MARCH/APRIL 2011,VOL 4, NO 2 by The Oncology Pharmacist

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MARCH/APRIL 2011

www.TheOncologyPharmacist.com

VOL 4, NO 2

For Payers, Purchasers, & Oncology P&T Committees CONFERENCE NEWS

CANCER CENTER PROFILE

St. Joseph Mercy Cancer Care Center A Cancer Hospital in a Small Community Has Big Plans By Dawn Lagrosa

Review of New Oncology Drugs at HOPA By Christin Melton

n a review of new drugs to hit the market, speaker Maribel Pereiras, PharmD, BCOP, BCPS, referred to 2010 as “quite the year for prostate and breast cancer.” Pereiras, a clinical assistant professor at Ernest Mario School of Pharmacy, Rutgers University, and a clinical oncology pharmacist with Hackensack University Medical Center, New Jersey, reviewed newly approved anticancer agents sipuleucel-T (Provenge),

cabazitaxel (Jevtana), eribulin (Halaven), and denosumab (Xgeva) for pharmacists attending the annual meeting of the Hematology/Oncology Pharmacy Association. She also discussed dabigatran etexilate (Pradaxa), an anticoagulant recently approved to prevent stroke and embolism in patients with atrial fibrillation, which she included because she anticipates some oncologists using it offContinued on page 8

CONFERENCE NEWS

Cost-Containment Strategies By Christin Melton

I Clockwise from top left: Walter M. Sahijdak, MD; Philip J. Stella, MD; Lara Blair, RN; and Vita McCabe, MD; of the multidisciplinary lung clinic at St. Joseph Mercy Cancer Care Center.

ollowing a lung cancer diagnosis, patients typically embark on a dizzying journey that takes them from one waiting room to another, as they follow their treatment plan from the medical oncologist to the surgical oncologist to the radiation oncologist and back again. Coordinating these visits imposes yet another burden on the patient and often leads to delays in care. Six years ago, St. Joseph Mercy Cancer Care Center in Ypsilanti, Michigan, decided to simplify life for their patients by opening a multidisciplinary lung cancer clinic.

Continued on page 30

n a “Technical Issues” session at the Hematology/Oncology Pharmacist Association annual meeting, Bhavesh Shah, RPh, BCOP, a clinical pharmacy specialist in hematology/oncology with Boston Medical Center, in Massachusetts, discussed dose-rounding, rapid infusion, and other strategies his center has adopted to reduce costs. Prior to establishing measures your oncology practice can implement to lower expenses, you need to review your physicians’ prescribing habits, identify causes of drug

For more CE Opportunities and to take the posttest for the CE article in this issue, visit

www.TheOncologyPharmacist.com

Dose-Rounding A cost-saving measure that some inpatient pharmacies have implemented is rounding the dose of certain biologic anticancer drugs to within 10% of the amount ordered. The purpose of doserounding strategies is threefold, said Shah: (1) to ensure the drug is measured Continued on page 6

INSIDE COMPLIMENTARY CE

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Maintenance Therapy for Non–Small Cell Lung Cancer, Part II CONFERENCE NEWS

VISIT US

waste at your facility, and look for outlays in time or product that are not captured in reimbursement channels.

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Making Cancer Drugs Worth the Cost Are You Talking to Patients About Smoking Cessation? DRUG SHORTAGES

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A Growing Crisis in Oncology

NEWS IN REVIEW

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FDA Panel Recommends Stricter Process of Accelerated Approval FDA Approves Ipilimumab for Melanoma Medicare Plans to Cover Provenge Variation in Prescribing Instructions Confuses Patients THE WHOLE PATIENT . . . . . . . . . .

Cancer Treatment–Induced Diarrhea Managing Comorbidities

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ducational S ivision o ational P S TAT E ervices, a d harmacy T echnician A ssociation IInc., nc., iis sa ccredited b y tthe he A ccreditation C ouncil ffor or P harmacy E ducation ((ACPE) ACPE) a sap rovider o ontinuing STAT Educational Services, division off N National Pharmacy Technician Association accredited by Accreditation Council Pharmacy Education as provider off ccontinuing p harmacy e ducation. du pharmacy education. This knowledge-based program has been accredited for 1.0 contact hours of continuing education for pharmacists, pharmacy techni cians, nurses, and risk managers. technicians, Learning Obj Objectives: ectives: At the completion activity completion of this act activity,, the participant will be able to: - Describe the e evidence for the genotoxicity of anti-cancer chemotherapy in patients; - Relate the sp pecific chromosomal chromo osomal targets g assoc ciated with various chemotherapy py drug drug g classes; specific that have been associated - Discuss the suf fficiency ficiency of current c safe-handling policies in light of recent evidence of worker exposure; sufficiency - Identify the concerns associated with handling hazardous medications; - Discuss pertinent aspects of the policy and procedure UNC Hospitals utilizes for handling hazardous medications; - Review future research opportunities around hazardous medications; - List ONS guidelines for safe handling; - Describe nursing basics for safe handling; - Describe proper donning of personal protective equipment (PPE).

Activity T Type: ype: Knowledge T arget Audience: Pharmacists, Pharmacy T echnicians, Nurses, & Risk Managers Target Technicians, Universal Activity Number (UAN): 0384-9999-1 1-002-C05-P 0384-9999-11-002-C05-P 0384-9999-1 1-002-C05-T 0384-9999-11-002-C05-T The University of Nebraska Medical Center College of Nursing Continuing Nursing Education is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center â&#x20AC;&#x2122;s Commission on Accreditation. Centerâ&#x20AC;&#x2122;s Provided under Iowa Provider #78. Provider approved by the California Board of Registered Nursing, Provider #13699.

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Editorial Board EDITOR-INCHIEF Patrick Medina, PharmD, BCOP Oklahoma University College of Pharmacy Tulsa, OK

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

Jim Koeller, MS University of Texas at Austin San Antonio, TX

Timothy G. Tyler, PharmD, FCSHP Desert Regional Medical Center Palm Springs, CA

Christopher Fausel, PharmD

Christopher J. Lowe, PharmD

John M. Valgus, PharmD, BCOP

Indiana University Simon Cancer Center Indianapolis, IN

Indiana University Hospital Indianapolis, IN

University of North Carolina Hospitals and Clinics Chapel Hill, NC

David Baribeault, RPh, BCOP

Rebecca S. Finley, PharmD, MS

Emily Mackler, PharmD, BCOP

Boston Medical Center Boston, MA

Jefferson School of Pharmacy Philadelphia, PA

University of Michigan Health System & College of Pharmacy Ann Arbor, MI

Gary C. Yee, PharmD, FCCP, BCOP

Betty M. Chan, PharmD, BCOP

David C. Gammon, BSPh

Laura Boehnke Michaud, PharmD, BCOP, FASHP

John F. Aforismo, BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT

USC/Norris Cancer Hospital Los Angeles, CA

OncologyPharmacist.net Warwick, RI

University of Nebraska College of Pharmacy Omaha, NE

Burt Zweigenhaft, BS BioPharma Partners LLC New York, NY

The University of Texas M. D. Anderson Cancer Center Houston, TX

Marlo Blazer, RPh, PharmD Steven L. Dâ&#x20AC;&#x2122;Amato, RPh, BCOP

Lew Iacovelli, BS, PharmD, BCOP, CPP

LeAnn Best Norris, PharmD, BCPS, BCOP

Maine Center for Cancer Medicine Scarborough, ME

Moses H. Cone Health System Greensboro, NC

South Carolina College of Pharmacy Columbia, SC

James Cancer Hospital & Solove Research Institute Columbus, OH

Heidi D. Gunderson, PharmD, BCOP Mayo Clinic Cancer Center Rochester, MN

Anjana Elefante, PharmD, BSc, BSc Pharm, RPh

Dwight Kloth, PharmD, FCCP, BCOP

Steve Stricker, PharmD, MS, BCOP

Roswell Park Cancer Institute Buffalo, NY

Fox Chase Cancer Center Philadelphia, PA

Samford University McWhorter School of Pharmacy Birmingham, AL

www.TheOncologyPharmacist.com

Kamakshi V. Rao, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC

March/aPril 2011 I VOl 4, NO 2

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From the Editor For Payers, Purchasers, & Oncology P&T Committees

PUBLISHING STAFF

ew HOPA president Moe Schwartz, PharmD, BCOP, welcomed oncology pharmacists to this year’s conference, where we had the chance to learn about new therapies and new oncology pharmacy practice management strategies. Our roundup of new drugs and management strategies presented should provide a quick reference guide for those of you looking to Patrick Medina, implement what you learned. PharmD, BCOP We also continue to publish the Editor-in-Chief latest research and evidence-based practical information to help you provide care throughout the continuum of cancer. To this end, we introduce The Whole Patient, a department that

Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com Editorial Director Christin Melton christin@greenhillhc.com Associate Editor Dawn Lagrosa dawn@greenhillhc.com Quality Control Director Barbara Marino Director, Client Services Joe Chanley joe@greenhillhc.com Production Manager Stephanie Laudien

will help you help your patients with all the things that lead to quality of life—be it lifestyle issues such as smoking cessation, polypharmacy and comorbidities among the elderly or supportive issues like treatment-induced diarrhea. Our feature highlights one of our biggest ongoing challenges—the oncology drug shortage—by illuminating our interconnectedness with our partners in care, various government agencies and multiple drug manufacturers. In reading this article, I am reminded that we are all in this together and need to work as a team to solve problems and provide the best care to patients. I remind you to vote for one of our four finalists for the T.O.P Pharmacist award. And as you read this issue, I hope it provides you with information that helps you in your practice, in your career, and in meeting the ever-changing challenges of today’s healthcare environment. We look forward to your feedback. ●

Business Manager Blanche Marchitto blanche@greenhillhc.com

News Notes

Executive Administrator Andrea Boylston Circulation Department circulation@greenhillhc.com

Vandetanib Approved for Medullary Thyroid Cancer

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The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN 1944-9593 (online) is published 8 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2011 by Green Hill Healthcare Communications LLC. All rights reserved. The Oncology Pharmacist® logo is a registered 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. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist®, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: editorial@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in The Oncology Pharmacist® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Pharmacist® 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. BPA Worldwide membership applied for April 2011.

March/aPril 2011 I VOl 4, NO 2

Vandetanib (Zactima) received full approval from the US Food and Drug Administration (FDA) for patients with nonresectable or metastatic medullary thyroid cancer (MTC). Vandetanib was initially approved under the FDA’s orphan drug program, becoming the first medical treatment for MTC. Approval was based on data from the phase 3 ZETA trial comparing vandetanib with placebo. Vandetanib did not improve overall survival (OS), but progressionfree survival (PFS) for patients in this arm was significantly better compared with the placebo group (22.6 mo vs 16.4 mo, respectively; P < .0001), resulting in a 65% reduction in risk of disease progression. Common adverse effects include diarrhea, rash, acne, nausea, hypertension, headache, fatigue, decreased appetite, and abdominal pain. Vandetanib’s label features a black-box warning about the risks of treatment-related QT prolongation, torsades de points, and sudden death, and notes that the drug’s 19-day half-life could delay resolution of adverse reactions. To distribute vandetanib, prescribers and pharmacies must be certified with AstraZeneca’s Risk Evaluation and Mitigation Strategies program.

ASCO Calls for EGFR Mutation Testing in Some Patients with Lung Cancer A provisional clinical opinion (PCO) by the American Society of Clinical Oncology (ASCO) recommends patients with newly diagnosed advanced non–small cell lung cancer (NSCLC) be tested for an EGFR mutation prior to first-line therapy with an EGFR tyrosine kinase inhibitor (TKI). The decision was made after 5 randomized, controlled trials demonstrated better PFS for patients with an EGFR mutation who took gefitinib (Iressa) or erlotinib (Tarceva). No study has linked targeting EGFR TKI therapy to an activating EGFR mutation with improvement in OS. Nearly 15% of patients with NSCLC have an activating EGFR mutation. Testing is available at most academic medical centers and some community practices. The 5 trials reviewed compared standard platinumbased chemotherapy with an EGFR TKI. The phase 3 IPASS trial reported a median PFS of 9.5 months for EGFR-positive patients receiving gefitinib compared with 6.3 months for EGFR-positive patients given

chemotherapy. In EGFR-negative patients, gefitinib was associated with significantly worse PFS than chemotherapy, underscoring the need for testing prior to EGFR TKI use. In second- and third-line studies of erlotinib, which is more commonly available in the United States than gefitinib, EGFR-positive patients experienced longer PFS than EGFR-negative patients. The PCO notes that the FDA has not approved gefitinib or erlotinib as a first-line treatment for advanced NSCLC, nor has the FDA given clearance to any EGFR mutation test. ASCO says results from fluorescence in situ hybridization and immunohistochemistry testing for EGFR are not sufficiently reliable to guide treatment.

Novartis Halts Trial of Nilotinib in GIST Novartis has discontinued a phase 3 trial assessing whether its TKI nilotinib (Tasigna) might be a more effective first-line therapy than imatinib (Gleevec) in patients with unresectable or metastatic gastrointestinal stromal tumors (GISTs). Nilotinib has shown better efficacy than imatinib in patients with newly diagnosed chronic myeloid leukemia and is approved for this indication. Investigators were disappointed that nilotinib did not similarly outperform imatinib in GIST.

Soy Foods Safe for Breast Cancer Survivors Isoflavones from soy foods do not increase breast cancer recurrence risks said researchers at the American Association for Cancer Research annual meeting. Isoflavones have estrogen-like properties, prompting some survivors to avoid soy foods. The study reviewed questionnaires on the eating habits of 9515 women in trials of breast cancer survivors. At a median follow-up of 7.4 years, recurrence risk was 35% lower and overall mortality was reduced 17% in the 10% of women who ate the most soy foods. Investigators did not examine the effects of isoflavones from soy supplementation.

Many Patients Still Smoke After Lung Cancer Diagnosis A study by the National Cancer Institute reports that approximately 1 in 5 patients with lung cancer continue to smoke after diagnosis. The authors say more needs to be done to counsel these patients on how and why to quit smoking. ●

www.TheOncologyPharmacist.com

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Conference News Cost-Containment Strategies Continued from cover accurately; (2) to minimize drug waste; and (3) to maximize cost avoidance. He listed the 10 drugs most amenable to dose-rounding (Table). “For any order that comes through the pharmacy, the pharmacist can round the dose to the nearest vile size for the concentration,” said Shah. There are exceptions, such as when the difference between the ordered dose and the nearest vile size exceeds 10%. “That’s when we try to round it to the nearest concentration size available.” A dose-rounding program is only as effective as the level of adherence by pharmacy clinicians. A retrospective study published in 2010 by Winger and associates found that a 3-month pilot program in 2005 to round doses for orders of 7 biologic anticancer agents would have produced a 42% reduction in drug wastage and $24,434 in savings had there been 100% compliance with the program. Because 29 of the 126 orders were not filled according to the dose-rounding protocol, savings only amounted to $15,922. A dose-rounding program should include measures for monitoring adherence. Chemotherapy Infusion Shah said changing how the facility handles chemotherapy infusion offers several opportunities for cost-containment. He outlined Boston Medical Center measures enacted to save thousands of dollars annually. Shift from Inpatient Administration to Outpatient Administration Encourage your physicians to shift from inpatient chemotherapy administration to outpatient chemotherapy administration. Shah said Boston Medical Center did this after observing a marked increase in the number of inpatient chemotherapy sessions. “We developed this because a lot of chemotherapy was being administered in the hospital, primarily due to convenience, where we got reimbursed by DRGs [diagnostic-related groups] but not based on what the patient was actually receiving,” Shah explained. Medicare allows only 1 DRG for inpatient claims, whereas outpatient claims can use multiple ambulatory payment classifications (APCs). Chemotherapy drugs are not bundled under APCs, allowing higher reimbursement. “Now, we always push our physicians to do it on the day of or the day after hospital release so we can capture that cost,” he said. Shah said implementing this program decreased orders for inhospital chemotherapy administration by 50%.

March/aPril 2011 I VOl 4, NO 2

Table The Top 10 Anticancer Agents Amenable to Dose-Rounding Drug Rounding Amount Infliximab Bevacizumab

Nearest 100 mg

Rituximab Docetaxel

Nearest 100 mg

Pemetrexed

Nearest 100 mg

Cetuximab

Nearest 100 mg

Oxaliplatin

Nearest 5 mg or 50 mg

Gemcitabine

Nearest 200 mg

Nearest 100 mg Nearest 20 mg

Panitumumab Nearest 20 mg or 100 mg Bendamustine Nearest 25 mg

Test Rituximab Before Infusion Another new policy at Boston Medical is to administer a test dose of rituximab prior to infusion. Shah said 80% of patients on rituximab have a reaction to their first infusion that leads to discontinuation and drug waste. In 2009, infusion reactions led to $50,000 in wasted rituximab. Now a 100-mg dose is administered to all patients scheduled for rituximab infusion who have not received the drug for ≥6 months. In fiscal year 2010, Boston Medical Center saved approximately $2000 per patient prescribed rituximab. Follow Guidelines for Pegfilgrastim When Shah and his colleagues were seeking ways to reduce costs, they saw that orders for pegfilgrastim had increased. Based on data from a study by Sugarman and colleagues in the 2009 issue of Breast Cancer Research and Treatment, they concluded it might be safe to delay administration of white blood cell growth factor support for patients treated with paclitaxel and tested the theory in a small group of patients. For 10 patients prescribed 4 cycles of paclitaxel (175 mg/m2 every 2 weeks), the center administered a single dose of pegfilgrastim with the first dose of the second cycle of paclitaxel. All patients completed therapy without delay, with no neutropenic events or hospitalizations observed. Shah speculated that delaying pefilgrastim led to less bone pain from paclitaxel-induced arthralgia. It also produced $60,000 in savings. Shah and his colleagues found pegfilgrastim was sometimes administered as primary prophylaxis in situations inconsistent with National Comprehensive Cancer Center and American Society of Clinical Oncology guidelines. “There was a lot of inappropriate utilization, in metastatic prostate cancer, stage IV non– small cell lung cancer [NSCLC], and metastatic colon cancer,” said Shah. They requested that physicians stop using

growth factor support when the intent was not curative and they could use dose reductions or delays. Physicians were also told to stop giving it to patients receiving chemotherapy with curative intent and an associated incidence of febrile neutropenia <20%. In requesting that physicians adhere to evidence-based guidelines for pegfilgrastim use, Shah said they required administering it in the adjuvant setting for patients with colorectal cancer and NSCLC, the neoadjuvant setting for patients with solid tumors whose operative procedure had curative intent, and for patients with a malignancy related to acquired immunodeficiency syndrome (AIDS). Even with requiring pegfilgrastim use in these circumstances, Shah said they decreased expenditures for the drug by $250,000 annually. This does not factor in costsavings that might have occurred as a result of ensuring that patients who should get the drug received it. Rapid Infusion Shah described himself as a fan of rapid infusion where appropriate, but he noted that no formal economic analysis has ever been presented on its cost-effectiveness. Agents to consider for rapid infusion are the monoclonal antibodies ri tuximab, bevacizumab, trastuzumab, cetuximab, and low-molecular-weight (LMW) iron dextran. “This can increase your resource utilization,” said Shah. A 2007 study published in Blood by Sehn and associates tested a 90-minute rituximab infusion in >1200 patients. They reported a 0% rate of grade 3/4 toxicity related to the faster infusion. Other studies have found 30-minute infusions of trastuzumab (6 mg/kg) and bevacizumab (0.5 mg/kg/min) and 60minute infusions of cetuximab (500 mg/m2) and LMW iron dextran (1 g) to be relatively safe. A higher rate of adverse events was observed in patients allergic to >2 drugs who received LMW iron dextran; several patients in the bevacizumab study who received 15 mg/kg over 30 minutes experienced hypersensitivity reactions. Shah cautioned that Dexferrum—another form of iron dextran—“shouldn’t be used in a rapid fashion.” “I think rapid infusions are great. It totally increases the volume for your clinic and decreases the absentees, and you can get your patients out faster.” Shah said it also increases satisfaction among patients and nurses. Cetuximab versus Panitumumab At Boston Medical Center, Shah said it was decided to switch from cetuximab to the lower-cost panitumumab for colorectal cancer based on studies showing

little difference in overall response rate, progression-free survival, or overall survival. Shah said although the cost per 100 mg is higher for panitumumab than for cetuximab ($618.81 vs $367.83, respectively), cetuximab requires an 8-vial loading dose. A cost analysis found that the cost for 4 weeks of panitumumab averaged $5953.70 compared with $8460.09 for cetuximab. In addition, reimbursement from the Centers for Medicare & Medicaid Services (CMS) was higher for panitumumab than for cetuximab ($49.737/10 mg vs $87.326/10 mg). Other savings were realized with panitumumab in reduced chair time, because it can be administered every 2 weeks, and in significantly less expense to treat febrile neutropenia. Handling Waste Any number of events can lead to drug waste. “There was a technician who put our cetuximab into the freezer and that had to be wasted,” said Shah. “There was a physician who decided not to treat the patient after it was mixed.” He related an occasion when a nurse spiked the bag. “We also see a lot of single-dose vial waste because you can’t round to the nearest vial size, like with oxaliplatin.” Shah said Boston Medical Center takes advantage of biooncology spoilage programs offered by pharmaceutical companies. “They’re not well known, and you have to actually call, but once you find the forms, it’s pretty easy,” he said. If the cause of the waste is not listed, most forms provide a space to add it. Shah said the companies evaluate the requests on a case-by-case basis. “We had about $20,000 in waste that we saved last year using these programs. Fill out a form and they send you a check for the drug that’s been wasted,” said Shah. Adopting programs to minimize waste allows you to request reimbursement from CMS for “discarded drug/ biological remaining in a single-use product after administering what is reasonable and necessary for the patient’s condition,” per Pub. 100-04, Chapter 17, Section 40 in the Medicare Claims Processing Manual. Shah said, “There’s a JW code that mirrors the J code you’re billing for.” The CMS policy requires documenting the cause of waste in the patient’s medical record, and that is another policy Boston Medical Center has implemented to ensure that those costs can be recovered. The most important consideration when looking for ways to save costs is patient safety. Shah recommended ensuring that all the changes you decide to implement align with evidence-based national guidelines for cancer care. ●

www.TheOncologyPharmacist.com

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Conference News

Making Cancer Drugs Worth the Cost By Christin Melton

s nations around the globe struggle to afford the growing cost of care for their citizens, more people are asking, “How much is too much?” when it comes to cancer. Although the John G. Kuhn Keynote Lecture delivered at the annual meeting of the Hematology/ Oncology Pharmacy Association was titled “The Cost of Cancer Therapy,” speaker Tito Fojo, MD, PhD, with the medical oncology branch of the National Cancer Institute (NCI), says cost is not the real issue. “If you frame the argument in terms of cost, you’re going to lose it,” he told the audience of pharmacists. Fojo said the real issues are “how effective drugs are and how toxic drugs are.” Fojo offered examples of drugs used in clinical practice that he believes not only fail to improve survival but actually harm patients, including cetuximab (Erbitux) in metastatic colorectal cancer (mCRC) and bevacizumab (Avastin) in breast cancer. He noted that controversy surrounds these examples and not everyone shares his views—including Giuseppe Giaccone, his supervisor at the NCI and a member of the American Society of Clinical Oncology (ASCO) panel responsible for adding the combination of cetuximab and paclitaxel to the ASCO guidelines for first-line therapy of mCRC. The examples Fojo cites are also found in the National Comprehensive Cancer Network (NCCN) treatment guidelines. Even if one disagrees with Fojo’s conclusions, his review of the pivotal trials used to support approval of cetuximab in mCRC and bevacizumab in breast cancer underscores important considerations for stakeholders when deciding how anticancer drugs should be developed, evaluated, and used. “Our drug development, drug approval, and drug consumption strategies need better focus,” said Fojo, who lamented that despite the decade that has elapsed since imatinib (Gleevec) ushered in the “targeted therapy revolution,” too many treatments are still used indiscriminately in broad patient populations. Fojo sees room for improvement at all levels: academia, the pharmaceutical industry, government agencies like the US Food and Drug Administration, and clinicians caring for patients with cancer. All are responsible for “our failure to deliver on the promise of personalized medicine.” The experience with cetuximab in mCRC supports Fojo’s contention that researchers need to analyze drugs prospectively, identifying predictive markers before initiating trials. Four years after cetuximab’s 2004 approval,

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investigators reported in the New England Journal of Medicine that it was ineffective in patients with mutated KRAS. In 2009 ASCO issued its Provisional Clinical Opinion recommending KRAS testing before prescribing cetuximab but called compliance with the opinion voluntary.

“Delaying symptoms is a worthwhile goal, but delaying PFS does not equal delaying symptoms.” —Tito Fojo, MD, PhD

Fojo said a prospective investigation might have uncovered the KRAS issue before trials were initiated. Cetuximab inhibits epidermal growth factor receptor (EGFR), and Fojo said, “As early as 1990, Bert Vogelstein at Hopkins had reported that as many as 50% of colorectal patients harbored KRAS.” In 1998, KRAS was reported to be in the EGFR signaling pathway. “Despite this, we went ahead and conducted studies without looking at this prospectively.” Continued investigation into the causes of poor response to cetuximab among some patients with wild-type KRAS will likely whittle the viable patient population down even further. “Eventually, we’ll be able to identify the 80% of patients that do not benefit and give it only to the 20% who benefit substantially, and a drug that was marginal to begin with will become highly effective,” explained Fojo. Fojo said he is concerned that “increasingly, therapies that demonstrate at best marginal improvement are being used in the treatment of cancer.” With breast cancer, we might even be going backwards he said, pointing to the controversy over bevacizumab. He emphasized that his views did not represent those of the NCI or anyone else. Fojo faulted the decision to approve bevacizumab based on data from the Eastern Cooperative Oncology Group (ECOG) 2100 study, which suggested adding it to paclitaxel significantly prolonged progression-free survival (PFS) but not overall survival (OS). Although the study showed nonsignificant improvement in OS favoring bevacizumab, Fojo said, “Nonsignificant improvement

is no improvement.” He added that it was unusual for a study to reflect major discordance between PFS and OS. Fojo and other researchers published a report in Lancet Oncology last year that reviewed major studies published since 1996 with a statistically significant PFS or OS and found “tight correlation between the two.” He therefore believes ECOG 2100 is an outlier. Even if bevacizumab does improve PFS, in Fojo’s opinion, PFS on its own is not an important end point. “Delaying symptoms is a worthwhile goal, but delaying PFS does not equal delaying symptoms,” he said. Studies need to focus more on whether the regimens used are harming patients. Fojo noted that in ECOG 2100, patients treated with bevacizumab experienced more than twice as many adverse events as the control group. Given its failure to improve OS and its cost, Fojo said the toxicity is unacceptable, but he acknowledged that many breast cancer specialists disagree. The FLEX trial, investigating cetuximab in mCRC, also found high rates of serious grade 3 and 4 toxicities related to cetuximab, particularly skin reactions that are sometimes disfiguring.

With the growing use of oral treatments, Fojo said it is important that studies not overlook the grade 1 and 2 toxicities. “The scale was developed for chemotherapy, but when you are taking a drug every day for months on end, a grade 1 or 2 event can be very difficult.” While cost is relevant for drugs that cause serious adverse effects but demonstrate minimal efficacy, Fojo said it comes down to the notion that you do not harm patients for little improvement in survival. Various attempts to combine therapies have hurt patients without helping them, and Fojo called for an end to this “incremental approach” to treatment. Finding better treatments requires determining the settings in which the drugs work best but also the ones in which they do not work. Fojo said this would require major journals to give greater weight to negative studies, which are often relegated to second- and third-tier journals. It also requires expanding incentives for pharmaceutical companies to take a more personalized approach to drug development, where rewards are likely to be less lucrative. ●

How Costly Is Cancer Care in the United States?

he National Cancer Institute set out to answer this question last year and published results of their investigation in the January 2011 issue of the Journal of the National Cancer Institute. The study’s authors point to flaws in previous cancer cost estimates, many of which did little more than take figures from 15 years ago and adjust them for inflation. When one considers the major transformations in cancer care in just the past decade, it is not hard to see why these earlier estimates are unreliable. Using the Surveillence, Epidemiology, and End Results database to obtain incidence rates and Medicare records for medical expenses, Mariotto and colleagues estimated the following: US Cancer Care Costs in 2010: $124.57 billion Projected US Cancer Costs in 2020: $157.77 billion-$207 billion*

*Lowest figure assumes constant incidence, survival, and cost; highest figure assumes increase for greater use of targeted therapies.

Most expensive Breast: Colorectal: Lymphoma: Lung: Prostate:

cancers in 2010 (in billions): $16.50 $14.14 $12.14 $12.12 $11.85

For men and women whose deaths were caused by cancer in 2010, costs were highest in the first 12 months after diagnosis and the last 12 months of life across all malignancies. The greatest increase in cost from the first year to the last year was for melanoma. For example, a woman aged <65 years accumulated $6057 in medical costs in the year of diagnosis and $85,175 in the final year of life. Source: Mariotto AB, et al. Projections of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst. 2011;103(2):117-128.

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Conference News Review of New Oncology Drugs at HOPA Continued from cover label. Ipilimumab (Yervoy) had not yet been approved at the time of the meeting and was included in a discussion of investigational drugs, which we will present in an upcoming issue.

Table 1 Efficacy End Points for TROPIC

Sipuleucel-T (Provenge) Sipuleucel-T is the first approved therapeutic vaccine in oncology and is indicated for men with asymptomatic or minimally symptomatic castration-resistant prostate cancer (CRPC). The drug is an autologous cellular immune therapy, manufactured for each individual patient in a process that involves training the patient’s T cells to attack prostate cancer cells. Approval was based on data from the randomized IMPACT trial, which reported a 4.1month improvement in overall survival (OS) for men treated with sipuleucel-T compared with those given placebo (25.8 vs 21.7 mo, respectively; P = .032). The process for treating patients with sipuleucel-T requires coordination among multiple individuals. To assist clinicians, Dendreon announced the ON Call program. After a physician orders the drug, Dendreon returns a treatment schedule. Once the patient confirms availability for the proposed dates, Dendreon approves the order. Sipuleucel-T is administered in three 1-hour infusions spaced 2 weeks apart. For each cycle, the patient undergoes leukapheresis to procure antigen-presenting cells (APCs) from his immune system, which are shipped to a Dendreon facility. The laboratory combines the APCs with prostatic acid phosphatase, found in 95% of prostate cancer cells, and granulocyte-macrophage colony-stimulating factor. In 2 to 3 days, the APC is considered active and shipped back to the institution for administration at the designated time. The drug arrives at the time of the appointment in a special insulated container within a cardboard box. Upon receipt, the pharmacist can open the box and remove the container to verify product and patient information but Pereiras said not to open the inside container until Dendreon has issued a Cell Product Disposition Form and the patient has been prepped. Universal precautions should be taken when handling the drug, which normally appears slightly pink and cloudy. Pereiras said 70% of patients have mild infusion reactions, consisting of chills, fatigue, fever, and pain. To mitigate adverse effects, she recommended giving patients acetaminophen and diphenhydramine ~30 minutes prior to infusion. Most reactions occur within 1 day of treatment and typically last no longer than 2 days. If a patient reacts during the infusion, Pereiras said the treat-

March/april 2011 I VOl 4, NO 2

End Point

Cabazitaxel

Mitoxantrone

P Value

Median OS, mo Median PFS, mo

15.1

12.7

<.0001

2.8

1.4

<.0001

ORR, % PSA response, %

14.4

4.4

.0005

39.2

17.8

.0002

ORR indicates overall response rate; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen. Source: de Bono J et al. Lancet. 2010;376(9747):1147-1154.

ment can be stopped and resumed if the reaction is not serious. She said to “think twice” before using steroids. “There have been some serious events reported, including a cerebrovascular accident.” Formal data are not available on possible drug interactions with sipuleucelT. Because it works by boosting the immune system, Pereiras said, “Anything given to suppress the immune system could counteract that, like chemotherapy or corticosteroids.” Due to the time-consuming and complicated manufacturing process, sipuleucel-T is currently available only at the 50 centers involved in the original clinical trials. No more than 2000 patients were expected to receive sipuleucel-T in 2010, but Pereiras said Dendreon plans to expand its manufacturing capacity soon. Cabazitaxel (Jevtana) In the summer of 2010, the FDA approved cabazitaxel, a microtubule inhibitor, for patients with metastatic CRPC that has progressed on or following treatment with a docetaxel-containing regimen. “Cabazitaxel works to bind free tubulin to promote their assembly into stable microtubules but then inhibits the disassembly, so [that] it ultimately freezes the cell within mitosis,” Pereiras explained. The patient receives a 25-mg/m2 injection of cabazitaxel every 3 weeks and takes 10 mg of oral prednisone daily throughout treatment. In the phase 3 TROPIC study, patients randomly assigned to receive

cabazitaxel plus prednisone demonstrated superior median OS, progression-free survival, and response compared with patients given mitoxantrone and prednisone (Table 1). Although cabazitaxel is a taxane, Pereiras said it has low affinity for P-glycoprotein–mediated efflux pumps associated with multidrug resistance and might be a means of overcoming taxane resistance in some patients. Cabazitaxel contains polysorbate 80 and the diluent contains ~13% ethanol. As a result, severe hypersensitivity reactions are possible, and patients should be premedicated with an antihistamine, corticosteroid, and a histamine-2 antagonist approximately half an hour before administration. The prescribing instructions also recommend antiemetic prophylaxis as needed. “It is really nice that we have something efficacious, but from an adverse event perspective, there really are some things to be concerned about,” she warned. In TROPIC, high rates of neutropenia, myelosuppression, and anemia were observed in the cabazitaxel arm. Gastrointestinal symptoms are common, with ~6% of patients experiencing diarrhea. Deaths have been reported from severe treatment-related diarrhea, and doses should be reduced for any patient with ≥grade 3 diarrhea. “This is an important counseling point to patients,” said Pereiras. “They need to know to stay hydrated, use antidiarrheals, and not go the whole weekend before contacting us.” In TROPIC, nearly 30% of patients

treated with cabazitaxel suffered grade 3/4 neutropenia and 7% developed neutropenic fevers, which might have been dose-related. Cabazitaxel is therefore contraindicated in patients with neutrophil counts ≤1500 cells/mm3. Pereiras said it is important for clinicians to stay on top of monitoring blood counts during therapy. Patients aged ≥65 years appear more prone to neutropenia-related fevers and deaths, and some clinicians recommend primary prophylaxis with granulocyte colony-stimulating factor for any patient with an elevated risk of febrile neutropenia. Some patients in TROPIC’s cabazitaxel arm experienced neurotoxicities or suffered cardiac-related events. A clinical trial is under way to investigate the effect of cabazitaxel on QTc intervals. Cabazitaxel is extensively metabolized by the liver via CYP 3A4/5 and, to a lesser extent, CYP 2C8. CYP 3A inhibitors or inducers might affect area under the curve concentrations and are to be avoided. A phase 1 trial is evaluating cabazitaxel in patients with hepatic impairment. “Some dose-adjustment may be needed in patients with hepatic dysfunction,” Pereiras cautioned. Excretion via the renal pathway is minimal, but because no data are available on patients with creatinine clearance <30 mL/min, she said patients with renal dysfunction should be monitored. A 2-step dilution process is used for cabazitaxel. Pereiras cautioned that in preparing the drug, it is essential to use a polyvinyl chloride–free bag and an inline filter. Eribulin Mesylate (Halaven) Eribulin is from a novel class of agents called halichondrins. “It is approved for metastatic breast cancer, specifically in those patients that have already had at least 2 chemotherapy regimens, which should have included an anthracycline and a taxane,” said Pereiras. Eribulin, a synthetic analogue of a sea sponge chemical, is a nontaxane, microtubule dynamics inhibitor. “But

Table 2 Denosumab Efficacy Outcomes mBC Denosumab Patients, N

1026

First On-Study SRE 315 (30.7) Patients, n (%) NR Median time to SRE, mo First and Subsequent SRE 0.46 Mean No./Patient

ZA 1020

Solid Tumors/MM Denosumab ZA 886 890

mCRPC Denosumab

950

951

372 (36.5) 26.4

278 (31.4) 20.5

323 (36.3) 16.3

341 (35.9) 20.7

386 (40.6) 17.1

0.60

0.44

0.49

0.52

0.61

mBC indicates metastatic breast cancer; mCRPC, metastatic castration-resistant prostate cancer; MM, multiple myeloma; NR, none reported; SRE, skeletal-related event; ZA, zoledronic acid. Sources: Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139; Fizazi K, et al. Lancet. 2011;377:813-822; Henry DH, et al. J Clin Oncol. 2011;29:1125-1132.

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Conference News when you get down to the basics, it’s just like any other taxane—it works on the microtubules,” she said. Unlike traditional microtubule inhibitors that halt cell division by stabilizing the microtubules, eribulin achieves cell cycle arrest by preventing microtubule growth without affecting microtubule shortening. In the EMBRACE study, a phase 3 randomized trial that compared eribulin with the physician’s choice of chemotherapy, OS was significantly improved for women who received eribulin (13.1 vs 10.6 mo, respectively; P = .041). Median PFS and the overall response rate were also better for the eribulin arm, but women taking eribulin had a shorter duration of response. The recommended dose for eribulin is 1.4 mg/m2 administered via intravenous push over 2 to 5 minutes on days 1 and 8 of a 21-day cycle. No premedications are required. “It can be given as straight drug or can be further diluted in normal saline. It is not compatible with dextrose,” she emphasized. Eribulin is minimally metabolized by CYP enzymes. “[There is] some inhibitor effect on CYP 3A4 and on P-glycoprotein, but this is thought to be minimal,” she said. No formal studies have evaluated eribulin in patients with renal dysfunction, but one pharmacokinetic study looked at patients with mild to moderate hepatic dysfunction. Pereiras directed clinicians to the package insert for specific recommendations on adjusting the eribulin dose for patients with hepatic or renal problems. At least one-quarter of patients in EMBRACE experienced anemia, weakness/tiredness, alopecia, nausea, and constitution. Most (82%) patients developed neutropenia, with 4% experiencing grade 3/4 febrile neutropenia. “Blood counts should be closely monitored and dose adjustments should be made if a patient experiences neutropenic fever or grade 4 neutropenia,” said Pereiras. Eribulin extends the QT interval, and she recommended monitoring in patients at risk of cardiovascular events, especially patients with a wider QT interval at baseline. She also advised clinicians to check magnesium potassium levels and correct any deficiencies prior to therapy. Grade 3/4 peripheral neuropathy, observed in several patients, was cited as the most common reason for discontinuation. For these patients, Pereiras suggested withholding eribulin and reintroducing once neuropathy falls to grade 2. Denosumab (Xgeva) “Oncology is not just about the chemotherapy agents we work with day in and day out. It’s also about supportive care,” said Pereiras, as she moved on to denosumab, a drug recently approved to prevent skeletal-related events (SREs) in

patients with solid tumors and bone metastases. It is marketed as Prolia to treat osteoporosis in postmenopausal women. Denosumab is a human monoclonal antibody with affinity for the receptor activator of nuclear factor kappa-β ligand (RANKL), a protein expressed by

patients with breast cancer; another, 1901 men with prostate cancer; and the third, 1776 patients with various solid tumors and multiple myeloma. In each study, a smaller percentage of patients in the denosumab arm experienced an onstudy SRE, and denosumab delayed the time to first on-site SRE (Table 2).

ERBITUX Increased Overall Survival in Both: Squamous Cell Carcinoma of the Head and Neck (SCCHN)

EGFR-Expressing Recurrent Metastatic Colorectal Cancer (mCRC)

in Combination With RT in Locoregionally Advanced Disease

after Irinotecan and Oxaliplatin Failure as a Single Agent

ERBITUX Indications Head and Neck Cancer ■ ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck

Metastatic Colorectal Cancer ■ ERBITUX, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens ■ Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations

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

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

www.TheOncologyPharmacist.com

osteoblasts that is critical to osteoclast formation. Denosumab binds to RANKL, interrupting osteoclast formation and thus preventing bone resorption. In 3 large, randomized trials, denosumab was compared with zoledronic acid (ZA), a bisphosphonate commonly used to prevent SREs. One trial enrolled 2046

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Conference News Xgeva is administered subcutaneously at a 120-mg dose every 4 weeks. Pereiras warned against confusing this with the dose for Prolia, which is 60 mg every 6 months. Obviously, Xgeva and Prolia should not be administered concurrently

because they are the same drug. Xgeva does not need to be reconstituted, and no dose adjustment is required for patients with renal dysfunction. “It is generally well tolerated, but there are a few things to be aware of,” said Pereiras. “It can cause more elec-

trolyte disturbances than ZA, particularly with regard to calcium creatinine clearance <30 mL/min.” These patients and those on dialysis were more likely to develop severe hypocalcemia, and she said electrolytes should be monitored. For all patients, she recommended eval-

uating calcium levels and correcting, if necessary, before treatment, as well as having patients take calcium and vitamin D supplements. Osteonecrosis of the jaw occurs in an estimated 2.2% of patients treated with denosumab. “It’s very important to

ERBITUX Significantly Increased SCCHN in Combination With RT in Locoregionally Advanced Disease Survival in Combination With RT (N=424)*1,2 ERBITUX (cetuximab) + RT (n=211)

Median overall survival 49.0 months

RT alone (n=213)

29.3 months

45%

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

3-year overall survival rate 55%

19.7 month improvement

P=0.05

RT=radiation therapy; HR=hazard ratio; CI=confidence interval. A multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration of locoregional control. Secondary endpoints included overall survival.1,2 Median follow-up=54 months.2

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

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

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Conference News counsel our patients on good oral hygiene and avoiding extensive dental procedures while on denosumab,” Pereiras said. Other adverse events include dermatitis, eczema, rash, limb pain, cataracts, and hypercholesterolemia. Pereiras said researchers are keen to

study whether denosumab has anticancer properties. She noted that during bone resorption, growth factors believed to spur tumor growth are released, so preventing bone resorption might theoretically contribute to better outcomes. This is only a hypothe-

sis, however, and denosumab is only approved to prevent bone loss. Dabigatran Etexilate (Pradaxa) Dabigatran, an oral direct thrombin inhibitor, is approved to prevent stroke and systemic embolism in patients with

nonvascular fibrillation. Pereiras said clinicians who treat cancer are increasingly likely to encounter patients already taking it. “It may get another indication which would open it up to some of our oncology patients,” she said. In explaining its mechanism of

Overall Survival in Both: EGFR-Expressing Recurrent mCRC after Irinotecan and Oxaliplatin Failure as a Single Agent

Median Overall Survival, All Patients (N=572)†1 6.14 months ERBITUX + BSC (n=287)

4.57 months BSC alone (n=285)

34% improvement

HR: 0.77; 95% CI: 0.64-0.92; P=0.0046

†

BSC=best supportive care. NCIC CTG CO.17 was a multicenter, open-label, randomized (1:1) clinical trial conducted with ERBITUX plus BSC or BSC alone. The main outcome measure of the trial was overall survival.1

■ The data presented above include patients with K-ras mutations because K-ras mutational status was not assessed at the time the study was conducted ■ Use of ERBITUX is not recommended for the treatment of colorectal cancer with K-ras mutations in codon 12 or 13 because retrospective subset analyses have not shown a treatment benefit for ERBITUX in these patients1

ERBITUX Safety Information for EGFR-Expressing mCRC ■ The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%) References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company; September 2010. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.

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

www.TheOncologyPharmacist.com

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Conference News action, Pereiras said, “We have an intrinsic pathway and an extrinsic pathway. Thrombin is affected by both pathways and works to convert fibrinogen to fibrin, which results in and aids thrombus formation. Dabigatran inhibits thrombin and therefore thrombus formation.”

While the drug is not yet indicated to prevent deep-vein thrombosis (DVT) or pulmonary embolism (PE)—thromboembolic events common in patients with cancer—the RECOVER study concluded that dabigatran (n = 1274) was noninferior to warfarin (n = 1265) at pre-

venting recurrent DVT/PE. RECOVER enrolled patients aged ~55 years with good renal function and found that, although dose adjustments were required for patients with renal impairment, dabigatran had a good safety profile. Adverse effects included bleeding

events and gastrointestinal effects, such as dyspepsia and gastritis-like symptoms. Nearly 17% of patients in the dabigatran arm experienced a bleeding event, and 1.5% of bleeding events were considered life-threatening. Only 5% of patients in each arm had cancer, however, and

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

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

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

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

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

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Conference News Pereiras said, “It’s going to be hard to say if right now we can carry that information over to our oncology patients.” Dabigatran is not an inhibitor or inducer of the CYP 450 enzyme system but is a substrate of P-glycoprotein. Data suggest drug–drug interactions

with rifampin, ketoconazole, verapamil, amiodarone, and clopidogrel. Pereiras noted that the package insert includes special instructions for converting patients to and from warfarin therapy and to or from parenteral anticoagulation.

“A very interesting tidbit that came out a short time ago is that once a bottle is opened, it’s only good for 30 days, so make sure you use your blister packs,” said Pereiras. She said the manufacturer has not explained what happens “between day 29 and day 30” and

expressed concern as to whether the drug is slowly losing efficacy over the 30-day period. ● Pereiras disclosed that she has received consulting fees from EUSA Pharma and fees for non–continuing education services from Sancusco.

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

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

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

Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%)

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

©2010 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. 693US10AB12704

12/10

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March/aPril 2011 I VOl 4, NO 2

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Conference News

Are You Talking to Patients About Smoking Cessation? By Christin Melton

t the annual meeting of the Hematology/Oncology Pharm acy Association, Jane Pruemer, PharmD, BCOP, FASHP, professor of clinical pharmacy practice at the University of Cincinnati’s James L. Winkle College of Pharmacy in Ohio,

said clinicians have an obligation to encourage patients with cancer who smoke to give up the habit. “It is inconsistent to provide healthcare and, at the same time, remain silent about a major health risk,” she said. Studies show intervention from a clinician nearly doubles

the chances of a patient succeeding an attempt to quit smoking compared with pharmacologic interventions alone or self-help materials. Although medical oncologists often tell smokers they should quit, Pruemer said they do not always explain why.

ERBITUX® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.] INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient. Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.] Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17% of patients. Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.] Use of Erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events. Hypomagnesemia and Electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

March/april 2011 I VOl 4, NO 2

“Patients may think, ‘I’ve already got cancer, what’s the reason to quit?’” She said, smoking and nicotine exposure decrease the effectiveness of certain anticancer therapies, tobacco use impairs wound healing after surgery and increases the risk of infection, and smoking is

Epidermal Growth Factor Receptor (EGFR) Expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions. 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. The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). Table 1:

Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 Fever1 29 1 13 1 Headache 19 <1 8 <1 15 3 2 0 Infusion Reaction2 Infection 13 1 9 1 Chills1 16 0 5 0 Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 3 43 2 21 1 Alanine Transaminase, high 3 38 1 24 1 Aspartate Transaminase, high 3 33 <1 24 0 Alkaline Phosphatase, high Respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneform Rash4 Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

3 4

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

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

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Conference News associated with greater epithelial damage in irradiated tissue and a higher incidence of mucositis. Perhaps the most important reason to quit is that patients who continue smoking have a higher risk of second cancers, shorter survival, and worse quality of life. The first step is finding out how much the patient smokes. “Do you know that 1 in 6 smokers really doesn’t tell the truth about how much they

smoke?” Pruemer asked. Healthcare providers need to be understanding when patients seem reluctant to discuss their tobacco use. “And if you don’t have a [tobacco cessation] program, refer them to one you know about. They are out there.” A successful program addresses the physiological and behavioral aspects of dependence. People highly dependent on ciga-

Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Table 2:

Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with Erbitux Monotherapy Erbitux plus BSC BSC alone (n=288) (n=274) Body System Any Grades Any Grades 2 Preferred Term Grades 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation Dry Skin Pruritus Other-Dermatology Nail Changes Body as a Whole Fatigue Fever Infusion Reactions3 Rigors, Chills Pain Abdominal Pain Pain-Other Headache Bone Pain Pulmonary Dyspnea Cough Gastrointestinal Constipation Diarrhea Vomiting Stomatitis Other-Gastrointestinal Mouth Dryness Infection Infection without neutropenia Neurology Insomnia Confusion Anxiety Depression

89 49 40 27 21

12 0 2 1 0

16 11 8 6 4

<1 0 0 1 0

89 30 20 13

33 1 5 <1

76 18

26 <1

59 51 33 15

14 16 4 3

52 34 11 7

16 7 0 2

48 29

16 2

43 19

12 1

46 39 37 25 23 11

4 2 6 1 10 0

38 20 29 10 18 4

5 2 6 <1 8 0

30 15 14 13

1 6 2 1

15 9 8 6

1 2 1 <1

Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls. Adverse events were graded using the NCI CTC, V 2.0. 3 Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated. BSC = best supportive care 2

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

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rettes find it harder to quit. This includes someone who smokes >1 pack a day or who lights up within 30 minutes of waking. People with psychiatric disorders or a history of chemical dependency also struggle. Another component of behavioral modification is identifying smoking triggers. “Make sure they understand the difference between a physical craving and habit.” Pruemer recommended working

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations. Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older. OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

ER-B0001A-09-10

Rev September 2010

with the patient to establish goals, such as relieving withdrawal symptoms, controlling urges, and abstinence. Pharmacologic options are essentially equal in effectiveness. Nicotine replacement therapy (NRT) comes in various forms and is a popular option, but it should be used with caution in patients with underlying cardiovascular disease. Pruemer said the standard dose is equivalent to 1 pack of nicotine and might not work for heavier smokers. Although researchers have not found an increase in adverse effects when using the dose equivalent of 2 patches, Pruemer said, “I would not do this unless patients are under the guidance of a physician that you’re working with.” Prescription options consist of bupropion SR (Zyban) and varenicline. “Bupropion works by increasing the central nervous system levels of dopamine, which makes patients feel better.” The drug is started 1 week prior to the scheduled quit date. Patients take 150 mg once daily for 3 days and then increase to twice-daily dosing for the remaining 7 to 10 weeks of therapy. The drug increases the risk of seizures, and Pruemer advised extreme caution for patients with a history of brain surgery or trauma, patients taking medications that increase seizure risk, and patients with severe cirrhosis. Bupropion is contraindicated in patients with bulimia, anorexia nervosa, or seizure disorders, and in those who are abruptly quitting alcohol or sedatives. Varenicline binds to nicotine receptors, blocking the usual dopaminergic boost patients get from smoking. It also helps alleviate withdrawal symptoms. As with bupropion, patients should start the drug 1 week prior to their quit date; it should be taken with food. The dose is titrated to 1 mg twice daily by the start of the second week. This dosing is continued for 10 weeks. Pruemer cautioned that varenicline increases the risk of depression. Patients unable to quit on a singleagent option might be candidates for therapy that combines NRT agents or uses an NRT agent with bupropion. Varenicline should not be used as part of a combination regimen. Another option is to continue on pharmacologic therapy beyond the standard treatment period. During the question and answer session, Pruemer was asked whether patients with rapidly progressive disease or in palliative care should quit. “Even those patients are going to have a higher risk of pneumonia and more complications at the end of life, and their quality of life is going to be poorer. There’s plenty of data that still recommends they should be quitting,” she responded. The benefits of smoking cessation are immediate and long-term for patients with cancer, and Pruemer said, “It can be one of the single most effective strategies to improve outcomes for our patients.” ●

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Drug Shortages

Drug Shortages: A Growing Crisis in Oncology By Christin Melton

rug shortages continue to plague the United States, compromising patient safety and placing additional strain on healthcare resources. The shortages encompass common drugs used to treat a range of conditions, from everyday infections to heart attacks. The problem has escalated in recent years, with the number of drugs deemed unavailable or scarce jumping from 74 in 2005 to more than 240 in 2010, according to the Drug Information Service (DIS) at the University of Utah Hospitals & Clinics. DIS, which started tracking drug shortages in January 2001, is among the first groups to recognize the problem. Erin Fox, PharmD, manages DIS and said in an interview, “I believe the current state of shortages is a crisis for the United States.” The shortages have hit oncology hard. “In so many cases there are no good alternative agents, particularly for chemotherapy agents. We have seen over 20 different chemotherapy drugs in short supply during 2010 and continuing into 2011,” Fox explained. The nonprofit Institute for Safe Medication Practices (ISMP) warns “there is little relief in sight.” Providers See the Effects of Drug Shortages Local news reports from Alaska, California, Maryland, Pennsylvania, Texas, Tennessee, Virginia, and elsewhere show that hospitals in virtually every state are struggling to manage the growing list of hard-to-get drugs. A hospital administrator in Tennessee told her local paper that drug shortages were “the new norm.” Small hospitals feel the burden more than large hospitals, which can use their purchasing power to stockpile drugs on the shortage list. Many hospitals in networks manage shortages by shifting supplies to whichever sister facility needs them. In 2010, ISMP surveyed 1800 pharmacists, physicians, nurses, and healthcare administrators at hospitals and long-term care facilities and found that nearly all had been affected by drug shortages. More than 80% complained that they were never warned of a looming drug shortage nor told how long it might last, and 82% said it required considerable resources to come up with a management plan. Shortages have also affected providers on a personal level, with 55% of physicians surveyed saying they felt anger toward other staff or the hospital when a drug was not available.

March/april 2011 I VOl 4, NO 2

Three-quarters of respondents told ISMP that drug shortages had cost their facility money. This corresponds with results of a survey by Premier, Inc, an alliance of 200 hospitals and health systems in the United States. From July to December 2010, Premier questioned 311 pharmacy experts about the effect of drug shortages on their practice. At least 98% acknowledged substituting a more expensive drug 1 or more times, and 40% said they had done so more than 21 times. Premier estimates oncology providers shelled out an additional $10.5 million in 2010 for the generic equivalents of drugs on the shortage list. Not every drug in short supply has a generic equivalent, and Premier says using the best therapeutic alternative increases treatment costs an average of 11%. Across all areas of care, hospitals paid an extra $200 million in 2010 for therapeutic substitutions. More than Dollars and Cents The highest costs of drug shortages have been borne by patients. Healthcare providers have only a few options when they are unable to give the patient the drug he or she needs: they can substitute an equivalent or nearequivalent agent, give nothing, or delay treatment until the drug becomes available. All these options could lead to worse outcomes. Respondents to the ISMP survey reported “more than 1000 near misses, errors, and adverse outcomes” attributable to drug shortages. Some errors led to a patient’s death. At one facility, hydromorphone was substituted for morphine, which was not available due to shortages. The provider administered the hydromorphone at the dose originally indicated for the morphine prescription, leading to the deaths of 2 patients and nonfatal overdose in another. Whenever a drug has been substituted for another, it is essential to ensure that the new drug is correctly dosed or that the correct infusion rate is used. Other dosing errors occur when the only way the hospital can get the drug is by ordering a different concentration. For example, when preloaded syringes of epinephrine were difficult to get, some hospitals ordered the drug in vials. Because epinephrine is typically used in emergencies, the nurse is pressured to draw the dose from the vial quickly, increasing the risk of delivering an underdose or overdose. Institutions might try to conserve supplies of a hard-to-get drug by using

“Last year, acyclovir was virtually unavailable for a few months, which put our patients at risk to develop viral infections.” —Beth Faiman, RN, MSN, APRN, BC, AOCN

smaller doses. ISMP said attempts to conserve propofol by cutting the dose at some hospitals led to inadequate sedation or anesthesia awareness. Some hospitals are shortening the duration of therapy when prescribing medications in short supply. For patients with cancer, both approaches could lead to worse outcomes. Substituting one drug for another compromises outcomes if the replacement drug proves to be less effective or less tolerable. Not every drug has a suitable replacement, such as amikacin and acyclovir. As Beth Faiman, RN, MSN, APRN, BC, AOCN, a nurse practitioner at the Cleveland Clinic Taussig Cancer

Institute in Ohio and editor-in-chief of The Oncology Nurse-APN/PA, explained, “Last year, acyclovir was virtually unavailable for a few months, which put our patients at risk to develop viral infections.” In addition to the detrimental physical effects of drug shortages on patients with cancer, Catherine Bishop, DNP, NP, AOCNP, doctor of nursing practice and an oncology nurse practitioner at Virginia Cancer Care, Inc, pointed out that there are also psychological considerations. “Some of the issues patients face are the likelihood or need to discontinue a certain medication, such as leucovorin or etoposide. For patients in the metasta-

Common Cancer Drugs in Short Supply The following is a list of drugs commonly used for patients with cancer that the American Society of Health-System Pharmacists (ASHP) classified as being in short supply in March. For some drugs, only certain doses or preparations are unavailable. Most shortages are attributable to manufacturing delays and/or increased demand. In some cases, the manufacturer discontinued the drug or offered no explanation for the short supply. A couple (ie, capecitabine [Xeloda] tablets and dexamethasone sodium phosphate) have been voluntarily recalled because of contamination concerns. To alleviate the shortage of capecitabine, the US Food and Drug Administration has granted the manufacturer permission to import the drug from the European Union. The ASHP Website provides suggestions for managing care when your facility does not have one of the products listed below. • Acyclovir injection

• Etoposide injection

• Acyclovir capsules and tablets

• Fentanyl injection

• Amikacin injection

• Fludarabine injection

• Capecitabine tablets

• Granisetron hydrochloride injection

• Carboplatin

• Idarubicin hydrochloride injection

• Cisplatin injection

• Leucovorin calcium injection

• Cytarabine

• Melphalan injection

• Dacarbazine powder for injection

• Morphine injection

• Daunorubicin hydrochloride

• Vancomycin hydrochloride injection

• Dexamethasone sodium phosphate • Doxorubicin injection

• Vincristine injection

www.TheOncologypharmacist.com

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ALOXI provides powerful CINV prevention that can’t be ignored. ®

ALOXI is the only IV 5-HT3 receptor antagonist specifically approved for the prevention of both acute and delayed CINV s Powerful CINV prevention in the first 24 hours and up to 5 days following moderately emetogenic chemotherapy1,2 s Lasts long against nausea following moderately emetogenic chemotherapy 3 s Powerful acute CINV prevention following highly emetogenic chemotherapy 4

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Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated in adults 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 s !,/8) IS CONTRAINDICATED IN PATIENTS KNOWN TO HAVE HYPERSENSITIVITY TO THE DRUG OR ANY of its components s -OST COMMONLY REPORTED ADVERSE REACTIONS IN CHEMOTHERAPY INDUCED NAUSEA AND VOMITING include headache (9%) and constipation (5%) Please see the brief summary of the Full Prescribing Information on the adjacent page. References: 1. 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. 2. 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. 3. Data on file. Eisai Inc., Woodcliff Lake, NJ. 4. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-1449.

STARTS STRONG. LASTS LONG.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc. © 2010 Eisai Inc. All rights reserved. Printed in USA. ALO000083C 08/10

TOP_April 2011_v2_TOP 4/19/11 3:01 PM Page 18

Drug Shortages

tic setting, this can produce a great deal of anxiety,” she said. Talking to patients about drug shortages is also tough on the practitioner. “For any provider to tell a patient that the drug that may benefit them the most is not currently available is difficult and almost impossible to explain,” she said.

Why Are So Many Drugs in Short Supply? The drug shortage crisis has emerged from a confluence of factors. “Our country depends on just a few generic manufacturers to make the majority of the critical drugs we need in our hospitals and operating rooms each

day,” said Fox. A problem at one facility or a decision by one manufacturer to reduce production is ultimately felt at the clinic. The Pharmaceutical Research and Manufacturers of America (PhRMA) released a statement on drug shortages in March, noting that “according to the

FDA [US Food and Drug Administration] and other experts, drug shortages can occur for any number of reasons.” PhRMA cited “natural disasters; shifts in clinical practices; wholesaler and pharmacy inventory practices; raw material shortages; changes in hospital and pharmacy contractual relationships with suppliers and wholesalers that can cause fluctuations in the availability of certain products; adherence to FDAmandated distribution protocols, which can impact patients’ timely access to medicines; individual company decisions to discontinue specific medicines; and manufacturing challenges” as some of the causes of the country’s drug shortage problem.

“Our country depends on just a few generic manufacturers to make the majority of the critical drugs we need in our hospitals and operating rooms each day.” —Erin F. Fox, PharmD

In 2010, the FDA reported that 40% of drug shortages were caused by manufacturing issues, which includes difficulty obtaining the drug’s raw materials or containers and quality control issues. Another 20% of shortages occurred when the manufacturer decided to stop making the drug, often because it was no longer profitable, and 20% resulted from production delays. Premier notes that foreign companies provide nearly 80% of the raw materials for drug manufacture in the United States. In 2010, concerns over the integrity of ingredients from China led some drug companies to look for a new supplier, disrupting production for some drugs and landing them on the shortage list. At the Drug Shortages Summit convened in November 2010 by the American Society of Health-System Pharmacists (ASHP), the American Society of Anesthesiologists, the American Society of Clinical Oncology, and the ISMP, participants recognized that regulatory issues can cause shortages. As part of the 2006 Unapproved Drugs Initiative, the FDA is requiring manufacturers of drugs approved prior to the adoption of stricter drug regulations in 1938 to conduct trials and file a New Drug Application for their generic product. Some drug companies balked at the expense of complying with the initiative and instead elected to stop making the drug. A drugmaker must also

March/april 2011 I VOl 4, NO 2

www.TheOncologypharmacist.com

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Drug Shortages

Is Anything Being Done? Fox expressed optimism about a few recent developments reguarding the drug shortage. “I am hopeful the problem may subside in part because 2 of the largest generic companies with multiple shortages seem to be resolving their manufacturing problems,” she said. If this happens, Fox said the number of shortages might fall to 2009 levels, which she notes were still too high. Congressional legislators have introduced US Senate Bill 296, the Preserving Access to Life-Savings Medications Act. The bill requires drugmakers to notify the FDA at least 6 months before stopping or delaying production for a drug. Many in the medical community support the bill. “There is widespread belief by many in the medical community that there needs to be oversight and regulations, which should be strictly enforced, so manufacturers cannot just decide to stop the manufacturing of a drug without significant notice,” said Bishop. Bill 296 also requires the FDA to identify drugs vulnerable to shortages and take steps to ensure that the supply is not interrupted. “The bill won’t solve all shortage problems, but it is a great start,” said

www.TheOncologyPharmacist.com

“Some of the issues patients face are the likelihood or need to discontinue a certain medication, such as leucovorin or etoposide. For patients in the metastatic setting, this can produce a great deal of anxiety.” —Catherine Bishop, DNP, NP, AOCNP

Fox. She encouraged clinicians to contact their congressional officials and urge them to support the bill. Some patients are not waiting for legislation to resolve the problem and have decided to head to court. Genzyme, which has been plagued with problems at its manufacturing facilities, has been named in a civil lawsuit by a group of patients with Fabry disease. Genzyme manufactures Fabrazyme, the primary drug used to treat the genetic disorder. In the past year, the company started rationing access to the drug and cutting dosages; the lawsuit claims at least 3 patients have died from this approach. Genzyme had similar manufacturing problems with Cerezyme, its drug for Gaucher disease, but believes it will soon have the situation corrected. As the Drug Shortages Summit participants pointed out, the FDA cannot require a drug manufacturer to keep making a product. They said Congress can and should, however, offer incentives to companies that manufacture life-saving generic medications, such as tax breaks and ex tended exclusivity rights. Taking Steps to Protect Patients Fox listed a few steps hospitals can take to minimize the effects of drug shortages

on their patients. “Pharmacists can discuss shortages with clinicians as far ahead as possible.” She noted that sometimes this is not possible, but “as much advance notice as possible can help when decisions about therapy are being made, particularly if another treatment choice is available and will work well for the patient.” She recommended that clinicians consider centralizing their supply of medications and tracking what they need based on their patient roster. “This strategy is particularly helpful with

Clinicians should consider centralizing their supply of medications and tracking what they need based on their patient roster. chemotherapy shortages,” Fox said. “Track out the needs of the patients and then, if insufficient drug is available, the physicians can decide the best action.” In some cases that might be not accepting a new patient, delaying treatment, or altering the treatment plan. ISMP recommends “establishing a shortage network” with other health-

Total drug shortages Drug shortages involving sterile injectables

175 150 125

Number

file an application with the FDA when it wants to change suppliers for active ingredients, and several have complained that the agency is slow to approve these applications. Complex packaging requirements and demands for risk evaluation and mitigation strategies for certain drugs have also contributed to delays. Premier outlines other potential causes for drug shortages. When the economy was in recession, many companies in the drug production chain scaled down the quantity of supplies kept on hand. Any disruption in one company’s ability to restock supplies has a ripple effect on the manufacturer’s ability to get the drug to market. Some pharmacists complain that “gray market distributors” are causing artificial drug shortages by buying large quantities of important, inexpensive drugs and reselling them at greatly inflated prices once the drugs are difficult to obtain. This is a bit like when a ticket outlet purchases all the premium tickets for a major rock concert or popular Broadway show and offers them at a high markup once the show has sold out. Providers who stockpile drugs for fear that they might become hard to get also contribute to artificial shortages. Temporary shortages occur when one drug is discontinued, everyone switches to the same alternative, and the manufacturer cannot keep up with supply.

100 75 50 25 0 2005

2006

2007

Year Figure. Drug shortages per year.

2008

2009

care providers. The organization also suggests adopting strategies to prevent errors when using substitutes and consulting the ethics committee about any decisions to prioritize or place limits on medications in short supply. Several online resources are available to identify ongoing and potential shortages and ways to manage a drug shortage. Fox recommended visiting www.ashp.org/shortage, which maintains a list of current shortages, resolved shortages, and drugs no longer available. The site also contains several resources on managing drug shortages and encourages clinicians to report possible shortages to ASHP. Because the vast majority of drugs in short supply or no longer available are injectables, nurses often have the final opportunity to ensure that the substitute drug provided is being used at the correct dose. The ASHP Website offers help with this, by highlighting the possibility of confusion or dosing errors with some substitute medications. For example, ASHP warns providers of the “potential for dosing errors when interchanging leucovorin and levoleucovorin (Fusilev),” noting that the levoleucovorin dose should be one-half the racemic leucovorin injection dose. Etoposide for injection is another drug in short supply, and many hospitals are substituting oral etoposide. The oral version has only half the bioavailability of the injectable. This means that the oral dose needs to be double that of the intravenous dose. As the ISMP study indicates, problems have also occurred with epinephrine dosing. Miscalculations have been made when switching between the 1-mg/mL strength of epinephrine and the 0.1-mg/mL dose. In addition, some hospitals are using the 1-mg/mL syringe that has an intracardiac needle permanently affixed. The ISMP warns providers not to attempt to remove this needle. To prevent errors due to confusion about differences in dosing, activity, adverse effects, etc, between the intended drug and its substitution, ASHP recommends updating automated systems and order-entry systems. Pharmacy staff should also communicate with nursing staff about alternative therapies and any special considerations. Talking to patients or caregivers about why you have to delay their surgery, interrupt their treatment, or cannot give them the most effective drug for their disease is probably one of the greatest difficulties providers face in dealing with the shortages. It is also one problem for which the organizations advising hospitals on how to manage drug shortages have few suggestions. ●

March/aPril 2011 I VOl 4, NO 2

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News in Review

FDA Panel Recommends Stricter Process for Accelerated Approval of Cancer Drugs By Christin Melton

he US Food and Drug Administration (FDA) held a public meeting in February to assess whether stricter criteria are needed when considering oncology drugs for accelerated approval. Measures enacted in 1992 allow the FDA to grant accelerated approval for drugs targeted at unmet needs in cancer based solely on data from single-arm studies and relying on end points other than the standard metric of overall survival. At the meeting, experts with the FDA’s Oncologic Drugs Advisory Committee (ODAC) criticized the FDA, with Silvana Martino, DO, who directs the Breast Cancer Program at the Angeles Clinic and Research Institute in Santa Monica, California, calling its actions “ignorant.” Gary Lyman, MD, MPH, professor of medicine and director of comparative effectiveness and outcomes research at Duke University School of Medicine and the Duke Comprehensive Cancer Center in Durham, North Carolina, sat on the ODAC panel and discussed the hearing with The Oncology NurseAPN/PA. “The major concern of the ODAC is that accelerated approval has been granted on the basis of a single-arm study in more than half of instances,

which limits a full comparative look at efficacy and safety,” he explained. Lyman said relying on such limited evidence might be appropriate in exceptional cases, such as for drugs to treat rare tumors or when a drug has very strong, observable treatment effects, but “the default recommendation is that this conditional approval be based on at least one well-designed randomized, controlled trial [RCT] reporting significant improvement in an outcome measurement likely to convey clinically meaningful benefit.” In every case, approval should be “based on the robustness of the results in terms of a strong treatment effect and a very favorable risk-to-benefit ratio,” said Lyman. On the rare occasions when accelerated approval is granted without data from an RCT, Lyman said ODAC recommends that the FDA require the drug’s maker to have an RCT under way or imminent. The FDA should review plans for the trial to ensure that its design allows for reliable results, suitable to support licensing approval. The review of the accelerated approval process was prompted by the FDA’s controversial decision in December to withdraw approval of

bevacizumab (Avastin) in breast cancer, which Lyman said was the first time the agency had rescinded an approved indication of a drug brought to market under this mechanism. “There are a number of others—including 6 that we reviewed yesterday—that have not fulfilled their postmarketing requirements and may be vulnerable,” he added. The drugs in question include Erbitux by Eli Lilly, Bexxar and Arranon by GlaxoSmithKline, Clolar by Genzyme, Vectibix by Amgen, and Gleevec by Novartis for its indication in gastrointestinal stromal tumors. At the meeting, the panel questioned manufacturers about their failure to submit requisite follow-up data for these 6 drugs, but the FDA gave no indication that their approval status is in jeopardy. Most of the manufacturers cited difficulty recruiting enough patients for clinical trials to produce meaningful results as the primary reason for the delays. Amgen’s representative told the committee the company was confident it had complied with the FDA requirements. Whereas most companies that receive accelerated approval for a drug show due diligence in complying with

follow-up requirements, Lyman said a few have taken a decade or longer to submit the requested data. “The ODAC members [believe] that plans for more frequent updates—perhaps annually—of studies with outstanding validation or postmarketing requirements would help shorten the time interval to completion and consideration for full approval.” Members of the ODAC panel also voiced concern that the FDA had occasionally granted full approval to a cancer drug without requiring solid data from an RCT. “The ODAC believes that, with few exceptions, such approval should be based on at least 2 well-done RCTs with consistent or robust results,” said Lyman. Lyman acknowledged that patients with cancer and advocacy groups have complained in the past that strict standards delay access to lifesaving medications. “It will be important that no unnecessary delays occur,” he said. If drug companies are pushed to fulfill their postmarketing requirements more promptly, Lyman said he expects it to shorten the time to full approval and decrease how long an ineffective or unsafe drug remains on the market. ●

Ipilimumab (Yervoy) Is First Melanoma Drug Approved in a Decade

atients with inoperable metastatic melanoma now have another treatment option as ipilimumab becomes the second immunotherapy drug approved by the US Food and Drug Administration (FDA) for the treatment of cancer. Fortunately for clinicians, ipilimumab also has a new, easier-to-pronounce name—Yervoy. Specifically, Yervoy is indicated for patients with unresectable metastatic melanoma that is newly diagnosed or progresses despite prior therapy. Ipilimumab is a recombinant, human monoclonal antibody. It works by in hibiting cytotoxic T-lymphocyte anti gen-4 (CTLA-4), a protein that is involved in downregulating T-cells, to keep the immune system from attacking healthy tissue. Ipilimumab blocks CTLA-4 so that the T-cells remain active and the patient’s immune system continues to fight the cancer as long as he or she is receiving treatment. Data from a pivotal phase 3 trial of ipilimumab, which were published in

March/april 2011 I VOl 4, NO 2

the New England Journal of Medicine in 2010, show that patients who received ipilimumab alone or in combination with gp100 had better survival outcomes than patients treated only with gp100. Median overall survival for patients in the ipilimumab trial arms reached 10 months compared with 6 months for patients in the gp100 monotherapy arm. The rate of 1-year survival was 46% for patients treated with ipilimumab versus 25% for patients on gp100 monotherapy. Investigators estimated the 2-year survival rate at 24% for the ipilimumab group and 14% for the gp100 arm. Ipilimumab was associated with a 34% reduction in risk of death (hazard ratio, 0.66; P = .0026). The overall response rate (ORR) was only 10.9% for patients receiving ipilimumab, but this was significantly higher than the ORR seen in the combination arm and the gp100 monotherapy group (5.7% vs 1.5%, respectively). The authors reported that the

mean duration of response was 11.5 months for the group that received ipilimumab and gp100 combined but had not been reached in the other groups because >50% of patients who experienced complete or partial responses had not relapsed. Approximately 10% of patients discontinued ipilimumab because of treatment-related adverse events. Among patients receiving ipilimumab alone, the most common adverse events (all grades) were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%). Some patients treated with ipilimumab did have severe or fatal immune-mediated adverse reactions, including enterocolitis (7%), endocrinopathy (4%), dermatitis (2%), hepatitis (1%), neuropathy (1%), nephritis (1%), and eosinophilia (1%). Some of these can be treated with corticosteroids, according to researchers practicing at one of the institutions that conducted phase 3 ipilimumab trials. In a review article on the drug, pub-

lished in Seminars in Oncology in 2010, Boasberg and colleagues warn that “colonic perforation can occur” and call for patients who develop diarrhea to be monitored carefully, “with strict adherence to treatment algorithms.” The researchers note that if adverse effects are caught promptly and managed properly, “Ipilimumab is an extremely safe drug to administer.” Bristol-Myers Squibb, which manufactures the drug, has worked with the FDA to develop a Risk Evaluation and Mitigation Strategy (REMS) for ipilimumab to help clinicians manage or prevent the most serious treatmentrelated adverse events. The company announced that it has launched a copayment program to assist “eligible, commercially insured patients who have been prescribed ipilimumab” in line with its approved indication. Information on ipilimumab and the REMS program is available at www.yervoy.com.—CM ● News in Review continues on page 29

www.TheOncologypharmacist.com

TOP_April 2011_v2_TOP 4/20/11 10:39 AM Page 21

Pushing Your Limits Current activities at www.COEXM.com include:

Scan Here to Register.

To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s web browser, and select “Download” • Visit the app store for your smartphone

COEKsize2711CE

TOP_April 2011_v2_TOP 4/19/11 3:59 PM Page 22

CONTINUING EDUCATION PROGRAM P10068 • RELEASE DATE: NOVEMBER 19, 2010 • EXPIRATION DATE: NOVEMBER 19, 2011 ESTIMATED TIME TO COMPLETE: 1.0 HOUR • COMPLETE THE POSTTEST AT WWW.THEONCOLOGYPHARMACIST.COM

Maintenance Therapy for Non–Small Cell Lung Cancer A Value-Based Approach to Improve Patient Care and Outcomes, Part II of II TARGET AUDIENCE This activity was developed for oncology pharmacists and other healthcare professionals practicing in oncology. LEARNING OBJECTIVES After completing this activity, the reader should be able to: • Evaluate the benefits and risks of maintenance therapy compared with re-treating upon disease progression in order to rationalize maintenance in patients with stage IIIB or IV non–small cell lung cancer (NSCLC) who have responded to or are stable after induction therapy • Identify molecular and histologic characteristics of NSCLC tumors that impact choice of therapeutic agent for specific patient populations and formulate strategies for value-based care • Develop optimal side effect management strategies for patients receiving maintenance therapy for NSCLC in order to provide optimal care while considering the associated costs.

mproving outcomes for patients with non–small cell lung cancer (NSCLC) is particularly relevant because NSCLC accounts for 85% of all cases of lung cancer.1 In the appropriate patients with advanced NSCLC, maintenance therapy may help control the disease and extend patients’ lives. Maintenance therapy is relatively new in NSCLC treatment, representing a change from the past approach of retreatment upon disease progression.2 Two chemotherapy agents previously approved by the US Food and Drug Administration (FDA) for the treatment of advanced NSCLC—pemetrexed and erlotinib— recently received FDA approval for a new indication for maintenance therapy of advanced NSCLC. Pemetrexed, a folate analog metabolic inhibitor, was granted FDA approval for maintenance therapy of advanced or metastatic lung cancer in July 2009.3 This new indication for pemetrexed is specifically for patients with nonsquamous NSCLC that has not progressed after 4 cycles of platinum-based first-line chemotherapy.4 Pemetrexed is also indicated as initial treatment in patients with locally advanced or metastatic nonsquamous NSCLC, in combination with cisplatin, and after prior chemotherapy as a single agent.4 Erlotinib, an endothelial growth factor receptor (EGFR) tyrosine kinase inhib-

March/april 2011 I VOl 4, NO 2

itor (TKI), received FDA approval in April 2010 for an expanded indication as a maintenance treatment in patients with locally advanced or metastatic NSCLC whose disease has not progressed after 4 cycles of platinum-based first-line chemotherapy.5,6 Erlotinib is also indicated to treat locally advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy regimen.6 Identifying the appropriate patients as characterized by histology (nonsquamous) or molecular (EGFR mutation) profile is an important consideration when selecting the appropriate maintenance therapy.7 Using predictive biomarkers to target specific agents for maintenance therapy may help improve benefits and reduce risks by tailoring a specific treatment to the appropriate patient.7 For example, pemetrexed is an option for maintenance therapy in patients with nonsquamous histology.1,4 In addition, a molecular-based strategy may be useful in selecting the appropriate patients best suited for maintenance therapy with erlotinib.7 Progression-free survival (PFS) was significantly longer in patients with EGFR-positive immunohistochemistry who were treated with erlotinib as maintenance therapy comSPONSOR

This activity is jointly sponsored by Medical Learning Institute, Inc. (a nonprofit medical accreditation company) and Center of Excellence Media, LLC. INSTRUCTIONS FOR CREDIT

1. Read the article in its entirety 2. Log on to www.TheOncologyPharmacist.com 3. Select “Continuing Education” 4. Click on this article’s title from the list shown 5. Select “Click here to complete the posttest and obtain a CE certificate online” 6. Complete and submit the CE posttest and CE Activity Evaluation 7. Print your Statement of Completion PHARMACIST DESIGNATION

Medical Learning Institute, Inc., 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 activity number for this activity is 0468-9999-10-059-H01-P.

pared with EGFR-positive patients who received placebo, based on a randomized, placebo-controlled study.8 In addition to histology and genetic markers, maintenance therapy decisions involve a number of other important considerations, including the latest clinical data, evidence-based clinical practice guidelines, and the patient’s performance status and personal preferences. Although maintenance therapy may slow the growth of disease and extend life, the benefits of treatment must be weighed against the potential toxicities and other side effects associated with extended treatment. Costs and resource utilization associated with maintenance therapy must also be considered. NSCLC: Burden and Economic Impact Lung cancer claims the lives of more Americans than any other type of cancer.1 Moreover, lung cancer imposes a substantial economic burden on our healthcare system. The estimated annual costs to the American public as well as lost productivity costs associated with lung cancer were previously outlined in the first part of this article.9 Treatment costs associated with lung This activity is provided free of charge to participants. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. FACULTY DISCLOSURES

Before the activity, all faculty will disclose the existence of any financial interest and/or relationship(s) they might have with the manufacturer(s) of any commercial product(s) to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speaker’s bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. Beth Eaby-Sandy, CRNP, is on the speaker’s bureau for Genentech, Eli Lilly and Company, and Merck. Corey J. Langer, MD, acknowledges grant/ research support from Bristol-Myers Squibb, Genentech, ImClone, Eli Lilly and Company, OSI, and Pfizer. Dr Langer is on the speaker’s bureau for Genentech, ImClone-BMS, Eli Lilly and Company, and OSI, and is a scientific advisor to Abbott, Abraxis, Amgen, AstraZeneca, Bayer-Onyx,

cancer, as well as treatment failure costs, are also substantial. A retrospective, case-control cohort study that followed patients for 2 years from the first diagnosis of lung cancer showed that the monthly cost per patient was $11,496 for initial treatment, $3733 per month for secondary treatment, and $9399 for terminal care treatment.10 Failure of initial treatment was associated with increased costs: patients who experienced treatment failure incurred an additional $10,370/month in initial treatment phase costs and $8779/month after starting the secondary and/or terminal care phase of treatment.10 Moreover, treatment failure was associated with incremental costs of $19,149/month and $74,697 across the study period.10 The study authors concluded that improvements in prevention or treatment of lung cancer, including new therapies or adjuvant chemotherapy, might reduce healthcare resource utilization and costs, and that strategies aimed at reducing hospitalizations and preventing or delaying treatment failure may offset the associated cost burden.10 More than 68% of all patients diagnosed with lung cancer are 65 years of age or older.11 The burden and cost of NSCLC may continue to grow as the Biodesix, Bristol-Myers Squibb, Caris DX, Clarient, Genentech, ImClone, Eli Lilly and Company, Morphotek, Novartis, Pfizer, and sanofi-aventis. Loretta Fala participated in the development of this article. She has no financial relationships to disclose. The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CE activity for any amount during the past 12 months. DISCLAIMER

The information provided in this CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Trade names used in this supplement are for the learner’s reference only. No promotion of or bias toward any product should be inferred. CommerCial Support aCknowledgment This activity is supported by an educational grant from Eli Lilly and Company.

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baby boom generation (people born between 1946 and 1964) reaches the age of 65 years and older over the next 20 years.12 Maintenance Therapy Agents for the Treatment of Advanced NSCLC Maintenance therapy, sometimes also referred to as consolidation therapy or early second-line therapy,7 is a relatively new approach to improving outcomes in patients whose disease either responded to initial chemotherapy or was stable following that, and is intended to improve survival without adversely affecting quality of life.13 Aside from improving outcomes, the optimal maintenance treatment should be well-tolerated by patients and associated with few or no cumulative toxicities.7 The National Comprehensive Cancer Network (NCCN) has established specific recommendations for the use of pemetrexed in maintenance therapy, as well as for the use of erlotinib.1 These guidelines also include recommendations for several other agents, including docetaxel, bevacizumab, and cetuximab.1 Pemetrexed Based on phase 3 study results, patients who received maintenance therapy with pemetrexed showed a significantly greater PFS (1.7 months longer), compared with the placebo group, and a significantly greater overall survival (OS) duration (2.8 months longer), compared with the placebo group.14 Specific findings from the study were previously highlighted in Part I of this article.9 Moreover, in patients with nonsquamous histology treated with pemetrexed, the OS was 5.2 months longer than in the placebo arm.14 The most common any-grade adverse reactions associated with pemetrexed included nausea (19%) and anorexia (19%).14 The pemetrexed group had a greater frequency of grade 3 or higher adverse events than the placebo group, including fatigue (5%) and neutropenia (3%).14 Another study that compared the combination of cisplatin plus pemetrexed with cisplatin plus gemcitabine in chemotherapy-na誰ve patients with advanced NSCLC demonstrated superior efficacy and reduced toxicity in the group receiving cisplatin plus pemetrexed.15 Erlotinib Based on a phase 3 study, patients who received maintenance therapy with erlotinib showed a greater PFS (0.8 weeks longer) and an improved OS (1 month longer), compared with the placebo group.6,8 In patients with EGFRpositive immunohistochemistry treated with erlotinib, compared with EGFRpositive patients receiving placebo, PFS

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was significantly greater (1.2 months longer) in the erlotinib group, compared with the placebo group, in patients with EGFR-positive immunohistochemistry treated with erlotinib.8 Specific study results were previously highlighted.9 The most common any-grade adverse reactions associated with erlotinib were rash (49.2%) and diarrhea (20.3%).6 The most common serious adverse event was pneumonia (2%), and the most common grade 3 or higher adverse events included rash (6%) and diarrhea (2%).8 Other Agents Included in Clinical Practice Guidelines Docetaxel Although docetaxel, a microtubule inhibitor, does not have a specific FDA approval for maintenance therapy in NSCLC, this agent is indicated as a single agent for locally advanced or metastatic NSCLC after failure on platinum therapy; and with cisplatin for unresectable, locally advanced, or metastatic untreated NSCLC.16 Based on a phase 3 randomized study that assessed the efficacy and safety of docetaxel administered either immediately after gemcitabine or at disease progression, immediate docetaxel was associated with a significantly greater PFS (5.7 months) compared with delayed docetaxel (2.7 months), and immediate docetaxel was associated with a greater median OS (12.3 months) compared with delayed docetaxel (9.7 months).17 However, the difference in median OS was not statistically significant (P = .0853). There was no significant difference in quality of life between the immediate and delayed docetaxel groups.17 Based on studies of docetaxel as monotherapy for NSCLC patients previously treated with platinum-based chemotherapy (n = 176), the most common grade 3/4 adverse reactions included neutropenia (65%), leukopenia (49%), and pulmonary effects (21%).16 The most common any-grade adverse reactions include neutropenia (84%); leukopenia (84%); anemia (91%); asthenia (53%); pulmonary effects (41%); infection (34%); nausea (34%); fluid retention (34%); neurosensory effects (34%); stomatitis (26%); diarrhea (23%); and vomiting (22%).16 In chemotherapy-na誰ve advanced NSCLC patients receiving docetaxel in combination with cisplatin (n = 406), the most common grade 3/4 adverse reaction was neutropenia (74%).16 The most common any-grade adverse reactions included neutropenia (91%); anemia (89%); alopecia (75%); asthenia (74%); nausea (72%); vomiting (55%); fluid retention (54%); diarrhea (47%); neurosensory effects (47%); anorexia (42%); infection (35%);

peripheral edema (34%); and fever (33%).16

To Receive cRediT, compleTe The posTTesT aT

Bevacizumab TheOncologyPharmacist.com Bevacizumab, a monoclonal antibody that inhibits vascular endothelial growth factor, is indicated for the treatment of nonsquamous NSCLC, with paclitaxel and carboplatin for the first-line treatment of unresectable, locally advanced, recurrent, or metastatic disease.18 According bination with vinorelbine and cisplatin to the NCCN clinical practice guide- showed no difference in PFS and a siglines, the criteria for bevacizumab thera- nificantly improved OS (11.3 months) py include a performance status of 0-1, compared with patients receiving nonsquamous histology, and no history vinorelbine and cisplatin alone (10.1 of hemoptysis.1 months).1,22 Treatment-related deaths Adding bevacizumab to chemothera- were similar in both groups.22 Patients py with paclitaxel plus carboplatin has receiving cetuximab had increased grade shown a significant improvement in 3/4 febrile neutropenia (22%) and grade median OS (12.3 months), compared 3 acne-like rash (10%).1,22 with chemotherapy alone (10.3 months), based on a randomized 3-year Evidence-Based Practice study of patients with recurrent or Guidelines advanced NSCLC (N = 878) conducted For the NCCN NSCLC clinical pracby the Eastern Cooperative Oncology tice guidelines (updated in March Group.19 An increased risk of treatment- 2010), a new section with maintenance related deaths were observed in the therapy recommendations was added.1 group treated with bevacizumab plus These recommendations categorized paclitaxel and carboplatin, and the rate maintenance therapy into 2 types: conof clinically significant bleeding was tinuation maintenance therapy and 4.4% in this arm.19 Other adverse events switch maintenance therapy. Conincluded grade 4 neutropenia (24%), tinuation maintenance therapy refers to grade 3/4 hemorrhage (4.5%), hemopty- the use of at least 1 of the agents adminsis (1.9%), and hypertension (6%).1 istered as first-line therapy.1 Switch According to the NCCN guidelines, maintenance therapy refers to the initicaution is advised when chemotherapy ation of an agent that was not included regimens with a high risk for thrombo- as part of the first-line treatment regicytopenia and/or possible bleeding are men.1 Based on 2 recent studies demonstrating a benefit in PFS and OS, the combined with bevacizumab.1 Further studies are needed to deter- guidelines now recommend initiation mine whether bevacizumab mainte- with pemetrexed or erlotinib for switch nance is associated with a survival ben- maintenance therapy in patients withefit compared with the combination of out disease progression (Category 2B chemotherapy and bevacizumab with- recommendation).1 Highlights of the NCCN guideline out maintenance bevacizumab.20 recommendations for continuation maintenance therapy and switch maintenance therapy were outlined previousThe optimal maintenance ly in the first part of this article.9 Information about the American treatment should be Society of Clinical Oncology (ASCO) well-tolerated by patients guideline update, as well as recent guidand associated with few ance from the National Institute for or no cumulative toxicities. Health and Clinical Excellence are also highlighted in that article.

Cetuximab Cetuximab, a monoclonal antibody that targets EGFR, is indicated for the treatment of specific head and neck cancers and colorectal cancers; however, this agent does not have an indication for the treatment of NSCLC.21 Cetuximab use is not recommended for patients with colorectal cancer whose tumors have KRAS mutations in codon 12 or 13.21 According to a study of patients (N = 1125) with advanced NSCLC (stage IIIB or IV; majority were stage IV), patients treated with cetuximab in com-

The Role of Histology and Molecular Biomarkers in Maintenance Therapy It is important to identify the histologic subtype of NSCLC (ie, squamous cell vs nonsquamous cell) when selecting maintenance therapy.23 Histologic information may be particularly useful when augmented by molecular testing.23 Detecting the bronchoalveolar subtype of NSCLC adenocarcinoma may suggest a specific treatment approach, particularly if it is associated with specific mutations in the EGFR tyrosine kinase domain, which indicates it may respond

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CONTINUING EDUCATION COMMENTARY

Maintenance Therapy in NSCLC: Personalized Perspectives By Corey J. Langer, MD Director of Thoracic Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia

aintenance therapy has be gun to emerge as a treatment standard for patients with non–small cell lung cancer (NSCLC) whose disease has not progressed after 4 to 6 cycles of frontline chemotherapy. But some caveats still apply. Although it may be suitable for fit, motivated patients who are highly symptomatic at the time of presentation, it is not yet clear if maintenance therapy should be routine. Based on the phase 3 data, use of pemetrexed is certainly justified in patients whose advanced NSCLC has stabilized or improved after 4 or more cycles of frontline therapy with a platinating agent, plus either gemcitabine or a taxane. Pemetrexed is particularly well tolerated and convenient, although its “maintenance” benefits are confined to nonsquamous histology and its utility is as yet unproven in patients who have received pemetrexed and/or bevacizumab as part of their first-line treatment. Similarly, erlotinib has yielded a survival advantage compared with placebo in the maintenance setting, although the extent of its benefit seems less pronounced compared with pemetrexed.

compared with maintenance with older regimens.7

Determining the Optimal Maintenance Therapy Agent The study by Fidias and colleagues laid the groundwork for pemetrexed as maintenance after chemotherapy,6 which was evaluated in a recent phase 3 study by Ciuleanu and colleagues.8 Patients were randomized 2:1 to pemetrexed or intravenous placebo. Disease progression was reduced by 40% (P <.001) overall and by 53% in patients with nonsquamous histology (P <.001), and deaths were reduced by 21% (P = .012) and 30% (P = .002), respectively. Pemetrexed was reasonably well-tolerated and devoid of cumulative toxicity. Benefits were particularly pronounced in patients with nonsquamous histology (they had a more than 5month survival advantage); there was no PFS or OS advantage in those with squamous histology.8 Although this was the first randomized, double-blind, placebo-controlled trial to show a significant survival benefit for maintenance treatment, one still needs to exercise caution in basing clinical decisions on this study. Prolonged Initial Chemotherapy Maintenance therapy is unrealistic Prolonged treatment with initial for many patients due to early disease chemotherapy (eg, 6 vs 3 cycles or in- progression, comorbidities, and patient definite treatment vs 4 cycles) has desire to stop treatment. Pemetrexed is shown no overall survival (OS) bene- of no value to patients with squamous fit1-3; neither have prior maintenance histology and is unproven in patients studies of attenuated dosing or single who have received first-line pemeagents yielded a survival benefit, trexed or bevacizumab. Furthermore, although “intriguing trends” in time to the survival improvement in the progression have been observed in Ciuleanu study would be more impresunderpowered efforts.4,5 sive had there been mandatory Switching to a new compound for crossover to pemetrexed at the time of maintenance therapy demonstrated disease progression in the control arm; some benefit in the well-designed unlike the Fidias trial, mandatory study by Fidias and colleagues, which crossover was not instituted in this evaluated immediate versus delayed trial. It is noteworthy that <20% of docetaxel upon disease progression after enrollees in the control arm received first-line carboplatin/gemcitabine.6 Pro - pemetrexed at the time of disease progression-free survival (PFS) improved gression, although a majority received from 2.7 months in the delayed arm to a standard second-line treatment. 5.7 months with maintenance (P Many patients look forward to the <.001), and median OS trended better prospect of a therapeutic holiday. If (12.3 vs 9.7 months; P = .085). In patients are closely monitored once they addition, a recent meta-analysis docu- have completed first-line therapy, there mented a 30% reduction in disease is often enough time to implement secprogression using maintenance thera- ond-line treatment when disease propy with a third-generation regimen gresses before symptoms have taken

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over. Finally, cost is the 800-lb gorilla in the room. Recent analyses of pemetrexed maintenance suggest a minimum incremental cost of >$120,000 per lifeyear saved.9 A recent phase 2 study evaluated pemetrexed plus bevacizumab for maintenance after 6 initial cycles of carboplatin, pemetrexed, and bevacizumab.9 Median PFS was 9.3 months and median OS was 14 months.10 Many practitioners are using this regimen increasingly in bevacizumab-eligible patients. These encouraging findings have led to a large, planned randomized phase 3 trial in the Eastern Cooperative Oncology Group (ECOG) 5508, which just opened and will randomize 1282 patients to bevacizumab, pemetrexed, or to a combination of bevacizumab and pemetrexed after 4 cycles of initial therapy with paclitaxel/carboplatin/bevacizumab. In addition, a separate phase 3 trial, POINT-BREAK, will compare this regimen to the “winning” arm of ECOG 4599 (a combination of paclitaxel, carboplatin, and bevacizumab), which yielded a significant and clinically meaningful survival advantage in this setting compared with chemotherapy alone. Finally, in Europe, pemetrexed maintenance is being compared with “observation” in patients who have stabilized or responded to a “standard” pemetrexed/cisplatin regimen. Erlotinib Maintenance Erlotinib has shown value as a maintenance agent in 2 key studies. The Sequential Tarceva® in Unresectable NSCLC (SATURN) trial found that erlotinib reduced the risk of progression by 29% (P <.001) and offered a 1-month OS benefit (P = .0088).11 In the Assessment of Treatment with Lisinopril And Survival (ATLAS) trial, maintenance therapy with erlotinib plus bevacizumab improved PFS by 39%, or by approximately 1 month (P = .0012), but no OS difference was shown.12 Moreover, toxicity associated with this approach is not trivial. Conclusions Docetaxel, pemetrexed, and erlotinib are each approved in the second-line setting, and all have shown a PFS benefit as maintenance therapy and at

least a trend toward improved survival, if not a statistically significant increase in survival. To date, both pemetrexed and erlotinib are US Food and Drug Administration–approved for maintenance therapy. At the end of the day, treatment should be individualized for all patients, taking into account not only clinical outcomes but patients’ personal preferences, disease burden, and comorbidities. ● References 1. Socinski MA, Schell MJ, Peterman A, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol. 2002;20:1335-1343. 2. von Plessen C, Bergman B, Andresen O, et al. Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer. Br J Cancer. 2006;95:966-973. 3. Smith IE, O’Brien ME, Talbot DC, et al. Duration of chemotherapy in advanced non-small-cell lung cancer: a randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin. J Clin Oncol. 2001;19:1336-1343. 4. Belani CP, Barstis J, Perry MC, et al. Multicenter, randomized trial for stage IIIB or IV non-small-cell lung cancer using weekly paclitaxel and carboplatin followed by maintenance weekly paclitaxel or observation. J Clin Oncol. 2003;21:2933-2939. 5. Brodowicz T, Krzakowski M, Zwitter M, et al. Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer. 2006;52:155-163. 6. Fidias P, Dakhil S, Lyss A, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small cell lung cancer. J Clin Oncol. 2009;27:591-598. 7. Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration of chemotherapy for advanced non-smallcell lung cancer: a systematic review and metaanalysis of randomized trials. J Clin Oncol. 2009; 27:3277-3283. 8. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non– small-cell lung cancer: a randomized, double-blind, phase 3 study. Lancet. 2009;374:1432-1440. 9. Klein R, Wielage R, Muehlenbein C, et al. Costeffectiveness of pemetrexed as first-line maintenance therapy for advanced nonsquamous non-small cell lung cancer. J Thorac Oncol. 2010;5:1263-1272. 10. Patel JD, Hensing TA, Rademaker F, et al. Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non–small-cell lung cancer. J Clin Oncol. 2009;27:3284-3289. 11. Capuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non–small-cell lung cancer: a multicentre, randomized, placebo-controlled phase III study. Lancet Oncol. 2010;11:521-529. 12. Miller VA, O’Connor P, Soh C, et al. A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). Presented at 2009 ASCO Annual Meeting. J Clin Oncol. 2009;27(18 suppl): LBA8002.

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To Receive cRediT, compleTe The posTTesT aT to treatment with an EGFR TKI.23 However, it is important to point out within this NSCLC subtype, there are also variabilities in histology and molecular information.23 Several predictive molecular bio-

markers play a key role in NSCLC treatment,1 and these biomarkers and associated characteristics were summarized in Part I.9 Initial retrospective studies suggest that approximately 90% of patients with a tumor response to erlotinib and

gefitinib (both EGFR TKI agents) TheOncologyPharmacist.com had EGFR mutations E19 deletion and L858R mutation, whereas patients without a response to these 2 agents did not carry these mutations.1 The NCCN guidelines recommend that

COMMENTARY

Nursing and Patient Management Considerations for Maintenance Therapy in Non–Small Cell Lung Cancer By Beth Eaby-Sandy, CRNP Outpatient Thoracic Oncology Nurse Practitioner, University of Pennsylvania Health System, Philadelphia

ignificant advances in treating non–small cell lung cancer (NSCLC) have been made over the past 10 years; nevertheless, survival improvement in this disease pales compared with many other solid tumors. Because maintenance chemotherapy offers improved survival in NSCLC, patients and doctors are justifiably excited. Nursing Considerations In my dealings with patients, there seem to be 2 distinct responses to maintenance treatment. On the one hand, patients are very happy that they can continue receiving some sort of therapy, because they feel that they are continuing the fight. Before the data supporting maintenance chemotherapy for NSCLC, we would stop therapy after 4 to 6 cycles and give a treatment break, and many patients were worried that they weren’t doing anything to treat their disease during this time. Conversely, I have also encountered many patients who are yearning for a break in therapy. Suggesting maintenance chemotherapy, which promises more toxicity similar to what the patient is already experiencing, leaves them bewildered. But because the treatment offers a survival advantage, patients usually will continue with it because they want to live longer. However, they frequently ask when there will be a break, and this often gives them the realization that they will be receiving this treatment for the rest of their lives. It is important for oncology treatment providers to have a detailed discussion with patients about the pros and cons of maintenance therapy for NSCLC. These patients have a terminal illness with average survival of around a year. Doctors and nurses must allow patients the autonomy to

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Nausea was also reported in 19% of patients in the pemetrexed arm versus 6% in the placebo arm.1 The targeted therapies erlotinib (in the switch maintenance setting) and bevacizumab and cetuximab (in the continuation maintenance setting) do not typically induce the same side effects as chemotherapy but rather carry their own set of unique toxiciManaging Toxicities ties. The toxicities from these agents As maintenance therapy becomes a can also interfere with a patient’s more widely used treatment option for quality of life and must be considered patients with NSCLC, it is important and addressed before embarking on to weigh its toxicities. Pemetrexed, maintenance therapy. which is US Food and Drug AdRash was the most common side ministration (FDA)-approved in the effect in patients receiving erlotinib maintenance setting, and docetaxel, in the maintenance trial. Grade 3/4 which has a recommendation (al - rash, causing interference with activthough not an FDA approval) for ities of daily living, was 6%.2 Because maintenance therapy, are both cytotox- good randomized data on treating this ic chemotherapy agents and pose con- rash have not emerged, management cerns different from other approved strategies have focused on best-pracmaintenance therapies. Common side tice recommendations. Depending on effects of chemotherapeutic agents, severity, papulopustular rash can be including risk for myelosuppression, treated with topical steroids or antibifatigue, and nausea, are a concern for otics, oral antibiotics, and even oral patients receiving maintenance thera- steroids in severe cases.3 These medpy, especially because there is no ications can be used in combination defined end date to it unless there is dis- or separately depending on the grade ease progression or unacceptable toxic- of rash. Although it is rarely lifeity. So patients may end up taking these threatening, rash can be uncomfortdrugs without a break for up to a year or able and disfiguring at times. In the cetuximab continuation trial, rash more. In the pemetrexed maintenance was present in approximately 70% study, anemia occurred in 15% of (382/548) of patients, with 10% patients in the pemetrexed mainte- experiencing grade 3/4 rash. Rates of grade 3/4 diarrhea in both nance arm versus 6% in the placebo arm.1 Patients receiving pemetrexed the cetuximab and erlotinib maintemay therefore require more frequent nance trials were 4% and 2%, respecblood transfusions and possibly colony- tively.2,4 It is usually easily controlled stimulating factors such as darbepoetin with loperamide and sometimes reor erythropoietin. Managing fatigue quires a prescription-strength antican become difficult for these patients, diarrheal. Concern for dehydration and considering that they are dealing may be an issue given that this with a terminal illness, fatigue must be patient population is often elderly, so taken into serious account in terms of prompt assessment and ensuring fluid its effect on the patient’s quality of life. intake are important. make decisions about receiving maintenance therapy, along with possible breaks to have a vacation or spend time with family. Maintenance therapy can continue indefinitely, which can leave a patient feeling that his/her life is a constant schedule of treatments and can cause tremendous emotional stress.

Bevacizumab is only approved for the use of nonsquamous NSCLC because of bleeding risk. The most common side effects of bevacizumab include hypertension and proteinuria,5 and assessing for these on each visit is recommended. Standard antihypertensives will usually control bevacizumab-associated hypertension; proteinuria often improves on holding the bevacizumab dose. In rare NSCLC cases, bevacizumab has the potential to cause fatal pulmonary hemorrhage, so it is essential that practitioners assess for hemoptysis and permanently discontinue bevacizumab if hemoptysis occurs. In summary, the improvement in survival for metastatic NSCLC by continuing a maintenance therapy after first-line treatment is modest, but it is certainly an advance. Conversations with patients about the schedule, toxicities, and benefits of therapy must be unbiased and thorough. Patients need to be able to voice their concerns and have ample opportunity to shape their treatment regimen because of their limited prognosis and possible effect of maintenance treatment on quality of life. ● References 1. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for nonsmall-cell lung cancer: a randomized, double-blind, phase 3 study. Lancet. 2009;74:1432-1440. 2. Cappuzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multi-center, randomized, placebo-controlled phase 3 study. Lancet Oncol. 2010;11:521-529. 3. Lynch T, Kim E, Eaby B, et al. Epidermal growth factor receptor (EGFR) inhibitor-associated rash: an evolving paradigm in clinical management. Oncologist. 2007;12:610-621. 4. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced nonsmall-cell lung cancer (FLEX): an open-label randomized phase III trial. Lancet. 2009;373:1525-1531. 5. Sandler A, Gray R, Perry MC, et al. Paclitaxel–carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med. 2007;355:2542-2550.

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CONTINUING EDUCATION pathological evaluation be performed to classify the lung cancer, determine its extent of invasion, determine the status of surgical margins, and identify molecular abnormalities that may predict the treatment response, or resistance to, EGFR TKI therapy.1 Other Maintenance Therapy Considerations The potential benefits of maintenance therapy—preventing cancer recurrence, slowing disease growth, and prolonging life—must be weighed against the potential risks—increased side effects and potential for toxicities, drug resistance, and more frequent doctor visits. Another consideration is that maintenance therapy does not provide the patient with a chemotherapy break, also referred to as a wait-and-see period.7 Data on the quality of life associated with maintenance therapy are limited, including data on cumulative toxicity associated with extended chemotherapy.7 Although maintenance therapy increases chemotherapy costs and may increase overall costs, it may conversely decrease costs associated with palliative radiotherapy and hospital admissions resulting from performance status deterioration.20 The value of maintenance therapy is the subject of ongoing discussion among clinicians, particularly in light of its cost and potential toxicity.24 Pemetrexed administered in 6 cycles at the average wholesale price of $3000 per cycle would total $18,000.24 The wholesale acquisition cost for erlotinib maintenance treatment would be $4000 per month ¥ a mean PFS of 3 months, for a total treatment cost of $12,000.24 Some of the challenges surrounding cost of added survival were presented at the 2010 ASCO meeting by Scott Ramsey, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle.24,25 Ramsey asserted that maintenance therapy was unlikely to be costeffective, based on a ratio that considers both the price over standard care and the months of OS benefit. However, he acknowledged that pharmacogenomic strategies may improve the cost-effectiveness of therapy and that the cost of testing will be a factor. Ramsey claimed that many new oncology agents do not meet the criteria for cost-effectiveness and that many economic analyses do not meet the guidelines for economic evaluation.24,25 Guideline-driven pharmacoeconomic studies may shed light on whether maintenance therapy is the most cost-effective. The rationale in favor of maintenance therapy was presented at the 2010

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Although maintenance therapy increases chemotherapy costs and may increase overall costs, it may conversely decrease costs associated with palliative radiotherapy and hospital admissions resulting from performance status deterioration.

ASCO meeting by Tracey Evans, MD, of the Abramson Cancer Center, University of Pennsylvania, in Philadelphia.26 According to Evans, “maintenance therapy for advanced NSCLC is absolutely a standard of care” that should be considered for all patients, particularly based on clinical data showing prolonged survival and tolerability.26 An opposing point of view was presented by Tom Stinchcombe, MD, of the Lineberger Comprehensive Cancer Center, at the University of North Carolina at Chapel Hill.27 According to Stinchcombe, maintenance therapy is not necessarily a standard of care for every patient but rather an option to be considered, which depends on toxicities as well as the patient’s disease burden, extent of symptoms, performance status, and preferences.27 He maintained that a treatment-free interval is still an option in this incurable disease setting.27

managing side effects warrant careful consideration. Optimally, the agent selected for maintenance therapy should be well-tolerated by the patient, demonstrate improved patient outcomes, and have minimal side effects/ cumulative toxicities.7 Recent clinical data and evidencebased guidelines are valuable decisionmaking tools for clinicians. However, data assessing quality of life, cost-effectiveness, and cumulative toxicity of maintenance therapy are lacking. Costs and resource utilization associated with maintenance therapy must be balanced against the risks and costs of not treating or of deteriorating performance status. A delay strategy may be associated with a shorter survival time and a faster disease progression than immediate additional therapy.28,29 In any case, the prospect of extended survival of several months, or even weeks, particularly if treatment is well-tolerated, represents an important milestone for patients with advanced NSCLC. ●

Maintenance therapy is not necessarily a standard of care for every patient but rather an option to be considered.

References

Conclusion Maintenance therapy, a relatively new approach in the treatment of patients with advanced NSCLC, has the potential to extend survival and improve outcomes. Key considerations for tailoring treatment for the appropriate patients include the histology of the carcinoma, genetic biomarkers, the extent of disease invasion, and the patient’s performance status and preferences. The benefits of maintenance therapy must be weighed against the potential toxicities and other side effects associated with extended treatment. Selecting the appropriate therapy for the appropriate patients and involving patients in the decision process are important aspects of the treatment plan. Strategies for

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Non-small cell lung cancer, V.2.2010. March 5, 2010. www.nccn.org/professionals/physician_gls/PDF/ nscl.pdf. Accessed September 15, 2010. 2. Peck P. Maintenance pemetrexed extends NSCLC survival by 3 months. Medpage Today. May 30, 2009. www.medpagetoday.com/tbprint.cfm?tbid=14437. Accessed September 22, 2010. 3. Riley K. FDA approves first maintenance drug therapy for advanced lung cancer [press release]. July 6, 2009. US Food and Drug Administration. www.fda.gov/NewsEvents/Newsroom/PressAnnoun cements/ucm170515.htm. Accessed September 22, 2010. 4. Alimta (pemetrexed disodium) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2010. 5. Waknine Y. FDA approves use of erlotinib as maintenance therapy for advanced non-small cell lung cancer [press release]. April 20, 2010. www.medscape.com/viewarticle/720446. Accessed September 22, 2010. 6. Tarceva (erlotinib) [package insert]. Melville, NY: OSI Pharmaceuticals Inc; and South San Francisco, CA: Genentech; 2010. 7. Owonikoko TK, Ramalingam SS, Belani CP. Maintenance therapy for advanced non-small cell lung cancer: current status, controversies, and emerging consensus. Clin Cancer Res. 2010;16:2496-2504. 8. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomized, placebo-controlled phase 3 study. Lancet Oncol. 2010;11:521-529. Epub May 20, 2010. 9. Maintenance therapy for non-small-cell lung cancer: a value-based approach to improve patient care

and outcomes, part I of II. Value-Based Cancer Care. 2010;1:24-26. 10. Kutikova L, Bowman L, Change S, et al. The economic burden of lung cancer and the associated costs of treatment failure in the United States. Lung Cancer. 2005;50:143-154. Epub August 19, 2005. 11. National Cancer Institute, US National Institutes of Health. Surveillance, Epidemiology, and End Results. SEER stat fact sheets: lung and bronchus. http://seer.cancer.gov/statfacts/html/ lungb.html. Accessed September 20, 2010. 12. Vincent GK, Velkoff VA. The Next Four Decades, the Older Population in the United States: 2010 to 2050. Current Population Reports, P25-1138. Washington, DC: US Census Bureau; May 2010. 13. American Society of Clinical Oncology. Explaining maintenance therapy. Cancer.net. Updated February 22, 2010. www.cancer.net/patient/ All+About+Cancer/Cancer.Net+Feature+Articles/ Treatments%2C+Tests%2C+and+Procedures/Explan ing+Maintenance+Therapy. Accessed September 20, 2010. 14. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non– small-cell lung cancer: a randomized, double-blind, phase 3 study. Lancet. 2009;374:1432-1440. Epub September 18, 2009. 15. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapynaive patients with advanced-stage NSCLC. J Clin Oncol. 2008;26:3543-3551. 16. Taxotere (docetaxel) [package insert]. Bridgewater, NJ: sanofi-aventis US, LLC; 2010. 17. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27:591-598. Epub December 15, 2008. 18. Avastin (bevacizumab) [package insert]. South San Francisco, CA: Genentech, Inc; 2009. 19. Sandler A, Gray R, Perry MC, et al. Paclitaxelcarboplatin alone or with bevacizumab for non– small-cell lung cancer. N Engl J Med. 2006;355: 2542-2550. 20. Eaton KD. Maintenance chemotherapy in nonsmall cell lung cancer. J Natl Compr Canc Netw. 2010;8:815-821. 21.Erbitux (cetuximab) [package insert]. Branchburg, NJ: ImClone Systems Inc; 2010; and Princeton, NJ: Bristol-Myers Squibb Company; 2010. 22. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non–small-cell lung cancer (FLEX): an open-label randomized phase III trial. Lancet. 2009;373:1525-1531. 23. Neal JW. Histology matters: individualizing treatment in non-small cell lung cancer [editorial]. Oncologist. 2010;15:3-5. Epub January 19, 2010. 24. Hayes E. Will maintenance sell in NSCLC? Experts weigh costs against benefits. Pharmaceutical Approvals Monthly. August/September 2010. 25. Ramsey S. Cost effectiveness in lung cancer trials and treatment. Presented at the 2010 American Society of Clinical Oncology Meeting—Education Session. June 4-8, 2010; Chicago, IL. 26. Evans TL. Maintenance therapy for advanced NSCLC is standard of care. Presented at the 2010 American Society of Clinical Oncology Meeting— Education Session. June 4-8, 2010; Chicago, IL. 27. Stinchcombe T. Maintenance therapy for advanced NSCLC is not standard of care. Presented at the 2010 American Society of Clinical Oncology Meeting—Education Session. June 4-8, 2010; Chicago, IL. 28. Belani CP, Liao J. Maintenance therapy for non-small cell lung cancer [comment]. Lancet. 2010;375:281-282; comment on Stinchcombe T, West H comment in: Lancet. 2009;374:1398-1400. 29. Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration of chemotherapy for advanced non-smallcell lung cancer: a systematic review and metaanalysis of randomized trials. J Clin Oncol. 2009;27:3277-3283. Epub May 26, 2009.

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The Whole Patient

Considerations for Cancer Treatment–Induced Diarrhea By Christin Melton

ancer treatment–induced diarrhea (CTID) occurs in 50% to 80% of patients receiving chemotherapy and 50% of patients undergoing radiotherapy. Older patients, women, patients on an irinotecan-containing regimen, and patients treated in the adjuvant setting are at higher risk of CTID, reported Kelly Markey, PharmD, BCOP. Markey is a clinical pharmacist with the gastrointestinal tumor program at Moffitt Cancer Center in Tampa, Florida, and discussed CTID at the annual meeting of the Hematology/Oncology Pharmacy Association. “There are many different sources for diarrhea in this patient population,” she said. It can be caused by surgery, nosocomial infection, treatment, graft-versus-host disease, and the patient’s malignancy. A diagnostic work-up for diarrhea requires obtaining a clinical history and a description of the stool. “Stool description is especially important, including not only the number of stools but the composition,” said Markey. “Are they watery or bloody? Did they occur nocturnally?” Patients should be checked for fever and asked if they have experienced dizziness, cramping, pain, or weakness.

“Sometimes fever can indicate infection or even bowel obstruction,” she noted. Current medications or diet might also contribute to diarrhea. Persistent diarrhea requires a stool work-up, complete blood count, and assessment of electrolyte levels. Markey said an abdominal examination is also necessary, as is an endoscopy in some cases, to check for Clostridium difficile or inflammatory bowel disease. “Nosocomial infections are most often associated with C difficile,” she said. Other culprits include Salmonella, Shigella, Campylobacter, and Escherichia coli. For diarrhea lasting >7 days, “You need to start thinking about your protozoa.” Patients meeting National Cancer Institute criteria for grade 1/2 persistent diarrhea but who do not have fever, dehydration, neutropenia, or blood in their stool can be seen at the office. Patients with grade 3/4 diarrhea require hospital admittance, even if they have no other symptoms. Markey said probiotics, which contain live bacteria or yeast, secrete acids that lower the pH level in the gastrointestinal (GI) tract, which thwarts the growth of pathogenic bacteria. “They also secrete toxins to these bacteria, such as hydrogen perox-

ide, and they inhibit the binding of these bacteria to the GI tract,” she explained. Caution is recommended when using probiotics in patients who are immunocompromised or have central venous devices. Probiotics should not be used in patients on an antifungal agent. A concern with probiotics is that they are not quality controlled by the US Food and Drug Administration. Several antimotility agents are used in the initial treatment of CTID. “Many times I find my patients haven’t maximized use of their first-line agents, such as loperamide, and we prematurely move them to a second-line agent,” said Markey. “You want to make sure you’re maximizing your dosing.” For patients with persistent diarrhea, long-acting and short-acting octreotide are available. “Long-acting wouldn’t be used in the refractory-treatment population, but it is being investigated as a prophylactic, particularly in the radiationinduced population,” she said. One study found continuous octreotide infusion effective in patients with colorectal cancer who were receiving 5-fluorouracil. Diphenoxylate, opium tincture, budesonide, and cholestyramine resin are other options for CTID.

If C difficile is the culprit, metronidazole or vancomycin are standard first-line options. “The problem with these agents is they can be efficacious up front, but 20% to 30% of patients are going to recur within 60 days...the majority recur within 2 weeks,” said Markey. Several new drugs for C difficile are on the market. In 2010, a small study by Basu and colleagues reported that 73% of pa tients who were refractory to metronidazole responded to rifamycin (Xifaxan). A 2011 study by Louie and associates determined that fidaxomicin (not yet approved) was noninferior to vancomycin as initial therapy for C difficile; it was associated with a lower rate of recurrence. Nitazoxanide (Alinia) is used against protozoa with similar effectiveness to vancomycin. It is also active against norovirus and rotavirus. Persistent diarrhea can be a lifethreatening complication of anticancer therapy. Even low-grade persistent diarrhea has a negative effect on quality of life. Persistent diarrhea requires prompt investigation, particularly when accompanied by fever. It is important to let patients with cancer know when diarrhea warrants calling their healthcare provider or seeking hospitalization. ●

Managing Elderly Patients Who Have Comorbidities

he median age for someone to receive a cancer diagnosis is 67 years according to the Sur veillance, Epidemiology, and End Results database and even higher for certain malignancies. For example, many gastrointestinal cancers are diagnosed in septuagenarians. With the advancing age and expanding waistlines of the US population, the number of patients seen at oncology clinics who have multiple chronic conditions is also expanding. Said Rowena Schwartz, PharmD, BCOP, director of oncology pharmacy at Johns Hopkins Hospital in Balti more, Maryland, and president of the Hematology/Oncology Pharmacy Association, “We know that as patients age, there are more comorbidities; and as patients age, the instance of cancer increases, so it makes sense that those go together.” Schwartz said elderly patients with comorbidities often have worse outcomes with anticancer therapies and said no one is certain why. “Is it because they have high comorbidities and they don’t tolerate treatments, or is it because we dose-modify to deal with the comorbidities? Is it because they don’t present until their disease is advanced because their

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“I like to do phone follow-ups because you can do it every day and get a better picture.” —Rowena Schwartz, PharmD, BCOP

cancer symptoms are confused with the comorbidities?” she asked. “We don’t know why. The data in comorbidities and the data in geriatrics are not really plentiful,” explained Schwartz. The COPIT (Cancer in the Oldest: Prevalence, Related-Illnesses, and Treatment Modalities) study looked at records for 194,797 US military veterans aged >70 years with cancer (99.6% were men) to assess the rates of various comorbidities in this aged population. The researchers found that 70% had hypertension, >50% had hyperlipidemia, 40% had heart disease, 25% had diabetes, 21% had osteoarthritis, 17% were medically frail, 10% had depression, and 6% had dementia. Some patients fell into more than 1 of these categories. A single-institution study by Wedding and colleagues found a high rate of comorbidity in adult patients with

cancer in all age demographics. Comorbidities were severe in approximately three-quarters of the elderly patients compared with half of the younger patients. The rate of severe comorbidities was similar in the cohort of elderly patients without cancer (79%). Schwartz said a 2010 literature review by Lee and associates looked at 34 studies and concluded that clinicians used chemotherapy less often or at lower doses for patients who had comorbidities, regardless of the type or stage of cancer. More than two-thirds (69%) of the 29 studies to report on overall survival found it was diminished in patients with cancer who had comorbidities. The prevalence, range of comorbid conditions, and their effects on treatment and outcomes point to the need for clinicians to consider comorbidities when caring for patients with cancer. Schwartz

believes this is something that must be done on an individual basis, but also at the clinical trial level. “There are no clinical trials that look at comorbidities and look at treatment in individual populations,” Schwartz said. “We may need to look at specific comorbidities in specific populations with specific types of disease.” Monitoring patients with comorbidities involves more than asking questions at a follow-up visit. Schwartz prefers to telephone patients, particularly when prescribing anticoagulation therapies. “I like to do phone followups because you can do it every day and get a better picture.” That daily interaction is important for some of the highest risk patients because “people’s memories just don’t jive with what actually happens,” she said. This is especially true for elderly patients, who, weeks later, might not remember to tell their clinician about a symptom that seemed important at the time. Schwartz said monitoring an elderly patient with comorbidities also requires engaging the people in their lives who provide support. “Figure out where they live and who provides that overview of care.”—CM ●

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News in Review

Medicare Plans to Cover Provenge By Christin Melton

he Centers for Medicare & Medicaid Services (CMS) has released a proposed decision memo that suggests it will cover the cost of sipuleucel-T (Provenge), the immunotherapy vaccine approved in April 2010 for men with asymptomatic or mildly symptomatic metastatic castrateresistant prostate cancer, for on-label use. CMS contractors will have discretion as to whether they will cover it for off-label use. To date, no studies have been published that support off-label use of sipuleucel-T, but CMS decided to leave the coverage question open so that patients in clinical trials investigating offlabel indications might have access to the drug. The agency noted that it does not expect clinicians to prescribe sipuleucel-T for indications unsupported by evidence, but if this occurs regularly, CMS said it would reconsider the ruling. When sipuleucel-T was first approved, CMS took the unusual step having the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) review the clinical trial data before agreeing to cover the drug’s estimated $93,000 cost. The committee completed its review in November 2010, and panel members rated the

drug an average of 3.6 for effectiveness despite concerns about flaws in the trials’ protocols and analyses. CMS also asked the Blue Cross & Blue Shield Technology Evaluation Center to conduct an independent investigation of the evidence for its effectiveness. The center concluded it had “moderate” efficacy. During an initial 30-day public comment period, 620 (94.4%) of the 657 comments received by CMS expressed support for covering sipuleucel-T. CMS also reviewed national guidelines and met with officials from Dendreon to discuss the trials. In issuing its proposed coverage decision, CMS noted the underrepresentation of nonwhite men in the trials and “encourage[d] researchers to take appropriate steps to assure that clinical trials enroll subject populations that reflect the distribution of patients affected by the disease.” Black men are more than twice as likely to die from prostate cancer as white men. CMS has initiated another call for public comments on its proposed determination. The agency says it will review these comments and issue its final ruling by June 30, 2011. ●

Voluntary Recall of Irinotecan Announced By Dawn Lagrosa

PP Pharmaceuticals has issued a voluntary recall of 5 lots of irinotecan hydro chloride injection (Camptosar) as a precautionary measure. No adverse events related to the recalled products have been reported. The following lots have been recalled: • 870DE00301 • 870CZ00301 • 870DE00101 • 870DE00201 • 870DE00401 APP issued the recall after receiving customer complaints associated with lot 870DE00301, in which particulates were observed in the product solution. An investigation of the vials returned to the manufacturer established that the particulate matter was a fungal microbial contaminant. After consulting with the US Food and Drug Administration, and as a precautionary measure, all lots produced immediately before and after lot 870DE00301 are being recalled. For complete details, visit www.apppharma.com. ●

very physician has a preferred way of writing prescription instructions, and pharmacists differ in how they translate those instructions to the pill bottle. A study published in the Annals of Internal Medicine by Wolf and associates found that the lack of a universal medication schedule (UMS) to standardize how prescriptions are written and filled contributes to poor patient adherence and increases safety concerns. Elderly patients or those with low health literacy are more prone to confusion when trying to follow a multidrug regimen. In a 2008 report, “Standardizing Medication Labels,” the Institute of Medicine (IOM) recommended implementing a UMS to reduce misunderstandings related to medication use. Noting that 90% of prescriptions require no more than 4 daily doses, the IOM called for delineating 4 standard dosage times—morning, noon, evening, and bedtime—to help patients taking multiple drugs to consolidate doses. Reception to the proposal was mixed, with calls for more research. To determine whether a UMS was needed, investigators assessed the ability of 464 patients aged 55 to 74 years to adhere to a hypothetical 7-drug prescription regimen. The patients were part of a broader study that incorporated a 2-hour interview to evaluate their adeptness at

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performing everyday health tasks. Most (84%) had at least 1 chronic health condition; approximately 61% were college educated and an equal proportion had household incomes >$50,000. Researchers gave every patient prescription bottles containing fake pills and mock labels for 7 retired drugs; dosing instructions varied between the drugs. Patients also received a pill box with 24 slots marked with consecutive 1-hour intervals, going from 12:00 AM to 11:00 PM. Each patient was verbally instructed to “imagine that your doctor has prescribed you these medications. I would like you to please show me when you would take these medicines over the course of 1 day,” and offered additional instruction as needed. Although the drugs could be neatly consolidated into 4 dosing intervals, participants sorted them into an average of 6 slots. Some consolidated the regimen into as few as 3 dosing periods, whereas others used as many as 14 slots. One-third of patients indicated 7 intervals each day for taking drugs; 14.9% indicated 4 times or fewer. Labels for 3 drugs had identical dosing instructions and could therefore have been taken simultaneously, yet one-third of patients failed to do so. Another 2 drugs required thrice-daily dosing, with 1 stipulating to take it with food and water. Only 50.5% of participants scheduled

Variation in Prescribing Instructions Confuses Patients on Multidrug Regimens

them to be taken together. Another 2 drugs needed to be taken twice a day; the label for one said “twice daily” and the other said “every 12 hours.” In all, 79% of patients failed to consolidate them into concurrent dosing intervals. For drugs calling for twice-daily dosing, an average of 10.3 hours elapsed between doses (range, 1 hour to 18 hours). For thrice-daily dosing, a mean of 5.4 hours elapsed between the first and second doses and 6.5 hours between the second and third doses. Low health literacy—ascribed to 20.7% of patients—was the only factor that independently predicted a greater likelihood of taking medications more

than 7 times per day. Patients with low health literacy and no chronic conditions had the worst rate of efficient consolidation. The authors said strategies are needed to help patients understand how to take prescriptions and how to consolidate multiple prescriptions. They said adopting a UMS could “unite medical and pharmacological practice” and suggested that an electronic health records system could be used to facilitate standardization in prescribing. They also recommended educating providers on how to identify patients likely to have trouble adhering to a complicated regimen.—CM ●

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Cancer Center Profile St. Joseph Mercy Cancer Care Center... Continued from cover “They can come in the morning and see everybody and come out with a plan,” explained Philip J. Stella, MD, the clinic’s medical director and medical oncologist. The multidisciplinary approach seems to be working. Not only has the program shaved more than two-thirds off the time between when lung cancer is suspected to initiation of a treatment plan, “We have very high rates of satisfaction from the patients and their families,” said Stella. Patients are not the only ones who appreciate St. Joseph Mercy’s efforts. Primary care physicians in the region have shown their satisfaction with the program by referring more patients to the lung cancer clinic. “We try to make it easy for them, so [that] when they have a patient with lung cancer, they don’t have to call 3 different offices… Just 1 call will get the patient seen in a timely fashion,” said Stella. The lung cancer clinic’s reputation continues to spread. Stella said the positive reception for the multidisciplinary approach has led to patient referrals from physicians outside the St. Joseph Mercy system and the need to expand. A Model in the Making Like other multidisciplinary clinics at St. Joseph Mercy, the lung cancer clinic is spearheaded by an advisory committee, which consists of physicians and other providers who tend to patients at the clinic and participate in tumor boards. Vita McCabe, MD, a cardiothoracic surgeon, chairs the committee and helps steer the program. McCabe described her philosophy of care: “When you are a cancer patient, you need to feel that you are in a highend department store, that you are completely cared for from every direction— [that] this is not a discount-shopping situation.” Department stores claim to operate according to the principle that the “customer is always right.” Although the patient might not always be right at St. Joseph Mercy, the lung cancer clinic’s multidisciplinary team factors the patient’s perspective into each decision. In developing the program from the perspective of the patient, it became clear that it would be important to assign each patient to a nurse navigator. The navigator serves as the point person for arranging visits and facilitating communication between the patient or the patient’s caregivers and the individuals on his or her care team. This is useful for coordinating not only anticancer treatment, but also support services. Along with medical oncologists, surgeons, and radiologists, many patients meet with researchers, social workers, and nutritionists at the clinic.

“They can come in the morning and see everybody and come out with a plan.” —Philip J. Stella, MD

Lara Blair, RN, is one of the program’s nurse navigators. “Even if someone just has a small question, when you have a team of 3 or 4 different doctors and other specialists, that can mean 20 phone calls,” said Blair. “One of my biggest jobs is cutting that process down and streamlining it for [the patients].” Benefits of this system are that “patients don’t have to wait for care, nor are they confused,” said McCabe. The clinic strives to stay at the forefront of lung cancer care, offering an array of advanced surgical and radiotherapy techniques. To handle growing demand, a second surgeon was recently added to the staff. With 2 surgeons onboard, the clinic has been able to expand the number of minimally invasive approaches available, to include video-assisted and robotic surgery and thoracoscopic procedures. St. Joseph Mercy became the first hospital in Michigan to offer the CyberKnife system for stereotactic body radiation therapy. As a result, “Medically inoperable patients are being treated for their lung cancers with a high degree of success and with minimal complications and side effects,” said Walter M. Sahijdak, MD, a radiation oncologist at the clinic. As a member of the Community Clinical Oncology Program (CCOP) network for the past 20 years, St. Joseph Mercy has actively recruited patients with cancer for a number of clinical trials. The CCOP affiliation allows patients treated at St. Joseph Mercy, including those seen in the lung cancer clinic, to enroll in trials conducted by major national research groups, such as the Mayo Clinic and the M. D. Anderson Cancer Center. The lung program currently has patients enrolled in several innovative studies its researchers are conducting, including trials comparing outcomes with CyberKnife versus standard resection in patients with solitary lung nodules. The lung cancer clinic recently moved into new space, which houses a nurse navigation office and the advisory committees for each of St. Joseph Mercy’s multidisciplinary clinics. Stella said the lung cancer program has been so successful he expects it to serve as a model for future multidisciplinary clinics focused on other tumor types.

Success Paves the Way The success of the lung cancer program no doubt factored into last year’s decision by the National Cancer Institute’s Community Cancer Centers Program (NCCCP) to designate St. Joseph Mercy as one of only 30 NCCCP sites in the nation. The NCCCP initiative seeks to develop a network of community hospitals tasked with researching ways to improve the quality of cancer care and prevention, as well as to reduce disparities in access to care and outcomes.

“Medically inoperable patients are being treated for their lung cancers with a high degree of success and with minimal complications and side effects.” —Walter M. Sahijdak, MD

An accompanying $2.5-million grant will allow St. Joseph Mercy to add several cancer specialists to its staff and develop new programs. In a press release announcing the designation, Stella, the

grant’s principal investigator, said, “This program allows St. Joseph Mercy Ann Arbor to accelerate the tempo of scientific research and advancement of cancer care… St. Joe’s is already recognized for our cancer research; this contract allows us to take our program to the next level and expand other areas of research and care. It underscores our dedication to providing our patients with the latest and most state-of-the-art care.” The NCCCP contract calls for St. Joseph Mercy to develop a tissue bank. Stella said while St. Joseph Mercy typically submits tissue from patients in its clinical trials for translational research, the center will now be preserving tumor tissue samples for all their patients with cancer. “We are going to…be able to provide that to investigators at academic centers around the country that want access to fresh tissue or paraffin-embedded tissue to do their translational work,” said Stella. “This is a very important part of this grant and the network as a whole,” he explained. “So much of what we are going to be learning about cancer is going to be through translational research.” Other plans include hiring a geneticist to counsel patients and evaluate those considered high risk and expanding outreach efforts to underserved communities. This will require hiring a minority coordinator to reach out to ethnic minority populations and adding a financial counselor to the staff to help low-income and indigent patients with obtaining oncologic care. “There is no way in this economic environment that the hospital would ever be able to provide these positions,” Stella said. “If it had not been for this grant, we absolutely would not be able to provide many of the services that I think we should be doing as a cancer program.” And had it not been for the stellar multidisciplinary lung cancer clinic at St. Joseph Mercy, it might have taken the NCCCP longer to recognize just how determined the center is to ensure that people with cancer have the best care possible. ●

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Newsletter Series

YOUR QUESTIONS ANSWERED

Editor in Chief

Sagar Lonial, MD

Stephanie A. Gregory, MD

Associate Professor of Hematology and Oncology Emory University School of Medicine

The Elodia Kehm Chair of Hematology Professor of Medicine Director, Section of Hematology Rush University Medical Center/Rush University

Topics include: â&#x20AC;˘ Newly Diagnosed Patients â&#x20AC;˘ Maintenance Therapy â&#x20AC;˘ Transplant-Eligible Patients â&#x20AC;˘ Retreatment â&#x20AC;˘ Transplant-Ineligible Patients â&#x20AC;˘ Cytogenetics â&#x20AC;˘ Side-Effect Management â&#x20AC;˘ Bone Health

Topics include: â&#x20AC;˘ Hodgkin Lymphoma â&#x20AC;˘ Follicular Lymphoma â&#x20AC;˘ Mantle Cell Lymphoma â&#x20AC;˘ Waldenstromâ&#x20AC;&#x2122;s Macroglobulinemia â&#x20AC;˘ Diffuse Large B-Cell Lymphoma â&#x20AC;˘ T-Cell Lymphoma

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

This activity is supported by educational grant from Cephalon Oncology, Millennium Pharmaceuticals, Inc., and Seattle Genetics, Inc.

Target Audience These activities were developed for physicians, nurses, and pharmacists.

Accreditation This activity has been approved for 1.0 AMA PRA Category 1 Creditâ&#x201E;˘ (a total of 14.0 credit hours will be issued for completion of all activities). Nursing and Pharmacy credit hours will also be provided. For complete learning objectives and accreditation information, please refer to each activity. This activity is jointly sponsored by Global Education Group and Medical Learning Institute, Inc. Coordination for this activity provided by Center of Excellence Media, LLC.

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