June 2011, Vol 4, No 4

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JUNE 2011

www.TheOncologyPharmacist.com

VOL 4, NO 4

For Payers, Purchasers, & Oncology P&T Committees PHARMACOGENOMICS

CANCER CENTER PROFILE

New Oncology Pharmacy Provides “Cleanest Possible Product” By Dawn Lagrosa

KRAS Status, EGFR Inhibition, and Colorectal Cancer By Katharine A. Kinsman, PharmD, BCOP Clinical Pharmacy Specialist in Medical Oncology, The Johns Hopkins Hospital, Baltimore, Maryland Rowena N. Schwartz, PharmD, BCOP Director of Weinberg and Oncology Pharmacy, The Johns Hopkins Hospital, Baltimore, Maryland

harmacogenomics is the study of the role of inherited and acquired genetic variation in drug response.1 A focus of research in recent years on genome-wide association studies ultimate-

P

ly may help identify patient- and/or cancer-specific biomarkers that will facilitate optimization of drug therapy including guiding drug selection, dose, and treatContinued on page 16

CONFERENCE NEWS

Oral Chemotherapy Should Mirror the Current Standards for IV Chemotherapy Technician Melinda Tunnell shows pharmacist Chris Shattuck what drug she will inject into the infusion bag.

his past April, Mountain States Health Alliance’s Regional Cancer Center celebrated the 1-year anniversary of its new, state-of-theart oncology pharmacy. Located in the Regional Cancer Center’s dedicated medical oncology facility, the pharmacy provides USP <797>-compliant chemotherapy and supportive care agents as well as the benefit of face-to-face collaboration between pharmacists and the rest of the cancer care team.

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Continued on page 24

Pharmacists Should Monitor Patients Proactively By Deborah Brauser

SALT LAKE CITY—Identifying safety measures for patients receiving oral chemotherapy is of the upmost importance, according to a presentation at the annual meeting of the Hematology/ Oncology Pharmacy Association. This includes monitoring the administration of and adherence to the treatment as well as ensuring the prevention of any medication errors.

“In my experience, patients do not think it’s the doctor’s job to educate them about their oral chemotherapy, thinking [the doctors] don’t have the time or don’t want to do that,” said Beth Chen, PharmD, BCOP, oncology clinical specialist at Biologics, Inc, in Cary, North Carolina. In addition, she noted that patients are Continued on page 6

INSIDE Complimentary Ce

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Prevention and Treatment of Venous Thromboembolism in Cancer ConferenCe news: Hopa

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Nutrition Support Treatment of Challenging Cancer Pain Radiation-Induced Toxicity Treatment Options Minimizing Chemo Toxicities in Metastatic Colon Cancer

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You voted for the

Identifying, Reporting, and Managing Medication Errors Controversies in Care: Breast Cancer, Bladder Cancer, and Pediatric Ewing Sarcoma supportive Care

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Treating Breakthrough Cancer Pain Managing Hypersensitivity Reactions pHarmaCy Careers

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The Pharmacy Reimbursement Specialist

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Find Out Who Won! Page 14

Pharmacist

©2011 Green Hill Healthcare Communications, LLC

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Going to ASHP Summer Meeting? Stop by booth #608 to get your copy of this new groundbreaking study.

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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. D’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

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For Payers, Purchasers, & Oncology P&T Committees

From the Editor

PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com

W

ith all the big news coming out at the annual meeting of the American Society of Clinical Oncology—vemurafenib and ipilimumab for melanoma, exemestane for breast cancer prevention, bevacizumab for ovarian cancer—smaller studies tend to be overlooked, at least at first. But for pharmacists, their results are no less important. These Patrick Medina, studies expand on our knowledge of PharmD, BCOP supportive care treatments and Editor-in-Chief pharmacy handling, as well as provide us with a point of view that is not pharmacist-specific (see below).

Publisher John W. Hennessy john@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Associate Editor Dawn Lagrosa dawn@greenhillhc.com Quality Control Director Barbara Marino Directors, Client Services Joe Chanley joe@greenhillhc.com Jack Iannaccone jack@greenhillhc.com Production Manager Stephanie Laudien

Amidst all the big news, everyday practice continues, however. With this issue of The Oncology Pharmacist, we finish our coverage of HOPA, highlighting some of the educational seminars. I hope you will be able to incorporate some of the practice strategies discussed. We also introduce a new column by Rowena Schwartz, PharmD, BCOP, and her colleagues at The Johns Hopkins Hospital. Over the next issues, they will discuss myriad implications of pharmacogenomics to our practice. This information should be shared with your nonpharmacy team members. In addition, this issue announces the winner of the inaugural T.O.P. Pharmacist award: Lindsay Kaster, PharmD, a clinical oncology pharmacist at Boise Veterans Affairs Medical Center in Idaho. Please join me in congratulating her for her hard work and dedication to oncology pharmacy and oncology patients. ●

Business Manager Blanche Marchitto blanche@greenhillhc.com

Abstracts of Interest

Executive Administrator Andrea Boylston Circulation Department circulation@greenhillhc.com

2011 Annual Meeting of the American Society of Clinical Oncology

Editorial Contact: Telephone: 732-992-1891 Fax: 732-656-7938

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

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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.

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NEUROPAIN-01: A Phase 2 Study of Oxycodone and Pregabalin In a comparison of 2 strategies involving the combination of oxycodone and pregabalin, researchers found that a fixed dose of oxycodone with an increasing dose of pregabalin provided better neuropathic pain control than a fixed dose of pregabalin with an increasing dose of oxycodone. In addition, the “increasing pregabalin” group experienced less frequent side effects. Garassino MC, et al. Abstract 9028. 5HT3 Antagonist plus Dexamethasone with or without Aprepitant in Multiple-Day Cisplatin Regimens Aprepitant combined with a 5HT3 antagonist and dexamethasone improved control of emesis in germ cell tumor patients receiving a 5-day course of treatment containing cisplatin. This double-blind, placebo-controlled, crossover phase 3 study randomized patients to aprepitant 125 mg on day 3 with 80 mg on days 4 to 7 or to placebo. All patients received a 5HT3 antagonist on days 1 to 5 and dexamethasone 20 mg on days 1 and 2. Patients crossed over for the second cycle of treatment. Blinded dexamethasone 8 mg twice daily or 4 mg twice daily was added in the placebo group, as was dexamethasone 4 mg twice daily on day 8 in the aprepitant group. Brames MJ, et al. Abstract 9013. LNH03-6B: Darbepoetin alfa Associated with Prolonged PFS Although the US Food and Drug Administration has limited the use of erythropoiesis-stimulating agents to patients receiving chemotherapy for noncurative intent, this randomized phase 3 trial found that prophylactic use of darbepoetin alfa was associated with improved progression-free survival (PFS). In this second interim analysis of 600 evaluable patients with diffuse large B-cell lymphoma, 3-year PFS rates were 66% for patients in the darbepoetin alfa group compared with 58% in the standard treatment group. Disease-free survival also improved; however, over-

all survival was not significantly longer in the darbepoetin alfa group. Serious adverse events were similar in the 2 groups. Delarue R, et al. Abstract 9048.

Guarana for Cancer-Related Fatigue Guarana (Paulinia cupana) taken orally as a dry extract during chemotherapy or radiation therapy improved both physical and mental fatigue, as measured by the Chalder Scale. In a set of 3 randomized, placebo-controlled trials with crossover, guarana, a plant that has been used as a stimulant since pre-Colombian times in the Amazon basin, not only significantly improved fatigue scores, but also did not produce any grade 3 or 4 toxicities. Del Giglio A, et al. Abstract e19706. FACT: Fosbretabulin Tromethamine with Carboplatin and Paclitaxel Adding fosbretabulin tromethamine to carboplatin and paclitaxel prolonged overall survival (OS) for patients with anaplastic thyroid cancer. The final results of this randomized phase 2/3 trial also found that the rate of patients achieving OS tripled and a 35% reduction in the risk of death. Patients in the fosbretabulin tromethamine arm did, however, have more grade 1/2 hypertension and grade 3/4 neutropenia. Sosa JA, et al. Abstract 5502. Patient Perspectives on Maintenance Therapy Patients are amenable to maintenance therapy as long as they experience no or mild side effects, according to this semistructured survey during patients’ fourth or subsequent cycle of chemotherapy. Patients with low-grade Hodgkin lymphoma, lung cancer, or colorectal cancer were surveyed regarding their preferred route of administration and willingness to tolerate side effects for hypothetical maintenance therapy. Patients identified oral therapy as their preferred route of administration. Unexpectedly, researchers found that patients anticipated an unrealistic prolongation of overall survival, prompting them to conclude that open and precise information on benefits and side effects is essential. Frank S, et al. Abstract e1953. ●

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Conference News Oral Chemotherapy Should Mirror... Continued from cover flooded with so much new information during an appointment that they often only remember a small portion of what they are told. It is paramount, therefore, that these patients understand exactly what their treatment entails—including how to prepare, administer, and dispose of it safely and properly. “Having a dedicated appointment for education is really the ideal situation, and we do this by phone,” said Chen, adding that these scheduled, periodic follow-up calls should become routine. “It may not always be the pharmacist who does this but consistency with specific staff to develop a relationship with the patient is good.” Other helpful recommendations for patients may include a simple dosing calendar, checklists of questions to ask the doctor at their next visit, and a journal to keep track of any treatment-related adverse effects. “We’re really the ones who need to be looking at drug interac-

tions, especially with TKIs [tyrosine kinase inhibitors]. Patients are often dismissive, and physicians may not be the best people to evaluate this,” said Chen. She noted that patients “very rarely” stop taking their medication because it is something they just want to do. Instead, it is often because the drug makes them feel worse, the cost may be too much after their initial fill, or they weren’t educated appropriately and don’t realize the seriousness of their situation. “Monitoring these situations should be proactive and not reactive.” A recent study examined the effects of adherence to treatment with imatinib on molecular response in 87 patients with chronic myelogenous leukemia (Marin D, et al. J Clin Oncol. 2010; 28:2381-2387). For those who had an adherence rate higher than 90%, 93.7% had a major molecular response (MMR) and 43.8% had a complete molecular response (CMR). For those who had an

adherence rate of 90% or less, only 13.9% had an MMR and none had a CMR. When the adherence was less than 80%, no patient achieved either an MMR or CMR. Although Chen said that no adherence monitoring method is perfect, it’s important to “select a couple that you can use together.” Possible methods may include: • Have patients bring in their medication, do a physical pill count, and report to the physician when there is a problem • Closely monitor refills to check for financial barriers • Use the microelectronic monitoring system to increase accessibility to healthcare. Unfortunately, reports of medication errors in regard to oral chemotherapy are common. According to a 2010 study quoted by Chen that looked at 508 incidents, these errors occurred most fre-

quently during the ordering (47.2%) and dispensing (31.1%) phases, and the most common error involved the wrong dose (38.8%). In addition, “the wrong number of days supplied accounted for 11% of errors but resulted in 39.3% of the adverse events reported.” She recommended that ways to reduce ordering and dispensing errors include not making any verbal orders (unless it’s to hold or discontinue treatment), implementing standardized data entry and a standardized order program, using only a medication’s generic name, including orders for supportive care, implementing bar-code scanning, and setting up a multiple-checkpoint system. “We should take what we are already doing for IV chemotherapy and translate that to oral therapy,” said Chen. Overall, “the use of oral chemotherapy increases the patient’s control but it also increases the responsibility for their cancer care.” ●

Nutrition Support Needs to Be Patient Specific The Pharmacist’s Role in Nutrition Risk SALT LAKE CITY—Early identification of nutrition status and treatmentrelated nutrition risk are important steps in the continuum of care for cancer patients, according to an oral presentation at the annual meeting of the Hematology/Oncology Pharmacy Association. However, “provision of nutrition support…is extremely patient specific. So there are a lot of gray areas and a lot of unknowns,” said Sharla Tajchman, PharmD, BCPS, BCNSP, critical care/ nutrition support clinical pharmacy specialist at The University of Texas M. D. Anderson Cancer Center in Houston, during her presentation. She noted that the American Cancer Society has estimated that almost 25% of all deaths “in Western society” result from cancer and up to 20% of these are directly attributed to cachexia/malnutrition. A past study by Dewys and colleagues found that at least 50% of all cancer patients have significant weight loss, with the highest frequency found among patients with pancreas and metastatic and nonmetastatic gastric cancer (Am J Med. 1980;69:491-497). These patients then often have a poorer response to chemotherapy, worse performance status, and shorter survival duration. Those who have inadequate oral intake for an extended time or no oral intake for 7 days or more are especially at risk nutritionally, according to

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Table Nutritional Considerations for Antitumor Therapies Surgical procedures that include some removal of the stomach can lead to vitamin B12 deficiency. Nutrition effects from radiation often subside within 2 months in those with acute/early illness, but strictures are common in head and neck cancers especially during the chronic/late stage. Placing a nasogastric tube in a patient before a cycle of chemotherapy may help with nutrition support, even if he or she has mucositis or stomatitis. Tajchman. She said it is also important to predict what impact anticancer treatment will have on nutrition (Table). Tajchman noted that after a patient’s nutritional risk is determined, it’s important to create a follow-up plan that defines the next move. “As pharmacists, we know these side effects and we mediate them. That’s our job.” This could involve counseling for the patient by an oncology-trained nutrition support specialist (especially if they have difficulty swallowing); nutrition-support therapy (NST); prophylactic pharmacotherapy for treatment-related side effects, such as nausea, vomiting, and pain; and assessments for long-term complications. The latter may include electrolyte imbalances caused by nephrotoxins from chemotherapy or adhesions and bowel obstruction from surgery. She urged caution, however, when it comes to using appetite stimulants, as the weight gain is usually seen in fat mass. “If our patients gain 5 lb of fat or 5 lb of water, how does that impact

mortality? How does that impact chemotherapy? It lends a feeling of comfort by letting patients feel they have control so it’s not all bad. It’s just that we don’t truly know their effect on outcomes.” In their guidelines for the care of adult cancer patients, the American Society of Parenteral and Enteral Nutrition (ASPEN) recommends that every patient should receive a formal nutrition screening on clinical presentation, as well as a formal follow-up plan. Although the guidelines include that nutrition support “should not be routinely used in patients undergoing active anticancer treatment,” Tajchman said that the studies that were used to make this assessment were limited and included “very heterogeneous” populations. The ASPEN guidelines note that nutrition support is appropriate for patients who are malnourished or predicted to be unable to ingest adequate nutrients for 7 to 14 days. “This recommendation is also for patients undergoing hematopoietic stem cell

transplant,” said Tajchman. Past studies on this, however, have shown conflicting outcomes. “There’s not a good answer for these patients. I come across this every day but unfortunately there are no studies to lead us in the right direction.” Overall, “the guideline recommendations are limited and should not replace clinical judgment,” said Tajchman. “The guidelines give you a starting point.” She added that past research has shown that nutritional markers such as pre-albumin can be improved with nutritional support, but no studies have shown improved survival or morbidity. Still, “there are studies that show you can improve quality of life if you maintain performance status.” Tajchman recommended that patients who are moderately to severely malnourished, have an anticipated prolonged inability to meet nutritional requirements, have continued weight loss despite adequate oral intake, and/or have complications related to malnutrition are the ones most likely to need NST. However, “there are more questions than answers” when it comes to nutrition in cancer patients overall. “The mantra is: ‘It’s always better to do something than nothing.’ But that’s not always true with nutrition support and must be weighed very carefully for every patient,” concluded Tajchman. ● —DB

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Conference News

Treatment of Challenging Cancer Pain Requires Close Monitoring Pharmacists Should Assess Patients for Risks SALT LAKE CITY—Choosing appropriate treatment options and then following strict monitoring parameters are essential for patients with challenging cancer pain, according to a presentation at the annual meeting of the Hematology/Oncology Pharmacy Association. “Cancer patients with pain have risks too. So risk stratification and risk minimization should be employed for all patients,” said David S. Craig, PharmD, BCPS, from the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. “Methadone pearls” from a recent study recommend an electrocardiogram for any high-risk patients (such as those at risk for heart rhythm disturbances) when concurrent QT prolonging drugs are used or there are significant drug– drug interactions, when treatment doses are higher than 100 mg/day, if an intravenous line is used, or if there are electrolyte abnormalities (Krantz M, et al. Ann Intern Med. 2009;150:387-395). Also, “if current QTc is greater than

When patients use opioids, monitoring parameters should include watching for constipation, sedation, or lethargy and keeping continuous watch of alanine transaminase/aspartate transaminase and renal function.

450 msec but less than 500 msec, monitor more frequently. If it is greater than 500 msec, watch out!” said Craig. He added that risk assessments can be conducted with the 5-question Opioid Risk Tool “to predict opioidrelated aberrant behavior,” the 17-item patient-assessed Current Opioid Mis use Measure, and the 24-item Screener and Opioid Assessment for Patients with Pain–Revised. For patients deemed at high risk for abuse, potential strategies can include frequent office visits, random urine drug screenings, and patient–provider

agreements. In addition, Craig recommended considering less abusable formulations, consultations with addiction specialists, and family member involvement. When patients use opioids, monitoring parameters should include watching for constipation, sedation, or lethargy and keeping continuous watch of alanine transaminase/aspartate transaminase (AST/ALT) and renal function. For nonsteroidal antiinflammatory drugs or corticosteroid use, gastrointestinal bleeding and renal and cardiovascular risks should

Radiation-Induced Toxicity Common Treatment Options for the Outpatient Setting SALT LAKE CITY—Although radiation-induced toxicities are common in an outpatient setting, several treatment options have proven very successful—as long as the appropriate monitoring parameters are in place, according to a presentation at the annual meeting of the Hematology/Oncology Pharmacy Association by Makala Pace, PharmD, BCOP, clinical pharmacy specialist at The University of Texas M. D. Anderson Cancer Center in Houston. She noted that the most widely used radiation therapy is currently external beam radiation, which includes 3dimensional conformal and intensitymodulated radiation therapies, stereotactic radiation therapy/surgery, and proton therapy. Internal radiation (including brachytherapy) and systemic radiation therapy (including radiopharmaceuticals) are also common. The development of radiation-related toxicity is dependent on several factors, including the area of body treated, the total dose given, the patient’s performance status, and concurrent therapy. The levels of toxicity are categorized into acute (occurring during treat-

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ment), subacute (developing between 2 weeks and 3 months after therapy), and chronic (occurring more than 6 months after treatment).

For dysgeusia, the recommendations include zinc sulfate, a weekly infusion of amifostine 500 mg, or time—as regeneration may take up to 4 months.

According to Pace, the most common adverse effects include radiation dermatitis, mucositis and dysgeusia, esophagitis, parotitis, otitis, genitourinary conditions such as acute cystitis or obstructive urinary symptoms, diarrhea, and proctitis. For grade 1 radiation dermatitis, the National Cancer Institute recommended application 3 times daily of nonionic

moisturizers, such as Cetaphil, Aveeno, or Lubriderm; of hydrocortisone 1% cream; or of Biafine topical emulsion. For grade 2 and 3, they recommend normal saline or modified Burow’s solution compresses, Polymyxin B/Neomycin cream, or a hydrogel. For grade 4, other treatment options include treating the infection, debridement of the tissue, application of vitamin E and pentoxifylline, and flexible hydroactive hydrocolloid dressings. The latter helps the wound to “autolytically debride itself ” and is “best applied to wounds that produce light to medium exudate or transudate,” explained Pace. She cautioned that these dressings should not be applied over infected wounds and can give off a foul odor 2 to 4 days after application. Regardless of grade, all patients with radiation dermatitis should keep sun exposure from the affected area, should be made aware that different affected areas may require different treatment approaches, and should not apply lotions or gels immediately before undergoing radiotherapy. Recommended treatments for muco-

be monitored; AST/ALT and serum creatinine should be watched when antiepileptics are used; anticholinergic side effects, QT prolongation, and suicide risk should be monitored for tricyclic antidepressants; and anticholinergic side effects, AST/ALT, and suicide risk should be watched with use of serotonin-norepinephrine reuptake inhibitors. Several resources offering guidance are available to oncology pharmacists, including the upcoming “Opioid Drugs and Risk Evaluation and Mitigation Strategies (REMS), Guidelines for the Management of Cancer Pain in Adults and Children” by the American Pain Society (www.ampain soc.org), and recommendations by the National Comprehensive Cancer Network (www.nccn.org) and the National Cancer Institute (www. cancer.gov). In addition, the state of Washington has released noncancer pain management guidelines, whereas Utah and Oklahoma as well as the government of Canada have released guidelines on prescribing opioids. “Always remember adjuvants, other alternatives, outcomes, and treatment plans” for cancer pain, summarized Craig. “And although opioids remain the mainstay, think outside the box when necessary.” ● —DB

sitis include an electrolyte solution, such as the supersaturated calcium phosphate rinse Caphosol that resembles human saliva, lidocaine/diphenhydramine/simethicone, antifungals, or a protective barrier such as sucralfate or Gelclair bioadherent oral gel. For dysgeusia, the recommendations include zinc sulfate, a weekly infusion of amifostine 500 mg, or time—as regeneration may take up to 4 months. Other radiation-induced side effects and recommended treatments include: • Dental caries/tooth decay: tooth extraction or fluoride gels • Esophagitis: lidocaine, nutritional support, protective barriers, or acid suppressants • Inflammation of a parotid gland: aspirin or nonsteroidal anti-inflammatory drugs • Dry mouth: pilocarpine, artificial saliva, amifostine, or cevimeline • Otis externa: hydrocortisone/ neomycin/polymyxin B ear drops (with decongestants or phenylephrine otic solution for serious otitis) • Acute cystitis: phenazopyridine or oxybutynin • Obstructive urinary symptoms: oxybutynin, tamsulosin, finasteride, or terazosin • Diarrhea: low-residue diet, loperamide, cholestyramine, or octreotide. ● —DB

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Conference News

Minimizing Chemo Toxicities for Patients with Metastatic Colon Cancer Reliable Tests Needed SALT LAKE CITY—Reliable tests are sorely needed to help determine the best dose regimen before chemotherapy to minimize toxicities for patients with metastatic colon cancer, according to a talk given at the annual meeting of the Hematology/Oncology Pharmacy Association. Marlo Blazer, PharmD, BCOP, outpatient oncology pharmacist at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at the Ohio State University Medical Center in Columbus, explained that dihydropyrimidine dehydrogenase deficiency (DPD) is responsible for the breakdown of the chemotherapy drug 5-fluorouracil (5FU). “The cytotoxic effects of capecitabine and 5FU can only occur after conversion into the active nucleotides—and the amount of 5FU available for conversion is determined by the extent of its breakdown.�

“No single test had sufficient sensitivity and specificity to detect true [DPD] deficiency.� —Marlo Blazer, PharmD, BCOP

Unfortunately, 3% to 5% of these patients have a partial DPD and 0.2% have a complete loss. “The central assumption to existing studies is that the degree of deficiency is proportionally related to severity of 5FU toxicity,� said Blazer. “For patients who are admitted for what we suspect is DPD, we see the classic triad of toxicities: febrile neutropenia, mucositis, and diarrhea. And we often see dehydration because of the mucositis and diarrhea.� There are currently several ways to test for DPD. However, a recent study from France of 252 white colon cancer patients found that these assays on their own did not correlate with 5FU toxicity (Boisdron-Celle M, et al. Cancer Lett. 2007;249:271-282). In fact, “no single test had sufficient sensitivity and specificity to detect true [DPD] deficiency.� Using a 2-step, 2-test approach (first testing for DPD single-nucleotide polymorphism and plasma uracil, then conducting another test) did increase the values, and provided 83% sensitivity and 84% specificity. In other words, “98.8% of those with a grade 3 or 4 tox-

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icity would have had their 5FU dose initially reduced. But 8% of the patients

would have had an unnecessary dose reduction,� said Blazer.

In addition, past research has not looked at the costs of these tests and few studies have assessed whether initial dose reductions were necessary—“only that incidence of toxicity was reduced,� explained Blazer. “So should you test for DPD prior to beginning treatment? And what if the test came back negative? To

Now Approved

YERVOY

™

(ipilimumab)

INDICATION YERVOY is indicated for the treatment of unresectable or metastatic melanoma.

Important Safety Information WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immunemediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. *NQPSUBOU 4BGFUZ *OGPSNBUJPO DPOUJOVFE PO BEKBDFOU QBHF

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Conference News reduce risk of toxicity, we usually reduce 75% to 80% upfront in these patients and step them up slowly based on tolerance. But there are no guidelines as far as dose reduction.� A polymorphism of the UGT1A1 gene also can lead to increased irinotecan-associated toxicity. A recent re-

view of 9 studies, however, had several limitations, including that the tumor type was not restricted to just colon cancer and the doses and frequency of the medication varied widely. Overall, the investigators found that the polymorphism did not put patients at a significantly increased risk of

severe diarrhea. Patients with the homozygous type of the polymorphism (UGT1A28*28), however, were 3.5 times more likely to have a severe neutropenia event compared with those with the wild type (UGT1A1*1). “At this point and time, this is the incidence that we see. Should we be

worried about giving the population at large irinotecan without testing first for the UGT1A1 polymorphism? We just don’t have a silver bullet for testing, where if we test them for UGT1A1 and they’re homozygous then we can prevent neutropenia,� said Blazer. � —DB

Important Safety Information (continued) Recommended Dose Modifications:

Immune-mediated Endocrinopathies:

Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for any of the following: t 1FSTJTUFOU NPEFSBUF BEWFSTF SFBDUJPOT PS JOBCJMJUZ UP SFEVDF corticosteroid dose to 7.5 mg prednisone or equivalent per day. t 'BJMVSF UP DPNQMFUF GVMM USFBUNFOU DPVSTF XJUIJO XFFLT GSPN administration of first dose. t 4FWFSF PS MJGF UISFBUFOJOH BEWFSTF SFBDUJPOT

t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT TFWFSF to life-threatening immune-mediated endocrinopathies (requiring IPTQJUBMJ[BUJPO VSHFOU NFEJDBM JOUFSWFOUJPO PS JOUFSGFSJOH XJUI BDUJWJUJFT of daily living; Grade 3-4) occurred in 9 (1.8%). – All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. o PG UIF QBUJFOUT XFSF IPTQJUBMJ[FE GPS TFWFSF FOEPDSJOPQBUIJFT t .PEFSBUF FOEPDSJOPQBUIZ SFRVJSJOH IPSNPOF SFQMBDFNFOU PS NFEJDBM intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome. t .FEJBO UJNF UP POTFU PG NPEFSBUF UP TFWFSF JNNVOF NFEJBUFE endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY. t .POJUPS QBUJFOUT GPS DMJOJDBM TJHOT BOE TZNQUPNT PG IZQPQIZTJUJT adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. – Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. – Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated. – Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. o *O B MJNJUFE OVNCFS PG QBUJFOUT IZQPQIZTJUJT XBT EJBHOPTFE CZ imaging studies through enlargement of the pituitary gland.

Immune-mediated Enterocolitis: t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT TFWFSF MJGF threatening or fatal (diarrhea of ≼7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred JO BOE NPEFSBUF EJBSSIFB XJUI VQ UP TUPPMT BCPWF CBTFMJOF abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients. t "DSPTT BMM :&370: USFBUFE QBUJFOUT O EFWFMPQFE intestinal perforation, 4 (0.8%) died as a result of complications, and XFSF IPTQJUBMJ[FE GPS TFWFSF FOUFSPDPMJUJT t .POJUPS QBUJFOUT GPS TJHOT BOE TZNQUPNT PG FOUFSPDPMJUJT TVDI BT diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). o * O TZNQUPNBUJD QBUJFOUT SVMF PVU JOGFDUJPVT FUJPMPHJFT BOE DPOTJEFS endoscopic evaluation for persistent or severe symptoms.

Immune-mediated Hepatitis: t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT TFWFSF MJGF threatening, or fatal hepatotoxicity (AST or ALT elevations >5X the upper limit of normal (ULN) or total bilirubin elevations >3X the ULN; Grade 3–5) occurred in 8 (2%), with fatal hepatic failure in 0.2% and IPTQJUBMJ[BUJPO JO t BEEJUJPOBM :&370: USFBUFE QBUJFOUT FYQFSJFODFE NPEFSBUF IFQBUPUPYJDJUZ NBOJGFTUFE CZ -'5 BCOPSNBMJUJFT "45 PS "-5 FMFWBUJPOT >2.5X but ≤5X the ULN or total bilirubin elevation >1.5X but ≤3X the ULN; Grade 2). t .POJUPS -'5T IFQBUJD USBOTBNJOBTF BOE CJMJSVCJO MFWFMT BOE BTTFTT patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. o * O QBUJFOUT XJUI IFQBUPUPYJDJUZ SVMF PVU JOGFDUJPVT PS NBMJHOBOU DBVTFT BOE JODSFBTF GSFRVFODZ PG -'5 NPOJUPSJOH VOUJM SFTPMVUJPO

Immune-mediated Dermatitis: t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT TFWFSF life-threatening or fatal immune-mediated dermatitis (e.g., StevensJohnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) patients. – 1 (0.2%) patient died as a result of toxic epidermal necrolysis. o BEEJUJPOBM QBUJFOU SFRVJSFE IPTQJUBMJ[BUJPO GPS TFWFSF EFSNBUJUJT t 5IFSF XFSF :&370: USFBUFE QBUJFOUT XJUI NPEFSBUF (SBEF dermatitis. t .POJUPS QBUJFOUT GPS TJHOT BOE TZNQUPNT PG EFSNBUJUJT TVDI BT SBTI and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.

Immune-mediated Neuropathies: t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT DBTF PG GBUBM Guillain-BarrĂŠ syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. t "DSPTT UIF DMJOJDBM EFWFMPQNFOU QSPHSBN PG :&370: NZBTUIFOJB HSBWJT and additional cases of Guillain-BarrĂŠ syndrome have been reported. t .POJUPS GPS TZNQUPNT PG NPUPS PS TFOTPSZ OFVSPQBUIZ TVDI BT unilateral or bilateral weakness, sensory alterations, or paresthesia.

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations: t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT DMJOJDBMMZ significant immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. t "DSPTT UIF DMJOJDBM EFWFMPQNFOU QSPHSBN GPS :&370: JNNVOF mediated adverse reactions also reported with <1% incidence were: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis.

Pregnancy & Nursing: t :&370: JT DMBTTJGJFE BT QSFHOBODZ DBUFHPSZ $ 5IFSF BSF OP BEFRVBUF and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus. t )VNBO *H( JT LOPXO UP DSPTT UIF QMBDFOUBM CBSSJFS BOE :&370: JT BO *H( UIFSFGPSF :&370: IBT UIF QPUFOUJBM UP CF USBOTNJUUFE GSPN UIF mother to the developing fetus. t *U JT OPU LOPXO XIFUIFS :&370: JT TFDSFUFE JO IVNBO NJML #FDBVTF many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY.

Common Adverse Reactions: t The most common adverse reactions (≼5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

1MFBTF TFF #SJFG 4VNNBSZ PG 'VMM 1SFTDSJCJOH *OGPSNBUJPO JODMVEJOH Boxed WARNING regarding immune-mediated adverse reactions, on following pages.

For additional information, please visit Š2011 Bristol-Myers Squibb, Princeton, NJ 08543 731US11AB08002 YERVOY is a trademark of Bristol-Myers Squibb. All rights reserved.

www.TheOncologyPharmacist.com

03/11

Printed in USA

www.YERVOY.com/hcp

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Conference News

Identifying, Reporting, and Managing Medication Errors Strategies for Each Stage of the Process SALT LAKE CITY—Although it’s important to strive for no chemotherapyrelated medication errors, it’s just as important to have an organized system

in place to identify, report, and manage these errors when they occur, according to a presentation at the annual meeting of the Hematology/Oncology

Pharmacy Association. “We’ve made progress in medication errors both from understanding their epidemiology in the past 15 years and

YERVOY™ (ipilimumab) Injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. [See Dosage and Administration (2.2) in Full Prescribing Information] Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. [See Warnings and Precautions] INDICATIONS AND USAGE YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma. CONTRAINDICATIONS

how we can mitigate them through technology, workflow, and system changes,� said Sylvia Bartel, RPh, MHP, from the Dana-Farber Cancer

The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY (ipilimumab). Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks. Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement. Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated. Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Dosage and Administration (2.2) in Full Prescribing Information] For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week. Immune-mediated Neuropathies

None. WARNINGS AND PRECAUTIONS YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Boxed Warning] Immune-mediated Enterocolitis In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3–5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis. The median time to onset was 7.4 weeks (range 1.6–13.4) and 6.3 weeks (range 0.3–18.9) after the initiation of YERVOY for patients with Grade 3–5 enterocolitis and with Grade 2 enterocolitis, respectively. Twenty-nine patients (85%) with Grade 3–5 enterocolitis were treated with high-dose (≼40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids. Of the 34 patients with Grade 3–5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve. Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms. Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least one month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than one week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Dosage and Administration (2.2) in Full Prescribing Information] Immune-mediated Hepatitis In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3–5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsyproven hepatitis to characterize the clinical course of this event.

In Study 1, one case of fatal Guillain-BarrÊ syndrome and one case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-BarrÊ syndrome have been reported. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-BarrÊ-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Dosage and Administration (2.2) in Full Prescribing Information] Immune-mediated Endocrinopathies In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3–4) occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and one case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY. Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13). Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated. Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland. Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosage and Administration (2.2) in Full Prescribing Information] Other Immune-mediated Adverse Reactions, Including Ocular Manifestations The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis. Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immunemediated adverse reactions.

Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.

Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosage and Administration (2.2) in Full Prescribing Information]

Permanently discontinue YERVOY in patients with Grade 3–5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Dosage and Administration (2.2) in Full Prescribing Information]

ADVERSE REACTIONS

Immune-mediated Dermatitis In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) YERVOY-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis.

The following adverse reactions are discussed in greater detail in other sections of the labeling.

t *NNVOF NFEJBUFE FOUFSPDPMJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE IFQBUJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE EFSNBUJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE OFVSPQBUIJFT [see Warnings and Precautions].

t *NNVOF NFEJBUFE FOEPDSJOPQBUIJFT [see Warnings and Precautions].

t 0 UIFS JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT JODMVEJOH PDVMBS NBOJGFTUBUJPOT [see Warnings and Precautions].

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Conference News Institute in Boston, Massachusetts. Still, errors occur for multiple reasons, including understaffing, a lack of knowledge, or system failures—and may include issues with order writing and communication, dose miscalculations, incorrect drug administration, or poor distribution.

“Our systems are really complicated, and sometimes we have mental lapses. We all work in very busy environments, and although we try to have a quiet space for pharmacists to process orders or for physicians to write them, in reality that is often not the case,� said Bartel. “We learn from this by looking at how our sys-

tems fail and seeing where we have redundancies and where we don’t have redundancies but should.� Because errors often start with the order, it’s imperative that providers keep everything clear, such as the drug, dose, and schedule. Dose miscalculations are also common, often because of compli-

Clinical Trials Experience

Immunogenicity

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.

In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.

The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY (ipilimumab) 3 mg/kg for four doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14) in Full Prescribing Information] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range 1 to 4 doses). YERVOY was discontinued for adverse reactions in 10% of patients. The most common adverse reactions (≼5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis. Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3–5 events. Table 1:

Percentage (%) of YERVOY 3 mg/kg n=131

Gastrointestinal Disorders Diarrhea Colitis Skin and Subcutaneous Tissue Disorders Pruritus Rash General Disorders and Administration Site Conditions Fatigue a

YERVOY 3 mg/kg+gp100 n=380

gp100 n=132

Any Grade

Grade 3–5

Any Grade

Grade 3–5

Any Grade

Grade 3–5

32 8

5 5

37 5

4 3

20 2

1 0

31 29

0 2

21 25

<1 2

11 8

0 0

41

7

34

5

31

3

Severe to Fatal Immune-mediated Adverse Reactions in Study 1 Percentage (%) of Patients

Any Immune-mediated Adverse Reaction Enterocolitisa,b Hepatotoxicitya Dermatitisa Neuropathya Endocrinopathy Hypopituitarism Adrenal insufficiency Other Pneumonitis Meningitis Nephritis Eosinophiliac Pericarditisa,c b c

No formal drug-drug interaction studies have been conducted with YERVOY (ipilimumab). USE IN SPECIFIC POPULATIONS Pregnancy

In a combined study of embryo-fetal and peri-postnatal development, severe toxicities including increased incidences of third-trimester abortion, stillbirth, premature delivery, low birth weight, and infant mortality occurred following intravenous administration of ipilimumab to pregnant cynomolgus monkeys every 21 days from the onset of organogenesis through parturition at doses of 2.6 or 7.2 times the recommended human dose of 3 mg/kg (by AUC). [See Nonclinical Toxicology (13.2) in Full Prescribing Information] In genetically engineered mice in which the gene for CTLA-4 has been deleted (a “knockout mouse�), offspring lacking CTLA-4 were born apparently healthy, but died within 3–4 weeks due to multi-organ infiltration and damage by lymphocytes. Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus. Nursing Mothers

Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1.

a

DRUG INTERACTIONS

There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Patientsa

Incidences presented in this table are based on reports of adverse events regardless of causality.

Table 2:

Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY with the incidences of antibodies to other products may be misleading.

Pregnancy Category C

Selected Adverse Reactions in Study 1

System Organ Class/ Preferred Term

Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100 n=380

15 7 1 2 1 4 4 0

12 7 2 3 <1 1 1 1

0 0 1 1 0

<1 <1 0 0 <1

It is not known whether ipilimumab is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother. Pediatric Use Safety and effectiveness of YERVOY have not been established in pediatric patients. Geriatric Use Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years). Renal Impairment No formal studies of YERVOY in patients with renal impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information] Hepatic Impairment No formal studies of YERVOY in patients with hepatic impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information] OVERDOSAGE There is no information on overdosage with YERVOY. PATIENT COUNSELING INFORMATION See MEDICATION GUIDE in Full Prescribing Information. t *OGPSN QBUJFOUT PG UIF QPUFOUJBM SJTL PG JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT t "EWJTF QBUJFOUT UP SFBE UIF :&370: .FEJDBUJPO (VJEF CFGPSF FBDI :&370: JOGVTJPO t "EWJTF XPNFO UIBU :&370: NBZ DBVTF GFUBM IBSN t "EWJTF OVSTJOH NPUIFST OPU UP CSFBTU GFFE XIJMF UBLJOH :&370:

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA

Including fatal outcome. Including intestinal perforation. Underlying etiology not established.

Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction. Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.

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cated formulas for determining body weight, and drug shortages can lead to the staff being unfamiliar with the substitute medication. “Chemo agents, by nature of what they are, can lend themselves to medication errors, particularly adverse drug reactions,� said Bartel. “We expect patients to be sick, to have fatigue and nausea, but is that really an expected adverse reaction or is it due to an error?� Although the person who discovers an error is supposed to call a specified phone number, put it into the computer system, or alert someone face to face, Bartel said that only 2% to 5% of errors are discovered through “spontaneous reporting.� Instead, she suggests taking a hard look periodically at a particular process and then gathering data on it.

1281558A2

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When it comes to managing an error, disclosing its occurrence to the patient should be the first step. “Look at orders, go back to the cart, look at the workflow process. When errors get reported, we really want to make sure we look at how it happened on multiple levels so that we get at the root cause,� she said. At Dana-Farber, they strive to make sure their error reporting system is anonymous, easy to use, and includes a severity rating scale to assess potential harm. The data then are used to develop process improvements. In addition, an oncology-specific self-assessment tool from the Institute of Safe Medication Practices is expected to be released this fall. When it comes to managing an error, disclosing its occurrence to the patient should be the first step, followed by giving support to staff members who might be upset and taking it personally. Bartel also suggested adopting a “Just Culture� approach. “Managers need to help their staff look at system changes as opposed to having a punitive environment to catalog in a performance review how many errors they were involved in. The individual is accountable for what is under their control but it’s part of the broader context of the system.� Overall, Bartel said that it’s important to create a work environment that rewards error reporting, values safety and continuous learning, and encourages managers and staff to have open discussions about potential risks and how best to avoid them. “It’s just a new way of thinking.� � —DB

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Conference News

Controversies in Care: New Treatment Considerations for Breast, Bladder Cancer and Pediatric Ewing Sarcoma Bisphosphonates, Neoadjuvant Therapy, and Dose-Dense Therapy Remain Debatable SALT LAKE CITY—Bisphosphonates may have a role as an adjuvant breast cancer treatment, cisplatin-based neoadjuvant chemotherapy should be considered for treating bladder cancer, and dose-dense chemotherapy may add benefit for patients with pediatric Ewing sarcoma, according to 3 presentations at the “Controversies in Care” session at the annual meeting of the Hematology/ Oncology Pharmacy Association. Bisphosphonates in Breast Cancer “We use bisphosphonates commonly in our practice but there are classifications based on whether they contain nitrogen,” said Jared M. Freml, PharmD, BCOP, clinical pharmacy specialist– oncology at Kaiser Permanente in Denver, Colorado, in his discussion on the early and delayed use of bisphosphonates in breast cancer patients. He explained that clodronate and etidronate are non-nitrogen treatments that bind to the bone surface. As they accumulate there, osteoclasts break down, resulting in the accumulation of cytotoxic levels. Nitrogen-containing bisphosphonates include pamidronate, ibandronate, risedronate, alendronate, and zoledronic acid (ZA). These treatments also bind to the bone and “are taken up by osteoclast,” resulting in cytotoxic levels. They also inhibit the mevalonate pathway. “I think it’s smart that we’ve looked at bisphosphonates as possible antitumor agents, as they have demonstrated antiproliferative and proapoptotic activity in cell and animal cultures,” said

Freml. In addition, bisphosphonates that contain nitrogen inhibit the migration and invasion of tumor cells. “Sequencing might be an important thing to consider as we’re giving these drugs,” he added. Doxorubicin and paclitaxel followed by ZA has shown synergistic antitumor effects, and pamidronate and ZA have been shown to inhibit angiogenesis in mouse models. Studies that have looked specifically at clinical outcomes for treatment with adjuvant bisphosphonates for patients with estrogen receptor– or progesterone receptor–positive breast cancer, however, have shown mixed results. Whereas in the randomized Austrian Breast and Colorectal Cancer Study Group Trial, 12 of 1803 patients (randomized to 4 treatment arms) showed a significant increase in disease-free survival for those receiving treatments containing ZA compared with hormonal treatment only, the 3360-patient Neo-Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial did not. Neither trial showed a statistically significant increase in overall survival. In these 2 trials, plus 2 others cited by Freml, there was a significant benefit in bone mineral density at 36 and 60 months for those who received ZA. “I think it’s important that [we] didn’t see any adverse reactions except as expected: flulike symptoms, pyrexia, bone pain, and headache.” The one exception was a higher incidence of osteonecrosis of the jaw in the AZURE trial. Freml said that although the role of bisphosphonate adjuvant therapy for

breast cancer “is evolving,” the optimal administration has yet to be defined, and it is unclear which patient group is most likely to benefit from this treatment. “There are some interesting theories being generated from early studies, but it is difficult to conclude that these are practice changing at this time,” he summarized. Neoadjuvant Therapy in Bladder Cancer Surgery is currently considered the standard-of-care treatment for bladder cancer. However, “we’re hoping neoadjuvant therapy will reduce tumor volume and lead to less invasive surgery and bladder preservation, and also give us good prognostic information when we assess response to chemotherapy,” said Jessica Poirier Duda, PharmD, BCOP, specialty practice pharmacist at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at the Ohio State University Medical Center in Columbus. She noted that there is a high risk of recurrence in these patients and low overall survival rates. “So there may be a lot of micrometastatic disease that we don’t know when tumor burden is low. And patients may be able to tolerate chemo better when we don’t have complications from surgery or radiation. “Although radical cystectomy is the gold standard for the treatment of localized muscle-invasive bladder cancer, cisplatin-based neoadjuvant combination chemotherapy should be considered based on performance status,” said Duda.

She noted, however, that large, randomized, multicenter trials assessing neoadjuvant chemotherapy are sorely lacking. Dose-Dense Therapy in Pediatric Ewing Sarcoma Surgery, if possible, is the current standard of care for local therapy, according to David Henry, MS, BCOP, FASHP, associate professor and interim chair–pharmacy practice at the University of Kansas School of Pharmacy, in his discussion of the potential benefits and risks of dose-dense therapy for pediatric Ewing sarcoma. Radiation is used commonly if surgery is not possible or for further control after surgery, but treatment can vary according to circumstances. The question of whether dose density can play a role in this setting has been raised in past studies. One found that increasing doses of doxorubicin was associated with better outcomes, although it compared less intense therapies than are used at present. Another found an increase in 5-year overall survival, from 61% to 72%, after adding ifosfamide and etoposide for half the cycles of vincristine/doxorubicin/ cyclophosamide/dactinomycin. There was no improvement found, however, for patients with metastatic disease, which is becoming common in several other studies too. “There are no data for metastatic disease for dose-dense therapy,” said Henry. “Overall, is there a role for dose intensity? Right now it’s a fairly debatable question.” ● —DB

SUPPORTIVE CARE

Treating Breakthrough Cancer Pain Requires Recognition, Matching Drug to Goal See also page 26. Pharmacists Should Parallel Pharmacokinetics with Pain By Wayne Kuznar

ANAHEIM—Effective management of breakthrough cancer pain requires optimizing background therapy for chronic pain and accurately assessing the type of breakthrough pain, said presenters at the 45th American Society of Health-System Pharmacists Midyear Clinical Meeting & Exposition. “Knowing the type of breakthrough cancer pain can help match the right drug with the right goal,” said Mary Lynn McPherson, PharmD, BCPS, CDE, who is professor and vice chair, Department

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of Pharmacy Practice and Science, University of Maryland School of Pharmacy in Baltimore. Newer rapidonset opioids are becoming the standard of management but opioids are often suboptimal when used alone. The prevalence of breakthrough cancer pain varies, with estimates ranging from 30% to 90%, said Steven D. Passik, PhD. The pathophysiology is complex, with simultaneous nociceptive and neuropathic pain processes occurring, he said.

Older cancer patients may need to be probed for cancer pain because they often underreport their pain or will indicate that it’s controlled when it may not be, said Passik, who is associate attending psychologist, Department of Psychiatry and Behavioral Sciences, Memorial Sloan-Kettering Cancer Center in New York City. Breakthrough cancer pain has been described as spikes of pain that occur on top of baseline well-controlled pain. Breakthrough pain typically has an

onset of less than 3 minutes, occurs 1 to 4 times daily, and has an average duration of 30 minutes. A combination of symptom assessment tools, patient history, and a physical examination to assess pain should be used to devise the treatment plan, said Passik. “Cancer pain patients are morphing into chronic pain patients,” he said. “You have to plan their opioid therapy in the same way as noncancer chronic pain patients.” Unfortunately, no tools specific for

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Supportive Care breakthrough cancer pain are validated fully for routine clinical use. Pain is but one item among many contained in general cancer symptom scales, but scales such as The M. D. Anderson Symptom Inventory, the Edmonton Symptom Assessment Scale, and the Memorial Symptom Assessment Scale can help put pain into the context of other symptoms. Key elements of the history include illnesses relevant to opioid therapy (ie, respiratory, hepatic, renal disease), medical illnesses suggestive of substance abuse (ie, hepatitis, HIV/AIDS, sexually transmitted diseases, liver disease, tuberculosis), and a history of substance abuse including alcohol, tobacco, and prescription drugs. “Cancer doesn’t protect a patient from having an addiction,” and patients with a history of addiction are not candidates for rapid-onset opioids, he said. Smokers have a higher rate of opioid abuse than nonsmokers, he added. The Mental Health Inventory-5 can be used as part of the psychiatric history, and a score of less than 52 should

trigger a formal evaluation. Urine screens to monitor compliance and possible diversion of opioids are useful even in cancer pain management, he said. The Current Opioid Misuse Measure is a 17-item tool to address ongoing medication misuse but because this tool “overidentifies” misuse and abuse, it should only be used to identify potential cases for follow-up. In the treatment of breakthrough cancer pain, controlling baseline persistent pain is paramount before moving forward, said McPherson. “The patients are in the driver’s seat, and we need to control their pain to their satisfaction,” she said. For some patients, this may mean that achieving a numerical rating scale pain score of 3 or 4 (on a 0 to 10 scale) is satisfactory to allow them to interact with their families, whereas in others it may be inadequate. One challenge in selecting the right drug is that the preferred option may not be possible because of cost and reimbursement barriers, problems with tolerability, and certain disease- or

cancer therapy–related barriers, such as dysphagia, mucositis, and nausea. The preferred pharmacologic agent to treat breakthrough pain will have pharmacokinetics that match the characteristics of the pain, she said. For pain brought on by predictable incidents, short-acting opioids with slower onset than fentanyl products can be used. Volitional pain, such as with wound care, should be premedicated. For idiopathic or spontaneous pain with intense and/or fast onset, such as unpredictable pain upon awakening, rapid-onset opioids are a good option. For end-of-dose pain, background therapy should first be optimized. Instead of more frequent administration of the dose, “stick with the dosage interval that’s approved and increase the dose,” advised McPherson. She recommends using the Alberta Breakthrough Pain Assessment Tool, a research tool, to educate patients about breakthrough cancer pain. After understanding the difference between pain types, patients should be encouraged to distinguish chronic pain from break-

Managing Hypersensitivity Reactions Premedication and Titration Useful Strategies ANAHEIM—Hypersensitivity or infusion reactions to chemotherapy agents or monoclonal antibodies can be lifethreatening but often can be managed with premedications or titration of infusion rates, said Catherine Christen, PharmD, at the 45th American Society of Health-System Pharmacists Midyear Clinical Meeting & Exposition. Medications associated with infusion reactions are platinum agents, taxanes, liposomal doxorubicin, etoposide, and monoclonal antibodies. Hypersensitivity reactions can be either allergic (IgE-mediated) or nonallergic (anaphylactoid). Type I hypersensitivity reactions are usually IgE reactions. They occur after multiple infusions and within minutes of exposure, although delayed reactions (hours later) can occur. “Positive skin tests are a helpful diagnostic tool [for type I hypersensitivity reactions],” because they have a very high negative predictive value, she said. Anaphylactoid reactions do not have an IgE basis, and may instead be caused by complement activation, said Christen, clinical assistant professor of pharmacy, College of Pharmacy, and clinical pharmacist, gynecology oncology, University of Michigan Health Systems, Ann Arbor. Anaphylactoid reactions occur with initial drug exposure; they usually respond to pretreatment with antihistamines and epinephrine. Cremophor-containing paclitaxel has been associated with hypersensitivity

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reactions, including anaphylaxis. For infusion reactions, start at a slow rate and titrate up the rate of infusion as tolerated, she said. Carboplatin Hypersensitivity reactions to carboplatin are more common than with other chemotherapeutic agents, she said. In one series of ovarian cancer patients with hypersensitivity reactions to carboplatin, successful desensitization was possible in 37 of 38 patients (105 of 106 successful desensitizations). Skin testing was performed before each desensitization; 5 of 7 patients with a remote history of hypersensitivity reactions became skin test–positive, and the authors concluded that such patients were at risk of developing more severe hypersensitivity reactions (Hesterberg PE, et al. J Allergy Clin Immunol. 2009; 123:1262-1267). Carboplatin desensitization protocols in which suboptimal doses are given incrementally to render mast cells and basophils unresponsive to antigens “require a 1:1 RN-to-patient ratio,” she said. Eight to 12 dilution steps are usually required. Castells and colleagues described a standardized 12-step rapid desensitization protocol for platinum-based chemotherapy (and paclitaxel, doxorubicin, and rituximab), in which the rate of infusion is increased every 15 minutes until the final dose is given (J Allergy Clin Immunol. 2008;122:574-

580). “The protocol takes 6 hours or more,” said Christen. Of 413 desensitizations performed, 94% elicited either mild or no reactions, and all patients were able to receive the full target dose. Desensitization protocols must be carried out each time drug therapy is given on an intermittent basis, as with chemotherapy. “You need to desensitize with every dose,” she said. Taxanes Paclitaxel hypersensitivity may be an anaphylactoid or IgE-mediated reaction, which tends to occur early, during the first or second infusion, said Christen. When encountering a reaction to paclitaxel, interrupt the infusion and administer protocol medicines—corticosteroids, diphenhydramine, and albuterol, she said. If the symptoms resolve, the infusion can then be restarted at a lower rate and titrated up. To avoid hypersensitivity reactions to future paclitaxel infusions, she advises premedicating with additional antihistamines and corticosteroids, and a slow infusion rate that is titrated up as tolerated. Substitution of another taxane or a desensitization protocol similar to the one described for carboplatin may be tried. Hypersensitivity occurs less frequently with docetaxel than with paclitaxel, and reactions to docetaxel can be managed similarly to those with paclitaxel. Etoposide/Teniposide

through cancer pain in pain diaries. Alternatively, 3 questions should be incorporated into the assessment: • Do you have pain flare-ups? • Are they predictable? If so, what are the causes? • How often do you have them? Addressing the cause of pain can be as simple as prescribing antitussive medication for cough that triggers pain and avoiding invasive procedures when they won’t change patient management. After selecting a therapy, counsel patients to preempt pain when they recognize a prodrome. In selecting the dose for a short-acting opioid for breakthrough, 10% to 15% of the daily background medication dose is a standard rule. When using rapid-onset opioids, always start at the lowest dose, even if switching from one fentanyl to another. Ensure that patients are opioid-tolerant before starting a rapid-onset agent: “You cannot start a transdermal fentanyl patch unless someone is opioidtolerant,” she said. ●

Hypersensitivity reactions to etoposide can occur with the first treatment or multiple courses, and can be anaphylactoid or IgE-mediated. Etoposide does not contain Cremophor; if infusion reactions occur, options are switching to teniposide or trying an etoposide desensitization protocol. Liposomal Doxorubicin Acute infusion-related reactions, possibly caused by activation of complement, have been documented in up to 10% of patients treated with a first infusion of liposomal doxorubicin. To minimize the risk of infusion reactions, Christen recommended an initial infusion rate of 1 mg/min. Reactions resolve over the course of several hours to 1 day after the infusion is stopped. Monoclonal Antibodies Infusion reactions to monoclonal antibodies can be IgE-mediated allergic reactions to foreign proteins or nonallergic reactions to cytokine release. Reactions to monoclonal antibodies occur primarily with chimeric products. To manage monoclonal antibody– induced infusion reactions, Christen advised pretreating with acetaminophen and an antihistamine and slowly titrating the infusion to the full rate. “Interrupt the infusion as needed and treat reactions,” she said. “You can usually restart the infusion at a 50% lower rate than titrate up to completion.” Risk factors for fatal outcomes in recipients of rituximab are chronic lymphocytic leukemia, mantle cell lymphoma, high circulating lymphocyte counts (>50 mm3), bulky disease, and

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TOP Pharmacist Idaho’s Lindsay Kaster Named T.O.P. Pharmacist By Daniel Denvir

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I love the patients because they’re so resilient,” she says. “I deal only with cancer patients. Some people think that’s depressing, but they’re so strong and courageous.” —Lindsay Kaster, PharmD

he Oncology Pharmacist congratulates Lindsay Kaster, PharmD, for being chosen by more than 750 of her peers as this year’s T.O.P. Pharmacist award winner. “The best part of the job,” says Kaster, a clinical oncology pharmacist at the Boise Veterans Affairs (VA) Medical Center in Idaho, “is that it just brings that team dynamic together.” Kaster has won accolades from colleagues like Brenda S. Dunn, PharmD, MBA, a pharmacy executive with Veterans Integrated Service Network 20, for her commitment to cost-cutting. “Lindsay’s proactive approach includes cost-avoidance measures for the veterans as well as the pharmacy, a dose-rounding program to reduce drug wasting, a comprehensive error-prevention process, a thorough review of adverse drug reactions with education to providers on how to eliminate or decrease future occurrences, development of a stability chart for pharmacy and nursing use, appropriate premedication practices, and strategies to effectively work with medication backorders and national shortages.” Kaster says that because she does not depend on reimbursements for her paycheck, she can focus all of her attention on cost and quality. With the increasing criticism of the fee-for-service reimbursement model dominating most of the healthcare industry, she is proud to say that she saves the government more money than she makes. “I’ll say, ‘we can do this instead, because it will save $1000 and it has the same efficacy data,’” she tells The Oncology Pharmacist. “Instead of pounding out orders, I spend my days trying to optimize the medications my patients are taking. A big part of my job is decreasing costs to taxpayers.” But Kaster’s attention to the bottom line does not come at the expense of patient care. Replacing costly medications with cheaper ones can save money without compromising value. And better yet, reducing the number of drugs a patient takes can improve his or her well-being. “I love the patients because they’re so resilient,” she says. “I deal only with cancer patients. Some people think that’s depressing, but they’re so strong and courageous.” Kaster sits in on physician clinics and consults with oncologists regularly on prescription decisions. Many VA patients take up to 10 medications, so Kaster must play a part in helping them with chronic care needs, such as hypertension and hyperlipidemia. The Past An Idaho native, Kaster grew up in Bruneau, which she calls “God’s country.” Her family was very involved with rodeos, and Kaster spent her childhood

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TOP Pharmacist

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“Despite the challenges of addressing cancer disease state management, Lindsay has continually built and maintained positive professional relationships with both staff and patients.”

—Brenda S. Dunn, PharmD, MBA, in her nomination of Kaster

riding horses—and tractors. She went to Carroll College in Helena, Montana, and did research at Seattle’s Fred Hutchinson Cancer Research Center. She has lived in Spain and traveled throughout Europe. Then, she returned home to get her Doctor of Pharmacy degree at Idaho State University. “I kind of stumbled into pharmacy,” Kaster says. “I wanted to go to medical school, and I shadowed a bunch of physicians and didn’t really like it too much. I was graduating from college with a degree in biology and didn’t really know what to do. My mom, who is a nurse, said she loved the pharmacists she worked with. So I applied.” The Present It is Kaster’s ability to work with people throughout the cancer center that stands out the most. “Lindsay is the most enthusiastic and motivated young pharmacist I have worked with,” says Amber K. Fisher, PharmD, BCPS, director of Boise VA Medical Center’s PGY2 Ambulatory Residency Program. “She is extremely talented at working with the oncology clinic staff, staff pharmacists, technicians, and patients.” She needs to be motivated. The national backorders for a number of important chemotherapy drugs have forced Kaster to think up creative solutions, from getting a delivery just moments before a patient arrives to sharing drugs with VA facilities in other parts of the country. “The whole pharmacy team has been really stretched thin because there have been so many shortages on drugs that we use on a daily basis. It can be really stressful not knowing one day to the next if we will be able to give a patient his life-saving medication.” This is especially important at the Boise clinic, where they have no physicians on staff. Doctors on contract come through once a week. But most of the time, she and the nurses run the show. “I believe that an oncology pharmacist is invaluable in the care of heme/onc patients, and this role will only continue to expand in the future,” Kaster tells The Oncology Pharmacist. “Ninety-eight percent of supportive care decisions in our clinic are made by a team of a pharmacist, nurse practitioner, and primary nurse.”

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Tim Santos, acting chief of pharmacy at the Boise VA, commends Kaster for her work implementing new inspection regulations from the VA’s Office of the Inspector General and The Joint Commission. Santos and Kaster worked together to get the facility compliant with new procedures governing the safe handling of hazardous drugs and chemotherapy transportation. “She applied her considerable talent for the tenacious pursuit of a goal by completing the development of the necessary forms, educating staff, and participating in the evaluation of appropriateness of the competencies chosen by staff members.” The Boise VA also serves a very particular population: Their patients are veterans, and most live in rural areas. Most have to travel 1 hour or more to visit the center. “We have to do things a little different here than you would do things at a bigger facility,” she says. She says that the teamwork drew her to oncology, and that makes it “really different from any other healthcare field.”

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Her dedication to continuous improvement of work processes and procedures has led to enhanced service delivery to our veterans.” —Tim Santos, in his nomination of Kaster

The Future Kaster is young, and she has impressed colleagues with her energy and commitment. And she has a lot more planned for the future. For one, this is the first year she is eligible to become board certified. Now that she has completed the required years of residency and practice,

she wants to make it happen. She also wants to teach, and perhaps one day, after she has more experience on the job, write a textbook. Kaster is already a preceptor and mentor for PGY1 residents, and she visits pharmacy students at Idaho State University each year to make a pitch for oncology, where she employs a creative touch by grabbing students’ attention with a David Letterman–style Top Ten list. “I think a lot of people overlook oncology because they think it’s depressing, so my goal is to get students interested,” she says. And her goals don’t stop there. She would like to do more research that will benefit Idahoans. “There’s a lot of research to get done, especially on the rural populations we have here.” Dunn says that someone like Kaster, both kind and shrewd, is the perfect person for the VA. “The Boise VA Medical Center is proud to have Dr Kaster as part of our clinical team, and we are extremely fortunate to have someone as kind-hearted and clinically minded as Lindsay to serve our veterans.” ●

A Commitment to Helping Those with Cancer

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s the T.O.P. Pharmacist award winner, Lindsay Kaster, PharmD, chose the Leukemia & Lymphoma Society to receive a donation.

The Leukemia & Lymphoma Society Lindsay chose the Leukemia & Lymphoma Society because it works to cure leukemia, lymphoma, Hodgkin disease, and myeloma and to improve the quality of life of patients and their families. As the world’s largest voluntary health agency dedicated to hematologic malignancies, the organization develops specific goals each year. This year’s vision includes a focus on funding research projects that offer the best chance of accelerating development of new, promising therapies, creating better access to clinical trials, and providing all people traversing the cancer continuum access to the information and services they need to fight and manage their disease. The Leukemia & Lymphoma Society also has developed long-term goals, which it terms the North Star 2015 Vision. This vision aims to create a better future for patients with hematologic malignancies. This includes achieving a high cure rate for most patients, helping those patients who continue to need treatment to manage their illness with good quality of life, and helping patients and their families and caregivers navigate the healthcare system. If you wish to join Lindsay in helping the Leukemia & Lymphoma Society, you can donate online at www.LLS.org or through the mail: The Leukemia & Lymphoma Society Donor Services P.O. Box 4072 Pittsfield, MA 01202

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Pharmacogenomics KRAS Status, EGFR Inhibition... Continued from cover ment duration.2 The identification of the role of KRAS mutations in select patients with colorectal cancer (CRC) who are candidates for epidermal growth factor receptor (EGFR) inhibitors is one example of the clinical application of the advances in pharmacogenomics. Targeting EGFR The current management of a patient with metastatic CRC may include surgery, local therapy with radiofrequency ablation, or transarterial chemoembolization, but the primary treatment remains pharmacotherapy with chemotherapy. Chemotherapy has been shown to improve disease-related symptoms and overall quality of life in patients with metastatic disease, downsize lesions in patients with potentially resectable disease, and ultimately prolong survival.3 The number of active chemotherapy agents is few, however, with treatment consisting of the combination of or single-agent therapy with fluorouracil, capecitabine, oxaliplatin, and/or irinotecan. One of the most significant advances in drug therapy for metastatic CRC in the past decade has been the addition of targeted therapy to chemotherapy. Cetuximab and panitumumab target EGFR, whereas bevacizumab targets angiogenesis. These agents have been shown to play a role in treatment of metastatic CRC but, unfortunately, not all patients benefit equally from them. Inhibition of the EGFR is one strategy for management of select malignancies. Cetuximab, a chimeric monoclonal antibody, and panitumumab, a fully humanized monoclonal antibody, target the external binding sites of the EGFR.4,5 Although the EGFR is expressed on many nonmalignant human cells, higher levels are expressed in certain cancers, such as CRC. The binding of the EGFR to the extracellular binding site of EGFR activates several signal transduction pathways, causing downstream changes in gene expression and ultimately cell growth and proliferation. Randomized trials with cetuximab and panitumumab, alone and combined with chemotherapy, have shown these drugs to benefit individuals with metastatic CRC, as measured by prolonged progression-free survival and increased time to disease progression.6-8 Single-agent cetuximab has been shown to improve overall survival in patients with metastatic CRC when compared with best supportive care.6,9 Despite the benefits seen with these agents, they are not without challenges. The cost of therapy is significant and may be prohibitive for some patients. In addition, these drugs have

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Katharine A. Kinsman, PharmD, BCOP

Rowena N. Schwartz, PharmD, BCOP

side effects, such as rash, and potentially serious infusion-related reactions.6-10 As with any drug therapy, there is interest in reserving these agents for those patients likely to benefit from treatment and avoiding the costs and risks in those unlikely to benefit from treatment.

WT and KRAS-mutated patients. Individually, these trials are difficult to compare, but a recent meta-analysis and retrospective consortium analysis summarize the data clearly.13,14 Individuals who are KRAS WT who have received anti-EGFR monoclonal antibody therapy have significantly improved overall survival compared with KRAS-mutated patients. In addition, KRAS WT patients had significantly longer progression-free survival and time to progression with anti-EGFR monoclonal therapy. Further, KRAS-mutated patients had significantly higher treatment failure rates with anti-EGFR monoclonal therapy.13-15

KRAS Status and EGFR Inhibition Mutations in KRAS have been identified, and select mutations appear to impact the activity of EGFR inhibitors in patients with malignancies such as CRC.11 Although these mutations have been evaluated in several tumors, the largest body of evidence for the implications of KRAS mutations, as well as the most significant effect on the treatment continuum, has occurred with metastatic CRC. Ap proximately 35% to 45% of patients with metastatic CRC will have mutations in the pathways downstream from the EGFR, which effectively provide an escape mechanism that allows the tumors to overcome the pharmacologic blockade induced by anti-EGFR molecules.11 This promotes a permanently active state where cells can evade apoptosis. KRAS is a protooncogene that is the most commonly mutated gene in this pathway. There are only a few mutations in the KRAS gene, and more than 90% involve 3 codons: 12, 13, and 61.11 If KRAS remains unmutated, it is referred to as KRAS wild type (WT). Because the number of mutations is low and testing for the mutations is relatively easy, tumor DNA testing has become an area of interest in predicting response to therapy and prognosis.12 There is a growing body of evidence addressing the relationship between KRAS mutation and response to antiEGFR monoclonal antibodies. Initial studies for cetuximab and panitumumab did not evaluate KRAS mutation status, but retrospective analyses have been completed since, and both singlearm and randomized trials provide comparisons of efficacy between KRAS

Anti-EGFR Therapy and CRC The unequivocal benefit seen in KRAS WT patients when compared with KRAS-mutant patients with metastatic CRC has led to additional studies attempting to replicate the findings in other solid tumors. Cetuximab is used in both non-small cell lung cancer and head and neck cancer, and it will be important to determine the role of KRAS mutation on the efficacy of cetuximab in these cancers. Thus far, trials comparing cetuximab plus chemotherapy with chemotherapy alone in non-small cell lung cancer have not shown differences in outcomes for patients with KRAS mutations. Further study is warranted. Other areas for continued research include further investigating components downstream of KRAS, identifying whether mutations in codon 12 or 13 are more predictive of response, and integrating additional molecular biomarkers, such as BRAF, PTEN, or PIK3CA aberrations. Finally, there are mixed results in the prognostic value of KRAS mutations, and further study is necessary before this information can be of use. Overall, the evidence to date illustrates that patients with CRC and KRAS mutations are virtually insensitive to anti-EGFR therapy. The data are so compelling that the prescribing information for both cetuximab and pani-

tumumab have been modified to indicate that these agents are only to be used in KRAS WT patients. Further, the National Comprehensive Cancer Network has issued guidelines that strongly recommend KRAS genotyping of tumor tissue (either primary tumor or metastatic disease) in all patients at the time of diagnosis of metastatic CRC.16 Although patients with mutations at codon 12 or 13 should not receive cetuximab or panitumumab, patients without mutations who receive these agents alone or in combination with other anticancer agents may derive significant benefit, including improved response rate, progression-free survival, and overall survival with the administration of cetuximab or panitumumab. With further study, we will continue, hopefully, to better identify subgroups of patients who will most benefit from targeted therapy and improve clinical outcomes for patients with metastatic CRC. � References 1. Weinshilboum RM, Wang L. Pharmacogenetics and pharmacogenomics: development, science, and translation. Ann Rev Genomics Hum Genet. 2006;7:223-245. 2. Wang L, McLeod HL, Weinshilboum RM. Genomics and drug response. N Engl J Med. 2011;364:1144-1153. 3. Cunningham D, Atkin W, Lenze HJ, et al. Colorectal cancer. Lancet. 2010;375:1030-1047. 4. Vectabix (panitumumab) [package insert]. Thousand Oaks, CA: Amgen Inc; 2011. 5. Erbitux (cetuximab) [package insert]. Branchburg, NJ: ImClone Systems Inc; 2011. 6. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337-345. 7. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25:1658-1664. 8. Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663-671. 9. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040-2048. 10. Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26: 2311-2319. 11. Rizzo S, Bronte F, Fanale D, et al. Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for antiEGFR therapy? Cancer Treat Rev. 2010;36S3:S56-S61. 12. Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Review Cancer. 2003;3:459-465. 13. Dahabreh IJ, Terasawa T, Castaldi PJ, Trikalinos TA. Systematic review: anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med. 2011;154:37-49. 14. DeRoock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11:753-762. 15. Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009;27:2091-2096. 16. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Colon Cancer. V.3.2011. www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed June 1, 2011.

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Pharmacy Careers

The Pharmacy Reimbursement Specialist By Susan S. Hendrick, PhD Texas Tech University and Southwest Cancer Center, Lubbock, Texas

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ith the ever-increasing cost of oncology drugs as well as patient copays, a new role was created to help patients manage their financial needs at the Southwest Cancer Center, in cooperation with the Central Pharmacy, University Medical Center, Lubbock, Texas, the county’s and Texas Tech University’s primary teaching hospital. The pharmacy reimbursement specialist works with unfunded/self-pay patients, locally funded patients, Medicare with Part D patients, insured patients offered some chemotherapy by their insurance but denied the best new therapies for their cancer, and insured patients whose insurance will pay for the therapy they need but who cannot themselves handle the expense of the copay ($10,000 per month for some oral chemotherapy agents).

Most manufacturers offer patient-assistance programs, and the reimbursement specialist is familiar with them all. Many not-for-profit organizations offer these programs as well. This specialist, Michelle Prieto Flores, spends upward of 80% of her time on the telephone, talking with drug manufacturers, dealing with specialty pharmacies, and systematically following the required procedures for enrollment in patient-assistance programs. Typically, the process of securing needed medications is initiated when a physician orders chemotherapy or supportive treatments, then the pathway becomes more complex, branching off based on the specific cancer and then into intravenous or oral agents. From there, the pathway diverges again, dependent on into which payment group the patient falls. Over time, the establishment of points of contact with manufacturers and pharmacies will help move the process along. Most manufacturers offer patientassistance programs, and the reimbursement specialist is familiar with them all. Many not-for-profit organizations offer these programs as well. In addition, certain specialty pharmacies can be helpful, often finding a patient-assistance program or foundation for a patient. This work creates a network of “care” for oncology patients that transcends

“One More Day” Why One Woman Became an Oncology Pharmacy Reimbursement Specialist

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ichelle Prieto Flores of Lubbock, Texas, had no idea that what seemed like just one temporary phase of her work life would become a passionate professional commitment. During her late teens, Prieto Flores worked with group homes for mentally challenged persons, eventually becoming the manager of one Michelle Prieto Flores of the homes. She was familiar with medications, having helped family with medication administration for several years. In addition, as a home manager, she frequently needed to pick up medications for residents under her care at the local pharmacy, where she became acquainted with a pharmacist. Deciding to change jobs, she applied for a position as a pharmacy clerk. She didn’t get the clerk position, but she got a phone call from the pharmacist she knew—a phone call that changed her career path forever. The pharmacist invited Prieto Flores to work for her as a pharmacy technician (which she did), subsequently helping Prieto Flores obtain her pharmacy technician license. When the pharmacist moved to the Central Pharmacy at University Medical Center, Prieto Flores moved with her. Working in the inpatient pharmacy, she learned virtually all aspects of the pharmacy. The pharmacy director saw Prieto Flores’s potential and asked her to take a new position, that of a Pharmacy Reimbursement Specialist. Her new role was to work with both unfunded/self-pay and county-funded oncology patients to try to secure needed medications. Although Prieto Flores still had her office in Central Pharmacy, much of her work moved to the Southwest Cancer Center (SCC). The position grew as the hematology/oncology patient base grew. As the SCC added clinics, physicians, and services,

geographic location to try to ensure that each patient receives the treatment he or she needs. Finding the right program for the patient, however, is only the beginning. The reimbursement specialist’s next step is providing medical forms. Often, this leads to completing the forms with/for the patient. For patients confronted by anxiety about their condition and what lies ahead, sometimes with added difficulties due to lack of education, low socioeconomic status, or language difficulties, the burden of medical paperwork can be overwhelming. By removing this burden, the reimbursement specialist can make the difference between a patient seeking appropriate treatment or giving up. The pharmacy reimbursement spe-

Prieto Flores was in demand. Within a couple of years, she was asked to work directly in the SCC a few days per week, and finally a full-time position was created for her. Administrators, physicians, extenders, and nurses appreciated the value in having this position staffed full time. Once again, Prieto Flores grew her position, both because of the increasing complexity of her job and because she was good at answering the requests of the physicians and meeting the needs of the patients, always with warmth and her characteristic smile. As she is quick to say, “At the end of the day, it’s for the patient.” When Michelle comes into a clinic room, there is an immediate sense that she is there to help. She doesn’t promise miracles, but rather she says, “The only promise I make is that I’ll give it all I’ve got,” which is quite a lot. Her dedication is important, because the world of medications and the patients who she serves have grown steadily since she began. The advent of oral chemotherapies changed the terrain, as did the development of Medicare Part D. So what does her job look like now? She now works with a diverse group of patients who have a diverse set of needs, and her aim is to “treat everyone as if he or she was a member of my family.” What keeps someone doing a tough job, day after day, hassle after hassle, form after form? The answer Prieto Flores gave was “I love what I do.” She also gave another answer, without necessarily even knowing it may be the primary motivation for her. She said that she goes home from work with gratitude for being allowed to spend just “one more day” with her loved ones. Some people don’t get that chance. The opportunity to have “just one more day” may be what causes patients to struggle with difficult chemotherapy regimens and sometimes debilitating radiation treatments. Outsiders and even insiders to the oncology world sometimes wonder why patients hang on to hope and treatment, even when the treatment is not working. Perhaps the answer is “just one more day with my loved ones.” And Prieto Flores does as much as she can to help as many patients as she can get “just one more day.”

cialist is a key member of the interdisciplinary teams that are required to meet current standards of care in oncology, particularly with patients who endure diseases that require expensive and/or

extensive medications. Delivering the finest and most comprehensive care is ultimately best practice on a healthcare level, a business level, an ethical level, and a human level. ●

Oncology News

YOUR Way • Access daily news impacting you and your patients • Easily share and post to social media sites • Earn continuing education credits

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Current activities at www.COEXM.com include:

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

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CONTINUING EDUCATION PROGRAM P10068 • RELEASE DATE: APRIL 22, 2011 • EXPIRATION DATE: APRIL 22, 2012 ESTIMATED TIME TO COMPLETE: 1.0 HOUR • COMPLETE THE POSTTEST AT WWW.THEONCOLOGYPHARMACIST.COM

Improving the Prevention and Treatment of Venous Thromboembolism in Cancer: The Strategic Role of the Health-System Pharmacist TARGET AUDIENCE This activity was developed for health-system pharmacists and oncology pharmacists. LEARNING OBJECTIVES After completing this activity, the reader should be able to: • Explain the epidemiology and risk factors of venous thromboembolism (VTE) in cancer • Summarize current evidence-based guidelines for prevention and treatment of VTE in cancer, with special attention to the differences and similarities across guidelines • Discuss key data from randomized clinical trials of low-molecular-weight heparins in prevention of recurrent VTE in cancer

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

SPONSOR

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.

This activity is sponsored by Medical Learning Institute, Inc., a nonprofit medical accreditation company, and Center of Excellence Media, LLC.

This activity is provided free of charge to participants. Upon completion of the evaluation and scor-

• Describe emerging strategies in VTE prophylaxis and treatment

ing 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. Paul Dobesh, PharmD, FCCP, BCPS, is a consultant to Ortho-McNeil and sanofi-aventis. Gary M. Owens, MD, is a consultant to Auxilium, Biosense Webster, Centocor Ortho Biotech, Eli Lilly, Genentech, and Novartis. Gary C. Yee, PharmD, FCCP, BCOP, is on the advisory board for Amgen.

Nancy Nesser, JD, PharmD, a reviewer for MLI, has nothing 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 sanofi-aventis.

Venous Thromboembolism a Major Concern in Patients with Cancer By Gary M. Owens, MD President, Gary Owens Associates, Philadelphia, Pennsylvania

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he risk of venous thromboembolism (VTE) in the general population is substantial, with an approximate incidence of 1 VTE case per 1000 individuals. This translates to more than 200,000 new cases annually in the United States.1 More important, almost 30% of patients with VTE will die within 30 days of the initial diagnosis.1 Although not all those deaths are directly related to VTE or its sequelae, approximately 20% of those dying within this 30-day period will be caused by pulmonary embolism (PE).1 Despite significant advances in the diagnosis and management of VTE, its incidence has not substantially changed since the 1980s.1 The risk of having VTE is elevated by a number of factors, including1: • Central venous catheter/transvenous pacemaker • Hospital or nursing home confinement • Hormone replacement therapy • Increasing age • Male sex • Malignancy

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• Neurologic disease with extremity paresis • Oral contraceptives • Pregnancy • Previous superficial vein thrombosis • Surgery • Trauma • Varicose veins. Venous Thromboembolism and Malignancy VTE may be a presenting sign of an occult malignancy. Of all new cases of VTE, approximately 20% are associated with active malignancy.2 It is remarkable to note that patients with cancer have a 4- to 6-fold higher risk for VTE compared with patients without cancer.3 Therefore, otherwise healthy adults presenting with VTE without an obvious cause may warrant additional testing to rule out occult malignancies. VTE is also a major concern for patients with cancer, and it must be considered a serious complication of an already diagnosed cancer. For patients with cancer, the incidence of VTE approaches 1 in 200 patients.4 Ap -

In men, tumors of the prostate, colon, lung, and brain are among the cancer types with the highest risk for VTE. In women, breast, ovarian, and lung cancers are associated with increased VTE risk.

proximately 20% of VTE cases occur in patients with cancer,2 which means that cancer-related cases of VTE account for more than 40,000 of the 200,000 cases seen annually in the United States. Fifteen percent of patients with cancer will have symptomatic, diagnosed VTE, and, astoundingly, almost 50% of patients with cancer are found to have VTE at postmortem examination.5 The risk of VTE in patients with cancer is compounded by the fact that many patients in this population are older people, aged >55 years. VTE is the second leading cause of death in hospitalized patients with cancer, and the risk of death from VTE in patients with cancer is 3- to 8-fold

higher than in comparable patients without cancer.6 Furthermore, patients with cancer and symptomatic deep-vein thrombosis (DVT) exhibit a high risk for recurrent DVT/PE that persists for many years after the initial episode.7 Other Risk Factors Other factors that increase the risk for VTE in patients with cancer include the type of malignancy. In men, tumors of the prostate, colon, lung, and brain are among the cancer types with the highest risk for VTE. In women, breast, ovarian, and lung cancers are associated with increased VTE risk.4,8 Hematologic malignancies, such as lymphoma and multiple myeloma, especially when the latter disease is

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No VTE

18

VTE

16

Mortality, %

14 12 10 8 6 4 2 0 All (N = 66,016)

Nonmetastatic (N = 20,591)

Metastatic (N = 17,360)

Hospital Deaths Figure. VTE and Inpatient Mortality. VTE indicates venous thromboembolism. Adapted with permission from Khorana AA, et al. J Clin Oncol. 2006;24:484-490.

treated with immunomodulators, have a very high risk for VTE events.4 Finally, VTE increases the risk for cancer-related death in hospitalized patients.9 The Figure illustrates that the percentage of patients who suffer in-hos-

pital death is higher with either metastatic or nonmetastatic disease when VTE is a comorbid condition.9 The risk for VTE is certainly increased in patients diagnosed with a malignancy. That risk can further be compounded by

To Receive cRediT, compleTe The posTTesT aT

such factors as the treatment of the disease by selected chemotherapeutic agents, the placement of a centrally dwelling catheter, or TheOncologyPharmacist.com even by surgical procedures targeted at removing the lesion. It is therefore essential that oncologists and other providers caring for patients with cancer are aware of these risks and take steps to prevent and to aggressively manage cancer-related VTE. impact of risk factors for deep vein thrombosis and pulAt a minimum, physicians must actively monary embolism: a population-based study. Arch Intern Med. 2002;162:1245-1248. intervene to prevent VTE in patients 3. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors with cancer who are undergoing surgery for deep vein thrombosis and pulmonary embolism: a popcase-control study. Arch Intern Med. or who are hospitalized. In addition, ulation-based 2000;160:809-815. strong consideration should be given to 4. Lee AY, Levine MN. Venous thromboembolism and consider preventive therapies for high- cancer: risks and outcomes. Circulation. 2003;107(23 suppl 1):I-17-I-21. risk ambulatory patients with cancer 5. El-Shami K, Griffiths E, Streiff M. Nonbacterial throm(eg, patients with myeloma receiving botic endocarditis in cancer patients: pathogenesis, diagand treatment. Oncologist. 2007;12:518-523. immunomodulatory therapy) and to nosis, 6. Heit JA, Silverstein MD, Mohr DN, et al. Predictors of engage in long-term treatment (>6 survival after deep vein thrombosis and pulmonary a population-based case-control study. Arch months) for patients with cancer who embolism: Intern Med. 1999;159:445-453. have VTE to prevent VTE recurrence. ● 7. Prandoni P, Lensing AW, Cogo A, et al. The long-term References 1. Heit JA. Venous thromboembolism epidemiology: implications for prevention and management. Semin Thromb Hemost. 2002;28(suppl 2):3-13. 2. Heit JA, O’Fallon WM, Petterson TM, et al. Relative

clinical course of acute deep vein thrombosis. Ann Intern Med. 1996;125:1-7. 8. Heit JA. Cancer and venous thromboembolism: scope of the problem. Cancer Control. 2005;12(suppl 1):5-10. 9. Khorana AA, Francis CW, Culakova E, et al. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol. 2006;24:484-490.

Guidelines for the Prevention and Treatment of Venous Thromboembolism in Cancer By Gary C. Yee, PharmD, FCCP, BCOP Professor of Pharmacy Practice and Associate Dean for Academic Affairs, College of Pharmacy, University of Nebraska Medical Center, Omaha, and a member of the utilization management committee and national pharmacy & therapeutics committee for a large pharmacy benefits manager

S

everal international organizations have developed clinical practice guidelines for the prevention and treatment of venous thromboembolism (VTE) in patients with cancer.1 In the United States, 3 organizations have developed guidelines for VTE—the American College of Chest Physicians (ACCP), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN).2-4 The guidelines differ in their scope and methods used to develop the guideline. The ACCP and ASCO guidelines are based on a systematic review and formal evaluation of study quality. The first set of NCCN guidelines was based on a systematic review, but annual revisions are based on review of recently published research and responses to questions asked by clinicians at member institutions.1 The ASCO and NCCN guidelines are limited to the prevention and treatment of VTE in patients with cancer. Prevention of Venous Thromboembolism The ACCP, ASCO, and NCCN guidelines agree that all hospitalized patients

www.Theoncologypharmacist.com

with cancer, including those undergoing surgery, should receive prophylactic anticoagulation (in the absence of contraindications).2-4 Recommended agents include low-dose unfractionated heparin, low-molecular-weight heparin (LMWH), or fondaparinux. Patients undergoing major abdominal or pelvic surgery should receive prolonged prophylaxis (ie, up to 4 weeks). For ambulatory cancer patients, the ACCP, ASCO, and NCCN guidelines agree that routine VTE prophylaxis is not recommended. The ASCO and NCCN guidelines list certain high-risk patient groups that are exceptions to the recommendation (Table). Although the ASCO and NCCN guidelines consider those who are receiving thalidomide or lenalidomide with chemotherapy or dexamethasone as high-risk patients, the NCCN guideline adds specific information on dexamethasone dose and incorporates a risk assessment model and recommendations developed by an international group of experts.5 In contrast to other VTE risk assessment models, that risk assessment model was developed specifically for patients with multiple myelo-

Table Comparison of Guidelines for the Prevention of VTE in Ambulatory Patients with Cancer

Definition of highrisk patients

ASCO

NCCN

Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone

Select patients receiving highly thrombotic antiangiogenic therapy (ie, multiple myeloma patients receiving thalidomide/lenalidomide and high-dose dexamethasone [≥480 mg/month]), doxorubicin, or multiagent chemotherapy) Myeloma patients with ≥2 individual or myeloma risk factors

Recommended agent(s)

LMWH or warfarin (INR ~1.5)

LMWH (eg, enoxaparin 40 mg sub cutaneous every 24 hr) or warfarin (INR 2-3) Low-risk myeloma outpatients: aspirin (81-325 mg/day)

ASCO indicates American Society of Clinical Oncology; INR, international normalized ratio; LMWH, low-molecular-weight heparin; NCCN, National Comprehensive Cancer Network; VTE, venous thromboembolism.

ma who are treated with thalidomide or lenalidomide. The recommended agents for VTE in high-risk patients vary depending on the guideline and risk category. The

ASCO guideline does not list aspirin as a recommended prophylactic agent, probably because its literature search only included randomized controlled trials published through the end of 2006.3

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CONTINUING EDUCATION The NCCN guidelines recommend LMWH or full-dose warfarin for most patients, but lists aspirin as an option for selected patients (eg, low-risk myeloma outpatients).4 This variability in the guideline recommendations reflects the lack of rigorous evidence on the prevention of VTE in patients with multiple myeloma. Guideline recommendations are likely to change as the results of randomized controlled trials are published. For example, Palumbo and colleagues recently reported the results of a randomized controlled comparison of aspirin (100 mg/day), fixed low-dose warfarin (1.25 mg/day), or LMWH (enoxaparin 40 mg/day) as VTE prophylaxis in 667 patients with multiple myeloma treated with thalidomidebased regimens.6 Of 659 analyzed

patients, 43 (6.5%) developed an event, a composite end point that included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment. The event rate for the different thromboprophylaxis arms was not significantly different. Validated risk assessment models are also needed to predict the risk of VTE in patients with multiple myeloma. Treatment of Venous Thromboembolism The ACCP, ASCO, and NCCN guidelines agree that all patients with cancer and established VTE should be treated with anticoagulation.2-4 Recommended agents include unfractionated heparin, LMWH, or fondaparinux, and the recommended duration of initial therapy

is a minimum of 5 days. Long-term therapy with LMWH is recommended for up to 6 months. Each of the guidelines recommends that anticoagulation be continued for longer than 6 months in selected patients with cancer. The ACCP guideline recommends “subsequent anticoagulation with LMWH or warfarin indefinitely or until the cancer is resolved” (grade 1C recommendation).2 The ASCO guidelines state that “indefinite anticoagulation should be considered for selected patients with active cancer, such as those with metastatic disease and those receiving chemotherapy” (panel consensus).3 The NCCN guidelines recommend indefinite anticoagulation if the patient has active cancer or persistent risk factors. ●

References 1. Khorana AA, Streiff MB, Farge D, et al. Venous thromboembolism prophylaxis and treatment in cancer: a consensus statement of major guideline panels and call to action. J Clin Oncol. 2009;27:4919-4926. 2. Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):454S-545S. 3. Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25:5490-5505. 4. National Comprehensive Cancer Network. Venous thromboembolic disease. Version 1. 2011. www.nccn. org/professionals/physician_gls/pdf/vte.pdf. Accessed April 14, 2011. 5. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423. 6. Palumbo A, Cavo M, Bringhen S, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011;29:986-993.

Case Scenarios in the Prevention and Treatment of VTE in Patients with Cancer By Paul Dobesh, PharmD, FCCP, BCPS Professor of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha

Case Scenario 1 J. B. is a 54-year-old obese man recently diagnosed with stage III colon cancer. He is admitted today for surgical resection of the involved bowel segment and will subsequently receive FOLFOX (5FU, leucovorin, and oxaliplatin) as adjuvant chemotherapy. He has no history of cancer or thrombo embolic events. Is thromboembolism a concern in this patient?

P

atients with cancer undergoing surgical procedures are at higher risk for the development of venous thromboembolism (VTE) compared with patients without cancer undergoing similar surgical procedures.1,2 Patients with cancer undergoing surgery are considered to be one of the highest risk groups for the development of VTE, with event rates similar to those in patients undergoing orthopedic surgery.3,4 This high risk for VTE is because patients undergoing cancer surgery end up with all 3 parts of Virchow’s triad: venous stasis, vascular damage, and a hypercoagulable state. Therefore, VTE prophylaxis in these patients is very recommended.3,4 The decision on what to use for prophylaxis has also been extensively studied. In the Enoxaparin in Cancer (ENOXACAN) study, 631 patients undergoing elective abdominal or pelvic surgery for cancer were random-

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ized to enoxaparin 40 mg subcutaneously once daily or to unfractionated heparin (UFH) 5000 units subcutaneously 3 times daily.5 The first dose of anticoagulant was given 2 hours before surgery and continued for 10 days. The primary end point of the ENOXACAN study was the incidence of total VTE determined by venography. Although the primary end point was reduced by almost 20% at 10 days with the use of enoxaparin compared with UFH, this difference was not significant (14.7% vs 18.2%). There was also no significant difference in the incidence of total bleeding or major bleeding (4.1% vs 2.9%) between the groups. In the Canadian Colorectal DVT Prophylaxis Trial, 1349 patients undergoing colorectal surgery were randomized to the same regimens of enoxaparin and UFH6 as in the ENOXACAN study. In this Canadian study, 35% of the patients (n = 475) were undergoing colorectal surgery for cancer. In this subgroup, the incidence of VTE was 13.9% in the enoxaparin group compared with 16.9% in the UFH group.6 The efficacy and safety between using a low-molecular-weight heparin (LMWH) or UFH for in-hospital VTE prophylaxis in patients undergoing surgery for cancer has been evaluated in a meta-analysis.7 This meta-analysis in cluded 14 randomized trials that compared these regimens in surgical cancer patients. Although patients receiving LMWH did not demonstrate any reduction in mortality (relative risk [RR],

0.89; 95% confidence interval [CI], 0.61-1.28), there was a significant reduction in deep-vein thrombosis (DVT) with the use of LMWH (RR, 0.72; 95% CI, 0.55-0.94). Most of this overall benefit to the use of LMWH was in the comparison to patients receiving UFH twice daily (RR, 0.66; 95% CI, 0.44-0.99), with less difference demonstrated in comparison to UFH 3 times daily (RR, 0.78; 95% CI, 0.53-1.15). There was also no significant difference between the 2 regimens with regard to minor or major bleeding.7

Another important question that arises with the use of VTE prophylaxis in patients having cancer surgery is the appropriate duration of prophylaxis. Another important question that arises with the use of VTE prophylaxis in patients having cancer surgery is the appropriate duration of prophylaxis. Although VTE prophylaxis for most indications is usually given for the duration of hospitalization or until the patient is mobile, data suggest that a longer duration is indicated in patients undergoing surgery for cancer. The ENOXACAN II study evaluated patients undergoing gastrointestinal tract, genitourinary tract, or female reproductive organ cancer surgery.8 All

patients received enoxaparin 40 mg subcutaneously once daily for 6 to 10 days. Patients (n = 332) were then randomized in a double-blind fashion to continue taking enoxaparin at the same dose or placebo for an additional 21 days. The primary end point was the incidence of venographic VTE at 1 month, which was significantly reduced by 60% with the use of enoxaparin compared with placebo (4.8% vs 12%; P = .02), as well as a 60% reduction in proximal DVT (0.6% vs 1.8%). This significant 60% reduction in the primary end point was still evident at the 3-month follow-up (5.5% vs 13.8%; P = .01). The use of extended prophylaxis with enoxaparin did not produce a significant increase in any bleeding event (5.1% vs 3.6%) or major bleeding (0% vs 0.4%) compared with placebo.8 These results have been confirmed by 2 additional studies.9,10 The Cancer, Bemiparin, and Surgery Evaluation (CANBESURE) study randomized 703 patients undergoing abdominal or pelvic surgery for cancer to bemiparin 3500 IU subcutaneously once daily or placebo after completing 6 to 10 days of bemiparin (same dose).9 At 3-month followup, major VTE was reduced by more than 80% with the use of extended bemiparin compared with placebo (0.8% vs 4.6%; P = .010). Major bleeding was not significantly different between the groups (0.6% vs 0.3%; P = .572).9 The Fragmin After Major Abdominal Surgery (FAME) trial was slightly different in that it enrolled all patients under-

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going abdominal surgery and had an open-label design.10 Patients were randomized to dalteparin 5000 IU subcutaneously once daily for 7 days or 28 days. Overall, VTE events were significantly reduced with extended-duration dalteparin prophylaxis at the 1-month follow-up (7.3% vs 16.3%; P = .012). Although 58% of the patients in the FAME trial had abdominal surgery for cancer, the results for the subgroup of patients with cancer are not provided. Minor and major bleeding were not significantly increased with the extended duration of VTE prophylaxis. Based on the results of these studies, extended VTE prophylaxis is recommended for patients undergoing abdominal or pelvic surgery for cancer.3,4

Case Scenario 2 A. K. is a 42-year-old woman diagnosed with stage IIB breast cancer. She had a lumpectomy with surgical axillary staging and has since been receiving radiation and chemotherapy. Two months into therapy, she presents to the hospital with right lower-leg pain, swelling, and tenderness. A duplex ultrasound is positive for proximal DVT. What should be the approach to treatment in this patient?

T

he treatment of VTE in patients with cancer requires a different approach compared with that for the patient without cancer. The typical patient without cancer who has VTE receives an injectable anticoagulant and warfarin together for a minimum of 4 days and until the international normalized ratio (INR) becomes therapeutic in the range of 2 to 3. At that time, the injectable anticoagulant (UFH, LMWH, or fondaparinux) is then discontinued and the patient continues taking warfarin for at least 3 to 6 months, depending on the etiology of the VTE.4 In patients with cancer, the management should be an LMWH for 3 to 6 months, without the typical initiation of warfarin. This different management strategy is srongly recommended in clinical guidelines and supported by well-conducted randomized clinical trials. Although dalteparin is currently the only LMWH to be approved by the US Food and Drug Administration for treatment of VTE in patients with cancer, all 3 LMWHs available in the United States have clinical evidence to support their use for VTE therapy. Tinzaparin was compared with a standard vitamin K antagonist in the treatment of VTE in the Trial of the Effect of Low-Molecular-Weight Heparin Versus Warfarin on Mortality in the Long-Term Treatment of Proximal Deep Vein

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Thrombosis (LITE).11 In the LITE trial, 200 patients with cancer with acute symptomatic proximal vein thrombosis were randomized in an open-label fashion to tinzaparin 175 IU/kg subcutaneously once daily for 3 months or to UFH intravenous bolus and infusion overlapped with warfarin until day 6 and the INR was therapeutic (2-3), with warfarin continued for 3 months. At 3 months, the incidence of recurrent VTE was reduced by 40% in the tinzaparin group compared with the usual-care group, but this did not achieve significance (6% vs 10%). Patients receiving tinzaparin did have a significant 56% reduction in recurrent VTE at the end of 12 months (7% vs 16%; P = .04). The incidence of minor bleeding, major bleeding, and death were similar between the groups.11 In another study, enoxaparin 1.5 mg/kg subcutaneously once daily for 3 months was compared with the same dose of enoxaparin overlapped with warfarin for at least 4 days, with warfarin continued at an INR of 2 to 3 for 3 months.12 The 146 patients with cancer in this trial were diagnosed with pulmonary embolism (PE) and/or DVT and then randomized to 1 of the 2 treatment groups in an open-label fashion. The primary outcome of recurrent VTE and major bleeding at 3 months occurred in 10.5% of enoxaparin patients and 21.1% of warfarin patients (P = .09). While mortality was cut by more than 50% with the use of enoxaparin compared with warfarin (11.3% vs 22.7%; P = .07), this trial was not large enough to find a significant difference in mortality. Fatal bleeding was significantly reduced with the use of enoxaparin compared with warfarin (0% vs 8%; P = .03), whereas other major bleeding did not achieve statistical significance (9% vs 17%; P = .07).12 Dalteparin was compared with warfarin therapy for treatment of PE and/or DVT in patients with cancer in the Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for Long-Term Anticoagulation in Cancer Patients with Venous Thromboembolism (CLOT) trial.13 Patients in the CLOT trial (n = 676) were randomized in an open-label fashion for 6 months of anticoagulant therapy. Patients randomized to dalteparin received 200 IU/kg (maximum dose of 18,000 IU) subcutaneously once daily for 1 month, and then approximately 150 IU/kg subcutaneously once daily for the remaining 5 months. The usual-care patients received dalteparin 200 IU/kg (maximum dose of 18,000 IU) subcutaneously once daily overlapped with a vitamin K antagonist for at least 5 days, and the INR was therapeutic (2-3), with the vitamin K antagonist continued for the remaining 6 months. At 6 months,

To Receive cRediT, compleTe The posTTesT aT

the primary end point of recurrent VTE was significantly reduced by 50% with the use of dalTheOncologyPharmacist.com teparin compared with usual care (8% vs 16%; P = .002). Mortality was not reduced at 6 months with the use of dalteparin compared with usual care (39% vs 41%; P = .53), and major bleeding was also not different between the groups (6% vs 4%; P = .27).13 In a 12-month follow-up of the CLOT and then once daily for another 4 weeks. trial, mortality was 59% in both groups (P Median survival was 8.0 months for = .62). In this trial, in 75% of the patients patients receiving nadroparin compared with metastases, the mortality rate with with 6.6 months for patients receiving dalteparin was similar to that of usual placebo (P = .021). Major bleeding was care (72% vs 69%; P = .46).14 In the 25% not significantly increased with the use of patients without metastases, there was of nadroparin (3% vs 1%; P = .021).15 Although these results with nadroa 45% significant reduction in mortality with the use of dalteparin compared with parin seem impressive, other trials of usual care (20% vs 36%; P = .03).14 LMWH for improvement in survival in Although these data are from a post hoc patients with cancer have not repeated analysis of the data, it clearly requires fur- these same findings. The Improving ther study in a larger patient sample. with Nadroparin the Prognosis in One of the major questions that Advanced Cancer Treatment (INPACT) remains unanswered from clinical trials trial evaluated 503 patients with horis what to do after the initial 6-month mone-refractory prostate cancer within 6 treatment with LMWH? There are at months of diagnosis (41%), locally least 4 options: advanced pancreatic cancer within 3 1. Give no further anticoagulation months of diagnosis (26%), or non-small therapy cell lung carcinoma (stage IIIB) within 3 2. Continue anticoagulation with months of diagnosis (33%).16 Patients in the INPACT trial were randomized to warfarin (INR 2-3) 3. Continue anticoagulation with observation or subcutaneous nadroparin. The nadroparin regimen consisted of fulltreatment doses of LMWH 4. Continue anticoagulation with dose treatment for 2 weeks, followed by half-dose treatment for 4 weeks. prophylaxis doses of LMWH. Future research will need to focus on Nadroparin was then given in up to 6 answering the best approach for contin- cycles of no nadroparin for 4 weeks followed by full dose for 2 weeks. All-cause ued therapy, if it is needed at all. mortality was not different between the nadroparin and observation patients Case Scenario 3 (57% vs 61%). These results were conM. S. is a 65-year-old man with sistent across all types of cancer includnewly diagnosed pancreatic cancer. ed in the trial. One limitation to the The oncology team has decided trial is the use of open-label nadroparin to initiate treatment with gem for the treatment of VTE in 30% of the citabine and radiation. He has no observation patients.16 In the FAMOUS trial, subcutaneous history of thrombophilia or VTE, dalteparin 5000 IU once daily or placebut the team wishes to discuss the bo was given for 1 year to 385 patients possible risks and benefits of priwith advanced malignancy.17 Mortality mary prevention in this patient. at 1, 2, and 3 years was not different between the groups (P = .19).17 urrent guidelines do not support Trials evaluating LMWH for the prithe use of primary VTE prophy- mary prevention of VTE have recently laxis in patients with cancer. been more consistent than the trials Despite the current lack of a recom- evaluating mortality. In the Promendation, clinical trials have begun phylaxis of Thromboembolism During to demonstrate a benefit in primary Chemotherapy (PROTECHT) trial, prophylaxis in certain patients at high 1150 patients with metastatic or localrisk for cancer. ly advanced solid organ cancer were A number of trials have evaluated the randomized in a double-blind fashion ability of LMWH to prevent mortality 2:1 to a prophylaxis dose of nadroparin in patients without a current VTE (3800 IU) subcutaneously once daily or event.15-19 One study evaluated the placebo for the duration of chemotherLMWH nadroparin for 6 weeks in apy (maximum of 4 months).18 The pripatients with metastasized or locally mary end point of venous or arterial advanced solid tumors.15 Patients were thromboembolic events was reduced by randomized to placebo or to therapeutic almost 50% with the use of nadroparin weight-adjusted nadroparin subcuta- compared with placebo (2% vs 3.9%; neously twice daily for the first 2 weeks P = .02). The benefit was provided with-

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CONTINUING EDUCATION out a significant increase in major (0.7% vs 0%; P = .18) or minor (7.4% vs 7.9%) bleeding.18 In the CONKO-004 trial 312 chemotherapy-naïve patients with advanced pancreatic cancer were randomized to observation or enoxaparin 1 mg/kg subcutaneously once daily for 12 weeks followed by enoxaparin 40 mg subcutaneously once daily.19 At the end of the initial 12 weeks of therapy, the primary end point of symptomatic VTE was reduced by 87% with the use of enoxaparin (1.3% vs 9.9%; P <.01). This provides a number needed to treat of only 12 patients to prevent one symptomatic VTE with the use of enoxaparin in this patient population. The incidence of bleeding was not significantly increased during this 12-week period with the use of enoxaparin (3.8% vs 2.6%; P = .6). After the median follow-up period of 30 weeks, the lower dose of enoxaparin still provided a significant reduction in symptomatic VTE (5% vs 14.5%; P <.05). The incidence in bleeding was increased in both groups compared with the 12-week assessment, but the difference was still not statistically significant (6.3% vs 9.9%).19 Results of the Evaluation of AVE5026

in the Prevention of Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy (SAVEONCO) trial should be available by mid-2011. This is the largest trial to evaluate the primary VTE prophylaxis in patients with cancer. The SAVE-ONCO trial is set to randomize 3200 patients to semuloparin 20 mg subcutaneously once daily or placebo for 3 to 7 months. Semuloparin is an ultra-LMWH with an anti-Xa to anti-IIa ratio of more than 30:1 compared with most LMWHs that have a ratio of 3:1 or 4:1.20 Semuloparin has a half-life of 16 to 20 hours, which allows for once-daily administration. Semuloparin has already demonstrated efficacy and safety in patients undergoing orthopedic and abdominal surgery.20 If the results of the SAVE-ONCO trial demonstrate a significant benefit of primary VTE prophylaxis, as seen in the PROTECHT and CONKO-004 trials, a change in the guidelines supporting primary VTE prophylaxis in appropriate patients with cancer may be warranted. ● References 1. Gallus AS. Prevention of post-operative deep leg vein thrombosis in patients with cancer. Thromb Haemost. 1997;78:126-132. 2. Rahr HB, Sørensen JV. Venous thromboembolism

and cancer. Blood Coagul Fibrinolysis. 1992;3:451-460. 3. Nicolaides A, Arcelus J, Belcaro G, et al. Prevention of venous thromboembolism. European Consensus Statement, 1-5 November 1991, developed at Oakley Court Hotel, Windsor, UK. Int Angiol. 1992;11:151-159. 4. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):381S-453S. 5. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicenter trial with venographic assessment. ENOXACAN Study Group. Br J Surg. 1997;84:1099-1103. 6. McLeod RS, Geerts WH, Sniderman KW, et al, for the Canadian Colorectal Surgery DVT Prophylaxis Trial. Subcutaneous heparin versus low-molecularweight heparin as thromboprophylaxis in patients undergoing colorectal surgery. Results of the Canadian Colorectal DVT Prophylaxis Trial: a randomized, double-blind trial. Ann Surg. 2001;233:438-444. 7. Akl EA, Terrenato I, Barba M, et al. Low-molecularweight heparin vs unfractionated heparin for perioperative thromboprophylaxis in patients with cancer: a systematic review and meta-analysis. Arch Intern Med. 2008;168:1261-1269. 8. Bergqvist D, Agnelli G, Cohen AT, et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med. 2002;346:975-980. 9. Kakkar VV, Balibrea JL, Martínez-González J, et al, for the CANBESURE Study Group. Extended prophylaxis with bemiparin for the prevention of venous thromboembolism after abdominal or pelvic surgery for cancer: the CANBESURE randomized study. J Thromb Haemost. 2010;8:1223-1229. 10. Rasmussen MS, Jorgensen LN, Wille-Jørgensen P, et al, for the FAME Investigators. Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter randomized open-label study. J Thromb Haemost. 2006;4:2384-2390.

11. Hull RD, Pineo GF, Brant RF, et al, for the LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006;119:1062-1072. 12. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002;162:1729-1735. 13. Lee AYY, Levine MN, Baker RI, et al, for the CLOT Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146-153. 14. Lee AYY, Rickles FR, Julian JA, et al. Randomized comparison of low-molecular-weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005;23:2123-2129. 15. Klerk CPW, Smorenburg SM, Otten H-M, et al. The effect of low-molecular-weight heparin on survival in patients with advanced malignancy. J Clin Oncol. 2005;23:2130-2135. 16. Buller HR, Prins MH. The effect of the low-molecular-weight heparin nadroparin on the survival in patients with cancer: a randomized trial (for the INPACT Investigators). J Thromb Haemost. 2009; 7(suppl 2):1203. Abstract LB-MO-004. 17. Kakkar AK, Levine MN, Kadziola Z, et al. Low-molecular-weight heparin, therapy with dalteparin, and survival in advanced cancer: the Fragmin Advanced Malignancy Outcome Study (FAMOUS). J Clin Oncol. 2004;22:1944-1948. 18. Agnelli G, Gussoni G, Bianchini C, et al, for the PROTECHT Investigators. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol. 2009;10:943-949. 19. Riess HB, Pelzer U, Opitz B, et al. A prospective, randomized trial of chemotherapy with and without the low molecular weight heparin (LMWH) enoxaparin in advanced pancreatic cancer patients. J Thromb Haemost. 2009;7(suppl 2):1203. Abstract LB-MO-003. 20. Eikelboom JW, Weitz JI. New anticoagulants. Circulation. 2010;121:1523-1532.

Cancer Center Profile New Oncology Pharmacy Provides... Continued from cover And although they might not know it, the patients benefit too. “Those of us in oncology sleep a whole lot better at night knowing that whatever is infused in the patient is the cleanest possible product that we can give,” Vanessa Bramble, director of oncology services, tells The Oncology Pharmacist. Karen Meyer, a pharmacist at the facility, seconds that opinion: “Knowing that we have aseptic technique and a sterile area in which to work makes a huge difference. Like Vanessa said, we know that we produce the best product that we can.” Each day, Monday through Friday, the pharmacy staffs 2 pharmacists and 2 technicians who, each week, prepare between 80 and 100 doses of chemotherapy for outpatients and an additional 15 doses for inpatients at the Johnson City Medical Center, across the street from the Regional Cancer Center in Northeast Tennessee. The facility has 2 chemotherapy hoods in its negativepressure room and 1 laminar horizontal flow hood for nonchemotherapy medication preparation in its buffer room, according to Bramble. Setting Up the Facility When building the new cancer center parent organization Mountain States

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The technician shows the pharmacist that it is the right drug in the right amount.

Health Alliance showed its commitment to patient-centered care and national quality standards by making a large financial investment in the new pharmacy, says Bramble. “We knew right at the inception of the project—building the dedicated outpatient center—that we wanted to be USP <797>-compliant,” says Bramble, noting that pharmacy staff were involved in the design. In addition,

an outside consultant who specializes in pharmacy design was engaged to do architectural drawings for the facility. Using the footprint of the space, the consultant worked with onsite pharmacy staff to ensure that the finished facility would be optimized for workflow processes while meeting all safe-handling criteria. In addition, separate air handlers and back-up generators were installed.

Enhancing Care The hospital’s electronic medical re cord system made the trip to the new facility with the cancer care team, smoothing the transition. And with the team “working much closer together, we have an opportunity to work on reviewing order sets, protocols, and the like,” says Bramble. “We’re so blessed to have the medical oncologists, nurses, pharmacists, and the entire team to confer with one another; communication has been enhanced.” In addition, the new space allows for a classroom area within the pharmacy to accommodate residents from Bill Gatton College of Pharmacy, part of East Tennessee State University. “It has really added to our program. Although the students are solely dedicated to the Gatton School of Pharmacy, they add that other layer to our physicians and our nurses and everybody—another person to call and discuss cases with among other things,” says Bramble. The new center not only allows for a range of multidisciplinary services in one location, but also has led to commendation from the American College of Surgeons’ Commission on Cancer, which noted in the accreditation process the facility’s range of state-of-the-art services and equipment. ●

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THANK YOU FOR MAKING US

#1

In a recent survey, oncology pharmacists said that they read The Oncology Pharmacist 1.5 times more* than its closest competitor in the pharmacy market. Source: Š Kantar Media, Custom Study of Oncology Pharmacy Publications among The Oncology Pharmacist Circulation (June 2010)

ead R * 1 # e Th acy m r a h P y Oncolog blication u Tabloid P

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Supportive Care

Hepatitis B Screening and Chemotherapy

See also page 12.

Prophylactic Use of Antivirals Can Prevent HBV Reactivation By Audrey Andrews HOLLYWOOD, FL—Patients receiving chemotherapy are at risk for reactivation of the hepatitis B virus (HBV), and this can have a significant negative impact on outcomes, including death from liver failure. According to Emmy Ludwig, MD, of Memorial Sloan-Kettering Cancer Center (MSKCC), New York, one-third of the world has been exposed to HBV, “making it an enormous problem.” Fortunately, HBV reactivation can be prevented with the prophylactic use of effective antiviral agents, for which recommendations were presented by Ludwig at the 2011 National Comprehensive Cancer Network (NCCN) annual meeting. Although reactivation can occur spontaneously, it typically occurs as a result of immunosuppressive therapies in cancer, autoimmune disease, and organ transplantation. The risk does not end when chemotherapy is completed, but persists for at least 6 months, possibly longer in stem cell transplant patients and in those receiving rituximab. The risk of liver failure from HBV reactiva-

tion has been linked to the use of rituximab—precipitating a black-box warning for these patients. Recommendations for Screening and Prophylaxis Antiviral prophylaxis can prevent chemotherapy-related HBV reactivation. A systematic review of 14 studies (Loomba R, et al. Ann Intern Med. 2008;148:519528) evaluated the use of lamivudine in patients with chemotherapy who tested positive for the hepatitis B surface antigen (HBsAg). Of 108 patients who received lamivudine prophylactically, none developed HBV reactivation or HBV-related liver failure. Other studies made similar findings among patients with cancer. Although lamivudine is effective, most patients will become resistant to lamivudine at 5 years, Ludwig noted. “We do not recommend lamivudine because of the high resistance rate,” she said. Newer agents such as entecavir are extremely effective, have less propensity for resistance, and are less likely to inter-

act with other medications. Entecavir, therefore, is the preferred antiviral at MSKCC, she said. In March 2009, MSKCC initiated HBV screening of all new patients receiving immunosuppressive therapy. Among 4065 patients screened, almost 10% tested positive for either the HBsAg or the hepatitis B core antibody (HBcAb). All of these patients were treated with antiviral prophylaxis, and none experienced HBV reactivation. The potential benefits have led many groups to endorse HBV screening for patients receiving immunosuppressive therapy, including the American, European, and Asian-Pacific Associations for the Study of Liver Diseases; the Infectious Diseases Society of America; the American Gastroenterology Association; the American College of Rheumatology; and the Centers for Disease Control and Prevention. The NCCN suggests that antiviral therapy “be strongly considered in patients with acute HBV infection undergoing hematopoietic stem cell transplant or

other intensive immunosuppression,” although this is based on limited data, the group acknowledged. Also in its Clinical Practice Guidelines for Non-Hodgkin’s Lymphomas (V.2.2011), the NCCN recommends HBsAg and HBcAb screening for all patients receiving rituximab. But such recommendations are not universal. Routine screening is not recommended by the American Society of Clinical Oncology, which deems the evidence to be “insufficient to determine the net benefits and harms of routine screening for chronic HBV infection in individuals with cancer who are about to receive cytotoxic or immunosuppressive therapy or who are already receiving therapy” (Artz AS, et al. J Clin Oncol. 2010;28: 3199-3202). Ludwig said that despite those reservations, she personally recommends universal screening. “The data, honestly, are imperfect, and there are no large, randomized trials. However, if I had hepatitis B and were getting chemotherapy, I would put myself on an antiviral,” she commented. ●

Myeloid Growth Factors for Prevention of Neutropenia NCCN Helps Guide Optimal Use HOLLYWOOD, FL—The evidence backing the use of myeloid growth factors in patients at high risk for febrile neutropenia is solid, according to Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, North Carolina. Myeloid growth factors are the primary means of preventing chemotherapy-induced neutropenia. This often leads to febrile neutropenia, which can be fatal in 10% of patients, according to a database of more than 40,000 individuals. Concerns recently have been raised, however, that their use is associated with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). As chairman of the National Comprehensive Cancer Network (NCCN)’s Myeloid Growth Factors Panel, Crawford reassured clinicians that benefits substantially outweigh any risks associated with the granulocyte colony-stimulating factors (G-CSFs) filgrastim and pegfilgrastim. Including a discussion of MDS/AML associated with the use of G-CSFs was the only major change to the guidelines in 2011, he noted during a presentation at the 2011 NCCN annual meeting. Timing of Growth Factor Use In a 2008 study conducted by Crawford’s group, febrile neutropenia developed during the first 3 cycles in 11% of patients. Because most febrile neutrope-

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nia events occur during the first cycle of chemotherapy, clinicians should initiate growth factors from the beginning of treatment, and continue them in subsequent treatments, in any patient with a 20% or higher risk.

Primary G-CSF prophylaxis should be determined by the chemotherapy regimen. “Our window for starting prophylaxis is not big. We should start 24 to 72 hours after chemotherapy is completed,” he noted. When administration is delayed, the duration of grade 4 neutropenia may be longer and the risk of febrile neutropenia greater, Crawford pointed out. “The data suggest that what we do in the very first cycle of treatment makes a big difference.” Some clinicians also try to lower febrile neutropenia risk by reducing the dose of chemotherapy, but this is not advised because it diminishes the survival benefit obtained from full-dose chemotherapy, he explained. Similarly, prophylactic antibiotics can add to the protective benefit of G-CSFs in selected settings but should not be used instead of growth factors. “The routine

application of prophylactic antibiotics should be limited to high-risk inpatients with hematologic malignancies and stem cell transplantation,” he said. Is Pegfilgrastim Better than Filgrastim? Is the newer, and costlier, G-CSF peg filgrastim superior to filgrastim? Pegfilgrastim has a unique neutrophilregulated clearance and, because of high sustained serum levels, is a longer-lasting drug, although clinical efficacy appears to be similar. Although the clinical outcomes for the single dose of pegfilgrastim and the daily dose of filgrastim were comparable in a 2007 meta-analysis (Kuderer NM, et al. J Clin Oncol. 2007;25:31583167), the impact of pegfilgrastim on overall survival and disease-free survival has been apparent in all major prognostic subgroups studied to date, Crawford said. Sargramostim is an alternative agent that is associated with more toxicity and has therefore received only a category 2B recommendation in the NCCN Clinical Practice Guidelines for Myeloid Growth Factors (V.1.2011). MDS/AML Risk Not a Major Concern It does appear that use of a G-CSF is

associated with an increased risk of MDS/AML, Crawford acknowledged. The risk was elevated in a recent metaanalysis, regardless of tumor type or treatment regimen (Lyman GH, et al. J Clin Oncol. 2010;28:2914-2924); however, all-cause mortality was significantly lower among patients who received growth factor support. “There was an increase in MDS and leukemia, but the all-cause mortality analysis showed a significant reduction in risk. Leukemia risk was 0.005%, but the survival benefit was 5%. This amounts to an almost 10-fold difference in probabilities,” he said. “There clearly is an overall net benefit of G-CSF.” Who Should Receive Prophylaxis? Primary G-CSF prophylaxis should be determined by the chemotherapy regimen, the NCCN guidelines, and treatment intent (curative vs palliative). Clinicians should then determine whether the patient’s risk is high (>20%), intermediate (10%-20%), or low (<10%). High-risk patients, whose risk is elevated 5-fold over low-risk patients, should receive growth factors, regardless of treatment intent; low-risk patients should not receive them; and intermediate-risk patients should be considered for treatment based on risk factors, Crawford said. ● —AA

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Newsletter Series

YOUR QUESTIONS ANSWERED

Editor in Chief

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: • Newly Diagnosed Patients • Maintenance Therapy • Transplant-Eligible Patients • Retreatment • Transplant-Ineligible Patients • Cytogenetics • Side-Effect Management • Bone Health

Topics include: • Hodgkin Lymphoma • Follicular Lymphoma • Mantle Cell Lymphoma • Waldenstrom’s Macroglobulinemia • Diffuse Large B-Cell Lymphoma • 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 Credit™ (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.

For information about the physician accreditation of this activity, please contact Global at 303-395-1782 or inquire@globaleducationgroup.com. COEKsize40611MM

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www.BioOncology.com

Taking a broader view — charting a unique course in cancer care

At Genentech BioOncology, not only are we leading the fight against cancer with innovative science, but we’re also dedicated to supporting patients and others within the oncology community. A commitment to patients — We created Genentech BioOncology™ Access Solutions®, a single source for all access and reimbursement issues, so healthcare providers can remain focused on patient care. Reducing barriers to treatment — We help make treatment possible for patients in financial need through our BioOncology Co-pay Card Program and ongoing charitable donations to various independent, nonprofit organizations in support of co-pay assistance. A commitment to care — Our first product was approved in 1985, and since then we have donated approximately $2.3 billion in medicine to uninsured patients through the Genentech® Access to Care Foundation and other donation programs. Our goal is to fundamentally change the way that cancer is treated by personalizing solutions to patient care.

© 2011 Genentech USA, Inc. All rights reserved. BIO0000330901 Printed in USA.

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