NOVEMBER/DECEMBER 2010| VOL 1| NO 6 by Value-Based Cancer Care

NOVEMBER/DECEMBER 2010 VOL 1 NO 6

www.ValueBasedCancer.com

Significant Impact for New Prostate Cancer Therapy

Continued Pressures on Community Cancer Centers

By Charles Bankhead

By Colin Gittens

Milan—Men with castration-resistant prostate cancer (CRPC) gained 4 months in overall survival (OS) when treated with the novel antiandrogen abiraterone acetate, data from a large randomized trial showed. Treatment with abiraterone and prednisone led to a median OS of 14.8 months compared with 10.9 months for prednisone alone (P <.001). Although seemingly modest, the difference will likely have a practice-changing impact on the treatment of CRPC, lead investigator Johann de Bono, MBBS, PhD, an oncologist at the Royal Marsden Hospital in London, said at the 35th European Society for Medical Oncology Congress. “In the history of prostate cancer, only 4 drugs have ever shown a sur-

vival benefit,” said Dr de Bono. Some patients treated with the agent have had long-lived responses, including 2 of his own Johann de Bono, MBBS, PhD patients who have been treated continuously for more than 4 years. Abiraterone blocks androgen synthesis by inhibiting the CYP17 rate-limiting enzyme necessary for conversion of testosterone precursors into the male hormone. Laboratory and clinical evidence have suggested that some prostate cancer cells generate intratumoral androgens despite androgen Continued on page 14

Contralateral Prophylactic Mastectomy Improves Survival, Is Cost-Effective in Some By Caroline Helwick National Harbor, MD—Multiple benefits were observed for contralateral prophylactic mastectomy (CPM), including cost-effectiveness, in studies presented at the 2010 ASCO Breast Cancer Symposium by investigators from the Mayo Clinic, Rochester, MN. CPM not only reduced the risk of breast cancer in the opposite breast by 95% among high-risk women with breast cancer, it improved survival as well. In addition, in younger women undergoing mastectomy and deemed to be at average risk, CPM was cost-

effective when compared with routine surveillance aimed at early detection for cancer in the opposite breast. “CPM provides Judy Boughey, MD good value, ie, cost/outcome, for select patient groups,” reported Benjamin Zendejas, MD, of the Department of Surgery at the Mayo Clinic, who authored the cost-effectiveness study. Continued on page 10

onsolidation and cost pressures remain key concerns for community cancer centers, according to Christian Downs, MHA, JD, the executive director of the Association of Community Cancer Centers (ACCC). Mr Downs presented additional results and analysis from the ACCC’s ongoing, 3-year member survey at the Managed Care Network Oncology Management Summit in Chicago, IL, on September 24. This survey traces the continued reaction of the community hospital cancer programs to legislative and economic changes that are reshaping community oncology practice. The survey data, which were collected in late 2009, show that community cancer center revenue is still largely tied to providing drugs to patients. In comparison to the physician office setting, where physicians are on the hook for drug costs, “drugs mean less to hos-

Christian Downs, MHA, JD

pitals,” Mr Downs pointed out. Hospitals are also beginning to contract with multiple group purchasing organizations as a means of controlling costs, and a large percentage of responContinued on page 8

Plan to attend the upcoming Association for Value-Based Cancer Care meeting. See page 29 for details.

CMS Releases Outpatient Payment Rules for Physicians and Hospitals Improved preventive coverage, continued payment concerns By Crystal Kuntz, MPA

n November 2, 2010, the Centers for Medicare & Medicaid Services (CMS) issued its Physician Fee Schedule and Hospital Outpatient Prospective Payment System final rules for 2011. These CMS regulations are important for all providers of care in the Medicare program, as they set the payment parameters for the upcoming year.

Payment to physicians under Medicare remains an unresolved and complicated issue. Under these new regulations, physicians would see a 24.9% overall pay cut beginning January 1, 2011 unless Congress takes action to stop it. The reasons for the payment cut are complex but stem from what is widely seen as flaws in the Continued on page 28

IN THIS ISSUE Building the VBCC reader community. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Cancer pathway profile: A statewide program in Michigan . . . . . . . . . . . . . 8 Denise Pierce on cancer cost discussions . . . . . . . . . . . . . . . . . . . . . . . . . 26 Continuing education for pharmacists on non–small-cell lung cancer . . . 34 ©2010 Engage Healthcare Communications, LLC

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

Proven CINV prevention in a single IV dose s Powerful CINV prevention in the first 24 hours and up to 5 days following moderately emetogenic chemotherapy 1,2 s Lasts long against nausea following moderately emetogenic chemotherapy 3 s Powerful acute CINV prevention following highly emetogenic chemotherapy 4 s Eisai offers a variety of support programs and resources

Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.

Important Safety Information s !,/8) IS CONTRAINDICATED IN PATIENTS KNOWN TO HAVE HYPERSENSITIVITY TO THE DRUG OR ANY of its components s -OST COMMONLY REPORTED ADVERSE REACTIONS IN CHEMOTHERAPY INDUCED NAUSEA AND VOMITING include headache (9%) and constipation (5%) Please see the brief summary of the Full Prescribing Information on the adjacent page. References: 1. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 2. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 3. Data on file. Eisai Inc., Woodcliff Lake, NJ. 4. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-1449.

STARTS STRONG. LASTS LONG.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc. © 2010 Eisai Inc. All rights reserved. Printed in USA. ALO000083A 08/10

LETTER TO OUR READERS

From Stakeholders to Community By Colin Gittens

s the last issue of this first year of publication of Value-Based Cancer Care (VBCC) reaches you, I wanted to take a moment to reflect on where VBCC has been so far ALOXIÂŽ (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: L =23@/B3:G 3;3B=53<71 1/<13@ 163;=B63@/>G K >@3D3<B7=< =4 /1CB3 /<2 23:/G32 </CA3/ /<2 D=;7B7<5 /AA=17/B32 E7B6 7<7B7/: /<2 @3>3/B 1=C@A3A L 756:G 3;3B=53<71 1/<13@ 163;=B63@/>G K >@3D3<B7=< =4 /1CB3 </CA3/ /<2 D=;7B7<5 /AA=17/B32 E7B6 7<7B7/: /<2 @3>3/B 1=C@A3A DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting =A/53 4=@ 2C:BA / A7<5:3 ;5 ) 2=A3 /2;7<7AB3@32 =D3@ A31=<2A =A7<5 A6=C:2 =11C@ />>@=F7;/B3:G ;7<CB3A 034=@3 B63 AB/@B =4 163;=B63@/>G Instructions for I.V. Administration "+ 7A AC>>:732 @3/2G 4=@ 7<B@/D3<=CA 7<831B7=< "+ A6=C:2 <=B 03 ;7F32 E7B6 =B63@ 2@C5A :CA6 B63 7<4CA7=< :7<3 E7B6 <=@;/: A/:7<3 034=@3 /<2 /4B3@ /2;7<7AB@/B7=< =4 "+ #/@3<B3@/: 2@C5 >@=2C1BA A6=C:2 03 7<A>31B32 D7AC/::G 4=@ >/@B71C:/B3 ;/BB3@ /<2 27A1=:=@/B7=< 034=@3 /2;7<7AB@/B7=< E63<3D3@ A=:CB7=< /<2 1=<B/7<3@ >3@;7B CONTRAINDICATIONS "+ 7A 1=<B@/7<271/B32 7< >/B73<BA 9<=E< B= 6/D3 6G>3@A3<A7B7D7BG B= B63 2@C5 =@ /<G =4 7BA 1=;>=<3<BA [see Adverse Reactions (6) 7< 4C:: >@3A1@707<5 7<4=@;/B7=< ] WARNINGS AND PRECAUTIONS Hypersensitivity G>3@A3<A7B7D7BG @3/1B7=<A ;/G =11C@ 7< >/B73<BA E6= 6/D3 3F6707B32 6G>3@A3<A7B7D7BG B= =B63@ '

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VOL. 1

NO. 6

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starting at VBCC, I attended the 36th Annual National Meeting of the Association of Community Cancer Centers in March, where speakers considered a host of topics that might not Pediatric Use &/43BG /<2 34431B7D3<3AA 7< >/B73<BA 03:=E B63 /53 =4

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E3@3 â&#x2030;Ľ G3/@A =:2 E67:3 E3@3 â&#x2030;Ľ G3/@A =:2 != =D3@/:: 27443@3<13A 7< A/43BG =@ 34431B7D3<3AA E3@3 =0A3@D32 03BE33< B63A3 AC0831BA /<2 B63 G=C<53@ AC0831BA 0CB 5@3/B3@ A3<A7B7D7BG 7< A=;3 =:23@ 7<27D72C/:A 1/<<=B 03 @C:32 =CB != 2=A3 /28CAB;3317/: ;=<7B=@7<5 /@3 @3?C7@32 4=@ 53@7/B@71 >/B73<BA "4 B63 /2C:B >/B73<BA 7< "+ #"!) 1:7<71/: ABC273A E3@3 â&#x2030;Ľ G3/@A =:2 != =D3@/:: 27443@3<13A 7< A/43BG E3@3 =0A3@D32 03BE33< =:23@ /<2 G=C<53@ AC0831BA 7< B63A3 ABC273A B6=C56 B63 >=AA707:7BG =4 63756B3<32 A3<A7B7D7BG 7< A=;3 =:23@ 7<27D72C/:A 1/<<=B 03 3F1:C232 != 27443@3<13A 7< 34I 1/1G E3@3 =0A3@D32 7< 53@7/B@71 >/B73<BA 4=@ B63 !) 7<271/B7=< /<2 <=<3 /@3 3F>31B32 4=@ 53@7/B@71 #"!) >/B73<BA =E3D3@ "+ 34I 1/1G 7< 53@7/B@71 >/B73<BA 6/A <=B 033< /23?C/B3:G 3D/:C/B32 Renal Impairment 7:2 B= ;=23@/B3 @3</: 7;>/7@;3/:=<=A3B@=< >6/@;/1=97<3B71 >/@/;3B3@A '=B/: AGAB3;71 3F>=AC@3 7<1@3/A32 0G />>@=F7;/B3:G 7< A3D3@3 @3</: 7;>/7@;3/B73<BA E7B6 /<G 235@33 =4 @3</: 7;>/7@;3/B71 7;>/7@;3/:=<=A3B@=< 1=;>/@32 B= B63 63/:B6G AC0831BA =A/53 /28CAB;3/B73<BA E7B6 /<G 235@33 =4 63>/B71 7;>/7@;3/:=<=A3B@=< >6/@;/1=97<3B71A E/A 16/@/1B3@7H32 7< BE3<BG 4=C@ 63/:B6G />/<3A3 AC0831BA =D3@ B63 2=A3 @/<53 =4 K ;15 95 '=B/: 0=2G 1:3/@/<13 E/A 67563@ 7< />/<3A3 AC0831BA 1=;>/@32 B= *67B3A 6=E3D3@ <= 2=A3 /28CAB;36/@;/1=97<3B71A =4 >/:=<=A3B@=< 7< :/19A 6/A <=B 033< /23?C/B3:G 16/@/1B3@7H32 OVERDOSAGE '63@3 7A <= 9<=E< /<B72=B3 B= "+ "D3@2=A3 A6=C:2 03 ;/</532 E7B6 AC>>=@B7D3 1/@3 74BG /2C:B 1/<13@ >/B73<BA E3@3 /2;7<7AB3@32 >/:=<=A3B@=/@B =4 / 2=A3 @/<57<5 ABC2G '67A 7A />>@=F7;/B3:G B7;3A B63 @31=;;3<232 2=A3 =4 ;5 '67A 2=A3 5@=C> 6/2 / A7;7:/@ 7<1723<13 =4 /2D3@A3 3D3<BA 1=;>/@32 B= B63 =B63@ 2=A3 5@=C>A /<2 <= 2=A3 @3A>=<A3 34431BA E3@3 =0A3@D32 7/:GA7A ABC273A 6/D3 <=B 033< >3@4=@;32 6=E3D3@ 2C3 B= B63 :/@53 D=:C;3 =4 27AB@70CB7=< 27/:GA7A 7A C<:793:G B= 03 /< 34431B7D3 B@3/B;3/:=<=A3B@=< =D3@2=A3 A7<5:3 7<B@/D3<=CA 2=A3 =4 >/:=<=A3B@=31B7D3:G 0/A32 =< 0=2G AC@4/13 /@3/ E/A :3B6/: B= @/BA /<2 ;713 '63 ;/8=@ A75<A =4 B=F717BG E3@3 1=<DC:A7=<A 5/A>7<5 >/::=@ 1G/<=A7A /<2 1=::/>A3 PATIENT COUNSELING INFORMATION &33 FDA-Approved Patient Labeling (17.2) in 4C:: >@3A1@707<5 7<4=@;/B7=< Instructions for Patients L #/B73<BA A6=C:2 03 /2D7A32 B= @3>=@B B= B637@ >6GA717/< /:: =4 B637@ ;3271/: 1=<27B7=<A /<G >/7< @32<3AA =@ AE3::7<5 7< /<2 /@=C<2 B63 7<4CA7=< A7B3 -see Adverse Reactions (6) 7< 4C:: >@3A1@707<5 7<4=@;/B7=<. L #/B73<BA A6=C:2 03 7<AB@C1B32 B= @3/2 B63 >/B736/@;/13CB71/:A :0C?C3@?C3 ! (& =@ #73@@3 /0@3 P271/;3<B #@=2C1B7=< 2@=< ?C7B/7<3 @/<13 /<2 3:A7<< 7@3F #6/@;/13CB71/:A C0:7< @3:/<2

ALOXIÂŽ 7A / @357AB3@32 B@/23;/@9 =4 3:A7<< 3/:B61/@3 & &E7BH3@:/<2 CA32 C<23@ :713<A3 7AB@70CB32 /<2 ;/@93B32 0G 7A/7 <1 *==21:744 /93 ! O 7A/7 <1 :: @756BA @3A3@D32 #@7<B32 7< (&

have been on the agenda just several years before. Healthcare reform, multidisciplinary cancer care, episodebased payment, Medicare reimbursement, business tools to drive quality, and comparative effectiveness were all considered. In June, research presented at the annual ASCO meeting also covered contentious ground, including survival benefits associated with combination therapies, genomic profiling and personalized care, and the cost-effectiveness of various treatments. And of course, the US Food and Drug Administrationâ&#x20AC;&#x2122;s approval of a $93,000 therapy (Provenge) and a subsequent coverage decision by the Centers for Medicare & Medicaid Services has generated much discussion all year. This publication has covered these meetings and these essential topics, and others, our first 6 issues. And we hope that this coverageâ&#x20AC;&#x201D;in the form of reporting, surveys of the literature, and analysis of new research and current events by the experts of our editorial boardâ&#x20AC;&#x201D;is providing information you need and cannot obtain through any other single source. Several small surveys indicate this is so. Medical and pharmacy director attendees at the Xcenda Managed Care Network Oncology Management Summit were questioned about the publication; 40% indicated a primary interest in original articles on cost and access to cancer care, with news and highlights from major meetings a close second (38%). Even more, 69% indicated that VBCC was a publication they anticipated reading. A separate web survey of hematologists/oncologists demonstrated similar results. We intend to continue to serve our readers in 2011 with our print and online publications (www.valuebased cancer.com), as well as with the establishment of the Association for ValueBased Cancer Care, which will hold its first meeting March 29-30, 2011, in Philadelphia. This association will serve to further inform the value considerations surrounding cancer care today. As I noted in the first issue of this publication, providers, payers, and policymakers all face new challenges as the world of cancer care is roiled by cost considerations, access issues, new scientific discoveries, and sweeping legislative changes. We remain certain of the need for such an organization and such a publication to bring together the individuals from these customarily discreet worlds. We look forward to you participating with both. Thank you for reading! â&#x2013;

www.ValueBasedCancer.com

TABLE OF CONTENTS Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Directors, Client Services John Hennessy john@greenhillhc.com 732-992-1886 Phil Pawelko phil@greenhillhc.com 732-992-1887 Cristopher Pires cris@engagehc.com 732-992-1896 Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889 Managing Editor Colin Gittens colin@engagehc.com 732-992-1536 Associate Editor Lara Reiman lara@engagehc.com 732-992-1892 Senior Production Manager Robyn Jacobs Business Manager Blanche Marchitto Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments. This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care. BPA Worldwide membership applied for August 2010. Contact Information: For subscription and reprint information please contact: circulation@valuebasedcare.com Telephone: 732-992-1538 Fax: 732-992-1881 Permission requests to reprint all or part of any article published in this magazine should be addressed to PERMISSIONS DEPARTMENT. Fax: 732-992-1881. Address all editorial correspondence to: editor@valuebasedcare.com Telephone: 732-992-1536 Fax: 732-992-1881 Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2010 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a trademark of Engage 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. The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

November/December 2010

Vol. 1 ASCO Shares Concerns Over the Future of Cancer Research

Letter to Our Readers 3 From Stakeholders to Community/Colin Gittens

5 FDA Updates Cancer Quick Takes 6 Reversing Light Chain–Induced Acute Renal Failure

AML Trials: Phases and Changes Bortezomib Bests Vincristine as Induction Therapy for Multiple Myeloma

7 Value Propositions Oncology Management Summit 8 Streamlining Cancer Care in Michigan Data Draw 10 Perception Versus Actual Testing for KRAS/Janna Radtchenko

No. 6

Costs of Care 26 Costs of Cancer Drugs Weigh on US, Canadian Minds VBCC Perspective 26 The Costs of Care: A Discussion We’re Not Prepared to Have—Yet/Denise K. Pierce Continuing Education 34 Maintenance Therapy for Non–Small-Cell Lung Cancer: A Value-Based Approach to Improve Patient Care and Outcomes, Part II of II

37 Maintenance Therapy in Advanced Non– Small-Cell Lung Cancer: Personalized Perspectives/Corey J. Langer, MD

38 Nursing and Patient Management

35th ESMO Conference 14 High Cost to Managing Colorectal Cancer Toxicities

Considerations for Maintenance Therapy in Non–Small-Cell Lung Cancer/ Beth Eaby-Sandy, CRNP

15 Benefit to Longer Chemotherapy in Metastatic Breast Cancer ECRI Personalized Medicine Conference 16 Determining Coverage for CER and Personalized Medicine

18 CER and Personalized Medicine Face Hurdles Targeted Therapy 20 Cancer Drugs: NICE Rejects Costly Treatments Some Biologics Fail in Early-Stage Tumors Clinical Research 22 Restoring Balance to the Cancer Research Regulation Equation

In this issue...

“I’m convinced now that the physicians are willing to take on the task of being good stewards of the state’s healthcare dollars, especially if those dollars remain in the local healthcare system.” —Kurt Neumann, MD, from “Streamlining Cancer Care in Michigan,” page 8

VBCC Editorial Board Bruce A. Cutter, MD, MMM Cancer Care Northwest Spokane, WA

Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL

Jatin J. Shah, MD M.D. Anderson Cancer Center Houston, TX

Craig Deligdish, MD Florida Comprehensive Cancer Network Melbourne, FL

Crystal Kuntz, MPA Astellas Pharma US Washington, DC

Jayson Slotnik, JD, MPH Foley Hoag Washington, DC

Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers Pittsburgh, PA

Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN

Brian K. Solow, MD, FAAFP Prescription Solutions Irvine, CA

Arlene A. Forastiere, MD ITA Partners Philadelphia, PA

Lynn Nishida, RPh Regence BlueCross BlueShield of Oregon Portland, OR

G. Rhys Williams, ScD, MS Amgen Thousand Oaks, CA

Tracy Gosselin, RN, MSN Duke University Medical Center Durham, NC

Naimish Pandya, MD University of Maryland Baltimore, MD

Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute New York, NY

Ed Pezalla, MD, MPH Aetna Pharmacy Management Hartford, CT

David Hom, MBA Solucia Farmington, CT

VALUE-BASED CANCER CARE

Nov/Dec 2010

Denise K. Pierce DK Pierce & Associates Zionsville, IN

Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS BioPharma Partners, LLC New York, NY

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FDA UPDATES Eribulin Approved for Advanced Breast Cancer Eribulin mesylate (Halaven) was approved for use in patients with metastatic breast cancer who have received at least 2 prior chemotherapy regimens. The effectiveness of the drug was established in a single study of 762 women, which demonstrated superior overall survival (13.1 months) compared with single agent therapy (10.6 months). (November 15, 2010)

alone demonstrated in a single, international, multicenter, open-label, randomized clinical trial. (October 20, 2010) GnRH Agonists Gain Warning The FDA has asked gonadotropinreleasing hormone (GnRH) agonist manufacturers to add new warnings to the labels of these products alerting

patients and healthcare professionals to the potential risk of heart disease and diabetes in men treated with these medications. GnRH agonists are used primarily to treat men with prostate cancer. In May, the FDA said that a preliminary and ongoing analysis found that patients receiving GnRH agonists were at a small increased risk for diabetes,

Help reduce the risk of infection in patients receiving moderate-risk* chemotherapy regimens

FDA OKs Everolimus for Rare Genetic Disorder The cancer drug everolimus (Affinitor) may now be used to treat patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS). TS causes benign tumors to grow in the brain and in other parts of the body, including the eyes, lungs, liver, heart, skin, and kidneys. SEGAs are the slow-growing tumors that are considered a major diagnostic feature of TS and can be fatal when they grow on the brain. These tumors are seen in 6% to 9% of patients; this approval was for treatments of SEGA that cannot be treated with surgery. The drug was approved under the US Food and Drug Administration’s (FDA) accelerated approval program. (November 1, 2010) Dasatinib Now Indicated for Rare Leukemia The FDA has approved dasatinib (Sprycel) for initial treatment of Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (Ph+ CP-CML). This rare blood cancer progresses slowly and is linked to a genetic abnormality. Dasatinib, an oral kinase inhibitor, is believed to inhibit the activity of certain proteins responsible for the growth of cancer cells. The action allows bone marrow to begin reproducing normal red and white blood cells. In June 2006, the FDA granted accelerated approval for dasatinib to treat adults with CP-CML with resistant disease or who were intolerant to prior therapy, including imatinib (Gleevec). (October 28, 2010) Trastuzumab Garners Gastric Indication The FDA has granted approval for trastuzumab (Herceptin) to be used in combination with cisplatin and a fluoropyrimidine (capecitabine or 5-fluorouracil) for the treatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease. The approval is based on a significant improvement in median overall survival of 2.5 months with trastuzumab plus chemotherapy treatment compared with chemotherapy

heart attack, stroke, and sudden death. The new labels will include updates in the Warnings and Precautions section about these potential risks. GnRH agonists are marketed under the brand names Eligard, Lupron, Synarel, Trelstar, Vantas, Viadur, and Zoladex; several generic products are available. (October 20, 2010)

Act before febrile neutropenia strikes Potential consequences of febrile neutropenia may be serious and can impact patient care First- and every-cycle Neulasta® achieved: ■ 94% reduction in febrile neutropenia (17% placebo vs 1% Neulasta®; P < 0.001).1,2 ■ 93% reduction in febrile neutropenia– related hospitalization (14% placebo vs 1% Neulasta®; P < 0.001).1,2 ■ 80% reduction in febrile neutropenia– related IV anti-infective use (10% placebo vs 2% Neulasta®; P < 0.001).1,2 Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta® is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Important Safety Information Do not administer Neulasta® to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Splenic rupture, including fatal cases, can occur following the administration of Neulasta®. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta®. Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta®. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta® for ARDS. Discontinue Neulasta® in patients with ARDS. Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta®. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta® in patients with serious allergic reactions. Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta®. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. The granulocyte colony-stimulating factor (G-CSF) receptor, through which pegfilgrastim and filgrastim act, has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded. Bone pain and pain in extremity occurred at a higher incidence in Neulasta®-treated patients as compared with placebo-treated patients. Please see brief summary of Neulasta® Prescribing Information on the adjacent page. *Regimens associated with 17% risk of febrile neutropenia. References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen. © 2010 Amgen. All rights reserved.

MC49047-A-1

04-10

www.neulasta.com

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www.ValueBasedCancer.com

CANCER QUICK TAKES Reversing Acute Renal Failure In patients with multiple myeloma with light chain–induced renal failure, treatment with a combination known as BDD (bortezomib [Velcade], doxorubicin [Adriamycin], and dexamethasone [Decadron]) resulted in a high rate of myeloma and renal responses that was well tolerated by patients BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use INDICATIONS AND USAGE Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. CONTRAINDICATIONS Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. WARNINGS AND PRECAUTIONS Splenic Rupture Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta. Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS. Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta in patients with serious allergic reactions. Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Use in Patients With Sickle Cell Disorders Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the Brief Summary: s 3PLENIC 2UPTURE ;3EE Warnings and Precautions] s !CUTE 2ESPIRATORY $ISTRESS 3YNDROME ;3EE Warnings and Precautions] s 3ERIOUS !LLERGIC 2EACTIONS ;3EE Warnings and Precautions] s 5SE IN 0ATIENTS WITH 3ICKLE #ELL $ISORDERS ;3EE Warnings and Precautions] s 0OTENTIAL FOR 4UMOR 'ROWTH 3TIMULATORY %FFECTS ON -ALIGNANT #ELLS ;3EE Warnings and Precautions] The most common adverse reactions occurring in r 5% of patients and with a between-group difference of r 5% higher in the pegfilgrastim arm in placebo controlled clinical trials are bone pain and pain in extremity. 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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Neulasta clinical trials safety data are based upon 932 patients receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma (n = 56) received Neulasta after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles. The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer

(J Clin Oncol. 2010;28:4635-4641). In this study, 68 patients (median age, 65.6 years) with light chain– induced renal failure (as defined by a decrease in glomerular filtration rate to <50 mL/min) were given BDD. If well tolerated after 2 cycles, the bortezomib dose was increased and doxorubicin was given on additional days. receiving docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and <1% Asian, Native American or other. Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients. Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3 System Organ Class Preferred Term

Placebo (N = 461)

Musculoskeletal and connective tissue disorders Bone pain

26%

31%

Pain in extremity

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post approval use of Neulasta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal relationship to Neulasta. Gastro-intestinal disorders: 3PLENIC RUPTURE ;SEE Warnings and Precautions] Blood and lymphatic system disorder: Sickle cell crisis ;SEE Warnings and Precautions] Respiratory, thoracic, and mediastinal disorder: ARDS ;SEE Warnings and Precautions] General disorders and administration site conditions: Injection site reactions Skin and subcutaneous tissue disorders: Allergic reactions/ hypersensitivity, including anaphylaxis, skin rash, and urticaria, Sweet’s syndrome, generalized erythema and FLUSHING ;SEE Warnings and Precautions] DRUG INTERACTIONS No formal drug interaction studies between Neulasta and other drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider these findings when interpreting boneimaging results. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Pegfilgrastim was embryotoxic and increased pregnancy loss in pregnant rabbits that received cumulative doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity occurred at these doses. Neulasta should be used during

Neulasta 6 mg SC on Day 2 (N = 467)

VALUE-BASED CANCER CARE

Myeloma responses were categorized as complete response (CR), nearcomplete response (nCR), very good partial response (VGPR), partial response (PR), and minor response (MR); renal responses were categorized as complete, partial, or minor. The median number of treatment cycles in the intent-to-treat and evaluable pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/ developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Nov/Dec 2010

AML Trials: Phases and Changes A discussion of new drug development using the example of acute myeloid leukemia (AML)—but that is applicable to a broad range of diseases— outlines the problems inherent in phase 2 clinical trials that may lead to falsepositive results, and how trial design can be improved and drug development be made more efficient and less costly (Blood. 2010;116:2420-2428). The authors provide a number of recommendations on how AML trials might be improved, among them, increasing study sizes; using an explicitly described control group; conducting multivariate analysis to adjust for patient heterogeneity; including explicit descriptions of inclusion/exclusion criteria; using validated surrogate end points; incorporating an integrated phase 2/3 trial design so there are no delays in conducting the phase 3 trial; and discouraging early publication so that mature data are published.

Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman. Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard DEVIATION ;3$= SYSTEMIC EXPOSURE !5#0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

Bortezomib Bests Vincristine as Induction Therapy for MM This study compared the safety and efficacy of a new regimen—bortezomib plus dexamethasone and vincristine— compared with vincristine (Oncovin), doxorubicin (Adriamycin), and dexamethasone (VAD) in previously untreated multiple myeloma (MM) (J Clin Oncol. 2010;28:4621-4629). This phase 3 study randomized 482 patients to VAD (n = 121), VAD plus dexamethasone, cyclophosphamide (Endoxan), etoposide (Eposin), and cisplatin (Platinol; DCEP) consolidation (n = 121), bortezomib plus dexamethasone (n = 121), or bortezomib plus dexamethasone plus DCEP (n = 119), followed by autologous stem-cell transplantation. The primary end point was postinduction complete/near-complete response (CR/nCR) rate. The rates of postinduction CR/nCR (14.8% vs 6.4%), at least very good partial response (37.7% vs 15.1%), and overall response (78.5% vs 62.8%) were significantly higher with bortezomib plus dexamethasone versus VAD. Bortezomib plus dexamethasone should now be considered a standard induction treatment before transplantation, say the authors.

Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim. Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed. NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product. This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2010 Amgen Inc. All rights reserved. www.neulasta.com 1-800-77-AMGEN (1-800-772-6436) v 11.0

population was 8; 26 patients (38%) achieved CR/nCR, 10 (15%) achieved VGPR, 9 (13%) achieved PR, and 4 (6%) achieved MR. Overall survival was 72% at 1 year and 58% at 2 years in the intent-to-treat population. Anemia was the most common hematologic toxicity, with 50% of patients presenting with either grade 3 or 4 toxicity; infection was the most common nonhematologic toxicity (19.1%).

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VALUE PROPOSITIONS Cancer Cost Concerns Creep North

CT Screening Shows Dramatic Benefit in Lung Cancer

It turns out that Americans are not the only ones worried about cancer treatment costs. According to a poll conducted by the Canadian Cancer Society, 85% of Canadians say that the cost of drugs would have a negative impact on their personal finances. Forty-seven percent said that negative impact would be “major,” and only 34% of Canadians are confident that their healthcare system will be able to provide affordable cancer drugs. The online survey was part of an effort to push the Canadian government to establish a catastrophic drug plan that would eliminate coverage disparities between provinces. The survey was conducted between September 9-13, 2010, and contained a sampling of 2334 Canadian adults. See page 26 of this issue for additional coverage of Canadian cost concerns.

A study comparing the use of computed tomography (CT) versus standard chest x-rays for screening those at high risk for lung cancer found that CT screening resulted in 20% fewer deaths from the disease. The large study looked at more than 53,000 people aged 55 to 74 years who had a smoking history of at least 30 pack-years, and continued for 8 years. The study was halted when the benefit of CT screening became clear; it was funded by the National Cancer Institute, and full results will be published in the coming months.

Free Is Good, Not Great, When It Comes to Screening

In response to Canadian research showing that the high price of cervical cancer vaccines was a key reason why the majority of young Canadian women have yet to be immunized, the manufacturer of Cervarix cut the cost of the vaccine by 30% effective October 25, 2010. GlaxoSmithKline, Inc, reduced the price from $134.95/dose to $90.00/dose; 3 doses are recommended.

Removing payment for health insurance deductibles leads to increased, although modest, improvements in the rates of screening for conditions such as cancer and elevated cholesterol (Meeker D, et al. Health Serv Res. 2010. Online doi:10.1111/j.1475-6773.2010.01188.x). The study analyzed preventive screening use among 44,106 people enrolled in preferred provider organizations that had initiated deductible-free coverage of 4 tests—lipid screening, mammography, fecal occult blood testing, and Pap smears— which reduced but did not eliminate patient out-of-pocket costs. Screening was accessed more often when deductibles were reduced; for highdeductible plans, mammography use actually dropped.

Filling in Funds Around NICE Gaps

Blood-Use Program Injects Clinical, Fiscal Control

The United Kingdom’s (UK) Department of Health has pledged £250 million toward a Cancer Drugs Fund that will pay for new treatments not available in the state-funded health system. An initial £50 million will provide interim coverage for the financial gap from now until next April; £200 million will then be spent over the next 3 years. These funds are intended to pay for therapies that may not have been approved by the National Institute for Health and Clinical Excellence (NICE), including bevacizumab (Avastin), lapatinib (Tyverb), and sorafenib (Nexavar). This may be the last hurrah for NICE, however; the UK’s new coalition government plans to strip the agency of its power to reject drugs in 2014.

A blood-use protocol program at Loyola University Hospital in Chicago has lowered the amount of blood products transfused per patient, which in turn has led to greater patient safety and lowered costs, according to research presented at the College of American Pathologists annual meeting in Chicago. The program implemented blood-use protocols that included evidence-based indications, educational programs for doctors and nurses, and oversight of the Blood Utilization Review Committee. Some patients now receive less blood or no blood at all without compromising patient care. For example, a doctor might now instead order 1 unit of blood and then reassess later to see if a second unit is needed instead of successively administering 2 units of blood. In 2009, the average amount of blood products transfused per patient at Loyola was 10% lower than it was in 2008, saving $453,355.

Price-Cutting May Spur Canadian Use of Cervical Vaccine

Researchers Bark Up New Tree to Manufacture Cancer Drug Paclitaxel (Taxol), which is produced from the bark of the yew, may become cheaper and easier to produce now that researchers have isolated and grown stem cells from that tree (Nat Biotechnol. Published online October 24, 2010. doi:10.1038/nbt.1693). The current manufacturing process is expensive, requires supplies of mature trees, and creates environmentally damaging by-products. Working from stem cells would eliminate the dangerous by-products and allow creation of large amounts of the drug. The scientists behind this research have also cultured stem cells from other plants with medicinal purposes.

Colorectal Cancer Screening: Spend Now to Save Later Spending money on colorectal cancer screening programs that target the pre-Medicare population (those between 50 and 64 years of age) is necessary to reduce the costs of colorectal cancer in the Medicare program, according to research presented at the American College of Gastroenterology’s 75th Annual Scientific Meeting in San Antonio, TX. Using a population-based model, researchers estimated screening and treatment costs for fecal occult blood tests (FOBTs); a mix of FOBT and colonoscopy; and colonoscopy, and compared them to current screening trends. Costs were increased in the pre-Medicare population as a result of use of all 3 programs; but those costs were offset by later savings in treatment costs in the older age-group.

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Shedding Tiers for Better Value “If evidence supports a better value for clinical and economic choices, and you throw those on a lower tier, that is to motivate member behavior towards the better value choices. Then, if the individual spends more money, it’s by choice, not need.” —Tim Heady, CEO of UnitedHealth Pharmaceutical Solutions at UnitedHealth Group, quoted in “Fourth Tiers Could Generate Drug Savings or Increase Medical Spend,” which appears in the October 2010 issue of Specialty Pharmacy News.

Teasing Out Value in Healthcare Spending Variations At the request of the US Secretary of Health and Human Services, the Institute of Medicine (IOM) will conduct a study on national variation in healthcare spending and utilization for individuals with Medicare, Medicaid, private insurance, or no insurance. A committee empaneled by the IOM—made up of health economists, clinicians, and policy experts— will examine care costs, supply, and quality; health outcomes; medical evidence to inform physician care decisions; access to care; and more. The study will inform changes to specific Medicare payment systems that would promote high-value care, especially for high-volume, high-cost decisions. The committee will meet again January 17-18, 2011.

www.ValueBasedCancer.com

ONCOLOGY MANAGEMENT SUMMIT

Streamlining Cancer Care in Michigan Statewide cancer pathway program requires cooperation and technology By Colin Gittens

etting up a statewide cancer pathway program requires sophisticated data collection and analytic capability, as well as a collaborative mindset among participants, according to Kurt Neumann, MD, Medical Director of Managed Care and Quality Initiatives for the International Oncology Network, a division of AmerisourceBergen Specialty Group. Dr Neumann described the conceptualization and construction of such a program in Michigan during a session at the Managed Care Network meeting in Chicago, IL, on September 24, 2010. In Michigan, as elsewhere, cancer care in the community setting is under financial pressure, Dr Neumann acknowledged. Adjuvant therapy is now used in more disease states for longer periods of time, in a sense turning cancer into a chronic condition. In addition, the rising expense of cancer drugs and the increasing number of cancer patients fostered by aging baby boomers will add further pressures. Nevertheless, the community-based chemotherapy delivery system is incredibly efficient for patients and

physicians, he argued, and allows for continuity of care. “It makes economic sense,” he said. What Was Done Dr Neumann described what he termed “a typical pathway project,” which originated as collaboration between many of the state’s oncolo-

“Don’t join because you think you’re going to get a lot of money at the end of the year. This is a quality initiative.” —Kurt Neumann, MD gists represented by an offshoot of the Michigan Society of Hematology and Oncology (of which Dr Neumann is a longstanding board member) and Blue Cross Blue Shield of Michigan (BCBSM). Both parties recognized variability and cost issues pertaining to the use of chemotherapy, growth factors, hospitalization, and end-of-life care; the Michigan team addressed these by focusing on chemotherapy and white and red cell growth factors in cancers that comprised the majority

Continued Pressures... dents are using the 340B program, which can provide financial relief through cost-shifting. “There are programs around the country that you can’t imagine are 340B hospitals,” he emphasized. “That’s a big, big change.” Mr Downs said that a future ACCC survey will focus on that particular issue. Traditional Approaches Changing Among the biggest trends noted are programs employing more physicians, mainly medical oncologists, and demographics are playing a key role in this change. Older oncologists (generally aged 50 years), who have traditionally been entrepreneurial in setting up group practices, are being followed by a younger generation (35-40 years old) that seeks to be an employee rather than a partner. As a result, these older entrepreneurs seek relationships with community centers or other organizations in lieu of new, traditional partnerships. In addition, the survey also notes consolidation among hospitals and a shift in thinking about community programs. There is renewed appreciation for not necessarily being part of an academic medical center that is conduct-

of the drug spend (ie, breast, colon, and lung cancers). An unusual feature of this pathway program, according to Dr Neumann, is that the physicians themselves were the drivers in setting it up, and that the contract is held by the physician group (comprised of nearly 80% of community oncologists in Michigan). An advan-

at a glance ➤ An ongoing survey of community hospital cancer programs shows that their revenue is still largely tied to drug provision ➤ Demographic shifts among oncologists are a contributing factor to consolidation among practices ➤ The use of patient navigators is increasing, but their level of responsibilities can vary widely ➤ Increased emphasis on technology may lessen the human factor in caregiving

Continued on page 9

Continued from cover

ing clinical trials, and a growth in philanthropic (or “named”) programs in the community setting. Another change involves the cost of the drugs themselves. According to Mr Downs, physicians are all too aware that, “15 years ago, I had $1 million worth of inventory. Now, I have $10 million worth of inventory.” In terms of overall finances, respondents reported cost-cutting, perceived

VALUE-BASED CANCER CARE

tage of this approach is that care is not mandated by a third party, which has in turn led to great physician acceptance. The fact that multiple practices came together under state leadership is unprecedented, he emphasized. The process began in the first quarter of 2009, with physicians generating a pathway/guideline program in collaboration with a third-party vendor and BCBSM. The first 3 months involved discussions and conceptualization on how the program should be formed. A

12-member steering committee representing both the major cancer centers and community physicians throughout the state hammered out the details of the program in approximately 2 months, followed by an additional month of legal review. The program requires 70% physician compliance with the chemotherapy pathways and 80% compliance with supportive care (ie, growth factors and antiemetics). Physicians joining the program are paid $5000 up front to assist practices with covering applicable start-up costs, and they are able to earn additional monies if the program saves BCBSM money. Physicians joining the pathways program were cautioned, however, not to join the program for additional financial gain as that could not be guaranteed for a new program. Dr Neumann pointed out, “don’t join because you think you’re going to get a lot of money at the end of the year. This is a quality initiative.” A key component of the pathway involves use of generics over branded medications when patient clinical outcomes are expected to be the same with

Nov/Dec 2010

their financial health as worse compared to the year before (78% vs 90%), and reported less money being spent on new initiatives such as patient navigators.

The work of patient financial counselors has shifted from setting up payment plans to talking more about access to free or reduced-price drugs. What Is New at the Community Level Patients are now paying more— according to Mr Downs, in some cases up to 400% more in the past 10 years. Concomitantly, the use of patient financial counselors has also increased rapidly, but the work of these individuals has shifted from setting up payment plans for patients to talking more about access to free or reduced-price drugs or receiving financial help from philanthropic foundations. The use of patient navigators is increasing, but in Mr Down’s experience, their level of responsibilities can vary widely. Some simply take patients

from point A to point B, whereas others are advanced practice nurses who lay out treatment options and the toxicities associated with them. “We would like to see more of the latter” sort, he said. Cancer care in hospitals is becoming “high tech rather than high touch,” he acknowledged, with institutions spending more money on the latest technology rather than on the person who would be delivering that technology. The attitude seems to be “get a gamma knife so we can put that up on the billboard on the highway, instead of getting additional patient navigators,” he quipped. Electronic health records are another high-tech tool expected to gain further use, but Mr Downs was shocked that some institutions are already using more than 1— perhaps as a result of consolidation among facilities. Despite the financial stresses in the community setting, Mr Downs was hopeful. Hospitals, particularly cancer centers, are getting much better about looking at their profit and loss—where they’re going to or not going to make money—and they’re going to have better decision-making information available to them, he said. ■

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Streamlining Cancer Care... either medication. Physicians are responsible for reviewing and modifying pathways quarterly or as needed, and physician groups are obliged to educate individual pathway outliers. Those individuals are given 2 quarters to come up to adherence or are removed from the program. Initial Results and Future Directions Early returns show physician compliance with the pathways at 80% to 90%. The high participation rate is encouraging, but it makes comparing results difficult—in effect, there is no control group. “Truthfully, I was amazed” at getting such a high level of participation, Dr Neumann confessed. “Before doing this, we had groups with 7 doctors with 7 different ways of doing things, and now we’ve gotten them to agree.” Expected cost-savings from the pathway will derive from converting to generic use where appropriate, limiting lines of biologic therapy, and standardizing care. Calculating those savings, however, will be difficult. Currently pathways are financially vetted through checking remittance information, which spares practices from undertaking additional data collection, but this is not as sophisticated as what would be generated through electronic medical records, which have yet to be widely used. But these early steps allow payers to monitor physician compliance with pathways. Although there are no overall financial results so far, Dr Neumann cited published studies showing that nononcology patient care expenses have also decreased through adherence to pathways. In the second year, the pathway program will expand to include lymphoma, myeloma, and ovarian and prostate cancers. Organizers will also de-emphasize the drug and reimbursement focus, instead having physicians concentrate on case-management issues to “better reward those who are more active in the program,” said Dr Neumann. Expanding pathways for diagnostics, endof-life care, and decision support is also planned, because these areas also involve wide treatment variability. Setting up these types of programs requires sophisticated data and analytics, and that is where involvement with organizations with strong understanding of working with providers, payment methodologies, and proven technical abilities is beneficial, suggested Dr Neumann. A collaborative approach is helpful—in this case, the sharing of any cost-savings between the physicians and BCBSM was sealed with a handshake.

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Continued from page 8

Dr Neumann foresees a transition to a population-based payment approach from the current episodic-based system, and this will depend on continued collaboration between payers and providers. An audience survey during

the session indicated that 73% of attendees planned to implement pathways for outpatient oncology in the next 2 years; cost management was given as the key reason for implementing them. “I’m convinced now that the phy-

sicians are willing to take on the task of being good stewards of the state’s healthcare dollars, especially if those dollars remain in the local healthcare system,” Dr Neumann said in closing. ■

NOW

AVAILABLE

www.halaven.com

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ASCO BREAST CANCER SYMPOSIUM

Contralateral Prophylactic Mastectomy... CPM Improves Survival Women undergoing mastectomy for breast cancer frequently opt for CPM. In fact, the rate of CPM has more than doubled over the past decade, said Judy Boughey, MD, principal investigator of the survival analysis. Although CPM is known to decrease the occurrence of contralateral breast cancer by 90% to 95%, debate continues regarding any survival advantage with CPM, because there are limited and conflicting data and a lack of long-term follow-up, she said. The aim of Dr Boughey’s study was to investigate whether CPM is associated with improved survival in women with a family history of breast cancer undergoing mastectomy for stage I or II breast cancer and CPM as well. All CPMs were performed at the Mayo Clinic in Rochester, MN, between 1971 and 1993, offering a look at the long-term outcomes of 385 highrisk patients who were matched 1:1 with a comparison cohort of 385 women having unilateral mastectomy and no CPM. Patients were matched according to age at diagnosis, year of diagnosis, tumor stage, and nodal status, although a family history of breast cancer was present for all the study population but only 35% of the unilateral mastectomy group. At a median follow-up of 17.3 years, only 2 patients (0.5%) in the CPM cohort developed contralateral breast cancer compared with 31 patients (8.1%) in the unilateral mastectomy cohort. This amounted to a 95% decrease in the risk of contralateral breast cancer (P <.001), Dr Boughey reported. “The result remained strongly signif-

icant after adjusting for age, stage, nodal status, and first-degree family history,” she noted. The 10-year overall survival estimates were 83% for the CPM group and 74% for the unilateral mastectomy group. After multivariate analysis, the reduction in the risk of death remained significant at 23% (P = .03). The disease-free survival difference between the 2 cohorts was also statistically sig-

“Base-case results show CPM to be cost-effective in the younger age-groups.” —Benjamin Zendejas, MD

nificant, with a 33% reduction resulting from CPM in the multivariate analysis (P = .0005), according to Dr Boughey. “We conclude that CPM significantly decreases the risk of contralateral events. Additionally, this study shows an association between CPM and improved survival and disease-free survival and a trend toward improved breast cancer– specific survival,” she said. Cost-Effectiveness Shown Dr Boughey and her colleagues also showed that CPM is cost-effective for younger patients at average risk, and for high-risk patients (BRCA positive) at any age. The study’s first author was Benjamin Zendejas, MD. “This study represents the first cost-

Table Results of Cost-Effectiveness Analysis of CPM in Younger Women Average-risk breast cancer

CPM

Surveillance

Total mean cost, $

30,222

29,076

QALYs

22.52

22.44

Mean death age, years

Mortality from disease, %

10.8

11.6

Contralateral breast cancer rate/10,000

101

2127

Number needed to treat

ICERa ($/QALY gained)

12,733

Continued from cover

effectiveness analysis comparing CPM to routine surveillance for patients with unilateral breast cancer,” Dr Zendejas noted. They used a Markov model to simulate the management of breast cancer patients from treatment (mastectomy) to death. All model parameters were gathered from published literature or national databases. Base-case analysis included end-of-life costs and focused on average-risk breast cancer patients with a starting age at treatment of 45 years. Costs were reported in 2007 US dollars. Outcomes were valued in quality-adjusted life-years (QALYs). Patients’ ages at treatment and breast cancer risk level were varied to assess their impact on the overall results. The main comparison was the CPM strategy versus surveillance, which included annual mammography with computer-aided detection. The analysis found that mean total breast cancer–related costs for women aged 45 to 60 years are comparable: $30,222 for the CPM strategy and $29,076 for the surveillance strategy (Table). The CPM strategy provides

DATA DRAW Perception Versus Actual Testing for KRAS By Janna Radtchenko, Senior Analyst, IntrinsiQ, LLC Both practice guidelines and thought leaders increasingly recommend biomarker tests for optimization of cancer care; there is, however, a gap between these recommendations, the way physicians practice, and the way they think they practice. Exploring how recommended tests are applied in clinical practice is important for bridging the gap between guidelines and clinical practice. During primary research, when physicians are asked about how often

KRAS status for CRC patients Figure treated in 2010 in second metastatic line and beyond mutated

37%

BRCA+

CPM

Surveillance

Total mean cost, $

31,044

35,909

QALYs

22.50

21.86

ICER ($/QALY gained)

–$7602

test not performed

test performed

59%

41% non-mutated

63%

aICER

compares 2 strategies by their difference in mean cost over the difference in mean outcome. CPM indicates contralateral prophylactic mastectomy; ICER, incremental cost-effectiveness ratio; NA, not applicable; QALY, quality-adjusted life-year.

VALUE-BASED CANCER CARE

Nov/Dec 2010

22.52 mean QALYs (ie, years in perfect health) compared with 22.44 for the surveillance strategy, resulting in an incremental cost-effectiveness ratio of $12,733 per QALY gained for CPM when compared with surveillance, Dr Zendejas reported. “Base-case results show CPM to be cost-effective in the younger agegroups (ie, <65 years of age). As expected, the rate of new contralateral breast cancers is significantly lower for the CPM group,” he noted. The model estimated that, on average, 5 prophylactic mastectomies would be needed to prevent the occurrence of 1 contralateral breast cancer. For the general population of breast cancer patients aged ≥65 years, however, CPM is less cost-effective, because its incremental cost-effectiveness ratio is above the $50,000 threshold for costeffectiveness, the study found. For BRCA-positive breast cancer patients, the CPM strategy is not only cost-effective but it is also a cost-saving strategy that provides “more QALYs while being less costly when compared to routine surveillance,” Dr Zendejas pointed out. ■

Data from IntrinsiQ, LLC. 2009-2010. Information on proprietary and nonpublished data is available at www.intrinsiq.com. Accessed October 27, 2010.

they test for KRAS in colorectal cancer (CRC), they typically respond that half of patients with CRC are tested for KRAS at diagnosis, with the other half tested upon progression. However, IntrinsiQ data show that only 40% of patients who have had disease progression treated in 2010 have been tested for KRAS at some point in their treatment (Figure). The American Cancer Society estimates that more than 147,000 patients will be diagnosed with CRC in 20101; 19% of them will be diagnosed with metastatic disease2 and therefore may be eligible for epidermal growth factor receptor–targeted therapies. The ability to quantify how physicians actually use biomarker tests rather than relying on theory or self-reported data is critical to accurately predicting product usage patterns, designing clinical trials, and managing the cost of care. References 1. American Cancer Society. Cancer Facts & Figures 2010. Atlanta: American Cancer Society; 2010. 2. Altekruse SF, Kosary CL, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2007. Bethesda, MD: National Cancer Institute; 2010. http:// seer.cancer.gov/csr/1975_2007. Accessed October 27, 2010.

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ZOMETA® (zoledronic acid) Injection Concentrate for Intravenous Infusion Initial U.S. Approval: 2001 BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE 1.1 Hypercalcemia of Malignancy Zometa is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of >12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (mid-range of measured albumin in mg/dL). 1.2 Multiple Myeloma and Bone Metastases of Solid Tumors Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. 1.3 Important Limitation of Use The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions has not been established. 4 CONTRAINDICATIONS 4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zometa Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported [see Adverse Reactions (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Drugs with Same Active Ingredient Zometa contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treated with Zometa should not be treated with Reclast. 5.2 Hydration and Electrolyte Monitoring Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zometa. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with Zometa in order to avoid hypocalcemia. Zometa should be used with caution with other nephrotoxic drugs. Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zometa. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary. 5.3 Renal Impairment Zometa is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased [see Adverse Reactions (6.1)]. Preexisting renal insufficiency and multiple cycles of Zometa and other bisphosphonates are risk factors for subsequent renal deterioration with Zometa. Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible. Zometa treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine >400 µmol/L or >4.5 mg/dL were excluded. Zometa treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine >265 µmol/L or >3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zometa 4 mg by 15-minute infusion with a baseline creatinine >2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance <30 mL/min [see Clinical Pharmacology (12.3) in the full prescribing information]. 5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.2)]. 5.5 Pregnancy ZOMETA SHOULD NOT BE USED DURING PREGNANCY. Zometa may cause fetal harm when administered to a pregnant woman. In reproductive studies in the pregnant rat, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure (an IV dose of 4 mg based on an AUC comparison) resulted in preand postimplantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. 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 a fetus [see Use In Specific Populations (8.1)]. 5.6 Musculoskeletal Pain In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes Zometa. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate [see Adverse Reactions (6.2)]. 5.7 Patients with Asthma While not observed in clinical trials with Zometa, there have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates. 5.8 Hepatic Impairment Only limited clinical data are available for use of Zometa to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zometa in these patients. 6 ADVERSE REACTIONS 6.1 Clinical Studies 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.

Hypercalcemia of Malignancy The safety of Zometa was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zometa 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials. Renal Toxicity Administration of Zometa 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4 mg is given as a 15-minute intravenous infusion. Zometa should be administered by intravenous infusion over no less than 15 minutes [see Warnings And Precautions (5) and Dosage And Administration (2) in the full prescribing information]. The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 3). Table 3 provides adverse events that were reported by 10% or more of the 189 patients treated with Zometa 4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug. Table 3. Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System Zometa Pamidronate 4 mg 90 mg n (%) n (%) Patients Studied Total No. of Patients Studied 86 (100) 103 (100) Total No. of Patients with any AE 81 (94) 95 (92) Body as a Whole Fever 38 (44) 34 (33) Progression of Cancer 14 (16) 21 (20) Cardiovascular Hypotension 9 (11) 2 (2) Digestive Nausea 25 (29) 28 (27) Constipation 23 (27) 13 (13) Diarrhea 15 (17) 17 (17) Abdominal Pain 14 (16) 13 (13) Vomiting 12 (14) 17 (17) Anorexia 8 (9) 14 (14) Hemic and Lymphatic System Anemia 19 (22) 18 (18) Infections Moniliasis 10 (12) 4 (4) Laboratory Abnormalities Hypophosphatemia 11 (13) 2 (2) Hypokalemia 10 (12) 16 (16) Hypomagnesemia 9 (11) 5 (5) Musculoskeletal Skeletal Pain 10 (12) 10 (10) Nervous Insomnia 13 (15) 10 (10) Anxiety 12 (14) 8 (8) Confusion 11 (13) 13 (13) Agitation 11 (13) 8 (8) Respiratory Dyspnea 19 (22) 20 (19) Coughing 10 (12) 12 (12) Urogenital Urinary Tract Infection 12 (14) 15 (15) The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with Zometa 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zometa. Acute Phase Reaction-like Events Symptoms consistent with acute phase reaction (APR) can occur with intravenous bisphosphonate use. Fever has been the most commonly associated symptom, occurring in 44% of patients treated with Zometa 4 mg and 33% of patients treated with Pamidronate 90 mg. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, flushing, bone pain and/or arthralgias, and myalgias. Mineral and Electrolyte Abnormalities Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, can occur with bisphosphonate use. Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of Zometa in patients with HCM are shown in Table 4 and 5. Table 4. Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 3 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

2/86 1/86 36/70 0/71

(2%) (1%) (51%) —

n/N

(%)

3/100 2/100 27/81 0/84

(3%) (2%) (33%) —

Table 5. Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM

Table 7. Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases

Grade 4 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Grade 3

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

0/86 0/86 1/70 0/71

— — (1%) —

1/100 0/100 4/81 1/84

(1%) — (5%) (1%)

Laboratory Parameter n/N Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

1Grade

3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) 3 (<7 mg/dL); Grade 4 (<6 mg/dL) 3Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) 4Grade 3 (<0.8 mEq/L); Grade 4 (<0.5 mEq/L) 2Grade

Injection Site Reactions Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours. Ocular Adverse Events Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zometa. No cases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing use [see Adverse Reactions (6.2)]. Multiple Myeloma and Bone Metastases of Solid Tumors The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2,042 patients treated with Zometa 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for Zometa 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors. Table 6 describes adverse events that were reported by ≥10% of patients. Adverse events are listed regardless of presumed causality to study drug. Table 6. Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System

Patients Studied Total No. of Patients Total No. of Patients with any AE Blood and Lymphatic Anemia Neutropenia Thrombocytopenia Gastrointestinal Nausea Vomiting Constipation Diarrhea Abdominal Pain Dyspepsia Stomatitis Sore Throat General Disorders and Administration Site Fatigue Pyrexia Weakness Edema Lower Limb Rigors Infections Urinary Tract Infection Upper Respiratory Tract Infection Metabolism Anorexia Weight Decreased Dehydration Appetite Decreased Musculoskeletal Bone Pain Myalgia Arthralgia Back Pain Pain in Limb

Zometa 4 mg

Zometa 4 mg n (%)

Pamidronate 90 mg n (%)

Placebo

1031 (100) 1015 (98)

556 (100) 548 (99)

455 (100) 445 (98)

344 (33) 124 (12) 102 (10)

175 83 53

(32) (15) (10)

128 (28) 35 (8) 20 (4)

476 333 320 249 143 105 86 82

(46) (32) (31) (24) (14) (10) (8) (8)

266 183 162 162 81 74 65 61

(48) (33) (29) (29) (15) (13) (12) (11)

171 122 174 83 48 31 14 17

(38) (27) (38) (18) (11) (7) (3) (4)

398 328 252 215 112

(39) (32) (24) (21) (11)

240 172 108 126 62

(43) (31) (19) (23) (11)

130 89 114 84 28

(29) (20) (25) (19) (6)

124 (12) 101 (10)

50 82

(9) (15)

41 30

(9) (7)

231 164 145 130

81 50 60 48

(15) (9) (11) (9)

105 61 59 45

(23) (13) (13) (10)

n (%)

(%)

7/529 6/973 115/973 19/971 1/971

(55) (23) (21) (15) (14)

316 143 131 106 84

(57) (26) (24) (19) (15)

284 74 73 40 52

Neoplasms Malignant Neoplasm Aggravated

205 (20)

(17)

89 (20)

Nervous Headache Dizziness (excluding vertigo) Insomnia Paresthesia Hypoesthesia

191 180 166 149 127

(19) (18) (16) (15) (12)

149 91 111 85 65

(27) (16) (20) (15) (12)

50 58 73 35 43

Psychiatric Depression Anxiety Confusion

146 (14) 112 (11) 74 (7)

95 73 39

(17) (13) (7)

49 (11) 37 (8) 47 (10)

Respiratory Dyspnea Cough

282 (27) 224 (22)

155 129

(28) (23)

107 (24) 65 (14)

Skin Alopecia Dermatitis

125 (12) 114 (11)

80 74

(14) (13)

36 38

(62) (16) (16) (9) (11)

(11) (13) (16) (8) (10)

(8) (8)

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of Zometa in patients with bone metastases are shown in Tables 7 and 8.

Placebo

(%)

4/268 4/536 38/537 2/535 0/535

(2%) (<1%) (7%) (<1%) —

n/N

(%)

4/241 0/415 14/415 8/415 1/415

(2%) — (3%) (2%) (<1%)

1Grade 3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) *Serum creatinine data for all patients randomized after the 15-minute infusion amendment 2Grade 3 (<7 mg/dL); Grade 4 (<6 mg/dL) 3Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) 4Grade 3 (>3 mEq/L); Grade 4 (>8 mEq/L) 5Grade 3 (<0.9 mEq/L); Grade 4 (<0.7 mEq/L)

Table 8. Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Grade 4 Laboratory Parameter

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

Zometa 4 mg

Pamidronate 90 mg

Placebo

n/N

(%)

n/N

(%)

n/N

(%)

2/529 7/973 5/973 0/971 2/971

(<1%) (<1%) (<1%) — (<1%)

1/268 3/536 0/537 0/535 1/535

(<1%) (<1%) — — (<1%)

0/241 2/415 1/415 2/415 0/415

— (<1%) (<1%) (<1%) —

Among the less frequently occurring adverse events (<15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa 4 mg and pamidronate groups) compared to the placebo group. Less common adverse events reported more often with Zometa 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the Zometa 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the Zometa 4 mg group (13%) compared with the pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear. Renal Toxicity In the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (≥1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zometa 4 mg over 15 minutes in these trials (see Table 9). Table 9. Percentage of Patients with Treatment Emergent Renal Function Deterioration by Baseline Serum Creatinine* Patient Population/Baseline Creatinine Zometa 4 mg n/N Normal Abnormal Total Solid Tumors

569 239 216 156 143

n/N

(1%) (<1%) (12%) (2%) (<1%)

Multiple Myeloma and Breast Cancer

(22) (16) (14) (13)

Pamidronate 90 mg

27/246 (11%) 2/26 (8%) 29/272 (11%) Zometa 4 mg n/N

Normal Abnormal Total Prostate Cancer Normal Abnormal Total

(%)

17/154 (11%) 1/11 (9%) 18/165 (11%) Zometa 4 mg n/N

(%)

12/82 4/10 16/92

(15%) (40%) (17%)

Pamidronate 90 mg n/N

(%)

23/246 (9%) 2/22 (9%) 25/268 (9%) Placebo n/N

(%)

10/143 (7%) 1/20 (5%) 11/163 (7%) Placebo n/N

(%)

8/68 (12%) 2/10 (20%) 10/78 (13%)

*Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of Zometa to 15 minutes. The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zometa (4 mg over 15 minutes), placebo, or pamidronate. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15-minute period. There have been instances of this occurring after the initial Zometa dose. 6.2 Postmarketing Experience The following adverse reactions have been reported during postapproval use of Zometa. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Osteonecrosis of the Jaw Cases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patients treated with intravenous bisphosphonates including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be a risk factor for ONJ. Data suggests a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged [see Warnings And Precautions (5)]. Musculoskeletal Pain Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphosphonate use [see Warnings And Precautions (5)]. Ocular Adverse Events Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.

Hypersensitivity Reactions There have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, and bronchoconstriction. Very rare cases of anaphylactic reaction/shock have also been reported. Additional adverse reactions reported in postmarketing use include:

CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; Gastrointestinal: dry mouth; Skin: increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchoconstriction; Renal: hematuria, proteinuria; General Disorders and Administration Site: weight increase; Laboratory Abnormalities: hyperkalemia, hypernatremia. 7 DRUG INTERACTIONS In-vitro studies indicate that zoledronic acid is approximately 22% bound to plasma proteins. In-vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In-vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug. However, no in-vivo drug interaction studies have been performed. 7.1 Aminoglycosides Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zometa clinical trials. 7.2 Loop Diuretics Caution should also be exercised when Zometa is used in combination with loop diuretics due to an increased risk of hypocalcemia. 7.3 Nephrotoxic Drugs Caution is indicated when Zometa is used with other potentially nephrotoxic drugs. 7.4 Thalidomide In multiple myeloma patients, the risk of renal dysfunction may be increased when Zometa is used in combination with thalidomide. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy ZOMETA SHOULD NOT BE USED DURING PREGNANCY. There are no studies in pregnant women using Zometa. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant [see Warnings And Precautions (5.4)]. Pregnancy Category D Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (≥0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (with a systemic exposure of ≥0.07 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality may have been related to drug-induced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonateclass effect. In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse effects included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects observed in the highdose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the lowdose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study. In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (≤0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas), no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatment groups (at doses ≥0.05 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia.

8.3 Nursing Mothers It is not known whether Zometa is excreted in human milk. Because many drugs are excreted in human milk, and because Zometa binds to bone long term, Zometa should not be administered to a nursing woman. 8.4 Pediatric Use Zometa is not indicated for use in children. The safety and effectiveness of zoledronic acid was studied in a one-year active-controlled trial of 152 pediatric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesis imperfecta, aged 1-17 years, 55% male, 84% Caucasian, with a mean lumbar spine BMD of 0.431 gm/cm2, which is 2.7 standard deviations below the mean for age-matched controls (BMD Z-score of -2.7). At one year, increases in BMD were observed in the zoledronic acid treatment group. However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zometa use in children did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemia of malignancy or bone metastases. However, adverse reactions seen more commonly in pediatric patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia, occurred most frequently within 3 days after the first infusion and became less common with repeat dosing. Because of long-term retention in bone, Zometa should only be used in children if the potential benefit outweighs the potential risk. Plasma zoledronic acid concentration data was obtained from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3-8 years and 6 in the age group of 9-17 years) infused with 0.05 mg/kg dose over 30 min. Mean Cmax and AUC(0-last) was 167 ng/mL and 220 ng.h/mL, respectively. The plasma concentration time profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed in adult cancer patients at an approximately equivalent mg/kg dose. 8.5 Geriatric Use Clinical studies of Zometa in hypercalcemia of malignancy included 34 patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zometa as compared to younger patients. Controlled clinical studies of Zometa in the treatment of multiple myeloma and bone metastases of solid tumors in patients over age 65 revealed similar efficacy and safety in older and younger patients. Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function. 10 OVERDOSAGE Clinical experience with acute overdosage of Zometa is limited. Two patients received Zometa 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively. In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose. A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100U/L, each value unknown). The outcome of this case is not known. In controlled clinical trials, administration of Zometa 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, Zometa 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zometa 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [see Dosage And Administration (2.4) in the full prescribing information]. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

REV: OCTOBER 2009 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland for Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

T2009-101

35TH ESMO CONFERENCE

High Cost to Managing Colorectal Cancer Toxicities By Caroline Helwick Milan—Because the toxicity profiles for the 3 monoclonal antibodies used in treating metastatic colorectal cancer (mCRC) differ, there are substantial differences in the cost of treating side effects, according to research presented at the 35th ESMO Congress.

events, and thrombotic events, and “febrile neutropenia” included infection, leukopenia, and neutropenia. Costs for the toxicities in the inpatient setting (grade 4) were estimated using 2007 Medicare payment schedules. For the outpatient setting (grade

“The cost of treating toxicities can inform the evaluation of the clinical and cost-effectiveness of monoclonal antibodies in managing patients with mCRC.”

curred with cetuximab and panitumumab—were among the least costly inpatient toxicities at $4424 and $6174, respectively, Dr Burudpakdee reported. For outpatients, costs were minimal, ranging from $185 for hypertension and rash to $585 for wound healing complications. Dr Burudpakdee acknowledged the

study’s limitations. The development of a comprehensive and standardized list of toxicities is limited by the variability among the trials (eg, sample sizes and differences in reporting or defining grade 3-4 adverse events of interest). Outpatient resource use was based on best clinical judgment and may not reflect all clinical practices, nor does it include outpatient drug use. ■

Table Major Inpatient Toxicity Costs

—Chakkarin Burudpakdee, PharmD Toxicity “The cost of treating toxicities can inform the evaluation of the clinical and cost-effectiveness of monoclonal antibodies in managing patients with mCRC,” said lead author Chakkarin Burudpakdee, PharmD, of IMS Health in Philadelphia, a healthcare market intelligence company. Bevacizumab, cetuximab, and panitumumab have different toxicity profiles but little is known about the direct costs for managing these toxicities. The study aimed to provide this information, he said. A comprehensive PubMed search identified 23 phase 2 and 3 trials evaluating these agents in mCRC. American Society of Clinical Oncology and ESMO websites were searched for abstracts (years 2008-2010), and package inserts were reviewed for toxicity data. For the purpose of estimating treatment costs for grade 3-4 toxicities, the identified toxicities were placed into representative groupings based on similarities in event type and treatment approach. For example, the “deep vein thrombosis” group included deep vein thrombophlebitis, venous thrombotic

3), in-depth clinical interviews were conducted to obtain resource use, then 2010 Medicare reimbursement rates were applied. All inpatient and outpatient costs were converted to 2010 values. Substantial Costs for Grade 4 Side Effects In total, 61 toxicities were identified in the studies. Clinically significant toxicities associated with bevacizumab included hypertension, arterial thrombosis, hemorrhage, gastrointestinal perforation, fistula, and wound healing complications. Treatment-related toxicities associated with cetuximab and panitumumab included skin rash, hypomagnesemia, and infusion reactions. The inpatient cost per event for gastrointestinal perforation was the highest ($32,443), followed by fistula ($29,062), arterial thrombosis ($20,346), wound healing complications ($13,240), hemorrhage ($12,956), infusion reaction ($10,877), and hypertension ($8453). Other, less common toxicities were also costly (Table), but skin rash and hypomagnesemia—which oc-

Gastrointestinal perforation

32,443

Fistula

29,062

Arterial thrombosis

20,346

Wound healing complication

13,240

Peripheral neuropathy

13,113

Interstitial lung disease

13,001

Hemorrhage

12,956

Febrile neutropenia

12,606

Pulmonary embolism

11,411

Infusion reaction

10,877

Renal failure

10,688

Reversible posterior leukoencephalopathy syndrome

10,116

Deep vein thrombosis/thrombophlebitis

8748

Hypertension

8453

Failure to thrive

8104

Urinary tract infection

6890

Anemia

6219

Hypomagnesemia

6174

Significant Impact for New Prostate Cancer... deprivation therapy (ADT), as do the adrenal glands. Abiraterone targets both adrenal and intratumoral androgen biosynthesis.

In the history of prostate cancer, only 4 drugs have ever shown a survival benefit. Response on Multiple End Points Dr de Bono reported findings from a multicenter study involving 1195 men with CRPC that had proved unrespon-

sive to docetaxel, in addition to conventional ADT. The patients were randomized 2:1 to prednisone plus abiraterone or placebo, and the primary end point was OS. In addition to the survival advantage, all secondary end points showed superiority for abiraterone acetate over placebo: • Time to prostate-specific antigen (PSA) progression, 10.2 versus 6.6 months; P <.001 • Radiologically confirmed progression-free survival, 5.6 versus 3.6 months; P <.001 • PSA response, 38% versus 10%; P <.001.

VALUE-BASED CANCER CARE

Nov/Dec 2010

Cost per event, $ (2010)

Continued from cover

Subgroup analysis showed consistent effects of treatment with abiraterone. Patients treated with abiraterone had a higher incidence of edema (30.5% vs 22.3%) and hyperkalemia (17.1% vs 8.4%). Abnormal liver function tests and cardiac disorders occurred in a similar proportion of patients in both groups, and grade 3-4 adverse events were uncommon in both groups. Impressive Results, Expensive Potential Invited discussant Cora Sternberg, MD, a genitourinary oncologist at Camillo Forlanini Hospital in Rome, said the study yielded “the most

impressive results that I’ve seen in a long time, in this patient population.” Abiraterone is the farthest along in development of several new antiandrogens under investigation and could lead the way toward new treatment strategies for CRPC, added Dr Sternberg. Dr de Bono said the findings create a potential for novel combination strategies, such as abiraterone and the recently approved immunotherapeutic agent sipuleucel-T (Provenge). Such combinations would have substantial cost implications, given the $93,000 price tag for a single course of the sipuleucel-T, which has yet to win approval for Medicare reimbursement. ■

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35TH ESMO CONFERENCE

Benefit to Longer Chemotherapy in Metastatic Breast Cancer By Charles Bankhead Milan—Continuing first-line chemotherapy for metastatic breast cancer until disease progression significantly improves overall (OS) and progression-free survival (PFS), according to a meta-analysis reported at the 35th ESMO Congress Prolonged therapy was associated with a 9% reduction in the mortality hazard and a 36% reduction in hazard for progression, and the results should provide information to aid decisionmaking about the duration of chemotherapy for metastatic breast cancer, said researcher Alessandra Gennari, MD, a medical oncologist at Galliera Hospital in Genova, Italy.

The optimal duration of first-line chemotherapy for metastatic breast cancer has yet to be defined. “The magnitude of the effect was consistent across all subgroups, suggesting the benefit reflected the impact of the duration of chemotherapy,” said Dr Gennari. The optimal duration of first-line chemotherapy for metastatic breast cancer has yet to be defined, leaving tolerability to dictate how long therapy continues for most patients. In an effort to clarify the potential benefits, Dr Gennari and colleagues performed a meta-analysis of 11 published clinical trials comparing different durations of chemotherapy in 2269 patients with newly diagnosed metastatic breast cancer. The principal objectives were to determine whether continuing chemotherapy beyond a prespecified number of cycles improves PFS and OS. Benefits and Lingering Questions Overall, longer duration of chemotherapy was associated with a mortality hazard ratio of 0.91 (P = .04) and a progression hazard ratio of 0.34 (P <.001). By meta-regression analysis, the findings remained independent of the time of randomization, study design, number of chemotherapy cycles in the control arm, and coadministration of endocrine therapy. Noting lack of evidence for a survival benefit with prolonged chemotherapy in metastatic breast cancer, the National Comprehensive Cancer Network clinical guidelines point out that the potential benefits should be weighed against potentially detrimental effects of longer-duration chemotherapy for every patient. The survival benefit and reduced

risk of progression observed in the meta-analysis provide justification for clinicians to recommend that patients continue chemotherapy until disease progression or until they can no longer

tolerate the therapy, said Dr Gennari. However, she acknowledged that several key issues remain unresolved, including the optimal duration of therapy, planned sequential therapies ver-

sus prolonged use of a single agent, the role of targeted therapies in prolonged treatment, and the economics of continuing therapy beyond a predetermined number of cycles. ■

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www.ValueBasedCancer.com

ECRI PERSONALIZED MEDICINE CONFERENCE

Determining Coverage for CER and Personalized Medicine Bends in the road on path to payment By Colin Gittens Bethesda, MD—Greater adoption of personalized medicine and comparative effectiveness research (CER) in healthcare will depend on coverage of these approaches by public and private payers. But payer evaluation of these approaches is hampered by legislative roadblocks and a lack of research in CER and slowness in adopting CER into clinical practice, according to speakers at a session of the ECRI Institute’s Comparative Effectiveness and Personalized Medicine: An Essential Interface conference.

ting had been done. The danger, he fears, is that personalized medicine may be thought of as giving physicians “carte blanche” to try treatments that are outside the evidence. In addition, before wading into the complexities of genomics, CER, and coverage issues, Dr Newcomer also cautioned that more prosaic comparative effectiveness matters need to remain in the forefront of consciousness. For example, 2 studies in the same issue of the New England Journal of Medicine looked at adjuvant chemo-

The danger is that personalized medicine may be thought of as giving physicians “carte blanche” to try treatments that are outside the evidence. —Lee Newcomer, MD For Lee Newcomer, MD, Senior Vice President of Oncology at United Healthcare, CER is a positive development, one that might weed out outmoded therapies, focus innovation, reduce toxicities, and allow rational pricing for competing therapies. Ultimately, it should accelerate the better use of healthcare resources. Personalized medicine will need to be evidence based, and for Dr Newcomer, CER is the way to supply that evidence. But in discussing UnitedHealthcare’s experience with physicians’ use of bevacizumab (Avastin), Dr Newcomer recounted how data showed that physicians were using this drug in the adjuvant setting, before any trials in that set-

at a glance ➤ Comparative effectiveness research (CER) may help to weed out outmoded therapies, focus innovation, reduce toxicities, and allow rational pricing for competing therapies ➤ CER can also help inform individual patients on which approach of several might be the best fit for them ➤ CER cannot be the sole basis for coverage determinations at the Centers for Medicare & Medicaid Services, but it may nevertheless influence the process

therapy with standard chemotherapy versus adjuvant chemotherapy with trastuzumab in breast cancer, and the first one indicated more complications with what has become the standard treatment approach in the United States (52 weeks of trastuzumab therapy [Romond EH, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673-1684]). The second study indicated 12 weeks of therapy was efficacious and did not cause the cardiac side effects seen in the first study (Joensuu H, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006; 354:809-820); nevertheless, there has been no outcry in the advocacy community for a comparative effectiveness study in this area. Research downstream from the original investigations has much potential value, he suggested. “That part of comparative effectiveness would benefit patients dramatically.” A second example offered by Dr Newcomer discussed the role of CER in evaluating various therapies for prostate cancer. Newer, increasingly expensive radiation therapies, including intensity-modulated radiation therapy, stereotactic body radiosurgery, and proton beam therapy, have all gained wide acceptance, despite a lack of comparative effectiveness studies on them. CER would help inform individual patients on which approach might be the best fit for them.

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Right now, we have “lots of technologies, and no idea how to use them [effectively],” he lamented. Evidence informs good decisions, Dr Newcomer stressed, and although some therapies may go away through the use of CER, they may disappear for the right reasons. Covering CER: the Public Side As a public payer responsible for more than 114 million American lives, the Centers for Medicare & Medicaid Services (CMS) is also dealing with covering personalized medicine and CER, albeit at a much greater scope. As noted by Barry M. Straube, MD, Chief Medical Officer and Director at the Office of Clinical Standards and Quality at CMS, those deliberations are shaped by the legislation that details what is covered and how CER information can and cannot be used. In some ways, Dr Straube acknowledged, CMS is still struggling to understand the intent of coverage language in bills crafted 40 years ago. Medicare coverage outlined under section 1862(a)(1) of the Social Security Act specified coverage is required for items and services deemed “reasonable and necessary for

healthcare reform, is also proscribed from developing or employing a dollars/quality-adjusted life-year threshold. Although Congress has legislated that cost-effectiveness is not allowed to be a factor in coverage determination, it is allowed under the Medicare Improvements for Patients and Providers Act of 2008 (Section 101), which covers preventive services. Whether personalized medicine is defined as a preventive service remains to be seen. So “although there’s been the mandate to do more comparative effectiveness research, clearly we have limitations,” Dr Straube acknowledged. There are difficulties in drafting coverage for CER, Dr Straube pointed out. If CER determines that a test or technology is far better than others, that single item may be the only one covered. But if something then prevents that technology from being used (ie, a manufacturing problem), there may be no reimbursable treatment. Patient outliers to approved treatments may also be left out if CER is adhered to as a strict doctrine. Legislation also must be carefully drafted so that unintended consequences do not crop up. A question from the audience, for example, pointed

Although CMS agrees that genetic counseling is a necessary service, the law does not allow this reimbursement. —Barry M. Straube, MD

the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.” According to Dr Straube, CMS has defined “reasonable and necessary” as demonstrating adequate evidence to conclude that the item or service or test improves clinically meaningful health outcomes for the Medicare population. And in evaluating therapies, he emphasized, CMS examines the new therapy compared to usual care, not another device or therapy. So a shift to using CER will require a fundamental change. But the healthcare reform law states explicitly that cost should not be a factor in coverage determinations, and that coverage cannot be denied “solely on the basis” of CER. Further, the Patient Centered Outcomes Research Institute, an independent advisory committee being set up as part of

out that genetic counselors are not considered providers and are therefore not reimbursed under Medicare. Although CMS agrees that genetic counseling is a necessary service, the law does not allow this reimbursement, and the ultimate solution will require further legislation, said Dr Straube. Finally, Dr Straube mentioned recommendations regarding CMS coverage for genetic testing arising from 2 Medicare Evidence Development & Coverage Advisory Committee meetings. These committees recommended the evidence standards for genetic and genomic testing need to be high. As Dr Straube noted at the outset of his presentation, when patients start coming in to medical offices, requesting access to the latest genetic tests and the treatments that result from them, the enormity of costs to society are frightening. ■

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Other pathways can contribute to prostate cancer promotion.5 References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68(15):6407-6415. 3. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66(5):2815-2825. 4. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11(13):4653-4657. 5. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12(6):1665-1671.

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ECRI PERSONALIZED MEDICINE CONFERENCE

CER and Personalized Medicine Face Hurdles Concept needs better understanding by research community and general public By Colin Gittens Bethesda, MD—Implementing and effectively using comparative effectiveness research (CER) and personalized medicine (PM) will require time and better communication among the research community conducting these types of studies and with the public that will be impacted by them, according to participants in a panel discussion on the societal implications of CER and PM held during the ECRI Institute’s Comparative Effectiveness and Personalized Medicine: An Essential Interface conference. For David Meltzer, MD, PhD, Associate Professor in the Department of Medicine at the University of Chicago, the flood of additional information provided by CER and PM may not necessarily be helpful in a system where individuals are disconnected from paying costs. For him, aspects of healthcare reform—increased patient costs and David Meltzer, MD, PhD copayments, bundled payments, and accountable care organizations—will have the beneficial effect of reconnecting patients with costs, thereby realigning incentives. CER will be essential for delineating the benefits and costs of care, and in cancer, PM will determine the highcost, low-value treatments that should not be used by most patients. Frances Miller, JD, Professor of Law at Boston University School of Law and Professor of Public Health at Boston University School of Public Health, also emphasized that innovations in CER and PM are inextricably linked to reimbursement. Describing that linkage as the “800-lb gorilla,” she wondered how to get the public to accept that link. She also expressed concern that the potentially ambiguous concepts of CER and PM may go over the heads of the American public, especially given the current climate surrounding health reform. “Everyone here to a greater or lesser extent accepts the value of comparative effectiveness and the promise of personalized medicine,” she said, referring to those attending the conference. Among the larger American population, however, “the level of accurate information is shockingly low.” Given the threat of healthcare reform repeal and challenges to the individual insurance mandate, Dr Miller said, “I’m worried.”

Also concerned was Gail Wilensky, PhD, Economist and Senior Fellow at Project Hope. Noting the attempts to paint CER as anti-individualized and intended to prevent people from receiving therapies from which they might benefit during the healthcare

“For goodness sake, stop talking about QALYs and DALYs when you’re out in public.” —Gail Wilensky, PhD

reform debate, Dr Wilensky pointed out that the current system does not provide adequate information on who is likely to benefit, particularly from complex, expensive therapies. Examining how conditions might be treated in varied groups is precisely the direction that PM and CER should be taking the country, she argued. This will get treatments beyond the “on average” approach. Advancing the CER/PM Agenda Reframing the terminology—think “patient-centered outcomes research” rather than CER—is one of several ways suggested by Dr Miller to foster CER and PM among the general public and keep the debate about these approaches rational. In addition, pointing out that similar types of research have long been conducted (ie, whether clinical trials for drugs and devices or research in the Veterans Administration

at a glance ➤ Comparative effectiveness research (CER) and personalized medicine (PM) may not necessarily be helpful in a system where individuals are disconnected from paying costs ➤ The current healthcare system does not provide adequate information on who is likely to benefit from complex, expensive therapies, and CER and PM may be helpful in this regard ➤ Simplifying the discourse about PM and CER may contribute to its wider acceptance by the general public

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setting) may also be helpful. Finally, she urged attendees to control the agenda and momentum, emphasizing that patient-centered medicine and effectiveness data will mean better care for individuals. She acknowledged, however, that this is a tough message to get across in the face of all the wellfinanced opposition that’s out there. For Dr Meltzer, CER and PM will help researchers get smarter about which studies will be valuable and what treatments may be obsolete, but only if the research is conducted in the real environments where care takes place. In addition, questions about the role of the public and private sectors in CER have created uncertainty in both those domains.

formularies because they are taking us in a lower-cost direction, we may see tiered pricing as well. Better communication among the research community is also essential to furthering CER’s use, according to session moderator Sean Tunis, MD, MSc, Founder and Director of the Center for Medical Technology Policy. Improving the discourse will depend on recognizing common themes and achieving mutual understanding within the community that does this work. “We have to recognize that there are really dramatic differences in perspective among the players in such areas as priority setting and methods, and we can’t continue to paper these over,” he said. One other potential confounder to

“We have to recognize that there are really dramatic differences in perspective among the players, and we can’t continue to paper these over.” —Sean Tunis, MD, MSc

For many, the specter of randomized clinical trials (RCTs) hangs over CER. Many stakeholders will only be convinced by data from an RCT, Dr Wilensky suggested, but she is hopeful that statistical approaches to data collection and analysis will gain traction as part of CER. J. Sanford (Sandy) Schwartz, MD, Leon Hess Professor of Medicine and Health Management and Economics at the Leonard Davis Institute of Health Policy and Economics, echoed the need for new approaches during the question session, saying “what we’re doing now is fundamentally different.” We need to figure out new methodologies and policies to support CER, he said, and this will take time. Although legislators will expect data tomorrow, he pointed out, “it’s going to take 3 to 5 years before data start coming out, if we’re lucky.” On the public side, Dr Wilensky suggested that the concepts of value-based reimbursement and value-based insurance will be essential in fostering public acceptance of CER and PM. In addition, plain speaking from researchers would be helpful—as she put it, “for goodness sake, stop talking about QALYs and DALYs [disability-adjusted life years] when you’re out in public.” For Dr Miller, tiered formularies offer an example of how the public might come to accept these new approaches. Pointing out that there has not been too much resistance to tiered

greater use of CER and PM may arise from planned cooperation between the US Food and Drug Administration and Centers for Medicare & Medicaid Services regarding approval and coverage. For Dr Wilensky, it is important to keep the functions of the 2 agencies separate, because coverage is very different from reimbursement. “CER is a reimbursement tool and not a coverage tool,” she posited. Dr Tunis sees parallel review as a good step, saying that from a product developer’s standpoint, it is not feasible to conduct 2 sets of required studies. For now, Dr Meltzer wondered if anything will change. The ascendance of CER and PM is a slow continuation of a process that will create ambiguity before it creates clarity and saves money. And given the many difficulties to implementation raised during the session, Dr Tunis summarized that the real challenge will be “to reconcile different public policy objectives while retaining the scientific integrity that is required.” ■

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References: 1. Gregory CW, Johnson RT Jr, Mohler JL, French FS, Wilson EM. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res. 2001;61:2892-2898. 2. Holzbeierlein J, Lal P, LaTulippe E, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgenresponsive genes and mechanisms of therapy resistance. Am J Pathol. 2004;164(1):217-227. 3. Yu S-Q, Lai K-P, Xia S-J, Chang H-C, Chang C, Yeh S. The diverse and contrasting effects of using human prostate cancer cell lines to study androgen receptor roles in prostate cancer. Asian J Androl. 2009;11(1):39-48. 4. Corey E, Quinn JE, Buhler KR, et al. LuCaP 35: a new model of prostate cancer progression to androgen independence. Prostate. 2003;55(4):239-246. 5. Loberg RD, St. John LN, Day LL, Neeley CK, Pienta KJ. Development of the VCaP androgen-independent model of prostate cancer. Urol Oncol. 2006;24(2):161-168.

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TARGETED THERAPY

Cancer Drugs: NICE Rejects Costly Treatments By Caroline Helwick

he floodgate has opened for molecularly targeted antitumor agents, and with each novel compound the cost of treating cancer soars ever higher. Approval by the US Food and Drug Administration (FDA) is usually based on a delay in disease progression, but just a 2-month benefit may be statistically significant in large randomized phase 3 trials. In contrast, the United Kingdom’s National Health Service (NHS) and its advisory branch, the National Institute for Health and Clinical Excellence (NICE), have been less supportive of their use.

approval in the United States: • Sorafenib (Nexavar) for the treatment of advanced hepatocellular carcinoma, stating “its high cost could not be justified by its marginal benefit.” Trial evidence showed that sorafenib increases survival by an average of 2.8 months, but at a cost of £27,000 per patient • Lapatinib (Tykerb) in combination with capecitabine (Xeloda) for advanced or metastatic HER2-positive breast cancer outside of clinical trials. Although GlaxoSmithKline has offered the drug free for the first 12 weeks of treatment, NICE said that lapatinib

NICE provides guidance to the NHS on the effective use of everlimited resources. In the past year or so, it has recommended against approval of the following targeted agents. NICE provides guidance to the NHS on the effective use of ever-limited resources. In the past year or so, it has recommended against approval (although some decisions are preliminary and still open to appeal; see www. nice.org.uk) of the following targeted agents, which have received FDA

“did not represent good value for the money when compared with the alternative, currently available treatment.” Lapatinib plus capecitabine costs approximately £25,207 annually • Bevacizumab (Avastin) in combination with a taxane for advanced breast cancer. The committee members

noted that although bevacizumab delays progression by 5.5 months over paclitaxel alone, they thought that an additional 1.7 months in overall survival (OS) is not clinically meaningful. Their report stated, “When bearing in mind the uncertainties over survival rates and quality-of-life data, the committee concluded that the cost of bevacizumab is too high for the limited and uncertain benefit it may offer patients.” NICE determined the incremental cost-effectiveness ratio (ICER) for bevacizumab plus a taxane is £115,000 to £259,000 per quality-adjusted life-year (QALY) gained • Erlotinib (Tarceva) for maintenance treatment of advanced non– small-cell lung cancer after completion of first-line therapy. “Erlotinib has been shown to have some clinical benefit, with the manufacturer estimating it can potentially extend life by approximately 3.3 months, however, our independent advisory committee felt…the overall cost of erlotinib had been underestimated…and the cost of the drug related to the benefits it brings means that erlotinib would not be a good use of NHS money,” the committee maintained. The ICER was estimat-

ed to exceed £59,000 per QALY gained • Ofatumumab (Arzerra) for chronic lymphocytic leukemia that is refractory to fludarabine and alemtuzumab. The appraisal committee concluded that the data, which are centered on interim results from a small subgroup of patients in an ongoing clinical trial, was not robust enough to show an OS benefit over best supportive care. “This uncertainty, combined with the additional cost of ofatumumab… meant the committee could not recommend the drug as an efficient use of NHS resources,” the report stated. The drug costs £182 per 100-mg vial, and the ICERs were figured at >£81,500 per QALY • Everolimus (Afinitor) for the second-line treatment of advanced renal cell carcinoma. “Even with the patient access scheme incorporated (first treatment free to the NHS and subsequent treatments discounted), the additional weight that would need to be assigned to the QALY benefits would be too great to fall within the range currently considered cost-effective,” the report stated. Cost-effectiveness was estimated at £58,300 per QALY. ■

Some Biologics Fail in Early-Stage Tumors

ome molecularly targeted agents are proving to be less effective, not more so, when administered earlier in the disease course. Researchers say this is counterintuitive, because advanced disease is associated with treatment refractoriness, and cancer agents will typically perform better in the adjuvant treatment setting than in the metastatic treatment setting. One such “failure” made headline news last summer, when results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-08 trial were announced at the American Society of Clinical Oncology (ASCO) annual meeting. Unexpectedly, bevacizumab did not improve outcomes in early-stage colon cancer, although it had become a standard treatment in advanced colon cancer. “We failed, and nobody likes to fail,” Norman Wolmark, MD, principal investigator, commented at a press conference. “Actually, it wasn’t bevacizumab that failed. If anything, we failed to provide our patients with a novel intervention that would increase cures.” The NSABP randomized 2710 patients with stage II and III colorectal cancer to a standard chemotherapy reg-

imen or the same plus bevacizumab for 6 additional months. At a median follow-up of 36 months, disease-free survival (DFS) was 75.5% in the control arm and 77.4% in the bevacizumab arm (hazard ratio, 0.89; P = .05). A significant benefit was, however, observed for the 1 year that patients were actually taking bevacizumab: a 3.6% absolute improvement in DFS and a 40% relative

trial of 1847 patients with colon cancer selected for the presence of nonmutated (wild-type) KRAS tumors (which are associated with cetuximab’s benefit in advanced disease), the addition of cetuximab provided no value over standard chemotherapy alone. Threeyear DFS was approximately 74% in each arm, and 3-year overall survival (OS) was 87% with chemotherapy and

“It is yet to be demonstrated that a targeted agent improves overall survival in NSCLC in the adjuvant setting, and, for the present, chemotherapy in good performance patients remains the treatment of choice.” —Glenwood D. Goss, MD risk reduction (P = .004). “So bevacizumab was effective, but this efficacy disappeared after bevacizumab was stopped,” Dr Wolmark said. “The challenge is to learn how to use bevacizumab to its maximum potential in the adjuvant setting.” Equally surprising was the recent announcement that cetuximab (Erbitux) confers no benefit for stage III resected colon cancer. In a randomized phase 3

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82% with chemotherapy plus cetuximab (P = .06), reported investigator Steven R. Alberts, MD, at the ASCO 2010 annual meeting. These findings, while disappointing, have important implications, according to Dr Alberts. “For one thing, what we learn in metastatic disease does not always apply to the adjuvant setting,” he said. “The findings also indicate that disease in earlier stages may be differ-

ent from disease in later stages.” Jennifer Obel, MD, of NorthShore University HealthSystem in Evanston, IL, commented that this study, combined with others, “casts doubt on whether biologics will play a role in early-stage colon cancer.” And in earlystage non–small-cell lung cancer (NSCLC), the epidermal growth factor receptor (EGFR) inhibitor gefitinib (Iressa) failed to provide benefit over resection alone in a Canadian study of 503 patients with resected stage IB-IIIA NSCLC. In an exploratory analysis, the presence of EGFR-sensitizing mutations (which are associated with response to EGFR inhibitors in advanced disease) were not predictive of a survival benefit, reported Glenwood D. Goss, MD, and colleagues from the Ottawa Hospital Research Institute in Canada. OS was 5.1 years in the placebo arm and 3.7 years in the gefitinib arm in patients with EGFR mutations. “It is yet to be demonstrated that a targeted agent improves overall survival in NSCLC in the adjuvant setting, and, for the present, chemotherapy in good performance patients remains the treatment of choice,” Dr Goss concluded.—CH ■

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CLINICAL RESEARCH

Restoring Balance to the Cancer Research Regulation Equation By Colin Gittens

linical cancer research is hampered by an overly complex and cautious regulatory system, which slows the development of lifesaving drugs, increases costs, and may be unethical, according to David J. Stewart, MD, of the University of Texas M.D. Anderson Cancer Center and colleagues (Stewart DJ, et al. Equipoise lost: ethics, costs, and the regulation of cancer clinical research. J Clin Oncol. 2010;28:2925-2935). Because of the urgency associated with a lethal disease such as cancer, there is a need to restore the balance between adequate safety regulation and innovation, say the authors. Among the many agencies, laws, and regulations that govern clinical research are institutional review boards (IRBs), the US Food and Drug Administration, the Office of Human Research Protections, the National Cancer Institute, the Cancer Therapy Evaluation Program, the Clinical Laboratory Improvement Amendments (CLIA) section of the Centers for Medicare & Medicaid Services, the Department of Health and Human Services, the Department of Veterans Affairs, the Internal Revenue Service, the Office of the Inspector General, the Patent and Trademark Office, and the Joint Commission. Although these overseeing bodies serve to prevent patient harm, the combined impact of this regulatory oversight is large—and negative—say the authors. The Scope of the Problem The slow pace of clinical trials resulting from regulatory bottlenecks hin-

ders activation of trials and wastes researcher and patient time. Regulatory requirements also drive up research costs. In examining whether regulation has actually increased

participation through restrictive eligibility and impractical study schedules. The number of physician-researchers has also declined, perhaps because of the burdens of running a trial.

Regulations have slowed the pace of research; time from drug discovery to marketing has reached 12 to 15 years today compared with 8 years in the 1960s.

patient safety, the authors looked at mortality in phase 1 clinical research between 1972 and 2002 and found that the more stringent regulations reduced the toxic death rate by no more than 0.3%. Increasing protocol complexity and the number of tests mandated by protocol have served to push the average cost to $26,000 to enter a patient into a clinical trial. The cost per lifeyear saved when all regulations are factored in is approximately $2.7 million; the consensus among oncologists is that $100,000 per life-year gained is good value. Higher costs also mean that fewer organizations are able to conduct trials, and that the number of testable ideas is reduced. Concentrating research in the hands of a few pharmaceutical firms can limit combined testing of agents from different firms, lessen explorations for rare diseases, and curb higherrisk strategies. Regulations have slowed the pace of research; time from drug discovery to marketing has reached 12 to 15 years today compared with 8 years in the 1960s. This slowing discourages patient

Streamlining the Regulatory Approach In terms of general principles, the authors argue that acceptable risk in clinical research should be substantially higher for uniformly fatal diseases compared with potentially curable conditions. The key is to inform patients of the risk, rather than presume for them what risks they should be allowed to take. The regulatory burden should also be adjusted

The key is to inform patients of the risk, rather than presume for them what risks they should be allowed to take. based on the population under study, and the authors push for a new, single regulatory body focusing on lethal diseases only to streamline this process. Other, more specific recommendations include:

• Reform toxicology and pharmacology procedures, testing subjects only for P450 interactions • Streamline study review to no more than 2 agencies, and centralize IRB review in multiinstitutional studies • Streamline reporting of adverse events, and centralize information on drug toxicity • Modify protocol adherence to acknowledge degrees of deviation. The definition of protocol violation should be changed to an event where the patient was harmed or the integrity of the data was compromised • Refocus documentation requirements on what truly matters, not trivial events • Simplify healthcare payment systems for patients in trials • Allow assignment of patients for therapy, even when laboratory tests are not CLIA-certified • Adjust study randomization so that studies are capable of showing large gains in a small population • Efficacy biomarkers should be identified initially based on their correlation with tumor shrinkage, not survival. The authors conclude that the current process “seems to be unethical and squanders research resources.” Targeting the subpopulations likely to benefit most from a therapy at the outset (ie, from the earliest phase 1 and 2 studies), among other strategies, would help restore the imbalance between the costs of life-years lost and gained as it exists under the current system. Regulations that do not add large demonstrable value should be discarded, they say. ■

ASCO Shares Concerns Over the Future of Cancer Research

effective clinical trials program. In addition, given new therapeutic approaches, it may be necessary to consider new ways of conducting trials. Among the George W. Sledge, Jr, MD challenges faced by researchers is inadequate existing infrastructure for biomarker analysis and the need to screen high numbers of patients to determine trial eligibility. In addition, understanding of cancer biology and the drivers of cancer development in multiple patients (with different patients having different drivers) is still emerging. Recruiting patients into

Photo by © ASCO/Todd Buchanan 2010

oncerns about the future of cancer research exist among the spectrum of researchers and regulators, and in remarks prepared for the President’s Cancer Panel: The Future of Cancer Research—Accelerating Scientific Innovation (held September 22, 2010, in Boston), American Society of Clinical Oncology (ASCO) President George W. Sledge, Jr, MD, outlined some of the organization’s concerns regarding new biological therapies and the future of cancer research. The pace of trials has slowed even as the amount of targeted therapies has increased, he noted, and it is essential to have adequate funding and an adequately trained national research capability to maintain a comprehensive and

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clinical trials can be done at the community level, but not unless the current low payment levels are increased.

Trials should also change with new technological developments. ASCO calls for a doubling of National Cancer Institute–funded cooperative clinical research to reinvigorate that system and ensure its future. In addition, the group emphasizes the importance of electronic health records to help drive clinical research. The regulatory schema also needs simplifying, Dr Sledge wrote. Processes concerning institutional review boards

(IRBs), informed consent, privacy rules, regulations surrounding the conduct of clinical trials, and the evaluation of efficacy end points need to be overhauled. Echoing the proposals of others, he suggests a centralized IRB review, a standard case report form, and a single approach across all sites. Trials should also change with new technological developments, he argued, writing that “the incorporation of bioinformatic principles into clinical trial methodology is in its infancy, but [this] represents a clear requirement for future progress in the genomic era.” To ensure that investigators capable of conducting these types of trials are trained, Dr Sledge argued the necessity of a “trained, incentivized clinicaltranslational workforce.”—CG ■

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For your patients receiving or about to start treatment with DOXIL® for recurrent ovarian cancer or relapsed/refractory multiple myeloma…

DOXIL® C.A.R.E.S. Provides Help and Support DOXIL® C.A.R.E.S. Complements the Efforts of the Healthcare Team With: ◗ Treatment follow-up — Regularly scheduled telephone calls from oncology nurses to review lifestyle tips to help manage potential side effects of DOXIL® therapy such as hand-foot syndrome and stomatitis ◗ Patient education materials Invite your patients to enroll in DOXIL® C.A.R.E.S.: 1-877-CARES-49 (1-877-227-3749) Monday to Friday, 9:30 AM to 10:00 PM (ET). To learn more, visit www.doxil.com.

INDICATIONS ◗ DOXIL® is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy ◗ DOXIL® in combination with VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma who have not previously received VELCADE and have received at least one prior therapy

IMPORTANT SAFETY INFORMATION BOXED WARNINGS Cardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution ◗ The use of DOXIL® may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2 — Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose — Cardiac toxicity may also occur at lower cumulative doses (400 mg/m2) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy ◗ Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL®. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate — Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have occurred. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use — The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions ◗ Severe myelosuppression may occur ◗ DOXIL® dosage should be reduced in patients with impaired hepatic function ◗ Accidental substitution has resulted in severe side effects. Do not substitute for doxorubicin HCl on a mg per mg basis CONTRAINDICATIONS ◗ Patients with a history of hypersensitivity reactions to a conventional doxorubicin formulation or the components of DOXIL® ◗ Nursing mothers

ADDITIONAL SAFETY INFORMATION ◗ Cardiac function should be carefully monitored — Congestive heart failure or cardiomyopathy may occur after discontinuation of anthracycline therapy — For patients with a history of cardiovascular disease, or if the results of cardiac monitoring indicate possible cardiac injury, the benefit of therapy must be weighed against the risk of myocardial injury — In the randomized multiple myeloma study, 25 patients (8%) in the VELCADE arm and 42 patients (13%) in the DOXIL® plus VELCADE arm experienced left ventricular ejection fraction decrease (defined as absolute decrease 15% over baseline or a 5% decrease below institutional lower limit of normal)

◗ Myelosuppression may occur; frequently monitor complete blood count (including platelet count), at least prior to each dose of DOXIL® — In patients with recurrent ovarian cancer, hematologic toxicity (based on platelet count or absolute neutrophil count) may require dose reduction or delay in administration of DOXIL® — In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL® and/or VELCADE — Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage — Sepsis occurring during neutropenia has resulted in discontinuation of treatment and in rare cases of death ◗ DOXIL® may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow ◗ Hand-foot syndrome (HFS) may occur during therapy with DOXIL® — Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL® may be required — HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier • The reaction was mild in most patients, resolving in 1 to 2 weeks • The reaction can be severe and debilitating in some patients, resulting in discontinuation of therapy ◗ DOXIL® is an irritant, not a vesicant; use precautions to avoid extravasation ◗ DOXIL® can cause fetal harm when used during pregnancy ◗ Recall reaction has occurred with DOXIL® administration after radiotherapy ◗ DOXIL® may interact with drugs known to interact with the conventional formulation of doxorubicin HCl ◗ In patients with recurrent ovarian cancer, the most common all-grade adverse reactions (ARs) 20% (DOXIL® vs topotecan, respectively) included: asthenia (40% vs 51%), fever (21% vs 31%), nausea (46% vs 63%), stomatitis (41% vs 15%), vomiting (33% vs 44%), diarrhea (21% vs 35%), anorexia (20% vs 22%), dyspnea (15% vs 23%), HFS (51% vs 1%), and rash (29% vs 12%) — In addition, 19% vs 52.3% reported alopecia (all grades) — Grade 3/4 hematologic ARs reported in 5% (DOXIL® vs topotecan, respectively) were neutropenia (12% vs 76%) and anemia (6% vs 29%) ◗ In patients with multiple myeloma, the most common all-grade ARs 20% (DOXIL® plus VELCADE vs VELCADE, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%), pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/ stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%) — In addition, 19% vs <1% reported HFS Please see brief summary of Prescribing Information, including Boxed WARNINGS, on adjacent pages. VELCADE is a registered trademark of Millennium Pharmaceuticals, Inc.

Distributed by: Centocor Ortho Biotech Products, L.P., Horsham, Pennsylvania 19044-3607 © Centocor Ortho Biotech Products, L.P. 2010 9/10 08D10019A

reaction at the recommended dose of 20 mg/m2 [see Adverse Reactions]. Leukopenia is the most common adverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsis occurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably related to DOXIL. Eleven patients (1.6%) discontinued study because of bone marrow suppression or neutropenia. Table 10 presents data on myelosuppression in patients with multiple myeloma receiving DOXIL and bortezomib in combination [see Adverse Reactions].

DOXIL® (doxorubicin HCl liposome injection) for intravenous infusion BRIEF SUMMARY. Please see Full Prescribing Information. WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTAL SUBSTITUTION 1. The use of DOXIL (doxorubicin HCl liposome injection) may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at a starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2 or between 500550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dosage. Cardiac toxicity may also occur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy [see Warnings and Precautions]. 2. Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes lifethreatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. DOXIL should be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [see Warnings and Precautions]. 3. Severe myelosuppression may occur [see Warnings and Precautions]. 4. Dosage should be reduced in patients with impaired hepatic function [see Full Prescribing Information]. 5. Accidental substitution of DOXIL for doxorubicin HCl has resulted in severe side effects. DOXIL should not be substituted for doxorubicin HCl on a mg per mg basis [see Full Prescribing Information]. INDICATIONS AND USAGE: Ovarian Cancer: DOXIL (doxorubicin HCl liposome injection) is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy. AIDS-Related Kaposi’s Sarcoma: DOXIL is indicated for the treatment of AIDS-related Kaposi’s sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy. Multiple Myeloma: DOXIL in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy. CONTRAINDICATIONS: DOXIL (doxorubicin HCl liposome injection) is contraindicated in patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of DOXIL [see Warnings and Precautions]. DOXIL is contraindicated in nursing mothers [see Full Prescribing Information]. WARNINGS AND PRECAUTIONS: Cardiac Toxicity: Special attention must be given to the risk of myocardial damage from cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin, particularly in patients who have received a total cumulative dosage of doxorubicin exceeding the currently recommended limit of 550 mg/m2. Lower (400 mg/m2) doses appear to cause heart failure in patients who have received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide. Prior use of other anthracyclines or anthracenodiones should be included in calculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered after discontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should be administered DOXIL only when the potential benefit of treatment outweighs the risk. Cardiac function should be carefully monitored in patients treated with DOXIL. The most definitive test for anthracycline myocardial injury is endomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have been used to monitor cardiac function during anthracycline therapy. Any of these methods should be employed to monitor potential cardiac toxicity in patients treated with DOXIL. If these test results indicate possible cardiac injury associated with DOXIL therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2, or between 500–550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. In this study, cardiotoxicity was defined as a decrease of >20% from baseline if the resting left ventricular ejection fraction (LVEF) remained in the normal range, or a decrease of >10% if the resting LVEF became abnormal (less than the institutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity and congestive heart failure (CHF) are in the table below. Table 1: Number of Patients With Advanced Breast Cancer Patients who Developed Cardiotoxicity (LVEF Defined) Cardiotoxicity (With Signs & Symptoms of CHF) Cardiotoxicity (no Signs & Symptoms of CHF) Patients With Signs and Symptoms of CHF Only

DOXIL (n=250) 10 0 10 2

In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiac failure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema and pulmonary edema) was similar in the DOXIL+bortezomib group and the bortezomib monotherapy group, 3% in each group. LVEF decrease was defined as an absolute decrease of 15% over baseline or a 5% decrease below the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and 42 patients in the DOXIL+bortezomib arm (13%) experienced a reduction in LVEF. Infusion Reactions: Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL in the randomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treated with DOXIL (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDSrelated Kaposi’s sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL therapy because of infusion-related reactions. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. The majority of infusion-related events occurred during the first infusion. Similar reactions have not been reported with conventional doxorubicin and they presumably represent a reaction to the DOXIL liposomes or one of its surface components. The initial rate of infusion should be 1 mg/min to help minimize the risk of infusion reactions [see Full Prescribing Information]. Myelosuppression: Because of the potential for bone marrow suppression, careful hematologic monitoring is required during use of DOXIL, including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With the recommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reduction or delay or suspension of DOXIL therapy. Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted in discontinuation of treatment and, in rare cases, death. DOXIL may potentiate the toxicity of other anticancer therapies. In particular, hematologic toxicity may be more severe when DOXIL is administered in combination with other agents that cause bone marrow suppression. In patients with relapsed ovarian cancer, myelosuppression was generally moderate and reversible. In the three single-arm studies, anemia was the most common hematologic adverse reaction (52.6%), followed by leukopenia (WBC <4,000 mm3; 42.2%), thrombocytopenia (24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most common hematologic adverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm3; 36.8%), neutropenia (ANC <1,000; 35.1%), and thrombocytopenia (13.0%) [see Adverse Reactions]. In patients with relapsed ovarian cancer, 4.6% received G-CSF (or GM-CSF) to support their blood counts [see Full Prescribing Information]. For patients with AIDS-related Kaposi’s sarcoma who often present with baseline myelosuppression due to such factors as their HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse

Hand-Foot Syndrome (HFS): In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL at 50 mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of the patients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skin toxicity. HFS toxicity grades are described in Dosage and Administration section [see Full Prescribing Information]. Among 705 patients with AIDS-related Kaposi’s sarcoma treated with DOXIL at 20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing. In the randomized multiple myeloma study, 19% of patients treated with DOXIL at 30 mg/m2 every three weeks experienced HFS. HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manage HFS [see Full Prescribing Information]. The reaction can be severe and debilitating in some patients and may require discontinuation of treatment. Radiation Recall Reaction: Recall reaction has occurred with DOXIL administration after radiotherapy. Fetal Mortality: Pregnancy Category D: DOXIL can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If DOXIL is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs in the first few months following treatment with DOXIL, the prolonged half-life of the drug must be considered. Women of childbearing potential should be advised to avoid pregnancy during treatment with Doxil. [see Full Prescribing Information]. Toxicity Potentiation: The doxorubicin in DOXIL may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-induced toxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration of doxorubicin HCl. Monitoring: Laboratory Tests: Complete blood counts, including platelet counts, should be obtained frequently and at a minimum prior to each dose of DOXIL [see Warnings and Precautions]. ADVERSE REACTIONS: Overall Adverse Reactions Profile: The following adverse reactions are discussed in more detail in other sections of the labeling. • Cardiac Toxicity [see Warnings and Precautions] • Infusion reactions [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hand-Foot syndrome [see Warnings and Precautions] The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. The most common serious adverse reactions observed with DOXIL are described in Section Adverse Reactions in Clinical Trials. The safety data described below reflect exposure to DOXIL in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma and 318 patients with multiple myeloma. Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The following tables present adverse reactions from clinical trials of DOXIL in ovarian cancer, AIDS-Related Kaposi’s sarcoma, and multiple myeloma. Patients With Ovarian Cancer: The safety data described below are from 239 patients with ovarian cancer treated with DOXIL (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in a randomized, multicenter, open-label study. In this study, patients received DOXIL for a median number of 98.0 days (range 1-785 days). The population studied was 27-87 years of age, 91% Caucasian, 6% Black and 3% Hispanic and other. Table 2 presents the hematologic adverse reactions from the randomized study of DOXIL compared to topotecan. Table 2: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian Cancer DOXIL Topotecan Patients Patients (n = 239) (n = 235) Neutropenia 19 (7.9%) 33 (14.0%) 500 - <1000/mm3 10 (4.2%) 146 (62.1%) <500/mm3 Anemia 6.5 - <8 g/dL 13 (5.4%) 59 (25.1%) <6.5 g/dL 1 (0.4%) 10 (4.3%) Thrombocytopenia 3 (1.3%) 40 (17.0%) 10,000 - <50,000/mm3 <10,000/mm3 0 (0.0%) 40 (17.0%) Table 3 presents a comparative profile of the non-hematologic adverse reactions from the randomized study of DOXIL compared to topotecan. Table 3: Ovarian Cancer Randomized Study Non-Hematologic Adverse Reaction 10% or Greater

Body as a Whole Asthenia Fever Mucous Membrane Disorder Back Pain Infection Headache Digestive Nausea Stomatitis Vomiting Diarrhea Anorexia Dyspepsia Nervous Dizziness Respiratory Pharyngitis Dyspnea Cough increased Skin and Appendages Hand-foot syndrome Rash Alopecia

DOXIL (%) treated (n = 239) All Grades grades 3-4

Topotecan (%) treated (n =235) All Grades grades 3-4

40.2 21.3 14.2

7.1 0.8 3.8

51.5 30.6 3.4

8.1 5.5 0

11.7 11.7 10.5

1.7 2.1 0.8

10.2 6.4 14.9

0.9 0.9 0

46.0 41.4 32.6 20.9 20.1 12.1

5.4 8.3 7.9 2.5 2.5 0.8

63.0 15.3 43.8 34.9 21.7 14.0

8.1 0.4 9.8 4.2 1.3 0

4.2

10.2

15.9 15.1 9.6

0 4.1 0

17.9 23.4 11.5

0.4 4.3 0

50.6 28.5 19.2

23.8 4.2 N/A

0.9 12.3 52.3

0 0.4 N/A

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks. Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis. Patients With AIDS-Related Kaposi’s Sarcoma: The safety data below is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m 2 and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2. Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients’ median CD4 count was 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm3. Patients received a variety of potentially myelotoxic drugs in combination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim) sometime during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi’s sarcoma. Those that did so included bone marrow suppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons. Table 4: Hematology Data Reported in Patients With AIDS-Related Kaposi’s Sarcoma Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 74) Neutropenia <1000/mm3 <500/mm3 Anemia <10 g/dL <8 g/dL Thrombocytopenia <150,000/mm3 <25,000/mm3

Total Patients With AIDS-Related Kaposi’s Sarcoma (n = 720)

34 8

(45.9%) (10.8%)

352 96

(48.9%) (13.3%)

43 12

(58.1%) (16.2%)

399 131

(55.4%) (18.2%)

45 1

(60.8%) (1.4%)

439 30

(60.9%) (4.2%)

Table 5: Probably and Possibly Drug-Related Non-Hematologic Adverse Reactions Reported in With AIDS-Related Kaposi’s Sarcoma Adverse Reactions

Nausea Asthenia Fever Alopecia Alkaline Phosphatase Increase Vomiting Diarrhea Stomatitis Oral Moniliasis

Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 77) 14 5 6 7 1 6 4 4 1

(18.2%) (6.5%) (7.8%) (9.1%) (1.3%) (7.8%) (5.2%) (5.2%) (1.3%)

Infections and infestations Herpes zoster Herpes simplex Investigations Weight decreased Metabolism and Nutritional disorders Anorexia Nervous system disorders Peripheral Neuropathy* Neuralgia Paresthesia/dysesthesia Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Rash** Hand-foot syndrome

11 10

2 0

0 0

9 6

2 1

0 0

42 17 13

7 3 <1

<1 0 0

45 20 10

10 4 0

1 1 0

22 19

1 6

0 0

18 <1

1 0

0 0

*Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. **Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized. Post Marketing Experience: The following additional adverse reactions have been identified during post approval use of DOXIL. 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. Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, StevensJohnson syndrome and toxic epidermal necrolysis have been reported. DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interact with drugs known to interact with the conventional formulation of doxorubicin HCl. USE IN SPECIFIC POPULATIONS: Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients have not been established.

5% of Patients

Total Patients With AIDS-Related Kaposi’s Sarcoma (n = 705) 119 70 64 63 55 55 55 48 39

Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. (continued) Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4

(16.9%) (9.9%) (9.1%) (8.9%) (7.8%) (7.8%) (7.8%) (6.8%) (5.5%)

The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi’s sarcoma. Incidence 1% to 5%: Body as a Whole: headache, back pain, infection, allergic reaction, chills. Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouth ulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia. Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1%: Body As A Whole: sepsis, moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic and Nutritional Disorders: dehydration. Respiratory: cough increase, pharyngitis. Skin and Appendages: maculopapular rash, herpes zoster. Special Senses: taste perversion, conjunctivitis. Patients With Multiple Myeloma: The safety data below are from 318 patients treated with DOXIL (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combination group were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 6 lists adverse reactions reported in 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma. Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4 Blood and lymphatic system disorders Neutropenia 36 22 10 22 11 5 Thrombocytopenia 33 11 13 28 9 8 Anemia 25 7 2 21 8 2 General disorders and administration site conditions Fatigue 36 6 1 28 3 0 Pyrexia 31 1 0 22 1 0 Asthenia 22 6 0 18 4 0 Gastrointestinal disorders Nausea 48 3 0 40 1 0 Diarrhea 46 7 0 39 5 0 Vomiting 32 4 0 22 1 0 Constipation 31 1 0 31 1 0 Mucositis/Stomatitis 20 2 0 5 <1 0 Abdominal pain 11 1 0 8 1 0

Geriatric Use: Of the patients treated with DOXIL in the randomized ovarian cancer study, 34.7% (n=83) were 65 years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. OVERDOSAGE: Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis. 0016716-5B Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Distributed by: Ortho Biotech Products, LP Raritan, NJ 08869-0670

An ALZA STEALTH® Technology Product

STEALTH® and DOXIL® are registered trademarks of ALZA Corporation.

COSTS OF CARE

Costs of Cancer Drugs Weigh on US, Canadian Minds By Colin Gittens

S and Canadian medical oncologists share similar attitudes on the costs, cost-effectiveness, and health policies concerning new cancer drugs, despite fundamental differences between the 2 countries regarding how these drugs are covered and paid for under their respective healthcare systems. These findings, reported in the Journal of Clinical Oncology (2010;28:4149-4153), emphasize the need for greater education of oncologists on understanding and communicating cost-effectiveness and cost information with patients. The authors surveyed a random sample of US oncologists who were members of the American Society of Clinical Oncology in the summer of 2008; the Canadian sample (n = 356) was drawn from the membership list of the Canadian Association of Medical Oncologists and other directories. The

at a glance ➤ Canadian and US physicians share concern for patients’ outof-pocket costs for new cancer drugs ➤ High numbers of doctors in both countries favored greater use of cost-effectiveness data in coverage and payment decisions ➤ However, fewer than 50% of physicians in both countries feel well prepared to interpret and use cost-effectiveness information in treatment decisions

Canadian survey was not translated into French, so responses from Quebec were not included in the analysis because of the low response rate from that province.

US oncologists are beginning to come to terms with the unavoidable reality of resource constraints. The overall response rate to the survey was 59%. Respondents were experienced clinicians, with a mean of 23.8 years of practice in the US and 23.2 years in Canada. Responses on cancer drug costs and cost effectiveness brought both concordance and divergence among the 2 nations’ doctors. When asked if patient out-of-pocket drug costs currently influence decisions regarding which cancer treatments to recommend for patients, 84% of US and 80% of Canadian physicians strongly or somewhat agreed. A much lower percentage in both countries felt well prepared to interpret and use costeffectiveness information in treatment decisions (42% US, 49% Canada). Opinions differed when questions turned to patient access to care. Sixtyseven percent of US oncologists indicated that every US/Canadian patient should have access to effective cancer treatments regardless of their cost, whereas only 52% of Canadian oncologists felt this way. Further refining the question to elucidate whether every US/Canadian patient should have access to effective cancer treatments only if the treatments provide “good value

for money” or are cost-effective, 58% of US oncologists strongly or somewhat agreed, compared with 75% of Canadian doctors. Fewer than half of physicians in both countries discussed the costs of cancer treatments with patients. In terms of health policies related to cancer drug costs, high numbers of doctors in both countries favored greater use of cost-effectiveness data in coverage and payment decisions (80% strongly or somewhat agreeing in the US, 69% in Canada), as well as more government research on the comparative effectiveness of cancer drugs (79% US, 85% Canada). Fifty-seven percent of US oncologists favored price controls for cancer drugs in the Medicare program, and doctors in both countries were less enthusiastic about increased patient cost-sharing for these drugs (29% US, 41% Canada). In both countries, doctors and nonprofit organizations were deemed most capable of determining whether a drug provides good value, while insurance companies and government agencies were seen as least effective in this regard. How to Address this Growing Problem The findings are not all that surprising, say the authors, given the changes in the oncology landscape in both countries. Despite government-funded healthcare in Canada, patients there are being exposed to higher out-of-pocket costs. And the reluctance of physicians to discuss costs has been well documented in other studies. What may be surprising is that Canadian physicians are already familiar with cost-effectiveness by its use in the Canadian system, but they still

express uncertainty over actually using this information in practice. The solution may be “better coordination among international researchers interested in the use of comparative effectiveness and cost-effectiveness data in funding expensive cancer drugs,” say the authors, which “might allow for better design of future prospective studies that could yield useful information for all countries involved.” Even more unexpected to the authors is the desire of US oncologists for greater use of cost-effectiveness data in coverage and payment decisions for cancer drugs. Although the American Recovery and Reinvestment Act of 2009 forbade using comparative effectiveness for coverage determinations under Medicare, the sentiments expressed in the survey “may reflect that US oncologists are beginning to come to terms with the unavoidable reality of resource constraints and may suggest some willingness on their part to accept comparative cost-effectiveness data in drug coverage decisions as is already happening in Canada and other countries,” the authors say. The authors caution that the physicians surveyed may not be a representative sample, but argue that the concordance of attitudes from the 2 countries suggest the findings could have wide relevance. Greater USCanadian collaboration regarding improved communication with patients about costs, practical education on using cost-effectiveness information, and the optimal processes for incorporating cost-effectiveness information in drug funding and coverage decisions could help address this widespread problem. ■

VBCC PERSPECTIVE

The Costs of Care: A Discussion We’re Not Prepared to Have—Yet By Denise K. Pierce

ach year, oncologists return to their respective practices after attending the annual American Society of Clinical Oncology or American Society of Hematology meetings armed with Denise K. Pierce is President, DK Pierce & Associates, Inc, Zionsville, IN, and a member of the editorial board of Value-Based Cancer Care.

knowledge of new drug/biologic combinations, modified regimen dosing, and other novel approaches that may provide incrementally better outcomes for cancer patients. But because the focus at these meetings has remained primarily clinical rather than on the cost effectiveness of individual drugs or regimens, progress in developing and accepting consistent pathways, or in considering cost-effec-

VALUE-BASED CANCER CARE

Nov/Dec 2010

tiveness data and value-based treatments for the patient and the healthcare system has been slow. The above article summarizing the attitudes of US and Canadian oncologists regarding costs, cost-effectiveness, and health policies associated with new cancer drugs, neatly illustrates how physicians in both countries face these issues, and raises a matter of great sensitivity for the

oncologist. Fewer than half of the physicians in both the United States and Canada always or frequently discuss the costs of cancer treatments with patients, according to this survey. This corresponds with the 2007 survey by Schrag and Hanger conducted with 167 practicing oncologists, wherein 42% discussed cancer treatment costs always or most of the time, 32% Continued on page 28

VOL. 1

NO. 6

Antibody-drug conjugates (ADCs):

Can an ADC be greater than the sum of its parts?

Antibody-drug conjugates (ADCs) ADCs are a unique combination of a precise and targeted monoclonal antibody, a stable linker, and a potent cytotoxic and are designed to selectively kill cancer cells while minimizing effects on normal tissue.1-4

Monoclonal antibody

Stable linker

Cytotoxic

targets antigens that are preferentially or exclusively expressed on the surface of cancer cells and may retain anticancer activities1,3,5-7

conjugates cytotoxic to monoclonal antibody and is designed to allow ADC to remain inactive while in circulation1,2,7,8

incorporated into an ADC can be up to 1000-fold more potent than currently used chemotherapies2,5,7

These investigational ADCs have multiple proposed mechanisms of action, including monoclonal antibodyâ&#x20AC;&#x201C;mediated anticancer activities and targeted intracellular delivery of a potent cytotoxic.5-7 Preclinical studies show that these anticancer activities may include prevention of signaling, antibody-dependent cellular cytotoxicity, and induction of apoptosis.3,5,6 To learn more, visit www.ResearchADCs.com References: 1. Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054. 2. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23:1137-1146. 3. Ricart AD, Tolcher AW. Technology insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Clin Pract Oncol. 2007;4:245-255. 4. Junutula JR, Raab H, Clark S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925-932. 5. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169. 6. Oflazoglu E, Stone IJ, Gordon K, et al. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008;14:6171-6180. 7. Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107. 8. Sanderson RJ, Hering MA, James SF, et al. In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. Clin Cancer Res. 2005;11:843-852.

HEALTH POLICY

CMS Releases Outpatient Rules...

Crystal Kuntz, MPA

payment formula that has been used to set physician reimbursement since 2002. Every year, this formula leads to physicians in Medicare facing significant cuts in their reimbursement. However, Congress typically steps in and temporarily “fixes” the cut. It is widely expected that Congress will do so again to ensure that physician payments under the Medicare program remain stable in 2011. Nevertheless, there is widespread agreement that the current payment system needs to be overhauled and a long-term fix enacted. But because of the complexities entailed in making any changes, there is disagreement in

Congress and among stakeholders over the best strategy. Numerous technical issues also exist regarding Medicare reimbursement for specific physician services. For example, Medicare is using new data from the American Medical Association’s Physician Practice Information Survey (PPIS) to estimate “practice expense” costs for various services. Practice expense includes items such as rental of office space or the cost of equipment. Some groups have voiced concern that the PPIS data is flawed and fails to adequately reimburse physicians for the cost of providing care. This is another area of longstanding controversy in the Medicare program with no clear path for moving forward. On the drug payment side, reimbursement in physician office and hospital outpatient settings remains stable—Medicare will continue to reimburse drugs at average sales price (ASP) + 6% in the physician office setting, whereas separately paid drugs in hospital outpatient departments will see their reimbursement increase from ASP + 4% in 2010 to ASP + 5% in 2011.

Continued from cover

Prevention Coverage Boosted The new Medicare rules also implement provisions of high importance to Medicare beneficiaries. Today, beneficiaries face a Part B deductible and 20% cost sharing for most preventive services, unless they have Medigap coverage that supplements Medicare. Under the new rules, which stem from requirements in the Affordable Care Act, Medicare beneficiaries will no longer have to pay cost sharing for preventive services with a Grade A (coverage “strongly recommended”) or Grade B (coverage “recommended) rating by the US Preventive Services Task Force. Thus, beneficiaries in 2011 will have no cost sharing for preventive services for certain screening tests for cancer: screening mammography, screening pap smear, and screening pelvic exam; colorectal cancer screening tests, and prostate specific antigen (PSA) tests. The importance of this provision could grow in the future if additional preventive services are added to Medicare that have Grade A or Grade B recommendations. One of the most notable aspects of

the newly released rules may be what they do not include. The Affordable Care Act grants the CMS with a host of new authorities aimed at developing innovative ways for paying providers, including establishing integrated health systems and bundling payments for inpatient and postacute care. As these efforts begin to unfold over the coming months, we could see significant implications for all stakeholders in oncology care. ■

necessary, but the oncologist infrequently plays the role of financial counselor. Social workers or dedicated insurance reimbursement specialists commonly better handle the ongoing demands of understanding confusing insurance requirements, discussing the overall cost of care and financial responsibilities, and helping patients manage ongoing issues of paying copays and coinsurance for their care. But beyond being discomfited by these conversations or possessing knowledge of insurance programs, physicians in both countries also reported feeling unprepared at a very fundamental level. Only 42% of US physicians strongly or somewhat strongly agreed that they were wellprepared to interpret and use costeffectiveness information in treatment decisions, while 49% of Canadian doctors felt this way. Clearly, more education in this area will be needed if costs and cost effectiveness continue to assume a larger role in healthcare decisions. A recent commentary argued that economic realities need to be better incorporated into medical education;4 although this commentary focused on bigger-

picture economic components and relationships, one of the points raised— that “cost-sensitive care can be compatible with and, indeed, serve patient needs and physician responsibilities”—is also pertinent to the matter of cost effectiveness. Cancer remains a diverse and challenging disease to treat no matter which side of the border and, despite the preference to avoid discussions about cost of care—whether among their colleagues or with patients — oncologists will continue to face increased pressure to apply cost effectiveness in relation to clinical outcomes within that diversity. ■

Representatives from Value-Based Cancer Care will be at the NCCN 16th Annual Conference: Clinical Practice Guidelines & Quality Cancer Care in Hollywood, FL, March 9-13, 2011.

VBCC PERSPECTIVE

The Costs of Care... sometimes did, and 26% rarely or never did.1 Cancer and Cost: An Essential Conversation It is understandable that oncologists have an aversion to conducting these conversations; however, financial counseling is indeed a significant and growing role in oncology practices across the United States. A 2010 survey by Kantar Health, conducted on behalf of the Association of Community Cancer Centers, outlined that 88% of the 84 responding cancer programs integrate financial counseling related to the cost of treatment.2 In addition, one need only Google key words such as “oncology financial counselor” to see the hundreds of resulting hits. These results include information from community-based oncology practices and comprehensive cancer centers regarding the role of the financial counselor to help patients better understand health insurance benefits and costshare responsibilities. One example of why financial counselors are now so important to oncology is exemplified by a 2009 study of the AARP Public Policy Institute.3 This

Continued from page 26

study assessed changes in patient cost share of chemotherapy specific to the Medicare Advantage (MA) managed care plan environment, and found that in 2009, only 21% of MA beneficiaries paid a fixed copayment amount for

Clearly, more education in this area will be needed if costs and cost effectiveness continue to assume a larger role in healthcare decisions. chemotherapy (down from 43% of beneficiaries in 2008). By 2009, MA plans had evolved to where 80% of beneficiaries required a coinsurance cost share—commonly 20% —of the medical cost of chemotherapy. For this cost share, the patient cannot obtain a supplemental insurance coverage (as compared to a beneficiary under fee-forservice Medicare). The MA example is but one of many scenarios increasing the economic constraints on patients. Conversations on costs of care and the implications of these costs to patients are

VALUE-BASED CANCER CARE

Nov/Dec 2010

References 1. Schrag D, Hanger M. Medical Oncologists’ views on communicating with patients about chemotherapy costs: A pilot survey. J Clin Oncol. 2007;25:233-237. 2. Association of Community Cancer Centers. Cancer Care Trends in Community Cancer Centers, 20092010. General introduction accessed on October 23, 2010 at: http://accc-cancer.org/surveys/pdf/Cancer_ Care_Trends-2010-Gatefold.pdf 3. AARP Public Policy Institute. Medicare Advantage Benefit Design: What Does It Provide, What Doesn’t It Provide, and Should Standards Apply? March, 2009. Accessed on October 23, 2010 at: http://assets.aarp. org/rgcenter/health/2009_03_medicare.pdf 4. Sessions SY, Detsky AS. Incorporating economic reality into medical education. JAMA. 2010;304: 1229-1230.

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NO. 6

First Annual Stakeholder Integration Conference Integrating Payers, Providers, and the Entire Oncology Team

March 29-30, 2011 Philadelphia, PA Loews Philadelphia Hotel

MEETING AGENDA*

PROGRAM OVERVIEW This is the first national stakeholder integration meeting dedicated to advancing the understanding of value in cancer care. Guided by the expertise of leaders in these fields, attendees will receive a thorough understanding of the evolution of the value equation as it relates to cancer therapies and will be able to implement, improve, and sustain their companies and institutions, while improving access for patients and ultimately patient care.

Tuesday, March 29 4:00 – 6:00 pm

Cancer Care from a Large Insurer’s Perspective The Role of Diagnostics from a PBM’s Standpoint

6:15 – 8:30 pm

Welcome/Networking Reception in the Exhibit Hall

Wednesday, March 30 7:30 – 8:30 am

Corporate-Sponsored Breakfast Symposium

8:30 – 8:45 am

Intro/Opening

8:45 – 9:30 am

General Session 1 – NCCN Guidelines Acceptance and Compliance

9:30 – 10:15 am

General Session 2 – The Impact of Personalized Oncology Therapies

10:20 – 10:50 am

Morning Break in the Exhibit Hall

11:00 – 12:30 pm

Provider Track • Community Oncology: Trends • Patient Navigation: Impact • Oncology Practices: Issues with Managed Care

WHO SHOULD ATTEND All stakeholders in a position to impact cancer patient care are invited to join this exciting forum. Specifically this conference is intended for: • Medical Oncologists • Advanced Practitioners • Hematologists/Oncologists • Managed Care Professionals • Surgical Oncologists • Medical Directors • Nurses • Practice Managers/Administrators • Pharmacists • Pharmacy Benefit Managers (PBMs)

GOAL The Association for Value-Based Cancer Care’s First Annual Stakeholder Integration Conference will foster an open dialogue between providers, payers, and/or other members of the oncology team in order for attendees to gain a better understanding of various points of view regarding cost, quality, and access in cancer care.

OBJECTIVES • Examine the impact of healthcare reform on all stakeholders involved in the management of patients with cancer • Identify issues and potential solutions to challenges with access and affordability of oncology therapeutics • Determine the value equation of cost, quality, and access when evaluating the diagnosis, treatment, and overall management of cancer patients • Define appropriate comparative effectiveness research and clinical pathways as tools to evaluate current recommendations for patient management • Analyze trends in the delivery of care in the management of cancer patients T H E A S S O C I AT I O N F O R

Payer Track • Medicare and Reimbursement Issues • Drug Reimbursement and Administration Issues • Evolutions in Oncology Pharmacy Management 12:30 – 2:00 pm

CE Lunch Symposium Best Practices for Management of CINV: A Value-Based Approach

2:00 – 2:45 pm

General Session 3 – Cancer Care and the New Healthcare Legislation: What to Expect Next

2:45 – 3:30 pm

General Session 4 – Strategies for Improving Oncology Pharmacy and Care Management Models

3:35 – 4:05 pm

Afternoon Break in the Exhibit Hall

4:10 – 4:55 pm

General Session 5 – Clinical Trends: Impact of Oral, Injected, and Infused Therapies

5:00 – 6:00 pm

Cocktails/Networking in the Exhibit Hall

*Preliminary agenda is subject to change.

www.ValueBasedCancer/association

In advanced RCC:

Afinitor doubled median PFS after progression on sunitinib*1 Progression-free survival (PFS) after progression on sunitinib or sorafenib1 100

Hazard Ratio=0.33 95% CI [0.25, 0.43] Kaplan-Meier medians Afinitor: (n=277) 4.9 months (95% CI, 4.0-5.5) Placebo: (n=139) 1.9 months (95% CI, 1.8-1.9) Log rank P value=<0.0001

Probability (%)

1.9

4.9

months

Placebo 40

Afinitor 20

Time (months)

4.9 months median PFS with Afinitor + BSCâ&#x20AC; (vs 1.9 months with placebo + BSC; P<0.0001)1 HR 0.33=67% reduction in risk of progression Effective for patients with all prognostic scores1 For more information about Afinitor, call 1-888-4Afinitor (1-888-423-4648) or visit www.AFINITOR.com For reimbursement questions, call 1-888-5AfiniTRAC (1-888-523-4648). *In the RECORD-1 trial, Afinitor extended PFS after progression on sunitinib or sorafenib.1,2 â&#x20AC; BSC=best supportive care.

Important Safety Information There have been reports of non-infectious pneumonitis and infections, some with fatal outcomes. Oral ulceration has been reported. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Please see Important Safety Information on right side of page. Please see Brief Summary of full Prescribing Information on the following pages.

Afinitor is indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Important Safety Information Afinitor is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. Non-infectious pneumonitis is a class effect of rapamycin derivatives, including Afinitor. Fatal outcomes have been observed. If symptoms are moderate or severe, patients should be managed with dose interruption until symptoms improve or discontinuation, respectively. Corticosteroids may be indicated. Afinitor may be reintroduced at 5 mg daily depending on the individual clinical circumstances. Afinitor has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoan infections, including infections with opportunistic pathogens. Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, and viral infections including reactivation of hepatitis B virus have occurred. Some of these infections have been severe (e.g. leading to respiratory or hepatic failure) or fatal. Complete treatment of pre-existing invasive fungal infections prior to starting treatment. While taking Afinitor be vigilant for signs and symptoms of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Afinitor. If a diagnosis of invasive systemic fungal infection is made, discontinue Afinitor and treat with appropriate antifungal therapy. Oral ulcerations (i.e. mouth ulcers, stomatitis, and oral mucositis) have occurred in patients treated with Afinitor. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes,

neutrophils, and platelets have been reported in clinical trials. Renal function, hematological parameters, blood glucose, and lipids should be evaluated prior to treatment and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on Afinitor. Avoid concomitant use with strong CYP3A4 or PgP inhibitors. If co-administration with moderate CYP3A4 or PgP inhibitors is required, use caution and reduce dose of Afinitor to 2.5 mg daily. Increase the Afinitor dose if co-administered with a strong CYP3A4 inducer. Afinitor should not be used in patients with severe hepatic impairment. Afinitor dose should be reduced to 5 mg daily for patients with moderate hepatic impairment. The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with Afinitor. Fetal harm can occur if Afinitor is administered to a pregnant woman. The most common adverse reactions (incidence ≥30%) were stomatitis (44%), infections (37%), asthenia (33%), fatigue (31%), cough (30%), and diarrhea (30%). The most common grade 3/4 adverse reactions (incidence ≥3%) were infections (9%), dyspnea (8%), fatigue (5%), stomatitis (4%), dehydration (4%), pneumonitis (4%), abdominal pain (3%), and asthenia (3%). The most common laboratory abnormalities (incidence ≥50%) were anemia (92%), hypercholesterolemia (77%), hypertriglyceridemia (73%), hyperglycemia (57%), lymphopenia (51%), and increased creatinine (50%). The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (18%), hyperglycemia (16%), anemia (13%), hypophosphatemia (6%), and hypercholesterolemia (4%). Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the Afinitor arm.

References: 1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2010. 2. Motzer RJ, Escudier B, Oudard S, et al; for the RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449-456. 2.5mg 5mg 10mg

Printed in U.S.A.

10/10

AFI-1002330

AFINITOR

(everolimus) tablets for oral administration Initial U.S. Approval: 2009 BRIEF SUMMARY: Please see package insert for full prescribing information.

while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label:

1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.

• Non-infectious pneumonitis [see Warnings and Precautions (5.1)].

4 CONTRAINDICATIONS Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives.

6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

5 WARNINGS AND PRECAUTIONS 5.1 Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. In the randomized study, non-infectious pneumonitis was reported in 14% of patients treated with AFINITOR. The incidence of Common Toxicity Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was 4% and 0%, respectively [see Adverse Reactions (6.1)]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at 5 mg daily. For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy and the use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with AFINITOR may be re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances. 5.2 Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoan infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)]. Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. 5.3 Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR. In the randomized study, approximately 44% of AFINITOR-treated patients developed mouth ulcers, stomatitis, or oral mucositis, which were mostly CTC grade 1 and 2 [see Adverse Reactions (6.1)]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions (7.1)]. 5.4 Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine, usually mild, have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematological Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. 5.5 Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or P-glycoprotein (PgP) should be avoided. Grapefruit, grapefruit juice and other foods that are known to affect cytochrome P450 and PgP activity should also be avoided during treatment [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.1)]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 inhibitor (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) or PgP inhibitor [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.1)]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer (e.g., St. John’s Wort (Hypericum perforatum), dexamethasone, prednisone, prednisolone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.2)]. 5.6 Hepatic Impairment The safety and pharmacokinetics of AFINITOR were evaluated in a study in eight patients with moderate hepatic impairment (Child-Pugh class B) and eight subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore a dose reduction is recommended. AFINITOR has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population [see Dosage and Administration (2.2) in the full prescribing information and Use in Specific Populations (8.7)]. 5.7 Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. 5.8 Use in Pregnancy Pregnancy Category D There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception

• Infections [see Warnings and Precautions (5.2)].

The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451) for patients receiving AFINITOR and 60 days (range 21-295) for those receiving placebo. The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common grade 3/4 adverse reactions (incidence ≥3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure (0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis. Table 1 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency. Table 1 Adverse Reactions Reported in at least 10% of Patients and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm AFINITOR 10 mg/day N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

Grade 3 %

Grade 4 %

Any Adverse Reaction

Gastrointestinal Disorders Stomatitisa Diarrhea Nausea Vomiting

44 30 26 20

4 1 1 2

<1 0 0 0

8 7 19 12

0 0 0 0

Infections and Infestationsb

<1 0 0 0 0

23 27 8 9 1

4 3 <1 0 0

0 <1 0 0 0

Respiratory, Thoracic and Mediastinal Disorders Cough 30 <1 Dyspnea 24 6 Epistaxis 18 0 c Pneumonitis 14 4

0 1 0 0

16 15 0 0

0 3 0 0

0 0 0 0

Skin and Subcutaneous Tissue Disorders Rash 29 Pruritus 14 Dry skin 13

1 <1 <1

0 0 0

7 7 5

0 0 0

<1 0

9 2

<1 0

0 0

Musculoskeletal and Connective Tissue Disorders Pain in extremity 10 1

General Disorders and Administration Site Conditions Asthenia 33 3 Fatigue 31 5 Edema peripheral 25 <1 Pyrexia 20 <1 Mucosal inflammation 19 1

Metabolism and Nutrition Disorders Anorexia 25 Nervous System Disorders Headache Dysgeusia

19 10

Median Duration of Treatment (d)

141

CTCAE Version 3.0 a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. b Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis (3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%). c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of <10% include: Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing (<1%) Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%) Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (<1%) Psychiatric disorders: Insomnia (9%) Nervous system disorders: Dizziness (7%), paresthesia (5%) Eye disorders: Eyelid edema (4%), conjunctivitis (2%)

Vascular disorders: Hypertension (4%)

In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft) and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities occurred at approximately 4% the exposure (AUC0-24h) in patients receiving the recommended dose of 10 mg daily. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose approximately 1.6 times the recommended human dose on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

Renal and urinary disorders: Renal failure (3%) Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%) Musculoskeletal and connective tissue disorders: Jaw pain (3%) Hematologic disorders: Hemorrhage (3%) Key treatment-emergent laboratory abnormalities are presented in Table 2. Table 2 Key Laboratory Abnormalities Reported at a Higher Rate in the AFINITOR Arm than the Placebo Arm Laboratory Parameter

AFINITOR 10 mg/day N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

92 51 23 14

12 16 1 0

1 2 0 <1

79 28 2 4

5 5 0 0

<1 0 <1 0

77 73 57 50 37

4 <1 15 1 6

0 0 <1 0 0

35 34 25 34 8

0 0 1 0 0

0 0 0 0 0

21 3

1 <1

0 <1

4 2

0 0

Hematologya Hemoglobin decreased Lymphocytes decreased Platelets decreased Neutrophils decreased Clinical Chemistry Cholesterol increased Triglycerides increased Glucose increased Creatinine increased Phosphate decreased Aspartate transaminase (AST) increased Alanine transaminase (ALT) increased Bilirubin increased

Grade 3 %

Grade 4 %

CTCAE Version 3.0 a Includes reports of anemia, leukopenia, lymphopenia, neutropenia, pancytopenia, thrombocytopenia. Information from further clinical trials In clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcomes. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At approximately 10% of the recommended human dose based on body surface area, there were no adverse effects on delivery and lactation and there were no signs of maternal toxicity. However, there was reduced body weight (up to 9% reduction from the control) and slight reduction in survival in offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Doses that resulted in embryo-fetal toxicities in rats and rabbits were ≥0.1 mg/kg (0.6 mg/m2) and 0.8 mg/kg (9.6 mg/m2), respectively. The dose in the pre- and post-natal development study in rats that caused reduction in body weights and survival of offspring was 0.1 mg/kg (0.6 mg/m2). 8.3 Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, 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 in pediatric patients have not been established. 8.5 Geriatric Use In the randomized study, 41% of AFINITOR-treated patients were ≥65 years in age, while 7% percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment is required in elderly patients [see Clinical Pharmacology (12.3) in the full prescribing information]. 8.6 Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

7.1 Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with:

8.7 Hepatic Impairment For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mg daily [see Dosage and Administration (2.2) in the full prescribing information, Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) in the full prescribing information].

• ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively.

The impact of severe hepatic impairment (Child-Pugh class C) has not been assessed and use in this patient population is not recommended [see Warnings and Precautions (5.6)].

• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 and PgP should not be used [see Warnings and Precautions (5.5)]. Use caution when AFINITOR is used in combination with moderate CYP3A4 or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose. [See Dosage and Administration (2.2) in the full prescribing information] 7.2 Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers: In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong inducers of CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) or PgP if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2) in the full prescribing information].

10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. 16 STORAGE Store AFINITOR (everolimus) tablets at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.] Store in the original container, protect from light and moisture. Keep this and all drugs out of the reach of children. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. AFINITOR tablets should not be crushed. Do not take tablets which are crushed or broken.

7.3 Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.8)] There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment.

Revised: June 2010 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

T2010-56

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Maintenance Therapy for Non–Small-Cell Lung Cancer: A Value-Based Approach to Improve Patient Care and Outcomes, Part II of II PROGRAM P10068

PHARMACISTS’ DESIGNATION

Initial Release Date: November 19, 2010 • Expiration Date: November 19, 2011. Estimated time to complete activity: 1 hour.

Medical Learning Institute, Inc., is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal activity number for this activity is 0468-9999-10-060-H01-P.

SPONSOR

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

This activity was developed for oncology pharmacists and other healthcare professionals practicing in oncology. LEARNING OBjECTIVES

• Evaluate the benefits and risks of maintenance therapy compared with re-treating upon disease progression in order to rationalize maintenance in patients with stage IIIB or IV non– small-cell lung cancer (NSCLC) who have responded to or are stable after induction therapy • Identify molecular and histologic characteristics of NSCLC tumors that impact choice of therapeutic agent for specific patient populations and formulate strategies for value-based care • Develop optimal side effect management strategies for patients receiving maintenance therapy for NSCLC in order to provide optimal care while considering the associated costs. COMMERCIAL SuPPORT ACKNOWLEDGMENT

This activity is supported by an educational grant from Eli Lilly and Company. INSTRuCTIONS FOR CREDIT

There is no fee for this activity. After reading this CE activity in its entirety, participants must complete the posttest and evaluation. The posttest and evaluation can be completed online at www.mlicme.org/P10068.html. 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. For questions regarding the accreditation of this activity, please contact Medical Learning Institute, Inc., at 609-333-1693 or cgusack@mlicme.org.

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

tients with locally advanced or metastatic nonsquamous NSCLC, in combination with cisplatin, and after prior chemotherapy as a single agent.4 Erlotinib, an endothelial growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), received FDA approval in April 2010 for an expanded indication as a maintenance treatment in patients with locally advanced or metastatic NSCLC whose disease has not progressed after 4 cycles of platinum-based first-line chemotherapy.5,6 Erlotinib is also indicated to treat locally advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy regimen.6 Identifying the appropriate patients as characterized by histology (nonsquamous) or molecular (EGFR mutation) profile is an important consideration when selecting the appropriate maintenance therapy.7 Using predictive biomarkers to target specific agents for maintenance therapy may help improve benefits and reduce risks by tailoring a specific treatment to the appropriate patient.7 For example, pemetrexed is an option for mainte-

I VALUE-BASED CANCER CARE I

Nov/Dec 2010

DISCLOSuRES

Before the activity, all faculty will disclose the existence of any financial interest and/or relationship(s) they might have with the manufacturer(s) of any commercial product(s) to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speaker’s bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. Beth Eaby-Sandy, CRNP, is on the speaker’s bureau for Genentech, Eli Lilly and Company, and Merck. Corey J. Langer, MD, acknowledges grant/research support from Bristol-Myers Squibb, Genentech, Imclone, Eli Lilly and Company, OSI, and Pfizer. Dr Langer is on the speaker’s bureau for Genentech, Imclone-BMS, Eli Lilly and Company, and OSI, and is a scientific advisor to Abbott, Abraxis, Amgen, AstraZeneca, Bayer-Onyx, Biodesix, Bristol-Myers Squibb, Caris DX, Clarient, Genentech, Imclone, Eli Lilly and Company, Morphotek, Novartis, Pfizer, and sanofi-aventis. Loretta Fala participated in the development of this article. She has no financial relationships to disclose. The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CE activity for any amount during the past 12 months. DISCLAIMER

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

nance therapy in patients with nonsquamous histology.1,4 In addition, a molecular-based strategy may be useful in selecting the appropriate patients best suited for maintenance therapy with erlotinib.7 Progression-free survival (PFS) was significantly longer in patients with EGFR-positive immunohistochemistry who were treated with erlotinib as maintenance therapy compared with EGFR-positive patients who received placebo, based on a randomized, placebo-controlled study.8 In addition to histology and genetic markers, maintenance therapy decisions involve a number of other important considerations, including the latest clinical data, evidence-based clinical practice guidelines, and the patient’s performance status and personal preferences. Although maintenance therapy may slow the growth of disease and extend life, the benefits of treatment must be weighed against the potential toxicities and other side effects associated with extended treatment. Costs and resource utilization associated with maintenance therapy must also be considered.

NSCLC: Burden and Economic Impact Lung cancer claims the lives of more Americans than any other type of cancer.1 Moreover, lung cancer imposes a substantial economic burden on our healthcare system. The estimated annual costs to the American public as well as lost productivity costs associated with lung cancer were previously outlined in the first part of this article.9 Treatment costs associated with lung cancer, as well as treatment failure costs, are also substantial. A retrospective, case-control cohort study that followed patients for 2 years from the first diagnosis of lung cancer showed that the monthly cost per patient was $11,496 for initial treatment, $3733 per month for secondary treatment, and $9399 for terminal care treatment.10 Failure of initial treatment was associated with increased costs: patients who experienced treatment failure incurred an additional $10,370/month in initial treatment phase costs and $8779/ month after starting the secondary and/or terminal care phase of treatment.10 Moreover, treatment failure

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CONTINUING EDUCATION was associated with incremental costs of $19,149/month and $74,697 across the study period.10 The study authors concluded that improvements in prevention or treatment of lung cancer, including new therapies or adjuvant chemotherapy, might reduce healthcare resource utilization and costs, and that strategies aimed at reducing hospitalizations and preventing or delaying treatment failure may offset the associated cost burden.10 More than 68% of all patients diagnosed with lung cancer are 65 years of age or older.11 The burden and cost of NSCLC may continue to grow as the baby boom generation (people born between 1946 and 1964) reaches the age of 65 and older over the next 20 years.12 Maintenance Therapy Agents for the Treatment of Advanced NSCLC Maintenance therapy, sometimes also referred to as consolidation therapy or early second-line therapy,7 is a relatively new approach to improving outcomes in patients whose disease either responded to initial chemotherapy or was stable following that, and is intended to improve survival without adversely affecting quality of life.13 Aside from improving outcomes, the optimal maintenance treatment should be well-tolerated by patients and associated with few or no cumulative toxicities.7 The National Comprehensive Cancer Network (NCCN) has established specific recommendations for the use of pemetrexed in maintenance therapy, as well as for the use of erlotinib.1 These guidelines also include recommendations for several other agents, including docetaxel, bevacizumab, and cetuximab.1 Pemetrexed Based on phase 3 study results, patients who received maintenance therapy with pemetrexed showed a significantly greater PFS (1.7 months longer), compared with the placebo group, and a significantly greater overall survival (OS; 2.8 months longer), compared with the placebo group.14 Specific findings from the study were previously highlighted in Part I of this article.9 Moreover, in patients with nonsquamous histology treated with pemetrexed, the OS was 5.2 months longer than in the placebo arm.14 The most common any-grade adverse reactions associated with pemetrexed included nausea (19%) and anorexia (19%).14 The pemetrexed group had a greater frequency of grade 3 or higher adverse events than the placebo group, including fatigue (5%) and neutropenia (3%).14 Another study that compared the combination of cisplatin plus pemetrexed with cisplatin plus gemcitabine

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in chemotherapy-na誰ve patients with advanced NSCLC demonstrated superior efficacy and reduced toxicity in the group receiving cisplatin plus pemetrexed.15 Erlotinib Based on a phase 3 study, patients who received maintenance therapy with erlotinib showed a greater PFS (0.8 weeks longer) and an improved OS (1 month longer), compared with the placebo group.6,8 In patients with EGFR-positive immunohistochemistry treated with erlotinib, compared with EGFR-positive patients receiving placebo, PFS was significantly greater (1.2 months longer) in the erlotinib group, compared with the placebo group, in patients with EGFR-positive immunohistochemistry treated with erlotinib.8 Specific study results were previously highlighted.9

Using predictive biomarkers to target specific agents for maintenance therapy may help improve benefits and reduce risks.

The most common any-grade adverse reactions associated with erlotinib were rash (49.2%) and diarrhea (20.3%).6 The most common serious adverse event was pneumonia (2%), and the most common grade 3 or higher adverse events included rash (6%) and diarrhea (2%).8 Other Agents Included in Clinical Practice Guidelines Docetaxel Although docetaxel, a microtubule inhibitor, does not have a specific FDA approval for maintenance therapy in NSCLC, this agent is indicated as a single agent for locally advanced or metastatic NSCLC after failure on platinum therapy; and with cisplatin for unresectable, locally advanced, or metastatic untreated NSCLC.16 Based on a phase 3 randomized study that assessed the efficacy and safety of docetaxel administered either immediately after gemcitabine or at disease progression, immediate docetaxel was associated with a significantly greater PFS (5.7 months) compared with delayed docetaxel (2.7 months), and immediate docetaxel was associated with a greater median OS (12.3 months) compared with delayed docetaxel (9.7 months).17 However, the difference in median OS was not statistically significant (P = .0853). There was no significant difference in quality of life between the immediate and delayed docetaxel groups.17

Based on studies of docetaxel as monotherapy for NSCLC patients previously treated with platinum-based chemotherapy (n = 176), the most common grade 3/4 adverse reactions included neutropenia (65%); leukopenia (49%); and pulmonary effects (21%).16 The most common any-grade adverse reactions include neutropenia (84%); leukopenia (84%); anemia (91%); asthenia (53%); pulmonary effects (41%); infection (34%); nausea (34%); fluid retention (34%); neurosensory effects; (34%); stomatitis (26%); diarrhea (23%); and vomiting (22%).16 In chemotherapy-na誰ve advanced NSCLC patients receiving docetaxel in combination with cisplatin (n = 406), the most common grade 3/4 adverse reaction was neutropenia (74%).16 The most common any-grade adverse reactions included neutropenia (91%); anemia (89%); alopecia (75%); asthenia (74%); nausea (72%); vomiting (55%); fluid retention (54%); diarrhea (47%); neurosensory effects (47%); anorexia (42%); infection (35%); peripheral edema (34%); and fever (33%).16 Bevacizumab Bevacizumab, a monoclonal antibody that inhibits vascular endothelial growth factor, is indicated for the treatment of nonsquamous NSCLC, with paclitaxel and carboplatin for the firstline treatment of unresectable, locally advanced, recurrent, or metastatic disease.18 According to the NCCN clinical practice guidelines, the criteria for bevacizumab therapy include a performance status of 0-1, nonsquamous histology, and no history of hemoptysis.1 Adding bevacizumab to chemotherapy with paclitaxel plus carboplatin has shown a significant improvement in median survival (12.3 months), compared with chemotherapy alone (10.3 months), based on a randomized 3-year study of patients with recurrent or advanced NSCLC (N = 878) conducted by the Eastern Cooperative Oncology Group.19 An increased risk of treatment-related deaths were observed in the group treated with bevacizumab plus paclitaxel and carboplatin, and the rate of clinically significant bleeding was 4.4% in this arm.19 Other adverse events included grade 4 neutropenia (24%), grade 3/4 hemorrhage (4.5%), hemoptysis (1.9%), and hypertension (6%).1 According to the NCCN guidelines, caution is advised when chemotherapy regimens with a high risk for thrombocytopenia and/or possible bleeding are combined with bevacizumab.1 Further studies are needed to determine whether bevacizumab maintenance is associated with a survival benefit compared with the combination of

chemotherapy and bevacizumab without maintenance bevacizumab.20 Cetuximab Cetuximab, a monoclonal antibody that targets EGFR, is indicated for the treatment of specific head and neck cancers and colorectal cancers; however, this agent does not have an indication for the treatment of NSCLC.21 Cetuximab use is not recommended for patients with colorectal cancer whose tumors have KRAS mutations in codon 12 or 13.21 According to a study of patients (N = 1125) with advanced NSCLC (stage IIIB or IV; majority were stage IV), patients treated with cetuximab in combination with vinorelbine and cisplatin showed no difference in PFS and a significantly improved OS (11.3 months) compared with patients receiving vinorelbine and cisplatin alone (10.1 months).1,22 Treatment-related deaths were similar in both groups.22 Patients receiving cetuximab had increased grade 3/4 febrile neutropenia (22%) and grade 3 acne-like rash (10%).1,22 Evidence-Based Practice Guidelines For the NCCN NSCLC clinical practice guidelines (updated in March 2010), a new section with maintenance therapy recommendations was added.1 These recommendations categorized maintenance therapy into 2 types: continuation maintenance therapy and switch maintenance therapy. Continuation maintenance therapy refers to the use of at least 1 of the agents administered as first-line therapy.1 Switch maintenance therapy refers to the initiation of an agent that was not included as part of the first-line treatment regimen.1 Based on 2 recent studies demonstrating a benefit in PFS and OS, the guidelines now recommend initiation with pemetrexed or erlotinib for switch maintenance therapy in patients without disease progression (Category 2B recommendation).1 Highlights of the NCCN guideline recommendations for continuation maintenance therapy and switch maintenance therapy were outlined previously in the first part of this article.9 Information about the American Society of Clinical Oncology (ASCO) guideline update, as well as recent guidance from the National Institute for Health and Clinical Excellence are also highlighted in that article. The Role of Histology and Molecular Biomarkers in Maintenance Therapy It is important to identify the histologic subtype of NSCLC (ie, squamous cell vs nonsquamous cell) when Continued on page 36

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CONTINUING EDUCATION

Maintenance Therapy for NSCLC... selecting maintenance therapy.23 Histologic information may be particularly useful when augmented by molecular testing.23 Detecting the bronchioloalveolar subtype of NSCLC adenocarcinoma may suggest a specific treatment approach, particularly if it is associated with specific mutations in the EGFR tyrosine kinase domain, which indicates it may respond to treatment with an EGFR TKI.23 However, it is important to point out within this NSCLC subtype, there are also variabilities in histology and molecular information.23 Several predictive molecular biomarkers play a key role in NSCLC treatment,1 and these biomarkers and associated characteristics were summarized in Part I.9 Initial retrospective studies suggest that approximately 90% of patients with a tumor response to erlotinib and gefitinib (both EGFR TKI agents) had EGFR mutations E19 deletion and L858R mutation, whereas patients without a response to these 2 agents did not carry these mutations.1 The NCCN guidelines recommend that pathological evaluation be performed to classify the lung cancer, determine its extent of invasion, determine the status of surgical margins, and identify molecular abnormalities that may predict the treatment response, or resistance to, EGFR TKI therapy.1 Other Maintenance Therapy Considerations The potential benefits of maintenance therapy—preventing cancer recurrence, slowing disease growth, and prolonging life—must be weighed against the potential risks—increased side effects and potential for toxicities, drug resistance, and more frequent doctor’s visits. Another consideration is that maintenance therapy does not provide the patient with a chemotherapy break, also referred to as a wait-andsee period.7 Data on the quality of life associated with maintenance therapy are limited, including data on cumulative toxicity associated with extended chemotherapy.7 Although maintenance therapy increases chemotherapy costs and may increase overall costs, it may conversely decrease costs associated with palliative radiotherapy and hospital admissions resulting from performance status deterioration.20 The value of maintenance therapy is the subject of ongoing discussion among clinicians, particularly in light of its cost and potential toxicity.24 Pemetrexed administered in 6 cycles at

the average wholesale price of $3000 per cycle would total $18,000.24 The wholesale acquisition cost for erlotinib maintenance treatment would be $4000 per month x a mean PFS of 3 months, for a total treatment cost of $12,000.24 Some of the challenges surrounding cost of added survival were presented at the 2010 ASCO meeting by Scott Ramsey, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle.24,25 Dr Ramsey asserted that maintenance therapy was unlikely to be cost-effective, based on a ratio that considers both the price over standard care and the months of OS benefit. However, he acknowledged that pharmacogenomic strategies may improve the costeffectiveness of therapy and that the cost of testing will be a factor. Dr Ramsey claimed that many new oncology agents do not meet the criteria for cost-effectiveness and that many economic analyses do not meet the guidelines for economic evaluation.24,25 Guideline-driven pharmacoeconomic studies may shed light on whether maintenance therapy is the most cost-effective.

NCCN guidelines now recommend initiation with pemetrexed or erlotinib for switch maintenance therapy in patients without disease progression. The rationale in favor of maintenance therapy was presented at the 2010 ASCO meeting by Tracey Evans, MD, of the Abramson Cancer Center, University of Pennsylvania, in Philadelphia.26 According to Dr Evans, “maintenance therapy for advanced NSCLC is absolutely a standard of care” that should be considered for all patients, particularly based on clinical data showing prolonged survival and tolerability.26 An opposing point of view was presented by Tom Stinchcombe, MD, of the Lineberger Comprehensive Cancer Center, at the University of North Carolina at Chapel Hill.27 According to Dr Stinchcombe, maintenance therapy is not necessarily a standard of care for every patient but rather an option to be considered, which depends on toxicities as well as the patient’s disease burden, extent of symptoms, performance status, and preferences.27 He maintained that a treatment-free interval is still an option in this incurable disease setting.27

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Conclusion Maintenance therapy, a relatively new approach in the treatment of patients with advanced NSCLC, has the potential to extend survival and improve outcomes. Key considerations for tailoring treatment for the appropriate patients include the histology of the carcinoma, genetic biomarkers, the extent of disease invasion, and the patient’s performance status and preferences. The benefits of maintenance therapy must be weighed against the potential toxicities and other side effects associated with extended treatment. Selecting the appropriate therapy for the appropriate patients and involving patients in the decision process are important aspects of the treatment plan. Strategies for managing side effects warrant careful consideration. Optimally, the agent selected for maintenance therapy should be well-tolerated by the patient, demonstrate improved patient outcomes, and have minimal side effects/cumulative toxicities.7 Recent clinical data and evidencebased guidelines are valuable decisionmaking tools for clinicians. However, data assessing quality of life, cost-effectiveness, and cumulative toxicity of maintenance therapy are lacking. Costs and resource utilization associated with maintenance therapy must be balanced against the risks and costs of not treating or of deteriorating performance status. A delay strategy may be associated with a shorter survival time and a faster disease progression than immediate additional therapy.28,29 In any case, the prospect of extended survival of several months, or even weeks, particularly if treatment is well-tolerated, represents an important milestone for patients with advanced NSCLC. ■ References 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Non-small cell lung cancer, V.2.2010. March 5, 2010. www.nccn. org/professionals/physician_gls/PDF/nscl.pdf. Accessed September 15, 2010. 2. Peck P. Maintenance pemetrexed extends NSCLC survival by 3 months. Medpage Today. May 30, 2009. www.medpagetoday.com/tbprint.cfm?tbid=14437. Accessed September 22, 2010. 3. Riley K. FDA approves first maintenance drug therapy for advanced lung cancer [press release]. July 6, 2009. US Food and Drug Administration. www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm 170515.htm. Accessed September 22, 2010. 4. Alimta (pemetrexed disodium) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2010. 5. Waknine Y. FDA approves use of erlotinib as maintenance therapy for advanced non-small cell lung cancer [press release]. April 20, 2010. www.medscape.com/ viewarticle/720446. Accessed September 22, 2010. 6. Tarceva (erlotinib) [package insert]. Melville, NY: OSI Pharmaceuticals Inc; and South San Francisco, CA: Genentech; 2010. 7. Owonikoko TK, Ramalingam SS, Belani CP.

Maintenance therapy for advanced non-small cell lung cancer: current status, controversies, and emerging consensus. Clin Cancer Res. 2010;16:2496-2504. 8. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomized, placebo-controlled phase 3 study. Lancet Oncol. 2010;11:521-529. Epub May 20, 2010. 9. Maintenance therapy for non-small-cell lung cancer: a value-based approach to improve patient care and outcomes, part I of II. Value-Based Cancer Care. 2010;1(5):24-26. 10. Kutikova L, Bowman L, Change S, et al. The economic burden of lung cancer and the associated costs of treatment failure in the United States. Lung Cancer. 2005;50:143-154. Epub, August 19, 2005. 11. National Cancer Institute, US National Institutes of Health. Surveillance Epidemiology and End Results. SEER Stat Fact Sheets: Lung and Bronchus. http://seer.cancer.gov/statfacts/html/lungb.html. Accessed September 20, 2010. 12. Vincent GK, Velkoff VA. The Next Four Decades, the Older Population in the United States: 2010 to 2050. Current Population Reports, P25-1138. US Census Bureau, Washington, DC; May 2010. 13. American Society of Clinical Oncology. Explaining maintenance therapy. Cancer.net. Updated February 22, 2010. www.cancer.net/patient/All+About+Cancer/ Cancer.Net+Feature+Articles/Treatments%2C+Tests %2C+and+Procedures/Explaining+Maintenance+ Therapy. Accessed September 20, 2010. 14. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non– small-cell lung cancer: a randomized, double-blind, phase 3 study. Lancet. 2009;374:1432-1440. Epub September 18, 2009. 15. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage NSCLC. J Clin Oncol. 2008;26:3543-3551. 16. Taxotere (docetaxel) [package insert]. Bridgewater, NJ: sanofi-aventis US, LLC; 2010. 17. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27:591-598. Epub December 15, 2008. 18. Avastin (bevacizumab) [package insert]. South San Francisco, CA: Genentech, Inc; 2009. 19. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non–smallcell lung cancer. N Engl J Med. 2006;355:2542-2550. 20. Eaton KD. Maintenance chemotherapy in nonsmall cell lung cancer. J Natl Compr Canc Netw. 2010;8:815-821. 21. Erbitux (cetuximab) [package insert]. Branchburg, NJ: ImClone Systems Inc; 2010; and Princeton, NJ: Bristol-Myers Squibb Company; 2010. 22. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non– small-cell lung cancer (FLEX): an open-label randomized phase III trial. Lancet. 2009;373:1525-1531. 23. Neal JW. Histology matters: individualizing treatment in non-small cell lung cancer [editorial]. Oncologist. 2010;15:3-5. Epub January 19, 2010. 24. Hayes E. Will maintenance sell in NSCLC? Experts weigh costs against benefits. Pharmaceutical Approvals Monthly. August/September 2010. 25. Ramsey S. Cost effectiveness in lung cancer trials and treatment. Presented at the 2010 American Society of Clinical Oncology Meeting—Education Session. June 4-8, 2010; Chicago, IL. 26. Evans TL. Maintenance therapy for advanced NSCLC is standard of care. Presented at the 2010 American Society of Clinical Oncology Meeting— Education Session. June 4-8, 2010; Chicago, IL. 27. Stinchcombe T. Maintenance therapy for advanced NSCLC is not standard of care. Presented at the 2010 American Society of Clinical Oncology Meeting— Education Session. June 4-8, 2010; Chicago, IL. 28. Belani CP, Liao J. Maintenance therapy for nonsmall cell lung cancer [comment]. Lancet. 2010. 375:281-282; comment on Stinchcombe T, West H comment in: Lancet. 2009;374:1398-1400. 29. Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration of chemotherapy for advanced non-smallcell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol. 2009;27:32773283. Epub May 26, 2009.

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

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

Prolonged Initial Chemotherapy Prolonged treatment with initial chemotherapy (eg, 6 vs 3 cycles or indefinite treatment vs 4 cycles) has shown no overall survival (OS) benefit1-3; neither have prior maintenance studies of attenuated dosing or single agents yielded a survival benefit, although “intriguing trends” in time to progression have been observed in underpowered efforts.4,5 Switching to a new compound for maintenance therapy demonstrated some benefit in the well-designed study by Fidias et al, which evaluated immediate versus delayed docetaxel upon disease progression after firstline carboplatin/gemcitabine.6 Progression-free survival (PFS) improved from 2.7 months in the delayed arm to 5.7 months with maintenance (P <.001), and median OS trended better (12.3 vs 9.7 months, P = .085). In addition, a recent meta-analysis documented a 30% reduction in disease progression using

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maintenance therapy with a third-generation regimen compared with maintenance with older regimens.7 Determining the Optimal Maintenance Therapy Agent The study by Fidias and colleagues laid the groundwork for pemetrexed as maintenance after chemotherapy,6 which was evaluated in a recent phase 3 study by Belani et al.8 Patients were randomized 2:1 to pemetrexed or intravenous placebo. Disease progression was reduced by 40% (P <.001) overall and by 53% in patients with nonsquamous histology (P <.001), and deaths were reduced by 21% (P = .012) and 30% (P = .002), respectively. Pemetrexed was reasonably well-tolerated and devoid of cumulative toxicity. Benefits were particularly pronounced in patients with nonsquamous histology (they had a more than 5-month survival advantage); there was no PFS or OS advantage in those with squamous histology.8 Although this was the first randomized, double-blind, placebo-controlled trial to show a significant survival benefit for maintenance treatment, one still needs to exercise caution in basing clinical decisions on this study. Maintenance therapy is unrealistic for many patients due to early disease progression, comorbidities, and patient desire to stop treatment. Pemetrexed is of no value to patients with squamous histology and is unproven in patients who have received firstline pemetrexed or bevacizumab. Furthermore, the survival improvement in the Belani study would be more impressive had there been mandatory crossover to pemetrexed at the time of disease progression in the control arm; unlike the Fidias trial, mandatory crossover was not instituted in the JMEN trial. It is noteworthy that <20% of enrollees in the control arm received pemetrexed at the time of disease progression, although a majority received a standard secondline treatment. Many patients look forward to the prospect of a therapeutic holiday. If patients are closely monitored once they have completed firstline therapy, there is often enough time to imple-

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

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

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

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

patients the autonomy to make decisions about receiving maintenance therapy, along with possible breaks to have a vacation or spend time with family. Maintenance therapy can continue indefinitely, which can leave a patient feeling that his/her life is a constant schedule of treatments and can cause tremendous emotional stress. Managing Toxicities As maintenance therapy becomes a more widely used treatment option for patients with NSCLC, it is important to weigh its toxicities. Pemetrexed, which is US Food and Drug Administration (FDA) approved in the maintenance setting, and docetaxel, which has a recommendation (although not an FDA approval) for maintenance therapy, are both cytotoxic chemotherapy agents and pose different concerns than other approved maintenance therapies. Common side effects of chemotherapeutic agents, including risk for myelosuppression, fatigue, and nausea, are a concern for patients receiving maintenance therapy, especially because there is no defined end date to it unless there is disease progression or unacceptable toxicity. So patients may end up taking these drugs without a break for up to a year or more. In the pemetrexed maintenance study, anemia occurred in 15% of patients in the pemetrexed maintenance arm versus 6% in the placebo arm.1 Patients receiving pemetrexed may therefore require more frequent blood transfusions and possibly colony-stimulating factors such as darbepoetin or erythropoietin. Managing fatigue can become difficult for these patients, and considering that they are dealing with a terminal illness, fatigue must be taken into serious account in terms of its effect on the patient’s quality of life. Nausea was also reported in 19% of patients in the pemetrexed arm versus 6% in the placebo arm.1

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The targeted therapies erlotinib (in the switch maintenance setting) and bevacizumab and cetuximab (in the continuation maintenance setting) do not typically induce the same side effects as chemotherapy but rather carry their own set of unique toxicities. The toxicities from these agents can also interfere with a patient’s quality of life and must be considered and addressed before embarking on maintenance therapy.

Conversations with patients about the schedule, toxicities, and benefits of therapy must be unbiased and thorough. Rash was the most common side effect in patients receiving erlotinib in the maintenance trial. Grade 3/4 rash, causing interference with activities of daily living, was 6%.2 Because good randomized data on treating this rash have not emerged, management strategies have focused on best-practice recommendations. Depending on severity, papulopustular rash can be treated with topical steroids or antibiotics, oral antibiotics, and even oral steroids in severe cases.3 These medications can be used in combination or separately depending on the grade of rash. Although it is rarely life-threatening, rash can be uncomfortable and disfiguring at times. In the cetuximab continuation trial, rash was present in 70% (382/548) of patients, with 10% experiencing grade 3/4 rash. Rates of grade 3/4 diarrhea in both the cetuximab and erlotinib maintenance trials were 4% and 2%, respectively.2,4 It is usually easily controlled with loperamide and sometimes requires a prescription-strength antidiarrheal. Concern for dehydration

may be an issue given that this patient population is often elderly, so prompt assessment and ensuring fluid intake are important. Bevacizumab is only approved for the use of nonsquamous NSCLC because of bleeding risk. The most common side effects of bevacizumab include hypertension and proteinuria,5 and assessing for these on each visit is recommended. Standard antihypertensives will usually control bevacizumab-associated hypertension; proteinuria often improves on holding the bevacizumab dose. In rare NSCLC cases, bevacizumab has the potential to cause fatal pulmonary hemorrhage, so it is essential that practitioners assess for hemoptysis and permanently discontinue bevacizumab if hemoptysis occurs. In summary, the improvement in survival for metastatic NSCLC by continuing a maintenance therapy after firstline treatment is modest, but it is certainly an advance. Conversations with patients about the schedule, toxicities, and benefits of therapy must be unbiased and thorough. Patients need to be able to voice their concerns and have ample opportunity to shape their treatment regimen becuase of their limited prognosis and possible effect of maintenance treatment on quality of life. ■ References 1. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for nonsmall-cell lung cancer: a randomized, double-blind, phase 3 study. Lancet. 2009;374:1432-1440. 2. Cappuzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multi-center, randomized, placebo-controlled phase 3 study. Lancet Oncol. 2010;11:521-529. 3. Lynch T, Kim E, Eaby B, et al. Epidermal growth factor receptor (EGFR) inhibitor-associated rash: an evolving paradigm in clinical management. Oncologist. 2007;12:610-621. 4. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced nonsmall-cell lung cancer (FLEX): an open-label randomized phase III trial. Lancet. 2009;373:1525-1531. 5. Sandler A, Gray R, Perry MC, et al. Paclitaxel–carboplatin alone or with bevacizumab for non–smallcell lung cancer. N Engl J Med. 2007;355:2542-2550.

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Demonstrating the Value of Innovation At Genentech, we continue to research new and better ways to identify appropriate patients. We develop innovative therapies with established product effectiveness that meet significant unmet medical needs. And we measure our success by making a difference in patients’ lives.

Image: Colored scanning electron micrograph (SEM) of a pancreatic cancer cell.

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