of the process is correct; this trust being reinforced by QA/QC procedures. The different analyses described below are represented in Figure 1 to illustrate which parts of the process that they were applied to. Note that the analyses are presented in order of increasing generality of focus; the first focusing upon staging of breast cancer, and the last focusing upon safety of the RT department in general. The next section describes an analysis that was applied to the “front-end” (Assessment in Figure 1) of the RT process; namely, staging of tumors and treatment decisions.

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Analysis IV 

Analysis II 

Analysis III  PRESCRIPTION Dose, fractionation, protraction Target volume localization

PATIENT ENTERS SYSTEM

Analysis I  External patient information

PATIENT LEAVES SYSTEM

ASSESSMENT History/physical examination Imaging and biochemical tests Pathology reviews

FOLLOW-UP Clinical examination of patient response Treatment of RT side effects

PREPARATION Dose distribution computation Simulation Treatment aid preparation

TREATMENT Patient setup Equipment setup Dose delivery

Figure 1. Process map and boundaries of analyses. Note that the boundary of Analysis IV is also the usual boundary of responsibility of the TBCC organization.

ANALYSIS I: SIMULATION OF THE IMPACT OF UNCERTAINTIES IN BREAST CANCER STAGING UPON TREATMENT DECISIONS

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Introduction Physicians and other clinical staff are constantly faced with interpreting the results of diagnostic tests. In a medical treatment decision, variations in patient physiology, heterogeneity of results across different clinical studies, imperfect expert knowledge of critical variables, and unknown or uncertain causal pathways and mechanisms all contribute to overall uncertainty. Bayesian modeling techniques are well suited for informing medical decisions under uncertainty [17]. Staging and treatment decisions for breast cancer patients presenting for adjuvant RT after surgery are explored here. Staging is the process of identifying characteristics of the cancer that are subsequently used to inform treatment decisions. Pathologic examinations of tissue from the patient for the presence of cancer cells (i.e., pathology reviews) are used to assess the stage and grade of non-metastatic cancer (note that pathology reviews, while not strictly “tests”, are placed under that generic categorization here for simplicity). Patients who have symptoms of metastasis (i.e., spread of cancer to distant tissues) are further assessed

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using appropriate imaging and biochemical tests. Uncertainty in staging can influence the particular RT technique that is chosen, and depending upon the degree of this uncertainty this choice may not be optimal.

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Methods A Bayesian Monte Carlo simulation model was designed to reflect the typical process of assessing breast cancer patients for RT after surgery. The simulation followed a cohort of hypothetical patients for which the true stage and required RT technique were defined a priori (i.e., the reference data). The model then simulated the test results that would result in the “real world”, assuming evidence based guidelines and given the uncertainties associated with the diagnostic tests, the pathology review process, and critical system variables. A comparison of the reference data with the simulated data informed the question: “What proportion of patients will be correctly staged and treated, given that physicians employ evidence-based decision-making?” The domain of the process map in Figure 1 of interest here was Assessment (more detail on this map is provided in the next section). A component of Assessment is staging, which is the process of identifying the stage of the cancer, using clinical and/or pathologic findings. The commonly used TNM (Tumor size, lymph Node involvement, and degree of distant Metastasis) system [18] classifies cancer patients into five main stages: 0, I, II, III and IV. Pathology reviews are used to determine Stages 0 to III of breast cancer, while imaging and biochemical tests are used to assess the presence of metastatic disease, which defines Stage IV cancer. The “correctness” or accuracy of staging is therefore dependent on the adequacy of surgery, the accuracy of the pathology review, and the accuracy of the imaging and biochemical tests employed. This in turn affects the correctness of the RT treatment technique prescription. Evidence based guidelines such as the Alberta Breast Cancer Program (ABCP) RT guide [19] provide guidance for which RT technique to employ and when. Generally, nonmetastatic disease is characterized as invasive or non-invasive; invasive being cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues and lymph nodes. For non-invasive disease, this particular guide recommends 2-field treatment. For invasive disease, the guide considers the number of nodes removed for evaluation during surgery and the number of positive nodes from those removed (for simplicity, it was assumed here that at least 10 nodes are always removed for evaluation). Lymph nodes are determined to be positive for cancer if cancer cells can be found in the lymphatic system. A 2-field technique is recommended for situations where 1 to 3 of the removed nodes are positive, and otherwise a 4-field treatment is recommended. The simulation model was constructed to represent a Canadian cancer treatment facility, which is publicly funded and has a fixed annual budget (note that different types of tests may be used in a privately funded facility, as cost is less of a constraint). In most cases, information from the peer-reviewed literature was used to define model inputs. In some cases where this information was not available or facility-specific information was necessary, the expert opinions of oncologists or medical physicists were used.

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In the simulation model, a cohort of hypothetical patients was followed through the system. The model allowed simulated test results to be affected by the degree of sensitivity, specificity and accuracy of pathology or tests. These parameters were defined in the model as distributions to account for the uncertainty surrounding the true value of the tests. The results of these tests were used to assign the stage of cancer, which in turn influenced the prescribed RT technique. The results of the simulation (diagnosed cancer stage, prescribed RT technique) were compared to the reference data (true cancer stage, optimal RT technique) assigned a priori to calculate the probability of incorrect staging decisions and RT treatment technique prescriptions. The simulation model included four modules: the data generating module, the cancer stage identification module, the RT technique module and the result analysis module. Figure 2 is a high-level representation of the model structure. The arrows indicate inputs and outputs to and from each computational module. Pathology staging results

Patient cohort

DATA GENERATING MODULE

Reference data (true cancer stage and optimal RT) technique)

Biochemical test results Imaging results

Reference data (# of positive lymph nodes)

Prescribed treatment technique

RESULT ANALYSIS MODULE

CANCER STAGING MODULE

Assigned cancer stage

RT TECHNIQUE MODULE

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Probability (correctly staging patient) Probability (prescribing correct RT technique)

Figure 2. Simulation model for treatment decisions.

Data Generating Module The input for this module was a hypothetical cohort (assuming an average of 500 breast cancer patients presenting for RT annually). Each hypothetical patient had already been assessed as indeed having breast cancer. Occasionally, this diagnosis could be wrong; thus, based upon expert opinion a probability of 0.1% was assigned to reflect that some of the patients may not actually have cancer, as originally diagnosed.

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For each hypothetical patient that had cancer, a stage was assigned based upon expert estimation that approximately 10% of new patients present with Stage 0, 45% with Stage I, 30% with Stage II, 10% with Stage III, and 5% with Stage IV cancer. The model uses this approximation as the true distribution of cancer stage for new patients presenting at a typical cancer treatment facility. The prescribed RT technique depends on the cancer stage and the ratio of positive (i.e., showing signs of cancer) to negative lymph nodes removed during surgery. The ABCP guidelines plus a consultation with an oncologist indicated that all diagnosed Stage 0 and I patients should be prescribed 2-field treatments, and all Stage IV patients palliative treatment. For Stage II and Stage III patients, the ratio of positive to negative lymph nodes becomes important in the assignment of an RT technique. Assuming that 10 or more nodes are removed during surgery, patients are assigned a stage in keeping with guidelines. In the TBCC, approximately 80% of Stage II patients and 30% of Stage III patients are prescribed 2 field treatments, while 20% of Stage II patients and 70% of Stage III patients are prescribed 4 field treatments. The diagnosed cancer stage is influenced by the true cancer stage (as represented by the reference data set), the accuracy of pathology reviews, and the accuracy of imaging and biochemical tests for discovery of metastases. All patients with Stage IV cancer were randomly assigned a primary site for metastases. The most common sites of metastases for breast cancer are the bone, liver, and lung [18]. Of the 5% of patients with actual Stage IV cancer, expert opinion suggested that 50% would have bone metastases, 30% liver metastases and 20% lung metastases. Based upon the primary site assignment, different biochemical and imaging tests are then employed to confirm metastasis. A review of current literature and consultation with TBCC oncologists identified the following tests that were routinely employed at the time of this analysis: bone scans (BS), carbohydrate antigen 15.3 (CA 15.3), carcinoembryonic antigen (CEA), and alkaline phosphate (AP) for detecting bone metastases; liver ultrasounds (LUS), aspartate aminotransferase/alanine aminotransferase (AST/ALT), CEA and gamma glutamyl transferase (GGT) tests for determining liver metastases; chest Xrays (CXR) and CEA tests for determining chest metastases. In practice, most facilities use a subset of these tests and not all of them simultaneously. However, for purposes of model generality, the most recognized tests were considered [20]. Staging Module This module used the information from the data generating module to simulate cancer stage for each patient. Given the true cancer stage from the reference data, the results of the pathology review process were simulated to reflect the accuracy of the process. Based upon expert opinion, all Stage IV patients, approximately 30% of Stage III patients and 10% of Stage II patients will show outward clinical symptoms of metastasis (e.g., severe bone pain, lumps in other areas, shortness of breath, ulcerations of skin, etc.) and will undergo further screening. The probability of metastases is calculated based upon the prior probability of metastases to the site in question, and the simulated test results. A decision threshold probability of 80% was used in this model; i.e., if the calculated probability of metastases is above this threshold, the patient was assigned Stage IV; otherwise the patient “retained” the original pathology-assigned stage. This threshold is a

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subjective value that reflects the readiness of an oncologist to make a stage IV diagnosis. A high threshold value will decrease the number of false positives (patients in whom metastasis is absent but the test result is positive) but there is the risk of increasing false negatives (patients in whom the condition is present but the test result is negative). Determining the statistical accuracy of pathology examinations was difficult due to the lack of a “gold standard” to which these reports may be compared. The most common approach to this problem in the literature is review of routine pathology reports by an expert pathologist (who may not be correct all of the time). In a few studies specific to breast cancer, the percentage of change of diagnosis was between 1.4% and 7.8% [21,22]. Although these do not truly reflect accuracy rates, they indicate the level of uncertainty associated with this process. Representing the accuracy rate of pathology reviews as a uniform distribution between 92.2% and 98.6%, pathology results were simulated such that mis-staging would be more likely to occur between adjacent stages on the TNM scale. For simplicity, the assumption was made that the accuracy of pathology reviews in identifying cancer stage was the same for all stages of cancer. A simulated patient was assumed to be in one of two health states with respect to metastases to a particular site: D (presence of distant metastasis) or D (absence of distant metastasis). Assuming that T is a binary test that attempts to distinguish between D and

D , the value of T is characterized by four conditional probabilities: P(T + | D ) (i.e., the probability of a positive test result given that the patient is in state D ), P(T + | D ) , P(T − | D ) , and P(T − | D ) . The first of these is commonly known as the sensitivity of the test, and the last as specificity. Although sensitivity and specificity are important characteristics of a test, they are not the probabilities most informative in making a decision to treat or not treat a patient given test results. Of greater utility are the positive predictive value P ( D | T + ) and the negative predictive value P ( D | T − ) of the test. The positive

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predictive value is the probability of a condition (in this case distant metastasis) given a positive test result, while the predictive negative value is the probability of the absence of a condition (no distant metastases) given a negative test result. To estimate these values, an estimate of the prior probability of disease P ( D ) in the sample population from which the patient is drawn is required. The sensitivity and specificity of tests are standard values that can be retrieved from the literature and the results of randomized trials (Table 1). Using Bayes’ rule, the positive predictive value of test T is calculated as:

P( D | T + ) =

P (T + | D ) * P ( D ) P (T + )

(1)

At the time of this analysis, there were no studies located that examined potential dependencies or correlation structures between the tests evaluated here. Therefore, independence was assumed. Given this assumption, when a battery of tests are used simultaneously (e.g., T1 , T2 , T3 , and T4 ) to diagnose a condition, the predictive value of the set of tests can be calculated on a case-by-case basis, depending on the individual test results.

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For example, assuming all positive results from four tests, the positive predictive value can be calculated as follows:

P( D | T1 +, T2 +, T3 +, T4 +) =

P(T1 + | D)* P(T2 + | D)* P(T3 + | D)* P(T4 + | D)* P( D) P(T1 +, T2 +, T3 +, T4 +)

(2)

The calculated predictive value is a probabilistic value that lies between 0 and 1. The decision maker will often set a subjective threshold value, such that when the predictive value is above the set threshold, the condition is assumed to exist and the patient is treated for it. Otherwise, either more testing is prescribed or the condition is assumed not to exist. Table 1. Sensitivity and specificity of tests used for detection of metastases in breast cancer patients. Uniform distributions are applied in all cases Test 1

BS LUS 2 CXR 3 AST/ALT 4 GGT 5 AP 6 CA 15.3 7 CEA 8

Sensitivity Uniform (0.78, 1.00) Uniform (0.58, 0.93) Uniform (0.30, 0.75) Uniform (0.38, 0.53) Uniform (0.60, 1.00) Uniform (0.58, 0.80) Uniform (0.64, 0.92) Uniform (0.40, 0.77)

Specificity Uniform (0.56, 0.96) Uniform (0.78, 1.00) Uniform (0.86, 0.99) Uniform (0.26, 0.54) Uniform (0.65, 0.98) Uniform (0.39, 0.98) Uniform (0.87, 0.98) Uniform (0.95, 0.99)

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References: 1 [20,23-28]; 2 [20,29-31,31-34]; 3 [20,35,36]; 4 [20,32]; 5 [20,37-40]; 6 [20,32,37,39,41-43]; 7 [20,41,42,44-48]; 8 [20,42,44-47]. Acronyms used in all tables in this section: AP: Alkaline phosphate; AST/ALT: Aspartate aminotransferase/alanine aminotransferase; S: Bone scan; CA 15.3: Carbohydrate antigen 15.3; CEA: Carcinoembryonic antigen; CXR: Chest x-rays; GGT: Gamma glutamyl transferase; LUS: Liver ultrasound.

The calculated predictive value is a probabilistic value that lies between 0 and 1. The decision maker will often set a subjective threshold value, such that when the predictive value is above the set threshold, the condition is assumed to exist and the patient is treated for it. Otherwise, either more testing is prescribed or the condition is assumed not to exist. Staging is primarily determined based upon pathology examination. The cancer stage is changed only if a test(s) for metastases is positive, in which case the patient is assigned Stage IV. In all cases, single sites of metastasis were assumed. RT Technique Module The assigned RT prescription was dependent on the diagnosed cancer stage and the number of identified positive nodes. All simulated patients classified as Stage 0 and I were prescribed 2-field treatments, and all Stage IV patients were prescribed palliative treatment in keeping with the ABCP recommendations. For patients classified as Stage II and III, the

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prescribed treatment was influenced by the accuracy of pathology reviews in identifying positive lymph nodes from a set of removed nodes. Result Analysis Module This module performed one-on-one comparisons of the simulated diagnosis and prescribed treatment with the reference data for each hypothetical patient in the model, and generated the probability of incorrect staging and RT technique decisions. The results of this model are presented as averages of the results from 100 iterations with a patient population size of 500 (i.e., a 2-dimensional simulation of 50,000 trials; Tables 2 and 3). Table 2. Simulation results for staging of breast cancer patients. Means and 95% confidence intervals are shown. True stage of cancer Stage X Stage 0 Stage I Stage II Stage III Stage IV

‘Stage X’ 86.57 ± 2.44 13.43 ± 2.44