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Editor-in-Chief, James O. Armitage, MD

GI Cancers Symposium

Multidisciplinary Strategies Encouraged for Managing Early Esophageal Cancer

Cancer Prevention and Early Detection: A Global Perspective

By Caroline Helwick

session devoted to esophageal cancer at the 2011 Gastrointestinal Cancers Symposium, held January 20–22 in San Francisco, offered a look at emerging strategies from different perspectives. The main message was the need for a multidisciplinary approach that engages medical oncologists, surgeons, and radiation therapists from day 1.

Novel Approaches to Screening and Treatment ■■ Molecular profiling of Barrett’s esophagus will lead to biomarkers

for risk stratification. The cytosponge holds potential for population screening.

■■ Endoscopic resection of malignant lesions should be accomplished at high-volume centers by experienced surgeons.

■■ A multidisciplinary approach to esophageal cancer treatment is critical for optimal outcomes.

■■ Endoscopic resection for low-risk cancer is emerging as an alternative to surgical resection, with less morbidity.

Molecular Screening for Barrett’s Esophagus Increasing understanding of the molecular pathogenesis of Barrett’s esophagus is paving the

way for the use of molecular biomarkers to detect and risk-stratify Barrett’s esophagus, according to Rebecca Fitzgerald, MD, of Hutchison/MRC Research Center in Cambridge, UK. She and her colcontinued on page 6

Palliative Care

Study Finds Wide Variation in End-of-life Care By Ronald Piana

urveys indicate that most patients with cancer would prefer to spend their final days at home, yet according to a new paper by the Dartmouth Atlas Project, nearly one-third of Medicare patients with cancer die in hospitals. The report identified noteworthy variations in end-of-life care among regions and institutions, but more than statistical patterns, the findings offer insight into ways to improve the difficult postcurative conversations and decisions that are imminent for most patients with cancer.

Palliative Care Skills

n much the same way a surgeon reviews a case preoperatively and then cuts exactly the tissue that is necessary to achieve an excellent surgical outcome, the hospice and palliative medicine physician is trained in exactly how to approach a family in a variety of challenging advanced illness cases. The skilled practitioner in this setting moves through the case, driving highly precise conversations about goals of care, to ensure the quality outcome of well informed choices by families.

■

SEE PAGE 47

Use your smartphone to view the full report issued by the Dartmouth Atlas Project and discussed in this story, as well as ASCO’s new guidance on discussing end-of-life care with your patients.

To determine nationwide patterns of end-of-life care, the researchers examined the records of 235,821 Medicare patients who died of advanced cancer. The report, “Quality of End-of-Life Cancer Care in Medicare Beneficiaries,” used analysis methods developed precisely for terminally ill patients with cancer and other poor-prognosis Medicare beneficiaries. Although the differential in costs between hospital and hospice care was not addressed, in today’s era of health-care cost-containment the implications were unavoidable. For instance, the study found a significant proportion of the hospitalized patients received advanced life-support interventions such as endotracheal intubation, total parenteral feeding, and CPR. Moreover, the use of chemotherapy in the last 2 weeks of a cancer patient’s life exceeded 10% in some regions and academic medical centers.

By Eliezer Robinson, MD

t is well known that in some cases cancer can be prevented and, in others, early detection can reduce mortality. In Israel and worldwide, our aim as oncology professionals is to reduce cancer morbidity and mortality. Herein, I will describe the six groups of individuals and agents who I believe can and should be involved in this important process.

Ideally, each Healthy Individuals: individual should take charge of his or her health, assume responsibility for preventing cancers that are preventable, and adhere to screening programs that have proven to be of value. Healthy behaviors should include avoiding smoking and obesity, exercising, maintaining a balanced diet, and drinking alcohol in moderation. continued on page 2

Based in Haifa, Israel, Dr. Robinson is Past Chairman of ASCO’s International Affairs Committee; Professor of Oncology, Faculty of Medicine, Israel Institute of Technology, Haifa, Israel; Chairman of the Israel Cancer Association; Chairman of Israel’s National Oncology Council; and a member of The ASCO Post’s International Editorial Advisory Board.

MORE IN THIS ISSUE Oncology Meetings Coverage 2011 Gastrointestinal Cancers Symposium �� 1, 3, 6, 12 Breast Cancer �� 4, 40, 42 A Conversation with Anthony L. Zietman �� 13 Direct from ASCO �� 21 Hematology-Oncology �� 25, 29, 31 Letters to the Editor �� 47

continued on page 7

A Harborside Press Publication

The ASCO Post | MARCH 1, 2011

PAGE 2

Opinion

Cancer Prevention and Detection continued from page 1

Editorial Board James O. Armitage, MD Editor-in-Chief Elizabeth Reed, MD Deputy Editor Division of Hematology & Oncology University of Nebraska Medical Center Omaha, Nebraska ASSOCIATE EDITORS Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University William T. McGivney, PhD National Comprehensive Cancer Network James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Taussig Cancer Center at Cleveland Clinic Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

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Governments: The World Health Organization (WHO), the Union for International Cancer Control (UICC), the U.S. Surgeon General, and other officials and organizations have recommended that governments prepare national cancer control programs promoting primary and secondary prevention. It is the role of government to secure continuing improvement in the general health of the population by imposing legislative, regulatory, and environmental measures, as well as by launching screening and educational programs for the general public. Most governments (168 of the 192 WHO member states) have signed the WHO Framework Convention on Tobacco Control, although not all nations have implemented all of its recommendations. Enacted in 2005, this evidence-based treaty sets forth worldwide standards on the dangers of tobacco and offers guidelines for limiting its use. Governments should also be responsible for public health by minimizing occupational cancers and exposure to known carcinogens, and by preparing national vaccination programs for diseases such as hepatitis B and human papillomavirus. Primary Care Physicians: Primary care physicians should help educate patients that some cancers can be prevented by changing behaviors and that other cancers, if detected early, can be cured. In addition, these front-line doctors need to raise awareness of the importance of cancer screening and cancer symptoms. When seeing a patient with symptoms, the primary care clinician should be able to diagnose or rule out cancer. Health Insurance Providers: Health insurance programs have a distinct role in enabling access to and provision of cancer care. These programs also have a clear role in access to and provision of cancer screening, which can improve compliance rates. Four factors are responsible for the success of cancer screening: public policy, an organizational system, the practice setting, and clinician/ patient participation. Strategies targeted at each of these levels can im-

prove cancer screening. Using multiple strategies with synergistic results can be the most effective approach. Oncologists: As experts in cancer care, oncologists are afforded opportunities for involvement in community-based cancer prevention studies and community education, including efforts related to cancer prevention and screening. The target population can consist of cancer survivors, families, healthy groups, high-risk groups, general practitioners, health personnel, and/ or health authorities. In the past, ASCO members generally focused on treatment. In November 2002, ASCO established the Cancer Prevention Committee (CaPC), which is committed to supporting oncologists in risk assessment and prevention. In addition to introducing the behavior modification interventions described above, the oncologist attempts to interrupt the initiation and progression of cancer in survivors of the disease and other individuals at high risk. Cancer Societies: The role of the cancer society includes the following functions: ■■ To serve as a catalyst in ascertaining that effective prevention and early detection programs are fully and properly implemented by relevant authorities ■■ To disseminate reliable information and conduct education programs for the general population, high-risk groups, and patients with cancer ■■ To serve as a “watchdog” in efforts to improve treatment modalities and rehabilitation methods for patients, their families, and survivors ■■ To conduct advocacy and lobbying activities so that the comprehensive oncology network and its targets are placed high on the national agenda In summary, the reduction of cancer morbidity and mortality can be achieved through cooperation and coordination among the six agents described herein. Everybody, including these individuals and organizations, shall be responsible and do the utmost to accomplish the important mission of reducing suffering caused by cancer. It is feasible and should be done.

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ASCOPost.com | MARCH 1, 2011

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2011 Gastrointestinal Cancers Symposium Colorectal Cancer

Genomic Profile Test Again Validated for Colon Cancer Recurrence By Barbara Boughton

he second independent validation study to test the prognostic value of the gene signature test ColoPrint has found that it can effectively identify patients with localized stage II colon cancer at high risk of recurrence. Researchers also found that ColoPrint was the only factor able to indicate the risk for development of distant metastasis with statistical significance. The German study of 135 patients with stage II colon cancer, who were followed for a median of 97 months, was presented at the 2011 Gastrointestinal Cancers Symposium in San Francisco.1 ColoPrint is a microarray-based diagnostic test in which the genetic profiles of colorectal tumors are analyzed for expression of 18 colon cancer recurrence–specific genes. The expression profile of these recurrence-specific genes from a given tumor is compared to those from a reference population. Hundreds of “normal” genes are used to control the quality of each test. In this way, ColoPrint determines a score that indicates whether a patient’s tumor is at high or low risk for recurrence.

Study Specifics In the German study, investigators examined tumor tissue from patients who

underwent surgical resection for stage II colorectal cancer from 1987 to 2003 at the University Hospital in Munich. ColoPrint effectively identified patients at higher risk of recurrence, according to senior author Robert Rosenberg, MD, an Assistant Professor at the University

Robert Rosenberg, MD

Hospital of the Technical University in Munich, Germany. Among the 135 patients whose tumors were analyzed, 74% were characterized as low risk, and just 5% experienced a recurrence within 5 years or more. By contrast, 27% of patients in the study received a high-risk score, and 20% within this group experienced a recurrence after 5 years. The 5-year distant metastasis–free survival rate among patients characterized by ColoPrint as low risk was 94.9% and among those identi-

Expert Point of View

edical oncologist Jennifer Obel, MD, of the NorthShore University HealthSystem in Evanston, Illinois, said the German ColoPrint study was important because it helps establish the prognostic value of this gene signature test in stage II colon cancer. “The test could be used to help provide important prognostic information in stage II colon cancer along with traditional clinical and pathologic parameters,” said Dr. Obel, a member of the ASCO Communications Committee. Dr. Obel noted that one limitation of the ColoPrint test is that, like the Oncotype DX assay for colon cancer, it does not predict benefit from chemotheraJennifer Obel, MD py. “Yet both these assays do add further prognostic information. In this study, the ColoPrint results had greater weight—even above those of clinical and pathologic factors,” she said. Compared to the available assays for breast cancer—MammaPrint and Oncotype DX—the colon cancer gene tests have not been as readily incorporated into clinical practice, according to Dr. Obel. The ColoPrint test is not yet commercially available, however. “Yet genes do determine the biology of a tumor, so these assays give us further information about who is at risk for micrometastases,” she said. Dr. Obel noted that the ColoPrint gene signature test would be most useful in patients with stage II colon cancer who could tolerate chemotherapy and who had microsatellite stable tumors without other high-risk features.

■

ColoPrint to Predict Colon Cancer Recurrence ■■ The second validation study of ColoPrint, a gene signature test for localized stage II colon cancer, confirmed that it was effective at identifying patients at higher risk of recurrence.

■■ In the study of 135 stage II colon cancer patients, ColoPrint was

the only factor that significantly predicted development of distant metastasis over 5 years or more.

fied as high risk was 80.5%. The hazard ratio for distant metastases among highrisk patients was 4.1 when compared to low-risk patients (P = .009). “Our results confirm previous validation studies on ColoPrint. The test was able to predict the development of distant metastasis in stage II colon cancer patients and those at low risk of recurrence, which facilitates the identification of patients who may not need chemotherapy,” Dr. Rosenberg said.

‘Compelling Results’ When the researchers compared the utility of ColoPrint to relevant clinical and histopathologic factors such as age, localization of tumor, grade, tumor stage, MSI status, and number of assessed lymph nodes (as used in the ASCO risk recommendations), the gene signature test was the only prognostic feature significantly associated with development of distant metastasis. “We used the ASCO recommendations as our guideline, and while these factors indicate a difference in distant metastasis–free survival between patients assessed as having low vs high clinical risk, these parameters did not reach statistical significance,” Dr. Rosenberg said. When the ColoPrint test scores and assessments of ASCO predictive clinical parameters were compared in multivariate analysis, the results were discordant for 50% of patients in the study. “These are very compelling results,” Dr. Rosenberg said. “There is certainly overlap between ColoPrint and ASCO results, but still there’s a large discordance in identification of high-risk patients,” he said.

International Research ColoPrint was developed by researchers who searched the entire genome for genes that had the highest correlation to a relapse event. The training set was established by three Dutch institutes, led by the Netherlands Cancer In-

stitute, who worked with Agendia, the company that developed ColoPrint and the FDA-approved MammaPrint test for breast cancer recurrence. An initial clinical validation study on ColoPrint was conducted in Barcelona and recently published in the Journal of Clinical Oncology,2 and a third validation study is currently underway in the United States. The Prospective Analysis of Risk Stratification by ColoPrint study, which will enroll 600 patients with stage II colon cancer from U.S., Asian, and European medical centers, will examine the accuracy of ColoPrint test results in predicting risk of relapse over 3 years compared to clinical prognostic factors. “It will be interesting to see how we might be able to combine ColoPrint results with clinical factors to identify high-risk patients,” Dr. Rosenberg said. “Our aim was to validate the genomic profile developed to identify high-risk patients with stage II colon cancer using ColoPrint, because we believe this group is not very precisely defined,” he added.

■

Reference 1. Rosenberg R, Maak M, Simon I, et al: Independent validation of a prognostic genomic profile (ColoPrint) for stage II colon cancer patients. Gastrointestinal Cancers Symposium. Abstract 358. Presented January 22, 2011. 2. Salazar R, Roepman P, Capella G, et al: Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol 29(1):1724, 2011. Financial disclosure: No potential conflicts of interest were reported by Robert Rosenberg, MD, and Jennifer Obel, MD.

SEE PAGE 47

Use your smartphone to view abstract 358 from the Gastrointestinal Cancers Symposium.

The ASCO Post | MARCH 1, 2011

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Perspective Breast Cancer

Breast Cancer Experts Foresee Changes in 2011 By Caroline Helwick

he year ahead could be a provocative year in breast cancer treatment and research, according to several breast cancer specialists polled by The ASCO Post during the 2010 San Antonio Breast Cancer Symposium. We asked them to comment on emerging issues that should be on the oncologist’s radar in 2011.

ular level of this subtype of breast cancer. “We are trying to understand the heterogeneity of triple-negative breast cancer, and there are big questions,” said Lisa Carey, MD, of the University

are not just used for endocrine therapy, but they have become the backbone for novel targeted therapies as well, so they are increasingly important. We are trying to understand the pharmacolog-

New Pathways Delineated In 2011, scientists expect to better understand oncogenic pathways that are revealing themselves to be important in breast cancer, much of this knowledge coming as a result of the tissue banking that is essentially routine in the current clinical trial setting. “We have seen a saturation of a certain set of analyses for endocrine therapy and chemotherapy, and we are now looking for the next wave of targeted treatments to come along,” said Harold Burstein, MD, of Dana-Farber Cancer Institute, Boston. “Whether that will be inhibitors of PI3-kinase, mTOR, insulin growth factor receptor-1, or others… we can expect new pathways to open up this field again.” Drugs targeting these pathways are in early-phase development, and the hope is that associated biomarker development “will be provocative and get oncologists excited for the next generation of breast cancer agents.”

of North Carolina, Chapel Hill, who has conducted seminal research in this field. “Much effort is going into determining how these tumors will behave, even when stratified within a clinically identifiable subset. We know that some of these patients do very well, while others do not. Clearly, multiple factors affect sensitivity to existing drugs, and these are currently are not well understood. With triple-negative breast cancer, it seems the more we know, the more we discover what we don’t know. “Clinically, one of the main questions relates to the PARP inhibitor story,” Dr. Carey commented. (Dr. Carey discusses the PARP inhibitor story in an upcoming issue of The ASCO Post.)

Triple-negative Breast Cancer Demystified

Personalization of Endocrine Therapy

Triple-negative breast cancer has stymied clinicians and scientists for the past several years. Current efforts are directed at drilling down to the molec-

One of the problems with endocrine therapy is the development of side effects that many patients find intolerable. “The aromatase inhibitors

Harold Burstein, MD

The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0905. Copyright ©2011 by Harborside Press, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $225; Individual International: $275; Institutional Domestic: $275; Institutional International $350. Contact subscriptions@harborsidepress.com.

Lisa Carey, MD

Paul Goss, MD

ic differences within this class of agents that interact with patient factors to produce toxicities, especially arthralgias and bone metabolism changes,” said Paul Goss, MD, PhD, professor of medicine at Harvard Medical School, Boston, and Avon Foundation senior

We are trying to understand the heterogeneity of triple-negative breast cancer, and there are big questions scholar. Based on his own experience with the MA.27 trial, which has the largest tumor tissue repository among breast cancer trials, he noted that the

era of personalized endocrine therapy is near. For example, four genetic polymorphisms have recently been shown to predispose to musculoskeletal side effects. Such information about tumor signatures will allow oncologists to more safely prescribe these agents, he said. “Advances in personalized medicine will come out of MA.27,” Dr. Goss commented, “and you will see many papers on this in 2011 and beyond.” Also in 2011, the oncology community will learn whether exemestane can prevent breast cancer, added Dr. Goss, who is heading up the NCIC CTG MAP3 trial. The study will follow more than 4,500 postmenopausal women with mildly elevated breast cancer risk receiving exemestane or placebo. Investigators hope to see as much as a two-thirds reduction in the incidence of breast cancer with exemestane treatment and will present their findings early in 2011. “This study is a vehicle to see if aromatase inhibitors are as powerful in preventing breast cancer as we think they are,” he said.

Biomarkers and Drug Development: Not as Encouraging The need for biomarkers in breast cancer research has been a rallying cry among investigators for several years. According to David Miles, MD, of Mount Vernon Cancer Centre, Northwood, Middlesex, UK, who was instrumental in trials of bevacizumab (Avastin), finding useful biomarkers and applying them to drug development may be a more daunting challenge than many realize.

Correspondence: Address general inquiries to Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: cara@harborsidepress.com. Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; email: leslie@harborsidepress.com. Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language appears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.” Advertiser and advertising agency accept and assume liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed, and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO, and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards. The publisher is not liable for delays in delivery and/or non-delivery in the event of Act of God, action by any government or quasi-governmental entity, fire, flood, insurrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation interruption of any kind, work slow-down, or any condition beyond the control of the publisher affecting production or delivery in any manner.

Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

ASCOPost.com | MARCH 1, 2011

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Perspective

“We have global problems in drug development. We are now at a point where developing drugs and making money at the end of the process is almost impossible,” Dr. Miles suggested. There is huge variability in gene expression within tumor specimens, he said, “and when you multiply this by the many statistical problems, you end up questioning whether we can even do biomarker trials at all. Every trial now has its translational studies, and the expectation is that somehow these will produce meaningful results. But the bottom line is there are a lot of false-positives, which is a problem. It’s discouraging.” Drug development timelines also impede progress in the search for biomarkers. “Drug development is where we are hitting a wall. Even when we get an interesting result in terms of a potential biomarker, the only way to nail it is to prospectively validate the biomarker in an additional clinical trial. By then, you’ve done your registration trial, and the company may feel there is no point in investing in a program that will use up too much of the remaining patent life,” he pointed out. “We need to be more intelligent about the markers we expect to prove useful, and we must have more collaboration among research centers. We need big patient populations, and, therefore, we must study these questions on a global level.”

cer, one of which is drug resistance in cell lines. Through repeated selection pressure, Dr. Pegram and colleagues have generated cell lines that are resistant to trastuzumab, lapatinib (Tykerb), and the combination of the two, as well as to antibody-dependent cellular cytotoxicity with trastuzumab. They are sequencing all the nucleotides

in these cell lines. “We will characterize the resistant cell lines and find out whether the resistance is associated with new genetic alterations,” he said. Preliminary data are expected in 2011.

New Drugs Will Target Bone The ability to prevent skeletal complications, and even bone metastases,

does not stop with the bisphosphonates or denosumab (Prolia, Xgeva). New drugs in the pipeline will target different pathways in bone health and may provide additional options for patients with bone metastases or bone loss in the future, according to Alison Stopeck, MD, of the Arizona Cancer Center, Tucson, continued on page 6

Next-generation Sequencing Will Characterize Cancer Cells Knowledge of DNA sequences has become indispensable for basic cancer research, and rapid sequencing was instrumental in deciphering the human genome. Now, so-called next-generation sequencing is unraveling the molecular mysteries of breast cancer. “I am really excited about the advent and utility of next-generation sequence technology applied to breast cancer and tumor biology in general,” said Mark Pegram, MD, who spearheaded many of the early lab studies of trastuzumab (Herceptin). “At the University of Miami we are participating in the NCI’s Human Tumor Genome Atlas, a campaign that will sequence some 1,000 breast tumors over the next couple of years. This will enhance our knowledge base about molecular alterations in breast cancer and, most importantly, in the subtypes of breast cancer.” His lab is also using next-generation sequencing technology to interrogate other biologic processes in breast can-

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2011 Gastrointestinal Cancers Symposium Esophageal Cancer

Multidisciplinary Strategies continued from page 1

leagues developed a simple tool for molecular population-based screening, the “cytosponge.” This is a capsule containing an expandable spherical mesh attached to a string, which is swallowed and dissolves in the stomach over 3 to 5 minutes, releasing the sponge. As the sponge is pulled back it collects cells that are assayed to define their origin as gastric cardia, squamous esophagus, or Barrett’s columnar epithelium. In gene profiling of samples from Barrett’s esophagus compared with adjacent healthy tissues, they identified a potentially useful biomarker, trefoil factor 3 (TFF3). The sensitivity and specificity of this biomarker for detecting 2 cm or more of Barrett’s esophagus are 90% and 94%, respectively, which is comparable to mammography for breast cancer screening, Dr. Fitzgerald said. Studies are underway in 1,000 individuals to validate this approach.

Evolution in the Surgical Management The past decade has seen major improvements in technical approaches and surgical outcomes associated with esophageal resection for Barrett’s esophagus with high-grade dysplasia, and early and locoregional cancer of the esophagus, according to Donald E. Low, MD, of Virginia Mason Medical Center in Seattle. The most significant technical evolution has been the expansion of minimally invasive esophageal resection, which about one-quarter of surgeons have adopted for esophagectomy. “Outcomes have not suffered with the introduction of minimally invasive techniques, and further review may show significant advantages,” he said. “In general, SEE PAGE 47 esophageal resec-

Breast Cancer Experts continued from page 5

who spearheaded research on denosumab. Key compounds in this regard are Src inhibitors and drugs directed against the Wnt inhibitor Dickkopf-1 (DKK1). Anti-DKK1 agents suppress tumor-induced bone resorption in murine models of multiple myeloma, and therefore, are being evaluated for the treatment of bone resorption in other malignant bone diseases. “They will have different efficacy and toxicity profiles, and we may be able to use them

tion for cancer has earned a reputation for high mortality and morbidity, and poor postoperative quality of life,” he acknowledged, “though such outcomes are strongly linked to the volume of esophagectomies done by individual surgeons and medical centers.” While recent national audits have found surgical-related mortality to be 5% to 7%, dedicated, high-volume esophageal specialty centers produce

tion as the standard treatment of early, low-risk esophageal malignancy. “Surgery, in my eyes, is overtreatment and a method that should be reserved,” he said. “Endoscopic treatment is associated with low morbidity rate and zero mortality, excellent long-term survival, and preservation of quality of life,” he noted in his presentation. In a recent case-control study from Dr. Ell’s group

Left to right: Donald E. Lowe, MD; Christian Ell, MD; Rebecca Fitzgerald, MD.

perioperative mortality rates of under 2%, and enhanced-recovery programs are reducing length of stay, operative blood loss, pain, intensive-care use, and cost, he said. “Nonsurgical practitioners should align themselves with a dedicatedhighvolume surgical esophageal team with a recognized record of low mortality, moderate morbidity, and long-term commitment to follow-up and recovery, as well as participation in National Clinical trials,” Dr. Low suggested. “A multidisciplinary approach to staging and treatment, which will include presentation at Tumor Board, will ensure the best possible outcomes when treating all stages of esophageal cancer.”

Endoscopic Treatment Options Christian Ell, MD, of the Dr. Horst Schmidt Klinik in Wiesbaden, Germany, advocated endoscopic resec-

comparing endoscopic with surgical resection, disease-free survival and overall survival were similar for the two treatments. However, endoscopic resection was completely free of major complications, whereas the complication rate was 33% with surgery (P < .001).1 This has held true for over 1,000 patients treated in Wiesbaden, he added. Efficacy is also maintained with the endoscopic approach, he added. In a study of 349 patients with high-grade intraepithelial neoplasia or mucosal Barrett’s cancer, complete responses were observed in 96.6%.2 Survival at almost 5 years is approximately 80%, which is equivalent to the normal German population, he said. Dr. Ell noted there are many different endoscopic techniques that involve resection and ablation, “but ablation techniques are not appropriate for the

in synergy with our current agents to greatly improve bone protection,” Dr. Stopeck said.

Changing Times for Community Oncologists The next year will be a time of greater practice consolidation among oncologists, as physicians accept that “more and more practices cannot survive on declining reimbursement,” said Lee Schwartzberg, MD, of the West Clinic in Memphis, Tennessee, who has long been active in commu-

Lee Schwartzberg, MD

nity oncology affairs. “In 2011 we will see a huge move toward practices discussing ways to partner with hos-

primary treatment of neoplastic Barrett’s epithelium,” he stressed. “The technique of choice is the ‘suck and cut’ resection.”

Endoscopic Strategy for cN0 Superficial Carcinoma Japanese investigators reported success with a strategy in cN0 superficial lesions. It aims for local control with endoscopic submucosal dissection first (rather than the standard, surgical resection), followed by additional treatment based on the histologic examination.3 They reviewed 140 patients diagnosed with M3-SM2 squamous cell carcinoma of the esophagus who underwent endoscopic mucosal resection or endoscopic submucosal dissection. The 83 who received additional treatment based on histology (more surgery or chemoradiotherapy) were further studied. The two-step approach was not associated with serious complications (15%, mainly stenosis), and clinical outcomes were good. Fiveyear relapse-free survival was 100% for patients who had additional surgery and 88% for those receiving chemotherapy; 5-year overall survival rates were 100% and 76%, reported Toshiro Iizuka, MD, of Toranomon Hospital in Tokyo.

■

References 1. Pech O, et al: Annals of Surgery. In press. 2. Pech O, Behrens A, May A, et al: Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett’s oesophagus. Gut 57:1200-1206, 2008. 3. Iizuka T, Kikuchi D, Hoteya S, et al: Therapeutic strategy involving endoscopic resection for cN0 superficial carcinoma of the esophagus. Gastrointestinal Cancers Symposium. Abstract 1. Presented January 20, 2011.

pitals—either selling their practices outright to hospitals, or making comanagement arrangements or professional services agreements. All these activities will accelerate.” But other changes have a more positive ring: greater movement toward electronic technology and ultimately more measurement of quality parameters. This will benefit patients and will be viewed positively from an economic standpoint. “Payers and Medicare are increasingly looking for value-based oncology,” he said.

■

ASCOPost.com | MARCH 1, 2011

PAGE 7

Palliative Care

End-of-life Care continued from page 1

It is well documented that hospice care tends to be less expensive than hospitalization, partly because family and friends are active caregivers, reducing the cost of health-care professionals, and high-cost lifesaving technology is rarely employed in the hospice setting. The Dartmouth report begs the question of why this valuable, cost-effective end-of-life resource remains underutilized.

es involved in caring for terminally ill patients. Unfortunately many communities don’t have inpatient hospices, so we end up sending our patients to the hospital, just to make them feel better,” noted Dr. Schapira.

Lack of Supportive Infrastructure It is never easy to talk about death. Consequently, patients and doctors often play a chess game of avoidance, skirting the difficult but essential dialogue needed for patients with advanced cancer and their caregivers to transition to the best possible end-oflife care. But over the past decade, the cancer care community has sought ways to improve awareness and access to palliative and hospice care for oncology patients. Like any culture change, it is a slow, multipronged process.

Lidia Schapira, MD

“But it’s important not to forget: one tragic part of the end-of-life issue is that we often ask family members to give detailed and specific care for which they’re not prepared. So, considering the logistics of home care that often includes skin care, administering meds, minding nutrition, shifting patients in bed, sometimes even managing catheters, how can we expect caregivers to do this without proper support?”

Scope of the Findings ■■ About 24% of U.S. patients with cancer were admitted to ICUs at least once during their last month of life; this finding varied more than sevenfold across hospital referral regions.

■■ Percent of patients receiving chemotherapy in last 2 weeks of life varied

fourfold among regions; in some regions 10% received chemotherapy in the last 2 weeks of life.

■■ Nationally, about 55% of patients with cancer used hospice services during the last month of life.

Communication specialist Lidia Schapira, MD, Assistant Professor of Medicine, Harvard Medical School, told The ASCO Post that vulnerable patients with cancer struggling with existential issues could inadvertently misread their doctor, especially when the prognosis has not been delivered with crystal clarity. “If the oncologist leaves wiggle room for hope that there might be a life-extending intervention out there, some patients will choose being in the hospital, where the interventions are,” said Dr. Schapira. She stressed that during end-stage cancer, patients are often so sick that family members are simply not emotionally or physically equipped to care for them at home. “Most oncologists would prefer that their patients die at home surrounded by family. But we also understand the multiple challeng-

Guidelines, Better Communication Needed The Dartmouth report found that hospice care varied markedly across regions and hospitals. In at least 50 academic medical centers, less than half of the patients with advanced cancer received hospice services. In some hospitals, hospice referral occurred so close to the actual day of death that it did not provide the level of high-quality care that comes with earlier intervention. Regarding the results of the Dartmouth study, Cameron Muir, MD, Executive Vice President, Capital Hospice, Falls Church, Virginia, said, “This is really a societal issue that begins with our system’s payment incentives. There’s a disconnect between the wishes of patients with cancer toward endof-life care, and the dominant forces in

New ASCO Guidance Addresses Unmet Need in End-of-life Care

atients who have incurable cancer need to be informed about the full range of palliative care options that can provide comfort and dignity during the remainder of their lives. However, discussing end-of-life care is so difficult that it is often delayed, leaving patients and their caregivers in a fragile state of emotional limbo. Acknowledging this void, ASCO has issued a new physician guidance to ensure that quality-of-life discussions are a priority throughout the course of advanced cancer. According to ASCO CEO Allen S. Lichter, MD, delivering quality care for patients with terminal disease begins with honest communication. “This is not a 15-minute conversation, and it should not happen in the back of an ambulance on the way to the ICU,” stressed Dr. Lichter. He emphasized that ASCO realizes the challenges of initiating open and honest dialogue centered on mortality issues. To that end, along with the guidance, the Society has developed an easy-to-read booklet to help families broach difficult questions about their prognosis and options. The guidance and booklet are available on Cancer.Net. Watch for more coverage of this important and emerging issue in upcoming editions of The ASCO Post.

■

health-care reimbursement that stall the early initiation of palliative care.” Dr. Muir explained that the benefits of early palliative intervention go beyond symptom management. “Studies show that timely palliative care extends survival in patients with cancer and leads to significantly reduced costs in terms of hospital utilization in the ER and acute care ICU.” While Dartmouth data find nationwide hospice utilization at about 50%, Dr. Muir noted, “In Capital Hospice, we have clinical intervention of palliative care that leads to an 87% transition to hospice care at the right point in time.” He also dispelled the notion that a lack of communication is the main driver of underutilization of palliative care and hospice services. “This is not necessarily a failure of communication; it is more of a failure to reach a certain level of ‘surgical’ communication with the patient, in which you get better outcomes,” said Dr. Muir. He also stressed that the skills needed for the compassionate yet probing communication he refers to as “surgical” need to be taught and incorporated V ISIT

The ASCO Post W E B S I T E A T:

ASCOPost.com

into practice guidelines.

No Clear Pattern From the black and white statistics of the Dartmouth Atlas Project, patterns of U.S. medical culture and patient preference emerged. It is apparent that in many clinical settings, the difficulty of having serious conversations about end-of-life issues, and— at times—a failure to listen to the actual fears of patients and their families, plays a large role in the patient’s quality-of-life assessment and care. The report’s findings illustrated that even among the nation’s leading medical centers, there is no consistent pattern of care or evidence that treatment patterns follow patient preferences. Although the data are partly the expression of patients, culture, and demographics, they are also a reflection of the challenge ahead for the oncology community to better understand this complicated issue. “There are a host of reasons why patients with cancer, who have otherwise expressed a wish to die at home, spend their final days in a hospital,” Dr. Schapira concluded.

■

In the treatment of advanced RCC

When prognostic risk is high —let evidence chart the course

Important Safety Information • TORISEL is contraindicated in patients with bilirubin >1.5 x ULN and should

be used with caution when treating patients with mild hepatic impairment (bilirubin >1 - 1.5 x ULN or AST >ULN but bilirubin ≤ULN). If TORISEL must be given to patients with mild hepatic impairment, reduce the dose of TORISEL to 15 mg/week. In a phase 1 study, the overall frequency of ≥grade 3 adverse reactions and deaths, including deaths due to progressive disease, was greater in patients with baseline bilirubin >1.5 x ULN. • Hypersensitivity reactions manifested by symptoms, including, but not limited to anaphylaxis, dyspnea, flushing, and chest pain have been observed with TORISEL. • Serum glucose, serum cholesterol, and triglycerides should be tested before and during treatment with TORISEL. – The use of TORISEL is likely to result in hyperglycemia and hyperlipemia. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy and/or lipid-lowering agents, respectively. • The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.

• Cases of interstitial lung disease, some resulting in death, have occurred.

Some patients were asymptomatic and others presented with symptoms. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics. • Cases of fatal bowel perforation occurred with TORISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen. • Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL. • Due to abnormal wound healing, use TORISEL with caution in the perioperative period. • Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving TORISEL. • Live vaccinations and close contact with those who received live vaccines should be avoided.

Powerful 1st-line evidence— TORISEL significantly extended overall survival in poor-risk patients

Powerful evidence

Survival distribution function

Overall survival (OS)* results—TORISEL vs IFN 1

10.9 months with TORISEL

1.00

(95% CI, 8.6, 12.7) (n=209)

P =.0078†‡

0.50

Hazard Ratio=0.73 (95% CI, 0.58, 0.92)§

7.3 months with IFN (95% CI, 6.1, 8.8) (n=207)

0.00 0

Months to death from randomization Results from a phase 3, multicenter, 3-arm, randomized, open-label study conducted in 626 previously untreated patients with advanced RCC.1

• Studied 1st-line in patients with ≥3 of 6 preselected prognostic risk factors1II • Median duration of treatment was 17 weeks (range 1 - 126 weeks) for the TORISEL arm and 8 weeks (range 1 - 124 weeks) for the IFN arm1

TORISEL has a Category 1 NCCN recommendation specific to poor-risk patients as 1st-line treatment2

• Patients and their partners should be advised to avoid pregnancy throughout

treatment and for 3 months after TORISEL therapy has stopped. • The most common (incidence ≥30%) adverse reactions observed with TORISEL are: rash (47%), asthenia (51%), mucositis (41%), nausea (37%), edema (35%), and anorexia (32%). The most common laboratory abnormalities (incidence ≥30%) are anemia (94%), hyperglycemia (89%), hyperlipemia (87%), hypertriglyceridemia (83%), elevated alkaline phosphatase (68%), elevated serum creatinine (57%), lymphopenia (53%), hypophosphatemia (49%), thrombocytopenia (40%), elevated AST (38%), and leukopenia (32%). • Most common grades 3/4 adverse events and laboratory abnormalities included asthenia (11%), dyspnea (9%), hemoglobin decreased (20%), lymphocytes decreased (16%), glucose increased (16%), phosphorus decreased (18%), and triglycerides increased (44%). • Strong inducers of CYP3A4/5 (eg, dexamethasone, rifampin) and strong inhibitors of CYP3A4 (eg, ketoconazole, atazanavir) may decrease and increase concentrations of the major metabolite of TORISEL, respectively. If alternatives cannot be used, dose modifications of TORISEL are recommended.

• St. John’s Wort may decrease TORISEL plasma concentrations, and grapefruit

juice may increase plasma concentrations of the major metabolite of TORISEL, and therefore both should be avoided. • The combination of TORISEL and sunitinib resulted in dose-limiting toxicity (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requ q iringg hosp pitalization). requiring hospitalization). Please see the brief summary of the full Prescribing Information on the next page. RCC=renal cell carcinoma. IFN =interferon alpha. CI=confidence interval. NCCN=National Comprehensive Cancer Network. * Time from randomization to death.1 † A comparison is considered statistically significant if the P-value is <.0159 (O’Brien-Fleming boundary at 446 deaths).1 ‡ Based on log-rank test stratified by prior nephrectomy and region.1 § Based on Cox proportional hazard model stratified by prior nephrectomy and region.1 II Prognostic risk factors included: <1 year from time of initial RCC diagnosis to randomization, Karnofsky Performance Status of 60 or 70, hemoglobin <lower limit of normal, corrected calcium >10 mg/dL, lactate dehydrogenase >1.5 x upper limit of normal, >1 metastatic organ site. References: 1. TORISEL® Kit (temsirolimus) Prescribing Information, Wyeth Pharmaceuticals Inc. 2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: kidney cancer. V.1.2011.

TRS00216

Printed in USA/February 2011

TORISEL® Kit

[tor-a<sel] (temsirolimus) injection

% only FOR INTRAVENOUS ADMINISTRATION Brief Summary of Prescribing Information This product’s label may have been revised after this insert was used in production. See package insert for full Prescribing Information. For further product information and current package insert, please visit www.wyeth.com or call our Medical Communications Department toll-free at 1-800-934-5556. INDICATIONS AND USAGE TORISEL is indicated for the treatment of advanced renal cell carcinoma. CONTRAINDICATIONS TORISEL is contraindicated in patients with bilirubin >1.5 x ULN. WARNINGS AND PRECAUTIONS Hepatic Impairment The safety and pharmacokinetics of TORISEL were evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment. Patients with baseline bilirubin >1.5 x ULN experienced greater toxicity than patients with baseline bilirubin ≤1.5 x ULN when treated with TORISEL. The overall frequency of ≥grade 3 adverse reactions and deaths, including deaths due to progressive disease, were greater in patients with baseline bilirubin >1.5 x ULN. TORISEL is contraindicated in patients with bilirubin >1.5 x ULN due to increased risk of death. Use caution when treating patients with mild hepatic impairment. Concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated AST or bilirubin levels. If TORISEL must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5 x ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of TORISEL to 15 mg/week (see USE IN SPECIFIC POPULATIONS, Hepatic Impairment). Hypersensitivity Reactions Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, and chest pain have been observed with TORISEL. TORISEL should be used with caution in persons with known hypersensitivity to temsirolimus or its metabolites (including sirolimus), polysorbate 80, or to any other component (including the excipients) of TORISEL. An H1 antihistamine should be administered to patients before the start of the intravenous temsirolimus infusion. TORISEL should be used with caution in patients with known hypersensitivity to an antihistamine, or patients who cannot receive an antihistamine for other medical reasons. If a patient develops a hypersensitivity reaction during the TORISEL infusion, the infusion should be stopped and the patient should be observed for at least 30 to 60 minutes (depending on the severity of the reaction). At the discretion of the physician, treatment may be resumed with the administration of an H1-receptor antagonist (such as diphenhydramine), if not previously administered, and/or an H2-receptor antagonist (such as intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before restarting the TORISEL infusion. The infusion may then be resumed at a slower rate (up to 60 minutes). Hyperglycemia/Glucose Intolerance The use of TORISEL is likely to result in increases in serum glucose. In the phase 3 trial, 89% of patients receiving TORISEL had at least one elevated serum glucose while on treatment, and 26% of patients reported hyperglycemia as an adverse event. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy. Serum glucose should be tested before and during treatment with TORISEL. Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination. Infections The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections (see ADVERSE REACTIONS). Interstitial Lung Disease Cases of interstitial lung disease, some resulting in death, occurred in patients who received TORISEL. Some patients were asymptomatic with infiltrates detected on computed tomography scan or chest radiograph. Others presented with symptoms such as dyspnea, cough, hypoxia, and fever. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics, while some patients continued treatment without additional intervention. Patients should be advised to report promptly any new or worsening respiratory symptoms. Hyperlipemia The use of TORISEL is likely to result in increases in serum triglycerides and cholesterol. In the phase 3 trial, 87% of patients receiving TORISEL had at least one elevated serum cholesterol value and 83% had at least one elevated serum triglyceride value. This may require initiation, or increase in the dose, of lipid-lowering agents. Serum cholesterol and triglycerides should be tested before and during treatment with TORISEL. Bowel Perforation Cases of fatal bowel perforation occurred in patients who received TORISEL. These patients presented with fever, abdominal pain,

metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen. Patients should be advised to report promptly any new or worsening abdominal pain or blood in their stools. Renal Failure Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL. Some of these cases were not responsive to dialysis. Wound Healing Complications Use of TORISEL has been associated with abnormal wound healing. Therefore, caution should be exercised with the use of TORISEL in the perioperative period. Intracerebral Hemorrhage Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving TORISEL. Co-administration with Inducers or Inhibitors of CYP3A Metabolism Agents Inducing CYP3A Metabolism: Strong inducers of CYP3A4/5 such as dexamethasone, carbamazepine, phenytoin, phenobarbital, rifampin, rifabutin, and rifampicin may decrease exposure of the active metabolite, sirolimus. If alternative treatment cannot be administered, a dose adjustment should be considered. St. John’s Wort may decrease TORISEL plasma concentrations unpredictably. Patients receiving TORISEL should not take St. John’s Wort concomitantly.

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. In the Phase 3 randomized, open-label study of interferon alfa (IFN- ) alone, TORISEL alone, and TORISEL and IFN- , a total of 616 patients were treated. Two hundred patients received IFN- weekly, 208 received TORISEL 25 mg weekly, and 208 patients received a combination of TORISEL and IFN- weekly. Treatment with the combination of TORISEL 15 mg and IFN- was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN- alone. Table 1 shows the percentage of patients experiencing treatment emergent adverse reactions. Reactions reported in at least 10% of patients who received TORISEL 25 mg alone or IFN- alone are listed. Table 2 shows the percentage of patients experiencing selected laboratory abnormalities. Data for the same adverse reactions and laboratory abnormalities in the IFN- alone arm are shown for comparison. Table 1—Adverse Reactions Reported in at Least 10% of Patients Who Received 25 mg IV TORISEL or IFN- in the Randomized Trial TORISEL 25 mg n=208 Adverse Reaction

Agents Inhibiting CYP3A Metabolism: Strong CYP3A4 inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin may increase blood concentrations of the active metabolite sirolimus. If alternative treatments cannot be administered, a dose adjustment should be considered.

Grades 3&4* n (%)

All Grades* n (%)

Grades 3&4* n (%)

208 (100)

139 (67)

199 (100)

155 (78)

Asthenia

106 (51)

23 (11)

127 (64)

52 (26)

Edemaa

73 (35)

7 (3)

21 (11)

1 (1)

Pain

59 (28)

10 (5)

31 (16)

4 (2)

Pyrexia

50 (24)

1 (1)

99 (50)

7 (4)

Weight Loss

39 (19)

3 (1)

50 (25)

4 (2)

Headache

31 (15)

1 (1)

30 (15)

0 (0)

Chest Pain

34 (16)

2 (1)

18 (9)

2 (1)

17 (8)

1 (1)

59 (30)

3 (2)

General disorders

Chills

Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with TORISEL. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Gastrointestinal disorders

Pregnancy Pregnancy Category D Temsirolimus administered daily as an oral formulation caused embryo-fetal and intrauterine toxicities in rats and rabbits at human sub-therapeutic exposures. Embryo-fetal adverse effects in rats consisted of reduced fetal weight and reduced ossifications, and in rabbits included reduced fetal weight, omphalocele, bifurcated sternabrae, notched ribs, and incomplete ossifications.

Mucositisb

86 (41)

6 (3)

19 (10)

0 (0)

Anorexia

66 (32)

6 (3)

87 (44)

8 (4)

Nausea

77 (37)

5 (2)

82 (41)

9 (5)

Diarrhea

56 (27)

3 (1)

40 (20)

4 (2)

Abdominal Pain

44 (21) 42 (20)

34 (17) 36 (18)

3 (2)

Constipation

9 (4) 0 (0)

Vomiting

40 (19)

4 (2)

57 (29)

5 (3)

Infectionsc

42 (20)

6 (3)

19 (10)

4 (2)

Urinary tract infection d

31 (15)

3 (1)

24 (12)

3 (2)

Pharyngitis

25 (12)

0 (0)

3 (2)

0 (0)

Rhinitis

20 (10)

0 (0)

4 (2)

0 (0)

28 (14)

7 (4)

1 (1)

Infections

In rats, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of 2.7 mg/m2/day (approximately 0.04-fold the AUC in cancer patients at the human recommended dose). In rabbits, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of ≥7.2 mg/m2/day (approximately 0.12-fold the AUC in cancer patients at the recommended human dose). Women of childbearing potential should be advised to avoid becoming pregnant throughout treatment and for 3 months after TORISEL therapy has stopped. Temsirolimus can cause fetal harm when administered to a pregnant woman. 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.

Musculoskeletal and connective tissue disorders Back Pain

41 (20)

Arthralgia

37 (18)

2 (1)

29 (15)

2 (1)

16 (8)

1 (1)

29 (15)

2 (1)

Myalgia

6 (3)

Respiratory, thoracic and mediastinal disorders

Men should be counseled regarding the effects of TORISEL on the fetus and sperm prior to starting treatment. Men with partners of childbearing potential should use reliable contraception throughout treatment and are recommended to continue this for 3 months after the last dose of TORISEL.

Dyspnea

58 (28)

18 (9)

48 (24)

11 (6)

Cough

53 (26)

2 (1)

29 (15)

0 (0)

Epistaxis

25 (12)

0 (0)

7 (4)

0 (0)

Skin and subcutaneous tissue disorders

Monitoring Laboratory Tests In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every two weeks. Laboratory monitoring for patients receiving TORISEL may need to be performed more or less frequently at the physician’s discretion. ADVERSE REACTIONS The following serious adverse reactions have been associated with TORISEL in clinical trials and are discussed in greater detail in other sections of the label (see WARNINGS AND PRECAUTIONS).

The most common (≥30%) adverse reactions observed with TORISEL are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common (≥30%) laboratory abnormalities observed with TORISEL are anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia.

All Grades* n (%)

Any

Concomitant use of TORISEL with sunitinib The combination of TORISEL and sunitinib resulted in dose-limiting toxicity. Dose-limiting toxicities (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization) were observed in two out of three patients treated in the first cohort of a phase 1 study at doses of TORISEL 15 mg IV per week and sunitinib 25 mg oral per day (Days 1-28 followed by a 2-week rest).

Hypersensitivity Reactions Hyperglycemia/Glucose Intolerance Interstitial Lung Disease Hyperlipemia Bowel Perforation Renal Failure

IFN- n=200

Rash e

97 (47)

10 (5)

14 (7)

0 (0)

Pruritus

40 (19)

1 (1)

16 (8)

0 (0)

Nail Disorder

28 (14)

0 (0)

1 (1)

0 (0)

Dry Skin

22 (11)

1 (1)

14 (7)

0 (0)

Acne

21 (10)

0 (0)

2 (1)

0 (0) 0 (0)

Nervous system disorders Dysgeusiaf

41 (20)

0 (0)

17 (9)

Insomnia

24 (12)

1 (1)

30 (15)

0 (0)

9 (4)

0 (0)

27 (14)

4 (2)

Depression

* Common Toxicity Criteria for Adverse Events (CTCAE), Version 3.0. a

Includes edema, facial edema, and peripheral edema

b Includes

aphthous stomatitis, glossitis, mouth ulceration, mucositis, and stomatitis

Includes infections not otherwise specified (NOS) and the following infections that occurred infrequently as distinct entities: abscess, bronchitis, cellulitis, herpes simplex, and herpes zoster

d Includes cystitis, dysuria, hematuria, urinary frequency, and urinary

tract infection

Includes eczema, exfoliative dermatitis, maculopapular rash, pruritic rash, pustular rash, rash (NOS), and vesiculobullous rash

Includes taste loss and taste perversion

The following selected adverse reactions were reported less frequently (<10%). Gastrointestinal Disorders – Fatal bowel perforation occurred in 1 patient (1%). Eye Disorders – Conjunctivitis (including lacrimation disorder) occurred in 15 patients (7%). Immune System – Allergic/Hypersensitivity reactions occurred in 18 patients (9%). Angioneurotic edema-type reactions have been observed in some patients who received TORISEL and ACE inhibitors concomitantly. Infections – Pneumonia occurred in 17 patients (8%); upper respiratory tract infection occurred in 14 patients (7%). General Disorders and Administration Site Conditions – Impaired wound healing occurred in 3 patients (1%). Respiratory, Thoracic and Mediastinal Disorders – Interstitial lung disease occurred in 5 patients (2%), including rare fatalities. Vascular – Hypertension occurred in 14 patients (7%); venous thromboembolism (including deep vein thrombosis and pulmonary embolus) occurred in 5 patients (2%); thrombophlebitis occurred in 2 patients (1%). Table 2—Incidence of Selected Laboratory Abnormalities in Patients Who Received 25 mg IV TORISEL or IFN- in the Randomized Trial TORISEL 25 mg n=208 Laboratory Abnormality

IFN- n=200

All Grades* n (%)

Grades 3&4* n (%)

All Grades* n (%)

Grades 3&4* n (%)

208 (100)

162 (78)

195 (98)

144 (72)

Hemoglobin Decreased

195 (94)

41 (20)

180 (90)

43 (22)

Lymphocytes Decreased**

110 (53)

33 (16)

106 (53)

48 (24)

Neutrophils Decreased**

39 (19)

10 (5)

58 (29)

19 (10)

Platelets Decreased

84 (40)

3 (1)

51 (26)

0 (0)

Leukocytes Decreased

67 (32)

1 (1)

93 (47)

11 (6)

Alkaline Phosphatase Increased

141 (68)

7 (3)

111 (56)

13 (7)

AST Increased

79 (38)

5 (2)

103 (52)

14 (7)

Creatinine Increased

119 (57)

7 (3)

97 (49)

Glucose Increased

186 (89)

33 (16)

Phosphorus Decreased

102 (49)

Any Hematology

Agents Inhibiting CYP3A Metabolism Co-administration of TORISEL with ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on temsirolimus Cmax or AUC; however, sirolimus AUC increased 3.1-fold, and Cmax increased 2.2fold compared to TORISEL alone. If alternative treatment cannot be administered, a dose adjustment should be considered. (see Dosage and Administration in full Prescribing Information). Interactions with Drugs Metabolized by CYP2D6 The concentration of desipramine, a CYP2D6 substrate, was unaffected when 25 mg of TORISEL was co-administered. No clinically significant effect is anticipated when temsirolimus is co-administered with agents that are metabolized by CYP2D6 or CYP3A4. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D (see WARNINGS AND PRECAUTIONS, Pregnancy). Nursing Mothers It is not known whether TORISEL is excreted into human milk, and due to the potential for tumorigenicity shown for sirolimus (active metabolite of TORISEL) in animal studies, a decision should be made whether to discontinue nursing or discontinue TORISEL, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of TORISEL in pediatric patients have not been established. Geriatric Use Clinical studies of TORISEL did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Renal Impairment No clinical studies were conducted with TORISEL in patients with decreased renal function. Less than 5% of total radioactivity was excreted in the urine following a 25 mg intravenous dose of [14C]labeled temsirolimus in healthy subjects. Renal impairment is not expected to markedly influence drug exposure, and no dosage adjustment of TORISEL is recommended in patients with renal impairment. TORISEL has not been studied in patients undergoing hemodialysis. Hepatic Impairment TORISEL was evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment as defined by AST and bilirubin levels and patients with liver transplant (Table 3). Table 3—Adverse Reactions in Patients With Advanced Malignancies Plus Normal or Impaired Hepatic Function Hepatic Function*

TORISEL Dose Range

Adverse Reactions Grade ≥ 3** n (%)

Death*** n (%)

Normal (n=25)

25 – 175

20 (80.0)

2 (8.0)

Mild (n=39)

10 – 25

32 (82.1)

5 (12.8)

2 (1)

Moderate (n=20)

10 – 25

19 (95.0)

8 (40.0)

128 (64)

6 (3)

Severe (n=24)

7.5 – 15

23 (95.8)

13 (54.2)

38 (18)

61 (31)

17 (9)

1 (50.0)

0 (0)

16 (8)

2 (1)

25 (13)

4 (2)

Total Cholesterol Increased

181 (87)

5 (2)

95 (48)

2 (1)

Triglycerides Increased

173 (83)

92 (44)

144 (72)

69 (35)

43 (21)

11 (5)

15 (8)

0 (0)

Chemistry

Total Bilirubin Increased

Potassium Decreased

* NCI CTC version 3.0 ** Grade 1 toxicity may be under-reported for lymphocytes and neutrophils. DRUG INTERACTIONS Agents Inducing CYP3A Metabolism Co-administration of TORISEL with rifampin, a potent CYP3A4/5 inducer, had no significant effect on temsirolimus Cmax (maximum concentration) and AUC (area under the concentration versus the time curve) after intravenous administration, but decreased sirolimus Cmax by 65% and AUC by 56% compared to TORISEL treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered (see Dosage and Administration in full Prescribing Information).

TRS000431A

Liver Transplant (n=2)

* Hepatic Function Groups: normal = bilirubin and AST ≤ULN; mild = bilirubin >1 – 1.5 x ULN or AST >ULN but bilirubin ≤ULN; moderate = bilirubin >1.5 – 3 x ULN; severe = bilirubin >3 x ULN; liver transplant = any bilirubin and AST. ** Common Terminology Criteria for Adverse Events, version 3.0, including all causality. *** Includes deaths due to progressive disease and adverse reactions. Because there is a need for dosage adjustment based upon hepatic function, assessment of AST and bilirubin levels is recommended before initiation of TORISEL and periodically thereafter (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Hepatic Impairment). OVERDOSAGE There is no specific treatment for TORISEL intravenous overdose. TORISEL has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m2. The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of TORISEL greater than 25 mg. This brief summary is based on TORISEL Prescribing Information W10524C010 ET01, revised 09/10. © 2010, Wyeth Pharmaceuticals Inc., Philadelphia, PA 19101

Printed in USA/January 2011

The ASCO Post | MARCH 1, 2011

PAGE 12

2011 Gastrointestinal Cancers Symposium Important News Briefs By Caroline Helwick

s always, the recent 2011 Gastrointestinal Cancers Symposium in San Francisco offered more research news than any one publication could present. The following are capsule summaries of some of the most interesting findings.

Postsurgical ‘Wait Time’ The time interval between surgery and adjuvant chemotherapy for colorectal cancer does matter, according to a meta-analysis performed at Queen’s University Cancer Research Institute in Canada (abstract 364). Based on a meta-analysis of nine studies involving 14,357 patients, for every 4 weeks of postsurgical “wait time,” mortality risk was increased by more than 12%. “This means that for a patient fit to initiate chemotherapy 4 weeks after surgery, if he is treated instead at 8 weeks he has a 12% increased mortality risk, which becomes a 25% increased risk if he is treated at 12 weeks,” said Jim Biagi, MD.

HGF and IGF-IR Pathway Inhibitors Promising efficacy was shown by a Use your smartphone to view original abstracts from the Gastrointestinal SEE PAGE 47 Cancers Symposium, including those discussed in this article.

hepatocyte growth factor (HGF) inhibitor when combined with panitumumab (Vectibix) in patients with metastatic colorectal cancer in an international randomized phase I/II trial (abstract 366). The study in 142 patients evaluated the HGF inhibitor rilotumumab (AMG 102) as well as an antagonist of insulin growth factor type 1 receptor (IGF-1R)

Jim Biagi, MD

Neoadjuvant Regimen for Pancreatic Cancer Neoadjuvant therapy with fulldose gemcitabine, oxaliplatin, and radiation proved feasible and safe in a phase II multi-institutional study of 68 patients with localized pancreatic cancer whose tumors were resectable (n = 24) or borderline resect-

Eric Van Cutsem, MD

ganitumumab (AMG 479). The HGF and IGF-1R pathways are thought to be interdependent of the epidermal growth factor receptor pathway. Thus, there is a rationale for combining them with panitumumab, explained Eric Van Cutsem, MD, of University Hospital Gasthuisberg, Leuven, Belgium. The rilotumumab/panitumumab combination was promising, as responses were observed in 31% of that arm, compared with 22% receiving panitumumab plus ganitumuab and 21% receiving only panitumumab. Median progression-free survival was 5.2 months with rilotumumab/panitumumab, 5.3 months with the ganitumumab combination, and 3.7 months with panitumumab alone.

Edward Kim, MD

able (n = 44) (abstract 239). “This neoadjuvant regimen achieved a high percentage of R0 resections in both groups,” reported Edward J. Kim, MD, PhD, of the University of Michigan. Patients were treated with two 28-day cycles of gemcitabine (1 g/ m2 over 30 min on days 1, 8, 15) and oxaliplatin (85 mg/m2 on days 1, 15) with radiotherapy during cycle 1 (30 Gy in 2-Gy fractions). After treatment, in those undergoing tumor removal, 82% of patients achieved R0 resections and 18% achieved R1. The 1-year disease-free survival rate was 41%. Median overall survival was 31 months for resectable patients and 21 months for borderline

Inside this issue of The ASCO Post ■■ Coverage of the 2011 Gastrointestinal Cancers Symposium  see pages 1, 3, 6, 12 ■■ Dr. Anthony Zietman discusses the need for proof of therapeutic value and the issue of overutilization of fee-for-service resources see page 13 ■■ Important breast cancer news, including data from the 33rd Annual San Antonio Breast Cancer Symposium see pages 4, 40, 42 ■■ Patient’s Corner: Living with multiple myeloma see page 29 ■■ Management of patients scheduled for cancer surgery at risk for alcohol withdrawal see page 35 ■■ Radioactive treatment for thyroid cancer and reducing the chance of radiation risks to others see page 44

resectable patients. “In borderline resectable patients, intensification of radiation may further increase R0 resection rates,” he added.

Lanreotide for Vomiting The somatostatin analog lanreotide (Somatuline) reduced the frequency of vomiting in 80 patients with malignant small bowel obstruction, in a multicenter French study (abstract 242). “We showed that lanreotide may reduce the frequency of vomiting and allow the removal of nasogastric tubes, which makes hospital discharge possible,” said Pascale Mariani, MD, of the Institut Curie in Paris. The study compared lanreotide microparticles (30 mg) to placebo in patients experiencing at least two vomiting episodes a day or with nasogastric tubes. In the perprotocol analysis (patients received at least one assigned treatment), responses (≤ 1 vomiting episode per day for 3 consecutive days or no recurrence of vomiting after nasogastric tube removal for 3 consecutive days) were observed in 57.7% of patients receiving lanreotide vs 30.4% of those receiving placebo, for an odds ratio of 3.599 favoring lanreotide (P = .0455). Vomiting frequency was reduced by 2.3 episodes by day 7 with lanreotide and by 1.3 episodes with placebo (P = .4510). Well-being was significantly improved in the lanreotide arm, while it was diminished in the placebo arm.

■

ASCOPost.com | MARCH 1, 2011

PAGE 13

Expert’s Corner

A Conversation with Anthony L. Zietman, MD The need for proof of therapeutic value By Ronald Piana

Anthony L. Zietman, MD

Anthony L. Zietman, MD, Professor of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, recently spoke with The ASCO Post about a growing trend in health care that rewards the application of technology ahead of evidence. In addition, Dr. Zietman, President of the American Society for Radiation Oncology (ASTRO), elucidated the meaning of Conscience-based Medicine in the Age of Temptation, following the presidential address to attendees at the 52nd ASTRO Annual Meeting.

Refocusing Practice The evocative title of your ASTRO presidential address on “Consciencebased medicine in the Age of Temptation” seems to offer up a challenge to the oncology community. Please describe the presentation’s salient points. Everyone knows that significant change in our health-care system is coming. We feel the rumbling of an earthquake but none of us know exactly what our world will look like after the quake hits. One thing, however, is clear—overutilization of fee-for-service resources is a huge problem in American health care and is a major target for health-care reformers. Put simply, overutilization means too much care, and that is as bad for our patients as too little care. We are going to have to kick the tires of what we do and ask what value do our treatments really bring to patients. At ASTRO, I was attempting to help radiation oncologists refocus their approach to practice—to think not only about bringing in new treatments but also winnowing out of redundant treatment of limited value. I used prostate cancer treatment as an exemplar of what’s good and what’s bad in modern

radiation oncology. The good news in prostate cancer is that we’ve done some fabulous randomized controlled trials in advanced malignancy and we have really moved the ball forward in what was previously incurable disease. But the problematic news is that most U.S. patients present with low-risk disease and many of these men have very little to gain from treatment, yet almost all are treated. Patients want treatment, especially after hearing the terrifying word cancer. Doctors are programmed to treat, trained to treat, paid to treat. Many men with low-risk disease could or should be managed with active surveillance, providing treatment down the line should their cancer progress. That rarely happens in the United States. In fact, despite the evidence, active surveillance is on the decline, not the rise, and one of the main reasons is that we’re not paid for that kind of care. That is likely to change and we must be prepared. We need to look to a future ideally when we’re paid for value. In the short term, it is more likely that we will be paid by a diagnosis; in other words, instead of being paid for treating the prostate cancer, we’ll be paid for managing the disease.

less than any other is nearly impossible. Impotence remains a problem because whether radiation is given by proton beam, IMRT, or brachytherapy, the nerves always receive the full dose, and it is hard to conceive of a mechanism that would make one superior to any other. Proton-beam centers are very costly to install, around $150 million. Some institutions have to take enormous loans and go to the brink of financial ruin to pay for this new device. There is no question that proton-beam therapy is very beneficial in selected clinical situations such as pediatric cancers, and certain brain and spine tumors. But those are all relatively rare and complex-to-treat cancers. If you want to amortize your $150 million investment, you need to treat a common disease, treat it simply and quickly, and crank the patients through. Naturally, prostate cancer fits the bill. Therein lies the problem. To cover their debts and generate profit, some proton centers abandon the firmer indications and concentrate exclusively on prostate cancer patients. Those centers that try to do right and treat the kids and complex spine tumors still need a huge supply of prostate cancer patients to stay afloat

Many men with low-risk disease could or should be managed with active surveillance, providing treatment down the line should their cancer progress. Proton-beam Therapy Prostate cancer advocates have touted proton-beam therapy as the treatment that is less likely to cause the two dreaded “I words”—incontinence and impotence. It’s a strong argument, is it valid? The proton-beam story exemplifies many of the problems with the American health-care system and the collision between our high-tech aspirations and our harsh economic reality, and it does so in an extreme way. We’ve studied protonbeam therapy over the past 2 decades, and contrary to the marketing, our data sadly do not suggest that proton therapy is less likely to produce impotence or cause incontinence in prostate cancer patients. I must add that radiation of any kind rarely causes incontinence, and so, proving that one technology produces

and balance the books. Elderly men with prostate cancer, who could well be left alone, are thus subsidizing the treatment of children. It is a bizarre arrangement and something of a trap—the ugly stepchild of our reimbursement system and our desire to have prestige technology in our institutions at any cost.

Reversing the Trend Toward Overtreatment You’ve spoken quite frankly about overtreatment of prostate cancer, especially in older men. How can we reverse this trend? Prostate cancer patients, particularly the elderly, have been the victims of a market free-for-all, and reversing that trend takes a concerted effort. If you simply look at the major Harvard hospitals, you’ll see many different practice

patterns for the management of low-risk prostate cancer. At Mass General, we do an awful lot of active surveillance; the majority of the others do substantially less. Why do we see these markedly different treatment patterns? Probably because Mass General has a multidisciplinary clinic in which the majority of new patients see a radiation oncologist, a surgeon, and a medical oncologist. We’re all together in the same room. We sort of hold each other’s hands to the flame of honesty. It is amazing how often the three specialties agree on a course of active surveillance. When the patient hears a unified decision from his three specialists, it carries weight, as opposed to having three separate consultations in which only one specialist might recommend active surveillance. Nine out of ten times, the patient goes with the majority opinion. Another problem, of course, is the “C word”—cancer—which sparks the overriding desire for treatment, even if there’s little benefit. We’ve actually debated, at a national level, changing the language of low-risk prostate cancer. “Idle tumor” is a term being used with more frequency. It is a loose acronym that stands for indolent tumor of epithelial origin and has a gentler sound than cancer.

Comparing Radiotherapies In this emerging era of comparative effectiveness research, do you feel that we should have trials comparing various radiotherapies? If a center actually believes they have a superior treatment, they can’t, in good conscience, do a randomization. However, I have considerable doubts about superiority and, together with the University of Pennsylvania, we are planning a randomized trial comparing protonbeam therapy against external-beam radiation in prostate cancer. I’m convinced that America needs proton therapy centers for certain clinical situations. The British reviewed this issue and concluded that two proton centers were required for their 60 million people. Similarly applied, we’d need 10 or 11 centers in the US, which is fine by me. I have no intention of using slow and lengthy trials to throw sand into the engine of technologic discovery. However, significant medical technologies need to continued on page 14

The ASCO Post | MARCH 1, 2011

PAGE 14

Expert’s Corner

Anthony L. Zietman continued from page 13

be tested through randomized controlled trials, or at least through comprehensive observational registries. America needs proton-beam therapy, but prostate cancer may not. Let’s gather the data, find out who we need to treat and who we don’t need to treat, and determine what additional value comes from the additional high cost of high technology. This could allow for a massive rationalization of the way we approach the disease. Alternatively, reimbursement reform that recognized and rewarded the complexity of pediatric proton radiotherapy, where the alternatives are poor, and disincentivized prostate treatment, where good alternatives exist, may help to fix the problem by refocusing our clinical effort on areas of need. Reimbursement reform that paid for patents being treated with new technology while on study would also be helpful. What I am keen to avoid is for the treatment of a disease to be dominated and distorted by hospital competition, aggressive marketing, and perverse financial incentives. That would be a tragic abuse of the health-care system and, one way or another, I think it will come to an end. We must be prepared for the evidence- and value-based future that will follow and help shape it. If we do not, our specialty and our technologies will simply be passed by.

radiation oncology is headed in this era of change? No one can deny that we live in an age of extraordinary scientific expansion that has brought incredible benefit to humanity. But now, faced with exponentially rising health-care costs, we’ve entered an era of recalibration. For the past de-

cade, practicing radiation oncology has been like driving a Ferrari at 140 mph down the freeway. Now we have to obey new rules of the road and slow down, or there’s going to be a wipeout. Change is coming, and I believe that U.S. health care will emerge with new organizational structures and a more evi-

dence-based system with fewer perverse incentives. Looking after cancer patients is sacred work, and to retain that privilege we must practice in a conscience-based way. If we do so, our specialty is going to be in great shape. It will be leaner for sure, but stronger, more diverse, and more satisfying than ever before.

■

For Locally or Regionally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)...

Select ERBITUX + RT

Looking Ahead Any last “big picture” thoughts on where

Contact

The ASCO Post Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 email: Editor@ASCOPost.com ASCOPost.com HarborsidePress.com

ERBITUX Indications ■ ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck ■ ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed

ERBITUX Boxed WARNINGS ■ Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions ■ Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

ASCOPost.com | MARCH 1, 2011

PAGE 15

FDA Update

Oncology Drug and Device News

Carfilzomib Receives Fast Track Designation

nyx Pharmaceuticals, Inc, announced that the FDA has granted Fast Track status for carfilzomib, a next-generation proteasome inhibitor

for the potential treatment of patients with relapsed and refractory multiple myeloma. The Fast Track designation process was developed by the FDA to

facilitate the development, and expedite the review of drugs to treat serious or life-threatening diseases and address unmet medical needs.

for Increased OVERALL SURVIVAL ERBITUX Is the Only Anti-EGFR MAb With Increased Overall Survival in Combination With RT Survival in Combination With RT*1,2 ERBITUX + RT (n=211)

RT alone (n=213)

Median overall survival 49.0 months

29.3 months

45%

19.7

month improvement

HR: 0.74; 95% CI: 0.57-0.97; P=0.03

3-year survival rate 55% P=0.05

22%

improvement†

EGFR=epidermal growth factor receptor; MAb=monoclonal antibody; RT=radiation therapy; HR=hazard ratio; CI=confidence interval. * A multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration of locoregional control. Secondary endpoints included overall survival.1,2 † Relative increase in improvement, from 45% to 55%; ([55-45]/45) x 100=22. Median follow-up=54 months.2

■ Primary endpoint: ERBITUX + RT (n=211) significantly improved median duration of locoregional control by 9.5 months (24.4 vs 14.9 months) vs RT alone (n=213) (log-rank P value=0.005; HR: 0.68 [95% CI: 0.52-0.89])1

ERBITUX Safety Information ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ ERBITUX Plus Radiation Therapy and Cisplatin: The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events ■ Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

Positive complete results from the phase IIb 003-A1 study evaluating single-agent carfilzomib in patients with relapsed and refractory

The ASCO Post | MARCH 1, 2011

PAGE 16

FDA Update

multiple myeloma were announced at the American Society of Hematology meeting in December 2010. Based on these results, Onyx has initiated a rolling submission of a New Drug Application (NDA) for potential accelerated approval of carfilzomib in the United States.

Through the Fast Track designation, Onyx is eligible to submit the carfilzomib NDA on a rolling basis, allowing Onyx to begin the NDA filing process immediately and giving the FDA an opportunity to review the completed sections of the registration application. Onyx intends to

complete its submission of the NDA for potential accelerated approval of carfilzomib in the United States as early as mid-2011. Carfilzomib was granted Orphan Drug designation by the FDA for the treatment of multiple myeloma in 2008.

First Diagnostic Radiology Application Approved for Mobile Devices A new mobile radiology application cleared by the FDA will allow physicians to view medical images on the iPhone and iPad manufactured by Apple Inc. The application

Important Safety Information Including Boxed WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions

Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last ERBITUX treatment — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed

Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects

ERBITUX Plus Radiation Therapy and Cisplatin ■ The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established — Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

ASCOPost.com | MARCH 1, 2011

PAGE 17

FDA Update

is the first cleared by the FDA for viewing images and making medical diagnoses based on CT, MRI, and nuclear medicine technology such as PET. It is not intended to replace full workstations and is indicated for use only when there is no access to a workstation.

Radiology images taken in the hospital or physician’s office are compressed for secure network transfer then sent to the appropriate portable wireless device via software called Mobile MIM. This software allows the physician to measure distance on the image and image intensity values

and display measurement lines, annotations, and regions of interest. In its evaluation, the FDA reviewed performance test results on various portable devices. These tests measured luminance, image quality (resolution), and noise in accordance with international standards

Electrolyte Depletion ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary

Late Radiation Toxicities ■ The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company; September 2010. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.

Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

© 2010 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company.

693US10AB12502

12/10

and guidelines. The FDA also reviewed results from demonstration studies with qualified radiologists under different lighting conditions. All participants agreed that the device was sufficient for diagnostic image interpretation under the recommended lighting conditions.

The ASCO Post | MARCH 1, 2011

PAGE 18

FDA Update

FDA Approves Generic Injection Hospira, Inc, announced that the FDA has approved Topotecan Injection, the first generic solution formulation of the oncology drug approved in the United States. The medication is a generic version of Hycamtin, which had 2010 U.S. sales of more than

$140 million. Hospira’s topotecan is indicated for treatment of chemotherapy-sensitive small cell lung cancer after failure of first-line chemotherapy. The solution formulation of topotecan, with a concentration of 4 mg/4 mL, is designed to improve caregiver convenience and safety.

IND Approved for Neuroprotective Agent CeNeRx BioPharma, Inc, announced FDA approval of its Investigational New Drug (IND) application and reported the first clinical results in humans for CXB909, a novel agent that has demonstrated utility in preclinical

eRbITUx eRbITUx®® (cetuximab) (cetuximab) injection, injection, for for intravenous intravenous infusion infusion Brief Brief Summary Summary of of Prescribing Prescribing Information. Information. For For complete complete prescribing prescribing information information consult consult official official package package insert. insert. WARNING: WARNING: seRIOUs seRIOUs INFUsION INFUsION ReACTIONs ReACTIONs and and CARDIOPULMONARY CARDIOPULMONARY ARResT ARResT Infusion Infusion Reactions: Reactions: Serious Serious infusion infusion reactions reactions occurred occurred with with the the administration administration of of Erbitux Erbitux in in approximately approximately 3% 3% of of patients patients in in clinical clinical trials, trials, with with fatal fatal outcome outcome reported reported in in less less than than 11 in in 1000. 1000. [See [See Warnings Warnings and and Precautions Precautions and and Adverse Adverse Reactions.] Reactions.] Immediately Immediately interrupt interrupt and and permanently permanently discontinue discontinue Erbitux Erbitux infusion infusion for for [See Warnings Warnings and and Precautions Precautions and and Dosage Dosage and and Administration Administration (2.4) (2.4) in in Full Full serious serious infusion infusion reactions. reactions. [See Prescribing Information.] Information.] Prescribing Cardiopulmonary Arrest: Arrest: Cardiopulmonary Cardiopulmonary arrest arrest and/or and/or sudden sudden death death occurred occurred in in 2% 2% of of 208 208 patients patients with with Cardiopulmonary squamous cell cell carcinoma carcinoma of of the the head head and and neck neck treated treated with with radiation radiation therapy therapy and and Erbitux. Erbitux. Closely Closely monitor monitor squamous [See serum serum electrolytes, electrolytes, including including serum serum magnesium, magnesium, potassium, potassium, and and calcium, calcium, during during and and after after Erbitux. Erbitux. [See Warnings and and Precautions.] Precautions.] Warnings INDICATIONs INDICATIONs AND AND UsAGe UsAGe squamous squamous Cell Cell Carcinoma Carcinoma of of the the Head Head and and Neck Neck (sCCHN) (sCCHN) ® ® Erbitux Erbitux (cetuximab) (cetuximab) isis indicated indicated in in combination combination with with radiation radiation therapy therapy for for the the initial initial treatment treatment of of locally locally or or Studies (14.1) (14.1) in in Full Full regionally regionally advanced advanced squamous squamous cell cell carcinoma carcinoma of of the the head head and and neck. neck. [See [See Clinical Clinical Studies Prescribing Prescribing Information.] Information.] Erbitux, Erbitux, as as aa single single agent, agent, isis indicated indicated for for the the treatment treatment of of patients patients with with recurrent recurrent or or metastatic metastatic squamous squamous cell cell carcinoma carcinoma of of the the head head and and neck neck for for whom whom prior prior platinum-based platinum-based therapy therapy has has failed. failed. [See [See Clinical Clinical Studies Studies (14.1) (14.1) in in Full Full Prescribing Prescribing Information.] Information.] Colorectal Colorectal Cancer Cancer Erbitux, Erbitux, as as aa single single agent, agent, isis indicated indicated for for the the treatment treatment of of epidermal epidermal growth growth factor factor receptor receptor (EGFR)-expressing (EGFR)-expressing metastatic metastatic colorectal colorectal cancer cancer after after failure failure of of both both irinotecanirinotecan- and and oxaliplatin-based oxaliplatin-based regimens. regimens. Erbitux, Erbitux, as as aa single single agent, agent, isis also also indicated indicated for for the the treatment treatment of of EGFR-expressing EGFR-expressing metastatic metastatic colorectal colorectal cancer cancer in in patients patients who who are are intolerant intolerant to to irinotecan-based irinotecan-based regimens. regimens. [See [See Clinical Clinical Studies Studies (14.2) (14.2) in in Full Full Prescribing Prescribing Information Information and and Warnings Warnings Precautions.] and and Precautions.] in combination combination with with irinotecan, irinotecan, isis indicated indicated for for the the treatment treatment of of EGFR-expressing EGFR-expressing metastatic metastatic colorectal colorectal Erbitux, Erbitux, in carcinoma carcinoma in in patients patients who who are are refractory refractory to to irinotecan-based irinotecan-based chemotherapy. chemotherapy. The The effectiveness effectiveness of of Erbitux Erbitux in in combination combination with with irinotecan irinotecan isis based based on on objective objective response response rates. rates. Currently, Currently, no no data data are are available available that that survival with with Erbitux Erbitux in in combination combination demonstrate demonstrate an an improvement improvement in in disease-related disease-related symptoms symptoms or or increased increased survival with with irinotecan irinotecan for for the the treatment treatment of of EGFR-expressing, EGFR-expressing, metastatic metastatic colorectal colorectal carcinoma. carcinoma. [See [See Clinical Clinical Studies Studies (14.2) (14.2) in in Full Full Prescribing Prescribing Information Information and and Warnings Warnings and and Precautions.] Precautions.] Retrospective Retrospective subset subset analyses analyses of of metastatic metastatic or or advanced advanced colorectal colorectal cancer cancer trials trials have have not not shown shown aa treatment treatment 13. Use Use of of Erbitux Erbitux isis not not benefit benefit for for Erbitux Erbitux in in patients patients whose whose tumors tumors had had KRAS KRAS mutations mutations in in codon codon 12 12 or or 13. recommended recommended for for the the treatment treatment of of colorectal colorectal cancer cancer with with these these mutations mutations [see [see Clinical Clinical Studies Studies (14.2) (14.2) and and Clinical Clinical Pharmacology Pharmacology (12.1) (12.1) in in Full Full Prescribing Prescribing Information]. Information]. CONTRAINDICATIONs CONTRAINDICATIONs None. None. WARNINGs WARNINGs AND AND PReCAUTIONs PReCAUTIONs Infusion Infusion Reactions Reactions Serious Serious infusion infusion reactions, reactions, requiring requiring medical medical intervention intervention and and immediate, immediate, permanent permanent discontinuation discontinuation of of Erbitux, Erbitux, included included rapid rapid onset onset of of airway airway obstruction obstruction (bronchospasm, (bronchospasm, stridor, stridor, hoarseness), hoarseness), hypotension, hypotension, shock, shock, loss loss of of consciousness, consciousness, myocardial myocardial infarction, infarction, and/or and/or cardiac cardiac arrest. arrest. Severe Severe (NCI (NCI CTC CTC Grades Grades 33 and and 4) 4) infusion infusion reactions reactions occurred occurred in in 2–5% 2–5% of of 1373 1373 patients patients in in clinical clinical trials, trials, with with fatal fatal outcome outcome in in 11 patient. patient. Approximately Approximately 90% 90% of of severe severe infusion infusion reactions reactions occurred occurred with with the the first first infusion infusion despite despite premedication premedication with with antihistamines. antihistamines. Monitor Monitor patients patients for for 11 hour hour following following Erbitux Erbitux infusions infusions in in aa setting setting with with resuscitation resuscitation equipment equipment and and other other agents agents to treat treat anaphylaxis anaphylaxis (eg, (eg, epinephrine, epinephrine, corticosteroids, corticosteroids, intravenous intravenous antihistamines, antihistamines, bronchodilators, bronchodilators, necessary necessary to and and oxygen). oxygen). Monitor Monitor longer longer to to confirm confirm resolution resolution of of the the event event in in patients patients requiring requiring treatment treatment for for infusion infusion reactions. reactions. infusion reactions. reactions. [See [See Boxed Boxed Immediately Immediately and and permanently permanently discontinue discontinue Erbitux Erbitux in in patients patients with with serious serious infusion Warning Warning and and Dosage Dosage and and Administration Administration (2.4) (2.4) in in Full Full Prescribing Prescribing Information.] Information.] Cardiopulmonary Cardiopulmonary Arrest Arrest Cardiopulmonary Cardiopulmonary arrest arrest and/or and/or sudden sudden death death occurred occurred in in 44 (2%) (2%) of of 208 208 patients patients treated treated with with radiation radiation therapy therapy and and Erbitux Erbitux as as compared compared to to none none of of 212 212 patients patients treated treated with with radiation radiation therapy therapy alone alone in in aa randomized, randomized, controlled controlled trial trial in in patients patients with with SCCHN. SCCHN. Three Three patients patients with with prior prior history history of of coronary coronary artery artery disease disease died died at at home, home, with with infarction as as the the presumed presumed cause cause of of death. death. One One of of these these patients patients had had arrhythmia arrhythmia and and one one had had myocardial myocardial infarction congestive congestive heart heart failure. failure. Death Death occurred occurred 27, 27, 32, 32, and and 43 43 days days after after the the last last dose dose of of Erbitux. Erbitux. One One patient patient with with no no prior prior history history of of coronary coronary artery artery disease disease died died one one day day after after the the last last dose dose of of Erbitux. Erbitux. Carefully Carefully consider consider use use of of combination with with radiation radiation therapy therapy in in head head and and neck neck cancer cancer patients patients with with aa history history of of coronary coronary artery artery Erbitux Erbitux in in combination congestive heart heart failure, failure, or or arrhythmias arrhythmias in in light light of of these these risks. risks. Closely Closely monitor monitor serum serum electrolytes, electrolytes, disease, disease, congestive including including serum serum magnesium, magnesium, potassium, potassium, and and calcium, calcium, during during and and after after Erbitux. Erbitux. [See [See Boxed Boxed Warning Warning and and Warnings Warnings and and Precautions.] Precautions.] Pulmonary Pulmonary Toxicity Toxicity Interstitial Interstitial lung lung disease disease (ILD), (ILD), including including 11 fatality, fatality, occurred occurred in in 44 of of 1570 1570 (<0.5%) (<0.5%) patients patients receiving receiving Erbitux Erbitux in in trials. Interrupt Interrupt Erbitux Erbitux for for acute acute onset onset or or worsening worsening of of pulmonary pulmonary symptoms. symptoms. Permanently Permanently discontinue discontinue clinical clinical trials. Erbitux Erbitux for for confirmed confirmed ILD. ILD. Dermatologic Dermatologic Toxicity Toxicity Dermatologic Dermatologic toxicities, toxicities, including including acneform acneform rash, rash, skin skin drying drying and and fissuring, fissuring, paronychial paronychial inflammation, inflammation, infectious infectious sequelae sequelae (for (for example example S. S. aureus aureus sepsis, sepsis, abscess abscess formation, formation, cellulitis, cellulitis, blepharitis, blepharitis, conjunctivitis, conjunctivitis, keratitis, keratitis, and hypertrichosis hypertrichosis occurred occurred in in patients patients receiving receiving Erbitux Erbitux therapy. therapy. Acneform Acneform rash rash occurred occurred in in 76–88% 76–88% cheilitis), cheilitis), and of of 1373 1373 patients patients receiving receiving Erbitux Erbitux in in clinical clinical trials. trials. Severe Severe acneform acneform rash rash occurred occurred in in 1–17% 1–17% of of patients. patients. Acneform Acneform rash rash usually usually developed developed within within the the first first two two weeks weeks of of therapy therapy and and resolved resolved in in aa majority majority of of the the patients patients although in in nearly nearly half, half, the the event event continued continued beyond beyond 28 28 days. days. Monitor Monitor patients patients after after cessation cessation of of treatment, treatment, although receiving receiving Erbitux Erbitux for for dermatologic dermatologic toxicities toxicities and and infectious infectious sequelae. sequelae. Instruct Instruct patients patients to to limit limit sun sun exposure exposure during during Erbitux Erbitux therapy. therapy. [See [See Dose Dose Modifications Modifications (2.4) (2.4) in in Full Full Prescribing Prescribing Information.] Information.] Use Use of of erbitux erbitux in in Combination Combination With With Radiation Radiation and and Cisplatin Cisplatin The The safety safety of of Erbitux Erbitux in in combination combination with with radiation radiation therapy therapy and and cisplatin cisplatin has has not not been been established. established. Death Death and and cardiotoxicity were were observed observed in in aa single-arm single-arm trial trial with with Erbitux, Erbitux, radiation radiation therapy, therapy, and and cisplatin cisplatin serious serious cardiotoxicity in patients patients with with locally locally advanced advanced SCCHN. SCCHN. Two Two of of 21 21 patients patients died, died, one one as as aa result result of of pneumonia pneumonia (100 (100 mg/m mg/m22)) in and and one one of of an an unknown unknown cause. cause. Four Four patients patients discontinued discontinued treatment treatment due due to to adverse adverse events. events. Two Two of of these these discontinuations discontinuations were were due due to to cardiac cardiac events. events. Hypomagnesemia Hypomagnesemia and and electrolyte electrolyte Abnormalities Abnormalities In In patients patients evaluated evaluated during during clinical clinical trials, trials, hypomagnesemia hypomagnesemia occurred occurred in in 55% 55% of of patients patients (199/365) (199/365) receiving receiving Erbitux Erbitux and and was was severe severe (NCI (NCI CTC CTC Grades Grades 33 and and 4) 4) in in 6–17%. 6–17%. The The onset onset of of hypomagnesemia hypomagnesemia and and accompanying accompanying electrolyte electrolyte abnormalities abnormalities occurred occurred days days to to months months after after initiation initiation of of Erbitux. Erbitux. Periodically Periodically monitor monitor patients patients for for hypomagnesemia, hypomagnesemia, hypocalcemia, hypocalcemia, and and hypokalemia, hypokalemia, during during and and for for at at least least 88 weeks weeks following following the the completion completion of of Replete electrolytes electrolytes as as necessary. necessary. Erbitux. Erbitux. Replete

models of neuroprotection and neurodegenerative disorders. CXB909 is a small-molecule, orally active agent that enhances the effects of nerve growth factor and is also believed to promote synthesis of acetylcholine. CeNeRx is preparing to launch further phase I studies of CXB909 targeting chemo-

epidermal epidermal Growth Growth Factor Factor Receptor Receptor (eGFR) (eGFR) expression expression and and Response Response Because Because expression expression of of EGFR EGFR has has been been detected detected in in nearly nearly all all SCCHN SCCHN tumor tumor specimens, specimens, patients patients enrolled enrolled in in the the head and and neck neck cancer cancer clinical clinical studies studies were were not not required required to to have have immunohistochemical immunohistochemical evidence evidence of of EGFR EGFR tumor tumor head expression prior prior to to study study entry. entry. expression Patients enrolled Patients enrolled in in the the colorectal colorectal cancer cancer clinical clinical studies studies were were required required to to have have immunohistochemical immunohistochemical evidence evidence of EGFR EGFR tumor tumor expression. expression. Primary Primary tumor tumor or or tumor tumor from from aa metastatic metastatic site site was was tested tested with with the the DakoCytomation DakoCytomation of ™ test EGFR pharmDx pharmDx™ test kit. kit. Specimens Specimens were were scored scored based based on on the the percentage percentage of of cells cells expressing expressing EGFR EGFR and and EGFR rate did did not not correlate correlate with with either either the the percentage percentage intensity intensity (barely/faint, (barely/faint, weak-to-moderate, weak-to-moderate, and and strong). strong). Response Response rate of positive of positive cells cells or or the the intensity intensity of of EGFR EGFR expression. expression. ADveRse ADveRse ReACTIONs ReACTIONs The The following following adverse adverse reactions reactions are are discussed discussed in in greater greater detail detail in in other other sections sections of of the the label: label: •• Infusion Infusion reactions reactions [See [See Boxed Boxed Warning Warning and and Warnings Warnings and and Precautions.] Precautions.] •• Cardiopulmonary Cardiopulmonary arrest arrest [See [See Boxed Boxed Warning Warning and and Warnings Warnings and and Precautions.] Precautions.] •• Pulmonary Pulmonary toxicity toxicity [See [See Warnings Warnings and and Precautions.] Precautions.] •• Dermatologic Dermatologic toxicity toxicity [See [See Warnings Warnings and and Precautions.] Precautions.] Hypomagnesemia and and Electrolyte Electrolyte Abnormalities Abnormalities [See [See Warnings Warnings and and Precautions.] Precautions.] •• Hypomagnesemia The most most common common adverse adverse reactions reactions with with Erbitux Erbitux (cetuximab) (cetuximab) (incidence (incidence ≥25%) ≥25%) are are cutaneous cutaneous adverse adverse The reactions (including (including rash, rash, pruritus, pruritus, and and nail nail changes), changes), headache, headache, diarrhea, diarrhea, and and infection. infection. reactions The most most serious serious adverse adverse reactions reactions with with Erbitux Erbitux are are infusion infusion reactions, reactions, cardiopulmonary cardiopulmonary arrest, arrest, dermatologic dermatologic The toxicity and and radiation radiation dermatitis, dermatitis, sepsis, sepsis, renal renal failure, failure, interstitial interstitial lung lung disease, disease, and and pulmonary pulmonary embolus. embolus. toxicity Across all all studies, studies, Erbitux Erbitux was was discontinued discontinued in in 3–10% 3–10% of of patients patients because because of of adverse adverse reactions. reactions. Across Clinical Trials Trials experience experience Clinical Because clinical clinical trials trials are are conducted conducted under under widely widely varying varying conditions, conditions, adverse adverse reaction reaction rates rates observed observed in in the the Because clinical trials trials of of aa drug drug cannot cannot be be directly directly compared compared to to rates rates in in the the clinical clinical trials trials of of another another drug drug and and may may not not clinical reflect the the rates rates observed observed in in practice. practice. reflect The data data below below reflect reflect exposure exposure to to Erbitux Erbitux in in 1373 1373 patients patients with with colorectal colorectal cancer cancer or or SCCHN SCCHN in in randomized randomized The Phase 33 (Studies (Studies 11 and and 3) 3) or or Phase Phase 22 (Studies (Studies 22 and and 4) 4) trials trials treated treated at at the the recommended recommended dose dose and and schedule schedule Phase for for aa median median of of 77 to to 14 14 weeks. weeks. [See [See Clinical Clinical Studies Studies (14) (14) in in Full Full Prescribing Prescribing Information.] Information.] reactions: Infusion Infusion reactions, reactions, which which included included pyrexia, pyrexia, chills, chills, rigors, rigors, dyspnea, dyspnea, bronchospasm, bronchospasm, Infusion Infusion reactions: angioedema, urticaria, urticaria, hypertension, hypertension, and and hypotension hypotension occurred occurred in in 15–21% 15–21% of of patients patients across across studies. studies. Grades Grades 33 angioedema, and 44 infusion infusion reactions reactions occurred occurred in in 2–5% 2–5% of of patients; patients; infusion infusion reactions reactions were were fatal fatal in in 11 patient. patient. and Infections: The The incidence incidence of of infection infection was was variable variable across across studies, studies, ranging ranging from from 13–35%. 13–35%. Sepsis Sepsis occurred occurred in in Infections: 1–4% of of patients. patients. 1–4% Renal: Renal Renal failure failure occurred occurred in in 1% 1% of of patients patients with with colorectal colorectal cancer. cancer. Renal: Squamous Cell Cell Carcinoma Carcinoma of of the the Head Head and and Neck Neck Squamous Table 11 contains contains selected selected adverse adverse events events in in 420 420 patients patients receiving receiving radiation radiation therapy therapy either either alone alone or or with with Erbitux Erbitux Table for locally locally or or regionally regionally advanced advanced SCCHN SCCHN in in Study Study 1. 1. Erbitux Erbitux was was administered administered at at the the recommended recommended dose dose and and for schedule (400 schedule (400 mg/m mg/m22 initial initial dose, dose, followed followed by by 250 250 mg/m mg/m22 weekly). weekly). Patients Patients received received aa median median of of 88 infusions infusions (range 1–11). 1–11). (range Table 1: 1: Table

Incidence of of selected selected Adverse Adverse events events (≥10%) (≥10%) in in Patients Patients with with Locoregionally Locoregionally Advanced Advanced Incidence sCCHN sCCHN erbitux erbitux plus plus Radiation Radiation Radiation Radiation Therapy Therapy Alone Alone (n=208) (n=208) (n=212) (n=212) body body system system Grades Grades Grades Grades Grades Grades Grades Grades Preferred Term Term 1–4 and 44 1–4 and 44 Preferred 1–4 33 and 1–4 33 and % of of Patients Patients % body as as aa Whole Whole body Asthenia 56 49 Asthenia 56 44 49 55 1 1 Fever 29 29 11 13 13 11 Fever Headache Headache 19 19 <1 <1 88 <1 <1 15 15 33 22 00 Infusion Infusion Reaction Reaction22 Infection Infection 13 13 11 99 11 16 16 00 55 00 Chills Chills11 Digestive Digestive Nausea Nausea 49 49 22 37 37 22 Emesis Emesis 29 29 22 23 23 44 Diarrhea Diarrhea 19 19 22 13 13 11 Dyspepsia Dyspepsia 14 14 00 99 11 Metabolic/Nutritional Metabolic/Nutritional Weight Weight Loss Loss 84 84 11 11 72 72 77 Dehydration Dehydration 25 25 66 19 19 88 3 3 43 43 22 21 21 11 Alanine Alanine Transaminase, Transaminase, high high 3 3 38 38 11 24 24 11 Aspartate Aspartate Transaminase, Transaminase, high high 3 3 33 33 <1 <1 24 24 00 Alkaline Alkaline Phosphatase, Phosphatase, high high Respiratory Respiratory Pharyngitis Pharyngitis 26 26 33 19 19 44 skin/Appendages skin/Appendages 87 87 17 17 10 10 11 Acneform Acneform Rash Rash44 Radiation Radiation Dermatitis Dermatitis 86 86 23 23 90 90 18 18 Application Application Site Site Reaction Reaction 18 18 00 12 12 11 Pruritus 16 00 44 00 Pruritus 16

11 22

33 44

Includes Includes cases cases also also reported reported as as infusion infusion reaction. reaction. Infusion Infusion reaction reaction isis defined defined as as any any event event described described at at any any time time during during the the clinical clinical study study as as “allergic “allergic reaction” reaction” or or “anaphylactoid “anaphylactoid reaction”, reaction”, or or any any event event occurring occurring on on the the first first day day of of dosing dosing described described as as “allergic “allergic reaction”, reaction”, “anaphylactoid “anaphylactoid reaction”, reaction”, “fever”, “fever”, “chills”, “chills”, “chills “chills and and fever”, fever”, or or “dyspnea”. “dyspnea”. Based Based on on laboratory laboratory measurements, measurements, not not on on reported reported adverse adverse events, events, the the number number of of subjects subjects with with tested tested samples varied varied from from 205–206 205–206 for for Erbitux Erbitux plus plus Radiation Radiation arm; arm; 209–210 209–210 for for Radiation Radiation alone. alone. samples Acneform Acneform rash rash isis defined defined as as any any event event described described as as “acne”, “acne”, “rash”, “rash”, “maculopapular “maculopapular rash”, rash”, “pustular “pustular rash”, rash”, “dry “dry skin”, skin”, or or “exfoliative “exfoliative dermatitis”. dermatitis”.

The The incidence incidence and and severity severity of of mucositis, mucositis, stomatitis, stomatitis, and and xerostomia xerostomia were were similar similar in in both both arms arms of of the the study. study. Late Radiation Radiation Toxicity Toxicity Late The overall overall incidence incidence of of late late radiation radiation toxicities toxicities (any (any grade) grade) was was higher higher in in Erbitux Erbitux in in combination combination with with radiation radiation The therapy therapy compared compared with with radiation radiation therapy therapy alone. alone. The The following following sites sites were were affected: affected: salivary salivary glands glands (65% (65% versus versus 56%), larynx (52% (52% versus versus 36%), 36%), subcutaneous subcutaneous tissue tissue (49% (49% versus versus 45%), 45%), mucous mucous membrane membrane (48% (48% versus versus 39%), 39%), 56%), larynx esophagus esophagus (44% (44% versus versus 35%), 35%), skin skin (42% (42% versus versus 33%). 33%). The The incidence incidence of of Grade Grade 33 or or 44 late late radiation radiation toxicities toxicities was was similar similar between between the the radiation radiation therapy therapy alone alone and and the the Erbitux Erbitux plus plus radiation radiation treatment treatment groups. groups.

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FDA Update

therapy-induced peripheral neuropathy as its first potential indication. CXB909 appears to enhance cholinergic tone and is a downstream enhancer of the effects of nerve growth factor, a naturally occurring neurotrophic factor that is important for the function and survival of several types

of neurons. Nerve growth factor may help prevent or reverse the neuronal damage that is implicated in the peripheral neuropathies associated with cancer chemotherapy, diabetes, kidney disease, and other conditions. Past attempts to use recombinant versions of nerve growth factor to pre-

Colorectal Colorectal Cancer Cancer Table 22 contains contains selected selected adverse adverse events events in in 562 562 patients patients receiving receiving best best supportive supportive care care (BSC) (BSC) alone alone or or with with Table Erbitux (cetuximab) (cetuximab) monotherapy monotherapy for for metastatic metastatic colorectal colorectal cancer cancer in in Study Study 3. 3. Erbitux Erbitux was was administered administered at at the the Erbitux 2 2 2 2 recommended dose dose and and schedule schedule (400 (400 mg/m mg/m initial initial dose, dose, followed followed by by 250 250 mg/m mg/m weekly). weekly). recommended Table Table 2: 2:

Incidence Incidence of of selected selected Adverse Adverse events events Occurring Occurring in in ≥10% ≥10% of of Patients Patients with with Advanced Advanced Colorectal Treated with with erbitux erbitux Monotherapy Monotherapy Colorectal Carcinoma Carcinoma11 Treated erbitux erbitux plus plus bsC bsC bsC bsC alone alone (n=288) (n=274) (n=288) (n=274) body Any Grades Any Grades body system system Any Grades Any Grades Preferred Preferred Term Term Grades Grades22 33 and and 44 Grades Grades 33 and and 44 % of of Patients Patients % Dermatology Dermatology Rash/Desquamation Rash/Desquamation Dry Dry Skin Skin Pruritus Pruritus Other-Dermatology Other-Dermatology Nail Nail Changes Changes body body as as aa Whole Whole Fatigue Fatigue Fever Fever Infusion Infusion Reactions Reactions33 Rigors, Rigors, Chills Chills Pain Pain Abdominal Abdominal Pain Pain Pain-Other Pain-Other Headache Headache Bone Bone Pain Pain Pulmonary Pulmonary Dyspnea Dyspnea Cough Cough Gastrointestinal Gastrointestinal Constipation Constipation Diarrhea Diarrhea Vomiting Vomiting Stomatitis Stomatitis Other-Gastrointestinal Other-Gastrointestinal Mouth Mouth Dryness Dryness Infection Infection Infection Infection without without neutropenia neutropenia Neurology Neurology Insomnia Insomnia Confusion Confusion Anxiety Anxiety Depression Depression

89 89 49 49 40 40 27 27 21 21

12 12 00 22 11 00

16 16 11 11 88 66 44

<1 <1 00 00 11 00

89 89 30 30 20 20 13 13

33 33 11 55 <1 <1

76 76 18 18

26 26 <1 <1

59 59 51 51 33 33 15 15

14 14 16 16 44 33

52 52 34 34 11 11 77

16 16 77 00 22

48 48 29 29

16 16 22

43 43 19 19

12 12 11

46 46 39 39 37 37 25 25 23 23 11 11

44 22 66 11 10 10 00

38 38 20 20 29 29 10 10 18 18 44

55 22 66 <1 <1 88 00

35 35

13 13

17 17

30 30 15 15 14 14 13 13

11 66 22 11

15 15 99 88 66

11 22 11 <1 <1

Adverse Adverse reactions reactions occurring occurring more more frequently frequently in in Erbitux-treated Erbitux-treated patients patients compared compared with with controls. controls. 22 Adverse Adverse events events were were graded graded using using the the NCI NCI CTC, CTC, VV 2.0. 2.0. 33 Infusion Infusion reaction reaction isis defined defined as as any any event event (chills, (chills, rigors, rigors, dyspnea, dyspnea, tachycardia, tachycardia, bronchospasm, bronchospasm, chest chest tightness, tightness, swelling, swelling, urticaria, urticaria, hypotension, hypotension, flushing, flushing, rash, rash, hypertension, hypertension, nausea, nausea, angioedema, angioedema, pain, pain, pruritus, pruritus, sweating, sweating, tremors, tremors, shaking, shaking, cough, cough, visual visual disturbances, disturbances, or or other) other) recorded recorded by by the the investigator investigator as as infusioninfusionrelated. related. BSC BSC == best best supportive supportive care care 11

The The most most frequently frequently reported reported adverse adverse events events in in 354 354 patients patients treated treated with with Erbitux Erbitux plus plus irinotecan irinotecan in in clinical clinical trials trials were were acneform acneform rash rash (88%), (88%), asthenia/malaise asthenia/malaise (73%), (73%), diarrhea diarrhea (72%), (72%), and and nausea nausea (55%). (55%). The The most most common common Grades Grades 3–4 3–4 adverse adverse events events included included diarrhea diarrhea (22%), (22%), leukopenia leukopenia (17%), (17%), asthenia/malaise asthenia/malaise (16%), (16%), and and acneform acneform rash rash (14%). (14%). Immunogenicity Immunogenicity As As with with all all therapeutic therapeutic proteins, proteins, there there isis potential potential for for immunogenicity. immunogenicity. Immunogenic Immunogenic responses responses to to cetuximab cetuximab were assessed assessed using using either either aa double double antigen antigen radiometric radiometric assay assay or or an an ELISA ELISA assay. assay. Due Due to to limitations limitations in in assay assay were performance performance and and sampling sampling timing, timing, the the incidence incidence of of antibody antibody development development in in patients patients receiving receiving Erbitux Erbitux has has not not been been adequately adequately determined. determined. Non-neutralizing Non-neutralizing anti-cetuximab anti-cetuximab antibodies antibodies were were detected detected in in 5% 5% (49 (49 of of 1001) 1001) of of evaluable evaluable patients patients without without apparent apparent effect effect on on the the safety safety or or antitumor antitumor activity activity of of Erbitux. Erbitux. The The incidence incidence of of antibody antibody formation formation isis highly highly dependent dependent on on the the sensitivity sensitivity and and specificity specificity of of the the assay. assay. Additionally, Additionally, the the observed observed incidence incidence of of antibody antibody (including (including neutralizing neutralizing antibody) antibody) positivity positivity in in an an assay assay may may be be influenced influenced by by several several factors factors including including assay assay methodology, methodology, sample sample handling, handling, timing timing of of sample sample collection, collection, concomitant concomitant medications, medications, and and underlying underlying disease. disease. For For these these reasons, reasons, comparison comparison of of the the incidence incidence of of antibodies antibodies to to Erbitux Erbitux with with the the incidence incidence of of antibodies antibodies to to other other products products may may be be misleading. misleading. Postmarketing Postmarketing experience experience The The following following adverse adverse reaction reaction has has been been identified identified during during post-approval post-approval use use of of Erbitux. Erbitux. Because Because this this reaction reaction was was reported reported from from aa population population of of uncertain uncertain size, size, itit was was not not always always possible possible to to reliably reliably estimate estimate its its frequency frequency or or establish aa causal causal relationship relationship to to drug drug exposure. exposure. establish •• Aseptic Aseptic meningitis meningitis DRUG DRUG INTeRACTIONs INTeRACTIONs AA drug drug interaction interaction study study was was performed performed in in which which Erbitux Erbitux was was administered administered in in combination combination with with irinotecan. irinotecan.There There was was no no evidence evidence of of any any pharmacokinetic pharmacokinetic interactions interactions between between Erbitux Erbitux and and irinotecan. irinotecan.

vent and treat neuron-damaging conditions were stymied by its lack of druglike properties. In contrast, CXB909 crosses the blood-brain barrier, has a long half-life, and is orally available. Results from an initial phase I study in 26 subjects showed that single doses of CXB909 administered orally resulted

Use Use IN IN sPeCIFIC sPeCIFIC POPULATIONs POPULATIONs Pregnancy Pregnancy Pregnancy Pregnancy Category Category CC There There are are no no adequate adequate and and well-controlled well-controlled studies studies of of Erbitux Erbitux (cetuximab) (cetuximab) in in pregnant pregnant women. women. Based Based on on animal animal models, EGFR EGFR has has been been implicated implicated in in the the control control of of prenatal prenatal development development and and may may be be essential essential for for normal normal models, organogenesis, proliferation, proliferation, and and differentiation differentiation in in the the developing organogenesis, developing embryo. embryo. Human Human IgG IgG isis known known to to cross cross the the placental barrier; therefore, therefore, Erbitux Erbitux may may be be transmitted transmitted from from the the mother mother to to the the developing developing fetus, fetus, and and has has the the placental barrier; potential potential to to cause cause fetal fetal harm harm when when administered administered to to pregnant pregnant women. women. Erbitux Erbitux should should be be used used during during pregnancy pregnancy only ifif the the potential potential benefit benefit justifies justifies the the potential potential risk risk to to the the fetus. fetus. only Pregnant cynomolgus cynomolgus monkeys monkeys were were treated treated weekly weekly with with 0.4 0.4 to to 44 times times the the recommended recommended human human dose dose of of Pregnant cetuximab (based cetuximab (based on on body body surface surface area) area) during during the the period period of of organogenesis organogenesis (gestation (gestation day day [GD] [GD] 20–48). 20–48). Cetuximab Cetuximab was was detected detected in in the the amniotic amniotic fluid fluid and and in in the the serum serum of of embryos embryos from from treated treated dams dams at at GD GD 49. 49. No No fetal fetal malformations malformations or or other other teratogenic teratogenic effects effects occurred occurred in in offspring. offspring. However, However, significant significant increases increases in in embryolethality embryolethality and and abortions abortions occurred occurred at at doses doses of of approximately approximately 1.6 1.6 to to 44 times times the the recommended recommended human human dose dose of of cetuximab cetuximab (based (based on on total total body body surface surface area). area). Nursing Nursing Mothers Mothers ItIt is is not not known known whether whether Erbitux Erbitux is is secreted secreted in in human human milk. milk. IgG IgG antibodies, antibodies, such such as as Erbitux, Erbitux, can can be be excreted excreted in in human milk. milk. Because Because many many drugs drugs are are excreted excreted in in human human milk milk and and because because of of the the potential potential for for serious serious adverse adverse human reactions in in nursing nursing infants infants from from Erbitux, Erbitux, aa decision decision should should be be made made whether whether to reactions to discontinue discontinue nursing nursing or or to to discontinue the drug, drug, taking taking into into account account the the importance importance of of the the drug drug to to the the mother. mother. IfIf nursing nursing isis interrupted, interrupted, discontinue the based based on on the the mean mean half-life half-life of of cetuximab cetuximab [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) in in Full Full Prescribing Prescribing Information], Information], nursing nursing should should not not be be resumed resumed earlier earlier than than 60 60 days days following following the the last last dose dose of of Erbitux. Erbitux. Pediatric Pediatric Use Use The The safety safety and and effectiveness effectiveness of of Erbitux Erbitux in in pediatric pediatric patients patients have have not not been been established. established. The The pharmacokinetics pharmacokinetics of of cetuximab cetuximab have have not not been been studied studied in in pediatric pediatric populations. populations. Geriatric Use Geriatric Use Of Of the the 1062 1062 patients patients who who received received Erbitux Erbitux with with irinotecan irinotecan or or Erbitux Erbitux monotherapy monotherapy in in five five studies studies of of advanced advanced colorectal cancer, cancer, 363 363 patients patients were were 65 65 years years of of age age or or older. older. No No overall overall differences differences in in safety safety or or efficacy efficacy were were colorectal observed between between these these patients patients and and younger younger patients. patients. observed Clinical studies of of Erbitux Erbitux conducted conducted in in patients patients with with head head and and neck neck cancer cancer did did not not include include sufficient sufficient number number of of Clinical studies subjects subjects aged aged 65 65 and and over over to to determine determine whether whether they they respond respond differently differently from from younger younger subjects. subjects. Of Of the the 208 208 patients patients with with head head and and neck neck cancer cancer who who received received Erbitux Erbitux with with radiation radiation therapy, therapy, 45 45 patients patients were were 65 65 years years of of age or or older. older. age OveRDOsAGe OveRDOsAGe The maximum maximum single single dose dose of of Erbitux Erbitux administered administered isis 1000 The 1000 mg/m mg/m22 in in one one patient. patient. No No adverse adverse events events were were reported reported for for this this patient. patient. NONCLINICAL NONCLINICAL TOxICOLOGY TOxICOLOGY Carcinogenesis, Carcinogenesis, Mutagenesis, Mutagenesis, Impairment Impairment of of Fertility Fertility Long-term animal animal studies studies have have not not been been performed performed to to test test cetuximab cetuximab for for carcinogenic carcinogenic potential, potential, and and no no Long-term mutagenic or or clastogenic clastogenic potential potential of of cetuximab cetuximab was was observed observed in in the the Salmonella-Escherichia Salmonella-Escherichia coli coli (Ames) (Ames) assay assay mutagenic or in in the the in in vivo vivo rat rat micronucleus micronucleus test. test. Menstrual or Menstrual cyclicity cyclicity was was impaired impaired in in female female cynomolgus cynomolgus monkeys monkeys receiving receiving weekly weekly doses doses of of 0.4 0.4 to to 44 times times the the human human dose dose of of cetuximab cetuximab (based (based on on total total body body surface surface area). area). Cetuximab-treated Cetuximab-treated animals animals exhibited exhibited increased increased incidences incidences of of irregular irregular or or absent absent cycles, cycles, as as compared compared to to control control animals. animals.These These effects effects were were initially initially noted noted beginning beginning week week 25 25 of of cetuximab cetuximab treatment treatment and and continued continued through through the the 6-week 6-week recovery recovery period. period. In In this this same same study, study, there there were were no no effects effects of of cetuximab cetuximab treatment treatment on on measured measured male male fertility fertility parameters parameters (ie, (ie, serum serum testosterone testosterone levels levels and and analysis analysis of of sperm sperm counts, counts, viability, viability, and and motility) motility) as as compared compared to to control control male male monkeys. monkeys. ItIt isis not not known known ifif cetuximab cetuximab can can impair impair fertility fertility in in humans. humans. Animal Animal Pharmacology Pharmacology and/or and/or Toxicology Toxicology In In cynomolgus cynomolgus monkeys, monkeys, cetuximab, cetuximab, when when administered administered at at doses doses of of approximately approximately 0.4 0.4 to to 44 times times the the weekly weekly human exposure (based (based on on total total body body surface surface area), area), resulted resulted in in dermatologic dermatologic findings, findings, including including inflammation inflammation at at human exposure the the injection injection site site and and desquamation desquamation of of the the external external integument. integument. At At the the highest highest dose dose level, level, the the epithelial epithelial mucosa mucosa of the the nasal nasal passage, passage, esophagus, esophagus, and and tongue tongue were were similarly similarly affected, affected, and and degenerative degenerative changes changes in in the the renal renal of tubular tubular epithelium epithelium occurred. occurred. Deaths Deaths due due to to sepsis sepsis were were observed observed in in 50% 50% (5/10) (5/10) of of the the animals animals at at the the highest highest dose dose level level beginning beginning after after approximately approximately 13 13 weeks weeks of of treatment. treatment. PATIeNT PATIeNT COUNseLING COUNseLING INFORMATION INFORMATION Advise Advise patients: patients: To report report signs signs and and symptoms symptoms of of infusion infusion reactions reactions such such as as fever, fever, chills, chills, or or breathing breathing problems. problems. •• To Of the the potential potential risks risks of of using using Erbitux Erbitux during during pregnancy pregnancy or or nursing nursing and and of of the the need need to to use use adequate adequate •• Of contraception in in both both males contraception males and and females females during during and and for for 66 months months following following the the last last dose dose of of Erbitux Erbitux therapy. therapy. •• That That nursing nursing isis not not recommended recommended during, during, and and for for 22 months months following following the the last last dose dose of of Erbitux Erbitux therapy. therapy. To limit limit sun sun exposure exposure (use (use sunscreen, sunscreen, wear wear hats) hats) while while receiving receiving and and for for 22 months months following following the the last last dose dose •• To of Erbitux. Erbitux. of Erbitux®® isis aa registered Erbitux registered trademark trademark of of ImClone ImClone LLC LLC aa wholly-owned wholly-owned subsidiary subsidiary of of Eli Eli Lilly Lilly and and Company. Company. Manufactured Manufactured by by ImClone ImClone LLC LLC aa wholly-owned wholly-owned subsidiary subsidiary of of Eli Eli Lilly Lilly and and Company, Company, Branchburg, Branchburg, NJ NJ 08876 08876 USA USA Distributed Distributed and and marketed marketed by by Bristol-Myers Bristol-Myers Squibb Squibb Company, Company, Princeton, Princeton, NJ NJ 08543 08543 USA USA Co-marketed Co-marketed by by Eli Eli Lilly Lilly and and Company, Company, Indianapolis, Indianapolis, IN IN 46285 46285 USA USA

Copyright Copyright © © 2004–2010 2004–2010 ImClone ImClone LLC LLC aa wholly-owned wholly-owned subsidiary subsidiary of of Eli Eli Lilly Lilly and and Company, Company, and and Bristol-Myers Squibb Squibb Company. Company. All All rights rights reserved. reserved. Bristol-Myers 1236886A7 1236886A7

ER-B0001A-09-10 ER-B0001A-09-10

Rev September Rev September 2010 2010

in good levels of drug exposure and were well tolerated.

FDA Issues Complete Response Letter for Dutasteride in Prostate Cancer Risk Reduction GlaxoSmithKline announced that it had received a Complete Response letter from the FDA for the supplemental New Drug Application (sNDA) for dutasteride (Avodart) for reducing the risk of prostate cancer in men at increased risk for the disease, defined as those who have had a prior negative biopsy due to clinical concern and have an elevated serum prostatespecific antigen. A Complete Response letter is issued by the FDA’s Center for Drug Evaluation and Research when the review of a file is completed and it cannot be approved in its present form. This notification refers solely to the supplemental file specific to a prostate cancer risk reduction indication and not the existing FDA-approved uses. Dutasteride is approved for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to improve symptoms, reduce the risk of acute urinary retention, and reduce the risk of the need for BPHrelated surgery. In combination with the alpha-blocker tamsulosin, dutasteride is also approved for the treatment of symptomatic BPH in men with an enlarged prostate.

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Contact

The ASCO Post ADVERTISING

Rates, reprints, or supplements Leslie Dubin email:

Leslie@harborsidepress.com Phone: 631.935.7660 Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

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Direct from ASCO

ASCO Partners with Societies in Developing Countries on Cancer Management Courses Curriculum custom-designed with host country to address local needs

n 2004, the Dominican Republic was the site of ASCO’s first Multidisciplinary Cancer Management Course (MCMC). ASCO teamed with the Dominican Society of Hematology and Oncology to present a 2-day program in Santo Domingo, designed specifically for local providers. Since then ASCO has worked with on-

cians, it will soon include nurses. “We have tried very hard to incorporate nursing as part of the course and give the message that nurses are vital, but we haven’t always had a module aimed at nurses,” Dr. Villar acknowledges. He says that breakout sessions for nurses will be part of every MCMC in the future.

We don’t want the course to be a one-time deal. We aim to leave a long-lasting legacy. It could be a tumor board that they do twice a month, or a breast cancer screening program. — Hugo Villar, MD

to leave a long-lasting legacy. It could be a tumor board that they do twice a month, or a breast cancer screening program.”

Train the Trainer Course Launched Last year MCMC piloted a trainthe-trainer course in Santiago, Chile, in collaboration with the Chilean Oncology Foundation. Twelve trainers from five different countries participated in the program, which teaches principles and strategies of adult education and presents information for regional leaders to organize their own courses.

Vol 28, No 34

December 1, 2010

J OURNAL OF C LINICAL O NCOLOGY Impact of Androgen-Deprivation Therapy on Cognitive Function in Men With Nonmetastatic Prostate Cancer. S.M.H. Alibhai et al Impact of Androgen-Deprivation Therapy on Physical Function and QOL in Men With Nonmetastatic Prostate Cancer. S.M.H. Alibhai et al Optimizing Collection of Adverse Event Data in Cancer Clinical Trials Supporting Supplemental Indications. L.D. Kaiser et al Editorial: D.J. Sargent et al Availability of Experimental Therapy Outside of Randomized Clinical Trials in Oncology. E.P. Hamilton et al Survival Patterns in Patients With Hodgkin’s Lymphoma With a Pre-Existing Autoimmune Disease. O. Landgren et al Prospective Analysis of Hepatitis B Virus Reactivation in Patients With Diffuse Large B-Cell Lymphoma After Rituximab Combination Chemotherapy N. Niitsu et al

cology societies to develop and present the course 18 times in countries of South and Central America, Asia, the Middle East, and Africa—countries where nonspecialists often treat cancer.

Multidisciplinary Approach “The main message is that to take good care of patients with cancer you need a multidisciplinary approach— medicine, radiation, social services, nursing. It’s not a one-man task,” says surgical oncologist Hugo Villar, MD, Professor of Surgery and Radiation Oncology at Arizona Cancer Center of the University of Arizona Health Sciences Center. Dr. Villar is a member of the MCMC Working Group, a 12-member ASCO group that oversees the entire MCMC process. He has served on the working group since its inception, and in fact began working in 1983 with the MCMC precursor, a standardized course offered by the American College of Surgeons to all of its state chapters and then throughout Mexico. “The mission is the same—to provide education and improve patient care,” Dr. Villar comments. Members of the working group represent all cancer subspecialties and come from countries around the globe. Although the group has been all physi-

Dr. Villar emphasizes the valuable contribution that ASCO makes in the global fight against cancer through MCMC and its other international programs. “ASCO’s financial commitment is vital, and the staff of the International Affairs Department are superb. They are multilingual—a huge plus—and a lot of the successes are due to their efforts.”

Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Continuous Treatment With Bortezomib-Thalidomide Compared With BortezomibMelphalan-Prednisone for Initial Treatment of Multiple Myeloma: A Randomized Controlled Trial. A. Palumbo et al Phase I Study of Everolimus Plus Weekly Paclitaxel and Trastuzumab in Patients With Metastatic Breast Cancer Pretreated With Trastuzumab F. Andre et al Review Article: Strategies for Prolonged Therapy in Patients With Advanced Non–Small-Cell Lung Cancer. P. Fidias et al Art of Oncology: Stand and Wait. G.F. Blackall Official Journal of the American Society of Clinical Oncology

JCO.org

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What’s Hot in

JCO Online Top 10 most-accessed articles recently published in Journal of Clinical Oncology

1. Comorbidity and Mortality Results From a Randomized Prostate Cancer Screening Trial E. David Crawford, et al 29(4): 355

How the Process Works Once the MCMC Working Group approves an MCMC application from an oncology-related professional organization, a host course director works with an ASCO-assigned course director to plan and implement the course. Each MCMC includes core modules covering cancer biology; radiation, medical, and surgical oncology; radiobiology; and multidisciplinary care. “After those, the local organizers decide what they want,” Dr. Villar explains. The course features lectures, case presentations, skills stations, and group discussions. ASCO sends two or three faculty members to work with local faculty identified by the host society. Dr. Villar points out that having local faculty as a basic part of the program is of great value. “We don’t want the course to be a one-time deal. We aim

www.jco.org

While the MCMC program has reached more than 2,000 clinicians in its 6 years, the train-the-trainer approach has the potential to multiply the outreach significantly. “We are refining how we can deliver the message that treating cancer is a multidisciplinary task,” Dr. Villar says. “If we want to leave a long-lasting legacy, we need to give leaders the tools to educate. I believe that education affects the quality of care and the outcome. It’s been one of my life’s passions.”

Phase II Study of the Antibody Drug Conjugate TrastuzumabDM1 for the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2) –Positive Breast Cancer After Prior HER2Directed Therapy Howard A. Burris III, et al 29(4): 398 Serum Prostate-Specific Antigen for the Early Detection of Prostate Cancer: Always, Never, or Only Sometimes? Peter R. Carroll, et al 29(4): 345 Trastuzumab-DM1: Building a Chemotherapy-Free Road in the Treatment of Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer Steven J. Isakoff, et al 29(4): 351 Intravenous Calcium and Magnesium for Oxaliplatin-Induced Sensory Neurotoxicity in Adjuvant Colon Cancer: NCCTG N04C7

Axel Grothey, et al 29(4): 421 6.

Gemtuzumab Ozogamicin: One Size Does Not Fit All—The Case for Personalized Therapy Farhad Ravandi 29(4): 349

Simple Rules Can Improve Prognostic Accuracy Lidia Schapira 29(4): 347

Addition of Bevacizumab to Chemotherapy for Treatment of Solid Tumors: Similar Results but Different Conclusions Alberto Ocaña, et al 29(3): 254

Vitamin D Deficiency Is a Cofactor of Chemotherapy-Induced Mucocutaneous Toxicity and Dysgeusia Michael Fink 29(4): e81

10. Identification of Patients With Acute Myeloblastic Leukemia Who Benefit From the Addition of Gemtuzumab Ozogamicin: Results of the MRC AML15 Trial Alan K. Burnett, et al 29(4): 369

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Direct from ASCO

Patient Navigators Have New Statewide Association in Georgia ASCO state affiliate grant helped start-up work

atient navigators in Georgia now have a statewide organization to turn to for education, resources, and networking. The society, Cancer Patient Navigators of Georgia (CPNG), began in 2009 after the Georgia Society of Clinical Oncology (GASCO) surveyed selfidentified patient navigators about their interest in such an organization. With just 30-days’ notice, more than 100 individuals attended an educational and organizational conference. GASCO received a $10,000 state affiliate grant from ASCO that went toward the direct expenses of these activities. “The idea for a state navigator society was stimulated by the collaborative environment among all cancer providers in Georgia,” says radiation oncologist Matthew Mumber, MD, who was GASCO president when it received the state affiliate grant. He adds that the state’s collaborative environment was established through the Georgia Cancer Coalition, which was funded by state dollars from the tobacco settlement fund. Dr. Mumber says that patient navigation will be a “key part of the system” in the multidisciplinary cancer center being opened this spring by his own practice, the Harbin Clinic in Rome, Georgia. “Our hypothesis is that patient navigation will improve compliance with recommendations that are evidence-based and simple to outline, yet hard for patients to implement, such as diet and lifestyle changes.”

Patient Navigation—A New and Evolving Field “The real work of the patient navigator is to facilitate access to qual-

ity medical care by identifying and bridging gaps and reducing barriers to care,” says Gail McCray, MA, a community health educator at Morehouse School of Medicine in Atlanta and cochair of the new organization, along with Deborah Kemp, NP, of Savannah.

CPNG will be a resource for communities, oncology practices, and in-

Noting that the terminology for and definitions of patient navigators and community health workers continue to evolve, Ms. McCray says there is now stronger recognition of their role in improving health outcomes along the continuum of care. “Patient navigators are valuable resources for patients and providers— from primary prevention to postdiagnosis and survivorship. They can be social workers, community health

stitutions across the state that want to start a cancer patient navigation program, according to Ms. Kemp, a nurse practitioner at the Nancy N. and J.C. Lewis Cancer & Research Pavilion in Savannah. “Maybe what has worked at one center can be adopted at another,” she says. Both Ms. McCray and Ms. Kemp note that the new organization for cancer patient navigators might also serve as a model for those in other disease ar-

workers, nurses, survivor volunteers, or others.”

New Society Can Help Navigation Services Proliferate

Save the Date 2011 ASCO Annual Meeting

eas such as diabetes and asthma. The society has about 140 people who have signed up to be members. CPNG’s organizers decided early on to be inclusive, embracing individuals providing clinical, psychosocial, and financial services to oncology patients across the continuum of care. CPNG’s mission is to “connect, educate, and share best practices among patient navigators in Georgia.” Ms. Kemp says that developing educational programs is a priority for the society right now. Georgia is the largest state east of the Mississippi River, with 159 counties and numerous single-hospital and multihospital systems. “We have to consider, statewide, where members are located and plan for that in providing education,” Ms. Kemp points out. In 2010, CPNG held a wellattended educational meeting during GASCO’s annual meeting—the first state affiliate annual meeting to use a physician educational program based on Best of ASCO®. CPNG will hold its annual educational track concurrently with the GASCO annual meeting in 2011. This year, CPNG is identifying resources throughout the state for use in collaborating on navigation for patient referrals between cancer care communities and will also be researching the role that a social media site may have in networking and education for patient navigators. For more information about patient navigation services in Georgia, contact GASCO Director Karen Beard: karen.beard@gasco.us.

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June 3-7, 2011 McCormick Place Chicago, Illinois

ASCOPost.com | MARCH 1, 2011

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To Ensure Progress Against Cancer, ASCO Advocates for an Increase in NIH Funding ASCO, along with more than 270 medical research stakeholders, sent a letter to each member of Congress stressing that long-term flat funding or a reduction in funding for the National Institutes of Health (NIH) “will slow research progress and squander invaluable scientific progress to the detriment of our nation’s health, our fragile economy, and our global competitiveness.”

ASCO Supports Legislation Addressing Drug Shortage At press time, Senator Amy Klobuchar’s office was drafting legislation that outlines steps to help alleviate drug shortages, which ASCO and the co-conveners of the November 2010 Drug Shortages Summit supports. The Preserving Access to Life-Saving Medications Act includes several of the recommendations from a report issued by

the summit co-conveners. The report calls for a coordinated effort to: ■■ Expand the FDA’s authority to require manufacturer notification of shortages and market withdrawals ■■ Provide incentives (eg, tax credits) to manufacturers that produce critical drug products in exchange for guarantees of continued production ■■ Require pharmaceutical manufacturers to confidentially notify the FDA when there is a single active pharmaceutical ingredient or manufacturing source ■■ Establish a modified or reduced user fee program for FDA approval of generic drugs that would support expedited review of applications ■■ Establish an expedited approval pathway for unapproved drugs that are deemed critical therapies The Summit—convened by ASCO, the American Society of Anesthesiologists (ASA), the

American Society of Health-System Pharmacists (ASHP), and the Institute for Safe Medication Practices (ISMP)—included participants from health professional organizations, pharmaceutical manufacturers, and supply chain entities. Representatives of the FDA and other regulatory agencies attended portions of the meeting as observers. The full report is available online at www.asco.org/ascoaction.

Access Patient Education Materials in Spanish

ASCO, along with 100 medical and physician specialty groups, sent a letter to Representative Phil Gingrey, MD (R-GA) offering support for H.R. 5, known as the Help Efficient, Accessible, Low-cost, Timely Healthcare (HEALTH) Act of 2011. The bill, introduced by Dr. Gingrey, includes recommendations to repair the medical liability system, reduce the growth of health-care costs, and protect patients’ access to care.

o improve access to ASCO’s oncologist-approved cancer information for patients and families, Cancer.Net has expanded the translated content on Cancer.Net en Español (www.cancer.net/espanol), including new articles on survivorship, late effects in adults and children, rehabilitation, caring for the whole patient, and depression and anxiety. In addition, a new Cancer.Net welcome video in Spanish provides an overview of the site for first-time visitors. For printed patient materials in Spanish including one-page fact sheets, guides to common cancer types, and a guide to managing the cost of cancer care visit ASCO’s bookstore (www.cancer. net/ordermaterials).

ASCO Supports Introduction of Legislation that Addresses Medical Liability

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ASCO University’s Online Tumor Boards Let Providers Interact with National Experts Cases presented, latest treatments and controversies discussed

he ASCO Tumor Boards deliver just what every oncologist needs when recommending treatment for a specific carcinoma: information on the latest advances in that field, straight talk from experts about the controversies surrounding certain treatments, and relevant reports from the literature. ASCO University®, the home for online oncology education, features the Tumor Boards as one of its free learning modules.

Topic Choice Based on Biggest Changes in Oncology “When choosing the topics to be presented, we consider where the field is changing the most,” says Robert Mennel, MD, of Texas Oncology in Dallas. Dr. Mennel works

Robert Mennel, MD

with Bhoomi Mehrotra, MB, of Long Island Jewish Medical Center in New York, to plan the educational series. “We look at which issues oncologist want to know about— what has the newest matter that is important to practice,” Dr. Mennel adds. The topic addressed in the Tumor Boards changes every month. On March 24, the new topic posted

Bhoomi Mehrotra, MB

on Tumor Boards will be triplenegative breast cancer, presented by a medical oncologist and a molecular pathologist.

Users Can Ask Questions, Receive Faculty Response To facilitate dialogue among participants and faculty, the Tumor Boards include an open discussion forum, offering users the

opportunity to post questions and exchange comments with others. The discussion board is open for the first month after a module is online. Individuals can enter comments or questions, and the faculty or other users can respond. The questions and comments remain a part of that module and can be read by users accessing the module later. A list of all topics presented so far appears in the box. These educational modules, with a transcript of comments are still available for users to access, although the discussion period has closed.

Presentations Offer Practical Information Narrating slides that the user can advance at will, the presenters discontinued on page 24

The ASCO Post | MARCH 1, 2011

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Online Tumor Boards continued from page 23

cuss very practical aspects of diagnosis and treatment, as exemplified by this list of questions addressed in the sarcoma module: ■■ What is the proper clinical work-

up of a sarcoma? ■■ Should a sarcoma be diagnosed with a core needle biopsy or an open biopsy? ■■ What is the proper pathology workup? ■■ When should radiation therapy

be used—pre- or postoperatively? ■■ What is the appropriate role of chemotherapy? ■■ How do you handle a small pulmonary nodule? Representatives from different areas of patient care present each topic.

Tumor Board Modules Available ■■ Prostate Cancer ■■ Pancreatic Cancer ■■ Soft-tissue Sarcoma

PHA

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■■ Glioblastoma

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■■ Mantle Cell Lymphoma

REN

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■■ Melanoma

REC

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■■ Carcinoma of Unknown

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Primary ■■ Renal Cell Carcinoma ■■ Colorectal Cancer ■■ Ovarian Cancer ■■ Lung Cancer A surgeon and a medical oncologist discussed soft-tissue sarcoma, for example, while a radiation oncologist and a medical oncologist teamed up to present pancreatic cancer.

Related Articles Provided, Current Research Discussed The slides include links to relevant articles that pop up as PDFs. “Having all the up-to-date material on a defined area within a specific disease is one of the best things about the program,” Dr. Mennel points out. “It’s a good way of building up a bibliography.” The modules also include new areas and treatments being investigated. For example, the module on pancreatic cancer, collaboratively developed with the Pancreatic Cancer Action Network®, discusses seven selected phase III clinical trials currently in progress and one that is pending activation. “The presenters are people who are moving the field along,” Dr. Mennel notes. “They have already thought about major areas that may change practice and distilled the problem to comment on the important issues.” To access ASCO Tumor Boards, hosted on ASCO University, visit http://university.asco.org/tumorboards.

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News Hematology

Rituximab Maintenance Improves Survival in Follicular Lymphoma By Alice Goodman

aintenance therapy with rituximab (Rituxan) improved survival in patients with relapsed or refractory follicular lymphoma who responded to induction therapy, according to a systematic review and meta-analysis of randomized, controlled trials presented at the 52nd Annual Meeting of the American Society of Hematology.1 Maintenance rituximab improved progression-free survival both after first-line treatment and in relapsed or refractory follicular lymphoma, and improved overall survival in relapsed or refractory follicular lymphoma, despite a higher rate of infection. The meta-analysis included eight randomized, controlled trials that compared maintenance rituximab therapy with observation or treatment at relapse.

progression-free survival for all patients with follicular lymphoma,” stated Anat Gafter-Gvili, MD, Tel Aviv University in Tel Aviv, Israel, who was second author of this poster presentation. Although follicular lymphoma is considered an indolent lymphoma, patients typically relapse after therapy and experience disease progression. Most patients present with advanced disease and are not curable with current therapy. The poster presentation at the ASH meeting updated a previous meta-analysis and included four more recent clinical trials.2

Updated Findings The trials were identified by a search of several databases, including The Cochrane Library, MEDLINE, EMBASE, LILACS, and proceedings of important conferences between 2000 and 2010, including ASH, ASCO, and EHA. All trials had overall survival as the primary outcome. Eight trials fulfilled criteria for the meta-analysis; median follow-up ranged from 25 months to 9.5 years.

Benefit Confirmed

SEE PAGE 47

“This meta-analysis confirms the benefit of maintenance rituximab in follicular lymphoma, showing prolonged

Expert Point of View

aintenance rituximab therapy for follicular lymphoma is the de facto standard, based on mounting data. This meta-analysis continues to support use of maintenance rituximab for patients with follicular lymphoma,” stated Paul Hamlin, MD, Memorial Sloan-Kettering Cancer Center. Nevertheless, Dr. Hamlin said that the decision to give maintenance rituximab should be considered on a case-by-case basis. “These [and other] data are provocative, and they should be discussed with patients,” he noted. Alternative strategies to maintenance rituximab are reasonable in certain scenarios, Dr. Hamlin continued. “For example, patients with hepatitis or hypogammaglobulinemia may not be appropriate for maintenance, and in some patients radioimmunotherapy consolidation may be a preferable strategy,” he stated.

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Maintenance Rituximab for Follicular Lymphoma ■■ According to an updated meta-analysis of contemporary trials, maintenance rituximab extends survival following induction chemotherapy in patients with relapsed follicular lymphoma.

■■ An improved progression-free survival with maintenance rituximab

was observed regardless of type of induction chemotherapy or number of lines of induction.

■■ Maintenance rituximab was associated with more grade 3 and 4 adverse events, including infections.

■■ Rituximab is approved by the FDA as a maintenance therapy for advanced follicular lymphoma.

Maintenance rituximab significantly improved overall survival compared with observation or treatment at relapse (no maintenance therapy) in a total of 2,283 patients. The hazard ratio for death was 0.75 (95% CI = 0.61–0.91). Maintenance rituximab also significantly improved progression-free survival compared with observation or treatment at relapse, regardless of whether it was initiated after first-line or subsequent therapy, and regardless of the type of induction therapy administered. Induction therapy included rituximab alone (n = 240 patients), chemotherapy alone (n = 208 patients), and rituximab plus chemotherapy (n = 1,352 patients). More infection-related adverse events occurred with maintenance rituximab than with observation alone or treatment at relapse (risk ratio = 1.99; 95% CI = 1.21–3.27). Overall, rituximab maintenance was associated with a higher rate of grade 3/4 adverse events (risk ratio = 1.47; 95% CI = 1.19–1.83). Three of the eight trials were stopped early after benefit of main-

tenance was shown. Dr. Gafter-Gvili and colleagues suggested that stopping trials early can overestimate treatment effects.

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Editor’s note: In January 2011, the FDA approved rituximab (Rituxan) as a maintenance therapy for advanced follicular lymphoma in patients who responded to induction therapy with rituximab plus chemotherapy. Approval of rituximab as maintenance therapy was based on results of the PRIMA study (Primary Rituxan and Maintenance), sponsored by the Groupe d’Etude des Lymphomes de l’Adulte (GELA). The PRIMA study was published in Lancet 377(9759):42-51, 2011. References 1. Vidal L, Gafter-Gvili A, Salles G, et al: Rituximab maintenance for the treatment of patients with follicular lymphoma: Systematic review and meta-analysis of randomized trials—2010 update. 52nd ASH Annual Meeting. Abstract 1798. Presented December 4, 2010. 2. Vidal L, Gafter-Gvili A, Leibovici L, et al: Rituximab maintenance for treatment of patients with follicular lymphoma: Systematic review and meta-analysis of randomized trials. J Natl Cancer Inst 101:248-255, 2009.

Coming in the March 15, 2011, issue of ■■ Continued coverage of the 2011 Gastrointestinal

■■ Important news and research in breast cancer, metastatic

■■ Coverage of the 2011 Genitourinary Cancers Symposium

■■ Plus Columns and Clinical Departments

Cancers Symposium

melanoma, lung cancer, hematologic cancers, and more

Be sure to visit The ASCO Post online at www.ASCOPost.com.

ASCOPost.com | MARCH 1, 2011

PAGE 29

Patient’s Corner

Living with Multiple Myeloma

When you have an incurable cancer, death is always staring you in the face. By Bill Stokes, DDS, PC As told to Jo Cavallo from home—meant that I had some life-altering decisions to make. After learning everything I could about myeloma and my treatment, I decided to give up my dental practice, a career I loved, and concentrate on getting well. But staying well has turned into a 10-year struggle, with no end in sight.

Ongoing Struggle Bill Stokes, DDS, PC

was just 47 when I was diagnosed with multiple myeloma in 2000. When I heard the news, I turned to my old medical books looking for information about the cancer, and the statistics were bleak, with survival rates hovering at a frightening 1 to 3 years. After meeting with an oncologist and researching my treatment options, I decided to fly to the Fred Hutchinson Cancer Research Center in Seattle, to participate in a clinical trial testing the effectiveness of having dual stem cell transplants: an autologous transplant, followed by a mini-allogeneic transplant using donor cells. Although it was a new clinical trial, I was told the initial results looked promising and that the protocol offered a potential cure for my myeloma, the most encouraging news I’d heard since I was diagnosed. Still, coming to terms with having such a deadly cancer and knowing that the treatment, even if it worked, was risky and would entail a long recovery period—much of it away

I was so debilitated after the two transplants that just taking a walk around the block left me out of breath and exhausted. And after being so intensely treated and isolated for so long because of my compromised immune system, I came back home filled with a lot of anxiety about being around people and fears about catching infections. Just going out to dinner with friends or standing in the checkout line at a store was

disappointing. Since then, I’ve had numerous bouts of pneumonia, four of which required hospital stays, a broken rib, bone lesions on my spine, kidney stones resulting from treatment, and graft-vs-host disease. So far, each time my disease has reared its ugly head, my doctors have been able to bring it somewhat back under control. I’ve even had several years of intermittent remissions thanks to the novel drug bortezomib (Velcade). But a year ago I became refractory to the treatment, and the myeloma came roaring back. Another trip to Seattle and enrollment in a clinical trial with lenalidomide (Revlimid) is keeping my cancer stable for the moment, but the specter of relapse and disease progression surrounds me. My doctors say that although my cancer is incurable, it’s treatable. But that

Enrollment in a clinical trial is keeping my cancer stable, but the specter of relapse and disease progression surrounds me. enough to set off panic attacks. Later, I also became anxious about how my friends now perceived me. They would say, “You look so healthy, you’re cured, aren’t you? When are you going back to work?” They really had no idea what I was going through. And then, just 3 years after undergoing the grueling transplants, I relapsed, which was excruciatingly

doesn’t mean it stays treatable for long periods of time, and I can never be sure what treatment will work, so the fear never leaves me. When you have an incurable cancer, death is always staring you in the face.

Bucket List of Accomplishments My goal for having the transplants was to buy enough time to make it to

Visit http://integrativecareftfuture.org/ for more information

Patient’s Corner is an occasional series in The ASCO Post that will profile individuals with cancer and provide their unique perspective and insight about their illness. at least 60 years old. I’m 57 now and I realize that I’m never going to be free of my cancer, so I’ve decided to enjoy every day. My wife, Mary Ellen, and I have made a vague bucket list of things we want to do and have begun to whittle it down. We’ve traveled all over the country and made a couple of long-awaited trips to Europe. Having the disease has also expanded our horizons. We went to Washington, DC, with the Multiple Myeloma Research Foundation to lobby Congress for more research dollars for blood cancers. And Mary Ellen and I, along with two other myeloma patients, started a myeloma support group in our community, which we have found to be immensely helpful. I’ve even taken up a few hobbies. Despite the physical, emotional, and financial toll this disease has taken on me—and my wife—I’m buoyed by the fact that new treatments have enabled me to outlive those dire survival statistics I found a decade ago. And with new drugs being approved every year for myeloma, hopefully, I’ll surpass my goal of seeing 60.

■

Bill Stokes, a retired dentist, lives with his wife, Mary Ellen, in Roanoke, Virginia.

The ASCO Post | MARCH 1, 2011

PAGE 30

In the Literature

Emerging Clinical Data on Cancer Management LUNG CANCER Endosonography with Surgical Staging for Nodal Staging of NSCLC Improves Sensitivity A staging strategy combining endosonography and surgical staging for patients with suspected non–small cell lung cancer (NSCLC) “resulted in greater sensitivity for mediastinal nodal metastases and fewer unnecessary thoracotomies” than surgical staging alone, according to a study in The Journal of the American Medical Association. In a randomized controlled trial, investigators at the Leiden University Medical Center in the Netherlands and other European centers compared surgical staging alone vs endosonography (combined transesophageal and endobronchial ultrasound) followed by surgical staging for patients with resectable (suspected) NSCLC in whom mediastinal staging was indicated based on CT or PET. Patients received either surgical staging or endosonography followed by surgical staging in case no nodal metastases were found at endosonography. Thoracotomy with lymph node dissection was performed when there was no evidence of mediastinal tumor spread. Among 241 randomly assigned patients, 118 underwent surgical staging and 123 had endosonography, including 65 who also underwent surgical staging. Nodal metastases were found in 41 patients (35%) by surgical staging vs 56 patients (46%) by endosonography, and in 62 patients (50%) by endosonography followed by surgical staging. This corresponded to sensitivities of 79% (41/52) vs 85% (56/66) and 94% (62/66), respectively, the authors noted. They reported that the number of unnecessary thoracotomies was 21 (18%) in the surgical staging group vs 9 (7%) in the endosonography group. There was no significant difference in the complication rate between the two groups—6% for surgical staging and 5% for endosonography. “We have shown that commencing mediastinal nodal staging with endosonography significantly improves the detection of nodal metastases and reduces the rate of unnecessary thoracotomies by more than half compared with surgical staging alone, in patients with resectable NSCLC,” the authors commented. “Furthermore, endosonography does not require general anesthesia, is preferred by

patients, and is considered cost-effective compared with surgical staging.”

Level of Expertise In an editorial accompanying the JAMA study, Mark D. Iannettoni,

MD, MBA, of the University of Iowa Hospitals and Clinics, pointed out that “highly skilled interventionalists are required to provide these exceptional outcomes,” and the level of expertise in endoscopic techniques in the study

INDICATIONS XELODA monotherapy is indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated, eg, patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents. Resistance is defined as progressive disease while on treatment, with or without initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen. XELODA in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.

is probably higher than that where most thoracic surgery procedures take place. “Until this modality can be reproduced at all centers where thoracic surgery is commonly performed, or until all of these patients are cared for

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XELODA is indicated as a single agent for adjuvant treatment in patients with Dukes’ C colon cancer who have undergone complete resection of the primary tumor when treatment with hyperbilirubinemia. Other adverse reactions, including serious fluoropyrimidine therapy alone is preferred. XELODA was nonadverse reactions, have been reported. inferior to 5-fluorouracil and leucovorin (5-FU/LV) for diseaseGENEXL-1043_Card_FM.indd 1 11/30/10 Important Safety Information – Monotherapy in MBC free survival (DFS). Although neither XELODA nor combination In a single arm study of XELODA monotherapy in metastatic chemotherapy prolongs overall survival (OS), combination breast cancer, serious adverse events (grade 3/4) occurring in therapy has been demonstrated to improve disease-free ≥5% of patients receiving XELODA (%) were lymphopenia (59), survival compared to 5-FU/LV. Physicians should consider diarrhea (15), hand-foot syndrome (11), hyperbilirubinemia these results when prescribing single-agent XELODA in the (11), fatigue (8), stomatitis (7), and dehydration (5). The most adjuvant treatment of Dukes’ C colon cancer. common adverse events for all grades occurring in ≥30% of Boxed WARNING and Additional Important Safety Information patients receiving XELODA were lymphopenia (94), anemia (72), diarrhea (57), hand-foot syndrome (57), nausea (53), Boxed WARNING fatigue (41), dermatitis (37), and vomiting (37). Warfarin Interaction—Coagulopathy Important Safety Information – Combination Therapy with >> Patients receiving concomitant capecitabine and oral Docetaxel in MBC coumarin-derivative anticoagulant therapy should have In a phase 3 study of XELODA combination therapy (XELODA their anticoagulant response (INR or prothrombin time) plus docetaxel) in metastatic breast cancer, serious adverse monitored frequently in order to adjust the anticoagulant events (grade 3/4) occurring at a ≥2% higher incidence in patients dose accordingly. receiving XELODA plus docetaxel vs docetaxel alone (%;%) were >> A clinically important XELODA-Warfarin drug interaction lymphocytopenia (89;84), hand-foot syndrome (24;1), stomatitis was demonstrated in a clinical pharmacology trial. (<18;5), diarrhea (<15;<6), anemia (10;<6), hyperbilirubinemia (9;4), nausea (7;2), vomiting (5;2), constipation (2;0), and nail >> Altered coagulation parameters and/or bleeding, disorder (2;0). The most common adverse events for all grades including death, have been reported in patients taking occurring at a ≥5% higher incidence in patients receiving XELODA concomitantly with coumarin-derivative XELODA plus docetaxel vs docetaxel alone were diarrhea (67;48), anticoagulants such as warfarin and phenprocoumon. stomatitis (67;43), hand-foot syndrome (63;8), nausea (45;36), >> Clinically significant increases in prothrombin time (PT) thrombocytopenia (41;23), vomiting (35;24), abdominal pain and INR have been observed in patients who were (30;24), hyperbilirubinemia (20;6), weakness (16;11), dyspepsia stabilized on anticoagulants at the time XELODA was (14;8), lacrimation increase (12;7), and appetite decrease (10;5). introduced. These events occurred within several days Important Safety Information – Monotherapy in Adjuvant and up to several months after initiating XELODA Colon Cancer therapy, and infrequently within 1 month after stopping XELODA. These events occurred in patients with and In a phase 3 study of XELODA monotherapy in colon cancer without liver metastases. in the adjuvant setting, serious adverse events (grade 3/4) occurring in ≥5% of patients receiving either XELODA or 5-FU/ >> Age greater than 60 and a diagnosis of cancer LV (%;%) were increase in bilirubin (20;7), hand-foot syndrome independently predispose patients to an increased risk (17;<1), decrease in lymphocytes (13;13), diarrhea (12;14), of coagulopathy. decrease in neutrophils/granulocytes (3;27), decrease in neutrophils (3;27), stomatitis (2;14), and neutropenia (<1;5). Contraindications The most common adverse events for all grades occurring in XELODA is contraindicated in patients with known ≥30% of patients receiving either XELODA or 5 FU/LV were hypersensitivity to capecitabine or to any of its components or hand-foot syndrome (60;9), diarrhea (47;65), nausea (34;47), to 5-fluorouracil. XELODA is also contraindicated in patients and stomatitis (22;60). A total of 18 deaths due to all causes with known dihydropyrimadine dehydrogenase (DPD) occurred either on study or within 28 days of receiving study deficiency, or severe renal impairment. drug: 8 (0.8%) patients randomized to XELODA and 10 (1.0%) randomized to 5-FU/LV Most Common Adverse Reactions The most common adverse reactions (≥30%) reported with Please see following brief summary of full Prescribing XELODA were diarrhea, hand-and-foot syndrome, nausea, Information, including Boxed WARNING, for additional vomiting, abdominal pain, fatigue/weakness, and Important Safety Information.

2:11 P

ASCOPost.com | MARCH 1, 2011

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In the Literature

at specialized centers, surgical staging must remain the gold standard for adequate preoperative evaluation,” Dr. Iannettoni stated. Annema JT, et al: JAMA 304:22452252, 2010. Iannettoni MD: JAMA 304:2296-2297, 2010.

MULTIPLE MYELOMA Newly Diagnosed Patients Show Improved Survival with Zoledronic Acid “Zoledronic acid significantly improved overall survival and progression-

free survival,” reported the authors of a large-scale trial comparing zoledronic acid with clodronic acid among patients with newly diagnosed multiple myeloma. Zoledronic acid reduced mortality by 16% vs clodronic acid and extended median overall survival by 5.5 months (to 50 vs 44.5 months). Progression-

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REACH OUT TO YOUR PATIENTS ON XELODA THERAPY TODAY. Terms and conditions No person or entity may seek reimbursement from any third-party payer for any amount provided using the card program. Genentech USA, Inc. reserves the right to deny payment under the card to anyone deemed ineligible in accordance with the stated program criteria. For full terms and conditions, questions about enrollment in other XELODA patient support programs, including nurse call support, call 1-877-987-2487 or visit www.xelodasupport.com. If your patients are not eligible, they may qualify for support offered by XELODA Access Solutions. To learn more call 1-888-249-4918.

free survival improved by 12% among patients receiving zoledronic acid, with increased median progression-free survival of 2 months (to 19.5 vs 17.5 months for patients receiving clodronic acid). Zoledronic acid also “significantly reduced the proportion of patients with continued on page 32

The ASCO Post | MARCH 1, 2011

PAGE 32

In the Literature

Zoledronic Acid in MM continued from page 31

a skeletal-related event.” The investigators noted, “zoledronic acid improved overall survival independently of the reduction in skeletal-related events, suggesting that the drug has underlying antimyeloma effects.”

The findings were based on 1,960 patients eligible for intention-to-treat analysis and published in The Lancet. All trial participants were at least 18 years old and enrolled from 120 centers in the United Kingdom. Patients were randomly assigned to receive either 4 mg of zoledronic acid as an infusion every 3 to

4 weeks or 1,600 mg of oral clodronic acid daily, along with intensive or nonintensive induction chemotherapy. Response rates did not differ significantly for patients receiving intensive vs nonintensive induction chemotherapy. “Both bisphosphonates were generally well tolerated, with similar oc-

currence of acute renal failure and treatment-emergent serious adverse events,” the investigators noted, “but zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw (35 [4%]) than was clodronic acid (3 [< 1%]). The authors concluded that their

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In the Literature

“findings support immediate treatment with zoledronic acid in patients with newly diagnosed multiple myeloma, not only for prevention of skeletalrelated events, but also for potential antimyeloma benefits.” Morgan GJ, et al: Lancet 376:19891999, 2010.

HEAD AND NECK CANCER Excellent Long-term Results with Regimen Containing Cetuximab With a stated goal of exploiting the chemo- and radiosensitizing

properties of cetuximab (Erbitux) to maximize the drug’s therapeutic effects, researchers at the University of Pittsburgh and its Cancer Institute designed and conducted a phase II trial incorporating cetuximab into induction therapy and subsequent chemoradiotherapy for

patients with locally advanced head and neck cancer. Of 39 enrolled patients, 36 had stage IV disease and 23 had an oropharyngeal primary. Trial participants received docetaxel and cisplatin on day 1, and cetuximab on days 1, 8, and 15 (after an initial cetuximab loading dose). This regimen, called TPE, was repeated every 21 days for three cycles. This was followed by a regimen, designated XPE, of radiotherapy with concurrent weekly cisplatin and cetuximab, and maintenance cetuximab for 6 months. Just 2 complete responses but 30 partial responses were observed after TPE, for an overall response rate of 86% in 37 evaluable patients. After XPE, the overall response rate was 100%, based on 24% complete responses and 76% partial responses, in 33 evaluable patients. With a median follow-up of 36 months, 3-year progression-free survival was 70% and overall survival was 74%.

Dermatitis and Clinical Outcome “Of interest,” the authors noted, “grade of dermatitis correlated with clinical outcome.” The higher the grade of dermatitis, the better the progression-free survival (P = .0088) and overall survival (P = .0117). Disease progression to locoregional sites occurred in eight patients, to distant sites in three patients, and one patient had progression to both locoregional and distant sites. All patients who experienced disease progression were smokers. Acute toxicities during TPE included neutropenic fever (10%), and during XPE, grade 3/4 oral mucositis (54%), dysphagia (48%), and hypomagnesemia (39%). The Functional Assessment of Cancer Therapy–Head and Neck (FACT-HN, version 4) quality-of-life scores showed no significant change during TPE, significantly decreased at 3 months after XPE, then normalized at 1 year after completion of chemoradiotherpy. “We found that a novel induction regimen incorporating cetuximab into a backbone of cisplatin and docetaxel had expected toxicities and substantial antitumor activity in patients with locally advanced [head and neck cancer],” the investigators concluded. They recommended further investigation of the TPE/XPE regimen.

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Argiris A, et al: J Clin Oncol 28:52945300, 2010.

S AVE

T HE

DATE

Breast Cancer Symposium 2011 SEPTEMBER 8-10, 2011 SAN FRANCISCO MARRIOTT MARQUIS SAN FRANCISCO, CALIFORNIA

For meeting updates, visit www.breastcasym.org. This activity has been approved for AMA PRA Category 1 Credit.™ TARG E T I NG

C A NC E R

C A RE

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Psychosocial Oncology

Management of Patients Scheduled for Cancer Surgery at Risk for Alcohol Withdrawal By Philip A. Bialer, MD

lcohol consumption is highly prevalent in the United States. National surveys indicate that approximately 52% of persons aged 12 and older are current drinkers. Heavy drinking, defined as having five or more drinks per day on at least 5 days in the past 30 days, was reported in 6.8% of the population or 17.1 million people.1 Approximately 6% of the population, or 15.4 million people, were classified as being dependent on or abusing alcohol according to DSM-IV criteria.2 People who are dependent on alcohol have developed tolerance and will experience withdrawal symptoms if they abruptly stop drinking. These individuals drink more than they intend, are unable to cut down or Dr. Bialer is Attending Psychiatrist at Memorial Sloan-Kettering Cancer Center, New York.

stop their drinking, and continue to drink despite known medical problems.

Associated Medical/Surgical Problems Heavy alcohol consumption is also associated with several types of cancer. Alcohol use disorders have been reported in over 50% of patients with upper GI tumors.3,4 Heavy alcohol users have also been shown to be at higher risk for head and neck cancers,5,6 hepatocellular cancers,7 highgrade prostate cancer,8 and, to a lesser extent, breast cancer9 and colorectal cancers.10 In addition, alcohol use is associated with numerous medical problems including gastritis, pancreatitis, cirrhosis, hepatic failure, cardiomyopathy, anemia, peripheral neuropathy, malnutrition, and dementia.

Relevant to surgical outcomes, heavy alcohol use is also associated with impaired hemostasis, immunosuppression, and increased stress response. One study that compared the postoperative course for misusers of alcohol to nonusers in patients admitted for elective colorectal surgery demonstrated that misusers experienced more postoperative complications (eg, bleeding, wound infection, pneumonia, intraabdominal abscess, and myocardial infarction), had longer hospital stays, and required more nursing care.11 Another study looking at postoperative outcomes in patients with head and neck cancer found that 40% of these patients suffered minor and major medical complications due to heavy alcohol and/or tobacco use; 11% suffered from alcohol withdrawal.12 The cost for patients with

Philip A. Bialer, MD

medical complications in this study was 71% higher than those without and was mostly attributed to ICU stays as well as an overall longer length of stay.

Surgical Alcohol Withdrawal Guidelines In order to address the postoperative complications associated with continued on page 36

Case Report: A Postsurgical Patient Undergoing Alcohol Withdrawal

r. E. is a 59-year-old man who was recently diagnosed with a locally advanced squamous cell cancer of the floor of the mouth. He was scheduled for surgery, which would include resection of the tumor with a partial glossectomy, and a left marginal mandibulectomy with a left modified radical neck dissection and flap reconstruction. Surgery was to be followed by external-beam radiation therapy to the face and neck. Five years earlier, this patient had been diagnosed with non–small cell lung cancer, which was treated by surgical resection and adjuvant chemotherapy. At that time he reported that he had been smoking 1 pack per day for 30 years and drank 1 pint of vodka per week. His postoperative course at that time was uneventful, and after his recovery and completion of his treatment he returned to work as a bus driver. He continued to smoke and resisted referrals to a smoking cessation program. When Mr. E. was going through his presurgical evaluation for the new head and neck cancer, he admitted that he was still smoking and said he would never be able to stop. The nurse also asked him if he was still drinking a pint of vodka

per week and he confirmed this. About 24 hours after his surgery, Mr. E. was noted to be mildly agitated. His pulse was running between 90 and 100 beats per minute, and his blood pressure was around 120/87 mm Hg. The surgical fellow thought the patient might be going through alcohol withdrawal (one of the nurses remembered him from his admission 5 years earlier and believed that he actually drank more than was reported on the admission note). The fellow ordered the administration of lorazepam, 1 mg IV every 6 hours, plus a one-time dose of thiamine, 100 mg.

Psychiatric Consultation The next day, a psychiatry consult was requested because the patient’s agitation was increasing and he seemed more confused. His pulse had risen to 100 to 106 beats per minute, and his blood pressure was also starting to rise. The psychiatry fellow tried to ask Mr. E. more questions about his drinking, and he continued to insist that he didn’t “drink that much—maybe a few drinks every day.” He was distracted and picking at his sheets but denied experiencing hallucinations. The psychiatry fellow was also concerned about alcohol withdrawal and recommended that the lorazepam be increased to 1 mg IV every 4 hours with 2 mg prn for

increased pulse and blood pressure. Since there were concerns that Mr. E. could also be mildly delirious from other causes such as infection or a reaction to opiate analgesia, the fellow also recommended haloperidol, 5 mg prn, for severe agitation. The nursing notes for the next 24 hours indicated that the patient continued to be mildly confused and agitated and that he calmed down when he received the prn lorazepam. He received four extra doses of lorazepam, 2 mg, in addition to the standing lorazepam, for a total of 14 mg over the next 24 hours. On postoperative day 3, Mr. E. started becoming much more agitated. When the psychiatry fellow returned, he noted that the patient’s pulse had increased to approximately 110 beats per minute and his blood pressure had increased to 180/100 mm Hg. Mr. E. was also now clearly experiencing visual hallucinations and was flushed and diaphoretic. The fellow had been able to contact the patient’s mother, with whom he lived, and learned that the patient had a long history of heavy alcohol use requiring two admissions for detoxification and that he was actually consuming at least 1 pint of vodka every day. The fellow determined that Mr. E. was now in delirium tremens and rec-

ommended that the lorazepam be increased to 2 mg every 4 hours and that he be evaluated for transfer to the ICU. Upon admission to the ICU, Mr. E. was placed on mechanical ventilation. He was sedated with propofol and fentanyl and placed on a lorazepam drip of 10 mg per hour.

Final Notes Mr. E. remained in the ICU for 10 days. Over that period, he was treated aggressively for medical problems including metabolic abnormalities and postsurgical infection. He was successfully weaned off the ventilator by day 6 of the ICU stay, and the lorazepam drip was tapered and finally discontinued on the day of his transfer out of the ICU. However the patient continued to appear tremulous, and his pulse and blood pressure both began to rise. He was placed back on a standing regimen of oral lorazepam, which was slowly and successfully tapered over the next 8 days. The patient was discharged 1 month after his surgical procedure. He refused a referral to an outpatient alcohol treatment program but did accept an appointment with our psychiatric clinic for follow-up.

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Psychosocial Oncology

Alcohol Withdrawal continued from page 35

long-term alcohol use and alcohol dependence we have developed a set of guidelines at Memorial Sloan-Kettering Cancer Center (MSKCC) to identify preoperatively the patients most at risk for alcohol withdrawal postoperatively. Those at increased risk for alcohol withdrawal include men who consume 60 or more grams of alcohol per day (12 oz of beer, 5 oz of wine, and 1.5 oz of spirits each contain about 15 g of alcohol), patients who have a past history of alcohol withdrawal seizures or delirium tremens, patients over 65, and patients with comorbid medical conditions. The amount of daily alcohol consumption that puts women at risk is less clear but, due to pharmacokinetic differences, is probably much less than in men. Our screening consists of asking patients the number of drinks or alcohol equivalents (15 g of alcohol, as defined above) they consume on a daily basis. In addition, each patient is administered the CAGE questionnaire, an instrument that was developed to identify clinical alcoholism in patients (see Table 1).13,14 This screening is done at two time points: during the first presurgical office visit and again when the patient comes in for presurgical testing. All patients are also given information cards educating them about the surgical

Table 1: CAGE Questionnaire* Have you ever felt you should Cut down on your drinking? Have people Annoyed you by criticizing your drinking? Have you ever felt bad or Guilty about your drinking? Have you ever had a drink first thing in the morning (Eye-opener) to steady your nerves or get rid of a hangover? *Time reference for screening at Memorial Sloan-Kettering Cancer Center is the past year.

risks of alcohol and advised to cut down or stop drinking prior to their surgery. Patients are screened positive if they report that they consume four or more drinks per day or have two or more positive answers on the CAGE questionnaire. These patients are then referred for a medical consultation to further evaluate their risk for postoperative alcohol withdrawal. The consultant will work with patients who are determined to be most at risk for alcohol withdrawal, to help them cut down or possibly detoxify, if time permits

Table 2: Alcohol Withdrawal Prophylactic Regimen ■■ Lorazepam, 1 mg IV every 6 hours for 8 doses ■■ Taper: Lorazepam, 0.5 mg every 6 hours for 8 doses ■■ Thiamine, 100 mg IV or po daily for 3 days ■■ Folic acid, 1 mg IV or po for 3 days Lorazepam is held for excessive sedation Medical/psychiatric consultant continues taper and discontinuation of lorazepam beyond above regimen if no indication of withdrawal

and adequate home support is available. Further psychiatric consultation may also be advised for patients with severe alcohol dependence or coexisting psychiatric disorders. For patients with cancer who are found to be alcohol dependent, however, preoperative detoxification is not usually possible or practical. For many of these patients, we recommend an alcohol withdrawal prevention regimen (see Table 2). This regimen was developed from evidence-based guidelines for the treatment of alcohol withdrawal,15 but because this is a prophylactic regimen, we begin with lower dosing. Although alcohol withdrawal usually begins approximately 24 hours after the last drink, symptoms may sometimes appear within 6 to 12 hours. The prophylactic regimen is therefore begun in the recovery room as soon as the patient reaches a specified level of consciousness. The prophylactic regimen is not used for patients undergoing outpatient surgery. When the patient is discharged from the recovery room, the medical or psychiatric consultant continues to work with the team to continue the taper and discontinuation of lorazepam. The consultant may also recommend modifications of the regimen as clinically indicated, ie, lower or discontinue lorazepam if the patient appears oversedated, or increase the dosing if the patient has signs and symptoms of withdrawal.

Effectiveness of Guidelines The most important part of these guidelines has been to do a better, more focused job of identifying patients at risk for alcohol withdrawal presurgically so that appropriate multidisciplinary measures can be implemented when the patient comes in for a procedure. Such identification may have prevented the severe withdrawal and prolonged hospitalization of the patient in the case example (see sidebar). While we chose to use the CAGE questionnaire as part of our screening, other instruments such as the Alcohol Use Disorders Identification Test (AUDIT-C) have also been found to be very useful for identifying

patients with alcohol dependence.16,17 Once patients at risk have been identified, the implementation of the prophylactic regimen is intended to prevent the onset of alcohol withdrawal and accompanying postoperative morbidity. We are currently evaluating the effectiveness of our guidelines through a quality assurance project, but preliminary observations indicate that fewer cases of postsurgical alcohol withdrawal have been seen since these guidelines went into effect.

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References 1. Substance Abuse and Mental Health Services Administration, Office of Applied Studies: Results from the 2009 National Survey on Drug Use and Health: Volume 1. Summary of National Findings. NSDUH Series H-38A, HHS Publication No. 10-4586Findings, Rockville, Maryland, 2010. 2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Association, 1994. 3. Layke J, Lopez P: Esophageal cancer: A review and update. Am Fam Physician 73:2187-2194, 2006. 4. Steevens J, Schouten LJ, Goldbohm RA, et al: Alcohol consumption, cigarette smoking and risk of subtypes of oesophageal and gastric cancer: A prospective cohort study. Gut 59:39-48, 2010. 5. Marur S, Forastiere A: Head and neck cancer: Changing epidemiology, diagnosis, and treatment. Mayo Clin Proc 83:489-501, 2008. 6. Argiris A, Karamouzis M, Raben D, et al: Head and neck cancer. Lancet 371:1695-1709, 2008. 7. Rehm J, Baliunas D, Borges GLG, et al: The relation between different dimensions of alcohol consumption and burden of disease: An overview. Addiction 105:817-843, 2010. 8. Gong Z, Kristal A, Schenk J, et al: Alcohol consumption, finasteride, and prostate cancer risk: Results from the Prostate Cancer Prevention Trial. Cancer 115:3661-3669, 2009. 9. Stolzenberg-Solomon R, Chang S-C, Leitzmann M, et al: Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Am J Clin Nutr 83:895-904, 2006.

10. Acott A, Theus S, Marchant-Miros K, et al: Association of tobacco and alcohol use with earlier development of colorectal cancer: Should we modify screening guidelines? Am J Surg 196:915-918, 2008. 11. Tonnesen H, Petersen KR, Hjgaard L, et al: Postoperative morbidity among symptom-free alcohol misusers. Lancet 340:334-337, 1992. 12. Jones N, Jarrahy R, Song JI, et al: Postoperative medical complications— not microsurgical complications—negatively influence the morbidity, mortality, and true costs after microsurgical reconstruction for head and neck cancer. Plast Reconstr Surg 119:2053-2060, 2007. 13. Ewing JA: Detecting alcoholism. The CAGE questionnaire. JAMA 252:1905-1907, 1984. 14. O’Brien CP: The CAGE questionnaire for detection of alcoholism: A remarkably useful but simple tool. JAMA 300:2054-2056, 2008. 15. Mayo-Smith MF: Pharmacological management of alcohol withdrawal. A meta-analysis and evidence-based practice guideline. American Society of Addiction Medicine Working Group on Pharmacological Management of Alcohol Withdrawal. JAMA 278:144-151, 1997. 16. Bush K, Kivlahan DR, McDonell MB, et al: The AUDIT Alcohol Consumption Questions (AUDIT-C): An effective brief screening test for problem drinking. Arch Intern Med 158:1789-1795, 1998. 17. Rubinsky A, Kivlahan D, Volk R, et al: Estimating risk of alcohol dependence using alcohol screening scores. Drug Alcohol Depend 108:29-36, 2010.

Jimmie Holland, MD, Guest Editor

Providing care beyond medical treatment, the multidisciplinary field of psychosocial oncology addresses the psychological, social, and emotional health of the patient with cancer. On an occasional basis, The ASCO Post will explore the realm of psychosocial oncology with a column guest edited by Jimmie Holland, MD, Wayne E. Chapman Chair in Psychiatric Oncology at Memorial Sloan-Kettering Cancer Center, New York.

ASCOPost.com | MARCH 1, 2011

PAGE 37

JOP Spotlight Survivorship

Assisting Cancer Survivors in Managing Unexplained Symptoms By Charlotte Bath

ever before in the history of the war on cancer have we had such a large number of individuals living with long-term and late effects” of cancer treatment, according to an article in the Journal of Oncology Practice.1

Journal of Oncology Practice

American Society of Clinical Oncology

THE AUTHORITATIVE RESOURCE

VOLUME 6

ISSUE 1

FOR

ONCOLOGY PRACTICES

JANUARY 2010

Filling the Gap: Development of the Oncology Nurse Practitioner Workforce “Developing new strategies for oncology care delivery by increasing the numbers and expanding the roles of nonphysician practitioners, such as nurse practitioners (NPs) and physician assistants (PAs), is critically important to meet the current and potential cancer care needs of the US population.”

By Brenda Nevidjon, MSN, RN, FAAN, et al

Ensuring Quality Cancer Care Through the Oncology Workforce

“There is a crisis in the oncology workforce. Health professionals . . . are experiencing significant workforce shortages . . . because of the rapidly growing population of Americans requiring cancer care, an aging oncology workforce, and inadequate numbers of newly trained workers. This mismatch between supply and demand for cancer care could threaten patient care, safety, and quality.”

Role of Advanced Nurse Practitioners and Physician Assistants in Washington State By Jonathan C. Britell, MD

Practical Model for Psychosocial Care By Susan S. Hendrick, PhD, et al

Physician Assistant Perspective on the ASCO Workforce Study Regarding the Use of Physician Assistants and Nurse Practitioners By Maura Polansky, MS, PA-C, et al

Georgia Society of Clinical Oncology Forms a Patient Navigator Affiliate Basic Steps to Building a Research Program By Allison Baer, RN, BSN, et al

By Laura Levit, JD, et al

http://jop.ascopubs.org

Currently, many survivors with persistent and unexplained symptoms after cancer diagnosis and treatment are “left to their own resolve to search for evaluation and treatment for these troublesome symptoms,” the authors reported. A better solution, they said, would be for oncologists and other health professionals “to assess and directly target these symptoms for appropriate triage to those who can best help these survivors reduce the symptoms and their impact.”

Unexplained but Significant While patients treated for cancer are often counseled to pay attention to symptoms that could indicate recurrence, any symptoms that apparently fail to indicate any change in tumor activity are often relegated to the unexplained symptoms category, defined as “symptoms for which no objective physical or pathological changes can be found.” These symptoms can, however, impact function or quality of life for patients. “Providers can assist these survivors in their efforts at long-term optimization of health, function, and well-being,” the authors stated, “by simply making appropriate referrals when unexplained symptoms negatively impact the survivor.” If evaluation reveals any negative impact on function, such as reduced endurance, flexibility, or strength, intervention options could include physical Use your smartphone to view the full text of the paper discussed in this article by SEE PAGE 38 Feuerstein et al, as published in the Journal of Oncology Practice (6:308-311, 2010).

medicine and rehabilitation, nutritional counseling, physical therapy, occupational therapy, complementary and alternative medicine, vocational counseling, and fitness training. If the patient

is experiencing fear, distress, or other negative effects on well-being, intervention options could include targeted medication, support groups, and culturally sensitive interventions.

■

Reference 1. Feuerstein M, Bruns GL, et al: Management of Unexplained Symptoms in Survivors of Cancer. J Oncol Pract 6:308311, 2010.

The ASCO Post | MARCH 1, 2011

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Expert’s Corner Growth Factors

A Conversation with Pediatric Oncologist Sheri L. Spunt, MD Making neutropenia treatment easier to endure for children with cancer By Jo Cavallo

Sheri L. Spunt, MD

heri L. Spunt, MD, Associate Member in the Department of Oncology’s Solid Tumor and Cancer Survivorship Divisions at St. Jude Children’s Research Hospital in Memphis, has dedicated her career to the study of childhood soft-tissue sarcomas and the late effects of treatment on pediatric patients with cancer. Last year, in collaboration with several other institutions, Dr. Spunt completed a randomized study comparing the safety and efficacy of the synthetic growth factors pegfilgrastim (Neulasta) and filgrastim (Neupogen) and how the agents are used and metabolized in young bodies. The study found that while both drugs were effective and safe in stimulating neutrophil production following chemotherapy, a single dose of pegfilgrastim was similar to multiple injections of filgrastim, improving quality of life for both patients and their families. The results are likely to make pegfilgrastim standard of care for pediatric patients with cancer requiring neutrophil growth factors, according to Dr. Spunt. In December, the NCI recognized Dr. Spunt’s body of work with a Cancer Clinical Investigator Team Leadership Award (see sidebar). The ASCO Post talked with Dr. Spunt about the results of her neutrophil study and what the NCI award means to her future research.

Impact of Study Will your study findings alter the way children are treated for neutropenia following chemotherapy treatments? Sheri L. Spunt: Yes, I hope so. Neutrophil growth factors have been very helpful in allowing the intensification of chemotherapy treatment. But until now, this has required daily subcutaneous injections beginning the day after

chemotherapy ends and continuing for 7 to 10 days. That’s obviously quite painful and burdensome for patients, and in the case of children, for their families as well. The benefit of using pegfilgrastim is that a single injection can be given the day after chemotherapy is completed and the drug remains in the body for the duration of low blood counts. Pegfilgrastim is a beautifully designed drug because it is metabolized by the white blood cells, so as the white blood cell count rises after chemotherapy, the drug is metabolized and goes away. Previously, we had to give daily injections of filgrastim until we thought that the white blood cell count had adequately recovered. That required a lot of blood tests and trips to the hospital. Pegfilgrastim allows us to give a single injection with no blood count monitoring at all. Not only does the drug save time, it also saves a lot of pain and suffering for patients.

Forthcoming Research How will winning the NCI Leadership Award help further your research? Dr. Spunt: Most people know me for my work on pediatric nonrhabdomyosarcoma soft-tissue sarcomas, which constitute about 4% of childhood cancers, but for which there have been few prospective studies. These tumors are also relatively common in adolescents and young adults, a group that has been neglected in clinical trials. I am running a phase III trial through the Children’s Oncology Group that is designed to determine the best therapy for these patients. Efforts are also underway to use what we’ve learned about the biology of these tumors to design the next clinical trial. In recent years, I’ve become interested in the late effects of treatment—not in terms of how to manage patients with late effects, but to figure out what late effects tell us about how we ought to make treatment decisions in the future. I’m using the NCI grant to make a transition into more late-effects research, and I’m planning to embark on studies of long-term survivors with sarcomas to elucidate some of these late effects.

Avoiding Late Effects Can some late effects be prevented? Could changes in treatment achieve that? Dr. Spunt: There are clinical situations where we have various options

for treatment and often we don’t know which is the best because they have similar outcomes in terms of survival. But we really don’t know what happens in terms of late effects. For example, in children with bladder rhabdomyosarcoma, both surgical removal of the bladder and radiation to the bladder are equally effective in curing the disease, and there’s a lot of controversy about which is the best approach in terms of long-term function. Studies looking at these issues will, hopefully, clarify the long-term consequences of both options and help us make better decisions

about how we treat these patients. The other thing that is not well understood is the burden of the various toxicities. We have studies that look specifically at cardiotoxicity, learning problems, or other individual toxicities, but we haven’t come up with a good way of measuring the overall burden of therapy for patients. Although we’re happy to be curing more of these children, we can’t be satisfied until we cure them with good long-term function.

■

Financial disclosure: Dr. Spunt has received research funding from Amgen.

NCI’s Cancer Clinical Investigator Team Leadership Awards

ast November, NCI announced the recipients of its Cancer Clinical Investigator Team Leadership Award for 2010, recognizing exceptional contributions to the advancement of new therapies through collaborative team science. The awardees were: ■■ Dr. Rafat Abonour, Indiana University Melvin and Bren Simon Cancer Center ■■ Dr. Jeffrey Bradley, Siteman Cancer Center ■■ Dr. Steven Cohen, Fox Chase Cancer Center ■■ Dr. Linda Duska, University of Virginia Cancer Center ■■ Dr. Naomi Haas, Abramson Cancer Center ■■ Dr. Elisabeth Heath, The Barbara Ann Karmanos Cancer Institute ■■ Dr. Susan Kelly, The University of Texas MD Anderson Cancer Center ■■ Dr. Smitha Krishnamurthi, Case Comprehensive Cancer Center ■■ Dr. Suresh Ramalingam, Winship Cancer Institute ■■ Dr. David Rizzieri, Duke Comprehensive Cancer Center ■■ Dr. Cheryl Saenz, Moores Cancer Center ■■ Dr. Sheri Spunt, St. Jude Children’s Research Hospital Designed for midlevel clinical investigators, the 2-year awards provide recognition and $50,000 in funding for those who lead cancer research programs and clinical trials at NCI-designated cancer centers. The funding is provided to the recipient’s institution and can be applied toward the investigator’s salary, fringe benefits, and associated facilities and administrative costs. Recipients are expected to devote 10% to 15% of their time to the activities associated with the award. The awards are the result of one of the recommendations of NCI’s Clinical Trials Working Group (CTWG), which was established to advise the Institute on methods to improve and enhance the publicly funded clinical trials enterprise. The broad clinical trials community, including the Clinical Trials and Translational Research Advisory Committee, provided input into the award’s development. “NCI is pleased to be able to recognize these key clinical investigators, without whom we couldn’t conduct clinical trials,” said Sheila Prindiville, MD, Director of NCI’s Coordinating Center for Clinical Trials, the office that oversees implementation of the CTWG’s recommendations. “These recipients have exceptional leadership skills in cancer clinical trial activities and have demonstrated a commitment to conducting cancer clinical trials that promise to advance care for patients.” The awards, available to investigators at all NCI-designated cancer centers that participate in NCI-funded collaborative clinical trials, ultimately support a shared culture in which investigators collaborate freely across disciplines, institutions, and programs to most expeditiously advance the design and conduct of cancer clinical trials.

■

ASCOPost.com | MARCH 1, 2011

PAGE 39

News Gynecologic Cancer

Phase III Study Meets Primary Endpoint in Ovarian Cancer

phase III study evaluating bevacizumab (Avastin) in combination with carboplatin and gemcitabine followed by continued use of bevacizumab alone until disease progression in women with recurrent, platinumsensitive ovarian cancer, met its primary endpoint, according to a statement released by Genentech, a member of the Roche Group. The study known as OCEANS is a multicenter, randomized, doubleblind, placebo-controlled phase III trial in 484 women with platinumsensitive recurrent ovarian, primary peritoneal or fallopian tube cancer. The primary endpoint of the study was progression-free survival. The secondary endpoints of the study included overall survival, objective response, duration of response, and safety.

zumab in combination with carboplatin and paclitaxel, followed by the continued use of bevacizumab alone, significantly increased the time women with ovarian cancer lived without their disease getting worse, compared to those treated with che-

motherapy alone. No new safety findings were observed and adverse events were consistent with those seen in previous pivotal trials of bevacizumab. Serious adverse events associated with bevacizumab in previous trials include gas-

trointestinal perforation, surgical and wound-healing problems, and severe bleeding. According to the statement, full data from the OCEANS study will be submitted for presentation at an upcoming medical meeting.

■

Key Finding According to the statement from Genentech, recently released data from the OCEANS study indicated that women who received a combination of bevacizumab (15 mg/kg every 3 weeks) and chemotherapy, followed by the continued use of bevacizumab alone, lived longer without their disease worsening, compared to women who received chemotherapy alone. Women in OCEANS had received no more than one treatment regimen prior to enrollment in the trial. The results from this trial build on findings from two previous phase III studies (GOG 0218 and ICON7) in women with newly diagnosed ovarian cancer. Both of these studies demonstrated that first-line bevaci-

Coming in future issues of

The ASCO Post Coverage of these important meetings: 2011 Genitourinary Cancers Symposium National Comprehensive Cancer Network 16th Annual Conference

Conquering

Cancer. Together, anything is possible. The Conquer Cancer Foundation. Our name says a lot. Our mission says even more: Conquering cancer worldwide by funding breakthrough research and sharing cutting-edge knowledge. We are the go-to organization in supporting the world’s pre-eminent cancer specialists, so one day we can live in a world free from the fear of cancer. To get to know us better now and be a part of our ambitious future, visit ConquerCancerFoundation.org.

ConquerCancerFoundation.org

The ASCO Post | MARCH 1, 2011

PAGE 40

News Breast Cancer

Six Chemotherapy Cycles Not Better than Four in Early Breast Cancer Longer treatment was more toxic By Caroline Helwick

onger duration of treatment for primary breast cancer was not superior to a shorter regimen in the Cancer and Leukemia Group B (CALGB) 40101 trial, whose first results were presented by Lawrence N. Shulman, MD, of Dana-Farber Cancer Institute, at the 33rd Annual San Antonio Breast Cancer Symposium.1

Study Rationale CALGB 40101 is a 2×2 factorial phase III trial that was initiated in 2002 to determine the equivalence of single-agent paclitaxel with doxorubicin/cyclophosphamide (AC) for

Further Reflection on CALGB 40101

earing the trial results of CALGB 40101 at the meeting, Steven Vogl, MD, of Bronx, New York, praised the study investigators for conducting one of the few trials to look at duration of chemotherapy as an isolated variable. On further reflection, he told The ASCO Post he hopes to see analyses of distant vs local relapse, compliance to the protocol, and an analysis of delivered treatment as well as intent to treat. Dr. Vogl added that data from the National Surgical Adjuvant Breast and Bowel Project’s Oncotype DX studies suggest that a large proportion of ER-positive nodenegative patients derive little or no benefit from chemotherapy in addition to hormonal therapy. It is likely that the study population in this trial was enriched for such patients, he suggested. “Obviously, giving ineffective therapy longer will not help patients,” he concluded.

■

Steven Vogl, MD

relapse-free survival, and to determine if longer therapy (six cycles) is superior to shorter therapy (four cycles), regardless of the agent. Patients were randomly assigned to AC or paclitaxel for four or six cycles (usually given every 2 weeks), followed by hormone therapy if their disease was estrogen receptor (ER)-positive and trastuzumab (Herceptin) if HER2positive. “Taxane-containing regimens have been compared to AC, showing favorable results but increased toxicity. Studies in locally advanced disease raise the possibility of equivalence of single-agent taxane to AC-based regimens, avoiding the anthracycline and potentially reducing short- and long-term toxicity. The ideal duration of adjuvant therapy for patients with good-prognosis breast cancer is unknown, and AC × 4 and other regimens given for six cycles are frequently used,” Dr. Shulman said. In September 2010, data were released for six vs four cycles, based on 3,173 patients followed for an average of 4.6 years. Most patients had T1 tumors, 94% were node-negative, 64% were ER-positive, and 20% were HER2-positive. This analysis looked just at duration of therapy. Data for AC vs paclitaxel have not yet been released.

Survival Rates Equivalent “Relapse-free survival was 92% in each arm. There was no superiority of six over four cycles,” Dr. Shulman announced (Table 1). “Also, in ER-positive patients there was no evidence that six cycles was better, nor was there for ER-negative patients.” Overall survival rates (a secondary endpoint) were also similar (95.3% vs 96.4% for six vs four cycles, respectively). For ER-positive patients, the relapse-free survival rate at 4 years was 93.8% with four cycles and 94.4% with six cycles, and overall survival was 98.0% and 97.7%, respectively. For ER-negative patients, relapse-free survival was 88.0% with four cycles and 85.5% with six cycles while overall survival rates were 93.3% and 91.3%, respectively For HER2-negative patients, relapse-free survival was 91.7% with four cycles and 91.1% with six cycles,

Chemotherapy Duration for Primary Breast Cancer ■■ Extending adjuvant chemotherapy with doxorubicin/

cyclophosphamide or paclitaxel from four to six cycles did not improve outcome in a trial of 3,173 patients with early breast cancer.

■■ Survival at 4 years was similar: roughly 92% relapse-free survival

regardless of treatment duration and 95.3% vs 96.4% overall survival for six vs four treatment cycles, respectively.

■■ Hematologic and cardiotoxicity were greatest with the doxorubicin/ cyclophosphamide regimen, especially in the six-cycle arm.

and overall survival was 96.2% and 95.9%, respectively. For HER2-positive patients, relapse-free survival was 93.4% and 92.6%, respectively, and overall survival was 96.6% and 96.0%, respectively.

Lawrence N. Shulman, MD

Toxicity Differences Hematologic toxicity was greater with both AC regimens, especially with six cycles. Neuropathy was seen only in the paclitaxel arms. Cardiac toxicity occurred mainly with six cycles of AC. Among 790 patients in this arm, grade 3 left-ventricular systolic dysfunction was observed in 2 patients, grade 4 in 2 patients, and grade 5 in 1 patient, while 1 patient had grade 3 restrictive cardiomyopathy. “AC × 6 is more cardiotoxic,” Dr.

Shulman emphasized. Acute myeloid leukemia developed within 1 to 2 years in five patients treated with AC × 6 and one with AC × 4. No such cases were seen with paclitaxel. By number of cycles, 65 of 1,593 patients have died in the four-cycle arm and 85 of 1,579 in the six-cycle arm, including 41 and 50 breast cancer deaths, respectively, and two and five treatment-related deaths. “All the treatment-related deaths were in the AC arms, and there were more deaths with six cycles of treatment,” he noted. “We conclude that six cycles of AC or paclitaxel for patients with primary breast cancer and zero to three positive axillary nodes is not superior to four cycles of therapy,” Dr. Shulman said. “Based on the present data, the Bayesian predictive probability of concluding superiority of six cycles is only 0.001.”

Relevant Findings Hearing the results, Steven Vogl, MD, of Bronx, New York, commented that he viewed the findings as relevant for his clinical practice. “I think

Table 1: Relapse-free and Overall Survival in Early Breast Cancer (N = 3,173) Number of Chemotherapy Cycles

Relapse-free survival at 4 yr

6 cycles

91.6%

4 cycles

P value

1.10 (0.87–1.39)

.42

Hazard Ratio for 6 vs 4 cycles (CI)

P value

1.31 (0.95–1.82)

.097

91.8% Overall Survival at 4 yr

6 cycles

Hazard Ratio for 6 vs 4 cycles (CI)

95.3% 96.4%

ASCOPost.com | MARCH 1, 2011

PAGE 41

News

this is an important study. It is one of the few actually looking at the duration of chemotherapy as the isolated variable.” Nevertheless, he said that the study did have its limitations (see sidebar). Dr. Vogl suggested that the investigators zero-in on distant metastases when assessing differences between the arms. “Because this is such a goodrisk population, you may not expect many of the relapse-free survival events to be affected by chemotherapy. We would hope that chemotherapy would reduce the incidence of distant metastases, and you should look at this as the study matures,” he offered. Dr. Shulman noted that at this point there are more breast cancer deaths with six cycles in the ER-positive group, although this difference is not statistically significant. This finding is consistent with results in the ER-negative subgroup. He also mentioned that six cycles should be more

likely to induce menopause and thus enhance the benefit of longer therapy in the ER-positive subgroup. “It did induce menopause, but the additional benefit was not observed,” he said. The good prognosis of the patient population, however, may have diluted an effect, he added.

■

Reference 1. Shulman LN, Cirrincione C, Berry DA, et al: Four vs 6 cycles of doxorubicin and cyclophosphamide or paclitaxel as adjuvant therapy for breast cancer in women with 0-3 positive axillary nodes: CALGB 40101. 33rd Annual San Antonio Breast Cancer Symposium. Abstract S6-3. Presented December 11, 2010.

Use your smartphone to view the abstract discussed in this article by Shulman SEE PAGE 47 et al from the 33rd Annual San Antonio Breast Cancer Symposium.

FDA Update

First 3D X-ray Mammography Imaging System

he FDA recently approved the Selenia Dimensions System, the first x-ray mammography device that provides three-dimensional (3D) images of the breast for breast cancer screening and diagnosis. The Selenia Dimensions System, an upgrade to Hologic’s existing FDA-approved two-dimensional (2D) system, can provide 2D and 3D x-ray images of the breasts. With the limitations of conventional 2D imaging, about 10% of women undergo additional testing after the initial screening exam for abnormalities that are later determined to be noncancerous. The 3D images may help physicians more accurately detect and diagnose breast cancer. As part of the approval process, the FDA reviewed results from two studies where board-certified radiologists were asked to review 2D and 3D images from more than 300 mammography exams. In both studies, radiologists viewing both the 2D and 3D images obtained a 7% improvement in their ability to distinguish between cancerous and noncancerous cases as compared to viewing 2D images alone.

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Other pathways can contribute to prostate cancer promotion.5 References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11): 4447-4454. 2. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68(15):64076415. 3. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66(5):2815-2825. 4. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11(13):4653-4657. 5. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12(6):1665-1671.

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News Breast Cancer

CYP2D6 Levels Not Predictive of Tamoxifen Efficacy in Two Major Trials By Caroline Helwick

ncologists concerned about cytochrome P450 2D6 (CYP2D6) metabolism in patients taking tamoxifen for breast cancer can relax a bit, based on two key studies and expert commentary from the 33rd Annual San Antonio Breast Cancer Symposium in December.

cines, particularly selective serotoninreuptake inhibitors (SSRIs). It has been proposed that knowing a patient’s CYP2D6 levels could help clinicians to individualize endocrine therapy, but the adjuvant studies presented at the San Antonio meeting call this into question. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial and Breast International Group (BIG) 1-98 trial found little association between variations in CYP2D6 levels and tamoxifen’s efficacy, leaving the value of CYP2D6 monitoring an open question.

ATAC James Rae, PhD

CYP2D6 is intricately involved in the metabolism of tamoxifen and its bioactive form, endoxifen. As the BIG 1-98 study (discussed below) showed, 9% of Caucasian women have an absence of activity of this enzyme and 27% have low enzyme activity. Several studies have suggested that patients who are poor metabolizers of CYP2D6 may not derive optimal benefit from tamoxifen. In addition, CYP2D6 can be inhibited by concomitant medi-

“Does the CYP2D6 genotype predict tamoxifen response? We thought it would be important to test this hypothesis in the ATAC trial,” said James Rae, PhD, of the University of Michigan, Ann Arbor.1 ATAC compared 5 years of adjuvant anastrozole against tamoxifen in 9,366 patients with early breast cancer. CYP2D6 genotype data for the seven most common alleles, including CYP2D6*4, were used to assign each patient a CYP2D6 score based on predicted allele activities, from 0 (no activity) to 2 (high activity).

CYP2D6 and Tamoxifen in Women with Breast Cancer ■■ Analyses from ATAC and BIG 1-98 found no significant association between CYP2D6 levels (ie, strength of metabolism) and outcomes with adjuvant tamoxifen.

■■ Hot flushes also were not predictive of tamoxifen efficacy. ■■ Patients should still use potent CYP2D6 inhibitors with caution. ■■ Testing for CYP2D6 level is possibly warranted only in select patients. The CYP2D6 scoring system separates patients into poor, intermediate, and extensive endoxifen metabolizers. The study looked at an activity/doseresponse relationship in 588 patients randomly assigned to receive tamoxifen and 615 who received anastrozole. After 10 years median follow-up, the investigators found 115 recurrences in the tamoxifen cohort, but these were not associated with CYP2D6 score. The hazard ratios were 1.06 for poor metabolizers, 0.92 for intermediate metabolizers, and 1.0 for extensive metabolizers, which were not significantly different. Also, no association was found between the 92 recurrences in the anastrozole cohort and CYP2D6 score. The use of SSRIs also had no dis-

cernible effect on CYP2D6 levels. “We controlled for potent CYP2D6 inhibitors, and we did not see an influence on outcomes,” Dr. Rae said. Dr. Rae concluded that there is insufficient evidence for recommending CYP2D6 genotyping for patients initiated on tamoxifen, nor is there a reason to avoid CYP2D6 inhibitors in these patients.

BIG 1-98 Similarly, for the BIG 1-98 trial, Brian Leyland-Jones, MD, PhD, of Emory Winship Cancer Institute, of Emory University, Atlanta, reported that CYP2D6 phenotype as well as reduced enzyme activity did not compromise disease control.2

Much Work Still Needed to Understand the Metabolism of Tamoxifen

atthew P. Goetz, MD, from the the International Tamoxifen PharmaMayo Clinic in Rochester, Mincogenomics Consortium showed no asnesota, discussed the papers at the San sociation between CYP2D6 genotype Antonio session and offered insight and disease-free survival with adjuvant into the discrepancies and confusion tamoxifen,” he noted.1 surrounding CYP2D6 and tamoxifen. Standard-defining Studies Since 2003, PubMed has listed 178 The new data are an important addipublications on CYP2D6 genotyption to the discussion, Dr. Goetz noted, ing and endocrine therapy. Of those, since ATAC and BIG 1-98 14 reported positive asare from large, prospective sociations, whereas 15 adjuvant trials “that defined reported no association. the standard of care for ear“Between-study varily-stage breast cancer.” He ability in the definition acknowledged, however, of metabolism, the specthat limitations still exist trum of CYP2D6 alleles with regard to their study tested, and differences in design. the determination of and The new studies, he said, duration of CYP2D6 inMatthew Goetz, MD circumvented some of the hibitor use, the patient limitations associated with populations, study deCYP2D6 testing based on tumor-derived sign, and endpoints have resulted in DNA. “The number of CYP2D6 alleles inconsistent findings,” he said. was about as good as you can get from “Last year at San Antonio, a pooled tumor-derived DNA,” and the study analysis of almost 3,000 patients in

“controlled for factors such as estrogenreceptor expression and chemotherapy administration—factors that have been problematic with other studies.” Part of the problem in elucidating any relationship is that CYP2D6 level only partially explains the wide variability in endoxifen pharmacokinetics, he said. There is also a need for studies to employ a standardized scoring system.

Clinical Recommendations Dr. Goetz called for prospective studies that might decisively define the role of tamoxifen and its metabolites, elucidate the critical threshold for endoxifen concentrations and tamoxifen efficacy, and decipher the interaction between tumor subtypes and the pharmacokinetics of tamoxifen. Meanwhile, Dr. Goetz made the following recommendations: ■■ Women should be informed of the controversy regarding the pharmacogenetics of tamoxifen. ■■ Caregivers should exert caution and

avoid potent endoxifen inhibitors in women treated with tamoxifen. ■■ Caregivers should not recommend routine CYP2D6 testing in postmenopausal women to preferentially select them for either tamoxifen or aromatase inhibitors. Testing CYP2D6 level remains controversial for routine use, Dr. Goetz maintained. However, he would consider the practice in certain postmenopausal women with high-risk disease who may be leaning toward a preference for tamoxifen.

■

Reference 1. Goetz MP, Berry DA, Klein TE, et al: Adjuvant tamoxifen treatment outcome according to cytochrome P450 2D6 (CYP2D6) phenotype in early stage breast cancer: Findings from the International Tamoxifen Pharmacogenomics Consortium. 32nd San Antonio Breast Cancer Symposium. Abstract 33. Presented December 11, 2009.

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BIG 1-98 compared 5 years of letrozole (Femara), tamoxifen, and sequences of letrozole and tamoxifen in 8,010 patients, of whom 4,628 were genotyped for CYP2D6 and classified (according to the CYP2D6 scoring system) as poor, intermediate, or extensive metabolizers. Again, no association was observed between CYP2D6 phenotype and breast cancer–free interval, the primary endpoint. Poor and intermediate metabolizers did not have worse disease control than the extensive metabolizers, Dr. Leyland-Jones reported.

Leyland-Jones said. He joined Dr. Rae in concluding that CYP2D6 testing is not justified to determine whether tamoxifen should be given, and further maintained that the incidence of hot flushes should not be used to gauge tamoxifen efficacy.

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References 1. Rae JM, Drury S, Hayes DF, et al: Lack of correlation between gene variants in tamoxifen metabolizing enzymes with primary endpoints in the ATAC trial. 33rd Annual San Antonio Breast Cancer Symposium. Abstract S1-7. Presented December 9, 2010.

2. Leyland-Jones B, Regan MM, Bouzk M, et al: Outcome according to CYP2D6 genotype among postmenopausal women with endocrine-responsive early invasive breast cancer randomized in the BIG 1-98 trial. 33rd Annual San Antonio Breast Cancer Symposium. Abstract S1-8. Presented December 9, 2010.

Brian Leyland-Jones, MD, PhD

In the multivariate analysis in the tamoxifen cohort (adjusted for nodal involvement, tumor size, local therapy, race, and other factors), the hazard ratio was 0.58 for poor metabolizers, 0.95 for intermediate metabolizers, and 1.0 for extensive metabolizers (P = .35). Moreover, the BIG 1-98 study was one of the first studies to report a distinct population (564 patients) receiving chemotherapy in this setting. Again, no association was observed between CYP2D6 phenotype and breast cancer–free interval; the hazard ratio was 0.76 for poor metabolizers, 0.57 for intermediate metabolizers, and 1.0 for extensive metabolizers (P = .23). The investigators also examined the occurrence of hot flushes in association with enzyme metabolism, and observed incidences of 48% of poor metabolizers, 49% of intermediate metabolizers, and 42% of extensive metabolizers, which were not significantly different. “The lowest hot flush incidence was in extensive metabolizers, and this does not support the hypothesis that poor [endoxifen] metabolism is associated with reduced hot flushes,” Dr. Use your smartphone to view the full text of the abstracts discussed in this article from SEE PAGE 47 the 33rd Annual San Antonio Breast Cancer Symposium.

References : 1. Gregory CW, Johnson RT Jr, Mohler JL, French FS, Wilson EM. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res. 2001;61:2892-2898. 2. Holzbeierlein J, Lal P, LaTulippe E, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol. 2004;164(1):217-227. 3. Yu S-Q, Lai K-P, Xia S-J, Chang H-C, Chang C, Yeh S. The diverse and contrasting effects of using human prostate cancer cell lines to study androgen receptor roles in prostate cancer. Asian J Androl. 2009;11(1):39-48. 4. Corey E, Quinn JE, Buhler KR, et al. LuCaP 35: a new model of prostate cancer progression to androgen independence. Prostate. 2003;55(4):239-246. 5. Loberg RD, St. John LN, Day LL, Neeley CK, Pienta KJ. Development of the VCaP androgen-independent model of prostate cancer. Urol Oncol. 2006;24(2):161-168.

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In the News

How Can Patients Who Receive Radioactive Iodine Treatment for Thyroid Cancer Reduce the Chance of Radiation Risks to Others? By Charlotte Bath

In the News focuses on media reports that your patients may have questions about at their next visit. This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

lthough patients treated with radioactive iodine (I-131) for thyroid cancer may theoretically expose those in their immediate environment to low levels of radiation for a few days, reports about radioactive patients released from the hospital and endangering those they meet seem to have taken on a half-life of their own. The issue continues to come up in Congress and the media, as it did recently when the Nuclear Regulatory Commission (NRC) met to review its recommendations on the medical use of radioactive materials. The NRC statement issued after the meeting on December 13, 2010,1 affirmed its previous analysis that patients treated with radioactive iodine can be safely discharged if their radiation dose to others is under 500 millirems (5 millisieverts [mSv]) and that radiation exposure can be effectively managed by following instructions based on NRC recommendations and provided by the treating facility to patients likely to expose others to radiation doses of 100 millirems (1 mSv) or more.

Specific Guidelines “The framework of this is that the lowest known levels of radiation that cause harm are somewhere between 10,000 to 100,000 millirems (100 to 1,000 mSv) and there is no evidence below 10,000 millirems of any harm,” stated Richard T. Kloos, MD, Professor, The Ohio State University, Divisions of Endocrinology and Nuclear Medicine, Co-Director of The Ohio State University Thyroid Cancer Unit, and Secretary/Chief Operating Officer of The American Thyroid Association. “People can go home if they are expected to not give anybody else in the public more than 5 mSv.…Verbal and written instructions are required for patients who might expose others to more than 1 mSv,” he added. “Each hospital has very specific written guidelines that define which patients can be treated as an outpatient

and which patients need to be admitted to the hospital for radioactive iodine therapy,” explained R. Michael Tuttle, MD, Attending Physician, Endocrinology Service, Memorial Sloan-Kettering Cancer Center, and Professor of Medicine at Weill Medical College of Cornell University. “In some of my thyroid cancer patients, I give 400 or 500 millicuries to treat radioactive iodine–avid metastatic disease, and I would never do that for an outpatient. There is no reliable way to make that safe.”

He said that he would also not administer radioactive iodine outpatient treatment to patients who, because of their age, other medical conditions, or cognitive impairment, might not be able to understand or follow precautions to minimize radiation exposure to others. “Those patients are not treated as outpatients,” he said. “We wouldn’t treat somebody as an outpatient unless we can be comfortable that they will follow the rules” about minimizing risks to others.

Current Standard of Practice The NRC statement is an update to 1997 modifications of a regulation acknowledging that a facility licensed to provide radiation treatment “is best qualified to assess the suitability of individual patients to release post-treatment and to provide personalized guidance to patients to assure compliance with the applicable release criteria.” According to a joint statement2 from the American Thyroid Association, The Endocrine Society, the Society of

Expect Questions from Your Patients

ecause patients receiving radio- number of days increases significantly active iodine (I-131) for thyroid if the patient is sharing a bed with a cancer are concerned about how that pregnant woman, infant, or child, with treatment will affect family members a range of 6 days for lower doses and and others, physicians should expect up to 21 days for a 200-mCi dose. questions and offer “guidance on keeping radiation exposure as low as pos- What about eating meals together? sible,” stated Richard T. Kloos, MD. Patients should sit across the table, Listed below are but not next to someone some general recomat the table. Radioactive mendations, adapted saliva can contaminate from several sources, food utensils, glassware, including interviews and dishes, so precauwith Dr. Kloos and R. tions apply to all of these Michael Tuttle, MD, and items. However, dispospatient education mateable food utensils require rials. Individual modispecial waste considerfications to these recations; washable utensils Richard T. Kloos, MD are preferable. After eatommendations should take into account facing, washing food utensils, tors such as the I-131 dose, the age of glassware, and dishes in a dishwasher the patient and family members, and or by hand will suffice; the dishes may whether anyone in the household is be washed with those of the family. pregnant. Can patients care for their children? What distance should patients rePatients should limit close conturning home after treatment with ra- tact with infants and toddlers (eg, no dioactive iodine keep between them- more than 30 minutes per day) for selves and others? 1 to 7 days, depending on the treatPatients should generally stay ment dose and proximity of contact. A about 3 feet or “an arm’s length away” friend or family member should take from family members for a few days, over major child care duties during Dr. Tuttle recommended. Dr. Kloos this time. advised increasing that distance to 6 feet away from children and pregnant When can treated patients return to women. work? Patients can generally return to What about sleeping arrangements? work 1 day after treatment but will Patients should sleep in a separate need to wait longer if their work brings bed, with at least 6 feet of separation them into prolonged close contact from another adult, for 1 to 4 days, with other people, particularly with depending on the I-131 dose. The children or pregnant women.

Should patients avoid public places? Patients should try to avoid public places where they might be in close contact with one or more people for more than 30 minutes. For example, patients should not go to the movies or a concert, but can take a walk. Does vomiting by patients pose an increased risk? Dr. Kloos estimates that fewer than 10% of patients receiving radioiodine vomit as a side effect. “Radioiodine is absorbed pretty quickly, and typically when people vomit, the amount of radiation involved is quite small, but the vomit is radioactive.” Within the first 24 hours of treatment, vomitus should be collected using disposable gloves and, preferably, flushed down the toilet. Gloves and nonflushable material, such as paper towels, should be placed in a heavy-duty, leak-proof bag. The treating facility can give instructions about collecting this bag from the patient. Otherwise, the bag should be tightly closed and stored in a secure place at least 6 feet away from people and animals. The bag can be disposed with the household trash after 80 days (10 half-lives of I-131), at which time radiation detectors should not produce alarms. To avoid vomiting, some patients may be given an antiemetic. Are patients themselves at future risk because of the 1-131 treatment? “The most serious side effect is a hematologic malignancy, which is rare,” Dr. Kloos said—“maybe 1 in 1,000”—usually among patients who receive repeated doses.

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In the News

SEE PAGE 47

Use your smartphone to view the full text of the reports discussed in this article.

Nuclear Medicine, and the American Association of Clinical Endocrinologists, “A goal of this rule change was to avoid isolation of a patient in the hospital for prolonged periods if the patient’s release to home would be safe for the patient, the patient’s family, and the public. This approach enhances patient satisfaction and is the current standard of medical practice.” Most patients with thyroid cancer usually have surgery first. “They go home in a day or two and then usually we give radioactive iodine somewhere between 1 and 2 months after the surgery,” Dr. Tuttle said. “So their surgical wound is healed.” Although dependent on the individual, the average I-131 dose for the treatment of thyroid cancer ranges from 30 to 200 mCi. Usually a single dose is all that is needed. “I used to be in the army, so I tell patients it is my heat-seeking missile,” Dr. Tuttle said. “They swallow it and it goes everywhere through their body, identifying and destroying thyroid cancer metastases.” He estimated that less than 10% of patients get a second dose 6 months or a year later.

The general advice offered by Dr. Tuttle is “to stay at arm’s length from everybody for a day or two.” The written instructions patients take with them are more detailed, “because the specifics of how long—whether it is 1, 2, or 3 days—depends on the dose that we give. It also depends on their age, be-

cause young people get rid of the radioactive iodine faster than older people.” Dr. Kloos tells patients to “act like you have the flu for the next day or two. Avoid close contact. Avoid swapping bodily fluids. Avoid kissing, sex, and sharing cups or utensils. Avoid food taste testing for others, and for the next day act like you

are infectious, keeping time and distance between you and another person,” he tells patients. If patients can do this, their risk of exposing others to radiation is low. “If they can’t, we talk about admitting them to the hospital.” Dr. Kloos reminds patients that continued on page 46

Self-motivated Patients The NRC statement says that “wellinformed patients are self-motivated and sensitive to the fact that they are radioactive for a period of time,” and they will “typically do as much as possible to reduce potential exposure to others.” Dr. Tuttle and Dr. Kloos agreed on this point. “It is definitely an issue that patients ask about because everybody is afraid that they are going to expose their family or anybody else to radiation,” Dr. Tuttle stated. “Most patients are more interested in that than they are about the side effects and how the radioactive iodine might hurt them. Because they are pretty convinced that it is a safe medicine for them.” Many patients knowing they will receive I-131 have researched the treatment and are often “reassured that actually what we ask them to do is much less imposing than what they thought it was going to be and is something they can easily follow,” Dr. Kloos said. “It is quite rare that someone is just so frightened or concerned about this that they elect not to receive radioiodine out of concern or fears.”

References: 1. Morote J, Orsola A, Planas J, et al. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol. 2007;178: 1290-1295. 2. Zlotta A, Debruyne FMJ. Expert opinion on optimal testosterone control in prostate cancer. Eur Urol Suppl. 2005;4:37-41. 3. Oefelein MG, Feng A, Scolieri MJ, Ricchiutti D, Resnick MI. Reassessment of the definition of castrate levels of testosterone: implications for clinical decision making. Urology. 2000;56(6):1021-1024. 4. Perachino M, Cavalli V, Bravi F. Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone-releasing hormone therapy: prognostic significance? BJU Int. 2009;105:648-651.

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In the News

Radioactive Iodine Treatment continued from page 45

they will not actually feel like they have the flu. “Most people feel nothing,” he said. “A few will feel a little nausea,” which can be treated with antiemetics. For advice for your patients, see the sidebar on page 44.

Room at the Inn? Radiation detectors have become increasingly prevalent and sensitive and “can detect minute amounts of radiation, way below levels that can cause any kind of harm,” Dr. Kloos said. “My patients will set off airport detectors for a week or 10 days after treatment,” Dr. Tuttle reported. “They will set off the detectors on the interstate,” he said. While police and transportation workers are generally aware that medical radiation can set off detectors, it can create anxiety among patients and fellow travelers. Patients treated at Memorial Sloan-Kettering Cancer Center receive a card indicating that they were treated with radioactive iodine. Although that may be helpful at U.S. airports, “in some other countries, nobody cares if you’ve got a card that says you were treated at Memorial Sloan-Kettering,” Dr. Tuttle noted. For that reason,

staff members often caution international patients to wait a few days after radiation treatment before flying home. But where do they stay? Some reports have raised concerns about staying in hotels and exposing workers there to radiation risks. “We tend to discourage people from staying at hotels, although when we look at the data, it seems perfectly fine for them to do so,” Dr. Tuttle said. “Many patients don’t have a choice because they are flying in for their treatments. If we treat them, they are usually not going to be able to fly for 2 or 3 days,” because of precautions to keep at least an arm’s distance from others and possibilities about setting off alarms. “We have carefully looked at this because we have lots of people flying in. When we set up these outpatient rules, we asked the question, ‘Should we just admit people if they have to stay at a hotel?’ Our physicists and nuclear medicine people very carefully went through all the data, and we are absolutely comfortable that it is safe for these patients to be in a hotel,” Dr. Tuttle said. Staying in a hotel “can be done safely and reasonably,” Dr. Kloos agreed, but physicians need to discuss with patients some additional risk-reduction strate-

If Radioactive Iodine Fails

t is really important, particularly for oncologists, to know that there are a number of small-molecule kinase inhibitor trials available for thyroid cancer patients with structurally progressive metastatic disease that is no longer responding to radioactive iodine,” noted R. Michael Tuttle, MD. These trials are producing “response rates of 50% or 60%,” he reported. “It is unacceptable to tell somebody with thyroid cancer who doesn’t respond to radioactive iodine that there is nothing left to do. There are options now.” R. Michael Tuttle, MD Among the agents being studied are sorafenib (Nexavar), sunitinib (Sutent), and vandetanib (Zactima). Dr. Tuttle said that while none of these agents has been approved by the FDA for thyroid cancer, National Comprehensive Cancer Network guidelines note that if clinical trials are not available, sorafenib, sunitinib, or pazopanib (Votrient) can be used off label because they appear to have activity in thyroid cancer and have previously been approved for other types of cancer. These and other trials are listed at the NCI clinical trials site, www.cancer. gov/search/clinicaltrials.

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gies. These measures include checking in before treatment so they can go directly to their room afterwards and avoiding interactions in the lobby.

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References 1. Nuclear Regulatory Commission Advisory Committee on the Medical Use

of Isotopes Patient Release Report, December 13, 2010. 2. Joint Statement on Radioactive Precautions Following Radioactive Iodine Therapy, American Thyroid Association, \Endocrine Society, Society of Nuclear Medicine, American Association of Clinical Endocrinologists, October 20, 2010.

‘Integrative Care for the Future’ Conference to Be Held in Amsterdam By Jo Cavallo

ver 400 oncologists and experts in the fields of economics, education, public health policy, and health insurance as well as representatives from patient organizations from around the world are gathering in Amsterdam, March 11–12, to participate in the First International Conference on Integrative Care for the Future. The purpose of the international meeting is to raise awareness of the increase in evidence-based research in complementary therapies to remedy the side effects associated with cancer and cancer treatments and dispel the confusion surrounding integrative medicine.

Meeting Rationale “One major reason we’re having this conference is that increasing evidence supports integrative oncology’s important role in cancer patients’ lives from diagnosis through survivorship to end-of-life care,” said Barrie Cassileth, PhD, Chief of the Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center in New York and conference Chair. “The second primary reason is to

hammer home the distincevidenced-based completion between evidencementary therapies more acbased complementary cessible to patients is one of therapies and ‘alternatives,’ the topics on the conference an unfortunate conflation agenda. perpetuated by the prob“The fact is we don’t lematic acronym CAM know what is going on (complementary and alaround the world in terms ternative medicine), which of regulatory activity. In puts together two unrelated Barrie Cassileth, PhD some countries, the term approaches,” Dr. Cassileth ‘integrative medicine’ has added. “Helpful adjunctive complebeen hijacked by those promoting mentary therapies bear no relationship quackery, creating confusion among to bogus alternative treatments. We patients and medical professionals need to start using a more accurate term alike,” said Dr. Cassileth. “We need to that describes what we and others are know what’s happening in other coundoing: integrative medicine or integratries and how governments and meditive oncology, not CAM.” cal organizations are responding to the problem. The role of evidence-based, Combating Quackery adjunctive integrative medicine is an Cancer quackery, which relies on essential component of today’s cancer false claims to sell alternative cancer care. We must attend to enduring physcures, is big business, not just in the ical and emotional symptoms caused United States—Dr. Cassileth quoted by successful cancer treatments. That estimates at over $40 billion—but in is what integrative medicine is about. It Europe, Australia, and in other counalso can bring down health-care costs.” tries as well. How to put cancer quackery Integrative medicine encompasses a out of business while making beneficial vast array of approaches, including mas-

sage therapy, meditation, acupuncture, nutritional and herbal counseling, yoga, qigong, and physical fitness regimens.

Conference Agenda The first day of the conference features a roundtable symposium on the status of integrative oncology in various parts of the world, with participants from the United States, Canada, South America, Asia, Europe, and the Middle East. On Saturday, March 12, a plenary session on the current state of integrative oncology internationally will take place, with discussions ranging from the role of acupuncture in modern cancer care to bringing evidence-based therapies into modern cancer care. The conference is sponsored by Integrative Care for the Future, an international organization dedicated to supporting the scientific investigation of complementary therapies for cancer care. For more information about the First International Conference on Integrative Care for the Future and to register for the event, go to Integrativecareftfuture.org.

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Letters to the Editor

Decision-making about Therapy with High Cost, Marginal Benefit

read with interest the two articles on spending in cancer care, one by Richard Boxer (The ASCO Post 2[2]:1, 2011), and a second by J. Russell Hoverman and Susan Russell (The ASCO Post 2[2]:29, 2011). Clearly the subject of spending in cancer care is of importance to the oncology community given that cancer consumes 5% of all medical costs and 10% of Medicare spending. Yet as the authors of these two articles point out, there are high-cost, marginalbenefit therapeutic options whose judicious use could help solve the burgeoning severe fiscal crises. As stated in the discussion by Dr. Boxer, Medicare and Medicaid make up 20% of the budget now and will consume 40% by 2050. As pointed out by Dr. Boxer, prioritizing health-care spending and weighing the cost-benefit of treatments makes eminent sense. With the often, limited success, that noncurative treatments have in improving the quality and length of life of a patient with cancer, it would behoove the oncology specialists caring for a patient to share treatment decisions with the patient and his or her family. They should be brought to understand their shared personal costs for

the particular treatment option(s) a patient may or may not receive. Thus the patient and his or her family can weigh for themselves the costs against the perceived benefits of treatment. Well-proven and effective palliative measures would be fully covered. As an example, the patient’s shared cost of second-line cancer therapy could be determined at 20%; the shared cost of third-line therapy may be 30%; and the shared cost of fourthline therapy may be 40%. Making patient and family increasingly vested with effectiveness of therapy can be a useful tool to reduce use of cancer drugs for marginal benefit. Such an approach will reduce the cost of cancer/hematological drugs currently estimated to be 40% of Medicare’s drug expenditure.

Expensive Technologies also an Issue Cost control of drugs is not the only concern. Specialized surgical and nonsurgical procedures like stereotactic radiosurgery (SRS) may similarly be evaluated. SRS may be optimum therapy for solitary brain metastasis, but third-line therapy for a patient with nine brain lesions. Overutilization of various other expensive

NIH Study Projects Survivorship and Costs of Cancer Care to Reach at Least $158 Billion in 2020

diagnostic and therapeutic technologies also could also be evaluated and better defined. Thus an individual oncologist would not be anguished with the decision to deny a patient tests and treatments of marginal benefits. At the same time the patient and his or her family could have the satisfaction of determining whether “every option has been exhausted.” The oncology community (like NCCN guidelines) would be charged with better defining which therapies

are first-line, second-line, third-line, and fourth-line. Scientific rationalization of extent of benefit will also encourage physicians to think specifically of therapeutic benefits and other alternatives. Thus we can provide patients the optimum value and benefits of “evidence-based medicine” as well as “comparative effectiveness research.”

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—Gilbert A. Lawrence, MD, DMRT, FRCR Radiation Oncology, Faxton Hospital Utica, New York

Using 2D Barcodes The 2D barcodes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading using the ScanLife application.

Getting the Application There are three ways to download the ScanLife application:

Simply text the word “scan” to 43588.

Go to www.getscanlife.com on your phone’s Web browser. The application will attempt to determine which model phone you have. If it’s successful, simply select “Download”.

Visit the application store for your smartphone (such as the iTunes Store or the Android Market).

Increased costs attributed to changes in the US population and cancer trends

ased on growth and aging of the U.S. population, medical expenditures for cancer in the year 2020 are projected to reach at least $158 billion (in 2010 dollars). This is an increase of 27% over 2010, according to a National Institutes of Health analysis.1 If newly developed tools for cancer diagnosis, treatment, and follow-up continue to be more expensive, medical expenditures for cancer could reach as high as $207 billion, said researchers from the National Cancer Institute. The projections were based on the most recent data available on cancer incidence, survival, and costs of care. In 2010, medical costs associated with cancer were projected to

reach $124.6 billion, with the highest costs associated with breast cancer ($16.5 billion), followed by colorectal cancer ($14 billion), lymphoma ($12 billion), lung cancer ($12 billion), and prostate cancer ($12 billion). These figures do not include other types of costs, such as lost productivity, which add to the overall financial burden of cancer. Watch upcoming issues of The ASCO Post for continued discussion on the financial toll of cancer.

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Reference 1. Mariotto AB, Yabroff KR, Shao Y, et al: Projections of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst 103(2):117-128, 2011.

ZOMETA® (zoledronic acid) Injection Concentrate for Intravenous Infusion

Initial U.S. Approval: 2001 BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE 1.1 Hypercalcemia of Malignancy Zometa is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of >12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (mid-range of measured albumin in mg/dL). 1.2 Multiple Myeloma and Bone Metastases of Solid Tumors Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. 1.3 Important Limitation of Use The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions has not been established. 4 CONTRAINDICATIONS 4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zometa Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported [see Adverse Reactions (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Drugs with Same Active Ingredient Zometa contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treated with Zometa should not be treated with Reclast. 5.2 Hydration and Electrolyte Monitoring Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zometa. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with Zometa in order to avoid hypocalcemia. Zometa should be used with caution with other nephrotoxic drugs. Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zometa. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary. 5.3 Renal Impairment Zometa is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased [see Adverse Reactions (6.1)]. Preexisting renal insufficiency and multiple cycles of Zometa and other bisphosphonates are risk factors for subsequent renal deterioration with Zometa. Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible. Zometa treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine >400 μmol/L or >4.5 mg/dL were excluded. Zometa treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine >265 μmol/L or >3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zometa 4 mg by 15-minute infusion with a baseline creatinine >2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance <30 mL/min [see Clinical Pharmacology (12.3) in the full prescribing information]. 5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.2)]. 5.5 Pregnancy ZOMETA SHOULD NOT BE USED DURING PREGNANCY. Zometa may cause fetal harm when administered to a pregnant woman. In reproductive studies in the pregnant rat, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure (an IV dose of 4 mg based on an AUC comparison) resulted in preand postimplantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. 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 a fetus [see Use In Specific Populations (8.1)]. 5.6 Musculoskeletal Pain In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes Zometa. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate [see Adverse Reactions (6.2)]. 5.7 Patients with Asthma While not observed in clinical trials with Zometa, there have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates. 5.8 Hepatic Impairment Only limited clinical data are available for use of Zometa to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zometa in these patients. 6 ADVERSE REACTIONS 6.1 Clinical Studies 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.

Hypercalcemia of Malignancy The safety of Zometa was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zometa 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials. Renal Toxicity Administration of Zometa 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4 mg is given as a 15-minute intravenous infusion. Zometa should be administered by intravenous infusion over no less than 15 minutes [see Warnings And Precautions (5) and Dosage And Administration (2) in the full prescribing information]. The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 3). Table 3 provides adverse events that were reported by 10% or more of the 189 patients treated with Zometa 4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug. Table 3. Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System Zometa Pamidronate 4 mg 90 mg n (%) n (%) Patients Studied Total No. of Patients Studied 86 (100) 103 (100) Total No. of Patients with any AE 81 (94) 95 (92) Body as a Whole Fever 38 (44) 34 (33) Progression of Cancer 14 (16) 21 (20) Cardiovascular Hypotension 9 (11) 2 (2) Digestive Nausea 25 (29) 28 (27) Constipation 23 (27) 13 (13) Diarrhea 15 (17) 17 (17) Abdominal Pain 14 (16) 13 (13) Vomiting 12 (14) 17 (17) Anorexia 8 (9) 14 (14) Hemic and Lymphatic System Anemia 19 (22) 18 (18) Infections Moniliasis 10 (12) 4 (4) Laboratory Abnormalities Hypophosphatemia 11 (13) 2 (2) Hypokalemia 10 (12) 16 (16) Hypomagnesemia 9 (11) 5 (5) Musculoskeletal Skeletal Pain 10 (12) 10 (10) Nervous Insomnia 13 (15) 10 (10) Anxiety 12 (14) 8 (8) Confusion 11 (13) 13 (13) Agitation 11 (13) 8 (8) Respiratory Dyspnea 19 (22) 20 (19) Coughing 10 (12) 12 (12) Urogenital Urinary Tract Infection 12 (14) 15 (15) The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with Zometa 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zometa. Acute Phase Reaction-like Events Symptoms consistent with acute phase reaction (APR) can occur with intravenous bisphosphonate use. Fever has been the most commonly associated symptom, occurring in 44% of patients treated with Zometa 4 mg and 33% of patients treated with Pamidronate 90 mg. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, flushing, bone pain and/or arthralgias, and myalgias. Mineral and Electrolyte Abnormalities Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, can occur with bisphosphonate use. Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of Zometa in patients with HCM are shown in Table 4 and 5. Table 4. Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 3 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

2/86 1/86 36/70 0/71

(2%) (1%) (51%) —

n/N

(%)

3/100 2/100 27/81 0/84

(3%) (2%) (33%) —

Table 5. Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM

Table 7. Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases

Grade 4 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Grade 3

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

0/86 0/86 1/70 0/71

— — (1%) —

1/100 0/100 4/81 1/84

(1%) — (5%) (1%)

Laboratory Parameter n/N Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

1Grade

3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) 3 (<7 mg/dL); Grade 4 (<6 mg/dL) 3Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) 4Grade 3 (<0.8 mEq/L); Grade 4 (<0.5 mEq/L) 2Grade

Ocular Adverse Events Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zometa. No cases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing use [see Adverse Reactions (6.2)]. Multiple Myeloma and Bone Metastases of Solid Tumors The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2,042 patients treated with Zometa 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for Zometa 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors. Table 6 describes adverse events that were reported by ≥10% of patients. Adverse events are listed regardless of presumed causality to study drug. Table 6. Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System

T:14”

B:14.25”

S:13”

Zometa 4 mg n (%)

Pamidronate 90 mg n (%)

Placebo

1031 (100) 1015 (98)

556 (100) 548 (99)

455 (100) 445 (98)

344 (33) 124 (12) 102 (10)

175 83 53

(32) (15) (10)

128 (28) 35 (8) 20 (4)

476 333 320 249 143 105 86 82

(46) (32) (31) (24) (14) (10) (8) (8)

266 183 162 162 81 74 65 61

(48) (33) (29) (29) (15) (13) (12) (11)

171 122 174 83 48 31 14 17

(38) (27) (38) (18) (11) (7) (3) (4)

398 328 252 215 112

(39) (32) (24) (21) (11)

240 172 108 126 62

(43) (31) (19) (23) (11)

130 89 114 84 28

(29) (20) (25) (19) (6)

124 (12) 101 (10)

50 82

(9) (15)

41 30

(9) (7)

231 164 145 130

81 50 60 48

(15) (9) (11) (9)

105 61 59 45

(23) (13) (13) (10)

569 239 216 156 143

(22) (16) (14) (13)

Pamidronate 90 mg (%)

7/529 6/973 115/973 19/971 1/971

n/N

(1%) (<1%) (12%) (2%) (<1%)

Placebo

(%)

4/268 4/536 38/537 2/535 0/535

(2%) (<1%) (7%) (<1%) —

n/N

(%)

4/241 0/415 14/415 8/415 1/415

(2%) — (3%) (2%) (<1%)

1Grade

Injection Site Reactions Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours.

Patients Studied Total No. of Patients Total No. of Patients with any AE Blood and Lymphatic Anemia Neutropenia Thrombocytopenia Gastrointestinal Nausea Vomiting Constipation Diarrhea Abdominal Pain Dyspepsia Stomatitis Sore Throat General Disorders and Administration Site Fatigue Pyrexia Weakness Edema Lower Limb Rigors Infections Urinary Tract Infection Upper Respiratory Tract Infection Metabolism Anorexia Weight Decreased Dehydration Appetite Decreased Musculoskeletal Bone Pain Myalgia Arthralgia Back Pain Pain in Limb

Zometa 4 mg

n (%)

(55) (23) (21) (15) (14)

316 143 131 106 84

(57) (26) (24) (19) (15)

284 74 73 40 52

Neoplasms Malignant Neoplasm Aggravated

205 (20)

(17)

89 (20)

Nervous Headache Dizziness (excluding vertigo) Insomnia Paresthesia Hypoesthesia

191 180 166 149 127

(19) (18) (16) (15) (12)

149 91 111 85 65

(27) (16) (20) (15) (12)

50 58 73 35 43

Psychiatric Depression Anxiety Confusion

146 (14) 112 (11) 74 (7)

95 73 39

(17) (13) (7)

49 (11) 37 (8) 47 (10)

Respiratory Dyspnea Cough

282 (27) 224 (22)

155 129

(28) (23)

107 (24) 65 (14)

Skin Alopecia Dermatitis

125 (12) 114 (11)

80 74

(14) (13)

36 38

(62) (16) (16) (9) (11)

(11) (13) (16) (8) (10)

(8) (8)

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of Zometa in patients with bone metastases are shown in Tables 7 and 8.

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

Zometa 4 mg

Pamidronate 90 mg

Placebo

n/N

(%)

n/N

(%)

n/N

(%)

2/529 7/973 5/973 0/971 2/971

(<1%) (<1%) (<1%) — (<1%)

1/268 3/536 0/537 0/535 1/535

(<1%) (<1%) — — (<1%)

0/241 2/415 1/415 2/415 0/415

— (<1%) (<1%) (<1%) —

1Grade

3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) *Serum creatinine data for all patients randomized after the 15-minute infusion amendment 2Grade 3 (<7 mg/dL); Grade 4 (<6 mg/dL) 3Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) 4Grade 3 (>3 mEq/L); Grade 4 (>8 mEq/L) 5Grade 3 (<0.9 mEq/L); Grade 4 (<0.7 mEq/L) Among the less frequently occurring adverse events (<15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa 4 mg and pamidronate groups) compared to the placebo group. Less common adverse events reported more often with Zometa 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the Zometa 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the Zometa 4 mg group (13%) compared with the pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear. Renal Toxicity In the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (≥1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zometa 4 mg over 15 minutes in these trials (see Table 9). Table 9. Percentage of Patients with Treatment Emergent Renal Function Deterioration by Baseline Serum Creatinine* Patient Population/Baseline Creatinine Multiple Myeloma and Breast Cancer

Zometa 4 mg n/N

Normal Abnormal Total Solid Tumors

27/246 (11%) 2/26 (8%) 29/272 (11%) Zometa 4 mg n/N

Normal Abnormal Total Prostate Cancer Normal Abnormal Total

(%)

17/154 (11%) 1/11 (9%) 18/165 (11%) Zometa 4 mg n/N

(%)

12/82 4/10 16/92

(15%) (40%) (17%)

Pamidronate 90 mg n/N

(%)

23/246 (9%) 2/22 (9%) 25/268 (9%) Placebo n/N

(%)

10/143 (7%) 1/20 (5%) 11/163 (7%) Placebo n/N

(%)

8/68 (12%) 2/10 (20%) 10/78 (13%)

*Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of Zometa to 15 minutes. The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zometa (4 mg over 15 minutes), placebo, or pamidronate. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15-minute period. There have been instances of this occurring after the initial Zometa dose. 6.2 Postmarketing Experience The following adverse reactions have been reported during postapproval use of Zometa. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Osteonecrosis of the Jaw Cases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patients treated with intravenous bisphosphonates including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be a risk factor for ONJ. Data suggests a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged [see Warnings And Precautions (5)]. Musculoskeletal Pain Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphosphonate use [see Warnings And Precautions (5)]. Ocular Adverse Events Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.

Hypersensitivity Reactions There have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, and bronchoconstriction. Very rare cases of anaphylactic reaction/shock have also been reported. Additional adverse reactions reported in postmarketing use include:

CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; Gastrointestinal: dry mouth; Skin: increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchoconstriction; Renal: hematuria, proteinuria; General Disorders and Administration Site: weight increase; Laboratory Abnormalities: hyperkalemia, hypernatremia. 7 DRUG INTERACTIONS In-vitro studies indicate that zoledronic acid is approximately 22% bound to plasma proteins. In-vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In-vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug. However, no in-vivo drug interaction studies have been performed. 7.1 Aminoglycosides Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zometa clinical trials. 7.2 Loop Diuretics Caution should also be exercised when Zometa is used in combination with loop diuretics due to an increased risk of hypocalcemia. 7.3 Nephrotoxic Drugs Caution is indicated when Zometa is used with other potentially nephrotoxic drugs. 7.4 Thalidomide In multiple myeloma patients, the risk of renal dysfunction may be increased when Zometa is used in combination with thalidomide. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy ZOMETA SHOULD NOT BE USED DURING PREGNANCY. There are no studies in pregnant women using Zometa. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant [see Warnings And Precautions (5.4)]. Pregnancy Category D Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (≥0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (with a systemic exposure of ≥0.07 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality may have been related to drug-induced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonateclass effect. In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse effects included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects observed in the highdose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the lowdose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study. In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (≤0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas), no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatment groups (at doses ≥0.05 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia.

8.3 Nursing Mothers It is not known whether Zometa is excreted in human milk. Because many drugs are excreted in human milk, and because Zometa binds to bone long term, Zometa should not be administered to a nursing woman. 8.4 Pediatric Use Zometa is not indicated for use in children. The safety and effectiveness of zoledronic acid was studied in a one-year active-controlled trial of 152 pediatric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesis imperfecta, aged 1-17 years, 55% male, 84% Caucasian, with a mean lumbar spine BMD of 0.431 gm/cm2, which is 2.7 standard deviations below the mean for age-matched controls (BMD Z-score of -2.7). At one year, increases in BMD were observed in the zoledronic acid treatment group. However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zometa use in children did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemia of malignancy or bone metastases. However, adverse reactions seen more commonly in pediatric patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia, occurred most frequently within 3 days after the first infusion and became less common with repeat dosing. Because of long-term retention in bone, Zometa should only be used in children if the potential benefit outweighs the potential risk. Plasma zoledronic acid concentration data was obtained from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3-8 years and 6 in the age group of 9-17 years) infused with 0.05 mg/kg dose over 30 min. Mean Cmax and AUC(0-last) was 167 ng/mL and 220 ng.h/mL, respectively. The plasma concentration time profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed in adult cancer patients at an approximately equivalent mg/kg dose. 8.5 Geriatric Use Clinical studies of Zometa in hypercalcemia of malignancy included 34 patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zometa as compared to younger patients. Controlled clinical studies of Zometa in the treatment of multiple myeloma and bone metastases of solid tumors in patients over age 65 revealed similar efficacy and safety in older and younger patients. Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function. 10 OVERDOSAGE Clinical experience with acute overdosage of Zometa is limited. Two patients received Zometa 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively. In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose. A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100U/L, each value unknown). The outcome of this case is not known. In controlled clinical trials, administration of Zometa 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, Zometa 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zometa 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [see Dosage And Administration (2.4) in the full prescribing information]. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

REV: OCTOBER 2009 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland for Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

T2009-101

Because skeletal-related events (SREs)† can have devastating consequences, help protect your patients with ZOMETA T:14”

B:14.25”

S:13”

Indication ZOMETA is indicated for the treatment of patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. Highlight from the Important Safety Information • Severe, and occasionally incapacitating bone, joint, and/or muscle pain may occur. Discontinue ZOMETA if severe symptoms occur Please see full Important Safety Information and full Prescribing Information on back.

More than

*ZOMETA should be used in prostate patients with bone metastases that have progressed after treatment with at least one hormonal therapy. † SRE=skeletal-related event, defined as pathologic fracture, spinal cord compression, hypercalcemia of malignancy, and the need for radiation or surgery to the bone.1

YEARS of real-world experience

ZOMETA: proven to help reduce and delay SREs across solid tumors with documented bone metastases and multiple myeloma 2

Metastatic breast cancer

Metastatic hormone-refractory prostate cancer

Multiple myeloma

Metastatic lung cancer and other solid tumors

Metastatic renal cell carcinoma

• Proven effective in all types of SREs3 — Including pathologic fracture, spinal cord compression, hypercalcemia of malignancy, and the need for radiation or surgery to bone • The most widely used bone-targeted agent in oncology — 3.8 million patients treated worldwide3 • A well-established tolerability profile — More than 200 completed or active clinical trials4 • Convenient, dependable, and rapid reimbursement support — 90% to 99% reimbursement rate3* *Claims reimbursed within 30 days; Medicare (99%) and commercial payers (90%).

Highlights from the Important Safety Information • Hypersensitivity reactions, including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported • Patients being treated with ZOMETA should not be treated with Reclast® (zoledronic acid) • Patients treated for hypercalcemia of malignancy should be adequately rehydrated prior to administration of ZOMETA and have their electrolytes monitored during treatment • There have been reports of renal toxicity with ZOMETA. Renal toxicity may be greater in patients with renal impairment. Treatment in patients with severe renal impairment is not recommended. Do not use doses greater than 4 mg and monitor serum creatinine before each dose • Osteonecrosis of the jaw has been reported. Preventive dental exams should be performed before starting ZOMETA and invasive dental procedures should be avoided • Because ZOMETA can cause fetal harm, women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant Please see brief summary on the following page. References: 1. Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer. 2000;88: 1082-1090. 2. ZOMETA Prescribing Information. Novartis Pharmaceuticals Corporation. 3. Data on file. Novartis Pharmaceuticals Corporation. 4. www.clinicaltrials.gov.http://www.clinicaltrials.gov. Accessed September 23, 2010.

More than

YEARS of real-world experience

September 2010

ZOM-1000713