clinical oncology news - September 2011, digital edition hematology edition

Independent News on Advances in Cancer Care

Hematology/Oncology Edition clinicaloncology.com • September 2011 • Vol. 6, No. 9

HematOlogic DISEASE

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New analysis of study comparing nilotinib to imatinib for CML yields clues to mutations.

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Optimal dosing of cytarabine investigated for AML.

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BRAF mutations play a role in hairy cell leukemia.

Evidence builds for zoledronic acid use in multiple myeloma.

SOLID TUMORS

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Erlotinib and other targeted therapies beat chemotherapy in non-small cell lung cancer.

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Axitinib superior to sorafenib as second-line therapy for metastatic renal cell carcinoma.

Decitabine Offers Alternative for Elderly AML Patients

New Analysis of FLEX Trial Reveals Intriguing Finding

Chicago—A five-day monthly course of IV decitabine (Dacogen, Eisai) appears to provide both higher response rates and an overall survival advantage in elderly patients with acute myeloid leukemia (AML) compared with either supportive care or the current standard treatment, low-dose cytarabine, according to results from a multinational Phase III trial.

Xavier Thomas, MD, PhD, of the Edouard Herriot Hospital in Lyon, France, presented the study at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO) (abstract 6504). The 485 enrolled patients, all with poor- or intermediate-risk cytogenetics, were randomized either to the five-day decitabine arm (DAC) or

Amsterdam—Patients with non-small cell lung cancer (NSCLC) who demonstrate high epidermal growth factor receptor (EGFR) expression have a roughly 2.5-month improvement in median overall survival (OS) when cetuximab is added to standard chemotherapy, according to a new analysis of the FLEX trial.

The Phase III study, conducted in patients with stage IIIb/IV disease, was presented at the recently held 14th World Conference on Lung Cancer (abstract 1557). The researchers, led by Robert Pirker, MD, of the Medical University of Vienna, divided their cohort of 1,121 patients into those with high (200300) and low tumor EGFR expression (below 200).

Patients with high EGFR expression had a median OS of 12 months

see DECITABINE, page 30 

Ridaforolimus shows promise for sarcoma.

see FLEX, page 26 

Vogl, New York PRN

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Maurie Markman, MD, discusses the potential impact of pretreatment anticipation of benefit on clinical outcomes.

EDUCATIONAL REVIEW

Soft Tissue Sarcomas of the Extremities and Trunk Between pages 16 and 17.

To Improve Curative Therapy of Gastric Cancer …

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n 2011, 4 core principles should be guiding oncologists and surgeons who treat patients with gastric cancer.

1. Do the right surgery, and have the right surgeon do it.

2. Do not split the chemotherapy.

3. If you have to irradiate, do it after chemotherapy.

4. If you give induction chemotherapy, monitor the primary tumor for response or progression.

These principles are based on my see VOGL, NY, page 12 

POLICY & MANAGEMENT

Who Benefits From Restricted Distribution?

W

hen ipilimumab (Yervoy, Bristol-Myers Squibb) was approved in March, concerns were raised about the high cost of the melanoma drug, and the issue is still being vigorously debated. But for some health systems, an even more top-ofmind issue is the requirement that ipilimumab only be purchased from three distributors—McKesson Specialty Care Distribution, McKesson Plasma and Biologics or Oncology Supply.

Niesha Griffith, MS, RPh, FASHP, director of pharmacy and infusion services at The Arthur G. James Cancer Hospital at The Ohio State University (OSU), in Columbus, said one of her main concerns is the operational burdens that such a restricted distribution network would place on many large hospitals that don’t use one of the three approved suppliers. “This drug costs more than $100,000 per treatment course,” Ms. Griffith said. “For us to treat 10 of our see IPILIMUMAB, page 28 

McMahonMedicalBooks.com Flow Cytometry in Hematopathology Doyen T. Nguyen

For more information, see page 2.

FDA News Brentuximab vedotin (Adcetris, Seattle Genetics) approved for two types of lymphoma.

See page 27.

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Advances in Malignant Hematology Hussain I. Saba; Ghulam Mufti

This comprehensive book captures and compiles new and current information on hematologic malignancies. The recent and ongoing expansion of knowledge on this topic has not previously been used to its full capacity due to its diffuse distribution scattered over the Internet and research publications. This book is written by experts from the American and European continent, sharing their current thoughts and knowledge on the pathobiology of malignant haematological diseases of the blood, as well as current treatment strategies and future developments in the area of these hematological diseases.

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Essential Haematology, 6th Edition (includes free desktop edition)

Victor Hoffbrand; Paul Moss

OrDEr ONLINE For pricing, a more complete review and easy ordering with a credit card, go to McMahonMedicalBooks.com.

We can supply any medical book in print, so if you don’t find the book you want, email your request with billing information to RMcMahon@McMahonMed.com.

If you are an author and would like your medical book featured in this book section, contact Ray McMahon, Publisher, at RMcMahon@McMahonMed.com.

Essential Haematology is established as the most authoritative introduction to haematology. Beautifully presented, it introduces the formation and function of blood cells and diseases that arise from dysfunction and disruption of these processes. Basic science, diagnostic tests, clinical features and management are all clearly explained. The book outlines the basic principles of clinical and laboratory haematology and shows how manifestations of blood diseases can be explained by new knowledge of the disease processes.

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Flow Cytometry in Hematopathology

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For Doctors Only: A Guide to Working Less & Building More, Third Edition

Doyen T. Nguyen

The second edition of this volume reflects the recent advances in the FCM analysis of hematopoietic disorders. The chapters have been revised to incorporate new text and figures. A companion CD containing case studies is also included.

Christopher R. Jarvis; David B. Mandell; Jason M. O’Dell This volume helps physicians move beyond theory and into practice by outlining how to find quality advisors and construct a collaborative, multidisciplinary planning team.

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Hematology: Clinical Principles and Applications: 4th Edition

Bernadette F. Rodak Featuring hundreds of full-color photomicrographs, this book prepares you for a job in the clinical lab by exploring the essential aspects of hematology. It shows how to accurately identify cells, simplifies hemostasis and thrombosis concepts, and covers normal hematopoiesis through diseases of erythroid, myeloid, lymphoid, and megakaryocytic origins.

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Myelodysplastic Syndromes, An Issue of Hematology/ Oncology Clinics of North America

Benjamin L. Ebert, MD, PhD The articles in this issue illustrate the rapid progress in MDS research, from molecular pathophysiology to improved therapies. Insights into the biology of MDS, the development of model systems to study MDS, and the application of new technologies with unprecedented power to interrogate the cancer genome promise to increase the rate of discovery, transforming our understanding of MDS and leading to improvements in the treatment of this disease.

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The Bethesda Handbook of Clinical Hematology

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Williams Manual of Hematology, 8th Edition

Griffin P. Rodgers; Neal S. Young

This book is a concise, complete hematology handbook designed for quick bedside consultation. It covers all hematologic disorders and provides residents, fellows and practitioners with need-to-know information on pathophysiology, natural history, risk factors, diagnosis, treatment and follow-up. It is ideal for board review as well as clinical reference.

This edition includes new information on supportive care and new therapies, including immunomodulatory drugs, growth factors and epigenetic-acting agents and their role in selected disorders.

Marshall A. Lichtman

This book is a concise and easy-to-navigate compilation of the pathogenic, diagnostic and therapeutic essentials of blood cell and coagulation protein disorders. This handy, easily transported reference has been carefully edited to deliver only the most clinical point-of-care facts.

CO0911

CLINICAL ONCOLOGY NEWS

Clinical Oncology News • September 2011

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center, Penn State University Hershey, PA

Breast Cancer

Prostate Cancer Michael A. Carducci, MD AEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD

Hematologic Malignancies

Andrew Seidman, MD

Jennifer R. Brown, MD, PhD

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Maura N. Dickler, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer Edward Chu, MD University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Cathy Eng, MD University of Texas, MD Anderson Cancer Center Houston, TX

Leonard Saltz, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer and Sarcoma Ephraim Casper, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Harry Erba, MD, PhD University of Michigan Ann Arbor, MI

Shaji Kumar, MD Mayo Clinic Rochester, MN

Richard Stone, MD

Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic Cancer

Lung, and Head and Neck Cancers

Michael J. Fisch, MD, MPH University of Texas MD Anderson Cancer Center Houston, TX

Steven Vogl, MD Medical Oncologist New York, NY

Symptom Control and Palliative Care William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

Oncology Nursing

Paul J. Ford, PhD

Betty Ferrell, RN, PhD City of Hope National Medical Center Duarte, CA

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Policy and Management

Pharmacy

Mary Lou Bowers, MBA Cindy O’Bryant, PharmD University of Colorado Cancer Center Denver, CO

The Pritchard Group Rockville, MD

Rhonda M. Gold, RN, MSN Sara S. Kim, PharmD The Mount Sinai Medical Center New York, NY

The Pritchard Group Rockville, MD

Editorial Philosophy The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the newsmagazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published.

Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print.

Additionally, all news articles that appear in Clinical Oncology News are sent to the sources quoted in each article to review and verify the accuracy of the article’s content.

Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

Steven D. Passik, PhD Vanderbilt University Medical Center Nashville, TN

Joseph V. Pergolizzi Jr., MD Johns Hopkins University School of Medicine Baltimore, MD

Hofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center Lake Success, NY

Cleveland State University Cleveland, OH

Mercy Medical Center St. Louis, MO

University of Texas, MD Anderson Cancer Center Houston, TX

Richard J. Gralla, MD

Joseph P. DeMarco, PhD

Memorial Sloan-Kettering Cancer Center New York, NY

John W. Finnie, MD

Edward S. Kim, MD

Lung Cancer, Emesis

Susan K. Seo, MD

Community Oncology

Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Bioethics

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Genitourinary Cancer Ronald M. Bukowski, MD

Infection Control

Russell K. Portenoy, MD Beth Israel Medical Center New York, NY

McMahon Publishing is a 38-year-old, family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications.

Charles F. von Gunten, MD

Clinical Oncology News (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Copyright 2011 McMahon Publishing, New York, NY. All rights reserved.

University of California, San Diego, CA

POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

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HEMATOLOGIC DISEASE

Clinical Oncology News • September 2011

CML

Nilotinib vs. Imatinib: Development of BCR-ABL Mutations Patients with chronic myeloid leukemia (CML) treated with nilotinib are less likely to progress to accelerated phase or blast crisis compared with patients treated with imatinib, due in part to nilotinib’s effectiveness in preventing the emergence of gene mutations sensitive to it.

This news comes from follow-up data from the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials—Newly Diagnosed Patients) study presented at the 2011 meeting of the American Society of Clinical Oncology (ASCO) (abstract 6502).

The ENESTnd trial—a Phase III randomized open-label, active-control study—was designed to evaluate the safety and efficacy of nilotinib (Tasigna, Novartis) compared with imatinib (Gleevec, Novartis) in 840 patients newly diagnosed with Philadelphia chromosome–positive, chronic-phase CML from 217 centers across 35 countries. Patients in the trial received either nilotinib (at a dose of either 300 or 400 mg twice daily) or imatinib (at a dose of 400 mg once daily). They then were assessed for major molecular response (MMR), complete cytogenic response (CCyR) and complete molecular response (CMR) at 12 months.

For the nilotinib-treated patients, MMR was 44% in the 300 mg twice-daily group and 43% in the 400 mg twicedaily group, compared with 22% for the patients who received imatinib. CCyR in the nilotinib treatment groups was 80% and 78%, respectively, compared with 65% in the imatinib group. CMR, defined as a BCR-ABL1 of 0.0032% or less, occurred in approximately 20% of patients receiving nilotinib therapy, compared with approximately 6% of patients receiving imatinib therapy. The study’s initial findings were published in The New England Journal of Medicine in 2010 (362:2251-2259).

Research has shown that clinical resistance to imatinib often results from

mutations of the BCR-ABL oncogene. To assess the role BCR-ABL gene mutations played in the results of the ENESTnd trial, the follow-up data presented at ASCO 2011 focused on the results of BCR-ABL gene mutation analysis performed on study participants at 24-month follow-up.

All study participants underwent mutation testing using long-range polymerase chain reaction amplification of BCR-ABL and direct sequencing prior to the start of the trial and at the end of treatment.

Additional mutation testing was performed on those patients who failed to achieve MMR at 12 months, patients who lost MMR during the study and patients who experienced a fivefold increase in BCR-ABL from the lowest levels achieved on the study.

nilotinib. For the 400 mg twice-daily group, these figures were eight and two, respectively. Of the 20 patients receiving imatinib with newly detectable mutations of the BCR-ABL gene, three were of the T315I variant and 13 were of other variants sensitive to nilotinib.

“Most of the patients who developed mutations had an intermediate or high Sokal risk score at the time of diagnosis,” said Giuseppe Saglio, MD, of the University of Torino, Italy, principal investigator and lead author of the ENESTnd trial.

According to Dr. Saglio, most of the patients with newly detectable mutations during therapy were suboptimal responders or treatment failures. Of the 10 suboptimal responders, five were in

‘Most of the patients who developed mutations had an intermediate or high Sokal risk score at the time of diagnosis.’

—Giuseppe Saglio, MD

Mutation analysis performed on the study population at diagnosis at the beginning of the ENESTnd trial revealed that 60 of the patients had one of several mutation variants of the BCR-ABL gene.

One polymorphism—E499E—occurred in 53 of the patients. During treatment, twice as many patients in the imatinib group (20) had newly detected mutations, compared with the nilotinib groups. In all, 10 patients receiving nilotinib 300 mg twice daily had newly detected mutations, and three of these were of the T315I sequence variant, which is insensitive to

the nilotinib 300 mg twice-daily treatment arm and four were in the imatinib arm. Of the 25 treatment failures, however, 16 were in the imatinib arm, compared with five in the nilotinib 300 mg twice-daily group and four in the nilotinib 400 mg twice-daily group.

“The association between the presence of mutations and progression to accelerated phase or blast crisis is really an interesting aspect,” said Dr. Saglio.

“Nilotinib produces a better response in terms of preventing progression to accelerated phase or blast crisis.

Progression is more frequent in the imatinib-treated patients. In more than 60% of the cases, progression to [accelerated phase or blast crisis] was associated with the presence of mutations [in the imatinib-treated patients].”

Additionally, of the nine patients who lost CCyR (defined as treatment failures according to the European Leukemia Network 2006 criteria), according to Dr. Saglio, five were found to have newly detectable mutations during treatment.

All five progressed to accelerated phase or blast crisis. Loss of MMR, meanwhile, was infrequent in all treatment arms.

“Nilotinib was effective in preventing the emergence of clones with nilotinibsensitive mutations,” Dr. Saglio said. “[The results show] that deeper molecular responses with nilotinib protect from the development of emerging mutations and progression to accelerated phase and blast crisis.”

According to Richard Stone, MD, director of the Adult Leukemia Program at Dana-Farber Cancer Institute, Boston. “It is reassuring but not surprising that the upfront administration of nilotinib, a potent BCR-ABL inhibitor, resulted in a lower incidence of nilotinib-sensitive mutations. However, also as expected, T315I mutations which are resistant to all currently available TKIs, remain a cause for resistance to nilotinib.”

—Brian Dunleavy

AML

Mid-dose Cytarabine Treats AML With Similar Efficacy, Less Toxicity From The New England Journal of Medicine

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ntermediate-dose cytarabine achieved antileukemic effects in patients with acute myeloid leukemia (AML) that were similar to those of standard high-dose cytarabine therapy with reduced toxicity, according to a recent study published in The New England Journal of Medicine (2011;364:1027-1036, PMID: 21410371).

High-dose cytarabine therapy has been a fundamental element in the treatment of AML for many years in both treatment-naive and relapsed patients after

studies found this regimen to be more effective than lowdose cytarabine. One such study was the News From landmark CALGB The JOURNALS (Cancer and Leukemia Group B) 8525 study (N Engl J Med 1994;331:896, PMID: 8078551). Highand intermediate-dose cytarabine therapy was not compared until the present Phase III European multicenter study that looked at remission-induction therapy in patients with AML, myelodysplastic syndrome (MDS) or refractory anemia

with excess blasts.

Investigators from the Dutch-Belgian Cooperative Trial Group for HematoOncology and the Swiss Group for Clinical Cancer Research compared two induction regimens in treatment-naive patients with AML aged 18 to 60 years.

The 431 patients in the intermediate-dose group received 200 mg/m2 of cytarabine by continuous IV infusion over 24 hours, which constituted cycle 1 of their induction therapy. The cycle 2 dose was 1,000 mg/m2 of cytarabine infused for three hours twice daily. The high-dose group totaled 429 patients. They received 1,000

mg/m2 of cytarabine every 12 hours during cycle 1, which increased during cycle 2 to 2,000 mg/m2 twice daily. Patients who experienced a complete response (CR) stopped further cytarabine therapy and underwent a third cycle consisting of mitoxantrone-etoposide consolidation chemotherapy or either autologous or allogeneic stem cell transplantation.

The investigators assessed survival rates, CR rates and toxic effects over a median follow-up of five years. Highdose cytarabine did not proffer any substantive advantage for any of the prognostic elements. Differences were not

HEMATOLOGIC DISEASE

Clinical Oncology News • September 2011

AML

significant between the intermediateand high-dose cytarabine groups in CR rates (80% vs. 82%, respectively), relapse rate (39% vs. 37%), event-free survival at five years (34% vs. 35%) and overall survival (OS) at five years (40% vs 42%).

However, the high-dose treatment group experienced delayed neutrophil recovery during cycle 2, delayed platelet recovery during cycles 2 and 3, prolonged hospitalization and higher incidences of grades 3 and 4 toxic effects during cycle 1 (51% in the intermediate-dose group compared with 61% in the high-dose group, with skin reactions and gastrointestinal and ocular toxic effects predominating).

Although no differences were noted in 30-day mortality, three-month mortality was greater in the high-dose group (72 vs.

52; hazard ratio, 1.41; P=0.057).

The investigators concluded that the maximal antileukemic effects had been achieved during induction therapy at the intermediate-dose level and that high-dose treatment resulted in excessive adverse effects without concomitant therapeutic benefit.

EXPERT INSIGHT Richard Stone, MD

TM

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MOST PATIENTS WITH MULTIPLE MYELOMA STILL

Director of the Adult Leukemia Program, Dana-Farber Cancer Institute, and Professor of Medicine, Harvard Medical School, Boston, Massachusetts

“The recently reported study by the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology and the Swiss Group for Clinical Cancer Research seems to call into question the long-held notion that high-dose cytarabine is the best anti-AML therapy to use during remission. Because the dosing schedule of 3 g/m2 over three hours twice daily on days 1, 3 and 5 used in the CALGB 8525 trial represents more drug than needed to provide maximal intracellular arabinoside cytosine (Ara-C) triphosphate, the toxic metabolite, the optimal AraC dose remains unclear. In the recent study, published in The New England Journal of Medicine, there was less total Ara-C given, even in the high-dose group, than in CALGB 8525, which might be reflected in the lower eventfree and OS rates seen in the current trial compared with CALGB 8525, in which all patients received one to two cycles of induction chemotherapy and four cycles of cytarabine-based chemotherapy followed by four cycles of maintenance chemotherapy. The four cycles of high-dose Ara-C plus the maintenance, absent from the current trial, may have been important in leading to the impressive disease-free survival results in the CALGB 8525 trial.”

The overall 5-year survival for patients with multiple myeloma has improved over the past 10 years.1 However, myeloma remains a largely incurable disease, and almost all patients will relapse.2

PROGRESS HAS BEEN MADE, BUT NEW THERAPIES ARE URGENTLY NEEDED. References: 1. National Cancer Institute. Surveillance Epidemiology and End Results. seer.cancer.gov /csr/1975_2007/browse_csr.php?section=18&page=sect_18_table.08.html#table1. Accessed April 6, 2011.

2. Chanan-Khan AA, Ivan Borrello I, Lee KP, et al. Development of target-specific treatments in multiple myeloma.

Br J Haematol. 2010;151(1):3–15.

Photograph courtesy of: © 2010 Rector and Visitors of the University of Virginia; Charles E. Hess, MD, and Lindsey Krstic, BA, RN.

Copyright © 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.

ONCO-1004328-0001-05/11

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HEMATOLOGIC DISEASE

Clinical Oncology News • September 2011

Leukemia

BRAF Mutations Play a Role in Hairy Cell Leukemia the BRAF V600E variant protein. The substitution of glutamic acid for valine at posimutation in the BRAF tion 600 of the BRAF protein is gene has been associ“a mutational hotspot in melNews From ated with hairy cell leukemia The JOURNALS anomas and papillary thyroid (HCL) and strongly implicancers,” the investigators notcated in the pathogenesis and treatment ed. This mutation was found in each of of the disease, according to an interna- the 47 patients with HCL. However, in tional multicenter study. a finding the investigators called “strikTo better elucidate the biology of HCL ing,” none of the other 195 patients carand uncover possible new approaches ried the BRAF V600E variant, which is to its diagnosis and treatment, the study oncogenic in other tumors. BRAF, the investigators looked at DNA in purified most frequently mutated gene, encodes leukemic and paired normal cells from a protein kinase. an index patient to identify recurrent HCL cells expressed phosphorylatsomatic mutations in protein-coding ed extracellular signal-regulated kinase genes (N Engl J Med 2011;364:2305-2315, (ERK) and mitogen-activated proteinPMID: 21663470). The results were then ERK kinase (MEK) in immunohistovalidated via Sanger sequencing in 47 logic and Western blot studies, suggestpatients with HCL and 195 patients with ing “constitutive activation of the RAFother B-cell lymphomas or leukemias.

MEK-ERK mitogen-activated protein Investigators—from centers in Italy, kinase pathway in HCL.” MEK is the the United States, Germany and Swit- immediate downstream kinase target of zerland—found five missense somat- BRAF, whereas ERK is the kinase phosic clonal mutations, one of which was phorylated by activated MEK. a heterozygous mutation that results in The investigators concluded that the From The New England Journal of Medicine

A

“A recent study published in The New England Journal of Medicine suggests Richard Stone, MD that cells from essentially all patients Director of the Adult with HCL contain a BRAF V600E mutaLeukemia Program, tion, a hotspot in melanomas and papilDana-Farber Cancer Institute, and lary thyroid cancers. The BRAF mutant Professor of Medicine, protein was specific for HCL; it was not Harvard Medical School, seen in other types of B-cell lymphoBoston, Massachusetts proliferative cancers. Not only is the BRAF V600E mutation associated with HCL, but it also seems to be involved in signaling in such cells based on activation of downstream targets (e.g., members of the MEK-ERK pathway). Detection of the BRAF V600E mutation is a possible important tool for confirming the diagnosis of HCL, and given the clinical development of RAF inhibitors for treatment of melanoma, one can contemplate their use in this indolent B-cell neoplasm.”

EXPERT INSIGHT

BRAF V600E mutation is “invariably associated with the disease” and strongly implicated in disease pathogenesis, noting that it was found in all of the patients with HCL yet in none of the patients with other peripheral B-cell lymphomas or leukemias. Their findings suggest that the mutated BRAF in HCL is the likely trigger for constitutive MEK and ERK activation. The investigators posit that

this finding can be used as a diagnostic tool to distinguish HCL from similar disorders. Furthermore, the BRAF V600E mutation is a potential target for therapeutic intervention in patients who have a poor response to initial purine analogue therapy or those experiencing relapse or unacceptable toxicity. Clinical studies of BRAF inhibitors would appear to be warranted.

MDS

Mutations Uncovered That Explain MDS Heterogeneity From The New England Journal of Medicine

S

everal specific somatic point mutations in patients with myelodysplastic syndromes (MDS) have been shown to predict poor overall survival (OS), according to the results of a National Institutes of Health–­funded study that validates earlier smaller studies.

The findings could mean improvements in predicting prognosis and generating therapeutic responses to MDS. Several mutations—TP53, NRAS, RUNX1, TET2, IDH1 and IDH2—were assessed in small studies and were reported to influence OS, but only mutations to the TP53 gene had been associated with poor prognostic markers like a complex karyotype. Interactions between these TP53 mutations and other mutated genes in these patients had not been studied in large trials, and thus their independent prognostic significance was not clear.

To further elucidate the role of these mutations, the investigators—from centers in Boston, New York and Houston—reviewed a robust sample set from patients with MDS for evidence of somatic mutations across a broad spectrum of cancer-associated genes (N Engl J Med 2011;364:2496-2506, PMID: 21714648). The goal was to identify specific contributions of selected mutations to both the clinical phenotype and OS.

The investigators obtained samples of mutations from bone marrow aspirate mononuclear cells and buccal swab samples from 439 patients with MDS. The mutations were identified using a variety of genomic techniques, including next-generation sequencing and mass spectrometry–based genotyping. The investigators then ascertained whether these mutations were accountable for the observed clinical variables, which included specific cytopenias, the proportion of blasts and OS rates.

They identified 18 mutations, of which two—ETV6 and GNAS—were reported as being mutated for the first time in these patients. In patients with normal cytogenetics, 52% had at least one point mutation, as did 51% of all the patients in this study.

Severe thrombocytopenia was strongly associated with mutations in RUNX1, TP53 and NRAS (P<0.001 for each comparison); these mutations also were associated with an increased proportion of bone marrow blasts (P<0.006 for each comparison). The presence of mutations in five genes was found to be independently associated with decreased OS in a multivariable Cox regression analysis: TP53 (hazard ratio [HR] for death from any cause, 2.48; 95% confidence interval [CI], 1.60-3.84), EZH2 (HR, 2.13; 95% CI, 1.36-3.33), ETV6 (HR, 2.04; 95% CI, 1.08-3.86), RUNX1 (HR,

1.47; 95% CI, 1.01-2.15) and ASXL1 (HR, 1.38; 95% CI, 1.00-1.89). Mutations in at least one of these genes were found in 137 of the 439 patients (31.2%).

According to the investigators, mutations in these genes explain the clinical heterogeneity found in MDS. They concluded that “the integration of mutation assessment in diagnostic classification and prognostic scoring systems has the potential to parse diverse myelodysplastic syndromes into a set of discrete diseases with predictable clinical phenotypes, prognosis and responses to therapy.”

is important because it provides critical information about the pathophysiology, albeit heterogeneous, of MDS and could point the way to both a better prognostic scoring system and novel therapeutic approaches.”

Visit Our Web Site

EXPERT INSIGHT Richard Stone, MD

“In a recent study, Bejar and colleagues from centers in Boston, New York and Houston looked for point mutations in samples from 439 patients with MDS. Up-to-date sequencing technology was used to identify mutations in 18 genes, two of which, ETV6 and GNAS, were reported as being mutated for the first time in these patients.

More than half of the MDS patients studied had at least one point mutation.

The presence of mutations in five genes (TP53, EZH2, ETV6, RUNX1 and ASXL1) was found to have independent prognostic significance compared with several other clinical features. This work

Please send comments to

korourke@mcmahonmed.com.

HEMATOLOGIC DISEASE

Clinical Oncology News • September 2011

Multiple Myeloma

Zoledronic Acid Bests Clodronic Acid in Myeloma From Lancet Oncology

P

atients with newly diagnosed multiple myeloma taking zoledronic acid (Zometa, Novartis) have an overall lower risk for skeletal-related events (SREs) than those taking clodronic acid, regardless of bone status at baseline, according to a study in Lancet Oncology (2011;12:743752, PMID 21771568).

The study is a secondary outcomes analysis of the randomized controlled MRC Myeloma IX trial. The primary end points of the trial—improved clinical outcomes, including progression-free survival and overall survival, all favoring zoledronic acid—were reported in the Lancet last year. The new analysis adds yet another benefit for IV zoledronic acid compared with the oral agent clodronic acid: bone stability.

At a median follow-up of 3.7 years, 27% of patients in the zoledronic acid group experienced SREs (defined as fractures, spinal cord compression, new osteolytic lesions and radiation or surgery to bone),

compared with 35% of those in the clodronic acid group (P=0.0004).

Patients who had bone lesions at baseline had fewer bone-related events with zoledronic acid than with clodronic acid (35% vs. 43%; P=0.0038), as did patients without bone lesions at baseline (10% vs. 17%; P=0.0068).

In an exploratory analysis that excluded new osteolytic lesions from the definition of SRE, the outcome was similar, and the reduction in risk for SREs

with zoledronic acid was still significant (P=0.0011).

“Although clinical guidelines recommend bisphosphonates for patients with documented bone lesions, all patients (i.e., with or without bone disease at baseline) could benefit when bisphosphonates are begun early in the course of multiple myeloma,” the authors wrote. “Moreover, the reductions in skeletal-related events with zoledronic acid versus clodronic acid

noted throughout the course of the trial support the continued use of zoledronic acid in patients with multiple myeloma at least until disease progression.”

They added that the optimum duration of zoledronic acid treatment is not known and speculated that some patients could benefit from continuing the drug—perhaps at a reduced dose—during remission.

The increased rate of cases of osteonecrosis of the jaw (ONJ) is one significant drawback. Although rare, it occurred with much greater frequency with zoledronic acid than with clodronic acid (5% vs less than 1%; P=0.0001).

EXPERT INSIGHT Shaji Kumar, MD Mayo Clinic Rochester, Minnesota

It’s well-known that mucins protect healthy cells, but did you know that aberrant overexpression of mucin 1 (MUC1) by tumor cells may play a role in tumor cell survival?1-3 At EMD Serono, we’re investigating the significance of MUC1 and its impact on your patients with NSCLC.

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“The results of this Phase III trial convey two important messages with two caveats. First, use of an IV administered, highly potent bisphosphonate (zoledronic acid) provides significant protection against bone-related events compared to an oral bisphosphonate such as clodronate, a difference that was still significant when you excluded radiographically detected new lytic lesions as skeletal events. Second, this benefit was seen even in patients with no bone disease at baseline, and taking into consideration the original results of the trial demonstrating an improved survival for patients on zoledronic acid, it makes a strong case for treating all patients with newly diagnosed myeloma with IV bisphosphonates.

The study, however, does not provide any definitive information regarding the optimal duration of therapy with bisphosphonates or how zoledronic acid compares with other IV bisphosphonates such as pamidronate or newer agents such as denosumab (Xgeva, Amgen). This is important, given the risk of ONJ that was seen more with zoledronic acid in this study and prior studies showing higher risk with prolonged use of bisphosphonates as well as with the more potent bisphosphonates.”

What role may MUC1 play in NSCLC

1. Ahmad R, Raina D, Joshi MD, et al. MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor. Cancer Res. 2009;69(17):7013-7021.

2. Behrens ME, Grandgenett PM, Bailey JM, et al. The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF. Oncogene. 2010;29(42): 5667-5677. 3. Raina D, Kosugi M, Ahmad R, et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther. 2011;10(5):806-816.

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EMD Serono, Inc. is an affiliate of Merck KGaA, Darmstadt, Germany

7

SOLID TUMORS

Clinical Oncology News • September 2011

Lung

Targeted Therapies Move to the Forefront in NSCLC Chicago—Recent studies pitting targeted therapies against chemotherapy in advanced

non-small cell lung cancer (NSCLC) are showing the novel agents—erlotinib (Tarceva, OSI/Genentech), gefitinib (Iressa, AstraZeneca) and MetMAb (Genentech)— can beat the old standby regimens.

Erlotinib Perhaps the most important of these studies was the Phase III, EURTAC (European Erlotinib Versus Chemotherapy) trial, which was presented at the 2011 American Society of Clinical Oncology (ASCO) annual meeting. This study compared the tyrosine kinase inhibitor (TKI) erlotinib to chemotherapy in NSCLC patients with epidermal growth factor receptor (EGFR) mutations (abstract 7503). At the interim analysis, erlotinib was associated with a significant advantage for the primary end point of progression-free survival (PFS).

The multinational EURTAC study was conducted in Europe with a primarily white population and yielded results that were comparable in many ways to IPASS (IRESSA Pan-Asia Study), conducted in China with gefitinib, a TKI that also targets EGFR (N Engl J Med 2009;361:947957, PMID: 19692680). In EURTAC, 174 NSCLC patients with EGFR mutationpositive tumors were randomized to a daily dose of 150 mg erlotinib or to a platinum-based doublet chemotherapy, given every three weeks for four cycles.

The groups were well matched for baseline characteristics.

At the preplanned interim analysis, the PFS was 9.4 months for erlotinib compared with 5.2 months for the chemotherapy, which generated a hazard ratio (HR) of 0.42 for progression (95% confidence interval [CI], 0.27-0.64; P<0.0001)(Figure 1). On a strict intention-to-treat analysis, the PFS rates (9.7 vs. 5.2 months) and HR (0.37) were similar. When stratified by Chemotherapy Erlotinib

9.4

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Figure 1. Comparison of PFS in EGFRpositive NSCLC. EGFR, epidermal growth factor; NSCLC, non-small cell lung cancer; PFS, progression-free survival

a long list of characteristics, such as gender, age and smoking status, the advantage of the TKI remained consistent. The objective response rates were 54.5% on erlotinib compared with 10.5% on chemotherapy (P<0.0001). The HR for overall survival (OS) was 0.80 (95% CI, 0.471.37; P=0.4), which was not significant, but these data were characterized as immature.

The safety profile of erlotinib relative to chemotherapy was characterized as comparable by the senior author Rafael Rosell, MD, PhD, chief, medical oncology, Catalan Institute of Oncology, Barcelona,

the exception is EURTAC, for which the PFS of 9.4 months with erlotinib was similar to that with gefitinib in IPASS when it was given to patients with EGFR mutation-positive NSCLC.

‘Is erlotinib a standard for first-line therapy in NSCLC patients with EGFR mutations? I think the answer is yes.’

—Tony Mok, MD

Spain. Although the types of dominant side effects differed, such as a greater rate of rash (80% vs. 3%) but a lower rate of anemia (11% vs. 40%) in the erlotinib arm, the toxicity in both arms was said to be acceptable.

“Is erlotinib a standard for first-line therapy in NSCLC patients with EGFR mutations? I think the answer is yes,” said ASCO-invited discussant Tony Mok, MD, professor in the Department of Medical Oncology, Chinese University of Hong Kong. Basing his conclusion on the EURTAC results and the studies that led up to this trial, Dr. Mok called the results “trustworthy” and predicted that the study will lead to regulatory approval of erlotinib as a first-line therapy in NSCLC patients who have an EGFR mutation.

Erlotinib Versus Gefitinib Addressing the parallels and differences between erlotinib and gefitinib, both of which have now been evaluated by several studies in the setting of EGFR mutation-positive cancer, Dr. Mok suggested that relative differences are unclear.

Only one small study has compared the two. In three of four studies with erlotinib, the PFS averaged about 14 months, which is higher than the average of 10 months observed with gefitinib. However,

Initially approved in 2003, the status of gefitinib was changed by the FDA in 2005 after a large randomized study, ISEL (Iressa Survival Evaluation in Lung Cancer), showed that the drug failed to significantly improve survival in patients with chemo-refractory NSCLC compared with placebo (Lancet 2005;366:1527-1537, PMID: 16257339).

The drug’s label was changed to indicate that only cancer patients who had already taken the medication and whose physicians believed that it was helping could receive the drug. No newly diagnosed lung cancer patients in the United States were given gefitinib after this time, but the drug has remained a therapeutic option in other countries.

Several recent studies have demonstrated that gefitinib can outperform chemotherapy in selected patients. For example, the INTEREST study demonstrated that gefitinib had similar activity to chemotherapy with docetaxel in previously treated patients (Lancet 2008;372:1809-1818, PMID: 19027483).

This study also showed an improved response and PFS in EGFR mutationpositive patients. A study conducted in Japan, presented in 2009 at the joint meeting of the European CanCer Organisation and Congress of the European

Society for Medical Oncology (ECCOESMO) (abstract LBA9) showed that gefitinib trumped treatment with carboplatin and paclitaxel in the first-line treatment of patients with advanced NSCLC who have EGFR mutations.

Recently, a meta-analysis of four randomized studies involving 2,000 patients published in the journal Lung Cancer showed the efficacy of gefitinib in EGFR mutation-positive patients (Lung Cancer 2011, May 10. [Epub ahead of print], PMID: 21565418). The four studies— IPASS, North-East Japan, West Japan and first-SIGNAL—compared gefitinib with chemotherapy in the first-line treatment of patients with advanced NSCLC. Overall, gefitinib was associated with significantly less toxicity than chemotherapy and improved quality of life. Gefitinib also produced higher response rates in the EGFR mutation-positive patients (72% vs. 38%), as well as improved PFS (HR, 0.45). OS was not significantly different between treatment groups.

MetMAb Promising results from another Phase II study presented at ASCO discussed Met, a protein that represents a negative prognostic marker when expressed in NSCLC tumor cells (abstract 7505).

In this study, 128 patients with NSCLC were randomized to receive erlotinib with MetMAb, an antibody that binds to the Met receptor, or erlotinib with placebo. All patients were required to have sufficient tissue to assess Met expression. Patients were stratified as being Met diagnostic-positive if at least 50% of cells in the sample stained positive at a moderate or greater level.

In the Met diagnostic-positive patients, the PFS for those receiving erlotinib plus MetMAb was 2.9 months compared with 1.5 months (P=0.04) for those receiving erlotinib and placebo, producing an HR of 0.53, reported David R. Spigel, MD, director, Lung Cancer Research Program, Sarah Cannon Research Institute, Nashville, Tenn. The OS advantage was even more impressive, reaching 12.6 months in the MetMAb group compared with 3.8 months in those who did not receive MetMAb (P=0.002) (Figure 2). Importantly, patients who were not Met-positive did worse in the MetMAb arm than see TARGETED, page 26 

Scan for abstract 7503. Instructions page 13.

Scan for abstract 7505. Instructions page 13.

SOLID TUMORS

Clinical Oncology News • September 2011

Kidney

In Second-line Therapy for Metastatic RCC …

Study Suggests Axitinib Is Superior to Sorafenib Chicago—Axitinib is superior to sorafenib as second-line therapy for metastatic renal cell carcinoma (mRCC), according to a head-to-head comparison in the Phase III AXIS trial. sunitinib, bevacizumab or temsirolimus, or on a cytokine-based therapy, such as interleukin-2, or interferon-a were randomized to a twice-daily regimen of either 5 mg axitinib or 400 mg sorafenib. Investigators had the option of increasing the dose of axitinib to 10 mg twice daily. All patients had an Eastern Cooperative Group performance status of 0 or 1 at the initiation of the study. More than 90% had undergone a prior nephrectomy. The most common metastases occurred

‘Axitinib should be the reference standard.’

Axitinib

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Axitinib (Pfizer) proved superior with respect to the primary end point of progression-free survival (PFS) and, according to a patient questionnaire administered to participants in the trial, it also performed significantly better at delaying symptoms of progression, providing a 25% risk reduction for a predefined composite measure of time to deterioration (TTD) (P=0.0001).

According to the investigators, the study indicates that small molecule tyrosine kinase inhibitors (TKIs) are

Second-line Therapy Choice

—Brian I. Rini, MD

6 4.7

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Figure. Comparison of PFS in mRCC.

good TKI administered after a first good TKI remains unclear. “Obviously, axitinib is no worse and may be better” than sorafenib, but he indicated that a bigger step forward might be provided by a therapy with a different target rather than by producing another TKI.

mRCC, metastatic renal cell carcinoma; PFS, progression-free survival

—Ted Bosworth

‘[Axitinib is] a reasonable option after a prior TKI.’ —Bruce Redman, DO

not interchangeable for this indication.

Due to its highly significant advantage over sorafenib (Nexavar, Bayer), “axitinib should be the reference standard” for second-line therapy in mRCC, said Brian I. Rini, MD, presenting the data with his colleagues during the 2011 annual meeting of the American Society of Clinical Oncology (abstracts 4503 and 4504). Dr. Rini, Department of Solid Tumor Oncology, Taussig Cancer Center, in Cleveland, labeled the overall safety of axitinib as both “acceptable” and “similar” to that of sorafenib, although the rates of specific adverse events differed.

“There was no difference between axitinib and sorafenib when patients remained on therapy … the difference was that more patients in the sorafenib arm came off treatment,” said David Cella, PhD, chairman, Department of Medical Social Services, Northwestern University, Chicago. Providing the quality-of-life data, Dr. Cella explained that a composite TTD end point—which included death, disease progression and symptom burden, as assessed by disease-specific questionnaire—was used to evaluate patient-reported outcomes in the context of the usual objective measures of disease control.

In this Phase III multinational study, 723 patients with mRCC with clear cell histology who had progressed on a front-line targeted therapy, such as

Axitinib

Sorafenib

in the lung; 80% of patients had lung metastases.

PFS was assessed via two methods.

In an independent review, PFS was 6.7 months in the axitinib arm compared with 4.7 months in the sorafenib arm (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.54-0.81; P<0.0001) (Figure). By investigator assessment, PFS was 8.3 months compared with 5.6 months, but the calculated HR and statistical difference were almost identical to that of the independent review.

The data are not yet sufficiently mature to calculate overall survival, a secondary end point, but the rate of objective response was approximately twice as great (19% vs. 9%; P=0.0001) in the axitinib group.

Quality of life was measured with the Functional Assessment of Cancer therapy-Kidney Symptom Index 15 (FKSI15), a 15-item patient-completed questionnaire, which included a diseaserelated symptoms subscale (FKSIDRS). These were administered prior to therapy, every four weeks while the patient was receiving therapy, and four weeks after therapy was stopped.

About 90% of patients completed all questionnaires.

On the basis of the FKSI tools, symptoms were not only contained, but also modestly alleviated over time. This was true regardless of the TKI to which the patient was randomized. However,

when disease progressed, patients came off therapy and more patients came off sorafenib, so the TTD composite score, driven largely by the FKSI tests, favored axitinib. Specifically, the HR for worsening symptoms was about 16% to 17% lower for axitinib on either measure (P=0.02).

Although ASCO-invited discussant Bruce Redman, DO, professor of medicine, University of Michigan, Ann Arbor, praised the quality of this study, he was more circumspect about the conclusions. He noted that there are several yet-to-be-answered questions generated by these data. In particular, he noted that the first-line therapy appeared to have a large effect on the relative superiority of axitinib. Both axitinib and sorafenib did much better after a prior cytokine-based therapy (PFS of 12.1 vs. 6.4 months, respectively; P<0.0001) than after sunitinib (4.8 vs. 3.4 months, respectively; P=0.0107).

In this study, sunitinib was the first-line agent in 54% of patients and cytokines were first-line in 35%.

Instead of characterizing axitinib as a reference standard, as did the authors, Dr. Redman suggested that it might be more appropriate to call axitinib “a reasonable option after a prior TKI.” Dr. Redman aligned himself with other experts who are questioning the utility of developing more and more TKIs, when the relative benefit of a second

Scan for abstract 4503. Instructions page 13.

Scan for abstract 4504. Instructions page 13.

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Clinical Oncology News • September 2011

Sarcoma

In Metastatic Sarcoma …

mTor Inhibitor Maintenance Demonstrates PFS Benefit Chicago—A large Phase III multinational trial has confirmed a progression-free survival (PFS) benefit for the mTor inhibitor ridaforolimus (Merck) when used as a maintenance therapy in patients with metastatic sarcoma. An overall survival (OS) benefit has not reached statistical significance, but PFS was the primary end point, and follow-up is continuing.

The unusual design of this study was to enroll patients with metastatic disease who had stable disease on their current regimen. The goal was to prolong disease control, according to Sant P. Chawla, MD, Sarcoma Cancer Center, Santa Monica, Calif. In a presentation at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO) (abstract 10005), Dr. Chawla emphasized that the trial “met its end point.”

PFS rate was 70% on ridaforolimus compared with 54% in the placebo group. At six months, the proportions were 34% and 23%, respectively.

The PFS advantage was reflected in the tumor response rate (40.6% vs. 28.6%; P<0.009), which was largely driven by stable disease. There were few objective responses. However, the average tumor size over the course of follow-up was reduced by 1.3% on active treatment but

‘I think the hope right now with the agent we have is that we will help our patients live longer with an acceptable quality of life.’

—Scott H. Okuno, MD

This study, which had remarkably rapid accrual, enrolled 711 patients. For entry, patients were required to have received at least one course of chemotherapy, but many had multiple lines of prior treatment. Prior surgery or radiotherapy were not exclusion criteria. Randomization to ridaforolimus, a rapamycin analog that inhibits signaling along the mTor pathway, or placebo was conducted in a 1:1 ratio. The trial permitted entry of patients with sarcoma of any histology.

The median PFS, as assessed by central radiological review, was improved by approximately three weeks among those randomized to ridaforolimus relative to those receiving placebo (17.7 vs.

14.6 weeks), producing a hazard ratio (HR) of 0.72 (P<0.0001). By investigator assessment, the PFS advantage was even greater on the mTor inhibitor (22.4 vs. 14.7 weeks), resulting in a longer period on maintenance treatment.

The OS was also longer on ridaforolimus (21.4 vs. 19.2 months), but the HR (0.88) did not reach statistical significance (P=0.2256). At three months, the

increased by 10.3% (P<0.001) on placebo.

When stratified by a variety of patient and tumor characteristics, “all subgroups benefited,” Dr. Chawla asserted. He also reported that when survival times were assessed after treatment was discontinued, no detrimental effect was identified for having received the mTor inhibitor therapy. Response rates within specific sarcoma subtypes have not yet been evaluated, but Dr. Chawla did note that there were some exceptional responses with a few patients still in PFS up to two years after starting therapy.

Grade 3 or higher adverse events (AEs) were more common on the mTor inhibitor than on placebo, but the rates were relatively low in both groups. These included thrombocytopenia (10% vs. 1%), stomatitis (9% vs. <1%), anemia (7% vs.

3%), infections (6% vs. 3%) and pneumonitis (3% vs. <1%). Dose reductions for toxicity were common, and ridaforolimus exposure was 74% of that planned (vs.

96% in the placebo arm), but compliance with treatment was greater than 95%.

Quality-of-life (QoL) analyses were

preplanned, but incomplete data prevented an exploratory analysis of the relative effect of ridaforolimus on such cancer symptoms as pain, cough and shortness of breath. Although Dr. Chawla said the types of AEs were “as expected,” QoL analyses may be helpful for better understanding the clinical value of this medication.

“There was major progress in the treatment of sarcoma 20 or 30 years ago, especially in Ewing’s sarcoma and osteosarcoma, but the prognosis in metastatic disease has been poor,” observed Dr. Chawla. With a clear benefit from ridaforolimus that was consistent with projections from earlier clinical trials, Dr. Chawla indicated that this treatment will be a useful option in a challenging malignancy.

Although he praised the size of the study and its ability to demonstrate activity with ridaforolimus, the ASCOinvited discussant, Scott H. Okuno, MD, Division of Medical Oncology, Mayo Clinic, Rochester, Minn., cautioned that the study leaves many questions unanswered. He suggested that the five-week discrepancy in PFS between radiological review and clinical assessment deserves further study, particularly as a threeweek benefit may not be judged to be an adequate benefit by those experiencing significant side effects.

“Most of the side effects are manageable, but there were some that could be significant if not optimally controlled,” Dr. Okuno suggested. Ridaforolimus will still be more attractive than most cytotoxic agents, but it will be helpful to know more about whether benefit varied across different sarcoma histologies. Still, he was impressed that there was no rapid progression after therapy was stopped and suggested that these data bring treatment of advanced sarcoma closer to the

Ridaforolimus Placebo

20

17.7

10

5

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Figure. Comparison of progression-free survival.

PFS, progression-free survival

‘There was major progress in the treatment of sarcoma 20 or 30 years ago, especially in Ewing’s sarcoma and osteosarcoma, but the prognosis in metastatic disease has been poor.’

—Sant P. Chawla, MD

emerging paradigm of sustained disease control rather than remission.

“I think the hope right now with the agent we have is that we will help our patients live longer with an acceptable quality of life,” Dr. Okuno said. He indicated that these are the criteria on which to judge newer agents such as ridaforolimus for advanced disease.

—Ted Bosworth Dr. Chawla disclosed he has a consultant or advisory role with Merck and has received research funding from the company.

Dr. Okuno reports no relevant disclosures.

The study was sponsored by Merck.

Let Us Visit Your Practice Please consider inviting the staff of Clinical Oncology News to visit your practice. We want to meet you and your colleagues, listen to your concerns, and observe the physical site of your practice.

You can help us improve Clinical Oncology News and fulfill our mission—to provide evidence-based, clinically relevant information that you can use to benefit your patients and practice.

If you are interested, please contact Kate O’Rourke, editor, at (212) 957-5300 ext. 265 or via e-mail at korourke@mcmahonmed.com.

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Clinical Oncology News • September 2011

Testicular

Radiation–Second Malignancy Link in Testicular Cancer Probed From Journal of Clinical Oncology

M

en with low-grade testicular cancer have a low risk for second malignancy of the abdomen–pelvis, irrespective of radiation exposure from diagnostic imaging, according to longterm data on more than 2,500 men (J Clin Oncol; 2011;29:2883-2888, PMID: 21690479).

During the first five years of followup, 14 patients had diagnoses of second abdominal–pelvic malignancy, which translated into a rate of five per 10,000 patient-years of observation. Diagnostic radiation exposure did not increase the risk for a second abdominal–pelvic malignancy, as reflected in a hazard ratio of 0.99 per 10 mSv increase in radiation (95% confidence interval [CI], 0.95-1.04).

Radiation exposure from diagnostic imaging has increased substantially over the past three decades. Per-capita exposure averaged 0.5 mSv in 1980, compared with 3.0 mSv in 2006. Computed tomography (CT) scans have accounted for much of the increase and currently constitute half of the cumulative effective dose, the authors noted.

Prior studies have calculated radiation exposure from diagnostic tests and used statistical models to estimate risk for malignancy. Few studies have measured radiation exposure and followed patients to determine actual tumor incidence.

Using population-based administrative data sets, the new study identified all diagnoses of testicular cancer in Ontario, Canada from 1991 to 2004. Exclusion for previous cancer, radiation therapy, retroperitoneal lymph node dissection and follow-up for less than five years resulted in EXPERT INSIGHT Ronald M. Bukowski, MD Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, Ohio

“Currently, men with stage 1 seminomatous and nonseminomatous testicular cancer undergo serial CT scanning surveillance of the retroperitoneum to identify recurrent disease. The current study is a population-based analysis of testicular cancer patients from the Ontario Cancer Registry and represents the largest cohort studied to assess second cancer risk associated with diagnostic radiation. The data demonstrate that second malignancies in the abdomen-pelvis were uncommon events in patients with low-risk testis cancer, and importantly, they did not demonstrate an association between second cancers and the amount of radiation exposure.”

a study population of 2,569 patients, who had a median age of 34.7 years at diagnosis and a median follow-up of 11.2 years.

Patients had a median of 10 CT scans during the first five years of follow-up (interquartile range [IQR], 4-18). Median cumulative radiation exposure from the studies was 110 mSv (IQR, 44-190 mSv).

Of the 14 abdominal–pelvic malignancies diagnosed during that time, colorectal and kidney cancers accounted for a majority of the malignancies (nine of 14).

The lack of association between radiation exposure and subsequent abdominal– pelvic malignancy in the primary analysis persisted in an analysis that included patients followed for less than five years (hazard ratio, 1.00; 95% CI, 0.96-1.04).

Noting that the median dose of radiation in their study exceeded that of most atomic bomb survivors, the authors cited evidence suggesting that the relationship between radiation and cancer risk might not be linear or cumulative.

According to the hypothesis, “a particular threshold rate, or flux, of radiation delivery is required News From to overwhelm cel- The JOURNALS lular repair mechanisms and start carcinogenesis. Low rates of radiation, such as those from radiographic examinations, may not exceed this threshold rate and therefore may not induce cancers.”

TRIAL CURRENTLY RECRUITING

A Randomized Phase II Trial for Newly Diagnosed Glioblastoma Patients: Cilengitide in subjects with newly diagnOsed glioblastoma multifoRme and unmethylated MGMT genE promoter A randomized, multicenter, open-label, controlled, phase II study investigating two cilengitide regimens in combination with standard treatment (TMZ with concomitant RT, followed by TMZ) versus standard therapy alone MAIN INCLUSION CRITERIA Newly diagnosed supratentorial glioblastoma (WHO grade IV) Unmethylated MGMT gene promoter status ECOG PS 0-1 Baseline Gd-MRI Stable or decreasing dose of steroids (for 5 days)

MAIN EXCLUSION CRITERIA Prior anti-angiogenic therapy Investigational agents within 30 days Chemotherapy within 5 years Prior cranial radiotherapy Placement of Gliadel® wafer Significant hepatic or renal impairment Coagulation disorder, myocardial insufficiency, peptic ulcer or another malignancy

MGMT: O6-methylguanine–DNA methyltransferase; RT: radiotherapy; TMZ: temozolomide Cilengitide (EMD 121974) currently is under clinical investigation and has not been approved for use in the United States, Canada, Europe, or elsewhere. The product has not been proved to be safe or effective and any claims of safety and effectiveness can be made only after regulatory review of the data and approval of the labeled claims.

Learn More About the CORE trial Please call 1-800-507-5284 or refer to ClinicalTrials.gov for more information (http://www.clinicaltrials.gov/ct2/show/NCT00813943) The CORE study is in collaboration with the Canadian Brain Tumour Consortium (CBTC).

101108 - 115024

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Clinical Oncology News • September 2011

Stomach EDITORIAL BOARD COMMENTARY

VOGL, NY continued from page 1 

interpretation of recently presented or published studies and my application of ideas that I believe are generally applicable in cancer therapy.

At the 2011 meeting of the American Society of Clinical Oncology (ASCO), Yung Bang, MD, presented CLASSIC, an adjuvant chemotherapy trial positive for disease-free survival (DFS) for XELOX after D2 resection of gastric cancer.1 With a median follow-up of 34 months, the predicted 3-year DFS was 74% in patients receiving XELOX compared with 60% in patients in the observationonly arm. Overall survival (OS) data are still immature. The real benefits of adjuvant XELOX (capecitabine [Xeloda, Roche] and oxaliplatin [Eloxatin, Sanofi]) are probably higher—of the 520 patients assigned to XELOX, 22 never started it and 105 withdrew consent during chemotherapy. There probably would have been fewer relapses among the XELOX patients if compliance had been higher.

In 2010, Songun et al published follow-up of a Dutch trial demonstrating prolonged survival benefit for D2 resection over D1 resection. There was an 8% increase in 15-year survival, an 11% decrease in deaths attributed to gastric cancer, and a 10% decrease in local recurrences.2 The D2 procedure involves dissection of nodes not only next to the stomach (a D1 lymphadenectomy), but also along the celiac axis and its 3 branches: the splenic, hepatic, and left gastric arteries. The benefits accrued in the Dutch study despite the D2 procedure having higher operative mortality (10% vs 4%), a higher complication rate (43% vs 25%), and higher rates of reoperation for complications (18% vs 8%). The Dutch (and most other surgeons) believe their results would now be even better with the reduced mortality and complication rate of D2 resection that preserves the spleen and distal pancreas.2 Mortality from D2 resection in recent prospective trials is 0.8% in Japan3 and 0% in Taiwan.4 The

Steven Vogl, MD Medical Oncologist, New York City

I propose a carrot-and-stick approach to encourage performance of the proper surgery by those trained in carrying out the procedure.

National Comprehensive Cancer Network and European Society for Medical Oncology have both embraced D2 resection as the standard of care, even though the survival difference was not formally statistically significant in the Dutch study (the difference was significant in a randomized D2 vs D1 study in Taiwan—5 year survival 60% vs 54%).4 There are problems, however, with the Dutch study: Randomization was done before the abdomen was opened, and only those assigned to D2 resection had a cadre of 11 skilled, specially trained surgeons doing the procedure at the local hospitals. Perhaps as a result, 24 more patients assigned to D2 resection were excluded from the study because peritoneal metastases were discovered at laparotomy (perhaps by the trained eyes and meticulous exploration of these skilled surgeons looking into the abdomens). Improved discovery of these doomed patients and their exclusion from analysis in the D2 arm could have made the D1 look worse when it was not worse. Also, only the 11 specially trained surgeons performed the D2 resections, whereas local surgeons in Holland performed the D1 resections. On the other hand, according to a Cochrane group meta-analysis, 51% of Dutch patients assigned to D2 dissection had no

nodes reported as resected from D2 sites.5 If these nodes were truly not resected, then D2 resections were not truly performed, and “real” D2 resections might have been even more beneficial.

Specially trained surgeons seem to be the key to success. In the positive Taiwan study, only 3 surgeons were involved and there was no operative mortality for either D1 or D2 resections.4 A recent Italian randomized study has reported low operative mortality (2.2% for D2 and 3% for D1 dissections) but has not yet reported 5-year survival.6 This study is being conducted by 10 specially trained surgeons. In a pilot study for this trial, these 10 surgeons plus 8 others working at 9 institutions achieved a 55% survival rate at 5 years with D2 resection performed for cure in 191 patients (another 106 patients were found to have incurable disease at laparotomy and excluded from analysis).7 This excellent result is much better than the surgery-only arms of the MacDonald et al randomized adjuvant chemoradiotherapy study8 and the MAGIC [Medical Research Council Adjuvant Gastric Cancer Infusional Chemotherapy] trial.9 The Italian study shows that surgery alone can achieve very impressive results in at least one “Western” population when the evaluation and operative skills of the surgeons are high.7 Some have suggested that Western populations have too much omental fat to allow safe dissection of perisplenic nodes in the left upper quadrant. Being able to identify and exclude such patients from getting a D2 dissection may be part of the skill set needed to achieve excellent results.

Clearly, D2 node dissections and the postoperative care needed after them are skills that are acquired with difficulty and not easily generalized. Operative mortality clearly goes up with resection of the spleen and distal pancreas (now thought to be rarely necessary, unless these organs or the vessels feeding them are involved by tumor). DiGiuli (leader of the Italian study) achieved his 2.2% operative mortality by largely avoiding splenectomy and pancreatectomy. Total gastrectomy (dictated by the size and location of the

Dr. Vogl with his 80-year-old patient and her granddaughter. The patient presented iron-deficient 2 years before with a tiny gastric ulcer that did not heal. Three months later she had a partial gastrectomy for a 1.5-cm moderately differentiated, intestinal type adenocarcinoma with a 2.6-cm proximal margin and a single node with a microscopic focus of cancer <1 mm in diameter among 19 nodes removed.

After 3 months, her abdominal wall wound finally healed, and 6 months of XELOX in cautiously escalating doses were well tolerated.

primary cancer), as opposed to distal gastrectomy, also increases operative mortality.5 Operative mortality seems to fall after each surgeon has done at least 30 cases.5 In a British randomized trial that compared D2 resection with D1 resection in which multiple surgeons were involved, and the only mandated training was a video describing the procedure, operative mortality was 13.5% for D2 and 7% for D1 resection.10 This difference is more than sufficient to wipe out the statistically significant 6% improvement in 5-year survival observed for D2 dissection over D1 in the Taiwan study.4

Endoscopic image of early stage stomach cancer. Histology is poorly differentiated adenocarcinoma with signet ring cells. From left to right; normal, FICE, acetate-stained, AIM stained.

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Clinical Oncology News • September 2011

Stomach

In the CLASSIC (Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer) trial, the survival of Korean, Chinese, and Taiwanese patients assigned to surgery alone was much better than in the trials of Dutch and English patients who were assigned to receive D2 resection. Patients in the CLASSIC trial were younger, most likely had fewer comorbidities, and probably had disease that was less commonly metastatic at diagnosis. Also, to be eligible for the CLASSIC trial, patients not only had to survive the D2 resection and gastrectomy, but also had to be sufficiently robust within 6 weeks in order to receive chemotherapy.

What Does All This Mean?

What are we, in North America and the Western world in general, to make of these trials? First, adjuvant chemotherapy works, whether given before (as in the MAGIC trial) or after the resection of gross disease (as in the CLASSIC trial).

Second, we need to offer greater numbers of our fit patients the opportunity to have more radical surgery. In the Dutch trial, the biggest advantage for D2 resection was in those who had 7 to 15 nodes involved by adenocarcinoma (15-year survival, 19% vs 0% for D1 dissection).2 We need to get these patients to surgeons skilled in performing the D2 dissection and providing the postoperative care. Rates of D2 resection were only 10% in the United States in the 1990s8 versus 40% at the same time in Britain in the MAGIC trial among those who actually had surgery.9 The rates were essentially 100% in Japan and Korea. If safe D2 resection is not in the armamentarium of the operating surgeon, then those patients with many involved nodes will not have removal of the nodes along the celiac axis branches, and those left with macroscopic disease in these nodes will likely die of their gastric cancers, even if adjuvant chemoradiation is given.

Does every patient with more than the most superficial gastric cancer need a D2 dissection? Probably not. However, a fit patient with many involved nodes near the stomach probably does, and it is clear from the high death rates from gastric cancer in the West that many such patients exist. Although fitness is not too hard to judge preoperatively, extensive nodal involvement may be difficult to judge even in the operating room. If the operating surgeon is sufficiently skilled to perform the D2 dissection with low mortality, then the demonstration of several positive nodes by frozen section should be enough to trigger the procedure. Most of the patients in whom gross nodal disease is left unresected in D2 sites can be expected to die from their disease (even if treated with radiation and concurrent chemotherapy), resulting in the low survival rates seen in North American gastric cancer adjuvant trials.

How Can We Increase the Frequency of D2 Node Resection?

What can the surgical establishment, medical establishment, and insurance system do to promote better surgery?

First, gastrectomy for cancer needs to be recognized as a complicated procedure for which special training is required. The goal should not be to have every general surgeon able to do it, but to have a few well-trained surgeons in each geographical area who are proficient in the procedure, as well as efficient mechanisms for getting the patients to them. The latter is not trivial in an era in which “for-profit” HMOs may see the cancer patient as a cost center for whom expenditures, even for cure, have to be contained.

I propose a certification effort similar to that made 20 years ago to assure competence in laparoscopic cholecystectomy. Certification would involve formal supervision by an expert in an adequate number of cases before the surgeon is left to perform D2 resection on his or her own. Because gastric cancer is much less common than cholecystitis, only a limited number of surgeons would find it worthwhile to undergo training and certification, appropriately making gastrectomy for cancer a procedure to be performed by experts only at a limited number of centers. DeGiuli spent 6 months in Japan learning how to do a D2 node dissection—this kind of training is probably what is needed.7 This will be an expensive, national undertaking that will take time to organize and considerable funds to run.

In the meantime, I propose a carrotand-stick approach to encourage performance of the proper surgery by those trained in carrying out the procedure.

The stick first: We should publicize the Dutch and Taiwanese results to surgical department chairmen, those who run quality assurance databases, and risk management departments. The latter should be involved, given the assumption that if D2 resection is the standard of care for fit patients, then plaintiff’s attorneys will soon get wind of it.

Any surgeon doing a D0 (minimal nodal dissection) or D1 resection (perigastric nodes only) operation for gastric cancer should be aware that he or she will be called on to justify the limited procedure. This would be easy in an 80-yearold patient with congestive heart failure and a prior stroke with hemiparesis, and very difficult in a fit 55-year-old patient with no comorbidities. Cases to be reviewed can be identified by the number of resected nodes (<15) and the location of the nodes (which should be identified as near the celiac axis and each of its branches in the pathology report). In the CLASSIC study reported by Yung Bang, pathologists identified a median of 42 resected nodes.

If a skilled surgeon is not immediately available when gastric cancer is

I propose that insurance companies, including Medicare and Medicaid in the United States, pay separately for the gastrectomy and the nodal resection. A D0 or D1 gastrectomy could be reimbursed at approximately $750, whereas a D2 gastrectomy at $2,250.

diagnosed, preoperative chemotherapy (which in England has become the standard therapy after publication of the MAGIC trial9) could allow time for arrangement of surgery at a center where surgical skill and supportive care for a D2 resection are available. Additionally, a few patients with major comorbidities might be “tuned up” enough during preoperative chemotherapy to become eligible for D2 resection. My opinions on which chemotherapy to give and how to monitor it come later.

Now the carrot: I propose that insurance companies, including Medicare and Medicaid in the United States, pay separately for the gastrectomy and the nodal dissection. The payment for the gastrectomy alone should be one-third of the total fee, whereas the D2 nodal dissection should comprise two-thirds of the fee. Thus, a D0 or D1 gastrectomy could be reimbursed at approximately $750, whereas a D2 gastrectomy at $2,250. The hospital diagnosis-related group payments should reflect the increased morbidity of the D2 resection and should be much higher for that procedure. Thus hospital administrators will push for the better-reimbursed procedure, and will be more inclined to hire staff surgeons trained to do it well. On the other hand, profit would be lower or nil for D1 and D0 resections, and might encourage referral elsewhere if the D2 procedure is not available in the local hospital.

Insurance companies and Medicare have been focused on bundling payments to save money by including increasingly more extensive procedures under single payments. The insurance industry can be a major force for improved quality by “unbundling” and paying more for greater effort and improved quality.

In the recent North American Intergroup 80101 study,11 35% of gastrectomies submitted less than 15 nodes (analysis of which node dissections were D0, D1, or D2 resections is in progress), suggesting

that even at research centers, D2 resections are not the rule. We can act immediately to make it unprofitable and uncomfortable for surgeons to perform suboptimal surgery.

Chemotherapy Preoperatively Or Postoperatively How do we decide whether to give the patient chemotherapy before gastrectomy or after? I propose we give chemotherapy first if the patient’s postoperative course is likely to be complicated and prolonged and thus chemotherapy may be delayed or perhaps never given. It is not easy to judge this, but those with chronic illnesses such as diabetes with organ complications, renal failure, or major coronary disease are probably much more likely to actually receive their chemotherapy if it is given before laparotomy. In the West, any but the most superficial tumors (on endoscopic ultrasound) have a sufficiently poor prognosis to justify neoadjuvant chemotherapy. Also, if immediate referral and surgery in a center with D2 expertise is not available, chemotherapy should be started while a multidisciplinary evaluation occurs.

Rather than attempt to compare preoperative with postoperative chemotherapy in a randomized trial, I suggest careful retrospective and prospective studies to refine identification of patients at diagnosis who are unlikely to be fit candidates for timely postoperative chemotherapy. Those patients should be offered preoperative chemotherapy, and offered participation in studies examining which drugs to give and for how many courses to administer them.

Chemotherapy Goal: Cure of Micrometastases I believe the goal of chemotherapy in gastric cancer is to destroy micrometastatic disease that would later grow and kill the patient. It makes no sense to give see VOGL, NY, page 14 

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Clinical Oncology News • September 2011

Stomach

VOGL, NY continued from page 13 

only 9 weeks of chemotherapy, then stop for 9 to 18 weeks (for surgery and recovery from surgery), allowing residual micrometastatic disease to grow back, and then give another 9 weeks of chemotherapy, as was planned in the MAGIC trial. I suspect that the design of the MAGIC trial was both a political and a medical compromise, involving concerns that a long delay in surgery in the induction chemotherapy group might compromise rate of surgical cure, and might cause some patients to miss surgery. In the MAGIC trial, of the 250 patients assigned to preoperative chemotherapy with infusional 5-fluorouracil (5-FU), epirubicin, and cisplatin, 95% started chemotherapy and 86% completed 3 cycles; 55% started postoperative chemotherapy and only 44% completed the 3 postoperative cycles. I suggest that most of the 5-year OS benefit (36 vs 23%) from chemotherapy in the MAGIC trial was from the first 3 cycles. It does not follow that a longer continuous chemotherapy course might not be even better—this is worthy of study.

I propose the initial staging should include endoscopic ultrasound, and that this be repeated after 9 weeks. If the primary tumor has regressed or disappeared, there can be little risk to completing another 9 weeks of chemotherapy before D2 resection (although I would welcome a randomized trial addressing the utility of a second 9 weeks of preoperative chemotherapy). If the primary tumor has grown, I would be fearful that letting it grow further might compromise the patient’s chance for complete resection, and would favor immediate D2 resection. Initial staging also could include laparoscopy to exclude those with obviously incurable peritoneal or liver surface metastasis from aggressive surgery with curative intent. This portion of pre-induction staging will not improve the likelihood of cure for the individual patient, so I would skip it for the frail or those who are high anesthesia risks.

I believe we do not have data to suggest that induction chemotherapy can reduce the required resection margin for the tumor or allow smaller resections. It makes all involved feel good if the resected stomach has little or no cancer after induction chemotherapy, but what is important is not what the surgeon has removed from the patient, but how much cancer the surgeon has left inside the patient. Thus, I am unimpressed with downstaging of the primary tumor as a trial end point—it means nothing to the patient.

Selecting a Chemotherapy Two studies show survival advantages for single-agent adjuvant chemotherapy over no therapy: 5-FU alone (which MacDonald et al used in a distinctly toxic and

probably suboptimal schedule in 5-day courses of bolus administration with leucovorin and regional radiation during the second 5-FU course) and a biomodulated preparation of a 5-FU prodrug called S1.8,12 One can reasonably argue that superiority has not been shown for multiple drugs over a single drug in the setting of resected gastric cancer, and that giving a single drug is the standard.

Indeed, the North American Intergroup 80101 study found no advantage to adding epirubicin and cisplatin to 5-FU alone in the MacDonald regimen.11 However, as I pointed out during the ASCO question and answer session after the presentation by Peter Enzinger, MD, only 3 doses of epirubicin and cisplatin were administered in the 80101 study, with the second and third doses given after a break for chemoradiation of 9 to 12 weeks, and

We need to offer greater numbers of our fit patients the opportunity to have more radical surgery.

at reduced doses because the intervening radiation made full doses too toxic.

So, the epirubicin and cisplatin were given too few times, at too wide an interval, and in doses that might have been too low.

I believe the study was well conducted, but poorly designed to test the efficacy of adding cisplatin and epirubicin.

Still, in treating metastatic disease, 2 or 3 drugs is probably better than 1, so I favor a relatively nontoxic, easy-to-administer regimen of 2 or 3 drugs. In choosing drugs, I favor capecitabine over infusional 5-FU because it is as efficacious in metastatic disease in English trials13 and does not require a Hickman catheter—3% of patients in the MAGIC trial stopped chemotherapy because of catheter problems.

I prefer oxaliplatin over cisplatin because it works just as well in metastatic disease,13 is much easier to give, has reversible neurotoxicity, causes no nephrotoxicity or deafness, and results in less emesis. Additionally, capecitabine and oxaliplatin are precisely the drugs Dr. Bang gave to yield the 44% relative reduction in death or relapse at 3 years. Whether to add epirubicin or docetaxel is a reasonable subject for a Phase III trial, although I am not sure it is worth conducting for anyone but a drug company with big profits at stake.

Why Didn’t Adjuvant Chemotherapy Work in the Past?

It makes sense to wonder why chemotherapy did not do much good as a surgical adjuvant in the past, a meta-analysis showing a small benefit notwithstanding.14 My best hypothesis is that chemotherapy could not do much good until

improved staging with laparotomy, computed tomography, liver magnetic resonance imaging, and positron emission scanning excluded more patients with overtly metastatic disease, and until either D2 resection or carefully done regional irradiation prevented enough regional recurrences, so that the modest benefit of chemotherapy against micrometastatic disease became detectable as a survival advantage. Also, many studies were too small.

When To Consider Chemoradiation In his comments after presenting Intergroup 80101 at ASCO 2011, Peter Enzinger, MD, of Dana-Farber Cancer Institute, in Boston, stated that the “MacDonald regimen” of postoperative 5-FU with radiation in the second 5-FU cycle remains the standard North American adjuvant therapy for gastric cancer. Many physicians (myself included) now consider postoperative chemoradiation only if the resection is inadequate (close margins or <D2 lymphadenectomy). If I think the patient needs radiation for local control, I would complete the chemotherapy first, then give radiation with concurrent infusional 5-FU, because giving radiation first makes later chemotherapy much more toxic. Capecitabine twice a day on radiation treatment days instead of 5-FU infusion is also a reasonable option. I realize that this proposal changes both the timing of radiation (at the end rather than in the middle of systemic chemotherapy) and the way radiosensitizing 5-FU is given (infusion, which is almost certainly less toxic and more effective, vs bolus for several days). The MacDonald regimen, however, was designed in the late 1980s. I think we have learned enough since then to be allowed to tinker with it. Even the person for whom the regimen is named, John MacDonald, MD, thinks so (personal communication).

Should Chemoradiation Be Administered After a D2 Node Resection?

It makes technical and medical sense to conduct a study looking at postoperative chemoradiation even after D2 resection.

What are your thoughts?

Clinical Oncology News welcomes letters to the editor. Do you have thoughts on Dr. Vogl’s commentary? Please send comments to

korourke@mcmahonmed.com.

Local recurrence rates after D2 resections without radiation in the Dutch trial were 12%, with regional recurrences in another 13%, so that halving these rates with chemoradiation could make a substantial contribution, provided those patients saved from local and regional recurrences do not die of systemic disease anyway.

Along these lines, the Dutch Colorectal Cancer Group began a study in 2006 giving all resectable patients 9 weeks of epirubicin, capecitabine, and cisplatin followed by gastrectomy and “D1+” lymphadenectomy. Patients are then randomized to chemoradiation with sensitizing capecitabine and cisplatin, or more of the same chemotherapy that was given in induction. This trial unfortunately changes 2 things—duration of chemotherapy and administration of chemoradiation—in its experimental arm. The result will be interpretable only if the chemoradiation consolidation postoperatively proves superior (although that would not rule out an added benefit for more chemotherapy as well).

Absent the results of the ongoing Dutch study, I would recommend a course of chemoradiation even after D2 resection and adjuvant chemotherapy (either pre- or postoperatively), if I thought the patient was at high risk for local or regional recurrence, either because of many levels of positive nodes, or close resection margins, or extension of tumor into soft tissues from the primary or the nodes, and if the patient appeared in sufficiently good condition to tolerate it once the surgery and chemotherapy are complete.

Dr. Bang and his colleagues are to be congratulated on the adjuvant trial of capecitabine and oxaliplatin after D2 resection of gastric cancer. We eagerly await the 5-year OS data 2 years hence see VOGL, NY, page 29 

Having trouble keeping up with all of the oncology and medical journals that cross your desk?

Beginning with this issue and continuing on a monthly basis, Clinical Oncology News will highlight key studies from the journals to help you stay up to date.

We hope you find this a useful tool.

See pages 4, 6, 7, 11, 15, 16, 17.

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Clinical Oncology News • September 2011

Lung

National Trial Shows CT Screening Reduces Lung Cancer Mortality From The New England Journal of Medicine

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ow-dose computed tomography (CT) screening reduces mortality from lung cancer compared with radiography, according to the results of the large, multicenter NLST (National Lung Screening Trial).

After studies indicated that lowdose CT detected lung tumors at earlier stages, NLST investigators at 33 U.S. centers designed a trial to determine whether that earlier detection translated into reduced mortality (N Engl J Med 2011;365:395-409, PMID: 21714641). Between August 2002 and April 2004, they randomized 53,454 patients at high risk for lung cancer to receive annual screenings using lowdose chest CT (n=26,722) or singleview posteroanterior chest radiography (n=26,732) for three years. The investigators followed patients through December 2009, collecting data on cases of lung cancer as well as on lung cancer mortality and overall mortality.

During that time, the investigators uncovered 1,060 cancers in the lowdose CT group and 941 cancers in the radiography group (rate ratio, 1.13; 95% confidence interval [CI], 1.03-1.23). The rate of positive screening tests was higher with CT: 24.2% versus 6.9% with radiography.

In the intent-to-treat population, there were 356 lung cancer–related deaths in the CT group and 443 such deaths in the radiography group, which corresponds to a 20% reduction in relative risk (RR) for death from lung cancer in the CT group (95% CI, 6.8-26.7; P=0.004). Among patients who actually had at least one screening, there were 346 deaths in the CT group (n=26,455) and 425 deaths in the radiography EXPERT INSIGHT Ed Kim, MD Assistant Professor, Department of Thoracic/ Head and Neck Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas

group (n=26,232). associated with major compliAll-cause mortality also cations. Specifically, in the lowwas significantly reduced dose CT group, 0.06% of positive in the low-dose CT group screening results that did not (1,877 deaths vs. 2,000 result in a diagnosis of lung canNews From deaths in the radiography The JOURNALS cer were associated with major group; RR, 6.7%; 95% CI, 1.2complications compared with 13.6; P=0.02).

0.02% of those in the radiography group.

Although adverse events related to the Despite the strong positive mortalactual screening procedures were “few ity findings, the investigators caution and minor,” positive screening tests that “before public policy recommendaled to invasive procedures that were tions are crafted, the cost-effectiveness

of low-dose CT screening must be rigorously analyzed.” They recommended that the mortality reduction “must be weighed against the harms from positive screening results and overdiagnosis, as well as the costs …[of ] not only the screening examination itself but also the diagnostic follow-up and treatment.”

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Clinical Oncology News • September 2011

Breast

Eribulin Superior to Physician’s Choice Treatment in MBC From Lancet

C

hallenging the prevailing wisdom that improved overall survival (OS) is an unrealistic expectation of new anticancer agents in the refractory setting, eribulin monotherapy appears to be significantly superior to physician’s choice treatment among women with locally recurrent or metastatic breast cancer, according to the Phase III openlabel, randomized EMBRACE study published in The Lancet (201;377:914923, PMID: 21376385).

Eribulin (Halaven, Eisai) is a nontaxane inhibitor of microtubule dynamics that appears to have a distinct mechanism of action from other tubulintargeting agents. The study, involving 135 centers in 19 countries, randomized 762 heavily pretreated women (between two and five previous chemotherapy agents) to either eribulin (n=508) or treatment of physician choice (TPC) (n=254).

At primary analysis, OS was significantly better in the eribulin group (median 13.1 months; 95% confidence interval [CI], 11.8-14.3) than in the TPC group (median

10.6 months; 95% CI, 9.3-12.5), generating a hazard ratio of 0.81 (95% CI, 0.66-0.99; P=0.041).

Eribulin also appeared superior for the secondary end points of median progression-free survival (PFS) and objective response (OR). Median PFS was 3.7 months with eribulin and 2.2 months with TPC (P=0.137, not statistically significant), whereas OR was recorded in 12% of patients receiving eribulin and 5% of patients receiving TPC (P=0.002).

The rate of serious adverse events (AEs) was comparable between groups, 25% for patients on eribulin and 26% for those on TPC. These AEs led to therapy discontinuation in 13% of eribulin patients and 15% of TPC patients. For both groups, the most common AEs were asthenia or fatigue and neutropenia; grade 3/4 AEs that occurred more often with eribulin than with TPC were neutropenia, leukopenia and peripheral neuropathy.

The authors suggested that the study establishes a new standard treatment option for women with heavily pre­­treated

“The Phase III EMBRACE Christina Herold, MD study randomized 762 Division of Hematology/ women with metastatOncology ic breast cancer who had Department of Medicine previously been treated with a Beth Israel Deaconess Medical Center and median of four prior chemotherapy regHarvard Medical School imens, to eribulin or to TPC. The innoBoston, Massachusetts vative study design of this trial provides a real-world clinical context for the use of eribulin in patients with heavily pretreated disease. Eribulin was safe, demonstrated a manageable toxicity profile and was generally as well tolerated as TPC. EMBRACE showed a statistically significant improvement in median overall survival, the primary study outcome, associated with use of eribulin (13.1 vs. 10.6 months).

The improvement in overall survival, although perhaps modest in absolute numbers, is nonetheless clinically significant and justifies the use of eribulin as a new standard of care for women with heavily pretreated metastatic breast cancer.”

EXPERT INSIGHT

metastatic breast cancer. Previously, they noted, there was no chemotherapy with a proven survival benefit in this group. “In a literature review, only five of 76 major Phase III studies of systemic therapy in metastatic breast cancer defined overall survival as their primary end point and none met its primary end point; the 15 studies reporting improved

overall survival all did so as a secondary end point and not in heavily pretreated patients,” they observed in a sidebar note on their research. “To our knowledge, EMBRACE is the first major singleagent study of a cytotoxic or biological agent to show significantly increased survival in patients with such heavily pretreated metastatic breast cancer.”

Study Bolsters Use of Tamoxifen for Five Years From Journal of Clinical Oncology

C

ompleting the full five-year course of tamoxifen—as opposed to stopping the drug after two years—substantially lowers the risk for recurrence or developing a contralateral breast cancer 15 years after initial treatment in women with early breast cancer, according to longterm results from the Cancer Research UK “Over 50s” trial.

Research has found that fewer than half of women taking tamoxifen or aromatase inhibitors complete the standard five-year course of treatment. A study published in 2010 by Hershman et al., involving nearly 8,800 women found that women aged younger than 40 years had the highest risk for discontinuing therapy early (J Clin Oncol 2010;28:4120-4128, PMID: 20585090). Some of the reasons cited for stopping hormone therapy included side effects, high cost and lack of insurance coverage.

But the latest findings from the British study, which appeared in a recent issue of the Journal of Clinical Oncology, underscore the perils of this trend (J Clin Oncol 2011;29:1657-1663, PMID: 21422412). At a median follow-up of more than 10 years, the trial found that for every 100 women who received tamoxifen for five years, 5.8 fewer experienced recurrence compared with those who received tamoxifen

for two years. The risk for were echoed in another contralateral breast cancer recent study, a also was significantly reduced meta-analysis of (hazard ratio, 0.70; 95% long-term data from confidence interval, 0.48-1.00).

20 trials involving News From “Women should therefore 21,457 women with The JOURNALS be encouraged to complete the breast cancer (J Clin Oncol full course [of tamoxifen],” concluded the 2010;28:509-518, PMID: 19949017). authors, part of Cancer Research UK and Christina Davies, MD, and colleagues in University College London Cancer Trials the international Early Breast Cancer Centre in London. They add that this Trialists’ Collaborative Group found that evidence also underscores the fact that five years of tamoxifen—with or without despite the superior disease-free survival chemotherapy—cuts women’s 15-year rates found with aromatase inhibitors, risk for breast cancer death by about tamoxifen can be an inexpensive and one-third. That reduction in mortality effective alternative. risk was not just confined to the first five Within a smaller group—the 50- to years after cancer treatment (relative 59-year age group—the full course of risk, 0.53, years 0 to 4) but continued to tamoxifen also yielded cardiovascular be significant in years 5 to 15 (0.68, years benefits. These women had a 35% 5 to 9; and 0.97, years 10 to 14). reduction in cardiovascular events (P=0.005) and 59% reduction in death as a EXPERT INSIGHT result of a cardiovascular event (P=0.02).

“Although neither the cardiovascular Christina Herold, MD death event and survival analysis nor “The updated results of the Cancer subanalyses by decades of age were preplanned, and should therefore be Research UK “Over 50s” trial, showing regarded with some caution, these data reduced breast cancer recurrence risk are still of considerable interest,” noted associated with five years of tamoxian accompanying editorial by Kathleen fen compared with two years are conI. Pritchard, MD, and Berta Sousa, MD, sistent with the growing body of litof Sunnybrooke Odette Cancer Center in erature supporting the principle that longer-term use of adjuvant endoToronto, Canada.

The findings of this study with regard crine therapy is superior. Furthermore, to the long-term benefits of tamoxifen the protective effects associated with

a longer duration of tamoxifen therapy are shown to be durable, with beneficial effects on breast cancer–specific outcomes extending to 10 years of followup. However, perhaps the most noteworthy aspects of this report are the observed beneficial effects of longer use of tamoxifen on cardiovascular outcomes. In this group of 3,449 women aged 50 to 81 years, there was an overall trend toward reductions in both cardiovascular events (hazard ratio [HR], 0.90; P=0.18) and cardiovascular death (HR, 0.79; P=0.08). In unplanned analyses by decade, women between aged 50 and 59 years experienced statistically significant improvements in both cardiovascular events (HR, 65%; P=0.005) and cardiovascular death (HR, 0.41; P=0.02). Although the large adjuvant trials have consistently shown improved disease-free survival with the use of aromatase inhibitors compared with tamoxifen, long-term follow-up of studies such as this provides valuable information regarding important secondary effects and toxicities of these agents.”

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approximately 1% of adult cancers and 15% of pediatric cancers.2 The most recent cancer statistics released by the American

Cancer Society (ACS) estimate that 10,980 new cases are projected to occur in the United States in 2011, with an associated 3,920 deaths.3

Although soft tissue sarcomas can occur anywhere in the body, these tumors occur most often in the extremities, such as the arms and legs (59%-60%), and trunk, such as the chest and back (19%), followed by the retroperitoneum (15%) and head and neck (9%).2,4 Numerous histologic types of soft tissue sarcomas

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have been identified (Table 1),1,5 with distribution of tumor types varying by age.1,6 The 2011 National Comprehensive Cancer Network (NCCN) clinical practice guidelines on soft tissue sarcomas divide management into the following 4 disease subtypes: tumors of the extremities and trunk,

C L I N I C A L O N CO LO GY N E WS â&#x20AC;˘ S E P T E M B E R 2 0 1 1

1

Table 1. Histologic Types Of Soft Tissue Tumors Tissue Origin

Malignant Tumor Type

Fat

Liposarcoma

Fibrous tissue

Fibrosarcoma

Skeletal muscle

Rhabdomyosarcoma

Smooth muscle

Leiomyosarcoma

Bone

Osteosarcoma

Cartilage

Chondrosarcoma

Synovium

Synovial sarcoma

Blood vessel

Angiosarcoma

Lymphatics

Lymphangiosarcoma, malignant hemangiopericytoma

Nerve

Neurofibrosarcoma

Mesothelium

Malignant mesothelioma

Tissue histiocyte

Malignant fibrous histiocytoma

Pluripotent

Malignant mesenchymoma

Uncertain

Ewingâ&#x20AC;&#x2122;s sarcoma; alveolar soft parts sarcoma; epithelioid sarcoma

Based on references 1 and 6.

retroperitoneal or intraabdominal tumors, gastrointestinal stromal tumors, and desmoid tumors.2 This review focuses on soft tissue sarcomas of the extremities and trunk and discusses risk factors, diagnosis, and staging, as well as treatment options for these more common sarcomas.

Risk Factors A variety of factors have been associated with the development of soft tissue sarcomas.5,7,8 These include both environmental and host factors. Exposure to ionizing radiation has long been recognized as a risk factor for soft tissue sarcomas.7,8 Patients treated with radiation for cancers of the breast, ovary, cervix, testes, and other carcinomas have been estimated to be at an 8- to 50-fold increased risk.7 Data also suggest that the risk for soft tissue sarcomas is related to the total radiation dose and radiation technique.8 Typically, the tumor develops after a mean latency period of 10 years.7,8 Exposure to chemicals such as phenoxyacetic acid herbicides, chlorophenols, and their contaminants also has been linked to soft tissue sarcomas in agricultural

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and manufacturing workers.7 Other chemicals that occasionally have been implicated include inorganic arsenic compounds and vinyl chloride.7,8 Some medicinal drugs, such as immunosuppressive agents, especially those used in transplant patients, also have been linked to an increased risk for soft tissue sarcomas. Additionally, risk for certain sarcomas increases after exposure to specific infectious pathogens. For example, human herpesvirus-8 has been detected in Kaposiâ&#x20AC;&#x2122;s sarcoma tissue of patients infected with HIV. Host factors such as chronic lymphedema, a condition in which fluid collects in the lymph nodes causing swelling, and various genetic abnormalities also have been associated with an increased risk for soft tissue sarcomas.7,8 Certain inherited diseases have been linked to soft tissue sarcomas, and studies have focused on the genetic changes associated with these diseases.8 For example, patients with Li-Fraumeni syndrome (ie, alterations in the p53 tumor suppressor gene) and those with neurofibromatosis (ie, alterations in the NF1 gene) are at an increased risk for developing soft tissue sarcomas.

Other conditions that increase risk include Werner syndrome and hereditary retinoblastoma.

Some historical literature has suggested that injury or trauma to an area may be a risk factor for sarcoma; however, more recent reviews conclude that there is no relationship between an acute injury and soft tissue sarcomas.1,5 Most likely, patients receiving medical care for an acute trauma are found to have an underlying soft tissue sarcoma that has been present for some time.

Diagnosis As stated above, some patients may seek medical care after an acute injury that results in the detection of a potential soft tissue sarcoma.1 The majority of patients will present with a painless mass; however, those who present with pain are more likely to have more aggressive tumor types. A detailed history and physical examination are essential to determine if a patient has a potentially malignant sarcoma.1,2 The medical history should assess symptoms such as pain, fever, or paresthesias; the duration of symptoms; recent changes in the size or consistency of the mass; past exposure to certain environmental factors, such as radiation or specific toxic chemicals; and family history of any genetic disorders.1 The physical examination should include the location of the mass; its shape, size, and consistency; position of the mass relative to surrounding tissues; and external evaluation of the regional lymph nodes.

Table 2. AJCC Staging System For Soft Tissue Sarcoma Primary Tumor (T)

The NCCN guidelines recommend that adequate imaging be performed on all tumors that are potentially malignant.2 Imaging usually is done with magnetic resonance imaging (MRI), the preferred imaging for extremity sarcomas, with or without computed tomography (CT). A plain radiograph of the primary tumor also is an option. Chest imaging is another essential test to determine if any hematogenous spread has reached the lungs because the lungs are the most common site of metastasis for sarcomas.1,2 The NCCN guidelines also recommend specific imaging techniques under certain circumstances. These include a positron emission tomography scan to help with prognostication, grading, and determining response to chemotherapy; an abdominal/pelvic CT for certain liposarcomas, epithelioid sarcomas, angiosarcomas, or leiomyosarcomas; an MRI of the total spine for certain liposarcomas; and central nervous system imaging for alveolar soft part sarcomas and angiosarcomas.

Furthermore, a carefully planned biopsy should be performed to establish the grade (see staging section) and histologic subtype of the sarcoma.2 Biopsies can be performed using a core needle or open incisional technique. According to NCCN, fine-needle aspiration cytology alone generally is not sufficient to make an accurate diagnosis, but it may be an acceptable option in selected institutions with clinical and pathological expertise. Biopsied samples are evaluated thoroughly to determine margins, morphology, stage, mitotic rate, presence or absence of vascular involvement, and the type and extent of inflammation.

To help with the morphologic assessment of samples, molecular genetic testing has become a useful tool to differentiate soft tissue sarcomas.2 The NCCN guidelines divide soft tissue sarcomas into 2 major genetic groups: sarcomas with specific genetic alterations, such as chromosomal translocations or point mutations and usually simple karyotypes, and those with nonspecific genetic alterations and complex unbalanced karyotypes.

Staging In 2010, the American Joint Committee on Cancer (AJCC) updated its staging system for soft tissue sarcomas.2,9 This staging system (Tables 2 and 3)2,9 takes into account histologic grade (G) in addition to the traditional primary tumor (T) size and depth, regional lymph node (N) involvement, and distant metastases (M). A key difference in the 2010 update is that the new version includes only a 3-tiered grading system (G1-G3), whereas previous versions used a 4-tiered grading

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

T1

Tumor 5 cm or less in greatest dimension

T1a

Superficial tumor

T1b

Deep tumor

T2

Tumor more than 5 cm in greatest dimension

T2a

Superficial tumor

T2b

Deep tumor

Regional Lymph Nodes (N) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastases

N1

Regional lymph node metastases

Distant Metastases (M) M0

No distant metastases

M1

Distant metastases

Histological Grade (G) GX

Grade cannot be assessed

G1

Grade 1

G2

Grade 2

G3

Grade 3

AJCC, American Joint Committee on Cancer Based on references 2 and 9.

system (G1-G4).2 NCCN continues to classify tumors as being either low or high grade.

Within the AJCC staging system, tumors are classified as superficial or deep.2,9 Superficial tumors are defined as those located exclusively above the superficial fascia without invasion of the fascia, whereas deep tumors are defined as being located either exclusively beneath the superficial fascia, superficial to the fascia with invasion of or through the fascia, or both superficial yet beneath the fascia. Once all the factors are grouped together, patients are staged as having IA, IB, IIA, IIB, III, or IV carcinoma (Table 3).2 Patients with

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Table 3. AJCC Anatomic Stage/ Prognostic Groups Stage IA

Stage IB

Stage IIA

Stage IIB

Stage III

Stage IV a

T1a

N0

M0

GX, G1

T1b

N0

M0

GX, G1

T2a

N0

M0

GX, G1

T2b

N0

M0

GX, G1

T1a

N0

M0

G2, G3

T1b

N0

M0

G2, G3

T2a

N0

M0

G2

T2b

N0

M0

G2

T2a, T2b

N0

M0

G3

Any T

N1

M0

Any G

Any T

Any N

M1

Any G

See Table 2 for explanation of abbreviations used here.

Based on reference 2.

soft tissue sarcomas of the extremities have a generally good 5-year overall survival (OS) rate if the tumor is in stage I (90%) or II (81%); however, 5-year OS drops to 56% for patients with stage III tumors, and exact survival information for stage IV disease has not been reported but is thought to be poor.1,5

Treatments All patients should be managed by a multidisciplinary team consisting of experts in the field of sarcoma.2 Based on the results of the initial workup, NCCN classifies patients into one of the following categories: stage I, II-III (both resectable and unresectable disease), IV, or recurrent disease, and gives specific treatment recommendations for these groups. The mainstay of treatment is surgery, with or without adjuvant radiation and/or chemotherapy.2,10

STAGE I For low-grade stage I soft tissue sarcoma (ie, T1a2b, N0, M0), the primary treatment approach per the NCCN guidelines is surgery without radiotherapy or chemotherapy.2 For the subset of patients who are acceptable candidates for surgical intervention alone, local control rates of 90% or greater have been reported.2,11 This successful outcome with surgery alone allows these patients to avoid the short- and longterm risks associated with adjuvant radiotherapy, such as edema, fibrosis, and second malignancies.11 Additionally, surgical intervention without radiotherapy

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for low-grade stage I disease does not negatively impact survival rates. In a prospective trial involving 88 patients with localized, nonmetastatic, T1, primary soft tissue sarcoma of the extremity or superficial trunk, patients who underwent surgical resection alone with microscopically negative (R0) final margins had favorable local recurrence and death rates.12 Cumulative incidence rates of local recurrence at 5 and 10 years were 7.9% and 10.6%, respectively. The sarcomaspecific death rate at both 5 and 10 years was 3.2%.

If final margins of a low-grade stage I tumor are 1 cm or less, NCCN recommends consideration of postoperative radiotherapy or observation (for T1a-b only).2 Postoperative radiotherapy is a category 1 recommendation for T2a-b tumors (high-level evidence with uniform NCCN consensus) and a category 2B recommendation for T1a-b tumors (lower-level evidence with nonuniform NCCN consensus). However, patients with tumors of up to 5 cm may not require radiotherapy because these tumors frequently are not associated with local recurrence.

STAGE II-III For stage II-III soft tissue sarcomas of the extremity or trunk, the NCCN guidelines recommend different treatment approaches depending on whether the sarcoma is resectable or unresectable (Table 4).2 For patients with resectable tumors and acceptable functional outcomes (ie, pain, joint range of motion, joint stability and deformity, overall function), surgical intervention alone or surgery followed by radiotherapy with or without adjuvant chemotherapy is the recommended primary treatment option.2,13 Preoperative intervention (ie, radiotherapy, chemoradiation, or chemotherapy) should be considered in patients with large (>8-10 cm) high-grade extremity sarcomas, who are at an elevated risk for local recurrence and metastases. Neoadjuvant chemotherapy or chemoradiation has been administered to downstage larger tumors to allow for surgical resection, particularly for those tumors that are found to be chemosensitive.2 In a Phase II trial, 66 patients with high-grade soft tissue sarcoma were administered 3 cycles of neoadjuvant modified mesna, doxorubicin, ifosfamide, and dacarbazine (MAID), preoperative radiation, and 3 cycles of modified MAID postsurgery.14 Of 64 patients in the final analysis, surgery was performed in 61 (58 R0 resections with 5 amputations; 3 R1 resections). Results revealed estimated 3-year rates for time to distant metastases, distant disease-free survival (DFS), and OS to be 28.4%, 64.5%, and 75.1%, respectively.

The role of adjuvant chemotherapy remains controversial for stage II-III soft tissue sarcoma because available evidence is limited and conflicting.2 The Sarcoma Meta-Analysis Collaboration evaluated data from 14 trials (N=1,568) of doxorubicin-based adjuvant chemotherapy to determine whether this treatment approach improved OS, recurrence-free survival (RFS), and local and distant recurrence-free intervals in patients with localized resectable soft tissue sarcoma compared with no chemotherapy after local treatment.15 Results revealed that adjuvant doxorubicinbased chemotherapy significantly improved RFS and time to local and distant recurrence; absolute benefits were 10% (P=0.0001), 6% (P=0.016), and 10% (P=0.0003), respectively, at 10 years. The investigators also observed an absolute OS benefit of 4% at 10 years, but this result was not significant (P=0.12).

Another more recent cohort analysis involving 674 patients with localized, high-risk, extremity soft tissue sarcoma found that the clinical benefits of doxorubicin-based adjuvant chemotherapy (ie, local, distant, and overall DFS and disease-specific survival) did not extend beyond 1 year after treatment.16 In contrast, a randomized cooperative trial involving 104 patients with soft tissue sarcomas of the extremities and girdles found a significant positive survival benefit for intensified adjuvant epirubicin and ifosfamide compared with that for observation alone.17 There were improvements in median DFS (48 vs 16 months; P=0.04) and median OS (75 vs 46 months; P=0.03) that significantly favored the adjuvant chemotherapy group at a median follow-up of 59 months.

NCCN also recommends that patients with stage III tumors involving the lymph nodes undergo regional lymph node dissection at the time of primary tumor resection with or without radiotherapy.2

STAGE IV For stage IV metastatic disease, primary treatment options vary initially, depending on whether there is single-organ involvement and limited tumor bulk/ regional nodes or disseminated metastases.2 Primary management for single-organ disease and disease with limited tumor bulk/regional nodes is similar to the approach used for stage II-III disease (Table 4). Other options should be considered, including metastasectomy with or without chemotherapy and/or radiotherapy, stereotactic radiosurgery/radiotherapy, chemotherapy, and observation.

For disseminated disease, the NCCN guidelines

recommend close observation and â&#x20AC;&#x153;watchful waitingâ&#x20AC;? for asymptomatic patients, particularly those with an extended disease-free interval and minimal metastatic burden.2 Alternatively, multiple palliative options are suggested including radiotherapy, chemotherapy, and surgery. Additionally, ablation procedures (ie, radiofrequency ablation or cryotherapy), embolization, or stereotactic radiosurgery/radiotherapy may be performed on symptomatic patients with disseminated disease. Overall, the guidelines are fairly vague with regard to management recommendations for patients with disseminated disease because many factors are taken into consideration in the choice of a treatment course, such as patient preference, performance status, and availability of treatment.

With regard to chemotherapeutic options, no particular single agent or combination regimen has been found to be clearly superior. Single-agent doxorubicin, ifosfamide, or dacarbazine, and combinations involving doxorubicin or epirubicin with ifosfamide and/or dacarbazine are among the more extensively administered regimens.18-22 There also have been some data suggesting that liposomal anthracyclines are active first-line treatment options for advanced soft tissue sarcoma.23,24 Other chemotherapeutic agents that have been investigated include gemcitabine plus docetaxel, gemcitabine plus vinorelbine, and temozolomide (Temodar, Schering).2

RECURRENT DISEASE The NCCN guidelines do not introduce new treatment recommendations for recurrent disease.2 Basically, patients with a local recurrence should be managed according to the recommendations provided for stage I, II, or III disease as if the recurrence were a new primary lesion. Similarly, metastatic disease recurrence should be managed according to whether the disease presented with single-organ involvement versus disseminated disease, as described above.

ROLE

OF

MAMMALIAN TARGET

OF

RAPAMYCIN INHIBITORS

The protein kinase mammalian target of rapamycin (mTOR) plays a role in the regulation of cell growth, proliferation, protein synthesis, and transcription in response to insulin and various other growth factors and often is abnormally activated in various human tumors.25 Due to the association between mTOR activation and cancer progression, inhibition of the mTOR pathway has become an important area of oncologic drug development.26 Commercially available

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Table 4. Treatment Approach for Stage II-III Soft Tissue Sarcomas

a

Stage II-III Type

Treatment Optionsa

Resectable with acceptable functional outcomes

Primary treatment: Surgery followed by radiotherapy with or without adjuvant chemotherapy OR Surgery alone for small tumors resected with wide margins Alternatives: Preoperative radiotherapy or chemoradiation followed by surgery and then consideration of radiotherapy boost/adjuvant chemotherapy OR Preoperative chemotherapy followed by surgery then radiotherapy with or without adjuvant chemotherapy

Potentially resectable with concern for adverse functional outcomes

Primary treatment: Preoperative radiotherapy or chemoradiation followed by surgery and then consideration of radiotherapy boost/adjuvant chemotherapy OR Preoperative chemotherapy followed by surgery and then radiotherapy with or without adjuvant chemotherapy

Unresectable primary disease

Primary treatment: Limb perfusion OR Preoperative radiotherapy OR Preoperative chemoradiation OR Preoperative chemotherapy

If tumor becomes resectable: Refer to recommendations for resectable stage II-III soft-tissue sarcomas If tumor remains unresectable: Options include definitive radiotherapy, observation if the tumor is not amenable to local control with definitive radiotherapy and the patient is asymptomatic, and a palliative approach for symptomatic patients that may include chemotherapy, surgery, or best supportive care

For stage II or III soft tissue sarcoma, the data supporting adjuvant chemotherapy administration are limited and conflicting (category 2B recommendation). For patients with resectable disease and acceptable functional outcomes, preoperative chemotherapy or chemoradiation also is a category 2B recommendation.

Based on reference 2.

mTOR inhibitors include sirolimus (Rapamune, Pfizer), temsirolimus (Torisel, Pfizer), and everolimus (Afinitor, Novartis).25 These agents are indicated for use as immunosuppressants following organ transplantation (sirolimus), in the treatment of advanced renal cell carcinoma (temsirolimus and everolimus), treatment of neuroendocrine tumors of pancreatic origin (everolimus), and in the management of rare subependymal giant cell astrocytoma brain tumors (everolimus). Additionally, there is an investigational mTOR inhibitor, ridaforolimus (Merck/Ariad), which is under evaluation for possible treatment of soft tissue sarcomas as well as other tumors.

Ridaforolimus is a non-prodrug rapamycin analog that has shown potential anti-tumor activity in a variety of tumor types.25 Ridaforolimus and other mTOR inhibitors are thought to exert antiangiogenic effects by inhibiting the expression of hypoxia-inducible factor and vascular endothelial growth factor, thereby halting tumor progression.26 Ridaforolimus was found to

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provide clinical benefit in a Phase II trial of 212 patients with advanced soft tissue or bone sarcomas.27 Of the enrolled patients, 79% had received at least 2 prior therapies for their disease and more than 90% had disease progression at the time of enrollment. Singleagent ridaforolimus was administered at a dose of 12.5 mg IV daily for 5 days every 2 weeks. Results revealed a clinical benefit response (ie, complete or partial response or stable disease for at least 16 weeks) of 29% with therapy. Additionally, the median OS was 40.1 weeks. The median OS was increased to 67.6 weeks in the subset of patients who achieved a clinical benefit response. This increase suggests that achieving a clinical benefit response may increase OS in patients with advanced soft tissue or bone sarcomas.

Results of a Phase III trial with ridaforolimus were presented at the 2011 American Society of Clinical Oncology (ASCO) annual meeting.28 The trial, known as SUCCEED (Sarcoma Multi-Center Clinical Evaluation of the Efficacy of Ridaforolimus), was an international,

Table 5. NCCN Recommended Monitoring Strategies Stages

Recommendations

Stage I

• • • •

Evaluate for rehabilitation (OT and PT) and continue until maximal function is achieved History and physical every 3 to 6 months for 2 to 3 years, then annually Consider chest imaging every 6 to 12 months Consider a postoperative baseline and periodic imaging of primary sites based on estimated risk for recurrence (MRI, CT, consider ultrasound)

Stage II, III (both resectable and unresectable); Stage IV

• •

Evaluate for rehabilitation (OT and PT) and continue until maximal function is achieved History and physical and chest imaging (plain radiograph or chest CT) every 3 to 6 months for 2 to 3 years, then every 6 months for next 2 years, then annually Consider a postoperative baseline and periodic imaging of primary sites based on estimated risk for recurrence (MRI, CT, consider ultrasound)

•

CT, computed tomography; MRI, magnetic resonance imaging; NCCN, National Comprehensive Cancer Network; OT, occupational therapy; PT, physical therapy Based on reference 2.

double-blind study that randomized 711 patients with metastatic soft tissue or bone sarcomas who had stable disease or a clinical benefit from prior standard cytotoxic chemotherapy. Patients were given either ridaforolimus 40 mg orally 5 days a week or placebo as maintenance therapy. Treatment with ridaforolimus resulted in an improvement in the primary end point of progression-free survival (PFS) compared with placebo (hazard ratio [HR] 0.72; P=0.001). Median PFS was 17.7 weeks in the ridaforolimus group compared with 14.6 weeks for placebo; a 21% improvement.

This benefit was noted in patients with soft tissue or bone sarcomas and in those on first-, second-, or thirdline prior chemotherapy. OS data were not available, but the investigators observed a favorable trend for ridaforolimus.

PROMISING DATA WITH TYROSINE KINASE INHIBITOR Promising Phase III data for pazopanib (Votrient, GlaxoSmithKline) in patients with advanced soft tissue sarcomas were also presented at ASCO’s 2011 meeting.29 Pazopanib, a multi-tyrosine kinase inhibitor of vascular endothelial growth factor receptors, was originally approved by the FDA in 2009 for treatment of patients with advanced renal cell carcinoma. 30 By affecting various tyrosine kinases, pazopanib has been shown to inhibit angiogenesis and the growth of tumors in in vivo models. The trial, known as PALETTE (Pazopanib Explored in Soft-Tissue Sarcoma), was an international, double-blind study that randomized 369 patients with metastatic soft tissue sarcoma who had failed at least 1 anthracycline-containing regimen to either pazopanib 800 mg once daily (n=246) or placebo (n=123). Treatment was given until tumor progression, unacceptable toxicity, death, or a patient’s request to withdraw. After a median duration of 15 months of follow-up, PFS was significantly

longer in patients treated with pazopanib compared with placebo (20 vs 7 weeks; HR, 0.31; P<0.0001).

Interim data for OS showed that results were similar in both groups.

Monitoring and Follow-up The NCCN guidelines provide specific recommendations for monitoring and follow-up.2 These recommendations, which are summarized in Table 5, include evaluations of physical functioning and periodic physical examinations and imaging procedures.

Conclusion Soft tissue sarcomas are relatively rare tumors that can occur anywhere in the body; however, most occur in the extremities and trunk. Environmental and host risk factors can contribute to the development of the disease. Diagnosis is made via a thorough history and physical examination, imaging, and a biopsy to establish tumor grade and histologic subtype. Based on the results of the initial workup, the tumor may be classified into various categories (stages I-IV or recurrent disease). The 2011 NCCN guidelines provide recommendations for clinicians with regard to management for each tumor category, with the mainstay of treatment being surgery with or without adjunctive radiation and/or chemotherapy.

References 1.

Morrison BA. Soft tissue sarcomas of the extremities. Proc (Bayl Univ Med Cent). 2003;16(3):285-290, PMID: 16278699.

2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines): soft tissue sarcoma, version 1.2011. http://www.nccn.org/professionals/physician_gls/ pdf/sarcoma.pdf. Accessed July 29, 2011.

3. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics: 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61(4):212-236, PMID: 21685461.

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4. Cormier JN, Pollock RE. Soft tissue sarcomas. CA Cancer J Clin.

2004;54(2):94-109, PMID: 15061599.

5. American Cancer Society. Sarcoma: adult soft tissue cancer. www. cancer.org/acs/groups/cid/documents/webcontent/003138-pdf. pdf. Accessed July 29, 2011.

6. Hueman MT, Thornton K, Herman JM, Ahuja N. Management of extremity soft tissue sarcomas. Surg Clin N Am. 2008;88(3): 539-557, PMID: 18514697.

7. Zahm SH, Fraumeni JF Jr. The epidemiology of soft tissue sarcoma.

Semin Oncol. 1997;24(5):504-514, PMID: 9344316.

8. Dileo P, Demetri GD. Update on new diagnostic and therapeutic approaches for sarcomas. Clin Adv Hematol Oncol. 2005;3(10): 781-791, PMID: 16258489.

9. American Joint Committee on Cancer. What is cancer staging? www.cancerstaging.org/mission/whatis.html. Accessed August 1, 2011.

10. Medenhall WM, Indelicato DJ, Scarborough MT, et al. The management of adult soft tissue sarcomas. Am J Clin Oncol.

2009;32(4):436-442, PMID: 19657238.

11. Pisters PW, Oâ&#x20AC;&#x2122;Sullivan B, Maki RG. Evidence-based recommendations for local therapy for soft tissue sarcomas. J Clin Oncol.

2007;25(8):1003-1008, PMID: 17350950.

12. Pisters PW, Pollock RE, Lewis VO, et al. Long-term results of prospective trial of surgery alone with selective use of radiation for patients with T1 extremity and trunk soft tissue sarcomas. Ann Surg. 2007;246(4):675-682, PMID: 17893504.

13. Davis AM, Oâ&#x20AC;&#x2122;Sullivan B, Bell RS, et al. Function and health status outcomes in a randomized trial comparing preoperative and postoperative radiotherapy in extremity soft tissue sarcoma. J Clin Oncol. 2002;20(22):4472-4477, PMID: 12431971.

14. Kraybill WG, Harris J, Spiro IJ, et al. Phase II study of neoadjuvant chemotherapy and radiation therapy in the management of highrisk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. J Clin Oncol.

2006;24(4):619-625, PMID: 16446334.

15. Adjuvant chemotherapy for localized resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-Analysis Collaboration. Lancet. 1997;350(9092):1647-1654, PMID: 9400508.

16. Cormier JN, Huang X, Xing Y, et al. Cohort analysis of patients with localized, high-risk, extremity soft tissue sarcoma treated at two cancer centers: chemotherapy-associated outcomes. J Clin Oncol.

2004;22(22):4567-4574, PMID: 15542808.

17. Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol.

2001;19(5):1238-1247, PMID: 11230464.

18. Antman K, Crowley J, Balcerzak SP, et al. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without

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ifosfamide and mesna in advanced soft tissue and bone sarcomas.

J Clin Oncol. 1993;11(7):1276-1285, PMID: 8315425.

19. Bramwell VH, Anderson D, Charette ML, Sarcoma Disease Site Group. Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft tissue sarcoma. Cochrane Database Syst Rev. 2003;(3):CD003293, PMID: 12917960.

20. Edmonson JH, Ryan LM, Blum RH, et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol. 1993;11(7):1269-1275, PMID: 8315424.

21. Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Sarcoma Group. J Clin Oncol. 1995;13(7):15371545, PMID: 7602342.

22. Lorigan P, Verweij J, Papai Z, et al. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group study. J Clin Oncol. 2007;25(21):3144-3150, PMID: 17634494.

23. Siehl J, Thiel E, Schmittel A, et al. Ifosfamide/liposomal daunorubicin is a well tolerated and active first-line chemotherapy regimen in advanced soft tissue sarcoma: results of a phase II study. Cancer.

2005;104(3):611-617, PMID: 15968689.

24. Siehl JM, Thiel E, Schmittel A, Hutter G, Keilholz U. Liposomal anthracyclines and ifosfamide in the first line treatment of advanced soft tissue sarcomas: a two cohort phase II study.

J Clin Oncol. 2006;24: Abstract 9563.

25. Blay JY. Updating progress in sarcoma therapy with mTOR inhibitors. Ann Oncol. 2010;22(2):280-287, PMID: 20591820.

26. Wan X, Helman LJ. The biology behind mTOR inhibition in sarcoma. Oncologist. 2007;12(8):1007-1018, PMID: 17766661.

27. Chawla SP, Tolcher AW, Staddon AP, et al. Survival results with AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas: update of phase II trial. J Clin Oncol.

2007;25: Abstract 10076.

28. Chawla SP, Blay J, Ray-Coquard IL, et al. Results of a phase III, placebo-controlled trial (SUCCEED) evaluating the mTOR inhibitor ridaforolimus (R) as maintenance therapy in advanced sarcoma patients (pts) following a clinical benefit from prior standard cytotoxic chemotherapy (CT). J Clin Oncol. 2011;29: Abstract 10005.

29. Votrient [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2009.

30. Van Der Graaf WT, Blay J, Chawla SP, et al. PALETTE: a randomized, double-blind, phase III trial of pazopanib versus placebo in patients (pts) with soft-tissue sarcoma (STS) whose disease has progressed during or following prior chemotherapy-an EORTC STBSG Global Network Study (EORTC 62072). J Clin Oncol.

2011;29: Abstract LBA10002.

SOLID TUMORS

Clinical Oncology News • September 2011

Prostate

SRC Beats PRC as Prostate Cancer Risk Calculator From Journal of Clinical Oncology

O

f two common prostate cancer risk calculators used in North America, the Sunnybrook nomogram-based prostate cancer risk calculator (SRC) outperformed the Prostate Cancer Prevention Trial–based risk calculator (PRC) in predicting risk for any prostate cancer, but especially aggressive prostate cancer, according to a recent study (J Clin Oncol 2011;29:2959-2964, PMID: 21690464).

However, according to the authors of the study, further research is needed to improve the ability of risk calculators to predict prostate cancer risk, particularly for higher-grade cancers (Gleason score of 7 or higher).

The area under the curve (AUC) was higher for the SRC than for the PRC: 0.67 (95% confidence interval [CI], 0.65-0.69) versus 0.61 (95% CI, 0.590.64), respectively. The SRC had an even greater ability than the PRC to predict prostate cancer risk for aggressive disease, according to AUC: 0.72 (95% CI, 0.70-0.75) versus 0.67 (95% CI, 0.64-0.70), respectively.

The prospective study included 2,130 participants who underwent a prostate biopsy for cancer detection at five centers. Of these, 867 men (40.7%) had cancer, whereas 1,263 (59.3%) did not.

Among the men with cancer, 464 (54%) had a Gleason score of 6, and 403 (46%) had a Gleason score of 7 or higher.

Among all study participants, median prostate-specific antigen (PSA) level was 5.7 ng/mL; 331 men (15.5%) had an abnormal digital rectal exam (DRE).

Median age at biopsy was 63 years.

Of the 443 men with PSA less than 4 ng/mL, 343 (77%) had a normal DRE. Known risk factors for prostate cancer were significantly associated with the disease in this study: age, family

history of prostate cancer, ethnicity, urinary voiding symptoms, PSA level, free-to-total PSA ratio and DRE. The SRC and PRC appeared to have comparable sensitivity, specificity, positive predictive value and negative predictive value over a range of nomogram probabilities for predicting any cancer, but the SRC appeared to have better sensitivity and negative predictive value for the low threshold range for predicting aggressive cancer.

Although there are no established ranges of threshold probabilities that would help prostate biopsy management, the threshold probabilities for prostate cancer between 10% and 40% were used in this study to determine the need for prostate biopsy. Some patients with a risk of 10% might not opt for biopsy, whereas those with a risk of 40% would probably be compelled to undergo an invasive biopsy, the authors wrote. Using this threshold, the SRC was consistently better in predicting risk for any cancer, especially for predicting aggressive, high-grade cancer. However, further research is needed to evaluate risk thresholds

that are acceptable to patients and News From physicians.

The JOURNALS The authors concluded, “An individual patient can receive a different message when using the more accurate SRC relative to the PRC.”

EXPERT INSIGHT Ronald M. Bukowski, MD Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, Ohio

“This publication reports the first prospective study validating North American–based prostate cancer risk calculators, and demonstrated that the SRC appeared to perform better.

The authors suggest that this method of calculating an individual’s risk of prostate cancer can be considered for clinical use in patients undergoing diagnostic prostate biopsies.”

Kidney

Temsirolimus-Bevacizumab Combination Disappoints in RCC From Lancet Oncology

T

he combination of temsirolimus (Torisel, Wyeth) and bevacizumab (Avastin, Genentech) offers limited efficacy and unexpectedly high toxicity in the treatment of metastatic renal cell carcinoma (mRCC), according to results of a recent Phase II clinical trial.

The TORAVA trial showed that patients treated with temsirolimus plus bevacizumab experienced more adverse events (AEs) and more serious AEs than those receiving the current standard therapies sunitinib (Sutent, Pfizer) and interferon-a plus bevacizumab. Progression-free survival (PFS), the primary end point of the study, also was lower among patients treated with the experimental regimen than among those on the older treatments.

The results were published in the July issue of Lancet Oncology (2011;12:673-680, PMID: 21664867), but the study is ongoing to assess longterm survival.

In the study, 171 adult patients with mRCC from 24

hospital centers in France were randomized to three treatment groups: 88 received temsirolimus plus bevacizumab, 42 received sunitinib and 41 received interferon-a plus bevacizumab. In the intent-to-treat analysis, PFS was assessed via computed tomography scan every 12 weeks for 48 weeks.

At 48 weeks, PFS was 29% in the temsirolimus plus bevacizumab group,

compared with 35% in the sunitinib group and 61% in the interferon a plus bevacizumab group, respectively. Additionally, 45 of the 88 patients in the temsirolimus plus bevacizumab group discontinued treatment for reasons other than progression, compared with five and 15, respectively, in the other two groups. These treatment stoppages were the result of adverse events such as fatigue, skin disorders, proteinuria and hypertension. Grade 3 or worse AEs, including hemorrhage, venous or arterial thromboembolism, pulmonary interstitial syndrome and gastrointestinal perforation were reported in 77% of the patients in the temsirolimus plus bevacizumab group, compared with 60% in the sunitinib group and 70% in the interferon-a plus bevacizumab group. Serious AEs were reported in 39 of the patients in the temsirolimus plus bevacizumab group, compared with 13 and 18 in the other two groups.

Although the authors describe the combination of temsirolimus and bevacizumab as disappointing with regard to its safety and efficacy, they noted that the agents used separately have shown promise in “control of advanced disease over time.” Both temsirolimus (mTOR inhibitor) and bevacizumab

(vascular endothelial growth factor inhibitor) plus interferon were approved by the FDA as therapy for mRCC in 2007 and 2010, respectively.

EXPERT INSIGHT Ronald M. Bukowski, MD

“This Phase II randomized trial addresses, in a preliminary fashion, the crucial issue of combination therapy utilizing targeted agents for mRCC. The questions of improved efficacy versus increased toxicity for the various treatment arms were investigated. The study design and size preclude definitive conclusions regarding treatment effects or the roles of combination versus sequential therapy; however, an ongoing Phase III trial comparing bevacizumab in combination with either temsirolimus or interferon (INTORACT, NCT00631371) is in progress, and should provide additional data. The standard of care for patients with untreated mRCC remains monotherapy with a tyrosine kinase inhibitor, such as sunitinib or pazopanib, or the combination of bevacizumab plus interferon.”

17

TASIGNA for adult patients with newly diagnosed Ph+ CML in chronic phase TASIGNA DOUBLED THE MAJOR MOLECULAR RESPONSE (MMR) RATE OF IMATINIB AT 12 MONTHS1

2 TASIGNA PATIENTS (<1%) PROGRESSED TO ACCELERATED PHASE OR BLAST CRISIS* (AP/BC) VS 17 IMATINIB PATIENTS (6%)1

MMR rates at 12 months1

Progression to AP/BC1 30

100

P<0.0001

60

25 20

44%

[95% CI, 38.4%-50.3%]

22%

40

[95% CI, 17.6%-27.6%]

Patients

Patients (%)

80

15 10

20

5

0

0

TASIGNA 300 mg bid (n=282)

n=17 (6%)

Imatinib 400 mg qd (n=283)

n=2 (0.7%) TASIGNA 300 mg bid (n=282)

Imatinib 400 mg qd (n=283)

ENESTnd study design: A randomized, controlled, open-label, multicenter Phase III trial of 846 patients with newly diagnosed Ph+ CML in chronic phase. Patients were randomized to receive either TASIGNA 400 mg bid (n=281), TASIGNA 300 mg bid (n=282), or imatinib 400 mg qd (n=283). The daily dose of imatinib could be escalated to 800 mg (400 mg bid), but no dose escalation was permitted with TASIGNA. A centralized laboratory was used for PCR testing.

The primary end point was MMR at 12 months. MMR was defined as ≤0.1% BCR-ABL/ABL by international scale measured by RQ-PCR, which corresponds to a ≥3-log reduction of BCR-ABL transcripts from standardized baseline.1,2

The distinct safety profile of TASIGNA supports its use in adult patients with newly diagnosed Ph+ CML in chronic phase1 ■ ■

Discontinuation for adverse events regardless of causality was observed in 7% of patients In ENESTnd, most side effects associated with TASIGNA did not lead to discontinuation in the first year

*Definition includes patients with clonal evolution and CML-related death. Time was censored at last assessment on treatment for patients without events.2,3

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

©2011 Novartis

Printed in USA

12/10

AM7-100030

Greater efficacy vs imatinib on every end point at 12 months TASIGNA (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of TASIGNA is based on major molecular response and cytogenetic response rates. The study is ongoing and further data will be required to determine long-term outcome.

Boxed WARNING and Additional Important Safety Information TASIGNA prolongs the QT interval. ECGs should be obtained to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, as well as following any dose adjustments. Sudden deaths have been reported in patients receiving TASIGNA. TASIGNA should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA administration and should be periodically monitored. The concomitant use of strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong the QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided. The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, and phenobarbital). Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment as nilotinib exposure is increased in patients with impaired hepatic function.

■ ■ ■ ■

■ ■

■

■

■

Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia Caution is recommended in patients with a history of pancreatitis

The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia (see Boxed WARNING)

The exposure of nilotinib is reduced in patients with total gastrectomy Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption

Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do

In chronic phase patients, the most commonly reported nonhematologic adverse drug reactions (>10%) were rash, pruritus, nausea, fatigue, myalgia, headache, constipation, diarrhea, and vomiting

In accelerated phase patients, the most commonly reported nonhematologic adverse drug reactions (>10%) were rash, pruritus, and fatigue

References: 1. TASIGNA® (nilotinib) capsules prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; January 2011. 2. Saglio G, Kim D-W, Issaragrisil S, et al; for ENESTnd investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251-2259. 3. Data on file. Novartis Pharmaceuticals Corporation. East Hanover, NJ.

Please see brief summary of Prescribing Information on the following pages.

Tasigna® (nilotinib) Capsules Initial U.S. Approval: 2007 BRIEF SUMMARY: Please see package insert for full prescribing information.

WARNING: QT PROLONGATION AND SUDDEN DEATHS Tasigna prolongs the QT interval (5.2). Sudden deaths have been reported in patients receiving nilotinib (5.3). Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome (4). Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored (5.2). Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided (5.7). Patients should avoid food 2 hours before and 1 hour after taking dose (5.8). A dose reduction is recommended in patients with hepatic impairment (5.9). ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments. (5.2, 5.3, 5.6, 5.12) 1 INDICATIONS AND USAGE 1.1 Newly Diagnosed Ph+ CML-CP Tasigna (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of Tasigna is based on major molecular response and cytogenetic response rates [see Clinical Studies (14.1) in the full prescribing information]. The study is ongoing and further data will be required to determine long-term outcome.

1.2 Resistant or Intolerant Ph+ CML-CP and CML-AP Tasigna is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates [see Clinical Studies (14.2) in the full prescribing information].

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing Tasigna should be taken twice daily at approximately 12 hour intervals and must not be taken with food. The capsules should be swallowed whole with water. No food should be consumed for at least 2 hours before the dose is taken and no food should be consumed for at least one hour after the dose is taken [see Boxed Warning, Warnings and Precautions (5.8), Clinical Pharmacology (12.3) in the full prescribing information].

For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in one teaspoon of applesauce (puréed apple). The mixture should be taken immediately (within 15 minutes) and should not be stored for future use [see Clinical Pharmacology (12.3) in the full prescribing information].

Tasigna may be given in combination with hematopoietic growth factors such as erythropoietin or G-CSF if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated.

Newly Diagnosed Ph+ CML-CP The recommended dose of Tasigna is 300 mg orally twice daily [see Clinical Pharmacology (12.3) in the full prescribing information].

Resistant or Intolerant Ph+ CML-CP and CML-AP The recommended dose of Tasigna (nilotinib) is 400 mg orally twice daily [see Clinical Pharmacology (12.3) in the full prescribing information].

2.2 Dose Adjustments or Modifications QT interval prolongation: Table 1: Dose Adjustments for QT Prolongation ECGs with a QTc >480 msec

1. Withhold Tasigna, and perform an analysis of serum potassium and magnesium, and if below lower limit of normal, correct with supplements to within normal limits. Concomitant medication usage must be reviewed.

2. Resume within 2 weeks at prior dose if QTcF returns to <450 msec and to within 20 msec of baseline.

3. If QTcF is between 450 msec and 480 msec after 2 weeks, reduce the dose to 400 mg once daily.

4. If, following dose-reduction to 400 mg once daily, QTcF returns to >480 msec, Tasigna should be discontinued.

5. An ECG should be repeated approximately 7 days after any dose adjustment.

Myelosuppression Tasigna may need to be withheld and/or dose reduced for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 2).

Table 2: Dose Adjustments for Neutropenia and Thrombocytopenia Newly diagnosed Ph+ CML in chronic phase at 300 mg twice daily Resistant or intolerant Ph+ CML in chronic phase or accelerated phase at 400 mg twice daily

ANC* <1.0 x 109/L and/or platelet counts <50 x 109/L

1. Stop Tasigna, and monitor blood counts 2. Resume within 2 weeks at prior dose if ANC >1.0 x 109/L and platelets >50 x 109/L 3. If blood counts remain low for >2 weeks, reduce the dose to 400 mg once daily

*ANC = absolute neutrophil count See Table 3 for dose adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases [see Adverse Reactions (6.1)].

Table 3: Dose Adjustments for Selected Non-hematologic Laboratory Abnormalities Elevated serum lipase or amylase ≥Grade 3

1. Withhold Tasigna, and monitor serum lipase or amylase 2. Resume treatment at 400 mg once daily if serum lipase or amylase return to ≤Grade 1

Elevated bilirubin ≥Grade 3

1. Withhold Tasigna, and monitor bilirubin 2. Resume treatment at 400 mg once daily if bilirubin return to ≤Grade 1

Elevated hepatic transaminases ≥Grade 3

1. Withhold Tasigna, and monitor hepatic transaminases 2. Resume treatment at 400 mg once daily if hepatic transaminases return to ≤Grade 1

Other Non-hematologic Toxicities If other clinically significant moderate or severe non-hematologic toxicity develops, withhold dosing, and resume at 400 mg once daily when the toxicity has resolved. If clinically appropriate, escalation of the dose back to 300 mg (newly diagnosed Ph+ CML-CP) or 400 mg (resistant or intolerant Ph+ CML-CP and CML-AP) twice daily should be considered. For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Test serum lipase levels monthly or as clinically indicated. For Grade 3 to 4 bilirubin or hepatic transaminase elevations, dosing should be withheld, and may be resumed at 400 mg once daily.

Test bilirubin and hepatic transaminases levels monthly or as clinically indicated [see Warnings and Precautions (5.4, 5.5), Use in Specific Populations (8.7) in the full prescribing information].

Hepatic Impairment If possible, consider alternative therapies. If Tasigna must be administered to patients with hepatic impairment, consider the following dose reduction: Table 4: Dose Adjustments for Hepatic Impairment (At Baseline) Newly diagnosed Ph+ CML in chronic phase at 300 mg twice daily

Mild, Moderate or Severe*

An initial dosing regimen of 200 mg twice daily followed by dose escalation to 300 mg twice daily based on tolerability

Resistant or intolerant Ph+ CML in chronic phase or accelerated phase at 400 mg twice daily

Mild or Moderate*

An initial dosing regimen of 300 mg twice daily followed by dose escalation to 400 mg twice daily based on tolerability

Severe*

A starting dose of 200 mg twice daily followed by a sequential dose escalation to 300 mg twice daily and then to 400 mg twice daily based on tolerability

*Mild = mild hepatic impairment (Child-Pugh Class A); Moderate = moderate hepatic impairment (Child-Pugh Class B); Severe = severe hepatic impairment (Child-Pugh Class C) [see Boxed Warning, Warnings and Precautions (5.9), Use in Specific Populations (8.7) in the full prescribing information].

Concomitant Strong CYP3A4 Inhibitors Avoid the concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit products may also increase serum concentrations of nilotinib and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, consider a dose reduction to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML-CP. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period should be allowed before the Tasigna dose is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors [see Boxed Warning, Warnings and Precautions (5.2, 5.7), Drug Interactions (7.2) in the full prescribing information].

Concomitant Strong CYP3A4 Inducers Avoid the concomitant use of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). Patients should also refrain from taking St. John’s Wort. Based on the nonlinear pharmacokinetic profile of nilotinib, increasing the dose of Tasigna when co-administered with such agents is unlikely to compensate for the loss of exposure [see Drug Interactions (7.2) in the full prescribing information].

3 DOSAGE FORMS AND STRENGTHS 150 mg red opaque hard gelatin capsules with black axial imprint “NVR/BCR”.

200 mg light yellow opaque hard gelatin capsules with a red axial imprint “NVR/TKI”.

4 CONTRAINDICATIONS Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning].

5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Perform complete blood counts every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated.

Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction [see Dosage and Administration (2.2)].

5.2 QT Prolongation Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner [see Adverse Reactions (6.1), Clinical Pharmacology (12.4) in the full prescribing information]. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated and following dose adjustments [see Warnings and Precautions (5.12)].

Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome.

Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)].

Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided [see Warnings and Precautions (5.7, 5.8)]. The presence of hypokalemia and hypomagnesemia may further enhance this effect [see Warnings and Precautions (5.6, 5.12)].

5.3 Sudden Deaths Sudden deaths have been reported in patients with CML treated with nilotinib in clinical studies (n= 5,661; 0.3%). The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.

5.4 Elevated Serum Lipase The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous history of pancreatitis. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated.

5.5 Hepatotoxicity The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated [see Warnings and Precautions (5.12)].

5.6 Electrolyte Abnormalities The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia.

Electrolyte abnormalities must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)].

5.7 Drug Interactions The administration of Tasigna with agents that are strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning, Dosage and Administration (2.2), Drug Interactions (7.2) in the full prescribing information].

5.8 Food Effects The bioavailability of nilotinib is increased with food. Tasigna must not be taken with food. No food should be taken at least 2 hours before and at least one hour after the dose is taken. Grapefruit products and other foods that are known to inhibit CYP3A4 should be avoided [see Boxed Warning, Drug Interactions (7.2) and Clinical Pharmacology (12.3) in the full prescribing information].

In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (>10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions (>1%) were thrombocytopenia, neutropenia and anemia.

In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (>10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (>1%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia.

Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steadystate was 10 msec. Increase in QTcF >60 msec from baseline was observed in 4.1% of the patients and QTcF of >500 msec was observed in 4 patients (<1%) [see Boxed Warning, Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.4) in the full prescribing information].

Discontinuation due to drug-related adverse reactions was observed in 16% of CML-CP and 10% of CML-AP patients.

Most Frequently Reported Adverse Reactions Tables 5 and 6 show the percentage of patients experiencing treatment-emergent adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of patients who received at least one dose of Tasigna are listed.

Table 5: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg twice daily or Gleevec 400 mg once daily groups)a

5.9 Hepatic Impairment Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment (at baseline) and QT interval should be monitored closely [see Boxed Warning, Dosage and Administration (2.2) and Use in Specific Populations (8.7) in the full prescribing information].

5.10 Total Gastrectomy The exposure of nilotinib is reduced in patients with total gastrectomy. More frequent follow-up of these patients should be considered. Dose increase or alternative therapy may be considered in patients with total gastrectomy [see Clinical Pharmacology 12.3) in the full prescribing information].

5.11 Lactose Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products or of glucose-galactose malabsorption.

5.12 Monitoring Laboratory Tests Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter. Chemistry panels, including the lipid profile, should be checked periodically. ECGs should be obtained at baseline, seven days after initiation and periodically thereafter, as well as following dose adjustments [see Warnings and Precautions (5.2)]. Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician’s discretion.

5.13 Use in Pregnancy There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in animals at maternal exposures that were lower than the expected human exposure at the recommended doses of nilotinib.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna [see Use in Specific Populations (8.1) in the full prescribing information].

6 ADVERSE REACTIONS The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of the package insert [see Boxed Warning, Warnings and Precautions (5)].

Patients with Newly Diagnosed Ph+ CML-CP

Sudden deaths [see Boxed Warning, Warnings and Precautions (5.3)] Elevated serum lipase [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Electrolyte abnormalities [see Boxed Warning, Warnings and Precautions (5.6)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Newly diagnosed Ph+ CML-CP The data below reflect exposure to Tasigna from a randomized trial in newly diagnosed patients with Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment in the nilotinib 300 mg twice daily group was 18.6 months. The median actual dose intensity was 593 mg/day in the nilotinib 300 mg twice daily group.

The most common (>10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue and myalgia. Upper abdominal pain, alopecia, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema and asthenia were observed less commonly (≤10% and >5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction. Pleural and pericardial effusions occurred in 1% of patients. Gastrointestinal hemorrhage was reported in 0.4% of patients.

Increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of >500 msec.

The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (17%), neutropenia (15%) and anemia (7%) See Table 7 for Grade 3/4 laboratory abnormalities.

TASIGNA 300 mg twice daily

GLEEVEC 400 mg once daily

N=279

N=280

N=279

N=280

CTC Gradesb 3 / 4 (%)

All Grades

Skin and subcutaneous tissue disorders

Rash Pruritus Alopecia

36 19 10

16 7 5

<1 <1 0

1 0 0

Gastrointestinal disorders

Nausea Constipation Diarrhea Vomiting Abdominal pain upper Abdominal pain

19 15 14 9

38 4 37 22

1 0 <1 0

1 0 2 <1

15 12

10 9

<1 1

<1 <1

Nervous system disorders

Headache

28

16

3

<1

General disorders and administration site conditions

Fatigue Pyrexia Asthenia Edema, peripheral

19 10 11 8

14 12 9 17

<1 0 <1 0

1 0 0 0

Musculoskeletal and connective tissue disorders

Myalgia Arthralgia Muscle spasms Pain in extremity Back pain

14 15 10 9 12

16 13 29 13 10

<1 <1 0 0 <1

0 0 <1 <1 1

Respiratory, thoracic Cough and mediastinal disorders

12

9

0

0

Infections and infestations

Nasopharyngitis Upper respiratory tract infection

19

15

0

0

Eye disorders

Eyelid edema

13

9

0

0

1

14

0

<1

aExcluding bNCI

laboratory abnormalities Common Terminology Criteria for Adverse Events, Version 3.0 Table 6: Most Frequently Reported Non-hematologic Adverse Reactions in Patients with Resistant or Intolerant Ph+ CML Receiving Tasigna 400 mg Twice Daily (Regardless of Relationship to Study Drug) (≥10% in any Group)a CML-CP

CML-AP

N=321 Body System and Preferred Term

N=137

All Grades (%)

CTC Gradesb 3 / 4 (%)

All Grades (%)

CTC Gradesb 3 / 4 (%)

Skin and subcutaneous tissue disorders

Rash Pruritus Night sweat Alopecia

36 32 12 11

2 <1 <1 0

29 20 27 12

0 0 0 0

Gastrointestinal disorders

Nausea Constipation Diarrhea Vomiting Abdominal pain Abdominal pain upper Dyspepsia

37 26 28 29 15

1 <1 3 <1 2

22 19 24 13 16

<1 0 2 0 3

14 10

<1 <1

12 4

<1 0

Headache

35

2

20

1

Discontinuation due to adverse events regardless of causality was observed in 7% of patients.

Resistant or intolerant Ph+ CML-CP and CML-AP In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the recommended dose of 400 mg twice daily.

The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1-1096) and 264 (range 2-1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151–1110) and 780 mg/day (range 150-1149), respectively and corresponded to the planned 400 mg twice daily dosing.

The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range 1-345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1–234).

GLEEVEC 400 mg once daily

Body System and Preferred Term

Myelosuppression [see Warnings and Precautions (5.1)] QT prolongation [see Boxed Warning, Warnings and Precautions (5.2)]

TASIGNA 300 mg twice daily

Nervous system disorders

(continued)

Table 6: Most Frequently Reported Non-hematologic Adverse Reactions in Patients with Resistant or Intolerant Ph+ CML Receiving Tasigna 400 mg Twice Daily (Regardless of Relationship to Study Drug) (≥10% in any Group)a CML-CP

CML-AP

N=321 Body System and Preferred Term

Metabolism and Nutrition Disorders: Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia. Uncommon: dehydration, decreased appetite, increased appetite. Unknown frequency: hyperuricemia, gout, hypoglycemia, dyslipidemia.

N=137

All Grades (%)

CTC Gradesb 3 / 4 (%)

All Grades (%)

CTC Gradesb 3 / 4 (%)

General disorders and administration site

Fatigue Pyrexia Asthenia Edema, peripheral Myalgia

32 22 16 15 19

3 <1 0 <1 2

23 28 14 12 16

<1 2 1 0 <1

Musculoskeletal and connective tissue disorders

Arthralgia Muscle spasms Bone pain Pain in extremity Back pain Musculoskeletal pain

26 13 14 20 17

2 <1 <1 2 2

16 15 15 18 15

0 0 2 1 <1

11

<1

12

1

Respiratory, thoracic Cough and mediastinal Dyspnea disorders Oropharyngeal pain

27 15 11

<1 2 0

18 9 7

0 2 0

Infections and infestations

Nasopharyngitis Upper respiratory tract infection

24

<1

15

0

12

0

10

0

Metabolism and nutritional disorders

Anorexia

12

<1

15

<1

Psychiatric disorders Insomnia

12

1

7

0

Vascular disorders

10

2

11

<1

Hypertension

aExcluding

laboratory abnormalities bNCI Common Terminology Criteria for Adverse Events, Version 3.0 Laboratory Abnormalities Table 7 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna.

Table 7: Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities Patient Population Resistant or Intolerant Ph+ Newly Diagnosed Ph+ CML-CP

CML-CP

CML-AP

TASIGNA 300 mg twice daily N=279 (%)

GLEEVEC 400 mg once daily N=280 (%)

TASIGNA 400 mg twice daily N=321 (%)

TASIGNA 400 mg twice daily N=137 (%)

Hematologic Parameters Thrombocytopenia Neutropenia Anemia Biochemistry Parameters Elevated lipase Hyperglycemia Hypophosphatemia Elevated bilirubin (total) Elevated SGPT (ALT) Hyperkalemia Hyponatremia Hypokalemia Elevated SGOT (AST) Decreased albumin

10 12 4

9 20 5

301 312 11

423 424 27

7 6 5 4 4 2 <1 <1 1 0

3 0 8 <1 3 1 <1 1 1 0

18 12 17 7 4 6 7 2 3 4

18 6 15 9 4 4 7 9 2 3

Biochemistry Parameters Hypocalcemia Elevated alkaline phosphatase Elevated creatinine

<1 0 0

0 <1 <1

2 <1 <1

5 1 <1

*NCI Common Terminology Criteria for Adverse Events, version 3.0 Thrombocytopenia: 12% were grade 3, 18% were grade 4 2CML-CP: Neutropenia: 16% were grade 3, 15% were grade 4 3CML-AP: Thrombocytopenia: 11% were grade 3, 32% were grade 4 4CML-AP: Neutropenia: 16% were grade 3, 26% were grade 4 1 CML-CP:

6.2 Additional Data from Clinical Trials The following adverse drug reactions were reported in patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (1%-10%), uncommon (0.1%-1%), and unknown frequency (single events). For adverse drug reactions listed under “Investigations”, very common events (≥10%), which were not included in Tables 5 and 6, are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category.

Infections and Infestations: Common: folliculitis. Uncommon: upper respiratory tract infection (including sinusitis, nasopharyngitis, pharyngitis), bronchitis, herpes virus infection, candidiasis pneumonia, urinary tract infection, gastroenteritis. Unknown frequency: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis.

Neoplasms Benign, Malignant and Unspecified: Common: Skin papilloma. Unknown frequency: papilloma.

Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocytosis, leukocytosis.

Immune System Disorders: Unknown frequency: hypersensitivity.

Endocrine Disorders: Uncommon: hyperthyroidism hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis.

Psychiatric Disorders: Common: depression, insomnia. Uncommon: anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria.

Nervous System Disorders: Common: dizziness, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia.

Unknown frequency: brain edema, optic neuritis, peripheral neuropathy, lethargy, dysesthesia.

Eye Disorders: Common: eye hemorrhage, periorbital edema, eye pruritus, conjunctivitis, dry eye. Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, eye irritation. Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctival hemorrhage, conjunctivitis allergic, conjunctival hyperemia, ocular hyperemia, ocular surface disease, scleral hyperemia.

Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus.

Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, pericardial effusion, coronary artery disease, cyanosis, cardiac murmur. Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, ejection fraction decrease.

Vascular Disorders: Common: hypertension, flushing. Uncommon: hypertensive crisis, hematoma. Unknown frequency: shock hemorrhagic, hypotension, thrombosis.

Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, epistaxis, cough, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing.

Gastrointestinal Disorders: Common: pancreatitis, abdominal discomfort, abdominal distension, dyspepsia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dysgeusia, dry mouth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, gastritis, hemorrhoids, hiatus hernia, rectal hemorrhage, sensitivity of teeth, gingivitis.

Hepatobiliary Disorders: Common: hepatic function abnormal. Uncommon: hepatitis, jaundice. Unknown frequency: cholestasis, hepatotoxicity, hepatomegaly.

Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis, dry skin. Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis, swelling of face. Unknown frequency: erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy.

Musculoskeletal and Connective Tissue Disorders: Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, flank pain. Uncommon: musculoskeletal stiffness, muscular weakness, joint swelling. Unknown frequency: arthritis.

Renal and Urinary Disorders: Common: pollakiuria. Uncommon: dysuria, micturition urgency, nocturia.

Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia.

Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction.

Unknown frequency: breast induration, menorrhagia, nipple swelling.

General Disorders and Administration Site Conditions: Common: pyrexia, chest pain, pain (including neck pain and back pain), chest discomfort, malaise. Uncommon: face edema, gravitational edema, influenza-like illness, chills. Unknown frequency: feeling hot, localized edema.

Investigations: Common: blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, weight decreased, weight increased. Uncommon: hemoglobin decreased, blood lactate dehydrogenase increased, blood urea increased. Unknown frequency: blood insulin increased, very low density lipoprotein increased, blood parathyroid hormone increased, blood pressure increased.

6.3 Postmarketing Experience The following additional adverse reactions have been reported during post approval use of Tasigna. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cases of tumor lysis syndrome have been reported in Tasigna treated patients with resistant or intolerant CML. Malignant disease progression, high WBC counts and/or dehydration were present in the majority of these cases.

10 OVERDOSAGE Overdose with nilotinib has been reported, where an unspecified number of Tasigna capsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

16 HOW SUPPLIED/STORAGE AND HANDLING Tasigna (nilotinib) 150 mg capsules are red opaque hard gelatin capsules, size 1 with black axial imprint “NVR/BCR”. Tasigna (nilotinib) 200 mg capsules are light yellow opaque hard gelatin capsules, size 0 with the red axial imprint “NVR/TKI.” Tasigna capsules are supplied in blister packs.

150 mg Carton of 4 blister packs of (4x28) ........................................................................................NDC 0078-0592-87 Blisters of 28 capsules............................................................................................................NDC 0078-0592-51 200 mg Carton of 4 blister packs of (4x28) ........................................................................................NDC 0078-0526-87 Blisters of 28 capsules............................................................................................................NDC 0078-0526-51 Each blister pack contains one folded blister card of 28 capsules each, for dosing two in the morning and two in the evening at 12 hour intervals over a 7 day period.

Tasigna (nilotinib) capsules should be stored at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

T2010-104 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland © Novartis

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936

PRN

Clinical Oncology News • September 2011

Doctor-Patient Communication

Potential Impact of Pretreatment Anticipation of Benefit on Outcomes Much has been written about the importance of the adequacy of communication between physicians and their patients.1 It is well recognized that this issue is particularly relevant in oncology, especially when the communication involves honest and open discussions regarding end-of-life issues.2 Less heard in this arena is any mention of another routine component of communication between oncologists and their patients: the specific benefits (e.g., relief of pain, improved appetite, etc.) that might be experienced by a patient undergoing a particular management program.

It is essential to note that complete disclosure of the known risks associated with a proposed management strategy is imperative to patient care. There is no intent to suggest that anything less is adequate for our patients. The issue to be highlighted in this commentary is the potential relevance of the manner in which therapeutic benefits of a proposed therapy are presented to the patient. Does it really make any difference to the outcome of a therapeutic intervention if an oncologist simply (and perhaps, rather dryly) lists possible outcomes versus if a physician specifically highlights reasonable and clinically meaningful effects of a proposed therapeutic intervention on symptoms, such as pain, that are being experienced by the individual patient?

Although a definitive answer to this meaningful question is surely not available, recently reported, rather provocative data from outside the realm of oncology begin to address this highly clinically relevant issue.

In a recent study published in the journal Science Translational Medicine, researchers administered the opioid remifentanil to a group of healthy volunteers following their exposure to “pain-provoking heat.”3 Prior to the administration of the pain medication, the research subjects were either informed that the opioid would have no effect on the sensation, would have a positive effect in relieving the pain, or would make the discomfort worse.

Despite the fact each study population received the identical painful stimulus and opioid medication, investigators found that individuals who were told their pain would be decreased experienced substantially more pain relief (“doubled”) compared with the groups that were informed the medication would either have no effect or increase the sensation.3 But of perhaps greatest interest, functional magnetic resonance imaging performed as part of the research project

EDITORIAL BOARD COMMENTARY Maurie Markman, MD Vice President of Patient Oncology Services and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

informed prior to initiating the therapy that there is no evidence the strategy impacts outcome (perhaps, the specific issue being evaluated) versus being told that the strategy substantially improves survival (perhaps, the final result of the clinical trial).

Is it not reasonable to conclude that in some—perhaps, many—circumstances the strong subjective feeling or belief by an individual patient that a specific therapeutic regimen will be beneficial to her or him may favorably impact the opportunity for that individual to experience a measurably positive clinical outcome? This seems to be a question that deserves further exploration by the oncology research community.

References 1. Levinson W, Pizzo PA. Patient–physician communication: it’s about time. JAMA. 2011;305:1802-1803, PMID: 21540424.

These data provide important support for the relevance and power of physician-directed communication focusing on optimizing the potential benefits of patients’ beliefs on achieving a favorable clinical outcome.

revealed both easily observable and quantifiable differences in the activity of specific regions of the brain that were associated with these favorable or negative subjective responses. Furthermore, these areas of the central nervous system are recognized to play an important role in the perception of pain.

The authors of this most interesting study concluded: “On the basis of subjective and objective evidence, we contend that an individual’s expectation of a drug’s effect critically influences its therapeutic efficacy and that regulatory brain mechanisms differ as a function of expectancy. We propose that it may be necessary to integrate patient’s beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes.”

Clearly, additional work in this complex and fascinating biological arena is needed. However, these data provide important support for the relevance and power of physician-directed communication focusing on optimizing the

potential benefits of patients’ beliefs on achieving a favorable clinical outcome.

In addition, it is reasonable to speculate that an individual patient’s pretherapy perceptions of possible benefit, originating from communication with her or his physician or obtained through other information sources (family, friends, support groups, Internet, etc.), may have important implications for both clinical trials (specifically “quality-of-life” studies) and the likelihood that routine (non–researchbased) treatment plans will be carried through to completion.

Consider, for example, patients being asked to undertake a 12- to 18-month maintenance chemotherapy program (following the completion of a 6- to 8-month “induction” regimen) as part of a research study. It is realistically quite possible that responses from individuals in this setting asked about their level of fatigue and general sense of well-being, as well as their willingness to continue participation in the trial, will be different if they have been

2. Peppercorn JM, Smith TJ, Helft PR, et al.

American Society of Clinical Oncology statement: toward individualized care for patients with advanced cancer. J Clin Oncol. 2011;29:755-760, PMID: 21263086.

3. Bingel U, Wanigasekera V, Wiech K, et al. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med. 2011;3:70ra14.

What are your thoughts?

Clinical Oncology News welcomes letters to the editor.

Do you have thoughts on Dr. Markman’s commentary?

Please send comments to

korourke@mcmahonmed.com.

OR

mauriemarkman@ctcahope.com.

23

24

PRN

Clinical Oncology News • September 2011

Community Oncology

Clinical Conundrums

Prepared by

Syed A. Abutalib, MD Assistant Director of Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

A Quiz for the Community Oncologist QUESTIONS

1.

A 65-year-old woman presents with fatigue, weight loss and hematuria.

She has no comorbid conditions. Her family history is unremarkable. Chest, abdomen, and pelvis scans reveal a single 10.2 cm right renal mass without associated lymphadenopathy. Which of the following is the correct management strategy for this patient? a. Right radical nephrectomy and lymph node resection followed by adjuvant therapy b. Right radical nephrectomy and lymph node sampling followed by careful surveillance or enrollment into a clinical trial c. Radiofrequency ablation (RFA) of the tumor followed by careful surveillance or enrollment into a clinical trial d. Neoadjuvant therapy with sunitinib (Sutent, Pfizer) followed by right radical nephrectomy e. Right partial nephrectomy and lymph node sampling followed by careful surveillance or enrollment into a clinical trial

2.

The patient described in question 1 undergoes laborious but successful surgery. The surgical pathology is consistent with stage III-pN1 disease with clear cell histology. What is the next best step for this patient? a. Adjuvant radiation therapy b. Careful surveillance or referral to a clinical trial c. Adjuvant sunitinib with or without radiation therapy

3.

A 55-year-old woman presents to you with a 2-month history of left leg pain. She is on appropriate anticoagulation therapy for a left femoral vein deep venous thrombosis (DVT) which was diagnosed approximately 4 months ago. Multiple repeated Doppler ultrasound scans have been negative for recurrent DVT. The patient is unable to carry on activities of daily living. Her past medical history is also remarkable for appropriately treated stage 1 colon cancer 3 months ago. She does not have any evidence of recurrent colon cancer. All of the following statements are correct about post-thrombotic syndrome (PTS) except: a. Daily use of elastic compression stockings (ECS) with an ankle pressure gradient of 30 to 40 mm Hg after proximal DVT appears to reduce symptoms of PTS but does not prevent PTS.

b. PTS develops in 20% to 50% of patients with DVT, despite appropriate anticoagulant therapy. c. PTS is more commonly seen in cancer patients with DVT. d. PTS is the most frequent complication of DVT.

transplantation was not part of therapy in patients analyzed with ISS. e. ISS does not apply to patients with smoldering multiple myeloma.

4.

6.

A 66-year-old woman is referred for treatment of multiple myeloma. Her only complaint is increasing fatigue. Past medical history is unremarkable. She is not taking any medications. The examination is unremarkable. Her laboratory evaluation reveals hemoglobin level of 9.5 g/ dL, creatinine value of 2 mg/dL, normal iron studies, corrected calcium of 11 mg/dL, and an albumin level of 3.6 g/dL. Serum protein electrophoresis shows immunoglobulin (Ig) G monoclonal protein of 3.8 g/dL, and urine protein electrophoresis reveals an IgG-l monoclonal protein. The free light-chain assay is abnormal. The b-2 microglobulin is 3.6 mg/L. Skeletal survey reveals diffuse lytic lesions in the spine and long bones. Bone marrow biopsy demonstrates 60% involvement with CD138 plasma cells, with no cytogenetic abnormalities detected by conventional cytogenetic analysis or fluorescence in situ hybridization. Serum creatinine was normal 6 months ago and the esophagogastroduodenoscopy and colonoscopy were normal 1 week ago. She is diagnosed with symptomatic multiple myeloma. What is her predicted median survival time according to International Staging System (ISS)? a. 62 months b. 44 months c. 29 months d. Cannot be determined

5.

All of the following statements regarding ISS for prognostic evaluation in symptomatic multiple myeloma are correct except: a. Older patients defined as more than 65 years of age have poorer survival than younger patients with the same ISS score. b. Compared with the Durie-Salmon system, the ISS provides more equal prognostic distribution of patients across the 3 stages. c. The data were gathered from 10,750 patients from 15 Asian, European, and North American institutions and groups. d. High-dose therapy (HDT) followed by autologous stem cell

A 19-year-old boy presents with a painful left leg. The pain started approximately 3 months previously following a soccer game. Past medical and surgical history is unremarkable. Examination reveals a tender 2cm hard mass, midway between the left knee and ankle. There is trace leg edema. Imaging demonstrates a left tibial destructive lesion. The left tibial core needle biopsy is consistent with Ewing’s sarcoma. Further imaging is negative for metastatic disease. Which of the following statements about osseous Ewing’s sarcoma is not correct? a. The tumor usually involves the diaphyseal region of the long bones. b. Trauma is a well-described risk factor for this disease. c. Diagnostic biopsy planning is of paramount importance because inappropriately conducted biopsy can jeopardize subsequent therapy. d. Radiographic bone findings have been described as onion-skinning, moth-eaten, and also include clinical signs of Codman’s triangle. e. The t(11:22) is not an uncommon abnormality.

7.

What is the most appropriate chemotherapy regimen for the patient described in question 6? a. Docetaxel and gemcitabine b. Vincristine, cyclophosphamide, and doxorubicin alternating with ifosfamide and etoposide c. High-dose methotrexate, cisplatin, and doxorubicin d. High-dose methotrexate, ifosfamide, and etoposide

8.

The infusion nurse informs you about extravasation of doxorubicin in the skin and soft tissue around the infusion line in your patient’s arm.

All of the following would be appropriate management steps except: a. Stop the infusion pump immediately, aspirate back as much as possible and do not flush the line. b. Apply cold pack to extravasation site every 15 to 20 minutes for 24 to 48 hours. c. Apply warm pack to extravasation

site every 15 to 20 minutes for 24 to 48 hours. d. Elevate the arm and do not apply pressure to the site of extravasation. e. If pain, erythema, and/or swelling persist beyond 48 hours, refer patient immediately to plastic surgery.

9.

Methotrexate has a broad range of antitumor activity as reflected by its administration in multiple malignancies including choriocarcinoma, osteosarcoma, head and neck cancer, breast cancer, bladder cancer, leukemias, and lymphomas. Which of the following statements about methotrexate is not correct? a. Methotrexate is an antifolate and is active in its parent form. b. Methotrexate is primarily eliminated by the kidney. c. Methotrexate excretion is inhibited by nonsteroidal anti-inflammatory drugs, trimethoprim-sulfamethoxazole, penicillin, cephalosporin, and ciprofloxacin. d. Proton pump inhibitors should be avoided especially during administration of high-dose methotrexate. e. Third-space fluid collections, such as pleural effusions and/or ascites, must be drained prior to methotrexate administration.

10.

Which of the following patients has an Eastern Cooperative Oncology Group (ECOG) performance scale of 3? a. A 70-year-old man with stage III colon cancer with no comorbid conditions who continues to work fulltime and is not symptomatic with his disease b. A 50-year-old man with stage III pancreatic cancer with no comorbid conditions who requires considerable assistance and is in bed most of his waking hours c. A 45-year-old man with stage III colon cancer who is unable to work, requires occasional assistance, but has no problems with self-care d. A 40-year-old man with stage IV germ cell tumor (GCT) who is unable to work out and has decreased his working hours e. A 40-year-old man with stage IV GCT who is disabled and requires special care

PRN

Clinical Oncology News • September 2011

Community Oncology

ANSWERS

Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma.

J Clin Oncol. 2005;23(15):3412-3420, PMID: 15809451.

1.

The answer is b. This patient has clinical stage II disease and appears to be a good surgical candidate. For this reason, as well as the fact that the tumor is quite large, RFA is not the preferred option in this patient. Partial or nephron-sparing surgery is an option in highly selected patients but not in this patient.

The answer is b. Currently there is no role for adjuvant therapy, but clinical trials are readdressing this issue with newly available targeted therapies.

Clark JI, Atkins MB, Urba WJ, et al. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial. J Clin Oncol.

2003;21(16):3133-3140, PMID: 12810695.

3.

The answer is c. PTS is a chronic complication of DVT that reduces quality of life and has important socioeconomic consequences. PTS is

5.

Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma.

J Clin Oncol. 2005;23(15):3412-3420, PMID: 15809451.

Santucci R, Levêque D, Lescoute A, Kemmel V, Herbrecht R. Delayed elimination of methotrexate associated with co-administration of proton pump inhibitors. Anticancer Res. 2010;30(9):3807-3810, PMID: 20944174.

6.

DeVita VT, Lawrence TS, Rosenberg SA. DePinho RA Weinberg RA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.

The answer is b. Trauma can unmask the underlying disease process but is not a risk factor. Inappropriately performed diagnostic biopsy can contaminate tissue planes.

2.

Helman LJ, Meltzer P. Mechanisms of sarcoma development. Nat Rev Cancer. 2003;3(9):685-694, PMID: 12951587.

burdensome and potentially debilitating to patients, and it is a condition for which patients frequently seek medical attention. Elastic compression stockings should be applied for at least 6 months.

The principal risk factors for PTS are persistent leg symptoms 1 month after the acute episode of DVT, extensive DVT, recurrent ipsilateral DVT, obesity, and older age. Underlying malignancy is not a risk factor for PTS. Kahn SR. How I treat postthrombotic syndrome. Blood. 2009;114(21):4624-4631, PMID: 19741190.

Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease. American College of Chest Physicians EvidenceBased Clinical Practice Guidelines. (8th ed.).

Chest. 2008;133(6 suppl):454S-545S; doi:10.1378/ chest.08-06580658.

4.

The answer is b. The patient has an ISS of II. Choices a and c would be correct for ISS I and ISS III, respectively.

9.

The answer is a. Methotrexate is an antifolate that is inactive in its parent form and requires polyglutamation by enzyme folylpolyglutamate synthase for its cytotoxic activity.

The answer is d. A total of 7,942 patients received standard therapy, and 2,808 patients received HDT as initial treatment.

Dash A, Vickers AJ, Schachter LR, Bach AM, Snyder ME, Russo P. Comparison of outcomes in elective partial vs radical nephrectomy for clear cell renal cell carcinoma of 4-7 cm. BJU Int. 2006;97(5):939-945, PMID: 16643474.

Bertelli G. Prevention and management of extravasation of cytotoxic drugs. Drug Saf. 1995;12(4):245-255, PMID: 7646823.

7.

The answer is b. The five-drug regimen (VDC/IE) is the current standard of care for localized Ewing’s sarcoma. Chemotherapy is followed by surgery. If response is demonstrated with this regimen, then it is continued postoperatively.

10.

The answer is b. The patients in choices a, c, d, and e have ECOG performance status of 0, 2, 1, and 4.

Oken MM, Creech RH, Tormey DC, et al.

Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.

1982;5(6):649-655, PMID: 7165009.

Shahid Raza, MD, assisted in preparing this manuscript.

Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348(8):694-701, PMID: 12594313.

8.

The answer is c. Accidental extravasation of doxorubicin into the tissues can cause serious injury, including tissue necrosis. All of the options to treat doxorubicin extravasation are correct except option c. In certain circumstances, topical dimethylsulfoxide and/ or systemic dexrazoxane can be useful.

Application of a warm pack is indicated for vinca alkaloids or epipodophyllotoxin extravasations.

FDA NEWS

Vemurafenib Approved For Melanoma

T

he FDA has approved vemurafenib (Zelboraf, Roche) for the treatment of BRAF V600E mutation-positive, inoperable or metastatic melanoma. The drug was approved along with the cobas 4800 BRAF V600 Mutation Test, a diagnostic test that can identify patients eligible for treatment. The drug targets and inhibits some mutated forms of the BRAF protein, which is found in about half of all cases of melanoma.

Approval is based on results from two clinical studies: BRIM3 and BRIM2.

BRIM3 is a global, randomized, openlabel, controlled, multicenter, Phase III study that compared vemurafenib with dacarbazine chemotherapy, a standard of care, in 675 patients with previously

untreated BRAF V600E mutationpositive, unresectable or metastatic melanoma. The end points of BRIM3 were overall survival (OS) and investigatorassessed progression-free survival (PFS). BRIM2 is a global, single-arm, multicenter, open-label Phase II study that enrolled 132 patients with previously treated BRAF V600E mutation-positive, unresectable or metastatic melanoma.

The primary end point of BRIM2 was confirmed overall response rate as assessed by independent review.

In BRIM3, the risk for death was reduced by 56% for people who received vemurafenib compared with those who received chemotherapy (hazard ratio [HR], 0.44; P<0.0001). At the time of the analysis, median OS of patients receiving vemurafenib had not been reached and was 7.9 months for those receiving

chemotherapy. Patients who received vemurafenib also had a 74% reduced risk for PFS compared with those who received chemotherapy (HR, 0.26; P<0.0001). Median PFS was 5.3 months for those who received vemurafenib compared with 1.6 months for those who received chemotherapy. The confirmed investigator-assessed response rate in patients who received vemurafenib was 48.4% (1% complete responses and 47.4%

partial responses) compared with 5.5% (partial responses) for patients who received chemotherapy (P<0.0001). In BRIM2, vemurafenib shrank tumors in 52% of trial participants.

The most common grade 3 or higher adverse events (AEs) seen in more people receiving vemurafenib compared with chemotherapy were cutaneous squamous cell carcinoma (cSCC) including keratoacanthomas (18% vs. <1%), rash, liver function abnormalities, joint pain and sensitivity to the sun. In cases of cSCC, the lesions were generally removed and the patients continued with treatment.

The most common (grade 3 or greater) AEs in the BRIM2 study were cSCC (26%), abnormal liver function, joint pain/arthritis and rash. In cases of cSCC, the lesions were generally removed and the patients continued with treatment.

25

SOLID TUMORS

Clinical Oncology News • September 2011

Lung

FLEX

Chemotherapy

15

P=0.011

10

9.6

5

0

Figure. Comparison of median overall survival in NSCLC patients with high EGFR expression.

EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer

‘Biomarker evaluation will be important for future studies regardless of the agent.’

—Ed Kim, MD

pared with 10.1 months without it (HR, 0.762; P=0.0441). And that one-month increase in survival came with a price: significantly increased toxicity, most notably febrile neutropenia, which was experienced by 22% of patients in the experimental arm and only 15% of patients in the control arm.

“That wasn’t sufficient to garner a regulatory approval of cetuximab in lung cancer,” noted Pasi Jänne, MD,

TARGETED continued from page 8 

in the erlotinib-alone arm.

Based on these results, a Phase III study to be conducted in Met-positive NSCLC patients is planned, but Dr. Mok reported that he will await results from this trial before drawing conclusions about the ability of MetMAb to improve the efficacy of erlotinib. Although he remains optimistic, he suggested that more data are needed to demonstrate that Met is a valid biomarker and a valid target for therapy.

Bevacizumab Rescue?

Although it is now clear that the advantage of EGFR-targeted TKIs over chemotherapy is restricted to NSCLC patients with EGFR mutation-positive tumors, a new study has provided evidence that the efficacy of erlotinib

—Pasi Jänne, MD, PhD

12

PhD, assistant professor of medicine at the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston. “The comment from the European regulatory agencies was that the side effects–versus-benefit profile did not warrant approval. While the OS benefit was statistically significant, people argued about its clinical significance.”

The new data change that picture, and it’s expected that cetuximab

in unselected NSCLC patients is not supported by bevacizumab (Avastin, Genentech), an antibody against the vascular epidermal growth factor receptor. In this Phase II study presented at ASCO, 224 NSCLC patients were randomized to the combination of bevacizumab and erlotinib or to a platinumbased doublet chemotherapy regimen (cisplatin and gemcitabine) plus bevacizumab (abstract 7504).

The median PFS rates were 3.5 months for patients receiving targeted therapy combinations compared with 7.7 months for patients receiving chemotherapy, producing an HR of 1.77 (95% CI, 1.33-2.36; P<0.0001), for progression in the erlotinib plus bevacizumab arm, according to lead investigator Michael Thomas, MD, head, thoracic oncology, ThoraxKlinik, University of Heidelberg, Germany. He noted that there was even a strong trend for improved OS among those in the

manufacturer Merck will return to the FDA to request approval of this indication for the drug in this subgroup of patients.

Dr. Jänne urges caution. “It’s an intriguing difference, but only if you can validate it prospectively or with another data set,” he said. “Absent that, I would say that the use of cetuximab in non-small cell lung cancer is still experimental. I wouldn’t use it in patients at the moment outside a trial setting.”

Not all doctors agree. Currently, cetuximab is included in the lung cancer guidelines from the National Comprehensive Cancer Network, and according to Edward Kim, MD, chief of the Section of Head and Neck Medical Oncology and associate professor at the University of Texas MD Anderson Cancer Center in Houston, some practitioners are using the drug off-label.

Hongbin Chen, MD, PhD, assistant professor in the Department of Medicine at Roswell Park Cancer Institute in Buffalo, N.Y., called the study presented at the World Conference on Lung Cancer intriguing, but said that more data are needed. “This is more like a hypothesis-generating analysis,” Dr. Chen said. “Although it is retrospective, the authors should be commended that they collected this information at the start of treatment. But I agree that we should wait for a prospective validation of these intriguing results.”

Those data may be on the way within

Erlotinib plus placebo

15

Overall survival, mo

with cetuximab (Erbitux, Merck) plus chemotherapy (generally cisplatin plus vinorelbine), compared with 9.6 months with chemotherapy alone (hazard ratio [HR], 0.73; P=0.011) (Figure). (About 31% of patients with NSCLC have high EGFR expression in their tumors.) In patients with low EGFR expression, no difference in OS was seen between the two treatment groups.

When the initial results of the FLEX trial were presented at the American Society for Clinical Oncology annual meeting in 2008, they were much less impressive. Unstratified by tumor EGFR expression level, the full study cohort showed a significant improvement in OS for patients receiving cetuximab, but it was relatively modest: 11.3 months with cetuximab com-

‘It’s an intriguing difference, but only if you can validate it prospectively or with another data set.’

Chemotherapy plus cetuximab

continued from page 1 

Survival, mo

26

Erlotinib plus MetMAb

12.6

10

5

3.8

the next two to three years. The Southwest Oncology Group has an ongoing four-arm Phase III trial (0819) that compares the outcomes for patients given standard treatment (either carboplatin and paclitaxel or carboplatin, paclitaxel and bevacizumab) or standard treatment plus cetuximab. EGFR expression is one of the biomarkers to be tested in the trial, which opened in 2009 and is expected to enroll approximately 1,500 participants.

“I think we should wait for that study’s findings before jumping in and using these data in lung cancer treatment,” Dr. Chen said. “I doubt that any practitioner who hasn’t started using it off-label already would start doing so now on the basis of this retrospective finding. But it’s an exciting and longawaited result, another example of personalized oncology in the era of targeted therapy.”

Oncologists emphasize that researchers need to incorporate biomarker analysis in future clinical trials for lung cancer patients. “Biomarker evaluation will be important for future studies regardless of the agent,” Dr. Kim said.

Cetuximab is approved by the FDA to treat certain patients with colorectal and head and neck cancer.

—Gina Shaw Drs. Jänne, Chen and Kim did not have any relevant disclosures.

Based on this and other data, Dr. Mok agreed that erlotinib does not appear to have a role as first-line therapy in NSCLC in the absence of EGFR mutations. Judging from the EURTAC trial, which screened 1,227 NSCLC patients to identify 174 with an EGFR mutation, less than 20% are candidates for this approach. However, additional biomarkers may further stratify patients for specific regimens.

—Ted Bosworth

0

Figure 2. Comparison of overall survival in MET-positive NSCLC. NSCLC, non-small cell lung cancer

chemotherapy arm relative to those in the arm receiving targeted therapies (P=0.06).

Dr. Mok disclosed being in a consultant or advisory role with and having received honoraria and research funding from AVEO. Dr. Rosell disclosed having a consultant or advisory role with Roche. Dr. Thomas disclosed being in a consultant or advisory role and having received honoraria from Boehringer Ingelheim, Lilly and Roche. He receives research funding from Roche.

Dr. Spigel disclosed being a consultant or having an advisory role with Genentech.

FDA NEWS

Clinical Oncology News • September 2011

Adcetris Approved To Treat Two Types of Lymphoma

demonstrated that 73% (95% confidence interval [CI], 65%-83%) of patients achieved an objective response following treatment with brentuximab, including 32% (95% CI, 23%-42%) with complete remissions and 40% (95% CI, 32%-49%) with partial remissions. The median duration of objective response was 6.7 months (95% CI, 4.014.8 months; range, 1.3 to 21.9 months).

In the systemic ALCL clinical trial, 58 patients with relapsed disease were enrolled. These data demonstrated that 86% (95% CI, 77%-95%) of patients achieved an objective response

T

he FDA has granted accelerated approval of brentuximab vedotin (Adcetris, Seattle Genetics) for two indications. The drug is approved for the treatment of patients with Hodgkin’s lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates.

It is also approved for the treatment of patients with systemic anaplastic large cell lymphoma (ALCL) after failure of at least one prior multiagent chemotherapy regimen.

The approvals were based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival. Brentuximab is the first drug approved by the FDA for Hodgkin’s lymphoma in more than 30 years.

The drug is an antibody-drug conjugate (ADC) comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE). The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

The approvals were based on data from two open-label, single-arm clinical trials: a trial in Hodgkin’s lymphoma patients who relapsed after ASCT and a trial in relapsed systemic ALCL patients. The primary end point of both trials was overall response rate as assessed by an independent review facility.

Where do you go? ✪ If you recall seeing an in-depth review of a topic but no longer have a hard copy?

✪ If you heard about an interesting piece from a colleague?

✪ If you see an installment from a multipart series but wish to see the other parts?

Clinicaloncology.com

In the Hodgkin’s lymphoma clinical trial, 102 patients were enrolled who had relapsed after ASCT. Data

27

following treatment with brentuximab, including 57% (95% CI, 44%-70%) with complete remissions and 29% (95% CI, 18%-41%) with partial remissions. The median duration of objective response was 12.6 months (95% CI, 5.7 months, not estimable; range, 0.1 to 15.9 months).

Seattle Genetics has established a patient assistance program named SeaGen Secure that offers patients and providers access to reimbursement support, benefit investigations and patient assistance programs. More information about SeaGen Secure is available at (855) 473-2436.

The Greenspan Meeting XXIX

November 8-12, 2011, New York City

CHEMOTHERAPY FOUNDATION SYMPOSIUM INNOVATIVE CANCER THERAPY FOR TOMORROW ® Practical Applications for the Practicing Oncologist New Agents, Clinical Trials, Emerging Developments Tuesday, November 8 Pediatric Oncology Therapeutic Advances in Cancers of Childhood

Saturday, November 12 Oncology Nurses, Physician Assistants, Case Managers, Pharmacists Therapeutic Advances, Treatment Related Complications, Supportive Care, Symptom Management, Targeted Therapies Schedule Nov. 8 Pediatric Oncology Nov. 9 Hematology, GI Cancers Nov. 10 GYN, Thyroid, Head & Neck, Breast Cancers Nov. 11 GU, Lung, Melanoma, Novel Agents, Neuroendocrine, Melanoma, Practice Issues Nov. 12 New Perspectives in Oncology Practice

Conference Highlights

Wednesday, November 9 Keynote Lecture: The Oncologic Time Warp James F. Holland, MD Thursday, November 10 Ezra M. Greenspan Memorial Lecture: Cure of Her2 Positive Breast Cancer With No Or Minimal Chemotherapy at The Door Step?

Martine Piccart, MD Friday, November 11 Judah Folkman Memorial Lecture: Anti-Angiogenesis: Paradise Lost?

Norman Wolkmark, MD

Complimentary Breakfasts, Lunches, Dinners

A CME Oncology Conference presented by the Mount Sinai School of Medicine and The Chemotherapy Foundation

Register on line at www.chemotherapyfoundationsymposium.org Contact: jaclyn.silverman@mssm.edu, (212) 866-2813

28

POLICY & MANAGEMENT

Clinical Oncology News • September 2011

Restricted Distribution

IPILIMuMAB continued from page 1 

melanoma patients, we have to order at least $1 million worth of medication. But we can’t do that without first completing a credit application with the vendor.”

Once the credit application hurdle is overcome, however, “we’re still not at the finish line,” she stressed.

“We then have to create a purchase order (PO) that has to be approved by at least five people in our system, up through the chain of command.”

Ms. Griffith added that the hassle factor doesn’t end there. “When our technicians order Yervoy, they can’t do it on a handheld device, which is linked to our regular ordering system; the staff have to remember to log on to a separate site. Plus, they have to remember to renew the PO when funds are low, so we are never put in a situation where we need to re-order the medication but can’t, thereby leading to a treatment delay. So there are a lot of extra layers of resources and staff time involved.“ One director of pharmacy at a large cancer center on the East Coast who did not want to be named said that the situation at OSU “actually is not all that typical; I don’t have a problem ordering this drug.”

The director declined to comment on why that is the case, but it may be due to the fact that McKesson—the parent company of two of the approved distributors—is the cancer center’s wholesaler.

Ms. Griffith countered that several pharmacy directors of large academic/ cancer centers share her concerns, such as James G. Stevenson, PharmD, FASHP, director of pharmacy services at the University of Michigan Hospitals and Health Centers, in Ann Arbor. Asked to comment on the issue, Dr. Stevenson said that he agreed that restricted distribution networks for cancer drugs “place an undue operational burden” on hospital pharmacies and thus “should be actively discouraged.” But he stressed that staff resources aren’t the only potential fallout of the restricted distribution model: hospitals that are forced to purchase ipilimumab and other drugs only from select distributors stand to lose millions of dollars in volume discounts they would otherwise earn by obtaining the drugs through their existing wholesalers. “In this era of cost containment and continuing financial pressures on our bottom line, we just cannot afford to lose those discounts,” Dr. Stevenson said.

Bonnie Kirschenbaum, a reimbursement expert and consultant based in Breckenridge, Colo., said that economic drivers are in fact at the heart of why so many newly approved medications are

funneled into restricted distribution networks. In such a model, she noted, manufacturers cut costs in a variety of ways.

For example, they can drastically reduce inventory levels due to the smaller number of distributors involved. That in turn yields significant savings from less waste due to expired or returned medications. The higher markups paid by hospitals that can no longer claim volume discounts is another huge economic benefit, she noted. Thus, “these types of programs are not going to go away, no matter how much you rail against them.”

Ms. Griffith said she was not so naive to think that financial considerations “aren’t a factor” in BMS’ decision to adopt a restricted distribution network for ipilimumab. “But it seems to me that a distribution program should be predicated primarily on what works best for the patient and provider of the drug.”

BMS Responds Asked to comment on the Yervoy distribution model, Sarah Koenig, a spokeswoman for BMS, said that it does in fact consider the needs of patients and providers. The model “is an innovative approach that was developed to help ensure the safe and appropriate use of Yervoy,” she stated in an email. “In fact, elements of the model have been incorporated into our official REMS [Risk Evaluation and Mitigation Strategy] from the FDA.” Another director of pharmacy who wished to remain anonymous said he is familiar with the BMS position that patient safety is a major driver of the ipilimumab distribution model. But in his view, there are “at least two objectively obvious [financial] reasons” why manufacturers might seek to restrict distribution for a particular drug. The first reason is the undercutting of volume drug discounts already cited. “Number two, the drug company gets instant access to definitive information about which hospitals bought exactly how many vials of their drug, on exactly what dates, etc.,”

the director said. “That type of data is probably extremely valuable to the manufacturers, not to mention individual sales representatives in terms of sales bonuses, etc, and restricted distribution could allow them to get it without paying fees to wholesalers and various data-gathering entities.”

Not So Restricted After All? As for the question of whether there is room for flexibility in who can purchase

other manufacturers adopt BMS’ position that restricted distribution is the best way to ensure REMS compliance, “this could put a huge additional burden on hospitals,” she explained. “There are a lot of specialty pharmacies and other alternate drug distributors out there. If we have to set up separate agreements with a large number of them in order to purchase any medication with a REMS program, it could lead to a logistical and financial nightmare.”

Ms. Griffith also questioned why, given the limited scope of the ipilimumab REMS, the drug even needs handling through limited channels. Several drugs have been approved with REMS that include far more complicated stipulations than the communication plan accompanying ipilimumab, and yet are available for purchase from all the major wholesalers, she noted, including the erythropoiesis-stimulating agents.

Dwight Kloth, PharmD, FCCP, BCOP, director of pharmacy at Fox Chase Cancer Center, in Philadelphia, said there is little logic to the idea that any REMS program automatically requires drug purchasing via a restricted distribution network. “If a drug company says that it has a new intravenous cytotoxic medication and it’s potentially toxic, and the only way

‘I would ask for objective evidence that restricted distribution for such new drugs is, in fact, necessary to ensure safe use, because I don’t think there is any evidence to that effect.’

—Dwight Kloth, PharmD, FCCP, BCOP

ipilimumab, Ms. Koenig stressed that the current system for obtaining the monoclonal antibody “is not a closed distribution model. Our existing [suppliers] have met the criteria required by BristolMyers Squibb and we are open to expanding our list of distributors, provided they meet these same criteria.”

Ms. Griffith said she “is encouraged that there may be movement on this issue.” In fact, she noted that at press time, Cardinal Health, OSU’s primary wholesaler, was in discussions with BMS and a Cardinal subsidiary to determine how the subsidiary could become an approved ipilimumab supplier. Tara Schumacher, a spokeswoman at Cardinal Health, confirmed that such discussions “are ongoing.”

A Dangerous Precedent Ms. Griffith stressed that her motivation for reaching out to BMS and her colleagues on this issue isn’t based solely on the hassle factors associated with the ipilimumab distribution model. “My biggest concern is the precedent it could establish moving forward.”

Given the large numbers of new cancer drugs with the potential to be approved with a REMS program, if

that they can ensure safety and appropriate consenting of patients and other compliance with a REMS is to restrict distribution, that implies that oncologists and oncology specialty hospitals can’t take care of these patients adequately unless the manufacturer makes the hospital work harder to access the drug via a restricted supply chain,” Dr. Kloth said.

“I would disagree completely with that stance, and I would ask for objective evidence that restricted distribution for such new drugs is, in fact, necessary to ensure safe use, because I don’t think there is any such evidence to that effect.”

Dr. Kloth added that “restricted distribution, per se, does absolutely nothing to enhance patient education or ensure that patients are properly consented prior to receiving chemotherapy, nor does it do anything to ensure appropriate patient monitoring. In fact, one can quite reasonably argue the opposite: that any distribution model that makes it more difficult to just procure the drug, requiring increased staff time and significantly increased risk for supply disruptions, could not possibly enhance safety.”

—David Bronstein

CLINICAL TRIALS

Clinical Oncology News • September 2011

New Phase II and III Clinical Trials

Supportive

Hematologic

Solid Tumors

The studies listed below are actively recruiting trials that were added to the National Cancer Institute’s list of U.S. clinical trials in the 30 days before August 17, 2011. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials/search, and enter the protocol ID.

Protocol Type

Age

Protocol ID

Trial Sites

Pazopanib Hydrochloride and Anastrozole Before Surgery in Treating Patients With Stage II-III Estrogen Receptor-Positive Breast Cancer, Phase II

18 and older

11-0269-04

AZ

Efficacy and Safety of Multi-Instillations of Apaziquone in Patients With Non-Muscle Invasive Bladder Cancer, Phase III

18 and older

SPI-1011

ID

Erlotinib Plus ARQ 197 Versus Single Agent Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer, Phase II

18 and older

ARQ 197-218

MD

Carboplatin and Paclitaxel With or Without Vorinostat in Treating Patients With Advanced Non-Small Cell Lung Cancer, Phase II

18 and older

PHII-102

IL, PA

Stereotactic Body Radiotherapy With Concurrent Boost for Low- and Intermediate-Risk Prostate Cancer, Phase II

18 and older

511-03

CO

Randomized Trial of MRI-Mapped Dose-Escalated Salvage Radiotherapy Post-Prostatectomy: The MAPS Trial, Phase III

35 to 85

EPROST20101056

FL

Trial of Hypofractionated External Beam Image-Guided Highly Targeted Radiotherapy: The HEIGHT Trial (prostate), Phase III

35 to 85

EPROST20100635

FL

Interstitial Photodynamic Therapy With Temoporfin for Advanced Head and Neck Cancers, Phase II

18 to 95

UAMS IRB 114294

AR

Everolimus and Bevacizumab in Advanced Non-Clear Cell Renal Cell Carcinoma, Phase II

18 and older

10-226

NY

Dasatinib Added to Gemcitabine for Subjects With Locally-advanced Pancreatic Cancer, Phase II

18 and older

287-11-201

CA, FL, KS, MN, NM, TX

Trial of ICM With or Without AZD2281 (Olaparib) in Patients With Advanced Pancreatic Cancer, Phase I/II

18 and older

J1070

MD

Study of Cixutumumab in Patients With Metastatic Uveal Melanoma, Phase II

17 and older

MDA-2010-0451

TX

Study of Akt Inhibitor MK2206 in Patients With Advanced Refractory Biliary Cancer, Phase II

18 and older

OSU-10104

CA, GA, NC, OH, TX

Post T-plant Infusion of Allogeneic Cytokine Induced Killer Cells as Consolidate Therapy in Myelodysplastic Syndromes/Myeloproliferative Disorders, Phase II

50 and older

SU-042020105724

CA

Carfilzomib, Lenalidomide and Dexamethasone in New Multiple Myeloma Patients, Phase II

18 and older

110221

MD

Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy, Phase II

18 and older

11-040

NY

MLN8237 in Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma Treated With Rituximab & Vincristine, Phase I/II

18 and older

C14011

AZ

MLN4924 Compared With MLN4924 Plus Chemotherapy for Large B-cell Lymphoma, Phase I

18 and older

110216

MD

Safety and Efficacy of ALD518 for Reducing Oral Mucositis in Head and Neck Cancer Subjects, Phase II

18 and older

ALD518-CLIN-009

NM, TX

Optimal Type of Aerobic Training in Breast Cancer, Phase I/II

21 to 90

Pro00022294

NC

Buffered Lidocaine for Loop Electrosurgical Excision Procedures (LEEPs) Pain, Phase III

18 and over

201104269

MO

Nuvigil or Placebo in Newly Diagnosed Malignant Glioma (fatigue), Phase II

18 and older

MCC-16233

FL

VOGL, NY continued from page 14 

to prove that the assumption of efficacy I have made in this editorial is correct.

Patients with gastric cancer are important—they deserve our efforts to get them the best surgical care as well as the most effective and least toxic adjuvant chemotherapy and irradiation.

References 1. Bang Y, Kim W, Yang H, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer: Results of the phase III CLASSIC trial.

J Clin Oncol. 2011;29(suppl). Abstract LBA4002.

2. Songun I, Putter H, Kranenbarg EM, et al.

Surgical treatment of gastric cancer: 15-year follow-up results of the randomized nationwide Dutch D1D2 trial. Lancet Oncol.

2010;11:439-449, PMID: 20409751.

3. Sasako M, Sano T, Yamamoto S, et al. D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. NEJM. 2008;359(5):453-462, PMID: 18669424.

4. Wu CW, Hsiung CA, Lo SS, et al. Nodal dissection for patients with gastric cancer: a randomised controlled trial. Lancet Oncol.

2006;7:309-315, PMID: 16574546. (Note: The study authors refer to D2 resection as D3.)

5. McCulloch P, Niita ME, Kazi H, et al. Gastrectomy with extended lymphadenectomy for primary treatment of gastric cancer. Br J Surg. 2005;92:5-13, PMID: 15635680.

6. Degiuli M, Sasako M, Ponti A, et al. Morbidity and mortality in the Italian Gastric Cancer Study Group randomized clinical trial of D1 versus D2 resection for gastric cancer. Br J Surg. 2010;97:643-649, PMID: 20186890.

7. Degiuli M, Sasako M, Ponti A, et al. Survival results of a multicentre Phase II study to evaluate D2 gastrectomy for gastric cancer. Br J Cancer. 2004;90:1727-1732, PMID: 15150592.

8. MacDonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345:725-730, PMID: 11547741.

9. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11-20, PMID: 16822992.

10. Cuschieri A, Fayers P, Fielding J, et al. Postoperative morbidity and mortality after D1 and D2 resections for gastric cancer: preliminary results of the MRC randomised controlled surgical trial. The Surgical Cooperative Group. Lancet. 1996; 347:995-999, PMID: 8606613.

11. Fuchs CS, Tepper JE, Niedzwiecki D et al.

Postoperative adjuvant chemoradiation for gastric or gastroesophageal junction (GEJ) adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (CRT) compared with bolus 5-FU/LV before and after CRT: Intergroup trial CALGB 80101. J Clin Oncol. 2011; 29 (suppl). Abtract 4003.

12. Sakuramoto S, Sasako M, Yamaguchi T, et al.

Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. NEJM. 2007;357:1810-1820, PMID: 17978289.

13. Cunningham D, Starling N, Rao S, et al.

Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36-46, PMID: 18172173.

14. Gastric (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) Group, Paoletti X, Oba K, et al.

Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis. JAMA. 2010;303:1729-1737, PMID: 20442389.

29

HEMATOLOGIC DISEASE

Clinical Oncology News • September 2011

AML

continued from page 1 

to the “patient’s choice with physician’s advice” arm (TC), which involved either supportive care or low-dose cytarabine daily for 10 consecutive days.

At the protocol-specified final analysis in 2009 (396 deaths, or 81.6%), there was a favorable trend toward increased overall survival among patients treated with DAC, who had a median survival of 7.7 months (95% confidence interval [CI], 6.2-9.2) compared with 5.0 months (95% CI, 4.3-6.3) in the TC arm, with a statistically nonsignificant P value of 0.10. A later unplanned analysis, performed in 2010 at 446 deaths (92%), showed the

‘We’ve considered offering this to patients for the last couple of years since it’s been available, but we couldn’t quantify for them what the benefit might be.’

—Mark Litzow, MD

Decitabine

10 8 6

Patient’s choice with physician’s advice

7.7

5.0

4 2 0

Figure 1. Comparison of OS in elderly patients with AML. AML, acute myeloid leukemia; OS, overall survival

same advantage in median internal medicine in the Divisurvival for DAC (7.7 vs. 5.0 sion of Hematology at Mayo months) but with a statisticalClinic in Rochester, Minn., ly significant P value (P=0.03) said the study provides some (Figure). of the first hard data to give For the secondary end point patients about the possible of complete remission (CR) benefits of this approach to plus CR in the absence of Scan for abstract treatment. “We’ve consid6504. total platelet recovery (CRp), ered offering this to patients See instructions, decitabine yielded a rate of for the last couple of years page 13.

17.8% for DAC compared with since it’s been available, but 7.8% for TC (P=0.001). we couldn’t quantify for them what the Adverse events in the DAC arm were benefit might be. While this trial isn’t consistent with the drug’s known profile a home run, it does offer some modest and consisted primarily of thrombocyto- encouragement.” penia, anemia, neutropenia and febrile Dr. Litzow noted that elderly patients neutropenia. with AML often tend to be in the poor- or These results give clinicians some- intermediate-risk cytogenetic subgroup, thing new to offer elderly patients as were the patients in this study. “When with AML, who have been a particu- I talk to patients in this situation, I tell larly challenging group to treat, said them, ‘The likelihood that we’re going to Harry Erba, MD, PhD, associate pro- cure you is not high,’” he said. “If they’re a fessor of internal medicine at the Uni- candidate for standard therapy, I explain versity of Michigan Health System, Ann that they will be tied to the medical cenArbor, and a reviewer for the ASCO oral ter and frequently in the hospital and abstract session on leukemia, myelodys- that, in some instances, we could shorten plasia and transplantation, at which the their lives with complications.” trial was presented.

Although the data on overall surviv“AML is a disease of older people, al improvement are not dramatic, they and they are often affected by the dis- are, at a bare minimum, comparable to ease and the treatments much more what can be achieved with intensive because of their age, comorbid illness- induction. “We’ve always said in AML es and their worse performance status,” that the only meaningful end point is Dr. Erba said. “Yet our treatment para- a complete remission, because that’s digm has remained the same for sever- what’s associated with improved sural decades, with no progress in improv- vival, and if you don’t get a complete ing overall survival among older AML remission, treatment probably isn’t patients. It remains around 10%. Under- worth it,” Dr. Litzow said. “But I think standably, there’s a reluctance to treat drugs like decitabine are making us patients with intense chemotherapy rethink this paradigm somewhat. We when mortality can be so high and out- often talk about quantity versus quality comes aren’t good.” of life, and it may be that decitabine can But the decision not to treat AML has offer some improvement in quality of drastic consequences. “Life expectancy life compared with intense chemotherwithout effective therapy is extremely apy, along with some potential increase short,” said Dr. Erba. “If we had thera- in quantity.” pies that older people could tolerate that Dr. Erba agreed. “As a clinician, having could lead to remission or prolong sur- a low-toxicity therapy that I can deliver vival, that would be important. And this to my patients in the outpatient setting is study does seem to indicate that we can very important,” he said. He wondered if improve responses and survival with a there were steps to take to improve outless toxic therapy.” comes, making them even better than Mark Litzow, MD, professor of the modest benefits seen in this trial.

50 40

Patients, %

DECITABINE

Median OS, mo

30

Decitabine Patient’s choice with physician’s advice

30 20

17.8

10

7.8

0

Figure 2. CR plus CR in the absence of total platelet recovery.

CR, complete remission

One possibility: a longer course of decitabine. At the 2009 ASCO meeting, Ohio State University researchers presented the results of a Phase II trial of decitabine in a similar group of patients; 14 of the 33 patients enrolled, or 44%, achieved CR. “The five-day schedule in the Phase III trial achieved an 18% complete remission rate,” Dr. Erba noted. “If five days led to a survival benefit with such a low remission rate, that suggests to me that there’s even more reason to use a 10-day schedule, because the complication rate remains remarkably low. The Ohio State group also did subset analysis that showed remissions in patients with complex karyotypes and a history of treatment-related AML, both poor-risk subgroups.”

The challenge, Dr. Erba said, is choosing the right patients for less intensive therapy. Not everyone who’s over 65 should be recommended for this approach. “If they’re over 65 but have molecular and cytogenetic markers associated with a higher chance of remission and maybe even cure, we wouldn’t use a regimen like this and would like to treat with standard chemotherapy.”

—Gina Shaw Drs. Thomas and Litzow reported no relevant disclosures. Dr. Erba is a promotional speaker for Celgene.

If you missed any recent issues of Clinical Oncology News, visit www.clinicaloncology.com.

CLINICAL ONCOLOGY NEWS

Clinical Oncology News • SEPTEMBER 2011

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