Contents

Foreword xiii

Nicholas J. Petrelli

Preface xv

Adam C. Yopp and Ronald P. DeMatteo

Commentary xix

Murray F. Brennan

Randomized Clinical Trials in Soft Tissue Sarcoma 1

Steven C. Katz and Murray F. Brennan

Soft tissue sarcomas (STS) are rare, but potentially lethal, extraskeletalmesenchymal neoplasms. It is estimated that approximately 12,000 casesof STS are reported annually in the United States, with 3,500 STS deaths.Few randomized controlled trials (RCTs) have been conducted since theprevious issue of this publication. The current understanding of STS biologyand, hence, ability to provide safe, effective therapy is predicated uponseminal trials performed in the 1980s and 1990s. The authors briefly sum-marize the trials presented in the previous issue and then critically assessthe more recent publications that have addressed the management of STS.

Randomized Clinical Trials in Melanoma 13

T. Peter Kingham, Giorgos Karakousis, and Charlotte Ariyan

The incidence of melanoma is increasing and it is estimated that, in theUnited States, the lifetime risk of developing melanoma is 1 in 55. Therehave been many randomized trials that have refined the treatment andminimized the morbidity of the intervention of this prevalent disease.From 1975 to 2000, there were 154 prospective randomized trials on thetreatment of local, regional, and metastatic melanoma. Between 2001and the end of 2008, there were 52 randomized controlled trials relatingto the treatment of patients with malignant melanoma. This article reviewsthe results of the major studies included in the prior article, and providesa detailed description of selected randomized controlled trials performedfrom 2001 to 2008.

Randomized Clinical Trials in Breast Cancer 33

Aimee M. Crago, Michelle Azu, Shannon Tierney,and Monica Morrow

Breast cancer remains the most common cancer diagnosed in womenand the second leading cause of cancer-related deaths in this group.

Randomized Clinical Trials in Surgical Oncology

Significant advances in the treatment of breast cancer and in the ability toscreen for the disease mean that it is also one of the most curable formsof cancer. Long-term updates of the trials reviewed in the previous editionof this article have demonstrated that breast-conserving therapy remainsa viable option for most patients, and that local control is related to over-all survival. New chemotherapeutic options and endocrine therapies areavailable to select subsets of patients, and the use of endocrine therapyin breast cancer prevention has been shown to be of clear benefit. Thesheer number of breast cancer-related randomized, controlled trialsmakes it impossible to review all level Ia evidence in this article but, wherepossible, extensive referencing and tabular review of related trials areused to provide the reader with a clear outline of the central data dictatingcurrent standard of care.

Randomized Clinical Trials in Esophageal Carcinoma 59

Stephen A. Barnett and Nabil P. Rizk

The treatment of esophageal cancer with curative intent remains highlycontroversial, with advocates of surgery alone, chemoradiotherapy alone,surgery with adjuvant therapy (including neoadjuvant and postoperative),and trimodality therapy each contributing prospective randomized con-trolled trials (PRCTs) to the body of scientific publications between 2000and 2008. Any improvements in survival have been small in absolute per-centage terms, and as such PRCTs published over the last decade havemet the same primary obstacle encountered by the studies from the twoprior decades, namely lack of power to detect small differences in out-come. Variations in staging methods, surgical technique, radiotherapytechnique, and chemotherapy regime have in turn been the subject ofPRCTs over the last nine years. In many cases primary end points havenot been survival but rather rates of complication or response. As wellas giving an overview of PRCTs, this article collates the level Ia evidencepublished to date.

Randomized Clinical Trials in Gastric Cancer 81

James J. Mezhir, Venu G. Pillarisetty, Manish A. Shah, and Daniel G. Coit

Minimally invasive resection has emerged as a surgical technique for gas-tric cancer, and there has been continued investigation to determine theappropriate extent of lymphadenectomy in gastric cancer patients. Therehas also been significant progress in evaluating the role of chemothera-peutic regimens used in the neoadjuvant and adjuvant settings for patientswith resectable disease. We also summarize a selection of RCT trials fo-cused on the perioperative care of the gastric cancer patient.

Randomized Clinical Trials in Gastrointestinal Stromal Tumors 101

Peter A. Learn, Jason K. Sicklick, and Ronald P. DeMatteo

Gastrointestinal (GI) stromal tumor (GIST) is the most common mesenchy-mal tumor of the GI tract, constituting 80% of all GI mesenchymal tumorsand approximately 20% of all small bowel malignancies, excluding lym-phomas. This article provides a summary of recent randomized clinical tri-als of these tumors.

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Randomized Clinical Trials in Pancreatic Adenocarcinoma 115

Udo Rudloff, Ajay V. Maker, Murray F. Brennan, and Peter J. Allen

This article critically reviews and ranks 107 prospective, randomized con-trolled trials (RCT) for pancreatic adenocarcinoma published between2000 and 2008 identified through a standard MEDLINE literature searchstrategy, according to a standardized, previously published 3-tiered sys-tem (Ia, Ib, and Ic). All trials included in this article are Ia or Ib. Typesof treatment reviewed include surgery, chemotherapy, molecular therapy,radiation therapy, immunotherapy, and palliative therapy.

Randomized Clinical Trials in Hepatocellular Carcinoma 151

Adam C. Yopp and William R. Jarnagin

Hepatocellular carcinoma is among the most common solid tumors, rank-ing behind only lung and gastric for cancer-related deaths worldwide. De-spite improved surveillance programs in many countries, most patientspresent with advanced-stage cancer and chronic hepatic dysfunction lim-iting the available treatment options. This article reviews the most pertinentrandomized controlled trials with respect to surgical and adjuvant interven-tions that shape the current treatment algorithm for hepatocellularcarcinoma.

An Update on Randomized Clinical Trials in Advanced and MetastaticColorectal Carcinoma 163

Shishir K. Maithel and Michael I. D’Angelica

During the past eight years, there have been significant advances in thetreatment and outcome of patients with metastatic colorectal cancer.This is likely the result of improved imaging, staging, chemotherapy, andsurgery. After conducting a standardized MEDLINE literature search, thisarticle reviews the prospective randomized controlled trials in advancedcolorectal cancer published between May 2001 and October 2008. Thereare a total of 96 studies, all chemotherapy-related trials, divided into fivecategories based on trial focus: (1) types of chemotherapy; (2) administra-tion of adjuvant or neoadjuvant chemotherapy for resectable liver metas-tases; (3) regional chemotherapy with hepatic arterial infusion; (4)molecular markers of chemotherapy efficacy; and (5) duration, dosing,and sequencing of chemotherapy.

Randomized Clinical Trials in Colon Cancer 183

Heather B. Neuman, Jason Park, and Martin R. Weiser

Surgery remains the mainstay of treatment for colon cancer and surgicalresection alone results in 5-year survival in more than 60% of patients.However, the use of fluorouracil (5-FU)-based adjuvant chemotherapyfor patients at high risk of recurrence further prolongs disease-free survivaland has become the standard of care. New areas of research focus on de-creasing the surgical trauma with minimally invasive approaches,

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improving the surgical staging of patients with colon cancer, and improv-ing adjuvant treatment regimens. We review those randomized controlledtrials that have most impacted the clinical management of patients withcolon cancer in 2009.

Randomized Clinical Trials in Rectal and Anal Cancers 205

Jason Park, Heather B. Neuman, Martin R. Weiser, and W. Douglas Wong

This article reviews randomized clinical trials (RCTs) published betweenApril 2001 and November 2008 on the management of patients with rectalcancer. In total, the authors reviewed 78 RCTs on therapy for rectal cancer.Of these, five met the authors’ criteria for level 1a evidence. The article dis-cusses the major RCTs and relevant findings that have impacted clinicalmanagement most and includes most but not all RCTs on therapy for rectalcancer published during this period.

Index 225

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