CMS Releases Outpatient PaymentRules for Physicians and HospitalsImproved preventive coverage, continued payment concernsBy Crystal Kuntz, MPA

Significant Impact for NewProstate Cancer TherapyBy Charles Bankhead

Continued Pressures onCommunity Cancer CentersBy Colin Gittens

©2010 Engage Healthcare Communications, LLC

Contralateral ProphylacticMastectomy Improves Survival, Is Cost-Effective in SomeBy Caroline Helwick

National Harbor, MD—Multiple bene-fits were observed for contralateral pro-phylactic mastectomy (CPM), includ-ing cost-effectiveness, in studiespresented at the 2010 ASCO BreastCancer Symposium by investigatorsfrom the Mayo Clinic, Rochester, MN.CPM not only reduced the risk of

breast cancer in the opposite breast by95% among high-risk women withbreast cancer, it improved survival aswell. In addition, in younger womenundergoing mastectomy and deemedto be at average risk, CPM was cost-

effective whencompared withroutine surveil-lance aimed atearly detection forcancer in theopposite breast.“CPM provides

good value, ie, cost/outcome, for selectpatient groups,” reported BenjaminZendejas, MD, of the Department ofSurgery at the Mayo Clinic, whoauthored the cost-effectiveness study.

Milan—Men with castration-resistantprostate cancer (CRPC) gained 4months in overall survival (OS) whentreated with the novel antiandrogenabiraterone acetate, data from a largerandomized trial showed.Treatment with abiraterone and

prednisone led to a median OS of 14.8months compared with 10.9 months forprednisone alone (P <.001). Althoughseemingly modest, the difference willlikely have a practice-changing impacton the treatment of CRPC, lead investi-gator Johann de Bono, MBBS, PhD, anoncologist at the Royal MarsdenHospital in London, said at the 35thEuropean Society for Medical On -cology 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 theagent have hadlong-lived re -sponses, includ-ing 2 of his ownpatients who havebeen treated continuously for morethan 4 years.Abiraterone blocks androgen synthe-

sis by inhibiting the CYP17 rate-limit-ing enzyme necessary for conversion oftestosterone precursors into the malehormone. Laboratory and clinical evi-dence have suggested that someprostate cancer cells generate intra -tumoral androgens despite androgen

www.ValueBasedCancer.com

IN THIS ISSUE

On November 2, 2010, theCenters for Medicare & Medi-caid Services (CMS) issued its

Physician Fee Schedule and HospitalOutpatient Prospective PaymentSystem final rules for 2011. These CMSregulations are important for allproviders of care in the Medicare pro-gram, as they set the payment parame-ters for the upcoming year.

Payment to physicians underMedicare remains an unresolved andcomplicated issue. Under these newregulations, physicians would see a24.9% overall pay cut beginningJanuary 1, 2011 unless Congress takesaction to stop it. The reasons for thepayment cut are complex but stemfromwhat is widely seen as flaws in the

Consolidation and cost pressuresremain key concerns for com-munity cancer centers, accord-

ing to Christian Downs, MHA, JD, theexecutive director of the Association ofCommunity Cancer Centers (ACCC).Mr Downs presented additional resultsand analysis from the ACCC’s ongo-ing, 3-year member survey at theManaged Care Network OncologyManagement Summit in Chicago, IL,on September 24. This survey traces thecontinued reaction of the communityhospital cancer programs to legislativeand economic changes that are reshap-ing community oncology practice. The survey data, which were collect-

ed in late 2009, show that communitycancer center revenue is still largelytied to providing drugs to patients. Incomparison to the physician office set-ting, where phy sicians are on the hookfor drug costs, “drugs mean less to hos-

pitals,” Mr Downs pointed out. Hospitals are also beginning to con-

tract with multiple group purchasingorganizations as a means of controllingcosts, and a large percentage of respon-

Continued on page 8

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

NOVEMBER/DECEMBER 2010 VOL 1 NO 6

Continued on page 10

Continued on page 28

Continued on page 14

Judy Boughey, MD

Johann de Bono, MBBS, PhD

Christian Downs, MHA, JD

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

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

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

STARTS STRONG. LASTS LONG.

Proven CINV prevention in a single IV dose Powerful CINV prevention in the fi rst 24 hours and up to 5 days following

moderately emetogenic chemotherapy1,2

Lasts long against nausea following moderately emetogenic chemotherapy3

Powerful acute CINV prevention following highly emetogenic chemotherapy4

Eisai offers a variety of support programs and resources

IndicationALOXI® (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

of its components

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 fi le. 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.

Asthe last issue of this first yearof publication of Value-BasedCancer Care (VBCC) reaches

you, I wanted to take a moment toreflect on where VBCC has been so far

and where it will be headed in 2011 andbeyond. The publication is inescapablya reflection of the times, and as we allknow, the times are turbulent. For example, barely 2 weeks after

starting at VBCC, I attended the 36thAnnual National Meeting of theAssociation of Community CancerCenters in March, where speakers con-sidered a host of topics that might not

have been on theagenda just sever-al years be fore.Healthcare re -form, multidisci-plinary cancercare, episode-based payment,Medicare reim-bursement, business tools to drivequality, and comparative effectivenesswere all considered.In June, research presented at the

annual ASCO meeting also covered con-tentious ground, including survival ben-efits associated with combination thera-pies, genomic profiling and personalizedcare, and the cost-effectiveness of varioustreatments. And of course, the US Foodand Drug Administration’s approval of a$93,000 therapy (Provenge) and a subse-quent coverage decision by the Centersfor Medicare & Medicaid Services hasgenerated much discussion all year. This publication has covered these

meetings and these essential topics,and others, our first 6 issues. And wehope that this coverage—in the form ofreporting, surveys of the literature, andanalysis of new research and currentevents by the experts of our editorialboard—is providing information youneed and cannot obtain through anyother single source. Several small sur-veys indicate this is so. Medical andpharmacy director attendees at theXcenda Managed Care NetworkOncology Management Summit werequestioned about the publication; 40%indicated a primary interest in originalarticles on cost and access to cancercare, with news and highlights frommajor meetings a close second (38%).Even more, 69% indicated that VBCCwas a publication they anticipatedreading. A separate web survey ofhematologists/oncologists demon-strated similar results.We intend to continue to serve our

readers in 2011 with our print andonline publications (www.valuebasedcancer.com), as well as with the estab-lishment of the Association for Value-Based Cancer Care, which will hold itsfirst meeting March 29-30, 2011, inPhiladelphia. This association willserve to further inform the value con-siderations surrounding cancer caretoday. As I noted in the first issue ofthis publication, providers, payers, andpolicymakers all face new challengesas the world of cancer care is roiled bycost considerations, access issues, newscientific discoveries, and sweepinglegislative changes. We remain certainof the need for such an organizationand such a publication to bring togeth-er the individuals from these customar-ily discreet worlds. We look forward toyou participating with both. Thankyou for reading! �

LETTER TO OUR READERS

3VOL. 1 NO. 6 www.ValueBasedCancer.com I

ALOXI® (palonosetron HCl) injection

BRIEF SUMMARY OF PRESCRIBING INFORMATION

INDICATIONS AND USAGE

Chemotherapy-Induced Nausea and VomitingALOXI is indicated for:

DOSAGE AND ADMINISTRATIONRecommended DosingChemotherapy-Induced Nausea and Vomiting

Instructions for I.V. Administration

CONTRAINDICATIONS

[see Adverse Reactions (6) ]

WARNINGS AND PRECAUTIONSHypersensitivity

ADVERSE REACTIONS

≥

Table 1: Adverse Reactions from Chemotherapy-Induced Nausea and Vomiting Studies ≥ 2% in any Treatment Group

Postmarketing Experience

DRUG INTERACTIONS

USE IN SPECIFIC POPULATIONSPregnancy

Labor and Delivery

Nursing Mothers

Pediatric Use

Geriatric Use

≥

≥ ≥

≥

Renal Impairment

Hepatic Impairment

Race

OVERDOSAGE

PATIENT COUNSELING INFORMATION FDA-Approved Patient Labeling (17.2) in

Instructions for Patients

see Adverse Reactions (6)

ALOXI®

EventALOXI

0.25 mg (N=633)

Ondansetron 32 mg I.V. (N=410)

Dolasetron 100 mg I.V.

(N=194)

From Stakeholders to CommunityBy Colin Gittens

4 I VALUE-BASED CANCER CARE I Nov/Dec 2010 VOL. 1 I NO. 6

PublisherNicholas Englezosnick@engagehc.com732-992-1884Associate PublisherMaurice Nogueiramaurice@engagehc.com732-992-1895Directors, Client ServicesJohn Hennessyjohn@greenhillhc.com732-992-1886Phil Pawelkophil@greenhillhc.com732-992-1887Cristopher Pirescris@engagehc.com732-992-1896Editorial DirectorDalia Bufferydalia@AHDBonline.com732-992-1889Managing EditorColin Gittenscolin@engagehc.com732-992-1536Associate EditorLara Reimanlara@engagehc.com732-992-1892Senior Production ManagerRobyn JacobsBusiness ManagerBlanche Marchitto

November/December 2010 Vol. 1 No. 6

VBCC Editorial Board

Mission StatementValue-Based Cancer Care provides a forum for payers,providers, and the entire oncology team to considerthe cost-value issues particular to cancer treatments.This unique focus is achieved through news coveragefrom major hematology/oncology meetings and thecancer literature, supplemented with commentariesand perspectives from those involved in evaluatingtherapies, treating patients, and paying for care.

BPA Worldwide membership appliedfor August 2010.

Contact Information:For subscription and reprint information please contact: circulation@valuebasedcare.comTelephone: 732-992-1538 Fax: 732-992-1881

Permission requests to reprint all or part of any articlepublished 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 ayear by Engage Healthcare Communica tions, LLC,241 Forsgate Drive, Suite 205A, Monroe Township,NJ 08831. Copyright © 2010 by Engage HealthcareCommunications, LLC. All rights reserved. Value-Based Cancer Care is a trademark of EngageHealth care Communi cations, LLC. No part of thispublication may be reproduced or transmitted in anyform or by any means now or hereafter known, elec-tronic or mechanical, including photocopy, record-ing, or any informational storage and retrieval sys-tem, without written permission from the publisher.Printed in the United States of America.

The ideas and opinions expressed in Value-BasedCancer Care do not necessarily reflect those of theeditorial board, the editors, or the publisher.Publication of an advertisement or other productmentioned in Value-Based Cancer Care should not beconstrued as an endorsement of the product or themanufacturer’s claims. Readers are encouraged tocontact the manufacturers about any features or limi-tations of products mentioned. Neither the editorsnor the publisher assume any responsibility for anyinjury and/or damage to persons or property arisingout of or related to any use of the material mentionedin this publication.

Postmaster: Correspondence regarding subscriptionsor change of address should be directed to CIRCU-LATION DIRECTOR, Value-Based Cancer Care, 241 Forsgate Drive, Suite 205A, Monroe Township,NJ 08831. Fax: 732-992-1881. Yearly subscriptionrates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

Bruce A. Cutter, MD, MMMCancer Care NorthwestSpokane, WA

Craig Deligdish, MDFlorida Comprehensive Cancer NetworkMelbourne, FL

Peter G. Ellis, MDUniversity of Pittsburgh School ofMedicine and UPMC Cancer CentersPittsburgh, PA

Arlene A. Forastiere, MDITA PartnersPhiladelphia, PA

Tracy Gosselin, RN, MSNDuke University Medical CenterDurham, NC

Scott Gottlieb, MDMount Sinai Medical Center and American Enterprise InstituteNew York, NY

David Hom, MBASoluciaFarmington, CT

Philip E. Johnson, MS, RPh, CPhH. Lee Moffitt Cancer CenterTampa, FL

Crystal Kuntz, MPAAstellas Pharma USWashington, DC

Lee Newcomer, MD, MHAUnitedHealthcareMinnetonka, MN

Lynn Nishida, RPhRegence BlueCross BlueShield of OregonPortland, OR

Naimish Pandya, MDUniversity of MarylandBaltimore, MD

Ed Pezalla, MD, MPHAetna Pharmacy ManagementHartford, CT

Denise K. PierceDK Pierce & AssociatesZionsville, IN

Jatin J. Shah, MDM.D. Anderson Cancer CenterHouston, TX

Jayson Slotnik, JD, MPHFoley HoagWashington, DC

Brian K. Solow, MD, FAAFPPrescription SolutionsIrvine, CA

G. Rhys Williams, ScD, MSAmgenThousand Oaks, CA

Winston Wong, PharmD CareFirst BlueCross BlueShieldBaltimore, MD

Yu-Ning Wong, MD, MSCEFox Chase Cancer CenterPhiladelphia, PA

Burt Zweigenhaft, BSBioPharma Partners, LLCNew York, NY

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 InductionTherapy for Multiple Myeloma

7 Value Propositions

Oncology Management Summit

8 Streamlining Cancer Care in Michigan

Data Draw

10 Perception Versus Actual Testing forKRAS/Janna Radtchenko

35th ESMO Conference

14 High Cost to Managing Colorectal CancerToxicities

15 Benefit to Longer Chemotherapy in MetastaticBreast Cancer

ECRI Personalized Medicine Conference

16 Determining Coverage for CER andPersonalized 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 ResearchRegulation Equation

ASCO Shares Concerns Over the Future of Cancer Research

Costs of Care

26 Costs of Cancer Drugs Weigh on US, Canadian Minds

VBCC Perspective

26 The Costs of Care: A Discussion We’re NotPrepared to Have—Yet/Denise K. Pierce

Continuing Education

34 Maintenance Therapy for Non–Small-Cell LungCancer: A Value-Based Approach to ImprovePatient Care and Outcomes, Part II of II

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

38 Nursing and Patient ManagementConsiderations for Maintenance Therapy in Non–Small-Cell Lung Cancer/Beth Eaby-Sandy, CRNP

TABLE OF CONTENTS

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 “StreamliningCancer Care in Michigan,” page 8

Eribulin Approved for Advanced

Breast Cancer

Eribulin mesylate (Halaven) wasapproved for use in patients withmetastatic breast cancer who havereceived at least 2 prior chemotherapyregimens. The effectiveness of the drugwas established in a single study of 762women, which demonstrated superioroverall survival (13.1 months) com-pared with single agent therapy (10.6months). (November 15, 2010)

FDA OKs Everolimus for Rare

Genetic Disorder

The cancer drug everolimus (Affinitor)may now be used to treat patients withsubependymal giant cell astrocytoma(SEGA) associated with tuberous sclero-sis (TS). TS causes benign tumors to growin the brain and in other parts of thebody, including the eyes, lungs, liver,heart, skin, and kidneys. SEGAs are theslow-growing tumors that are consid-ered a major diagnostic feature of TS andcan be fatal when they grow on the brain.These tumors are seen in 6% to 9% ofpatients; this approval was for treat-ments of SEGA that cannot be treatedwith surgery. The drug was approvedunder the US Food and Drug Admin -istration’s (FDA) accelerated approvalprogram. (November 1, 2010)

Dasatinib Now Indicated for Rare

Leukemia

The FDA has approved dasatinib(Sprycel) for initial treatment of Phil -adelphia chromosome-positive chro -nic-phase chronic myeloid leukemia(Ph+ CP-CML). This rare blood cancerprogresses slowly and is linked to agenetic abnormality. Dasatinib, an oralkinase inhibitor, is believed to inhibitthe activity of certain proteins respon-sible for the growth of cancer cells. Theaction allows bone marrow to beginreproducing normal red and whiteblood cells. In June 2006, the FDAgranted accelerated approval for dasa-tinib to treat adults with CP-CML withresistant disease or who were intoler-ant to prior therapy, including imatinib(Gleevec). (October 28, 2010)

Trastuzumab Garners Gastric

Indication

The FDA has granted approval fortrastuzumab (Herceptin) to be used incombination with cisplatin and a fluo-ropyrimidine (capecitabine or 5-fluo-rouracil) for the treatment of patientswith HER2 overexpressing metastaticgastric or gastroesophageal junctionadenocarcinoma who have not re -ceived prior treatment for metastaticdisease. The approval is based on a sig-nificant improvement in median over-all survival of 2.5 months withtrastuzumab plus chemotherapy treat-ment compared with chemotherapy

alone demonstrated in a single, interna-tional, multicenter, open-label, random-ized clinical trial. (October 20, 2010)

GnRH Agonists Gain Warning

The FDA has asked gonadotropin-releasing hormone (GnRH) agonistmanufacturers to add new warnings tothe labels of these products alerting

patients and healthcare professionals tothe potential risk of heart disease anddiabetes in men treated with these med-ications. GnRH agonists are used pri-marily to treat men with prostate cancer.In May, the FDA said that a preliminaryand ongoing analysis found thatpatients receiving GnRH agonists wereat a small increased risk for diabetes,

heart attack, stroke, and sudden death.The new labels will include updates inthe Warnings and Pre cautions sectionabout these potential risks. GnRH ago-nists are marketed under the brandnames Eligard, Lupron, Synarel,Trelstar, Vantas, Viadur, and Zoladex;several generic products are available.(October 20, 2010)

FDA UPDATES

5VOL. 1 NO. 6 www.ValueBasedCancer.com I

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

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 InformationDo 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

CANCER QUICK TAKES

6 I VALUE-BASED CANCER CARE I Nov/Dec 2010 VOL. 1 I NO. 6

Reversing Acute Renal Failure

In patients with multiple myelomawith light chain–induced renal failure,treatment with a combination knownas BDD (bortezomib [Velcade], doxoru-bicin [Adriamycin], and dexametha-sone [Decadron]) resulted in a highrate of myeloma and renal responsesthat was well tolerated by patients

(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 adecrease in glomerular filtration rate to<50 mL/min) were given BDD. If welltolerated after 2 cycles, the bortezomibdose was increased and doxorubicinwas given on additional days.

Myeloma responses were catego-rized as complete response (CR), near-complete response (nCR), very goodpartial response (VGPR), partialresponse (PR), and minor response(MR); renal responses were categorizedas complete, partial, or minor. Themedian number of treatment cyclesin the intent-to-treat and evaluable

population was 8; 26 patients (38%)achieved CR/nCR, 10 (15%) achievedVGPR, 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-treatpopulation. Anemia was the mostcommon hematologic toxicity, with50% of patients presenting with eithergrade 3 or 4 toxicity; infection was themost common nonhematologic toxici-ty (19.1%).

AML Trials: Phases and Changes

A discussion of new drug develop-ment using the example of acutemyeloid leukemia (AML)—but that isapplicable to a broad range of diseases—outlines the problems inherent in phase2 clinical trials that may lead to false-positive results, and how trial design canbe improved and drug development bemade more efficient and less costly(Blood. 2010;116:2420-2428). The authors provide a number of

recommendations on how AML trialsmight be improved, among them,increasing study sizes; using an explic-itly described control group; conduct-ing multivariate analysis to adjust forpatient heterogeneity; including explic-it descriptions of inclusion/exclusioncriteria; using validated surrogate endpoints; incorporating an integratedphase 2/3 trial design so there are nodelays in conducting the phase 3 trial;and discouraging early publication sothat mature data are published.

Bortezomib Bests Vincristine as

Induction Therapy for MM

This study compared the safety andefficacy of a new regimen—bortezomibplus dexamethasone and vincristine—compared with vincristine (Oncovin),doxorubicin (Adriamycin), and dex-amethasone (VAD) in previously un -treated multiple myeloma (MM) (J ClinOncol. 2010;28:4621-4629). This phase 3 study randomized 482

patients to VAD (n = 121), VAD plusdexamethasone, cyclophosphamide(Endoxan), etoposide (Eposin), and cis-platin (Platinol; DCEP) consolidation(n = 121), bortezomib plus dexametha-sone (n = 121), or bortezomib plusdexamethasone plus DCEP (n = 119),followed by autologous stem-cell trans -plantation. The primary end point waspostinduction complete/near-completeresponse (CR/nCR) rate. The rates of postinduction CR/nCR

(14.8% vs 6.4%), at least very good par-tial response (37.7% vs 15.1%), and over-all response (78.5% vs 62.8%) were sig-nificantly higher with bortezomib plusdexamethasone versus VAD.Bortezomib plus dexamethasone

should now be considered a standardinduction treatment before transplan-tation, say the authors.

BRIEF SUMMARY OF PRESCRIBING INFORMATIONNeulasta® (pegfilgrastim) injection, for subcutaneous use

INDICATIONS AND USAGENeulasta 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.

CONTRAINDICATIONSDo not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

WARNINGS AND PRECAUTIONSSplenic RuptureSplenic 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 SyndromeAcute 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 ReactionsSerious 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 DisordersSevere 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 CellsThe 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 REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the Brief Summary:

Warnings and Precautions] Warnings

and Precautions] Warnings and Precautions]

Warnings and Precautions]

Warnings and Precautions]The most common adverse reactions occurring in 5% of patients and with a between-group difference of 5% higher in the pegfilgrastim arm in placebo controlled clinical trials are bone pain and pain in extremity.

Clinical Trials ExperienceBecause 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

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.

Nursing MothersIt 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 UseSafety 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

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 UseOf 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.

Renal ImpairmentIn 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 ADMINISTRATIONThe 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.

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)

Neulasta 6 mg SC on Day 2

(N = 467)

Musculoskeletal and connective tissue disorders

Bone pain 26% 31%

Pain in extremity 4% 9%

LeukocytosisIn clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with non-myeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies.

ImmunogenicityAs 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 ExperienceThe 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: Warnings and Precautions]Blood and lymphatic system disorder: Sickle cell crisis

Warnings and Precautions]Respiratory, thoracic, and mediastinal disorder: ARDS

Warnings and Precautions]General disorders and administration site conditions: Injection site reactionsSkin and subcutaneous tissue disorders: Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, and urticaria, Sweet’s syndrome, generalized erythema and

Warnings and Precautions]

DRUG INTERACTIONSNo 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 bone-imaging results.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category CThere 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® (pegfilgrastim)

Manufactured by:Amgen Inc.One Amgen Center DriveThousand Oaks, California 91320-1799

© 2010 Amgen Inc. All rights reserved.www.neulasta.com1-800-77-AMGEN (1-800-772-6436)

v 11.0

7VOL. 1 NO. 6 www.ValueBasedCancer.com I

VALUE PROPOSITIONSCancer Cost Concerns Creep NorthIt turns out that Americans are not the only ones worried about cancer

treatment costs. According to a poll conducted by the Canadian CancerSociety, 85% of Canadians say that the cost of drugs would have a negativeimpact on their personal finances. Forty-seven percent said that negativeimpact would be “major,” and only 34% of Canadians are confident thattheir healthcare system will be able to provide affordable cancer drugs. Theonline survey was part of an effort to push the Canadian government toestablish a catastrophic drug plan that would eliminate coverage disparitiesbetween provinces. The survey was conducted between September 9-13,2010, and contained a sampling of 2334 Canadian adults. See page 26 of thisissue for additional coverage of Canadian cost concerns.

Price-Cutting May Spur Canadian Use of CervicalVaccineIn response to Canadian research showing that the high price of cervical

cancer vaccines was a key reason why the majority of young Canadianwomen have yet to be immunized, the manufacturer of Cervarix cut thecost of the vaccine by 30% effective October 25, 2010. GlaxoSmithKline,Inc, reduced the price from $134.95/dose to $90.00/dose; 3 doses arerecommended.

Filling in Funds Around NICE GapsThe United Kingdom’s (UK) Department of Health has pledged £250 mil-

lion toward a Cancer Drugs Fund that will pay for new treatments not avail-able in the state-funded health system. An initial £50 million will provideinterim coverage for the financial gap from now until next April; £200 mil-lion will then be spent over the next 3 years. These funds are intended topay for therapies that may not have been approved by the National Institutefor Health and Clinical Excellence (NICE), including bevacizumab(Avastin), lapatinib (Tyverb), and sorafenib (Nexavar). This may be the lasthurrah for NICE, however; the UK’s new coalition government plans tostrip the agency of its power to reject drugs in 2014.

Researchers Bark Up New Tree to ManufactureCancer DrugPaclitaxel (Taxol), which is produced from the bark of the yew, may

become cheaper and easier to produce now that researchers have isolatedand grown stem cells from that tree (Nat Biotechnol. Published onlineOctober 24, 2010. doi:10.1038/nbt.1693). The current manufacturing processis expensive, requires supplies of mature trees, and creates environmentallydamaging by-products. Working from stem cells would eliminate the dan-gerous by-products and allow creation of large amounts of the drug. Thescientists behind this research have also cultured stem cells from otherplants with medicinal purposes.

Colorectal Cancer Screening: Spend Now to Save LaterSpending money on colorectal cancer screening programs that target the

pre-Medicare population (those between 50 and 64 years of age) is neces-sary to reduce the costs of colorectal cancer in the Medicare program,according to research presented at the American College of Gastro -enterology’s 75th Annual Scientific Meeting in San Antonio, TX. Using apopulation-based model, researchers estimated screening and treatmentcosts for fecal occult blood tests (FOBTs); a mix of FOBT and colonoscopy;and colonoscopy, and compared them to current screening trends. Costswere increased in the pre-Medicare population as a result of use of all 3 pro-grams; but those costs were offset by later savings in treatment costs in theolder age-group.

CT Screening Shows Dramatic Benefit in Lung CancerA study comparing the use of computed tomography (CT) versus standard

chest x-rays for screening those at high risk for lung cancer found that CTscreening resulted in 20% fewer deaths from the disease. The large studylooked at more than 53,000 people aged 55 to 74 years who had a smoking his-tory of at least 30 pack-years, and continued for 8 years. The study was haltedwhen the benefit of CT screening became clear; it was funded by the NationalCancer Institute, and full results will be published in the coming months.

Free Is Good, Not Great, When It Comes toScreeningRemoving payment for health insurance deductibles leads to increased,

although modest, improvements in the rates of screening for conditionssuch 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 pre-ventive screening use among 44,106 people enrolled in preferred providerorganizations that had initiated deductible-free coverage of 4 tests—lipidscreening, mammography, fecal occult blood testing, and Pap smears—which reduced but did not eliminate patient out-of-pocket costs. Screeningwas accessed more often when deductibles were reduced; for high-deductible plans, mammography use actually dropped.

Blood-Use Program Injects Clinical, Fiscal ControlA blood-use protocol program at Loyola University Hospital in Chicago

has lowered the amount of blood products transfused per patient, which inturn has led to greater patient safety and lowered costs, according toresearch presented at the College of American Pathologists annual meetingin Chicago. The program implemented blood-use protocols that includedevidence-based indications, educational programs for doctors and nurses,and oversight of the Blood Utilization Review Committee. Some patientsnow receive less blood or no blood at all without compromising patientcare. For example, a doctor might now instead order 1 unit of blood andthen reassess later to see if a second unit is needed instead of successivelyadministering 2 units of blood. In 2009, the average amount of blood prod-ucts transfused per patient at Loyola was 10% lower than it was in 2008,saving $453,355.

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 behaviortowards the better value choices. Then, if the individual spends moremoney, it’s by choice, not need.”

—Tim Heady, CEO of UnitedHealth Pharmaceutical Solutions atUnitedHealth Group, quoted in “Fourth Tiers Could Generate Drug Savings orIncrease Medical Spend,” which appears in the October 2010 issue of SpecialtyPharmacy News.

Teasing Out Value in Healthcare Spending VariationsAt the request of the US Secretary of Health and Human Services, the

Institute of Medicine (IOM) will conduct a study on national variation inhealthcare spending and utilization for individuals with Medicare,Medicaid, private insurance, or no insurance. A committee empaneled bythe IOM—made up of health economists, clinicians, and policy experts—will examine care costs, supply, and quality; health outcomes; medical evi-dence to inform physician care decisions; access to care; and more. Thestudy will inform changes to specific Medicare payment systems thatwould promote high-value care, especially for high-volume, high-cost deci-sions. The committee will meet again January 17-18, 2011.

ONCOLOGY MANAGEMENT SUMMIT

8 I VALUE-BASED CANCER CARE I Nov/Dec 2010 VOL. 1 I NO. 6

dents are using the 340B program,which can provide financial reliefthrough cost-shifting. “There are pro-grams around the country that youcan’t imagine are 340B hospitals,” heemphasized. “That’s a big, bigchange.” Mr Downs said that a futureACCC survey will focus on that partic-ular issue.

Traditional Approaches Changing

Among the biggest trends noted areprograms employing more physicians,mainly medical oncologists, and demo-graphics are playing a key role in thischange. Older oncologists (generallyaged 50 years), who have traditionallybeen entrepreneurial in setting upgroup practices, are being followed by ayounger generation (35-40 years old)that seeks to be an employee rather thana partner. As a result, these older entre-preneurs seek relationships with com-munity centers or other organizations inlieu of new, traditional partnerships.In addition, the survey also notes

consolidation among hospitals and ashift in thinking about community pro-grams. There is renewed appreciationfor not necessarily being part of an aca-demic medical center that is conduct-

ing clinical trials, and a growth in phil-anthropic (or “named”) programs inthe community setting.Another change involves the cost of

the drugs themselves. According to MrDowns, physicians are all too awarethat, “15 years ago, I had $1 millionworth of inventory. Now, I have $10million worth of inventory.”In terms of overall finances, respon-

dents reported cost-cutting, perceived

their financial health asworse comparedto the year before (78% vs 90%), andreported lessmoney being spent on newinitiatives such as patient navigators.

What Is New at the Community

Level

Patients are now paying more—according to Mr Downs, in some casesup to 400% more in the past 10 years.Concomitantly, the use of patient finan-cial counselors has also increased rap-idly, but the work of these individualshas shifted from setting up paymentplans for patients to talkingmore aboutaccess to free or reduced-price drugs orreceiving financial help from philan-thropic foundations.The use of patient navigators is

increasing, but in Mr Down’s experi-ence, their level of responsibilities canvary widely. Some simply take patients

from pointA to point B, whereas othersare advanced practice nurses who layout treatment options and the toxicitiesassociated with them. “We would liketo see more of the latter” sort, he said.Cancer care in hospitals is becoming

“high tech rather than high touch,”he acknowledged, with institutionsspending more money on the latesttechnology rather than on the personwho would be delivering that technol-ogy. The attitude seems to be “get agamma knife so we can put that up onthe billboard on the highway, insteadof getting additional patient naviga-tors,” he quipped. Electronic healthrecords are another high-tech toolexpected to gain further use, but MrDowns was shocked that some institu-tions are already using more than 1—perhaps as a result of consolidationamong facilities.Despite the financial stresses in the

community setting, Mr Downs washopeful. Hospitals, particularly cancercenters, are getting much better aboutlooking at their profit and loss—wherethey’re going to or not going to makemoney—and they’re going to have bet-ter decision-making information avail-able to them, he said. �

The work of patient financialcounselors has shifted fromsetting up payment plans totalking more about access tofree or reduced-price drugs.

Continued Pressures... Continued from cover

at a glance� An ongoing survey of commu-

nity 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 tech-

nology may lessen the human

factor in caregiving

Setting up a statewide cancer path-way program requires sophisti-cated data collection and analytic

capability, as well as a collaborativemindset among participants, accord-ing to Kurt Neumann, MD, MedicalDirector of Managed Care and QualityInitiatives for the International On -cology Network, a division of Ameri -sourceBergen Specialty Group. DrNeumann described the conceptual-ization and construction of such a pro-gram in Michigan during a session atthe Managed Care Network meetingin Chicago, IL, on September 24, 2010.In Michigan, as elsewhere, cancer

care in the community setting is un -der financial pressure, Dr Neumannacknowledged. Adjuvant therapy isnow used in more disease states forlonger periods of time, in a senseturning cancer into a chronic condi-tion. In addition, the rising expense ofcancer drugs and the increasing num-ber of cancer patients fostered byaging baby boomers will add furtherpressures. Nevertheless, the community-based

chemotherapy delivery system isincredibly efficient for patients and

physicians, he argued, and allows forcontinuity of care. “It makes economicsense,” he said.

What Was Done

Dr Neumann described what hetermed “a typical pathway project,”which originated as collaborationbetween many of the state’s oncolo-

gists represented by an offshoot of theMichigan Society of Hematology andOncology (of which Dr Neumann is alongstanding board member) and BlueCross Blue Shield of Michigan(BCBSM). Both parties recognizedvariability and cost issues pertainingto the use of chemotherapy, growthfactors, hospitalization, and end-of-lifecare; the Michigan team addressedthese by focusing on chemotherapyand white and red cell growth factorsin cancers that comprised the majority

of the drug spend (ie, breast, colon,and lung cancers).An unusual feature of this pathway

program, according to Dr Neumann, isthat the physicians themselves werethe drivers in setting it up, and that thecontract is held by the physician group(comprised of nearly 80% of communi-ty oncologists in Michigan). An advan-

tage of this approach is that care is notmandated by a third party, which hasin turn led to great physician accept-ance. The fact that multiple practicescame together under state leadership isunprecedented, he emphasized.The process began in the first quarter

of 2009, with physicians generating apathway/guideline program in collab-oration with a third-party vendor andBCBSM. The first 3 months involveddiscussions and conceptualization onhow the program should be formed. A

12-member steering committee repre-senting both the major cancer centersand community physicians throughoutthe state hammered out the details ofthe program in approximately 2months, followed by an additionalmonth of legal review. The program requires 70% physician

compliance with the chemotherapypathways and 80% compliance withsupportive care (ie, growth factors andantiemetics). Physicians joining theprogram are paid $5000 up front toassist practices with covering applica-ble start-up costs, and they are able toearn additional monies if the programsaves BCBSM money. Physicians join-ing the pathways program were cau-tioned, however, not to join the pro-gram for additional financial gain asthat could not be guaranteed for a newprogram. Dr Neumann pointed out,“don’t join because you think you’regoing to get a lot of money at the end ofthe year. This is a quality initiative.” A key component of the pathway

involves use of generics over brandedmedications when patient clinical out-comes are expected to be the same with

Streamlining Cancer Care in MichiganStatewide cancer pathway program requires cooperation and technologyBy Colin Gittens

“Don’t join because you think you’re going toget a lot of money at the end of the year. Thisis a quality initiative.” —Kurt Neumann, MD

Continued on page 9

ONCOLOGY MANAGEMENT SUMMIT

9VOL. 1 NO. 6 www.ValueBasedCancer.com I

either medication. Physicians are re-sponsible for reviewing and modifyingpathways quarterly or as needed, andphysician groups are obliged to educateindividual pathway outliers. Thoseindividuals are given 2 quarters to comeup to adherence or are removed fromthe program.

Initial Results and Future

Directions

Early returns show physician compli-ance with the pathways at 80% to 90%.The high participation rate is encourag-ing, but it makes comparing results diffi-cult—in effect, there is no control group.“Truthfully, I was amazed” at gettingsuch a high level of participation, DrNeumann confessed. “Before doing this,we had groups with 7 doctors with 7 dif-ferent ways of doing things, and nowwe’ve gotten them to agree.”Expected cost-savings from the path-

way will derive from converting togeneric use where appropriate, limit-ing lines of biologic therapy, andstandardizing care. Calculating thosesavings, however, will be difficult.Currently pathways are financially vet-ted through checking remittance infor-mation, which spares practices fromundertaking additional data collection,but this is not as sophisticated as whatwould be generated through electronicmedical records, which have yet to bewidely used. But these early stepsallow payers to monitor physiciancompliance with pathways. Althoughthere are no overall financial results sofar, Dr Neumann cited published stud-ies showing that nononcology patientcare expenses have also decreasedthrough adherence to pathways. In the second year, the pathway pro-

gram will expand to include lymphoma,myeloma, and ovarian and prostate can-cers. Organizers will also de-emphasizethe drug and reimbursement focus,instead having physicians concentrateon case-management issues to “betterreward those who are more active in theprogram,” said Dr Neumann. Ex -panding pathways for diagnostics, end-of-life care, and decision support is alsoplanned, because these areas alsoinvolve wide treatment variability. Setting up these types of programs

requires sophisticated data and analyt-ics, and that is where involvementwith organizations with strong under-standing of working with providers,payment methodologies, and proventechnical abilities is beneficial, sug-gested Dr Neumann. A collaborativeapproach is helpful—in this case, thesharing of any cost-savings betweenthe physicians and BCBSM was sealedwith a handshake.

Dr Neumann foresees a transition toa population-based payment approachfrom the current episodic-based sys-tem, and this will depend on continuedcollaboration between payers andproviders. An audience survey during

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

sicians are willing to take on thetask of being good stewards of thestate’s healthcare dollars, especiallyif those dollars remain in the localhealthcare system,” Dr Neumannsaid in closing. �

www.halaven.com

NOW

AVAILABLE

HALAVEN™ is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2010 Eisai Inc. All rights reserved. ERI 65A

Streamlining Cancer Care... Continued from page 8

ASCO BREAST CANCER SYMPOSIUM

10 I VALUE-BASED CANCER CARE I Nov/Dec 2010 VOL. 1 I NO. 6

Contralateral Prophylactic Mastectomy... Continued from cover

CPM Improves Survival

Women undergoing mastectomy forbreast cancer frequently opt for CPM.In fact, the rate of CPM has more thandoubled over the past decade, saidJudy Boughey, MD, principal investi-gator of the survival analysis. Although CPM is known to decrease

the occurrence of contralateral breastcancer by 90% to 95%, debate continuesregarding any survival advantage withCPM, because there are limited andconflicting data and a lack of long-termfollow-up, she said. The aim of DrBoughey’s study was to investigatewhether CPM is associated withimproved survival in women with afamily history of breast cancer under-going mastectomy for stage I or IIbreast cancer and CPM as well. All CPMs were performed at the

Mayo Clinic in Rochester, MN,between 1971 and 1993, offering a lookat the long-term outcomes of 385 high-risk patients who were matched 1:1with a comparison cohort of 385women having unilateral mastectomyand no CPM. Patients were matchedaccording to age at diagnosis, year ofdiagnosis, tumor stage, and nodalstatus, although a family history ofbreast cancer was present for all thestudy population but only 35% of theunilateral mastectomy group. At a median follow-up of 17.3 years,

only 2 patients (0.5%) in the CPM cohortdeveloped contralateral breast cancercompared with 31 patients (8.1%) in theunilateral mastectomy cohort. Thisamounted to a 95% decrease in the riskof contralateral breast cancer (P <.001),Dr Boughey reported.“The result remained strongly signif-

icant after adjusting for age, stage,nodal status, and first-degree familyhistory,” she noted.The 10-year overall survival esti-

mates were 83% for the CPM groupand 74% for the unilateral mastectomygroup. After multivariate analysis, thereduction in the risk of death remainedsignificant at 23% (P = .03). The dis-ease-free survival difference betweenthe 2 cohorts was also statistically sig-

nificant, with a 33% reduction resultingfrom 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 associ-ation between CPM and improved sur-vival and disease-free survival and atrend toward improved breast cancer–specific survival,” she said.

Cost-Effectiveness Shown

Dr Boughey and her colleagues alsoshowed that CPM is cost-effective foryounger patients at average risk, andfor high-risk patients (BRCA positive)at any age. The study’s first author wasBenjamin Zendejas, MD.“This study represents the first cost-

effectiveness analysis comparing CPMto routine surveillance for patientswith unilateral breast cancer,” DrZendejas noted.They used a Markov model to sim-

ulate the management of breast can-cer patients from treatment (mastec-tomy) to death. All model parameterswere gathered from published litera-ture or national databases. Base-caseanalysis included end-of-life costsand focused on average-risk breastcancer patients with a starting age attreatment of 45 years. Costs werereported in 2007 US dollars. Out -comes were valued in quality-adjust-ed life-years (QALYs). Patients’ agesat treatment and breast cancer risklevel were varied to assess theirimpact on the overall results.The main comparison was the CPM

strategy versus surveillance, whichincluded annual mammography withcomputer-aided detection. The analysis found that mean total

breast cancer–related costs for womenaged 45 to 60 years are comparable:$30,222 for the CPM strategy and$29,076 for the surveillance strategy(Table). The CPM strategy provides

22.52 mean QALYs (ie, years in perfecthealth) compared with 22.44 for thesurveillance strategy, resulting in anincremental cost-effectiveness ratio of$12,733 per QALY gained for CPMwhen compared with surveillance, DrZendejas reported. “Base-case results show CPM to be

cost-effective in the younger age-groups (ie, <65 years of age). As expect-ed, the rate of new contralateral breastcancers is significantly lower for theCPM group,” he noted.The model estimated that, on aver-

age, 5 prophylactic mastectomieswould be needed to prevent the occur-rence of 1 contralateral breast cancer.For the general population of breastcancer patients aged ≥65 years, howev-er, CPM is less cost-effective, becauseits incremental cost-effectiveness ratiois above the $50,000 threshold for cost-effectiveness, the study found. For BRCA-positive breast cancer

patients, the CPM strategy is not onlycost-effective but it is also a cost-savingstrategy that provides “more QALYswhile being less costly when comparedto routine surveillance,” Dr Zendejaspointed out. �

“Base-caseresults showCPM to becost-effectivein the youngerage-groups.”

—Benjamin Zendejas, MD

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 79 79

Mortality from disease, % 10.8 11.6

Contralateral breast cancer rate/10,000 101 2127

Number needed to treat 5 NA

ICERa ($/QALY gained) 12,733 NA

BRCA+ CPM Surveillance

Total mean cost, $ 31,044 35,909

QALYs 22.50 21.86

ICER ($/QALY gained) –$7602 NA

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.

Perception Versus Actual Testing for KRASBy Janna Radtchenko, Senior Analyst, IntrinsiQ, LLC

Both practice guidelines andthought leaders increasingly recom-mend biomarker tests for optimiza-tion of cancer care; there is, however,a gap between these recommenda-tions, the way physicians practice,and the way they think they practice.Exploring how recommended tests

are applied in clinical practice is impor-tant for bridging the gap betweenguidelines and clinical practice.During primary research, when

physicians are asked about how often

they test forKRAS in colorectal cancer(CRC), they typically respond thathalf of patients with CRC are testedfor KRAS at diagnosis, with the otherhalf tested upon progression. How-ever, IntrinsiQ data show that only40% of patients who have had diseaseprogression treated in 2010 have beentested for KRAS at some point in theirtreatment (Figure). The AmericanCancer Society estimates that morethan 147,000 patients will be diag-nosed with CRC in 20101; 19% ofthemwill be diagnosedwithmetasta-tic disease2 and thereforemay be eligi-ble for epidermal growth factor recep-tor–targeted therapies.The ability to quantify how physi-

cians actuallyuse biomarker tests ratherthan relying on theory or self-reporteddata is critical to accurately predictingproduct usage patterns, designing clini-cal trials, andmanaging the cost of care.

References1. American Cancer Society. Cancer Facts & Figures2010. 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 October27, 2010.

DATA DRAW

FigureKRAS status for CRC patientstreated in 2010 in secondmetastatic line and beyond

Data from IntrinsiQ, LLC. 2009-2010. Informationon proprietary and nonpublished data is availableat www.intrinsiq.com. Accessed October 27, 2010.

59%

test not performed

mutated37%

non-mutated63%

test performed41%

ZOMETA® (zoledronic acid) InjectionConcentrate for Intravenous InfusionInitial U.S. Approval: 2001BRIEF SUMMARY: Please see package insert for full prescribing information.1 INDICATIONS AND USAGE

1.1 Hypercalcemia of MalignancyZometa is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected cal-cium (cCa) of >12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (mid-range ofmeasured 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 bonemetastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer shouldhave 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 orwith other nontumor-related conditions has not been established.

4 CONTRAINDICATIONS4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zometa Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphy-lactic reaction/shock have been reported [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS5.1 Drugs with Same Active Ingredient Zometa contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treatedwith 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 cau-tion in combination with Zometa in order to avoid hypocalcemia. Zometa should be used with caution withother nephrotoxic drugs.Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, andmagnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy withZometa. If hypocalcemia, hypo phosphatemia, or hypomagnesemia occur, short-term supplemental therapymay be necessary.

5.3 Renal Impairment Zometa is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adversereactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limitedin 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 factorsfor subsequent renal deterioration with Zometa. Factors predisposing to renal deterioration, such as dehydra-tion 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 beconsidered only after evaluating the risks and benefits of treatment. In the clinical studies, patients withserum 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. Inthe clinical studies, patients with serum creatinine >265 µmol/L or >3.0 mg/dL were excluded and therewere 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 ClinicalPharmacology (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 intravenousbisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and cortico-steroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greaterfrequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dentalstatus (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reportsof 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 den-tistry prior to treatment with bisphosphonates.While on treatment, these patients should avoid invasive dental procedures if possible. For patients whodevelop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patientsrequiring dental procedures, there are no data available to suggest whether discontinuation of bisphospho-nate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the man-agement 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 administeredto a pregnant woman. In reproductive studies in the pregnant rat, subcutaneous doses equivalent to 2.4 or4.8 times the human systemic exposure (an IV dose of 4 mg based on an AUC comparison) resulted in pre-and postimplantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malforma-tions. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, thepatient 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 hasbeen reported in patients taking bisphosphonates. This category of drugs includes Zometa. The time toonset of symptoms varied from one day to several months after starting the drug. Discontinue use if severesymptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symp-toms 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 broncho constriction in aspirinsensitive patients receiving bisphosphonates.

5.8 Hepatic Impairment Only limited clinical data are available for use of Zometa to treat hypercalcemia of malignancy in patientswith hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or howto safely use Zometa in these patients.

6 ADVERSE REACTIONS6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may notreflect the rates observed in practice.

Hypercalcemia of MalignancyThe safety of Zometa was studied in 185 patients with hypercalcemia of malignancy (HCM) who receivedeither 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 mggiven as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusionhas not been adequately studied in controlled clinical trials.Renal ToxicityAdministration of Zometa 4 mg given as a 5-minute intravenous infusion has been shown to result in anincreased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renalfailure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4 mg isgiven as a 15-minute intravenous infusion. Zometa should be administered by intravenous infusion over noless than 15 minutes [see Warnings And Precautions (5) and Dosage And Administration (2) in the full pre-scribing information].The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (seeTable 3).Table 3 provides adverse events that were reported by 10% or more of the 189 patients treated with Zometa4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumedcausality to study drug.

Table 3. Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System

Zometa Pamidronate4 mg 90 mgn (%) n (%)

Patients StudiedTotal No. of Patients Studied 86 (100) 103 (100)Total No. of Patients with any AE 81 (94) 95 (92)

Body as a WholeFever 38 (44) 34 (33)Progression of Cancer 14 (16) 21 (20)

CardiovascularHypotension 9 (11) 2 (2)

DigestiveNausea 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 SystemAnemia 19 (22) 18 (18)

InfectionsMoniliasis 10 (12) 4 (4)

Laboratory AbnormalitiesHypophosphatemia 11 (13) 2 (2)Hypokalemia 10 (12) 16 (16)Hypomagnesemia 9 (11) 5 (5)

MusculoskeletalSkeletal Pain 10 (12) 10 (10)

NervousInsomnia 13 (15) 10 (10)Anxiety 12 (14) 8 (8)Confusion 11 (13) 13 (13)Agitation 11 (13) 8 (8)

RespiratoryDyspnea 19 (22) 20 (19)Coughing 10 (12) 12 (12)

UrogenitalUrinary Tract Infection 12 (14) 15 (15)

The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by agreater percentage of patients treated with Zometa 4 mg than with pamidronate 90 mg and occurred with afrequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of pre-sumed causality to study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulo cytopenia,thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headacheand somnolence.Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zometa. Acute Phase Reaction-like EventsSymptoms 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 Zometa4 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 AbnormalitiesElectrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, canoccur with bisphosphonate use.Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, andserum 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 3Laboratory Parameter Zometa Pamidronate

4 mg 90 mgn/N (%) n/N (%)

Serum Creatinine1 2/86 (2%) 3/100 (3%)Hypocalcemia2 1/86 (1%) 2/100 (2%)Hypophosphatemia3 36/70 (51%) 27/81 (33%)Hypomagnesemia4 0/71 — 0/84 —

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

Grade 4Laboratory Parameter Zometa Pamidronate

4 mg 90 mgn/N (%) n/N (%)

Serum Creatinine1 0/86 — 1/100 (1%)Hypocalcemia2 0/86 — 0/100 —Hypophosphatemia3 1/70 (1%) 4/81 (5%)Hypomagnesemia4 0/71 — 1/84 (1%)1Grade 3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal)2Grade 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)

Injection Site ReactionsLocal 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 EventsOcular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zometa. Nocases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seenin postmarketing use [see Adverse Reactions (6.2)].Multiple Myeloma and Bone Metastases of Solid TumorsThe safety analysis includes patients treated in the core and extension phases of the trials. The analysisincludes the 2,042 patients treated with Zometa 4 mg, pamidronate 90 mg, or placebo in the three controlledmulticenter 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 phasesand were followed for 2 years (or 21 months for the other solid tumor patients). The median duration ofexposure for safety analysis for Zometa 4 mg (core plus extension phases) was 12.8 months for breast can-cer 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 regard-less 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

Zometa Pamidronate Placebo4 mg 90 mgn (%) n (%) n (%)

Patients StudiedTotal No. of Patients 1031 (100) 556 (100) 455 (100)Total No. of Patients with any AE 1015 (98) 548 (99) 445 (98)

Blood and LymphaticAnemia 344 (33) 175 (32) 128 (28)Neutropenia 124 (12) 83 (15) 35 (8)Thrombocytopenia 102 (10) 53 (10) 20 (4)

Gastrointestinal Nausea 476 (46) 266 (48) 171 (38)Vomiting 333 (32) 183 (33) 122 (27)Constipation 320 (31) 162 (29) 174 (38)Diarrhea 249 (24) 162 (29) 83 (18)Abdominal Pain 143 (14) 81 (15) 48 (11)Dyspepsia 105 (10) 74 (13) 31 (7)Stomatitis 86 (8) 65 (12) 14 (3)Sore Throat 82 (8) 61 (11) 17 (4)

General Disorders and Administration SiteFatigue 398 (39) 240 (43) 130 (29)Pyrexia 328 (32) 172 (31) 89 (20)Weakness 252 (24) 108 (19) 114 (25)Edema Lower Limb 215 (21) 126 (23) 84 (19)Rigors 112 (11) 62 (11) 28 (6)

InfectionsUrinary Tract Infection 124 (12) 50 (9) 41 (9)Upper Respiratory Tract Infection 101 (10) 82 (15) 30 (7)

MetabolismAnorexia 231 (22) 81 (15) 105 (23)Weight Decreased 164 (16) 50 (9) 61 (13)Dehydration 145 (14) 60 (11) 59 (13)Appetite Decreased 130 (13) 48 (9) 45 (10)

MusculoskeletalBone Pain 569 (55) 316 (57) 284 (62)Myalgia 239 (23) 143 (26) 74 (16)Arthralgia 216 (21) 131 (24) 73 (16)Back Pain 156 (15) 106 (19) 40 (9)Pain in Limb 143 (14) 84 (15) 52 (11)

NeoplasmsMalignant Neoplasm Aggravated 205 (20) 97 (17) 89 (20)

NervousHeadache 191 (19) 149 (27) 50 (11)Dizziness (excluding vertigo) 180 (18) 91 (16) 58 (13)Insomnia 166 (16) 111 (20) 73 (16)Paresthesia 149 (15) 85 (15) 35 (8)Hypoesthesia 127 (12) 65 (12) 43 (10)

PsychiatricDepression 146 (14) 95 (17) 49 (11)Anxiety 112 (11) 73 (13) 37 (8)Confusion 74 (7) 39 (7) 47 (10)

RespiratoryDyspnea 282 (27) 155 (28) 107 (24)Cough 224 (22) 129 (23) 65 (14)

SkinAlopecia 125 (12) 80 (14) 36 (8)Dermatitis 114 (11) 74 (13) 38 (8)

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

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 3Laboratory Parameter Zometa Pamidronate Placebo

4 mg 90 mgn/N (%) n/N (%) n/N (%)

Serum Creatinine1* 7/529 (1%) 4/268 (2%) 4/241 (2%)Hypocalcemia2 6/973 (<1%) 4/536 (<1%) 0/415 —Hypophosphatemia3 115/973 (12%) 38/537 (7%) 14/415 (3%)Hypermagnesemia4 19/971 (2%) 2/535 (<1%) 8/415 (2%)Hypomagnesemia5 1/971 (<1%) 0/535 — 1/415 (<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 amendment2Grade 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 4Laboratory Parameter Zometa Pamidronate Placebo

4 mg 90 mgn/N (%) n/N (%) n/N (%)

Serum Creatinine1* 2/529 (<1%) 1/268 (<1%) 0/241 —Hypocalcemia2 7/973 (<1%) 3/536 (<1%) 2/415 (<1%)Hypophosphatemia3 5/973 (<1%) 0/537 — 1/415 (<1%)Hypermagnesemia4 0/971 — 0/535 — 2/415 (<1%)Hypomagnesemia5 2/971 (<1%) 1/535 (<1%) 0/415 —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 amendment2Grade 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)

Among the less frequently occurring adverse events (<15% of patients), rigors, hypokalemia, influenza-likeillness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa 4 mgand pamidronate groups) compared to the placebo group.Less common adverse events reported more often with Zometa 4 mg than pamidronate included decreasedweight, which was reported in 16% of patients in the Zometa 4 mg group compared with 9% in thepamidronate 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 ofthese small differences is not clear.Renal ToxicityIn the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients withnormal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baselinecreatinine (≥1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receivingZometa 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 CreatinineMultiple Myeloma and Breast Cancer Zometa 4 mg Pamidronate 90 mg

n/N (%) n/N (%)Normal 27/246 (11%) 23/246 (9%)Abnormal 2/26 (8%) 2/22 (9%)Total 29/272 (11%) 25/268 (9%)Solid Tumors Zometa 4 mg Placebo

n/N (%) n/N (%)Normal 17/154 (11%) 10/143 (7%)Abnormal 1/11 (9%) 1/20 (5%)Total 18/165 (11%) 11/163 (7%)Prostate Cancer Zometa 4 mg Placebo

n/N (%) n/N (%)Normal 12/82 (15%) 8/68 (12%)Abnormal 4/10 (40%) 2/10 (20%)Total 16/92 (17%) 10/78 (13%)*Table includes only patients who were randomized to the trial after a protocol amendment that lengthened theinfusion duration of Zometa to 15 minutes.

The risk of deterioration in renal function appeared to be related to time on study, whether patients werereceiving Zometa (4 mg over 15 minutes), placebo, or pamidronate.In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis haveoccurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mginfused 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 thesereports are from a population of uncertain size and are subject to confounding factors, it is not possible toreliably estimate their frequency or establish a causal relationship to drug exposure.Osteonecrosis of the JawCases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patientstreated with intravenous bisphosphonates including Zometa. Many of these patients were also receivingchemotherapy and cortico steroids 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 WarningsAnd Precautions (5)].Musculoskeletal PainSevere and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphospho-nate use [see Warnings And Precautions (5)].Ocular Adverse EventsCases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edemahave been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.

Hypersensitivity ReactionsThere have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, andbronchoconstriction. 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: drymouth; Skin: increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, brady-cardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlyingrisk factors); Respiratory: bronchoconstriction; Renal: hematuria, proteinuria; General Disorders andAdministration Site: weight increase; Laboratory Abnormalities: hyperkalemia, hypernatremia.

7 DRUG INTERACTIONSIn-vitro studies indicate that zoledronic acid is approximately 22% bound to plasma proteins. In-vitro stud-ies also indicate that zoledronic acid does not inhibit micro somal CYP450 enzymes. In-vivo studies showedthat zoledronic acid is not metabolized, and is excreted into the urine as the intact drug. However, no in-vivodrug interaction studies have been performed.

7.1 Aminoglycosides Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents mayhave an additive effect to lower serum calcium level for prolonged periods. This effect has not been reportedin Zometa clinical trials.

7.2 Loop Diuretics Caution should also be exercised when Zometa is used in combination with loop diuretics due to an increasedrisk 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 combi-nation with thalidomide.

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy ZOMETA SHOULD NOT BE USED DURING PREGNANCY. There are no studies in pregnant women usingZometa. If the patient becomes pregnant while taking this drug, the patient should be apprised of the poten-tial harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant [seeWarnings And Precautions (5.4)]. Pregnancy Category DBisphosphonates are incorporated into the bone matrix, from where they are gradually released over periodsof weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount avail-able for release back into the systemic circulation, is directly related to the total dose and duration of bisphos-phonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm inanimals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into mater-nal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a womanbecomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such astime between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, andthe 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 daysbefore mating and continuing through gestation, the number of stillbirths was increased and survival ofneonates was decreased in the mid- and high-dose groups (≥0.2 times the human systemic exposure fol-lowing an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observedin all dose groups (with a systemic exposure of ≥0.07 times the human systemic exposure following anintravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortalityin pregnant rats allowed to deliver. Maternal mortality may have been related to drug-induced inhibition ofskeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonate-class effect.In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gesta-tion, 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 postimplantationlosses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletaleffects 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 high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reductionof lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenousdose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dosegroup and included reduced body weights and food consumption, indicating that maximal exposure levelswere achieved in this study.In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day duringgestation (≤0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surfaceareas), no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatmentgroups (at doses ≥0.05 times the human intravenous dose of 4 mg, based on a comparison of relative bodysurface areas). Adverse maternal effects were associated with, and may have been caused by, drug-inducedhypocalcemia.

8.3 Nursing Mothers It is not known whether Zometa is excreted in human milk. Because many drugs are excreted in humanmilk, and because Zometa binds to bone long term, Zometa should not be administered to a nursingwoman.

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 pedi-atric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesisimperfecta, 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 oneyear, increases in BMD were observed in the zoledronic acid treatment group. However, changes in BMD inindividual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for frac-ture or the incidence or severity of chronic bone pain. The adverse events observed with Zometa use in chil-dren did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemiaof malignancy or bone metastases. However, adverse reactions seen more commonly in pediatric patientsincluded 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 commonwith repeat dosing. Because of long-term retention in bone, Zometa should only be used in children if thepotential 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 concentrationtime profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed inadult 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 patientsreceiving 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 efficacyand safety in older and younger patients. Because decreased renal function occurs more commonly in theelderly, special care should be taken to monitor renal function.

10 OVERDOSAGEClinical 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 maycause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevantreductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenousadministration 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 single48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episodeof hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patientwas discharged seven days after the overdose.A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for atotal dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increasedGGT (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 hasbeen shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minuteintravenous infusion. In controlled clinical trials, Zometa 8 mg has been shown to be associated with anincreased risk of renal toxicity compared to Zometa 4 mg, even when given as a 15-minute intravenousinfusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [seeDosage 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 T2009-101Manufactured by:Novartis Pharma Stein AGStein, Switzerland forNovartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©Novartis

35TH ESMO CONFERENCE

14 I VALUE-BASED CANCER CARE I Nov/Dec 2010 VOL. 1 I NO. 6

deprivation therapy (ADT), as do theadrenal glands. Abiraterone targetsboth adrenal and intratumoral andro-gen biosynthesis.

Response on Multiple End Points

Dr de Bono reported findings from amulticenter study involving 1195 menwith CRPC that had proved unrespon-

sive to docetaxel, in addition to con-ventional ADT. The patients were ran-domized 2:1 to prednisone plus abi-raterone or placebo, and the primaryend point was OS.In addition to the survival advan-

tage, all secondary end points showedsuperiority for abiraterone acetate overplacebo:• Time to prostate-specific antigen(PSA) progression, 10.2 versus 6.6months; P <.001

• Radiologically confirmed progres-sion-free survival, 5.6 versus 3.6months; P <.001

• PSA response, 38% versus 10%; P<.001.

Subgroup analysis showed consistenteffects of treatment with abiraterone.Patients treatedwith abiraterone had

a higher incidence of edema (30.5% vs22.3%) and hyperkalemia (17.1% vs8.4%). Abnormal liver function testsand cardiac disorders occurred in asimilar proportion of patients in bothgroups, and grade 3-4 adverse eventswere uncommon in both groups.

Impressive Results, Expensive

Potential

Invited discussant Cora Sternberg,MD, a genitourinary oncologist atCamillo Forlanini Hospital in Rome,said the study yielded “the most

impressive results that I’ve seen in along time, in this patient population.”Abiraterone is the farthest along indevelopment of several new antiandro-gens under investigation and could leadthe way toward new treatment strate-gies for CRPC, added Dr Sternberg.Dr de Bono said the findings create a

potential for novel combination strate-gies, such as abiraterone and the recent-ly approved immunotherapeutic agentsipuleucel-T (Provenge). Such combi-nations would have substantial costimplications, given the $93,000 price tagfor a single course of the sipuleucel-T,which has yet to win approval forMedicare reimbursement. �

Significant Impact for New Prostate Cancer... Continued from cover

In the history of prostatecancer, only 4 drugs haveever shown a survivalbenefit.

Milan—Because the toxicity profilesfor the 3 monoclonal antibodies used intreating metastatic colorectal cancer(mCRC) differ, there are substantial dif-ferences in the cost of treating sideeffects, according to research presentedat the 35th ESMO Congress.

“The cost of treating toxicities caninform the evaluation of the clinicaland cost-effectiveness of monoclonalantibodies in managing patients withmCRC,” said lead author ChakkarinBurudpakdee, PharmD, of IMS Healthin Philadelphia, a healthcare marketintelligence company.Bevacizumab, cetuximab, and pani-

tumumab have different toxicity pro-files but little is known about the directcosts for managing these toxicities. Thestudy aimed to provide this informa-tion, he said.A comprehensive PubMed search

identified 23 phase 2 and 3 trials evalu-ating these agents in mCRC. AmericanSociety of Clinical Oncology andESMO websites were searched forabstracts (years 2008-2010), and pack-age inserts were reviewed for toxicitydata. For the purpose of estimating treat-

ment costs for grade 3-4 toxicities, theidentified toxicities were placed intorepresentative groupings based onsimilarities in event type and treatmentapproach. For example, the “deep veinthrombosis” group included deep veinthrombophlebitis, venous thrombotic

events, and thrombotic events, and“febrile neutropenia” included infec-tion, leukopenia, and neutropenia. Costs for the toxicities in the inpa-

tient setting (grade 4) were estimatedusing 2007 Medicare payment sched-ules. For the outpatient setting (grade

3), in-depth clinical interviews wereconducted to obtain resource use,then 2010 Medicare reimbursementrates were applied. All inpatient andoutpatient costs were converted to2010 values.

Substantial Costs for Grade 4

Side Effects

In total, 61 toxicities were identifiedin the studies. Clinically significant tox-icities associated with bevacizumabincluded hypertension, arterial throm-bosis, hemorrhage, gastrointestinalperforation, fistula, and wound healingcomplications.Treatment-related toxicities associat-

ed with cetuximab and panitumumabincluded skin rash, hypomagnesemia,and infusion reactions. The inpatient cost per event for gas-

trointestinal perforation was the high-est ($32,443), followed by fistula($29,062), arterial thrombosis ($20,346),wound healing complications ($13,240),hemorrhage ($12,956), infusion reac-tion ($10,877), and hypertension($8453). Other, less common toxicitieswere also costly (Table), but skin rashand hypomagnesemia—which oc -

curred with cetuximab and panitu-mumab—were among the least costlyinpatient toxicities at $4424 and$6174, respectively, Dr Burudpakdeereported.For outpatients, costs were minimal,

ranging from $185 for hypertensionand rash to $585 for wound healingcomplications.Dr Burudpakdee acknowledged the

study’s limitations. The developmentof a comprehensive and standardizedlist of toxicities is limited by the vari-ability among the trials (eg, samplesizes and differences in reporting ordefining grade 3-4 adverse events ofinterest). Outpatient resource use wasbased on best clinical judgment andmay not reflect all clinical practices, nordoes it include outpatient drug use. �

High Cost to Managing Colorectal Cancer ToxicitiesBy Caroline Helwick

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

—Chakkarin Burudpakdee, PharmDTable Major Inpatient Toxicity Costs

Toxicity Cost per event, $ (2010)

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

35TH ESMO CONFERENCE

15VOL. 1 NO. 6 www.ValueBasedCancer.com I

Milan—Continuing first-line chemo-therapy for metastatic breast canceruntil disease progression significantlyimproves overall (OS) and progres-sion-free survival (PFS), according to ameta-analysis reported at the 35thESMO CongressProlonged therapy was associated

with a 9% reduction in the mortalityhazard and a 36% reduction in hazardfor progression, and the results shouldprovide information to aid decision-making about the duration of chemo -therapy for metastatic breast cancer,said researcher Alessandra Gennari,MD, a medical oncologist at GallieraHospital in Genova, Italy.

“The magnitude of the effect wasconsistent across all subgroups, sug-gesting the benefit reflected the impactof the duration of chemotherapy,” saidDr Gennari.The optimal duration of first-line

chemotherapy for metastatic breastcancer has yet to be defined, leavingtolerability to dictate how long therapycontinues for most patients. In an effort to clarify the potential bene-

fits, Dr Gennari and colleagues performeda meta-analysis of 11 published clinical tri-als comparing different durations ofchemotherapy in 2269 patients withnewly diagnosed metastatic breast cancer.The principal objectives were to

determine whether continuing chemo -therapy beyond a prespecified numberof cycles improves PFS and OS.

Benefits and Lingering Questions

Overall, longer duration of chemo -therapy was associated with a mortali-ty hazard ratio of 0.91 (P = .04) and aprogression hazard ratio of 0.34 (P<.001). By meta-regression analysis, thefindings remained independent of thetime of randomization, study design,number of chemotherapy cycles in thecontrol arm, and coadministration ofendocrine therapy.Noting lack of evidence for a sur-

vival benefit with prolonged chemo -therapy in metastatic breast cancer, theNational Comprehensive CancerNetwork clinical guidelines point outthat the potential benefits should beweighed against potentially detrimen-tal effects of longer-duration chemo -therapy for every patient.The survival benefit and reduced

risk of progression observed in themeta-analysis provide justification forclinicians to recommend that patientscontinue chemotherapy until diseaseprogression 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 ther-apy, planned sequential therapies ver-

sus prolonged use of a single agent, therole of targeted therapies in prolongedtreatment, and the economics of con-tinuing therapy beyond a predeter-mined number of cycles. �

Benefit to Longer Chemotherapy in Metastatic Breast CancerBy Charles Bankhead

The optimal duration of first-line chemotherapy formetastatic breast cancer hasyet to be defined.

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resources. After all, isn’t cancer a disease we should manage together?

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Bethesda, MD—Greater adoption ofpersonalized medicine and compara-tive effectiveness research (CER) inhealthcare will depend on coverage ofthese approaches by public and privatepayers. But payer evaluation of theseapproaches is hampered by legislativeroadblocks and a lack of research inCER and slowness in adopting CERinto clinical practice, according tospeakers at a session of the ECRIInstitute’s Comparative Effectivenessand Personalized Medicine: An Essen -tial Interface conference.

For Lee Newcomer, MD, SeniorVice President of Oncology at UnitedHealthcare, CER is a positive devel-opment, one that might weed out out-moded therapies, focus innovation,reduce toxicities, and allow rationalpricing for competing therapies.Ultimately, it should accelerate thebetter use of healthcare resources.Personalized medicine will need tobe evidence based, and for DrNewcomer, CER is the way to supplythat evidence. But in discussing UnitedHealthcare’s

experience with physicians’ use ofbevacizumab (Avastin), Dr Newcomerrecounted how data showed that physi-cians were using this drug in the adju-vant setting, be fore any trials in that set-

ting had been done. The danger, hefears, is that personalized medicinemay be thought of as giving physicians“carte blanche” to try treatments thatare outside the evidence. In addition, before wading into the

complexities of genomics, CER, andcoverage issues, Dr Newcomer alsocautioned that more prosaic compara-tive effectiveness matters need toremain in the forefront of conscious-ness. For example, 2 studies in thesame issue of the New England Journalof Medicine looked at adjuvant chemo -

therapy with standard chemotherapyversus adjuvant chemotherapy withtrastuzumab in breast cancer, and thefirst one indicated more complicationswith what has become the standardtreatment approach in the UnitedStates (52 weeks of trastuzumab ther-apy [Romond EH, et al. Trastuzumabplus adjuvant chemotherapy for oper-able HER2-positive breast cancer. NEngl J Med. 2005;353:1673-1684]). Thesecond study indicated 12 weeks oftherapy was efficacious and did notcause the cardiac side effects seen inthe first study (Joensuu H, et al.Adjuvant docetaxel or vinorelbinewith or without trastuzumab forbreast cancer. N Engl J Med. 2006;354:809-820); nevertheless, there hasbeen no outcry in the advocacy com-munity for a comparative effective-ness study in this area. Researchdownstream from the original investi-gations has much potential value, hesuggested. “That part of comparativeeffectiveness would benefit patientsdramatically.”A second example offered by Dr

Newcomer discussed the role of CERin evaluating various therapies forprostate cancer. Newer, increasinglyexpensive radiation therapies, includ-ing intensity-modulated radiation ther-apy, stereotactic body radiosurgery,and proton beam therapy, have allgained wide acceptance, despite a lackof comparative effectiveness studies onthem. CER would help inform individ-ual patients on which approach mightbe the best fit for them.

Right now, we have “lots of technolo-gies, and no idea how to use them [effec-tively],” he lamented. Evidence informsgood decisions, Dr Newcomer stressed,and although some therapies may goaway through the use of CER, they maydisappear for the right reasons.

Covering CER: the Public Side

As a public payer responsible formore than 114 million American lives,the Centers for Medicare & MedicaidServices (CMS) is also dealing with cov-ering personalized medicine and CER,albeit at a much greater scope. As notedby Barry M. Straube, MD, ChiefMedical Officer and Director at theOffice of Clinical Standards andQuality at CMS, those deliberations areshaped by the legislation that detailswhat is covered and how CER informa-tion can and cannot be used. In someways, Dr Straube acknowledged, CMSis still struggling to understand theintent of coverage language in billscrafted 40 years ago. Medicare coverage outlined under

section 1862(a)(1) of the SocialSecurity Act specified coverage isrequired for items and servicesdeemed “reasonable and necessary for

the diagnosis or treatment of illness orinjury or to improve the functioningof a malformed body member.”According to Dr Straube, CMS hasdefined “reasonable and necessary” asdemonstrating adequate evidence toconclude that the item or service ortest improves clinically meaningfulhealth outcomes for the Medicarepopulation. And in evaluating thera-pies, he emphasized, CMS examinesthe new therapy compared to usualcare, not another device or therapy. Soa shift to using CER will require a fun-damental change. But the healthcare reform law states

explicitly that cost should not be a fac-tor in coverage determinations, andthat coverage cannot be denied “solelyon the basis” of CER. Further, thePatient Centered Outcomes ResearchInstitute, an independent advisorycommittee being set up as part of

healthcare reform, is also proscribedfrom developing or employing a dol-lars/quality-adjusted life-year thresh-old. Although Congress has legislatedthat cost-effectiveness is not allowed tobe a factor in coverage determination,it is allowed under the Medicare Im -provements for Patients and Pro vidersAct of 2008 (Section 101), which coverspreventive services. Whether person-alized medicine is defined as a preven-tive service remains to be seen. So“although there’s been the mandate todo more comparative effectivenessresearch, clearly we have limitations,”Dr Straube acknowledged.There are difficulties in drafting cov-

erage for CER, Dr Straube pointed out.If CER determines that a test or technol-ogy is far better than others, that singleitem may be the only one covered. But ifsomething then prevents that technolo-gy from being used (ie, a manufacturingproblem), there may be no reimbursabletreatment. Patient outliers to approvedtreatments may also be left out if CER isadhered to as a strict doctrine. Legislation also must be carefully

drafted so that unintended conse-quences do not crop up. A questionfrom the audience, for example, pointed

out that genetic counselors are not con-sidered providers and are therefore notreimbursed under Medicare. AlthoughCMS agrees that genetic counseling is anecessary service, the law does notallow this reimbursement, and the ulti-mate solution will require further legis-lation, said Dr Straube. Finally, Dr Straube mentioned rec-

ommendations regarding CMS cover-age for genetic testing arising from 2Medicare Evidence Development &Coverage Advisory Committee meet-ings. These committees recommendedthe evidence standards for genetic andgenomic testing need to be high.As Dr Straube noted at the outset of

his presentation, when patients startcoming in to medical offices, request-ing access to the latest genetic testsand the treatments that result fromthem, the enormity of costs to societyare frightening. �

ECRI PERSONALIZED MEDICINE CONFERENCE

16 I VALUE-BASED CANCER CARE I Nov/Dec 2010 VOL. 1 I NO. 6

The danger is that personalized medicine may be thought of as giving physicians “carteblanche” to try treatments that are outside the evidence.

—Lee Newcomer, MD

Although CMS agrees that genetic counselingis a necessary service, the law does not allowthis reimbursement.

—Barry M. Straube, MD

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

Determining Coverage for CER and Personalized MedicineBends in the road on path to paymentBy Colin Gittens

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. © Centocor Ortho Biotech Inc. 2010 4/10 08ADA10012

Bethesda, MD—Implementing andeffectively using comparative effective-ness research (CER) and personalizedmedicine (PM) will require time andbetter communication among theresearch community conducting thesetypes of studies and with the publicthat will be impacted by them, accord-ing to participants in a panel discus-sion on the societal implications of CERand PM held during the ECRIInstitute’s Comparative Ef fectivenessand Personalized Medicine: AnEssential Interface conference.For David Meltzer, MD, PhD,

Associate Professor in the Departmentof Medicine at the University ofChicago, the flood of additional infor-mation provided by CER and PM may

not necessarily behelpful in a sys-tem where indi-viduals are dis-connected frompaying costs. Forhim, aspects ofhealthcare re -form—increasedpatient costs andcopayments, bun-

dled payments, and accountable careorganizations—will have the beneficialeffect of reconnecting patients withcosts, thereby realigning incentives.CER will be essential for delineatingthe benefits and costs of care, and incancer, PM will determine the high-cost, low-value treatments that shouldnot be used by most patients.Frances Miller, JD, Professor of Law

at Boston University School of Lawand Professor of Public Health atBoston University School of PublicHealth, also emphasized that innova-tions in CER and PM are inextricablylinked to reimbursement. Describingthat linkage as the “800-lb gorilla,” shewondered how to get the public toaccept that link. She also expressedconcern that the potentially ambiguousconcepts of CER and PM may go overthe heads of the American public, espe-cially given the current climate sur-rounding health reform. “Everyone here to a greater or lesser

extent accepts the value of comparativeeffectiveness and the promise of person-alized medicine,” she said, referring tothose attending the conference. Amongthe larger American population, howev-er, “the level of accurate information isshockingly low.” Given the threat ofhealthcare reform repeal and challengesto the individual insurance mandate, DrMiller said, “I’m worried.”

Also concerned was Gail Wilensky,PhD, Economist and Senior Fellow atProject Hope. Noting the attempts topaint CER as anti-individualized andintended to prevent people fromreceiving therapies from which theymight benefit during the healthcare

reform debate, Dr Wilensky pointedout that the current system does notprovide adequate information on whois likely to benefit, particularly fromcomplex, expensive therapies. Exam -ining how conditions might be treatedin varied groups is precisely the direc-tion that PM and CER should be takingthe country, she argued. This will gettreatments beyond the “on average”approach.

Advancing the CER/PM Agenda

Reframing the terminology—think“patient-centered outcomes research”rather than CER—is one of severalways suggested by Dr Miller to fosterCER and PM among the general publicand keep the debate about theseapproaches rational. In addition, point-ing out that similar types of researchhave long been conducted (ie, whetherclinical trials for drugs and devices orresearch in the Veterans Administration

setting) may also be helpful. Finally, sheurged attendees to control the agendaand momentum, emphasizing thatpatient-centered medicine and effec-tiveness data will mean better care forindividuals. She acknowledged, how-ever, that this is a tough message to getacross in the face of all the well-financed opposition that’s out there.For Dr Meltzer, CER and PM will

help researchers get smarter aboutwhich studies will be valuable andwhat treatments may be obsolete, butonly if the research is conducted in thereal environments where care takesplace. In addition, questions about therole of the public and private sectors inCER have created uncertainty in boththose domains.

For many, the specter of randomizedclinical trials (RCTs) hangs over CER.Many stakeholders will only be con-vinced by data from an RCT, DrWilensky suggested, but she is hopefulthat statistical approaches to data col-lection and analysis will gain traction aspart of CER. J. Sanford (Sandy)Schwartz, MD, Leon Hess Professor ofMedicine and Health Management andEconomics at the Leonard DavisInstitute of Health Policy andEconomics, echoed the need for newapproaches during the question ses-sion, saying “what we’re doing now isfundamentally different.” We need tofigure out new methodologies and poli-cies to support CER, he said, and thiswill take time. Although legislators willexpect data tomorrow, he pointed out,“it’s going to take 3 to 5 years beforedata start coming out, if we’re lucky.”On the public side, Dr Wilensky sug-

gested that the concepts of value-basedreimbursement and value-based insur-ance will be essential in fostering pub-lic acceptance of CER and PM. In addi-tion, plain speaking from researcherswould be helpful—as she put it, “forgoodness sake, stop talking aboutQALYs and DALYs [disability-adjust-ed life years] when you’re out in pub-lic.” For Dr Miller, tiered formulariesoffer an example of how the publicmight come to accept these newapproaches. Pointing out that there hasnot been too much resistance to tiered

formularies because they are taking usin a lower-cost direction, we may seetiered pricing as well. Better communication among the

research community is also essential tofurthering CER’s use, according to ses-sion moderator Sean Tunis, MD, MSc,Founder and Director of the Center forMedical Technology Policy. Improvingthe discourse will depend on recogniz-ing common themes and achievingmutual understanding within the com-munity that does this work. “We haveto recognize that there are really dra-matic differences in perspective amongthe players in such areas as priority set-ting and methods, and we can’t contin-ue to paper these over,” he said. One other potential confounder to

greater use of CER and PM may arisefrom planned cooperation be tween theUS Food and Drug Administration andCenters for Medicare & MedicaidServices regarding approval and cover-age. For Dr Wilensky, it is important tokeep the functions of the 2 agenciesseparate, because coverage is very dif-ferent from reimbursement. “CER is areimbursement tool and not a coveragetool,” she posited. Dr Tunis sees paral-lel review as a good step, saying thatfrom a product developer’s standpoint,it is not feasible to conduct 2 sets ofrequired studies. For now, Dr Meltzer wondered if

anything will change. The ascendanceof CER and PM is a slow continuationof a process that will create ambiguitybefore it creates clarity and savesmoney. And given the many difficul-ties to implementation raised duringthe session, Dr Tunis summarized thatthe real challenge will be “to reconciledifferent public policy objectives whileretaining the scientific integrity that isrequired.” �

ECRI PERSONALIZED MEDICINE CONFERENCE

18 I VALUE-BASED CANCER CARE I Nov/Dec 2010 VOL. 1 I NO. 6

“For goodness sake, stoptalking about QALYs andDALYs when you’re out in public.”

—Gail Wilensky, PhD

“We have to recognize that there are really dramaticdifferences in perspective among the players, and we can’t continue to paper these over.”

—Sean Tunis, MD, MSc

at a glance� Comparative effectiveness

research (CER) and personal -

ized 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

David Meltzer, MD, PhD

CER and Personalized Medicine Face HurdlesConcept needs better understanding by research community and general publicBy Colin Gittens

TM

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 androgen-responsive 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. © Centocor Ortho Biotech Inc. 2010 9/10 08ADA10027A

20 I VALUE-BASED CANCER CARE I Nov/Dec 2010 VOL. 1 I NO. 6

TARGETED THERAPY

Cancer Drugs: NICE Rejects Costly TreatmentsBy Caroline Helwick

Some Biologics Fail in Early-Stage Tumors

The floodgate has opened formolecularly targeted antitumoragents, and with each novel com -

pound the cost of treating cancer soarsever higher. Approval by the US Foodand Drug Administration (FDA) isusually based on a delay in diseaseprogression, but just a 2-month benefitmay be statistically significant in largerandomized phase 3 trials. In contrast,the United Kingdom’s National HealthService (NHS) and its advisory branch,the National Institute for Health andClinical Excellence (NICE), have beenless supportive of their use.

NICE provides guidance to the NHSon the effective use of ever-limitedresources. In the past year or so, it hasrecommended against approval (al -though some decisions are preliminaryand still open to appeal; see www.nice.org.uk) of the following targetedagents, which have received FDA

approval in the United States:• Sorafenib (Nexavar) for the treat-

ment of advanced hepatocellular carci-noma, stating “its high cost could not bejustified by its marginal benefit.” Trialevidence showed that sorafenib increas-es 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 ad -vanced or metastatic HER2-positivebreast cancer outside of clinical trials.Although GlaxoSmithKline has offeredthe drug free for the first 12 weeks oftreatment, NICE said that lapatinib

“did not represent good value for themoney when compared with the alter-native, currently available treatment.”Lapatinib plus capecitabine costsapproximately £25,207 annually• Bevacizumab (Avastin) in combi-

nation with a taxane for advancedbreast cancer. The committee members

noted that although bevacizumab de -lays progression by 5.5 months overpaclitaxel alone, they thought that anadditional 1.7 months in overall sur-vival (OS) is not clinically meaningful.Their report stated, “When bearing inmind the uncertainties over survivalrates and quality-of-life data, the com-mittee concluded that the cost ofbevacizu mab is too high for the limitedand uncertain benefit it may offerpatients.” NICE determined the incre-mental cost-effectiveness ratio (ICER)for bevacizumab plus a taxane is£115,000 to £259,000 per quality-adjust-ed life-year (QALY) gained• Erlotinib (Tarceva) for mainte-

nance treatment of advanced non–small-cell lung cancer after completionof first-line therapy. “Erlotinib has beenshown to have some clinical benefit,with the manufacturer estimating itcan potentially extend life by approxi-mately 3.3 months, however, our inde-pendent advisory committee felt…theoverall cost of erlotinib had beenunderestimated…and the cost of thedrug related to the benefits it bringsmeans that erlotinib would not be agood use of NHS money,” the commit-tee maintained. The ICER was estimat-

ed to exceed £59,000 per QALY gained• Ofatumumab (Arzerra) for chron-

ic lymphocytic leukemia that is refrac-tory to fludarabine and alemtuzumab.The appraisal committee concludedthat the data, which are centered oninterim results from a small subgroupof patients in an ongoing clinical trial,was not robust enough to show an OSbenefit over best supportive care.“This uncertainty, combined with theadditional cost of ofatumumab…meant the committee could not rec-ommend the drug as an efficient useof 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 sec-

ond-line treatment of advanced renalcell carcinoma. “Even with the pa -tient access scheme incorporated (firsttreatment free to the NHS and subse-quent treatments discounted), theadditional weight that would need tobe assigned to the QALY benefitswould be too great to fall within therange currently considered cost-effec-tive,” the report stated. Cost-effec-tiveness was estimated at £58,300per QALY. �

Some molecularly targeted agentsare proving to be less effective,not more so, when administered

earlier in the disease course. Re-searchers say this is counterintuitive,because advanced disease is associatedwith treatment refractoriness, and can-cer agents will typically perform betterin the adjuvant treatment setting thanin the metastatic treatment setting.One such “failure” made headline

news last summer, when results fromthe National Surgical Adjuvant Breastand Bowel Project (NSABP) C-08 trialwere announced at the AmericanSociety of Clinical Oncology (ASCO)annual meeting. Unexpectedly, beva-cizumab did not improve outcomes inearly-stage colon cancer, although ithad become a standard treatment inadvanced colon cancer.“We failed, and nobody likes to fail,”

Norman Wolmark, MD, principalinvestigator, commented at a press con-ference. “Actually, it wasn’t bevacizu-mab that failed. If anything,we failed toprovide our patients with a novel inter-vention that would increase cures.”The NSABP randomized 2710 pa-

tients with stage II and III colorectalcancer to a standard chemotherapy reg-

imen or the same plus bevacizumab for6 additional months. At a median fol-low-up of 36 months, disease-free sur-vival (DFS) was 75.5% in the controlarm and 77.4% in the bevacizumab arm(hazard ratio, 0.89; P = .05). A signifi-cant benefit was, however, observed forthe 1 year that patients were actuallytaking bevacizumab: a 3.6% absoluteimprovement inDFS and a 40% relative

risk reduction (P = .004). “So beva-cizumab was effective, but this efficacydisappeared after bevacizumab wasstopped,” Dr Wolmark said. “The chal-lenge is to learn how to use bevacizum-ab to its maximum potential in theadjuvant setting.”Equally surprising was the recent

announcement that cetuximab (Erbitux)confers no benefit for stage III resectedcolon cancer. In a randomized phase 3

trial of 1847 patients with colon cancerselected for the presence of nonmutat-ed (wild-type) KRAS tumors (whichare associated with cetuximab’s benefitin advanced disease), the addition ofcetuximab provided no value overstandard chemotherapy alone. Three-year DFS was approximately 74% ineach arm, and 3-year overall survival(OS) was 87% with chemotherapy and

82% with chemotherapy plus cetux-imab (P = .06), reported investigatorSteven R. Alberts, MD, at the ASCO2010 annual meeting.These findings, while disappointing,

have important implications, accord-ing to Dr Alberts. “For one thing, whatwe learn in metastatic disease does notalways apply to the adjuvant setting,”he said. “The findings also indicate thatdisease 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, com-bined with others, “casts doubt onwhether biologics will play a role inearly-stage colon cancer.”And in early-stage non–small-cell lung cancer(NSCLC), the epidermal growth factorreceptor (EGFR) inhibitor gefitinib(Iressa) failed to provide benefit overresection alone in a Canadian study of503 patients with resected stage IB-IIIANSCLC. In an exploratory analysis, thepresence of EGFR-sensitizing muta-tions (which are associated with re-sponse to EGFR inhibitors in advanceddisease) were not predictive of a sur-vival benefit, reported Glenwood D.Goss, MD, and colleagues from theOttawa Hospital Research Institute inCanada. OS was 5.1 years in the place-bo arm and 3.7 years in the gefitinibarm in patients with EGFR mutations.“It is yet to be demonstrated that a

targeted agent improves overall sur-vival in NSCLC in the adjuvant set-ting, and, for the present, chemothera-py in good performance patientsremains the treatment of choice,” DrGoss concluded.—CH �

“It is yet to be demonstrated that a targeted agent improvesoverall survival in NSCLC in the adjuvant setting, and, for thepresent, chemotherapy in good performance patientsremains the treatment of choice.”

—Glenwood D. Goss, MD

NICE provides guidance to the NHS on the effective use of ever-limited resources. In the past year or so, it has recommendedagainst approval of the following targeted agents.

CLINICAL RESEARCH

22 I VALUE-BASED CANCER CARE I Nov/Dec 2010 VOL. 1 I NO. 6

Clinical cancer research is ham-pered by an overly complexand cautious regulatory system,

which slows the development of life-saving drugs, increases costs, and maybe unethical, according to David J.Stewart, MD, of the University of TexasM.D. Anderson Cancer Center and col-leagues (Stewart DJ, et al. Equipoiselost: ethics, costs, and the regulation ofcancer clinical research. J Clin Oncol.2010;28:2925-2935). Because of theurgency associated with a lethal dis-ease such as cancer, there is a need torestore the balance between adequatesafety regulation and innovation, saythe authors. Among the many agencies, laws,

and regulations that govern clinicalresearch are institutional reviewboards (IRBs), the US Food and DrugAdministration, the Office of HumanResearch Pro tections, the NationalCancer Institute, the Cancer TherapyEvaluation Pro gram, the ClinicalLaboratory Improve ment Amend -ments (CLIA) section of the Centersfor Medicare & Medicaid Services, theDepartment of Health and HumanServices, the Department of VeteransAffairs, the Internal Revenue Service,the Office of the Inspector General, thePatent and Trademark Office, and theJoint Commission. Although theseoverseeing bodies serve to preventpatient harm, the combined impact ofthis regulatory oversight is large—andnegative—say the authors.

The Scope of the Problem

The slow pace of clinical trials result-ing from regulatory bottlenecks hin-

ders activation of trials and wastesresearcher and patient time. Regu -latory requirements also drive upresearch costs. In examining whetherregulation has actually increased

patient safety, the authors looked atmortality in phase 1 clinical researchbetween 1972 and 2002 and found thatthe more stringent regulations reducedthe toxic death rate by no more than0.3%. Increasing protocol complexityand the number of tests mandated byprotocol have served to push the aver-age cost to $26,000 to enter a patientinto a clinical trial. The cost per life-year saved when all regulations are fac-tored in is approximately $2.7 million;the consensus among oncologists isthat $100,000 per life-year gained isgood value. Higher costs also mean that fewer

organizations are able to conduct trials,and that the number of testable ideas isreduced. Concentrating research in thehands of a few pharmaceutical firmscan limit combined testing of agentsfrom different firms, lessen explora -tions for rare diseases, and curb higher-risk strategies. Regulations have slowed the pace of

research; time from drug discovery tomarketing has reached 12 to 15 yearstoday compared with 8 years in the1960s. This slowing discourages patient

participation through restrictive eligi-bility and impractical study schedules.The number of physician-researchershas also declined, perhaps because ofthe burdens of running a trial.

Streamlining the Regulatory

Approach

In terms of general principles, theauthors argue that acceptable risk inclinical research should be substan-tially higher for uniformly fatal dis-eases compared with potentially cur-able conditions. The key is to informpatients of the risk, rather than pre-sume for them what risks theyshould be allowed to take. The regu-latory burden should also be adjusted

based on the population under study,and the authors push for a new, sin-gle regulatory body focusing onlethal diseases only to streamline thisprocess. Other, more specific recommenda-

tions include:

• Reform toxicology and pharmacolo-gy procedures, testing subjects onlyfor P450 interactions

• Streamline study review to no morethan 2 agencies, and centralize IRBreview in multiinstitutional studies

• Streamline reporting of adverseevents, and centralize informationon drug toxicity

• Modify protocol adherence to ac -knowledge degrees of deviation. Thedefinition of protocol violation shouldbe changed to an event where thepatient was harmed or the integrity ofthe data was compromised

• Refocus documentation require-ments on what truly matters, nottrivial events

• Simplify healthcare payment sys-tems for patients in trials

• Allow assignment of patients fortherapy, even when laboratory testsare not CLIA-certified

• Adjust study randomization so thatstudies are capable of showing largegains in a small population

• Efficacy biomarkers should be identi-fied initially based on their correlationwith tumor shrinkage, not survival.The authors conclude that the cur-

rent process “seems to be unethicaland squanders research resources.”Target ing the subpopulations likely tobenefit most from a therapy at the out-set (ie, from the earliest phase 1 and 2studies), among other strategies,would help restore the imbalancebetween the costs of life-years lost andgained as it exists under the currentsystem. Regulations that do not addlarge demonstrable value should bediscarded, they say. �

Concerns about the future of can-cer research exist among thespectrum of researchers and

regulators, and in remarks preparedfor the President’s Cancer Panel: TheFuture of Cancer Research—Accel-erating Scientific Innovation (heldSeptember 22, 2010, in Boston),American Society of Clinical Oncology(ASCO) President GeorgeW. Sledge, Jr,MD, outlined some of the organiza-tion’s concerns regarding new biologi-cal therapies and the future of cancerresearch.The pace of trials has slowed even as

the amount of targeted therapies hasincreased, he noted, and it is essential tohave adequate funding and an ade-quately trained national research capa-bility to maintain a comprehensive and

effective clinicaltrials program. Inaddition, givennew therapeuticapproaches, itmay be neces-sary to considernewwaysof con-ducting trials.Among the

challenges facedby researchers is inadequate existinginfrastructure for biomarker analysisand the need to screen high numbers ofpatients to determine trial eligibility. Inaddition, understanding of cancer biol-ogy and the drivers of cancer develop-ment in multiple patients (with differ-ent patients having different drivers) isstill emerging. Recruiting patients into

clinical trials can be done at the com-munity level, but not unless the currentlow payment levels are increased.

ASCO calls for a doubling of Na-tional Cancer Institute–funded cooper-ative clinical research to reinvigoratethat system and ensure its future. Inaddition, the group emphasizes theimportance of electronic health recordsto help drive clinical research.The regulatory schema also needs

simplifying, Dr Sledge wrote. Processesconcerning institutional review boards

(IRBs), informed consent, privacy rules,regulations surrounding the conduct ofclinical trials, and the evaluation of effi-cacy end points need to be overhauled.Echoing the proposals of others, he sug-gests a centralized IRB review, a stan-dard case report form, and a singleapproach across all sites.Trials should also change with new

technological developments, he ar-gued, writing that “the incorporationof bioinformatic principles into clinicaltrial methodology is in its infancy, but[this] represents a clear requirement forfuture progress in the genomic era.” Toensure that investigators capable ofconducting these types of trials aretrained, Dr Sledge argued the necessityof a “trained, incentivized clinical-translational workforce.”—CG �

Restoring Balance to the Cancer Research Regulation EquationBy Colin Gittens

ASCO Shares Concerns Over the Future of Cancer Research

The key is to inform patientsof the risk, rather thanpresume for them what risks they should be allowed to take.

Trials should also changewith new technologicaldevelopments.

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

George W. Sledge, Jr, MD

Photo by © ASCO/Todd Buchanan 2010

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.

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

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

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

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 INFORMATIONBOXED WARNINGSCardiotoxicity, 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.

DOXIL® C.A.R.E.S. Provides Help and Support

12:56 PM

DOXIL®(doxorubicin HCl liposome injection) for intravenous infusionBRIEF SUMMARY. Please see Full Prescribing Information.

INDICATIONS AND USAGE: Ovarian Cancer: DOXIL (doxorubicin HCl liposome injection) is indicated for thetreatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-basedchemotherapy. AIDS-Related Kaposi’s Sarcoma: DOXIL is indicated for the treatment of AIDS-related Kaposi’ssarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy. MultipleMyeloma: DOXIL in combination with bortezomib is indicated for the treatment of patients with multiple myelomawho 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 ahistory 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 myocardialdamage 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 currentlyrecommended limit of 550 mg/m2. Lower (400 mg/m2) doses appear to cause heart failure in patients who havereceived radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agentssuch as cyclophosphamide. Prior use of other anthracyclines or anthracenodiones should be included incalculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered afterdiscontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should beadministered DOXIL only when the potential benefit of treatment outweighs the risk. Cardiac function should becarefully monitored in patients treated with DOXIL. The most definitive test for anthracycline myocardial injury isendomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have beenused to monitor cardiac function during anthracycline therapy. Any of these methods should be employed tomonitor potential cardiac toxicity in patients treated with DOXIL. If these test results indicate possible cardiacinjury associated with DOXIL therapy, the benefit of continued therapy must be carefully weighed against the riskof myocardial injury. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL atstarting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2, orbetween 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 theinstitutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity andcongestive heart failure (CHF) are in the table below.

Table 1: Number of Patients With Advanced Breast CancerDOXIL (n=250)

Patients who Developed Cardiotoxicity 10(LVEF Defined)

Cardiotoxicity (With Signs & Symptoms of CHF) 0Cardiotoxicity (no Signs & Symptoms of CHF) 10

Patients With Signs and Symptoms of CHF Only 2

In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiacfailure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema andpulmonary edema) was similar in the DOXIL+bortezomib group and the bortezomib monotherapy group, 3% ineach group. LVEF decrease was defined as an absolute decrease of 15% over baseline or a 5% decreasebelow the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and42 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 therandomized 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 andthroat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. Inmost 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 treatedwith DOXIL (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDS-related Kaposi’s sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL therapy because ofinfusion-related reactions. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusionreactions have been reported. Medications to treat such reactions, as well as emergency equipment, should beavailable for immediate use. The majority of infusion-related events occurred during the first infusion. Similarreactions have not been reported with conventional doxorubicin and they presumably represent a reaction to theDOXIL liposomes or one of its surface components. The initial rate of infusion should be 1 mg/min to help minimizethe risk of infusion reactions [see Full Prescribing Information].

Myelosuppression: Because of the potential for bone marrow suppression, careful hematologic monitoring isrequired during use of DOXIL, including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With therecommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reductionor 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 indiscontinuation of treatment and, in rare cases, death. DOXIL may potentiate the toxicity of other anticancertherapies. In particular, hematologic toxicity may be more severe when DOXIL is administered in combination withother agents that cause bone marrow suppression. In patients with relapsed ovarian cancer, myelosuppressionwas generally moderate and reversible. In the three single-arm studies, anemia was the most commonhematologic 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 commonhematologic 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 patientswith AIDS-related Kaposi’s sarcoma who often present with baseline myelosuppression due to such factors astheir HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse

reaction at the recommended dose of 20 mg/m2 [see Adverse Reactions]. Leukopenia is the most commonadverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsisoccurred 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 presentsdata on myelosuppression in patients with multiple myeloma receiving DOXIL and bortezomib in combination [seeAdverse Reactions].

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 thepatients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skintoxicity. HFS toxicity grades are described in Dosage and Administration section [see Full PrescribingInformation]. 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% ofpatients treated with DOXIL at 30 mg/m2 every three weeks experienced HFS. HFS was generally observed after2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to twoweeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manageHFS [see Full Prescribing Information]. The reaction can be severe and debilitating in some patients and mayrequire 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 thefetus. If pregnancy occurs in the first few months following treatment with DOXIL, the prolonged half-life of thedrug must be considered. Women of childbearing potential should be advised to avoid pregnancy duringtreatment 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-inducedtoxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration ofdoxorubicin HCl.

Monitoring: Laboratory Tests: Complete blood counts, including platelet counts, should be obtained frequentlyand 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 moredetail in other sections of the labeling. • Cardiac Toxicity [see Warnings and Precautions] • Infusion reactions [seeWarnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hand-Foot syndrome [seeWarnings 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 andanemia. The most common serious adverse reactions observed with DOXIL are described in Section AdverseReactions 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 multiplemyeloma.

Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, theadverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflectthe rates observed in clinical practice. The following tables present adverse reactions from clinical trials of DOXILin 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 treatedwith DOXIL (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in arandomized, 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% Hispanicand 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 CancerDOXIL Topotecan

Patients Patients(n = 239) (n = 235)

Neutropenia500 - <1000/mm3 19 (7.9%) 33 (14.0%)<500/mm3 10 (4.2%) 146 (62.1%)

Anemia6.5 - <8 g/dL 13 (5.4%) 59 (25.1%)<6.5 g/dL 1 (0.4%) 10 (4.3%)

Thrombocytopenia10,000 - <50,000/mm3 3 (1.3%) 40 (17.0%)<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 ofDOXIL compared to topotecan.

Table 3: Ovarian Cancer Randomized StudyNon-Hematologic DOXIL (%) treated Topotecan (%) treatedAdverse Reaction 10% or Greater (n = 239) (n =235)

All Grades All Grades grades 3-4 grades 3-4

Body as a WholeAsthenia 40.2 7.1 51.5 8.1Fever 21.3 0.8 30.6 5.5Mucous Membrane 14.2 3.8 3.4 0DisorderBack Pain 11.7 1.7 10.2 0.9Infection 11.7 2.1 6.4 0.9Headache 10.5 0.8 14.9 0

DigestiveNausea 46.0 5.4 63.0 8.1Stomatitis 41.4 8.3 15.3 0.4Vomiting 32.6 7.9 43.8 9.8Diarrhea 20.9 2.5 34.9 4.2Anorexia 20.1 2.5 21.7 1.3Dyspepsia 12.1 0.8 14.0 0

Nervous Dizziness 4.2 0 10.2 0

RespiratoryPharyngitis 15.9 0 17.9 0.4Dyspnea 15.1 4.1 23.4 4.3Cough increased 9.6 0 11.5 0

Skin and AppendagesHand-foot syndrome 50.6 23.8 0.9 0Rash 28.5 4.2 12.3 0.4Alopecia 19.2 N/A 52.3 N/A

WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTALSUBSTITUTION1. The use of DOXIL (doxorubicin HCl liposome injection) may lead to cardiac toxicity. Myocardial damage maylead 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 startingdose 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%. Prior use of other anthracyclinesor anthracenediones should be included in calculations of total cumulative dosage. Cardiac toxicity may alsooccur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrentcyclophosphamide therapy [see Warnings and Precautions]. 2. Acute infusion-related reactions including, butnot limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in thechest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL. In mostpatients, these reactions resolve over the course of several hours to a day once the infusion is terminated. Insome patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treatsuch reactions, as well as emergency equipment, should be available for immediate use. DOXIL should beadministered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [see Warnings andPrecautions]. 3. Severe myelosuppression may occur [see Warnings and Precautions]. 4. Dosage should bereduced in patients with impaired hepatic function [see Full Prescribing Information]. 5. Accidentalsubstitution of DOXIL for doxorubicin HCl has resulted in severe side effects. DOXIL should not be substitutedfor doxorubicin HCl on a mg per mg basis [see Full Prescribing Information].

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer withdoses administered every four weeks.

Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombo phlebitis, hypotension, cardiacarrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic andLymphatic: 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. SpecialSenses: 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 753patients with AIDS-related Kaposi’s sarcoma enrolled in four studies. The median age of the population was 38.7years (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. Themedian time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m2

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 immunesystem, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients’ median CD4 countwas 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count atstudy entry was approximately 3,000 cells/mm3. Patients received a variety of potentially myelotoxic drugs incombination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or moreantiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% onzalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) onsulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarilyfluconazole (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 patientswith AIDS related Kaposi’s sarcoma. Those that did so included bone marrow suppression, cardiac adversereactions, 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 SarcomaPatients With Total Patients

Refractory or Intolerant WithAIDS-Related AIDS-Related

Kaposi’s Sarcoma Kaposi’s Sarcoma(n = 74) (n = 720)

Neutropenia<1000/mm3 34 (45.9%) 352 (48.9%)<500/mm3 8 (10.8%) 96 (13.3%)

Anemia<10 g/dL 43 (58.1%) 399 (55.4%)<8 g/dL 12 (16.2%) 131 (18.2%)

Thrombocytopenia<150,000/mm3 45 (60.8%) 439 (60.9%)<25,000/mm3 1 (1.4%) 30 (4.2%)

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

Adverse Patients With Total PatientsReactions Refractory or Intolerant With

AIDS-Related AIDS-RelatedKaposi’s Sarcoma Kaposi’s Sarcoma

(n = 77) (n = 705)Nausea 14 (18.2%) 119 (16.9%)Asthenia 5 (6.5%) 70 (9.9%)Fever 6 (7.8%) 64 (9.1%)Alopecia 7 (9.1%) 63 (8.9%)Alkaline Phosphatase 1 (1.3%) 55 (7.8%)Increase Vomiting 6 (7.8%) 55 (7.8%)Diarrhea 4 (5.2%) 55 (7.8%)Stomatitis 4 (5.2%) 48 (6.8%)Oral Moniliasis 1 (1.3%) 39 (5.5%)

The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi’ssarcoma. 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: mouthulceration, 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 andNutritional 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 threeweeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combinationgroup 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 reportedin 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 MedDRATerminology.

Adverse DOXIL + bortezomib BortezomibReaction (n=318) (n=318)

Any Grade Grade Any Grade Grade(%) 3 4 (%) 3 4

Blood and lymphatic system disordersNeutropenia 36 22 10 22 11 5Thrombocytopenia 33 11 13 28 9 8Anemia 25 7 2 21 8 2General disorders and administration site conditionsFatigue 36 6 1 28 3 0Pyrexia 31 1 0 22 1 0Asthenia 22 6 0 18 4 0Gastrointestinal disordersNausea 48 3 0 40 1 0Diarrhea 46 7 0 39 5 0Vomiting 32 4 0 22 1 0Constipation 31 1 0 31 1 0Mucositis/Stomatitis 20 2 0 5 <1 0Abdominal pain 11 1 0 8 1 0

Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiplemyeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRATerminology. (continued)

Adverse DOXIL + bortezomib BortezomibReaction (n=318) (n=318)

Any Grade Grade Any Grade Grade(%) 3 4 (%) 3 4

Infections and infestationsHerpes zoster 11 2 0 9 2 0Herpes simplex 10 0 0 6 1 0InvestigationsWeight decreased 12 0 0 4 0 0Metabolism and Nutritional disordersAnorexia 19 2 0 14 <1 0Nervous system disordersPeripheral Neuropathy* 42 7 <1 45 10 1Neuralgia 17 3 0 20 4 1Paresthesia/dysesthesia 13 <1 0 10 0 0Respiratory, thoracic and mediastinal disordersCough 18 0 0 12 0 0Skin and subcutaneous tissue disordersRash** 22 1 0 18 1 0Hand-foot syndrome 19 6 0 <1 0 0*Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathyperipheral, 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 approvaluse of DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is notalways 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 andMediastinal 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 whosetreatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interactwith 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 havenot been established.

Geriatric Use: Of the patients treated with DOXIL in the randomized ovarian cancer study, 34.7% (n=83) were 65years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL incombination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years ofage or older. No overall differences in safety or efficacy were observed between these patients and youngerpatients.

OVERDOSAGE: Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, andthrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patientwith hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis.

0016716-5BManufactured by:Ben Venue Laboratories, Inc.Bedford, OH 44146Distributed by:Ortho Biotech Products, LPRaritan, NJ 08869-0670

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

TM

An ALZA STEALTH®

Technology Product

26 I VALUE-BASED CANCER CARE I Nov/Dec 2010 VOL. 1 I NO. 6

COSTS OF CARE

US and Canadian medical oncol-ogists share similar attitudeson the costs, cost-effectiveness,

and health policies concerning newcancer drugs, despite fundamental dif-ferences between the 2 countriesregarding how these drugs are coveredand paid for under their respectivehealthcare systems. These findings,reported in the Journal of ClinicalOncology (2010;28:4149-4153), empha-size the need for greater education ofoncologists on understanding andcommunicating cost-effectiveness andcost information with patients. The authors surveyed a random

sample of US oncologists who weremembers of the American Society ofClinical Oncology in the summer of2008; the Canadian sample (n = 356)was drawn from the membership listof the Canadian Association of MedicalOncologists and other directories. The

Canadian survey was not translatedinto French, so responses from Quebecwere not included in the analysisbecause of the low response rate fromthat province.

The overall response rate to the sur-vey was 59%. Respondents were expe-rienced clinicians, with a mean of 23.8years of practice in the US and 23.2years in Canada. Responses on cancerdrug costs and cost effectivenessbrought both concordance and diver-gence among the 2 nations’ doctors.When asked if patient out-of-pocketdrug costs currently influence deci-sions regarding which cancer treat-ments to recommend for patients, 84%of US and 80% of Canadian physiciansstrongly or somewhat agreed. A muchlower percentage in both countries feltwell prepared to interpret and use cost-effectiveness information in treatmentdecisions (42% US, 49% Canada).Opinions differed when questions

turned to patient access to care. Sixty-seven percent of US oncologists indicat-ed that every US/Canadian patientshould have access to effective cancertreatments regardless of their cost,whereas only 52% of Canadian oncolo-gists felt this way. Further refining thequestion to elucidate whether everyUS/Canadian patient should haveaccess to effective cancer treatments onlyif the treatments provide “good value

for money” or are cost-effective, 58% ofUS oncologists strongly or somewhatagreed, compared with 75% of Canadiandoctors. Fewer than half of physicians inboth countries discussed the costs ofcancer treatments with patients. In terms of health policies related to

cancer drug costs, high numbers ofdoctors in both countries favoredgreater use of cost-effectiveness data incoverage and payment decisions (80%strongly or somewhat agreeing in theUS, 69% in Canada), as well as moregovernment research on the compara-tive effectiveness of cancer drugs (79%US, 85% Canada). Fifty-seven percentof US oncologists favored price con-trols for cancer drugs in the Medicareprogram, and doctors in both countrieswere less enthusiastic about increasedpatient cost-sharing for these drugs(29% US, 41% Canada). In both coun-tries, doctors and nonprofit organiza-tions were deemed most capable ofdetermining whether a drug providesgood value, while insurance compa-nies and government agencies wereseen as least effective in this regard.

How to Address this

Growing Problem

The findings are not all that surpris-ing, say the authors, given the changesin the oncology landscape in bothcountries. Despite government-fundedhealthcare in Canada, patients there arebeing exposed to higher out-of-pocketcosts. And the reluctance of physiciansto discuss costs has been well docu-mented in other studies. What may be surprising is that

Canadian physicians are already famil-iar with cost-effectiveness by its use inthe Canadian system, but they still

express uncertainty over actually usingthis information in practice. The solu-tion may be “better coordinationamong international researchers inter-ested in the use of comparative effec-tiveness and cost-effectiveness data infunding expensive cancer drugs,” saythe authors, which “might allow forbetter design of future prospectivestudies that could yield useful informa-tion for all countries involved.”Even more unexpected to the

authors is the desire of US oncologistsfor greater use of cost-effectivenessdata in coverage and payment deci-sions for cancer drugs. Although theAmerican Recovery and ReinvestmentAct of 2009 forbade using comparativeeffectiveness for coverage determina-tions under Medicare, the sentimentsexpressed in the survey “may reflectthat US oncologists are beginning tocome to terms with the unavoidablereality of resource constraints and maysuggest some willingness on their partto accept comparative cost-effective-ness data in drug coverage decisions asis already happening in Canada andother countries,” the authors say. The authors caution that the physi-

cians surveyed may not be a represen-tative sample, but argue that the con-cordance of attitudes from the 2countries suggest the findings couldhave wide relevance. Greater US-Canadian collaboration regardingimproved communication withpatients about costs, practical educa-tion on using cost-effectiveness infor-mation, and the optimal processes forincorporating cost-effectiveness infor-mation in drug funding and coveragedecisions could help address this wide-spread problem. �

Each year,oncologistsreturn to

their respective practices after attend-ing the annual American Society ofClinical Oncology or American Societyof Hematology meetings armed with

knowledge of new drug/biologiccombinations, modified regimen dos-ing, and other novel approaches thatmay provide incrementally better out-comes for cancer patients. But becausethe focus at these meetings hasremained primarily clinical ratherthan on the cost effectiveness of indi-vidual drugs or regimens, progress indeveloping and accepting consistentpathways, or in considering cost-effec-

tiveness data and value-based treat-ments for the patient and the health-care system has been slow.The above article summarizing the

attitudes of US and Canadian oncolo-gists regarding costs, cost-effective-ness, and health policies associatedwith new cancer drugs, neatly illus-trates how physicians in both coun-tries face these issues, and raises amatter of great sensitivity for the

oncologist. Fewer than half of thephysicians in both the United Statesand Canada always or frequently dis-cuss the costs of cancer treatmentswith patients, according to this survey.This corresponds with the 2007 sur-vey by Schrag and Hanger conductedwith 167 practicing oncologists, where-in 42% discussed cancer treatmentcosts always or most of the time, 32%

Costs of Cancer Drugs Weigh on US, Canadian MindsBy Colin Gittens

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

US oncologists are beginningto come to terms with theunavoidable reality ofresource constraints.

at a glance� Canadian and US physicians

share concern for patients’ out-

of-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

VBCC PERSPECTIVE

Denise K. Pierce is President, DK Pierce &Associates, Inc, Zionsville, IN, and a member of the editorial board of Value-Based Cancer Care. Continued on page 28

the sum of its parts?

Antibody-drug conjugates (ADCs):

Can an ADC be greater than

© 2010 Genentech USA, Inc. All rights reserved. TDM0000065200 Printed in USA.

To learn more, visit www.ResearchADCs.com

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

These investigational ADCs have multiple proposed mechanisms of action, including monoclonal antibody–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

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

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

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

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-specifi c 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. Ofl azoglu 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 specifi city 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.

References:

payment formula that has been used toset physician reimbursement since2002. Every year, this formula leads tophysicians in Medicare facing signifi-cant cuts in their reimbursement.However, Congress typically steps inand temporarily “fixes” the cut. It is widely expected that Con gress

will do so again to ensure that physi-cian payments under the Medi careprogram remain stable in 2011.Nevertheless, there is widespreadagreement that the current paymentsystem needs to be overhauled and along-term fix enacted. But because ofthe complexities entailed in makingany changes, there is disagreement in

Congress and among stakeholdersover the best strategy.Numerous technical issues also exist

regarding Medicare reimbursement forspecific physician services. For exam-ple, Medicare is using new data fromthe American Medical Association’sPhysician Practice Information Survey(PPIS) to estimate “practice expense”costs for various services. Practiceexpense includes items such as rentalof office space or the cost of equipment.Some groups have voiced concern thatthe PPIS data is flawed and fails to ade-quately reimburse physicians for thecost of providing care. This is anotherarea of longstanding controversy in theMedicare program with no clear pathfor moving forward.On the drug payment side, reim-

bursement in physician office and hos-pital outpatient settings remains sta-ble—Medicare will continue toreimburse drugs at average sales price(ASP) + 6% in the physician office set-ting, whereas separately paid drugs inhospital outpatient departments willsee their reimbursement increase fromASP + 4% in 2010 to ASP + 5% in 2011.

Prevention Coverage Boosted

The new Medicare rules also imple-ment provisions of high importance toMedicare beneficiaries. Today, benefici-aries face a Part B deductible and 20%cost sharing for most preventive servic-es, unless they have Medigap coveragethat supplements Medicare. Under thenew rules, which stem from require-ments in the Affordable Care Act,Medicare beneficiaries will no longerhave to pay cost sharing for preventiveservices with a Grade A (coverage“strongly recommended”) or Grade B(coverage “recommended) rating bythe US Preventive Services Task Force. Thus, beneficiaries in 2011 will have

no cost sharing for preventive servicesfor certain screening tests for cancer:screening mammography, screeningpap smear, and screening pelvic exam;colorectal cancer screening tests, andprostate specific antigen (PSA) tests.The importance of this provisioncould grow in the future if additionalpreventive services are added toMedicare that have Grade A or GradeB recommendations.One of the most notable aspects of

the newly released rules may be whatthey do not include. The AffordableCare Act grants the CMS with a host ofnew authorities aimed at developinginnovative ways for paying providers,including establishing integratedhealth systems and bundling pay-ments for inpatient and postacute care.As these efforts begin to unfold overthe coming months, we could see sig-nificant implications for all stakehold-ers in oncology care. �

HEALTH POLICY

28 I VALUE-BASED CANCER CARE I Nov/Dec 2010 VOL. 1 I NO. 6

CMS Releases Outpatient Rules... Continued from cover

sometimes did, and 26% rarely ornever did.1

Cancer and Cost: An Essential

Conversation

It is understandable that oncologistshave an aversion to conducting theseconversations; however, financialcounseling is indeed a significant andgrowing role in oncology practicesacross the United States. A 2010 surveyby Kantar Health, conducted on behalfof the Association of CommunityCancer Centers, outlined that 88% ofthe 84 responding cancer programsintegrate financial counseling relatedto the cost of treatment.2 In addition,one need only Google key words suchas “oncology financial counselor” tosee the hundreds of resulting hits.These results include information fromcommunity-based oncology practicesand comprehensive cancer centersregarding the role of the financial coun-selor to help patients better understandhealth insurance benefits and cost-share responsibilities.One example of why financial coun-

selors are now so important to oncolo-gy is exemplified by a 2009 study of theAARP Public Policy Institute.3 This

study assessed changes in patient costshare of chemotherapy specific to theMedicare Advantage (MA) managedcare plan environment, and found thatin 2009, only 21% of MA beneficiariespaid a fixed copayment amount for

chemotherapy (down from 43% of ben-eficiaries in 2008). By 2009, MA planshad evolved to where 80% of benefici-aries required a coinsurance costshare—commonly 20% —of the med-ical cost of chemotherapy. For this costshare, the patient cannot obtain a sup-plemental insurance coverage (as com-pared to a beneficiary under fee-for-service Medicare). The MA example isbut one of many scenarios increasingthe economic constraints on patients.Conversations on costs of care and the

implications of these costs to patients are

necessary, but the oncologist infrequent-ly plays the role of financial counselor.Social workers or dedicated insurancereimbursement specialists commonlybetter handle the ongoing demands ofunderstanding confusing insurancerequirements, discussing the overall costof care and financial responsibilities, andhelping patients manage ongoing issuesof paying copays and coinsurance fortheir care.But beyond being discomfited by

these conversations or possessingknowledge of insurance programs,physicians in both countries alsoreported feeling unprepared at a veryfundamental level. Only 42% of USphysicians strongly or somewhatstrongly agreed that they were well-prepared to interpret and use cost-effectiveness information in treat-ment decisions, while 49% ofCanadian doctors felt this way.Clearly, more education in this areawill be needed if costs and cost effec-tiveness continue to assume a largerrole in healthcare decisions. A recentcommentary argued that economicrealities need to be better incorporat-ed into medical education;4 althoughthis commentary focused on bigger-

picture economic components andrelationships, one of the pointsraised— that “cost-sensitive care canbe compatible with and, indeed,serve patient needs and physicianresponsibilities”—is also pertinent tothe matter of cost effectiveness.Cancer remains a diverse and chal-

lenging disease to treat no matterwhich side of the border and, despitethe preference to avoid discussionsabout cost of care—whether amongtheir colleagues or with patients —oncologists will continue to faceincreased pressure to apply cost effec-tiveness in relation to clinical outcomeswithin that diversity. �

References1. Schrag D, Hanger M. Medical Oncologists’ views oncommunicating with patients about chemotherapycosts: A pilot survey. J Clin Oncol. 2007;25:233-237.2. Association of Community Cancer Centers. CancerCare Trends in Community Cancer Centers, 2009-2010. General introduction accessed on October 23,2010 at: http://accc-cancer.org/surveys/pdf/Cancer_Care_Trends-2010-Gatefold.pdf3. AARP Public Policy Institute. Medicare AdvantageBenefit Design: What Does It Provide, What Doesn’t ItProvide, and Should Standards Apply? March, 2009.Accessed on October 23, 2010 at: http://assets.aarp.org/rgcenter/health/2009_03_medicare.pdf4. Sessions SY, Detsky AS. Incorporating economicreality into medical education. JAMA. 2010;304:1229-1230.

The Costs of Care... Continued from page 26

VBCC PERSPECTIVE

Clearly, more education in this area will be needed ifcosts and cost effectivenesscontinue to assume a largerrole in healthcare decisions.

Crystal Kuntz, MPA

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.

E

u

p

www.ValueBasedCancer/associationREGISTER ONLINE AT

Tuesday, March 294:00 – 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 307:30 – 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

Payer Track• Medicare and Reimbursement Issues• Drug Reimbursement and Administration Issues• Evolutions in Oncology Pharmacy Management

12:30 – 2:00 pm CE Lunch SymposiumBest 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.

MEETING AGENDA*PROGRAM OVERVIEWThis is the first national stakeholder integration meeting dedicated to advanc-ing the understanding of value in cancer care. Guided by the expertise of leadersin these fields, attendees will receive a thorough understanding of the evolutionof the value equation as it relates to cancer therapies and will be able to implement, improve, and sustain their companies and institutions, while im-proving access for patients and ultimately patient care.

WHO SHOULD ATTENDAll stakeholders in a position to impact cancer patient care are invited tojoin 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)

GOALThe Association for Value-Based Cancer Care’s First Annual StakeholderIntegration Conference will foster an open dialogue between providers,payers, and/or other members of the oncology team in order for attendeesto 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 themanagement of patients with cancer

• Identify issues and potential solutions to challenges with access andaffordability of oncology therapeutics

• Determine the value equation of cost, quality, and access when evaluatingthe diagnosis, treatment, and overall management of cancer patients

• Define appropriate comparative effectiveness research and clinical pathwaysas tools to evaluate current recommendations for patient management

•Analyze trends in the delivery of care in the management of cancer patients

THE ASSOCIATION FOR

March 29-30, 2011Philadelphia, PA

Loews Philadelphia Hotel

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

Progression-free survival (PFS) after progression on sunitinib or sorafenib1

100

80

60

40

20

Time (months)

Prob

abili

ty (%

)

Afinitor

4.9 months

1.9 months

Placebo

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

Hazard Ratio=0.3395% CI [0.25, 0.43]

0 2 4 86 10 12 14

4.9 months median PFS with Afinitor + BSC† (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

Afinitor doubled median PFS after progression on sunitinib*1

In advanced RCC:

For more information about Afinitor, call 1-888-4Afinitor (1-888-423-4648) or visit www.AFINITOR.comFor 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

†BSC=best supportive care.

Important Safety InformationThere have been reports of non-infectious pneumonitis and infections, some with fatal outcomes. Oralulceration has been reported. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions ofhemoglobin, 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.

Ins

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

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936 ©2010 Novartis Printed in U.S.A. 10/10 AFI-1002330

2.5mg 5mg 10mg

Afinitor is indicated for the treatment of patients withadvanced renal cell carcinoma after failure of treatmentwith sunitinib or sorafenib.Important Safety InformationAfinitor is contraindicated in patients with hypersensitivityto everolimus, to other rapamycin derivatives, or to any ofthe excipients.Non-infectious pneumonitis is a class effect of rapamycinderivatives, including Afinitor. Fatal outcomes have beenobserved. If symptoms are moderate or severe, patientsshould be managed with dose interruption until symptomsimprove or discontinuation, respectively. Corticosteroidsmay be indicated. Afinitor may be reintroduced at 5 mgdaily depending on the individual clinical circumstances.Afinitor has immunosuppressive properties and maypredispose patients to bacterial, fungal, viral or protozoaninfections, including infections with opportunisticpathogens. Localized and systemic infections, includingpneumonia, other bacterial infections, invasive fungalinfections, and viral infections including reactivation ofhepatitis B virus have occurred. Some of these infectionshave been severe (e.g. leading to respiratory or hepaticfailure) or fatal. Complete treatment of pre-existing invasivefungal infections prior to starting treatment. While takingAfinitor be vigilant for signs and symptoms of infection; ifa diagnosis of infection is made, institute appropriatetreatment promptly and consider interruption ordiscontinuation of Afinitor. If a diagnosis of invasivesystemic fungal infection is made, discontinue Afinitor andtreat with appropriate antifungal therapy. Oral ulcerations (i.e. mouth ulcers, stomatitis, and oralmucositis) have occurred in patients treated with Afinitor. Insuch cases, topical treatments are recommended, butalcohol- or peroxide-containing mouthwashes should beavoided. Antifungal agents should not be used unlessfungal infection has been diagnosed.Elevations of serum creatinine, glucose, lipids, andtriglycerides and reductions of hemoglobin, lymphocytes,

neutrophils, and platelets have been reported in clinicaltrials. Renal function, hematological parameters, bloodglucose, and lipids should be evaluated prior to treatmentand periodically thereafter. When possible, optimal glucoseand lipid control should be achieved before starting apatient on Afinitor.Avoid concomitant use with strong CYP3A4 or PgPinhibitors. If co-administration with moderate CYP3A4 orPgP inhibitors is required, use caution and reduce dose ofAfinitor 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 hepaticimpairment.The use of live vaccines and close contact with those whohave received live vaccines should be avoided duringtreatment with Afinitor.Fetal harm can occur if Afinitor is administered to apregnant 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 mostcommon laboratory abnormalities (incidence ≥50%) were anemia (92%), hypercholesterolemia (77%),hypertriglyceridemia (73%), hyperglycemia (57%),lymphopenia (51%), and increased creatinine (50%). Themost common grade 3/4 laboratory abnormalities(incidence ≥3%) were lymphopenia (18%), hyperglycemia(16%), anemia (13%), hypophosphatemia (6%), andhypercholesterolemia (4%). Deaths due to acute respiratoryfailure (0.7%), infection (0.7%), and acute renal failure(0.4%) were observed on the Afinitor arm.

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

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

4 CONTRAINDICATIONSHypersensitivity 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 respiratoryimpairment) have been observed with everolimus and other rapamycin derivatives.

5 WARNINGS AND PRECAUTIONS5.1 Non-infectious PneumonitisNon-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. In the ran-domized study, non-infectious pneumonitis was reported in 14% of patients treated with AFINITOR. Theincidence 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 respiratorysigns and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neo-plastic, and other causes have been excluded by means of appropriate investigations. Advise patients toreport promptly any new or worsening respiratory symptoms.Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or nosymptoms may continue AFINITOR therapy without dose alteration. If symptoms are moderate, considerinterrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITORmay be reintroduced at 5 mg daily.For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy andthe use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with AFINITOR maybe re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances.5.2 InfectionsAFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, orprotozoan infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)].Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infec-tions, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virushave occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading torespiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk ofinfection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to startingtreatment with AFINITOR. While taking AFINITOR be vigilant for signs and symptoms of infection; if adiagnosis of an infection is made, institute appropriate treatment promptly and consider interruption ordiscontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinueAFINITOR and treat with appropriate antifungal therapy.5.3 Oral UlcerationMouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR. In the ran-domized study, approximately 44% of AFINITOR-treated patients developed mouth ulcers, stomatitis, ororal mucositis, which were mostly CTC grade 1 and 2 [see Adverse Reactions (6.1)]. In such cases, topi-cal treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoidedas they may exacerbate the condition. Antifungal agents should not be used unless fungal infection hasbeen diagnosed [see Drug Interactions (7.1)].5.4 Laboratory Tests and MonitoringRenal FunctionElevations 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 cre -atinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter.Blood Glucose and LipidsHyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [seeAdverse 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 lipidcontrol should be achieved before starting a patient on AFINITOR.Hematological ParametersDecreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of com plete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.5.5 Drug-drug InteractionsDue to significant increases in exposure of everolimus, co-administration with strong inhibitors ofCYP3A4 (e.g., ketoconazole, itraconazole, clarithro mycin, atazanavir, nefazodone, saquinavir, telithromycin,ritonavir, indinavir, nelfinavir, voriconazole) or P-glycoprotein (PgP) should be avoided. Grapefruit, grape-fruit juice and other foods that are known to affect cytochrome P450 and PgP activity should also beavoided during treatment [see Dosage and Administration (2.2) in the full prescribing information andDrug Interactions (7.1)].A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4inhibitor (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) orPgP inhibitor [see Dosage and Administration (2.2) in the full prescribing information and Drug Inter -actions (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, car-bamazepine, rifampin, rifabutin, rifapentine, phenobarbital) [see Dosage and Administration (2.2) in thefull prescribing information and Drug Interactions (7.2)].5.6 Hepatic ImpairmentThe safety and pharmacokinetics of AFINITOR were evaluated in a study in eight patients with moderatehepatic impairment (Child-Pugh class B) and eight subjects with normal hepatic function. Exposure wasincreased 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) andshould not be used in this population [see Dosage and Administration (2.2) in the full prescribing infor-mation and Use in Specific Populations (8.7)].5.7 VaccinationsThe use of live vaccines and close contact with those who have received live vaccines should be avoidedduring 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 PregnancyPregnancy Category DThere are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based onmechanism 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 humanexposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if thepatient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard tothe fetus. Women of childbearing potential should be advised to use an effective method of contraception

while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations(8.1)].

6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in another section of the label:• Non-infectious pneumonitis [see Warnings and Precautions (5.1)].• Infections [see Warnings and Precautions (5.2)].6.1 Clinical Studies ExperienceBecause clinical trials are conducted under widely varying conditions, the adverse reaction ratesobserved cannot be directly compared to rates in other trials and may not reflect the rates observed inclinical practice.The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized,controlled trial in patients with meta static renal cell carcinoma who received prior treatment with sunitiniband/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 patientsreceiving 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 commonlaboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia,hyperglycemia, lymphopenia, and increased creatinine. The most common grade 3/4 laboratory abnor-malities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hyper -cholesterolemia. 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-emergentadverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% forthe AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irre-spective 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. Themost common medical interventions required during AFINITOR treatment were for infections, anemia, andstomatitis.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 organclass, 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 Placebo

N=274 N=137All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

% % % % % %Any Adverse Reaction 97 52 13 93 23 5Gastrointestinal Disorders

Stomatitisa 44 4 <1 8 0 0Diarrhea 30 1 0 7 0 0Nausea 26 1 0 19 0 0Vomiting 20 2 0 12 0 0

Infections and Infestationsb 37 7 3 18 1 0General Disorders and Administration Site Conditions

Asthenia 33 3 <1 23 4 0Fatigue 31 5 0 27 3 <1Edema peripheral 25 <1 0 8 <1 0Pyrexia 20 <1 0 9 0 0Mucosal inflammation 19 1 0 1 0 0

Respiratory, Thoracic and Mediastinal DisordersCough 30 <1 0 16 0 0Dyspnea 24 6 1 15 3 0Epistaxis 18 0 0 0 0 0Pneumonitisc 14 4 0 0 0 0

Skin and Subcutaneous Tissue DisordersRash 29 1 0 7 0 0Pruritus 14 <1 0 7 0 0Dry skin 13 <1 0 5 0 0

Metabolism and Nutrition DisordersAnorexia 25 1 0 14 <1 0

Nervous System DisordersHeadache 19 <1 <1 9 <1 0Dysgeusia 10 0 0 2 0 0

Musculoskeletal and Connective Tissue DisordersPain in extremity 10 1 0 7 0 0

Median Duration of Treatment (d) 141 60CTCAE Version 3.0aStomatitis (including aphthous stomatitis), and mouth and tongue ulceration.bIncludes all preferred terms within the ‘infections and infestations’ system organ class, the most commonbeing nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis(3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%).

cIncludes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonarytoxicity, and alveolitis.

Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with anincidence 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 erythro -dysesthesia 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 ofdiabetes mellitus (<1%)Psychiatric disorders: Insomnia (9%)Nervous system disorders: Dizziness (7%), paresthesia (5%)Eye disorders: Eyelid edema (4%), conjunctivitis (2%)

Vascular disorders: Hypertension (4%)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 Armthan the Placebo Arm

Laboratory Parameter AFINITOR 10 mg/day PlaceboN=274 N=137

All grades Grade 3 Grade 4 All grades Grade 3 Grade 4% % % % % %

Hematologya

Hemoglobin decreased 92 12 1 79 5 <1Lymphocytes decreased 51 16 2 28 5 0Platelets decreased 23 1 0 2 0 <1Neutrophils decreased 14 0 <1 4 0 0

Clinical ChemistryCholesterol increased 77 4 0 35 0 0Triglycerides increased 73 <1 0 34 0 0Glucose increased 57 15 <1 25 1 0Creatinine increased 50 1 0 34 0 0Phosphate decreased 37 6 0 8 0 0Aspartate transaminase (AST)

increased 25 <1 <1 7 0 0Alanine transaminase (ALT)

increased 21 1 0 4 0 0Bilirubin increased 3 <1 <1 2 0 0

CTCAE Version 3.0aIncludes reports of anemia, leukopenia, lymphopenia, neutropenia, pancyto penia, thrombocytopenia.

Information from further clinical trialsIn clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, includingfatal outcomes.

7 DRUG INTERACTIONSEverolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug effluxpump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.7.1 Agents that may Increase Everolimus Blood ConcentrationsCYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to AFINITOR treatment alone therewere significant increases in everolimus exposure when AFINITOR was coadministered with:• ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and

15.0-fold, respectively.• 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 alterna-tive 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 ConcentrationsCYP3A4 Inducers: In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer ofCYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, compared to everolimustreatment alone. Consider a dose increase of AFINITOR when co-administered with strong inducers ofCYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) or PgP ifalternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpre-dictably and should be avoided [see Dosage and Administration (2.2) in the full prescribing information].7.3 Agents whose Plasma Concentrations may be Altered by EverolimusStudies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactionsbetween AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and prava -statin (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 POPULATIONS8.1 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 onmechanism 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 humanexposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if thepatient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard tothe fetus. Women of childbearing potential should be advised to use an effective method of contraceptionwhile receiving AFINITOR and for up to 8 weeks after ending treatment.

In animal reproductive studies, oral administration of everolimus to female rats before mating andthrough organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantationand post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft) andretarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetaltoxicities occurred at approximately 4% the exposure (AUC0-24h) in patients receiving the recommendeddose of 10 mg daily. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oraldose approximately 1.6 times the recommended human dose on a body surface area basis. The effect inrabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lacta-tion. At approximately 10% of the recommended human dose based on body surface area, there were noadverse effects on delivery and lactation and there were no signs of maternal tox icity. However, therewas reduced body weight (up to 9% reduction from the control) and slight reduction in survival in off-spring (~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 MothersIt is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passedinto the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because manydrugs are excreted in human milk and because of the potential for serious adverse reactions in nursinginfants from everolimus, a decision should be made whether to discontinue nursing or to discontinue thedrug, taking into account the importance of the drug to the mother.8.4 Pediatric UseThe safety and effectiveness in pediatric patients have not been established.8.5 Geriatric UseIn the randomized study, 41% of AFINITOR-treated patients were ≥65 years in age, while 7% percentwere 75 and over. No overall differences in safety or effectiveness were observed between these subjectsand younger subjects, and other reported clinical experience has not identified differences in responsesbetween the elderly and younger patients, but greater sensitivity of some older individuals cannot beruled 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 pre-scribing information].8.6 Renal ImpairmentNo clinical studies were conducted with AFINITOR in patients with decreased renal function. Renalimpairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recom -mended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].8.7 Hepatic ImpairmentFor patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mgdaily [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].The impact of severe hepatic impairment (Child-Pugh class C) has not been assessed and use in thispatient population is not recommended [see Warnings and Precautions (5.6)].

10 OVERDOSAGEIn animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity wereobserved 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 beenadministered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

16 STORAGEStore 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 guide-lines on this subject have been published.AFINITOR tablets should not be crushed. Do not take tablets which are crushed or broken.

Revised: June 2010 T2010-56

Manufactured by:Novartis Pharma Stein AGStein, Switzerland

Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936

©Novartis

CONTINUING EDUCATION

34 I VALUE-BASED CANCER CARE I Nov/Dec 2010 VOL. 1 I NO. 6

Improving outcomes for patientswith non–small-cell lung cancer(NSCLC) is particularly relevant

because NSCLC accounts for 85% of allcases of lung cancer.1 In the appropriatepatients with advanced NSCLC, main-tenance therapy may help control thedisease and extend the patient’s life.Maintenance therapy is relatively newin NSCLC treatment, representing achange from the past approach ofretreatment upon disease progression.2

Two chemotherapy agents previouslyapproved by the US Food and DrugAdministration (FDA) for the treatmentof advanced NSCLC—pemetrexed anderlotinib—recently received FDA ap-proval for a new indication for mainte-nance therapy of advanced NSCLC.Pemetrexed, a folate analogmetabol-

ic inhibitor, was granted FDAapprovalfor maintenance therapy of advancedor metastatic lung cancer in July 2009.3

This new indication for pemetrexed isspecifically for patients with nonsqua-mous NSCLC that has not progressedafter 4 cycles of platinum-based first-line chemotherapy.4 Pemetrexed is alsoindicated as initial treatment in pa-

tients with locally advanced or meta-static nonsquamous NSCLC, in combi-nation with cisplatin, and after priorchemotherapy as a single agent.4

Erlotinib, an endothelial growth fac-tor receptor (EGFR) tyrosine kinaseinhibitor (TKI), received FDAapprovalin April 2010 for an expanded indica-tion as a maintenance treatment inpatients with locally advanced ormetastatic NSCLC whose disease hasnot progressed after 4 cycles of plat-inum-based first-line chemotherapy.5,6

Erlotinib is also indicated to treat local-ly advanced or metastatic NSCLC afterfailure of at least 1 prior chemotherapyregimen.6

Identifying the appropriate patientsas characterized by histology (non-squamous) or molecular (EGFR muta-tion) profile is an important considera-tion when selecting the appropriatemaintenance therapy.7 Using predic-tive biomarkers to target specificagents for maintenance therapy mayhelp improve benefits and reduce risksby tailoring a specific treatment to theappropriate patient.7 For example,pemetrexed is an option for mainte-

nance therapy in patients with non-squamous histology.1,4 In addition, amolecular-based strategy may be use-ful in selecting the appropriate patientsbest suited for maintenance therapywith erlotinib.7 Progression-free sur-vival (PFS) was significantly longer inpatients with EGFR-positive immuno-histochemistry who were treated witherlotinib as maintenance therapy com-pared with EGFR-positive patientswho received placebo, based on a ran-domized, placebo-controlled study.8

In addition to histology and geneticmarkers, maintenance therapy deci-sions involve a number of otherimportant considerations, includingthe latest clinical data, evidence-basedclinical practice guidelines, and thepatient’s performance status and per-sonal preferences. Although mainte-nance therapy may slow the growth ofdisease and extend life, the benefits oftreatment must be weighed against thepotential toxicities and other sideeffects associated with extended treat-ment. Costs and resource utilizationassociated with maintenance therapymust also be considered.

NSCLC: Burden and Economic

Impact

Lung cancer claims the lives of moreAmericans than any other type of can-cer.1 Moreover, lung cancer imposes asubstantial economic burden on ourhealthcare system. The estimatedannual costs to the American public aswell as lost productivity costs associat-ed with lung cancer were previouslyoutlined in the first part of this article.9

Treatment costs associated with lungcancer, as well as treatment failurecosts, are also substantial. A retrospec-tive, case-control cohort study that fol-lowed patients for 2 years from the firstdiagnosis of lung cancer showed thatthe monthly cost per patient was$11,496 for initial treatment, $3733 permonth for secondary treatment, and$9399 for terminal care treatment.10

Failure of initial treatment was associ-ated with increased costs: patients whoexperienced treatment failure incurredan additional $10,370/month in initialtreatment phase costs and $8779/month after starting the secondaryand/or terminal care phase of treat-ment.10 Moreover, treatment failure

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

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

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 professionalspracticing in oncology.

LEARNING OBjECTIVES

• Evaluate the benefits and risks of maintenance therapy compared with re-treating upon dis-ease 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 thera-peutic agent for specific patient populations and formulate strategies for value-based care

• Develop optimal side effect management strategies for patients receiving maintenancetherapy 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 mustcomplete the posttest and evaluation. The posttest and evaluation can be completed online atwww.mlicme.org/P10068.html. Upon completion of the evaluation and scoring 70% or bet-ter on the posttest, you will immediately receive your certificate online. If you do not achieve ascore of 70% or better on the posttest, you will be asked to take it again. Please retain a copyof 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.

PHARMACISTS’ DESIGNATION

Medical Learning Institute, Inc., is accredited by the Accreditation Council forPharmacy Education (ACPE) as a provider of continuing pharmacy education.Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing edu-

cation credit. The universal activity number for this activity is 0468-9999-10-060-H01-P.

DISCLOSuRES

Before the activity, all faculty will disclose the existence of any financial interest and/or rela-tionship(s) they might have with the manufacturer(s) of any commercial product(s) to be dis-cussed during their presentation(s): honoraria, expenses, grants, consulting roles, speaker’sbureau membership, stock ownership, or other special relationships. Presenters will informparticipants 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 bureaufor 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 relationshipsto disclose.The associates of Medical Learning Institute, Inc., the accredited provider for this activity, andCenter of Excellence Media, LLC, do not have any financial relationships or relationships toproducts or devices with any commercial interest related to the content of this CE activity forany amount during the past 12 months.

DISCLAIMER

The information provided in this CE activity is for continuing education purposes only and is notmeant to substitute for the independent medical judgment of a healthcare provider relative todiagnostic and treatment options of a specific patient’s medical condition. Trade names usedin this supplement are for the learner’s reference only. No promotion of or bias toward anyproduct should be inferred.

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35VOL. 1 NO. 6 www.ValueBasedCancer.com I

was associated with incremental costsof $19,149/month and $74,697 acrossthe study period.10 The study authorsconcluded that improvements in pre-vention or treatment of lung cancer,including new therapies or adjuvantchemotherapy, might reduce health-care resource utilization and costs, andthat strategies aimed at reducing hos-pitalizations and preventing or delay-ing treatment failure may offset theassociated cost burden.10

More than 68% of all patients diag-nosed with lung cancer are 65 years ofage or older.11 The burden and cost ofNSCLC may continue to grow as thebaby boom generation (people bornbetween 1946 and 1964) reaches the ageof 65 and older over the next 20 years.12

Maintenance Therapy Agents for

the Treatment of Advanced NSCLC

Maintenance therapy, sometimes alsoreferred to as consolidation therapy orearly second-line therapy,7 is a relativelynew approach to improving outcomesin patients whose disease eitherresponded to initial chemotherapy orwas stable following that, and is intend-ed to improve survivalwithout adverse-ly affecting quality of life.13 Aside fromimproving outcomes, the optimal main-tenance treatment should be well-toler-ated by patients and associatedwith fewor no cumulative toxicities.7

The National Comprehensive Can-cer Network (NCCN) has establishedspecific recommendations for the useof pemetrexed in maintenance therapy,as well as for the use of erlotinib.1

These guidelines also include recom-mendations for several other agents,including docetaxel, bevacizumab, andcetuximab.1

PemetrexedBased on phase 3 study results,

patients who received maintenancetherapy with pemetrexed showed asignificantly greater PFS (1.7 monthslonger), compared with the placebogroup, and a significantly greater over-all survival (OS; 2.8 months longer),compared with the placebo group.14Specific findings from the study werepreviously highlighted in Part I of thisarticle.9 Moreover, in patients withnonsquamous histology treated withpemetrexed, the OS was 5.2 monthslonger than in the placebo arm.14The most common any-grade ad-

verse reactions associated with peme-trexed included nausea (19%) andanorexia (19%).14 The pemetrexedgroup had a greater frequency of grade3 or higher adverse events than theplacebo group, including fatigue (5%)and neutropenia (3%).14

Another study that compared thecombination of cisplatin plus peme-trexed with cisplatin plus gemcitabine

in chemotherapy-naïve patients withadvanced NSCLC demonstrated supe-rior efficacy and reduced toxicity inthe group receiving cisplatin pluspemetrexed.15

ErlotinibBased on a phase 3 study, patients

who received maintenance therapywith erlotinib showed a greater PFS(0.8 weeks longer) and an improvedOS (1 month longer), compared withthe placebo group.6,8 In patients withEGFR-positive immunohistochemistrytreated with erlotinib, compared withEGFR-positive patients receivingplacebo, PFS was significantly greater(1.2 months longer) in the erlotinibgroup, compared with the placebogroup, in patients with EGFR-positiveimmunohistochemistry treated witherlotinib.8 Specific study results werepreviously highlighted.9

The most common any-grade ad-verse reactions associated with erlotinibwere rash (49.2%) anddiarrhea (20.3%).6

The most common serious adverseevent was pneumonia (2%), and themost common grade 3 or higheradverse events included rash (6%) anddiarrhea (2%).8

Other Agents Included in Clinical

Practice Guidelines

DocetaxelAlthough docetaxel, a microtubule

inhibitor, does not have a specific FDAapproval for maintenance therapy inNSCLC, this agent is indicated as a sin-gle agent for locally advanced ormetastatic NSCLC after failure on plat-inum therapy; and with cisplatin forunresectable, locally advanced, ormetastatic untreatedNSCLC.16 Based ona phase 3 randomized study thatassessed the efficacy and safety of doc-etaxel administered either immediatelyafter gemcitabine or at disease progres-sion, immediate docetaxel was associat-ed with a significantly greater PFS (5.7months) compared with delayed doc-etaxel (2.7 months), and immediate doc-etaxel was associated with a greatermedian OS (12.3 months) comparedwith delayed docetaxel (9.7 months).17

However, the difference in median OSwas not statistically significant (P =.0853). There was no significant differ-ence in quality of life between the imme-diate and delayed docetaxel groups.17

Based on studies of docetaxel asmonotherapy for NSCLC patients pre-viously treated with platinum-basedchemotherapy (n = 176), the most com-mon grade 3/4 adverse reactionsincluded neutropenia (65%); leuko-penia (49%); and pulmonary effects(21%).16 The most common any-gradeadverse reactions include neutropenia(84%); leukopenia (84%); anemia (91%);asthenia (53%); pulmonary effects(41%); infection (34%); nausea (34%);fluid retention (34%); neurosensoryeffects; (34%); stomatitis (26%); diarrhea(23%); and vomiting (22%).16

In chemotherapy-naïve advancedNSCLC patients receiving docetaxel incombination with cisplatin (n = 406),the most common grade 3/4 adversereaction was neutropenia (74%).16 Themost common any-grade adverse reac-tions included neutropenia (91%); ane-mia (89%); alopecia (75%); asthenia(74%); nausea (72%); vomiting (55%);fluid retention (54%); diarrhea (47%);neurosensory effects (47%); anorexia(42%); infection (35%); peripheraledema (34%); and fever (33%).16

BevacizumabBevacizumab, amonoclonal antibody

that inhibits vascular endothelialgrowth factor, is indicated for the treat-ment of nonsquamous NSCLC, withpaclitaxel and carboplatin for the first-line treatment of unresectable, locallyadvanced, recurrent, or metastatic dis-ease.18 According to the NCCN clinicalpractice guidelines, the criteria for beva-cizumab therapy include a performancestatus of 0-1, nonsquamous histology,and no history of hemoptysis.1

Adding bevacizumab to chemo-therapy with paclitaxel plus carbo-platin has shown a significant im-provement in median survival (12.3months), compared with chemothera-py alone (10.3 months), based on arandomized 3-year study of patientswith recurrent or advanced NSCLC(N = 878) conducted by the EasternCooperative Oncology Group.19 Anincreased risk of treatment-relateddeaths were observed in the grouptreated with bevacizumab plus pacli-taxel and carboplatin, and the rate ofclinically significant bleeding was4.4% in this arm.19 Other adverseevents included grade 4 neutropenia(24%), grade 3/4 hemorrhage (4.5%),hemoptysis (1.9%), and hypertension(6%).1 According to the NCCN guide-lines, caution is advised whenchemotherapy regimens with a highrisk for thrombocytopenia and/orpossible bleeding are combined withbevacizumab.1

Further studies are needed to deter-mine whether bevacizumab mainte-nance is associatedwith a survival ben-efit compared with the combination of

chemotherapy and bevacizumab with-out maintenance bevacizumab.20

CetuximabCetuximab, a monoclonal antibody

that targets EGFR, is indicated for thetreatment of specific head and neckcancers and colorectal cancers; howev-er, this agent does not have an indica-tion for the treatment of NSCLC.21

Cetuximab use is not recommendedfor patients with colorectal cancerwhose tumors have KRASmutations incodon 12 or 13.21

According to a study of patients (N =1125) with advanced NSCLC (stage IIIBor IV; majority were stage IV), patientstreated with cetuximab in combinationwith vinorelbine and cisplatin showedno difference in PFS and a significantlyimproved OS (11.3 months) comparedwith patients receiving vinorelbineand cisplatin alone (10.1 months).1,22

Treatment-related deaths were similarin both groups.22 Patients receivingcetuximab had increased grade 3/4febrile neutropenia (22%) and grade 3acne-like rash (10%).1,22

Evidence-Based Practice

Guidelines

For the NCCN NSCLC clinical prac-tice guidelines (updated in March2010), a new section with maintenancetherapy recommendations was added.1

These recommendations categorizedmaintenance therapy into 2 types: con-tinuation maintenance therapy andswitch maintenance therapy. Con-tinuation maintenance therapy refersto the use of at least 1 of the agentsadministered as first-line therapy.1

Switch maintenance therapy refers tothe initiation of an agent that was notincluded as part of the first-line treat-ment regimen.1 Based on 2 recent stud-ies demonstrating a benefit in PFS andOS, the guidelines now recommendinitiation with pemetrexed or erlotinibfor switch maintenance therapy inpatients without disease progression(Category 2B recommendation).1

Highlights of the NCCN guidelinerecommendations for continuationmaintenance therapy and switch main-tenance therapy were outlined previ-ously in the first part of this article.9

Information about theAmerican Societyof Clinical Oncology (ASCO) guidelineupdate, as well as recent guidance fromthe National Institute for Health andClinical Excellence are also highlightedin that article.

The Role of Histology and

Molecular Biomarkers in

Maintenance Therapy

It is important to identify the histo-logic subtype of NSCLC (ie, squamouscell vs nonsquamous cell) when

Using predictive biomarkersto target specific agents formaintenance therapy mayhelp improve benefits andreduce risks.

Continued on page 36

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selecting maintenance therapy.23

Histologic informationmay be particu-larly useful when augmented bymolecular testing.23 Detecting the bron-chioloalveolar subtype of NSCLC ade-nocarcinoma may suggest a specifictreatment approach, particularly if it isassociated with specific mutations inthe EGFR tyrosine kinase domain,which indicates it may respond totreatment with an EGFR TKI.23

However, it is important to point outwithin this NSCLC subtype, there arealso variabilities in histology andmolecular information.23

Several predictive molecular bio-markers play a key role inNSCLC treat-ment,1 and these biomarkers and asso-ciated characteristics were summarizedin Part I.9 Initial retrospective studiessuggest that approximately 90% ofpatients with a tumor response toerlotinib and gefitinib (both EGFR TKIagents) had EGFR mutations E19 dele-tion and L858R mutation, whereaspatients without a response to these 2agents did not carry these mutations.1

The NCCN guidelines recommend thatpathological evaluation be performedto classify the lung cancer, determine itsextent of invasion, determine the statusof surgicalmargins, and identifymolec-ular abnormalities that may predict thetreatment response, or resistance to,EGFR TKI therapy.1

Other Maintenance Therapy

Considerations

The potential benefits of mainte-nance therapy—preventing cancerrecurrence, slowing disease growth,and prolonging life—must be weighedagainst the potential risks—increasedside effects and potential for toxicities,drug resistance, and more frequentdoctor’s visits. Another considerationis that maintenance therapy does notprovide the patient with a chemothera-py break, also referred to as await-and-see period.7 Data on the quality of lifeassociated with maintenance therapyare limited, including data on cumula-tive toxicity associated with extendedchemotherapy.7 Although maintenancetherapy increases chemotherapy costsand may increase overall costs, it mayconversely decrease costs associatedwith palliative radiotherapy and hospi-tal admissions resulting from perform-ance status deterioration.20

The value of maintenance therapy isthe subject of ongoing discussionamong clinicians, particularly in lightof its cost and potential toxicity.24

Pemetrexed administered in 6 cycles at

the average wholesale price of $3000per cycle would total $18,000.24 Thewholesale acquisition cost for erlotinibmaintenance treatment would be $4000per month x a mean PFS of 3 months,for a total treatment cost of $12,000.24

Some of the challenges surroundingcost of added survival were presented atthe 2010 ASCO meeting by ScottRamsey, MD, PhD, of the FredHutchinson Cancer Research Center inSeattle.24,25 Dr Ramsey asserted thatmaintenance therapy was unlikely to becost-effective, based on a ratio that con-siders both the price over standard careand the months of OS benefit. However,he acknowledged that pharmacoge-nomic strategies may improve the cost-effectiveness of therapy and that the costof testing will be a factor. Dr Ramseyclaimed that many new oncology agentsdo not meet the criteria for cost-effective-ness and that many economic analysesdo not meet the guidelines for economicevaluation.24,25 Guideline-driven phar-macoeconomic studies may shed lighton whether maintenance therapy is themost cost-effective.

The rationale in favor of mainte-nance therapy was presented at the2010 ASCO meeting by Tracey Evans,MD, of the Abramson Cancer Center,University of Pennsylvania, inPhiladelphia.26 According to Dr Evans,“maintenance therapy for advancedNSCLC is absolutely a standard ofcare” that should be considered for allpatients, particularly based on clinicaldata showing prolonged survival andtolerability.26 An opposing point ofview was presented by TomStinchcombe, MD, of the LinebergerComprehensive Cancer Center, at theUniversity of North Carolina at ChapelHill.27 According to Dr Stinchcombe,maintenance therapy is not necessarilya standard of care for every patient butrather an option to be considered,which depends on toxicities as well asthe patient’s disease burden, extent ofsymptoms, performance status, andpreferences.27 He maintained that atreatment-free interval is still an optionin this incurable disease setting.27

Conclusion

Maintenance therapy, a relatively newapproach in the treatment of patientswith advanced NSCLC, has the poten-tial to extend survival and improve out-comes. Key considerations for tailoringtreatment for the appropriate patientsinclude the histology of the carcinoma,genetic biomarkers, the extent of diseaseinvasion, and the patient’s performancestatus and preferences. The benefits ofmaintenance therapy must be weighedagainst the potential toxicities and otherside effects associated with extendedtreatment. Selecting the appropriatetherapy for the appropriate patientsand involving patients in the decisionprocess are important aspects of thetreatment plan. Strategies for manag-ing side effects warrant careful consid-eration. Optimally, the agent selectedfor maintenance therapy should bewell-tolerated by the patient, demon-strate improved patient outcomes, andhave minimal side effects/cumulativetoxicities.7

Recent clinical data and evidence-based guidelines are valuable decision-making tools for clinicians. However,data assessing quality of life, cost-effec-tiveness, and cumulative toxicity ofmaintenance therapy are lacking. Costsand resource utilization associatedwithmaintenance therapymust be bal-anced against the risks and costs of nottreating or of deteriorating perform-ance status. A delay strategy may beassociated with a shorter survival timeand a faster disease progression thanimmediate additional therapy.28,29 Inany case, the prospect of extended sur-vival of several months, or evenweeks,particularly if treatment is well-tolerat-ed, represents an important milestonefor patients with advanced NSCLC. �

References1. National Comprehensive Cancer Network. NCCNClinical Practice Guidelines in Oncology™. Non-smallcell 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 NSCLCsurvival 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 ther-apy for advanced lung cancer [press release]. July 6,2009. US Food and Drug Administration. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm170515.htm. Accessed September 22, 2010.4. Alimta (pemetrexed disodium) [package insert].Indianapolis, IN: Eli Lilly and Company; 2010.5. Waknine Y. FDA approves use of erlotinib as main-tenance therapy for advanced non-small cell lung can-cer [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 celllung cancer: current status, controversies, and emerg-ing consensus. Clin Cancer Res. 2010;16:2496-2504.8. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinibas maintenance treatment in advanced non-small-celllung cancer: a multicentre, randomized, placebo-con-trolled 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 andoutcomes, part I of II. Value-Based Cancer Care.2010;1(5):24-26.10. Kutikova L, Bowman L, Change S, et al. The eco-nomic burden of lung cancer and the associated costsof treatment failure in the United States. Lung Cancer.2005;50:143-154. Epub, August 19, 2005. 11. National Cancer Institute, US National Institutes ofHealth. 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 to2050. Current Population Reports, P25-1138. USCensus Bureau, Washington, DC; May 2010.13. American Society of Clinical Oncology. Explainingmaintenance therapy. Cancer.net. Updated February22, 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 careversus placebo plus best supportive care for non–small-cell lung cancer: a randomized, double-blind,phase 3 study. Lancet. 2009;374:1432-1440. EpubSeptember 18, 2009. 15. Scagliotti GV, Parikh P, von Pawel J, et al. Phase IIIstudy comparing cisplatin plus gemcitabine with cis-platin plus pemetrexed in chemotherapy-naivepatients 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 IIIstudy of immediate compared with delayed docetaxelafter front-line therapy with gemcitabine plus carbo-platin in advanced non-small-cell lung cancer. J ClinOncol. 2009;27:591-598. Epub December 15, 2008.18. Avastin (bevacizumab) [package insert]. South SanFrancisco, CA: Genentech, Inc; 2009. 19. Sandler A, Gray R, Perry MC, et al. Paclitaxel-car-boplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med. 2006;355:2542-2550. 20. Eaton KD. Maintenance chemotherapy in non-small 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. Cetuximabplus chemo therapy in patients with advanced non–small-cell lung cancer (FLEX): an open-label random-ized phase III trial. Lancet. 2009;373:1525-1531.23. Neal JW. Histology matters: individualizing treat-ment 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. PharmaceuticalAp provals Monthly. August/September 2010. 25. Ramsey S. Cost effectiveness in lung cancer trialsand treatment. Presented at the 2010 American Societyof Clinical Oncology Meeting—Education Session.June 4-8, 2010; Chicago, IL.26. Evans TL. Maintenance therapy for advancedNSCLC is standard of care. Presented at the 2010American Society of Clinical Oncology Meeting—Education Session. June 4-8, 2010; Chicago, IL.27. Stinchcombe T. Maintenance therapy for advancedNSCLC is not standard of care. Presented at the 2010American Society of Clinical Oncology Meeting—Education Session. June 4-8, 2010; Chicago, IL.28. Belani CP, Liao J. Maintenance therapy for non-small cell lung cancer [comment]. Lancet. 2010.375:281-282; comment on Stinchcombe T, West H com-ment in: Lancet. 2009;374:1398-1400.29. Soon YY, Stockler MR, Askie LM, Boyer MJ.Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analy-sis of randomized trials. J Clin Oncol. 2009;27:3277-3283. Epub May 26, 2009.

NCCN guidelines nowrecommend initiation withpemetrexed or erlotinib forswitch maintenance therapyin patients without diseaseprogression.

Maintenance Therapy for NSCLC... Continued from page 35

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Maintenance therapy hasbegun to emerge as a treat-ment standard for patients

with non–small-cell lung cancer(NSCLC) whose disease has not pro-gressed after 4 to 6 cycles of frontlinechemotherapy. But some caveats stillapply. Although it may be suitable forfit, motivated patients who are highlysymptomatic at the time of presenta-tion, it is not yet clear if maintenancetherapy should be routine. Based on the phase 3 data, use of

pemetrexed is certainly justified inpatients whose advanced NSCLC hasstabilized or improved after 4 or morecycles of frontline therapy with a plati-nating agent, plus either gemcitabineor a taxane. Pemetrexed is particularlywell tolerated and convenient, al -though its “maintenance” benefits areconfined to nonsquamous histologyand its utility is as yet unproven inpatients who have received peme-trexed and/or bevacizumab as part oftheir firstline treatment.Similarly, erlotinib has yielded a sur-

vival advantage compared with place-bo in the maintenance setting, althoughthe extent of its benefit seems less pro-nounced compared with pemetrexed.

Prolonged Initial Chemotherapy

Prolonged treatment with initialchemotherapy (eg, 6 vs 3 cycles orindefinite treatment vs 4 cycles) hasshown no overall survival (OS) bene-fit1-3; neither have prior maintenancestudies of attenuated dosing or singleagents yielded a survival benefit,although “intriguing trends” in time toprogression have been observed inunderpowered efforts.4,5

Switching to a new compound formaintenance therapy demonstratedsome benefit in the well-designed studyby Fidias et al, which evaluated imme-diate versus delayed docetaxel upondisease progression after firstline carbo-platin/gemcitabine.6 Progression-freesurvival (PFS) improved from 2.7months in the delayed arm to 5.7months with maintenance (P <.001),and median OS trended better (12.3 vs9.7 months, P = .085). In addition, arecentmeta-analysis documented a 30%reduction in disease progression using

maintenance therapy with a third-gen-eration regimen comparedwithmainte-nance with older regimens.7

Determining the Optimal

Maintenance Therapy Agent

The study by Fidias and colleagueslaid the groundwork for pemetrexedas maintenance after chemotherapy,6

which was evaluated in a recent phase3 study by Belani et al.8 Patients wererandomized 2:1 to pemetrexed or intra-venous placebo. Disease progressionwas reduced by 40% (P <.001) overalland by 53% in patients with nonsqua-mous histology (P <.001), and deathswere reduced by 21% (P = .012) and30% (P = .002), respectively. Pemetre -xed was reasonably well-tolerated anddevoid of cumulative toxicity. Benefitswere particularly pronounced inpatients with nonsquamous histology(they had a more than 5-month sur-vival advantage); there was no PFS orOS advantage in those with squamoushistology.8

Although this was the first random-ized, double-blind, placebo-controlledtrial to show a significant survival ben-efit for maintenance treatment, one stillneeds to exercise caution in basing clin-ical decisions on this study.Maintenance therapy is unrealistic

for many patients due to early diseaseprogression, comorbidities, and patientdesire to stop treatment. Pemetrexed isof no value to patients with squamoushistology and is unproven in patientswho have received firstline peme-trexed or bevacizumab. Furthermore,the survival improvement in the Belanistudy would be more impressive hadthere been mandatory crossover topemetrexed at the time of disease pro-gression in the control arm; unlike theFidias trial, mandatory crossover wasnot instituted in the JMEN trial. It isnoteworthy that <20% of enrollees inthe control arm received pemetrexed atthe time of disease progression,although a majority received a stan-dard secondline treatment.Many patients look forward to the

prospect of a therapeutic holiday. Ifpatients are closely monitored oncethey have completed firstline therapy,there is often enough time to imple-

ment secondline treatment when dis-ease progresses before symptoms havetaken over. Finally, cost is the 800-lbgorilla in the room. Recent analyses ofpemetrexed maintenance suggest aminimum incremental cost of>$120,000 per life-year saved.9

A recent phase 2 study evaluatedpemetrexed plus bevacizumab formaintenance after 6 initial cycles of car-boplatin, pemetrexed, and bevacizu -mab.9 Median PFS was 9.3 months andmedian OS was 14 months.10 Manypractitioners are using this regimenincreasingly in bevacizumab-eligiblepatients. These encouraging findingshave led to a large, planned random-ized phase 3 trial in the EasternCooperative Oncology Group (ECOG5508), which just opened and will ran-domize 1282 patients to bevacizumab,pemetrexed, or to a combination ofbevacizumab and pemetrexed after 4cycles of initial therapy with paclitax-el/carboplatin/bevacizumab. In addi-tion, a separate phase 3 trial [POINT-BREAK] will compare this regimen tothe “winning” arm of ECOG 4599 (acombination of paclitaxel, carboplatin,and bevacizumab), which yielded asignificant and clinically meaningfulsurvival advantage in this setting com-pared with chemotherapy alone.Finally, in Europe, pemetrexed mainte-nance is being compared with “obser-vation” in patients who have stabilizedor responded to a “standard” peme-trexed-cisplatin regimen.

Erlotinib Maintenance

Erlotinib has shown value as a main-tenance agent in 2 key studies. TheSequential Tarceva® in UnresectableNSCLC (SATURN) trial found thaterlotinib reduced the risk of progres-sion by 29% (P <.001) and offered a 1-month OS benefit (P = .0088).11 In theATLAS trial, maintenance therapywith erlotininb plus bevacizumabimproved PFS by 39%, or by approxi-mately 1 month (P = .0012), but no OSdifference was shown.12 Moreover, tox-icity associated with this approach isnot trivial.

Conclusions

Docetaxel, pemetrexed, and erlotinib

are each approved in the secondlinesetting, and all have shown a PFS ben-efit asmaintenance therapy and at leasta trend toward improved survival, ifnot a statistically significant increase insurvival. To date, both pemetrexed anderlotinib are US Food and DrugAdministration–approved for mainte-nance therapy. At the end of the day,treatment should be individualized forall patients, taking into account notonly clinical outcomes but patients’personal preferences, disease burden,and comorbidities. �

References1. Socinski MA, Schell MJ, Peterman A, et al. Phase IIItrial comparing a defined duration of therapy versuscontinuous therapy followed by second-line therapyin 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 con-veys no survival or consistent quality-of-life benefitsin advanced non-small-cell lung cancer. Br J Cancer.2006;95:966-973.3. Smith IE, O’Brien ME, Talbot DC, et al. Duration ofchemotherapy in advanced non-small-cell lung can-cer: a randomized trial of three versus six courses ofmitomycin, 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-celllung cancer using weekly paclitaxel and carboplatinfollowed by maintenance weekly paclitaxel or obser-vation. J Clin Oncol. 2003;21:2933-2939.5. Brodowicz T, Krzakowski M, Zwitter M, et al.Cisplatin and gemcitabine first-line chemotherapy fol-lowed by maintenance gemcitabine or best supportivecare in advanced non-small cell lung cancer: a phaseIII trial. Lung Cancer. 2006;52:155-163.6.Fidias P, Dakhil S, Lyss A, et al. Phase III study ofimmediate compared with delayed docetaxel afterfront-line therapy with gemcitabine plus carboplatinin advanced non-small cell lung cancer. J Clin Oncol.2009;27:591-598.7. Soon YY, Stockler MR, Askie LM, Boyer MJ. Durationof chemotherapy for advanced non-small-cell lungcancer: a systematic review and meta-analysis of ran-domized trials. J Clin Oncol. 2009;27:3277-3283.8.Ciuleanu T, Brodowicz T, Zielinski C, et al.Maintenance pemetrexed plus best supportive careversus 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-effec-tiveness of pemetrexed as first-line maintenance ther-apy for advanced nonsquamous non-small cell lungcancer. J Thorac Oncol. 2010;5:1263-1272.10. Patel JD, Hensing TA, Rademaker F, et al. Phase IIstudy of pemetrexed and carboplatin plus bevacizu -mab with maintenance pemetrexed and bevacizumabas first-line therapy for nonsquamous non–small-celllung cancer. J Clin Oncol. 2009;27:3284-3289.11. Capuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinibas maintenance treatment in advanced non–small-celllung cancer: a multicentre, randomized, placebo-con-trolled 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 orwithout erlotinib after completion of chemotherapywith B for first-line treatment of locally advanced,recurrent, or metastatic non-small cell lung cancer(NSCLC). Presented at 2009 ASCO Annual Meeting. JClin Oncol. 2009;27(18 suppl):LBA8002

Maintenance Therapy in NSCLC: Personalized PerspectivesBy Corey J. Langer, MDDr Langer is Director of Thoracic Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia.

COMMENTARY

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38 I VALUE-BASED CANCER CARE I Nov/Dec 2010 VOL. 1 I NO. 6

Significant ad van -ces in treat ingnon–small-cell

lung cancer (NSCLC)have been made overthe past 10 years; nev-ertheless, survival im -provement in this disease pales com-pared with many other solid tumors.Because maintenance chemo therapyoffers improved survival in NSCLC,patients and doctors are justifiablyexcited.

Nursing Considerations

In my dealings with patients, thereseem to be 2 distinct responses tomaintenance treatment. On the onehand, patients are very happy thatthey can continue receiving some sortof therapy, because they feel that theyare continuing the fight. Before thedata supporting maintenance chemo -therapy for NSCLC, we would stoptherapy after 4 to 6 cycles and give atreatment break, and many patientswere worried that they weren’t doinganything to treat their disease duringthis time. Con versely, I have alsoencountered many patients who areyearning for a break in therapy.Suggesting maintenance chemothera-py, which promises more toxicity sim-ilar to what the patient is already expe-riencing, leaves them bewildered. Butbecause the treatment offers a survivaladvantage, patients usually will con-tinue with it because they want to livelonger. However, they frequently askwhen there will be a break, and thisoften gives them the realization thatthey will be receiving this treatmentfor the rest of their lives. It is important for oncology treat-

ment pro viders to have a detailed dis-cussion with patients about the prosand cons of maintenance therapy forNSCLC. These patients have a terminalillness with average survival of arounda year. Doctors and nurses must allow

pa tients the autonomy to make deci-sions about receiving maintenancetherapy, along with possible breaks tohave a vacation or spend time withfamily. Maintenance therapy can con-tinue indefinitely, which can leave apatient feeling that his/her life is a con-stant schedule of treatments and cancause tremendous emotional stress.

Managing Toxicities

As maintenance therapy becomes amore widely used treatment option forpatients with NSCLC, it is important toweigh its toxicities. Pemetrexed, whichis US Food and Drug Administration(FDA) approved in the maintenancesetting, and docetaxel, which has a rec-ommendation (although not an FDAapproval) for maintenance therapy, areboth cytotoxic chemotherapy agentsand pose different concerns than otherapproved maintenance therapies.Common side effects of chemothera-peutic agents, including risk for myelo-suppression, fatigue, and nausea, are aconcern for patients receiving mainte-nance therapy, especially be cause thereis no defined end date to it unless thereis disease progression or unacceptabletoxicity. So patients may end up takingthese drugs without a break for up to ayear or more.In the pemetrexed maintenance

study, anemia occurred in 15% ofpatients in the pemetrexed mainte-nance arm versus 6% in the placeboarm.1 Patients receiving pemetrexedmay therefore require more frequentblood transfusions and possiblycolony-stimulating factors such as dar-bepoetin or erythropoietin. Managingfatigue can become difficult for thesepatients, and considering that they aredealing with a terminal illness, fatiguemust be taken into serious account interms of its effect on the patient’s qual-ity of life. Nausea was also reported in19% of patients in the pemetrexed armversus 6% in the placebo arm.1

The targeted therapies erlotinib (inthe switch maintenance setting) andbevacizumab and cetuximab (in thecontinuation maintenance setting) donot typically induce the same sideeffects as chemotherapy but rathercarry their own set of unique toxicities.The toxicities from these agents canalso interfere with a patient’s quality oflife and must be considered andaddressed before embarking on main-tenance therapy.

Rash was the most common sideeffect in patients receiving erlotinib inthe maintenance trial. Grade 3/4 rash,causing interference with activities ofdaily living, was 6%.2 Because goodrandomized data on treating this rashhave not emerged, management strate-gies have focused on best-practice rec-ommendations. Depending on severi-ty, papulopustular rash can be treatedwith topical steroids or antibiotics, oralantibiotics, and even oral steroids insevere cases.3 Thesemedications can beused in combination or separatelydepending on the grade of rash.Although it is rarely life-threatening,rash can be uncomfortable and disfig-uring at times. In the cetuximab contin-uation trial, rash was present in 70%(382/548) of patients, with 10% experi-encing grade 3/4 rash.Rates of grade 3/4 diarrhea in both

the cetuximab and erlotinib mainte-nance trials were 4% and 2%, respec-tively.2,4 It is usually easily controlledwith loperamide and sometimes re-quires a prescription-strength anti-diarrheal. Concern for dehydration

may be an issue given that this patientpopulation is often elderly, so promptassessment and ensuring fluid intakeare important. Bevacizumab is only approved for

the use of nonsquamous NSCLCbecause of bleeding risk. The mostcommon side effects of bevacizumabinclude hypertension and protein-uria,5 and assessing for these on eachvisit is recommended. Standard anti-hypertensives will usually controlbevacizumab-associated hyperten-sion; pro tein uria often improves onholding the bevacizumab dose. In rareNSCLC cases, bevacizumab has thepotential to cause fatal pulmonaryhemorrhage, so it is essential thatpractitioners assess for hemoptysisand permanently discontinue beva-cizumab if hemoptysis occurs. In summary, the improvement in

survival for metastatic NSCLC by con-tinuing a maintenance therapy afterfirstline treatment is modest, but it iscertainly an advance. Conversations withpatients about the schedule, toxicities,and benefits of therapy must be unbi-ased and thorough. Patients need to beable to voice their concerns and haveample opportunity to shape their treat-ment regimen becuase of their limitedprognosis and possible effect of main-tenance treatment on quality of life. �

References1. Ciuleanu T, Brodowicz T, Zielinski C, et al.Maintenance pemetrexed plus best supportive careversus placebo plus best supportive care for non-small-cell lung cancer: a randomized, double-blind,phase 3 study. Lancet. 2009;374:1432-1440.2. Cappuzo F, Ciuleanu T, Stelmakh L, et al. Erlotinibas maintenance treatment in advanced non-small-celllung cancer: a multi-center, randomized, placebo-con-trolled phase 3 study. Lancet Oncol. 2010;11:521-529.3. Lynch T, Kim E, Eaby B, et al. Epidermal growth fac-tor receptor (EGFR) inhibitor-associated rash: an evol -ving paradigm in clinical management. Oncologist.2007;12:610-621.4. Pirker R, Pereira JR, Szczesna A, et al. Cetuximabplus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label random-ized phase III trial. Lancet. 2009;373:1525-1531.5. Sandler A, Gray R, Perry MC, et al. Paclitaxel–car-boplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med. 2007;355:2542-2550.

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

Conversations with patientsabout the schedule,toxicities, and benefits oftherapy must be unbiasedand thorough.

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