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AUGUST 2011

www.TheOncologyPharmacist.com

VOL 4, NO 5

CONFERENCE NEWS: ASCO

CANCER CENTER PROFILE

Porter Cancer Care Center Prolonged Treatment with Imatinib Recommended for Oncology Pharmacists Manage Patients’ Pain High-Risk GIST By Dawn Lagrosa

3-Year Treatment Reduces Risk of Recurrence By Audrey Andrews

CHICAGO—Results from an important phase 3 trial presented at the plenary session could lead to prolonged treatment with adjuvant imatinib for gastrointestinal stromal tumors (GIST). The extension of imatinib treatment

Robin Mower, PharmD, consults with a patient and his wife to help manage his pain.

linical oncology pharmacists evaluate and treat pain through pain management consultations at Porter Cancer Care Center. As part of the comprehensive cancer treatment program at Porter Adventist Hospital in Denver, Colorado, Robin Mower, PharmD, and colleagues provide one-on-one pain evaluation consults to enhance the quality of life of patients with cancer. Fortunately, Colorado allows collaborative drug therapy management (CDTM) between physicians and pharmacists, allowing the clinical pharmacists at Porter Adventist Hospital to provide pain management under the CDTM protocol. In addition to inpatient oncology pain management consults, the clinical pharmacists provide pain management for outpatients in radiation oncology and the outpatient medical oncology clinics. Furthermore,

C

Continued on page 21

to 3 years, compared with the usual 1 year, resulted in a 54% reduced risk of recurrence and 55% reduced risk of death within 5 years for patients with high-risk disease, reported Heikki Continued on page 8

Amrubicin Better Than Topotecan for Second-Line Therapy of SCLC? Amrubicin Offers Similar OS Plus Improves Response Rates and PFS CHICAGO—The phase 3 ACT-1 trial suggests that amrubicin may have some advantages over topotecan as secondline treatment for small-cell lung cancer (SCLC). Both drugs achieved similar overall survival (OS) as second-line treatment, but amrubicin improved response rates, improved progressionfree survival (PFS), and improved control of lung cancer–associated symp-

toms, whereas topotecan worsened those symptoms. Prespecified subgroup analysis suggested that amrubicin achieved a modest improvement in OS compared with topotecan in patients who were refractory at baseline. This study suggests some benefit for amrubicin in the second-line setting, said lead author Robert Jotte, MD, PhD, Continued on page 12

BREAST CANCER

Differences and Similarities Among Ixabepilone and the Taxanes in Metastatic Breast Cancer By Teresa Davis, RN, OCN Clinical Trials Coordinator, Jackson Oncology Associates, PLLC, Jackson, Mississippi

P

aclitaxel and docetaxel are among the most active chemo therapy options for metastatic breast cancer.1,2 Use of these agents continues to evolve, as evidenced by their increasing use in early breast cancer and the emergence of a Cremophor

EL–free formulation of paclitaxel (nanoparticle albumin-bound paclitaxel), which exhibits improved efficacy and tolerability profiles. Use of taxanes, however, almost always leads to taxane resistance at some point, which

INSIDE Complimentary Ce

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The Evolving Role of Outcomes and End Points in Evaluating Therapy for Hematologic Malignancies ConferenCe news

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Decitabine Improve Overall Survival in Older AML Patients Flaxseed No More Effective Than Placebo for Hot Flashes Optimal Length of Treatment of NonHodgkin Lymphoma Debated

Continued on page 26

©2011 Green Hill Healthcare Communications, LLC

pharmaCoeConomiCs

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Upper GI Cancers: Are We Getting Value for the Money?

Koeller’s Corner

Ne Featuw re

Shooting from the Hip

Specialization in Oncology From the Beginning Page 33


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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

August 2011 I VOL 4, NO 5

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

W

ith the release of the new edition of the Drug Information Handbook for Oncology: A Complete Guide to Combination Chemotherapy Regimens (Lexi-Comp, Inc; July/August 2011), I am reminded of the ever-evolving dynamic of our profession. Since last year, this handbook has added 18 new drug monographs and 38 new chemotherapy regimens for a total of Patrick Medina, 304 monographs and 378 combinaPharmD, BCOP tion regimens. And this does not Editor-in-Chief take into account myriad supportive care and palliative care treatments. This is why I am proud that The Oncology Pharmacist helps keep you up to date not only on new drugs and drug combinations but also on practice processes to enhance patient care. At the American Society of Clinical Oncology (ASCO) annual meeting, we gleaned new survival benefits for imatinib, amrubicin, and decitabine, among others. Plus, at more specialized ASCO meetings,

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 Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrator Andrea Boylston

we discovered new targeted treatments for prostate and colorectal cancer. In addition, “the whole patient” needs to be considered. Our new column describes, comorbidities can both affect cancer treatments and result from cancer care. The transition from bench to bedside, however, can be confusing for practicing pharmacists. To help, Ms Davis brings clarity to the pros and cons of the epothilones and the taxanes. And value, an integral part of drug purchasing, is also an integral part of pharmacy practice. New studies on cost-effectiveness offer priceless data on which products proffer the most benefits with the least toxicities at a reasonable cost. Finally, with this issue, we introduce Koeller’s Corner. Jim Koeller, an oncology pharmacist well-known by many of us, provides a forum to discuss issues in our field. Our hope is that his insights into the everyday aspects of practicing oncology pharmacy will assist you in caring for your patients and his openness to readers’ comments will create a dialogue among pharmacists. As always, we welcome your comments and look forward to your feedback. ●

Circulation Department circulation@greenhillhc.com Editorial Contact: Telephone: 732-992-1891 Fax: 732-656-7938

What inspired you to enter the oncology field?

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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.

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t takes a very special person to become an oncology pharmacist. All of us at The Oncology Pharmacist are inspired by the dedication and compassion we routinely observe from our reading community. As part of our reader polls, and in recognition of the important work you do, we’d like to invite you to share your inspiration for working in this field.

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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.

Please log on to www.TheOncologyPharmacist.com to share your story. www.TheOncologyPharmacist.com


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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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Noteworthy Numbers

Noteworthy Numbers

I

ncreased awareness, earlier detection through screening, and advances in treatment have led to a decline in breast cancer death rates in the United States since 1990. Sadly, breast cancer continues to claim more women’s lives than any other cancer, besides lung cancer. For more statistical data on this prevalent disease, let’s take a look at breast cancer by the numbers.

About 1 in 8 (12%) women in the United States will develop invasive breast cancer over the course of her lifetime. In 2010, an estimated 207,090 new cases of invasive breast cancer were expected to be 6

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diagnosed in women in the United States, along with 54,010 new cases of noninvasive breast cancer. About 1970 new cases of invasive breast cancer were expected to be diagnosed in men in 2010…

Less than 1% of all new breast cancer cases occur in men. From 1999 to 2006, breast cancer incidence rates in the United States decreased by about 2% per year… Besides skin cancer, breast cancer is the

most commonly diagnosed cancer among US women… More than 1 in 4 (about 28%) cancers in women are breast cancer. Compared with AfricanAmerican women, white women are slightly more likely to develop breast www.TheOncologyPharmacist.com


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Noteworthy Numbers cancer, but less likely to die of it.

About 70% to 80% of breast cancers occur in women who have no A woman’s risk of breast family history of breast cancer approximately cancer. doubles if she has a first-degree relative who has been diagnosed with breast cancer… About 20% to 30% of women diagnosed with breast cancer have this family history although some are attributed to chance.

The most significant risk factors for breast cancer are gender (being a woman) and age (growing older).

In 2010, there were more than 2.5 million breast cancer survivors in the United States. Source: BreastCancer.org

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

EGFR-Expressing Recurrent Metastatic Colorectal Cancer (mCRC)

in Combination With RT in Locoregionally Advanced Disease

after Irinotecan and Oxaliplatin Failure as a Single Agent

About 5% to 10% of breast cancers can be linked to gene muta tions inherited from one’s mother or father… Mutations of the BRCA1 and BRCA2 genes are the most common…

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

Women with these mutations have up to an 80% risk of developing breast cancer during their lifetime, and they are more likely to be diagnosed at a younger age…

Colorectal Cancer ■ ERBITUX, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent, is also indicated for the treatment of EGFRexpressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens ■ ERBITUX, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of ERBITUX in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with ERBITUX in combination with irinotecan for the treatment of EGFR-expressing metastatic colorectal carcinoma ■ Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations

ERBITUX Boxed WARNINGS

An increased ovarian cancer risk also is associated with these genetic mutations. In men, about 1 in 10 breast cancers are believed to be associated with BRCA2 mutation. www.theOncologyPharmacist.com

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

Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

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Conference News The following articles are based on presentations at the 2011 Annual Meeting of the American Society of Clinical Oncology held June 3-7, in Chicago, Illinois.

Prolonged Treatment with Imatinib... Continued from cover Joensuu, MD, of Helsinki University Central Hospital in Finland. “These data are pretty compelling,”

Joensuu commented. “I would not be surprised if the standard will be 3 years of adjuvant imatinib in the near future.”

Mark G. Kris, MD, who moderated a press briefing and is chair of the ASCO Cancer Communications Committee,

agreed. “The entire oncology community was extremely excited when we saw the survival curve and those num-

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

Median overall survival 49.0 months

vs

RT alone (n=213)

vs

29.3 months

vs

45%

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

3-year overall survival rate 55%

19.7 month improvement

P=0.05

*

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

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

ERBITUX Safety Information for SCCHN ■ The most serious adverse reactions associated with ERBITUX® (cetuximab) across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%) ■ ERBITUX Plus Radiation Therapy and Cisplatin: The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events ■ Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

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bers at 5 years. It’s one of the amazing stories in oncology, and it is the kind of data that change guidelines,” he said. Study Details The SSGXVIII/AIO study, which was conducted by the Scandinavian Sarcoma Group and Sarcoma Group of the AIO,

Germany, was an open-label phase 3 study that evaluated 36 months versus 12 months of adjuvant imatinib administered after surgical resection to 400 GIST patients considered to have a high risk of recurrence. At a median follow-up of 54 months, recurrences or death were observed in 50

of 198 (25%) patients receiving 36 months of imatinib compared with 84 of 199 (42%) patients receiving 12 months of treatment. The recurrence-free survival rate was 86.6% at 3 years and 65.6% at 5 years with 36 months of treatment compared with 60.1% and

Photo by © GMG/Scott Morgan 2011.

Conference News

Mark G. Kris, MD

47.9%, respectively, with 12 months of treatment. This represented a 54% reduction in risk of recurrence that was highly significant (P <.0001), Joensuu reported. Overall survival was 96.3% at 3 years and 92.0% at 5 years

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

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

vs

4.57 months BSC alone (n=285)

34% improvement

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

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

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

ERBITUX Safety Information for EGFR-Expressing Recurrent mCRC ■ The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%) ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=354) treated with ERBITUX plus irinotecan in clinical trials (incidence ≥50%) were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse events (≥ 10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%) References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company; March 2011. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.

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

www.theOncologyPharmacist.com

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Conference News with 36 months of treatment compared with 94.0% and 81.7%, respectively, with 12 months of imatinib, representing a 55% mortality risk reduction (P = .019). Grade 3 or 4 adverse events were more common with longer treatment, and more patients discontinued treatment in the 36-month arm.

More May Be Better, Discussant Agreed Charles D. Blanke, MD, chief of medical oncology, University of British Columbia, Vancouver, critiqued the SSGXVIII/AIO study, noting that its conclusions were “valid.” He suggested that oncologists who typically initiate

imatinib on relapse might want to rethink this strategy. “If you have a patient who has high-risk GIST, at least as defined by the study, giving him or her 3 years of imatinib represents the new gold standard,” he maintained. “The overall survival benefit demonstrated

with immediate postoperative imatinib means it is no longer acceptable to withhold treatment in the adjuvant setting, hoping to ‘catch up’ when a patient has recurrent metastatic disease.” He acknowledged, however, staying on treatment for 3 years could be

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

Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In three patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. ■ Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy

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

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

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

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Conference News “The entire oncology community was extremely excited when we saw the survival curve and those numbers at 5 years. It’s one of the amazing stories in oncology, and it is the kind of data that changes guidelines.” —Mark G. Kris, MD

problematic for many patients, as suggested by a higher rate of side effects and more than a doubling in the dropout rate among patients who received imatinib for that long. Although it is possible that treatment even beyond 3 years could be even more beneficial, he noted, “Difficulties on the

3-year arm of SSGXVIII/AIO may bode poorly for therapy lasting even longer.” “For now, if I were a patient with a resected GIST and I had a compliant oncologist, I would request more,” he said. “As a compliant oncologist, I personally will offer patients treatment to eternity, meaning indefinitely.” ●

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

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

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

Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%) ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%) ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=354) treated with ERBITUX plus irinotecan in clinical trials (incidence ≥50%) were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse events (≥10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%)

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

©2011 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. 693US11AB15201

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Conference News Amrubicin Better Than Topotecan... Continued from cover director of thoracic oncology, Rocky Mountain Cancer Center, US Oncology, Denver, Colorado. “Topotecan is too difficult to use and is not a good option for our patients,” he noted during his presentation of study results.

SCLC has a dismal prognosis, with a 5-year survival of about 6%, and more effective treatments are a pressing need, he told the audience. The ACT1 investigators compared 2 drugs to see if outcomes could be improved.

Topotecan is approved in the United States and Europe as second-line treatment of SCLC, and amrubicin, a potent topoisomerase II inhibitor, is approved in Japan for SCLC and non-SCLC.

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

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The study randomized 637 patients in a 2:1 ratio to amrubicin 40 mg/m2 intravenously (IV) on days 1 to 3 or topotecan 1.5 mg/m2 IV on days 1 to 5 with growth factors given in the last third of the trial. Baseline characteristics were

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

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

3 4

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

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

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Conference News Both arms received a median of 4 cycles of chemotherapy. More patients received full-dose chemotherapy in the amrubicin arm: 92.7% versus 86.9%, respectively. More than three quarters of the amrubicin patients did not require dose reductions compared with 55.3% of the topotecan-treated patients.

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

Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with Erbitux Monotherapy Erbitux plus BSC BSC alone (n=288) (n=274) Body System Any Grades Any Grades Preferred Term Grades2 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation 89 12 16 <1 Dry Skin 49 0 11 0 Pruritus 40 2 8 0 Other-Dermatology 27 1 6 1 Nail Changes 21 0 4 0 Body as a Whole Fatigue 89 33 76 26 Fever 30 1 18 <1 3 Infusion Reactions 20 5 Rigors, Chills 13 <1 4 0 Pain Abdominal Pain 59 14 52 16 Pain-Other 51 16 34 7 Headache 33 4 11 0 Bone Pain 15 3 7 2 Pulmonary Dyspnea 48 16 43 12 Cough 29 2 19 1 Gastrointestinal Constipation 46 4 38 5 Diarrhea 39 2 20 2 Vomiting 37 6 29 6 Stomatitis 25 1 10 <1 Other-Gastrointestinal 23 10 18 8 Mouth Dryness 11 0 4 0 Infection Infection without neutropenia 35 13 17 6 Neurology Insomnia 30 1 15 1 Confusion 15 6 9 2 Anxiety 14 2 8 1 Depression 13 1 6 <1

1

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

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

OS was not significantly or numerically different between the 2 groups; median OS was 7.5 months in the amrubicin arm compared with 7.8 months in the topotecan arm. The hazard ratio of 0.880, however, suggested that amrubicin achieved some improvement over topotecan after 6 months, Jotte said.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group. Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older. OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

Copyright © 2004–2011 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved. 1236886A8

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ER-B0001A-03-11

Rev March 2011

Looking at OS in sensitive versus refractory patients, amrubicin appears to have a modest advantage in refractory patients (median OS, 6.2 months vs 5.7 months, respectively), but not in sensitive patients (median OS, 9.2 months vs 9.9 months, respectively). Jotte noted that the hazard ratio of 0.766 for refractory patients suggested that amrubicin improved survival after 6 months in this subgroup.

Photo by © GMG/Todd Buchanan 2011

well matched between the groups. Median age was 62 years, about 58% were men, and groups were well matched for sensitive patients and refractory patients (who progressed after first-line therapy) and for extensive and limited disease at diagnosis. One prior line of chemotherapy was allowed for enrollment.

“The hazard ratio of 0.766 for refractory patients suggested that amrubicin improved survival after 6 months in this [sensitive patients] subgroup.” —Robert Jotte, MD, PhD

Overall response rates significantly favored amrubicin: 31.1% compared with 16.9% for topotecan (P = .0001), and time to PFS also favored amrubicin: 4.1 months compared with 3.5 months for topotecan (P = .0182). Amrubicin achieved better control of SCLC symptoms, with improved appetite, cough, and dyspnea, whereas these symptoms worsened on topotecan. Both treatments caused fatigue, but fatigue was about 3 times greater in the topotecan arm. There were more infections (13.2% vs 8.6% with topotecan) but fewer transfusions needed (31.8% vs 52.8% with topotecan) in the amrubicin arm. More anemia, neutropenia, and thrombocytopenia were reported on the topotecan arm. About 11% of patients in both arms died on treatment. Although there was concern about cardiotoxicity with amrubicin, with cumulative dosing, no difference in left ventricular ejection fraction was reported between the 2 arms. During the question-and-answer session, Steven Vogel, MD, a community oncologist in New York City, said that there are other available second-line options for this poor-risk population, some of whom will respond to etoposide and cisplatin. Vogel said that in his practice, whether he uses amrubicin will depend on cost. ●

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Conference News

Decitabine Improves Overall Survival in Older AML Patients Phase 3 Trial Also Finds 20% Reduction in the Risk of Mortality By Wayne Kuznar

CHICAGO—Decitabine extends overall survival and improves response rates compared with standard therapies in the treatment of older patients with newly diagnosed acute myelogenous leukemia (AML), said Xavier G. Thomas, MD, PhD. The treatment options for older patients with AML are limited. Intensive chemotherapy is generally poorly tolerated in this group, the initial mortality rate is high (exceeding 30% at 8 weeks), the response rate to chemotherapy is poor, and relapse rates are high. Recently, DNA hypermethylation has been demonstrated in the promoter region in AML. Hypomethylating agents may affect tumor suppression genes and have been shown to be beneficial in AML cell lines, said Thomas, who is with the department of hematology, Edouard-Herriot Hospital, Lyon, France. Among the hypomethylating agents,

The protocol-specified final analysis (after 396 deaths) showed a nonsignificant but favorable trend for increased overall survival for patients treated with decitabine. decitabine has been approved for patients with myelodysplastic syndrome, and has demonstrated activity in a previous phase 2 trial of patients older than 60 years with AML. Based on these results, a phase 3 multicenter, controlled, open-label trial was designed to compare decitabine with patients’ choice of treatment on overall survival in patients 65 years and older

with newly diagnosed de novo or secondary AML and poor- or intermediaterisk cytogenetics. The 485 patients enrolled were randomized to decitabine, 20 mg/m2 as a 1-hour intravenous infusion once daily for 5 consecutive days, every 4 weeks, or treatment of choice. Patients assigned to treatment of choice could select low-dose cytarabine, 20mg/m2 subcutaneous injection once daily for 10 days, every 4 weeks (n = 243), or supportive care (n = 28). Patients assigned to decitabine had a median duration of treatment of 4.4 months compared with 2.4 months for those on the treatment-of-choice arm. The protocol-specified final analysis (after 396 deaths) showed a nonsignificant but favorable trend for increased overall survival for patients treated with decitabine, with a median survival of 7.7 months compared with 5.0 months in the treatment-of-choice arm (P = .10).

Flaxseed No More Effective Than Placebo for Hot Flashes Hunt Continues for Complementary Treatments for Reduction By Bonnie Gillis

CHICAGO—Flaxseed failed to have a significant effect on reducing hot flashes in women compared with placebo, according to results of a randomized, placebo-controlled trial supported by the North Central Cancer Treatment Group. The study included breast cancer survivors as well as women who had never had breast cancer who experienced frequent hot flashes throughout the day and night. These results were disappointing, said lead investigator Sandhya Pruthi, MD, Mayo Clinic, Rochester, Minnesota. “Hot flashes are bothersome, and although there are effective therapies, these have side effects. We need to balance side effects with efficacy. Although the present study was disappointing, we need to continue to try to identify complementary treatments [with fewer side effects] that can relieve hot flashes,” she said at a presentation. Hot flashes compromise quality of life. They can be socially awkward as well as interfere with sleep. At present, there are 2 effective options for treatment of hot flashes—venlafaxine and

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gabapentin—but both have side effects that may not be acceptable. After hearing anecdotal evidence that flaxseed controlled hot flashes, Pruthi and colleagues conducted a pilot study in 30 women with hot flashes, and results showed that flaxseed decreased both the severity and frequency of hot flash-

es. That pilot trial led to the randomized, placebo-controlled trial. The current study enrolled 188 participants who experienced >28 hot flashes per week at baseline; 75% were aged 50 years and older; 51% had a history of breast cancer. Among women with a breast cancer history, 15% were taking

Seventy-five patients received disease-modifying therapy after treatment failure following randomization. When these 75 patients were censored from the analysis, median overall survival improved to 8.5 months in the decitabine group and 5.3 months in the treatment-of-choice arm, corresponding to a 20% reduction in the risk of mortality in the decitabine arm, and the difference became statistically significant (P = .044). An updated unplanned overall analysis was performed with 446 deaths, or approximately an additional year of patient follow-up. This updated analysis showed the same median survival in the 2 groups (7.7 vs 5.0 months) but the effect became significant (nominal P = .037). “This analysis increases the strength and validity of the first clinical cutoff,” said Thomas. The secondary end point of complete remission with incomplete platelet recovery or complete remission with incomplete blood count recovery was achieved by 17.8% of the decitabine arm compared with 7.8% on treatment of choice. Adverse event rates were consistent with the known decitabine safety profile and without major differences between the treatment arms. ●

an aromatase inhibitor and 25% were taking tamoxifen. Patients were randomized to 1 flaxseed bar per day containing 410 mg lignans and fiber or to 1 placebo bar per day with 2 g protein and fiber; treatment was continued for 6 weeks. The flaxseed bars achieved a 33% decrease in hot flash score from baseline compared with a 29% decrease for placebo bars. Mean hot flash scores were reduced by 4.9 units in the flaxseed group and 3.5 units in the placebo group. This difference between treatment arms was not significant, Pruthi said. In both groups, about one third of the women received a 50% reduction in their hot flashes. No significant differences in toxicity were observed between the 2 arms. Abdominal distension, gas, and diarrhea were common in both arms, presumably as a result of fiber content, she said. “As oncologists, we need to deal with the rollercoaster effects of our research. [Some trials appear promising and then pan out not to have efficacy.] Hot flashes have a negative impact on quality of life, and we need to find the most effective treatment. There are some effective treatments for hot flashes. Patients should discuss treatment options with their doctors,” said Mark G. Kris, MD, chief of Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center in New York City, who moderated the press conference where Pruthi presented the results. ●

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Conference News S9704 trial of 253 patients with NHL that was presented at the meeting by Patrick J. Stiff, MD, of Loyola University Medical Center, Chicago. ASCT after CHOP-based induction therapy improved PFS in patients who had an aggressive form of the disease, receiving the 21-day regimen, probably as indicated by their high or highbecause the 14-day group received intermediate International Prognostic growth factors, although thrombocy- Index score. Patients responding to CHOP, with topenia was more frequent with RCHOP-14, probably because of greater or without rituximab, had a 2-year PFS rate of 69% with ASCT compared dose intensity. According to Cunningham, the re- with 56% with the induction therapy sults do not support a shift in clinical alone, which translates to a 72% practice from R-CHOP-21 to R- increase in PFS (P = .005). The 2-year OS rates CHOP-14. were similar between the Transplant Improves 2 groups, at 74% and Outcomes in High-Grade 71%, respectively; howevAggressive NHL er, many patients in the Julie M. Vose, MD, of the control arm underwent a University of Nebraska Medical salvage transplant, which Center, Omaha, discussed the may have confused this UK trial’s findings and agreed. analysis, Stiff pointed out. But she added that in younger The survival benefit Julie M. Vose, MD patients at high risk for recurwas most apparent in parence, R-CHOP-21, followed by autol- tients with high International Prognostic ogous transplantation of peripheral Index score; in this subgroup, the 2-year stem cells, should be offered as a stan- PFS rate was 75% with transplant comdard of care. pared with 41% with standard care, and This strategy was shown to be effec- the 2-year OS rates were 82% and 64%, tive in the phase 3 intergroup SWOG respectively. ●

Optimal Length of Treatment of Non-Hodgkin Lymphoma Debated By Caroline Helwick

CHICAGO—Several This randomized phase 3 studies addressed key questrial involved 1080 patients tions in the treatment of with diffuse large B-cell NHL, non-Hodgkin lymphoma all of whom were to receive (NHL). One evaluated a R-CHOP. The Treatmentshorter, more intense rituxnaïve patients were randomly imab-based regimen, and assigned to receive either 8 another evaluated the bencycles of R-CHOP for 21 days efit of autologous stem-cell David Cunningham, MD or 6 cycles of R-CHOP for 14 transplantation (ASCT) in days plus granulocyte colonyhigh-risk patients. The 21-day regimen stimulating factors, succeeded by 2 of rituximab plus cyclophosphamide, cycles of single-agent rituximab. doxorubicin, vincristine, and predAfter a median follow-up of 37 nisolone (R-CHOP) is still the standard months, the rates of overall survival of care for this paient population. (OS) and progression-free survival Rituximab revolutionized the care of (PFS) were similar, as were objective NHL and is essentially part of the treat- response rates. ment for all patients with this disease, No subgroup appeared to derive a but researchers continue to evaluate var- greater benefit from accelerated Rious schedules for delivering the drug. CHOP, reported David Cunningham, One debate during ASCO 2011 MD, of the Royal Marsden Hospital, focused on whether the standard 21-day who presented the results for the UK regimen can be shortened to 14 days; National Cancer Research Institute however, investigators from the United Lymphoma Clinical Study Group. Kingdom reported no advantage with Neutropenia and febrile neutropethe 14-day regimen. nia were more frequent in patients

KIDNEY CANCER

Approved Sunitinib Dosing Recommended for Metastatic Renal Cell Carcinoma By John Schieszer

ORLANDO—Oncology pharmacists can stick with the approved dosing for sunitinib in the treatment of advanced renal cell carcinoma (RCC), according to a study by New York investigators. A dosing schedule of 50 mg daily for 4 weeks, followed by 2 weeks off treatment (4/2) of sunitinib appears to be the optimal dosing schedule as first-line treatment of advanced RCC. In a phase 2 study, researchers compared different dosing schedules of this vascular endothelial growth factor inhibitor and found that patients treated with a 37.5mg continuous daily dose (CDD) regimen had similar overall response rates (ORRs) and overall survival (OS) to patients receiving 4/2 dosing. However, there was a trend toward inferior time to tumor progression (TTP) with the CDD regimen. “The median time to progression for the 4/2 schedule was 9.9 months compared with 7.1 months with continuous dosing. Although there wasn’t a statistically significant difference, there was a trend toward superiority with the 4/2

www.TheOncologyPharmacist.com

schedule,” said lead study investigator Robert Motzer, MD, who is an attending physician at Memorial Sloan-Kettering Cancer Center, New York, New York. “We felt that this study was important to do because there has been a lot of interest in looking at alternative dosing.”

A dosing schedule of 50 mg daily for 4 weeks, followed by 2 weeks off treatment (4/2) of sunitinib appears to be the optimal dosing schedule as firstline treatment of advanced RCC.

Motzer, who presented the study findings at the 2011 Genitourinary Cancers Symposium, said these findings are important because they add to the

growing body of evidence supporting the approved dosing schedule of sunitinib in advanced RCC. An oral agent, sunitinib is a receptor protein-tyrosine kinase inhibitor that has been shown in a randomized phase 3 trial to provide superior progression-free survival to interferon-alfa (11 vs 5 months) as firstline metastatic RCC therapy. Previous studies have suggested that continuous dosing of sunitinib 37.5 mg has antitumor activity with a manageable safety profile in first- and second-line treatment for metastatic RCC. Motzer and his colleagues conducted a study comparing the CDD regimen to the 4/2 schedule in 292 patients who had clear cell, locally recurrent, or metastatic disease. Sunitinib was continued until disease progression, unacceptable toxicity, or up to 2 years. The primary end point was TTP, and secondary end points were ORR, OS, and adverse events. All the patients were randomized (146 patients in each arm) between January 2007 and June 2008. As of October 2010, 289 patients had received suni-

tinib, and all patients were off therapy. The median age of the patients was 62 years, and 65% were men. In addition to the increase in TTP, the researchers found that ORR was 32.2% for the 4/2 dosing schedule compared with 28.1% for the CDD regimen. Median OS was 23.1% for the 4/2 dosing group compared with 23.5% for the CDD group. “We looked at patient-reported outcomes, and we found no difference in quality of life between the 2 dosing schedules, but we found in another analysis of time to progression and time to death that there was a statistically significant improvement with the standard 4/2 schedule compared with continuous dosing,” said Motzer in an interview with The Oncology Pharmacist. He said the most common drugrelated adverse events were fatigue (62% in both arms), nausea (56% for the 4/2 dosing group vs 49% for the CDD group), and diarrhea (56% for the 4/2 dosing group vs 64% for the CDD group). ●

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CONTINUING EDUCATION PROGRAM P11067E • RELEASE DATE: JULY 15, 2011 • EXPIRATION DATE: JULY 15, 2012 ESTIMATED TIME TO COMPLETE: 1.0 HOUR • COMPLETE THE POSTTEST AT WWW.THEONCOLOGYPHARMACIST.COM

The Evolving Role of Outcomes and End Points in Evaluating Therapy for Hematologic Malignancies: Value-Driven Benefit Design and Utilization Management Strategies 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: • Compare and contrast the primary end points used in pivotal clinical trials for hematologic malignancies • Determine which end points are the most appropriate and clinically relevant for assessing the efficacy of novel targeted agents for multiple myeloma, chronic myeloid leukemia, and nonHodgkin lymphoma • Evaluate surrogate end points as they relate to optimal long-term outcomes for patients with hematologic malignancies • Analyze the results from clinical trials to assess the justification of incorporating novel targeted agents into standards of care and effective benefit design and utilization management approaches SPONSOR

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

W

hile healthcare reform is on the horizon, the pipeline for new cancer therapies continues to grow and cancer care costs are on the rise. More than 90% of the anticancer agents approved by the US Food and Drug Administration (FDA) between 2004 and 2008 cost more than $20,000 for a 12-week course of treatment.1 The practice of managed care pharmacy frequently involves making decisions about whether a given drug or a regimen is covered under a patient’s pharmacy benefit or health insurance plan. The question that managed care payers are asking is, will the health outcomes produced by these expensive therapies justify the increased cost? Payers are increasingly insisting that newly introduced agents and regimens demonstrate improvement in patient outcomes before their cost will be fully reimbursed.

End Point versus Outcome: What Is the Difference? Avedis Donabedian, MD, MPH, public health pioneer, defined outcomes as the “consequences to the health and welfare of individuals and of society.”2 He noted that “outcomes, by and large, remain the ultimate validation of the effectiveness and quality of medical

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INSTRUCTIONS fOR CREDIT

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

Medical Learning Institute, Inc., is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal activity number for this activity is 04689999-10-059-H01-P.

fACULTy DISCLOSURES

Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute, Inc., for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. Shelly Chun, PharmD, a reviewer for MLI, has nothing to disclose. Linda Ritter, PhD, Center of Excellence Media, has nothing to disclose.

This activity is provided free of charge to participants. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.

Chair James T. Kenney Jr, RPh, MBA, has nothing to disclose.

care.”2 Ultimately, cure is the desired outcome for patients with any disease. However, this is not currently a realistic goal for most patients with cancer who are undergoing the therapies available today. As advances are made in our understanding of molecular oncology and new targeted therapies are developed, many malignancies are being treated as chronic diseases, and patients diagnosed today may expect to live longer than patients diagnosed in years past. A patient’s quality of life and freedom from disease progression may become more important outcomes than survival if differences in overall survival (OS) are not apparent when comparing therapies and regimens. The economic evaluations involved in making managed care decisions often consider the likely costs and outcomes of new therapies over time, based primarily on safety and efficacy end point data from the clinical trials that led to the approval. A clinical trial will usually define or specify a primary end point as an objective measure that will indicate the success of the therapy being investigated. A trial may also define 1 or more secondary end points that will be measured and are expected to be met. Some of these end points may be surrogate end points, which are biomarkers

that may correlate with a real clinical outcome but do not necessarily have a guaranteed relationship. In addition, a primary end point that supports efficacy in previous and ongoing clinical trials may be different from the primary end point in subsequent trials, making it difficult to compare agents and regimens and their effect on the desired outcome. Although an improvement in OS had historically been the gold standard end point for a new oncology drug approval, 68% of the regular approvals and 100% of the accelerated approvals for oncology drugs between 1990 and 2002 were based on clinical trial end points other than survival, including the objective response rate, progressionfree survival (PFS), disease-free survival (DFS), and time to progression (TTP).3 In 2003, the FDA began a project to evaluate potential end points for cancer drug approval.4 End points were examined for the most common cancers during public workshops, important issues were identified, and these issues were discussed in meetings of the Oncologic Drugs Advisory Committee. Subsequently, a guidance document was published in 2007, describing the FDA’s current thinking on end points for cancer drug approval.5 Although the FDA still regarded OS as the preferred end

Faculty Michael Mauro, MD, receives research grants from Novartis Oncology and Bristol-Myers Squibb.

Gary Yee, PharmD, FCCP, BCOP, 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. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for the agent discussed in this program should be inferred. COmmERCIAL SUPPORT ACkNOwLEDGmENT This activity is supported by educational grants from Millennium Pharmaceuticals and Novartis Pharmaceuticals.

point in a cancer trial, FDA members found a clear disadvantage in the necessity of a long observation period. During this same period (2001 to present), the targeted therapies for multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and chronic myeloid leukemia (CML) that are in common use today entered the clinical arena. Multiple Myeloma MM is the second most frequently diagnosed hematologic malignancy.6 Although MM remains incurable, outcomes have significantly improved in recent years with the introduction of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib, and with advancements in supportive care (Table). The early introduction of effective management strategies that include ≥1 of these novel agents have improved survival for patients with MM. In fact, between 1975 and 1979, a patient receiving a diagnosis of MM had only a 53% probability of surviving 2 years.7 In comparison, 2-year survival rates for patients diagnosed within the past few years have been reported as high as 88%, and the 5-year survival rate has increased to more than 40% for patients diagnosed in 2003.7

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Consistency in the conduct of clinical trials and in the analysis and reporting of results is essential to ensuring valid and reliable results that can be compared with those of other trials. Early in 2011, the International Myeloma Workshop Consensus Panel 1 recommended PFS as the primary end point for clinical trials in lieu of long-term OS data.8 An analysis of PFS includes all patients and is calculated from the beginning of treatment to disease progression or death from any cause. TTP has also been used as the primary end point in clinical trials for MM. An analysis of TTP is essentially the same as that for PFS, but deaths that are not directly related to the disease are not counted in TTP. However, as data from trials initiated in the past decade mature, a PFS or TTP trial end point benefit does not always translate into an OS benefit.

In December 2009, survival benefit was added to the VMP label after further analysis of the VISTA trial demonstrated that OS continued to improve significantly in the VMP arm during a median follow-up of 36.7 months despite subsequent therapies, including bortezomib-based regimens.10 Median OS was not reached with VMP versus 43.1 months with MP (P <.001); after 3 years, the OS rates were 68.5% versus 54.0%, respectively.9 Several phase 3 trials have compared the use of melphalan, prednisone, and thalidomide (MPT) with that of MP for the treatment of newly diagnosed MM in patients who were not eligible for ASCT,11-15 showing mixed results. Although these trials have consistently shown better response rates with MPT than with MP, only 4 of the 5 trials showed a significant improvement in PFS, and only 2 showed a significant improvement in OS (P <.05). A metaanalysis of these 5 trials (N = 1568) showed a pooled hazard ratio (HR) of 0.68 for PFS (P <.001; 95% confidence interval [CI], 0.55-0.82) and 0.80 for OS (P = .07; 95% CI, 0.63-1.02) in favor of MPT.16 Although the addition of thalidomide to MP results in significantly improved PFS, MP alone demonstrates only a nonsignificant improvement in OS, with the additional burden of significantly increased toxicity. Recently, data were reported from a phase 3 trial comparing the combination of lenalidomide plus MP (MPR) with MP in patients aged ≥65 years who were ineligible for ASCT (N = 459).17 Patients were randomized to receive either MP alone, MPR (fixed dose schedule), or MPR followed by continuous lenalidomide maintenance (MPR-R). At a median follow-up of 25 months, patients who received MPR-R demon-

To Receive cRediT, compleTe The posTTesT aT

strated a significant improvement in PFS (31 months) compared with patients who received MPR (14 months) or MP (13 months; P TheOncologyPharmacist.com <.001). However, the significant PFS advantage did not apply to patients aged >75 years (MPR-R vs MPR; P = .118). Although a median OS has not been reached among any of the 3 arms, there is currently no significant difference between the arms in the estimated 1-year and 2-year OS 16% for those achieving very good partial response (VGPR).20 Significant difrates. ferences in OS and PFS were found between the CR and nCR groups (P = .01 and P = .002, respectively), as well as between CR and VGPR (P = .0001 and The postinduction .003). A plateau in OS was observed response rate of VGPR or after 11 years; 35% of patients achieving better was 42% in patients CR are alive at 17 years. For patients who are transplant-eligireceiving bortezomib, ble, recent clinical trials have evaluated doxorubicin, and combined modality induction regimens dexamethasone and 15% with the novel agents in an attempt Transplant-ineligible patients to increase the rate of response to inducin those receiving The combination of melphalan and tion therapy to improve the quality vincristine, doxorubicin, prednisone (MP) had historically of response to transplantation. In the and dexamethasone. been the regimen of choice for newly HOVON-65/GMMG-HD4 (Dutchdiagnosed MM in patients who were Bel gian Hemato-Oncology/German not eligible for autologous stem-cell Cooperative Groups) trial, patients were transplant (ASCT). In 2008, the randomized to induction therapy with Transplant-eligible patients FDA approved bortezomib “for the bortezomib, doxorubicin, and dexamethaThe quality of posttransplantation re- sone (PAD) or with vincristine, doxorutreatment of patients with multiple sponse, especially the achievement of bicin, and dexamethasone (VAD).21 myeloma.” This approval was based complete response (CR), is now well After undergoing high-dose therapy and on the VISTA (Velcade as Initial established as a prognostic indicator of ASCT, patients who were randomized Standard Therapy in Multiple improved long-term survival for previ- to PAD received bortezomib as mainteMyeloma) trial, in which the combiously untreated MM in patients who re- nance therapy for as long as 2 years, and nation of bortezomib, melphalan, and ceive high-dose therapy and ASCT.18,19 those randomized to VAD received prednisone (VMP) was compared In a retrospective analysis of 344 pa- thalidomide. The postinduction rewith MP in 682 patients with newly tients with MM who underwent trans- sponse rate of VGPR or better was 42% diagnosed MM who were ineligible for plantation between 1989 and 1998, in patients receiving PAD and 15% in ASCT.9 The median TTP—the primary efficacy end point in the study— after a median follow-up of 12.75 years, those receiving VAD (P <.001). The was 24.0 months in the VMP group the OS rate at 12 years was 35% for response rates improved to 61% and compared with 16.6 months in the patients achieving CR, 22% for those 36%, respectively, posttransplantation MP group (P <.001). demonstrating near CR (nCR), and and to 76% and 55% during maintenance. Patients receiving PAD induction with bortezomib maintenance Table Label Indication and Registration Trial Information for Thalidomide, Lenalidomide, and Bortezomib showed significantly improved PFS Registration trial (HR = 0.75; P = .005) and OS (HR = 0.73; P = .02). Primary In the phase 3 GIMEMA (Gruppo Drug Indication Design/patients end point Result Italiano Malattie Ematologiche dell’ Thalidomidea In combination with dexamethasone Newly diagnosed patients with MM ORR, % 51.5 vs 35.6 Adulto) trial, the safety and efficacy of for the treatment of patients with N = 207 induction therapy and consolidation newly diagnosed MM TD vs high-dose dexamethasone with thalidomide plus dexamethasone Lenalidomideb In combination with dexamethasone Relapsed/refractory MM Median Study 1: 13.9 vs 4.7 (TD) is being compared with that of for the treatment of patients with (at least 1 previous treatment) TTP, mo P <.001 bortezomib, thalidomide, and dexa MM who have received at least 1 Study 1: N = 353 Study 2: 12.1 vs 4.7 methaone (VTD) in combination with previous therapy Study 2: N = 351 P <.001 double ASCT and dexamethasone LD vs high-dose dexamethasone maintenance.22 The addition of bortezTreatment of patients with MM Newly diagnosed patients with MM Median 20.7 vs 15.0 Bortezomibc omib to TD significantly improved the N = 682 TTP, mo P <.0001 CR rate after induction, first transplanVMP vs MP tation, second transplantation, and Relapsed/refractory MM (after 1-3 Median 6.2 vs 3.5 consolidation. Treatment with VTD previous therapies) TTP, mo P <.0001 resulted in a significant 37% reduction N = 669 in the relative risk for progression or Bortezomib vs high-dose dexamethasone death (HR = 0.63; P = .0061), but at a Thalomid [package insert]. Summit, NJ: Celgene; 2010. median follow-up of 36 months, no difRevlimid [package insert]. Summit, NJ: Celgene; 2010. ference in OS has been seen (HR = Velcade [package insert]. Cambridge, MA: Millennium; 2010. LD indicates lenalidomide/dexamethasone (high-dose); MM, multiple myeloma; MP, melphalan/prednisone; ORR, overall response rate; TD, thalidomide/dexamethasone (high-dose); 0.76; P = .3071). TTP, time to progression; VMP, bortezomib/melphalan/prednisone. Two additional promising novel a

b c

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CONTINUING EDUCATION

Chronic Myeloid Leukemia Approximately 0.6 to 2.0 cases of Philadelphia chromosome-positive (Ph+) CML are diagnosed globally per 100,000 persons each year. Approximately 1.5 cases per 100,000 persons are diagnosed each year in the United States.7,25 Historically, chemotherapy with alkylating agents and hydroxyurea provided a median survival of only 3 to 4 years.26 Median survival improved to 6 to 7 years in the early 1980s with the advent of interferon-alpha, but the 10year survival rate was still only 30% to 40%, and patients had few options after the failure of first-line therapy.27 Before 2000, survival was the primary goal of therapy for patients with CML in chronic phase (CML-CP). The introduction of the tyrosine kinase inhibitor (TKI) imatinib in 2001 has revolutionized management strategies, refocusing the outcome on prevention of progression rather than on survival. The annual mortality rate has decreased to approximately 1% to 2%, and the estimated 5year survival rate has increased to approximately 90%.7 This translates to an increasing prevalence that may exceed 200,000 cases in the United States within the next 20 years.26 The importance of early optimal response It was established that patients with CML had prolonged survival after achieving a cytogenetic response (CyR) to interferon-alpha.28 In 2001, imatinib was approved for newly diagnosed CMLCP based on the surrogate end points of major CyR and complete CyR (CCyR).29 Since then, much has been learned regarding the accepted milestones for response to first-line therapy and the timing of those responses. Patients with suboptimal or poor response within the first 6 months of therapy are far more likely to experience early disease progression to advanced phase or blast crisis, in which long-term responses to TKIs are unlikely to occur and overall healthcare costs are much higher.

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Figure Kinetics of Resistance to Imatinib in the IRIS Trial Event rate or patients at AP/BC, %

combination regimens in phase 2 studies have reported high rates of CR after induction. One is the combination of bortezomib, lenalidomide, and dexamethasone (VRD), and the other is that of bortezomib, dexamethasone, and cyclophosphamide (VDC).23,24 VRD showed a VGPR rate of 74%, and VDC (modified to add an additional dose of cyclophosphamide at day 15) showed a VGPR rate of 53%. In addition, until more data and longer follow-ups are available, consolidation and maintenance therapy with novel agents may improve posttransplant responses and provide patients with a significant survival advantage.

10 9 8

AP/BC

Event Loss of CHR Loss of MCyR AP/BC Death

7.5

7 6 4.8

5 4

3.3 2.8

3 2

1.8

1.7

1.7 0.9

1

1.4 0.8

0.5

0.3

0

0 1

2

3

4

5

1.3

6

0

7

0.4

8

Year AP/BC indicates advanced phase/blast crisis; CHR, complete hematologic response; IRIS, Insulin Resistance Intervention after Stroke; MCyR, major cytogenetic response. Source: Deininger M, et al. Blood. 2009;114(suppl):462. Abstract 1126.

In a study comparing patients with a suboptimal response or failure within 6 months of initiating imatinib therapy and those who responded during that same period, the likelihood of achieving CCyR was 39% versus 96%, respectively (P <.0001), the rate of PFS was 87% versus 98% (P = .04), and the rate of OS was 70% versus 92% (P = .001).30 In the IRIS (Insulin Resistance Intervention after Stroke) trial, patients who achieved a CCyR had a lower annual incidence of events (loss of response, transformation to advanced phase or blast crisis, or death) than the overall group after 5 years of follow-up.31 In addition, 100% of patients in the imatinib arm of the IRIS trial who had achieved both a CCyR and a major molecular response (MMR) by 12 months were free from progression to advanced phase or blast crisis at 8 years, and the achievement of CCyR by 12 months was associated with improved survival.32 Second-generation TKIs Second-generation TKIs (nilotinib, dasatinib, and bosutinib) are being compared with imatinib in clinical trials in patients with newly diagnosed CMLCP. Nilotinib (300 mg twice daily) received FDA approval in June 2010 for the treatment of newly diagnosed CML, based on results from the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials—Newly Diagnosed Patients) trial. The primary end point in this trial is the MMR rate at 12 months. After a median follow-up of 18.5 months, the rate of MMR for nilotinib at 12 months (44%) was twice (22%) that for imatinib (P <.0001).33 By 12 months, the rate of CCyR was also significantly higher among patients receiving nilotinib (80%) than among those receiving imatinib (65%; P <.001). The Kaplan-Meier estimate of the median time to MMR was shorter

(8.6 months) for patients receiving nilotinib than for those receiving imatinib (median not yet achieved). An updated analysis of data covering a median follow-up of 24 months was presented at the 2010 American Society of Hematology’s (ASH) annual meeting.34 At 24 months, the MMR rate was 62% for nilotinib versus 37% for imatinib (P <.0001) and the CCyR rates were 87% versus 77%, respectively (P = .0018). In addition, significantly fewer patients receiving nilotinib (0.7%) than those receiving imatinib (4.2%) had progressed to advanced phase or blast crisis or had died (P = .0059). Fewer patients receiving nilotinib discontinued therapy because of adverse events.

In January 2011, nilotinib and dasatinib were added to the NCCN treatment guidelines as category 1 options for the primary treatment of Ph+ or BCR-ABL+ CML.

Dasatinib received FDA approval for newly diagnosed CML-CP in October 2010 based on results from the DASISION (Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients) trial, which compared dasatinib with imatinib. The primary end point was the rate of confirmed CCyR at 12 months.35 After a median follow-up period of 14 months, the rate of confirmed CCyR at 12 months was significantly higher in patients receiving dasatinib (77%) than in those receiving imatinib (66%; P = .007). In addition, the rate of MMR at any time was

significantly higher among patients receiving dasatinib (52%) than among patients receiving imatinib (34%; P <.0001). Among patients who achieved an MMR, the median time to MMR was 8.3 months for dasatinib and 11.8 months for imatinib. Fewer patients receiving dasatinib (1.9%) than those receiving imatinib (3.5%) had progressed to advanced phase or blast crisis. The rates of discontinuation as a result of adverse events were similar for dasatinib and imatinib. An updated analysis of data covering a median follow-up of 18 months was presented at ASH 2010.36 First-line second-generation TKIs provide optimal outcomes In January 2011, nilotinib and dasatinib were added to the National Comprehensive Cancer Network (NCCN) treatment guidelines as category 1 options for the primary treatment of Ph+ or BCR-ABL+ CML. With 3 FDA-approved and NCCN-recommended therapies, what will drive the choice of treatment? Should the higher cost of the second-generation TKIs be a factor? A recent study examined the association between adherence to imatinib therapy and direct healthcare costs and resource utilization in a large group (N = 592) of privately insured patients with CML.37 Patients with CML who do not adhere to treatment may have suboptimal outcomes and higher rates of progression to advanced phase or blast crisis. In this study, patients with low adherence had more all-cause inpatient visits (4.1) compared with those who demonstrated higher adherence (0.4; P <.001) and more all-cause inpatient days (14.8 days vs 1.8 days, respectively; P <.001). In regression models, non-imatinib costs were 283% higher in the nonadherent group ($324) than in the adherent group ($56; P <.001). Therapy failure occurred in approximately 22% of patients receiving first-line imatinib therapy (the vast majority of failures being early events) compared with approximately 4% of patients receiving first-line therapy with a second-generation TKI. One may ask, “Why not wait until patients have a suboptimal response to imatinib or fail treatment before prescribing a higher-priced second-generation TKI?” This may be too risky, and, in the long run, incur higher costs. Treatment at suboptimal response or failure is salvage therapy. In such cases, the likelihood that the patient has developed drug-resistant mutations has increased, requiring the use of a thirdgeneration TKI or a very expensive stem-cell transplant. The 8-year analysis of the IRIS trial demonstrated that imatinib was effec-

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tive in preventing prospective events but not the loss of response or progression events that occur early (Figure).32 The ENESTnd and DASISION trials suggest that frontline therapy with second-generation TKIs produces higher rates of CCyR and MMR than the standard-dose imatinib, and these responses are achieved at earlier time points. On the basis of data derived from the IRIS trial that highlighted the prognostic importance of achieving early CCyR and MMR, it is reasonable to expect that the use of nilotinib or dasatinib in the frontline setting might render higher rates of event-free survival and transformation-free survival and may therefore offset the high costs associated with progression. Non-Hodgkin Lymphoma NHL is a highly heterogeneous group of cancers affecting the lymph system, with variable cytogenetic, cellular, and clinical features and natural histories that range from indolent to very aggressive.38 NHL is the most common hematologic malignancy in the United States.6 It is estimated that 65,540 Americans were diagnosed with various forms of NHL in 2010, and 20,210 deaths were attributed to the disease. The prevalence of NHL in the United States is approximately 440,000 patients.7 Most patients with NHL have a B-cell subtype: 31% of patients with NHL have diffuse large Bcell lymphoma (DLBCL), 22% have follicular lymphoma, 5% to 10% have marginal zone lymphoma (MZL), and 6% have mantle-cell lymphoma (MCL).39 T-cell lymphomas comprise about 15% of NHL cases.40 Indolent versus aggressive: desired outcomes of therapy Both B-cell and T-cell lymphomas are categorized into indolent and aggressive types. DLBCL, MCL, peripheral T-cell lymphoma, and anaplastic large-cell lymphoma (ALCL) are considered aggressive lymphomas. The goal of treatment is to cure an aggressive lymphoma; this may be achieved in 30% to 60% of patients for some subtypes.41 DLBCL can be cured in a significant proportion of patients,42 but MCL cannot.43 The response rate and OS are often the end points in clinical trials for aggressive lymphomas that are curable, whereas response rate and duration of response and PFS are end points in trials for those that are not. For aggressive lymphomas that cannot be consistently cured at this time, the search continues for treatment that can become a curative standard of care. The lack of cure along with treatment failure exacts an enormous socioeconomic toll. For example, the mean cost of treatment failure in aggressive NHL

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has been reported to be as high as $14,174 monthly and reaches $85,934 over a period of <2 years (in 1999-2000 dollars).44 In contrast, indolent lymphomas are characterized by long, slowly progressive clinical courses; examples include follicular lymphoma, MZL, Waldenstrom’s macroglobulinemia, and the cutaneous T-cell lymphoma mycosis fungoides. The goal of treatment is often long-term management, as indolent lymphomas are rarely cured unless diagnosed when still localized. The response rate, DFS, eventfree survival, duration of response, and PFS are often the primary end points in clinical trials for indolent lymphomas. Clinical trials have attempted to improve on the best available accepted therapy by adding an additional agent or substituting one active agent for another; therefore, there is a virtual “alphabet soup” of therapeutic regimens available to treat this group of cancers. In the past decade, the treatment of NHL has changed dramatically, with the advent of molecularly targeted anticancer therapies. For example, the development of the CD20 monoclonal antibody rituximab has changed the treatment paradigm for Bcell lymphomas and, in some subtypes of the disease, has markedly improved prognosis. Bortezomib, lenalidomide, bendamustine, alemtuzumab, and other novel agents have also demonstrated clinical benefit in B-cell lymphomas. T-cell subtypes and ALCL are being treated with a number of approved and investigational targeted agents, including romidepsin, pralatrexate, brentuximab vedotin, denileukin diftitox, and vorinostat. The use of targeted therapies for NHL, combined with refinements in cytotoxic chemotherapy and stem-cell transplantation, continue to alter the therapeutic landscape at a rapid pace. Indolent versus aggressive: clinical trial end points In 1999, an international working group of clinicians, radiologists, and pathologists with expertise in the evaluation and management of patients with NHL published guidelines for response assessment and outcomes measurement.45 These were revised in 2007, when interobserver and intraobserver variations were identified and recommended technologies were no longer considered state-of-the-art.46 In addition to defining response criteria and making recommendations for disease evaluation, this group proposed that the major end points of clinical trials should reflect the histology, clinical situation, and objectives of the study and be defined consistently across clinical trials. Response rates as a trial end point are greatly influenced by the defined

To Receive cRediT, compleTe The posTTesT aT

response criteria used. In addition, response rates do not necessarily influence other measures of TheOncologyPharmacist.com overall clinical benefit or outcome in patients with NHL. OS is the least ambiguous of the trial end points, but it is not optimal for use in an indolent or incurable aggressive lymphoma trial. PFS is often considered the preferred end point in lymphoma clinical trials, especially those involving Evolving Outcomes and End Points incurable subtypes (indolent and aggres- and Value-Based Care sive). Event-free survival is generally As progress is made in the treatment of not encouraged by the FDA, because it MM, CML, and NHL, as with any cancombines efficacy, toxicity, and patient cer, the ultimate outcome of therapy for withdrawal. However, it may be useful patients also evolves. Although OS in the evaluation of novel agents that remains the optimal outcome for may be highly toxic and have a high patients with MM, surrogate end points risk-benefit ratio. Duration of response, used in clinical trials do not always transif associated with measures of clinical late into a survival benefit as long-term benefit, may also be an important and data mature. The use of TKIs for CMLCP has drastically changed the natural relevant end point in lymphoma trials. One of the most important outcomes history of this disease. Freedom from for patients with NHL has been evi- treatment failure and from progression to dence of clinical benefit. Clinical bene- advanced phase or blast crisis is the prefit may reflect improvement in quality of ferred outcome. Early and durable CCyR life or a reduction in symptoms, transfu- and MMR are reliable surrogate end sion requirements, frequent infections, points for this outcome. For patients or other parameters. As the symptoms with some subtypes of aggressive NHL, a associated with lymphoma can greatly cure is possible and OS is both the trial impact a patient’s quality of life, time to end point and the desired outcome. reappearance or progression of lym- However, for patients with indolent and phoma-related symptoms may also be an incurable-aggressive NHL, an extended important measure, especially for incur- period without progression that may be compounded by lymphoma-associated able lymphomas. symptoms is preferred. PFS and duration of response are acceptable surrogate end points for this outcome. ●

The mean cost of treatment failure in aggressive NHL has been reported to be as high as $14,174 monthly and reaches $85,934 over a period of <2 years (in 1999-2000 dollars).

Rituximab was first approved by the FDA in 1997 for the treatment of relapsed or refractory low-grade or follicular, B-cell NHL as a single agent based on the overall response rate.47 Since that time, rituximab has received 5 additional indications as a single agent or as part of a chemotherapeutic regimen. The Appendix (available at www.theonclo gypharmacist.com/P10067E) lists some of the targeted agents and new therapies approved within the past decade for various subtypes of NHL and the primary and secondary end points used in the registration trials. Care must be taken when making cross-trial comparisons to ensure that the patient populations are comparable and that defined end points and response criteria have been used consistently.

References 1. Cohen H. Drug Topics Red Book 2008. 112th ed. Montvale, NJ: Thomson Healthcare/Thomson PDR; 2008. 2. Donabedian A. Evaluating the quality of medical care. Milbank Memorial Fund Quarterly. 1966;44:166-206. 3. Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol. 2003;21:1404-1411. 4. US Food and Drug Administration. The Center for Drug Evaluation and Research. Cancer Drug Approval Endpoints. www.fda.gov/AboutFDA/CentersOffices/ CDER/ucm117709.htm#background. Accessed July 23, 2010. 5. US Food and Drug Administration. Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. May 2007. www.fda. gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm071590.pdf. Accessed July 23, 2010. 6. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277-300. 7. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD. http://seer.cancer. gov/csr/1975_2008/, based on November 2010 SEER data submission, posted to the SEER Web site, 2011. Accessed June 30, 2011. 8. Rajkumar SV, Harousseau JL, Durie B, et al, for the International Myeloma Workshop Consensus Panel 1. Consensus recommendations for the uniform reporting of clinical trials. Blood. 2011;117:4691-4695. 9. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008; 359:906-917. 10. Mateos MV, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28:2259-2266.

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CONTINUING EDUCATION 11. Facon T, Mary JY, Hulin C, et al, for the Intergroupe Francophone du Myélome. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 9906): a randomised trial. Lancet. 2007;370:1209-1218. 12. Palumbo A, Bringhen S, Liberati AM, et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008;112:3107-3114. 13. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009;27:36643670. 14. Wijermans P, Schaafsma M, Termorshuizen F, et al, for the Dutch-Belgium Cooperative Group HOVON. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol. 2010;28:3160-3166. 15. Waage A, Gimsing P, Fayers P, et al, for the Nordic Myeloma Study Group. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood. 2010;116:1405-1412. 16. Kapoor P, Rajkumar SV, Dispenzieri A, et al. Melphalan and prednisone versus melphalan, prednisone and thalidomide for elderly and/or transplant ineligible patients with multiple myeloma: a meta-analysis. Leukemia. 2011;25:689-696. 17. Palumbo A, Dimopoulos MA, Delforge M, et al. A phase III study to determine the efficacy and safety of lenalidomide in combination with melphalan and prednisone (MPR) in elderly patients with newly diagnosed multiple myeloma. Presented at the 51st American Society of Hematology Annual Meeting; New Orleans, LA; December 5-8, 2009. Abstract 613. http://ash.con fex.com/ash/2009/webprogram/Paper22787.html. Accessed June 28, 2011. 18. Harousseau JL, Avet-Loiseau H, Attal M, et al. Achievement of at least very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy: long-term analysis of the IFM 99-02 and 99-04 trials. J Clin Oncol. 2009;27:5720-5726.

19. van de Velde H, Liu X, Chen G, et al. Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica. 2007;92:1399-1406. 20. Martinez-Lopez J, Blade J, Mateos MV, et al. Longterm prognostic significance of response in multiple myeloma after stem cell transplantation. Blood. 2011 Apr 11. Epub ahead of print. 21. Sonneveld P, Schmidt-Wolf I, van der Holt B, et al. HOVON-65/GMMGHD4 randomized phase III trial comparing bortezomib, doxorubicin, dexamethasone (PAD) vs VAD followed by high-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients with newly diagnosed multiple myeloma (MM). Presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 47, 2010. Abstract 40. http://ash.confex.com/ash/2010/ webprogram/Paper29306.html. Accessed June 28, 2011. 22. Cavo M, Perrone G, Buttignol S, et al. Bortezomibthalidomide-dexamethasone compared with thalidomide-dexamethasone as induction and consolidation therapy before and after double autologous transplantation in newly diagnosed multiple myeloma: results from a randomized phase 3 study. Presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 4-7, 2010. Abstract 42. 23. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-686. 24. Kumar S, Flinn IW, Richardson PG, et al. Novel three- and four-drug combination regimens of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide, for previously untreated multiple myeloma: results from the multi-center, randomized, phase 2 EVOLUTION Study. Presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 4-7, 2010. Abstract 621. 25. Rohrbacher M, Hasford J. Epidemiology of chronic myeloid leukaemia (CML). Best Pract Res Clin Haematol. 2009;22:295-302. 26. Kantarjian H, O’Brien S, Cortes J, et al. Therapeutic advances in leukemia and myelodysplastic syndrome

over the past 40 years. Cancer. 2008;113(7 suppl):19331952. 27. Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med. 1999;131:207-219. 28. Kantarjian H, Smith TL, O’Brien S, et al. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-a. The Leukemia Service. Ann Intern Med. 1995;122:254-261. 29. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004. 30. Marin D, Milojkovic D, Olavarria E, et al. European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood. 2008;112:4437-4444. 31. Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417. 32. Deininger M, O’Brien SG, Guilhot F, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CMLCP) treated with imatinib. Presented at the 51st American Society of Hematology Annual Meeting; New Orleans, LA; December 5-8, 2009. Abstract 1126. 33. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251-2259. 34. Hughes TP, Hochhaus A, Saglio G, et al. ENESTnd update: continued superiority of nilotinib versus imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 4-7, 2010. Abstract 207. 35. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronicphase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-2270. 36. Shah N, Kantarjina H, Hochhaus A, et al. Dasatinib versus imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) in the

DASISION Trial: 18-month follow-up. Presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 4-7, 2010. Abstract 206. 37. Wu EQ, Johnson S, Beaulieu N, et al. Healthcare resource utilization and costs associated with non-adherence to imatinib treatment in chronic myeloid leukemia patients. Curr Med Res Opin. 2010;26:61-69. 38. National Comprehensive Cancer Network. NonHodgkin’s Lymphoma. V.2.2009. www.nccn.org. Accessed June 23, 2011. 39. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. 40. Portlock C, Vose JM, Cheson BD. T-cell lymphomas. www.lymphoma.org/atf/cf/%7B0363CDD6-51B5427B-BE48-E6AF871ACEC9%7D/T-CELL%20LYMPHOMAS.PDF. Accessed June 23, 2011. 41. PDQ (Physician Data Query) Modification of REAL Classification of Lymphoproliferative Diseases. National Cancer Institute of the National Institutes of Health. www.cancer.gov/cancertopics/pdq/treat ment/adult-nonhodgkins/healthprofessional/allpages#Section_31. Accessed June 28, 2011. 42. Coiffier B. Standard treatment of advanced-stage diffuse large B-cell lymphoma. Semin Hematol. 2006; 43:213-220. 43. Witzig TE. Current treatment approaches for mantle-cell lymphoma. J Clin Oncol. 2005;23:6409-6414. 44. Kutikova L, Bowman L, Chang S, et al. Medical costs associated with non-Hodgkin’s lymphoma in the United States during the first two years of treatment. Leuk Lymphoma. 2006;47:1535-1544. 45. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999; 17:1244. 46. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579-586. 47. Drugs@FDA.gov. Drug details. Rituximab. www. accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm ?fuseaction=Search.DrugDetails. Accessed June 28, 2011.

COMMENTARY

New End Points Create Novel Challenges for Health Plans in Oncology Drug Management By James T. Kenney Jr, RPh, MBA Mr Kenney is Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA

T

he management of complex oncology drugs in pharmacy and in medical benefits presents unique challenges for all parties who seek cost-effective, positive clinical outcomes for patients with cancer. New therapies are offering the exciting prospect of improved outcomes, prolonged life, and, in some cases, a cure for specific diseases. Targeted oncolytics and pharmacogenomics, which carry the promise of improved likelihood of successful treatment, have become welcome additions to the current standards of care. The concept of cancer as a chronic disease is becoming accepted in pharmacy oncology management. Targeted therapies are now standard treatments for multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and chronic myelogenous leukemia (CML). Recent trials in MM have used time

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to progression and progression-free survival as primary end points (as recommended by the International Myeloma Workshop Consensus Panel 1). The use of different end points in clinical trials for the same disease, however, has complicated the analysis and evaluation process for the pharmacy and therapeutics (P & T) committees of health plans in comparing competing therapies to select the most efficacious and cost-effective treatment options for their members. The ability to diagnose cancer earlier in the disease process and to begin life-saving treatments sooner place additional strain on pharmacy managers to maximize the value from all therapies in the treatment algorithm of a particular cancer type. The tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML by extending survival.

It is now possible to achieve longterm success with these agents if treatment is initiated early enough in the course of disease, and a positive early response can be a good predictor of long-term survival. As clinical studies are able to demonstrate clinically meaningful differentiations between first- and second-generation TKIs, health plans can consider promoting specific treatment pathways to maximize cost-savings and outcomes. NHL affects a diverse population of patients with various disease subtypes that require careful diagnosis to be matched with specific drug treatment protocols. The International Working Group has attempted to define appropriate clinical trial end points and response criteria to effectively differentiate treatments. This process is critical for managed care plans to manage specific therapies effectively

and control costs in the treatment of NHL and other cancer types. It is clear that in the near-term, overall survival will remain the gold standard for P & T committees in their assessment of drug efficacy. However, other end points will continue to be assessed as clinical trial results become available. The development of pharmaceuticals with biomarkers can increasingly give providers and health plans the confidence that patients will have a greater likelihood of response. This new trend also has the potential to decrease waste and the risk of untoward side effects in patients who are not good candidates for a particular treatment. As health plans progress in the management of oncology drugs, the ability to target patients, predict outcomes, and reduce costs will drive the most successful programs. ●

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Cancer Center Profile Porter Cancer Care Center... Continued from cover pain consults at Porter Adventist Hospital are not limited to oncology; the clinical pharmacists also help any hospital inpatient who suffers from acute and/or chronic pain. Located on the oncology floor, the program grew out of a need to focus on this aspect of cancer care. By having pharmacists involved in the management of pain, the program uses their specialized medication knowledge to optimize treatment. Members of the cancer care team have found that this service helps them with time management, allowing physicians and nurses to focus on other aspects of their patients’ care. How It Works “The physicians can write for a ‘pharmacist pain consult,’ and the clinical pharmacists provide pain management services. Under CDTM protocols, the physicians allow us to write orders for pain medications in addition to pain medication side-effect management, such as bowel regimens for treatment of opioid-induced constipation,” Mower tells The Oncology Pharmacist. “We meet with the patients to assess and evaluate their pain. We check to see where the pain is located, what type of pain it is, how the patients rate the pain, what makes it better, what makes it worse, and what have they tried in the past. We also discuss what the patients’ pain goals are and work on realistic goals together. We decide what medications might be best based on their history and comorbid conditions, and are able to write an order for the pain medications.” Follow-up is very important. Mower sees patients regularly to ensure their pain is controlled. “For example, in the

“We meet with the patients to assess and evaluate their pain. We check to see where the pain is located, what type of pain it is, how the patients rate the pain, what makes it better, what makes it worse, and what have they tried in the past.” —Robin Mower, PharmD

radiation oncology clinic, many patients visit every day and I can therefore meet with them every couple of days face-to-face; occasionally it might be a phone contact,” she illustrates. “The nurses play a crucial role in identifying patients that may need a pain consult by the pharmacist. We work closely together. If they feel like a patient isn’t getting his or her pain controlled, they will talk to the physicians and suggest they get a clinical pharmacist involved. I would say that we have a close working relationship with the physicians and that 99% of the time they take the recommendation and an order for a pain consult begins.” For pain management issues that are not amenable to treatment by medications alone, Porter Cancer Care Center has a palliative care team to which the pharmacists can refer a patient. This team comprises a medical director, an advanced practice nurse, a case manager, a social worker, and a chaplain, and it has access to anesthesiologists and psychiatrists.

PROSTATE CANCER

Novel Drugs in Prostate Cancer By Alice Goodman

ORLANDO—Interim results of a randomized, controlled, phase 3 trial showed that abiraterone acetate significantly prolonged overall survival (OS) in patients with metastatic castrationresistant prostate cancer (CRPC) who progressed after docetaxel-based chemotherapy. The survival benefit was consistent across all prespecified subgroups. Lead author Howard Scher, MD, Memorial Sloan-Kettering Cancer Center, New York, said abira terone is poised to become a new standard of care during his presentation at the 2011 Genitourinary Cancers Symposium. The study enrolled 1200 patients with metastatic CRPC who failed on

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pharmacy, with other pharmacists in the main hospital pharmacy performing order entry. “My office is on the oncology floor in the inpatient unit. For the outpatients, it is a short walk to the outpatient clinic and I can provide services there,” she explains. “Since my office is located on the inpatient nursing unit, it enhances the care patients receive in that I am readily available for questions by nurses or physicians. In addition, we have multidisciplinary rounds which help identify patients who may benefit from a pharmacist pain consult.”

docetaxel and ≤1 additional chemo therapy regimen. Patients were randomized to abiraterone and prednisone or prednisone and placebo. Groups were well balanced for demographic and disease characteristics. Patients on abiraterone achieved significantly superior median OS versus placebo (14.8 months vs 10.9 months; P <.001), representing a 35% reduction in the relative risk of mortality. Preplanned analyses found survival benefit consistent across all subgroups, regardless of prior chemotherapy lines, performance status, pain scores, and radiographic progression-free survival. The abiraterone group also had higher rates of total and confirmed responses

Patient-Focused Care Ten years ago, when Mower began at Porter Adventist Hospital, there were no pain management consults. Pain was treated by the physicians, along with all of the other aspects of cancer care. “When I came here, the nurses were asking, ‘I am giving quite a bit of hydromorphone to this patient, what can we do differently?’ or ‘This pain is not controlled well, what can we do?’” To Mower, the solution seemed clear: She should offer her services for pain consultations. With her residency in hematology/oncology and her focus on pain management during undergraduate study and doctoral training, Mower did just that. From there, the program grew, now encompassing not only oncology inpatients and outpatients but also inpatients from all units of the hospital. Mower trained the hospital’s other clinical pharmacists to provide the service as well, so all patients in need can have help with their pain. With this success, Mower has been able to focus all of her time on clinical

according to prostate-specific antigen (PSA) testing. Rates of overall and serious adverse events were similar between both groups and considered manageable. Oliver Sartor, MD, Tulane Uni versity School of Medicine, New

MDV3100 demonstrated durable antitumor activity, based on median times to PSA and radiographic progression. Orleans, Louisiana, moderated the prostate cancer session. “This is a game-changer. To me this will change practice,” he said. Positive 42-month data were also presented for MDV3100, a novel, triple-

Future Goals With all of their success, one goal still eludes the pharmacists offering pain management—reimbursement for their services. “Right now, our services are free,” Mower notes. Given the improved pain relief experienced by the patients and the cost-savings associated with such tailored drug therapy, she is working on it. “That is something I am looking into; I haven’t had success just yet.” She is exploring the possibility of setting up a true clinic similar to the hospital’s anticoagulation clinic, which might allow the pharmacists to bill for their services in pain management. The oncology pharmacists are rewarded in other ways. “The physicians seem satisfied with the service. They don’t have to worry about pain management so they can focus on something else. The patients seem satisfied because they have somebody focusing on the pain, which is one of the biggest complaints of oncology patients, and for that matter all patients. Knowing that I have personally helped relieve one of the most traumatic symptoms of a disease is reward in itself.” ●

acting, oral androgen-receptor antagonist for CRPC. In a phase 1/2 study, MDV3100 demonstrated durable antitumor activity, based on median times to PSA and radiographic progression. Celestia S. Higano, MD, and associates enrolled 140 men with progressive disease resistant to standard antiandrogen treatments. As of the meeting, 18 men remained on active treatment. Median time to PSA progression was 316 days in the postchemotherapy group and not yet reached in the chemotherapy-naïve cohort. Median time to radiographic progression was 392 days versus 175 days, respectively. Circulating tumor cell counts remained favorable for 91% of patients with favorable counts at baseline. MDV3100 is currently being studied in the randomized phase 3 AFFIRM and PREVAIL trials. Both trials are actively recruiting patients. ●

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Colorectal Cancer

A Wealth of Targets Identified in Colorectal Cancer By Caroline Helwick

SAN FRANCISCO—For patients with colorectal cancer (CRC), advances in molecular profiling have led to an explosion in novel agents specific for targets above and beyond the epidermal growth factor receptor (EGFR). Joseph Tabernero, MD, director of clinical research at Vall d’Hebron Institute of Oncology in Barcelona, Spain, previewed the future of treatment for CRC at the 2011 Gastrointestinal Cancers Symposium. “The good news is there are lots of new compounds. The challenge will be to profile patients accurately and to identify the gene signatures of those who will benefit from the individual drugs and combinations,” said Tabernero. EGFR Remains a Target Many patients with CRC are resistant to the currently approved EGFR inhibitors cetuximab and panitumumab. The KRAS gene has been identified as playing an important role, with constitutive mutations of KRAS serving as predictors of resistance to anti-EGFR monoclonal antibodies.

Novel Strategies

for Treating CRC • More efficient anti-EGFR monoclonal antibodies • Monoclonal antibodies directed to other members of the EGFR/HER family • Monoclonal antibodies directed to other receptors (c-MET, IGF-1R) • Inhibitors of downstream effectors (MAPK/ERK) • Rationally based combinations • Identification of populations likely to benefit from specific therapies

Researchers are examining the role of genetic mutations associated with other signal transducer proteins, including mutations in BRAF, NRAS, PIK3CA, AKT, PTEN, and TP53. Tabernero said any of these might prove to be a useful “on/off” biomarker for EGFR expression in metastatic CRC. “More effective monoclonal antibodies are coming,” Tabernero promised. Encouraging results have been observed with the investigational compounds GA201 and SYM004, including seemingly durable responses. “Objective response rates have been achieved in very refractory patients,” he noted. HER3 is a new target in CRC. It has been implicated as a potential mechanism of resistance to EGFR inhibitors. A handful of anti-HER3 compounds are in development, including the monoclonal antibody MEHD7945A (a dual antiEGFR and HER3 inhibitor), MM121, and U3-1287-AMG888. Other Targets Under Study Researchers are developing monoclonal antibodies specific for receptors other than EGFR. One target is insulin-like growth factor-1 receptor (IGF-1R) protein, which is expressed in 90% of colon cancers but not found at all in normal mucosa. Expression levels correspond with proliferation and tumor stage. Overexpression of IGF-1R, observed in ~50% of patients, is an independent prognostic factor for worse survival. Research into therapeutics for this novel target took a step back when a randomized phase 2 clinical trial of IMCA12, an investigative inhibitor of IGF1R, failed to improve outcomes in patients with CRC refractory to EGFR inhibitors. Ongoing studies are attempting to refine the gene signature and develop effective agents. Two possible new targets are the li -

gand of the c-MET receptor and hepatocyte growth factor (HGF) receptor. Both have been implicated in tumor invasiveness, metastasis, and proliferation; angiogenesis; and resistance to treatment. The HGF inhibitor rilotumumab (AMG102) showed promising efficacy in metastatic CRC when combined with panitumumab. Eric Van Cutsem, MD, University of Leuven, Belgium, presented data from an international, randomized, phase 1/2 trial involving 142 patients that compared panitumumab alone; rilotumumab plus panitumumab; and ganitumumab (AMG479), a novel IGF-IR inhibitor, plus panitumumab. Van Cutsem said the doublet of rilotumumab and panitumumab was promising, producing an overall response rate (ORR) of 31% compared with an ORR of 22% in the ganitumumab arm and 21% in the panitumumab monotherapy group. Median progression-free survival was 5.2 months with rilotumumab plus panitumumab, 5.3 months with the ganitumumab combination, and 3.7 months with panitumumab alone. Another avenue being pursued in volves the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and its receptors. TRAIL inhibits the growth of colon cancer cells, and TRAIL-R1 expression correlates with improved disease-free survival. Con atumumab (AMG655) is a monoclonal antibody that binds to TRAIL-R2 and has produced partial responses in early trials. It is also being studied in combination with standard chemotherapy regimens. Looking at Downstream Pathways Some researchers are looking into inhibiting critical downstream pathways, such as the mitogen-activated protein kinase (MAPK)/extracellular signal-reg-

ulated kinase (ERK) pathway. Protein kinases along this pathway regulate cell proliferation, differentiation, and survival and respond to external stimuli. Tabernero said investigators have identified at least 2 therapeutic targets in the MAPK/ERK pathway, namely RAF and MEK. Already more than a dozen inhibitors are in development. In 50% of patients with advanced disease, PIK3CA is dysregulated. PIK3CA activation triggers a signal transduction cascade that promotes cell growth and survival. Druggable targets in this pathway include PIK3CA, AKT, mTOR, TORC 1/2, and pS6K. Nearly 20 relevant compounds are being investigated, including some multikinase inhibitors. It is thought that many novel agents might be most effective when combined. Promising marriages are between 2 ERK pathway inhibitors (ie, a RAF inhibitor and a MEK inhibitor); 2 PIK3CA pathway inhibitors (ie, a dual PIK3CA inhibitor and a TORC 1/2 inhibitor); 1 ERK pathway inhibitor and 1 PI3K pathway inhibitor (ie, a MEK inhibitor with either an AKT, TORC 1/2, or PIK3CA inhibitor). Any of these agents could potentially be combined with a cytotoxic agent, as well. Despite an apparent plethora of opportunities for arresting proliferation of CRC cells, Tabernero cautioned that huge challenges lie ahead. The molecular profile of a specific cancer cell influences its behavior, and cancer cells operate under “plastic and evolutive phenomena” that extend to the gene level (expression, mutation, amplification/deletion, etc) and the proteomic level (activation, phosphorylation). “Cells change under the pressure of stress,” he said, noting that treatment induces stress. ●

PHARMACOECONOMICS

Novel Dosing of Rasburicase Reduces Cost of Prevention ORLANDO—Novel dosing regimens of rasburicase can prevent tumor lysis syndrome (TLS) at costs that are much lower than conventional dosing, according to studies presented at the 2010 American Society of Hematology Annual Meeting & Exposition. Rasburicase is a recombinant urate oxidase approved for the prevention of TLS, an oncologic emergency that produces metabolic disturbances and the potential for acute renal failure and death. Currently, rasburicase is US Food

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AugusT 2011 I VOL 4, NO 5

and Drug Administration (FDA)approved for prevention. In adults, the recommended dose is 0.2 mg/kg intravenous (IV) per day up to 5 days, which translates into more than $5100 for treatment of a 75-kg person. Low Dose versus Standard Dose Investigators from the Mayo Clinic in Rochester, Minnesota, evaluated the effectiveness of the 0.1-mg/kg dose as compared with the recommended dose in the prevention of TLS among 125

Table Cost of Single-Dose versus Weight-Based Rasburicase Cost per patient

Total cost (30 events)

Single 4.5-mg dose regimen

$1919

$53,549

5-day regimen

$31,988

$959,655

Dosing

Total savings

$906,106

Cost was calculated using August 2010 AmeriSourceBergen Bluebook Average Wholesale Price. One 1.5-mg vial of rasburicase costs $639.77. For a 75-kg patient dosed at 0.2 mg/kg, the cost would be approximately $6397 and $31,988 for a 1-dose and 5-day therapy, respectively.

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Pharmacoeconomics cancer patients receiving rasburicase on the first day of chemotherapy. The drug was dosed at either 0.1 mg/kg (low dose) or 0.2 mg/kg (standard dose), per clinician discretion, and was repeated as necessary. Additional doses were required in 14.6% of the low-dose patients and in 21.4% of the standarddose patients, which was not a significant difference. Although reduction in uric acid, the intended effect, was higher with the standard dose (97.1% vs 88.7%; P = .002), renal outcomes were similar, reported Alfonso Eirin, MD. “The low-dose patients received an average of 6 mg per dose versus 12 mg in the standard group. This represents a savings of $2601 per patient,” he said. Treatment of a 75-kg patient with the standard dose costs $6504, which is lowered to just $3252 using the lower dose. Only the standard-dose patients experienced renal insufficiency (7.4%). Rates of dialysis were numerically higher with the standard dose but not significantly different (18.6%) compared with 7.3% with the low dose (P = .07). Dialysis often was initiated for hyperkalemia and hyperphosphatemia. Only 12.5% of doses were started for elevations in serum creatinine. “Our results suggest that low-dose rasburicase may be as effective as 0.2 mg/kg. While high-dose rasburicase was more effective at reducing uric acid, it did not reduce the need for dialysis because dialysis was often precipitated for hyperkalemia and hyperphosphatemia, which rasburicase does not affect,” Eirin explained. “Despite bias, our results suggest low-dose rasburicase may be a viable alternative and the potential savings could be enormous.” Single-Dose Approach Effective and Less Expensive Since rasburicase came to market, various studies have examined single doses (3 mg and 6 mg) in the adult population, in an effort to find a dosing regimen that is as effective as the FDA-approved dose but less expensive. A single-center study evaluated a 4.5mg dose for its ability to lower uric acid levels versus the conventional weightbased approach and to determine its cost-effectiveness. The results were reported by Barbara Yim, PharmD, BCOP, of the John H. Stroger Jr. Hospital of Cook County, Chicago. “The cost of rasburicase is a problem for us. We found that using a single dose could save our hospital a lot of money,” Yim commented (Table). The retrospective study included 25 patients with hematologic malignancies receiving chemotherapy or planning to initiate chemotherapy within

www.TheOncologyPharmacist.com

24 hours of rasburicase administration. Patients at low risk for TLS were excluded. There were 30 hyperuricemic events, and 93% were successfully managed with the single dose of rasburicase. Responders were defined as patients achieving more than a 50% reduction in the uric acid level at 24 hours, 48 hours, or 96 hours. Three patients required a second dose to achieve response. ● —CH

What inspired you to enter the oncology field? As part of our reader polls, and in recognition of the important work you do, we’d like to invite you to share your inspiration for working in this field.

Please log on to www.TheOncologyPharmacist.com to share your story.

CEU’s for PHARMACISTS Y ONCOLOGY MEETING HARMACISTS A AV VAILABLE AIILABLE AT AT FOUR DA DAY M The The Greenspan Meeting XXIX XX IX

CHEMOTHERAPY FOUNDA FOUNDATION TION SYMPOSIUM ATION INNOV VATIVE T CANCER THERAPY FOR TOMORROW ® INNOVATIVE November No vember 8-12, 2011, New New York York City Tuesday ues sday y, November 8

ADV DV VANCES IN ONCOLOGY PEDIA ATRIC T Wednesday-Friday y-Friday y, November Novembe 9-11

INNOV VATIVE CANCER THERAPY FOR TOMORROW Practical Applications For The Medical Oncologist New Agents, Clinical Trials and Emerging Therapies Saturday y, November 12

NEW PERSPECTIVES IN ONCOLOGY PRACTICE Empowering the Clinical Care T Team eam Therapeutic Advances, Multidisciplinary Issues, Oncologic Emergencies, New T echnologies, Oral Medications, Technologies, Medication Cost Issues, Symptom Management, Medication Safety November 8-12 (inclusive) Tuesday or Saturday only

$150 $50

Complimentarry Breakffasts asts, Lunches, Dinners

Pharmacists will be eligible for CEU’s for the Tuesday-Friday sessions, November 8-11 plus additional contact hours for the Saturday session on November 12 provided by the New York State Council of Health-System Pharmacists (NYSCHP) an approved provider of continuing pharmaceutical education by the Accreditation Council for Pharmaceutical Education (ACPE). Total number of contact hours available to pharmacists will be 34.5. Cer tification of Attendance will be provided to all professionals.

Register on line at www.chemotherapyfoundationsymposium.org www.chemotherapyfoundationsymposium.org Contact: jaclyn.silverman@mssm.edu, (212) 866-2813

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Pharmacoeconomics

Upper GI Cancers: Are We Getting Value for the Money? By Caroline Helwick

CHICAGO—At the ASCO session “Moving the Bar in Upper GI Malignancies,” 2 speakers examined whether recent trials of targeted agents are clinically meaningful or just statistically positive, and whether value is being gained for the enormous amount of money being spent in treating noncolorectal gastrointestinal (GI) cancer. Eileen Mary O’Reilly, MD, of Memorial Sloan-Kettering Cancer Center, weighed in by examining the bottom line of the major trials. The only true “practice-changing” study, in her opinion, involved trastuz umab as treatment for gastric cancer. The rationale is strong, she noted, based on the discovery that human epidermal growth factor receptor (HER) 2 is overexpressed in many gastric tumors. In the phase 3 Trastuzumab for Gastric Cancer (ToGA) trial, trastuzumab added to capecitabine and cisplatin improved overall survival (OS) from 11.1 months to 13.8 months with chemotherapy alone, constituting a 26% reduction in death. The effect was robust in the subset who strongly overexpressed HER2. In contrast, in pancreatic cancer, the pivotal National Cancer Institute of Canada Clinical Trials Group PA.3 trial of erlotinib plus gemcitabine versus gemcitabine alone is “an example of a statistically significant phase 2 trial that has clinically limited therapeutic impact,” O’Reilly maintained. The median OS was improved by <1 month, as was progression-free survival (PFS); however, these small differences were statistically significant, and the US Food and Drug Administration approved erlotinib for pancreatic cancer based on these results. For pancreatic neuroendocrine tumors, “we don’t yet fully know” the true benefit of everolimus and sunitinib, which have led to improvements in outcomes and represent new options for a rare malignancy. Many questions remain, such as the best time to initiate therapy with these drugs and how to sequence and combine them with other treatments, O’Reilly said. “In the era of cost constraints, we must recognize that all these agents are palliative, all are expensive, and all have added toxicity,” she concluded. Future investigations must be based on strong biologic rationale, robust earlyphase results, and intelligent trial design, she added. Neal J. Meropol, MD, of Case Western Reserve University in Cleveland, who speaks often about the economics of cancer care, said he was

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Table 1 Value of Upper GI Cancer Treatments Cancer type, regimen

Clinical benefit

New drug

Annual cost of drug, $a

Value

Pancreatic Gemcitabine/erlotinib

Very low

Erlotinib

53,954

Very low

Liver cancer Single-agent sorafenib

Modest

Sorafenib

115,866

Low

Gastric Chemotherapy/trastuzumab

Modest

Trastuzumab

51,225 (excluding loading dose)

Modest

Biliary Gemcitabine/cisplatin

Modest

Cisplatin

364

Higher

Neuroendocrine tumor Single-agent sunitinib

Higher

Sunitinib

108,569

Higher

Neuroendocrine tumor Single-agent everolimus

Higher

Everolimus

201,516

Modest

a

Based on average wholesale price for oral drugs, average sale price for intravenous drugs. GI indicates gastrointestinal.

Table 2 Impact of Personalized Medicine on Pharma Clear advantages Longer treatment duration Potential new indications, new markets Competitive advantage with “personalized” approach Comarketing of diagnostic tests, necessary to define treatment population Clear disadvantages Reduced market size Uncertain consequences Development time of new therapeutic Success in bringing pipeline therapeutic to market Impact of higher-value therapeutic on pricing/willingness to pay Adapted from Peppercorn J, et al. Lancet Oncol. In press.

“providing perspective on how to interpret these claims.” His ranking of the clinical benefit of upper GI cancer treatment, largely based on the magnitude of the statistically significant differences in PFS and OS, compared with standard treatment was as follows: • Very low benefit: erlotinib in pancreatic cancer • Modest benefit: sorafenib in liver cancer, trastuzumab in gastric cancer, and gemcitabine/cisplatin in biliary cancer • Higher benefit: sunitinib in neuroendocrine tumor, everolimus in neuroendocrine tumor. Meropol then assessed the value of the new upper GI cancer regimens, demonstrating that clinical benefit is often not parallel with value (Table 1).

on breast cancer, is minimal. In metastatic breast cancer, trastuzumab prolonged median OS by nearly 5 months; in advanced gastric cancer, it added a median of 2.7 months. In patients with highly overexpressed HER2, however, the additional benefit exceeded 4 months, thus offering somewhat higher value in this subset, he acknowledged. The “lessons,” according to Meropol, are that diagnostics development must begin early and in concert with clinical development, that all cancers will be “rare” cancers once their molecular profile is understood, that “blockbuster drugs” will become dinosaurs (ie, no one drug will fit all), that the bar must be set high early in drug development, and that treatment based on site of origin will be replaced by treatment based on phenotype.

Lessons Learned from Trastuzumab Meropol said the “trastuzumab story” is informative regarding the future of oncology clinical trials and oncology care. He reminded the audience that although trastuzumab has become an important treatment in gastric cancer, its effect, compared with the drug’s impact

Ever-Greater Targeting Will Be the Norm Smaller patient populations will eventually become defined for essentially all tumor types, necessitating ever more targeted treatments as the norm. The effect of this on drug development and cost control remains unclear (Table 2).

“Will this prolong drug development time and reduce the chances of bringing drugs to market? Will the higher value of the targeted approach bring even higher prices to make up for smaller markets? The answers to these questions are unknown,” he said. Where We Need to Go Meropol offered some concrete suggestions for “where we need to go” in the future treatment of cancer. His suggestions included the following: • Reduce overutilization: eliminate nonbeneficial interventions • Raise the bar for drug approval • Link payment to value via costsharing • Authorize the Centers for Medicare & Medicaid Services to negotiate price • Reduce incentives for development of marginal advances • Improve the evidence base with comparative effectiveness research. Value-based insurance design may be a viable strategy for achieving some of these goals and is gaining traction, he noted. “Not all effective treatments have equivalent value. Cost-sharing can be used to discourage low-value treatment and encourage high-value treatment, in contrast with current plans that base coverage on cost,” he said. “There would be the potential for different coverage based on the disease and stage.” “The low-hanging fruit is cost-sharing that is not based on the cost of the intervention but its value,” he maintained. Finally, he emphasized that in the allocation of finite resources “the goal is to move from implicit decisions about allocation to explicit and transparent ones,” adding that politics will impact this process. ●

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Breast Cancer Differences and Similarities Among Ixabepilone... Continued from cover limits their clinical efficacy and application. Ixabepilone is the first of a new class of cytotoxic agents: the epothilones. This relatively newly approved agent may still be unfamiliar to many oncology nurses; they may equate ixabepilone to taxanes because both are microtubule-stabilizing agents. Ixabepilone, however, is highly active in several tumor types and is less susceptible to many of the cellular resistance mechanisms that affect the use of taxanes.3 In preclinical models of taxane-resistant cancer, for example, ixabepilone has higher anticancer activity than the taxanes in cell lines that overexpress drug efflux pump proteins, presumably because ixabepilone is less susceptible than taxanes to binding and removal from the cell by this mechanism.4 In addition, although taxanes and ixabepilone both bind to β-tubulin to mediate their cytotoxic activity, ixabepilone maintains efficacy in cancer cells that have high levels of class III β-tubulin, a form of β-tubulin to which taxanes cannot bind effectively.4 This preclinical efficacy has translated into clinical benefit for patients with taxane-pretreated breast cancer, as this article will discuss.5-7 Currently, ixabepilone is indicated for use in combination

Ixabepilone is highly active in several tumor types and is less susceptible to many of the cellular resistance mechanisms that affect the use of taxanes. —Teresa Davis, RN, OCN

with capecitabine in patients with metastatic or locally advanced breast cancer after failure of an anthracycline and a taxane (or following taxane failure when further anthracycline therapy is contraindicated).5 Ixabepilone also is indicated as monotherapy in metastatic or locally advanced breast cancer after failure of an anthracycline, a taxane, and capecitabine.5 Although ixabepilone is similar to the taxanes in many ways, oncology nurses should be aware of important differences in their clinical response and tolerability profiles (Table 1). Clinical Efficacy Taxanes are one of the many approved therapies for metastatic breast cancer,

Table 1 Comparison of Ixabepilone with Paclitaxel and Docetaxel Paclitaxel Class Taxane Mechanism of action Microtubule stabilizer Most common severe adverse effects Nonhematologica Myalgia/arthralgia, peripheral neuropathy, alopecia

Hematologicd

Contraindications

either alone or in combination with anthracyclines or other agents, such as capecitabine and gemcitabine. Taxanes are of particular value when patients have already been treated with anthracyclines.2 Regimens combining taxanes with anthracyclines or other agents such as capecitabine and gemcitabine produce response rates of about 40% to 60%, median progression-free survival (PFS) of 6 to 9 months, and median overall survival of 15 to 22 months.11-14 To explore the clinical benefits of ixabepilone, 2 clinical trials involving nearly 2000 patients combined assessed the efficacy of ixabepilone plus capecitabine in patients with locally advanced or metastatic breast cancer who had been pretreated with an

anthracycline and a taxane.6,7 In the first trial, all patients met strict resistance criteria for taxanes and anthracyclines.6 In the subsequent confirmatory trial, all patients had been pretreated with a taxane and an anthracycline, but only about half met the strict definition of resistance used in the original trial.7 In both trials, patients received 21-day cycles of either intravenous ixabepilone 40 mg/m2 on day 1 plus oral capecitabine 2000 mg/m2/day on days 1 through 14, or oral capecitabine 2500 mg/m2/day alone on days 1 through 14. The combination of ixabepilone plus capecitabine showed superior efficacy on a range of outcome measures. In the original and confirmatory trials, respectively, the median PFS was 5.3 months and 6.2 months with ixabepilone plus capecitabine, respectively, approximately 1.5 months longer than with capecitabine alone. In addition, response rates associated with ixabepilone plus capecitabine were approximately 40%, more than 1.5-fold greater than with capecitabine alone.6,7 Direct comparisons of ixabepilone with taxane therapy currently are under way in multiple stages of breast cancer, mostly in sequence or combination with a variety of other agents (Table 2, page 28). Interim data from a 3-arm phase 2

nab-paclitaxel Taxane Microtubule stabilizer

Docetaxel Taxane Microtubule stabilizer

Ixabepilone Epothilone Microtubule stabilizer

Peripheral neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia

Fatigue/asthenia, myalgia/arthralgia, stomatitis/mucositis, peripheral neuropathy, cutaneous reactions, diarrhea, alopecia, fluid retentionb

Peripheral neuropathy, fatigue/asthenia, myalgia/arthralgia, stomatitis/mucositis, hand-foot syndrome,c diarrheac

Neutropenia

Neutropenia

Neutropenia, leukopenia, febrile neutropeniab

Neutropenia, leukopenia

Neutrophils <1500/mm3; previous hypersensitivity reaction to paclitaxel or Cremophor EL

Neutrophils <1500/mm3

Hepatic impairment,e neutrophils <1500/mm3; previous severe hypersensitivity reaction to docetaxel or polysorbate 80

Moderate/severe hepatic impairment,f neutrophils <1500/mm3, platelets <100,000/mm3; previous severe hypersensitivity reaction to Cremophor EL

a Grade 3/4 severity and affecting ≥5% of patients, with the exception of alopecia, which was not graded for severity. Alopecia is included because of its significance for patients and high incidence (≥75% of patients). Listed in order of incidence. b

Dose-dependent. Incidence ≥5% with docetaxel 100 mg/m2, but less common with 60 mg/m2.

c

Ixabepilone in combination with capecitabine.

d

Severe (grade 3/4) in ≥40% of patients.

e

Not defined as a contraindication, but labeling carries a boxed warning that docetaxel should generally not be given to patients with bilirubin levels above the ULN, or to patients with AST and/or ALT >1.5 x ULN concomitant with ALP >2.5 x ULN. f

The use of ixabepilone in combination with capecitabine is contraindicated in patients with AST or ALT levels >2.5 x ULN or bilirubin levels above the ULN.

ALP indicates alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; nab, nanoparticle albumin-bound; ULN, upper limit of normal. Sources: References 5, 8-10.

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BUILDING

pillars of knowledge IN SUPPORTIVE CARE

BONE HEALTH

LOG ON TODAY TO PARTICIPATE

www.coexm.com/ace05 Release Date: June 24, 2011 Expiration Date: June 23, 2012

TARGET AUDIENCE The educational series is intended for nurses, pharmacists and others with clinical, research, and management interests in the treatment of bone health in cancer

EDUCATIONAL OBJECTIVES On completion of this activity, participants should be able to: • Describe the potentially serious consequences of skeletal-related events (SREs) associated with cancer and cancer-related treatments • Review recent advances in the management of bone health in cancer patients, with emphasis on treatment with the bisphosphonates and denosumab • Examine approaches for improving bone health and outcomes for patients with skeletal complications, based on key clinical evidence and practice guidelines

ACCREDITATION STATEMENTS Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This knowledge-based activity has been assigned ACPE # 0245-0000-11015-H01-P and will award 1.0 contact hour (0.10 CEUs) of continuing pharmacy education credit. CEC complies with the Criteria for Quality for continuing education programming.

FACULTY Regina Cunningham, PhD, RN, AOCN Senior Director, Oncology The Tisch Cancer Institute Mount Sinai Medical Center New York, NY

R. Donald Harvey, PharmD, BCPS, BCOP, FCCP Assistant Professor, Hematology/ Medical Oncology Director, Phase I Unit Winship Cancer Institute Emory University School of Medicine Atlanta, GA

For further information and to participate, please go to: www.coexm.com/ace05

NURSING Creative Educational Concepts, Inc. (CEC) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. CEC provides this activity for 1.0 contact hour. Learners are advised that accredited status does not imply endorsement by the provider or ANCC of any commercial products displayed in conjunction with an activity. Your statement of credit will be issued immediately upon successful completion of the posttest and evaluation form.

This activity is supported by an educational grant from Amgen Inc.


TOP_August 2011_FINAL_TOP 8/18/11 3:58 PM Page 28

Breast Cancer trial comparing ixabepilone (Arm A: 16 mg/m2 weekly; Arm B: 40 mg/m2 every 3 weeks) with paclitaxel (Arm C: 90 mg/m2 weekly), each in combination with the antiangiogenic agent bevacizumab (10 mg/kg every 2 weeks in Arms A and C; 15 mg/kg every 3 weeks in Arm B), reveal equivalent response rates and 24-week PFS for all 3 arms, suggesting that ixabepilone produced results that were comparable with weekly paclitaxel in this setting.15 Tolerability Overall, ixabepilone and the taxanes exhibit fairly similar tolerability profiles, because both ixabepilone and the taxanes operate by inhibiting the function of microtubules within cancer cells. However, because ixabepilone is chemically unrelated to taxanes and interacts with microtubules in a different manner, it does have a distinct adverse event profile. In patients with advanced breast cancer, these adverse events are generally predictable and manageable with supportive care, dose reductions, and treatment delays. Nonhematologic adverse events. Whether used alone or with capecitabine, one of the most common adverse effects with ixabepilone is sensory chemotherapy-induced peripheral neuropathy (CIPN). CIPN affects approximately 60% of patients treated with ixabepilone and is severe (grade 3/4) in about 15% to 25% of pa tients.6,16,17 CIPN is also a common adverse effect with taxanes, with reported incidence of severe CIPN more variable and highly dependent on the cumulative and per-cycle dose.18 Incidence rates range from 2% to 32% with conventional paclitaxel to 4% to 11% with nab-paclitaxel to 0% to 17% with docetaxel. For ixabepilone-induced CIPN, even grade 3/4 events are responsive to dose reduction or delays,6,17,18 and guidelines for managing dose reduction based on the severity of symptoms have been established (Table 3). Notably, in the original ixabepilone trial, patients with grade 1 neuropathy were able to receive the same amount of therapy as the general population.6 Also in this trial, the onset of grade 3/4 neuropathy occurred after a median of 4 cycles.6 These events are reversible in most patients after discontinuation of ixabepilone, with a median time to resolution to baseline or grade 1 of 5 to 6 weeks,6,16,17 which is more rapid than that reported with conventional taxanes.19 Ixabepilone should be used with caution in patients with diabetes mellitus or preexisting moderate-to-severe neuropathy, both of whom may be at increased risk for CIPN.5,17,19 There are no proven agents or interventions that prevent or eliminate CIPN more effectively than early

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Table 2 Clinical Trials Comparing Ixabepilone with Taxanes in Breast Cancer Clinical trial identifier Phase Patients Study design NCT00490646 2 Locally advanced and/or metastatic • Ixabepilone 40 mg/m² vs docetaxel 100 mg/m² (day 1 every 21 days) • Each with trastuzumab 2 mg/kg (loading dose, 4 mg/kg; day 1 every 21 days) NCT00789581

3

Triple-negative, early stage

• Ixabepilone 40 mg/m² (day 1 every 21 days) vs paclitaxel 80 mg/m² (weekly) • Each following cyclophosphamide 600 mg/m² and doxorubicin 60 mg/m² (day 1 every 21 days)

NCT00630032a

3

• Ixabepilone vs docetaxel • Following combination chemotherapy (tamoxifen, aromatase inhibition, anthracyclines)

NCT00785291a

3

Locally recurrent stage IIIB or IV

• Ixabepilone vs nab-paclitaxel vs paclitaxel (days 1, 8, and 15 every 28 days) • Each with bevacizumab (days 1 and 15 every 28 days)

a

Dosing and/or schedule not provided.

detection by routine clinical assessment of neurologic function. The National Comprehensive Cancer Network (NCCN) Task Force for Management of Neuropathy in Cancer strongly recommends that patients be questioned directly regarding common signs and symptoms of neuropathy, because patients may tend to bucket neuropathic symptoms together with other forms of cancer pain when selfreporting. Patients also should be given neurologic assessments before initial treatment, to establish a baseline, and periodically thereafter. For a more extensive review of commonly used grading scales, critical questions to ask patients, and functional assessments, please refer to the recently published NCCN Task Force report.19 Several of the main themes of supportive care in patients receiving ixabepilone therapy have parallels in the taxane drug class, and experience with taxanes will be useful in managing ixabepilone-treated patients. In addition to neuropathy, both taxanes and ixabepilone are associated with a predictable assortment of other nonhematologic adverse events, such as fatigue/ asthenia, myalgia/arthralgia, stomatitis/mucositis, nausea and vomiting, and diarrhea.8-10 Although not mandatory, a 20% reduction in the dose of ixabepilone is an option for mitigating transient grade 3 fatigue.5 Patients with symptoms of fatigue may benefit from reducing activity levels overall, planning activities around times when energy levels tend to be highest, and structured routines; nurses should be prepared to provide guidance in these areas. Nurses also should consider addressing underlying contributors to fatigue, such as inadequate nutrition or

Table 3 Dose-Adjustment Guidelines for Ixabepilone in Chemotherapy-Induced Peripheral Neuropathy Grade

Dosage adjustment

Grade 2 (moderate) lasting ≥7 days

Decrease by 20%

Grade 3 (severe) lasting <7 days

Decrease by 20%

Grade 3 (severe) lasting ≥7 days

Discontinue treatment

Grade 4 or disabling

Discontinue treatment

Source: Reference 5.

nighttime sleep, anemia, or stress, should symptoms occur.20 Alopecia occurs as well, but is notably more common with taxanes than with ixabepilone, affecting 75% to 90% of patients treated with taxanes8-10 compared with 48% of patients treated with ixabepilone monotherapy and 31% of patients treated with ixabepilone plus capecitabine.5 Although the risk is lower, nurses should prepare their patients for the possible onset of alopecia during ixabepilone therapy and discuss potential coping mechanisms when relevant. As a general rule, the dose of ixabepilone should be reduced by 20% for persistent grade 3 nonhematologic reactions, including transient fatigue if necessary, and treatment should be stopped for grade 4 reactions (refer to prescribing information). Resumption of treatment may be considered if toxicities resolve or improve to grade 1 (mild). Hematologic adverse events. At least 90% of patients treated with ixabepilone alone or in combination with capecitabine will experience some hematologic toxicity.6,16 As with the taxanes, myelosuppression is the most common dose-limiting toxicity with ixabepilone. Common toxicities in this category include anemia and thrombocytopenia (mild to moderate in most

cases), severe (grade 3/4) neutropenia (affecting approximately 50% to 70% of patients), and severe leukopenia (affecting approximately 50% to 60% of patients). Despite the high incidence of neutropenia, the incidence of ixabepilone-related serious febrile neutropenia is low, approximately 3% to 5%.6,16 Moderate or transient hematologic toxicity and febrile neutropenia generally can be managed by reducing the ixabepilone dose by 20%. In addition, although not required, hematopoietic growth factor support (ie, colony-stimulating factors) may be provided. Patients should not begin a new treatment cycle with ixabepilone until neutrophil counts are ≥1500 cells/mm3. To help ensure that neutropenia is managed promptly, patients treated with ixabepilone should receive complete blood counts before treatment begins to establish a baseline, and periodically thereafter. Patients should be counseled in the areas of hygiene, protecting themselves from infections, and recognizing early signs of an infection. Hepatic impairment. The risk of toxicity and neutropenia-related death associated with the ixabepilone plus capecitabine combination regimen is increased in patients with significant baseline hepatic impairment.6 Thus,

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

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

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Breast Cancer this regimen is contraindicated in patients with preexisting moderate and severe hepatic impairment; specifically, those with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels that exceed 2.5 x the upper limit of normal (ULN), or those with bilirubin levels that exceed ULN. Ixabepilone monotherapy can be used cautiously, at a lower dose, in patients with mild-to-moderate baseline hepatic impairment. If a patient’s AST and ALT levels do not exceed 2.5 x ULN and bilirubin does not exceed ULN, she may receive the full dose of ixabepilone monotherapy, 40 mg/m2. As long as a patient’s AST and ALT levels do not exceed 10 x ULN and if bilirubin levels do not exceed 1.5 x ULN, she may receive ixabepilone at 32 mg/m2, or she should receive between 20 mg/m2 and 30 mg/m2 if her bilirubin levels exceed 1.5 times ULN but do not exceed 3 x ULN (refer to the prescribing information for details).5

Most patients receiving ixabepilone, however, need only receive prophylactic H1/H2 antagonists to prevent hypersensitivity reactions.

Hypersensitivity reactions. There is a risk of hypersensitivity reactions to the solvents used in ixabepilone preparations and in the conventional formulations of the taxanes. Standard paclitaxel (containing Cremophor EL) and docetaxel (containing polysorbate 80) may cause severe hypersensitivity in 2% to 4% of patients, necessitating a recommendation for standard premedication with corticosteroids and H1/H2 antagonists (nab-paclitaxel is solvent-free and does not need premedication).8-10 The incidence of severe hypersensitivity reactions (including anaphylaxis) is lower with ixabepilone, which contains

13 Comorbid Conditions Decrease Survival, Increase Mortality in Elderly Breast Cancer Patients By Dawn Lagrosa

F

or breast cancer patients aged 66 years and older, nurses should consider comorbidities when discussing prognosis, according to an analysis of Surveillance, Epidemiology and End Results–Medicare data. In a US population of 64,034 patients diagnosed with breast cancer at a median age of 75 years, Patnaik and colleagues identified 13 comorbid conditions associated with decreased overall survival and increased all-cause mortality (Table). Among the study population, 58% had none of the selected comorbidities, 28.0% had 1 comorbidity, 8.8% had 2 comorbidities, and 4.9%

had ≥3 of the conditions. Kaplan-Meier survival curves showed that comorbidities are associated with survival, meaning that for a patient with comorbid conditions diagnosed at an early stage, that patient had similar or worse survival than a patient with no comorbid conditions diagnosed at a later stage. The investigators concluded that their findings suggest that “careful attention to the effective management of comorbid conditions, as well as to the management of a patient’s cancer, may result in longer overall survival for older breast cancer patients.” ●

Table

Comorbid Conditions Associated with Decreased Survival Hazard ratio Comorbid condition Patients, % (95% confidence interval) Previous cancer 1.27 (1.23-1.30) 16.3 1.41 (1.36-1.45) Diabetes 13.0 Chronic obstructive 8.8 1.52 (1.47-1.58) pulmonary disease Congestive heart failure 6.7 1.70 (1.64-1.76) Stroke 4.3 1.35 (1.28-1.42) Liver disease 0.3 2.32 (1.97-2.73) Myocardial infarction 1.7 1.11 (1.03-1.19) Peripheral vascular disease 2.6 1.36 (1.28-1.44) Dementia 1.4 1.96 (1.82-2.10) Paralysis 0.6 1.23 (1.09-1.38) Chronic renal failure 0.9 2.20 (2.02-2.41) Stomach ulcer 1.1 1.12 (1.02-1.23) Rheumatoid arthritis 2.0 1.27 (1.18-1.37) Source: Patnaik JL, Byers T, DiGuiseppi G, et al. The influence of comorbidities on overall survival among older women diagnosed with breast cancer. J Natl Cancer Inst. 2011;103:1101-1111.

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AugusT 2011 I VOL 4, NO 5

Cremophor EL but less than standard paclitaxel—about 1%. H1/H2 antagonist premedication is required (eg, oral diphenhydramine 50 mg and oral ranitidine 150 mg to 300 mg, or equivalent). Unlike taxanes, however, corticosteroid premedication is required only in cases of a history of hypersensitivity to ixabepilone.5 As with taxanes, if a severe hypersensitivity reaction occurs, ixabepilone must be stopped immediately and aggressive supportive care started. Patients should not receive ixabepilone if any previous reaction to a Cremophor EL–containing agent was severe. Because of the risk of hypersensitivity to ixabepilone, patients should be monitored for signs of hypersensitivity, such as hives, itching (pruritus), rash, flushing, swelling, or difficulty breathing or swallowing, either during or shortly after treatment. Conclusions Like the taxanes, ixabepilone kills tumor cells by inhibiting the function of microtubules. It is associated, therefore, with a similar spectrum of adverse events. Ixabepilone is chemically unrelated to the taxanes, however, which yields clinical benefit in patients whose disease has progressed after taxanes fail, as well as unique features of its adverse event profile. CIPN associated with ixabepilone is more likely to be reversible, generally resolving to grade 1 or baseline in a median time of 5 to 6 weeks. Like the taxanes (with the exception of nab-paclitaxel), ixabepilone is given intravenously and carries the risk of hypersensitivity reactions to its polyethoxylated diluent. Most patients receiving ixabepilone, however, need only receive prophylactic H1/H2 antagonists to prevent hypersensitivity reactions, and corticosteroid premedication is needed only in patients with a history of hypersensitivity reactions to ixabepilone. As yet, no randomized comparative data are available from head-to-head trials comparing ixabepilone and the taxanes in breast cancer patients, but several trials are ongoing. In addition, several other trials are evaluating ixabepilone, either as a single agent or as part of sequential or combination therapy, in earlier lines of breast cancer therapy. As the patients in these trials are less heavily pretreated than the patients in the registrational trials, it is expected that ixabepilone may show promising results.

Acknowledgment The author takes full responsibility for the content of this publication and confirms that it reflects her viewpoint and medical expertise. She also wishes to acknowledge StemScientific, funded by Bristol-Myers Squibb, for providing writing and editing support. Neither Bristol-Myers Squibb nor StemScientific influenced the content of the manuscript, nor did the author receive financial compensation for authoring the manuscript. ● References 1. O’Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. Oncologist. 2005; 10(suppl 3):20-29. 2. O’Shaughnessy J, Twelves C, Aapro M. Treatment for anthracycline-pretreated metastatic breast cancer. Oncologist. 2002;7(suppl 6):4-12. 3. Lee FY, Borzilleri R, Fairchild CR, et al. Preclinical discovery of ixabepilone, a highly active antineoplastic agent. Cancer Chemother Pharmacol. 2008;63:157-166. 4. Lee FY, Smykla R, Johnston K, et al. Preclinical efficacy spectrum and pharmacokinetics of ixabepilone. Cancer Chemother Pharmacol. 2009;63:201-212. 5. Ixempra kit (ixabepilone) for injection [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2010. 6. Thomas ES, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007;25:5210-5217. 7. Hortobagyi G, Perez E, Vrdoljak E, et al. Analysis of overall survival among patients with metastatic breast cancer receiving either ixabepilone plus capecitabine or capecitabine alone and a review of results from two randomized phase III trials. Presented at: American Society of Clinical Oncology Breast Cancer Symposium. September 5-7, 2008; Washington, DC:Abstract 186. 8. Abraxane for injectable suspension (paclitaxel protein-bound particles for injectable suspension) [package insert]. Bridgewater, NJ: Abraxis BioScience; 2010. 9. Taxol (paclitaxel) injection [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2011. 10. Taxotere (docetaxel) injection [package insert]. Bridgewater, NJ: sanofi; 2010. 11. Piccart-Gebhart MJ, Burzykowski T, Buyse M, et al. Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer. J Clin Oncol. 2008;26:1980-1986. 12. Nabholtz JM, Falkson C, Campos D, et al; for the TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003;21:968-975. 13. O’Shaughnessy J, Miles D, Vukelja S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002;20:2812-2823. 14. Albain KS, Nag SM, Calderillo-Ruiz G, et al. Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008; 26:3950-3957. 15. Rugo HS, Campone M, Amadori D, et al. Randomized phase II study of weekly versus every-3week ixabepilone plus bevacizumab (ixa/bev) versus paclitaxel plus bev (pac/bev) as first-line therapy for metastatic breast cancer (MBC). J Clin Oncol. 2009;27(15S):Abstract 1029. 16. Perez EA, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007;25:3407-3414. 17. Perez EA, Pivot X, Vrdoljak E, et al. A prospective characterization of the resolution of ixabepilone induced peripheral neuropathy: data from a large registrational program in patients with metastatic breast cancer. Cancer Res. 2009;69(suppl):Abstract 6140. 18. Swain SM, Arezzo JC. Neuropathy associated with microtubule inhibitors: diagnosis, incidence, and management. Clin Adv Hematol Oncol. 2008;6:455-467. 19. Stubblefield MD, Burstein HJ, Burton A, et al. NCCN Task Force Report: management of neuropathy in cancer. J Natl Compr Canc Netw. 2009;7(suppl 5): S1-S28. 20. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue. V.1.2011. www.nccn.org/professionals/physician_gls/ pdf/fatigue.pdf. Accessed June 20, 2011.

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The Whole Patient

Tamoxifen Associated with Increased Risk of Type 2 Diabetes By Alice Goodman

SAN DIEGO—Current or recent tamoxifen therapy was associated with an increased risk of developing type 2 diabetes in women older than 65 years who survived invasive breast cancer. No association was found between aromatase inhibitors (AIs) and development of type 2 diabetes, but the numbers of women on AIs was small. These findings of a population-based, case-control study in Toronto, Ontario, Canada, were presented at the 71st Scientific Sessions of the American Diabetes Association. “To our knowledge, this is the first study to examine the association between tamoxifen and risk of type 2 diabetes. We found a modest odds ratio for the association, and this suggests that tamoxifen may exacerbate an underlying risk of diabetes in susceptible women. Further studies are needed to explore this association,” said Lorraine L. Lipscombe, MD, Women’s College Research Institute, University of Toronto, Canada.

“We found a modest odds ratio for the association, and this suggests that tamoxifen may exacerbate an underlying risk of diabetes in susceptible women.” —Lorraine L. Lipscombe, MD

Lipscombe explained that type 2 diabetes is increased in women with breast cancer and it portends a worse prognosis. “The reverse also may be true; that is, that breast cancer patients may be at increased risk of diabetes,” she noted. “For some time, the association between estrogen and diabetes has been known. Tamoxifen is an estrogen receptor antagonist, and case reports suggest an increased risk of factors associated with diabetes in patients on tamoxifen, such as hypertriglyceridemia, steatohepatitis, and visceral fat.” The study was based on a cohort of

14,360 women with invasive breast cancer diagnosed between 1996 and 2008 identified in the large Ontario Cancer Registry and physicians’ claims and hospital abstracts. Exclusions were metastasis, known diabetes, previous cancer, surgery, and expected survival of less than 1 year. In total, 1445 cases of incident diabetes diagnosed during that period were matched with up to 5 controls, who did not have diabetes, for age and date of breast cancer diagnosis (n = 7220). Of the cases of type 2 diabetes identified, 531 (37%) were prescribed tamox-

ifen, and 127 (9%) were prescribed an AI. Tamoxifen use was defined as filling at least 2 prescriptions. Cases and controls were stratified according to current/recent (within 6 months) tamoxifen users and previous users (stopped 6 months ago or more). Current/recent tamoxifen use was associated with a significant increase in risk of type 2 diabetes (adjusted odds ratio, 1.24 [95% confidence interval, 1.08-1.41]; P = .0027). The risk began to increase at years 2 and 3 of tamoxifen use. Previous tamoxifen use and AI use were not associated with an increased risk of diabetes. Lipscombe cited several limitations of the study, including incomplete cancer data, and no data on risk factors such as body mass index, metabolic factors, family history, or ethnicity. “We cannot exclude bias from this observational study, but this is the first report of this association and it is hypothesis-generating,” she told listeners. ●

Prandial Insulin May Be Associated with Cancer Risk SAN DIEGO—Use of prandial insulin (ie, insulin given at mealtimes) appears to be linked to cancer risk, according to a substudy of the large randomized Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial presented at the 71st Scientific Sessions of the American Diabetes Association. Other factors associated with development of cancer in this substudy included increasing body mass index (BMI), older age, and smoking. “Insulin exposure has been proposed as a possible risk factor for the increased risk of cancer in patients with type 2 diabetes. Although we found no association with insulin, basal insulin, or insulin glargine, there was an association with use of prandial insulin. This is hypothesis-generating and needs to be studied further,” stated presenting author Marwan Hamaty, MD, an endocrinologist at the Cleveland Clinic in Ohio. ACCORD was a large randomized, double 2 × 2 factorial designed trial of 10,251 patients with type 2 diabetes. All patients were randomized to receive either intensive or standard glycemic therapy. Those with moderate levels of dyslipidemia (n = 5518) were further randomized to either intensive or standard lipid-lowering therapy. The re maining 4733 patients were randomized

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AugusT 2011 I VOL 4, NO 5

to achieve intensive or standard blood pressure targets. The substudy presented focused on the glycemia therapy arm; 5076 patients were randomized to intensive glycemia control and 5070 to standard glycemia control. Among these patients, there were 304 cancer events: hospitalization for cancer but no deaths in 101 patients and cancer-related deaths in 203. The incidence of cancer was not affected by gender, but as would be expected, was higher in cigarette and tobacco smokers and lower in never-smokers. Also, cancer incidence was higher in patients older than 70 years, and in patients with increased BMI. No association was found between alcohol use and insulin use at baseline. Increasing hemoglobin A1c was associated with risk of cancer. “For every 1% increase in A1c, cancer risk increased by 30%, even after adjustment for the glycemia intervention,” Hamaty told listeners. After adjusting for a number of covariates (baseline age, sex, BMI, insulin use, tobacco use, alcohol use, history of cardiovascular events, assignment to glycemia treatment group, intensive versus standard blood pressure, and lipid lowering), a significant

©iStockphoto.com/Villiers

association was found between prandial insulin and cancer risk, with a hazard ratio (HR) of 2.30 (95% confidence interval [CI], 1.08-4.90; P = .03). This association remained significant even after correction for basal insulin exposure (HR, 2.41 [95% CI, 1.05-5.49]; P = .03). The study had several limitations,

Hamaty noted. It was a post-hoc analysis, not a prespecified one, and there were a relatively small number of cancer-related events. Also, the use of concomitant medications was not accounted for and might have influenced results. Nevertheless, these findings suggest that further study is needed, he said. ● —AG

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Koeller’s Corner Shooting from the Hip

Specialization in Oncology From the Beginning

I

would like to welcome everyone to the inaugural edition of “Koeller’s Corner.” The intent is for this to be a regular column for The Oncology Pharmacist. For this introductory edition, I would like to introduce myself to the readers and describe the intent of my column as we move forward. First, my name is Jim Koeller, and I am currently a full professor at the University of Texas at Austin College of Pharmacy and an adjoint professor of medicine and oncology at the University of Texas Health Science Center in San Antonio. Some have affectionately referred to me as one of the old-timers in oncology pharmacy. And my 32-year career as an oncology pharmacy specialist has been an interesting journey so far. I hope to share some of that perspective, reflection, commentary, and, hopefully, thought-provoking discussion with you. I may not always have the answers, but for those who know me, I always have something to say. I can tell you that I am not exactly sure what direction this column will take. I have not been given any marching orders or guidelines as to what to say or how to say it, so we will have to see where this goes.… I do read the Hematology/Oncology Pharmacy Association (HOPA) listserv religiously, and some topics will come from those discussions; other topics will just be things I think we need to talk about. Our Past Much of what exists today in oncology training, continuing education, and licensure have their roots from those early days when others like me were looking to create a forum for our specialty. Many of the formal oncology interest groups, residencies, and fellowships were created in the early 1980s. Back when I started in this business, specialty pharmacy practice was in its

infancy, so with little direction a group of us forged a path ahead for oncology pharmacy practice. Our specialty arose out of an American Society of HealthSystem Pharmacists’ (ASHP) special interest group. In 1986, I headed a group from across the country, sponsored by ASHP, who were responsible to create a petition for oncology as a specialty that would go to the Board of Pharmaceutical Specialties (BPS). This turned out to be a 7-year odyssey. That first submission was denied by BPS. This was quite a setback and almost doomed the recognition of our specialty. But a handful of us persevered and, 2 years later, submitted a proposal that was accepted. A group of us were asked to serve on the first BPS Special Council on Oncology Pharmacy, which created the inaugural specialty examination in 1995. A successful specialist now could be a Board Certified Oncology Pharmacist (BCOP). With an identified specialty, the next issue was continuing education that focused on oncology pharmacy practice. Neither ASHP nor the American College of Clinical Pharmacy offered adequate oncology specialty content to satisfy annual BCOP requirements or the overall needs of specialists. The American Society of Clinical Oncology annual meeting was an option, but not all oncology pharmacists were able to attend. In addition, the only standalone oncology pharmacy program was the M. D. Anderson Cancer Conference, but that was primarily an M. D. Anderson –created event using M. D. Anderson staff. During this same timeframe, a group of oncology specialists formed ONC, a subgroup of a medical education company that specifically created oncology pharmacy continuing education. From this group, the second stand-alone oncology pharmacy national conference was

formed: Making a Difference. This meeting was a success, but following the sales of the medical education company, the Making a Difference conference was idled. Phil Johnson and a handful of others, however, resurrected the conference, ultimately becoming the HOPA annual meeting when the organization launched in 2005.

Back when I started in this business, specialty pharmacy practice was in its infancy, so with little direction a group of us forged a path ahead for oncology pharmacy practice. Our Future I thought a little look backward to how our specialty came to be, would interest some of the younger oncology pharmacy specialists. Today, there are more than 1000 identified oncology specialty pharmacists. As the old Virginia Slims TV commercial once said, “we’ve come a long way baby.” I was just looking through my desk drawer for a pen, and do you think I could find one? Not one, no druglabeled pens, nada. Where have all the pens and sticky pads gone? I remember when pens and sticky pads were as common as fire ants in a Texas yard. Now, because I’m not trusted to make an unbiased drug assessment, all those enticements have been revoked. No more trips or junkets. Believe me, things have not stopped there. Most health science centers and health system rules currently outlaw the taking of any item from a drug company—and I mean any-

thing. And if that’s not bad enough, at a rescent drug company lecture I gave, pharmacists were not allowed to attend unless they paid for their own dinner. Now employers are telling you what you can do on your own time. Are we really so sleazy that we can be bought with a pen, pad, or dinner? Maybe the answer is yes for some, but what heresy do these varmints speak (I am speaking about those of us who speak for pharmaceutical companies) that is so toxic? The industry is so regulated and monitored now that to clear the numerous legal internal hurdles that exist, a company-sponsored lecture is so cleansed and squeaky clean, it basically mirrors the package insert. Don’t get me wrong, I appreciate the continuing medical education (CME)-designated lectures I get a chance to hear from time to time, but the rules for CME have become quite tedious and not always reasonable for every lecture. With all this being said, my question is still: How do we get good, up-to-date information on cancer drugs and treatment to us in practice in a reasonable and timely fashion, without having to spend thousands of dollars to go to a national meeting? I do realize there is web-based programming available. However, much us this is limited and many times does not deal with the disease or treatment of interest at the time. I’m not sure what the answer is, but I do understand the ethics surrounding receiving gifts for using a specific product and how that could taint the decision process. When I look back at how we made decisions and used drugs in the ‘80s and ‘90s and how we do things now, I really don’t see a big difference. Is it just me, or is my sight failing me in my old age? If you don’t agree, let me know where I’m off base or just wrong. ●

Would you like straight-shooter Jim Koeller to respond to a particular topic? E-mail your ideas to editorial@greenhillhc.com. www.TheOncologyPharmacist.com

AugusT 2011 I VOL 4, NO 5

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BRIEF SUMMARY

GEMCITABINE FOR INJECTION, USP 1

INDICATIONS AND USAGE 1.1 Ovarian Cancer 1.2 Breast Cancer 1.3 Non-Small Cell Lung Cancer 1.4 Pancreatic Cancer 2 DOSAGE AND ADMINISTRATION 2.1 Ovarian Cancer 2.2 Breast Cancer 2.3 Non-Small Cell Lung Cancer 2.4 Pancreatic Cancer 2.5 Preparation and Administration Precautions 2.6 Preparation for Intravenous Infusion Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Infusion Time 5.2 Hematology 5.3 Pulmonary 5.4 Renal 5.5 Hepatic 5.6 Pregnancy 5.7 Laboratory Tests 5.8 Radiation Therapy 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Post-Marketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal 8.7 Hepatic 8.8 Gender 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Ovarian Cancer 14.2 Breast Cancer 14.3 Non-Small Cell Lung Cancer (NSCLC) 14.4 Pancreatic Cancer 14.5 Other Clinical Studies 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION 17.1 Low Blood Cell Counts 17.2 Pregnancy 17.3 Nursing Mothers *Sections or subsections omitted from the full prescribing information are not listed. 1 INDICATIONS AND USAGE 1.1 Ovarian Cancer Gemcitabine for Injection in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. 1.2 Breast Cancer Gemcitabine for Injection in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracyclinecontaining adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. 1.3 Non-Small Cell Lung Cancer Gemcitabine for Injection is indicated in combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer. 1.4 Pancreatic Cancer Gemcitabine for Injection is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemcitabine is indicated for patients previously treated with 5-FU. 2 DOSAGE AND ADMINISTRATION Gemcitabine for Injection is for intravenous use only. Gemcitabine may be administered on an outpatient basis. 2.1 Ovarian Cancer Gemcitabine for Injection should be administered intravenously at a dose of 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Carboplatin AUC 4 should be administered intravenously on Day 1 after gemcitabine for injection administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count â&#x2030;Ľ1500 x 106/L and a platelet count â&#x2030;Ľ100,000 x 106/L prior to each cycle. Dose Modifications Gemcitabine for Injection dosage adjustment for hematological toxicity within a cycle of treatment is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, gemcitabine for injection dosage should be modified according to guidelines in Table 1.

2.4

Table 3: Dosage Reduction Guidelines Absolute granulocyte count Platelet count % of (x 106/L) full dose (x 106/L) â&#x2030;Ľ1000 And â&#x2030;Ľ100,000 100 500 to 999 Or 50,000 to 99,999 75 <500 Or <50,000 Hold

4 5 5.1 5.2

5.3

5.4

5.5

5.6

5.7

5.8

Table 1: Day 8 Dosage Reduction Guidelines for Gemcitabine for Injection in Combination with Carboplatin Absolute granulocyte count Platelet count % of (x 106/L) full dose (x 106/L) â&#x2030;Ľ1500 And â&#x2030;Ľ100,000 100 1000 to 1499 and/or 75,000 to 99,999 50 <1000 and/or <75,000 Hold

2.2

In general, for severe (Grade 3 or 4) non-hematological toxicity, except nausea/vomiting, therapy with gemcitabine for injection should be held or decreased by 50% depending on the judgment of the treating physician. For carboplatin dosage adjustment, see manufacturerâ&#x20AC;&#x2122;s prescribing information. Dose adjustment for gemcitabine for injection in combination with carboplatin for subsequent cycles is based upon observed toxicity. The dose of gemcitabine for injection in subsequent cycles should be reduced to 800 mg/m2 on Days 1 and 8 in case of any of the following hematologic toxicities: â&#x20AC;˘ Absolute granulocyte count <500 x 106/L for more than 5 days â&#x20AC;˘ Absolute granulocyte count <100 x 106/L for more than 3 days â&#x20AC;˘ Febrile neutropenia â&#x20AC;˘ Platelets <25,000 x 106/L â&#x20AC;˘ Cycle delay of more than one week due to toxicity If any of the above toxicities recur after the initial dose reduction, for the subsequent cycle, gemcitabine for injection should be given on Day 1 only at 800 mg/m2. Breast Cancer Gemcitabine for Injection should be administered intravenously at a dose of 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3-hour intravenous infusion before gemcitabine administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count â&#x2030;Ľ1500 x 106/L and a platelet count â&#x2030;Ľ100,000 x 106/L prior to each cycle. Dose Modifications Gemcitabine dosage adjustments for hematological toxicity is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, gemcitabine dosage should be modified according to the guidelines in Table 2.

Table 2: Day 8 Dosage Reduction Guidelines for Gemcitabine in Combination with Paclitaxel Absolute granulocyte count Platelet count % of (x 106/L) full dose (x 106/L) â&#x2030;Ľ1200 And >75,000 100 1000 to 1199 Or 50,000 to 75,000 75 700 to 999 And â&#x2030;Ľ50,000 50 <700 Or <50,000 Hold

2.3

In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with gemcitabine should be held or decreased by 50% depending on the judgment of the treating physician. For paclitaxel dosage adjustment, see manufacturerâ&#x20AC;&#x2122;s prescribing information. Non-Small Cell Lung Cancer Dose Modifications Dosage adjustments for hematologic toxicity may be required for gemcitabine and

for cisplatin. Gemcitabine dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on the day of therapy. Patients receiving gemcitabine should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet counts. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3. For cisplatin dosage adjustment, see manufacturerâ&#x20AC;&#x2122;s prescribing information. In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with gemcitabine plus cisplatin should be held or decreased by 50% depending on the judgment of the treating physician. During combination therapy with cisplatin, serum creatinine, serum potassium, serum calcium, and serum magnesium should be carefully monitored (Grade 3/4 serum creatinine toxicity for gemcitabine plus cisplatin was 5% versus 2% for cisplatin alone). Pancreatic Cancer Dose Modifications Dosage adjustment is based upon the degree of hematologic toxicity experienced by the patient [see Warnings and Precautions (5.2)]. Clearance in women and the elderly is reduced and women were somewhat less able to progress to subsequent cycles [see Warnings and Precautions (5.2) and Clinical Pharmacology(12.3)]. Patients receiving gemcitabine should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3.

6 6.1

Laboratory evaluation of renal and hepatic function, including transaminases and serum creatinine, should be performed prior to initiation of therapy and periodically thereafter. Gemcitabine for Injection should be administered with caution in patients with evidence of significant renal or hepatic impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Patients treated with gemcitabine who complete an entire cycle of therapy may have the dose for subsequent cycles increased by 25%, provided that the absolute granulocyte count (AGC) and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and if non-hematologic toxicity has not been greater than WHO Grade 1. If patients tolerate the subsequent course of gemcitabine at the increased dose, the dose for the next cycle can be further increased by 20%, provided again that the AGC and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and that non-hematologic toxicity has not been greater than WHO Grade 1. CONTRAINDICATIONS Gemcitabine is contraindicated in those patients with a known hypersensitivity to the drug. WARNINGS AND PRECAUTIONS Patients receiving therapy with gemcitabine should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents. Infusion Time Caution â&#x20AC;&#x201C; Prolongation of the infusion time beyond 60 minutes and more frequent than weekly dosing have been shown to increase toxicity [see Clinical Studies (14.5)]. Hematology Gemcitabine can suppress bone marrow function as manifested by leukopenia, thrombocytopenia, and anemia [see Adverse Reactions (6.1)], and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)]. Pulmonary Pulmonary toxicity has been reported with the use of gemcitabine. In cases of severe lung toxicity, gemcitabine therapy should be discontinued immediately and appropriate supportive care measures instituted [see Adverse Reactions (6.1 and 6.2)]. Renal Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of gemcitabine. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been reported. The majority of the cases of renal failure leading to death were due to HUS [see Adverse Reactions (6.1 and 6.2)]. Gemcitabine should be used with caution in patients with preexisting renal impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations [see Use In Specific Populations (8.6)]. Hepatic Serious hepatotoxicity, including liver failure and death, has been reported in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.1 and 6.2)]. Gemcitabine should be used with caution in patients with preexisting hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of gemcitabine in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency [see Use In Specific Populations (8.7)]. Pregnancy Gemcitabine can cause fetal harm when administered to a pregnant woman. In preclinical studies in mice and rabbits, gemcitabine was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of gemcitabine in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use In Specific Populations (8.1)]. Laboratory Tests Patients receiving gemcitabine should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. Suspension or modification of therapy should be considered when marrow suppression is detected [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)]. Laboratory evaluation of renal and hepatic function should be performed prior to initiation of therapy and periodically thereafter [see Dosage and Administration (2.4)]. Radiation Therapy A pattern of tissue injury typically associated with radiation toxicity has been reported in association with concurrent and non-concurrent use of gemcitabine. Non-concurrent (given >7 days apart) â&#x20AC;&#x201C; Analysis of the data does not indicate enhanced toxicity when gemcitabine is administered more than 7 days before or after radiation, other than radiation recall. Data suggest that gemcitabine can be started after the acute effects of radiation have resolved or at least one week after radiation. Concurrent (given together or â&#x2030;¤7 days apart) â&#x20AC;&#x201C; Preclinical and clinical studies have shown that gemcitabine has radiosensitizing activity. Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of gemcitabine, frequency of gemcitabine administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. In a single trial, where gemcitabine at a dose of 1000 mg/ m2 was administered concurrently for up to 6 consecutive weeks with therapeutic thoracic radiation to patients with non-small cell lung cancer, significant toxicity in the form of severe, and potentially life-threatening mucositis, especially esophagitis and pneumonitis was observed, particularly in patients receiving large volumes of radiotherapy [median treatment volumes 4795 cm3]. Subsequent studies have been reported and suggest that gemcitabine administered at lower doses with concurrent radiotherapy has predictable and less severe toxicity. However, the optimum regimen for safe administration of gemcitabine with therapeutic doses of radiation has not yet been determined in all tumor types. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced. Gemcitabine has been used in a wide variety of malignancies, both as a single-agent and in combination with other cytotoxic drugs. Single-Agent Use: Myelosuppression is the principal dose-limiting toxicity with gemcitabine therapy. Dosage adjustments for hematologic toxicity are frequently needed [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)]. The data in Table 4 are based on 979 patients receiving gemcitabine as a singleagent administered weekly as a 30-minute infusion for treatment of a wide variety of malignancies. The gemcitabine starting doses ranged from 800 to 1250 mg/m2. Data are also shown for the subset of patients with pancreatic cancer treated in 5 clinical studies. The frequency of all grades and severe (WHO Grade 3 or 4) adverse reactions were generally similar in the single-agent safety database of 979 patients and the subset of patients with pancreatic cancer. Adverse reactions reported in the single-agent safety database resulted in discontinuation of gemcitabine therapy in about 10% of patients. In the comparative trial in pancreatic cancer, the discontinuation rate for adverse reactions was 14.3% for the gemcitabine arm and 4.8% for the 5-FU arm. All WHO-graded laboratory adverse reactions are listed in Table 4, regardless of causality. Non-laboratory adverse reactions listed in Table 4 or discussed below were those reported, regardless of causality, for at least 10% of all patients, except the categories of Extravasation, Allergic, and Cardiovascular and certain specific adverse reactions under the Renal, Pulmonary, and Infection categories. Hematologic â&#x20AC;&#x201C; In studies in pancreatic cancer myelosuppression is the dose-limiting toxicity with gemcitabine, but <1% of patients discontinued therapy for either anemia, leukopenia, or thrombocytopenia. Red blood cell transfusions were required by 19% of patients. The incidence of sepsis was less than 1%. Petechiae or mild blood loss (hemorrhage), from any cause, was reported in 16% of patients; less than 1% of patients required platelet transfusions. Patients should be monitored for myelosuppression during gemcitabine therapy and dosage modified or suspended according to the degree of hematologic toxicity [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)]. Gastrointestinal â&#x20AC;&#x201C; Nausea and vomiting were commonly reported (69%) but were usually

of mild to moderate severity. Severe nausea and vomiting (WHO Grade 3/4) occurred in <15% of patients. Diarrhea was reported by 19% of patients, and stomatitis by 11% of patients. Hepatic â&#x20AC;&#x201C; In clinical trials, gemcitabine was associated with transient elevations of one or both serum transaminases in approximately 70% of patients, but there was no evidence of increasing hepatic toxicity with either longer duration of exposure to gemcitabine or with greater total cumulative dose. Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.2)]. Renal â&#x20AC;&#x201C; In clinical trials, mild proteinuria and hematuria were commonly reported. Clinical findings consistent with the Hemolytic Uremic Syndrome (HUS) were reported in 6 of 2429 patients (0.25%) receiving gemcitabine in clinical trials. Four patients developed HUS on gemcitabine therapy, 2 immediately post-therapy. The diagnosis of HUS should be considered if the patient develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, reticulocytosis, severe thrombocytopenia, and/ or evidence of renal failure (elevation of serum creatinine or BUN). Gemcitabine therapy should be discontinued immediately. Renal failure may not be reversible even with discontinuation of therapy and dialysis may be required [see Adverse Reactions (6.2)]. Fever â&#x20AC;&#x201C; The overall incidence of fever was 41%. This is in contrast to the incidence of infection (16%) and indicates that gemcitabine may cause fever in the absence of clinical infection. Fever was frequently associated with other flu-like symptoms and was usually mild and clinically manageable. Rash â&#x20AC;&#x201C; Rash was reported in 30% of patients. The rash was typically a macular or finely granular maculopapular pruritic eruption of mild to moderate severity involving the trunk and extremities. Pruritus was reported for 13% of patients. Pulmonary â&#x20AC;&#x201C; In clinical trials, dyspnea, unrelated to underlying disease, has been reported in association with gemcitabine therapy. Dyspnea was occasionally accompanied by bronchospasm. Pulmonary toxicity has been reported with the use of gemcitabine [see Adverse Reactions (6.2)]. The etiology of these effects is unknown. If such effects develop, gemcitabine should be discontinued. Early use of supportive care measures may help ameliorate these conditions. Edema â&#x20AC;&#x201C; Edema (13%), peripheral edema (20%), and generalized edema (<1%) were reported. Less than 1% of patients discontinued due to edema. Flu-like Symptoms â&#x20AC;&#x201C; â&#x20AC;&#x153;Flu syndromeâ&#x20AC;? was reported for 19% of patients. Individual symptoms of fever, asthenia, anorexia, headache, cough, chills, and myalgia were commonly reported. Fever and asthenia were also reported frequently as isolated symptoms. Insomnia, rhinitis, sweating, and malaise were reported infrequently. Less than 1% of patients discontinued due to flu-like symptoms. Infection â&#x20AC;&#x201C; Infections were reported for 16% of patients. Sepsis was rarely reported (<1%). Alopecia â&#x20AC;&#x201C; Hair loss, usually minimal, was reported by 15% of patients. Neurotoxicity â&#x20AC;&#x201C; There was a 10% incidence of mild paresthesias and a <1% rate of severe paresthesias. Extravasation â&#x20AC;&#x201C; Injection-site related events were reported for 4% of patients. There were no reports of injection site necrosis. Gemcitabine is not a vesicant. Allergic â&#x20AC;&#x201C; Bronchospasm was reported for less than 2% of patients. Anaphylactoid reaction has been reported rarely. Gemcitabine should not be administered to patients with a known hypersensitivity to this drug [see Contraindications (4)]. Cardiovascular â&#x20AC;&#x201C; During clinical trials, 2% of patients discontinued therapy with gemcitabine due to cardiovascular events such as myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension. Many of these patients had a prior history of cardiovascular disease [see Adverse Reactions (6.2)]. Combination Use in Non-Small Cell Lung Cancer: In the gemcitabine plus cisplatin versus cisplatin study, dose adjustments occurred with 35% of gemcitabine injections and 17% of cisplatin injections on the combination arm, versus 6% on the cisplatin-only arm. Dose adjustments were required in greater than 90% of patients on the combination, versus 16% on cisplatin. Study discontinuations for possibly drug-related adverse reactions occurred in 15% of patients on the combination arm and 8% of patients on the cisplatin arm. With a median of 4 cycles of gemcitabine plus cisplatin treatment, 94 of 262 patients (36%) experienced a total of 149 hospitalizations due to possibly treatment-related adverse reactions. With a median of 2 cycles of cisplatin treatment, 61 of 260 patients (23%) experienced 78 hospitalizations due to possibly treatment-related adverse reactions. In the gemcitabine plus cisplatin versus etoposide plus cisplatin study, dose adjustments occurred with 20% of gemcitabine injections and 16% of cisplatin injections in the gemcitabine plus cisplatin arm compared with 20% of etoposide injections and 15% of cisplatin injections in the etoposide plus cisplatin arm. With a median of 5 cycles of gemcitabine plus cisplatin treatment, 15 of 69 patients (22%) experienced 15 hospitalizations due to possibly treatment-related adverse reactions. With a median of 4 cycles of etoposide plus cisplatin treatment, 18 of 66 patients (27%) experienced 22 hospitalizations due to possibly treatment-related adverse reactions. In patients who completed more than one cycle, dose adjustments were reported in 81% of the gemcitabine plus cisplatin patients, compared with 68% on the etoposide plus cisplatin arm. Study discontinuations for possibly drug-related adverse reactions occurred in 14% of patients on the gemcitabine plus cisplatin arm and in 8% of patients on the etoposide plus cisplatin arm. The incidence of myelosuppression was increased in frequency with gemcitabine plus cisplatin treatment (~90%) compared to that with the gemcitabine monotherapy (~60%). With combination therapy gemcitabine dosage adjustments for hematologic toxicity were required more often while cisplatin dose adjustments were less frequently required. Table 5 presents the safety data from the gemcitabine plus cisplatin versus cisplatin study in non-small cell lung cancer. The NCI Common Toxicity Criteria (CTC) were used. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatmentrelated deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm. Nine cases of febrile neutropenia were reported on the combination therapy arm compared to 2 on the cisplatin arm. More patients required RBC and platelet transfusions on the gemcitabine plus cisplatin arm. Myelosuppression occurred more frequently on the combination arm, and in 4 possibly treatment-related deaths myelosuppression was observed. Sepsis was reported in 4% of patients on the gemcitabine plus cisplatin arm compared to 1% on the cisplatin arm. Platelet transfusions were required in 21% of patients on the combination arm and <1% of patients on the cisplatin arm. Hemorrhagic events occurred in 14% of patients on the combination arm and 4% on the cisplatin arm. However, severe hemorrhagic events were rare. Red blood cell transfusions were required in 39% of the patients on the gemcitabine plus cisplatin arm, versus 13% on the cisplatin arm. The data suggest cumulative anemia with continued gemcitabine plus cisplatin use. Nausea and vomiting despite the use of antiemetics occurred more often with gemcitabine plus cisplatin therapy (78%) than with cisplatin alone (71%). In studies with single-agent gemcitabine, a lower incidence of nausea and vomiting (58% to 69%) was reported. Renal function abnormalities, hypomagnesemia, neuromotor, neurocortical, and neurocerebellar toxicity occurred more often with gemcitabine plus cisplatin than with cisplatin monotherapy. Neurohearing toxicity was similar on both arms. Cardiac dysrhythmias of Grade 3 or greater were reported in 7 (3%) patients treated with gemcitabine plus cisplatin compared to one (<1%) Grade 3 dysrhythmia reported with cisplatin therapy. Hypomagnesemia and hypokalemia were associated with one Grade 4 arrhythmia on the gemcitabine plus cisplatin combination arm. Table 4: Selected WHO-Graded Adverse Reactions in Patients Receiving Single-Agent Gemcitabine WHO Grades (% incidence)a Pancreatic Cancer Discontinuations All Patientsb Patientsc (%)d All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 All Patients Laboratorye Hematologic Anemia 68 7 1 73 8 2 <1 Leukopenia 62 9 <1 64 8 1 <1 Neutropenia 63 19 6 61 17 7 Thrombocytopenia 24 4 1 36 7 <1 <1 Hepatic <1 ALT 68 8 2 72 10 1 AST 67 6 2 78 12 5 Alkaline Phosphatase 55 7 2 77 16 4 Bilirubin 13 2 <1 26 6 2 Renal <1 Proteinuria 45 <1 0 32 <1 0 Hematuria 35 <1 0 23 0 0 BUN 16 0 0 15 0 0 Creatinine 8 <1 0 6 0 0 Non-laboratoryf Nausea and Vomiting 69 13 1 71 10 2 <1 Fever 41 2 0 38 2 0 <1 Rash 30 <1 0 28 <1 0 <1 Dyspnea 23 3 <1 10 0 <1 <1 Diarrhea 19 1 0 30 3 0 0 Hemorrhage 17 <1 <1 4 2 <1 <1 Infection 16 1 <1 10 2 <1 <1 Alopecia 15 <1 0 16 0 0 0 Stomatitis 11 <1 0 10 <1 0 <1 Somnolence 11 <1 <1 11 2 <1 <1 Paresthesias 10 <1 0 10 <1 0 0 a 'RADEBASEDONCRITERIAFROMTHE7ORLD(EALTH/RGANIZATION7(/  b.TOALLPATIENTSWITHLABORATORYORNON LABORATORYDATA c.TOALLPANCREATICCANCERPATIENTSWITHLABORATORYORNON LABORATORYDATA d. e2EGARDLESSOFCAUSALITY f 4ABLEINCLUDESNON LABORATORYDATAWITHINCIDENCEFORALLPATIENTSâ&#x2030;Ľ&ORAPPROXIMATELYOFTHEPATIENTS NON LABORATORY ADVERSEREACTIONSWEREGRADEDONLYIFASSESSEDTOBEPOSSIBLYDRUG RELATED

Table 6 presents data from the randomized study of gemcitabine plus cisplatin versus etoposide plus cisplatin in 135 patients with NSCLC. One death (1.5%) was reported on the gemcitabine plus cisplatin arm due to febrile neutropenia associated with renal failure which was possibly treatment-related. No deaths related to treatment occurred on the etoposide plus cisplatin arm. The overall incidence of Grade 4 neutropenia on the gemcitabine plus cisplatin arm was less than on the etoposide plus cisplatin arm (28% versus 56%). Sepsis was experienced by 2% of patients on both treatment arms. Grade 3 anemia and Grade 3/4 thrombocytopenia were more common on the gemcitabine plus cisplatin arm. RBC transfusions were given to 29% of the patients who received gemcitabine plus cisplatin versus 21% of patients who received etoposide plus cisplatin. Platelet transfusions were given to 3% of the patients who received gemcitabine plus cisplatin versus 8% of patients who received etoposide plus cisplatin. Grade 3/4 nausea and vomiting were also more common on the gemcitabine plus cisplatin arm. On the gemcitabine plus cisplatin arm, 7% of participants were hospitalized due to febrile neutropenia compared to 12% on the etoposide plus cisplatin arm. More than twice as many patients had dose reductions or omissions of a scheduled dose of gemcitabine as


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6.2

7

compared to etoposide, which may explain the differences in the incidence of neutropenia and febrile neutropenia between treatment arms. Flu syndrome was reported by 3% of patients on the gemcitabine plus cisplatin arm with none reported on the comparator arm. Eight patients (12%) on the gemcitabine plus cisplatin arm reported edema compared to one patient (2%) on the etoposide plus cisplatin arm. Combination Use in Breast Cancer: In the gemcitabine plus paclitaxel versus paclitaxel study, dose reductions occurred with 8% of gemcitabine injections and 5% of paclitaxel injections on the combination arm, versus 2% on the paclitaxel arm. On the combination arm, 7% of gemcitabine doses were omitted and <1% of paclitaxel doses were omitted, compared to <1% of paclitaxel doses on the paclitaxel arm. A total of 18 patients (7%) on the gemcitabine plus paclitaxel arm and 12 (5%) on the paclitaxel arm discontinued the study because of adverse reactions. There were two deaths on study or within 30 days after study drug discontinuation that were possibly drug-related, one on each arm. Table 7 presents the safety data occurrences of â&#x2030;Ľ10% (all grades) from the gemcitabine plus paclitaxel versus paclitaxel study in breast cancer. The following are the clinically relevant adverse reactions that occurred in >1% and <10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse reactions (gemcitabine plus paclitaxel versus paclitaxel): febrile neutropenia (5% versus 1.2%), infection (0.8% versus 0.8%), dyspnea (1.9% versus 0), and allergic reaction/hypersensitivity (0 versus 0.8%). No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65. Combination Use in Ovarian Cancer: In the gemcitabine plus carboplatin versus carboplatin study, dose reductions occurred with 10.4% of gemcitabine injections and 1.8% of carboplatin injections on the combination arm, versus 3.8% on the carboplatin alone arm. On the combination arm, 13.7% of gemcitabine doses were omitted and 0.2% of carboplatin doses were omitted, compared to 0% of carboplatin doses on the carboplatin alone arm. There were no differences in discontinuations due to adverse reactions between arms (10.9% versus 9.8%, respectively). Table 8 presents the adverse reactions (all grades) occurring in â&#x2030;Ľ10% of patients in the ovarian cancer study. In addition to blood product transfusions as listed in Table 8, myelosuppression was also managed with hematopoietic agents. These agents were administered more frequently with combination therapy than with monotherapy (granulocyte growth factors: 23.6% and 10.1%, respectively; erythropoietic agents: 7.3% and 3.9%, respectively). The following are the clinically relevant adverse reactions, regardless of causality, that occurred in >1% and <10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse reactions (gemcitabine plus carboplatin versus carboplatin): AST or ALT elevation (0 versus 1.2%), dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1%), hypersensitivity reaction (2.3% versus 2.9%), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0). No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65. Post-Marketing Experience The following adverse reactions have been identified during post-approval use of gemcitabine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions have occurred after gemcitabine single-agent use and gemcitabine in combination with other cytotoxic agents. Decisions to include these events are based on the seriousness of the event, frequency of reporting, or potential causal connection to gemcitabine. Cardiovascular â&#x20AC;&#x201C; Congestive heart failure and myocardial infarction have been reported very rarely with the use of gemcitabine. Arrhythmias, predominantly supraventricular in nature, have been reported very rarely. Vascular Disorders â&#x20AC;&#x201C; Clinical signs of peripheral vasculitis and gangrene have been reported very rarely. Skin â&#x20AC;&#x201C; Cellulitis and non-serious injection site reactions in the absence of extravasation have been rarely reported. Severe skin reactions, including desquamation and bullous skin eruptions, have been reported very rarely. Hepatic â&#x20AC;&#x201C; Increased liver function tests including elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, and bilirubin levels have been reported rarely. Serious hepatotoxicity including liver failure and death has been reported very rarely in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs. Hepatic veno-occlusive disease has been reported. Pulmonary â&#x20AC;&#x201C; Parenchymal toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported rarely following one or more doses of gemcitabine administered to patients with various malignancies. Some patients experienced the onset of pulmonary symptoms up to 2 weeks after the last gemcitabine dose. Respiratory failure and death occurred very rarely in some patients despite discontinuation of therapy. Renal â&#x20AC;&#x201C; Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of gemcitabine. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS. Injury, Poisoning, and Procedural Complications â&#x20AC;&#x201C; Radiation recall reactions have been reported [see Warnings and Precautions (5.8)]. DRUG INTERACTIONS No specific drug interaction studies have been conducted. Information is available on the pharmacodynamics and pharmacokinetics of gemcitabine in combination with cisplatin, paclitaxel, or carboplatin [see Clinical Pharmacology (12.2 and 12.3)]. Table 5: Selected CTC-Graded Adverse Reactions From Comparative Trial of Gemcitabine Plus Cisplatin Versus Single-Agent Cisplatin in NSCLC CTC Grades (% incidence)a Gemcitabine plus Cisplatinb All Grades Grade 3 Grade 4 All Grades

Cisplatinc Grade 3

Grade 4

Laboratoryd Hematologic Anemia 89 22 3 67 6 1 RBC Transfusione 39 13 Leukopenia 82 35 11 25 2 1 Neutropenia 79 22 35 20 3 1 Thrombocytopenia 85 25 25 13 3 1 Platelet Transfusionse 21 <1 Lymphocytes 75 25 18 51 12 5 Hepatic Transaminase 22 2 1 10 1 0 Alkaline Phosphatase 19 1 0 13 0 0 Renal Proteinuria 23 0 0 18 0 0 Hematuria 15 0 0 13 0 0 Creatinine 38 4 <1 31 2 <1 Other Laboratory Hyperglycemia 30 4 0 23 3 0 Hypomagnesemia 30 4 3 17 2 0 Hypocalcemia 18 2 0 7 0 <1 Non-laboratoryf Nausea 93 25 2 87 20 <1 Vomiting 78 11 12 71 10 9 Alopecia 53 1 0 33 0 0 Neuro Motor 35 12 0 15 3 0 Neuro Hearing 25 6 0 21 6 0 Diarrhea 24 2 2 13 0 0 Neuro Sensory 23 1 0 18 1 0 Infection 18 3 2 12 1 0 Fever 16 0 0 5 0 0 Neuro Cortical 16 3 1 9 1 0 Neuro Mood 16 1 0 10 1 0 Local 15 0 0 6 0 0 Neuro Headache 14 0 0 7 0 0 Stomatitis 14 1 0 5 0 0 Hemorrhage 14 1 0 4 0 0 Dyspnea 12 4 3 11 3 2 Hypotension 12 1 0 7 1 0 Rash 11 0 0 3 0 0 a 'RADEBASEDON#OMMON4OXICITY#RITERIA#4# 4ABLEINCLUDESDATAFORADVERSEREACTIONSWITHINCIDENCEâ&#x2030;ĽINEITHERARM b.TOALLGEMCITABINEPLUSCISPLATINPATIENTSWITHLABORATORYORNON LABORATORYDATA'EMCITABINEATMGMON$AYS  ANDANDCISPLATINATMGMON$AYEVERYDAYS c .TOALLCISPLATINPATIENTSWITHLABORATORYORNON LABORATORYDATA#ISPLATINATMGMON$AYEVERYDAYS d 2EGARDLESSOFCAUSALITY e 0ERCENTOFPATIENTSRECEIVINGTRANSFUSIONS0ERCENTTRANSFUSIONSARENOT#4# GRADEDEVENTS f .ON LABORATORYEVENTSWEREGRADEDONLYIFASSESSEDTOBEPOSSIBLYDRUG RELATED Table 6: Selected WHO-Graded Adverse Reactions From Comparative Trial of Gemcitabine Plus Cisplatin Versus Etoposide Plus Cisplatin in NSCLC WHO Grades (% incidence)a Gemcitabine plus Cisplatinb Etoposide plus Cisplatinc All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratoryd Hematologic Anemia 88 22 0 77 13 2 RBC Transfusionse 29 21 Leukopenia 86 26 3 87 36 7 Neutropenia 88 36 28 87 20 56 Thrombocytopenia 81 39 16 45 8 5 Platelet Transfusionse 3 8 Hepatic ALT 6 0 0 12 0 0 AST 3 0 0 11 0 0 Alkaline Phosphatase 16 0 0 11 0 0 Bilirubin 0 0 0 0 0 0 Renal Proteinuria 12 0 0 5 0 0 Hematuria 22 0 0 10 0 0 BUN 6 0 0 4 0 0 Creatinine 2 0 0 2 0 0 f, g Non-laboratory Nausea and Vomiting 96 35 4 86 19 7 Fever 6 0 0 3 0 0 Rash 10 0 0 3 0 0 Dyspnea 1 0 1 3 0 0 Diarrhea 14 1 1 13 0 2 Hemorrhage 9 0 3 3 0 3 Infection 28 3 1 21 8 0 Alopecia 77 13 0 92 51 0 Stomatitis 20 4 0 18 2 0 Somnolence 3 0 0 3 2 0 Paresthesias 38 0 0 16 2 0 a 'RADEBASEDONCRITERIAFROMTHE7ORLD(EALTH/RGANIZATION7(/  b .TOALLGEMCITABINEPLUSCISPLATINPATIENTSWITHLABORATORYORNON LABORATORYDATA'EMCITABINEATMGMON$AYS ANDANDCISPLATINATMGMON$AYEVERYDAYS c .TOALLCISPLATINPLUSETOPOSIDEPATIENTSWITHLABORATORYORNON LABORATORYDATA#ISPLATINATMGMON$AYANDINTRAVENOUSETOPOSIDEATMGMON$AYS  ANDEVERYDAYS d 2EGARDLESSOFCAUSALITY e 0ERCENTOFPATIENTSRECEIVINGTRANSFUSIONS0ERCENTTRANSFUSIONSARENOT7(/ GRADEDEVENTS f .ON LABORATORYEVENTSWEREGRADEDONLYIFASSESSEDTOBEPOSSIBLYDRUG RELATED G 0AINDATAWERENOTCOLLECTED

Table 7: Adverse Reactions From Comparative Trial of Gemcitabine Plus Paclitaxel Versus Single-Agent Paclitaxel in Breast Cancera CTC Grades (% incidence) Gemcitabine plus Paclitaxel (N=262) Paclitaxel (N=259) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratoryb Hematologic Anemia 69 6 1 51 3 <1 Neutropenia 69 31 17 31 4 7 Thrombocytopenia 26 5 <1 7 <1 <1 Leukopenia 21 10 1 12 2 0 Hepatobiliary ALT 18 5 <1 6 <1 0 AST 16 2 0 5 <1 0 Non-laboratoryc Alopecia 90 14 4 92 19 3 Neuropathy-sensory 64 5 <1 58 3 0 Nausea 50 1 0 31 2 0 Fatigue 40 6 <1 28 1 <1 Myalgia 33 4 0 33 3 <1 Vomiting 29 2 0 15 2 0 Arthralgia 24 3 0 22 2 <1 Diarrhea 20 3 0 13 2 0 Anorexia 17 0 0 12 <1 0 Neuropathy-motor 15 2 <1 10 <1 0 Stomatitis/pharyngitis 13 1 <1 8 <1 0 Fever 13 <1 0 3 0 0 Rash/desquamation 11 <1 <1 5 0 0 a'RADEBASEDON#OMMON4OXICITY#RITERIA#4# 6ERSIONALLGRADESâ&#x2030;Ľ  b2EGARDLESSOFCAUSALITY c.ON LABORATORYEVENTSWEREGRADEDONLYIFASSESSEDTOBEPOSSIBLYDRUG RELATED Table 8: Adverse Reactions From Comparative Trial of Gemcitabine Plus Carboplatin Versus Single-Agent Carboplatin in Ovarian Cancera CTC Grades (% incidence) Gemcitabine plus Carboplatin (N=175) Carboplatin (N=174) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratoryb Hematologic Neutropenia 90 42 29 58 11 1 Anemia 86 22 6 75 9 2 Leukopenia 86 48 5 70 6 <1 Thrombocytopenia 78 30 5 57 10 1 RBC Transfusionsc 38 15 9 3 Platelet Transfusionsc Non-laboratoryb Nausea Alopecia Vomiting Constipation Fatigue Neuropathy-sensory Diarrhea Stomatitis/pharyngitis Anorexia

69 49 46 42 40 29 25 22 16

6 0 6 6 3 1 3 <1 1

0 0 0 1 <1 0 0 0 0

61 17 36 37 32 27 14 13 13

3 0 2 3 5 2 <1 0 0

When gemcitabine (1250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m2 on Day 1) were administered in NSCLC patients, the clearance of gemcitabine on Day 1 was 128 L/hr/m2 and on Day 8 was 107 L/hr/m2. The clearance of cisplatin in the same study was reported to be 3.94 mL/min/m2 with a corresponding half-life of 134 hours [see Drug Interactions (7)]. Analysis of data from metastatic breast cancer patients shows that, on average, gemcitabine has little or no effect on the pharmacokinetics (clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of gemcitabine. Data from NSCLC patients demonstrate that gemcitabine and carboplatin given in combination does not alter the pharmacokinetics of gemcitabine or carboplatin compared to administration of either single-agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed. 14 CLINICAL STUDIES 14.1 Ovarian Cancer Gemcitabine was studied in a randomized Phase 3 study of 356 patients with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either gemcitabine 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after gemcitabine on Day 1 of each cycle or single-agent carboplatin AUC 5 administered on Day 1 of each 21-day cycle as the control arm. The primary endpoint of this study was progression free survival (PFS). Patient characteristics are shown in Table 10. The addition of gemcitabine to carboplatin resulted in statistically significant improvement in PFS and overall response rate as shown in Table 11 and Figure 1. Approximately 75% of patients in each arm received poststudy chemotherapy. Only 13 of 120 patients with documented poststudy chemotherapy regimen in the carboplatin arm received gemcitabine after progression. There was not a significant difference in overall survival between arms.

Table 10: Gemcitabine Plus Carboplatin Versus Carboplatin in Ovarian Cancer â&#x20AC;&#x201C; Baseline Demographics and Clinical Characteristics

0 0 <1 0 0 0 0 0 0

Number of randomized patients Median age, years Range Baseline ECOG a performance status 0-1 Disease Status Evaluable Bidimensionally measurable Platinum-free intervalb 6 to 12 months >12 months First-line therapy Platinum-taxane combination Platinum-non-taxane combination Platinum monotherapy

a'RADEBASEDON#OMMON4OXICITY#RITERIA#4# 6ERSIONALLGRADESâ&#x2030;Ľ  b2EGARDLESSOFCAUSALITY

c0ERCENTOFPATIENTSRECEIVINGTRANSFUSIONS4RANSFUSIONSARENOT#4# GRADEDEVENTS"LOODTRANSFUSIONSINCLUDEDBOTHPACKEDREDBLOOD

CELLSANDWHOLEBLOOD

8 8.1

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D. See â&#x20AC;&#x2DC;Warnings and Precautionsâ&#x20AC;&#x2122; section. Gemcitabine can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, gemcitabine is expected to result in adverse reproductive effects. There are no adequate and well-controlled studies of gemcitabine in pregnant women. Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 1/200 the recommended human dose on a mg/m2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 1/600 the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.6)]. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from gemcitabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of gemcitabine in pediatric patients has not been established. Gemcitabine was evaluated in a Phase 1 trial in pediatric patients with refractory leukemia and determined that the maximum tolerated dose was 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. Gemcitabine was also evaluated in a Phase 2 trial in patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) using 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation, which were similar to those reported in adults. No meaningful clinical activity was observed in this Phase 2 trial. 8.5 Geriatric Use Gemcitabine clearance is affected by age [see Clinical Pharmacology (12.3)]. There is no evidence, however, that unusual dose adjustments [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)] are necessary in patients over 65, and in general, adverse reaction rates in the single-agent safety database of 979 patients were similar in patients above and below 65. Grade 3/4 thrombocytopenia was more common in the elderly. In the randomized clinical trial of gemcitabine in combination with carboplatin for recurrent ovarian cancer [see Clinical Studies (14.1)], 125 women treated with gemcitabine plus carboplatin were <65 years and 50 were â&#x2030;Ľ 65 years. Similar effectiveness was observed between older and younger women. There was significantly higher Grade 3/4 neutropenia in women 65 years of age or older. Overall, there were no other substantial differences in toxicity profile of gemcitabine plus carboplatin based on age. 8.6 Renal Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of gemcitabine. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been reported. The majority of the cases of renal failure leading to death were due to HUS [see Adverse Reactions (6.1 and 6.2)]. Gemcitabine should be used with caution in patients with preexisting renal impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations [see Warnings and Precautions (5.4)]. 8.7 Hepatic Serious hepatotoxicity, including liver failure and death, has been reported in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.1 and 6.2)]. Gemcitabine should be used with caution in patients with preexisting hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of gemcitabine in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency [see Warnings and Precautions (5.5)]. 8.8 Gender Gemcitabine clearance is affected by gender [see Clinical Pharmacology (12.3)]. In the single-agent safety database (N=979 patients), however, there is no evidence that unusual dose adjustments [see Dosage and Administration (2)] are necessary in women. In general, in single-agent studies of gemcitabine, adverse reaction rates were similar in men and women, but women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia. There was a greater tendency in women, especially older women, not to proceed to the next cycle. 12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics Gemcitabine demonstrated dose-dependent synergistic activity with cisplatin in vitro. No effect of cisplatin on gemcitabine triphosphate accumulation or DNA double-strand breaks was observed. In vivo, gemcitabine showed activity in combination with cisplatin against the LX-1 and CALU-6 human lung xenografts, but minimal activity was seen with the NCI-H460 or NCI-H520 xenografts. Gemcitabine was synergistic with cisplatin in the Lewis lung murine xenograft. Sequential exposure to gemcitabine 4 hours before cisplatin produced the greatest interaction. 12.3 Pharmacokinetics Absorption and Distribution The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m2 following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m2. Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and gender. Gemcitabine plasma protein binding is negligible. Excretion Clearance of gemcitabine was affected by age and gender. The lower clearance in women and the elderly results in higher concentrations of gemcitabine for any given dose. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations. Table 9 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and gender.

Age 29 45 65 79

Table 9: Gemcitabine Clearance and Half-Life for the â&#x20AC;&#x153;Typicalâ&#x20AC;? Patient Clearance Clearance Half-Lifea Half-Lifea Men Women Men Women 2 2 (L/hr/m ) (L/hr/m ) (min) (min) 92.2 69.4 42 49 75.7 57 48 57 55.1 41.5 61 73 40.7 30.7 79 94

a

b

Gemcitabine/ Carboplatin Carboplatin 178 178 59 58 36 to 78 21 to 81 94%

95%

7.9% 91.6%

2.8% 95.5%

39.9% 59%

39.9% 59.6%

70.2% 28.7% 1.1%

71.3% 27.5% 1.1%

Nine patients (5 on the gemcitabine plus carboplatin arm and 4 on the carboplatin arm) did not have baseline Eastern Cooperative Oncology Group (ECOG) performance status recorded. Three patients (2 on the gemcitabine plus carboplatin arm and 1 on the carboplatin arm) had a platinum-free interval of less than 6 months.

Table 11: Gemcitabine Plus Carboplatin Versus Carboplatin in Ovarian Cancer â&#x20AC;&#x201C; Results of Efficacy Analysis Gemcitabine/ Carboplatin Carboplatin (N=178) (N=178) PFS Median (95%, C.I.) months Hazard Ratio (95%, C.I.) Overall Survival Median (95%, C.I.) months Hazard Ratio (95%, C.I.) Adjusteda Hazard Ratio (95%, C.I.) Investigator Reviewed Overall Response Rate CR PR + PRNMb Independently Reviewed Overall Response Ratec, f CR PR + PRNM

8.6 (8, 9.7) 5.8 (5.2, 7.1) 0.72 (0.57, 0.9)

p=0.0038d

18 (16.2, 20.3) 17.3 (15.2, 19.3) 0.98 (0.78, 1.24)

p=0.8977d

0.86 (0.67, 1.1) e

47.2% 14.6% 32.6%

30.9% 6.2% 24.7%

p=0.0016

46.3% 9.1% 37.2%

35.6% 4% 31.7%

p=0.11

e

a

Treatment adjusted for performance status, tumor area, and platinum-free interval.

b

Partial response non-measurable disease Independent reviewers could not evaluate disease demonstrated by sonography or physical exam. Log Rank, unadjusted Chi Square Independently reviewed cohort â&#x20AC;&#x201C; Gemcitabine/ Carboplatin N=121, Carboplatin N=101

c

d e f

Figure 1: Kaplan-Meier Curve of Progression Free Survival in Gemcitabine Plus Carboplatin Versus Carboplatin in Ovarian Cancer (N=356) 14.5 Other Clinical Studies When gemcitabine was administered more frequently than once weekly or with infusions longer than 60 minutes, increased toxicity was observed. Results of a Phase 1 study of gemcitabine to assess the maximum tolerated dose (MTD) on a daily x 5 schedule showed that patients developed significant hypotension and severe flu-like symptoms that were intolerable at doses above 10 mg/m2. The incidence and severity of these events were dose-related. Other Phase 1 studies using a twice-weekly schedule reached MTDs of only 65 mg/m2 (30-minute infusion) and 150 mg/m2 (5-minute bolus). The dose-limiting toxicities were thrombocytopenia and flu-like symptoms, particularly asthenia. In a Phase 1 study to assess the maximum tolerated infusion time, clinically significant toxicity, defined as myelosuppression, was seen with weekly doses of 300 mg/m2 at or above a 270-minute infusion time. The half-life of gemcitabine is influenced by the length of the infusion [see Clinical Pharmacology (12.3)] and the toxicity appears to be increased if gemcitabine is administered more frequently than once weekly or with infusions longer than 60 minutes [see Warnings and Precautions (5.1)]. 17 PATIENT COUNSELING INFORMATION 17.1 Low Blood Cell Counts Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur [see Warnings and Precautions (5.2)]. 17.2 Pregnancy There are no adequate and well-controlled studies of gemcitabine in pregnant women. Based on animal studies gemcitabine can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the risks to the fetus need to be discussed with their physician [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. Manufactured by: APP Pharmaceuticals, LLC Schaumburg, IL 60173 Manufactured For:

Teva Parenteral Medicines, Inc. Irvine, CA 92618

a

Half-life for patients receiving a short infusion (<70 min). Gemcitabine half-life for short infusions ranged from 42 to 94 minutes, and the value for long infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer infusions. Drug Interactions

451249 Issued: May 2011


TOP_August 2011_v7_TOP 8/18/11 1:03 PM Page 36

Now Available from Teva…

Gemcitabine for Injection, USP ®*

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To place your order, call your wholesaler or distributor today. Please see brief summary of prescribing information on adjacent page.

CONCENTRATION/ TOTAL DOSE

DESCRIPTION

NDC

UNIT OF SALE

200 mg/vial

10 mL SD Glass Vial

00703-5775-01

1

1 gm/vial

50 mL SD Glass Vial

00703-5778-01

1

Store at 20˚ to 25˚C (68˚ to 77˚F); excursions permitted to 15˚ to 30˚C (59˚ to 86˚F)

* Gemzar® is a registered trademark of Eli Lilly and Co. ©2011, Teva Pharmaceuticals USA 10360B

800.729.9991 ð www.tevausa.com

August Volume 4, No 5  

The Oncology Pharmacist August Volume 4, No 5

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