May 2008 Vol. 1 No. 1 by The Oncology Nurse

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EDITOR’S LETTER

BREAST CANCER

HPV VACCINATION

A forum addressing the clinical, professional, and personal concerns of oncology nurses in practice and in training

Strategies for maximizing adherence to aromatase inhibitors

HPV vaccination benefits may extend to older women

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MAY 2008 • VOL. 1, NO.1

The

Yoga helps alleviate menopause symptoms in women with breast cancer

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MEDICAL MINUTES

www.theoncologynurse.com

Oncology Nurse

The Official Newspaper of Record for the Hem/Onc Nurse

™

Why Certify? A No-brainer for Oncology Nurses

ANNOUNCING CE CREDIT AT NO CHARGE

BY FRANK P. WHYTE, RN, OCN MT. CARMEL HOSPICE, WESTERVILLE, OHIO NOT UNLIKE THE ORAL traditions of the past, the transfer of knowledge and technique in the isolated world of oncology nursing was, for decades, passed along from one generation of oncology nurses to the next. In the latter 20th century, however, specialty certification became the gold standard in the field of oncology nursing. As the related knowledge and technology underwent a virtual explosion in the intervening years, this professional evolution led to oncology nursing certification becoming a

near-imperative in this highly technical nursing specialty. Oncology nursing certification, administered by the Oncology Nursing Certification Corporation, awards certification to oncology nurses, pediatric oncology nurses, oncology nurse practitioners, and oncology clinical nurse specialists. OCN® CPON® AOCNP®

AOCNS®

Oncology Certified Nurse Certified Pediatric Oncology Nurse Advanced Oncology Certified Nurse Practitioner Advanced Oncology Clinical Nurse Specialist

Criteria vary according to the certification being sought, but testing is a component of each, and certification is renewable following an initial recognition period of 4 years. Eligibility criteria for initial candidates for OCN certification are shown in the Table. So what might you consider to

Green Hill HealthCare Communications, LLC, is partnering with the University of Nebraska Medical Center (UNMC) Center for Continuing Education and the UNMC College of Nursing, Continuing Nursing Education to provide a complimentary CE activity in each issue.

be the benefits of oncology nursing certification? Preparation for testing can broaden general oncological knowledge in a nursing population often hyperfocused on a single subspecialty area, such as head and neck radiation oncology or stem cell transplantation. It also leads to greater acceptance from an extremely disease- and treatment-savvy patient group, who demand technological expertise from their professional caregivers. Certification as an oncology nurse often leads us to financial reward as well. This increased financial compensation may be realized as an increased hourly rate, an annual bonus, or as an advanced rating on our nursing clinical ladders. A 2004 survey conducted by Nursing Magazine indicated that certified nurses have a full-

THE US FOOD AND DRUG Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) on March 13, 2008, recommended that the use of erythropoiesisstimulating agents (ESAs) be substantially limited in the treatment of anemia in patients with cancer. The committee made the recommendation after hearing additional evidence from a recently published meta-analysis showing that ESAs increase the risk of blood clots and death in patients taking these agents for chemotherapyinduced anemia. The committee recommended that use of ESAs be restricted to only those cancer patients with advanced disease and that all patients receiving these drugs be

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POLICY WATCH

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Further Limits on Use of ESAs in Cancer Patients Expected

CLINICAL TRIALS

Approval of biogenerics seen as one way to reduce healthcare spending

Multinational trial to compare targeted therapies for breast cancer

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RECENT FDA APPROVALS New drugs approved for CLL, breast cancer, osteosarcoma

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For additional information, visit www.gelclair.com or call 1-877-GELCLAIR. Ingredients: Water, Maltodextrin, Propylene Glycol, Polyvinylpyrrolidone (PVP), Sodium Hyaluronate, Potassium Sorbate, Sodium Benzoate, Hydroxyethylcellulose, PEG-40 Hydrogenated Castor Oil, Disodium Edetate, Benzalkonium Chloride, Flavoring, Saccharin Sodium, Glycyrrhetinic Acid. Contents: 15 mL per single-use packet. Commercial boxes contain 15 single-use packets. (NDC 24477-010-15) Indications: GELCLAIR® has a mechanical action indicated for the management of pain and relief of pain by adhering to the mucosal surface of the mouth, soothing oral lesions of various etiologies, including oral mucositis/stomatitis (may be caused by chemotherapy or radiation therapy), irritation due to oral surgery, traumatic ulcers caused by braces or ill-fitting dentures, or disease. Also indicated for diffuse aphthous ulcers. Contraindications: The administration of GELCLAIR® is contraindicated in any patient with a known or suspected hypersensitivity to any of its ingredients. Side effects: At the time of producing this leaflet, no adverse effects have been reported in clinical trials with the use of GELCLAIR®. Postmarketing reports have included infrequent complaints of burning sensation in the mouth. Reference: 1. Innocenti M, Moscatelli G, Lopez S. Efficacy of Gelclair® in reducing pain in patients with oral lesions: preliminary findings from an open pilot study. J Pain Symptom Manage. 2002;24:455-457. GELCLAIR® is a registered trademark of Helsinn Healthcare SA, Lugano, Switzerland. Manufactured for Helsinn Healthcare SA, Lugano, Switzerland. Marketed and distributed by EKR Therapeutics, Inc., Cedar Knolls, NJ 07927.

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MEDICAL MINUTES

Medical Minutes Medical Minutes

A ONE-OF-A-KIND YOGA PROGRAM that combines yoga exercises, meditation, and group discussion may alleviate the ills of menopause in female survivors of breast cancer, according to a new study presented at the Symposium on Yoga Therapy and Research in Los Angeles, California. The researchers found that early-stage breast cancer survivors enrolled in the yoga program witnessed a significant decline in hot flash severity and frequency, fatigue, joint pain, and frequency of sleep disturbances. The study group, comprising 37 currently disease-free women with reported menopausal symptoms, continued to show significant improvement even after they stopped attending the yoga program sessions. Menopausal symptoms in breast cancer survivors have traditionally been difficult to treat as recent studies have indicated that hormone replacement therapy increases breast cancer incidence. Furthermore, tamoxifen, which is used to treat breast cancer, can intensify symptoms of menopause. Some research has also indicated that tamoxifen can trigger menopause-like symptoms in young women who have not yet reached menopause. “Breast cancer survivors have very few options to seek treatment,” said coauthor James Carson, PhD, who is an assistant professor of anesthesiology and perioperative medicine at the Oregon Health & Science University School of Medicine, Portland. “Taking into account previous research I’d done on cancer-related pain and yoga, it seemed as if this yoga program, tailored to the needs of menopausal women, might help.” The yoga program, which was developed by Dr Carson and his wife Kimberly Carson, MPH, is a unique blend of yoga postures found in many US gyms, in-depth meditation practices, and group discussions about the practice of yoga. In the study, which was conducted at Duke University Medical Center, women enrolled in the 2-month yoga program attended eight 2-hour sessions and also practiced yoga at home. The control group was placed on the yoga program’s waitlist for 6 months.

nursing education opportunities. The authors’ long-run strategies focus on how to change the long-term growth rates for the nursing workforce, such as removing barriers associated with educating more men and reinforcing pay-for-performance systems. The current nursing shortage began in 1998 and has continued for a decade, making it the longest lasting nursing shortage in the past 50 years. Inadequate nurse staffing in hospitals is associated with reductions in hospital bed capacity, delays in the timeliness of patient care, long length of stay by patients, interruptions in care delivery processes, and increased risk of adverse patient outcomes, including mortality.

An Apple Peel a Day May Help Keep Cancer at Bay Eating an apple a day with the peel still on it may help lower a person’s overall risk for cancer, according to researchers at Cornell University. They have identified a dozen compounds (triterpenoids) in apple peel that either inhibit or kill cancer cells in laboratory cultures. Three of the compounds have not previously been described in the literature. “We found that several compounds have potent antiproliferative activities against human liver, colon, and breast cancer cells and may be partly responsible for the anticancer activities of whole apples,” said senior study author Rui Hai Liu, an associate professor of food science at Cornell University, Ithaca, New York. In previous Cornell studies, apples have been found not only to fight cancer cells in the laboratory, but also to reduce the number and size of mammary tumors in animal models. The Cornell researchers now think that the triterpenoids may be responsible for much of the anticancer effect. Dr Liu and his colleagues analyzed the peel from 230 pounds of Red Delicious apples from the Cornell Orchard and isolated their individual compounds. After identifying the structures of the promising compounds in the peel, the researchers tested the pure compounds against cancer cell growth in the laboratory. In the past, Dr Liu has also identified phytochemicals (mainly flavonoids and phenolic acids) in apples and other foods that appear to have anticancer properties, including inhibiting tumor growth in human breast cancer cells. “We believe that a recommendation that consumers eat five to 12 servings of a wide variety of fruits and vegetables daily is appropriate to reduce the risk of chronic diseases, including cancer, and to meet nutrient requirements for optimum health,” said Dr Liu.

BY JOHN SCHIESZER

John Schieszer is an award-winning national journalist and radio broadcaster of The Medical Minute. He can be reached at medminutes@aol.com.

MEDICAL MINUTES MEDICAL MINUTES MEDICAL MINUTES MEDICAL

Yoga May Benefit Breast Cancer Patients Battling Menopause Symptoms

Researchers Sound Warning about Growing Nursing Shortage The US healthcare system needs to brace for a severe shortage of nurses, according to researchers at Vanderbilt University. “It is a matter of supply and demand in a profession that is the front line of our healthcare system,” said study author Peter Buerhaus, PhD, who is with the Vanderbilt University School of Nursing, Nashville, Tennessee. “While there have been some notable and important improvements, our data show that we have in no way solved this emerging long-term problem.” In The Future of the Nursing Workforce in the United States: Data, Trends and Implications, Dr Buerhaus and his colleagues point out that the demand for nurses is expected to continue to grow at a rate of 2% to 3% a year, as it has done for the past four decades. At the same time, the supply of nurses is expected to grow very little as large numbers of nurses begin to retire. An increased deficit of nurses is expected to begin in 2015, grow to an estimated 285,000 full-time nurses in 2020, and reach 500,000 (16%) by 2025. The authors make recommendations to policymakers for both the short-term and long-term. Transition strategies are intended to help endure future shortages in the least costly way while assuring patients have high-quality care. These include adopting more technology among nurses, accommodating an older workforce, and expanding

May 2008

©iStockphoto.com/Eliza Snow

T HE O NCOLOGY N URSE

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Vol. 1, No. 1

May 2008

CONTENTS

Feature Articles Maximizing adherence to aromatase inhibitors

CONTENTS CONTENTS CONTENTS CONTENTS CONTENTS CONTENTS CONTENTS

15 Gastrointestinal Cancers Study of flat or depressed colorectal lesions stirs debate

Medical Minutes

Policy Watch

20 Genitourinary Cancers New agent shows promise for advanced prostate cancer

PUBLISHING STAFF Publisher Philip Pawelko phil@greenhillhc.com

Trends in Breast Cancer

Trends in Hematologic Cancers

Senior Production Manager Stephanie Laudien

Trends in Colorectal Cancer

Client Service Managers John W. Hennessy john@greenhillhc.com

Trends in Lung Cancer

Russell Hennessy russell@greenhillhc.com

Nursing Life

Trends in Prostate Cancer

Director of Human Resources Blanche Marchitto blanche@greenhillhc.com

Clinical Trials Update Recent FDA Approvals

22 Head & Neck Cancers

™

Editorial Director Karen Rosenberg karen@greenhillhc.com

17 Pediatric Cancers Childhood cancer survivors face long-term health issues

Oncology Nurse

The Official Newspaper of Record for the Hem/Onc Nurse

Departments

8 Gynecologic Cancers

The

Meetings

Circulation circulation@greenhillhc.com

GH Green Hill HealthCare Communications

, LLC ™

™

Your Innovative Partners in Medical Media

241 Forsgate Drive, Suite 205C Jamesburg, NJ 08831

Nursing interventions affect quality of life

Editorial Board EDITOR-IN-CHIEF Beth Faiman, RN, MSN,APRN, BC,AOCN Cleveland Clinic Taussig Cancer Center Cleveland, OH Isabell Castellano, RN Bristol-Myers Squibb Children’s Hospital Robert Wood Johnson University Hospital New Brunswick, NJ Deena Damsky Dell, RN, MSN,AOCN, BC Clinical Nurse Specialist Fox Chase Cancer Center Philadelphia, PA

Connie Visovsky, RN, PhD,APRN University of Nebraska, College of Nursing Omaha, NE

Kena C. Miller, RN, MSN, FNP Roswell Park Cancer Institute Buffalo, NY

Jeanne Westphal, RN Meeker County Memorial Hospital Litchfield, MN

Dolores “Jeff” Nordquist, RN, MS, CS, FNP Mayo Clinic Rochester, MN

Frank P. Whyte, RN, OCN Mount Carmel Hospital—St.Ann’s Westerville, OH

Leah A. Scaramuzzo, MSN, RN,AOCN The Cancer Institute of New Jersey New Brunswick, NJ

Karla Wilson, RN, MSN, FNP-C, CPON City of Hope National Medical Center Duarte, CA

Wendy DiSalvo, BSN, MSN, FNP,AOCN Dartmouth Hitchcock Medical Center Norris Cotton Cancer Center Lebanon, NH

Lisa Schulmeister, MN, RN,APRN-BC, OCN, FAAN New Orleans, LA

Denice Economou, RN, MN,AOCN City of Hope National Medical Center Duarte, CA

Gary Shelton, MSN,ARNP,AOCN NYU Cancer Institute New York, NY

Lyssa Friedman, RN, MPA, OCN Mill Valley, CA

Lori Stover, RN, BSN Western Pennsylvania Cancer Institute Pittsburgh, PA

Cassandra J. Hammond, RN, MSN, CRNP Avid Education Partners, LLC Sharpsburg, MD Taline Khoukaz, MSN,ACNP-C University of Southern California Norris Cancer Center & Hospital Los Angeles, CA

Sandra E. Kurtin, RN, MS,AOCN,ANP-C Arizona Cancer Center Tucson, AZ

T HE O NCOLOGY N URSE

Joseph D.Tariman, RN, MN,ARNP-BC, OCN University of Washington School of Nursing Seattle,WA

OTHER SPECIALTIES Susan Goodin, PharmD, FCCP, BCOP Cancer Institute of New Jersey New Brunswick, NJ Barbara Savage, LISW Cleveland Clinic Taussig Cancer Center Cleveland, OH Amanda Salvidar, MS, RD, LD Cleveland Clinic Taussig Cancer Center Cleveland, OH

Pamela Hallquist Viale, RN, MS, CS,ANP,AOCN Saratoga, CA

May 2008

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Editor’s Letter EDITOR’S LETTER

Introducing The Oncology Nurse

EDITOR’S LETTER EDITOR’S LETTER EDITOR’S LETTER EDITOR’S EDITOR’S LETTER

BETH FAIMAN, RN, MSN, APRN, BC, AOCN

EDITOR-IN-CHIEF

ONCOLOGY NURSES ARE CONSTANTLY INUNDATED with new information from medical meetings and courses, the medical literature, pharmaceutical companies, and other sources. Why then another oncology publication? For several reasons! For one, The Oncology Nurse features articles written by and for oncology nurses, and specifically addresses the issues nurses and their colleagues face every day in clinical practice. For example, each issue will include not only news on the latest research findings and results of large clinical trials but also articles with more immediate practical applications, such as the articles in this issue on improving adherence to breast cancer and how nursing interventions can improve quality of life in patients with head and neck cancer. For another, The Oncology Nurse includes representatives of related specialties, such as pharmacy, nutrition, and social work, to reflect the multidisciplinary team approach to cancer care. Also, each issue of The Oncology Nurse will include articles of interest to student nurses, such as the article in this issue by Frank P. Whyte on the benefits of specialty certification to nurses, themselves, and their institutions.

Because nurses seeking to obtain or maintain their certification need continuing education credits, The Oncology Nurse has entered into a partnership with the Center for Continuing Education and College of Nursing Continuing Nursing Education at the University of Nebraska Medical Center and, starting next month, will provide a continuing education article each issue. Finally, The Oncology Nurse will address the personal and professional interests of nurses as well as their clinical concerns with articles on lifestyle topics such as nutrition, stress management, and personal finance. Perhaps most important of all, The Oncology Nurse seeks to be an interactive forum for oncology nurses in practice and in training to discuss the issues—clinical, professional, and personal—of greatest concern to them. To this end, we invite your comments, suggestions, and contributions about topics that you would like to see addressed, people you would like to read about, and tips you would like to share. Please write to us at editorial@greenhillhc.com and tell us what you would like to see in upcoming issues.

Green Hill HealthCare Communications to Partner with University of Nebraska Medical Center for Complimentary Continuing Education for Healthcare Professionals TO HELP MEET THE CONTINUING EDUCATION needs of busy practitioners, Green Hill HealthCare Communications, LLC, publisher of The Oncology Nurse and The Oncology Pharmacist, is partnering with the University of Nebraska Medical Center (UNMC), Center for Continuing Education and the UNMC College of Nursing Continuing Nursing Education to provide a complimentary continuing education activity in each issue, starting in the June 2008 issue. Accredited articles will provide a concise review of a recent article in the peer-reviewed literature or a report on a presentation at a major medical meeting, accompanied by a case report illustrating the key clinical points and commentaries by an oncology nurse and an oncology pharmacist on how the findings may apply to oncology practice. The UNMC College of Nursing Continuing Nursing Education is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC) Commission on Accreditation. Additionally, the nursing activities will be provided under Iowa Provider #78. Provider also approved by the California Board of Registered Nursing, Provider #13699. The UNMC, Center for Continuing Education is accredited by the

Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. The editorial boards of The Oncology Nurse and The Oncology Pharmacist will review the medical literature and presentations at major medical meetings to identify topics of interest to both oncology nurses and oncology pharmacists. Articles will be reviewed by the UNMC, Center for Continuing Education and the UNMC College of Nursing Continuing Nursing Education for medical accuracy and balance and to ensure that they meet criteria for continuing education materials set by the ANCC, the Iowa Board of Nursing, the California Board of Registered Nursing, and the ACPE. Readers will be able to complete the post-test and receive credit online. Upcoming issues will feature an article on identifying patients at risk for anaphylaxis associated with EGFR inhibitor therapy and one on dosing considerations when administering cancer drugs to obese patients. We invite your suggestions about topics of greatest concern to you and your colleagues as well as feedback on how well we are meeting your educational needs. Please write to us at editorial@greenhillhc.com and let us know what you would like to see in future issues.

EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Nurse™, 241 Forsgate Drive, Suite 205C, Jamesburg, NJ 08831. E-mail: editorial@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications LLC, 241 Forsgate Drive, Suite 205C, Jamesburg, NJ 08831. The ideas and opinions expressed in The Oncology Nurse™ do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mentioned in The Oncology Nurse™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director. ISSN #Applied for in April 2008. The Oncology Nurse™ is published 6 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Jamesburg, NJ 08831. Telephone: 732.992.1899. Fax: 732.656.7938. Copyright ©2008 by Green Hill Healthcare Communications, LLC. All rights reserved. The Oncology Nurse™ logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

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Our

vision extends beyond science

…making today’s therapies more accessible and tomorrow’s breakthroughs more achievable Supporting today The Genentech® Access to Care Foundation makes our marketed products available to qualified patients in need* Genentech BioOncology™ Access Solutions™, formerly known as SPOC® (Single Point of Contact) — For patients and their healthcare providers, Genentech BioOncology Access Solutions provides coverage and reimbursement support, patient assistance, and informational resources Investing in tomorrow Genentech BioOncology invests deeply in research and development and is an industry leader in investing a percentage of annual revenues back into R&D Genentech BioOncology funds grant and fellowship programs to support medical education, partner with professional societies, and encourage independent research *The Genentech Access to Care Foundation was established to help qualified patients with unmet medical needs who are uninsured or rendered uninsured by payer denial and who meet specific medical criteria to receive proper medical treatment. The Genentech Access to Care Foundation may be available to help those who are not able to obtain Genentech therapeutics for financial reasons.

www.BioOncology.com

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Policy Watch

Employers, health insurers, and pharmacy benefit managers are exploring novel ways to contain spending, including approval of biogenerics Report Cites Progress and Challenges in Improving State Pain Policies Both cancer patients and survivors commonly experience pain that, if unrelieved, can adversely affect their functioning, productivity, and even their will to live. “Increasingly, unrelieved pain is becoming recognized as a significant public health problem in the United States,” according to a recent report by Aaron M. Gilman, PhD, and other members of the Pain & Policy Studies Group (PPSG) (CA Cancer J Clin. 2007;57:341-353). Among the factors contributing to inadequate pain management are healthcare practitioners’ concerns about regulatory scrutiny and restrictive drug control and healthcare policies governing medical use of prescription drugs. The PPSG established a research program to evaluate US federal and state policies on medical use of pain medication using a methodology based on the principle of Balance. The group’s latest report, which describes the results of three national policy evaluations, shows “there

May 2008

De rnie

MEMBERS OF CONGRESS, THE BUSH ADMINISTRATION, and private payers are calling for legislation that would allow approval of generic biologics, or biogenerics, as one way to reduce spending on specialty pharmaceuticals for cancer and other conditions. According to a report in The Wall Street Journal (March 20, 2008), employers, health insurers, and pharmacy benefit managers are exploring novel ways to contain spending, including approval of biogenerics, because specialty drugs are a major factor in escalating healthcare costs. Other measures being considered are tighter enforcement of step-therapy policies, restrictions on off-label drug use, and a “pay-for-performance” strategy in which the price of a drug depends on its efficacy. Specialty drugs account for about 60% of new medications submitted for US Food and Drug Administration (FDA) approval, and The New York Times (April 19, 2008) reports that spending on these drugs increased 16.5% in 2006, totaling about $62 billion, or about 23% of overall drug sales in the United States that year. Bills that could lead to an approval pathway for biogenerics have been introduced in both the House and Senate but there is controversy about the details. According to the American Society of Clinical Oncology (www.asco.org), “One of the main points of contention in these legislative proposals is the degree to which biogenerics can be substituted for the brand name product (so-called interchangeability).” A bill introduced in the Senate last year (S. 1695) includes basic data requirements needed to categorize a biogeneric as a “biosimilar” product, whereas the House bill (H.R. 1038) contains fewer data requirements and allows the FDA greater leeway in determining whether a biogeneric is “comparable” to the brand product. Provisions of both bills would allow substitution of the biosimilar or comparable product without approval of the healthcare professional who prescribed it if the manufacturer has provided evidence that the biosimilar product can be expected to produce the same clinical result as the brand product in any given patient.

has been substantial progress since the policy-evaluation process began in 2000,” the authors state, “but there is much more opportunity for improvement.” They say it is crucial for healthcare practitioners to be familiar with their state’s pain policies and offer suggestions for the role they can play in improving these policies. “Positive policy change is a crucial first step….but with no implementation has little practical value,” they write. “Policies must be put into practice through advocacy and education.”

©iS toc kph oto .co m/A ndr ew

Legislators, Payers Support Approval of Biogenerics

Massachusetts Proposal to Limit Drug Reps Gifts Stirs Controversy A bill being drafted by Massachusetts legislators would prohibit physicians from accepting even token gifts, such as a pen or a slice of pizza, from drug manufacturers. Doctors who accepted such a gift could have to pay up to $5,000 in fines and serve up to 2 years in prison. The proposed legislation has generated heated discussion by supporters and opponents of the bill, as shown by responses posted on The Wall Street Journal’s Health Blog (http:// blogs.wsj.com/health/2008/04/17/bring-on-the-drug-reps/?mod= WSJBlog?mod=WS...). Some argue that the company sales representatives do provide some useful information, especially about new drugs. Others, though skeptical about the information drug representatives provide say they want to decide for themselves whether or not to see them, without government interference. In an April 17, 2008 editorial in The Boston Herald (www.bostonherald.com/news/ opinion/op_ed/view.bg?articleid=1087609), Drs Dennis Ausiello and Thomas Stossel write, “We believe the best approach to optimize cost effectiveness of product prescribing is to promote more, not less, interaction among all stakeholders involved in health-care delivery, including company marketing reps.”

Survey Shows Physicians Increasingly Favor National Health Insurance Results of a nationwide survey indicate that the majority of US physicians now support the concept of national health insurance (Ann Intern Med. 2008;148:566-567). Of 2,193 physicians who responded to the survey, 59% expressed support for legislation to establish a national health insurance program, whereas 32% opposed it, and 9% had no opinion. The number in favor of national health insurance represents a 10% increase compared with a similar poll conducted in 2002, in which only 49% of respondents endorsed such a plan. Fifty-five percent of respondents favored an incremental approach to achieving universal coverage, whereas 25% opposed incremental reform. Another 14% favored incremental reform but were opposed to national health insurance. The American Medical Association is against government-run national health insurance and instead proposes expanding coverage through tax credits.

T HE O NCOLOGY N URSE

POLICY WATCH POLICY WATCH POLICY WATCH POLICY WATCH POLICY WATCH

POLICY WATCH

Policy Watch

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Gynecologic Cancers GYNECOLOGIC CANCERS

Maximizing Adherence to Aromatase Inhibitors for Early-stage Breast Cancer THE FLOOD OF NEW DATA flowing to clinicians via their computer screens and in medical libraries is making it clear that oral therapies are effective for first- or second-line treatment of early-stage breast cancer. What is not clear, however, is how many patients are adherent, hence whether they are receiving the full short- and long-term benefits from these treatments. A recent study has shown that adherence to aromatase inhibitors falls as low as 62% by the time patients have taken these drugs for 3 years. The standard of care is to take adjuvant hormone therapy for a total of 5 years. “The problem of compliance is under-recognized; I talk to oncologists around the country, and often they’ll say, It’s a problem, but not with my patients. It’s my partner’s patients, or the other clinics’ patients,’” said Lawrence Wickerham, MD, associate chairman, National Surgical Adjuvant Breast and Bowel Project (NSABP). “And nothing could be farther from the truth—lack of compliance is not linked to economic status or level of education; it’s very pervasive. The take-home message is oral medications in oncology are going to be more common, so we need to recognize this as an issue and work with our patients to improve it.”

Adherence to oral antineoplastic agents in typical care settings is dramatically worse than that seen in clinical trials, and this may translate into lower efficacy of therapy when compared with outcomes observed in clinical trials.

GYNECOLOGIC CANCERS GYNECOLOGIC GYNECOLOGIC CANCERS

Data Support Aromatase Use in Early Breast Cancer The aromatase inhibitors anastrozole, exemastane, and letrozole were all approved in late 2005 by the US Food and Drug Administration as oral therapies for adjuvant treatment of earlystage breast cancer in postmenopausal women. Anastrazole and exemastane were approved for hormone-receptor-positive disease, while letrozole was approved for both receptor-positive and receptorstatus-unknown cases. Moreover, anastrozole and letrozole were approved as first-line therapy, while exemastane was approved for use after initial tamoxifen treatment. The effectiveness of each of the three third-generation aromatase inhibitors is backed up by a hefty evidence base. For example, a study presented at the San Antonio Breast Cancer Symposium last December and published in January 2008 in The Lancet bolstered the evidence on the efficacy of anastrozole as adjuvant treatment for early-stage breast cancer (Lancet. 2008;9:45-53). The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial results showed that, after

©iStockphoto.com/Paul-André Belleisle

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a median of 100 months, anastrozole resulted in a 15% higher probability of disease-free survival compared with tamoxifen. Anastrozole was also associated with a lower average time to recurrence, a lower incidence of new contralateral breast cancer and a longer time to distant recurrence, although it did not have an appreciable effect on rates of death after recurrence or overall survival. Hot on the heels of this are several papers demonstrating the efficacy of letrozole. For example, letrozole produced significantly higher rates of disease-free survival in a study of 4,922 postmenopausal women with receptor-positive early breast cancer randomized to letrozole or tamoxifen (J Clin Oncol. 2008;26:1972-1979). It also provided a 63% higher probability of disease-free survival even after a substantial period had passed since discontinuation of prior tamoxifen adjuvant therapy, according to the National Cancer Institute of Canada (NCIC) Clinical Trials Group’s MA.17 study (J Clin Oncol. 2008 Mar 10 [Epub ahead of print]). Exemastane is also proving to be an effective treatment option. For example, among women switched from placebo to exemastane after premature closure of the NCIC MA.17 study, the medication was associated with a statistically significant 2% higher rate of 4-year relapse-free survival compared with tamoxifen, and a near-significant 2% higher rate of 4-year disease-free survival (J Clin Oncol. 2008 Mar 10 [Epub ahead of print]).

Adherence Levels Far From Perfect In the midst of these heartening results, however, another new study is shedding some rain on the parade. A review of the records of more than 12,000 women enrolled in three large, commercial health insurance programs showed adherence rates are not even close to 100% among women taking aromatase inhibitors (J Clin Oncol. 2008;26:556-562). The research, led by Ann Partridge, MD, MPH, found the rates were 82% to 88% in the first year after women started taking the medications, and dropped as low as 62% during the third year. Dr Partridge, medical oncologist, Dana-Farber Cancer Institute, and an assistant professor of medicine, Harvard Medical School, Boston, and her co-investigators pooled claims data between January 2002 and March 2004 from the MarketScan employer-based claims database and from two large American health plans. They captured the records of 7,132 women with early breast cancer and at least 12 months of followup records of women who were taking anastrazole, including 999 with at least 24 months of follow-up data. Anastrozole initiation was defined as no evidence of endocrine therapy for at least 4 consecutive months before the first anastrozole-prescription claim. The team found the annual mean medication possession ratio— the ratio of number of days elapsed to number of days during which the patients were covered by a prescription they had filled for anastrozole or another hormonal agent they had switched to—was approximately 86% among the women who had taken anastrozole for 12 consecutive months. By the second year, the rates had fallen a notch, however, to 75% among women

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What can be done? One question is whether increased adherence is associated with improved outcome. Another is how the adherence rates can be increased. Perhaps surprisingly, the first question has not been answered yet, but a lot of effort has been made to answer the second one. Many clinicians are trained that the best approach to improving adherence is to remind their patients at each visit that they should take every single pill prescribed because this is the only way to maximize benefits from the medications. But does that work? Many experts strongly feel a more individualized and respectful twoway dialog is necessary. A recently published paper by Dr Partridge, Dr Wickerham, and three other researchers outlined recommendations for increasing adherence to adjuvant therapy for breast cancer (Community Oncol. 2007;4:725-730). The authors are all part of the Compliance Strategic Initiative, a multidisciplinary collaborative effort created to optimize adherence. The team’s recommendations include tailoring communication to the individual patient, keeping messages simple, and enhancing the patient’s equal value in the “adherence equation” by means such as encouraging use of pill boxes or medication diaries. Dr Wickerham adds that nurses are critical to this equation. “Often patients are reluctant to admit to the doctor that they’re having trouble taking their medication, but they’ll be more open with the nurses or other medical professionals in the office,” said Dr Wickerham. “I hear it all the time because I talk about this around the country. And we’ve

been dealing with this in our clinical trials for a long time; we teach our nurses how best to improve adherence.” Wendy Smith, MSN, nurse practitioner, West Clinic, Corinth, Miss, and board member, Community Oncology Alliance, Washington, DC, affirms that developing a solid, trusting relationship is more valuable than any other patient-clinician factor, particularly for early-stage breast cancer, when the cost-benefit ratio may appear to patients to be skewed against them. “Communication skills are the basis for everything,” said Ms Smith. “For example, if they come to us and say, ‘Cost is an issue,’ we can see how we can work with them, such as directing them to a patient prescription assistance program or helping them get coverage through their insurance program.…Or if they have side effects such as hot flashes and muscle aches when they start therapy, if we can be good listeners we can often help them cope; as a result many women can adjust to those side effects and continue to take the medication.” Dr Partridge also concurs that making patients partners in their treatment is critical. “We have to try harder to understand why people are not adherent, educate them about the goals of therapy, and help them to make the best decisions for themselves,” she observed. “For some people, not taking a drug might be the right thing for them. If it makes the patient miserable, she might say, ‘No thank you, I’d rather take my chances with not using the medication.’ But our job is at least to help patients understand the value of the medications—because if they don’t understand that, how can they make the right decision about taking the medication?” A putative approach is to profile patients and target only those who are most likely to be nonadherent. Some work is being done in that area, says Dr Wickerham, but it has not made much headway. He notes that for the foreseeable future, the bulk of success in increasing patient adherence will rest on individual clinics’ priorities and their staff’s people skills. “Some are far superior to others. It comes down to a nurse or nurses who are willing and able to take the time to impact adherence,” he said. “And that, in turn, comes from the people who run the clinics, who make this a priority.”

GYNECOLOGIC CANCERS GYNECOLOGIC GYNECOLOGIC CANCERS

in the MarketScan database, 82% among those enrolled in one of the large national plans, and 68% among those in the other national plan. By the third year, the rates fell even lower to 72%, 79%, and 62%, respectively. The investigators found that women who stopped taking anastrozole during the first year appeared to do so gradually. “Our findings of suboptimal adherence among a substantial proportion of women in the so-called real world provide further evidence that adherence to oral antineoplastic agents in typical care settings is dramatically worse than that seen in clinical trials, and this may translate into lower efficacy of therapy when compared with outcomes observed in clinical trials,” the investigators concluded.

GYNECOLOGIC CANCERS

Gynecologic Cancers

—Rosemary Frei

Specialized Care Not Consistently Superior for Ovarian Cancer Treatment New studies by American and European researchers have stimulated further debate about the value of specialized care for ovarian cancer. At stake is the willingness of insurance companies to fund referral centers that purport to provide superior care. A Dutch team uncovered a significantly lower mortality rate among early-stage ovarian-cancer patients treated at specialized centers compared with general hospitals (J Natl Cancer Inst. 2008;100:399-406). Surprisingly, however, treatment by a gynecologic oncologist in general or semi-specialized hospitals was associated with lower mortality than when these specialists provided the care in a specialized hospital. These findings complement a pair of studies presented at the Society of Gynecologic Oncology’s 2007 annual meeting by Robert Bristow, MD, and colleagues showing treatment of ovarian cancer at high-volume centers is more cost-effective than at lower-volume centers, but that surgery by a gynecologic oncologist is not associated with longer survival than treatment by a general surgeon. “The minutiae that go into survival for advanced ovarian cancer are [likely] masked in the Dutch analysis — they didn’t include the type of operations, by whom [they were performed], or what kind of chemotherapy was given. There are also significant differences between how patients are treated in the United States and in Europe,” commented Don Dizon, MD, director of medical oncology and director of integrative care, Program in Women’s Oncology, Women’s and Infant’s Hospital, The Warren Alpert Medical School, Brown University, Providence, RI. “We would expect that care at a tertiary center would be associated with a benefit even in advanced cancer.”

May 2008

The Dutch investigators examined data from the Netherlands Cancer Registry on all 8,621 women diagnosed with ovarian cancer from 1996 to 2003. They found the 5-year overall survival rate of patients treated in general hospitals was 38%, compared with 39.4% and 40.3% in semi-specialized and specialized centers, respectively. Furthermore, patients with early-stage ovarian cancer and those aged 50 to 75 years with stage I-IIa disease had lower risks of mortality from the cancer when they were treated in semi-specialized or specialized hospitals than if they were treated in general hospitals. Although those with advanced disease did not appear to gain survival time with treatment in specialized hospitals, treatment by gynecologic oncologists in general, semi-specialized, or specialized hospitals was associated with the lowest overall probability of death—with a hazard ratio of 0.52 (95% confidence interval 0.43-0.63)—compared with treatment by a general gynecologist in a general hospital. “Of course a gynecologic oncologist probably works in a bigger team. We couldn’t explore that explicitly in the study, but that’s probably part of the explanation of the results,” said lead investigator Flora Vernooij, MD, PhD, researcher, Department of Gynecologic Surgery and Oncology, and gynecology resident, Utrecht University Medical Center, Holland. “To me it makes sense, that if you have more people working together, you’re going to get better care. But I’m not sure they showed that in this study,” commented Mary Pat Lynch, CRNP, MSN, administrator, Joan Karnell Cancer Center, Pennsylvania Hospital, Philadelphia. —RF

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Gynecologic Cancers GYNECOLOGIC CANCERS

Studies Show Protective Benefits, Fewer Procedures with HPV Vaccination

GYNECOLOGIC CANCERS GYNECOLOGIC GYNECOLOGIC CANCERS

TAMPA–WOMEN VACCINATED AGAINST the human papillomavirus (HPV) have significantly fewer abnormal Pap smears and fewer procedures and surgery to evaluate abnormal test results, according to an analysis of data from three randomized clinical trials of the vaccine. All categories of abnormal histology decreased significantly in vaccinated versus unvaccinated women, led by a 43% decline in the incidence of high-grade squamous intraepithelial lesions, Warner K. Huh, MD, reported at the Society of Gynecologic Oncologists (SGO) meeting. The need for definitive therapy decreased by 42% in the vaccinated group. “This is important because a lot of physicians across the United States may never see a case of cervical cancer in their lifetime,” said Dr Huh, a gynecologic oncologist at the University of Alabama at Birmingham. “However, almost every clinician involved in women’s healthcare—and every woman—is familiar with the importance of an abnormal Pap smear.” The results do not prove the vaccine prevents cervical cancer, he added, but they do show that vaccination prevents cellular changes that often trigger procedures and surgery and that the benefits of vaccination occur early. Two other studies reported at the SGO meeting provided additional insights into the vaccine’s efficacy and therapeutic potential. One study showed the vaccine protects against HPV infection for at least 6 years. The other showed that sexually active women up to age 45 might benefit from vaccination. Dr Huh presented data from three randomized clinical trials of the HPV quadrivalent vaccine, which targets the four HPV subtypes most closely linked to cervical cancer (6, 11, 16, and 18). The trials involved a total of 18,000 patients ages 16 to 26 years. All participants had negative Pap smears and negative results for 14 common HPV subtypes. Study participants were randomized to three doses of the vaccine or to placebo. The primary end point of Dr Huh’s analysis was the rate of abnormal

©iStockphoto.com/Stephanie Swartz

Pap smears and the frequency of cervical procedures during follow-up. In addition to reduction in high-grade squamous intraepithelial lesions, the incidence of other types of premalignant changes decreased by 16% to 35% in the vaccine group. Vaccinated women also had significantly fewer cervical procedures, including coloposcopy and biopsy, in addition to definitive therapy. Whether vaccinated patients will require periodic boosters has yet to be determined. However, data from 76 months of follow-up showed the vaccine continues to protect against infection for at least that length of time. None of 505 vaccinated women had developed cervical intraepithelial neoplasia caused by infection with HPV 16 or 18, compared with 25 cases in the placebo group, reported Diane Harper, MD, associate professor of community and family medicine and of obstetrics and gynecology at Dartmouth College in Hanover, NH. A third report involving the HPV vaccine suggested that the most common age target for vaccination, 16 to 26 years, excludes many women who might benefit

from vaccination. A study of 3,817 women ages 24 to 45 years showed that two thirds had no evidence of exposure to any of the four HPV subtypes covered by the vaccine, said Sharmila Makhija, MD, associate professor of obstetrics and gynecology at the University of Alabama at Birmingham. As a result, the vaccine could protect sexually active women at least up to age 45 years. Of the remaining one third of the study population, 92% were infected with one of the four HPV subtypes covered by the vaccine and fewer than 1% were infected with all four subtypes. In that population, the vaccine might afford at least partial protection, said Dr Makhija. During 4 years of follow-up, which included Pap smears every 6 months, 41 of 1,908 women in the placebo group reached the primary end point of persistent infection with one or more of the four HPV subtypes or any cervical, vulvar, or vaginal lesions. In contrast, four of 1,911 women in the vaccine group met the primary end point, representing a 91% reduction in risk. —Charles Bankhead

Inappropriate Use of Antibiotics Frequent in Gynecologic Surgery TAMPA–ALMOST HALF OF PATIENTS undergoing gynecologic surgery received inappropriate antibiotic prophylaxis, investigators in an ongoing surveillance study reported at the Society of Gynecologic Oncologists (SGO) meeting. Most cases of inappropriate prophylaxis involved administration of antibiotics that were not indicated. However, some patients who should have received antibiotics did not get them. “The problem of antibiotic resistance is well recognized, and clinicians who give antibiotics that are not indicated or who continue treatment for too long may be contributing to that problem,” Monjri Shah, MD, of Columbia University in New York, reported at the SGO meeting. “These results indicate that inappropriate

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use occurs fairly often, despite the existence of clinical guidelines that define appropriateness.” Dr Shah presented data abstracted from records on 486 women who had gynecologic surgery from 2005 to 2007. Each record was examined for adherence to American College of Obstetricians/Gynecologists (ACOG) guidelines for antibiotic prophylaxis. Investigators recorded overall antibiotic use, the type of antibiotic used, and the duration of prophylaxis. The analysis showed that 45% of patients received inappropriate antibiotic prophylaxis. The total consisted of 203 cases in which patients received antibiotics that were not indicated by the guidelines and 14 cases when prophylaxis was indicated but not given.

Dr Shah found that 11% of patients received a drug that is not recommended by the ACOG guidelines. Of 204 patients who were admitted to the hospital after surgery, 58 (29%) received more than the recommended one dose of antibiotics, and one patient did not receive prophylaxis when it was indicated. “Overutilization of antibiotics in patients who did not require prophylaxis and inappropriately prolonged courses of drug are common,” said Dr Shah. “Given the emergence of multidrug-resistant organisms, efforts should be made to improve the quality of antibiotic prophylaxis for gynecologic surgery. —CB

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Trends in Breast Cancer Mammography and MRI Combined Provide Greater Benefit for Women with BRCA1 Mutation ANNUAL SCREENING USING A COMBINATION of mammography and magnetic resonance imaging (MRI) was shown to have greater benefit for women who carry the BRCA1 mutation. The study was conducted using a Markov computer model consisting of 500,000 women 25 years of age who were asymptomatic BRCA1 carriers to determine the effect of MRI screening on clinical outcomes of breast cancer. Three screening strategies were compared: clinical surveillance, annual MRI, and annual combined MRI/mammography.The annual combined strategy of MRI/mammography detected the most cancers, with a program sensitivity of 70% versus 39% with mammography alone. Cancers were also identified earlier and were smaller: the median invasive tumor size seen with mammography alone was 1.9 cm, and 36% to 52% of tumors were 2 cm or smaller; with MRI, 1.3 cm, and 66% of all tumors were 2 cm or smaller; with combination screening, 1.1 cm, and 73% of tumors were 2 cm or smaller. An increase in average life expectancy of 1.38 years and a reduction in breast cancer mortality of 22% were also observed with combination screening. This strategy, however, was associated with a high rate of false-positive results: between 80% and 84% of women eventually had at least one false-positive result, and more than 25% underwent unnecessary biopsies. (Lee JM, et al. Radiology. 2008;246:763-771.)

Genomic Information Along with Clinical Risk Stratification May Refine Breast Cancer Prognoses INTEGRATING GENE EXPRESSION SIGNATURES with clinical risk stratification may more accurately determine the prognosis of breast cancer patients, according to an analysis of 964 breast tumor samples. Using a clinicopathologic prognostic model, subjects were divided into three relapse risk categories: low, intermediate, and

WHY CERTIFY? Continued from cover time annual income that is $10,000 greater than their uncertified counterparts.1 In an American Nurses Association press release in 1999, it was noted that only one of three individuals were aware that there even was an entity such as nursing specialty certification. (American Nurses Asso-

Table—Eligibility Criteria for Initial Candidates for OCN® Certification • Current, active, unrestricted RN license • ≥ 1 year of experience as an RN within 3 years prior to application • ≥ 1000 hours of oncology nursing practice within 2½ years prior to application • Completion of ≥ 10 contact hours of accredited continuing education in oncology nursing or an academic elective in oncology Source: Oncology Nursing Certification Corporation (www.oncc.org)

May 2008

high. In each category, gene expression signatures showed subclusters having prognostic significance. Among low-risk patients five clusters were found, each with distinctive prognostic significance (P <.02). Median relapse-free survival time for patients in cluster 4 (poor prognosis) was 16 and 19 months less than those in clusters 1 and 5 (good to intermediate prognosis), respectively. Patients at intermediate risk had six clusters of prognostic significance. Median relapse-free survival time for cluster 3 (poor prognosis) was 54 months less than cluster 2 (good prognosis). Findings were similar for high-risk patients; genomic differences indicated patients in cluster 4 (poor prognosis) had inferior relapse-free survival compared with those in other clusters (cluster 1, P = .03; cluster 5, P = .01). Median relapse-free survival time for cluster 4 was 15 and 8 months less than clusters 1 and 5 (good prognosis), respectively. Additionally, based on gene expression signatures, the researchers predicted which patients may be sensitive to various chemotherapies; for example, patients with a poor prognosis were likely to be resistant to adriamycin and paclitaxel and sensitive to docetaxel, etoposide, and topotecan. (Acharya CR, et al. JAMA. 2008;299:1574-1587.)

COX-2 Expression May Predict Breast Cancer Risk in Women with Atypical Hyperplasia EXPRESSION OF THE CYCLOOXYGENASE-2 (COX-2) enzyme may help predict breast cancer risk, according to a recent study that included 331 women with atypical hyperplasia. The women underwent a benign breast biopsy and were then followed up for a median of 15 years. Among 100 women having atypical ductal hyperplasia, 77% had no or weak COX-2 staining (categories 0 or 1+), 13% had moderate (category 2+) staining, and 10% had strong (category 3+) staining; 122 women had atypical lobular hyperplasia, and 47 (39%) had categories 0 or 1+ staining, 53 (43%) had category 2+ staining, and 22 (18%) had category 3+ staining (P <.001). Strong staining also correlated with increasing age (>45

ciation. Press Release, May 6, 1999). By 2002, however, another survey conducted by the American Association of Critical Care Nurses concluded that eight of 10 people were aware that nurses could be certified in a given specialty area. This finding suggested that American citizens were more aware of nurse certification than they were of certifications available for teachers or physicians.2 It is an older population that is seeking cancer treatment in today’s healthcare environment, and it is likely that this population will grow in the near future. It has been projected that by 2030, the US population of adults older than 65 years of age will increase by 104.2% from the 2004 figures.3 Older patients have a significantly higher incidence of comorbidities and must rely on experienced and knowledgeable nurses to recognize subtle changes in their conditions and take appropriate corrective action. Consistently, oncology-certified nurses have shown that they have the necessary skills for the job. Oncology nursing certification also benefits organizations. By hiring and retaining high percentages of oncology-certified nurses, healthcare organizations can garner higher credibility in the exceptionally competitive and lucrative cancer care market. Increased numbers of certified nurses also prove beneficial when seeking endorsement from the Joint Commission on Accreditation of Healthcare Institutions, the Association of Community Cancer Centers, or when attempting to achieve Magnet status.4

years, P = .01). Of the 235 women for whom COX-2 staining was available, 41 (17%) developed breast cancer, indicating a borderline statistically significant relationship (P = .07). Specifically, risk after 15 and 20 years of follow-up among women with categories 0 or 1+ COX-2 staining was 13% and 14%; category 2+ staining, 19% and 24%; and category 3+ staining, 25% and 31%, respectively. Median time to breast cancer development among the 18 women who had category 0 or 1+ staining was 11.4 years and among the 23 women who had category 2+ and 3+ staining, 11.8 years. (Visscher DW, et al. J Natl Cancer Inst. 2008;100:421-427.)

Radiation Given in Higher Doses, Fewer Fractions Similar to Conventional Schedule THE STANDARDISATION of Breast Radiotherapy (START) Trial A was one of two parallel studies that tested radiation schedules using fraction sizes larger than 2 Gy. A total of 2236 women undergoing radiation after breast cancer surgery were randomized to either the conventional 50 Gy in 25 fractions, 41.6 Gy in 13 fractions, or 39 Gy in 13 fractions, all given over 5 weeks. Primary end points included local-regional tumor control, normal tissue effects, and quality of life. Results showed 93 (4%) patients experienced local-regional tumor relapse; estimated absolute differences at 5 years were 0.2% after 41.6 Gy and 0.9% after 39 Gy compared with 50 Gy. An estimated maximum risk of 2.1% and 3.2% was associated with 41.6 Gy and 39 Gy compared with 50 Gy, respectively, and no evidence was found indicating that either of the 41.6 or 39 Gy schedules caused clinically significant harm. Changes in breast appearance and breast hardness were most common; rates of moderate or marked effects by 5 years were similar after 41.6 Gy and 50 Gy. Hazard ratios, compared with the 50 Gy group, were 1.09 (P = .62) after 41.6 Gy and 0.69 (P = .01) after 39 Gy. A significantly lower rate of change in skin appearance was noted after 39 Gy than after 50 Gy (P = .004). (The START Trialists’ Group. Lancet Oncol. 2008;9:331-341.)

Perhaps greater than any of these tangible rewards, however, is the self-satisfaction and professional recognition that accompanies oncology nursing certification. Statistics indicate that satisfied nurses are much more likely to remain in their current positions, an important consideration in light of the sustained shortage of nurses, and much less likely to be continually searching for the pot of gold at the end of the rainbow. For further information about oncology nurse certification requirements and testing dates, contact the Oncology Nursing Certification Corporation (Phone: 877-769-ONCC; Web site: www.oncc.org; E-mail: oncc@ons.org).

References 1. Robinson, ES. Nursing 2004 Salary Survey. Nursing. October 2004. http://www.findarticles.com/ p/articles/mi_qa3689/ is_200410/ai_n9431354. Accessed June 28, 2007. 2. Harris Interactive, Inc. American Association of Critical Care Nurses Survey. November 2002. http://www.aacn.org/ AACN/mrkt.nsf/Files/HarrisPollRpt/$file/HarrisPollRpt. pdf. Accessed June 28, 2007. 3. Population Projections. Change in Total Population and Population 65 years and Older by State 2000 to 2030. Washington, DC. Population Projections Program, Population Division, US Census Bureau; 2004. http:// www.census.gov/population/projections/PressTab4.xls. Accessed June 27, 2007. 4. Oncology Nursing Certification. http://www.oncc.org/ publications/certification.shtml. Accessed June 27, 2007.

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NUR NURSING EDUCATION AND TRAINING RENDS IN BREAST CANCER

TRENDS IN BREAST CANCER

Trends in Breast Cancer

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CRs Correlate with Clinical Benefit in APEX1 OVERALL SURVIVAL STRATIFIED BY QUALITY OF RESPONSE 1.0 0.9

Proportion of Patients

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0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Time (months) CR (n=27)

PR with ≥90% decrease (n=31)

PR with ≥50% and <90% decrease (n=77)

All other (n=180)

CLINICAL BENEFIT OF VELCADE® BY QUALITY OF RESPONSE* CR

(≥90% M-protein reduction)

(≥50% and <90% M-protein reduction)

Patients, n (%)

27 (9)

31 (10)

77 (24)

Median cycles

Treatment-free interval (months)

24.1 (9.7, 24.4)

6.9 (5.5, 11.1)

6.4 (4.4, 10.3)

Time to next treatment (months)

27.1 (15.2, 32.0)

13.6 (10.0, 17.3)

14.0 (12.6, 16.1)

Time to progression (months)

9.7 (7.8, 17.7)

10.8 (8.1, 14.4)

8.5 (7.0, 9.9)

Not yet reached

Overall survival

M CRs deliver greater clinical benefit than any other responses *In APEX, 315 VELCADE patients were evaluable for response. Responses were based on criteria established by the European Group for Blood and Marrow Transplantation (EBMT). Complete response (CR) required 100% disappearance of the original myeloma protein from blood and urine on at least 2 determinations 6 weeks apart by immunofixation, <5% plasma cells in the bone marrow, stable bone disease, and normal calcium. Partial response was stratified into 2 categories; M-protein reduction of either ≥ 90% or of ≥ 50% and <90% determined on at least 2 occasions, 6 weeks apart. Both categories required ≥ 90% reduction in urine myeloma protein upon at least two determinations six weeks apart, stable bone disease and normal calcium.

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. References: 1. Data on file. Millennium Pharmaceuticals, Inc.

Please see Brief Summary of full Prescribing Information on adjacent page, also available at www.VELCADE.com.

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Supportive Care SUPPORTIVE CARE

FURTHER LIMITS ON USE OF ESAs Continued from cover

SUPPORTIVE CARE SUPPORTIV TRENDS IN HEMATOLOGIC CANCERS

required to complete a written consent form before using one of these agents. The committee also recommended that these drugs not be used in patients with breast cancer or head and neck cancer. This was the third ODAC meeting held just to examine safety issues with ESAs, and it now appears even further restrictions will soon be placed on the use of ESAs in patients with cancer. There are currently three FDA-approved ESAs on the market in the United States: epoetin alfa (Procrit), epoetin alfa (Epogen), and darepoetin alfa (Aranesp). The FDA revised label warnings on ESAs in 1997, 2004, 2005, and 2007 to reflect new safety information. “There are now eight trials in which patients with cancer who received ESAs have shorter survival and/or poorer tumor control than patients receiving similar anticancer treatments but no ESAs. The committee advised the FDA that product labeling be revised,” FDA spokeswoman Crystal Rice said in an interview. “In addition, ODAC recommended that patients should not take ESAs until their hemoglobin level falls below 10 g/dL. The FDA is considering the advice of the ODAC in planning the next steps.” Taken together, all eight studies showed more rapid tumor growth or shortened survival when patients with breast, non–small-cell lung, head and neck, lymphoid, or cervical cancers received ESAs compared with patients who did not receive ESAs. In all these recent studies, ESAs were administered in an attempt to achieve a hemoglobin level of 12 g/dL or greater, although many patients did not reach that level. ESAs are a bioengineered version of a natural protein made in the kidneys that stimulates the bone marrow to produce more red blood cells. FDA-approved uses of ESAs are for the treatment of anemia in patient with

chronic kidney failure and for cancer patients whose anemia is caused by chemotherapy. ESAs are also approved for patients infected with HIV whose anemia is caused by the HIV drug zidovudine. ESAs are also approved to reduce the number of transfusions during and after major surgery. On November 30, 2007, Amgen, manufacturer of the three ESAs, provided the FDA with information from the 733-patient PREPARE study of women who received chemotherapy before undergoing surgery for breast cancer. After 3 years, 14% of the patients who received darepoetin alfa to treat their anemia had died compared with 9.8% of those who did not receive the drug. Tumor growth was also faster in patients receiving the ESA. Charles L. Bennett, MD, PHD, and his colleagues conducted a phase 3 trial to examine the rate of venous thromboembolism (VTE) and death associated with ESA administration for the treatment of anemia in cancer patients (JAMA. 2008;299:914-924). The findings indicated that the risk of death was significantly higher for cancer patients who were treated with an ESA compared with the placebo group. The researchers identified 51 clinical trials involving 13,611 patients and compared survival rates. VTE was evaluated in 38 trials that included 8,172 patients. The researchers found that there was a significantly increased risk (57%) of VTE among patients receiving ESAs compared with those who received placebo. “The basic science and clinical data raise a real concern. We are far from confirmed about what is happening here, but it appears the patients will now have to decide if they want to take the risks,” said Dr Bennett, in interview. “The data show a 10% increase in mortality in patients on ESAs, so there are quantity of life and a quality of life issues involved.” Dr Bennett, who is professor of geriatrics and economics at the Northwestern University Feinberg School of Medicine, Chicago, Ill, said it is important for clini-

cians to be fully aware of what basic science and clinical data show in regard to the use of ESAs. He said the data do not support the idea that these agents improve quality or quantity of life. But not everyone agrees. Some clinicians and pharmacists are concerned that further restrictions on the use of ESAs may greatly impact the care of many cancer patients and put prescribing physicians in a difficult position. “If you are going to restrict a drug, what becomes the clinicians’ alternative for treatment? The alternative for clinicians is a blood transfusion, and blood transfusions are not without their problems related to risk, toxicity, cost, inconvenience, and just accessibility,” said Byron Peters, RPh, director of the Washington University Cancer Center Pharmacy, St. Louis, Mo. “Our blood supply in this country is not good. We have a war in Iraq, and we have many shortages in parts of the country every day. There are consequences for every action,” he continued. “These patients are still going to need to be treated, and we may have to go back to blood transfusions. The ESAs are more long-lasting whereas transfusions are short-lived.” Mr Peters also questions the validity of the latest review studies because they include data from when prescribing practices were much different than they are today. “There are a lot of data that are not pertinent to today’s practice, but they are still being considered in the FDA’s ultimate decision on these drugs,” he said “In the meta-analysis studies, they were using it at much higher stopping points, and that is not standard of practice today. They were treated at significantly higher hemoglobin levels and, clearly, the higher you go, the higher the risk for problems.” —John Schieszer

Hemotologic Trends Trends in Hematologic Cancers Fused PET/CT Imaging Useful in Determining Response to Radiotherapy in B-cell NHL

TRENDS

A NEW STUDY SUGGESTS THAT USE of combined fusion fluorine 18 fluorodeoxyglucose (FDG) positron emission tomographic (PET)/computed tomographic (CT) imaging is superior to CT imaging alone in the evaluation of yttrium 90 (90Y)–ibritumomab tiuxetan radioimmunotherapy treatment of B-cell nonHodgkin’s lymphoma. A group of 10 patients (mean age, 52 years) with relapsed or refractory non-Hodgkin lymphoma underwent FDG PET/CT imaging both 14 to 27 days before treatment with 90Y–ibritumomab tiuxetan and 4 to 6 months after treatment. Interpretation of CT images alone resulted in classification of eight patients as responders to treatment, of whom two were classified as having a complete response. At reevaluation with fused PET/CT imaging, two patients had residual lesions at CT that did not show evidence of FDG avidity. Both of these patients were classified as partial responders according to CT criteria alone and reclassified as complete responders at PET/CT. Both of these patients were free of evident disease after ≥18 months of follow-up. The researchers concluded that the use of CT imaging alone may underestimate 90 Y–ibritumomab tiuxetan responses by classifying inactive residual CT masses as residual disease. Combined PET/CT scanning could help avoid unneces-

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sary follow-up treatments. (Ulaner GA, et al. Radiology. 2008;246:895-902.)

SGX393 Inhibits CML Mutant Clone and Helps Preempt Emergence of Resistance SGX393 is a potent inhibitor of native and T315Imutant Bcr-Abl, a deregulated tyrosine kinase that causes chronic myeloid leukemia (CML). Bcr-AblT315I is resistant to Abl kinase inhibitors in current use and is emerging as the most frequent cause of salvage therapy failure in patients with CML. In preclinical studies, SGX393 blocked the growth of leukemia cell lines and primary hematopoietic cells expressing Bcr-AblT315I, with minimal toxicity against Bcr-Ablnegative cell lines or normal bone marrow. Screening for Bcr-Abl mutants emerging in the presence of SGX393 revealed a concentration-dependent reduction in the number and range of mutations. Combining SGX393 with nilotinib or dasatinib preempted the emergence of resistant Bcr-Abl subclones, including Bcr-AblT315I. These findings suggest that treatment with the combination of SGX393 and currently available Abl kinase inhibitors may be a useful strategy for inhibiting the emergence of BcrAbl mutants in patients with Philadelphia chromosome-positive CML. (O’Hare T, et al. Proc Natl Acad Sci. 2008;105:5507-5512.)

Chemotherapy Plus Radioimmunotherapy Effective in Untreated Follicular NHL The combination of fludarabine and mitoxantrone plus yttrium-90 (90Y)-labelled ibritumomab tiuxetan is effective and tolerable in previously untreated patients with follicular non-Hodgkin’s lymphoma (NHL). In a nonrandomized, open-label, phase 2 study, 61 patients with stage III or IV untreated indolent follicular NHL received oral fludarabine and intravenous mitoxantrone every 28 days for six cycles. Patients who had at least a partial response (PR) without significant hematologic toxicity at 4 to 6 weeks after completion of the sixth cycle of chemotherapy received one course of 90Ylabelled ibritumomab tiuxetan. Of the 61 patients who received six cycles of fludarabine and mitoxantrone, 43 had a complete response (CR) and 17 had a PR. A total of 57 patients (43 with CR and 14 with PR) were deemed eligible for subsequent 90Y-labelled ibritumomab tiuxetan. Of the 14 patients who had PR after the initial treatment, 12 achieved CR after 90Y-labelled ibritumomab tiuxetan. By the end of the entire treatment regimen, 55 of 57 patients achieved CR. Three-year progression-free survival was 76% and 3-year overall survival was 100%. Of the 57 patients who completed therapy, 36 had grade 3 or 4 hematologic side effects, and 21 received blood transfusions. (Zinzani PL, et al. Lancet Oncol. 2008;9:352-358.)

May 2008

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Gastrointestinal Cancers the same time it can be removed completely to prevent cancer.” However Jerome Waye, MD, one of the investigators in the multicenter American National Polyp Study, counsels caution when evaluating the results. “If you look at the lesions that contained invasive carcinoma in the JAMA study, there were only two in the flat adenoma group, and two in the depressed adenoma group — that’s only one tenth of one percent of the cases,” said Dr Waye, who is a gastroenterologist in private practice and a clinical professor of medicine, Mount Sinai School of Medicine, New York. “And the field has really abandoned the term carcinoma in situ in favor of high-grade dysplasia, because the word carcinoma is misleading. In the colon, high-grade dysplasia is not ominous, because it’s not cancer.” Dr Waye added that a post hoc analysis of the National Polyp Study specimens by him and his colleagues supports the view that nonpolypoid lesions are not dangerous. They confirmed in a review of the pathology slides that while 27% of all of the adenomas they removed were flat, lesions with this type of morphology were not associated with a higher risk for high-grade dysplasia at initial colonoscopy compared with the sessile lesions (Clin Gastroenterol Hepatol. 2004;2:905-911). Furthermore, they also were not associated with a higher rate of advanced adenoma at follow-up surveillance. Robert Petras, MD, national director, gastrointestinal pathology, AmeriPath/Quest Diagnostics, Cleveland, agrees with Dr Waye’s points—including his underlying contention that clinicians are not missing nonpolypoid lesions. “There isn’t a whole lot of evidence that we in America are missing these flat

lesions,” said Dr Petras. “If we were missing them, you’d expect a tremendous number of interval cancers—a much higher rate than we have. …We may also have nomenclature differences. This may also explain why the Japanese have such a marvelous survival rate following resection for stomach cancer —many of what they report as cancer cases don’t actually have cancer by Western criteria.” The Flat Lesion Study led by Dr Soetikno involved 1,819 patients undergoing elective colonoscopy at the Veterans Affairs Palo Alto Health Care System between July 2003 and June 2004. Of the 1,819 patients, 0.94% had a total of 2,770 lesions; 1,535, were neoplastic and 1,235 were nonneoplastic. Among the neoplastic lesions, 1,308 were polypoid. Of these, 209 were flat—including the two invasivecancer and seven high-grade dysplasia lesions—and another 18 were depressed—including two invasive cancers and four high-grade dysplasia lesions. Among the 1,235 nonneoplastic lesions, 1,155 were polyploid and 80 were flat. The investigators removed every polyp they detected, including using endoscopic mucosal resection to remove four of the seven flat lesions with high-grade dysplasia, and surgery to remove the other three. “At the end of the day, one interval cancer is one too many,” said Dr Soetikno. “The patient, referring physician, and insurer expect a high-quality colorectal cancer screening colonoscopy—one that encompasses the detection, diagnosis, and removal of all neoplasms, both polypoid and nonpolypoid.” —Rosemary Frei

Routine H pylori Screening Recommended by High-powered Consensus Group ROUTINE HELICOBACTER PYLORI SCREENING of American populations at high risk for gastric cancer may be on its way. Attendees of the Asia-Pacific Gastric Cancer Consensus conference are calling for H pylori screening and treatment in all adults at high risk of gastric cancer, including asymptomatic individuals (Am J Gastroenterol. 2008;103:510-514; J Gastroenterol Hepatol. 2008;23:351-365). “There is no doubt that this set of recommendations will generate controversy.… However, after carefully weighing all of the available evidence, it is our opinion that waiting another 20 years to obtain all the hard data will lead to a substantial number of unnecessary deaths from preventable cancer,” the consensus panel authors conclude. According to the panel, populations in the United States at high risk for gastric cancer may be candidates for routine screening programs. These include Korean men in Los Angeles, who have an age-standardized gastric-cancer incidence rate of more than 40/100,000, and Alaskan native men, who have a rate of 36/100,000. Moreover, the rate of gastric cancer in Asian men in California and in Iowa is higher than among other American men, at 22.2 and 49.7 cases/100,000, respectively. This is according to infor-

May 2008

mation from the Surveillance Epidemiology and End Results database from 2000-2004. The consensus conference was supported by the Journal of Gastroenterology and Hepatology and by the Asian Pacific Association of Gastroenterology. Two of the three lead authors have consulted for, been on advisory boards or speakers’ bureaus for, or received research support from, a variety of drug companies, including the manufacturers of the drugs they recommend for H pylori eradication. The team reviewed the literature, and also performed a meta-analysis, which indicated that the pooled relative risk of developing gastric cancer after H pylori eradication is 0.56 (95% confidence interval 0.40.8). They concluded that eradication would lead to reduction of not only gastric cancer rates, but also of peptic ulcer disease, peptic ulcer bleeding and deaths, and dyspepsia and functional dyspepsia, and that it would decrease the number of upper endoscopies and amount of long-term acid suppression required. The team noted the optimal choice of antibiotic therapy for positive cases depends on local and national treatment guidelines, but that 1 week of triple therapy, such as with clarithromycin, amoxicillin, and a proton pump inhibitor should suffice. The

most commonly used proton pump inhibitors include esomeprazole and omeprazole. The team said they believe such treatment will not increase the prevalence of antibiotic resistance, nor other potential negative sequalae. Martin Blaser, MD, who is Frederick H. King professor of internal medicine, chair, Department of Medicine, and professor of microbiology, Langone Medical Center, New York University, wrote in 1999 that H pylori eradication may cause a marked increase in cases of gastroesophageal reflux disease, Barrett’s esophagus, and esophageal adenocarcinoma (J Infect Dis. 1999;179:1523-1530). “They misquoted me in the consensus recommendation paper—they said I believed eradicating H pylori has more risks than benefits. But I didn’t say that; I said we don’t know. And we still don’t know,” Dr Blaser told The Oncology Nurse. “For example, we don’t yet know how to accurately identify all the high-risk people. And also, we have been involved in studies that show children who don’t have H pylori are at higher risk of having asthma.… Everybody’s painting the world in a black and white way—and H pylori is gray.” —RF

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GASTROINTESTINAL CANCERS GASTROINTESTINAL CANCERS

PREVENTION OF COLORECTAL CANCER (CRC) has traditionally focused on detecting and removing polypoid, or protruding, lesions. A new study that showed a higher percentage of high-grade dysplasia and submucosal invasive cancer in flat or depressed colorectal lesions than in polypoid lesions (JAMA. 2008; 299:1027-1035) has generated much discussion. The investigators found that four (0.96%) of the 227 flat or depressed neoplasms detected contained invasive cancer, and another 11 (3.3%) harbored high-grade dysplasia. Eight (0.61%) of 1,308 polypoid neoplasms found in the patients harbored invasive cancer, and five (0.38%) contained high-grade dysplasia. In the published analysis, the investigators grouped together high-grade dysplasia—which they label carcinoma in situ—and submucosal invasive carcinoma. They concluded that nonpolypoid morphology is associated with an adjusted odds ratio of 9.78 for “containing carcinoma.” These findings and their implications for clinical practice are subject to different interpretations, however. Lead investigator Roy Soetikno, MD, MSc, and his coauthors stand by their nomenclature and findings, concluding that if clinicians miss flat or depressed lesions, this can have serious consequences for patients. “In the West, there is a tendency to avoid the terminology carcinoma [and use high-grade dysplasia instead of carcinoma in situ], but this has no relevance to the pathologic criteria or to the implications of the diagnosis,” said Dr Soetikno, chief of gastroenterology, Veterans Affairs Palo Alto Health Care System. “Carcinoma in situ or high-grade dysplasia is dangerous; it is just one step before invasive cancer. But at

GASTROINTESTINAL CANCERS

Study Stirs Debate About Importance of Flat or Depressed Colorectal Lesions

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Trends in Colorectal Cancer TRENDS IN COLORECTAL CANCER

Trends in Colorectal Cancer KRAS Mutations Predictive of Response to Panitumumab Monotherapy in mCRC

TRENDS IN COLOR

KRAS STATUS SHOULD be considered when determining whether patients with metastatic colorectal cancer (mCRC) are candidates for panitumumab monotherapy because KRAS mutations are predictive of lack of clinical response to the epidermal growth factor inhibitor. This finding comes from a phase 3 study comparing panitumumab monotherapy with best supportive care (BSC) in patients with chemotherapy-refractory mCRC. The investigators used polymerase chain reaction on DNA from tumor secretions to detect KRAS mutations, and they compared the effect of panitumumab monotherapy on progression-free survival (PFS) in patients with mutant versus wild-type (WT; ie, nonmutated) KRAS. Of 463 patients in whom KRAS status was ascertained, 427 (92%) had KRAS mutations. The effect of panitumumab on PFS was significantly greater (P < .0001) in patients with WT KRAS than in those with mutant KRAS. In the WT KRAS group, median PFS was 12.3 weeks for panitumumab-treated patients compared with 7.3 weeks for those who received BSC. Seventeen percent of patients with WT KRAS but none of those with mutant KRAS responded to panitumumab. Overall survival was longer in the WT KRAS group than in the mutant KRAS group. Consistent with longer exposure to the drug, more grade III treatment toxicities were observed in the WT KRAS group. No significant differences in toxicity were found between the WT KRAS group and the overall population. (Amado RG, et al. J Clin Oncol. 2008;26:1626-1634.)

The effect of panitumumab on PFS was significantly greater (P < .0001) in patients with WT KRAS than in those with mutant KRAS. Colonoscopy Follow-up Guidelines Found to Have Limited Predictive Value RESULTS OF A NATIONAL CANCER INSTITUTE study suggest that the number and size of polyps removed at colonoscopy are of limited value in predicting recurrence of advanced adenoma. The findings raise questions about the adenoma-based risk-stratification system used in current postpolypectomy colonoscopy surveillance guidelines. The subjects of the study were 1,905 participants in the Polyp Prevention Study who had adenoma removed at baseline and underwent repeat colonoscopy at 1 year and 4 years. At 4 years, 6.6% of patients had recurrence of advanced adenoma. The rate of advanced adenoma recurrence was 9% for those classified as at high risk under the current guidelines and 4% for those considered to be at low risk. The authors note that misclassification of patients as high or low risk may mean that potentially preventable colorectal cancers are missed or that limited endoscopic resources are unduly burdened. The findings, they say, point to the need to improve the predictive ability of the guidelines. (Laiyemo A, et al. Ann Intern Med. 2008;148:419-426.)

CT Colonography May Be Better than Colonoscopy for CRC Screening COMPUTED TOMOGRAPHIC COLONOGRAPHY (CTC) may be both more clinically effective and cost-

effective than colonoscopy with or without ultrasonography for screening for colorectal cancer (CRC), Italian researchers report. The advantages, however, are seen when findings such as extracolonic cancer and abdominal aortic aneurysms as well as colorectal neoplasia are considered. The researchers used a computerized Markov model to simulate the occurrence of colorectal neoplasia, extracolonic cancers, and abdominal aortic aneurysms in a hypothetical cohort of 100,000 50year-old subjects. They compared CTC with optical colonoscopy (OC) with or without one-time abdominal ultrasonograph (OC-US). In the simulated population, CTC was found to be the dominant screening strategy, adding 1,458 life-years compared with OC and 462 life-years compared with OC-US. CTC was also less costly than the other techniques, the savings being $266 and $449 per person compared with OC and OC-US, respectively. The gains for CTC were largely attributable to a reduced number of deaths due to abdominal aortic aneurysm. The CRC prevention rate was slightly better with optical colonoscopy with or without ultrasonography than with CTC; this was offset, however, by gains related to abdominal aortic aneurysm. All three methods were more costeffective than no screening. (Hassan C, et al. Arch Intern Med. 2008;168:696-705.)

TRENDS IN LUNG CANCER

Trends in Lung Cancer Trends in Lung Cancer Combination Chemotherapy Better than Erlotinib in First-line Management of NSCLC

TRENDS IN LUNG

COMBINATION CHEMOTHERAPY with carboplatin and paclitaxel is superior to erlotinib in previously untreated patients with advanced nonâ&#x20AC;&#x201C;small-cell lung cancer (NSCLC), according to the findings of a phase 2 study. A group of 103 patients with advanced NSCLC were randomized to receive erlotinib 150 mg orally daily until progression or to standard therapy with carboplatin and paclitaxel for up to four cycles. Partial responses were 2% in the erlotinib group and 12% in the standard therapy. Median progressionfree survival was 1.9 months in the erlotinib group and 3.5 months in the standard therapy group (hazard ratio [HR] = 1.45; P = .06). Median survival times were 6.5 and 9.7 months in the erlotinib and standard therapy groups, respectively (HR = 1.73; P = .018). Rash and diarrhea were more common with

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ProApolipoprotein A1 was significantly increased (P <.05) in patients with central nervous system disease. erlotinib; emesis, alopecia, peripheral neuropathy, and fatigue were more common with standard therapy. Quality of life was similar in both groups. (Lilenbaum R, et al. J Clin Oncology. 2008;26:863-869.)

ProApolipoprotein Provides Early Detection of Brain Metastases in Patients with Lung Cancer SERUM PROAPOLIPOPROTEIN A1 MAY be an effective tool when used in conjunction with serum S100â&#x20AC;&#x161; for imaging-independent diagnosis of metastatic brain tumors in patients with lung cancer. Serum markers of blood-brain barrier dysfunction were measured in 103 patients with lung cancer. More than 50% of the

patients presented with magnetic resonance imaging changes consistent with chronic cerebrovascular disease and reflected by elevated serum S100 levels. Proteomic techniques allowed discrimination between patients with brain metastases and those affected by cerebrovascular ischemic changes without infiltrating tumor. ProApolipoprotein A1, transferrin, haptoglobin, and transthyretin were upregulated in patients affected by chronic cerebrovascular disease and brain metastases compared with those affected only by vascular diseases. ProApolipoprotein A1 was significantly increased (P <.05) in patients with central nervous system disease. (Marchi N, et al. Cancer. 2008;112:1313-1324.)

May 2008

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Survivors of Childhood ALL Face Long-term Health Issues A 25-YEAR FOLLOW-UP STUDY of survivors of childhood acute lymphoblastic leukemia (ALL) shows that these survivors continue to experience excess mortality, chronic morbidity, and poor socioeconomic outcomes for many years after completion of treatment. At 25 years from diagnosis, 13% had died, and 21% had chronic medical conditions, the researchers found. The cure rate for children with ALL has increased dramatically, from less than 30% in the 1960s to 80% to 86% currently. Exposure to rigorous therapies at very young ages, however, can lead to problems that manifest later in life. The risks seem to be greatest in those who receive radiation therapy or experience a relapse. Joseph P. Neglia, MD, MPH, of the University of Minnesota School of Medicine, Minneapolis, and his colleagues from other institutions, used data from the Childhood Cancer Survivor Study (CCSS) to study long-term health outcomes of childhood ALL survivors (Blood. 2008. doi.10.1182/blood-2007-10117150). They compared a cohort of 5760 ALL survivors who were younger than 21 years old at diagnosis and treated between 1970 and 1986 with the general population and a cohort of 3899 siblings. Among the survivors, cumulative mortality at 25

Compared with siblings, ALL survivors were 2.8 times more likely to have multiple chronic medical conditions and 3.7 times more likely to have severe or life-threatening chronic medical conditions. years was 13%, recurrent ALL and secondary cancers being the leading causes of death. Compared with siblings, ALL survivors were 2.8 times more likely to have multiple chronic medical conditions and 3.7 times more likely to have severe or lifethreatening chronic medical conditions, musculoskeletal, cardiac, and neurological conditions being the most common. At 25 years, 21.3% of ALL survivors had died or had severe chronic medical conditions (23.3% and 13.4% for irradiated and nonirradiated survivors, respectively). Furthermore, survivors reported worse general and mental health and more functional impairment and activity limitations compared with siblings. They were also less likely to be married, to be college graduates, to be employed, or to have health insurance. The authors suggest that limiting the use of radiation therapy and developing treatments that reduce the risk of relapse could lessen the late

Independent Safety Monitoring Committee Often Lacking in Pediatric Drug Trials CLINICAL TRIALS IN CHILDREN are essential to provide evidence for best treatment strategies, but a review of trials published over a 7-year period showed that only 2% included an independent safety monitoring committee (SMC). Helen M. Sammons, of the University of Nottingham Medical School and Derbyshire Children’s Hospital, Derby, United Kingdom, and her associates reviewed 739 trials of oral and intravenous medicines in children performed between 1996 to 2002 to determine whether there was an SMC and whether adverse events were found (Acta Paediatrica. 2008. doi.10.1111/j.1651-2227.2008.00676.x). The researchers did not include trials of HIV or cancer drugs because of concern that there would be a high mortality rate due to the disease itself. Of the 739 trials, only 13 (2%) had SMCs. Adverse events not necessarily related to a drug were reported in 523 (71%) trials; in 151 (20%) trials, a serious adverse event occurred. In 270 (36.5%) trials, an adverse drug reaction occurred, and in 80 (11%) of these trials, the adverse drug reaction was judged to be moderate or severe. Six trials, all of which had SMCs, were terminated early because of significant drug toxicity. Deaths were reported in 83 (11%) trials, but in most cases, the deaths were not thought to be related to drug use. The researchers conclude that all drug trials involving children should have an SMC and that, as part of the consent process, parents should be informed of the potential for an adverse drug reaction and the steps that will be taken to ensure their child’s safety. —KR

May 2008

adverse effects of ALL therapy. They note, however, that with the growing number of leukemia survivors in the population, it is important for health professionals, educators, legislators, and society in general to be cognizant of the long-term issues survivors experience. Another report from the CCSS showed similar results for survivors of childhood and young adult acute myeloid leukemia (AML) (Cancer. 2008. doi.10.1002/cncr.23405). Daniel A. Mulrooney, MD, MS, and his associates found that although longterm survival 5 or more years after diagnosis of AML was favorable, late-occurring medical events remained a concern, and socioeconomic achievement was lower than expected with individual families, although it was not different from that in the general US population. —Karen Rosenberg

ASCO Introduces Generic Template to Document Cancer Treatment and Survivorship Care THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY (ASCO) has developed a generic chemotherapy treatment plan and summary template that can be customized for almost any cancer diagnosis. The new template is designed to improve documentation and coordination of cancer treatment and survivorship care. “The transition from active treatment to posttreatment is critical to long-term health,” said Joseph Jacobson, MD, chair-elect of ASCO’s Quality of Care Committee. Without planning and coordination, he added, “cancer survivors may be left without knowledge of their heightened risks or a follow-up plan of action.” ASCO had previously developed treatment templates for breast and colorectal cancer. Core elements of each of these templates include: • The patient’s diagnosis, including cancer site, histology, and stage; • A summary of the chemotherapy and other treatment that is planned and delivered; • Information on appropriate follow-up care and relevant providers; • Information on evidence-based survivorship and surveillance guidelines from ASCO. After treatment is complete, patients are advised to keep the document and share it with other healthcare professionals who provide their followup care. ASCO templates are published in modifiable form so that they can be customized for individual patients and practices. The templates are available online at http://www.asco.org/treatmentsummary.

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PEDIATRIC CANCERS PEDIATRIC CANCERS PEDIATRIC CANCERS PEDIATRIC

PEDIATRIC CANCERS

Pediatric Cancers

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The

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Oncology Nurse

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About Multidisciplinary Cancer Care Multidisciplinary Cancer Care newsletters provide a forum for sharing expert interdisciplinary treatment perspectives on patient care with the ultimate goal of promoting ongoing professional education to physicians, nurses, and pharmacists in the hematology/oncology community. Target Audience This educational publication is designed for physicians, nurses, and pharmacists who wish to enhance their knowledge concerning the management of patients with multiple myeloma and renal dysfunction.

Learning Objectives At the completion of this educational activity, you should be able to • Describe the prevalence of renal insufficiency among patients with multiple myeloma (MM) • Recognize the special challenges in pharmacologic treatment of the many patients with MM who also have renal insufficiency, especially those requiring dialysis • Discuss the results of studies showing treatments that are active and safe in MM patients with renal impairment, including those with advanced renal failure requiring dialysis

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Pharmacists CME Consultants is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity has been designated for 1 contact hour (0.100 CEU). In order to receive credit, all participants must complete an evaluation, request for credit form, and a posttest. Statements of Credit will be mailed to participants within six weeks. ACPE #309-999-08-012-H01-P Initial Release Date: 05/07/08. Planned Expiration Date: 05/07/09. Nurses CME Consultants is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. CME Consultants designates this program for 1 contact hour. Participants should claim only those contact hours actually spent in the educational activity. In order to receive credit for this program, each participant must complete the evaluation form, posttest, and certificate request form. Certificates will be mailed to program participants in approximately four to six weeks after receipt of the completed evaluation form, posttest, and certificate request form.

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Nursing Life CARING FOR PATIENTS WITH CANCER IS A STRESSFUL, demanding job and nurses often work long hours, leaving little time for themselves and their families. To perform their jobs well and avoid burnout, nurses need to follow the healthy lifestyle tips they give their patients. In this section, The Oncology Nurse will provide recipes for healthy treats and other lifestyle suggestions you can enjoy yourself or recommend to your patients.

Strawberries—a Healthy, Delicious Summer Treat The arrival of ripe strawberries at your local farmers market or fresh produce aisle marks the very beginning of the summer. If you live in a four-season climate, these bright little berries will be coming in during early June. July 4th signals the end of their seasonality, although wild strawberry varieties like Tri-stars are available through the late summer. (Check with a local farmer for these extra sweet, extra tiny treats). Unlike other treats, strawberries are snacks that are both delicious and nutritious. A half-cup serving contains 42 mg of vitamin C and packs quite a wallop of an antioxidant punch!

Some Serving/Preparation Suggestions for Strawberries: • Clean them by swishing them around in cold water and then laying them out on paper towels to dry. • To best store strawberries, cover with plastic and refrigerate without washing them for up to 2 days. Be careful not to crowd them, as they bruise easily. • If you find some sour strawberries, sprinkle them with about 1 teaspoon of good-quality balsamic vinegar, 1 tablespoon of sugar, and let them sit covered at room temperature for a half hour. The balsamic vinegar actually “blooms” the strawberries and brings out their sweet taste. • Strawberries are delightful eaten whole. Dip them in brown sugar or sour cream and enjoy the simplicity of their sweetness.

HERE’S A HEALTHY RECIPE FROM cookbook author Peter Berley. It is simple to prepare, low in sugar, and will satisfy your appetite for something creamy and sweet. This recipe can be served as a dessert or as a breakfast smoothie, depending on how you garnish it.

Strawberry Buttermilk Soup from Peter Berley’s Fresh Food Fast 2 pints strawberries, hulled 1/2 cup buttermilk 1/3 cup sugar, preferably organic washed cane sugar 3-4 ice cubes 1. Slice 4 strawberries and set them aside for garnish. In the bowl of a blender or food processor combine the remaining strawberries, buttermilk, sugar, and ice. Puree until smooth. 2. Spoon the soup into 4 small serving bowls and garnish with the reserved strawberry slices. Serve with shortbread cookies if desired.

—Amy Johansson Yield: 4 servings

What’s Your Favorite Healthy Recipe? With a little creativity, healthy foods can be delicious as well as nutritious. Do you have a favorite healthy recipe that you would like to share with your colleagues and patients? Send your recipe and its source (family recipes are welcome) to editorial@greenhillhc.com.

May 2008

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NURSING LIFE NURSING LIFE NURSING LIFE NURSING LIFE NURSING LIFE NURSING

NURSING LIFE

Nursing Life

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Genitourinary Cancers GENITOURINARY CANCERS

New GnRH Blocker is Effective in Advanced Prostate Cancer

GENITOURINARY CANCERS GENITOURINARY CANCERS

MILAN—New findings demonstrate that the investigational gonadotropin-releasing hormone (GnRH) blocker degarelix is not only as effective as standard androgen deprivation therapy (ADT) involving the GnRH agonist leuprolide in patients with prostate cancer but also accelerates testosterone suppression. Data are from a phase 3 trial presented at the 23rd Annual Meeting of the European Association of Urology. Laurento Boccon-Gibod, MD, professor of urology at CHU Hopital Bichat-Claude Bernard in Paris, presented results in 610 men who received one of two doses of subcutaneous degarelix (80 or 160 mg monthly) or leuprolide depot, 7.5 mg monthly, over 12 months. The trial enrolled men with histologically confirmed adenocarcinoma of the prostate (of any stage) for which androgen ablation was indicated. Men who required neoadjuvant hormonal therapy were ineligible. “GnRH agonists are the mainstay of ADT for prostate cancer; however, important limitations include a delayed effect on testosterone and

Results showed that both doses of degarelix were at least as effective as leuprolide in terms of response to treatment. prostate-specific antigen (PSA) along with a testosterone surge and possible symptoms of flare,” Dr Boccon-Gibod pointed out. In the trial, suppression of testosterone to ≤ 0.5 ng/mL at all monthly measurements from day 28 to day 364 was considered a treatment response. The study was designed to demonstrate statistical noninferiority of degarelix versus leuprolide 7.5 mg for treatment response. Results showed that both doses of degarelix were at least as effective as leuprolide in terms of response to treatment. Suppression of testosterone levels to ≤ 0.5 ng/mL occurred significantly faster in patients receiving degarelix than in those receiving leuprolide. By day 3, 97% and 96% of degarelixtreated patients (160 mg and 80 mg, respectively) and 0% of those receiving leuprolide demonstrated a treatment response.

The GnRH blocker did not cause a testosterone surge or microsurge and was associated with a more rapid reduction in PSA levels than leuprolide. After 14 days of treatment, median PSA levels had declined by 65% and 64% in patients receiving degarelix (160 and 80 mg, respectively) and 18% in patients receiving leuprolide. Degarelix was well tolerated with no serious side effects that were deemed treatment-related. “We need treatments that better mimic surgical castration but without the devastating sequelae, and degarelix has a nearly immediate effect on testosterone levels on a par with that of surgery,” John Anderson, MD, consultant urologic surgeon, Royal Hallamshire Hospital in Sheffield, UK, said at a news conference. —Jill Stein

Study Raises Questions about Frequency of Testis Cancer Tumor-marker Testing RESULTS OF A SURVEILLANCE, EPIDEMIOLOGY, and End Results (SEER) database review suggest that use of tumor-marker testing in patients with testis cancer in the United States is suboptimal. This is based on the finding that 44.7% of men were given alpha fetoprotein (AFP) and human chorionic gondotropin (HCG) testing to confirm a diagnosis of testis cancer, and just 16% were tested for those two markers plus lactate dehydrogenase (LDH)(Urolog Oncol. 2008;26:153-157).

the rate of measurement of at least AFP and HCG was 44.7%. The rate of testing of AFP, HCG plus LDH was 16.8%, while testing for LDH plus AFP and/or HCG occurred in 21.3% of cases. The mean age at diagnosis was 34.5 years, 85% of cases were white and 78.8% had stage I disease. Detroit, Los Angeles, and San Francisco-Oakland had the lowest rates of testing for a minimum of AFP and HCG, at 6.7%, 21.8%, and 39.1% of cases, respectively, from 1998-2003. Hawaii and Utah had

Site by site, PSA testing was always performed in a higher percentage of men to diagnose prostate cancer than was HCG/AFP or HCG/AFP/LDH testing to confirm the presence of testis cancer. Scott M. Gilbert, MD, MS, clinical lecturer, Department of Urology, University of Michigan, Ann Arbor, and his associates examined the records of all men diagnosed with testis cancer between 1998 and 2002 in the SEER database. The team used the rate of testing for prostate-specific antigen (PSA) in suspected prostate-cancer cases as a benchmark at each of the 10 SEER sites from New Mexico to Iowa. Among the 4,742 incident testis cancer cases,

T HE O NCOLOGY N URSE

the highest rates, at 73.1% and 83%, respectively. Site by site, PSA testing was always performed in a higher percentage of men to diagnose prostate cancer than was HCG/AFP or HCG/AFP/LDH testing to confirm the presence of testis cancer. The rate of testis tumor-marker testing did not improve from 1998 to 2003 at most sites. “Although PSA testing has diffused into routine practice for prostate cancer, the use of tumor markers in testis cancer appears to be less common. This

is concerning, given the markers provide additional prognostic information, direct subsequent cancer therapy, and are accurate markers of the course of the disease,” concluded Dr Gilbert. “Although additional validation is unquestionably necessary, the low rates observed in our study signal possible quality shortcomings.” Another expert, however, questioned Dr Gilbert’s interpretation of the findings. While Timothy Gilligan, MD, agrees that the rate of testing in America is suboptimal, he does not believe the results accurately reflect practice in his center or elsewhere across the country. “I don’t think we can believe these results without further validation. The finding that the SEER database doesn’t have data on testis-cancer tumor markers does not necessarily mean that tumor markers weren’t measured,” said Dr Gilligan, Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Center. “I have treated hundreds of men with testis cancer and have only seen one or two who did not have tumor markers checked at the time of diagnosis. However, I have always worked at cancer centers with extensive experience in testis cancer, and thus my experience is not representative of the nation as a whole.” —RF

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MR Imaging Helps Predict Prostate Cancer Recurrence Pretreatment endorectal magnetic resonance (MR) imaging findings are important predictors of posttreatment metastatic recurrence in patients undergoing external-beam radiation therapy for prostate cancer. The finding is based on a retrospective study of 80 men (mean age, 59 years) with biopsy-proved prostate cancer who underwent endorectal MR imaging of the prostate prior to external-beam radiation therapy. All MR imaging studies were independently reviewed by two experienced readers who recorded tumor T stage and the radial diameter of extracapsular extension if present. After a mean follow-up of 43 months, four patients developed metastases. Significant predictors of the development of metastases on univariate analysis were baseline serum prostate-specific antigen level, presence of extracapsular extension at MR imaging, and degree of extracapsular extension. The sole independent predictive variable on multivariate analysis was mean diameter of extracapsular extension (relative hazard ratio, 2.06; P = .007). Of five patients with extracapsular extension of more than 5 mm at pretreatment MR imaging, three developed metastases at 24 to 63 months after therapy. (McKenna DA, et al. Radiology. 2008; 247:141-146.)

mismatches did not significantly increase with clinical complexity. The strategy of watchful waiting was used infrequently, even in patients with contraindications to all treatment options. Treatment choices were associated with patient age and comorbidities but not preexisting dys-

Overall, more than one third of the patients received mismatched treatments. function. Mismatched BT and EBRT led to worsened urinary and bowel symptoms, respectively, and NSRP did not improve

outcomes in patients with baseline sexual dysfunction. (Chen RC, et al. Cancer. 2008;112:61-68).

POWER AND PERFORMANCE VIDAZA hits MDS with the strength of transfusion independence.1,2 • 44% of red blood cell (RBC) transfusion-dependent patients achieved RBC transfusion independence.1* • Median time to RBC transfusion independence was about 2.5 months.1 • In responding patients,† transfusion independence was durable, lasting a median of 330 days.2

Prostate Cancer Patients Pick Treatments That May Worsen Quality of Life Patients with prostate cancer and preexisting dysfunction often select relatively contraindicated or mismatched treatments associated with worsening of symptoms and poorer outcomes, according to researchers at Massachusetts General Hospital. Prostate cancer treatment choices were examined in 438 patients with prostate cancer, of whom 389 (89%) reported preexisting dysfunction. Preexisting obstructive uropathy and bowel dysfunction were considered relative contraindications to brachytherapy (BT) and external-beam radiation therapy (EBRT), respectively, because they increase patients’ vulnerability to treatment-related toxicity. Baseline sexual dysfunction was considered to negate the intended benefit of nerve-sparing radical prostatectomy (NSRP), which is to preserve sexual function. Overall, more than one third of the patients received mismatched treatments. Treatment

May 2008

Important Safety Information • VIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol and in patients with advanced malignant hepatic tumors. • In clinical studies, the most commonly occurring adverse reactions by SC route were nausea (70.5%), anemia (69.5%), thrombocytopenia (65.5%), vomiting (54.1%), pyrexia (51.8%), leukopenia (48.2%), diarrhea (36.4%), fatigue (35.9%), injection site erythema (35.0%), constipation (33.6%), neutropenia (32.3%), and ecchymosis (30.5%). Other adverse reactions included dizziness (18.6%), chest pain (16.4%), febrile neutropenia (16.4%), myalgia (15.9%), injection site reaction (13.6%), aggravated fatigue (12.7%), and malaise (10.9%). The most common adverse reactions by IV route also included petechiae (45.8%), weakness (35.4%), rigors (35.4%), and hypokalemia (31.3%). • Because treatment with VIDAZA is associated with neutropenia and thrombocytopenia, complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. • Because azacitidine is potentially hepatotoxic in patients with severe preexisting hepatic impairment, caution is needed in patients with liver disease. In addition, azacitidine and its metabolites are substantially excreted by the kidneys and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. • VIDAZA may cause fetal harm. While receiving treatment with VIDAZA, women of childbearing potential should avoid becoming pregnant, and men should avoid fathering a child. In addition, women treated with VIDAZA should not nurse.

VIDAZA is FDA-approved for the treatment of all myelodysplastic syndrome (MDS) subtypes2‡: RA or RARS (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), RAEB, RAEB-T, or CMMoL. 9221 Study Design: A randomized, open-label, phase III study comparing the efficacy and safety of VIDAZA plus supportive care vs supportive care alone. 191 patients (132 male, 59 female, age 31–92) with all 5 subtypes of MDS classified according to the French, American, British (FAB) classification system were studied. VIDAZA was administered to patients subcutaneously at a dose of 75 mg/m2 daily for 7 days every 4 weeks. Dosage adjustments were allowed based on response or adverse events. The primary study endpoint was response rate. Response Criteria: Complete response was defined as <5% blasts in the bone marrow, absence of blasts in the peripheral circulation, and normal CBC (if abnormal at baseline) maintained for at least 4 weeks. Partial response was defined as at least a 50% decrease in bone marrow blasts and improvement of bone marrow dyspoiesis (for RAEB, RAEB-T, and CMMoL only) plus, for all subtypes, at least a 50% restoration in the deficit from normal of baseline white cells, hemoglobin, and platelets (if abnormal at baseline) and no blasts in the peripheral circulation maintained for at least 4 weeks. For CMMoL, if white cells were elevated at baseline, PR also required at least a 75% reduction in the excess count over the upper limit of normal, maintained for at least 4 weeks.

Please see the brief summary of prescribing information on the adjacent page.

*Of the 66 VIDAZA-treated patients who were RBC transfusion dependent at baseline, 29 (44%) achieved RBC transfusion independence.1 CR + PR = 16%. ‡ According to the FAB Classiﬁcation System.

References: 1. Data on ﬁle. Pharmion Corporation. 2. VIDAZA full prescribing information.

000862_phvirt_jco_power_fa4.indd1 1

†

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TRENDS IN PROSTATE CANCER TRENDS IN PROSTATE CANCER

Trends in Prostate Cancer

TRENDS IN PROSTATE CANCER

Trends in Prostate Cancer

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Head & Neck Cancer HEAD & NECK CANCER

Nursing Interventions Can Affect Quality of Life in Patients with Head and Neck Cancer A PROSPECTIVE STUDY HAS demonstrated that symptoms of depression, decreased quality of life, and smoking at the time of diagnosis with head and neck cancer are significant predictors of further deterioration of quality of life (QOL) (Arch Otolaryngol

Brief Summary of Prescribing Information VIDAZA (azacitidine for injection) only For subcutaneous and intravenous use only INDICATIONS AND USAGE VIDAZA is indicated for treatment of patients with the following myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. CONTRAINDICATIONS VIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol. VIDAZA is also contraindicated in patients with advanced malignant hepatic tumors. (See PRECAUTIONS). WARNINGS Pregnancy - Teratogenic Effects: Pregnancy Category D VIDAZA may cause fetal harm when administered to a pregnant woman. Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m (approximately 8% of the recommended human daily dose on a mg/m basis) azacitidine on gestation day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3–12 mg/m (approximately 4%–16% the recommended human daily dose on a mg/m basis). In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4–8 (postimplantation) at a dose of 6 mg/m (approximately 8% of the recommended human daily dose on a mg/m basis), although treatment in the preimplantation period (on gestation days 1–3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single IP dose of 3–12 mg/m (approximately 8% the recommended human daily dose on a mg/m basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3-12 mg/m on gestation days 9 and 10; average live animals per litter was reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies (exencephaly/ encephalocele), limb anomalies (micromelia, clubfoot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities). There are no adequate and well-controlled studies in pregnant women using VIDAZA. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with VIDAZA. Use in Males Men should be advised to not father a child while receiving treatment with VIDAZA. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility for discussion of premating effects of azacitidine exposure on male fertility and embryonic viability.) PRECAUTIONS General Treatment with VIDAZA is associated with neutropenia and thrombocytopenia. Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the ﬁrst cycle, dosage for subsequent cycles should be reduced or delayed based on nadir counts and hematologic response as described in DOSAGE AND ADMINISTRATION. Safety and effectiveness of VIDAZA in patients with MDS and hepatic or renal impairment have not been studied as these patients were excluded from the clinical trials. Because azacitidine is potentially hepatotoxic in patients with severe preexisting hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been rarely reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin <30 g/L. Azacitidine is contraindicated in patients with advanced malignant hepatic tumors (See CONTRAINDICATIONS). Renal abnormalities ranging from elevated serum creatinine to renal failure and death have been reported rarely in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for nonMDS conditions. In addition, renal tubular acidosis, deﬁned as a fall in serum bicarbonate to <20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium <3 mEq/L) developed in 5 patients with CML treated with azacitidine and etoposide. If unexplained reductions in serum bicarbonate <20 mEq/L or elevations of BUN or serum creatinine occur, the dosage should be reduced or held as described in DOSAGE AND ADMINISTRATION. Patients with renal impairment should be closely monitored for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys (see DOSAGE AND ADMINISTRATION section). Information for Patients Patients should inform their physician about any underlying liver or renal disease. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with VIDAZA. Men should be advised to not father a child while receiving treatment with VIDAZA. Laboratory Tests Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each cycle. Liver chemistries and serum creatinine should be obtained prior to initiation of therapy. Drug Interactions No formal assessments of drug-drug interactions between VIDAZA and other agents have been conducted. (See CLINICAL PHARMACOLOGY.) ®

HEAD & NECK CANCER HEAD & NECK CANCER HEAD & NECK CANCER

Head Neck Surg. 2008;134:241-248). The presence of a feeding tube, and undergoing surgery, radiation therapy, or chemotherapy also are associated with decreases in some aspects of QOL. The study also confirmed that people diagnosed with head and neck

Carcinogenesis, Mutagenesis, Impairment of Fertility The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m , approximately 8% the recommended human daily dose on a mg/m basis) administered IP 3 times per week for 52 weeks. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine IP at 2.0 mg/kg (6.0 mg/m , approximately 8% the recommended human daily dose on a mg/m basis) once a week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m (approximately 20%–80% the recommended human daily dose on a mg/m basis) revealed an increased incidence of testicular tumors compared with controls. The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells. Administration of azacitidine to male mice at 9.9 mg/m (approximately 9% the recommended human daily dose on a mg/m basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats three times per week for 11 or 16 weeks at doses of 15–30 mg/m (approximately 20%–40%, the recommended human daily dose on a mg/m basis) resulted in decreased weight of the testes and epididymides, and decreased sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m resulted in an increase in abnormal embryos in mated females when examined on day 2 of gestation. (See WARNINGS.) Pregnancy Teratogenic Effects: Pregnancy Category D. (See WARNINGS.) Nursing Mothers It is not known whether azacitidine or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for azacitidine in animal studies and the potential for serious adverse reactions, women treated with azacitidine should not nurse. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of patients in the 3 clinical studies described in CLINICAL STUDIES, above, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition there were no relevant differences in the frequency of adverse events observed in patients 65 years and older compared to younger patients. Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION section). ADVERSE REACTIONS Overview Adverse Reactions Described in Other Labeling Sections: neutropenia, thrombocytopenia, elevated serum creatinine, renal failure, renal tubular acidosis, hypokalemia, hepatic coma. Most Commonly Occurring Adverse Reactions (SC or IV Route): nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, fatigue, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by IV route also include petechiae, rigors, weakness and hypokalemia. Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (SC or IV Route): Discontinuation: leukopenia (5.0%), thrombocytopenia (3.6%), neutropenia (2.7%). Dose Held: leukopenia (4.5%), neutropenia (4.5%), febrile neutropenia (2.7%). Dose Reduced: leukopenia (4.5%), neutropenia (4.1%), thrombocytopenia (3.2%). Discussion of Adverse Reactions Information The data described below reﬂect exposure to VIDAZA in 268 patients, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately 1 year). VIDAZA was studied primarily in supportive-care-controlled and uncontrolled trials (n = 150 and n = 118, respectively). The population in the subcutaneous studies (n = 220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the IV study (n = 48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m . The following table presents the most common adverse events, whether or not considered drug related by investigators, occurring in at least 5% of patients treated with VIDAZA in the supportive-care-controlled trial and the uncontrolled subcutaneous trial combined. It is important to note that duration of exposure was longer for the VIDAZA-treated group than for the observation group: patients received VIDAZA for a mean of 11.4 months while mean time in the observation arm was 6.1 months. 2

cancer experience a significant decrease in physical functioning over time. “The most important take-home messages for nurses from this study are the effects on quality of life of smoking and depression,” noted lead investigator David

Table 4: Most Frequently Observed Adverse Events (>5% in All VIDAZA)a Preferred Termb

All VIDAZAc Observationd (N=220) (N=92) At least 1 TEAE 219 (99.5) 89 (96.7) Nausea 155 (70.5) 16 (17.4) Anemia 153 (69.5) 59 (64.1) Thrombocytopenia 144 (65.5) 42 (45.7) Vomiting 119 (54.1) 5 (5.4) Pyrexia 114 (51.8) 28 (30.4) Leukopenia 106 (48.2) 27 (29.3) Diarrhea 80 (36.4) 13 (14.1) Fatigue 79 (35.9) 23 (25.0) Injection site erythema 77 (35.0) 0 Constipation 74 (33.6) 6 (6.5) Neutropenia 71 (32.3) 10 (10.9) Ecchymosis 67 (30.5) 14 (15.2) Cough 65 (29.5) 14 (15.2) Dyspnea 64 (29.1) 11 (12.0) Weakness 64 (29.1) 19 (20.7) Rigors 56 (25.5) 10 (10.9) Petechiae 52 (23.6) 8 (8.7) Injection site pain 50 (22.7) 0 Arthralgia 49 (22.3) 3 (3.3) Headache 48 (21.8) 10 (10.9) Anorexia 45 (20.5) 6 (6.5) Pain in limb 44 (20.0) 5 (5.4) Pharyngitis 44 (20.0) 7 (7.6) Back pain 41 (18.6) 7 (7.6) Contusion 41 (18.6) 9 (9.8) Dizziness 41 (18.6) 5 (5.4) Edema peripheral 41 (18.6) 10 (10.9) Erythema 37 (16.8) 4 (4.3) Chest pain 36 (16.4) 5 (5.4) 36 (16.4) 9 (9.8) Epistaxis Febrile neutropenia 36 (16.4) 4 (4.3) Myalgia 35 (15.9) 2 (2.2) Weight decreased 35 (15.9) 10 (10.9) Abdominal pain 34 (15.5) 12 (13.0) Pallor 34 (15.5) 7 (7.6) Nasopharyngitis 32 (14.5) 3 (3.3) Pitting edema 32 (14.5) 9 (9.8) 32 (14.5) 8 (8.7) Skin lesion Dyspnea exertional 31 (14.1) 15 (16.3) Injection site bruising 31 (14.1) 0 Rash 31 (14.1) 9 (9.8) Injection site reaction 30 (13.6) 0 Anxiety 29 (13.2) 3 (3.3) Appetite decreased 28 (12.7) 8 (8.7) Fatigue aggravated 28 (12.7) 4 (4.3) 28 (12.7) 12 (13.0) Hypokalemia Upper respiratory tract 28 (12.7) 4 (4.3) infection Pruritus 27(12.3) 11 (12.0) Abdominal tenderness 26 (11.8) 1 (1.1) Depression 26 (11.8) 7 (7.6) Productive cough 25 (11.4) 4 (4.3) Insomnia 24 (10.9) 4 (4.3 Malaise 24 (10.9) 1 (1.1) Pain 24 (10.9) 3 (3.3) Pneumonia 24 (10.9) 5 (5.4) Abdominal pain upper 23 (10.5) 3 (3.3) Crackles lung 23 (10.5) 8 (8.7) Sweating increased 23 (10.5) 2 (2.2) Cardiac murmur 22 (10.0) 8 (8.7) 22 (10.0) 2 (2.2) Rhinorrhea Gingival bleeding 21 (9.5) 4 (4.3) Lymphadenopathy 21 (9.5) 3 (3.3) Herpes simplex 20 (9.1) 5 (5.4) Hematoma 19 (8.6) 0 Night sweats 19 (8.6) 3 (3.3) Rales 19 (8.6) 8 (8.7) Tachycardia 19 (8.6) 6 (6.5) Wheezing 19 (8.6) 2 (2.2) Cellulitis 18 (8.2) 4 (4.3) Dysuria 18 (8.2) 2 (2.2) Breath sounds 17 (7.7) 1 (1.1) decreased Lethargy 17 (7.7) 2 (2.2) Oral mucosal 17 (7.7) 3 (3.3) petechiae Stomatitis 17 (7.7) 0 Urinary tract infection 17 (7.7) 5 (5.4) Peripheral swelling 16 (7.3) 5 (5.4) Dyspepsia 15 (6.8) 4 (4.3) 15 (6.8) 1 (1.1) Hemorrhoids Hypotension 15 (6.8) 2 (2.2) Injection site pruritus 15 (6.8) 0 Transfusion reaction 15 (6.8) 0 Pleural effusion 14 (6.4) 6 (6.5) Abdominal distension 13 (5.9) 4 (4.3) Muscle cramps 13 (5.9) 3 (3.3) Post procedural 13 (5.9) 1 (1.1) hemorrhage

Table 4: Most Frequently Observed Adverse Events (>5% in All VIDAZA)a Continued Preferred Termb

All VIDAZAc Observationd (N=220) (N=92) At least 1 TEAE 219 (99.5) 89 (96.7) Postnasal drip 13 (5.9) 3 (3.3) Rhonchi 13 (5.9) 2 (2.2) Syncope 13 (5.9) 5 (5.4) Urticaria 13 (5.9) 1 (1.1) Anemia aggravated 12 (5.5) 5 (5.4) Loose stools 12 (5.5) 0 Nasal congestion 12 (5.5) 1 (1.1) Atelectasis 11 (5.0) 2 (2.2) Chest wall pain 11 (5.0) 0 Dry skin 11 (5.0) 1 (1.1) Dysphagia 11 (5.0) 2 (2.2) Dyspnea exacerbated 11 (5.0) 3 (3.3) Hypoesthesia 11 (5.0) 1 (1.1) Injection site 11 (5.0) 0 granuloma Injection site 11 (5.0) 0 pigmentation changes Injection site swelling 11 (5.0) 0 Mouth hemorrhage 11 (5.0) 1 (1.1) Post procedural pain 11 (5.0) 2 (2.2) Sinusitis 11 (5.0) 3 (3.3) Skin nodule 11 (5.0) 1 (1.1) Tongue ulceration 11 (5.0) 2 (2.2) a Mean VIDAZA exposure = 11.4 months. Mean time in observation arm = 6.1 months. b Multiple reports of the same preferred terms for a patient are only counted once within each treatment group. c Includes events from all patients exposed to VIDAZA, including patients after crossing over from observation. d Includes events from observation period only; excludes any events after crossover to VIDAZA. For SC VIDAZA administration, nausea, vomiting, diarrhea, and constipation all tended to increase in incidence with increasing doses of VIDAZA. Nausea, vomiting, injection site erythema, constipation, rigors, petechiae, injection site pain, dizziness, injection site bruising, anxiety, hypokalemia, insomnia, epistaxis, and rales tended to be more pronounced during the first 1-2 cycles of SC VIDAZA treatment compared with later cycles of treatment. There did not appear to be any adverse events that increased in frequency over the course of treatment. There did not appear to be any relevant differences in adverse events by gender. Overall, adverse reactions were qualitatively similar between the IV and SC studies. Adverse reactions that appeared to be specifically associated with the IV route of administration included infusion site reactions (e.g., erythema or pain) and catheter site reactions (e.g., infection, erythema, or hemorrhage). In clinical studies of either SC or IV VIDAZA, the following serious treatment-related adverse events occurring at a rate of <5% (not described in Table 4) were reported: Blood and lymphatic system disorders: agranulocytosis, bone marrow depression, splenomegaly. Cardiac disorders: atrial fibrillation, cardiac failure, cardiac failure congestive, cardiorespiratory arrest, congestive cardiomyopathy. Gastrointestinal disorders: diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess. General disorders and administration site conditions: catheter site hemorrhage, general physical health deterioration, systemic inflammatory response syndrome. Hepatobiliary disorders: cholecystitis Immune system disorders: anaphylactic shock, hypersensitivity. Infections and infestations: abscess limb, bacterial infection, blastomycosis, injection site infection, Klebsiella sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis. Metabolism and nutrition disorders: dehydration. Musculoskeletal and connective tissue disorders: bone pain aggravated, muscle weakness, neck pain. Neoplasms benign, malignant and unspecified: leukemia cutis. Nervous system disorders: convulsions, intracranial hemorrhage. Psychiatric disorders: confusion. Renal and urinary disorders: hematuria, loin pain, renal failure. Respiratory, thoracic and mediastinal disorders: hemoptysis, lung infiltration, pneumonitis, respiratory distress. Skin and subcutaneous tissue disorders: pyoderma gangrenosum, rash pruritic, skin induration. Surgical and medical procedures: cholecystectomy. Vascular disorders: orthostatic hypotension. Manufactured for: Pharmion Corporation Boulder, CO 80301 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Edition Date: 9 January 2007 Brief Summary of Prescribing Information VIDAZA is a registered trademark of Pharmion Corporation. © 2007 Pharmion Corporation. All rights reserved. VIDB010907A January 2007 Printed in USA.

Ronis, PhD, research health science specialist, Veterans Affairs Ann Arbor Healthcare System, and associate research scientist and director, Statistical Computing Team, School of Nursing, University of Michigan, Ann Arbor. “Those are both things—especially smoking—that nurses can intervene briefly with, and have an impact. In a previously published study we showed a nurse-based smoking intervention doubled their rate of quitting from 15% to 31%.” Three hundred and sixteen people were enrolled as they were diagnosed with head and neck cancer at the two Ann Arbor and one Detroit hospitals. Most patients—76.9%—underwent more than one of the following treatments in the first year after diagnosis: surgery, chemotherapy, or radiation. Subjects’ scores on the physical functioning component of the Short Form 36 (SF-36) declined significantly, as did their scores of ability to perform standard physical activities/roles. Patients’ mental health index scores on the SF-36 significantly improved after one year, as did their mental distress scores on the Head and Neck QOL (HNQOL) scale. This reflects patients’ adaptation to the condition and its effects on their lives, which has been documented in other studies. When Dr Ronis and his co-investigators performed a multivariate regression analysis, they found several factors that significantly predicted reduction in scores at 1 year on some subscales of the SF-36 and HNQOL: having smoked in the month before diagnosis, the presence of depressive symptoms at diagnosis, an overall low QOL at diagnosis, having a feeding tube in place at 1 year, and having undergone radiation therapy, chemotherapy, or surgery. “This article underscores several areas in which nursing interventions may help improve outcomes.The identification of patients with significant mood disorders, particularly depression, is especially important,” noted Barbara Murphy, MD, director of the Pain and Symptom Management Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville. “Planning and carrying out head and neck cancer treatment is complicated and time-consuming, and nurses are often responsible for referrals for the emotional and physical sequelae of the cancer. Mood disorders are something nurses are trained to identify; they can do the screening, and bring patients with depression to the attention of the physician.” —RF

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CLINICAL TRIALS UPDATE

Clinical Trials Update Clinical Trials Update Two widely used targeted therapies for human epidermal growth factor 2 (HER2)-positive breast cancer will be compared in the large multinational Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial. Women in North America are now being enrolled in the phase 3 trial, which will recruit 8,000 women with HER2-positive breast cancer in 50 countries. The study is the first global initiative jointly developed by academic breast cancer research networks in different parts of the world in which all care and data collection are standardized regardless of where patients are treated. The two networks are the Breast Cancer Intergroup of North America and the Breast International Group. Both agents being used in the trial—trastuzumab (Herceptin) and lapatinib (Tykerb) are already approved by the US Food and Drug Administration (FDA) for HER2-positive breast cancer. Women with stage I or II breast cancer who have already had surgery to remove their tumors will be randomized to receive either trastuzumab or lapatinib alone, trastuzumab followed by lapatinib, or the two agents in combination. All participants must have completed four or more cycles of anthracycline-based chemotherapy, and those for whom taxane chemotherapy is indicated will receive paclitaxel (Taxol) along with their assigned target therapy. Edith Perez, MD, of the Mayo Clinic in Jacksonville, Fla, is the North American coordinator of the trial, which it is hoped will establish a model for global clinical trials.

Phase 3 Trial of Sodium Thiosulfate to Prevent Cisplatin-associated Hearing Loss in Children Announced Adherex Technologies of Research Triangle Park, NC, has announced activation of a phase 3 trial of sodium thiosulfate (STS) to prevent hearing loss in children treated with cisplatin. The trial is being conducted in collaboration with the Children’s Oncology Group. More than 60% of children treated with cisplatin experience some degree of hearing loss and some become deaf. The multicenter trial will enroll children 1 to 18 years of age who are scheduled to receive cisplatin for newly diagnosed germ cell, liver, brain, nerve tissue, or bone cancer. Participants will be randomized to

STS or placebo, and their hearing sensitivity will be evaluated at baseline and at follow-up using standardized audiometric tests. The trial is expected to enroll up to 120 children over approximately 3 years in up to 230 COG centers in the United States, Canada, Australia, and Europe. David Freyer, MD, professor of medicine, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, is principal investigator.

Monoclonal Antibody for Ewing Sarcoma to Be Studied Enrollment in a trial of a new treatment for Ewing sarcoma has begun in the United States. Centers across the United States and in France, Italy, Germany, and the United Kingdom will also participate in the trial, which will investigate the use of an investigational monoclonal antibody, R1507, in patients with Ewing sarcoma. The agent, made by Hoffman-LaRoche, inhibits insulin-like growth factor 1 receptor (IGF-1R). Ewing sarcoma, which affects mostly children, adolescents, and young adults, has been linked with mutated genes that promote production of IGF-1R.

CLINICAL TRIALS UPDATE

Targeted Therapies for HER2-positive Breast Cancer to Be Compared in ALTTO Trial

Enrollment in Phase 2 Trial of PDX for PTCL Completed Enrollment in a phase 2 trial of pralatrexate (PDX) for relapsed or refractory peripheral T-cell lymphoma (PTCL), for which there is currently no approved treatment. The trial known as the Pralatrexate in Patients with Relapsed or Refractory Peripheral T-cell Lymphoma (PROPEL) is an international, multicenter, open-label, single-arm study. Patients with relapsed or refractory PTCL who progressed after at least one prior treatment receive 30 mg/m2 of PDX once a week for 6 weeks followed by 1 week of rest per treatment cycle. Participants also receive vitamin B12 and a folic acid supplement. An independent data monitoring committee has completed three interim analyses of safety data and has recommended continuation of the trial at each analysis. PROPEL is being conducted under an agreement with the FDA under its Special Protocol Assessment process. PDX received orphan drug status for T-cell lymphoma in July 2006 and was fast-tracked in September 2006.

• Bevacizumab for Advanced HER2-negative Breast Cancer. The FDA has granted accelerated approval for bevacizumab (Avastin; Genentech) in combination with paclitaxel for first-line treatment of women who have not received chemotherapy for metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Use of the antiangiogenesis agent for advanced cancer was granted under the FDA’s accelerated approval program. A full review of data from two phase 3 trials will be required for the accelerated approval to be converted into a full approval. • Levoleucovorin for Osteosarcoma. Spectrum Pharmaceuticals has received FDA approval for Levoleucovorin for Injection (formerly known as ISO-Vorin) for treatment of osteosarcoma. The novel folate analog is indicated after high-dose methotrexate therapy in patients with osteosarcoma and to diminish the toxicity and counteract the effects of impaired methotrexate elimination or inadvertent overdose of folic acid antagonists.

May 2008

• CellSearch for Monitoring Prostate Cancer. The FDA has granted an expanded clearance for the CellSearch System (Veridex, LLC) as an aid in monitoring patients with metastatic prostate cancer. The system is currently cleared monitoring patients with metastatic breast or colorectal cancer. It is the first diagnostic test that automates detection and enumeration of circulating tumor cells in a blood sample, which aids in predicting progression-free and overall survival in patients with metastatic breast, colorectal, and prostate cancer. • Amrubicin for Small-cell Lung Cancer. Amrubicin (Celgene) has been granted orphan drug status by the FDA for the treatment of small-cell lung cancer. The third-generation synthetic anthracycline analog is being studied for use alone or in combination with other therapies for a variety of solid tumors, including lung and breast cancer.

FDA APPROVALS

• Bendamustine for Chronic Lymphocytic Leukemia. The US Food and Drug Administration (FDA) has approved bendamustine hydrochloride (Treanda; Cephalon) for injection for first- and second-line treatment of chronic lymphocytic leukemia (CLL). The novel chemotherapy agent is the first product approved for CLL since 2001. CLL is an orphan indication, but Cephalon has filed bendamustine for use in non-Hodgkin’s lymphoma.

FDA APPROVALS

Recent FDA Approvals

FDA Appoints First Chief Scientist Frank M. Torti, MD, MPH, a clinician, scientist, and researcher in molecular oncology, has been appointed Principal Deputy Commissioner of the FDA and the agency’s first Chief Scientist. In this position, Dr Torti will support the launch of the FDA Fellowship Program, which potentially could attract as many as 2,000 professionals of varying disciplines for a 2-year training program. His office will also work to ensure the quality and regulatory focus of the FDA’s intramural research programs and place special emphasis on the importance of clinical research trials. Dr Torti is currently Charles L. Spurr Professor of Medicine, Chair, Department of Cancer Biology, and Director, Comprehensive Cancer Center at Wake Forest University School of Medicine in Winston-Salem, NC.

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Meetings

October 23-26

November 13-18

November 30-December 5

2008 Meetings

10th Annual Lynn Sage Breast Cancer Symposium Chicago, IL www.lynnsagebreastcancer.org

2008 Multidisciplinary Lung Cancer Symposium Chicago, IL www.oncologymeetings.org

94th Scientific Assembly and Annual Meeting Radiological Society of North America Chicago, IL www.rsna.org

June 4-7

October 30-November 1

Oncology Nursing Society Institutes of Learning Seattle, WA www.ons.org

June 12-15 13th Congress of the European Hematology Association Copenhagen, Denmark www.ehaweb.org Ninth International Lung Cancer Congress Koloa, HI www.cancerconferences.com/thoracic/9th_lcc/ index.php

June 22-25 World Conference on Interventional Oncology Los Angeles, CA www.wcio2008.com

June 25-28 10th World Congress on Gastrointestinal Cancer Barcelona, Spain www.worldgicancer.com

June 26-28 21st International Supportive Care in Cancer Symposium Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology Houston, TX www.mascc.org

July 19-23 7th International Conference on Head and Neck Cancer The American Head and Neck Society San Francisco, CA www.ahns.info

July 24-26 3rd Interamerican Breast Cancer Conference Cancun, Mexico www.imedex.com/calendars/oncology.asp

August 3-7 Joint AACR-Metastasis Research Society International Conference Vancouver, BC, Canada www.aacr.org

August 27-31 International Union Against Cancer (UICC) World Cancer Congress Geneva, Switzerland www.uicc-congress08.org

September 5-7 2008 Breast Cancer Symposium Washington, DC www.astro.org

September 19-20 9th Annual Perspectives in Colorectal Cancer Miami, FL www.imedex.com

September 21-25 American Society for Therapeutic Radiology and Oncology (ASTRO) 50th Annual Meeting Boston, MA www.astro.org

September 25-28 4th Annual Oncology Congress San Francisco, CA www.oncologycongress.com

September 25-27 5th Annual Meeting International Society of Gastrointestinal Oncology Arlington, VA www.isgio.org

October 16-18 9th Meeting of the International Society of Geriatric Oncology Montreal, Canada www.cancerworld.org/siog

October 21-25 50th Annual Meeting American Society for Therapeutic Radiology and Oncology Baltimore, MD www.astro.org

May 2008

61st Annual Symposium on Cancer Research Houston, TX www.mdanderson.org

November 5-8 Chemotherapy Foundation Symposium XXVI New York, NY www.chemotherapyfoundation.org

RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information. WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse Reactions]. Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan [see Warnings and Precautions, Adverse Reactions]. Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions]. Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions].

INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) is indicated for the treatment of patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing (including stable disease), low-grade, CD20positive B-cell NHL, as a single agent, after first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, consider resumption of the infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with preexisting cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (>25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within 12–24 hours after the first infusion. Fatal TLS cases have occurred after administration of Rituxan. A high number of circulating malignant cells (*25,000/mm3) or high tumor burden confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases for which Rituxan has not been approved. The majority of patients with hematologic malignancies diagnosed with PML received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy and were diagnosed with PML within 12 months of their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B Virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of Rituxan and approximately one month after the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following Rituxan therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who develop viral hepatitis, and institute appropriate treatment including antiviral therapy. Insufficient data exist regarding the safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions.] Other Viral Infections The following additional serious viral infections, either new, reactivated, or exacerbated, have been identified in clinical studies or postmarketing reports. The majority of patients received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred as late as one year following discontinuation of Rituxan and have resulted in death. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or lifethreatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with hematologic malignancies. Renal toxicity has occurred in patients with high numbers of circulating malignant cells (>25,000/mm3) or high tumor burden who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an approved treatment regimen. Use extreme caution if this non-approved combination is used in clinical trials and monitor closely for signs of renal failure. Consider discontinuation of Rituxan for patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal

November 16-19 7th International Conference on Frontiers in Cancer Prevention Research Washington, DC www.aacr.org

December 6-7 Inflammatory Breast Cancer Conference Houston, TX www.mdanderson.org

December 6-9 50th Annual Meeting and Exposition American Society of Hematology www.hematology.org

perforation was 6 (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and institute appropriate treatment for complaints of abdominal pain, especially early in the course of Rituxan therapy. [See Adverse Reactions.] Immunization The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live virus vaccines is not recommended. For NHL patients, the benefits of primary or booster vaccinations should be weighted against the risks of delay in initiation of Rituxan therapy. Laboratory Monitoring Because Rituxan binds to all CD20positive B lymphocytes (malignant and non-malignant), obtain complete blood counts (CBC) and platelet counts at regular intervals during Rituxan therapy and more frequently in patients who develop cytopenias [see Adverse Reactions]. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period. ADVERSE REACTIONS The most common adverse reactions of Rituxan (incidence *25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. The most important serious adverse reactions of Rituxan are infusion reactions, tumor lysis syndrome, mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML, other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation. Clinical Trials Experience Non-Hodgkin’s Lymphoma 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. The data described below reflect exposure to Rituxan in 1606 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n = 356 and n = 1250). These data were obtained in adults with low-grade, follicular, or DLBCL NHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. Single-Agent Rituxan Adverse reactions in Table 1 occurred in 356 patients with relapsed or refractory, lowgrade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. Most patients received Rituxan 375 mg/m2 weekly for 4 doses. Table 1 Incidence of Adverse Events in *5% of Patients with Relapsed or Refractory, LowGrade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b

and 4 adverse reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving RCHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia (Study 8). Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, antihuman anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in rituximab treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during postapproval use of Rituxan in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic: prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure. Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection. Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneous reactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatal bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUG INTERACTIONS Formal drug interaction studies have not been performed with Rituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. NonHodgkin’s lymphoma and severe rheumatoid arthritis are serious conditions that require treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Rituximab is a genetically engineered IgG molecule, and IgG crosses the human placenta. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Other than target B lymphocytes, rituximab is not known to bind to any normal human tissues in an ex vivo assay. However, it is not known if binding occurs to unique embryonic or fetal tissue receptors in vivo. Nursing Mothers It is not known whether Rituxan is secreted into human milk. However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from gastrointestinal or limited systemic exposure to Rituxan should be weighed against the known benefits of breastfeeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) frequently among elderly patients. Serious pulmonary adverse reactions were also Any Adverse Events 99 57 Respiratory System 38 4 more common among the elderly, including pneumonia and pneumonitis. LowBody as a Whole 86 10 Increased Cough 13 1 Fever 53 1 Rhinitis 12 1 Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan in Chills 33 3 Bronchospasm 8 1 low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient Infection 31 4 Dyspnea 7 1 Asthenia 26 1 Sinusitis 6 0 numbers of patients aged 65 and over to determine whether they respond Headache 19 1 Metabolic and Nutritional Abdominal Pain 14 1 Disorders 38 3 differently from younger subjects. OVERDOSAGE There has been no experience Pain 12 1 Angioedema 11 1 with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have Back Pain 10 1 Hyperglycemia 9 1 Throat Irritation 9 0 Peripheral Edema 8 0 been given in dose-escalation clinical trials. NONCLINICAL TOXICOLOGY Flushing 5 0 LDH Increase 7 0 Heme and Lymphatic System 67 48 Digestive System 37 2 Carcinogenesis, Mutagenesis, Impairment of Fertility No long term animal Lymphopenia 48 40 Nausea 23 1 Leukopenia 14 4 Diarrhea 10 1 studies have been performed to establish the carcinogenic or mutagenic potential Neutropenia 14 6 Vomiting 10 1 of Rituxan or to determine potential effects on fertility in males or females. Thrombocytopenia 12 2 Nervous System 32 1 Anemia 8 3 Dizziness 10 1 PATIENT COUNSELING INFORMATION Patients should be provided the Rituxan Skin and Appendages 44 2 Anxiety 5 1 Night Sweats 15 1 Musculoskeletal System 26 3 Medication Guide and provided an opportunity to read prior to each treatment Rash 15 1 Myalgia 10 1 session. Because caution should be exercised in administering Rituxan to patients Pruritus 14 1 Arthralgia 10 1 Urticaria 8 1 Cardiovascular System 25 3 with active infections, it is important that the patient’s overall health be assessed Hypotension 10 1 Hypertension 6 1 at each visit and any questions resulting from the patient’s reading of the Medication Guide be discussed. Rituxan is detectable in serum for up to six a Adverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by months following completion of therapy. Individuals of childbearing potential NCI-CTC criteria. In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and should use effective contraception during treatment and for 12 months after up to 6 months after Rituxan infusion. Rituxan in Combination With Rituxan therapy. Chemotherapy Adverse reactions information below is based on 1250 patients who received Rituxan in combination with chemotherapy or following chemotherapy. Rituxan in Combination With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm experienced a higher incidence of Revised 1/2008 (4835504) infusional toxicity and neutropenia compared to patients in the CVP arm. The Jointly Marketed by: following adverse reactions occurred more frequently (*5%) in patients receiving Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactions were reported more frequently (*5%) in patients receiving Rituxan following CVP compared to patients who received no further therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. ©2008 Biogen Idec Inc. and Genentech, Inc. 7140916 March 2008 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (*2%) in the Rituxan arm compared with those who received no further therapy (4% vs. 1%). Rituxan in Combination With Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions, regardless of severity, were reported more frequently (*5%) in patients age *60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3

T HE O NCOLOGY N URSE

MEETINGS MEETINGS MEETINGS MEETINGS MEETINGS MEETINGS MEETINGS

10th International Conference on Malignant Lymphoma Lugano, Switzerland www.lymphcon.ch/

November 14-16

MEETINGS

TON May_v3

5/2/08

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For previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens

When planning a treatment course for DLBCL

Take the essential path toward improved survival RITUXAN+CHOP is proven to prolong survival in DLBCL

47% INCREASE

in 7-year OS in GELA* trial 1,2

• At 7 years, 8 cycles of RITUXAN+ CHOP increased overall survival (OS) from 36% to 53% compared with CHOP alone1 • At 5 years, 8 cycles of RITUXAN+ CHOP increased OS from 46% to 58% compared with CHOP alone5

BOXED WARNINGS and Additional Important Safety Information The most important serious adverse reactions of RITUXAN are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.5 RITUXAN in Combination with CHOP Chemotherapy for DLBCL: The following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs 46%), lung disorder (31% vs 24%), cardiac disorder (29% vs 21%), and chills (13% vs 4%). In the GELA LNH 98-5 study, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs 1.0% for CHOP).5 The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs 7%) and lung disorder (6% vs 3%). Other Grade 3 or 4 adverse reactions reported more frequently among patients receiving R-CHOP were viral infection (GELA LNH 98-5 study), neutropenia (GELA LNH 98-5 and MInT studies), and anemia (MInT study).5

Please see brief summary of prescribing information on adjacent page. Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion. *GELA (Groupe d’Etude des Lymphomes de l’Adulte) LNH 98-5 trial: A Phase III trial of 399 previously untreated elderly (age ≥60 years) DLBCL patients.3,4 †CHOP: Cyclophosphamide, doxorubicin, vincristine, and prednisone. References: 1. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. J Clin Oncol. 2007;25(suppl 18S):443s. Abstract 8009. 2. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. Paper presented at: 43rd American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Ill. Abstract 8009. 3. Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-242. 4. Data on file, Genentech, Inc. 5. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.

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