October 2010, Vol 1, No 5

Breast Cancer ScreeningRecommendations: Evidence, Fear, and PoliticsBy Michael K. Gusmano, PhD, and Bradford H. Gray, PhD

Dr Gusmano is Research Scholar, The Hastings Center, Garrison, NY, and AdjunctAssistant Professor, Department of Health Policy and Management, ColumbiaUniversity; Dr Gray is Senior Fellow with the Urban Institute, Washington, DC.

Adding Comparative Effectiveness to Formulary EvidenceWellPoint argues for real-world informational needsAn interview with Brian Sweet, RPh, MBA

Accelerated Approval: GoodIntentions, Difficult ImplementationBy Margot J. Fromer

©2010 Engage Healthcare Communications, LLC

Guiding Patients Through Cost-Based Treatment ChoicesAssistance with a topic not yet on medical school curriculumBy Rosemary Frei, MSc

Having a conversation withpatients about the cost benefitof their cancer treatments is

difficult, and many clinicians areunprepared for this discussion. For -tunately, however, resources are be -coming available to help clinicians aidpatients in determining how much theyare willing and able to pay for treat-ments that may cure them—or onlybuy a few extra weeks of life.

PAF Brochures

for Providers

and Patients

At the annualmeeting of theAmeri can Societyof Clinical Oncol -ogy, representa-tives from thePatient Ad vocate

In May 2010, the health benefits com-pany WellPoint, Inc, announced apolicy of using comparative effective-

ness research (CER) as part of the firm’sformulary decision-making process. Thisis not surprising given the emphasis onCER after the dedication of $1.1 billionfor these efforts in the AmericanRecovery and Reinvestment Act of 2009,but for WellPoint Chief PharmacyOfficer Brian Sweet, RPh, MBA, this isboth a natural development in the com-pany’s evolution as well as a reflection ofthe times. We were curious to know howthe CER formulary policy has played outso far for this early adopter, so we asked

www.ValueBasedCancer.com

IN THIS ISSUE

In November 2009, the US Pre ventiveServices Task Force (USPSTF) pub-lished new recommendations about

routine breast cancer screening mam-mography.1 If followed, the new recom-mendations would substantially re ducethe use of the procedure among womenaged 40 to 49 years.2 The recommenda-tions were touted by some leadinghealth policy researchers as “rational”3

and “objective.”4 Yet, the positive evalu-ations were overwhelmed by an ava-lanche of negative reactions from pro-fessional associations, patient advo cates,and elected officials from both politicalparties.5 Within a month, the Senate

agreed by voice vote to an amendmentthat effectively required the federalgovernment to ignore the Task Force’srecommendations.6

Lessons Learned

It is not unprecedented for new prac-tice guidelines to generate powerfulopposition. Professional and advocacyopposition, along with financial inter-ests and ideological concerns aboutgovernment “rationing,” may createbarriers to the implementation of com-parative effectiveness research (CER)and evidence-based medicine (EBM),

AUS Food and Drug Adminis -tra tion (FDA) decision original-ly set for September 17, 2010,

on using bevacizumab (Avastin) inbreast cancer has been postponed untilDecember 17, 2010. Although beva-cizumab is the first antiangiogenicdrug for treating cancer and is the best-selling cancer drug in the world, theFDA Oncologic Drugs AdvisoryCommittee (ODAC) recommendedthat approval for this indication berevoked in an almost unanimous vote(12-1) at a July 20, 2010, meeting.

Accelerated Approval

This particular indication was grant-ed in 2008 under the FDA’s acceleratedapproval (AA) program. Unlike tradi-tional approval, AA is based on a sur-

rogate end point, an indirect or substi-tute marker representing a clinicallymeaningful outcome.

Progression-free survival is often cho-sen as the primary end point for AA tri-als, because it measures a direct effect oftreatment. Overall survival (OS), ordi-narily the “gold standard” of clinical tri-als, is increasingly difficult to measurefor first-line treatment, because treat-ments administered after a clinical trialhas ended cannot be controlled.

The FDA decides whether a particu-lar surrogate end point is acceptable fora clinical trial and generally bases itsdecision on whether the end point isreasonably likely to predict a real clini-cal end point.

AA is predicated on the condition thatContinued on page 5

Recent highlights from the oncology literature............................................ 9

An interview with David Meltzer, MD, PhD, on the utility of health economics .............................................................. 11

Jason Slotnik considers premarket parallel review ................................... 17

Continuing education for pharmacists on non–small-cell lung cancer....... 24

Yu-Ning Wong, MD, MSCE

OCTOBER 2010 VOL 1 NO 5

Continued on page 22


Continued on page 7

VBCC_October_100810_Follow ASCO Tabloid 10/12/10 2:34 PM

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.


Glass Flakes Spur Recall of Some

Epoetin Alfa

The FDA and Amgen announced arecall of some lots of epoetin alfa(Epogen and Procrit) after extremelythin glass flakes (called lamellae)were found in some vials. The lamel-lae result from the drug interactingwith the glass vials over the shelf life

of the product. The precautionary re -call is intended to prevent potentialserious adverse events includingembolic, thrombotic, and other vas-cular events (eg, phlebitis) associatedwith intravenous delivery, and for-eign body granuloma, local injectionsite reactions, and increased im -munogenicity resulting from subcu-

taneous injection. In a “Dear Health -care Professional Letter,” the manu-facturer noted the potential for limit-ed, short-term availability of 2000-,3000-, 4000-, and 40,000-unit Procritvials. Information on the affected lotscan be found at www.fda.gov/Safety/Recalls/ucm227202.htm. (September24, 2010)

Pioglitazone/Bladder Cancer Link

Sparks Safety Review

The FDA has begun a safety reviewof the diabetes drug pioglitazone(Actos) after early results from anongoing, long-term epidemiologicstudy indicated an increased risk ofbladder cancer for patients with thelongest exposure to pioglitazone andthose with the highest cumulative doseof the drug. The 10-year observationalstudy is being conducted by the manu-facturer, Takeda Pharma ceuticals ofNorth America, Inc, and these findingsstem from 5-year data. The agencyemphasizes that it has not concludedthat the drug increases the risk of blad-der cancer and that their review isongoing. Healthcare professionalsshould continue to follow the prescrib-ing recommendations in the drug label,and patients should continue to takethe drug until otherwise advised bytheir physician. (September 17, 2010)

FDA Lights into E-Cigarette

Manufacturers

The FDA has moved to regulateelectronic cigarettes and at the sametime issued warning letters to 5 elec-tronic cigarette distributors for vari-ous violations of the Federal Food,Drug, and Cosmetic Act. In general,FDA approval is contingent on a man-ufacturer demonstrating that a prod-uct is safe and effective for intendeduse, and that manufacturing methodsare adequate to preserve the strength,quality, and purity of its product. TheFDA has not reviewed the evidencereporting the companies’ claims thattheir products help users quit smok-ing, but in a letter to the ElectronicCigarette Association, it stated that“the FDA invites electronic cigarettefirms to work in cooperation with theagency toward the goal of assuringthat electronic cigarettes sold in theUnited States are lawfully marketed.”Certain companies were also warnedfor including unapproved liquidforms of drugs in their inhalers.(September 9, 2010)

Lymphadenopathy Added to

Cervarix Adverse Reactions

The FDA approved a request byGlaxoSmithKline Biologicals to supple-ment its Biologics License Applicationfor human papillomavirus (HPV)bivalent (types 16 and 18) vaccine(Cervarix) to add lymphadenopathy tothe Adverse Reactions, PostmarketingExperience Section of the prescribinginformation. Cervarix was approved inOctober 2009 for the prevention of cer-vical pre-cancers and cervical cancerassociated with oncogenic HPV types16 and 18 for use in girls and youngwomen (aged 10-25 years). (September2, 2010)

FDA UPDATES

3VOL. 1 NO. 5 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)


4 I VALUE-BASED CANCER CARE I October 2010 VOL. 1 I NO. 5

PublisherNicholas [email protected]

Associate PublisherMaurice [email protected]

Directors, Client ServicesJohn [email protected]

Phil [email protected]

Cristopher Pirescris@engage hc.com732-992-1896

Editorial DirectorDalia [email protected]

Managing EditorColin [email protected]

Senior Production ManagerRobyn Jacobs

Business ManagerBlanche Marchitto

October 2010 Vol. 1 No. 5

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 applied for August 2010.

Contact Information:For subscription and reprint information please contact: [email protected]: 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: [email protected] 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 SUBSCRIPTIONS OR CHANGEOF ADDRESS should be directed to CIRCULA-TION DIRECTOR, Value-Based Cancer Care, 241 Forsgate Drive, Suite 205A, Monroe Township,NJ 08831. Fax: 732-992-1881. YEARLY SUBSCRIP-TION RATES: One year: $99.00 USD; Two years:$149.00 USD; Three 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

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

FDA Updates

3 Glass Flakes Spur Recall of Some Epoetin Alfa

Pioglitazone/Bladder Cancer Link SparksSafety Review

FDA Lights into E-Cigarette Manufacturers

Lymphadenopathy Added to Cervarix AdverseReactions

Value Propositions

8 Stopping Hospice Care Boosts HealthcareCosts

Similar Thoughts on Cancer Costs in theUnited States and Canada

Hard Times Bring Medication Discontinuance

Economic Downturn Threatens CancerPrevention Gains

Cancer Quick Takes

9 Cancer Costs: What Do Patients, PhysiciansThink?

Higher Quality Care, But Later Diagnosis, for Uninsured Breast Cancer Patients

Myelodysplastic Syndromes Common and Costly

Health Economics

10 Real-World Decision Makers DecryInformation Provided

11 Improving Health Economics Research

Commentary

17 CMS-FDA Proposed Premarket ParallelReview—The Devil is in the Details

18 Who Decides on Healthcare Value?

Colon Cancer

20 CRC Screening Economics: DiminishingReturns as Technology Advances?

As Economy Worsens, Financial Factors MayHinder CRC Screening

VBCC Perspective

22 Resource Allocation for Colorectal CancerScreening/Naimish Pandya, MD

Continuing Education

24 Maintenance Therapy for Non–Small-CellLung Cancer: A Value-Based Approach toImprove Patient Care and Outcomes, Part I

In this issue...

“CER will be an addition to the informa-

tion available and could leave con-

sumers better off—in some instances,

it could lead to lower prices.”

—David Meltzer, MD, PhD, from “Improving HealthEconomics Research,” page 11

TABLE OF CONTENTS


the sponsor will conduct postmarketingtrials. If the sponsor fails to conductthese trials, or if they do not confirm clin-ical benefit, the FDA can revoke the AAand remove the drug from the market.

GAO Finds Fault

AA has not been without its prob-lems and detractors, one of which is theGovernment Accountability Office(GAO). Last year, it took the FDA totask with a report that concentrated onsurrogate end points. The report notedthat the FDA granted 90 AAs (79 forcancer) based on surrogate end pointsfrom 1992 through the end of 2008 andthat 69 of the 204 drugs approved viathe traditional process were newmolecular entities, many for cancer. Ofthe 175 postmarketing studies request-ed, half have been closed as ofFebruary 2009.

The GAO report concluded that“weaknesses in FDA’s monitoring andenforcement process hamper its abilityto effectively oversee postmarketingstudies.” Moreover, the agency doesnot consider this oversight a priority.

Even more troublesome, the FDA hasthe authority to remove a drug fromthe market if a sponsor does not com-ply with the law, but it has not speci-fied the conditions under which itwould do so. “It has never exercised itsauthority, even when study require-ments have gone unfulfilled for nearly13 years,” the report stated.

The GAO recommended that theFDA commissioner clarify the condi-tions under which the agency wouldexercise its authority.

Two Examples of AA Gone Awry

Gemtuzumab (Mylotarg) was grant-ed accelerated approval in May 2000

for the treatment of acute myeloidleukemia. However, postmarketingstudies cast doubt on the agent’s effec-tiveness and a shadow over its safety.

Accelerated Approval... Continued from cover

REGULATORY


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

Continued on page 6

at a glance� Accelerated approval (AA) can

allow earlier availability of drugs,

but the programs necessitate

proactive follow-up by manufac -

turers and regulators.

� The FDA decides whether a

surrogate end point in AA is

acceptable for a clinical trial,

based on whether the end point

is reasonably likely to predict a

real clinical end point.

� Current FDA oversight of the

AA process has been deemed

lacking by the Government

Accountability Office, especially

regarding surrogate end points.

“When lives are at stake, we need tomaintain a regulatory system that ensuresthat perfect is not the enemy of good, oranalysis is not the enemy of action.”

—Kip Piper, MA, FACHE


REGULATORY


Initial approval was granted on thebasis of surrogate end points in 3 clinicaltrials with a total of 142 patients. A con-firmatory trial with 627 patients wasbegun in 2004 to determine if adding

gemtuzumab to standard chemothera-py would improve survival. The trialwas stopped early because in additionto not being proved more efficacious,more patients in the gemtuzumab study

arm died than in the control arm.Moreover, gemtuzumab was associatedwith an increasing incidence of veno-occlusive liver disease.

A second trial of 1100 patients con-

firmed the dismal results. As a result,gemtuzumab will be withdrawn as ofOctober 15, 2010.

In the case of bevacizumab, at theirJuly 20 2010 meeting, members ofODAC reviewed 2 postmarketingstudies comprising almost 2000patients and concluded that beva-cizumab does not favor benefit overrisk. Specifically, there was no addi-tional OS or time to disease progres-sion, and the agent caused significantserious side effects.

Bevacizumab is a highly lucrativesource of income for Roche: $6 billionin annual sales, $1 billion of whichderives from breast cancer. Even if theFDA withdraws approval, it could stillbe used off label for that indication.However, Medicare and most privateinsurers would refuse to reimburse forit, and at a cost of upwards of $50,000per year, few patients could afford it.

Picture Not All Bleak

Kip Piper, MA, FACHE, President,Health Results Group, Washington,DC, is positive about the AA process.“No regulatory process is perfect, butthousands of lives have been savedbecause treatments for cancer andother life-threatening conditions re -ceived expedited approval. From apop ulation health perspective, the ben-efits of AA far outweigh the risks.”

Unfortunately, he added, we live in arisk-aversive, fear-centric country. “Ex -cep tions get amplified, small risks areexaggerated, scientific nuances areobliterated, clinical context is lost in the24-hour news cycle, and costs are con-fused with benefits.”

For life-threatening conditions, pri-ority must be on ensuring that patientshave maximum access to treatments,but premarket studies will nevermatch the scope of postmarket clinicalexperience.

Patients may be negatively impactedby an on-again, off-again AA process.“But when lives are at stake, we needto maintain a regulatory system thatensures that perfect is not the enemy ofgood, or analysis is not the enemy ofaction,” he said. �

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

Accelerated Approval... Continued from page 5

“Thousands of lives havebeen saved... . From a pop -ulation health perspective,the benefits of AA faroutweigh the risks.”

—Kip Piper, MA, FACHE


COMPARATIVE EFFECTIVENESS RESEARCH


Mr Sweet to discuss the preliminary out-comes and lessons learned.

What is the genesis of the WellPointCER formulary process?

WellPoint had been working withHealthcore, Inc, a Delaware-based clin-ical outcomes research firm, since thelate 1990s, before ac quiring the compa-ny in 2003. Healthcore re searchersstudy the real-world safety and effec-tiveness of drugs, medical devices, andcare management interventions to sup-port evidence-based medicine, productdevelopment decisions, coverage deci-sions, and overall cost-effective care.Our alliance with them has been help-ful in identifying the data elementsmissing from traditional researchefforts that would be used for coveragedecisions and how they could be addedto comparative effectiveness efforts.Healthcore researchers are kept sepa-rate from the WellPoint Pharmacy &Therapeutics (P&T) Committee, how-ever, to avoid any conflict of interest.

Why this change now?Data beyond that produced by ran-

domized clinical trials (RCTs) are need-ed. Although RCTs have strong scienceand produce very good evidence, theypossess significant limitations thatdon’t give us insights as to what couldhappen when the drug is released intothe real world.

In addition, using these types of out-comes reflects the global call for betteroutcomes data that has occurred overthe past 15 to 20 years, as witnessed bythe National Institute for Health andClinical Excellence in the UnitedKingdom and like-minded health eco-nomic efforts in Australia and Toronto,Canada.

How does the WellPoint outcomes-based formulary work, and howdoes it differ from other types offormularies?

Rather than focusing on surrogatemarkers that a physician would use totrack progress in clinical practice, suchas whether a drug lowers blood pres-sure or hemoglobin A1C, WellPointinstead looks at end points such as didheart attack or stroke rates go down,were the number of nephropathies orretinopathies reduced, did we putpeople back to work, did we keepthem out of the hospital, did wereduce the emergency departmentvisit rate, or did we improve theirquality of life? Clinical markers areimportant, but they don’t always cor-respond to an end point that mattersto patients. The basis of the formulary

is that we are utilizing end points thatreally matter to patients to make cov-erage decisions.

In terms of the mechanics of theprocess, WellPoint has a formal druginformation specialist team (comprisedof pharmacists and doctors of pharma-cy) that regularly monitors and evalu-ates the literature, the US Food andDrug Administration website, other

government websites, and the websitesof pharmaceutical firms. They alsomonitor the drug pipeline using ap -proximately 30 informational sources tokeep up with new drugs, as well as newindications for existing drugs. The drugevaluation team rates both clinical andcost impact on a scale of 1 to 3, becausewe understand it’s about value, not justclinical end points. Employers are con-cerned with improving the health andproductivity of their members, andthese improvements have a directimpact on their costs.

To further draw in the real-worldperspective, Healthcore has developedthe Integrated Research Network,which registers practicing physiciansin both general practice and specialties(eg, rheumatology, cardiology, endo -crinology, psychiatry, oncology, andgastroenterology) to serve as subjectmatter experts on a particular study.These physicians will advise on thetypes of data to be collected, recordclinical information, and participate inprospective and comparative effective-ness studies.

In addition, WellPoint consults withnational physician communities thatweigh in on the type of evidence thatwould be appropriate for making ahealthcare decision. The process is anopen one, and we have been very trans-parent in publishing what we accept asevidence in making a coverage decision.

As part of the CER process, theInstitute of Medicine established apriority-setting agenda. DidWellPoint do the same?

WellPoint works with Healthcore toprioritize research efforts, includingannual planning on drug categories tobe reviewed and identifying whereRCTs might be leaving gaps in out-comes or safety information. Although

we don’t do a CER study for everydrug category, we do focus on the oneswith these information gaps, or if thereis something that has a really high-profile impact on our population.

What, if anything, are your customerssaying about your use of CER? Dothey even notice or care?

Although most employer customersare not aware of this procedural shift, ithas caught the attention of the drugindustry. Our newly published formu-lary criteria detail what kinds of studiesare appropriate, how they will be grad-ed, and what studies will be thrownout. But at least 1 customer so far hasrenewed with WellPoint because of thisCER effort. In this age of health reform,everyone is asking for better health andproductivity and better value for theirhealthcare dollar, and nothing caninform us better than this type of work.

How often is CER incorporated intothe WellPoint decision-makingprocess?

Roughly 50% of our reviews at thispoint include some sort of CER/totalcost of care/health outcome analysis.We do select 2 to 3 categories of drugseach quarter that would be suitable forthis work, and focus on them. WhetherCER is used depends on the drug cate-gory and the answers we are gettingwith traditional research.

What have been the early lessonslearned regarding using CER?

As CER and observational studiesbecome more common, it is essential tohave appropriate critical appraisal andevidence review standards. Until thishappens, there may be instances wherepoorly designed studies are used to

make decisions or well-designed CERstudies are thrown out. It is for this rea-son that we emphasize the transparen-cy of our guideline process, where it isclear what comprises a well-designedstudy and what evidence will beaccepted in the process.

Second, we wouldn’t ever want tosee a CER study in itself be used tomake a decision. Randomized trials arestill the gold standard for efficacy, safe-ty, and tolerability, and where these fallshort regarding health and productivi-ty data, CER studies can add to thebody of evidence. But CER observa-tional and claims data also have limita-tions, so decision makers will need tolook at the entire body of evidence, andthen triangulate around to ensurewe’re making the best decision withthe evidence today.

Third, coverage or formulary deci-sion evaluations should never be timestamped; instead, these should drawon a continuous quality improvementmodel. We make provisional decisionsbased on available evidence, and thenreview new evidence as it comes out—even if it is a month later, we’ve got todo the right thing so we protect thehealth and safety of our members.

How available so far is the CERevidence you want to use?

Although CER data are available,we’d like to see more. Most (90%) ofthe evidence reviewed by the Well -Point committee is coming from ran-domized trials, but the body of CERevidence should increase in the nextseveral years.

Has using CER caused you toexpend more resources (ie, finding,interpreting, and evaluating) onthese studies compared withtraditional studies?

WellPoint has retained the samenumber of drug information evalua-tors, but did add 2 CER style analystslate last year to help analyze data andbring them to the WellPoint P&TCommittee. In addition, Healthcorehas been adding resources in healthoutcomes and comparative effective-ness research. �

Adding Comparative Effectiveness... Continued from cover

at a glance� WellPoint has instituted a

formal process of using

comparative effectiveness

research (CER) in their formulary

decision-making.

� CER is helpful in identifying

the data elements missing from

traditional research efforts and

supplementing information

gathering.

� At this point, CER is used in

roughly 50% of WellPoint’s

reviews, and more CER

evidence should be available in

the next several years.

We have been verytransparent in publishingwhat we accept as evidencein making a coveragedecision.

We make provisionaldecisions based on availableevidence, and then review new evidence as it comes out—even if it is a month later.



VALUE PROPOSITIONS

Stopping Hospice Care Boosts Healthcare CostsCare costs for patients who disenrolled from hospice care were nearly

5 times higher than for patients who remained with hospice, a new studyfinds (J Clin Oncol. 2010;28:4371-4375). Medicare data from 90,826patients with cancer served by 1384 hospices were analyzed, and nearly11% of patients disenrolled from hospice care. Nearly 34% of disenrolleeswere admitted to an emergency department (vs 3.1% who remained inhospice) and nearly 40% were admitted as hospital inpatients (vs 1.6% inthe hospice group). Overall costs from time of hospice enrollment untildeath were $6537 in the hospice group versus $30,848 among those leav-ing hospice.

Similar Thoughts on Cancer Costs in the UnitedStates and Canada

A survey comparing US (n = 1355) and Canadian (n = 238) oncologists’attitudes toward costs, cost-effectiveness, and health policies regardingexpensive cancer drugs (J Clin Oncol. 2010;28:4149-4153) finds attitudesgenerally similar despite the differences in healthcare systems. The over-all response rate was 59%; more US than Canadian oncologists favoredaccess to effective treatments regardless of costs (67% vs 52%), and moreCanadians favor access to treatments only if they are cost-effective (75%vs 58%). A majority of oncologists favor expanded use of cost-effective-ness data in coverage decisions (80% US, 69% Canadian), but fewer thanhalf in both countries feel well-equipped to use this information.Determining the value of drugs should be the responsibility of physiciansand nonprofit agencies, as indicated by oncologists in both countries.

Robots Taking Over as Cost Driver“It is unlikely that robot-assisted surgeries will completely replace con-

ventional surgeries for the full range of procedures for which cost studieshave been done. If such a substitution did occur, however, it would gen-erate nearly $1.5 billion in additional healthcare costs annually—exclud-ing the (amortized) cost of the robots, which would bring the total tomore than $2.5 billion.”

—From a perspective in the New England Journal of Medicine(2010;363:701-704) examining the reasons for growth in robotic surgery use andthe associated costs. The authors suggest that comparative effectiveness researchcould rein in the fragmented decision-making that has led to this growth. Alsosee Value-Based Cancer Care, September 2010, page 19, for more on roboticsurgery in prostate cancer.

New Healthcare Environment Demands NewFocus on Costs

“The exciting explosion in new medical treatments creates an economicchallenge that cannot be ignored. The pricing of medications and otherinterventions is one issue to consider, but the range of patients in whomthe treatments are used—beginning with patients in whom the treat-ments may be most beneficial and cost-effective but rapidly expanding tothose for whom the benefit and cost-effectiveness may be less clear—should also be considered.”

—From an editorial in the New England Journal of Medicine (2010;363:1278-1280) discussing a study showing clinical benefit in fondaparinux(Arixtra) use for superficial-vein thrombosis in the legs. Even with positive clin-ical findings, the economic component of drug therapies cannot be overlooked,the authors say, and they recommend that the FDA push for “phase 3.5 trials”to document cost, quality of life, and cost-effectiveness of new therapies.

Hard Times Bring Medication DiscontinuanceA letter to the editor in the August 5 issue of the New England Journal of

Medicine (2010;363:596-598) describes how 3 patients of a California prac-tice who had metastatic gastrointestinal stromal tumor discontinued ima-tinib therapy as a result of economic hardship. High-dose imatinib canrestore control to tumors refractory to other treatments, but the retail costcan exceed $4500 per month. One patient discontinued treatment becauseof decreased earnings; the second patient was unable to purchase anaffordable insurance policy because of the preexisting condition, and thelast patient stopped taking the drug after his business failed. The practicenow emphasizes the importance of medication adherence, referringpatients to social workers and financial counselors, and providing infor-mation about drug manufacturers’ patient-assistance programs.

Economic Downturn Threatens CancerPrevention Gains

A special issue of the European Journal of Cancer (September 2010;46[14])focused on cancer prevention considers a number of ways that economicpressures fostered by the current global financial crisis could impact can-cer rates. Public donations to cancer research and government and indus-try funding of research may decrease, and occupational exposure to car-cinogens may increase as safety shortcuts are taken, thereby boostingcancer rates. On the reduction side, people may reduce unhealthy andcancer-causing habits to reduce personal expenditures, or governmentsmay increase taxes on unhealthy goods such as tobacco.

Putting Economic Reality into MedicalClassrooms

A JAMA commentary (2010;304:1229-1230) urges that medical educa-tion be expanded to include economic considerations as part of the cur-riculum. The authors argue that a core, required course covering econom-ic factors that shape medical research, available treatments, developmentof clinical guidelines, and definition of diseases, as well as the playersaffecting cost and consumption, and the interactions of these forces,should be created. Second, a revision of the medical school curricula thatreflects the core course should be undertaken. Instead of considering eco-nomic forces as extraneous, physicians need to realize their dual role aspatient advocates and allocators of resources, the authors say. Also see“Guiding Patients Through Cost-Based Treatment Choices” (cover) formore on physician–patient economic discussions.

NIH Makes Pharmacogenomics PushTargeting drug therapies through genomic information can improve

patient outcomes, and the National Institutes of Health (NIH) has recent-ly announced several grants that will foster research in the area of phar-macogenomic research. The first one, a $15-million grant over 5 years,will support the Pharmacogenomics Knowledge Base (PharmGKB),which began in 2000 as a catalog of links between human genetic varia-tion and drug responses. PharmGKB genetic information was used by aworldwide team of researchers in 2009 to better predict optimal warfarindosing. A second grant of $161.3 million over 5 years will expand thePharmacogenomics Research Network, which has already discoveredgene variants linked to responses for treating several cancers, heart dis-ease, asthma, and nicotine addiction.



CANCER QUICK TAKES

Cancer Costs: What Do Patients,

Physicians Think?

A literature review on patient andphysician attitudes re garding commu-nication on the cost of cancer carefinds that limitations—on what isknown about these communications,and on techniques and tools toimprove it—hamper discussions, evenas costs continue to rise (J Oncol Pract.2010;6:188-192).

Costs have intruded into decision-making, say the authors, with oncolo-gists reluctant to bring up intrusivetopics or ones for which they have nosolution. And despite ASCO issuingguidance stating that “discussion of costis an important component of high-quality care,” there is little evidence onpatient perspectives on the costs of care.

Tools and techniques to foster discus-sion include prompt lists (question-naires that suggest topics for discussiondistributed in waiting rooms), decisionaids, a greater willingness on the part ofphysicians to broach the cost discus-sion, and directly providing patientswith information on costs. Beyond this,physicians must be ready to discussalternative treatment strategies if costdiscussions indicate that patients can-not afford a suggested treatment.

Higher Quality Care, But Later

Diagnosis, for Uninsured Patients

Uninsured California women withbreast cancer treated under the Breastand Cervical Cancer Treat ment Pro -gram (BCCTP) generally receivedhigh-quality care, but these womenalso presented at a later disease stage(J Clin Oncol. 2010;28: 3479-3484).

The authors examined quality ofcare using 29 evidence-based qualitymeasures developed for the NationalInitia tive for Cancer Care Quality(NICCQ), studying 658 women withstage I to III breast cancer who receivedcare under the state/federal program.Adherence to recommended careranged from 87% for posttreatmentsurveillance to 97% for diagnostic eval-uation; on average, patients received93% of recommended care, a rate thatbested all but one of the NICCQdomains. For 4 of 5 measures address-ing the need to provide patients withinformation on diagnostic and treat-ment options, adherence was lowerthan 85%. Twenty-three percent of thecohort presented with stage III cancer,a point that “underscores the chal-lenges in obtaining timely diagnosis inan uninsured population,” even whenprograms like BCCTP exist, say theauthors.

Myelodysplastic Syndromes

Common and Costly

Myelodysplastic syndromes (MDS)are a common and costly hematologic

malignancy of the elderly, and patientswith this disease are at greater risk ofcomorbidities (J Clin Oncol. 2010;28:2847-2852).

Authors conducted a retrospectivereview of Medicare claims–identifiedpatients newly diagnosed with MDSin 2003, and followed them for 3years, recording comorbidities dur-

ing that period.In the 3-year follow-up period, 76.8%

of patients with MDS were hospital-ized, nearly 80% had at least 1 emer-gency department visit, and almost40% received growth factor treatments.Medicare payments for patients withMDS were substantially higher in eachof the 3 years, with payment spiking in

the first year after diagnosis ($16,181compared with $1575 for a non-MDSMedicare beneficiary). This more than10-fold greater expenditure alarms theauthors, who write, “As the US popula-tion continues to age, MDS will becomea more prominent medical problemwith a significant impact on the health-care system.” �

Copyright © 2010 US Oncology, Inc. All rights reserved.

UNITEDWE HEAL

IN THE WAR ON CANCER, THERE’S ONLY ONE SIDE.

With a unique focus on supporting the patient throughout their care continuum, Innovent Oncology

offers health plans and oncology practices a comprehensive solution that enhances the quality and

consistency of patient care. With evidence-based medicine as the foundation of the program, we

further help patients by providing direct, personalized support and education between office visits

as well as advance care planning regarding future treatment and care preferences. Through this

patient-centric approach, we help health plans and oncology practices collaborate by aligning

incentives to drive better patient outcomes as well as encourage the efficient use of healthcare

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

To learn more about how Innovent Oncology is transforming cancer care, visit us at innoventoncology.com or call 866-214-2194.


HEALTH ECONOMICS


Atlanta, GA—A plenary sessionbilled as a “candid discussion with

medical and pharmacy directors” onthe value of health economics researchin real-world decision-making provedto be all that and more, with several ofthe managed care medical directors onthe panel taking issue with the type andquality of health outcomes researchsupplied by researchers and the phar-maceutical industry.

Even as he acknowledged the healthservices research expertise of the audi-ence members at the InternationalSociety for Pharmacoeconomics andOutcomes Research (ISPOR) meeting,Albert J. Rizzoli, MD, a medical direc-tor at Presbyterian Health Plan inAlbuquerque, NM, also expressedskepticism regarding their work,because decision makers such as him-self only see a very small part of whatthose researchers do. “Largely, whatwe see in managed care are pharma-coeconomic models that are brought tous by the pharma industry,” he said.“That’s almost entirely what we see.”

Models Lack Real-World

Connection

There is a disconnect between mod-els and real-world experience thatoften leaves the real world not meetingbest-case modeling assumptions, DrRizzoli argued. For a model to actuallywork, “the best result has to happenfrom…linked studies,” he said. Modelsalso often consider indirect costs andtout the importance of the employer’sperspective, said Dr Rizzoli, but thesefactors are difficult for managed caredecision makers to digest. Studies fre-quently emphasize the importance ofthe treatment on the patient’s quality oflife, he said, and seem to say, “we knowthis costs a lot of money, but thinkabout the quality of life,” with theimplication that if the quality of life isimproved, the medical care costs willbe lessened.

Another difficulty is presented by thecurrent US Food and Drug Admin is -tration approach of comparing drugswith placebo, which makes it necessary

for a decision maker to compare oneplacebo study with another, Dr Rizzolisaid. There is very little comparison ofnew therapies to existing products, sothere is no way of knowing whether thenew product provides any advantageover an existing product.

The research time frame is also anissue, Dr Rizzoli said. Companies mayoffer an argument for long-term returnon investment—usually many years—

but “in managed care, we’re lookingfor return on investment over a shortperiod of time,” he said. Despite argu-ments about the positive impact of effi-cacious treatments to the broaderbudget, pharmacy costs are still con-tained in a silo. Dr Rizzoli knows “bet-ter than anybody that everything wedo has an effect on the entire system,”but that’s still not the way the worldlooks at it. “You don’t get much creditfor medical cost-savings,” he lamented.In addition, Dr Rizzoli worries thatwidespread off-label use distorts cost-control efforts, as do coupons andcopays offered by manufacturers,which allow patients to get arounddrug tiering systems.

Concern for Economic End Points

From the perspective of Kenneth L.Schaecher, MD, a medical director withSelectHealth in Salt Lake City, UT,health outcomes research represents anattempt to add an economic end pointto studies that are traditionally clinical-ly focused, thereby creating economicvalue. But in his eyes, those end pointsare rarely pertinent. “If you don’t giveus anything pertinent, we’re going tomake the best decisions we can. We’renot trying to ration care,” he said,adding that when controlling cost is

part of the mission, “you’re going tomake a conservative decision.”

“Gleevec was a game-changer,” DrSchaecher pointed out, but “the fifthARB [angiotensin receptor blocker] inthe class was not a game changer.”Nevertheless, health services researchwas used to support both drugs,despite only 1 truly being innovative,he said. “We are a cynical, skeptical lotin the insurance industry,” he acknowl-edged.

John Watkins, RPh, MPH, a pharma-cy manager in formulary developmentat Premera BlueCross, a network planin Seattle, WA, also worries aboutslanted studies. “It’s a no-brainer—funding bias is something forefront inour mind,” he said, pointing out thatstudy funders get to control the framearound that study. Nevertheless, 2-way communication and some level oftrust must be developed. He empha-sized that when his group evaluatesstudies, they try not to be cynical, butwill give a fair hearing to the evidencepresented. At Premera, Mr Watkinsshows a model’s decision-analytic treeto his clinical experts and asks if itresembles how patients are treated. Ifit bears no real-world resemblance, itgoes no further.

A final panelist, Harold “Hank” L.Gardner, MD, at HCMS group inCheyenne, WY, argued for less com-plexity and the primacy of the con-sumer. How do outcomes get translat-ed into verbiage that patients andbusiness managers at employers canunderstand, he asked.

Putting Meaning to Models

Overall, Mr Watkins took a morecharitable view of relationships be -tween pharma, healthcare researchers,and decision makers, and offered sev-eral suggestions about what might bedone to improve them. First, he sug-gested, manufacturers should keepseveral pragmatic questions in mind.

“What is the decision that [decisionmakers] need to make, what data dothey need to properly inform thatdecision, and how do I get from thereto studies that will provide that infor-

mation?” he asked. He suggested it isessential to keep in mind who thedecision maker is and who the enduser is, because this may influence themodel used.

Mr Watkins said he would like toraise the bar in cost-effectiveness mod-eling studies by having clinical andeconomic end points included in thetrial design, and making sure the stud-ies are adequately powered for theirend points. The outcomes researchdevelopers should be at the table whenthe trial registration process is beingplanned, he argued.

Changing Models’ Focus

Dr Schaecher had several sugges-tions. First, health outcomes researchshould include appropriate financialoutcomes related to the therapy andthe intended population. Conductingstudies that will get a drug coveredwill also be increasingly important,and when those studies are conduct-ed, they will be considered and maychange his firm’s policies, DrSchaecher said. “Evidence that showsquality will lead to an improvementin cost of care over time,” he said. Inaddition, it is important not to settlefor surrogate end points when it ispossible to measure meaningful endpoints.

For Dr Rizzoli, the minimum re -quirement is that models should betransparent, understandable, and focusonly on cost and utilization. “We havea hard time quantifying quality of lifeand translating that into financialdata,” he emphasized. And althoughthe National Institute for Health andClinical Excel lence in the UnitedKingdom has engendered much con-troversy, Dr Rizzoli said that this maybe an approach worth trying. “We des-perately need that kind of model in theUnited States. We need somebodyobjective,” he argued.

During the question session, MiltWeinstein, PhD, of Harvard Univer -sity, indicated disbelief at what hewas hearing from Drs Rizzoli andSchaecher, saying it sounded like theydid not care about outcomes, but onlyabout costs. Marc Berger, MD, of EliLilly, pointed out that insurers haveonly recently started to ask for betterevidence, and he echoed the impor-tance of a skeptical, not cynical,approach to evidence by decisionmakers and “the need for good dia-logue. If there’s cynicism on eitherside, we’re not going to get where weneed to get to.” �

Real-World Decision Makers Decry Information ProvidedHealth economics tools often difficult to applyBy Colin Gittens

“What is the decision that [decisionmakers] need to make, what data do theyneed to properly inform that decision, andhow do I get from there to studies thatwill provide that information?”

—John Watkins, RPh, MPH

“We have a hard time quantifying quality of life and translating that intofinancial data.”

—Albert J. Rizzoli, MD


How would you respond tocomplaints on the utility of healtheconomics research?

It is true that some branches of aca-demic economics sometimes valuetheoretical insights and technicaldetails over pragmatic results that canbe broadly applied. However, most ofthe core insights of economic analysistend to be accessible and have highlypragmatic implications. An importantpart of the art of being a good econo-mist is being able to crystallize com-plex ideas down to their essence andthen explain them to others. Goodteachers have to do this, and so dogood researchers and others who wishto see sophisticated economic argu-ments translated into practice. In allthese cases, the key is simplifying theidea to its essence so that the basicintuition behind an insight can beexplained. After that, additional com-plexities can be explored if need be.

Health economics studies oftenemphasize a long-term time framefor outcomes and return oninvestment, but managed careorganizations [MCOs] and insurershave shorter outlooks—quarterly oryearly. Can these perspectives bereconciled?

Incentive problems are real, and thesolution is good public policy. Say there

is an operation that is an investmentnow and saves money in the future (eg,bariatric surgery). Any insurer thatpays for that is going to have to chargehigher premiums to cover costs, whichmeans that people looking to savemoney on their premiums will look

elsewhere. This puts that plan at a com-petitive disadvantage, because peoplewill sign up for the expensive policywhen they need the expensive treat-ment, and then switch to the cheaperpolicy once they’ve got it.

The solution is for the government tomandate coverage. The current marketis not a complete market—if that weretrue, you would have to pay a penaltyif you chose an insurance policy thatdid not cover this sort of treatment thatproduces long-run savings, and that’snot the case.

Can quality of life [QOL] bequantified better in healtheconomics studies?

I’m sure QOL can be quantified bet-

ter, and there are important limitationsin the current QOL measures, butthese are better than the immediatealternative—which is to not considerthem at all.

QOL is a hard thing to measure, andit certainly does have an idiosyncratic

element to it, but it is also an importantarea for research. It is the kind of thingthat both firms and the NIH [NationalInstitutes of Health] are interested in,and that people are interested in.

Do you see comparativeeffectiveness research [CER]changing the current practice ofcomparing placebo studies againstone another? Are head-to-headcomparisons in our future?

People who make coverage deci-sions and patients probably reallydo want these head-to-head trials,because they are the most meaning-ful. I don’t think they are the onlysort of evidence—approvals, forexample, should not be based on only

head-to-head trials. CER will be anaddition to the information availableand could leave consumers betteroff—in some instances, it could leadto lower prices and provide moreinformation for patients. It is going toprovide useful information about rel-ative value.

Can studies presenting economicend points be made more relevant?Can more meaningful end points,rather than surrogate end points,be used?

There is a challenge in thinkingabout economic end points and overallend points. The perspectives of an indi-vidual, an MCO, or society are all valid,but no single perspective is relevant toeveryone.

The field needs to move to multipleperspective studies—what are the costsand benefits to different parties whomight be affected by this? We need toknow what must be done in terms of aregulation or a subsidy for it to havethe desired effect. Take the example ofbariatric surgery. You can say this isgoing to save healthcare costs, but it’snot going to save them for MCOs, sowhy would they pay for it? What youwant to do is say this has societal ben-efits, and we need to figure out whowins and who loses so that the desiredthing happens. �

HEALTH ECONOMICS


Improving Health Economics ResearchA conversation with David Meltzer, MD, PhDDr Meltzer is with the Department of Medicine and the Harris School of Public Policy and Department of Economics, The University of Chicago

Most of the core insights of economicanalysis tend to be both accessible and to

have highly pragmatic implications.

www.ValueBasedCancer.comTo access all the great content from this innovative new publication please visit

and sign up for a free subscription.

NCCN Roundtable: Clinical andEconomic Issues Impacting Cancer Care Delivery “Collision course” in sight

©2010 Engage Healthcare Communications, LLCContinued on page 24

Baltimore, MD—A long-held businesstruism is that “if you can’t measure it,you can’t manage it.” The application of this belief to the oncology setting was demonstrated at a session of theAssociation of Community Cancer Cen ters’ (ACCC) 36th Annual NationalMeeting. Kimberly Bergstrom, PharmD,chief clinical officer for McKessonSpecialty Care Solutions, told attendeesof the growing importance of developingand using standardized chemotherapytreatment regimens, and of the tools that

can benchmark performance and fostercompliance with treatment guidelines.Public and private payers are mov-

ing to control exploding healthcarecosts, Dr Bergstrom told attendees,and because increased cost controlwas inevitable, it is in providers’interest to get a seat at the table. “It is an important topic, because

this is one of those things, if we don’tget a handle on it, it’s going to happento us,” she said. “People and groupsand organizations are going to startdictating how we provide cancer care,and we can’t let that happen.”

Hollywood, FL—Clinical practiceguidelines issued by the NationalComprehensive Cancer Network(NCCN) are followed by conscien-tious oncologists in their everydaypractice, but they are developedbased on clinical efficacy and withoutregard to costs. At a roundtable heldduring the NCCN’s 15th AnnualConference, moderator CliffordGoodman, PhD, Senior Vice Presidentat The Lewin Group, predicted, “Theappropriate use of evidence-basedguidelines is on a collision coursewith the financial nonsustainability ofthe healthcare system.”

Dr Goodmanalluded to a levelof frustration thathas never beenhigher in cancercare. “Too manypatients are stilldying young. Weneed innovations and a cure,” he said.But the inadequacy of current treat-ments for cancer is no longer the mainproblem. Equally challenging, he sug-gested, is finding a means to pay forthe ever-costlier care that threatens tobankrupt the healthcare system. As society struggles to find solu-

tions, “the ground is shaking beneathus,” Dr Goodman commented.

Continued on page 8



By Audrey Andrews

SEER-Medicare Database AnalysisConfirms Expensive ProstateCancers Gaining SupremacyBut cost-effectiveness of this move remains to be determined

San Francisco, CA—The popularity ofminimally invasive radical prostatec-tomy (MIRP), intensity-modulatedradiation therapy (IMRT), and ofbrachytherapy combined with IMRTfor prostate cancer started to take offafter 2002, a new database analysishas confirmed.At the American Society of Clinical

Oncology’s 2010 Genitourinary Can -cers Symposium, Paul L. Nguyen,MD, presented the results of histeam’s analysis of data from theSurveillance, Epidemiology and EndResults (SEER)-Medicare database.Dr Nguyen, director of Prostate

Brachytherapy, Dana-Farber/Brigham

and Women’s Hospital, HarvardMedical School, Boston, and his co-investigators found MIRP jumpedfrom 1.5% of radical prostatectomies(RPs) in 2002 to 28.7% in 2005. Theyalso found that IMRT soared from8.7% of external radiation treatmentsfor prostate cancer to 81.7%. In addi-

By Rosemary Frei, MSc

New Tools Arriving to Measure andManage Chemotherapy CareBusiness, clinical concerns now connected in value-focused approach By Daniel Denvir

Breast Cancer Survival Improves,Thanks to New Therapies

The 2010 Genitourinary CancersSymposium: Progress in Multi -disciplinary Management was heldMarch 5-7 in San Francisco. All ses-sions emphasized a multidisciplinaryap proach to care; a number of thembrought out the cost and value issuesassociated with caring for genitouri-nary cancers.

Value-Based Cancer Carewill be at the ASCO Annual Meeting, June 4-8, in Chicago. Please visit us at booth 18121

Barcelona—Survival for patients withmetastatic breast cancer has improveddramatically in the last 20 years, espe-cially in the subgroup of patients withHER2-positive tumors, according toresearch presented at the 7th European

Breast Cancer Confer ence (EBCC7).This improvement, the researcherssuggest, is due to in creased use ofanthracyclines and the rise of targetedtherapies.“There is no doubt that trastuzu -

mab (Herceptin), which targets theHER2 gene, is the most important

By Colin Gittens

www.ValueBasedCancer.com

��

Photo by © ASCO/Todd Buchanan 2009

Publicatus innovatus.

Website maximus.



HEALTH POLICY

particularly when existing practices arechallenged. This seems more likelywhen health policy issues are highlysalient to industry, professional, andconsumer organizations.

With the adoption of US healthcarereform and the future expansion ofgovernment-funded health insurance,healthcare costs will continue to be amajor concern for policymakers. Bothgovernmental and private purchasers

of care will continue to have to makedecisions about what services to payfor. Although analysts disagree aboutthe potential for CER to reduce health-care spending,7-9 the idea of using evi-dence to improve healthcare policydecisions enjoys support from a broadrange of actors.8,10-13 Nevertheless, thestrong negative reaction to the 2009mam mography recommendations fromthe USPSTF is a powerful signal thatthe implementation of CER and EBMcan encounter great resistance, particu-larly when this research suggests thatbroadly accepted healthcare technolo-gies that have been promoted by thehealthcare community and patientadvocates may not be worth the cost.Although, to date, controversies re -garding practice guidelines have beenunusual, the conditions that producedthe objections in the mammographycase could become more important,and more common, as the use of CERand EBM is extended.

The USPSTF did not base its mam-mography recommendations on possi-ble cost-savings, but proponents ofCER and EBM often claim that thisresearch will reduce spending by elim-inating unnecessary care.8 The reac-tions to the mammography recom-

mendations suggest that the healthservices research community needs tounderstand better what the publicbelieves about evidence and ways thathealthcare costs might be constrained.Greater focus on likely public reactions

may encourage the research communi-ty and entities like the USPSTF to workwith the media, anticipate possiblemisinterpretations, and reduce publicanxiety. Leaders at the Agency forHealthcare Research and Quality and

the USPSTF appear to be moving inthat direction already by providingadditional opportunities for publiccomment on forthcoming recommen-dations, which will be posted atwww.preventiveservices.ahrq.gov.14

Breast Cancer Screening... Continued from cover

at a glance� Comparative effectiveness

research and evidence-based

medicine that challenge existing

practices are difficult to implement.

� Health services researchers

need to understand public beliefs

about evidence and ways to

constrain healthcare costs.

� Providing opportunities for

public comment may help build

support.

Indication

ZOMETA is indicated for the treatment of patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy.

Highlights from the Important Safety Information

ZOMETA is contraindicated in patients with hypersensitivity to zoledronic acid or any components of ZOMETA. Hypersensitivity reactions, including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock, have been reported. Patients being treated with ZOMETA should not be treated with Reclast® (zoledronic acid) as they contain the same active ingredient.

In patients with impaired renal function, the risk of adverse reactions (especially renal adverse reactions) may be greater. ZOMETA treatment is not recommended in patients with bone metastases with severe renal impairment. Preexisting renal insufficiency and multiple cycles of ZOMETA and other bisphosphonates are risk factors for subsequent renal deterioration with ZOMETA. Do not use doses greater than 4 mg. ZOMETA should be administered by IV infusion over no less than 15 minutes. Monitor serum creatinine before each dose.

Please see brief summary on the following page.

B

Z

References: 1. Lipton A, Zheng M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer. 2003;98:962-969. 2. ZOMETA Prescribing Information. Novartis Pharmaceuticals Corporation. 3. Aredia Prescribing Information. Novartis Pharmaceuticals Corporation. 4. Actonel Prescribing Information. Procter & Gamble Pharmaceuticals. 5. Boniva Prescribing Information. Roche Laboratories Inc. 6. Didronel Prescribing Information. Procter & Gamble Pharmaceuticals. 7. Fosamax Prescribing Information. Merck & Co. 8. Skelid Prescribing Information. sanofi-aventis US LLC. 9. Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer. 2000;88:1082-1090.

© 2010 Novartis

This article was adapted from “Evidence andFear: Navigating the Politics of Evidence-BasedMedicine,” which ap peared in the June 2010issue of AcademyHealth Reports. To read thefull article, please visit www.academyhealth.org/f i les/publ icat ions/academyhealthreports/AHReportsJune2010.pdf.


Providing such opportunities forpublic comment may help the healthservices research community buildsupport for basing policy decisions andpractice guidelines on a strong evi-dence base and perhaps increase under-standing of and confidence in theresearch base for such decisions. The

new health reform legislation calls forestablishment of a methodology com -mittee to advise the Patient-CenteredOutcomes Research Institute, which ischarged with conducting CER. Themethodology committee is required to“develop and improve the science andmethods of comparative clinical effec-

tiveness research.”15 Establishing thecredibility of its methods among abroad array of stakeholders will notinsulate the new institute, or healthservices researchers more generally,from controversy. Never the less, estab-lishing broader support for the value ofhealth services research, coupled with

sustained efforts to communicate moreeffectively with the public, is crucial asthe United States grapples with howbest to improve the quality and efficien-cy of its health system. �

References for this article are listed on -line at www.valuebasedcancer.com.

HEALTH POLICY


Morethan of real-world

experience

YEARS

Metastatic renal cell carcinoma

Multiple myeloma

Metastatic breast cancer

Metastatic lung cancer and other solid tumors

Metastatic hormone-refractory prostate cancer

Because skeletal-related events (SREs)† can have devastating consequences, help protect your patients with ZOMETA

• ZOMETA may help reduce and delay SREs in more malignancies than any other bone-targeted agent1-8

April 2010 C-ZOM-100050

* ZOMETA should be used in prostate patients with bone metastases that have progressed after treatment with at least one hormonal therapy.

† SRE=skeletal-related event, defined as pathologic fracture, spinal cord compression, hypercalcemia of malignancy, and the need for radiation or surgery to the bone.9


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


COMMENTARY


On June 25, 2010, the Centers forMedicare & Medicaid Services(CMS) and the Food and Drug

Administration (FDA) entered into aMemorandum of Understanding(MOU) stating that the agencies willwork together to “promote initiativesrelated to the review and use of FDA-regulated drugs, biologics, medicaldevices, and foods, including dietarysupplements.”1 Quickly following upon the MOU, the agencies jointly pub-lished a notice on September 17,requesting comments regarding theagencies’ joint proposal to establish aprocess for “Parallel Review of MedicalProducts” (hereafter “parallel reviewnotice”) in the premarket setting.2

These coordinated actions taken byCMS and FDA will have dramaticimplications for the pharmaceutical,biotechnology, and device industries.

The CMS-FDA parallel review noticeproposes a new premarket process forinnovators to consider in lieu of thecurrent staggered process. The newprocess, if finalized, would be com-pletely voluntary. Currently, mostinnovators seek FDA approval andthen, after that approval is secured,coverage, coding, and reimbursementdecisions from CMS. The new processwould combine these sequential eventssuch that the innovator would haveboth market approval and nationalcoverage at the end of the sameprocess. Although superficially, thismay seem to be a “good government”initiative, this proposal in fact raisesmany significant issues for innovatorsbecause of the new analysis that eachsponsor must do on each asset, whichpotentially impacts the commercialviability for any given product.

Issues to Consider

The proposal states that the productsponsor will be able to decide whetheror not to engage in the process, yet italso contemplates the possibility ofallowing another party other than theproduct sponsor to be able to initiate arequest for the parallel review. Will theagencies allow a competitor, for exam-

ple, to ask for a parallel review? If so,how could such a system plausibly becalled “voluntary”? This raises ques-tions about what kinds of criteria theagencies will use in selecting the prod-ucts for the new review system.

Additionally, and perhaps of greaterconcern, is the effect this process willhave on clinical development. Forexample, should a sponsor decide notto volunteer for this process, whatguarantees will be put into place thatthis decision will not haunt the sponsorlater on? One can envision discussionswith either agency questioning thesponsor for not using the parallelreview process. During FDA delibera-tions, the agency could state that cer-tain problems could have been avoidedhad the sponsor chosen the parallelreview path.

The sponsor could face similar issueswith CMS should the process not beused. The process envisions a positivenational coverage decision (NCD)immediately or shortly after FDAapproval, and the proposal states that

this will expedite market uptake. Ittherefore seems reasonable to expect,given the tone and text of the proposal,that a sponsor ignoring parallel reviewshould expect the year-long NCDprocess once the product is approvedby the FDA. Ignoring the process, itseems, could easily result in significantdelays caused by either regulatoryagency.

Conversely, should the sponsor usethis process, it will necessitate jointmeetings with the FDA and CMS to dis-cuss, among other things, clinical trialdesign to ascertain the informationneeded for both FDA and CMSapproval. When negotiating a clinicaltrial program with the government on anew technology, how confident should

the sponsor be that the representatives(particularly CMS) on the other side ofthe table have a good understandingof the technology, the costs and bur-dens of clinical trial recruitment, andthe sponsor’s obligations to itsinvestors? A firm could leave this meet-ing with a recipe to make a unicorn.What is the sponsor to do then?

Shifting Regulatory Goalposts

Of further concern regarding thisnotice is the introduction of cost andquality data into the preapprovalprocess. As the notice states, and stat-ed above, the agencies believe theymust address a need to “speed[] con-sumer access to and spur[] develop-ment of new, affordable, reliable, safer,and more effective medical productsand services” (emphasis added).2 Al -though this may seem like somethingthat CMS would consider in coverageand payment decisions, it is a newconcept in the realm of the FDA, whichhas traditionally focused on “safetyand effectiveness.”

The CMS-FDA parallel review noticealso suggests possible future consider-ation of “comparative effectiveness” asthe agencies state in the notice that cur-rently “materials submitted by manu-facturers to FDA may not adequatelyaddress the issues of importance topayers . . . and the incremental clinicalutility of these products compared tocurrently available technologies.”3 Inaddition, the notice describes CMS’current NCD process as including areview of the product “as compared toalternative treatments or diagnosticsalready covered by the program”(emphasis added).3 Will the sponsorneed to demonstrate affordability andsuperiority in order to gain FDA andCMS approval?

Underlying these concerns is theuncertainty about if—and if so, how—the agencies will share data and furtherprotect confidential data between FDAand CMS as a product is reviewed.

As discussed above, the recentlypublished CMS-FDA notice andrequest for comments (which are dueno later than December 16, 2010) on theproposed parallel review process raisesnumerous and potentially significantissues for innovator companies.Should this process or something simi-lar be finalized, it seems to me that aspart of any due diligence process orclinical evaluation, one should ask whyor why not the sponsor decided to vol-unteer or ignore the parallel reviewprocess. �

References1. Memorandum of Understanding between UnitedStates Food and Drug Administration and Centers forMedicare & Medicaid Services. 75 Federal Register48699 (August 11, 2010). 2. CMS-FDA Parallel Review of Medical Products,Notice and Request for Comments. 75 Federal Register57045 (September 17, 2010).3. CMS-FDA Parallel Review of Medical Products,Notice and Request for Comments. 75 Federal Register57046 (September 17, 2010).

CMS-FDA Proposed Premarket ParallelReview—The Devil is in the DetailsBy Jayson Slotnik, JD, MPHMr Slotnik is an attorney at Foley Hoag, LLP, and an editorial board member of Value-Based Cancer Care.

Should a sponsor decide not to volunteer for this process,what guarantees will be put into place that this decision will not haunt the sponsor later on?

at a glance� A concurrent, parallel review by

the FDA and CMS is intended to

speed the regulatory process.

� This process holds serious

potential implications for

technical innovation.

� Comments regarding the

“Parallel Review of Medical

Products” are due no later than

December 16, 2010.

Representatives from Value-Based Cancer Care will be at the American Society of Hematology Annual Meeting

in Orlando, FL, December 4-7.

Please visit us at booth 150.

AcknowledgmentRoss Margulies assisted in thepreparation of this acticle.


VBCC_October_100810_Follow ASCO Tabloid 10/12/10 2:35 PM Page 19

COLON CANCER


Treating colon cancer is expensive,with a recent study estimatingthe cost 1 year after diagnosis at

$29,196 in a cohort of Medicare coloncancer patients aged 66 years and older.1

Reducing colorectal cancer (CRC) inci-dence through screening could restrain

these expenditures, and several recentstudies have pointed out screening’sbenefits. A 2006 study looked atwhether changes in Medicare’s reim-bursement policy to provide for cover-age of screening colonoscopies forpatients with increased risk for coloncancer (in 1998) and then for all individ-uals (in 2001) led to an increase incolonoscopy use or early-stage coloncancer diagnosis.2 Colonoscopy useincreased from an average of 285 of100,000 before the policy change to 1919of 100,000 after the change. The changeswere also strongly associated with can-cer being diagnosed at an early stage.

Rabeneck and colleagues conducteda naturalistic, 14-year follow-up ofCanadian men and women aged 50 to90 years who underwent varying inten-sities of colonoscopy.3 Col onoscopyincreased in all regions during 1993-2006, and among this cohort of 2,412,077persons, the authors found that for each1% increase in colonoscopy rates, therewas a concomitant 3% decrease in coloncancer deaths.

Cost-Effectiveness of Screening

Emerging

Because of the number of screeningtests available, studies have also begunto examine the cost-effectiveness ofindividual screening methods. AnotherCanadian study modeled the costs and

quality-adjusted life expectancy of notscreening and screening with any of 10tests.4 The authors found that an annualhigh-sensitivity fecal occult blood test(FOBT), such as a fecal immunochemi-cal test, or colon oscopy every 10 years,offered the best value.

The Centers for Medicare & MedicaidServices (CMS) has begun to commis-sion cost-effectiveness studies of CRCscreening approaches. Cur rently, Medi -care covers the following screeningtests: annual FOBT; flexible sigmoi-doscopy every 5 years (both alone andin conjunction with annual FOBT), andcolonoscopy every 10 years. One studyevaluated the conditions under whichstool DNA testing could be cost-effec-tive compared with these currentlyreimbursed tests.5 Using microsimula-tion modeling, the authors looked atlifetime expectancy, lifetime costs, incre-mental cost-effectiveness ratios, andthreshold costs in a population aged 65years. At a cost of $350 per test, testingevery 3 or 5 years yielded fewer life-years and higher costs than the currentrecommended screening strategies. Theauthors conclude that there is no wayfor the test to be cost-effective at thisrate; the journal’s editors suggest that“stool DNA testing will not be a cost-effective screening test for the foresee-able future.”

Computed tomographic colonogra-phy (CTC) has emerged as anotheroption in colon cancer screening, butthe test is also relatively costly and theCMS has decided not to cover the pro-cedure. The authors of the previousstudy also explored what the reim-bursement rate for CTC would have tobe for this procedure to be cost-effec-tive relative to other screening meth-ods (and for the CMS to cover it).6 The

simulation models used in the paperfound that although the number ofundiscounted life-years gained fromCTC screening was comparable to 5-yearly sigmoidoscopy with annualFOBT, the strategy was the most costlyone when it was reimbursed at a per-scan rate of $488 (slightly less than thereimbursement for colonoscopy with-out polypectomy). The strategy couldbe cost-effective, however, when reim-bursed at $108 to $205 per scan.

Cost-Benefits and Harms

An editorial accompanying this sec-ond study, by Russell Harris, MD,MPH, of the University of NorthCarolina School of Medicine, cautionsof the dangers associated with both

CTC and optical colonoscopy andwonders if there might be a thirdoption.7 In terms of cost-effectiveness,

an im proved fecal test could well bethe new “gold standard,” he writes.But in a follow-up interview withValue-Based Cancer Care, Dr Harrisexplained that “net effectiveness,”which considers costs and benefitsminus harms, might be an additional,helpful way of considering cost-effec-tiveness.

“What you want with a colorectalcancer screening test is one that’s lesssensitive than colonoscopy,” so thatclinically unimportant findings arenot acted on, Dr Harris said. “Wherecolonoscopy is going too far, we needto back up a bit and find some testthat is better suited to what we’relooking for.” �

References1. Luo Z, Bradley CJ, Dahman BA, Gardiner JC. Coloncancer treatment costs for Medicare and dually eligi-ble beneficiaries. Health Care Financ Rev. 2010;31:35-50.2. Gross CP, Anderson MS, Krumholz HM, et al.Relation between Medicare screening reimbursementand stage at diagnosis for older patients with coloncancer. JAMA. 2006;296:2815-2822.3. Rabeneck L, Paszat FL, Saskin R, Stukel TA, et al.Association between colonoscopy rates and colorectalcancer mortality. Am J Gastroenterol. 2010;105:1627-1632.4. Telford JJ, Levy AR, Sanbrook JC, et al. The cost-effectiveness of screening for colorectal cancer. CMAJ.2010;182:1307-1313.5. Lansdorp-Vogelaar I, Kuntz KM, Knudsen AB, et al.Stool DNA to screen for colorectal cancer in theMedicare population. Ann Intern Med. 2010;153:368-377.6. Knudsen AB, Lansdorp-Vogelaar I, Rutter CM, et al.Cost-effectiveness of computed tomographic col -onography screening for colorectal cancer in the Medi -care population. J Natl Cancer Inst. 2010;102:1238-1252.7. Harris R. Speaking for the evidence: colonoscopy vscomputed tomographic colonography. J Natl CancerInst. 2010;102:1212-1214.

CRC Screening Economics: Diminishing Returns as Technology Advances?By Colin Gittens

at a glance� Colorectal cancer (CRC)

screening leads to diagnosis

at earlier-stage disease and

decreased number of deaths.

� CRC screening can be too

effective, revealing nonsignificant

findings that are nonetheless

treated.

� The cost-effectiveness of vari-

ous CRC screening approaches

is presently being evaluated.

“What you want with a colorectal cancerscreening test is one that’s less sensitivethan colonoscopy,” so that clinicallyunimportant findings are not acted on.

—Russell Harris, MD, MPH

Simulation models foundthat although the number of undiscounted life-yearsgained from CTC screeningwas comparable to 5-yearlysigmoidoscopy with annualFOBT, the strategy was themost costly one.

Even as screening rates for col-orectal cancer (CRC) remaindown as a result of low patient

awareness of benefit or their choice toforego a potentially unpleasant proce-dure, that low rate may decrease fur-ther because of the worsening nationaleconomic situation. The reasons forthis decrease are varied.

A comprehensive review of morethan 100 studies conducted between1998 and 2009 found that high out-of-pocket costs, lack of health insurance,and low household income were someof the reasons people did not getscreened.1 Lead author Debra Holden,

PhD, acknowledged that access to careis only part of the problem; the study,which was funded by the Agency forHealthcare Research and Quality,emphasized the need for policy-levelinterventions to improve screening.

A second recent study found thatdespite expanded Medicare coveragefor CRC screening, the procedure wasstill underused for a number of rea-sons, including lack of supplementalhealth insurance.2

In addition, as new technologies forCRC screening are developed, financialobstacles related to whether these newtechnologies are covered by insurers

As Economy Worsens,Financial Factors May HinderCRC Screening


COLON CANCER


may hamper screening. Computedtomographic colonography (CTC) canbe used for CRC screening, but theCenters for Medicare & MedicaidServices has so far denied coverage,saying “the evidence is inadequate toconclude that CT colonography is anappropriate colorectal cancer screeningtest”.3 A study of 68 patients surveyingtheir willingness to pay for CTC foundthat they were not willing to pay whennot covered by insurance.4 What theywere willing to pay ($244 mean, $150median) is well below the currentlycharged procedural rate (between $500and $1500). But because the CTC test isless invasive, there is thinking in somequarters that it could increase screeningrates, especially for those at higher riskof disease.5

Legislative Remedies

Legislation to cover CTC as a coloncancer screening technique was intro-duced by Rep Danny Davis (D-IL) onMay 28, 2010 (HR 5461), and this is now

under review by House subcommit-tees. Another, more general policy rem-edy to address cost barriers was intro-duced in the last session of Congress.Rep Kay Granger (R-TX) authored andintroduced legislation intended tomake grants that provide CRC screen-ing to individuals aged 50 years orolder or who are at high risk for suchcancer. The legislation would alsodevelop and disseminate public infor-mation and education programs for thedetection and control of CRC and pro-mote the benefits of receiving screen-ings through this program. Called theColorectal Cancer Early Detection,Prevention, and Treatment Act (HR1189), the legislation was introducedFebruary 25, 2009, and has been re -ferred to committee as the first step inthe deliberative process.—CG �

References1. Holden DJ, Jonas DE, Porterfield DS, et al.Systematic review: enhancing the use and quality ofcolorectal cancer screening. Ann Intern Med. 2010;152:668-676.2. Doubeni CA, Laiyemo AO, Young AC, et al.Primary care, economic barriers to health care, anduse of colorectal cancer screening tests among

Medicare enrollees over time. Ann Fam Med. 2010;8:299-307.3. Centers for Medi care & Medicaid. Decision memofor screening computed tomography colonography(CTC) for colorectal cancer (CAG-00396N). May 12,2009. www.cms.gov/mcd/viewdecisionmemo.asp?from2=viewdecisionmemo.asp&id=220&. AccessedSeptember 13, 2010.

4. Ho W, Broughton DE, Doneland K, et al. Analysis ofbarriers to and patients’ preferences for CT colonogra-phy for colorectal cancer screening in a nonadherenturban population. AJR Am J Roentgenol. 2010;195:393-397.5. Finlayson E. Computed tomographic colonographyfor patients at high risk of colorectal cancer: tradingaccuracy for access and compliance. JAMA. 2009;301:2498-2499.

As Economy Worsens... Continued from page 20

Legislation intended to make grants that provideCRC screening to individualsaged 50 years or older or who are at high risk for such cancer has beenintroduced.

©2010 Bristol-Myers Squibb. All rights reserved. 731US10AB00724 4/10

We are committed to the discovery and development of

innovative immunotherapeutic approaches aimed at helping

patients ght cancers, such as advanced melanoma.

Together, we can make a difference.

We are here, where youneed us most

TM


Foundation (PAF) unveiled a primerfor providers on discussing healthcaretreatment costs with patients (www.patientadvocate.org/pdf/pubs/gu_provider_cost.pdf) and a companionbrochure for patients.

Beth Patterson, President of MissionDelivery at the PAF, said the material isbeing well-received, as is the founda-tion’s advice to clinicians dispensed overthe phone on how to help patients makewhat can be extremely tough decisions.

“Providers realize the financialimplications of medical care are a

major issue for their patients, but it fallsoutside the scope of their healthcaretraining,” Ms Patterson explained. “It’snot an area that they’re confident andcomfortable in talking about yet. Sothey’re very appreciative of having atleast a starting point.”

She said the 4 recommendations thatproviders have found most useful are:• Gain the patients’ trust and encour-

age them to see their relationshipwith you as a partnership. This willhelp ensure open and honest com-munication

• Ensure that your staff creates a chartof insurance plans with which youroffice is contracted, and list each one’sreferral requirements. Also create a listof approved facilities for such servicesas laboratory tests, blood work, imag-ing, and hospital admittance

• Have your office verify what type ofcoverage each patient has, andarrange a meeting with the patient todiscuss the treatment protocol andout-of-pocket requirements

• Have a list available in your office ofpractical and financial resources for

patients, including the Patient Ad -vocate Foundation, CancerCare, theAmerican Cancer Society, and theNational Coalition for Cancer Sur -vivorship. The list should also includeresources such as national copay pro-grams, discounted drug programsoffered by pharmaceutical companiesand pharmacies, and pharmaceuticalcompanies’ indigent-drug programs.Charity-care programs that are avail-able through the physician’s localoffice/institution/community shouldalso be listed. “Unless patients are in

VBCC PERSPECTIVE


PATIENT COMMUNICATIONS

Guiding Patients Through Cost... Continued from cover

More than 142,000 estimatednew cases of colorectal can-cer will be diagnosed in the

United States in 2010, and more than51,000 will die from this disease thisyear.1 However, this could have beenprevented among all individuals if thecancer was caught in an early stage.Unlike many other cancers, we recog-nize that in most cases there is a clearlink from benign polyp formationthrough progression to eventual col-

orectal cancer. If these are successfullyidentified early, and eventually re -moved, colorectal cancer can be pre-vented. There are numerous screeningtools currently approved for the use ofidentifying colon cancer amongasymptomatic individuals, includingfecal occult blood testing (FOBT),immunochemical FOBT, double-con-trast barium enema, flexible sigmoi-doscopy, and colonoscopy. Recom -mendations from various task forcesand organizations vary, but all havemostly agreed that, among the generalpopulation, a colonoscopy performedonce every 10 years after age 50 is use-ful to identify cancer early and is also

cost-effective. Few organizations havealso recommended using FOBT andsigmoidoscopy testing between these10-year intervals. Although screeningrates have increased since the 1980s,only 50% to 60% of the population isestimated to have been screened in2006. This dismal rate is attributed tolack of awareness, barriers to access tohealthcare, lower education level, lowminority participation, and avoidanceof undergoing a bowel preparation forcolonoscopy evaluation.2 Many strate-gies are being developed to addressthese issues and improve overallscreening rates.

In trying to address some of these

concerns, additional noninvasive testshave been developed and added to therepertoire of screening tools. Com -puted tomography (CT) colonographyis a noninvasive look at the colon usinga CT scan and is recommended to beperformed once every 5 years. Advan -tages of this procedure include avoid-ance of sedation and an invasive proce-dure, and being fairly safe and quick.However, disadvantages include re -quire ment of a full bowel prep, inabili-ty to identify small lesions, ultimaterequirement of a colonoscopy (if suspi-cious lesions are found that requirebiopsy), exposure to unnecessary radi-ation, and finding extracolonic lesions

that increase unnecessary proceduresto the patient and cost to the healthcaresystem. At the current cost of the pro-cedure, the Centers for Medicare &Medicaid Services has recently deter-mined that it is not a cost-effectivescreening tool and has refused reim-bursement.3 Stool DNA testing avoidsthe unpleasantries of a bowel prep andthe invasive procedure and sedation.However, it, too, is neither specific norsensitive enough, when comparedwith a colonoscopy, and would stillrequire the invasive procedure, shouldit be positive. Furthermore, because itperforms various genetic analyses, thecost of the procedure is quite exorbi-tant. A recent analysis determined thatthis test is only cost-effective if screen-ing adherence increased by more than50% its current rate; otherwise, the costof the test would have to be about 10%its current cost levels to justify its use.4

Screening Rates the Real Issue

Although new screening tools per-haps add to improved detection andpotentially improved patient experiencewhile undergoing the testing, neither ofthese new tools would address theunderlying problem of low screeningrates. Supposedly, these tools wouldjust add to the menu of options for thepatients to choose from when decidingto undergo screening, likely adding tothe confusion of the lay person in deter-mining which is the better screeningtest. Indeed some US states have passedlegal mandates that all screening toolsbe available to citizens based on guide-lines set forth by various medical soci-eties and task force opinions. Unfor -tunately, discussions on the pros and

cons of various tests and the conse-quences of results are never preemp-tively discussed by healthcare profes-sionals (or occur infrequently) or are notprocessed properly by all patients.Therefore, it is appropos for third-partypayers to weigh in on the appropriate-ness of each screening tool, and usefinancial incentives to direct the publictoward the more medically and cost-effective test. As a practicing gastroin-testinal medical oncologist, it is regret-table to be treating so many patientsannually, when one recognizes thatmany of these cases were likely prevent-able. Progress in medical care, both indiagnostics and in therapeutics, occursby developing ever more molecular,more sophisticated, and more moderntools that are less unpleasant or burden-some to the patient. However, given thehigh colorectal cancer mortality thatexists today, it would be more useful, atthe population level, to spend preciouscapital in overcoming barriers to screen-ing that numerous patients face.Improving this will not only drivedown costs of screening tests, whichcould allow for newer and better screen-ing tools, but also drive down costs ofoverall healthcare-related expenses forcolorectal cancer by prevention. �

References1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics,2010. CA Cancer J Clin. 2010;60:277-300.2. Holden DJ, Jonas DE, et al. Systematic review:enhancing the use and quality of colorectal cancerscreening. Ann Intern Med. 2010;152: 668-676.3. Knudsen AB, Lansdorp-Vogelaar I, Rutter CM, et al.Cost-effectiveness of computed tomographic colonog-raphy screening for colorectal cancer in the Medicarepopulation. J Natl Cancer Inst. 2010;102:1238-1252.4. Lansdorp-Vogelaar I, Kuntz KM, Knudsen AB, et al.Stool DNA testing to screen for colorectal cancer in theMedicare population: a cost-effectiveness analysis.Ann Intern Med. 2010;153:368-377.

Resource Allocation for Colorectal Cancer ScreeningBy Naimish Pandya, MDDr Pandya is Assistant Professor at the University of Maryland Medical Center/Marlene & Stewart Greenebaum Cancer Center, Baltimore, MD, and a member of the editorial board of Value-Based Cancer Care.

It is appropos for third-party payers to weigh in on theappropriateness of each screening tool, and use financialincentives to direct the public toward the more medically and cost-effective test.


a financial crisis, and unless theylocate one of these charity-care pro-grams on their own, they might notbe aware that these are options,” saidMs Patterson.

Guiding Points of Discussion

A recent study corroborates thatpatients may be less willing to committo high copayments for treatments withmodest benefit (Wong YN, et al.Understanding how out-of-pocketexpenses, treatment value, and patientcharacteristics influence treatmentchoices. Oncologist. 2010;15:566-576). Italso showed patients who had madesacrifices to be able to afford treatment

in the past were far less willing to accepthigher copayments than were thosewho had not made such sacrifices. Thiscan be critical information for clinicians,says lead author Yu-Ning Wong, MD,MSCE, Attending Physician and Assis -tant Professor, Medical Oncology, FoxChase Cancer Center, Philadel phia, PA.

“If a patient wants to go for broke fortheir treatment, that’s a personal deci-sion, but we need to help them put it incontext of their other financial respon-sibilities,” she told Value-Based CancerCare. “It was only after one of mypatients died that I found out his wifehad spent all their money providing forhis care.… Should families spend a sig-nificant portion of their savings onnoncurative treatments that may onlyextend life for a short period of time?Those are uncomfortable conversa-tions, but we need to get better at hav-ing them.”

The authors of a 6-step protocol fordiscussions about the cost of medicalcare proposed using the simple ques-tion, “Are you having financial worriesabout your treatment?” to broach thetopic (McFarlane J, et al. SPIKE$: a six-step protocol for delivering bad newsabout the cost of medical care. J ClinOncology. 2008;26:4200-4204). They alsorecommend modifying the standardpatient–physician discussion form toinclude financial issues such as levels ofcopayments, out-of-pocket payments,

and any insurance denials. They sug-gest a discussion that follows theacronym SPIKES—Setting and listeningskills, Patient perception, Information,Knowl edge in giving facts, Exploreemotions and options, and Strategy and

summary—to ensure financial issuesare covered.

“If we want patients and families tomake the most informed decisions, theoncologist must give an honest andrealistic estimate of the benefit of a

treatment and put that in terms relativeto its cost,” urge the authors. “Almostall data suggest that patients want us togive them the most complete informa-tion available, even if they choose toignore it or misinterpret it.” �

PATIENT COMMUNICATIONS


Guiding Patients Through Cost...

We focus on the humanin human health care

© 2009 Eisai Inc. CO-0100-0905

At Eisai (a•zi), caring for people is our work

Satisfying unmet medical needs and increasing benefits to patients, their families,

and caregivers is Eisai’s human health care (hhc) mission.

This includes the development of innovative medicines–notably the discovery

of the world’s most widely used treatment for Alzheimer’s disease.

Eisai is recognized for our business and patient advocacy partnerships,

as well as our commitment to working with healthcare professionals

to achieve improved patient care worldwide.

That is our quest. That is our promise. That is what makes us Eisai.

Ingenuity that Drives Innovationin Neurology, GI Disorders,

and Oncology/Critical Care

Visit us at www.eisai.com, or 1-888-274-2378

“If a patient wants to go for broke for theirtreatment, that’s a personaldecision, but we need tohelp them put it in contextof their other financialresponsibilities.”

—Yu-Ning Wong, MD, MSCE


CONTINUING EDUCATION


Lung cancer is the most commontype of cancer in the UnitedStates.1,2 An estimated 221,520

people (115,750 men and 105,770women) will be diagnosed with cancerof the lung and bronchus in 2010, andonly 15.8% of patients with lung cancersurvive 5 years or more after diagnosis.3

Lung cancer accounts for more cancerdeaths in the United States than anyother type of cancer.4 Advances in surgi-cal techniques and combined therapieshave helped increase the 1-year relativesurvival for patients with lung cancer to42% in 2002-2005, from 35% 2 decadesearlier in 1975-1979.2 Although the 5-year survival rate is greater than 50% forearly-stage disease, unfortunately only15% of lung cancers are detected whenthe disease is still localized.2

According to the National CancerInstitute, lung cancer costs theAmerican public an estimated $10.3billion a year and is the third costliestcancer after breast cancer and colorec-tal cancer.5 Furthermore, lung cancertops the list in terms of lost productivi-ty, accounting for $36.1 billion in lostlifetime earnings—lost productivitycosts 3 times greater than those associ-ated with breast cancer or colorectal

cancer.5 The financial burden of cancermay continue to expand with the agingof the US population, improved sur-vival, and the increasing cost of cancertreatments.5

The median age at diagnosis of lungcancer is 71 years.3 As the baby boomgeneration (people born between 1946and 1964) reaches age 65 and olderover the next 2 decades,6 the number ofAmericans in this age-group is expect-ed to increase by 36% from 2010 to2020.7 Because lung cancer is wide-spread and carries a dire prognosis,urgency prevails in the search for bet-ter therapies and improved outcomesfor patients. Efforts are particularlyrobust in non–small-cell lung cancer(NSCLC), which accounts for 85% ofall cases.4

For patients with advanced NSCLC,maintenance therapy may help controlthe disease and extend a patient’s life.8

Administered after induction chemo -therapy and generally in lower dosesthan initial chemotherapy, mainte-nance therapy often involves standardchemotherapy (an agent used in theinitial treatment plan therapy or anoth-er drug), or it may include a combina-tion of therapies, including vaccines,

hormones, or other drugs.8 Decisionsabout maintenance therapy includeconsideration of the associated bene-fits, risks, and costs, as well as patient-specific factors and preferences. Twochemotherapy agents have recentlyreceived US Food and Drug Admin -istration (FDA) approval for the main-tenance therapy of patients withadvanced NSCLC.

Recent advances have also yielded anumber of novel agents that target spe-cific molecular pathways in tumor

cells, and research on these discoveriesis ongoing. The molecular/genetic pro-filing of NSCLC can now be used tocharacterize tumors by their expressionof specific markers. These molecularprofiles hold promise for their poten-tial in predicting a response, or resist-ance, to specific standard or novel ther-

apies and in identifying a benefit froma new or standard agent, based on clin-ical trial evidence.9

Maintenance Therapy Brings

a New Treatment Approach for

Advanced NSCLC

Maintenance therapy, a relativelynew paradigm in the treatment ofNSCLC, constitutes a shift from thepast paradigm of treating recurrentdisease.10 However, maintenance ther-apy has been used for years in thetreatment of patients with acute lym-phocytic leukemia and acute myeloidleukemia to lower the risk of diseaserecurrence, and it is also being studiedin a number of other cancers.8 His -tologic information about the lung car-cinoma is particularly useful for tailor-ing maintenance therapy towardimproving outcomes for patients withNSCLC.11 Molecularly targeted agents,including those that inhibit epidermalgrowth factor receptor (EGFR) andvascular endothelial growth factor,also represent a crucial inroad into per-sonalized therapy for patients withlung cancer.9

Maintenance therapy has been shownto prolong progression-free survival

Maintenance Therapy for Non–Small-Cell Lung Cancer: A Value-Based Approach to Improve Patient Care andOutcomes, Part I of IIPROGRAM P10065

Initial Release Date: October 15, 2010 • Expiration Date: October 15, 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/P10065.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.

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 0468-9999-10-059-H01-P.For questions regarding the accreditation of this activity, please contact Medical Learning

Institute, Inc., at 609-333-1693 or [email protected].

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.

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.

For patients with advancedNSCLC, maintenancetherapy may help controlthe disease and extend a patient’s life.




(PFS) and overall survival (OS) in theappropriate patients, based on ran-domized, controlled studies of 2agents—pemetrexed and erlotinib.12-14

PemetrexedIn July 2009, pemetrexed was the

first drug to be FDA-approved formaintenance therapy of advanced ormetastatic lung cancer.15 Pemetrexed, afolate analog metabolic inhibitor,received this new indication specifical-ly for patients with nonsquamousNSCLC that has not progressed after 4cycles of platinum-based first-linechemotherapy.16 Pemetrexed is alsoindicated for initial treatment in combi-nation with cisplatin, as well as afterprior chemotherapy as a single agent inpatients with locally advanced ormetastatic nonsquamous NSCLC.16

Based on a randomized, double-blind, phase 3 international study (N =663), patients with stage IIIB or IVNSCLC (without progress after 4 cyclesof platinum-based chemotherapy) whowere treated with pemetrexed showeda significant improvement in PFS: 4.3months (95% confidence interval [CI],4.1-4.7) compared with 2.6 months(95% CI, 1.7-2.8) in the placebo group(hazard ratio [HR], 0.50; 95% CI, 0.42-0.61; P <.001).13 The pemetrexed groupalso showed a significantly greater OS:13.4 months (95% CI, 11.9-15.9) versus10.6 months (95% CI, 8.7-12.0) in theplacebo group (HR, 0.79; 95% CI, 0.65-0.95; P = .012). No pemetrexed-associ-ated mortalities occurred.13 Grade 3 orhigher adverse events were more fre-quent in the pemetrexed group than inthe placebo group, and includedfatigue (5% vs 1%) and neutropenia(3% vs 0).13 The most common any-grade adverse reactions comparedwith placebo were nausea (19% vs 6%)and anorexia (19% vs 5%).16

ErlotinibIn April 2010, the FDA approved an

expanded indication for erlotinib, atyrosine kinase inhibitor (TKI), as amaintenance treatment for patientswith locally advanced or metastaticNSCLC whose disease has not pro-gressed after 4 cycles of platinum-based first-line chemotherapy.17,18

Erlotinib is also indicated for the treat-ment of locally advanced or metastaticNSCLC after failure of at least 1 priorchemotherapy regimen.18

Results from a randomized, double-blind, international phase 3 study (N =889) showed a significant median PFSof 12.3 weeks for patients in theerlotinib group versus 11.5 weeks forthe placebo group (HR, 0.71; 95% CI,0.62-0.82; P <.001).14 In patients withEGFR-positive immunohistochemistrytreated with erlotinib, compared withEGFR-positive patients receiving

placebo, PFS was also significantlylonger in the erlotinib group (12.3weeks) versus the placebo group (11.1weeks; HR, 0.69; 95% CI, 0.58-0.82; P <.001).14 The study also showed animprovement in OS of 1 month witherlotinib versus placebo as mainte-nance therapy (HR, 0.81; 95% CI, 0.70-0.95; P = .009).18

Serious adverse events were report-ed in 11% of the patients in the erlotinibgroup compared with 8% in the place-bo group; the most common seriousadverse events were pneumonia (2%with erlotinib vs <1% with placebo).14

The most common grade 3 or higheradverse events included rash (9% inthe erlotinib group vs 0 in the placebogroup) and diarrhea (2% in theerlotinib group vs 0 in the placebogroup).14 The most common any-gradeadverse reactions compared withplacebo were rash (49.2% vs 5.8%) anddiarrhea (20.3% vs 4.5%).18

Maintenance Therapy: Benefits,

Risks, and Costs

Maintenance therapy is associatedwith several potential benefits, includ-ing preventing the recurrence of cancer,slowing disease growth, and prolong-ing life.8 However, these benefits mustbe weighed against potential risks,which include increased side effects,more frequent doctor visits, and drugresistance.8 Maintenance therapy mayalso be associated with higher treat-ment costs.8 In addition, the data on thesurvival benefits associated with main-tenance therapy are limited,8 as aredata on the quality of life associatedwith maintenance therapy8,19—in par-ticular, the cumulative toxicity of pro-longed chemotherapy.19 Other studylimitations include the variability inmeasurable end points such as the def-inition of progression (in PFS) and fre-quency of response assessment; addi-tionally, the use of multiple agents inthe poststudy setting may confoundthe impact of maintenance treatment.19

Although patients receiving mainte-nance therapy may not have the oppor-tunity of a reprieve from chemothera-py during the “wait-and-see” period,this period is often accompanied byanxiety about disease progression orrecurrence.19

The rising cost of cancer care persistsas a major healthcare challenge. TheAmerican Society of Clinical Oncology(ASCO) encourages members to dis-

cuss the cost of care directly withpatients.10 Although maintenancechemotherapy for advanced NSCLC isassociated with increased costs, it maydecrease costs related to palliativeradiotherapy and hospital admissionsresulting from deteriorating perform-ance status.12 Furthermore, the conceptof extended survival—in terms ofadditional months, or even weeks oflife—may represent an immeasurablebenefit for patients and their lovedones.

The Importance of Histology and

Molecular Biomarkers

Lung cancer is classified as eithernon–small-cell or small-cell, based onits biology, therapy, and prognosis.4

The 5-year survival rate for NSCLC is17%, compared with a lower survivalrate of 6% for small-cell lung cancer.2

NSCLC is categorized into 2 types:nonsquamous carcinoma (adenocarci-noma, large-cell carcinoma, and others)and squamous cell carcinoma.4 Squa -mous cell lung carcinoma accounts for25% of lung cancers in the UnitedStates, whereas large-cell carcinoma(nonsquamous) accounts for 10% to20% of all lung cancers.20

Identifying the histologic subtype ofNSCLC is an essential step in selectingthe appropriate therapy, and it mayalso be particularly useful when aug-mented by molecular testing.21 Forexample, the detection of the bron-choalveolar subtype of NSCLC adeno-carcinoma may suggest a specifictreatment strategy, particularly if itcarries specific mutations in the EGFRtyrosine kinase domain, suggesting itwill respond to treatment with anEGFR TKI.21

Several of the key predictive molecu-lar biomarkers in the treatment ofNSCLC include4:• Presence of the EGFR exon 19 dele-

tion or exon 21 L858R mutation isassociated with a treatment benefitfrom EGFR TKI therapy

• High levels of ERCC1 expression areassociated with a poor response toplatinum-based chemotherapy

• The presence of KRAS mutations isassociated with a lack of benefit fromplatinum/vinorelbine chemothera-py or from EGFR TKI therapy

• High levels of RRM1 expression areassociated with a poor response togemcitabine-based chemotherapy.Patients with EGFR mutations E19

deletion and L858R mutation haveshown a significantly better responseto erlotinib or gefitinib (both EGFRTKI agents), with initial retrospectivestudies suggesting that an estimated90% of patients with a tumor responseto these agents had mutations, whereaspatients without a response did nothave these mutations.4

According to the National Compre -hen sive Cancer Network (NCCN)practice guidelines for NSCLC, patho-logic evaluation should be performedto classify the lung cancer, determineits extent of invasion, determine thestatus of surgical margins, and identifymolecular abnormalities that may pre-dict the benefit of, or resistance to,EGFR TKI therapy.4 Pre operativeassessment may include bronchialbrushings or washings, fine-needleaspiration biopsy, core needle biopsy,endobronchial biopsy, transbronchialbiopsy, as well as sampling of medi-astinal lymph nodes to stage the dis-ease and help determine therapeuticoptions. Intraoperative (lobectomy orpneumonectomy) evaluation mayinclude determining the surgical resec-tion margin status, diagnosing anyincidental nodules found during thesurgery, or checking the status ofregional lymph nodes.4 Postoperativepathology provides information neces-

sary for classifying the tumor type,stage, and prognostic factors. Accord -ing to NCCN guidelines, the surgicalpathology report should use the histo-logic classifications established by theWorld Health Organization for lungcarcinomas.4

Adequate tissue sampling may pro-vide the key to identifying the treat-ment most appropriate for a specificpatient and improving the likelihoodof identifying an effective treatment asearly as possible.21 Refinements in his-tology and the evolving role of molec-ular testing will undoubtedly play arole in predicting responses to particu-lar treatments for NSCLC.21

Clinical Practice Guidelines for

Maintenance Therapy

The NCCN practice guidelines forNSCLC, which were updated in March2010, added a new section with recom-mendations on maintenance therapy(Table). Although ASCO released aclinical practice guideline update onchemotherapy for stage IV NSCLC, theguideline went to press in 2009 withoutthe opportunity of a comprehensivedata review on recent data supportingthe indication/use of pemetrexed for

Although maintenancechemotherapy for advancedNSCLC is associated withincreased costs, it maydecrease costs related topalliative radiotherapy and hospital admissions.

Maintenance therapyconstitutes a shift from thepast paradigm of treatingrecurrent disease.





maintenance therapy in patients withadvanced NSCLC.22 In this 2009update, ASCO included an announce-ment that an update would be forth-coming on consideration of relevantdata on the use of pemetrexed in main-tenance therapy. Results of 2 studiesevaluating erlotinib as maintenancetherapy were also anticipated by theASCO review committee at the time ofthe 2009 guideline publication.22

In June 2010, the National Institutefor Health and Clinical Excellence,based in London, issued guidance tothe National Health Service, UnitedKingdom, recommending pemetrexedfor the maintenance treatment ofNSCLC.23 The guidance states thatpemetrexed is recommended as anoption for maintenance therapy in peo-ple with locally advanced or metastaticNSCLC other than predominantlysquamous cell histology if the cancerhas not progressed immediately afterplatinum-based chemotherapy in com-

bination with gemcitabine, paclitaxel,or docetaxel.23,24 It also states that peo-ple who have received pemetrexed incombination with cisplatin as first-linetherapy cannot receive pemetrexedmaintenance treatment.23,24

Maintenance Therapy

Considerations

Treatment considerations includethe stage of the cancer and invasionstatus, the type of cancer, the patient’sperformance status, patient-specificpreferences, the costs of treatment, aswell as other patient- and agent-specif-ic factors. Evidence-based clinical prac-tice guidelines can be a valuable deci-sion-support resource for clinicians.

Selecting the appropriate patientpopulation, as characterized by histo-logic (nonsquamous) or molecular(EGFR mutation) profile, is a guidingfactor in selecting the appropriatemaintenance therapy.19 Furthermore,the use of a well-characterized tumorprofile as a tool for selecting the appro-priate patients for maintenance therapymay improve the therapeutic index,and thereby improve the survival bene-fit in these patients.19 In addition, iden-tifying predictive biomarkers for specif-ic agents used in maintenance therapymay help to improve the benefits andreduce risks. Pemetrexed is a mainte-nance therapy option for pa tients with

nonsquamous histology.4 Moreover, amolecular-based strategy may beimportant for selecting the appropriatesubgroup of patients best suited formaintenance therapy with erlotinib.19

The risks and benefits of mainte-nance therapy must be considered andweighed, along with the safety, effica-cy, and tolerability of the agents used inthis setting. Similarly, the risks associ-ated with delaying additional therapymust also be considered: a delay strate-gy may be associated with a faster dis-ease progression and shorter survivaltime than immediate additional thera-py.25,26 Extending chemotherapy, partic-ularly with a third-generation regimen,has been shown to improve PFS sub-stantially, and OS modestly.26

Conclusion

Maintenance therapy represents anew treatment paradigm for patientswith advanced NSCLC, given itspotential for improved survival.Ideally, the agent selected for mainte-nance therapy should be well-toleratedby the patient, have minimal sideeffects/cumulative toxicities, anddemonstrate improved patient out-comes.19 The histology of the carcino-ma is an important tool in tailoringmaintenance therapy for a specificpatient. In addition, molecular profil-ing can help characterize tumors andpredict response or resistance afterstandard or novel therapies.27 Mole -cular tests will continue to play animportant role in redefining patientswith NSCLC into specific subgroupsthat may respond to different optimaltreatment pathways.22

The risks and benefits of maintenancetherapy must be considered andaddressed with the patient. Similarly, therisks and benefits of a delayed/wait-and-see treatment approach must like-wise be weighed carefully. The futureholds promise, based on recent advancesthat foster targeted, personalized treat-ment approaches with the potential toimprove response and survival forpatients with advanced NSCLC. �

References1. National Cancer Institute, National Institutes ofHealth. Common cancer types. www.cancer.gov/cancertopics/typescommoncancers. Accessed September21, 2010.2. American Cancer Society. Cancer Facts & Figures2010. Atlanta, GA: American Cancer Society; 2010.3. National Cancer Institute, 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, 2010.4. 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. AccessedSeptember 15, 2010.

5. Wang BH. The financial burden of cancer—NCIbenchmarks. April 23, 2010. http://benchmarks.cancer.gov/2010/04/the-financial-burden-of-cancer/.Accessed September 20, 2010.6. Vincent GK, Velkoff VA. The Next Four Decades, theOlder Population in the United States: 2010 to 2050.Current Population Reports, P25-1138. Washington,DC: US Census Bureau: May 2010.7. US Department of Health and Human Services,Administration on Aging. A Profile of Older Amer -icans: 2007. www.agingcarefl.org/aging/AOA-2007profile.pdf. Accessed August 27, 2010.8. 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, 2010.9. Herbst RS, Lippman SM. Molecular signatures oflung cancer—toward personalized therapy [editorial].N Engl J Med. 2007;356:76-78. 10. Peck P. Maintenance pemetrexed extends NSCLCsurvival by three months. Medpage Today. May 30,2009. www.medpagetoday.com/tbprint.cfm?tbid=14437.Accessed September 22, 2010. 11. Lilly receives fourth FDA approval for ALIMTA—first chemotherapy approved as maintenance therapyfor nonsquamous non-small cell lung cancer. MedicalNews Today. July 8, 2009. www.medicalnewstoday.com/articles/156659.php. Accessed September 22, 2010.12. Eaton KD. Maintenance chemotherapy in non-small cell lung cancer. J Natl Compr Canc Netw. 2010;8:815-821.13. 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. 14. Cappuzzo F, Ciuleanu T, Stelmakh L, et al.Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomized,placebo-controlled phase 3 study. Lancet Oncol.2010;11:521-529. Epub May 20, 2010.15. Riley K. FDA approves first maintenance drugtherapy for advanced lung cancer [press release]. July6, 2009. US Food and Drug Administration. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm170515.htm. Accessed September 22, 2010.16. Alimta (pemetrexed disodium) [package insert].Indianapolis, IN: Eli Lilly and Company; 2010.17. 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. 18. Tarceva (erlotinib) [package insert]. Melville, NY:OSI Pharmaceuticals Inc; and South San Francisco,CA: Genentech; 2010.19. 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;16:2496-2504.20. Cleveland Clinic. Lung cancer overview. ReviewedOctober 23, 2008. http://my.clevelandclinic.org/disorders/Lung_Cancer/hic_Lung_Cancer.aspx.Accessed September 23, 2010. 21. Neal JW. Histology matters: individualizing treat-ment in non-small cell lung cancer [editorial].Oncologist. 2010;15:3-5. Epub January 19, 2010.22. Azzoli CG, Baker S Jr, Temin S, et al. AmericanSociety of Clinical Oncology clinical practice guidelineupdate on chemotherapy for stage IV non-small-celllung cancer. J Clin Oncol. 2009;27:6251-6266.23. NICE recommends pemetrexed for the mainte-nance treatment of non-small-cell lung cancer [pressrelease]. Medical News Today. June 23, 2010. www.medicalnewstoday.com/articles/192709.php. AccessedSeptember 22, 2010.24. National Institute for Health and Clinical Excel -lence (NICE). Final appraisal determination—peme-trexed for the maintenance treatment of non-small celllung cancer. March 2010. www.nice.org.uk/nicemedia/live/12091/48303/48303.pdf. Accessed Septem ber22, 2010.25. Belani CP, Liao J. Maintenance therapy for non-small cell lung cancer [comment]. Lancet. 2010;375:281-282; Stinchcombe T, West H. Comment in: Lancet.2009;374:1398-1400.26. 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. 27. Herbst RS, Heymach JV, Lippman SM. Molecularorigins of cancer. N Engl J Med. 2008;359:1367-1380.

Selecting the appropriatepatient population is aguiding factor in selectingthe appropriate maintenancetherapy.

Table NCCN Guideline Recommendations (March 2010) for NSCLC Maintenance Therapy

Continuation Maintenance Therapya Switch Maintenance Therapyb

Continue with biologic agents (giveninitially in combination with conven-tional chemotherapy) until disease pro-gression or unacceptable toxicity (perclinical trial design that led to approval):• Bevacizumab may be continued

beyond 4-6 cycles of platinum-doubletchemotherapy given with bevacizumab(Category 1)

• Cetuximab may be continued beyond4-6 cycles of therapy with cisplatin,vinorelbine, and cetuximab (Category 1)

• Pemetrexed may be continued after 4-6 cycles of therapy with cisplatin andpemetrexed for patients with nonsqua-mous cell carcinoma (Category 2B)

Initiation of pemetrexed or erlotinibafter first-line chemotherapy (4-6 cycles)in patients without disease progression,based on 2 recent studies demonstratinga benefit in progression-free survival andoverall survival:• Pemetrexed may be initiated after 4-6

cycles of first-line platinum-doubletchemotherapy in patients with non-squamous cell carcinoma (Category2B)

• Erlotinib may be initiated after 4-6cycles of first-line platinum-doubletchemotherapy (Category 2B)

• Docetaxel may be initiated after 4-6cycles of first-line platinum-doubletchemotherapy (Category 3)

• No randomized trial data are available to support continuing maintenance ofconventional cytotoxic agents beyond 4-6 therapy cycles

• Pemetrexed is not recommended for patients with squamous cell carcinoma• Close follow-up without therapy is a reasonable alternative to switch

maintenanceaContinuation maintenance = use of at least 1 of the agents administered as first-line therapy.bSwitch maintenance = initiation of an agent that was not included as part of the first-line treatment regimen.NCCN indicates National Comprehensive Cancer Network; NSCLC, non–small-cell lung cancer.Data adapted from reference 4. Refer to that source for definitions of evidence categories.

Maintenance Therapy for NSCLC... Continued from page 25


A Friday Satellite Symposium preceding the 52nd ASH

Annual Meeting

December 3, 2010 Rosen Centre Hotel Ballrooms A & B, Orlando, Florida

Challenging Cases in Multiple Myeloma A Dialogue Between Community and Academic Clinicians to Improve Patient Care and Outcomes

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

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

Register online today atwww.myelomacases.com/register

This continuing medical education symposium will serve as a forum for discussion of cur-rent questions and concerns regarding the treatment and management of patientsthrough the multiple myeloma (MM) life cycle. A panel of domestic and internationalmyeloma experts will be joined by representatives from community cancer care facili-ties and private oncology practices. By thoroughly engaging participants with interac-tive cases and physician point-counterpoint-style discussions, this symposium will provideevidence-based treatment and management recommendations and address newtreatment regimens and management strategies based on recent clinical trials andemerging data. In addition to considering differences in domestic and internationalcare, barriers and/or limitations faced by community cancer centers and private-prac-tice oncologists will be debated.

This activity has been developed for hematologists and medical oncologists, as well asnurses, pharmacists, and other allied health professionals who are interested in meetingthe challenges faced when treating patients with multiple myeloma in academic andcommunity settings.

TARGET AUDIENCE

ACKNOWLEDGMENT

At the end of this activity participants will be able to:• Apply early management strategies that consider new diagnostic and staging criteriafor SMM, MGUS, and MM and new imaging studies in order to improve prognosis foryour patients.

• Evaluate novel therapeutic regimens as induction therapy for your patients consider-ing an SCT in order to provide the most rapid response and allow the largest amountof stem cell collection, while maintaining safety and tolerance.

• Integrate novel agent-based regimens that provide optimal outcomes and a survivalbenefit into your management strategy for patients ineligible for SCT after appraisingemerging data from clinical trials.

• Identify patient- and disease-associated factors that impact choice of therapeuticagent and formulate management strategies using a risk-adapted approach to treatment of MM.

• Construct optimal treatment regimens based on novel combinations and make informed treatment decisions in order to improve the long-term outlook for myelomapatients across the life cycle of the disease.

LEARNING OBJECTIVES

PROGRAM DESCRIPTION

Leon Dragon, MD, FACPMedical DirectorKellogg Cancer CenterNorthshore University HealthSystemHighland Park, IL

Charles M. Farber, MD, PhDSection Chief of Hematology and OncologyDepartment of MedicineCarol G. Simon Cancer Center, Morristown, NJ

Shoba Kankipati, MDAssociate Physician EPIC Care East Bay Partners in Cancer CareSan Francisco Bay Area, CA

Jonathan L. Kaufman, MD Assistant Professor Blood and Marrow Transplantation Department of Hematology and Medical Oncology Emory University School of Medicine Member, Winship Cancer Institute Emory University, Atlanta, GA

Stefan Knop, MDUniversity Hospital WürzburgWürzburg, Germany

Noopur Raje, MDAssociate Professor of MedicineHarvard Medical SchoolDirector, Center for Multiple MyelomaMassachusetts General HospitalBoston, MA

G. David Roodman, MD, PhDProfessor of MedicineVice Chair for Research Department of MedicineDirector, Myeloma ProgramDirector, Bone Biology CenterUniversity of Pittsburgh Medical CenterPittsburgh, PA

Ari Umutyan, MDRedwood Regional Medical GroupHematology and Medical OncologyNapa, CA

ACCREDITATION INFORMATION Physician AccreditationThe University of Cincinnati designates this activity for a maximum of 3 AMA PRA Category1 Credits™. The University of Cincinnati is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.Physicians should only claim credit commensurate with the extent of their participationin the activity.

Registered Pharmacy DesignationMedical Learning Institute is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 3.0 contact hours (0.3 CEUs)of continuing education credit.

The universal activity number for this activity is 0468-9999-10-058-L01-P.

Registered Nurse DesignationMedical Learning Institute, Inc. (MLI)

Provider approved by the California Board of Registered Nursing, Provider Number15106, for 3.0 contact hours.

12:30 - 1:00 PM Registration and Lunch Service

1:00 - 1:10 PM Welcome and Introduction Sundar Jagannath, MD - Chair

CASE PRESENTATIONSEach case will be presented by an expert faculty member and discussed by the international and community panel.

1:10 – 1:40 PM Case 1: Difficult diagnosis G. David Roodman, MD, PhD

1:40 – 2:10 PM Case 2: Newly diagnosed, stem cell transplant eligible patientSundar Jagannath, MD

2:10 – 2:40 PM Case 3: First-line therapy in a non-SCT eligible patient Stefan Knop, MD

2:40 – 3:10 PM Case 4: Multiple risk factors Jonathan L. Kaufman, MD

3:10 – 3:40 PM Case 5: Treatment of MM across the life cycle Noopur Raje, MD

3:40 - 3:50 PM Question & Answer Session

3:50 - 4:00 PM Closing Remarks Sundar Jagannath, MD

PROGRAM AGENDA

CHAIR: Sundar Jagannath, MDProfessor, Hematology and Medical OncologyMount Sinai School of Medicine’s Tisch Cancer Institute Director of the Multiple Myeloma Program, The Mount Sinai Medical CenterNew York, NY

FACULTY

�� VBCC_October_100810_Follow ASCO Tabloid 10/12/10 2:35 PM Page 27

©2010 Millennium Pharmaceuticals, Inc. All rights reserved.

To learn more, visit us at millennium.com.

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

goal

One goal: discovering and delivering breakthrough medicines to combat cancer.

Now the innovative science of a leading American biopharmaceutical company joins the global

assets of Takeda, Japan’s largest pharmaceutical company, for a global commitment to oncology.

Millennium: The Takeda Oncology Company is developing an extensive pipeline — among the top

in oncology worldwide — with more than 17 compounds in development for a broad range of solid

and hematological cancers.

Our pipeline — rich in novel compounds — includes multiple candidates that target seven disease

pathways: protein homeostasis, anti-angiogenesis, growth-signaling inhibition, cell-cycle inhibition,

apoptosis, immunomodulators and hormone regulation.

We are dedicated to a strong partnership with the oncology community. Together we can make a

dramatic impact on cancer therapeutics over the next decade.


October 2010, Vol 1, No 5

Documents

Transcript of October 2010, Vol 1, No 5