September/October 2009, Vol 1, No 5 by Green Hill Healthcare Communications, LLC

CONFERENCE NEWS Coverage of the 45th annual meeting of the American Society of Clinical Oncology continues

HEALTH ECONOMICS Radioimaging techniques may reduce cost of disease diagnosis, treatment

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Photo courtesy of American Society of Clinical Oncology.

SEPTEMBER/OCTOBER 2009 • VOL. 1, NO. 5

To Re da gi y st ww fo er rY w. co ou ex r m .co m

Mu Sec lti ond ple a My nnu elo al m Con an s ew ide sle rat tte ion www.jomcc.com rs si er n ies .

er t d a e n L The burseme or im dates f e R in e Up ity Cod ommun ts C ologis Onc praCtiCe management

viewpoint

Private Practice Survival: The Role of the Oncology Pharmacist

Federal Policy Oversteps Bounds into Medical Decision-making for Oral versus IV Treatment Dawn Holcombe, MBA, FACMPE, ACHE DGH Consulting and Connecticut Oncology Association, South Windsor, Connecticut

Steven L. D’Amato, RPh, BCOP Maine Center for Cancer Medicine, Scarborough

T Steven L. D’Amato, RPh, BCOP

he landscape of oncology care continues to change. The majority (>80%) of this care continues to be delivered in the outpatient setting, and the complexities involved in providing comprehensive, costeffective care can overwhelm the best of prac-

tices. The passage of the Medicare Modernization Act (MMA) in 2003 started the chain of events that leads us to the present. It was not long ago that private practices never worried about patients who were underinsured or uninsured. The reimbursement margins on the Continued on page 28

CanCer Center profile

Cer initiative

High-quality Patient Outcomes Achieved in the Community Setting

Comparative Effectiveness Research Initiative Rolling Out

Early this year, a multidisciplinary team from southern California published a report on their community hospital’s success with breast-conservation treatment outcomes (Breast J. 2009;15:76-84). Their patient-centered quality care, along with their multimodality breast team approach provide breast cancer patients in their community a disease-free survival rate for stage 0 to II cancer of 91% at 5 years. For their patients who require mastectomy, they also

WASHINGTON, DC—The Obama administration has committed to spending $1.1 billion on comparative effectiveness research (CER) in medicine. It will be allocated in the form of grants from the Department of Health and Human Services (HHS), the National Institutes of Health (NIH), and the Agency for Healthcare Research and Quality (AHRQ). The funds should start flowing next spring. This initiative is being met with mixed feelings by members of the medical community. Everyone agrees

Continued on page 26

Continued on page 15

lending multiple toxic drugs to treat cancer is dangerous enough, but a new element has been added to the mix for patients and physicians in Connecticut and New York. National Government Services (NGS), the claims administrator for Medicare patients in these states, announced that as of April 1, Dawn Holcombe, MBA, FACMPE, ACHE 2009, they were “clarifying” the rules Continued on page 18

MULTIDISCIPLINARY TUMOR BOARD CASE STUDY Treating a Male Patient with Moderately Differentiated, Infiltrating Ductal Carcinoma of the Breast Michael J. Schultz, MD, FACS James W. Eagan Jr, MD Rima J. Couzi, MD

D. Randy Tabb, MD Jason R. Citron, MD

Page 12

STRONG. FROM THE START.

HELP ESTABLISH A SUCCESSFUL CINV PREVENTION STRATEGY FROM THE FIRST CYCLE When your patients experience acute chemotherapyinduced nausea and vomiting (CINV) during their first cycle of chemotherapy, they may have an increased risk of CINV on subsequent days and in subsequent cycles.1-3 ALOXI®: Starts strong to prevent CINV4 A single IV dose lasts up to 5 days after MEC4,5* Can be used with multiple-day chemotherapy regimens6† * Moderately emetogenic chemotherapy. † Based on sNDA approval in August 2007, the restriction on repeated dosing of ALOXI (palonosetron HCl) injection within a 7-day interval was removed.

Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy. Important Safety Information • ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components • Most commonly reported adverse reactions in chemotherapy-induced nausea and vomiting include headache (9%) and constipation (5%) Please see the following brief summary of prescribing information. REFERENCES: 1. The Italian Group for Antiemetic Research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med. 2000;342:1554-1559. 2. Hickok JT, Roscoe JA, Morrow GR, et al. 5-hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6:765-772. Epub September 13, 2005. 3. Cohen L, de Moor CA, Eisenburg P, Ming EE, Hu H. Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497-503. Epub November 14, 2006. 4. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 5. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 6. ALOXI® (palonosetron HCl) injection full prescribing information.

www.ALOXI.com

News Notes ■ GAO Confirms Unequal Access to Medicaid for Breast Cancer Treatment A new report from the Government Accountability Office (GAO) highlights the disparity in access to screening for and treatment of breast cancer. Lack of funding is responsible for more than half of eligible low-income, uninsured women not receiving recomALOXI® (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: • Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses • Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat courses DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Dosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy. Instructions for I.V. Administration ALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit. CONTRAINDICATIONS ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information ] WARNINGS AND PRECAUTIONS Hypersensitivity Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT 3 receptor antagonists. ADVERSE REACTIONS 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 reported in practice. In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1). Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies ≥ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=633) (N=194) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 (< 1%) 4 (1%) 4 (2%) Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%) Insomnia 1 (< 1%) 3 (1%) 3 (2%) In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study. In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear. Dermatological: < 1%: allergic dermatitis, rash. Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia. Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and flatulence.

September/October 2009

mended breast cancer screening. In addition, restrictions to Medicaid coverage for breast and cervical cancer screening in more than a dozen states effectively eliminate all but a small fraction of low-income women from benefiting from screening programs. The Komen Advocacy Alliance worked with Senators Max Baucus (DMT), Barbara Mikulski (D-MD), and General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome. Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy. Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia. Musculoskeletal: < 1%: arthralgia. Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia. Psychiatric: 1%: anxiety, < 1%: euphoric mood. Urinary System: < 1%: urinary retention. Vascular: < 1%: vein discoloration, vein distention. Postmarketing Experience The following adverse reactions have been identified during postapproval use of ALOXI. 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. Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting. DRUG INTERACTIONS Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low. Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone. In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase). A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction. In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents. Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category B Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/ kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed. Labor and Delivery Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown. Nursing Mothers It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Debbie Stabenow (D-MI) to request the study. The report identified that 16 states plus the District of Columbia limit access to Medicaid coverage, that 60% of eligible women do not receive breast cancer screening from any provider, and that few statewide options for treatment are available to low-income, uninsured women who are not eligible for Medicaid (Susan G. Komen for the Cure). Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established. Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients. Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI efficacy in geriatric patients has not been adequately evaluated. Renal Impairment Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment. Hepatic Impairment Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment. Race Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized. OVERDOSAGE There is no known antidote to ALOXI. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed. Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.2) in full prescribing information Instructions for Patients • Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information]. • Patients should be instructed to read the patient insert. Rx Only Mfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677. © 2009 Eisai Inc. All rights reserved. Printed in USA. AL449 08/09

■ Endocrine Therapy for ERαnegative, HER2-positive Breast Cancer? Trastuzumab treatment may sensitize estrogen receptor alpha (ERα)-negative cancers to endocrine therapy, according to a study presented at the annual meeting of the Endocrine Society. Previous studies have found that letrozole-resistant cells and tumors had decreased levels of ERα and increased levels of human epidermal growth factor receptor type 2 (HER2), and that HER2 may be a negative regulator of ERα. For the current study, Sabnis and colleagues examined the effect of trastuzumab on ERα protein expression. The researchers treated ER-negative, HER2-positive breast cancer (SKBr-3) cells with trastuzumab. This treatment upregulated ERα protein levels in a time-dependent manner and aromatase activity in a dose-dependent manner. They found that when pretreated with trastuzumab, estradiol and androstenedione stimulated the growth of SKBr-3 cells. In addition, the growth of SKBr-3 cells was inhibited synergisitically when trastuzumab (100 μg/mL) was combined with antiestrogens (tamoxifen, fulvestrant) and aromatase inhibitors (letrozole, anastrozole, exemestane). The researchers believe that their findings suggest that HER2 is a negative regulator of ERα and that inhibition of HER2 results in upregulation of ERα and activation of ER-mediated signaling. These actions render the cells sensitive to estrogens and antihormone therapy, thus opening a new avenue of treatment for patients with HER2-positive tumors (ENDO 2009. Abstract OR38-2). ■ KRAS Status Added to Cetuximab/Vectibix Label The US Food and Drug Administration has approved revisions to the prescribing information for cetuximab (Erbitux, ImClone Systems) and panitumumab (Vectibix, Amgen). The new labels include a modification to the indication for patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer. The addition is supported by recently updated guidelines by the American Society of Clinical Oncology and the National Comprehensive Cancer Network, which recommend that all patients with metastatic colorectal cancer be tested for KRAS gene mutations before treatment with an anti-EGFR monoclonal antibody therapy. “Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux/Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux/ Vectibix is not recommended for the treatment of colorectal cancer with these mutations.” Revisions regarding KRAS status were also added to the clinical studies and clinical pharmacology section of the labels (ImClone Systems; Amgen). ■

G REEN H ILL H EALTHCARE C OMMUNICATIONS

NEWS NOTES

News Updates of Relevance to Everyday Oncology Practice

A Letter from the Editor EDITOR’S LETTER

A Clinician’s Viewpoint on Measuring the Value of Cancer Care

mark J. kraSna, mD St. JoSeph CanCer inStitute EDITOR-IN-CHIEF

his edition of Journal of Multidisciplinary Cancer Care highlights treatment of breast cancer in the multidisciplinary setting. This disease shows the innate benefits of working together. The team from California has done an excellent job demonstrating how its combined multidisciplinary approach to breast cancer has resulted in better care and shorter turnaround times. The group at St. Joseph Medical Center highlights its approach to an unusual situation, male breast cancer. Here too, the team approach has its benefits; discussing rare cancers prospectively allows a clear understanding of the goals and direction that clinicians should pursue. It keeps us from skipping steps or missing important new treatment options, upon which one specialty may have a better handle. The two articles on “private practice” and use of oral and intravenous anticancer drugs highlight another very important aspect: the economics of cancer care. In this era of reducing reimbursement and increasing copays, a balance must be struck between the feasibility of utilizing an outpatient facility to integrate all the patient’s care, including receiving therapies like white blood cell–stimulating or epoetin-stimulating drugs as well as oral anticancer and sublingual antiemetics, and the cost to the patient’s prescription plan. If the plan finds the costs prohibitive, we may be looking at a future where these treatments are shifted back to the cancer centers, because they can be billed to the patient’s hospitalization coverage rather than the prescription plan coverage.

Finally, this edition hosts the second part of the roundtable discussion regarding the National Community Cancer Centers Program (NCCCP). This unique National Cancer Institute (NCI)-sponsored program has created a new model—one of excellent, multidisciplinary cancer care in the community that is focused on clinical research and disparities outreach. The results of the clini-

As summarized by Drs Petrelli and Salner, “85% of cancer care in this country is given in the community cancer center.” This is why multidisciplinary cancer care is so crucial, especially in community cancer centers. Not every center can have weekly multidisciplinary cancer clinics where all patients are seen at one time. The goal, however, should be to aim at

The team approach has its benefits; discussing rare cancers prospectively allows a clear understanding of the goals and direction that the clinicians should pursue. It keeps us from skipping steps or missing important new treatment options, upon which one specialty may have a better handle. cal trials committees have shown improvements in patient accrual using a network approach with a formalized electronic record for patient screening and follow-up (Grubb SS, et al. J Clin Oncol. 2009;27(15S):Abstract 6586). Likewise, using multidisciplinary care clinics has shown a benefit for patient outcomes in thoracic oncology programs within the NCCCP. Specific goals for years 3 and 4 of the program will hopefully determine the effect of outreach programs on increasing screening and accrual to clinical trials of disparate populations.

100% prospective case presentation as the least common denominator. This allows collaborative case discussion and gives the patient the benefit of multiple expert opinions in the shortest possible timeframe. Only in this way will we truly make a difference in cancer care throughout the United States. This is not only the mission for NCI-designated cancer centers, but should be a goal of all community cancer centers wherever possible. Multidisciplinary care has become the standard for cancer care in the United States. ■

EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Journal of Multidisciplinary Cancer Care™, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: karen@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, Monroe Twp, NJ 08831. The ideas and opinions expressed in Journal of Multidisciplinary Cancer Care™ do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mentioned in Journal of Multidisciplinary Cancer Care™ 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 # 1949-0321. Journal of Multidisciplinary Cancer Care™ is published by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2009 by Green Hill Healthcare Communications, LLC. All rights reserved. Journal of Multidisciplinary Cancer Care™ 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.

G REEN H ILL H EALTHCARE C OMMUNICATIONS

September/October 2009

No. 5

September/October 2009 Departments

Feature Articles CONTENTS

Health Economics

Radioimaging techniques may reduce cost of disease diagnosis, treatment

Multidisciplinary Tumor Board Case Study Treating a male patient with moderately differentiated, infiltrating ductal carcinoma of the breast

Editor’s Letter

Letter to the Editor

Managing Editor Dawn Lagrosa Directors, Client Services John W. Hennessy john@greenhillhc.com Cristopher Pires cris@greenhillhc.com

Healthcare reform and how we treat the elderly

Conference News New study warns against taking some antidepressants with tamoxifen Novel HER2-targeted therapy BIG 1-98: cognitive function better with letrozole than with tamoxifen In endocrine treatment of breast cancer, sequential letrozole-tamoxifen found cost-effective

Practice Management

The Patient’s Voice

Editorial Director Karen Rosenberg karen@greenhillhc.com

News Notes

Production Manager Marie RS Borrelli Business Manager Blanche Marchitto blanche@greenhillhc.com

FDA Approvals

Executive Administrator Andrea Boylston

Health Economics Updates from ASCO

Multidisciplinary Cancer Care: A New Model for Community Cancer Centers. Part 2 The National Community Cancer Centers Program

PUBLISHING STAFF Publisher Philip Pawelko phil@greenhillhc.com

Oncology Drug Codes Breast cancer Supportive treatment

In the Literature

GH Green Hill Healthcare Communications

, LLC ™

Your Innovative Partners in Medical Media

™

241 Forsgate Drive, Suite 205C Monroe Twp, NJ 08831

Patient’s persistence leads to diagnosis of inflammatory breast cancer

eDitorial BoarD EDITOR-IN-CHIEF

Mark J. Krasna, MD St. Joseph Cancer Institute Thoracic Surgery

Practice Management Section Editor Steven L. D’Amato, RPh, BCOP Maine Center for Cancer Medicine Oncology Pharmacy John F. Aforismo, BSc, Pharm, RPh, FASCP RJ Health Systems International Oncology Pharmacy Elizabeth Bilotti, RN, MSN, APNc John Theuer Cancer Center Hackensack University Medical Center Oncology Nursing Nicole A. Bradshaw, MS, CIC Mountain States Tumor Institute Performance Improvement

G REEN H ILL H EALTHCARE C OMMUNICATIONS

Anna M. Butturini, MD Children’s Hospital Los Angeles Hematology-Oncology

Patrick Medina, PharmD, BCOP Oklahoma University College of Pharmacy Oncology Pharmacy

Scott E. Eggener, MD University of Chicago Genitourinary Cancer

Patricia Molinelli, RN, MSN, AOCNS Somerset Medical Center Oncology Nursing

Beth Faiman, RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Institute Oncology Nursing

Judy A. Olson, RT(R), RDMS St. Luke’s Mountain States Tumor Institute Breast Care

Mehra Golshan, MD Dana-Farber Cancer Institute Breast Cancer

Nicholas Petrelli, MD Helen F. Graham Cancer Center Christiana Care Health System Surgical Oncology

Patrick A. Grusenmeyer, ScD Christiana Care Health System Practice Management

Greg Pilat, MBA Advocate Health Care Practice Management

Marilyn L. Haas, PhD, CNS, ANP-BC Mountain Radiation Oncology Oncology Nursing

™

Andrew Salner, MD Hartford Radiation Oncologists Association Radiation Oncology

Dawn Holcombe, MBA, FACMPE, ACHE DGH Consulting Practice Management

Ritu Salani, MD Ohio State University Medical Center Gynecologic Malignancies

Shaji K. Kumar, MD Mayo Clinic Hematologic Malignancies

Timothy G. Tyler, PharmD, FCSHP Comprehensive Cancer Center Desert Regional Medical Center Oncology Pharmacy

Terry Macarol, RT(R)(M)(QM) Advocate Health Care Breast Imaging

Gary C. Yee, PharmD, FCCP, BCOP University of Nebraska Medical Center Oncology Pharmacy

September/October 2009

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LETTER TO THE EDITOR

Letter to the Editor Healthcare Reform and How We Treat the Elderly To the Editor:

t wasn’t supposed to happen this way. The 1000page House of Representatives healthcare reform bill, America’s Affordable Health Choices Act, was supposed to follow the new congressional passage sequence: distribute it to all the usual suspects, read it on the cab ride to the hotel, and immediately sign it into law. So when congressional members on both sides of the aisle started boring into the draft of the bill and came back with concern over language that only suggested a troubling threat to seniors, political veterans were caught off guard. Since then, with protests ringing across the country at town hall meetings and every other conceivable venue, it has become clear that Americans want a healthcare system bent on healing. The immediate concern was over the now infamous end-of-life counseling provision, Section 1233, which would have authorized Medicare to pay for a consultation between a patient and doctor or nurse about how much or little medical care is desired in the event of incapacitation, informing patients about the benefits of hospice and palliative care. At first blush, there was nothing alarming here. Providers and payers have been wrestling to draw the line between aggressive care for the terminally ill, and the pointless, wasteful use of costly drugs that do little to improve or extend life in terminally ill patients. But there is an existing context for this language and the net effect of other provisions in the House bill that are intended to ration care, which would lead to the same result: an early and cost-effective death, all in the name of efficient healthcare resource allocation. (Note that there is all the difference in the world between a medically driven consultation with one’s doctor and an agenda-driven consultation designed a priori to discourage care.) Concern arose immediately over end-of-life counseling and rationing for the elderly, with fears that it signaled the start of limiting access to healthcare for our sickest, usually oldest, patients. Fueling this fear is the fact that a quarter of Medicare funds go to patients in the last year of their lives. Because policy must be drafted with an eye to clarity, the public wanted assurances that the government was not simply implementing a cost-saving measure designed to convince seniors to opt out of appropriate treatment when they are terminally ill. Evaluating the language within the context of political policy, the concern is that the bill is an incremental move toward replacing a progressive healthcare system with a regressive one, with the elderly as its first victims. The ensuing debate has helped to bring a central issue out in the forefront: will seniors receive the care they need? It is important that we decide whether we are committed to a progressive healthcare system—one that aggressively pursues disease prevention, intervention, and innovation—or to a Brave New World of limited healthcare resources, concluding that the best years of healthcare are behind us. If the latter, then we must become adept at rationing care for the elderly, ultimately endorsing euthanasia, assisted suicide, and rationed care as practical remedies. Society must choose sides—it cannot finesse both ends of the spectrum, because the war on disease takes all the resolve

of a true all-out war. As healthcare reform takes shape, we must take stock of how we treat our elderly, a fundamental measure of the decency of our society. And as we look at new initiatives for dealing with end-of-life care, we must ask if the United States will follow the lead of Great Britain and provide coverage based on quality-adjusted life-years, calculating coverage eligibility based on the cost of intervention measured against one’s age. By encouraging hospice-oriented care for the elderly and the rationing of care, is government embracing a regressive healthcare system? Is government’s healthcare vision one of reduced access to care for the elderly and infirm, coupled with reduced development of new life-saving drugs because payer coverage strategies are skewed against coverage of branded medications, the profits of which are needed for innovation? If this is the picture, would the affluent consent to the terms that a regressive healthcare system proffers to the public at large? Would the wealthy accept a government mandate that says it is your turn to die? Be it death counseling or rationing, the end goal is the same: death is good for the bottom line. It has not escaped notice of policymakers that the major epidemiologic factor facing American healthcare is the aging of the baby boomers. The real crisis facing America’s healthcare system is what will happen 10 years from now when baby boomers begin contracting geriatric disease states and consuming vast healthcare resources, if nothing is done to improve current efficiencies to healthcare. But it is the nature of a free people to reorder their circumstances to overcome challenges to their survival. In the face of the graying of America, some policymakers would have us encourage the elderly and infirm to die quickly and “will their estates” to the young. This is classical pessimism reincarnated 21st-century style under the guise of “death-with-dignity” allocation of resources. It is an easy guess that lawmakers and the wealthy endorsing this process for the public at large would exempt themselves from it. It is also an easy guess that most lawmakers do not want this to happen. If that is the case, it is imperative to insert language into the final healthcare bill that ensures the elderly have an “even playing field,” where healthcare eligibility is not driven by age or productivity. Visit the National Museum of the Marine Corps and you see testimony to patriots who faced down seemingly invincible armies by an unshakable resolve to win. Their approach was simple: the enemy was out to annihilate America, and surrender was not an option. As politicians set out to assist the healthcare system, it is imperative that they adopt the same strategy. Disease is not something to run from, but to address head on. Ultimate solutions for solving the entire picture do not constitute reform, just utopianism. In a recent appearance on Charlie Rose, Mayo Clinic CEO and president Denis Cortese advised we undertake healthcare reform one chunk at a time, not all at once. He also faulted the bill for its emphasis on cost-containment instead of balancing this with quality; combine them and you have value, not just cost-savings, he warned. The ultimate abdication from quality of care is the

restriction of access to care for the oldest and sickest, the facilitation of death via dehydration, starvation, avoidance of cardiac resuscitation or ventilator use, or simply rationing care. The concern over the aforementioned consultations in the healthcare reform bill stems from apprehension over realpolitik, where cost trumps quality and politics trumps cost. Is the bill the first stage of a strategy to entice seniors to sign boilerplate forms amounting to “do not resuscitate”? If so, it is placing American healthcare on the slippery slope to icy utilitarianism. If not, then the language must clearly forbid it. The American spirit of can-do that the Marines showed at Belleau Wood and Iwo Jima in World War II is the proper approach to American healthcare system reform. But first, government must stop trying to dominate the triangle of sectors (clinical, business, regulatory) and instead support the clinical and business systems. Periodically, each of these three sectors regards itself as the one with the answers and seeks hegemony over the system, when it is balance of power that is needed. Enlightened government is measured not by its power over citizens, but its protection of their liberty. Government healthcare policy must avoid domination of the healthcare process and policies that encourage—and eventually mandate—terminally ill patients to die quickly and inexpensively. The language of the healthcare bill must be crafted to pursue healing, not dying. It must keep the emerging American healthcare system true to our positive core values: life, liberty, and pursuit of happiness—not quality-adjusted life-years. To be progressive and effective, the American healthcare system must embrace prevention, intervention, and innovation, conspicuous by its absence is any fourth point called do not resuscitate. Instead of planning for an ultimate retreat from healthcare for seniors, policymakers should embrace strategies that encourage development of new drugs and devices that save lives and money spent when illness drives patients into nursing homes and hospitals. A society not committed to taking care of its elderly is essentially indecent and on its way out. We are better than that. We can and will take care of the sickest—not with foolhardy, reckless usage of costly medications that do little to prolong or improve life, but with new treatments and medications, and equally resourceful payer utilization processes that deliver quality on the high road of medicine. We must continue to define our healthcare system as one befitting a free people, a system supportive of progress and the health of its citizens, a system confident in the ability of science and physicians to find the cures needed to sustain our healthcare system. The best is yet to come if we remain positive and avoid surrendering up our sickest out of fear that we do not yet have all the resources to treat them. As we codify our healthcare system, let us retain its noblest elements and reward our oldest citizens with the resolve to heal, not abandon them in their last years. ■ BY ROBERT EMMETT HENRY

Editor-in-Chief American Health & Drug Benefits

Send comments on this and other topics to Karen@greenhillhc.com. All comments will be posted on our website: www.jomcc.com. 8

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September/October 2009

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Health Economics HEALTH ECONOMICS

Radioimaging Techniques May Reduce Cost of Disease Diagnosis, Treatment TORONTO—Nuclear medicine continues to increase the cost-effectiveness of diagnosis and treatment significantly, according to a past president of the Society of Nuclear Medicine (SNM). In his summary of some of the highlights of the SNM’s 2009 annual meeting, Henry N. Wagner, Jr, MD—a professor at the Johns Hopkins University Bloomberg School of Public Health in Baltimore—focused on several presentations that suggest a nuclear-medicine approach can reduce the resources used to diagnose or treat patients.

Diagnosis and treatment Earlier in the meeting, SNM officials revealed the society’s 2009 image of the year and the retrospective study it was derived from. Sixty-seven patients with non-Hodgkin’s lymphoma were treated with one of two types of radioimmunotherapy: tositumomab and iodine131 tositumomab (Bexxar) or yttrium90 ibritumomab tiuxetan (Zevalin). An objective response was induced in 22 (71%) of the 31 patients who received tositumomab and iodine-131 tositumomab and in 28 (78%) of the 36 patients who received yttrium-90 ibritumomab tiuxetan. Eleven (35.5%) patients in the former group had complete response, as did 15 (41.7%) in the latter group. The image shows two patients who each had complete response within 3 months of treatment with the agents (Figure). Wagner pointed out that the cost of one of these regimens is only half that of the standard therapy of six cycles of rituximab-cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP). “These therapies are definitely underused, and there is a lack of knowledge about them in the community,” said lead investigator Andrei Iagaru, MD, instructor of nuclear medicine, Department of Radiology, Stanford University Medical School, Stanford, California. Another radiolabeled moiety to improve accuracy and reduce costs was examined in a breast-imaging study. Imaging with technetium-labeled radiotracers is emerging as an alternative to mammography for diagnosing primary breast tumors when it is coupled with a high-resolution, dedicated breast camera. Technetium-99m tetrofosmin was used to image patients’ breasts that had been found to have lesions on clinical examination or with mammography. Of 321 patients, 26 were found to have occult cancer with mammography. Molecular imaging revealed these to comprise 20 invasive tumors in dense tissue, five tumors in situ, and one contralateral tumor. Molecular imaging also uncovered additional tumor foci in 15 of 36 patients with multifocal disease, 10

while detecting an intraductal component around an invasive tumor in 44 patients. The overall sensitivity of molecular imaging in this study, on a per-patient basis, was 96.4% and the overall specificity was 86.4%.

Cancer screening A Japanese nationwide survey also demonstrated the benefits of nuclear medicine, this time in cancer screening. 18 Fluorodeoxyglucose-positron emission tomography (FDG-PET) cancer screening for healthy adults is relatively common in that country. Five investigators sent questionnaires to facilities that conducted such screening between 2005 and 2007. They received responses from 153 centers that examined 126,103 people over that period. Cancer was detected in 1499 (1.19%) patients, with a sensitivity of 77.9% and a positive predictive value of 30.7%. Lesions were found most frequently in men aged 60 to 69 years and women aged 50 to 59 years. Most of the cancers were stage I and located in the colon, rectum, thyroid gland, lung, or breast. Wagner said that his calculations show, based on approximately $1000 per FDG-PET screening, that the cost of detecting each tumor is $100,000. Another team sought to determine whether PET-computed tomography (CT) scans of patients suspected of having head and neck cancer should be

Figure. Positron emission tomography (PET) scans of two non-Hodgkin’s lymphoma patients 1 month before and 3 months after treatment with tositumomab and iodine-131 tositumomab (two scans on the left) or yttrium-90 ibritumomab tiuxetan (two scans on the right). Neither patient had metabolically active nonHodgkin’s lymphoma 3 months after treatment. This won the “Image of the Year” designation at the Society of Nuclear Medicine’s 56th annual meeting because it demonstrates both the power of PET imaging and the efficacy of radioimmunotherapy. been found by a limited scan. Heiko Schöder, MD, associate attending physician, Department of Radiology, and associate professor of radiology and director of PET imaging, Memorial Sloan-Kettering Cancer Center, New York, was asked to comment on the study by the Journal of Multidisciplinary Cancer Care. He noted the low rate of missed lesions may have

Imaging with technetium-labeled radiotracers is emerging as an alternative to mammography for diagnosing primary breast tumors when it is coupled with a high-resolution, dedicated breast camera. limited to the area above the aortic arch, rather than the standard ear-tomidthigh approach. This could reduce the cost of the initial scan and, more important, of further unnecessary testing of “false alarms.” For example, a suspected bowel lesion can require an endoscopy and a biopsy at a cost of $6000 to $7000. A team led by James Fletcher, MD, professor and director, Division of Nuclear Medicine/PET, Department of Radiology, Indiana University School of Medicine, Indianapolis, reviewed the records of 627 patients the department had scanned for head and neck cancer between 2004 and 2007. Only 11 (1.8%) of 599 lesions would have been missed by a limited scan. However, 62 (10.3%) false alarms would have been detected by a fulltorso scan, none of which would have

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been because the center has a large catchment area and, therefore, a relatively lower percentage of the study subjects had distant metastases. “The probability of distant disease increases with the size of the primary tumor and the extent of nodal neck disease,” said Schöder. “In our institution, we use FDG-PET primarily for patients with locally advanced disease. Therefore, our clinical experience would suggest that it does pay off to not stop scanning at the aortic arch.” He added that his group uses radiation doses of 80 mAs rather than the 140 mAs used by the Indianapolis team. This dose provides sufficient structural information, while exposing the patients to less radiation. The utility of a similar type of scan— FDG-PET/CT—to monitor disease course was examined by another team in

239 patients with multiple myeloma. Twyla Bartel, MBA, DO, chief of nuclear medicine and director of the PET facility in the Radiology Department at the University of Arkansas for Medical Sciences, Little Rock, and her colleagues found that baseline severity of lesions on FDG-PET/CT had a higher correlation with disease course or outcome than did a metastatic bone survey or magnetic resonance imaging. “Based on these data, FDG-PET/CT is definitely justified for cases that would warrant a change in management, reduction in therapy, or even a watch-andwait approach,” said Bartel. SNM’s president-elect, Dominique Delbeke, MD, PhD, professor and director of nuclear medicine/PET, Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, was part of the effort that recently succeeded in having FDG-PET/CT scanning of multiple myeloma patients approved for reimbursement by the Centers for Medicare & Medicaid Services. “This team has shown that imaging studies such as FDG-PET/CT have great prognostic value for these patients,” Delbeke commented. “Now that they have produced this evidence-based information, maybe other clinicians will be convinced to start using this approach for multiple myeloma patients.” Wagner concluded that the data presented at the meeting “should be reanalyzed by the investigators in order to more precisely determine the cost-effectiveness of each imaging procedure, including but not limited to its effect on prolonging survival.” ■ —Rosemary Frei September/October 2009

CASE STUDY

Multidisciplinary Tumor Board Case Study Treating a Male Patient with Moderately Differentiated, Infiltrating Ductal Carcinoma of the Breast Michael J. Schultz, MD, FACS; D. Randy Tabb, MD; James W. Eagan Jr, MD; Jason R. Citron, MD; Rima J. Couzi, MD Breast cancer is the most common cancer diagnosed in women in the United States (other than skin cancer) and the second most common cause of cancer death. The American Cancer Society estimates that in 2009 there will be 192,370 cases diagnosed and 40,170 deaths.1 In men, however, breast cancer is rare, with an estimated 1910 cases diagnosed and 440 deaths in 2009.2 Because it is so rare in men, there is very little medical literature to help guide management decisions. The following commentaries reflect on a case of male breast cancer and the specific challenges regarding treatment management decisions in a less common cancer.

CASE PRESENTATION Chief complaint: A 48-year-old man had bloody discharge from his right nipple. History of present illness: “Some wetness” had come from the right nipple several months previously, and thereafter, intermittently; right breast had a nontender lump.

Family history: Mother: breast cancer at age 55 years; subsequent death from ovarian cancer, which she developed at age 63. Maternal aunt: ovarian cancer in her 60s. Paternal grandmother: bilateral mastectomies for breast cancer. Medications: None. Allergies: None known.

Medical history: Unremarkable; no previous breast problems. Surgical history: Negative.

Surgical oncologist’s perspective A 48-year-old man presented to the office with bloody discharge from his right nipple. He indicated that “some wetness” came from his right nipple several months previously, and thereafter, interMichael J. Schultz, mittently. Upon feelMD, FACS ing a nontender lump, he consulted his internist, who confirmed Dr Schultz is medical director of and a breast surgeon at The Breast Center, The Cancer Institute at St. Joseph Medical Center, Towson, Maryland. Dr Tabb is a breast imaging specialist at Advanced Radiology, Towson, Maryland. Dr Eagan is a pathologist at The Cancer Institute at St. Joseph Medical Center, Towson, Maryland. Dr Citron is medical director of the Radiation Oncology Center, The Cancer Institute at St. Joseph Medical Center, Towson, Maryland. Dr Couzi is a medical oncologist at The Cancer Institute at St. Joseph Medical Center, Towson, Maryland. 12

Imaging studies: Mammography: Right breast: wellcircumscribed lobulated mass, measur-

the mass and sent him for evaluation. His medical history was completely unremarkable. He was on no medications and had had no prior breast problems. Family history was quite significant in that his mother had had breast cancer at age 55 years and had died of ovarian cancer, which she developed less than 10 years later. A maternal aunt also had ovarian cancer in her 60s. A paternal grandmother underwent bilateral mastectomies for breast cancer, but died following a motor vehicle accident. Genetic testing was advised; it was delayed, however, pending resolution of insurance issues.

Radiologist’s perspective Mammography demonstrated a wellcircumscribed lobulated mass, measuring 0.9 cm, situated deep and eccentric to the right nipple on craniocaudal projection. This presentation is unlike most D. Randy Tabb, MD cases of unilateral gynecomastia, the main differential in men, which typically presents on mam-

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ing 0.9 cm, situated deep, eccentric to nipple; no calcifications; no axillary adenopathy. Left breast: normal fatty tissue. Ultrasound: 1.2-cm well-circumscribed mass, off-center to nipple, with spiculated margins. Positron emission tomography/computed tomography scan: Uptake in right breast subareolar nodular density; small right axillary lymph node (standard uptake variable = 2.1)

mogram as a flame-shaped density radiating from and symmetrical to the nipple, feathering out into the deeper portions of the breast. No calcifications were identified, which was as expected as calcifications are very uncommon in male breast cancer. No axillary adenopathy was identified. Mammography of the left breast revealed normal male pattern fatty tissue. Ultrasound of the right breast revealed a 1.2-cm well-circumscribed mass, offcenter of the nipple, with spiculated margins. This finding would be very unusual for gynecomastia, which commonly starts as a masslike density but typically with indistinct, often shaggy margins. In later stages, however, the margins of gynecomastia involvement can become more spiculated. Usually the best clue to the mass’s etiology is its symmetry to the nipple (more typical for gynecomastia) versus asymmetry (more typical for malignancy). Essentially, any density by ultrasound that is not symmetrical to the nipple, or shows distinct margins, must be considered indeterminate.

Surgical oncologist’s perspective Physical examination demonstrated a firm, irregular, infiltrative mass just beneath the 9:00 position in the periareolar aspect of the right breast.

measuring 0.8 cm, morphologically benign in character. Pathology: Estrogen receptor (ER)positive (>90%); progesterone receptor–positive (>50%), human epidermal growth factor receptor type 2–negative by fluorescence in situ hybridization, 1.04; Ki-67, 20% to 30%. Genetic testing: Oncotype DX assay: recurrence score, 3; ER score by reverse transcription-polymerase chain reaction, 10.6.

Ultrasound confirmed an irregular hypoechoic mass with marked shadowing, which had infiltrated the dermis, measuring just greater than 1 cm. Ultrasound-guided core biopsies demonstrated an estrogen receptor (ER)-positive (>90%), progesterone receptor (PR)positive (>50%), human epidermal growth factor receptor type 2 (HER2)negative by fluorescence in situ hybridization of 1.04, infiltrating, moderately differentiated ductal carcinoma of Elston/Nottingham grade 2. Ki-67 was 20% to 30%. Subsequent positron emission tomography/computed tomography imaging confirmed uptake in the right breast subareolar nodular density, as well as a small right axillary lymph node (standard uptake variable = 2.1) measuring 0.8 cm, morphologically benign in character, but otherwise unremarkable. The multidisciplinary breast conference committee recommended a right mastectomy with sentinel lymph node biopsy. At surgery, the sentinel lymph node demonstrated a 0.5-cm metastatic focus. None of the additional 17 axillary lymph nodes resected demonstrated tumor.

Pathologist’s perspective Diagnosis of mass lesions of the male September/October 2009

biopsy material, again that of a moderately differentiated, infiltrating ductal carcinoma. This morphologic identity with female cancers is important because of the small number of patients who present with what appears to be male breast cancer, only to be found to have secondary involvement of the breast from distant primary tumors, such as the prostate or colon. A single sentinel lymph node was obtained, which proved to have multiple metastatic deposits, the largest of which measured 0.5 cm and qualified as a “macrometastasis.” Final pathologic staging was pT1c pN1a M0 (stage IIA).

Medical oncologist’s perspective In men, 90% of breast cancers are

invasive ductal cancers, and 90% express the estrogen receptor. The HER2 overexpression rate is lower in men than in women with invasive breast cancer. Given the paucity of data specific to male Rima J. Couzi, MD breast cancer, we follow the general principles for management of female breast cancer when treating men with this disease. The largest case series on male breast cancer comes from M.D. Anderson Cancer Center. It reviewed the outcomes of 135 men treated over a 57-year period. Among 57 men with node-posi-

tive breast cancer, there was a nonstatistically significant lower risk of death in the 25 men who received adjuvant chemotherapy (87% anthracycline-containing regimens) compared with the 32 men who did not (hazard ratio = 0.78; 95% confidence interval, 0.39-1.55).5 Our patient was young and in excellent health. He had stage II disease. One lymph node had multiple foci of metastatic ductal cancer, the largest deposit measuring 0.5 cm. The National Comprehensive Cancer Network guidelines recommend adjuvant chemotherapy for patients with one or more metastases >2 mm to one or more lymph nodes.6 In keeping with these guidelines and considering the patient’s wishes to be as aggressive as possible in decreasing the

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HER2, which has similar prognostic/ therapeutic implications as in women, proved to be negative. On microscopic examination, the parallels with female cancers are noted as well. This patient’s needle biopsy specimen demonstrated a moderately differentiated, infiltrating ductal carcinoma, grade 2 in the Elston/Nottingham system (Figure). It was positive for both estrogen and progesterone receptors, with positivity for hormonal receptors typically more frequent in men than in women.4 HER2, which has similar prognostic/therapeutic implications as in women, proved to be negative. Proliferative fraction, as measured by the Ki-67 marker, was in the moderate range at 20% to 30%. In the subsequent mastectomy specimen, the tumor measured 1.3 cm at maximum diameter, and was centrally located with a 0.7-cm rim of normal tissue noted between it and the deep margin. The microscopic appearance was identical to that seen in the needle September/October 2009

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CASE STUDY

breast, in biopsy or resection material, is infrequent in the average pathology practice, with the substantial majority of such lesions proving to be gynecomastia.3,4 As always, the pathologist’s first James W. Eagan Jr, step should be recMD ognition of the clinical information provided, with signs such as nipple discharge and bleeding as exhibited by this patient suggesting that one is not dealing with routine gynecomastia. Radiologic information may also be quite helpful in setting the diagnostic stage, and this should always be taken into account when available. As in the present case, the majority of male breast cancers are invasive at the time of presentation. Pure in situ carcinomas are seen much less frequently in men than in women, presumably related to mammographic screening of the latter population.4 For both in situ and invasive malignancies, however, morphologic identity between the two sexes is noted, with essentially all subtypes of disease seen in women also found in men. One difference among invasive tumors is a smaller percent of lobular carcinomas in men, although these may be seen on occasion, despite the essential absence of acinar development in the male breast. On gross examination, an invasive cancer in the male breast is similar to that in the female, typically appearing as a firm, minimally resilient, somewhat irregular mass. This is in contrast to gynecomastia, which demonstrates a more diffusely rubbery appearance, without a well-defined mass.

CASE STUDY

risk of breast cancer recurrence, he was started on a regimen of docetaxel, doxorubicin, and cyclophosphamide adjuvant chemotherapy. Unfortunately, on day 8 of the first cycle of chemotherapy, he was evaluated in an emergency room for severe abdominal pain, fever, and hypotension. He had grade 4 neutropenia, despite receiving growth factor support. He was diagnosed with neutropenic enterocolitis (typhilitis) based on the clinical presentation and radiologic appearance of an inflamed, thickened cecum and an ascending colon. He was treated aggressively with intravenous fluids, pressors, broad-spectrum antibiotics, and antifungals. He made a gradual recovery to normal health over a couple of months. Given the severity of this complication and the potential for recurrence with further chemotherapy, his insurance company, after initially denying coverage, agreed on appeals to cover the cost of Oncotype DX testing. Oncotype DX is a 21-gene recurrence score assay that is run on paraffinembedded invasive breast cancer tissue.7 The main use of this test is to identify patients with node-negative, ER-positive breast cancers who are more likely to benefit from adjuvant chemotherapy. The recurrence score is classified as low-, intermediate-, or high-risk. Patients with low-risk scores derive no significant benefit from chemotherapy, and thus can be spared potentially toxic therapies. Those with high-risk scores derive significant benefit from chemotherapy in reducing the risk of breast cancer recurrence. These results have been mirrored in a study on node-positive patients.8 The results are intriguing, but at present this assay has not gained widespread acceptance, nor is it recommended for routine use for patients with node-positive breast cancer. For our patient, we felt that given the severe complications he experienced, we needed some reassurance that the biology of his cancer is not aggressive and that his prognosis would not be adversely affected by stopping adjuvant chemotherapy. His recurrence score was 3, with an ER score by reverse transcription polymerase chain reaction of 10.6. These

scores reflected a risk of distant recurrence of 4% by 10 years, if given 5 years of tamoxifen therapy. Given this very favorable recurrence score, the patient was started on adjuvant hormonal therapy with tamoxifen 20 mg daily for an initial 5-year period, the agent of choice for men. Although aromatase inhibitors are superior to tamoxifen in postmenopausal women, there is concern that these agents lower estrogen levels less effectively in men.9

Radiation oncologist’s perspective Again, because breast cancer is rare in men, management decisions for radiation therapy are usually made by extrapolating from the literature on therapy in women. With regard to local Jason R. Citron, MD treatment options, various therapies have been investigated extensively in women, and wellaccepted consensus guidelines have been published regarding these therapies.10 In particular, modified radical mastectomy is considered equivalent to

ment of skin or pectoralis muscle, or four or more positive lymph nodes.14 It is more controversial as to whether women with one to three positive lymph nodes benefit from radiation.15 Some evidence suggests that these women do benefit; however, the benefit is probably limited to certain subsets of women.12,13,15 One approach when evaluating a woman with one to three positive lymph nodes is to consider other prognostic factors to help determine the risk of local-regional recurrence without radiation before prescribing a course of adjuvant radiation. These prognostic factors include size of primary tumor, number of involved lymph nodes (one, two, or three), patient age, and hormonal status. Using a combination of these prognostic factors, if the risk of local-regional failure without radiation is deemed high enough, a course of radiation treatment to the chest wall and drainage of the lymphatics is typically recommended. Two publications are particularly useful in helping to predict this risk of recurrence.16,17 Unfortunately, there are only limited amounts of retrospective data on the potential benefit of postmastectomy radiation therapy in men. In addition,

Extrapolating from the literature regarding female breast cancer, his risk of having an isolated local-regional recurrence was estimated at approximately 6% to 9% without radiation, and therefore, radiation treatment was not recommended. breast conservation therapy, which consists of lumpectomy followed by whole breast radiation therapy.11 Furthermore, a subset of women who undergo modified radical mastectomy benefit from postmastectomy radiation therapy.11-13 In general, standard indications for postmastectomy radiation in women include primary tumor ≥5 cm, involve-

most of these series include too few patients to draw meaningful conclusions regarding the benefit of postmastectomy radiation therapy in men.18-22 Therefore, the decision regarding radiation treatment for our patient was extrapolated from the literature investigating women. Specifically, this patient had one positive node of 18. Because he fell into the one-to-three positive lymph nodes category, other prognostic factors were evaluated. His other factors were all favorable, including a tumor size of 1.3 cm, ER/PR-positive, and no evidence of lymphovascular invasion. Furthermore, the surgical margins were widely negative. Therefore, extrapolating from the literature regarding female breast cancer, his risk of having an isolated local-regional recurrence was estimated at approximately 6% to 9% without radiation, and therefore, radiation treatment was not recommended.16,17 ■

References

Figure. Needle biopsy specimen showing a moderately differentiated, infiltrating ductal carcinoma, Elston/Nottingham grade 2 (Hematoxylin and Eosin staining, original magnification x400). 14

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1. American Cancer Society. Cancer Facts and Figures 2009. Atlanta, GA: American Cancer Society; 2009. www.cancer.org/downloads/STT /500809web.pdf. Accessed August 31, 2009. 2. Jemal A, Siegel R, Ward E, et al. Cancer statistics 2009. CA Cancer J Clin. 2009;59:225-249. 3. Badve S. Disease of the male breast. In: O’Malley FP, Pinder SE, eds. Breast Pathology. Philadelphia, PA: Churchill LivingstoneElsevier; 2006:303-312. 4. Tavassoli FA, Devilee P, eds. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. Lyon, France: IARC Press;

2003:110-112. 5. Giordano SH, Perkins GH, Broglio K, et al. Adjuvant systemic therapy for male breast carcinoma. Cancer. 2005;104:2359-2364. 6. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Breast Cancer. V.1.2009. www.nccn.org/professionals/ physician_gls/PDF/breast.pdf. Accessed September 1, 2009. 7. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817-2826. 8. Albain K, Barlow W, Shak S, et al; for the Southwest Oncology Group and The Breast Cancer Intergroup of NA. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal, node-positive, ERpositive breast cancer (S8814,INT0100). San Antonio Breast Symposium. 2007; Abstract 10. 9. Mauras N, O’Brien KO, Klein KO, Hayes V. Estrogen suppression in males: metabolic effects. J Clin Endocrinol Metab. 2000;85:23702377. 10. Goldhirsch A, Wood WC, Gelber RD, et al; for the 10th St. Gallen conference. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol. 2007;18:11331144. 11. Clarke M, Collins R, Darby S, et al; for the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366:2087-2106. 12. Ragaz J, Olivotto IA, Spinelli JJ, et al. Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer Inst. 2005;97:116-126. 13. Nielsen HM, Overgaard M, Grau C, et al. Loco-regional recurrence after mastectomy in high-risk breast cancer—risk and prognosis. An analysis of patients from the DBCG 82 b&c randomization trials. Radiother Oncol. 2006;79: 147-155. 14. Recht A, Edge SB, Solin LJ, et al; for the American Society of Clinical Oncology. Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001;19:1539-1569. 15. Olivotto IA, Truong PT, Chua B. Postmastectomy radiation therapy: who needs it? J Clin Oncol. 2004;22:4237-4239. 16. Taghian A, Jeong JH, Mamounas E, et al. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol. 2004;22:4247-4254. 17. Recht A, Gray R, Davidson NE, et al. Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: experience of the Eastern Cooperative Oncology Group. J Clin Oncol. 1999;17:1689-700. 18. Yoney A, Kucuk A, Unsal M. Male breast cancer: a retrospective analysis. Cancer Radiother. 2009;13:103-107. 19. Stranzl H, Mayer R, Quehenberger F, et al. Adjuvant radiotherapy in male breast cancer. Radiother Oncol. 1999;53:29-35. 20. Schuchardt U, Seegenschmiedt MH, Kirschner MJ, et al. Adjuvant radiotherapy for breast carcinoma in men: a 20-year clinical experience. Am J Clin Oncol. 1996;19:330-336. 21. Chakravarthy A, Kim CR. Post-mastectomy radiation in male breast cancer. Radiother Oncol. 2002;65:99-103. 22. Zabel A, Milker-Zabel S, Zuna I, et al. External beam radiotherapy in the treatment of male breast carcinoma: patterns of failure in a single institute experience. Tumori. 2005;91:151-155.

Did You Know? In follow-up interviews with patients with breast cancer, 61% reported using antioxidant supplements (ie, vitamin E, beta-carotene, or selenium) during adjuvant therapy. Source: Cancer. 2009. Jun 8.

September/October 2009

Comparative Effectiveness Research that, in the age of budget constraints, healthcare spending must be kept in check. But they also worry that it is near impossible to sort through the huge volume of evidence to arrive at a completely accurate and impartial conclusion on any topic—with the task made even more difficult by the ambitious array of therapeutic areas to be tackled under very tight timelines—and that any conclusion favoring one treatment may well lead to other treatments being barred. John I. Allen, MD, MBA, a member of the American Gastroenterological Association’s governing board and a clinical associate professor of medicine at the University of Minnesota in Minneapolis, agrees that most people are “onboard” with the concept of evidence-based medicine. “But I think skepticism comes from the fact that it’s an extraordinarily complicated and costly proposition to arrive at evidence-based medicine in general, and to arrive at decisions about every area of medicine at once will compound the complexity and cost to an unobtainable level,” Allen said. “So we’re concerned that this is going to be superficial and not reflect the complexity of real-world patient care. We’re also concerned that comparative effectiveness analysis will lead to decisions that might restrict choices for patient care and development of new technologies and treatments.” Douglas Blayney, MD, president of the American Society of Clinical Oncology (ASCO), Alexandria, Virginia, has a similar view. “I think that it is valuable to call attention to the fact that comparative effectiveness research is important for doctors’ and patients’ decision-making,” Blayney said in an interview with the Journal of Multidisciplinary Cancer Care. “But in general, ASCO also wants to have the decisionmaking remain in the hands of physicians and patients.”

2008. Hence it is emphasized in the IOM report, as well as in the June 29, 2009, Report to the President and the Congress by the Federal Coordinating Council for Comparative Effectiveness Research (available at www.hhs.gov/rec overy/programs/cer/cerannualrpt.pdf). The Coordinating Council’s report sketched out a framework for arriving at priorities for research, investment of human and scientific capital, assembly of data and infrastructure, and dissemination and translation of CER.

In the list in the IOM report, the fourth priority is to compare the effectiveness of upper endoscopy use and frequency for patients with gastroesophageal reflux disease on morbidity, quality of life, and diagnosis of esophageal adenocarcinoma. The tenth priority is comparing the effectiveness of management strategies for localized prostate cancer. Other top priorities include management strategies for ductal carcinoma in situ; imaging technologies for diagnosing, staging, and moni-

toring patients with cancer; and genetic and biomarker testing used to prevent and treat breast, colorectal, prostate, lung, and ovarian cancers. “The report is meant to address the fear that if one treatment comes out ahead, the other treatments will be denied,” Sheldon Greenfield, MD, professor of medicine at University of California Irvine and cochair of the IOM committee that produced the Continued on page 28

FREE CONTINUING EDUCATION CREDITS Current activities at www.COEXM.com include:

How did we get here? This is part of the rolling out of the American Recovery and Reinvestment Act of 2009. The legislation, signed into law February 17 by President Barack Obama, allocated $400 million to the Office of the Secretary in the HHS, $400 million to the NIH, and $300 million to the AHRQ for CER. The law also called for the creation of the Federal Coordinating Council for Comparative Effectiveness Research. In addition, the act called for the Institute of Medicine (IOM) to form a committee to recommend priorities for the funding allocated to the Office of the Secretary of the HHS. The IOM committee solicited input from the public, healthcare professionals, and medical organizations before voting on the results and coming up with the final 100. The report was released on June 30 and is available at http://books.nap.edu/ catalog.php?record_id=12648. Cancer was one of the 14 priority conditions set by the HHS Secretary in September/October 2009

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CER INITIATIVE

Continued from cover

Conference News CONFERENCE NEWS

New Study Warns Against Taking Some Antidepressants with Tamoxifen ORLANDO—Up to 30% of tamoxifen users may be taking drugs that reduce the drug’s effectiveness against breast cancer, a study presented at the annual meeting of the American Society of Clinical Oncology suggests. Researchers have found that certain antidepressants inhibit an enzyme, cytochrome P450 2D6 (CYP2D6), that helps tamoxifen work effectively. In a study involving almost 1300 women who were newly prescribed tamoxifen to treat breast cancer, researchers found that taking some antidepressants could more than double the risk of a breast cancer recurrence for women on both medications. Tamoxifen is metabolized to its active form, endoxifen, by hepatic CYP2D6. Diminished CYP2D6 function by concurrent use of pharmacologic inhibitors can significantly reduce endoxifen plasma concentrations and may lead to reduced tamoxifen effectiveness. The antidepressants at issue are three widely used selective serotonin reuptake inhibitors (SSRIs), fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zol oft), as well as the atypical antidepressant bupropion (Wellbutrin). These four medications are CYP2D6 inhibitors, commonly prescribed to treat depression and anxiety as well as hot flashes in women with breast cancer. The three SSRIs are considered to be moderate-topotent CYP2D6 inhibitors. Several other SSRIs examined in the study are weak CYP2D6 inhibitors and did not raise breast cancer recurrence risks for patients using them along with tamoxifen. Those SSRIs included citalopram (Celexa), escitalopram (Lexapro), and fluvoxamine (Luvox). “While we expected to see some

impact on the disease recurrence rate based on already existing evidence, what is remarkable is that the effect is consistent with the pharmacologic potency of these antidepressants as CYP2D6 inhibitors. This lends biological plausibility to the data,” said study investigator David Flockhart, MD, chief, clinical pharmacology at Indiana University School of Medicine, Indianapolis. In this study, all the women were prescribed tamoxifen between 2003 and 2005 and were monitored for at least 2 years. The mean follow-up was 2.7 years. All the study subjects had to be at least 70% compliant with their tamoxifen therapy, and, on average, compliance was 90% throughout the study period. The average duration that patients used

breast cancer recurrence. Comparisons were made between the cohorts using a CYP2D6 inhibitor and a group on tamoxifen only. The researchers found that women taking a moderate-to-potent CYP2D6 inhibitor had a 2-year breast cancer recurrence rate of 13.9%, 1.9 times higher than the 7.5% recurrence rate of those using tamoxifen alone. Because 60% of the women in the study on a CYP2D6 inhibitor were using an SSRI, the researchers examined a subset that included only those patients taking an SSRI and divided it into two cohorts. One group included 213 women on a moderate-to-potent CYP2D6-inhibiting SSRI and the other group included 137 women using a weak CYP2D6-inhibiting SSRI.

Women taking a moderate-to-potent CYP2D6 inhibitor had a 2-year breast cancer recurrence rate of 13.9%, 1.9 times higher than the 7.5% recurrence rate of those using tamoxifen alone. tamoxifen and a CYP2D6 inhibitor concurrently was 340 days. The analysis first looked at two different cohorts, one with 353 women (about 27%) who were taking a moderate-topotent CYP2D6 inhibitor, which included but was not limited to antidepressants, in conjunction with tamoxifen, and a group of 945 women on tamoxifen who were not taking any CPY2D6 inhibitor. The patients’ pharmacy and medical records were analyzed to determine the medications used and the incidence of a

The results showed an even greater increase in the risk of a recurrence among those taking a moderate-topotent CYP2D6-inhibiting SSRI as compared with the initial analysis. These women had a rate of breast cancer recurrence of 16%, 2.2 times higher than the women only taking tamoxifen. The women using weak CYP2D6-inhibiting SSRIs had a breast cancer recurrence rate of 8.8% and were not deemed to be at any increased risk for the disease. “It is important that doctors and

nurses know that there is a deleterious interaction with tamoxifen and these three major antidepressants,” said Flockhart in an interview. “There are more than 200 drugs that use this pathway but these four drugs (fluoxetine, paroxetine, sertraline, and bupropion) are of real concern. So, they may want to choose another antidepressant rather than one of these four.” Marisa Weiss, MD, who is president and founder of Breastcancer.org and a breast cancer oncologist at Lankenau Hospital, Philadelphia, said these findings are very important. She said tamoxifen has been used successfully to treat millions of women diagnosed with hormone receptor–positive breast cancer. Studies suggest the drug can reduce the risk of recurrence by about 50%. “With the life-saving advantages of tamoxifen, it is imperative that women taking it derive the greatest benefit they can. Women make a daily commitment to tamoxifen and deserve to get the maximum benefit this medicine affords,” Weiss said. “Since tamoxifen is the cornerstone of care for hundreds of thousands of women across the globe, this study will likely raise a lot of questions about whether to continue to use tamoxifen or change treatments, as well as whether women who stopped taking tamoxifen should restart. These data represent an important insight into maximizing the effectiveness of breast treatment.” Based on this study, the US Food and Drug Administration is considering adding information about the potential interaction between tamoxifen and certain antidepressants to the drug labels. ■ —John Schieszer

Novel HER2-targeted Therapy Making News ORLANDO—Benefits from preliminary studies were confirmed at the annual meeting of the American Society of Clinical Oncology for a novel human epidermal growth factor receptor 2 (HER2)-targeted agent, trastuzumab-DM1 (T-DM1), an antibody-conjugate that is the only single-agent molecule in this investigational class. TDM1 combines the HER2-inhibiting properties of trastuzumab with targeted delivery of a potent antimicrotubule derivative, DM1. The result is that the drug directly enters the cancer cell, with minimal toxicity to surrounding tissues. The open-label, single-arm, multicenter study included 112 patients with advanced breast cancer who experienced disease progression after treatment with at least two HER2-targeted therapies (60% with lapatinib). Patients 16

received 3.6 mg/kg of T-DM1 intravenously every 3 weeks. The overall response rate to the single agent was 25% by independent review and 38% by investigator review, and the clinical benefit rate (response or stable disease) was 35% and 45%, respectively, at ≥6 months’ follow-up. Toxicity was minimal, mostly grade 3/4 thrombocytopenia in approximately 7% of patients, reported Charles Vogel, MD, of Lynn Regional Cancer Center, Boca Raton, Florida. Results from a biomarker analysis of the study were presented by Ian E. Krop, MD, of Dana-Farber Cancer Institute, Boston. HER2-positivity was confirmed by central laboratory review in 78% of the patients; 22% were found to be HER2-normal. Confirmed HER2-positivity corresponded with higher response

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rates and disease-free survival. HER2-positive patients had response rates of 32% by independent review and 48% by investigator review, compared with 5% and 9%, respectively, in the HER2-normal subset. Disease-free survival was 7.4 months for HER2-positive patients and 2.6 months for HER2-normal patients, Krop reported. “These differences show the need for high-quality HER2 testing in trials and in practice,” he said. Commenting on the findings was John Mackey, MD, who is professor of oncology at Cross Cancer Institute and the University of Alberta, Canada. Mackey observed that T-DM1 appears to be specifically delivering a potent cytotoxic to HER2-positive cells, with minimal cardiotoxicity and only transient thrombocytopenia.

“It appears less toxic than combinations of trastuzumab and taxanes, and it has impressive activity in a pretreated population, especially with central confirmation of HER2 positivity, without loss of activity after prior lapatinib treatment,” Mackey commented. Adding to the commentary was Jose Baselga, MD, professor of oncology at Vall d’Hebron University Hospital, Barcelona, Spain, and president of the European Society for Medical Oncology, “To see such efficacy with a monotherapy is highly unusual. It is important that we continue to explore this promising agent in phase 3 studies.” ■ —Audrey Andrews Conference News continued on page 22

September/October 2009

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Federal Policy Oversteps Bounds Continued from cover

VIEWPOINT

of medical necessity not just for drugs that physicians use to treat Medicare patients, but also as to whether the physicians would be allowed to use the oral or intravenous (IV) form of a drug that comes in both formulations. Shortly after the announcement, physicians across both states agreed that, where possible, it does make sense to use oral medications. The NGS announcement, however, went beyond the authority of Medicare and moved into the realm of medical decision-making, placing its policy between the physician and his/her analysis of what is in the patient’s best interest. The unintended consequences of this policy intrusion have raised costs, caused disruption of patient care, and raised the specter of losing ground in the battle against cancer for patients. What is even more troubling is that neither NGS nor the Centers for Medicare & Medicaid Services (CMS) is accepting responsibility for this policy. NGS has stated that it is merely following national CMS policy, and CMS has stated in a letter to the affected state oncology associations that the policy is up to interpretation by the local carrier.

Background In November 2008, NGS started notifying a modest number of attendees at professional meetings that the NGS interpretation of the standing Medicare policy on drugs and biologics had implications for oncology drugs and that NGS was making oncology practices aware of its interpretation of the policy, as well as providing sample definitions of medical necessity. The policy was revised to include those interpretations and published on the NGS website.1 Not only does the indication for the use of the drug need to meet medical necessity requirements, but the route of administration is also subject to medical necessity criteria. Contractors must continue to apply the policy that not only the drug is medically reasonable and necessary for any individual claim, but also that the route of administration is medically reasonable and necessary. That is, if a drug is available in both oral and injectable forms, the injectable form of the drug must be medically reasonable and necessary as compared to using the oral form (Pub 100-02, Medicare Benefit Policy Manual, Chapter 15, Section 50.2—Determining Self-Administration of Drug or Biological [Rev. 91; Issued: 06-20-08; Effective/Implementation Date: 07-21-08]). Medication given by injection (parenterally) is not covered if standard medical practice indicates that the administration of the medication by mouth (orally) is effective and is an accepted or preferred method of administration (Pub 100-02, Medicare Benefit Policy Manual, Chapter 15, Section 50.4.3). Specifically, for antiemetic medication, CMS states: It is recognized that a limited number of patients will fail on oral antiemetic drugs. Intravenous antiemetics may be covered 18

(subject to the rules of medical necessity) when furnished to patients who fail on oral antiemetic therapy (Pub 100-02, Medicare Benefit Policy Manual, Chapter 15, Section 50.5.4). Examples of medical necessity when the IV preparation would be indicated include but are not limited to: • a patient who suffers from esophageal cancer and cannot swallow • a patient who has had recent head and neck irradiation and has severe mucositis and cannot swallow • a patient who is already suffering from severe nausea and vomiting when the medication is needed. Medical necessity is not demonstrated in the cases where a patient has not taken the oral medication, for patient or provider convenience purposes, or for financial or emotional reasons; and such claims are subject to denial. On January 13, 2009, NGS posted the following announcement on its website.2 National Government Services would like to remind providers that the use of injectable medications when an oral form of the same medication is available must meet medical necessity requirements for use of the drug, and for the route of administration. Documentation should indicate that the patient was unable to tolerate the oral preparation prior to initiation of the intravenous form of the medication. An example is a failed course of the oral antiemetic before starting an intravenous form of the same antiemetic. Instruction regarding this topic is from the Centers for Medicare & Medicaid Services (CMS) and is a national not a local determination. NGS later clarified this policy with an article identifying diagnosis codes to be used when the IV form of a drug with a clinically equivalent oral was used.3 When billing for an IV drug which has an available oral form, please also report one of the following ICD-9 codes (whichever is appropriate). 579.3: Other and unspecified postsurgical nonabsorption 579.9: Unspecified intestinal malabsorption 995.29: Unspecified adverse effect of other drug, medicinal, and biological substance V12.79: Personal history of other specified digestive system diseases. Letters were written in February 2009 by the American Society of Clinical Oncology (ASCO), US Oncology, and collaboratively the Connecticut Oncology Association, the Hematology/ Oncology Managers of New York, the New York Medical Oncology Hematology Society, and the Upstate New York Society of Medical Oncology and Hematology to request that the CMS and NGS reconsider the applications of limitations on the use of injectable medications when an oral equivalent is available in the oncology setting and to note that the NGS policy disfavoring coverage of IV antiemetics is inconsistent with national Medicare policy and

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must be rescinded. Most physicians in the affected states believe that these letters clearly articulated the issues and are awaiting policy changes based on the issues set forth in the letters (and are spending their time struggling to treat patients while waiting for the policy to be revised). CMS and NGS personnel, however, seem to feel that because physicians in the field have not repeatedly raised their concerns since the policy enforcement began in April, those earlier letters were more noise than substance and have stated that the policy seems to be appropriate.

Why is this policy a hardship for cancer patients? The focus of comments from all concerned was that the complexity and logistics of cancer care make a blanket application of the policy both contrary to national Medicare policy and the interests of cancer patients covered by Medicare. Although a few drugs used in oncology treatment do have IV and oral

Although the drugs in both forms are covered under Medicare Part B reimbursement, most physician practices are not set up to provide the oral versions of these drugs, thus requiring the patient to make additional trips to the pharmacy to receive these drugs under the Medicare Part D benefit and to pay the Part D copayment and “doughnut hole” costs. When patients are unable to afford the drugs under Part D, they are faced with a choice of foregoing that drug and risking the changes in outcomes from that omission in their treatment (which ultimately costs Medicare much more than the cost of the initial drug in the IV version). Physicians who are able to dispense the oral versions of these drugs are reporting significant financial losses due to delays in reimbursement when billed through the durable medical equipment regional carrier.

How does this policy affect use of antiemetics? Often the discussion and comments focus on the application of this policy to

Oral medications absorb into the body differently from IV medications, and have a variable effect that can reduce efficacy and increase toxicity of the chemotherapy regimen, thereby increasing the duration and cost of treatment. forms that are identified as clinically equivalent, the mechanisms of action vary widely with the different routes of administration. The current standard of care in oncology for many chemotherapy regimens is to use IV formulations, particularly because current cancer treatments are increasingly complex, and timing of absorption and uptake of treatments can affect the efficacy of a multiple-drug regimen. Oral medications absorb into the body differently from IV medications, and have a variable effect that can reduce efficacy and increase toxicity of the chemotherapy regimen, thereby increasing the duration and cost of treatment. If all drugs in a regimen are administered via IV infusion, the drugs involved are distributed more evenly, which increases the likelihood of completed and more efficacious treatment, with lessened toxicity and more easily managed side effects. Cost is also a significant issue.

antiemetics because that category of drugs has the most instances of drugs with indicated clinically equivalent oral and injectable forms (Table). The NGS enforcement is intended to apply to all drugs and biologics with clinically equivalent oral and IV forms, although the example given is for antiemetics, according to interpretations in the notifications sent to oncology practices by medical director Paul Deutsch, MD. Specifically for antiemetics, much of the success in battling cancer has resulted from success in the management of nausea and vomiting in patients receiving increasingly dose-dense therapies with higher risk of side effects. The goal in effective treatment has been to prevent nausea and vomiting from the start, not to manage it after it has begun. Common medical practice is to not risk disruption of care with failures or even the onset of anticipatory nausea and vomiting—a common occurrence for patients with cancer. To require fail-

Table. Antiemetic Agents Currently Available in the United States Antiemetic agent Aprepitant (Emend brand) Dolasetron (Anzemet) Granisetron (Kytril brand or generic) Ondansetron (Zofran) Palonosetron (Aloxi)

Injectable form

Oral form

Yes Yes Yes Yes Yes

Yes Yes Yes Yes No September/October 2009

CMS and NGS overstepping their bounds Only NGS, of all the Medicare carriers, is taking this comprehensive, blanket approach to defining medical decision-making for any drug that has oral and IV clinically equivalent formulations. By setting forth stipulations about when an IV version can be used and by stating that a physician’s definition of medical necessity cannot take into account patient or practice convenience, patient preference, or patient or practice financial considerations, NGS and CMS are attempting to circumvent Medicare law as set by Congress by limiting payment for appropriately indicated Part B drugs administered in a physician’s office to the least costly alternative. Congress has approved several compendia to indicate what is medically appropriate treatment. These compendia do not limit use of drugs to one route of administration over another for drugs with both oral and IV forms for very valid reasons, linked to the medical judgment of the physician and each patient’s situation. As US District Judge Henry H. Kennedy Jr. wrote in a ruling set forth October 16, 2008, from the US District Court for the District of Columbia, “It does not make sense to conclude that Congress, having minutely detailed the reimbursement rates for covered items and services, intended that the Secretary [CMS being under the responsibility of the Secretary of Health and Human Services] could ignore these formulas whenever [he or she] determined that the expense of an item or service was not reasonably necessary.”4 CMS and NGS are moving further into the role of medical decision-making, stepping between the patient and the physician without full medical knowledge of the patient’s health status or situation, by extending this policy to all drugs that are made with a clinically equivalent oral and IV version. Oncologists note, for instance, that data suggest that giving the oral version of cyclophosphamide to patients with breast cancer may increase the risk of myelodysplastic syndromes more than giving the IV version of the same drug. In addition, a substantial number of patients given the oral version of the drug dexamethasone get gastritis. Even the national oncology guidelines set forth by ASCO and the National Comprehensive Cancer Net-

work do not limit use of drugs to one route of administration over another for patients with cancer. These guidelines leave that choice to the patient’s physician based on that patient’s situation and needs. As of the end of June 2009, CMS and NGS were standing firm behind this policy, although each is claiming that it is the other’s policy. In the meantime, some Medicare patients in Connecticut and New York are choosing to forego therapy rather than pay for treatments when they cannot afford the oral version of a drug. Other patients take oral drugs before presenting to the office for treatment and then find that they are clinically unable to receive treatment

that day and so took costly drugs to no avail. Increasing numbers are experiencing nausea and vomiting to prove failure of the oral version of a drug before being allowed to receive the IV version, thus leaving them at significantly greater risk for further complications and the onset of anticipatory nausea and vomiting. Many congressional members have stepped up and hopefully will soon become involved in this blatant overstepping of CMS authority into medical decision-making. If the NGS policy for Connecticut and New York is allowed to stand as is, patients in other carrier locales across the country may soon also be affected by similar restrictions. ■

References 1. National Government Services. LCD for drugs and biologicals, coverage of, for label and offlabel uses (L25820). www.ngsmedicare.com/ NGSMedicare/lcd/L25820_active_lcd.htm. Accessed July 2, 2009. 2. National Government Services. What’s new: use of injectable medications when an oral equivalent is available. www.ngsmedicare.com/ NGSMedicare/PartA/NewsandPublications/Wh atsNew/PartANews08/ngs_011309_injectable. aspx. Accessed July 2, 2009. 3. National Government Services. Archive article for drugs and biologicals, coverage of, for label and off-label uses—supplemental instructions article (A44930). www.ngsmedicare.com/NGS Medicare/lcd/L25820_r5_sia.htm. Accessed July 2, 2009. 4. Hays, Dey v Leavitt (US District Court, District of Columbia 2008). https://ecf.dcd.uscourts.gov/ cgi-bin/show_public_doc?2008cv1032-22. Accessed July 2, 2009.

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November 11

Hematology, GI Cancers

November 12

GYN, Breast, Melanoma, Head & Neck, Sarcoma

November 13

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September/October 2009

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6/29/09 3:56:06 PM

VIEWPOINT

ure of an oral medication in managing nausea and vomiting before use of an IV version is setting the medical practice of cancer back to the late 1980s. NGS, however, has repeatedly stated that failure on an oral version is required to prove medical necessity for use of the IV version of that drug. The crux of the problem is that oral drugs are not simply and universally a full-blanket replacement for the IV version of the same chemical compound. Although oral versions can be used in some settings, in others, the oral version leads to complications. The physician needs the flexibility to determine the appropriate treatment for each patient, because only the physician is examining the medical, physical, and situational aspects of the patient’s status.

ABRAXANE delivers ®

nab defined: nab technology exploits the natural properties of albumin, facilitating the delivery of water-insoluble compounds to the tumor. ®

ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. WARNING: ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS.

IMPORTANT SAFETY INFORMATION The use of ABRAXANE has not been studied in patients with hepatic or renal dysfunction. In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL. ABRAXANE can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ABRAXANE. Men should be advised to not father a child while receiving treatment with ABRAXANE. It is recommended that nursing be discontinued when receiving ABRAXANE therapy. ABRAXANE contains albumin (human), a derivative of human blood. Caution should be exercised when administering ABRAXANE concomitantly with known substrates or inhibitors of CYP2C8 and CYP3A4. ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/ mm3. It is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3.

efficacy* to make more possible

In a pivotal phase III trial in metastatic breast cancer patients,

ABRAXANE速 delivered nearly double the overall response rate* vs solvent-based paclitaxel1

21.5% vs 11.1%

15.5% vs 8.4%

(P=.003) for all study patients.1 95% Cl, 16.2% to 26.7% for ABRAXANE 95% Cl, 6.9% to 15.1% for solvent-based paclitaxel

(P=NS) for study patients who failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapy.1 95% Cl, 9.3% to 21.8% for ABRAXANE 95% Cl, 3.9% to 12.9% for solvent-based paclitaxel

BOUND AND DETERMINED

In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses is recommended. Sensory neuropathy occurs frequently with ABRAXANE. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial. These events included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary embolism, and hypertension. In the randomized metastatic breast cancer study, the most important adverse events included alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), asthenia (any 47%; severe 8%), myalgia/arthralgia (any 44%; severe 8%), anemia (all 33%; severe 1%), infections (24%), nausea (any 30%; severe 3%), vomiting (any 18%; severe 4%), diarrhea (any 27%; severe <1%), and mucositis (any 7%; severe <1%). Other adverse reactions have included ocular/visual disturbances (any 13%; severe 1%), fluid retention (any 10%; severe 0%), hepatic dysfunction (elevations in bilirubin 7%, alkaline phosphatase 36%, AST [SGOT] 39%), renal dysfunction (any 11%; severe 1%), thrombocytopenia (any 2%; severe <1%), hypersensitivity

reactions (any 4%; severe 0%), cardiovascular reactions (severe 3%), and injection site reactions (<1%). During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE. Reference: 1. ABRAXANE [prescribing information]. Los Angeles, Calif: Abraxis Oncology, a division of Abraxis BioScience, Inc; August 2007. Please see the Brief Summary of the ABRAXANE full prescribing information on the next page. ABRAXANE, Abraxis, Abraxis Oncology, nab, and ARC of Support are registered trademarks, and Abraxis Oncology Resource Center is a service mark, of Abraxis BioScience, LLC. Abraxis Oncology速 is a division of Abraxis BioScience, LLC. 息2009 Abraxis BioScience, LLC. All Rights Reserved. AO 1304 06/09 Printed in USA

速 SM

Conference News CONFERENCE NEWS

Continued from page 16

BIG 1-98: Cognitive Function Better with Letrozole than with Tamoxifen ORLANDO—An unexpected finding in a cognitive substudy of the Breast International Group (BIG) 1-98 trial underscores cognitive dysfunction risks of tamoxifen among postmenopausal women with hormone receptor–posi®

Rx Only

tive, early-stage breast cancer. Cognitive dysfunction, stated substudy author Karen Ribi, PhD, of the International Breast Cancer Study Group, Bern, Switzerland, has been recognized as a potential long-term side effect of adjuTable 1: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule (Continued) Percent of Patients ABRAXANE Paclitaxel Injection 260/30minb 175/3hc,d (n=229) (n=225)

Brief Summary of Full Prescribing Information. WARNING ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. INDICATION: ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. CONTRAINDICATIONS: ABRAXANE should not be used in patients who have baseline neutrophil counts of <1,500 cells/mm3. WARNINGS: Bone marrow suppression (primarily neutropenia) is dose dependent and a dose limiting toxicity. ABRAXANE should not be administered to patients with baseline neutrophil counts of <1,500 cells/mm3. Frequent monitoring of blood counts should be instituted during ABRAXANE treatment. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. The use of ABRAXANE has not been studied in patients with hepatic or renal dysfunction. In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL. Pregnancy – Teratogenic Effects: Pregnancy Category D ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryo- and fetotoxicity, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women using ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving 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 ABRAXANE. Use in Males Men should be advised to not father a child while receiving treatment with ABRAXANE (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility for discussion of effects of ABRAXANE exposure on male fertility and embryonic viability). Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. PRECAUTIONS: Drug Interactions No drug interaction studies have been conducted with ABRAXANE. The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE (paclitaxel protein-bound particles for injectable suspension) concomitantly with known substrates or inhibitors of CYP2C8 and CYP3A4 (see CLINICAL PHARMACOLOGY). Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors (such as ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials. Hematology ABRAXANE therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses of therapy is recommended (see DOSAGE AND ADMINISTRATION). Nervous System Sensory neuropathy occurs frequently with ABRAXANE. The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose modification. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE (see DOSAGE AND ADMINISTRATION). Injection Site Reaction Injection site reactions occur infrequently with ABRAXANE and were mild in the randomized clinical trial. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of ABRAXANE has not been studied. Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). ABRAXANE was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay. Administration of paclitaxel protein-bound particles to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a mg/m2 basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females. A low incidence of skeletal and soft tissue fetal anomalies was also observed at doses of 3 and 12 mg/m2/week in this study (approximately 1% to 5% of the daily maximum recommended human exposure on a mg/m2 basis). Testicular atrophy/degeneration has also been observed in single-dose toxicology studies in rodents administered paclitaxel protein-bound particles at 54 mg/m2 and dogs administered 175 mg/m2 (see WARNINGS). Pregnancy – Teratogenic Effects: Pregnancy Category D (See WARNINGS section). Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Following intravenous administration of carbon-14 labeled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving ABRAXANE therapy. Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated. Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE, 11% were at least 65 years of age and <2% were 75 years or older. No toxicities occurred notably more frequently among elderly patients who received ABRAXANE. ADVERSE REACTIONS: The following table shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer. Table 1: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 260/30minb 175/3hc,d (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L < 0.5 x 109/L Thrombocytopenia < 100 x 109/L < 50 x 109/L Anemia < 11 g/dL < 8 g/dL Infections Febrile Neutropenia Bleeding

80 9

82 22

2 <1

3 <1

33 1 24 2 2

25 <1 20 1 2 (Continued)

Hypersensitivity Reactione All 4 12 0 2 Severef Cardiovascular Vital Sign Changesg Bradycardia <1 <1 Hypotension 5 5 3 4 Severe Cardiovascular Eventsf Abnormal ECG All patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 10 2 Severe Symptomsf Myalgia/Arthralgia Any Symptoms 44 49 Severe Symptomsf 8 4 Asthenia Any Symptoms 47 39 8 3 Severe Symptomsf Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsf 0 <1 Gastrointestinal Nausea Any symptoms 30 22 Severe symptomsf 3 <1 Vomiting Any symptoms 18 10 4 1 Severe Symptomsf Diarrhea Any Symptoms 27 15 f Severe Symptoms <1 1 Mucositis Any Symptoms 7 6 f Severe Symptoms <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade b ABRAXANE dose in mg/m2/duration in minutes c 2 paclitaxel injection dose in mg/m /duration in hours d paclitaxel injection pts received premedication e Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. f Severe events are defined as at least grade 3 toxicity g During study drug dosing. Myelosuppression and sensory neuropathy were dose related. Adverse Event Experiences by Body System Unless otherwise noted, the following discussion refers to the primary safety database of 229 patients with metastatic breast cancer treated with single-agent ABRAXANE in the randomized controlled trial. The frequency and severity of important adverse events for the study are presented above in tabular form. In some instances, rare severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hematologic Neutropenia, the most important hematologic toxicity, was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m 2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. In the randomized metastatic breast cancer study, infectious episodes were reported in 24% of the patients treated with a dose of 260 mg/m2 given as a 30-minute infusion. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications. Febrile neutropenia was reported in 2% of patients in the ABRAXANE arm and 1% of patients in the paclitaxel injection arm. Thrombocytopenia was uncommon. In the randomized metastatic breast cancer study, bleeding episodes were reported in 2% of the patients in each treatment arm. Anemia (Hb <11 g/dL) was observed in 33% of patients treated with ABRAXANE in the randomized trial and was severe (Hb <8 g/dL) in 1% of the cases. Among all patients with normal baseline hemoglobin, 31% became anemic on study and 1% had severe anemia. Hypersensitivity Reactions (HSRs) In the randomized controlled metastatic breast cancer study, Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients in the randomized metastatic breast cancer trial. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial. These events included chest pain, cardiac arrest, supraventricular tachycardia, edema,thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported rarely. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients in the metastatic breast cancer randomized trial. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Reports of dyspnea (12%) and cough (6%) were reported after treatment with ABRAXANE in the randomized trial. Rare reports (<1%) of pneumothorax were reported after treatment with ABRAXANE. Rare reports of interstitial pneumonia, lung fibrosis, and pulmonary embolism have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of radiation pneumonitis have been received in paclitaxel injection patients receiving concurrent radiotherapy. There is no experience with the use of ABRAXANE with concurrent radiotherapy. Neurologic The frequency and severity of neurologic manifestations were influenced by prior and/or concomitant therapy with neurotoxic agents. In general, the frequency and severity of neurologic manifestations were dose-dependent in patients receiving single-agent ABRAXANE. In the randomized trial, sensory neuropathy was observed in 71% of patients (10% severe) in the ABRAXANE arm and in 56% of patients (2% severe) in the paclitaxel injection arm. The frequency of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients in the randomized trial. In the randomized comparative study, 24 patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No incidences of grade 4 sensory neuropathies were reported in the clinical trial. Only one incident of motor neuropathy (grade 2) was observed in either arm of the controlled trial. Reports of autonomic neuropathy resulting in paralytic ileus have been received as part of the continuing surveillance of paclitaxel injection safety. Cranial nerve palsies have been reported during postmarketing surveillance of ABRAXANE. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established. Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE in single arm and randomized trials and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients in a single arm study who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. However, rare reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection have suggested persistent optic nerve damage. Arthralgia/Myalgia Forty-four percent of patients treated in the randomized trial experienced arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days. Hepatic Among patients with normal baseline liver function treated with ABRAXANE in the randomized trial, 7%, 36%, and 39% had elevations in bilirubin, alkaline phosphatase, and AST (SGOT), respectively. Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial.

G REEN H ILL H EALTHCARE C OMMUNICATIONS

vant chemotherapy for breast cancer. “It was expected,” Ribi said in an interview, “that because of the estrogen deprivation associated with aromatase inhibitors, patients who received letrozole would have worse cognitive function compared

Rare reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Gastrointestinal (GI) Nausea/vomiting, diarrhea, and mucositis were reported by 33%, 27%, and 7% of ABRAXANE treated patients in the randomized trial. Rare reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, were observed in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction Injection site reactions have occurred infrequently with ABRAXANE and were mild in the randomized clinical trial. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported rarely. Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Asthenia Asthenia was reported in 47% of patients (8% severe) treated with ABRAXANE in the randomized trial. Asthenia included reports of asthenia, fatigue, weakness, lethargy and malaise. Other Clinical Events Rare cases of cardiac ischemia/infarction and thrombosis/embolism possibly related to ABRAXANE treatment have been reported. Alopecia was observed in almost all of the patients. Nail changes (changes in pigmentation or discoloration of nail bed) were uncommon. Edema (fluid retention) was infrequent (10% of randomized trial patients); no patients had severe edema. The following rare adverse events have been reported as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment: skin abnormalities related to radiation recall as well as reports of Stevens-Johnson syndrome, toxic epidermal necrolysis, conjunctivitis, and increased lacrimation. As part of the continuing surveillance of ABRAXANE, skin reactions including generalized or maculo-papular rash, erythema, and pruritis have been observed. Additionally, there have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysaesthesiae. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established. Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. OVERDOSAGE: There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. DOSAGE AND ADMINISTRATION: After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. Hepatic Impairment The appropriate dose of ABRAXANE for patients with bilirubin greater than 1.5 mg/dL is not known. Dose Reduction Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For grade 3 sensory neuropathy hold treatment until resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE. Preparation and Administration Precautions ABRAXANE is a cytotoxic anticancer drug and, as with other potentially toxic paclitaxel compounds, caution should be exercised in handling ABRAXANE. The use of gloves is recommended. If ABRAXANE (lyophilized cake or reconstituted suspension) contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure to paclitaxel, events may include tingling, burning and redness. If ABRAXANE contacts mucous membranes, the membranes should be flushed thoroughly with water. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Limiting the infusion of ABRAXANE to 30 minutes, as directed, reduces the likelihood of infusion-related reactions (see PRECAUTIONS: Injection Site Reaction). No premedication to prevent hypersensitivity reactions is required prior to administration of ABRAXANE. Preparation for Intravenous Administration ABRAXANE is supplied as a sterile lyophilized powder for reconstitution before use. AVOID ERRORS, READ ENTIRE PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION. Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel. 1. Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP. 2. Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over minimum of 1 minute, using the sterile syringe to direct the solution flow onto the INSIDE WALL OF THE VIAL. 3. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized cake as this will result in foaming. 4. Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of the lyophilized cake/powder. 5. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any cake/powder occurs. Avoid generation of foam. 6. If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides. Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient: Dosing volume (mL) = Total dose (mg)/5 (mg/mL). The reconstituted suspension should be milky and homogenous without visible particulates. If particulates or settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. Discard any unused portion. Inject the appropriate amount of reconstituted ABRAXANE into an empty, sterile IV bag (plasticized polyvinyl chloride (PVC) containers, PVC or non PVC type IV bag). The use of specialized DEHP-free solution containers or administration sets is not necessary to prepare or administer ABRAXANE infusions. The use of an in-line filter is not recommended. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Stability Unopened vials of ABRAXANE are stable until the date indicated on the package when stored between 20°C to 25°C (68°F to 77°F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Stability of Reconstituted Suspension in the Vial Reconstituted ABRAXANE should be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) for a maximum of 8 hours if necessary. If not used immediately, each vial of reconstituted suspension should be replaced in the original carton to protect it from bright light. Discard any unused portion. Stability of Reconstituted Suspension in the Infusion Bag The suspension for infusion prepared as recommended in an infusion bag should be used immediately, but may be stored at ambient temperature (approximately 25°C) and lighting conditions for up to 8 hours. HOW SUPPLIED: Product NDC No. No. 103450 68817-134-50 100 mg of paclitaxel in a single use vial, individually packaged in a carton. Storage Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from bright light. Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. U.S. Patent Numbers: 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868; 6,753,006 REFERENCES: 1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Publication No. 83-2621. For sale by the Superintendent of Documents, US Government NIH Printing Office, Washington, DC 20402. 2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA. 1985;253(11):1590-1592. 3. National Study Commission on Cytotoxic Exposure Recommendations for Handling Cytotoxic Agents. Available from Louis R Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences. 179 Longwood Avenue, Boston, Massachusetts 02115. 4. Clinical Oncology Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia. 1983;1:426-428. 5. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians. 1983; (Sept/Oct) 258-263. 6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990;47:1033-1049. 7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE GUIDELINES.) Am J Health-Syst Pharm. 1996;53:1669-1686. 8. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41.

ABRAXANE, Abraxis, and Abraxis Oncology are registered trademarks of Abraxis BioScience, LLC. Abraxis Oncology® is a division of Abraxis BioScience, LLC. ©2009 Abraxis BioScience, LLC. All Rights Reserved. AO 1304 08/07 Printed in USA

with those who received tamoxifen.” Ribi presented the data at the annual meeting of the American Society of Clinical Oncology (ASCO). Women in BIG 1-98 were randomized to tamoxifen for 5 years, letrozole for 5 years, tamoxifen for 2 years followed by letrozole for 3 years, or letrozole for 2 years followed by tamoxifen for 3 years, as adjuvant endocrine treatment. Among 120 women (mean age, 64.5 years) included in the cognitive substudy, components of objective cognitive function (speed of psychomotor function, visual attention, working and verbal memory, learning) were evaluated by computerized tests during the fifth year of trial treatment. Although Ribi’s analysis revealed only one cognitive domain component to favor letrozole significantly (visual attention, P = .05), it showed a significant advantage for letrozole in the composite score, the substudy primary end point (P = .04). Also, although impairment was found with both drugs for all cognitive tasks, the greatest difference appeared for memory, impaired by 6.2% among those receiving letrozole compared with 25.5% for those receiving tamoxifen (P = .003). “These substudy findings do refute our initial hypothesis,” Ribi said, “and show better cognitive function for patients taking letrozole.” She noted limitations of the substudy, including its lack of a true baseline assessment before endocrine therapy, a lack of longitudinal design allowing evaluation of changes during treatment, and low accrual numbers. Further, the population was mixed. This mix, which included women undergoing various types of surgery, various treatment types, components, and sequences, also weakened the strength of conclusions, said ASCO discussant Vered Stearns, MD, of Johns Hopkins University School of Medicine. Stearns affirmed, however, that the findings are consistent with other data sets, such as that from the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) study, which showed worsened verbal memory and executive functioning compared with healthy controls with 1 year of tamoxifen. The TEAM study demonstrated further that there are no significant differences in any cognitive domain for the aromatase inhibitor exemestane when compared with healthy controls. Stearns concluded that further study is needed to verify the cognitive effects and to determine their potential magnitude, which domains are affected, and predictive factors. ■ —Walter Alexander Conference news continued on page 24

September/October 2009

PRACTICE MANAGEMENT

Practice Management Multidisciplinary Cancer Care: A New Model for Community Cancer Centers. Part 2 The National Community Cancer Centers Program A roundtable discussion with Mark J. Krasna, MD; Nicholas Petrelli, MD; and Andrew Salner, MD

he National Cancer Institute’s (NCI) National Community Cancer Centers Program (NCCCP) is a 3-year pilot program to test the concept of a national network of community cancer centers to expand cancer research and deliver the latest, most advanced cancer care to a greater number of Americans in the communities in which they live. In this roundtable discussion, Mark J. Krasna, MD, medical director of the St. Joseph Cancer Institute in Towson, Maryland, Nicholas Petrelli, MD, medical director of the Helen F. Graham Cancer Center at Christiana Care in Wilmington, Delaware, and Andrew Salner, MD, director of the Helen and Harry Gray Cancer Center at Hartford Hospital in Connecticut, all pilot program principal investigators, discuss the NCCCP and its goals as they relate to practicing multidisciplinary cancer care. Part 1 of this discussion appeared in the July/August issue.

Program goals Nicholas Petrelli (NP): About 85% of cancer patients in our country are diagnosed in hospitals in their communities. It is only the other 15% that are diagnosed or treated Nicholas Petrelli, MD at NCI-designated cancer centers, which now number 65. Many patients are not treated at major cancer centers because of personal or economic reasons and certainly because of distance from home. The NCCCP was developed by NCI Director Dr John E. Niederhuber, because the overwhelming majority of patients get treated in community cancer centers. The pilot program is taking a look at several pillars (Table) in an attempt to improve the quality of care in community cancer centers. Mark J. Krasna (MK): Among those centers that were chosen to participate in the pilot program, multidisciplinary care was intuitively viewed as the best cancer care. The NCI has enMark J. Krasna, MD dorsed the concept that clinical trials and multidisciplinary care are the best ways to receive cancer care. Therefore, participating centers were not charged with proving that September/October 2009

multidisciplinary care works; rather, they were charged with determining the impact that multidisciplinary care can have on the overall cancer experience. Andrew Salner (AS): The NCCCP involves 16 hospitals—eight hospitals and two hospital systems. All 16 hospitals are both different and the same. They are geographically different—urban, rural and, Andrew Salner, MD suburban. They serve different populations—Native Americans, African Americans, Hispanic Americans. Some are faith-based, and some are not. Some have smaller cancer centers, and some have larger cancer centers. Each center represents the geographic and cultural diversity of its location. Yet they are the same in many ways. They have demonstrated excellence in quality of care, with much of that care being multidisciplinary. They have demonstrated a commitment to clinical research and to outreach to help reduce cancer disparities. The pilot program can therefore study how improvements in metrics in each of the pilot areas can occur across a diversity of environments. MK: These hospitals represent a microcosm of American cancer care. This is important to remember as we talk about the pillars, because they are being measured in hospitals with different demographics, in different geographic locations, and in areas that may or may not have challenges regarding access to care. This is an important difference between the NCCCP program and some of the other NCI-launched programs; the NCCCP hospitals truly represent a “snapshot” of typical cancer care in America.

Program pillars AS: The NCCCP program is built around six pillars (Table). One is outreach, which is a commitment to attempting to reduce cancer disparities by reaching the public with education about cancer prevention, early detection, and screening services. Outreach also represents trying to provide every patient with the whole spectrum of cancer services and ensuring that each receives the same standard of care. A second pillar is quality of care. The NCCCP has worked on multiple facets of programming to look at quality of care, including multidisciplinary care. Quality of care also encompasses using

Table. Six Pillars of the National Cancer Institute National Community Cancer Centers Program • Draw more patients into clinical trials in community-based settings • Reduce cancer healthcare disparities • Explore standards for collecting and storing cancer research specimens • Link to national computer networks for conducting research and sharing results • Quality of care, multidisciplinary care • Survivorship care, patient advocacy our own data to make sure our care is as good as it can be. We are working on a pilot project with the American College of Surgeons on rapid abstracting of cases so that we can use that data as a quality-improvement effort. We are also working with the American Society of Clinical Oncology on its Quality Oncology Practice Initiative program. Clinical research is a third pillar. Clinical research is essential. On average, only 2% of cancer patients in the United States participate in clinical trials. Not nearly enough to meet the needs of the scientific community that is studying cutting-edge treatments and translational approaches. Every important advance in cancer therapy has resulted from the courage of patients and efforts of clinicians who have participated in clinical trials. The NCI-designated cancer centers cannot accomplish any of these goals alone; they need the help of the community centers to reach the next order of magnitude. To me, one of the reasons for the NCCCP is to demonstrate examples of how this partnership could leverage our work nationally. MK: Clinical trials are important for more reasons than just furthering our knowledge and science. The NCI has stated that better cancer care results from being in a clinical trial because of the access to unique devices or treatments and because of the more careful and thorough follow-up involved when you have a dedicated research nurse or assistant who is following each patient prospectively. In addition, the results are not “guesstimated.” They are collected prospectively in a very careful, monitored fashion. That’s another advantage. One of the challenges in disparate communities, again whether because of access, distance from care, or racial or ethnic disparity, is that patients cannot get into clinical trials because they either cannot afford to or because they do not speak the English language. This

challenge is being met by the NCCCP. We are developing language-sensitive, race/ethnicity-sensitive, and gendersensitive tools to allow patients in these situations access to clinical trials, which will also improve accrual to clinical trials. NP: Another pillar deals with translational research, that is, bringing problems from the bedside into the laboratory, trying to solve those problems and, when you think you have a solution, translating that solution back from the laboratory to the bedside. To do translational research, one has to collect, store, and share blood and tissue samples. The NCCCP has allowed for several institutions to adopt “NCI best practices” to collect biospecimen resources. Two of the NCCCP programs are now part of The Cancer Genome Atlas, a first for community cancer centers. Another pillar is developing a national database for electronic medical records. NCCCP institutions have access to the NCI’s cancer Biomedical Informatics Grid (caBIG), an information network enabling all constituencies in the cancer community—researchers, physicians, and patients—to share data and knowledge. In addition, as you know, the Obama administration is making an effort to get electronic medical records more widely used, and the NCCCP is involved in this along with the caBIG. Then there is survivorship, which includes patient advocacy. Survivorship represents a wide variety of programs and strategies to enhance patient and family support and quality of life over the entire continuum. This ties in with what Dr Salner was talking about earlier, tracking our quality of care. Many NCCCP institutions have a patient advocacy committee, which helps the institution identify how it can improve the efficiency of its systems. What better people to talk with and learn from Continued on page 29

G REEN H ILL H EALTHCARE C OMMUNICATIONS

THE PATIENT’S VOICE

The Patient’s Voice Patient’s Persistence Leads to Diagnosis of Inflammatory Breast Cancer

ommah Seray was 28 years old when she felt a consistent pain in her right breast. She consulted her primary care physician, who told her that she had a benign cyst that would go away over time and did not recommend treatment. The pain continued to increase, however, and over the next 7 months, she experienced a variety of symptoms. “I felt the following symptoms: lots of pain in the breast area, inverted nipple and discharge, a mass behind my nipple, heated breast, redness, dimpling of skin, pain under my right arm, and an enlarged/swollen breast.” Because of these worsening symptoms, Seray questioned the doctor’s diagnosis and made frequent visits, only to be reassured that the cyst was benign and surgery was not necessary. She persisted, however, and requested to have the cyst removed as a precautionary measure. The surgeon agreed to perform the operation, and, on doing so found three tumors and cancerous tissue in the lymph nodes under Seray’s right arm. The results took her doctors by surprise. “The surgeon was so shocked that he had a difficult time telling me because he had reassured me that I had a cyst. I have been told that he has changed the way he treats his female patients because of what happened to me. He acknowledges that he only operated on me because I insisted, not because of medical concern.” Looking back on her experience,

Seray says that healthcare providers should take their patients’ concerns seriously and not make assumptions. “If initially they are receptive to you, if they do make a mistake, you are more apt to understand and forgive. But if they are adamant, it builds up a barrier.” After the diagnosis of breast cancer was confirmed, Seray decided to seek treatment at City of Hope (COH) because she was aware of the level of expertise it offered. The doctors there told her that she had inflammatory breast cancer (IBC), a rare and aggressive type of breast cancer that is frequently misdiagnosed. She received chemotherapy and underwent a mastectomy of her right breast, during which lymph nodes in her right underarm were removed. She then had radiation therapy to prevent recurrence. Nonetheless, later that year, Seray developed lumps in her left breast and had another mastectomy. She made a good recovery and, although she was advised that she may not be able to have children, she gave birth to a son early this year. Although Seray had no previous medical background, after her diagnosis, she set out to learn what she could about IBC so that she could participate in decisions about her treatment. She says, “my nurse at COH was wonderful and equipped me with what I needed to know walking out the door.” She also cautioned her to be selective about the information available on the Internet

and to rely on reputable sources like the National Cancer Institute. “My doctors at COH included me in the decision-making process. They considered me as a person and my concerns were heard and addressed. I was greeted by name with hugs and words of encouragement regularly. I truly believe they cared about me. I wasn’t just a number.” Seray’s doctors and nurses encouraged her to bring another person to her appointments. “I was included in the decision-making process from day 1, and my fiancé and mother were included as well. It was a team effort. I automatically involved my family because I knew that they were affected by my disease too.” Having someone there to filter and interpret information, she found, can help bridge communication gaps between patients and their healthcare providers. “It is something that doctors should proactively implement. It is an important element for the patient,” she says. Because of her own experiences, Seray decided to start a foundation to promote awareness of IBC and the importance of early detection. “There are a number of reasons I started the Kommah Seray Inflammatory Breast Cancer Foundation (KSIBCF). One of them is, after looking at the survival rate for IBC, I was not sure how long I had to live, so I wanted to leave something for my family to remember me by. I wanted them to help others who were

victims of IBC in hopes that they would live beyond treatment. Fortunately, I am blessed with my second chance at life, and I am able to work at the foundation and help others battling cancer and educate people about IBC.” KSIBCF has created an educational program called Amey’s Plight: Breast Cancer 101, which is county-based and funded through grants. The program is named after a former client, Cynthia Amey, who lost her life to IBC as a result of misdiagnosis. It is being implemented in the Inland Empire (a region of southeastern California) with funding from the Inland Empire Affiliate of Susan G. Komen for the Cure. “Our goal is to make people aware of the symptoms of IBC and promote early detection of regular breast cancer. Our target audience is women aged 12 years and older. Because IBC has been known to victimize girls as young as 12, I feel it is my job to make them aware of the symptoms as well,” Seray explains. “We also speak to breast cancer survivors about the importance of checking their breasts regularly and managing lymphedema. Lastly, we speak to the medical community so that those on the front line are aware of the symptoms of IBC to reduce misdiagnosis, which could be a matter of life or death for a patient. We also encourage doctors to listen to their patients and to rule things out before dismissing their concerns.” ■

ConferenCe newS In Endocrine Treatment of Breast Cancer, Sequential Letrozole-Tamoxifen Found Cost-effective ORLANDO—An independent analysis of a large breast cancer adjuvant trial that compared tamoxifen with an aromatase inhibitor found no financial benefit for giving the older, less expensive agent. Based on data from the phase 3 Breast International Group (BIG) 1-98 trial, investigators found that initiating endocrine therapy with letrozole upfront was cost-effective, compared with giving tamoxifen alone for the full treatment period, according to Chris Skedgel, MD, of Dalhousie University School of Medicine, Halifax, Nova Scotia. The BIG 1-98 trial (N = 8010) found survival rates to be higher in women treated for 5 years with letrozole than for those initiated on tamoxifen, in a comparison of the monotherapy arms. The study did not, however, establish clinical superiority for either of the sequential strategies—letrozole for 2 to 3 years then switching to tamoxifen (LET-TAM) or tamoxifen then switching to letrozole (TAM-LET)—or letrozole monotherapy 24

over a sequential treatment. Disease-free survival was approximately 87% regardless of the approach. Canadian investigators evaluated whether one of the strategies might be preferred on the basis of relative costeffectiveness versus the conventional standard tamoxifen. Their economic analysis used cost per quality-adjusted lifeyears (QALYs) gained, calculated over a 25-year horizon for hypothetical cohorts of postmenopausal women undergoing adjuvant endocrine treatment. They used direct within-arm comparisons and indirect between-arm comparisons of drug costs (based on 2008 Canadian average wholesale prices) and cumulative costs, all discounted at 3%. Cumulative costs included the cost of drug ($11/month for tamoxifen and $179/month for letrozole), follow-up examinations, and treatment of local and distant recurrences. Adverse events have not yet been reported for the BIG 1-98 trial; therefore, costs related to treating

G REEN H ILL H EALTHCARE C OMMUNICATIONS

toxicities were not part of the analysis.

Upfront letrozole most cost-effective strategy Among all the treatment strategies, sequential treatment with LET-TAM was the most cost-effective approach, Skedgel and colleagues found. This, sequential approach was considerably more cost-effective than 5 years of letrozole (same QALYs gained) and also superior to tamoxifen, which was associated with poorer outcomes. “The economic superiority of LETTAM appears to be driven by the relative cost savings derived from the shorter duration of relatively expensive letrozole with the sequential LET-TAM strategy, compared with upfront letrozole,” he said. “I think letrozole upfront simply delivers enough value for the money that it overcomes the higher drug cost.” In the indirect comparison, treatment with LET-TAM versus tamoxifen added 0.4 QALYs while TAM-LET diminished

QALYs by 0.3. The incremental costeffectiveness for LET-TAM was $5063, relative to tamoxifen monotherapy. “This suggests that LET-TAM may be an economically preferred strategy, even though the BIG 1-98 trial did not demonstrate a statistically significant difference in clinical benefit between the upfront and sequential strategies,” he said. “In this sense, an economics evaluation is a useful aid in clinical decision-making.” “Although these results suggest that LET-TAM may be the economically preferred strategy,” he cautioned, “it is important to note that the results do not consider the impact of adverse events on economics or health.” “You have two equally effective treatments, but one is half the cost of the other,” Skedgel said. “But the caveat is that, while this is an independent analysis, it is still an incomplete analysis.” ■ —Caroline Helwick September/October 2009

GEMZAR/carboplatin is one option for 2nd-line treatment of your patients with platinum-sensitive* advanced ovarian cancer. Myelosuppression is usually the dose-limiting toxicity with GEMZAR therapy.

G MZ GE ZAR AR iin n cco om mb bin nat atio ion wi with t car th arbo bo b opl p attin n is in ndi d ca c te ed fo for or th t e tr t eaatm t en e t of o pattie ient nsw nt wiith th adv d an a ced ce ed o ovvar aria ian n caanc n er e tha h t has haas rre elaapsed psed ps d aatt le easst 6 mo m ntth hss aft fter er er comp co m le mp eti t on o of p pllat atin inum in u -b um -bas baasse ed d the eraapyy. My M ye ellossu up p ppr p essssiion pr on is us usua ua allly th he do ose se-l -lim -l im mittin ng to oxi x ciitty y wit ith h GEMZ GEMZ GE M AR A th he era rapy py py. y.

Overall response rate (%)†

Median progression-free survival (months) GEMZAR plus Carboplatin

95% Cl (8.0-9.7) (N=178)

Carboplatin 95% Cl (5.2-7.1) (N=178)

(p=0.0038)

GEMZAR plus Carboplatin (N=178)

8.6

Carboplatin (N=178)

5.8 6

(p=0.0016)

10%

47.2%

30.9% 20%

30%

40%

50%

* Pl Plat a in at num m-s -sen en nsiti siitive tivee ti †

pat a ie ient nts ar nt aree de defi fine ine ned d as pat a ie i ntts wh w o deve deveelo de lop di lop dise sease se asse pr prog oggre ress s ioon ≥6 m ss moont n hs h aft f er er rec ecei eivi ei viingg firrst st-l -lin -l inee p in pllat a in inum um-b um -bas asseed d che h mo m th ther erap er ap apy. py. Inve In veest stig iggat ator or-rrev or evie vie iewe wd we d..

The Th eo ovverralll su surv r iv rv ival a dif al iffe f rre fe enc n e be b tw wee een G GE EM EMZ MZ ZAR A /c /car a bo ar opl p attin ((18 18 8.0 mon nths) th hs) vs ca carb bop oplaattiin (1 opla ( 7. 7 3 mo mont nths nt nths hs)) wa was no ot si s gn g if i iccan nt (p=0 0.8 897 977) 7. 7) Se S ele ecctt IImp mp m por ortta an ntt Saffet ety y In nfo orm matio attio on GEMZ GE M AR MZ R ssho houl ho u d no ul not be b adm dmin inis in isste tere re red ed tto o pat a iie en ntts wi with th h kno nown wn nh hyp yper yp per e se s ns n itiv ittiv ivit itty tto o thi hs drrug. ug g. Infu In nfu usiion n times im mes es of GE GEMZ MZ ZAR A lon onge ge er th than an n 60 mi m nu nute t s an te nd mo more e fre requ qu q ue en n ntt th han week we e lyy dos ek osin ing in g ha ave e bee een n sh s ow wn to o in nccre reas asse to oxi xici c tyy. P ci Pu ulm lmon on nar aryy to oxxiiciityy has a be ee en en re epo port rted rt e . In casses ed e of se eve ere e lun u g to t xi xici c ty ci ty,, GE EMZ M AR AR the h ra apyy ssho houl ho uld ul d be b dis i co cont cont n in nu ue ed im mme medi d attel eya an nd ap ppr p op opri riiatte ssu upp por orti t ve ti e ccar arre m me eas asur u ess iins ur nssti n t tu ute ed. d Hem e ol o yytticc U em Ur micc Syndr yn ndrrom ome e (H HUS US)) an a d d//or o re en nal ffai aiilu l rre e havve be een n rrep epo epor ep orrte ted d ffo olllow o in ng on one e or mo ore ed dos o es os es of GEMZ GEMZ GE MZAR AR A R. Re R na n l fa f ililur ure ur e le ead din i g to o dea dea eath th h or re equ quir uir i in ng di d al a ys y is is,, de desp spit ie it d sccon di nti t nu nuat a iio at on of o tthe he h era apyy, ha h s be been e rarrel en e y re epo p rt rted e . Th ed he ma m jo jori r ty of th ri the e ca ase es of o r nal re na al fa f illur u e le lead ad ding in ng to o dea eath t wer ere e du due e to t HUS US.. Se eri r ou o s he h pa atto oto oxi x ci city ityy, in incllud udin din ing g lilive v r fa ve faililiurre a an nd de eat ah h,, has bee e n re r po p rt rted d vver eryy ra er are elyy in p pa ati te en nts ts rrec e eiivi ec ving ng g GEM MZA AR allon one or o in co c mb mbin in na attio on wi with tth h oth ther ther e potten nti t al a lyy h hep e at ep atot otoxxicc drru ug gss. GE EMZ M AR R is Prreg P e n na anc ncyy C Ca ate t go g ryy D. GE G MZ ZAR A can n cau usse e fet e al a ha arrm rm wh when n admin dmin dm nisste ere red d to to a pr p eg gna nant nt wom oman a . Use an Usse ca c ut u io ion n in pat pat atie ie ient entts wi with h pre re-e - xist -e xiissttin ing g re en na al impa im mpa air irme m n me ntt or hep e atticc iins n uffffiici ns c en ncyy. Ad A mi mini nisttra ni attiion n of GE EMZ MZAR AR A R may a exa acerb ce erb bat ate e un u d de erl r yi ying ng g he epa pati ticc in nsu uff f ic icie ienc ie n y. y T The h opt he p im i um u reg egim men n for saf afe e ad dmi m ni nist s ra st ati to on n of of GE EMZ MZAR A AR wiith the w the era r pe p ut utic iicc doses osess of ra os radi diat attio on ha as no nott ye et be been e det en ee errmine miin ne ed in n all tum u or ttyp yp pes e . G MZ GE ZAR R hass rrad adio ad io ose ens nsit itiz it izzin ng a accti t vi v ty ty a and nd d ra ad dia iati tion ti on n re eccal all re reac acti ac t on ti ns ha ave v bee een n repo re po p ort rted ed d. It iiss not no ot kn know ow o wn wh whet e he et h r GE GEMZ MZA AR R or itts meta me eta abo b liite es ar are e exxcrret e ed e in GEMZ G E AR AR® iss a rregistered gist s ere st ered e d tra t dema m rk ma k of E Eli Li L lly ly y and an n C Comp ompany om any. ny y GC58321 GC58 GC5 3 321 0509 PRIN 0509 NTED IN USA S © 200 09, Lilly USA USA, L LLC C. ALL RIGHT HT TS RE R SE SERV ER ED. ERV ED

human hu ma an mi m lk lk.. Th T e ef effe fect fe cttiivven e esss off G GEM EMZA EM ZA AR in in ped dia atrric ic pat a ie ent ntss h ha as n no ot be been e en de d emo on nsstrat trrat a ed ed.. Th T e to toxi xici xi citi ci t es ti e of GE G MZ MZAR A obsser erve v d in ve n ped e ia iatr ttrric pattie entts we were re e sim millar a to tho osse e rep epor orte or t d in te i adu d ltts. GEM MZA ZAR cl c eara ea ara ranc ncce is i aff ffec e te ec ed by b age g as we elll as gend ge end nder err. Pa ati t en nts reccei e viing g tthe he era r py py wit ith GE GEM MZ ZAR AR sho houl oul uld d be be mo on nit i or o ed clo lose osse elyy b byy a ph hys ysic icia ia an exp ex pe erriien ence ce ed in the eu use sse e of ca c nc ncer e cche er he emo moth her erap ap peu e ttiic ag agen ents en nts ts.. Ab bb brrev e ia ate ed Ad Adve Adve vers rsse Ev ven e ts t (% in ncciide enc nce e)) The most Th mo ostt sev e er e e ad adve vve ers rse e evve en nts t (Gr G ad des 3//4 4) wi w th h GEM MZA AR pl p us u car a bo op pllat atin in n ver ersu suss su cca arbop rb bopla opla op atin tin a ti allon one, e rres e, esspe ecttiv ivel e y, ffor el or the he tre eattm me ent n of pa pati tiien e ts wit ith ha ad dvva anc n ed d ovari va ari r an a c nc ca ncer er werre ne er euttro op pe eniia (7 71 vs v 12) 2));; th hro romb mb m boc o yt ytop open op e ia ia (35 3 vs 11 1); leu uko ope p ni n a (5 53 vss 7); a em an e ia a ((28 28 vs 11 28 1);; nau use ea (6 vs 3 3)); vo vomi m ti mi t ng g ((6 6 vs v 3 3); );; and nd const onst on stip ip ipat pat a io i n (7 7 vs 3) 3).. Th The e mo most stt comm co mm m mon na adv d er dv erse se e eve v nt ntss (a (alll Gra ade es) we erre ne neut u ro ut ope peni n a (9 90 vs v 5 58) 8);; leuk 8) leuk le u op open pen enia ia ((86 8 vs 7 86 70 0); ) an nem mia a (86 6 vs 75 7 ); thr h om mbo ocy cyto yto tope peniia (7 peni pe 78 vs v 57)); R RB BC trran nsf sfus u io us on (3 38 vs vs 15) 5 ; al a op o eccia a (4 49 vs vs 1 17) 7)); ne neur urrop opat atth a hyy/s /sen e sory en soryy (2 so 29 9 vs 27 7));; nau ause se ea (6 (69 9 vs 61) 1);; fa fati t gue ti gu ue (4 40 vs v 32)); vo omi m ting tiing (4 46 vs v 36)); di d ar a rhea rh hea a ((25 25 5 vs 14 4); ); and n con onst s ip st i a attio on (4 42 vss 37) 7).. Fo F or ad a di diti tion ti on nal a saf a etty in info ffo ormat rmat rm atio ion, n, pleas le ea asse se see e Br B iie ef Su S mm mmar a y of ar of Pre esc s ri r biing g IIn nfo form rm ma attion io on on o adj d ac a e en nt p pa age ge.. Fo or mo ore r iinf nffor n orma m ti ma to on n abo b utt can ance cerr tr ce trea ea e atm me en nt wi witth h GEM E ZA AR, vis isit itt GE G MZ ZAR AR.c .cco om m.

CANCER CENTER PROFILE

High-quality Patient Outcomes Continued from cover provide access to the array of reconstructive options available in the university setting. In this interview, the team members discuss how they achieved this level of success.

For your patients, what are the advantages of getting treated at a community oncology center over a research institution? John Barstis (JB): The Los Angeles region is extremely congested, and it is very difficult for patients to go to a tertiary care center. It could be a 3-hour

trip because of the traffic. So if quality care can be provided in a community setting, it is extremely valuable. Our goal was to develop a comprehensive program in the community setting for breast cancer, and it has proved to be very successful.

Can you describe how the program works? For example, do you hold weekly tumor boards or communicate on an ongoing dayto-day basis?

GEMZAR姞 (GEMCITABINE HCl) FOR INJECTION BRIEF SUMMARY (OVARIAN). For complete safety please consult the package insert for complete prescribing information. INDICATION AND USAGE: THERAPEUTIC INDICATION—Ovarian Cancer—Gemzar in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. CLINICAL STUDIES: Ovarian Cancer—Gemzar was studied in a randomized Phase 3 study of 356 patients with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either Gemzar 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after Gemzar on Day 1 of each cycle or single-agent carboplatin AUC 5 administered on Day 1 of each 21-day cycle as the control arm. The primary endpoint of this study was progression free survival (PFS). The addition of Gemzar to carboplatin resulted in statistically significant improvement in PFS and overall response rate. Approximately 75% of patients in each arm received poststudy chemotherapy. Only 13 of 120 patients with documented poststudy chemotherapy regimen in the carboplatin arm received Gemzar after progression. There was not a significant difference in overall survival between arms. CONTRAINDICATION: Gemzar is contraindicated in those patients with a known hypersensitivity to the drug (see Allergic under ADVERSE REACTIONS). WARNINGS: Caution—Prolongation of the infusion time beyond 60 minutes and more frequent than weekly dosing have been shown to increase toxicity (see CLINICAL STUDIES in the full Prescribing Information). Hematology—Gemzar can suppress bone marrow function as manifested by leukopenia, thrombocytopenia, and anemia (see ADVERSE REACTIONS), and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy. See DOSAGE AND ADMINISTRATION in the full Prescribing Information for recommended dose adjustments. Pulmonary—Pulmonary toxicity has been reported with the use of Gemzar. In cases of severe lung toxicity, Gemzar therapy should be discontinued immediately and appropriate supportive care measures instituted (see Pulmonary under Single-Agent Use and under Post-marketing experience in ADVERSE REACTIONS in the full Prescribing Information). Renal—Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemzar. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS (see Renal under Single-Agent Use and under Post-marketing experience in ADVERSE REACTIONS in the full Prescribing Information). Hepatic—Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs (see Hepatic under Single-Agent Use and under Post-marketing experience in ADVERSE REACTIONS in the full Prescribing Information). Pregnancy—Pregnancy Category D. Gemzar can cause fetal harm when administered to a pregnant woman. Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 1/200 the recommended human dose on a mg/m2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 1/600 the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. There are no studies of Gemzar in pregnant women. If Gemzar is used during pregnancy, or if the patient becomes pregnant while taking Gemzar, the patient should be apprised of the potential hazard to the fetus. PRECAUTIONS: General—Patients receiving therapy with Gemzar should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse events are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced. There was a greater tendency in women, especially older women, not to proceed to the next cycle. Laboratory Tests—Patients receiving Gemzar should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. Suspension or modification of therapy should be considered when marrow suppression is detected (see DOSAGE AND ADMINISTRATION in the full Prescribing Information). Laboratory evaluation of renal and hepatic function should be performed prior to initiation of therapy and periodically thereafter (see WARNINGS). Carcinogenesis, Mutagenesis, Impairment of Fertility—Long-term animal studies to evaluate the carcinogenic potential of Gemzar have not been conducted. Gemcitabine induced forward mutations in vitro in a mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabine was negative when tested using the Ames, in vivo sister chromatid exchange, and in vitro chromosomal aberration assays, and did not cause unscheduled DNA synthesis in vitro. Gemcitabine IP doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m2 basis) in male mice had an effect on fertility with moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day IV (about 1/200 the human dose on a mg/m2 basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day IV (about 1/1300 the human dose on a mg/m2 basis). Pregnancy—Category D. See WARNINGS. Nursing Mothers—It is not known whether Gemzar or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from Gemzar in nursing infants, the mother should be warned and a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother and the potential risk to the infant. Elderly Patients—Gemzar clearance is affected by age (see CLINICAL PHARMACOLOGY in the full Prescribing Information). There is no evidence, however, that unusual dose adjustments (i.e., other than those already recommended in DOSAGE AND ADMINISTRATION section in the full Prescribing Information) are necessary in patients over 65, and in general, adverse reaction rates in the single-agent safety database of 979 patients were similar in patients above and below 65. Grade 3/4 thrombocytopenia was more common in the elderly. Gender—Gemzar clearance is affected by gender (see CLINICAL PHARMACOLOGY in the full Prescribing Information). In the single-agent safety database (N=979 patients), however, there is no evidence that unusual dose adjustments (i.e., other than those already recommended in DOSAGE AND ADMINISTRATION section in the full Prescribing Information) are necessary in women. In general, in single-agent studies of Gemzar, adverse reaction rates were similar in men and women, but women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia. Pediatric Patients—The effectiveness of Gemzar in pediatric patients has not been demonstrated. Gemzar was evaluated in a Phase 1 trial in pediatric patients with refractory leukemia and determined that the maximum tolerated dose was 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. Gemzar was also evaluated in a Phase 2 trial in patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) using 10 mg/m2/min for 360 minutes three times weekly followed by a one week rest period. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation, which were similar to those reported in adults. No meaningful clinical activity was observed in this Phase 2 trial. Patients with Renal or Hepatic Impairment—Gemzar should be used with caution in patients with preexisting renal impairment or hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of Gemzar in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency. GEMZAR姞 (GEMCITABINE HCl) FOR INJECTION

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JB: We have a regular set of programs. We meet for a working tumor conference, in which we discuss our cases—as many as we can every 2 weeks. Represented are all the specialties—surgical oncology, medical oncology, pathology, diagnostic radiology, radiation oncology, and reconstructive surgery, as well as our nurse facilitator and a representative of the administration. We keep minutes. We keep track of our cases. We have a working process. We are a cancer center without walls—

Drug Interactions—No specific drug interaction studies have been conducted. For information on the pharmacokinetics of Gemzar and cisplatin in combination, see Drug Interactions under CLINICAL PHARMACOLOGY. Radiation Therapy—A pattern of tissue injury typically associated with radiation toxicity has been reported in association with concurrent and non-concurrent use of Gemzar. Non-concurrent (given >7 days apart)—Analysis of the data does not indicate enhanced toxicity when Gemzar is administered more than 7 days before or after radiation, other than radiation recall. Data suggest that Gemzar can be started after the acute effects of radiation have resolved or at least one week after radiation. Concurrent (given together or ≤7 days apart)—Preclinical and clinical studies have shown that Gemzar has radiosensitizing activity. Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of Gemzar, frequency of Gemzar administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. In a single trial, where Gemzar at a dose of 1000 mg/m2 was administered concurrently for up to 6 consecutive weeks with therapeutic thoracic radiation to patients with non-small cell lung cancer, significant toxicity in the form of severe, and potentially life-threatening mucositis, especially esophagitis and pneumonitis was observed, particularly in patients receiving large volumes of radiotherapy [median treatment volumes 4795 cm3]. Subsequent studies have been reported and suggest that Gemzar administered at lower doses with concurrent radiotherapy has predictable and less severe toxicity. However, the optimum regimen for safe administration of Gemzar with therapeutic doses of radiation has not yet been determined in all tumor types. ADVERSE REACTIONS: Combination Use in Ovarian Cancer—In the Gemzar plus carboplatin versus carboplatin study, dose reductions occurred with 10.4% of Gemzar injections and 1.8% of carboplatin injections on the combination arm, versus 3.8% on the carboplatin alone arm. On the combination arm, 13.7% of Gemzar doses were omitted and 0.2% of carboplatin doses were omitted, compared to 0% of carboplatin doses on the carboplatin alone arm. There were no differences in discontinuations due to adverse events between arms (10.9% versus 9.8%, respectively). Table 1 presents the adverse events (all grades) occurring in ≥10% of patients in the ovarian cancer study. Table 1: Adverse Events From Comparative Trial of Gemzar Plus Carboplatin Versus Single-Agent Carboplatin in Ovarian Cancera CTC Grades (% incidence) Gemzar plus Carboplatin (N=175) Carboplatin (N=174) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratory b Hematologic Neutropenia 90 42 29 58 11 1 Anemia 86 22 6 75 9 2 Leukopenia 86 48 5 70 6 <1 Thrombocytopenia 78 30 5 57 10 1 38 15 RBC Transfusions c c 9 3 Platelet Transfusions Non-laboratory b Nausea 69 6 0 61 3 0 Alopecia 49 0 0 17 0 0 Vomiting 46 6 0 36 2 <1 Constipation 42 6 1 37 3 0 Fatigue 40 3 <1 32 5 0 Neuropathy-sensory 29 1 0 27 2 0 Diarrhea 25 3 0 14 <1 0 Stomatitis/pharyngitis 22 <1 0 13 0 0 Anorexia 16 1 0 13 0 0 a Grade based on Common Toxicity Criteria (CTC) Version 2.0 (all grades ≥10%). b Regardless of causality. c Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood. In addition to blood product transfusions as listed in Table 1, myelosuppression was also managed with hematopoetic agents. These agents were administered more frequently with combination therapy than with monotherapy (granulocyte growth factors: 23.6% and 10.1%, respectively; erythropoetic agents: 7.3% and 3.9%, respectively). The following are the clinically relevant adverse events, regardless of causality, that occurred in >1% and <10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse events (Gemzar plus carboplatin versus carboplatin): AST or ALT elevation (0 versus 1.2%), dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1%), hypersensitivity reaction (2.3% versus 2.9%), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0). No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65. Post-marketing experience—The following adverse events have been identified during post-approval use of Gemzar. These events have occurred after Gemzar single-agent use and Gemzar in combination with other cytotoxic agents. Decisions to include these events are based on the seriousness of the event, frequency of reporting, or potential causal connection to Gemzar. Cardiovascular—Congestive heart failure and myocardial infarction have been reported very rarely with the use of Gemzar. Arrhythmias, predominantly supraventricular in nature, have been reported very rarely. Vascular Disorders—Clinical signs of peripheral vasculitis and gangrene have been reported very rarely. Skin—Cellulitis and non-serious injection site reactions in the absence of extravasation have been rarely reported. Severe skin reactions, including desquamation and bullous skin eruptions, have been reported very rarely. Hepatic—Increased liver function tests including elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, and bilirubin levels have been reported rarely. Serious hepatotoxicity including liver failure and death has been reported very rarely in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs. Pulmonary—Parenchymal toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported rarely following one or more doses of Gemzar administered to patients with various malignancies. Some patients experienced the onset of pulmonary symptoms up to 2 weeks after the last Gemzar dose. Respiratory failure and death occurred very rarely in some patients despite discontinuation of therapy. Renal—Hemolytic-Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemzar. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS. Injury, Poisoning, and Procedural Complications — Radiation recall reactions have been reported (see Radiation Therapy under PRECAUTIONS). Dosage and administration: Gemzar is for intravenous use only. Please consult full prescribing information for complete dosage and administration guidelines.

Literature revised May 7, 2007 PV 4067 AMP

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a group of doctors who work together. Barbara Florentine (BF): From our patients’ perspective, we are one big doctor, because we communicate as needed. For example, every time I get a breast biopsy from radiology, I look up the result on my computer. If it doesn’t correlate, I call the radiologist and then we decide on the next step together. Greg Senofsky (GS): Every time I do a breast cancer surgery, I have Dr Florentine or her partner in the operating room with me, and we look at the edges together while the patient is still under anesthesia. We get real-time information about the margins rather than letting the circulating nurse put the specimen in formalin fixative, letting it sit overnight, and not getting Team Members John Barstis, MD, Medical Director, Oncology and Hematology, Henry Mayo Newhall Memorial Hospital; UCLA/ Santa Clarita Valley Cancer Center, Valencia; Clinical Faculty, Department of Hematology and Oncology, The David Geffen School of Medicine, University of California, Los Angeles Barbara D. Florentine, MD, Medical Director, Pathology and Laboratory Services, Henry Mayo Newhall Memorial Hospital, Valencia; Clinical Associate Professor of Pathology, Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles Theodore Hittle, MD, Department of Radiology, Henry Mayo Newhall Memorial Hospital, Tower Imaging Medical Group, Valencia; St. John’s Hospital, Santa Monica, California Daniel Kirsch, MD, Mammography and Radiology, Henry Mayo Newhall Memorial Hospital; Medical Director, Breast Imaging and Intervention, Tower Imaging Medical Group, Valencia; Associate Professor of Radiology, UCLA Department of Radiology, The David Geffen School of Medicine, University of California, Los Angeles; St. John’s Hospital, Santa Monica, California Greg Senofsky, MD, Surgical Oncology, Henry Mayo Newhall Memorial Hospital; Founder and Surgical Director, The Breast Institute, Valencia; Clinical Faculty, UCLA Department of Surgery, The David Geffen School of Medicine, University of California, Los Angeles James P. Watson, MD, Plastic and Reconstructive Surgery, Henry Mayo Newhall Memorial Hospital, Valencia; St. John’s Hospital, Santa Monica; Providence Tarzana, Tarzana; Glendale Adventist, Glendale; Huntington Memorial, Pasadena; Ronald Regan UCLA Medical Center, Los Angeles, California Robert P. Zimmerman, MD, Radiation Oncology, Henry Mayo Newhall Memorial Hospital; Medical Director, Vantage Oncology, Santa Clarita Radiation Therapy Center, Valencia, California September/October 2009

Do you feel that your collaborative approach is the reason for your success? JB: It is a major one. Another factor is that because we created a cohesive team, we have been able to attract donors. For a community hospital, we’ve been fortunate enough to have recently built an endowed mammography suite/diagnostic radiology suite. We have state-of-the-art digital mammography technology and trained mammographers to use it. Furthermore, our approach provides options. If, after the initial diagnostics, a patient needs a mastectomy, our standard is, if at all possible, a skin-sparing mastectomy. And if we feel the procedure requires completion in a tertiary care center, then our patient knows that we will have her get her surgery at the best location. Most of our surgeries can be performed at our community hospital. But, in some situations, we feel it is better that the surgery be performed at another hospital. The idea is whatever can be provided optimally in the community, we do; when we need a tertiary care center like UCLA, we use one. Our surgeons can operate wherever they need to. BF: What you can find in our setting that you probably will not find in a big university setting, is care tailored toward the individual patient and an open-door policy. For example, I’m a pathologist, and in a university setting, I would never expect a patient to call me up and say, “Dr Florentine, can we review these slides together? Dr Senofsky told me that you could explain things to me.” And that happens all the time here. The same thing with the radiologists. Dr Hittle or Dr Kirsch will talk to the patient, see the patient, and discuss the radiology viewpoint with them directly. This makes the patient feel a part of the care. It’s not anonymous. It’s individualized; it’s caring. TH: We also have developed techniques for localizing a small area of the September/October 2009

breast whereby we put small wires in to help Dr Senofsky find the area during surgery. Although putting a wire in to find an area of surgery is pretty standard, rather than just putting one wire in and hoping that he gets the area, we developed a technique whereby we put in multiple wires, at least two to bracket the area. That way we’re not putting the wire right through the tumor; we are showing him the whole area that he needs to take out. GS: This helps me greatly with margins. As our published study showed, we feel that getting good margins—getting a bigger margin of clearance around the

can do almost everything in the community setting for breast cancer. JW: On our smaller scale, patients are not as often lost to follow-up, and pathology reports are more often communicated adequately to the appropriate doctors, for example, HER2 status, changes in status of recurrent disease, or abnormal findings. The university is probably the place to go for a very complicated case, a very sick patient, or somebody wanting to participate in a clinical protocol. However, we do offer clinical protocols that patients can participate in even in the community hospital. Robert Zimmerman: I think there

On our smaller scale, patients are not as often lost to follow-up, and pathology reports are more often getting communicated adequately to the appropriate doctors. cancer upon removal—limits the risk of the cancer returning in the future. That is, as long as the patients who are supposed to get radiation, get the radiation. It also improves the cosmetic results of the surgery when we can get the margins in the first surgery, and it also limits the rate of mastectomy. Even if, ultimately, we have one or two positive margins on the final pathology, we can frequently take those patients back into surgery and resize those specific margins rather than having to convert them to a mastectomy. This is a main reason why we have an extremely low mastectomy rate among our faculty. When we do mastectomies, we have two phenomenal plastic and reconstructive surgeons who are capable of executing every type of free flap imaginable, which is something that can rarely be offered. James Watson (JW): For breast reconstruction, we feel the patient should be given a choice. We don’t say it has to be done, but we give the patient the option of saying “yes” or “no.” We feel that providing the option is what is most important; does the patient want an immediate reconstruction? We will not do immediate reconstruction if any of the oncologists feels it is not safe. But for the majority of patients with stage III cancers, we can offer immediate reconstruction in the community hospital setting, with the same options offered at a university hospital. That includes tissue expanders as well as flaps, and flaps done without muscle. BF: It is important to realize that community hospitals can’t offer all kinds of surgeries. The doctors and the hospital need to know what they can and can’t do, which is what Dr Barstis was saying about some patients getting referred to a tertiary center. But breast cancer is so prevalent in the community, we get so many cases, that this is an area that we can and do excel at. GS: Occasionally, there is a case that I cannot treat at this hospital. If that’s the case, I’ll take the patient to one of the larger hospitals or UCLA to perform the procedure. But there are very few cases in which I have to do this. We

are two reasons why our results are as good as or better than in the national study (National Cancer Database Benchmark Reports: Patterns of Diagnosis and Treatment for Selected Cancers Diagnosed 1997-2001) or any other place locally or nationally. First, all of our patients have negative margins that

are clear by at least 5 mm. Around the country, many places will accept even a 1-mm margin. Second, almost all of our patients who have a lumpectomy also receive radiation therapy, which is very important in minimizing the risk of local recurrence. GS: I’d like to add a third corollary. When I do breast-conserving surgery, I frequently use oncoplastic techniques. If I have to do medium lumpectomies in small breasts or big lumpectomies in medium-sized breasts, I will employ oncoplastic techniques so I do not leave a divit or dip in the breast. I find a way to rearrange the breast tissue so it looks good after the lumpectomy, which makes a huge difference to patients and allows me to get significant margins with no cosmetic downside.

You mentioned you did patient navigation. Do you continue through to survivorship care? GS: We just brought a nurse navigator on board about 5 months ago. She will follow the patients through from the very beginning to the very end of treatment. We are also integrating long-term care into our services. Our goal is to go from a level one to a level three center. We believe that we have the faculties and the staff and the structure to do that. ■ —Dawn Lagrosa

Recent FDA Approvals • Onsolis for Breakthrough Pain Management The US Food and Drug Administration (FDA) has approved a fentanyl buccal soluble film (Onsolis, BioDelivery Sciences International) to help manage breakthrough pain in certain cancer patients. With this product, an absorbable film is adhered to the inside of the mouth and fentanyl is delivered through the mucous membranes. The drug is indicated for patients with cancer, aged 18 and older, who use opioid pain medication around the clock and who need and are able to safely use high doses of an additional opioid medication. This medication was approved with a risk evaluation and mitigation strategy (REMS).

• Avastin for Metastatic Renal Cell Carcinoma The FDA has approved bevacizumab (Avastin, Genentech) for treatment of metastatic renal cell carcinoma in combination with interferon alfa. Approval for this new indication is based on the phase 3 AVOREN study, which found that by adding bevacizumab to interferon alfa progression-free survival was almost doubled from a median of 5.4 to 10.2 months, and tumor response was significantly increased from 12.8% to 31.4%. Bevacizumab, a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor, has been previously approved for use in metastatic colorectal cancer, nonsquamous non–small-cell lung cancer, metastatic breast cancer, and glioblastoma.

• Morphine-Naltrexone Combo The FDA has approved morphine sulfate and naltrexone hydrochloride extendedrelease capsules (Embeda, King) for oral use. The long-acting Schedule II opioid analgesic is indicated for management of moderate-to-severe pain when a continuous, around-the-clock analgesic is needed. The new product is the first FDAapproved long-acting opioid designed to reduce drug liking and euphoria when tampered with by crushing or chewing. If taken as directed, the morphine relieves pain while the sequestered naltrexone passes through the body with nonintended effect. If the capsule is curshed or chewed, however, the naltrexone is released and absorbed with the morphine, reversing morphine’s subjective and analgesic effect. The clinical significance of this reduction has not yet been established. ■ G REEN H ILL H EALTHCARE C OMMUNICATIONS

CANCER CENTER PROFILE

that information for 2 or 3 days. BF: The radiologist is also involved in real time. While the patient is being operated on, he takes the radiograph and analyzes it. Theodore Hittle (TH): We take an x-ray or ultrasound of the specimen while the patient is still under anesthesia to make sure that Dr Senofsky got what we sent him to remove when we localized the lesion. GS: He is checking that I not only got it, but that I got it with a good clear margin on the specimen radiograph, because when I remove pieces of breast, whether for cancer or precancer situations, I cannot feel the lumps. We send the lumps to the radiology department before the pathologist ever gets them. When the radiologist gets them, he does special mammograms or ultrasounds with the pieces of breast tissues in different orientations. In other words, he is able to tell me not only do I have it, but that I have it with what looks like a healthy rim of normal tissue attached. We try to clear the margins both radiographically and pathologically. Then the pathologist gets the specimen. She takes it, cuts it, and brings it into the operating room. As a group, we look at the margins that way as well.

PRACTICE MANAGEMENT

Private Practice Survival Continued from cover pharmaceuticals delivered before the MMA were large enough to allow practices to “absorb” the loss of that revenue. That is no longer possible for private practice survival. Private practices have had to change their business model in many different areas in an effort to continue to treat their patients, maintain viability, and prevent staff reductions. Oncology pharmacy is a relatively new subspecialty of pharmacy practice. The first wave of board-certified oncology pharmacists were certified in 1998. As of January 2009, 860 board-certified oncology pharmacists were registered with the Board of Pharmaceutical Specialties. Board certification is desirable, but not mandatory, for a pharmacist to be an effective member of the oncology team. What can an oncology pharmacist bring to a private practice, and why should you consider employing one? Some responsibilities and skills an oncology pharmacist can offer include: • Chemotherapy order verification • Chemotherapy safety (USP <797>/

National Institute for Occupational Safety and Health [NIOSH]) • Prior authorization assistance • Diagnosis code support • Inventory management • Contracting/purchasing • Technician staff management (if applicable) • Electronic health record (EHR) management • Research protocol management • Oral adherence program development.

Safety First and foremost, a pharmacist in the outpatient setting can ensure the safe delivery of chemotherapeutic and supportive care regimens. If a practice operates in a manual system, the oncology pharmacist can develop ordering templates that help eliminate transcription errors and minimize variance. Practices that use an EHR system can use the oncology pharmacist to build evidence-based chemotherapeutic regimens, set dose limits, and standardize the use of supportive care agents. The

Cer initiative Comparative Effectiveness Research Continued from page 15 report, told the Journal of Multidisciplinary Cancer Care. “If one treatment is found to work well, and another treatment works only somewhat better, someone will look at what indications and subpopulations the second treatment works well in. So, subgroup analyses will be important.” On August 6, AHRQ officials announced that in the fall they will publish solicitations for research projects and that the funding will commence in the spring of 2010. In addition, on August 21, the agency announced it was suspending the appeals procedure for investigators applying for grants. The stated reason was “due to the time sensitivity of the Recovery Act granting process.” HHS officials have not yet revealed when they will notify the medical research community of the research areas for which they can apply for funding, nor when the money will be awarded. However, officials at the NIH are incorporating CER funding into grants on an ongoing basis (see http://grants.nih.gov/grants/guide/rfafiles/RFA-OD-09003.html#PartI).

What does this mean for you? While the wording and timing of the grant solicitations is being worked out, there is little for clinicians across the country to do but wait, worry, and 28

cross their fingers. Gary H. Lyman, MD, MPH, examined oncology CER in the July issue of Cancer Investigation, of which he is the editor-in-chief (2009;27:593-597). Lyman is a professor of medicine and director, Health Services, Effectiveness and Outcome Research, Division of Medical Oncology, Department of Medicine, Duke University School of Medicine and Duke Comprehensive Cancer Center, Durham, North Carolina. In the article, Lyman, who also chairs four ASCO guidelines committees and is on the US Food and Drug Administration’s Oncology Drug Advisory Committee, laid out how systematic reviews, prospective clinical trials, longitudinal registries, comparative effectiveness simulations, and clinical practice guidelines can deliver the apparent intent of the Obama initiative, which is to optimally inform clinical decisions. “But first, we have to carefully define what comparative effectiveness re search is. And second, let’s make sure there are no hidden issues here. Let’s make sure there’s no subterfuge for rationing drugs, or for funding your research,” Lyman told the Journal of Multidisciplinary Cancer Care. ■ —Rosemary Frei

G REEN H ILL H EALTHCARE C OMMUNICATIONS

pharmacist can verify the drugs and doses ordered, review laboratory results that can have an impact on drug dosing, and review medication profiles for potential drug interactions. Working with hazardous agents, such as chemotherapy, requires a special set of skills and knowledge. The oncology pharmacist can develop and implement policies and procedures surrounding these activities to minimize the risk to patients and staff. The pharmacist can help the practice implement USP <797> and NIOSH standards for safe handling.

Economics The financial domain is one of the most critical areas of private practice. Prior authorizations are becoming the norm, and the data required to successfully submit prior authorizations require clinical knowledge. The oncology pharmacist can help provide the data necessary to minimize claim rejections. A successful claim submission requires accurate diagnosis and agent coding. Collaboration between pharmacy, nursing, and billing staff is important to develop a process that ascertains that claims are correct before they are submitted. In most outpatient facilities, pharmaceutical charges are generated by the pharmacy. This is usually accomplished through a manual or electronic transfer system that converts the agent dispensed into billable units. Keeping abreast of changes to J codes and billable units is critical. The pharmacist can be instrumental in maintaining these databases to prevent errors in billing and lost charges. Effective inventory management can reduce overall costs to the practice. The pharmacist can help minimize or eliminate drug waste and also ensure that drug waste is billed when appropriate to prevent financial loss. Tracking reimbursement rates of pharmaceuticals should be a mandatory function to assess the financial impact on the practice from quarter to quarter. This may lead to formulary changes within the practice to maximize revenue. The pharmacist can lend expertise in contracting and purchasing pharmaceuticals and supplies. Selecting a group purchasing organization that offers the practice the most value is very important. Contracts vary with regard to brand and generic selections. Selection of supportive care agents based on cost and reimbursement can have a large financial impact, and the pharmacist can make those decisions. Management The pharmacist can also have an impact on the organizational structure of a private practice. Pharmacists can become effective managers and leaders, and many already perform those functions. Integrating a pharmacist into operational and leadership roles within the practice can help solidify relationships between departments and provide expertise and problem-solving skills. Many practices employ pharmacy technicians,

and a pharmacist can educate and mentor these technicians. The emergence of the EHR has forced practice staff to develop new skills. Private practices and institutions that implement EHRs must reexamine and sometimes redesign their operations to maximize the utility of these data-driven tools. Not only is selection of an EHR a critical step, but also implementation of the EHR in a private practice requires extensive preparation, teamwork, and commitment to the product and practice goals set forth for implementation. The pharmacist can build therapeutic, research, and supportive care regimens. To name but a few functions, the pharmacist can establish dose limits and rounding methods, review formulas that are used for calculations, designate solution volumes and rates, confirm J codes and billable units, incorporate special instructions and information where applicable, and train other clinicians in system utilization. Many private practices conduct research protocols. These can be cooperative group and/or industry-sponsored trials. Having a pharmacist to acquire, monitor, dispense, and record investigational drug activities is a huge benefit to the practice. The pharmacist can help negotiate contracts for industry-sponsored trials and be a valuable asset during audits and clinical trial monitoring visits. Cancer drug development has now exploded into a multimillion-dollar industry. The targeted drug therapy revolution has arrived, with increasing numbers of molecular targets being identified. New drugs are being designed to interact with these newly identified targets. Today, more than 700 drugs are in development for the treatment of cancer. It is estimated that 20% to 30% of these agents will be oral agents. With the emergence of new oral targeted therapies have come restricted drug delivery systems. These systems require patients and healthcare providers to go through a third party to obtain specific oral chemotherapeutic agents. This process involves multiple forms that must be filled out and submitted to the third party before the agent is delivered to the patient. Many new clinics and cancer centers are implementing full-service pharmacies or embarking on physician-dispensing models to address the problems of access and delivery of these new oral agents as they enter the marketplace. Having a pharmacist to implement any of these approaches and to develop a patient-adherence program for the practice is a valuable service to provide to patients.

Teamwork The challenges to provide cost-effective, patient-centered, oncology care are enormous. It takes a team of dedicated professionals to provide the services needed. A clinical pharmacist can be a vital member of that team. Practices that have had the luxury of having a pharmacist in the roles described herein would never go back. ■ September/October 2009

Continued from page 23 than patients who have gone through the process and have now become advocates for cancer care? We are also partnering with NCI-designated cancer centers to help speed up the research process to get results out into the community quicker. We do not see ourselves as separate from NCI-designated centers or university programs. We see ourselves as part of one group, collaborating to get research from the academic centers into the standard of care in the community as quickly and efficiently as possible. MK: In other words, we let the scientists discover the next new gene; we want that gene test as soon as it is available so we can apply it to improve our patients’ care as quickly as possible. AS: As much as we have had this wonderful and challenging journey of attempting to make advances in each of the pillars, we know that we cannot alter cancer care in the country alone. We know that we need to work with the NCI-designated centers and, ultimately, with a greater number of community cancer centers to have the impact that the NCI and the NCCCP would like to have; that is, to get prevention and earlier detection messages out to the public to reduce cancer disparities and make headway in all six pillars of the NCCCP that we have discussed.

The future MK: This June we completed year 2 of the pilot program. We are just starting year 3, and we have just been notified that there will be funding for a year 4, which will allow us to accomplish more of the specific programmatic pillar goals and prove that multidisciplinary care makes a difference. But I think there’s another untold message, which is crucial—we would love to have more NCCCP sites. We do not need or want to be exclusive. We hope to prove that this pilot program works and have the federal government fund another 10, maybe someday another 50, community cancer centers across the country. The thing that gets us the most excited is how can we have the greatest impact on the 85% of cancer patients treated in the community setting. If we can get additional cancer centers to replicate what we are doing, that will be the greatest success. That even goes for academic medical centers; there may be things that we learn and that we do in terms of a multidisciplinary clinic that not every academic medical center does; we would like to see them adopt those processes. If we can show that something is a best practice, we think all cancer centers should incorporate it. AS: This is an exciting and challenging point in time for us who have worked so collaboratively in NCCCP. We have done some really great things with this program, but we need to demonstrate some of these outcomes to September/October 2009

the NCI and to the scientific community at large so that they can see the benefits and plans can be made to implement the next steps after the completion of the pilot program. MK: One of the great things we have accomplished is communication among the NCCCP sites. The three of us talk almost every week, and we talk with our other colleagues in the 10 community

cancer centers at least once a month. Staff from each pilot site participate in a conference call monthly for each pillar area. This network allows us to share best practices freely, because we each want to share with the others the ideas that will help their patients the most and the fastest. This communication allows us to move a little more nimbly and to facili-

tate best practices a lot easier than if each of us had to reinvent the wheel. So the network of pilot sites is already paying off in terms of sharing best practices; in the future we hope to apply for additional grant funding to allow us to answer specific questions relating to our goals. ■ —Dawn Lagrosa

In moderate-risk* chemotherapy regimens

Start every cycle with confidence by helping reduce the risk of febrile neutropenia

Neulasta® is given once per chemotherapy cycle and should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Important Safety Information Splenic rupture (including fatal cases), acute respiratory distress syndrome, and sickle cell crises have been reported. Allergic reactions, including anaphylaxis, have also been reported. The majority of these reactions occurred upon initial exposure. However, in rare cases, allergic reactions, including anaphylaxis, recurred within days after discontinuing anti-allergic treatment. In a placebo-controlled trial, bone pain occurred at a higher incidence in Neulasta®-treated patients as compared to placebotreated patients (31% vs. 26%). The most common adverse events reported in either placebo- or active-controlled trials were consistent with the underlying cancer diagnosis and its treatment with chemotherapy, with the exception of bone pain.

Consequences of febrile neutropenia, such as hospitalization, may impact patient care I In a prospective registry study (N = 2,692), febrile neutropenia affected more than 1 in 10 patients overall (10.7%) in the first 3 cycles of chemotherapy in select tumor types.1

First- and subsequent-cycle Neulasta® achieved significant results in patients receiving moderate-risk* regimens: I 94% reduction in febrile neutropenia vs. placebo (17% vs. 1%).2,3 I 93% reduction in febrile neutropenia–related hospitalization vs. placebo (14% vs. 1%).2,3 *Regimens associated with ≥ 17% risk of febrile neutropenia.

Start with support

G REEN H ILL H EALTHCARE C OMMUNICATIONS

PRACTICE MANAGEMENT

The National Community Cancer Centers Program

Health Economics HEALTH ECONOMICS

Updates from the 2009 American Society of Clinical Oncology Annual Meeting uBudget Impact Analysis of Sargramostim Use Health plans can realize substantial cost savings by substituting sargramostim (a dual granulocyte-macrophage colony-stimulating factor [GM-CSF]) for filgrastim and pegfilgrastim (granulo-

cyte colony-stimulating factors [GCSFs]) in patients with chemotherapyinduced neutropenia. Researchers computed annual and per-member-permonth costs associated with CSFs. Analysis included cancer prevalence, the proportion of patients receiving

chemotherapy and G/GM-CSFs, incidence and cost of relevant adverse events, and G/GM-CSF drug acquisition and administration costs. Incidence and cost of infection- and febrile neutropenia–related hospitalizations, based on recent analysis of medical insurance

References: 1. Crawford J, et al. J Natl Compr Canc Netw. 2008;6:109-118. 2. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 3. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen.

Start with support BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. CONTRAINDICATIONS Neulasta is contraindicated in patients with known hypersensitivity to E coli-derived proteins‚ pegfilgrastim‚ Filgrastim, or any other component of the product. WARNINGS General The safety and efficacy of Neulasta for peripheral blood progenitor cell (PBPC) mobilization has not been evaluated in adequate and well-controlled studies. Neulasta should not be used for PBPC mobilization. Splenic Rupture SPLENIC RUPTURE, INCLUDING FATAL CASES, HAS BEEN REPORTED FOLLOWING THE ADMINISTRATION OF NEULASTA AND ITS PARENT COMPOUND, FILGRASTIM. PATIENTS RECEIVING NEULASTA WHO REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIP PAIN SHOULD BE EVALUATED FOR AN ENLARGED SPLEEN OR SPLENIC RUPTURE. Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) has been reported in patients receiving Neulasta, and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Patients receiving Neulasta who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS. In the event that ARDS occurs, Neulasta should be discontinued and/or withheld until resolution of ARDS and patients should receive appropriate medical management for this condition. Allergic Reactions Allergic reactions to Neulasta, including anaphylaxis, skin rash, urticaria, and erythema/flushing have been reported in postmarketing experience. The majority of reported events occurred upon initial exposure. In some cases, symptoms recurred with rechallenge, suggesting a causal relationship. In rare cases, allergic reactions including anaphylaxis, recurred within days after initial anti-allergic treatment was discontinued. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. Neulasta should be permanently discontinued in patients with serious allergic reactions. Sickle Cell Disorders Severe sickle cell crises have been associated with the use of Neulasta in patients with sickle cell disorders. Severe sickle cell crises, in some cases resulting in death, have also been associated with Filgrastim, the parent compound of pegfilgrastim. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disorders should prescribe Neulasta for such patients, and only after careful consideration of the potential risks and benefits. PRECAUTIONS General Use With Chemotherapy and/or Radiation Therapy Neulasta should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy (see DOSAGE AND ADMINISTRATION) because of the potential for an increase in sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy. The use of Neulasta has not been studied in patients receiving chemotherapy associated with delayed myelosuppression (eg, nitrosoureas, mitomycin C). The administration of Neulasta concomitantly with 5-fluorouracil or other antimetabolites has not been evaluated in patients. Administration of pegfilgrastim at 0, 1, and 3 days before 5-fluorouracil resulted in increased mortality in mice; administration of pegfilgrastim 24 hours after 5-fluorouracil did not adversely affect survival. The use of Neulasta has not been studied in patients receiving radiation therapy. Potential Effect on Malignant Cells Pegfilgrastim is a growth factor that primarily stimulates neutrophils and neutrophil precursors; however, the G-CSF receptor through which pegfilgrastim and Filgrastim act has been found on tumor cell lines, including some myeloid, T-lymphoid, lung, head and neck, and bladder tumor cell lines. The possibility that pegfilgrastim can act as a growth factor for any tumor type cannot be excluded. Use of Neulasta in myeloid malignancies and myelodysplasia (MDS) has not been studied. In a randomized study comparing the effects of the parent compound of Neulasta, Filgrastim, to placebo in patients undergoing remission induction and consolidation chemotherapy for acute myeloid leukemia, important differences in remission rate between the two arms were excluded. Disease-free survival and overall survival were comparable; however, the study was not designed to detect important differences in these endpoints.* Information for Patients Patients should be informed of the possible side effects of Neulasta and be instructed to report them to the prescribing physician. Patients should be informed of the signs and symptoms of allergic drug reactions and be advised of appropriate actions. Patients should be counseled on the importance of compliance with their Neulasta treatment, including regular monitoring of blood counts. If it is determined that a patient or caregiver can safely and effectively administer Neulasta (pegfilgrastim) at home, appropriate instruction on the proper use of Neulasta (pegfilgrastim) should be provided for patients and their caregivers, including careful review of the “Information for Patients and Caregivers” insert. Patients and caregivers should be cautioned against the reuse of needles, syringes, or drug product, and be thoroughly instructed in their proper disposal. A puncture-resistant container for the disposal of used syringes and needles should be available. Laboratory Monitoring To assess a patient’s hematologic status and ability to tolerate myelosuppressive chemotherapy, a complete blood count and platelet count should be obtained before chemotherapy is administered. Regular monitoring of hematocrit value and platelet count is recommended. Drug Interaction No formal drug interaction studies between Neulasta and other drugs have been performed. Drugs such as lithium may potentiate the release of neutrophils;

patients receiving lithium and Neulasta should have more frequent monitoring of neutrophil counts. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. Carcinogenesis, Mutagenesis, and Impairment of Fertility No mutagenesis studies were conducted with pegfilgrastim. The carcinogenic potential of pegfilgrastim has not been evaluated in long-term animal studies. In a toxicity study of 6 months duration in rats given once weekly subcutaneous injections of up to 1000 mcg/kg of pegfilgrastim (approximately 23-fold higher than the recommended human dose), no precancerous or cancerous lesions were noted. When administered once weekly via subcutaneous injections to male and female rats at doses up to 1000 mcg/kg prior to, and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected. Pregnancy Category C Pegfilgrastim has been shown to have adverse effects in pregnant rabbits when administered subcutaneously every other day during gestation at doses as low as 50 mcg/kg/dose (approximately 4-fold higher than the recommended human dose). Decreased maternal food consumption, accompanied by a decreased maternal body weight gain and decreased fetal body weights were observed at 50 to 1000 mcg/kg/dose. Pegfilgrastim doses of 200 and 250 mcg/kg/dose resulted in an increased incidence of abortions. Increased post-implantation loss due to early resorptions was observed at doses of 200 to 1000 mcg/kg/dose, and decreased numbers of live rabbit fetuses were observed at pegfilgrastim doses of 200 to 1000 mcg/kg/dose, given every other day. Subcutaneous injections of pegfilgrastim of up to 1000 mcg/kg/dose every other day during the period of organogenesis in rats were not associated with an embryotoxic or fetotoxic outcome. However, an increased incidence (compared to historical controls) of wavy ribs was observed in rat fetuses at 1000 mcg/kg/dose every other day. Very low levels (< 0.5%) of pegfilgrastim crossed the placenta when administered subcutaneously to pregnant rats every other day during gestation. Once weekly subcutaneous injections of pegfilgrastim to female rats from day 6 of gestation through day 18 of lactation at doses up to 1000 mcg/kg/dose did not result in any adverse maternal effects. There were no deleterious effects on the growth and development of the offspring and no adverse effects were found upon assessment of fertility indices. There are no adequate and well-controlled studies in pregnant women. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Nursing Mothers It is not known whether pegfilgrastim is excreted in human milk. Because many drugs are excreted in human milk‚ caution should be exercised when Neulasta is administered to a nursing woman. Pediatric Use The safety and pharmacokinetics of Neulasta were studied in 37 pediatric patients with sarcoma. The mean (± Standard Deviation) systemic exposure (AUC 0-inf) of Neulasta after subcutaneous administration at 100 mcg/kg was 22.0 (±13.1) mcg·hr/mL in the 6–11 years age group (n = 10), 29.3 (±23.2) mcg·hr/mL in the 12–21 years age group (n = 13) and 47.9 (±22.5) mcg·hr/mL in the youngest age group (0–5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (±11.3) hours, 21.2 (±16.0) hours and 30.1 (±38.2) hours, respectively. The most common adverse reaction was bone pain. The 6 mg fixed dose single-use syringe formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. ADVERSE REACTIONS (See WARNINGS, Splenic Rupture, Acute Respiratory Distress Syndrome (ARDS), Allergic Reactions, and Sickle Cell Disorders.) Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Neulasta cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to Neulasta use and for approximating rates. The data described below reflect exposure to Neulasta in 932 patients. Neulasta was studied in placebo- and active-controlled trials (n = 467, and n = 465, respectively). The population encompassed an age range of 21 to 88 years. Ninety-two percent of patients were female. The ethnicity of the patients was as follows: 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with solid tumors (breast [n = 823], lung and thoracic tumors [n = 53]) or lymphoma (n = 56) received Neulasta after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles. In the placebo-controlled trial, bone pain occurred at a higher incidence in Neulasta-treated patients as compared to placebo-treated patients. The incidence of other commonly reported adverse events were similar in the Neulasta- and placebo-treated patients, and were consistent with the underlying cancer diagnosis and its treatment with chemotherapy. The data in Table 1 reflect those adverse events occurring in at least 10% of patients treated with Neulasta in the placebo-controlled study. Table 1. Adverse Events Occurring in ≥ 10%a of Patients in the Placebo-Controlled Study Event Alopecia Bone Painb Diarrhea Pyrexia (not including febrile neutropenia) Myalgia Headache Arthralgia Vomiting Asthenia Peripheral Edema Constipation

Neulasta (n = 467) 48% 31% 29%

Placebo (n = 461) 47% 26% 28%

23%

22%

21% 16% 16% 13% 13% 12% 10%

18% 14% 13% 11% 11% 10% 6%

Events occurring in ≥ 10% of Neulasta-treated patients and at a higher incidence as compared to placebo-treated patients Bone pain is limited to the specified adverse event term “bone pain”

In the active controlled studies, common adverse events occurred at similar rates and severities in both treatment arms (Neulasta, n = 465; Filgrastim, n = 331). These adverse experiences occurred at rates between 72% and 15% and included: nausea, fatigue, alopecia, diarrhea, vomiting, constipation, fever, anorexia, skeletal pain, headache, taste perversion, dyspepsia, myalgia, insomnia, abdominal pain, arthralgia, generalized weakness, peripheral edema, dizziness, granulocytopenia, stomatitis, mucositis, and neutropenic fever. Bone Pain The analysis of bone pain described below is based on a composite analysis using multiple, related, adverse event terms. In the placebo-controlled study, the incidence of bone pain was 57% in Neulasta-treated patients compared to 50% in placebo-treated patients. Bone pain was generally reported to be of mild-to-moderate severity. Among patients experiencing bone pain, approximately 37% of Neulasta-and 31% of placebo-treated patients utilized non-narcotic analgesics and 10% of Neulasta- and 9% of placebo-treated patients utilized narcotic analgesics. In the active-controlled studies, the use of non-narcotic and narcotic analgesics in association with bone pain was similar between Neulasta-and Filgrastimtreated patients. No patient withdrew from study due to bone pain. Laboratory Abnormalities In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. Leukocytosis was not associated with any adverse effects. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading. Cytopenias resulting from a neutralizing antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors. There is a theoretical possibility that an antibody directed against pegfilgrastim may cross-react with endogenous G-CSF, resulting in immune-mediated neutropenia. This has not been observed in clinical studies of Neulasta. Postmarketing Experience The following adverse reactions have been identified during postapproval of Neulasta. 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. • splenic rupture (see WARNINGS: Splenic Rupture) • acute respiratory distress syndrome (ARDS) (see WARNINGS: Acute Respiratory Distress Syndrome) • allergic reactions (including anaphylaxis, skin rash, urticaria, erythema/flushing) (see WARNINGS: Allergic Reactions) • sickle cell crisis (see WARNINGS: Sickle Cell Disorders) • injection site pain • Sweet’s syndrome (acute febrile dermatosis) OVERDOSAGE The maximum amount of Neulasta that can be safely administered in single or multiple doses has not been determined. Single subcutaneous doses of 300 mcg/kg have been administered to 8 healthy volunteers and 3 patients with non-small cell lung cancer without serious adverse effects. These patients experienced a mean maximum ANC of 55 x 109/L, with a corresponding mean maximum WBC of 67 x 109/L. The absolute maximum ANC observed was 96 x 109/L with a corresponding absolute maximum WBC observed of 120 x 109/L. The duration of leukocytosis ranged from 6 to 13 days. Leukapheresis should be considered in the management of symptomatic individuals. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle. Neulasta should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy (see PRECAUTIONS). The 6 mg fixed-dose formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg. No dosing adjustment is necessary for renal dysfunction. Neulasta should be visually inspected for discoloration and particulate matter before administration. Neulasta should not be administered if discoloration or particulates are observed. Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 4,810,643; 4,999,291; 5,582,823; 5,580,755, as well as other patents or patents pending. REFERENCE *Heil G, Hoelzer D, Sanz MA, et al. A randomized, double-blind, placebocontrolled, phase III study of Filgrastim in remission induction and consolidation therapy for adults with de novo Acute Myeloid Leukemia. Blood. 1997;90:4710-4718. v.10 Issue Date: 11/2008

claims data, were also used. Cost-savings (2006 $US) were assessed for utilization share switches from G-CSF to GM-CSF. An estimated 976 patients received G/GM-CSF annually. Increasing baseline utilization shares for pegfilgrastim, filgrastim, and sargramostim of 70%/ 30%/0%, respectively, to alternative shares of 50%/25%/25% yielded substantial cost-savings, primarily related to G/GM-CSF acquisition and administration costs. The researchers concluded that with 25% sargramostim substitution, the cost-saving could reach $2 million for a health plan with 1 million members, or a saving of 16 cents permember per-month. Duh M, Toy EL, Porter CL, et al. Abstract e20596. This study was supported by Bayer HealthCare Pharmaceuticals, Inc.

uMedical Oncologists’ Understanding of the Cost of Therapy A recent survey of 50 medical oncologists revealed that they have a poor understanding of the monetary costs of the newer treatments they are prescribing. Physicians were asked to calculate the cost of treatments to the patient and not the acquisition price of drugs. They were asked to calculate the cost based on a patient completing adjuvant therapy or treatment in the first-line metastatic setting, which was defined by each physician. If desired, this included the use of maintenance therapy.

Physicians underestimated the actual cost of treatment to the patient by 25% to 40%. In almost all cases where intravenous or oral targeted therapies were used, physicians underestimated the actual cost of treatment to the patient by 25% to 40%. When “conventional” intravenous chemotherapy was used, they were either correct or overestimated the cost of treatment by 25% to 33%, especially when generic substitution of branded drugs were available. This translates to a dollar difference of up to $50,000 when targeted therapies are used and approximately $5000 when conventional treatments are used. Nearly all the physicians estimated the cost of oral medications near the actual cost. The researchers concluded that more education is needed in the economics, including monetary cost-benefit analysis, of oncology practice to better explain the cost of treatment to patients. Hoffman KR. Abstract 6629.■ —Dawn Lagrosa

G REEN H ILL H EALTHCARE C OMMUNICATIONS

September/October 2009

ONCOLOGY DRUG CODES

Oncology Drug Codes Medications Used for the Treatment of Breast Cancer The following sections include: • Associated ICD-9-CM codes used for the classification of breast cancer • Drugs that have been FDA-approved in breast cancer. Please note: if a check mark appears in the FDA column it will NOT appear in the Compendia section even if a drug is included in the NCCN (National Comprehensive Cancer Network) Drugs & Biologics Compendium • Drugs included in the NCCN Drugs & Biologics Compendium for off-label use in breast cancer. NCCN is recognized by the Centers for Medicare & Medicaid Services (CMS) as a referencing source • Corresponding HCPCS/CPT codes and code descriptions • Current Code Price (AWP-based pricing) • Most recent ASP plus 6% (Medicare allowable) • Possible CPT Administration Codes for each medication.

Associated ICD-9-CM Codes Used for Breast Cancer 174

Malignant neoplasm of female breast Use additional code to identify estrogen-receptor status (V86.0, V86.1) Includes: breast (female) connective tissue soft parts Paget’s disease of: breast nipple Excludes: skin of breast (172.5, 173.5) 174.0 Nipple and areola 174.1 Central portion 174.2 Upper inner quadrant 174.3 Lower inner quadrant 174.4 Upper outer quadrant 174.5 Lower outer quadrant 174.6 Axillary tail 174.8 Other specified sites of female breast Ectopic sites Inner breast Lower breast Malignant neoplasm of contiguous or overlapping sites of breast whose point of origin cannot be determined Midline of breast Outer breast Upper breast 174.9 Breast (female), unspecified

175 Malignant neoplasm of male breast Use additional code to identify estrogen-receptor status (V86.0, V86.1) Excludes: skin of breast (172.5, 173.5) 175.0 Nipple and areola 175.9 Other and unspecified sites of male breast Ectopic breast tissue, male

FDAapproved for breast cancer

NCCN Drugs & Biologics Compendium off-label use for breast cancer

Current code price (AWP-based pricing), effective 10/1/09

Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09

CPT administration codes

Generic (brand) name

HCPCS code: code description

anastrozole (Arimidex)

✓

anastrozole (Arimidex)

J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified S0170: anastrozole, oral, 1 mg

✓

NDC level pricing $13.04

bevacizumab (Avastin) capecitabine (Xeloda) capecitabine (Xeloda) carboplatin (Paraplatin)

J9035: injection, bevacizumab, 10 mg J8520: capecitabine, oral, 150 mg J8521: capecitabine, oral, 500 mg J9045: injection, carboplatin, 50 mg

✓

$68.75

NDC level pricing S0170: not payable by Medicare $57.48

✓

$7.76

$5.79

N/A

✓

$25.85

$19.09

N/A

$85.10

$4.60

September/October 2009

✓

N/A

96413, 96415

96409, 96413, 96415

G REEN H ILL H EALTHCARE C OMMUNICATIONS

ONCOLOGY DRUG CODES

Generic (brand) name

HCPCS code: code description

cisplatin (Platinol AQ) cisplatin (Platinol AQ) cyclophosphamide oral (Cytoxan) cyclophosphamide injection (Cytoxan) cyclophosphamide injection (Cytoxan) cyclophosphamide injection (Cytoxan) docetaxel (Taxotere) doxorubicin HCl (Adriamycin) doxorubicin HCl liposome (Doxil)

J9060: cisplatin, powder or solution, per 10 mg J9062: cisplatin, 50 mg J8530: cyclophosphamide, oral, 25 mg J9090: cyclophosphamide, 500 mg J9091: cyclophosphamide, 1.0 g J9092: cyclophosphamide, 2.0 g J9170: injection, docetaxel, 20 mg J9000: injection, doxorubicin HCl, 10 mg J9001: injection, doxorubicin HCl, all lipid formulations, 10 mg J9178: injection, epirubicin HCl, 2 mg J8499a: prescription drug, oral, nonchemotherapeutic, not otherwise specified J8560: etoposide, oral, 50 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified S0156: exemestane, 25 mg

epirubicin (Ellence) estradiol (Estrace) etoposide (Vepesid) exemestane (Aromasin) exemestane (Aromasin)

FDAapproved for breast cancer

fluorouracil (Adrucil) fluoxymesterone (Androxy)

J9190: injection, fluorouracil, 500 mg J8499a: prescription drug, oral, nonchemotherapeutic, not otherwise specified fulvestrant J9395: injection, (Faslodex) fulvestrant, 25 mg gemcitabine J9201: injection, (Gemzar) gemcitabine HCl, 200 mg goserelin acetate J9202: goserelin acetate implant, (Zoladex 3.6 mg ONLY) per 3.6 mg ixabepilone J9207: injection, (Ixempra) ixabepilone, 1 mg lapatinib ditosylate J8999a: prescription drug, (Tykerb) oral, chemotherapeutic, not otherwise specified letrozole J8999a: prescription drug, (Femara) oral, chemotherapeutic, not otherwise specified leuprolide (Eligard, J9217: leuprolide acetate Lupron Depot) (for depot suspension), 7.5 mg leuprolide J9218: leuprolide acetate, (Lupron) per 1 mg megestrol J8999a: prescription drug, (Megace) oral, chemotherapeutic, not otherwise specified

G REEN H ILL H EALTHCARE C OMMUNICATIONS

NCCN Drugs & Biologics Compendium off-label use for breast cancer

Current code price (AWP-based pricing), effective 10/1/09

Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09

CPT administration codes

✓

$4.33

$2.07

96409, 96413, 96415

✓

$21.66

$10.34

96409, 96413, 96415

✓

$2.09

$0.81

✓

$30.34

$21.51

96409, 96413, 96415

✓

$54.62

$43.03

96409, 96413, 96415

✓

$98.30

$86.06

96409, 96413, 96415

✓

$456.53

$345.54

96413

✓

$13.20

$3.69

96409

$559.32

$459.18

96413

✓

$8.16

$2.59

✓

NDC level pricing $47.64

NDC level pricing $0.46

✓

NDC level pricing $12.38

✓

$3.30

NDC level pricing S0156: not payable by Medicare $1.52

✓

N/A

96409, 96413 N/A

N/A N/A

N/A

96409

✓

NDC level pricing $96.33

NDC level pricing $82.18

96402

✓

$169.46

$141.77

96413

✓

$451.19

$196.73

96372, 96402

✓

$73.76

$63.74

96413, 96415

✓

NDC level pricing NDC level pricing $352.56

NDC level pricing NDC level pricing $214.57

96402

✓

$27.44

$5.40

96402

NDC level pricing

N/A

✓

NDC level pricing

N/A

September/October 2009

NCCN Drugs & Biologics Compendium off-label use for breast cancer

Current code price (AWP-based pricing), effective 10/1/09

Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09

CPT administration codes

Generic (brand) name

HCPCS code: code description

megestrol (Megace)

S0179: megestrol acetate, oral, 20 mg

✓

$0.66

methotrexate

J8610: methotrexate, oral, 2.5 mg J9250: methotrexate sodium, 5 mg J9260: methotrexate sodium, 50 mg J9264: injection, paclitaxel protein-bound particles, 1 mg J9265: injection, paclitaxel, 30 mg J7506: prednisone, oral, per 5 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified S0187: tamoxifen citrate, oral, 10 mg

✓

$3.56

S0179: not payable by Medicare $0.12

✓

$0.27

$0.21

✓

$2.73

$2.12

✓

$10.97

$9.26

96372, 96374, 96401, 96409, 96450 96372, 96374, 96401, 96409, 96450 96413

✓

$19.89

$9.11

96413, 96415

$0.05

$0.04

N/A N/A

J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified J9340: injection, thiotepa, 15 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified J9355: injection, trastuzumab, 10 mg J9360: injection, vinblastine sulfate, 1 mg J9390: injection, vinorelbine tartrate, per 10 mg

✓

NDC level pricing $138.00

NDC level pricing S0187: not payable by Medicare NDC level pricing $99.57

✓

NDC level pricing $74.49

NDC level pricing $64.73

✓

$3.18

$0.96

96409

$42.60

$12.18

96409

methotrexate sodium methotrexate sodium paclitaxel (Abraxane) paclitaxel (Taxol) prednisone tamoxifen (Nolvadex) tamoxifen (Nolvadex) testolactone (Teslac) thiotepa (Thiotepa) toremifene citrate (Fareston) trastuzumab (Herceptin) vinBLAStine vinorelbine (Navelbine)

✓

NDC level pricing $1.89

✓

ONCOLOGY DRUG CODES

FDAapproved for breast cancer

N/A

51720, 96409 N/A

96413, 96415

When billing a nonclassified medication using a CMS 1500 claim form you must include both the HCPCS code (ie, J8999 for tamoxifen) in Column 24D and the drug name, strength, and National Drug Code (NDC) in Box 19 in order to ensure appropriate reimbursement.

This information was supplied by:

MORE ONCOLOGY DRUG CODES ONLINE Chemotherapy-induced Anemia

www.jomcc.com PO BOX 290616, Wethersfield, CT 06109 T: (860) 563-1223 • F: (860) 563-1650 • www.RJHealthSystems.com

September/October 2009

G REEN H ILL H EALTHCARE C OMMUNICATIONS

Medications Used for Supportive Treatment ONCOLOGY DRUG CODES

The following sections include: • Associated ICD-9-CM codes used for the classification of supportive therapies • Drugs that have been FDA-approved in the prevention of chemotherapy-induced nausea and vomiting and neutropenia. Please note: if a check mark appears in the FDA column it will NOT appear in the Compendia section even if a drug is included in the NCCN (National Comprehensive Cancer Network) Drugs & Biologics Compendium • Drugs included in the NCCN Drugs & Biologics Compendium for off-label use in chemotherapy-induced nausea and vomiting and neutropenia. NCCN is recognized by the Centers for Medicare & Medicaid Services (CMS) as a referencing source • Corresponding HCPCS/CPT codes and code descriptions • Current Code Price (AWP-based pricing) • Most recent ASP plus 6% (Medicare allowable) • Possible CPT Administration Codes for each medication.

787 Symptoms involving digestive system Excludes: constipation (564.00-564.09) pylorospasm (537.81) congenital (750.5) 787.0 Nausea and vomiting Emesis Excludes: hematemesis, not otherwise specified (578.0) vomiting: bilious, following gastrointestinal surgery (564.3) cyclical (536.2) associated with migraine (346.2) psychogenic (306.4) excessive, in pregnancy (643.0-643.9) habit (536.2) of newborn (779.3) psychogenic, not otherwise specified (307.54) 787.01 Nausea with vomiting 787.02 Nausea alone 787.03 Vomiting alone

FDAapproved for prevention of nausea and vomiting

Generic (brand) name

HCPCS code: code description

Aprepitant (Emend) alprazolam (Xanax)

J8501: oral, aprepitant, 5 mg J8499a: oral, prescription drug, nonchemotherapeutic, not otherwise specified J8540: oral, dexamethasone, 0.25 mg J1100: injection, dexamethasone sodium phosphate, 1 mg J1200: injection, diphenhydramine HCl, up to 50 mg J8499a: oral, prescription drug, nonchemotherapeutic, not otherwise specified Q0163: oral, diphenhydramine HCl, 50 mgb J1260: injection, dolasetron mesylate, 10 mg Q0180: oral, dolasetron mesylate, 100 mgc S0174: oral, dolasetron mesylate, 50 mg (for circumstances falling under the Medicare statute, use Q0180) Q0167: oral, dronabinol, 2.5 mgb Q0168: oral, dronabinol, 5 mgb J1453: injection, fosaprepitant, 1 mg

dexamethasone (Decadron) dexamethasone sodium phosphate diphenhydramine (Benadryl) diphenhydramine (Benadryl) diphenhydramine (Benadryl) dolasetron mesylate (Anzemet) dolasetron mesylate (Anzemet) dolasetron mesylate (Anzemet)

dronabinol (Marinol) dronabinol (Marinol) fosaprepitant (Emend)

Associated ICD-9-CM Codes Used for the Prevention of Chemotherapy-induced Nausea and Vomiting

G REEN H ILL H EALTHCARE C OMMUNICATIONS

NCCN Drugs & Biologics Compendium off-label use for prevention of nausea and vomiting

Current code price (AWPbased pricing), effective 10/1/09

Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09

CPT administration codes

$6.59

$5.52

N/A

NDC level pricing $0.38

N/A

✓

NDC level pricing $0.09

✓

$0.15

$0.08

96372, 96374

✓

$1.13

$0.86

96372, 96374

✓

NDC level pricing $0.05

NDC level pricing $0.02

N/A

✓

$4.68

$4.41

96374

✓

$76.24

$58.40

N/A

✓

$57.52

S0174: not payable by Medicare

N/A

✓

$5.89

$6.80

N/A

✓

$12.26

$13.57

N/A

✓

$1.88

$1.58

✓

N/A

96374, 96375

September/October 2009

HCPCS code: code description

granisetron (Kytril) granisetron (Kytril, Granisol) granisetron (Kytril, Granisol)

J1626: injection, granisetron HCl, 100 μg Q0166: oral, granisetron HCl, 1 mgc S0091: granisetron HCl, 1 mg (for circumstances falling under the Medicare statute, use Q0166) J3490a: unclassified drugs

granisetron (Sancuso) haloperidol (Haldol) haloperidol (Haldol) lorazepam (Ativan) lorazepam (Ativan) metoclopramide (Reglan) metoclopramide (Reglan) nabilone (Cesamet) olanzapine (Zyprexa) ondansetron (Zofran) ondansetron (Zofran) ondansetron (Zofran)

palonosetron (Aloxi) prochlorperazine maleate (Compazine) prochlorperazine maleate (Compazine) prochlorperazine maleate (Compazine) prochlorperazine maleate (Compazine) prochlorperazine maleate (Compazine)

promethazine (Phenergan)

J1630: injection, haloperidol, up to 5 mg J8499a: oral, prescription drug, nonchemotherapeutic, not otherwise specified J2060: injection, lorazepam, 2 mg J8499a: oral, prescription drug, nonchemotherapeutic, not otherwise specified J2765: injection, metoclopramide HCl, up to 10 mg J8499a: oral, prescription drug, nonchemotherapeutic, not otherwise specified J8650: oral, nabilone, 1 mg J8499a: oral, prescription drug, nonchemotherapeutic, not otherwise specified J2405: injection, ondansetron HCl, per 1 mg Q0179: oral, ondansetron HCl, 8 mgb S0181: oral, ondansetron HCl, 4 mg (for circumstances falling under the Medicare statute, use Q0179) J2469: injection, palonosetron HCl, 25 μg J0780: injection, prochlorperazine, up to 10 mg J8499a: oral, prescription drug, nonchemotherapeutic, not otherwise specified Q0164: oral, prochlorperazine maleate, 5 mgb Q0165: oral, prochlorperazine maleate, 10 mgb S0183: oral, prochlorperazine maleate, 5 mg (for circumstances falling under the Medicare statute, use Q0164-Q0165) J2550: injection, promethazine HCl, up to 50 mg

September/October 2009

NCCN Drugs & Biologics Compendium off-label use for prevention of nausea and vomiting

Current code price (AWPbased pricing), effective 10/1/09

Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09

CPT administration codes

✓

$10.61

$2.00

96374

✓

$58.95

$7.08

N/A

✓

$58.95

S0091: not payable by Medicare

N/A

✓

NDC level pricing $7.04

NDC level pricing $1.63

N/A

NDC level pricing $1.01

NDC level pricing $0.80

NDC level pricing $0.37

NDC level pricing $0.35

NDC level pricing $19.20

NDC level pricing None listed

✓

NDC level pricing $0.60

NDC level pricing $0.25

✓

$39.36

$10.42

N/A

✓

$24.20

S0181: not payable by Medicare

N/A

✓

$41.04

$17.52

✓

$3.30

$2.11

✓

NDC level pricing $0.59

NDC level pricing $0.04

N/A

✓

$0.89

$0.05

N/A

✓

$0.59

S0183: not payable by Medicare

N/A

✓

$2.22

$1.60

✓

ONCOLOGY DRUG CODES

DRUG CODES

Generic (brand) name

FDAapproved for prevention of nausea and vomiting

96372 N/A N/A 96365, 96366, 96372, 96374 N/A

96372, 96374 N/A

N/A N/A

96372, 96374

96374 96372, 96374 N/A

96372, 96374

G REEN H ILL H EALTHCARE C OMMUNICATIONS

ONCOLOGY DRUG CODES

Generic (brand) name

HCPCS code: code description

promethazine (Phenergan)

J8499a: oral, prescription drug, nonchemotherapeutic, not otherwise specified Q0169: oral, promethazine HCl, 12.5 mgb Q0170: oral, promethazine HCl, 25 mgb

promethazine (Phenergan) promethazine (Phenergan)

FDAapproved for prevention of nausea and vomiting

NCCN Drugs & Biologics Compendium off-label use for prevention of nausea and vomiting

Current code price (AWPbased pricing), effective 10/1/09

Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09

CPT administration codes

✓

NDC level pricing $0.49

NDC level pricing $0.43

N/A

✓

$0.51

$0.15

N/A

✓

N/A

Associated ICD-9-CM Codes Used for the Prevention of Chemotherapy-induced Neutropenia 288 Diseases of white blood cells Excludes: leukemia (204.0-208.9) 288.03 Drug-induced neutropenia Use additional E code to identify drug E933 Primary systemic agents E933.1 Antineoplastic and immunosuppressive drugs Examples: azathioprine busulfan chlorambucil cyclophosphamide cytarabine fluorouracil mechlorethamine hcl mercaptopurine thiotepa Excludes: antineoplastic antibiotics (E930.7) E930.7 Antineoplastic antibiotics Actinomycins Examples: bleomycin dactinomycin daunorubicin mitomycin Excludes: other antineoplastic drugs (E933.1)

Generic (brand) name

HCPCS code: code description

filgrastim (Neupogen) filgrastim (Neupogen) pegfilgrastim (Neulasta) sargramostim (Leukine)

J1440: injection, filgrastim (G-CSF), 300 g J1441: injection, filgrastim (G-CSF), 480 g J2505: injection, pegfilgrastim, 6 mg J2820: injection, sargramostim (GM-CSF), 50 μg

FDAapproved for neutropenia

NCCN Drugs & Biologics Compendium off-label use for neutropenia

Current code price (AWPbased pricing), effective 10/1/09

Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09

CPT administration codes

✓

$267.24

$212.55

✓

$425.58

$330.68

✓

$3762.00

$2264.81

96365, 96366, 96369, 96370, 96372, 96374 96365, 96366, 96369, 96370, 96372, 96374 96372

✓

$39.60

$23.75

96365, 96366, 96372

When billing a nonclassified medication using a CMS 1500 claim form you must include both the HCPCS code (ie, J3490 for Sancuso) in Column 24D and the drug name, strength, and National Drug Code (NDC) in Box 19 in order to ensure appropriate reimbursement. b FDA-approved prescription antiemetic, for use as a complete therapeutic substitute for an intravenous antiemetic at time of chemotherapy treatment, not to exceed a 48-hour dosage regimen. c

FDA-approved prescription antiemetic, for use as a complete therapeutic substitute for an intravenous antiemetic at time of chemotherapy treatment, not to exceed a 24-hour dosage regimen. References • HCPCS Level II Expert, 2009 • CPT 2009; 2008 • ICD-9-CM for Professionals Volumes 1 & 2; 2009 • The Drug Reimbursement Coding and Pricing Guide, Vol 6, No 4; RJ Health Systems International LLC; 4th Quarter 2009 • FDA-approved indication (from products’ prescribing information) • NCCN • National Cancer Institute • www.ReimbursementCodes.com powered by RJ Health Systems International, LLC, Wethersfield, Connecticut • CMSMedicare allowable 4th Quarter 2009 (effective dates 10/1/09-12/31/09). Prices listed herein are effective as of October 1, 2009. ASP indicates average sales price; AWP, average wholesale price; CMS, Centers for Medicare & Medicaid Services; CPT, Current Procedural Terminology; FDA, US Food and Drug Administration; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte macrophage-colony stimulating factor; HCPCS, Healthcare Common Procedure Coding System; NCCN, National Comprehensive Cancer Network.

G REEN H ILL H EALTHCARE C OMMUNICATIONS

September/October 2009

Presents The Second Annual 2009 Curriculum for

CONSIDERATIONS IN MULTIPLE MYELOMA A Newsletter Series for Cancer Care Professionals Center of Excellence Media, along with Editor-in-Chief Sagar Lonial, MD, of Emory University, are pleased to offer your multidisciplinary cancer team with this series of newsletters focusing on the challenges in treating patients with multiple myeloma.

SAGAR LONIAL, MD Associate Professor of Hematology and Oncology Emory University

# Earn Continuing Education Credits # Eight part newsletter series

CLINICAL TOPICS: • Retreatment Settings • Maintenance Therapy • Do CRs Correlate with Clinical Benefit?

• Perspectives on Relevant Endpoints of Clinical Trials • Stem Cell Mobilization • Cytogenic Testing in the MM Patient

• To Transplant or Not to Transplant…That is the Question • Sequencing Strategies in MM: Treatment with Case Studies

Each newsletter will feature: • Contributions from thought-leading physicians, pharmacists, and nurses

• Continuing Education credits available to physicians, pharmacists, and nurses

PARTICIPATE TODAY at www.COEXM.com Stem Cell Mobilization Statement of Need The purpose of this activity is to enhance knowledge concerning the treatment of patients with multiple myeloma (MM). Target Audience This activity was developed for physicians, nurses, and pharmacists. Learning Objectives At the completion of this activity participants should be able to: • Explain how various agents and combination regimens used in induction regimens for multiple myeloma (MM) may affect stem cell mobilization • Describe the safety and efficacy of standard agents used for stem cell mobilization in patients with MM • Interpret data from clinical trials evaluating novel approaches to stem cell mobilization as reported at the 2008 ASH meeting Physician Accreditation This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group (Global) and Medical Learning Institute, Inc. (MLI). Global is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designation Global Education Group designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Registered Nurse Designation Medical Learning Institute, Inc. Provider approved by the California Board of Registered Nursing, Provider 15106, for 1.0 contact hour. Registered Pharmacy Designation MLI is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal program number for this activity is 468-999-09-027-H01-P. Agenda: 1 hour Articles/Commentaries: 45 minutes Evaluation/Posttest: 15 minutes Date of original release: August 31, 2009 Valid for CME credit through: August 31, 2010

This activity is jointly sponsored by

This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.

IN THE LITERATURE

In the Literature Concise Reviews of Studies Relevant to Breast Cancer Care ■ Tamoxifen May Increase Risk of ER-negative Contralateral Breast Cancer Background: Preliminary data suggest that tamoxifen use appears to decrease the risk of estrogen-receptor (ER)–positive contralateral breast tumors, but to increase the risk of ER-negative contralateral tumors in breast cancer survivors. Design: A population-based nested case-control study compared 367 women diagnosed with both first primary ERpositive invasive breast cancer and second primary contralateral breast cancer with 728 matched controls with only a first breast cancer. Using conditional logistic regression, the researchers quantified associations between adjuvant hormonal therapy and risk of hormone receptor–specific subtypes of contralateral breast cancer. Summary: Use of tamoxifen for ≥5 years reduced the risk of ER-positive contralateral breast cancer (odds ratio, 0.4; 95% CI, 0.3-0.7) and increased the risk of ER-negative contralateral breast cancer 4.4-fold (95% CI, 1.03-19.0). Use for <5 years was not associated with ER-negative contralateral breast cancer risk. Takeaway: Although risk increases for ER-negative contralateral breast tumors, this study does not negate the positive benefits of adjuvant hormonal therapy or significantly change the riskbenefit ratio. Li CI, et al. Cancer Res. August 25, 2009. Epub ahead of print. ■ Dasatinib Synergizes with Doxorubicin Background: Src kinases control cycle progression, survival, and metastasis of cancer cells. The mechanism of action of dasatinib, an orally active Src kinase inhibitor that may block these functions, is unknown in breast cancer. Design: Dasatinib-resistant and moderately resistant breast cancer cell lines were treated with dasatinib as a single agent and in combination with doxorubicin. The actin cytoskeleton and associated signaling pathways were also treated. Summary: The sensitivity to growth inhibition varied widely. In the most sensitive cell line, dasatinib treatment induced significant G1 accumulation with little apoptosis, disrupted cellular morphology, blocked migration, inhibited invasion through Matrigel (P <.01), and blocked the formation of invadopodia (P <.001). Combination treatment resulted in synergistic growth inhibition in all cell lines and blocked the migration and invasion of the highly metastatic, triple-negative cell line. Takeaway: The idea of using dasatinib as an effective addition to multidrug regimens with doxorubicin for the treatment of invasive breast cancers warrants future investigation. Pichot CS, et al. Br J Cancer. 2009; 101:38-47. ■ 38

G REEN H ILL H EALTHCARE

the AC-T arm, 24 months in the AC-TH arm. In Studies 1 and 2, 6% of patients were not permitted to initiate Herceptin following completion of AC chemotherapy due to cardiac dysfunction (LVEF <50% or 15 point decline in LVEF from baseline to end of AC). Following initiation of Herceptin therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving Herceptin and paclitaxel as compared to those receiving paclitaxel alone in Studies 1 and 2, and in patients receiving Herceptin monotherapy compared to observation in Study 3 (see Table 5, Figures 1 and 2). Table 5a Per-patient Incidence of New Onset Myocardial Dysfunction (by LVEF) Studies 1, 2, 3 and 4 LVEF <50% and Absolute Decrease from Baseline

Studies 1 & 2b AC TH (n=1606) AC T (n=1488) Study 3 Herceptin (n=1678) Observation (n=1708) Study 4c TCH (n=1056) AC TH (n=1068) AC T (n=1050)

LVEF ≥10% ≥16% <50% decrease decrease

Absolute LVEF Decrease <20% and ≥10% ≥20%

22.8% 18.3% (366) (294) 9.1% 5.4% (136) (81)

11.7% (188) 2.2% (33)

33.4% (536) 18.3% (272)

9.2% (148) 2.4% (36)

8.6% (144) 2.7% (46)

7.0% (118) 2.0% (35)

3.8% (64) 1.2% (20)

22.4% (376) 11.9% (204)

3.5% (59) 1.2% (21)

8.5% (90) 17% (182) 9.5% (100)

5.9% (62) 13.3% (142) 6.6% (69)

3.3% (35) 9.8% (105) 3.3% (35)

34.5% (364) 44.3% (473) 34% (357)

6.3% (67) 13.2% (141) 5.5% (58)

a For Studies 1, 2 and 3, events are counted from the beginning of Herceptin treatment. For Study 4, events are counted from the date of randomization. b Studies 1 and 2 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC T) or paclitaxel plus Herceptin (AC TH) c Study 4 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC T) or docetaxel plus Herceptin (AC TH); docetaxel and carboplatin plus Herceptin (TCH)

Figure 1 Studies 1 and 2: Cumulative Incidence of Time to First LVEF Decline of 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is initiation of paclitaxel or Herceptin + paclitaxel therapy. Figure 2 Study 3: Cumulative Incidence of Time to First LVEF Decline of 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is the date of randomization. Figure 3 Study 4: Cumulative Incidence of Time to First LVEF Decline of 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is the date of randomization. The incidence of treatment emergent congestive heart failure among patients in the metastatic breast cancer trials was classified for severity using the New York Heart Association classification system (I–IV, where IV is the most severe level of cardiac failure) (see Table 2). In the metastatic breast cancer trials the probability of cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracyclines. Infusion Reactions During the first infusion with Herceptin, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of Herceptin infusion); permanent discontinuation of Herceptin for infusional toxicity was required in <1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusional toxicity occurred in 21% and 35% of patients, and was severe in 1.4% and 9% of patients, on second or

subsequent Herceptin infusions administered as monotherapy or in combination with chemotherapy, respectively. In the post-marketing setting, severe infusion reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported. Anemia In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% [Study 5]), of selected NCI-CTC Grade 2–5 anemia (12.5% vs. 6.6% [Study 1]), and of anemia requiring transfusions (0.1% vs. 0 patients [Study 2]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. Following the administration of Herceptin as a single agent (Study 6), the incidence of NCI-CTC Grade 3 anemia was < 1%. Neutropenia In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI-CTC Grade 4–5 neutropenia (2% vs. 0.7% [Study 2]) and of selected Grade 2–5 neutropenia (7.1% vs. 4.5 % [Study 1]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. In a randomized, controlled trial in patients with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Infection The overall incidences of infection (46% vs. 30% [Study 5]), of selected NCI-CTC Grade 2–5 infection/febrile neutropenia (22% vs. 14% [Study 1]) and of selected Grade 3–5 infection/febrile neutropenia (3.3% vs. 1.4%) [Study 2]), were higher in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. The most common site of infections in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract. In study 4, the overall incidence of infection was higher with the addition of Herceptin to AC-T but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)]. The incidences of NCI-CTC grade 3-4 infection were similar [25% (AC-TH), 21% (TCH), 23% (AC-T)] across the three arms. In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Pulmonary Toxicity Adjuvant Breast Cancer Among women receiving adjuvant therapy for breast cancer, the incidence of selected NCICTC Grade 2–5 pulmonary toxicity (14% vs. 5% [Study 1]) and of selected NCI-CTC Grade 3–5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4 % vs. 1% [Study 2]) was higher in patients receiving Herceptin and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI-CTC Grade 2–5: 12% vs. 4% [Study 1]; NCI-CTC Grade 2–5: 2.5% vs. 0.1% [Study 2]). Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving Herceptin compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving Herceptin, one as a component of multi-organ system failure, as compared to 1 patient receiving chemotherapy alone. In Study 3, there were 4 cases of interstitial pneumonitis in Herceptin-treated patients compared to none in the control arm. Metastatic Breast Cancer Among women receiving Herceptin for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have been reported in the post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, and acute respiratory distress syndrome. For a detailed description, see Warnings and Precautions. Thrombosis/Embolism In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving Herceptin and chemotherapy compared to chemotherapy alone in three studies (3.0% vs. 1.3% [Study 1], 2.5% and 3.7% vs. 2.2% [Study 4] and 2.1% vs. 0% [Study 5]). Diarrhea Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2–5 diarrhea (6.2% vs. 4.8% [Study 1]) and of NCI-CTC Grade 3–5 diarrhea (1.6% vs. 0% [Study 2]), and of grade 1-4 diarrhea (7% vs. 1% [Study 3]) were higher in patients receiving Herceptin as compared to controls. In Study 4, the incidence of Grade 3–4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1–4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving Herceptin. Of patients receiving Herceptin as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving Herceptin in combination with chemotherapy for treatment of metastatic breast cancer. Glomerulopathy In the postmarketing setting, rare cases of nephrotic syndrome with pathologic evidence of glomerulopathy have been reported. The time to onset ranged from 4 months to approximately 18 months from initiation of Herceptin therapy. Pathologic findings included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Complications included volume overload and congestive heart failure. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Among 903 women with metastatic breast cancer, human anti-human antibody (HAHA) to Herceptin was detected in one patient using an enzyme-linked immunosorbent assay (ELISA). This patient did not experience an allergic reaction. Samples for assessment of HAHA were not collected in studies of adjuvant breast cancer. The incidence of antibody formation is highly dependent on the sensitivity and the specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample

collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Herceptin with the incidence of antibodies to other products may be misleading. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category D [see Warnings and Precautions] Herceptin can cause fetal harm when administered to a pregnant woman. Postmarketing case reports suggest that Herceptin use during pregnancy increases the risk for oligohydramnios during the second and third trimester. If Herceptin is used during pregnancy or if a woman becomes pregnant while taking Herceptin, she should be apprised of the potential hazard to a fetus. In the postmarketing setting, oligohydramnios was reported in women who received Herceptin during pregnancy, either alone or in combination with chemotherapy. In half of these women, amniotic fluid index increased after Herceptin was stopped. In one case, Herceptin was resumed after the amniotic fluid index improved, and oligohydramnios recurred. Women using Herceptin during pregnancy should be monitored for oligohydramnios. If oligohydramnios occurs, fetal testing should be done that is appropriate for gestational age and consistent with community standards of care. Additional intravenous (IV) hydration has been helpful when oligohydramnios has occurred following administration of other chemotherapy agents, however the effects of additional IV hydration with Herceptin treatment are not known. Reproduction studies in cynomolgus monkeys at doses up to 25 times the recommended weekly human dose of 2 mg/kg trastuzumab have revealed no evidence of harm to the fetus. However, HER2 protein expression is high in many embryonic tissues including cardiac and neural tissues; in mutant mice lacking HER2, embryos died in early gestation. Placental transfer of trastuzumab during the early (Days 20-50 of gestation) and late (Days 120-150 of gestation) fetal development period was observed in monkeys. [See Nonclinical Toxicology] Because animal reproduction studies are not always predictive of human response, Herceptin should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Registry Pregnant women with breast cancer who are using Herceptin are encouraged to enroll in MotHER- the Herceptin Pregnancy Registry: phone 1-800-690-6720. Nursing Mothers It is not known whether Herceptin is excreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the breast milk of lactating cynomolgus monkeys given 12.5 times the recommended weekly human dose of 2 mg/kg of Herceptin. Infant monkeys with detectable serum levels of trastuzumab did not have any adverse effects on growth or development from birth to 3 months of age; however, trastuzumab levels in animal breast milk may not accurately reflect human breast milk levels. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from Herceptin, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of trastuzumab and the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Herceptin in pediatric patients has not been established. Geriatric Use Herceptin has been administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients in both those receiving treatment for metastatic disease in Studies 5 and 6, or adjuvant therapy in Studies 1 and 2. Limitations in data collection and differences in study design of the 4 studies of Herceptin in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of Herceptin in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of Herceptin treatment in older patients is different from that observed in patients <65 years of age for metastatic disease and adjuvant treatment. OVERDOSAGE There is no experience with overdosage in human clinical trials. Single doses higher than 8 mg/kg have not been tested. PATIENT COUNSELING INFORMATION • Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Boxed Warning: Cardiomyopathy]. • Advise women with reproductive potential to use effective contraceptive methods during treatment and for a minimum of six months following Herceptin [see Pregnancy]. • Encourage pregnant women who are using Herceptin to enroll in MotHER- the Herceptin Pregnancy Registry [see Pregnancy]. HERCEPTIN® [trastuzumab] Manufactured by: 4839803 Genentech, Inc. Initial US Approval: Sept. 1998 1 DNA Way Revision Date: March 2009 South San Francisco, CA LK0726 7172911 94080-4990 7172713 ©2009 Genentech, Inc.

HERCEPTIN® (trastuzumab) Brief Summary For full Prescribing Information, see package insert. WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, and PULMONARY TOXICITY Cardiomyopathy Herceptin can result in sub-clinical and clinical cardiac failure manifesting as CHF and decreased LVEF. The incidence and severity of left ventricular cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracycline-containing chemotherapy regimens. Evaluate left ventricular function in all patients prior to and during treatment with Herceptin. Discontinue Herceptin treatment in patients receiving adjuvant therapy and strongly consider discontinuation of Herceptin treatment in patients with metastatic breast cancer for clinically significant decrease in left ventricular function. [see Warnings and Precautions and Dosage and Administration] Infusion Reactions; Pulmonary Toxicity Herceptin administration can result in serious infusion reactions and pulmonary toxicity. Fatal infusion reactions have been reported. In most cases, symptoms occurred during or within 24 hours of administration of Herceptin. Herceptin infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinue Herceptin for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. [see Warnings and Precautions] INDICATIONS AND USAGE Adjuvant Breast Cancer Herceptin is indicated for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies]) breast cancer • as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel • with docetaxel and carboplatin • as a single agent following multimodality anthracycline based therapy. Metastatic Breast Cancer Herceptin is indicated: • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer • As a single agent for treatment of HER2overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Cardiomyopathy Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy ]. Herceptin can also cause asymptomatic decline in left ventricular ejection fraction (LVEF). There is a 4–6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving Herceptin as a single agent or in combination therapy compared with those not receiving Herceptin. The highest absolute incidence occurs when Herceptin is administered with an anthracycline. Withhold Herceptin for 16% absolute decrease in LVEF from pre-treatment values or an LVEF value below institutional limits of normal and 10% absolute decrease in LVEF from pretreatment values. [see Dosage and Administration] The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied. Cardiac Monitoring Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended: • Baseline LVEF measurement immediately prior to initiation of Herceptin • LVEF measurements every 3 months during and upon completion of Herceptin • Repeat LVEF measurement at 4 week intervals if Herceptin is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration] • LVEF measurements every 6 months for at least 2 years following completion of Herceptin as a component of adjuvant therapy. In Study 1, 16% (136/844) of patients discontinued Herceptin due to clinical evidence of myocardial dysfunction or significant decline in LVEF. In Study 3, the number of patients who discontinued Herceptin due to cardiac toxicity was 2.6% (44/1678). In Study 4, a total of 2.9% (31/1056) patients in the TCH arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued Herceptin due to cardiac toxicity. Among 32 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive heart failure, one patient died of cardiomyopathy and all other patients were receiving cardiac medication at last follow-up. Approximately half of the surviving patients had recovery to a normal LVEF (defined as 50%) on continuing medical management at the time of last follow-up. Incidence of congestive heart failure is presented in Table 1. The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied. Table 1 Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies Study 1 & 2a 3 4 4 a b

Regimen ACb Paclitaxel+ Herceptin Chemo Herceptin ACb Docetaxel+ Herceptin Docetaxel+Carbo+ Herceptin

Incidence of CHF Herceptin Control 2% (32/1677) 2% (30/1678)

0.4% (7/1600) 0.3% (5/1708)

2% (20/1068)

0.3% (3/1050)

0.4% (4/1056)

0.3% (3/1050)

Includes 1 patient with fatal cardiomyopathy. Anthracycline (doxorubicin) and cyclophosphamide

Table 2 Incidence of Cardiac Dysfunctiona in Metastatic Breast Cancer Studies

Study 5 (AC)b 5 (paclitaxel)

Incidence NYHA I-IV NYHA III-IV Herceptin Control Herceptin Control

Event Cardiac 28% 7% 19% 3% Dysfunction Cardiac 11% 1% 4% 1% Dysfunction Cardiac 6 7% N/A 5% N/A Dysfunctionc a Congestive heart failure or significant asymptomatic decrease in LVEF. b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide c Includes 1 patient with fatal cardiomyopathy. Infusion Reactions Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia. [see Adverse Reactions]. In postmarketing reports, serious and fatal infusion reactions have been reported. Severe reactions which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable including progressive worsening, initial improvement followed by clinical deterioration, or delayed post-infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction. Interrupt Herceptin infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical therapy administered, which may include: epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions. There are no data regarding the most appropriate method of identification of patients who may safely be retreated with Herceptin after experiencing a severe infusion reaction. Prior to resumption of Herceptin infusion, the majority of patients who experienced a severe infusion reaction were pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated Herceptin infusions, others had recurrent severe infusion reactions despite pre-medications. Exacerbation of Chemotherapy-Induced Neutropenia In randomized, controlled clinical trials in women with metastatic breast cancer, the perpatient incidences of NCI CTC Grade 3-4 neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was not significantly increased. [see Adverse Reactions]. Pulmonary Toxicity Herceptin use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions [see Warnings and Precautions (5.2)]. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity. HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been shown. Assessment for HER2 overexpression and of HER2 gene amplification should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Several FDA-approved commercial assays are available to aid in the selection of patients for Herceptin therapy. These include HercepTestTM and Pathway® HER-2/neu (IHC assays) and PathVysion® and HER2 FISH pharmDxTM (FISH assays). Users should refer to the package inserts of specific assay kits for information on the validation and performance of each assay. Limitations in assay precision (particularly for the IHC method) and in the direct linkage between assay result and overexpression of the Herceptin target (for the FISH method) make it inadvisable to rely on a single method to rule out potential Herceptin benefit. A negative FISH result does not rule out HER2 overexpression and potential benefit from Herceptin. Treatment outcomes for metastatic breast cancer (Study 5) as a function of IHC and FISH testing are provided in Table 9. Treatment outcomes for adjuvant breast cancer (Studies 2 and 3) as a function of IHC and FISH testing are provided in Table 7. HER2 Protein Overexpression Detection Methods HER2 protein overexpression can be established by measuring HER2 protein using an IHC method. HercepTest®, one test approved for this use, was assessed for concordance with the Clinical Trial Assay (CTA), using tumor specimens collected and stored independently from those obtained in Herceptin clinical studies in women with metastatic breast cancer. Data are provided in the package insert for HercepTest®. HER2 Gene Amplification Detection Method The presence of HER2 protein overexpression and gene amplification are highly correlated, therefore the use of FISH to detect gene amplification may be employed for selection of patients appropriate for Herceptin therapy. PathVysion®, one test approved for this use, was evaluated in an exploratory, retrospective assessment of available CTA 2+ or 3+ tumor specimens collected as part of patient screening for clinical studies in metastatic breast cancer (Studies 5 and 6). Data are provided in the package insert for PathVysion®. Embryo-Fetal Toxicity (Pregnancy Category D) Herceptin can cause fetal harm when administered to a pregnant woman. Postmarketing case reports suggest that Herceptin use during pregnancy increases the risk of oligohydramnios during the second and third trimesters. If Herceptin is used during pregnancy or if a woman becomes pregnant while taking Herceptin, she should be apprised of the potential hazard to a

fetus. [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Cardiomyopathy [see Warnings and Precautions] • Infusion reactions [see Warnings and Precautions] • Exacerbation of chemotherapy-induced neutropenia [see Warnings and Precautions] • Pulmonary toxicity [see Warnings and Precautions] The most common adverse reactions in patients receiving Herceptin are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions requiring interruption or discontinuation of Herceptin treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and Administration]. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adjuvant Breast Cancer Studies The data below reflect exposure to Herceptin across three randomized, open-label studies, Studies 1, 2, and 3, with (n= 3355) or without (n= 3308) trastuzumab in the adjuvant treatment of breast cancer. The data summarized in Table 3 below, from Study 3, reflect exposure to Herceptin in 1678 patients; the median treatment duration was 51 weeks and median number of infusions was 18. Among the 3386 patients enrolled in Study 3, the median age was 49 years (range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian. Table 3 Adverse Reactions for Study 3, All Gradesa: MedDRA (v. 7.1) 1 Year Herceptin Adverse Event Preferred Term (n= 1678) Cardiac Hypertension 64 (4%) Dizziness 60 (4%) Ejection Fraction Decreased 58 (3.5%) Palpitations 48 (3%) Cardiac Arrhythmiasb 40 (3%) Cardiac Failure Congestive 30 (2%) Cardiac Failure 9 (0.5%) Cardiac Disorder 5 (0.3%) Ventricular Dysfunction 4 (0.2%) Respiratory Thoracic Mediastinal Disorders Nasopharyngitis 135 (8%) Cough 81 (5%) Influenza 70 (4%) Dyspnea 57 (3%) URI 46 (3%) Rhinitis 36 (2%) Pharyngolaryngeal Pain 32 (2%) Sinusitis 26 (2%) Epistaxis 25 (2%) Pulmonary Hypertension 4 (0.2%) Interstitial Pneumonitis 4 (0.2%) Gastrointestinal Disorders Diarrhea 123 (7%) Nausea 108 (6%) Vomiting 58 (3.5%) Constipation 33 (2%) Dyspepsia 30 (2%) Upper Abdominal Pain 29 (2%) Musculoskeletal & Connective Tissue Disorders Arthralgia 137 (8%) Back Pain 91 (5%) Myalgia 63 (4%) Bone Pain 49 (3%) Muscle Spasm 46 (3%) Nervous System Disorders Headache 162 (10%) Paraesthesia 29 (2%) Skin & Subcutaneous Tissue Disorders Rash 70 (4%) Nail Disorders 43 (2%) Pruritis 40 (2%) General Disorders Pyrexia 100 (6%) Edema Peripheral 79 (5%) Chills 85 (5%) Aesthenia 75 (4.5%) Influenza-like Illness 40 (2%) Sudden Death 1 (.06%) Infections Nasopharyngitis 135 (8%) UTI 39 (3%) Immune System Disorders Hypersensitivity 10 (0.6%) Autoimmune Thyroiditis 4 (0.3%)

Observation (n= 1708) 35 (2%) 29 (2%) 11 (0.6%) 12 (0.7%) 17 (1%) 5 (0.3%) 4 (0.2%) 0 (0%) 0 (0%) 43 (3%) 34 (2%) 9 (0.5%) 26 (2%) 20 (1%) 6 (0.4%) 8 (0.5%) 5 (0.3%) 1 (0.06%) 0 (0%) 0 (0%) 16 (1%) 19 (1%) 10 (0.6%) 17 (1%) 9 (0.5%) 15 (1%) 98 (6%) 58 (3%) 17 (1%) 26 (2%) 3 (0.2%) 49 (3%) 11 (0.6%) 10 (.6%) 0 (0%) 10 (0.6%) 6 (0.4%) 37 (2%) 0 (0%) 30 (2%) 3 (0.2%) 0 (0%) 43 (3%) 13 (0.8%) 1 (0.06%) 0 (0%)

a The incidence of Grade 3/4 adverse reactions was <1% in both arms for each listed term. b Higher level grouping term.

The data from Studies 1 and 2 were obtained from 3206 patients enrolled, of which 1635 patients received Herceptin; the median treatment duration was 50 weeks. The median age was 49.0 years (range: 24-80); 84% of patients were White, and 7% were Black, 4% were Hispanic, and 4% were Asian. In Study 1, only Grade 3-5 adverse events, treatment-related Grade 2 events, and Grade 2-5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following noncardiac adverse reactions of Grade 2-5 occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (31% vs. 28%), fatigue (28% vs. 22%), infection (22% vs. 14%), hot flashes (17% vs. 15%), anemia (13% vs. 7%), dyspnea (12% vs. 4%), rash/desquamation (11% vs. 7%), neutropenia (7% vs. 5%), headache (6% vs. 4%), and insomnia (3.7% vs. 1.5%). The majority of these events were Grade 2 in severity. In Study 2, data collection was limited to the following investigator-attributed treatment-related adverse reactions NCICTC Grade 4 and 5 hematologic toxicities, Grade 3–5 nonhematologic toxicities, selected Grade 2–5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, sensory neuropathy) and Grade 1–5 cardiac toxicities occurring during chemotherapy and/or Herceptin treatment. The following non-cardiac adverse reactions of

Grade 2–5 occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (11% vs. 8.4%), myalgia (10% vs. 8%), nail changes (9% vs. 7%), and dyspnea (2.5% vs. 0.1%). The majority of these events were Grade 2 in severity. Safety data from Study 4 reflect exposure to Herceptin as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068; TCH: n = 1056]. The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms. The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase and every three week dosing in the monotherapy period. Among these patients, the median age was 49 years (range 22 to 74 years). In Study 4, the toxicity profile was similar to that reported in Studies 1, 2, and 3 with the exception of a low incidence of CHF in the TCH arm. Metastatic Breast Cancer Studies The data below reflect exposure to Herceptin in one randomized, openlabel study, Study 5, of chemotherapy with (n=235) or without (n=234) trastuzumab in patients with metastatic breast cancer, and one single-arm study (Study 6; n=222) in patients with metastatic breast cancer. Data in Table 5 are based on Studies 5 and 6. Among the 464 patients treated in Study 5, the median age was 52 years (range: 25–77 years). Eighty-nine percent were White, 5% Black, 1% Asian and 5% other racial/ethnic groups. All patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for 6 months and 12 months were 58% and 9%, respectively. Among the 352 patients treated in single agent studies (213 patients from Study 6), the median age was 50 years (range 28–86 years), 100% had breast cancer, 86% were White, 3% were Black, 3% were Asian, and 8% in other racial/ ethnic groups. Most of the patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for 6 months and 12 months were 31% and 16%, respectively. Table 4 Per-Patient Incidence of Adverse Reactions Occurring in 5% of Patients in Uncontrolled Studies or at Increased Incidence in the Herceptin Arm (Studies 5 and 6) (Percent of Patients) Herceptin Single + Paclitaxel Herceptin ACb Agenta Paclitaxel Alone + ACb Alone n = 352 n = 91 n = 95 n = 143 n = 135 Body as a Whole Pain 47 61 62 57 42 Asthenia 42 62 57 54 55 Fever 36 49 23 56 34 Chills 32 41 4 35 11 Headache 26 36 28 44 31 Abdominal pain 22 34 22 23 18 Back pain 22 34 30 27 15 Infection 20 47 27 47 31 Flu syndrome 10 12 5 12 6 Accidental injury 6 13 3 9 4 Allergic reaction 3 8 2 4 2 Cardiovascular Tachycardia 5 12 4 10 5 Congestive 7 11 1 28 7 heart failure Digestive Nausea 33 51 9 76 77 Diarrhea 25 45 29 45 26 Vomiting 23 37 28 53 49 Nausea and 8 14 11 18 9 vomiting Anorexia 14 24 16 31 26 Heme & Lymphatic Anemia 4 14 9 36 26 Leukopenia 3 24 17 52 34 Metabolic Peripheral edema 10 22 20 20 17 Edema 8 10 8 11 5 Musculoskeletal Bone pain 7 24 18 7 7 Arthralgia 6 37 21 8 9 Nervous Insomnia 14 25 13 29 15 Dizziness 13 22 24 24 18 Paresthesia 9 48 39 17 11 Depression 6 12 13 20 12 Peripheral neuritis 2 23 16 2 2 Neuropathy 1 13 5 4 4 Respiratory Cough increased 26 41 22 43 29 Dyspnea 22 27 26 42 25 Rhinitis 14 22 5 22 16 Pharyngitis 12 22 14 30 18 Sinusitis 9 21 7 13 6 Skin Rash 18 38 18 27 17 Herpes simplex 2 12 3 7 9 Acne 2 11 3 3 <1 Urogenital Urinary tract 5 18 14 13 7 infection a Data for Herceptin single agent were from 4 studies, including 213 patients from Study 6. b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide The following subsections provide additional detail regarding adverse reactions observed in clinical trials of adjuvant breast, metastatic breast cancer, or post-marketing experience. Cardiomyopathy Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. In Study 3, the median duration of follow-up was 12.6 months (12.4 months in the observation arm; 12.6 months in the 1-year Herceptin arm); and in Studies 1 and 2, 23 months in

In the adjuvant treatment of HER2+ breast cancer

Herceptin in combination with Taxotere® and carboplatin (TCH), a nonanthracycline regimen, significantly improved disease-free survival (DFS) vs AC →T1 TCH demonstrated DFS benefit consistent with AC→TH1

Proportion event-free

DFS at 3 years1,2 * 1.0

Absolute DFS at 3 years

0.8

86.3% (TCH) 88.0% (AC→TH) 82.3% (AC→T)

TCH vs AC→T HR=0.67 (95% CI: 0.54-0.84)† P=0.0006

0.6 0.4

AC→TH vs AC→T HR=0.60 (95% CI: 0.48-0.76) P<0.0001

0.2 0.0 0.0

1.0

2.0 DFS (years)

3.0

4.0

971 1023 1018

802 885 877

417 457 447

103 126 126

Number at risk AC→ T AC→ TH TCH

1073 1074 1075

AC→T (n=1073) AC→TH (n=1074) TCH (n=1075)

AC=doxorubicin/cyclophosphamide T=Taxotere

C=carboplatin H=Herceptin

• 33% reduction in risk of recurrence with TCH (HR=0.67, CI: 0.54-0.84; P=0.0006) • 40% reduction in risk of recurrence with AC→TH (HR=0.60, CI: 0.48-0.76; P<0.0001)

Reduced risk of congestive heart failure with TCH vs AC→TH1 • 0.4% (TCH) vs 2% (AC →TH) and 0.3% (AC →T) Adjuvant indications

Metastatic indications

Herceptin is indicated for adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature‡) breast cancer: • As part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel • With docetaxel and carboplatin • As a single agent following multi-modality anthracycline-based therapy

Herceptin is indicated: • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer • As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease

‡High-risk

features for patients with ER/PR+ breast cancer include: tumor size > 2 cm, age <35 years, and histologic and/or nuclear grade 2/3.

Boxed WARNINGS and Additional Important Safety Information Herceptin administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure and decreased left ventricular ejection fraction. Serious infusion reactions and pulmonary toxicity have occurred; fatal infusion reactions have been reported. Exacerbation of chemotherapy-induced neutropenia has also occurred. Herceptin can cause oligohydramnios and fetal harm when administered to a pregnant woman. The most common adverse reactions associated with Herceptin use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Taxotere is a registered trademark of sanofi-aventis U.S. LLC. *BCIRG 006 study design: Conducted by the Breast Cancer International Research Group (BCIRG), this clinical trial evaluated the efficacy and cardiac safety of two regimens vs control in a 1:1:1 randomization. The TCH arm consisted of concurrent docetaxel, carboplatin, and Herceptin and the AC→TH arm consisted of AC (doxorubicin and cyclophosphamide), followed by docetaxel and Herceptin. Control did not include Herceptin. Hormonal and/or radiotherapy were given as appropriate. † HR = hazard ratio; CI = confidence interval.

Please see accompanying brief summary of full Prescribing Information, including Boxed WARNINGS and additional important safety information, on the following pages. References: 1. Herceptin Prescribing Information. Genentech, Inc. March 2009. 2. Data on file. Genentech, Inc.

So. San Francisco, CA

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