AUGUST 2011 VOL 2 NO 5

Benchmarks for Measuring theSuccess of a MedicalHome in OncologyBy Robert “Bo” Gamble and Mary KruczynskiMr Gamble is Director of Strategic Practice Initiatives, andMs Kruczynski is Director of Policy Analysis, CommunityOncology Alliance, Washington, DC

Upper GI Cancers: Are WeGetting Value for the Money?By Audrey Andrews

©2011 Engage Healthcare Communications, LLC

www.ValueBasedCancerCare.com

Chicago, IL—Nearly 2% of patientswith cancer may file for personal bank-ruptcy 5 years after their diagnosis,according to researchers from FredHutchinson Cancer Research Center inSeattle who presented their data at the2011 American Society of ClinicalOncology (ASCO) Annual Meeting. “We found that bankruptcy is a par-

ticular risk for patients with cancer,”said Scott D. Ramsey, MD, PhD,Professor of Medicine, Fred Hutch in -son Cancer Re search Center, Univer -sity of Wash ington School of Medi cine,and Direc tor, Cancer Pre vention Clinic,Seattle Cancer Care Alliance.Dr Ramsey and colleagues studied

data for >230,000 patients with cancershowing that rates varied widely

across cancer types, that youngerpatients aged <44 years were particu-larly at risk, and that bankruptciesincreased over time.Bankruptcy rates averaged 0.5% at 1

year but rose to 1.9% at 5 years post -diagnosis. In comparison, the bank-ruptcy rate in the general population ofwestern Washington State was only0.28%. Using the Surveillance, Epidemi -

ology and End Results registry, theresearchers identified 231,799 adultswith newly diagnosed first primarycancers between 1995 and 2009 livingin western Washington State. Theylinked these to bankruptcy filings(Chapters 7 and 13) in federal bank-

As we move forward in thescheme of healthcare reform,we are being directed toward

an integrated care model, one withhigh quality and economic efficiency.Recently, a model known as an ac-

countable care organization (ACO)was introduced by the US Departmentof Health and Human Services in theform of a proposed rule open for pub-lic comment. Although the final rule

Chicago, IL—“Moving the Bar inUpper GI Malignancies” was a plena-ry session at ASCO 2011, with 2experts discussing whether results ofrecent clinical trials of targeted agentsare clinically meaningful or just statis-tically positive, and what is the valueof the enormous amount of money

spent in treating noncolorectal gas-trointestinal (GI) cancer.

Clinical versus Statistical

Significance

Eileen Mary O’Reilly, MD, ofMemorial Sloan-Kettering Cancer

Continued on page 8

Continued on page 10


AUGUST 2011 VOL 2 NO 5

FDA UPDATES . . . . . . . . . . . . . . . . . . . . . . . . 3Novel nasal spray of fentanyl citrate for cancer pain

VALUE PROPOSITIONS . . . . . . . . . . . . . . 7NICE backs thalidomide and bortezomib for multiple myeloma

ASCO ANNUAL MEETING . . . . . . . . . 10Genomic medicine in lung cancerEmerging regimen for metastatic pancreatic cancerOff-label drug use, advanced technologies driving up Medicare costs

HEALTH POLICY . . . . . . . . . . . . . . . . . . . 26What does deficit reduction mean for oncology?

ONCOLOGY PHARMACY . . . . . . . . . . 28Dose-monitoring, split fills reduce oralchemotherapy waste, save cost

ELECTRONIC HEALTH RECORDS . 32Impact of EHRs on oncology practice

ONCOLOGY REIMBURSEMENT . . . 33Post-ASCO: oncologists’ and payers’treatment and coverage decisions

I N S I D E

Patients with Cancer at Risk for BankruptcyFilings increase drastically at 5 years after diagnosisBy Caroline Helwick

Northwestern UniversityComprehensive Cancer CenterAdvancing patient care through state-of-the-art clinicalcoordination and researchInterview with Al B. Benson III, MD, FACPProfessor of Medicine and Associate Director for Clinical Investigations, Robert H.Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL

ONCOLOGY BEST PRACTICES

Q: How would you define the concept of best practices, and whatmakes an oncology center, such as the Northwestern UniversityRobert H. Lurie Comprehensive Cancer Center, be among the bestoncology practices in the country?

Dr Benson: “Best practices” is a critical area for Northwestern and, in par-ticular, is an important area of responsibility for our cancer center as amemberof the National Comprehensive Cancer Network (NCCN). The NCCN has avery productive Best Practices Committee that has been active for many years.The committee members do surveys of NCCN practices and have very


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VBCC_Aug_11_2_Follow ASCO Tabloid 8/12/11 12:44 PM

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VBCC_Aug_11_2_Follow ASCO Tabloid 8/11/11 9:22 AM

THE FIGHT IS CHANGING.It’s more personal than ever. Now, genetic biomarker tests may help deliver the right cancer treatment to the right patient.

Bio-specific medicine is changing the way we treat cancer. In many instances, doctors can now test a tumor’s distinct profile with the goal of providing more targeted, more effective treatments with fewer side effects.

The battle is being redefined. And it starts by testing. See how at www.canceritspersonal.com

CRI00102/280033-01 ©2011 P�zer Inc. All rights reserved.


4 I VALUE-BASED CANCER CARE I August 2011 VOL. 2 I NO. 5

IN THIS ISSUE

PublisherNicholas [email protected]

Associate PublisherMaurice [email protected]

Editorial DirectorDalia [email protected]

Associate EditorsBrett [email protected] [email protected]

Editorial AssistantJennifer [email protected]

Director, Client ServicesCristopher [email protected]

Senior Production ManagerRobyn Jacobs

Quality Control Director Barbara Marino

Business ManagerBlanche Marchitto

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 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 [email protected]

Address all editorial queries to: [email protected]: 732-992-1889 Fax: 732-992-1881

Value-Based Cancer Care, ISSN 2153-4888 (print);ISSN 2153-4896 (online), is published 7 times ayear by Engage Healthcare Communica tions, LLC,241 Forsgate Drive, Suite 205A, Monroe Township,NJ 08831. Copyright © 2011 by Engage HealthcareCommunications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark ofEngage Health care Communi cations, LLC. No partof this publication may be reproduced or transmittedin any form or by any means now or hereafter known,electronic or mechanical, including photocopy,recording, or any informational storage and retrievalsystem, without written permission from the publish-er. Printed in the United States of America.

The ideas and opinions expressed in Value-BasedCancer Care do not necessarily reflect those of theeditorial board, the editors, or the publisher.Publication of an advertisement or other productmentioned in Value-Based Cancer Care should not beconstrued as an endorsement of the product or themanufacturer’s claims. Readers are encouraged tocontact the manufacturers about any features or limi-tations of products mentioned. Neither the editorsnor the publisher assume any responsibility for anyinjury and/or damage to persons or property arisingout of or related to any use of the material mentionedin this publication.Postmaster: Correspondence regarding subscriptionsor change of address should be directed to CIRCU-LATION DIRECTOR, Value-Based Cancer Care, 241 Forsgate Drive, Suite 205A, Monroe Township,NJ 08831. Fax: 732-992-1881. Yearly subscriptionrates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

VBCC Editorial Board

IN THE LITERATURECombination therapy improves survival in intermediate-risk prostate cancer

Vemurafenib improves survival in metastaticmelanoma with BRAF V600E

More….

ASCO ANNUAL MEETINGNew regimen with an old drug boosts survival in pediatric ALL

The oncology drug pipeline is promisingComparing the value of denosumab versus zoledronic acid

More….

ONCOLOGY BEST PRACTICESNorthwestern Comprehensive Cancer Center

HEALTH POLICY Hanging in limbo: what does deficit reductionmean for oncology?

More….

ONCOLOGY PHARMACY Dose-monitoring, split-fill programs curb waste of oral chemotherapy

More….

ELECTRONIC HEALTH RECORDSImpact of EHRs on oncology practice

ONCOLOGY REIMBURSEMENT Post-ASCO survey: oncologists’ and payers’treatment decisions

CANCER SCREENINGScreening for pancreatic cancer is effective, has value

More….

METASTATIC MELANOMAA new era in management

CONTINUING EDUCATIONCost implications for novel therapies in the treatment of NSCLC

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

Mark J. Krasna, MD Medical Director, The Cancer Institute Principal Investigator, NCI CommunityCancer Centers Program Towson, MD

Ira Klein, MD, MBAAetnaHartford, CT

Crystal Kuntz, MPAAstellas Pharma USWashington, DC

Lee Newcomer, MD, MHAUnitedHealthcareMinnetonka, MN

Lynn Nishida, RPhRegence BlueCross BlueShield of OregonPortland, OR

Ted Okon, BS, MBAExecutive DirectorCommunity Oncology Alliance

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, MPHPartnerHealth Policy Strategies, LLCWashington, DC

Brian K. Solow, MD, FAAFPPrescription SolutionsIrvine, CA

Timothy Tyler, PharmD, FCSHPDirector of Pharmacy ServicesComprehensive Cancer CenterDesert Regional Medical CenterPalm Springs, 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, NYSection EditorDawn Holcombe, FACMPE,MBA, ACHEPresident, DGH ConsultingSouth Windsor, CT

Al B. Benson III, MD, FACPProfessor of MedicineAssociate Director for ClinicalInvestigationsRobert H. Lurie ComprehensiveCancer Center of NorthwesternUniversity Chicago, ILImmediate Past President, ACCCPast Chair, NCCN Board of Directors

Scott Breidbart, MDChief Medical OfficerEmpire BlueCross BlueShield, NY

Bruce A. Cutter, MD, MMMCutter HealthCare ConsultingSpokane, WA

Craig Deligdish, MDFlorida Comprehensive CancerNetwork, Melbourne, 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


Novel Nasal SprayFormulation of FentanylCitrate for Cancer PainThe US Food and Drug Admin-

istration (FDA) approved a new nasalspray formulation of fentanyl citrate(Lazanda; Archimedes) for the rapidrelief of cancer-related breakthroughpain in adults who have developedresistance to their opioid regimen.The recommended dosage is 100 µg

sprayed once in each nostril for eachcancer-related pain episode. If ade-quate analgesia is not obtained within30 minutes, the dose should be titratedup with each subsequent episode.Approval was based on evidence

from 500 patients enrolled in a double-blind, placebo-controlled clinical trialthat included an open-label titrationphase. Pain relief was maintained for60 minutes after dosing. During thetitration phase, 73% of patientsobtained adequate relief. The mostcommon adverse events were nausea,vomiting, pyrexia, and dizziness.The nasal spray formulation, which

is approved with a Risk Evaluationand Mitigation Strategy program, willbecome available in the second half ofthis year. (June 30, 2011)

New Molecular TestApproved to Detect HER2 inWomen with Breast CancerA new test for detecting the HER2

gene in women with breast cancer hasreceived FDA approval. The test,called Inform Dual ISH (VentanaMedical Systems), facilitates the use ofstandard microscopy to measure thenumber of copies of chromosome 17and HER2 genes in a tumor sample onthe same slide. Unlike traditionalHER2 amplification, which uses fluo-rescence microscopy, the Inform DualISH test enables laboratory staff toview samples directly under a micro-scope, and for longer periods.In a study involving tumor samples

from 510 US patients with breast can-cer, the test was effective in detectingan excessive number of copies of theHER2 gene in 96% of the HER2-posi-tive tumor samples and a normalnumber of copies in 92.3% of HER2-negative samples. (June 14, 2011)

FDA Warns Oncologists:Thermography No Substitutefor MammographyThe FDA has issued a warning to

healthcare providers against substitut-ing breast thermography formammog-raphy in screening for breast cancer.Some providers prefer thermogra-

phy over mammography because itdoes not expose women to radiation orbreast compression. The FDA, howev-er, points to the absence of valid evi-dence showing that when used alone,

thermography is effective in detectingbreast cancer. The FDA has warnedproviders to stop making such claimsin light of these claims appearing onprovider websites. “Mammography is still the most

effective screening method for detect-ing breast cancer in its early, mosttreatable stages,” said Helen Barr, MD,

Director of the Division of Mam mog -raphy Quality and Radiation Pro -grams in the FDA’s Center for Devicesand Radiological Health. “Women should not rely solely on

thermography for the screening or diag-nosis of breast cancer. While there isplenty of evidence that mammographyis effective in breast cancer detection,

there is simply no evidence that ther-mography can take its place,” she said.The FDA has not approved any

telethermographic devices as stand-alone screening or diagnostic tools forbreast cancer, although the agency hascleared such devices for use as anadditional method to confirm a breastcancer diagnosis. (June 2, 2011) �

FDA UPDATES

5VOL. 2 NO. 5 www.ValueBasedCancerCare.com I

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

Act before febrile neutropenia strikesPotential 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


Combination TherapyImproves Survival in Menwith Intermediate-Risk,Early-Stage Prostate CancerA new large clinical trial funded by

the National Cancer Institute hasdemonstrated the best approach totherapy for men with intermediate-

risk, early-stage prostate cancer thatcan prolong survival. In comparingtreatments for early-stage prostatecancer, investigators found strong evi-dence that short-term androgen-depri-vation therapy (ADT) in combinationwith radiotherapy is more effectivethan radiation therapy alone for men

with intermediate risk (Jones CU, et al.N Engl J Med. 2011;356:107-118). This 212-center study included 1979

men with early-stage prostate cancer.All patients had localized prostate can-cer and prostate-specific antigen (PSA)levels ≤20 ng/mL. Among the pa -tients, 395 were black men, who are

known to have greater rates of prostatecancer than other men. Patients were randomly assigned to

treatment with radiotherapy alone (N= 992; 197 black men) or to radiothera-py plus 4 months of ADT that consist-ed of drugs that block the natural pro-duction of testosterone (N = 987; 198black men). Of note, previous studieshave shown that short-term ADTimproves survival among patientswith later-stage prostate cancer. The median follow-up in this study

was 9.1 years. Results showed thatshort-term ADT plus radiotherapy sig-nificantly improved the 10-year over-all survival (OS) compared with ra -diation therapy alone (62% vs 57%,respectively). The addition of short-term ADT to

radiation therapy led to significantlyfewer prostate cancer–related deaths(4% vs 8%, respectively; P = .001). Thebenefits of short-term ADT were truefor white and black men. In a later analysis looking at the

patients by disease risk, participantswere divided into 3 groups—high,intermediate, and low risk, using vari-ous variables, including PSA levels,tumor grade, and disease stage. The patients with intermediate-risk

benefited from the combination thera-py, unlike those with low or high risk.In those with intermediate risk, the 10-year OS rate significantly increasedfrom 54% with radiotherapy alone to61% with the combination of short-term ADT plus radiotherapy, and dis-ease-specific death rate was reducedfrom 10% to 3%.

No Access to RadiotherapyCannot Explain ReducedSurvival in Black WomenPost–Breast Cancer SurgeryBlack women who undergo mastec-

tomy or lumpectomy for advancedbreast cancer have shorter survivalduration than their white, Hispanic,and Asian counterparts, regardless ofwhether they undergo radiation ther-apy after the procedure, according to anew study (Martinez SR, et al. Cancer.Epub ahead of print. June 20, 2011).Radiation therapy is recommended

for all patients who undergo mastec-tomy or lumpectomy. In a previousstudy, black women with advancedbreast cancer were less likely thanwhites or Asians to receive radiothera-py. Therefore, the investigator wantedto find out whether this disparity inaccess to radiotherapy would explainthe poorer survival in black womenwith metastatic breast cancer.In this new study, the researchers

used data from the Surveillance,Epidemiology and End Results to

IN THE LITERATURE


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

INDICATIONS AND USAGENeulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically signifi cant 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 pegfi lgrastim or fi lgrastim.

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 infi ltrates 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 pegfi lgrastim or fi lgrastim.

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 fi lgrastim, the parent compound of pegfi lgrastim.

Potential for Tumor Growth Stimulatory Effects on Malignant CellsThe granulocyte-colony stimulating factor (G-CSF) receptor through which pegfi lgrastim and fi lgrastim act has been found on tumor cell lines. The possibility that pegfi lgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfi lgrastim is not approved, cannot be excluded.

ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the Brief Summary:• Splenic Rupture [See Warnings and Precautions]• Acute Respiratory Distress Syndrome [See Warnings

and Precautions]• Serious Allergic Reactions [See Warnings and Precautions]• Use in Patients with Sickle Cell Disorders [See Warnings

and Precautions]• Potential for Tumor Growth Stimulatory Effects on Malignant

Cells [See Warnings and Precautions]The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher in the pegfi lgrastim 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 refl ect 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 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 disordersBone 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 nonmyeloid 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 pegfi lgrastim 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 pegfi lgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfi lgrastim 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 specifi city of the assay, and the observed incidence of antibody positivity in an assay may be infl uenced 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 identifi ed 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: Splenic rupture [see Warnings and Precautions]Blood and lymphatic system disorder: Sickle cell crisis [see Warnings and Precautions]Hypersensitivity reactions: Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, and urticaria, Sweet’s syndrome, generalized erythema and fl ushing [see Warnings and Precautions]Respiratory, thoracic, and mediastinal disorder: ARDS [see Warnings and Precautions]General disorders and administration site conditions: Injection site reactionsSkin and subcutaneous tissue disorders: Cutaneous vasculitis

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 fi ndings when interpreting bone-imaging results.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category CThere are no adequate and well-controlled studies in pregnant women. Pegfi lgrastim 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 pregnancy only if the potential benefi t to the mother justifi es the potential risk to the fetus.In animal reproduction studies, when pregnant rabbits received pegfi lgrastim 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 pegfi lgrastim 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 pegfi lgrastim 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 profi le and pharmacokinetics of pegfi lgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfi lgrastim 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 pegfi lgrastim.Therefore, pegfi lgrastim 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 prefi lled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product.This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfi lgrastim)

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

© 2011 Amgen Inc. All rights reserved.www.neulasta.com 1-800-77-AMGEN (1-800-772-6436)

v 12.0 MC45288-B

Continued on page 9



VALUE PROPOSITIONS

77,000 Early Adopters to CMS’s EHR IncentiveProgram Exceed Requirements, Reflecting Value toPatients and Providers

Approximately 77,000 healthcare providers have already registered byJuly of this year with the Centers for Medicare & Medicaid Services(CMS) for the electronic health records (EHRs) program. CMS is collect-ing data on early adopters to the EHR incentive program, which willbegin in 2014 but is requiring providers to meet the first stage of “mean-ingful use” much sooner. By registering with the incentive program, theproviders or clinical centers indicate that they meet the first set of require-ments associated with instituting an EHR system.

CMS has found that clinicians are using the EHR system for a higherproportion of their patients than is required by the program, suggestingthat the value in instituting such a program is more than just the antici-pated reimbursement.

So far 21 states have launched the Medicaid EHR program, with themost recent 4—Arizona, Connecticut, Rhode Island, and West Virginia—registering in July 2011. (See also article on EHRs in oncology on page 32.)

Inexpensive Immunochemical Stool Test EffectiveOption for Colon Cancer Screening

The immunochemical fecal occult blood test (iFOBT), a new version ofthe traditional FOBT, has demonstrated 90% specificity in detecting colongrowths. This new version of the FOBT has been gradually replacing theold FOBT in screening for colon cancer. This high level of specificity firm-ly establishes the benefit of this test (Chiang TH, et al. CMAJ. Epub aheadof print. August 2, 2011).

Although the FOBT is more expensive than the old FOBT, at a cost ofapproximately $30, its value is considerable compared with colonoscopy,which averages about $3000 per procedure. This newly validated level ofspecificity and the low cost will likely enhance the value of this newer ver-sion of the stool test as a screening option for a potentially deadly cancer.

NICE Backs Value of Thalidomide, Bortezomib for Multiple Myeloma

In July, the United Kingdom’s National Institute for Health and ClinicalExcellence (NICE) approved the use of thalidomide (Thalomid) for thefirst-line treatment of multiple myeloma in patients in whom high-dosechemotherapy with stem-cell transplantation is deemed inappropriate.

At the same time, NICE also approved bortezomib (Velcade) in combi-nation with an alkylating agent and a corticosteroid for first-line treat-ment of multiple myeloma when high-dose chemotherapy with stem-celltransplantation is considered inappropriate and the patient cannot toler-ate or has contraindications to thalidomide.

Carole Longson, the Director of the Centre for Health TechnologyEvaluation at NICE, said in a statement regarding the approval, “We aredelighted to be able to recommend these 2 new treatment options for peo-ple with this condition.” Noting that almost 4000 cases of multiple myelo-ma are diagnosed every year in the United Kingdom, she added that“there is currently no cure for the disease, only treatments to stop theprogress of the condition and help relieve symptoms. Thalidomide andbortezomib regimens have been shown to be more effective at delayingdisease progression and improving patients’ life expectancy than the cur-rent treatment of an alkylating agent and corticosteroid alone.”

These decisions by NICE indicate that these 2 treatment regimens havebeen found cost-effective for these indications.

Value of Screening High-Risk Individuals for LungCancer Confirmed, but Who Will Pay for It?

New results from the National Lung Cancer Screening Trial haveshown that in individuals at high risk for lung cancer, screening with low-dose computed tomography (CT) significantly reduces mortality in thissubpopulation (N Engl J Med. 2011;365:395-409).

Based on these findings, the American Society of Clinical Oncology, inconcert with other cancer organizations, is developing new practiceguidelines to immediately affect current screening practices for those athigh risk for lung cancer. However, at a price between $300 and $500 perCT procedure, the question of who will carry the cost burden remains tobe determined.

FDA Grants Priority Review for Ruxolitinib for the Treatment of Myelofibrosis

The US Food and Drug Administration (FDA) has granted priorityreview for the investigational drug ruxolitinib as a potential treatment forpatients with myelofibrosis, a blood cancer with few treatment options.There are currently no FDA-approved treatments for this condition. Thestatus of a priority review indicate that the drug either is perceived asoffering a major advance in treatment or provides treatment to a condi-tion with no approved therapies.

Personalized Approach to Mammography Most Cost-Effective, but at What Risk to Women?

The most recent mammography screening recommendations call onwomen to begin annual screening for breast cancer at age 40 years,regardless of their risk for the disease. This “one-size-fits-all” approach,based on age alone, leads to too many screenings for some women andnot enough for others, according to investigators of a recent cost-analysis(Schousboe JT, et al. Ann Intern Med. 2011;155:10-20).

With a cost-effectiveness threshold of $100,000 per quality-adjusted life-year (QALY), biennial mammography is most cost-effective for womenaged 40 to 49 years, the researchers claim. With a cost per QALY of$340,000 for annual screening, the current strategy is not cost-effective,regardless of the woman’s age or breast density, these investigators say.

Nevertheless, clinicians take a different approach. The AmericanCongress of Obstetricians and Gynecologists recently issued new screen-ing guidelines recommending annual screening for all women aged 40 to49 years, which was a reversal of its previous recommendation for bien-nial screening for that age-group.

And the American Society of Breast Disease (ASBD) has recently issueda statement expressing support for this strategy. According to the ASBD,recent evidence from several studies in Canada and Sweden shows thatscreening this younger women group can reduce deaths from breast can-cer by 40% to 50%.

Younger women tend to have denser breasts and faster-growingtumors, so screening them is important, because the majority (>80%) ofwomen with breast cancer have no known risk factors. The question ofvalue in screening for breast cancer remains pertinent in the current eco-nomic situation, but when faced with the potential for life-threateningcancer, defining value is key to policy decisions.


MEDICAL HOME


has not yet been released, the varioussubmitted commentaries, at least as faras cancer care is concerned, were notvery supportive of the model.

When we incorporate a diagnosis ofcancer into the ACO model, however,we struggle to find the perfect fit. In aneffort to conform to the newly outlinedstandards of quality and efficiency,The Community Oncology Alliance isleaning toward a more precise modelthat is better able to address themany services needed by patientswith cancer. That model is known asthe patient-centered medical home(PCMH) in general, and as translatedinto cancer care, patient-centeredoncology medical home.

Cancer care is not well understoodin the United States. One would thinkthat because cancer ranks third in theUS total healthcare expenses,1 it wouldget more mention in healthcare reformand accountable care proposals.

A proposed rule by the Centers forMedicare & Medicaid Services forACOs mentions “quality” 817 times,“standard” 208 times, and “cancer”only 8 times (5 of which refer to screen-ing measures vs actual cancer care).2

The National Committee for QualityAssurance’s (NCQA) outline for thePCMH mentions “quality” 62 times,“standard” 107 times, and “cancer”only twice.3

It is perplexing and indeed ironicthat cancer is not understood, particu-larly in the context of cancer care as amedical home. Yet, most patients withcancer would refer to their communitycancer center as their “medical home”and often their actual “home,” with“home” being a place of intense nur-turing, support, care, love, and encour-agement. Yet, to date, there is not anorganized recognition entity that pro-motes and supports quality, patient-centric cancer care with applicablebenchmarks.

The medical home model has merit,in that it has demonstrated improvedefficiency, lower costs, and overallpatient satisfaction.4 The incentiveswithin this model also promote posi-tive entrepreneurial competition,notably within an entire industry.ACOs, however, tend to create compe-tition among themselves, which hasdiminishing marginal return. Themedical home model appears to bemore sustainable and more applicablenot only for the medical community,but also for the diverse specialtieswithin that community.

Successful Components of the

Medical Home Model in Oncology

To be successful for all stakeholders,

the medical home requires severalqualities.

Collaboration. According to theNCQA’s white paper, 7676 cliniciansand 1506 practices have achieved rec-ognition as a PCMH, mostly throughhard work and perseverance.5 Thegoal is to remain self-assured that thismodel is right for patients and forpractices alike. What is needed now isrecognition of this significant achieve-ment. Most recognition models areeither provider-driven with hopes thatpayers will follow, or payer-drivenwith hopes that providers will follow.

The oncology community is devel-oping a medical home model thatincludes representation of the majorstakeholders. The oncology-specificPCMH is steered by patients, oncolo-gists, oncology practice administra-tors, payers, patient advocate groups,oncology support organizations, andother value-added partners. “Quality”has been defined by some people as“when you get what you thought youbought.” Each of these entities has itsown definition of “get,” and that per-spective of the deliverable needs to beconsidered and measured, if there isgoing to be a comprehensive approachto establishing and nurturing a med-ical home.

Easy implementation. The prevail-ing theme of oncology practices, andthose who are supporting and encour-aging these teams of passionate mis-sion-minded caregivers, is “please, notanother project.” Oncology practicesare busy trying to keep quality patient

care a priority, while trying to imple-ment physician quality-reporting ini-tiatives, e-prescribing, and meaningfuluse, and simultaneously lobbying forlegislative support for cancer care,maintaining staff and physicianmorale, and hundreds of other top-priority issues.

Oncology practices will need assis-tance with implementing the policies,procedures, and workflow changes toachieve any type of recognition pro-gram. However, these tools and tech-niques need to be balanced to the pointof promoting ownership and action,while easing the administrative bur-den of yet another major project.

Benchmarked quality measures. Thelargest obstacle and one of the mostcritical components to a successfulprogram will be the standardized,comprehensive, and automated sub-mission of key quality measures.Many of the current quality programsrequire manual chart abstractions orconsist of subjective questions that arenot measurable (eg, yes/no answers).

Quality measures need to includeratio-oriented and well-defined nu -mer ators and denominators; auto -mation through systematic data cap-ture techniques from valued electronicmedical records (EMRs) or middle-ware vendors; and allowances so thatpractices can readily compare them-selves to their peers.

Physicians and practice administra-tors will need to encourage their EMRvendors and group purchasing ven-dors to automate the reporting andsubmission of quality measures to acommon data repository. This mayalso require database engineers to cre-ate discrete data dictionaries, wherethey currently do not exist.

Standardized patient satisfactionmeasures. Most oncology practicesgather patient satisfaction informationon an ongoing basis, or they have doneso in the past. The typical textualresults include, “My physician walkson water”; “You guys are great—keepup the great work”; “So thankful tohave such a team”; “Your kindnessmakes my day”; “Perfect—do notchange a thing.” However, if we stan-dardized the questions with a numericscale, a consistent score of 95% maypale in comparison to benchmarkedscores of ≥99%.

The benchmarking repositoryshould also include submitted patientsatisfaction scores. This survey needsto be simple, easily gathered at strate-gic points during the patient’s treat-ment, quantitative, and reflective ofhow a patient perceives quality.

Value. All these benchmarks must

be structured and wrapped so thateach group of stakeholders receivesperceived value. The barometer ofachievement needs to be high enoughto allow for a real sense of accomplish-ment. Payers need to understand andsupport the significance of the effortand be willing to support the valuefinancially.

The practice team should note thedifferences in the process through per-ceived increased efficiency and collab-orative teamwork within all disci-plines of care. Most important,patients and their families need to per-ceive and receive greater valuethrough higher patient satisfaction.

Quality, Value, and Efficiency

in Cancer Care

We are in a season of transition inthe cancer care delivery system.Patients, payers, other providers, andgovernment entities are campaigningand demanding quality, value, andincreased efficiency. All these expecta-tions will best be met through a modelthat encourages, promotes, and en -dorses ongoing achievement of theseattributes. Although most oncologypractices are meeting these expecta-tions, a lack of understanding and clar-ity remains regarding how well theseexpectations are being achieved.

Benchmarking key ratios of consis-tent quality, value, and efficiency willgo far to bridge the gap between theexpected, perceived, and actual quali-ty achieved. The biggest challenge isshifting the mindset of the entire can-cer community toward a new empha-sis on tools, processes, and measure-ments that promote and validate whycancer care in the United States is thebest. Only then will we get what wethought we bought. �

References1. Stanton MW. The High Concentration of US HealthCare Expenditures. June 2006. Rockville, MD: Agencyfor Healthcare Research and Quality. Research inAction; Issue 19. AHRQ Pub. No. 06-0060. www.ahrq.gov/research/ria19/expendria.htm. Accessed August1, 2011.2. Centers for Medicare & Medicaid Services,Medicare Shared Savings Program: Accountable CareOrgan izations. March 24, 2011. CMS-1345-P, RIN 0938-AQ22. www.ftc.gov/opp/aco/cms-proposedrule.PDF.Accessed August 1, 2011.3. Standards and Guidelines for NCQA’s Patient-Centered Medical Home 2011. Washington, DC:National Committee for Quality Assurance. March 28,2011.4. Grumbach K, Grundy P. Outcomes of implementingpatient-centered medical home interventions: areview of the evidence from prospective evaluationstudies in the United States. Washington, DC: Patient-Centered Primary Care Collaborative; November 16,2010. www.pcpcc.net/files/evidence_outcomes_in_pcmh.pdf. Accessed August 1, 2011.5. National Committee for Quality Assurance.NCQA’s Patient-Centered Medical Home 2011overview white paper. January 31, 2011. www.ncqa.org/LinkClick.aspx?fileticket=l_KicggGGsQ%3d&tabid=1302&mid=5343&forcedownload=true. AccessedAugust 1, 2011.

Benchmarks for Measuring the Success of... Continued from cover

The medical home model hasdemonstrated improvedefficiency, lower costs, andoverall patient satisfaction.When we incorporate adiagnosis of cancer into theACO model, however, westruggle to find the perfect fit.


identify women with breast cancerassociated with ≥10 metastatic lymphnodes diagnosed between 1988 and2005. A total of 12,653 met the studyeligibility criteria. Radiation therapy was associated

with a 22% all-cause decreased riskof death and a 19% disease-specificreduced mortality risk from breastcancer; however, black race was asso-ciated with a 54% all-cause increasedmortality and a 53% breast cancer–specific increased mortality risk.This pattern did not change after

stratifying the results by type of sur-gery and the use of radiation therapy.The use of radiation therapy improvedOS and disease-specific survival inwhites and Asians, but not in blacks. The persistence of this disparity in

survival regardless of use of radiationtherapy and type of surgery, the inves-tigators note, suggests that limitedaccess to radiotherapy does notexplain the poorer survival ratesamong black women with metastaticbreast cancer. They add that blackwomen may be less responsive to radi-ation therapy, and their poorer OSrates may be associated with comor-bidities, or with tumor-related biologythat require further investigation inthis specific subpopulation. A study that focuses on black

women with metastatic breast canceris, therefore, warranted, the authorsnote, to elucidate the cause for this dis-parity in survival rates.

Vemurafenib ImprovesSurvival in MetastaticMelanoma with BRAF V600EMutationThe prognosis for patients with

metastatic melanoma is poor, rangingfrom 8 to 18 months, with only 1 drugcurrently approved in the UnitedStates for this patient population.Results of a phase 3 trial comparingthat drug with the investigationalagent vemurafenib show promise forpatients with BRAF V600E mutation(Chapman PB, et al.N Engl J Med. 2011;364:2507-2516).Approximately 40% to 60% of cuta-

neous melanomas involve mutationsin the BRAF gene that can activatetumor growth through the mitogen-activated protein kinase pathway.Previous studies have suggested thatmelanomas with the BRAF V600Emutation are more aggressive and lesssensitive to chemotherapy than thosewith the BRAF wild-type mutation.In early-phase clinical trials, vemu-

rafenib, a BRAF kinase inhibitor that

targets the BRAF V600Emutation, wasassociated with response rates >50% inpatients with BRAF V600E mutationmelanoma. Now, in the phase 3 BRAFInhibitor in Melanoma (BRIM)-3 clini-cal study, the benefits of vemurafeniband dacarbazine (DTIC-Dome)—theonly US and Food and Drug Admin -

istration–approved chemotherapeuticagent for the treatment of metastaticmelanoma—were compared in pa -tients with metastatic cancer.A total of 675 patients with previ-

ously untreated, unresectable stageIIIC or stage IV melanoma with theBRAF V600E mutation were random-

ly assigned to oral vemurafenib 960mg twice daily (N = 337) or to dacar-bazine 1000 mg/m2 infused every 3weeks (N = 338). At 6 months, the OS was 84% among

patients receiving vemurafenib versus64% among those receiving dacar-

IN THE LITERATURE


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No Access to Radiotherapy...Continued from page 6


Chicago, IL—Whole genome sequenc-ing was the topic of a session at the2011 ASCO annual meeting in whichspecialists discussed the implicationsof “genome-forward medicine” inlung cancer.This entails “how to get to the nature

of tumors and their heterogeneity,”said Elaine Mardis, PhD, Codirector ofthe Genome Institute at WashingtonUniversity, St Louis, MO. Next-genera-tion sequencing, she said, will eventu-ally guide treatment decisions.“Cancer is well known to be a dis-

ease of the genome,” Dr Mardis stated.“This is not limited to point mutationson genes but to the full spectrum ofsomatic alterations.”According to Dr Mardis, the genom-

ic discovery methods used by re-searchers are being applied to end-

stage and difficult-to-diagnose patientsto shape genome-guided treatmentdecisions. Currently, the patient popu-

lation is small, “but this is actively hap-pening today at somemedical centers,”she explained.

The next step is to make the processuser-friendly in the clinic. “We have tocompress the process into a time framethat is meaningful and appropriate forthe patient, which is the time betweendiagnosis and decisions about treat-ment—about 4weeks,” she pointed out.The stage is also being set, she said,

for moving genome-forward medicineinto clinical trials, to test expensive tar-geted agents in more enriched patientsubsets.

Targeted Agents Work in NSCLC

Ramaswamy Govindan, MD, also ofthe Genome Institute, emphasized that“targeted therapies in targeted patientswork. With mutation-targeted agentssuch as the epidermal growth factorreceptor [EGFR] inhibitors in non–small-cell lung cancer [NSCLC], re-

sponses can be durable.”The challenge now is to identify all

the other targets in lung cancer. Mosttargets that can be treated with drugshave been identified for adenocarcino-ma; fewer have been established forsquamous-cell carcinoma.“No one believes that EGFR is the

only player. Large populations ofmuta-tions are virtually unknown,” he noted.Researchers at the International

Cancer Genome Consortium CancerGenome Projects and the CancerGenome Atlas Research Network aresequencing thousands of genes in anintelligent fashion. They will prospec-tively collect fresh tumor samples fromprimary, recurrent, and metastatictumors, to be optimized for genomicanalysis of genetic mutations, as well

ASCO ANNUAL MEETING


Patients with Cancer at Risk for Bankruptcy... Continued from cover

ruptcy court records to determine therates of bankruptcy after cancer.“We found that persons filing for

bankruptcy tended to be younger,female, and nonwhite, and to be diag-nosed with local or regional diseaserather than distant disease,” DrRamsey said. “Also, across all cancerswe studied, young patients were atparticular risk. We think this is likelydue to the fact that young people havelower incomes, fewer assets, and lessaccess to insurance.”The 5 cancers with the highest associ-

ation with bankruptcy at 5 years were:• Lung cancer, 7.7%• Thyroid cancer, 4.8%• Leukemia/lymphoma, 3.6%• Uterine cancer, 3.2%• Colorectal cancer, 3.1%. The next 3 top cancers were mela -

noma, 3.0%; breast cancer, 2.9%; andprostate cancer, 1.7%.“We were puzzled that thyroid [can-

cer] was one of the most common,” DrRamsey said. “We think it’s becausethis is a cancer that occurs often inyoung women who may have fewerassets, lower income, and perhaps less

insurance coverage, because they maybe less likely to be employed. Thyroidcancer treatment is fairly straight -forward, but treatment actually costsmore than one would think. A courseof radioactive iodine is about $40,000,so this could be a factor as well.”

The 5-Year Postdiagnosis Trend

For the 231,799 patients investigated,after mean follow-up of 4.3 years, 4805(2.1%) filed for bankruptcy. Mediantime to bankruptcy was 2.5 years. Rates of bankruptcy filings generally

began to rise 1 year after diagnosis andpeaked before the Bankruptcy AbusePrevention and Consumer ProtectionAct of 2005. Rates then declinedsharply, before climbing again after2007 in conjunction with the recent“financial crisis.” For all patients,regardless of the cancer, rates steadilyclimbed to 5 years postdiagnosis. “The bankruptcy laws of 2005 influ-

enced the timing of bankruptcy filings.There was a huge spike prior to enact-

ment, followed by a very large decline,then a big increase after the financialcrisis,” Dr Ramsey said. Uncertainties regarding the poten-

tial impact of the bankruptcy law ledto a rush to file. For example, one ofthe law’s features is a “means test” thatcan disqualify some individuals frombankruptcy protection. Many lawyers,therefore, counseled patients who feltthey were at risk to file before imple-mentation of the law.“After the law was passed and ex -

perience with the procedures wasgained, lawyers realized the barrierswere not as great as they had assumed.As the legal community became com-fortable, there was a rebound in filing,which was accelerated by the financialcrisis,” he added.

Young Age a Risk Factor

Across all cancer types, a strongtrend was evident for increased ratesin younger populations, in a multivari-ate model adjusted for cofactors. Thehazard ratios (HRs) by age, in thisnon-Medicare population, are shownin the Table.In the multivariate model, other fac-

tors were shown to be influential:• Enforcement of new bankruptcylaws in 2005: HR, 0.31-0.42

• Female sex versus male: HR, 0.75(lung)

• Regional stage of disease at diagno-sis versus local stage: HR, 1.32-1.77

• Married versus nonmarried: HR,0.61 (breast cancer). �

“We found that bankruptcy is a particularrisk for patients with cancer….Personsfiling for bankruptcy tended to beyounger, female, and nonwhite, and tobe diagnosed with local or regionaldisease rather than distant disease.”

—Scott D. Ramsey, MD, PhD

Table Age-Related Risk for Filing Bankruptcy

Cancer typeHazard ratio, age 21-44 yrs

Hazard ratio, age 45-64 yrs

Lung 2.8 2.3

Breast 5.5 3.1

Prostate 3.6 1.8

Colorectal 4.1 2.8

Thyroid 3.0 2.3

Melanoma 4.7 2.5

Leukemia/lymphoma 3.8 2.2

Uterine 4.6 2.8

Genome-Forward Medicine in Lung CancerMutation rates are high in this malignancy By Caroline Helwick

“We have to compress theprocess into a time framethat is meaningful andappropriate for the patient,which is the time betweendiagnosis and decisionsabout treatment—about 4 weeks.”

—Elaine Mardis, PhD



Chicago, IL—The use of high-dosemethotrexate (HD-MTX) has demon-strated a significant improvement inevent-free survival in patients withpediatric acute lymphoblastic leu -kemia (ALL) at 5 years compared withthe standard regimen. The results of this large randomized

clinical trial were reported at theASCO 2011 annual meeting. “Pediatric ALL was once a deadly

form of leukemia, and now it’s one ofthe most curable,” said the study’slead investigator, Eric C. Larsen, MD,Director of the Maine Children’sCancer Program and the Division ofPediatric Hematology/Oncology atthe Barbara Bush Children’s Hospital,Portland. “With these results, we now have an

approach that will raise cure rates evenhigher,” he remarked.Dr Larsen was quick to point out the

oddity of finding a new approach totreatment using such an old drug—methotrexate has been available in oneform or another for more than 50 years.“To be perfectly honest with you, whenthis study was conceived 10 years ago,we didn’t have some new targeted ther-apy to be excited about, so we decidedto see if we could optimize an agent

that’s been around for a long time.”Methotrexate blocks the ability of

leukemia cells to use the essential Bvitamin folate, which leads to thedeath of leukemia cells. An early formof methotrexate, aminopterin, wasused by renowned cancer researcherSidney Farber, MD, to induce the firstleukemia remissions in children in1947. It later became an essentialcomponent of standard treatment inchildren with ALL; however, therehave been longstanding debatesregarding the optimization of themethotrexate dosing.The current clinical trial was

designed to test a higher-than-stan-dard dose of methotrexate—the so-called Capizzi regimen—in pediatricpatients with high-risk ALL—childrenwith a very high white blood cellcount at diagnosis, which indicatespoorer cure rates. A total of 3154 patients (aged 1-30

years) were randomized to either HD-MTX or the standard Capizzi escalat-ing methotrexate dose plus asparagi-nase (C-MTX) during a 2-monthinterim maintenance phase of therapyafter standard induction and consoli-dation chemotherapy.The trial began enrolling and treat-

ing patients in 2004 and was stoppedearly in 2011, after a planned interimanalysis demonstrated that the HD-MTX was clearly superior to the stan-dard regimen. “Results showed thatthe 5-year event-free survival rate was82% for HD-MTX versus 75% for C-MTX—a statistically significant differ-ence,” said Dr Larsen. It was thought that the higher dose

of methotrexate might incur greaterrates of adverse events in patients;however, no significant increases in

side effects were observed. In fact, theincidence of febrile neutropenia wassignificantly lower in the HD-MTXgroup, although the reason for thisfinding remains unclear. The overall impact of these findings

was striking. “The implementation ofHD-MTX in children with high-riskALL changed immediately as soon aswe stopped the protocol,” said DrLarsen. “Patients in the trial who hadbeen randomized to Capizzi and werenot too far into therapy were given thechoice of coming back and switching,and most did,” he said. “We feel this is now the new stan-

dard of care for children with high-riskALL,” Dr Larsen said. Based on theseresults, the Children’s OncologyGroup will soon be updating its treat-ment guidelines. �

ASCO ANNUAL MEETING


Genome-Forward Medicine...Continued from page 10

New Regimen with an Old Drug Boosts Survival in Pediatric ALLA new standard of care in children with high-risk diseaseBy Neil Canavan

“Results showed that the 5-year event-free survivalrate was 82% for HD-MTXversus 75% for C-MTX—a statistically significantdifference. With theseresults, we now have anapproach that will raise cure rates even higher.”

—Eric C. Larsen, MD

at a glance� High-dose methotrexate has

demonstrated a significant

improvement in event-free

survival in pediatric acute

lymphoblastic leukemia at 5

years compared with the

standard regimen

� Methotrexate blocks the ability

of leukemia cells to use the

essential B vitamin folate,

thereby leading to the death of

leukemia cells

� The results of this trial will

change the approach to therapy

of this patient population

� The Children’s Oncology

Group will soon be updating its

treatment guidelines based on

these new results

as other cancer processes. “By the endof this year we will see importantpapers coming from this research,” DrGovindan predicted.The clinical implications of genetic

analysis in NSCLC are the identifica-tion of new targets that can be treatedwith drugs; discovery of mechanismsof tumor resistance to treatment; sub-categorization of the disease that willdictate treatment approaches; and pre-diction, through genetic profiling, ofpersons at risk for lung cancer.“One thing has become obvious so

far: lung cancer is a more complex dis-ease than we once thought,” he point-ed out. “Compared to childhoodmalignancies, for example, the muta-tion rates are much higher.”An example of the complexity is the

“stunning difference” in the number ofmutations observed in tumors thatcome from nonsmokers versus smok-ers. Smokers’ tumors have multiple

mutations in DNA repair pathwaysthat are completely absent in tumors ofnonsmokers.

“We must get used to the notion thatcancer is heterogeneous. We areunlikely to find common mutations inmore than about 5% of patients,” DrGovindan stated. �

“Lung cancer is a morecomplex disease than weonce thought….We must getused to the notion thatcancer is heterogeneous. Weare unlikely to find commonmutations in more thanabout 5% of patients.”

—Ramaswamy Govindan, MD

Register Now

Register online at www.AVBCConline.org

2011 REGIONAL MEETINGSSeptember 24Chicago, IL

October 1San Francisco, CA

November 19Tampa, FL


ASCO ANNUAL MEETING


Emerging Regimen for Metastatic Pancreatic Cancer HasSurvival Benefit, but Is It Cost-Effective?By Neil Canavan

Chicago, IL—Acost analysis presentedat ASCO 2011 and performed at theUniversity of Toronto, Odette CancerCenter, Ontario, showed that theemerging combination regimen thatincludes oxaliplatin (Eloxatin), iri -no tecan (Camptosar), fluorouracil(Adrucil) and leucovorin (FOLFIRI-NOX) is not cost-effective when con-sidered within the framework of a willingness-to-pay threshold of$100,000 per quality-adjusted life-year(QALY). Nevertheless, treatment withFOLFIRINOX may provide the mostclinical benefit for patients withmetastatic pancreatic cancer.The $100,000 per QALY amount is

the benchmark generally used in theUnited States to consider cost-effec-tiveness of a treatment. “Right now the standard treatment

for metastatic pancreatic cancer isgemcitabine [Gemzar],” said VincentC. Tam, MD, lead investigator and

Gastrointestinal Oncology Fellow atOdette Cancer Center. In the setting of metastatic pancreat-

ic cancer, “there are also variantson the gemcitabine theme—addingcapecitabine [Xeloda] for instance, orthe targeted-agent erlotinib [Tarceva]….But most treatments have been shownto be effective only by way of meta-analysis, because of the small numberof patients enrolled in many trials,”Dr Tam said.Dr Tam and colleagues undertook

the current cost analysis, becauseFOLFIRINOX has recently beenshown in another study to have supe-rior survival rates when comparedwith the standard therapy with gem -citabine. Those results were presentedlast year at ASCO 2010 and have justbeen published (Conroy T, et al. N EnglJ Med. 2011;364:1817-1825).“This is going to be the emerging

treatment,” said Dr Tam. “We need tonow consider the price tag.”

Cost Analysis

To determine cost-effectiveness, aMarkov model was constructed for ahypothetical cohort of patients with

metastatic pancreatic cancer to assessthe costs and outcomes of the 4 treat-ment options—gemcitabine, gem -citabine plus capecitabine, gemcitabineplus erlotinib, and FOLFIRINOX—over a 2-year period. The primary outcome was the incre-

mental cost-effectiveness ratio (ICER),measured in dollars per QALY. Ef -ficacy data for all 4 treatments wereobtained from the published results ofphase 3 clinical trials. Resource utilization data were

derived from reviewing charts of con-secutive patients treated at PrincessMargaret Hospital between 2008 and2009, and supplemented with resourceutilization data from the medical liter-ature. Unit costs were obtained from

the Ontario Ministry of Health andLong-Term Care, Sunnybrook HealthSciences Centre, and the literature.Both cost and effectiveness were dis-counted at 3%.The results of this analysis show that

the ICERs of gemcitabine plus cape -citabine, gemcitabine plus erlotinib,and FOLFIRINOX compared withgemcitabine were $82,982/QALY,$204,952/QALY, and $154,323/QALY,respectively (Table). “The model is mostly driven by the

acquisition cost of drugs, and it may besensitive to the relative efficacy oftreatments,” reported Dr Tam. He saidthat in Canada, the unit price ofFOLFIRINOX (primarily the oxali-platin component) would have to bereduced to attain the $100,000 green-light threshold. As is, the gemcitabineplus capecitabine regimen is morecost-effective.

Significant Survival Advantage

The issue of price and the newlypublished results showing a 3- to4-month survival advantage forFOLFIRINOX will certainly becomethe subject of debate among pro -viders, patients, and payers. “Patientswill be pushing for this treatment,”said Dr Tam, while drug manufactur-ers will be pushing for FOLFIRINOXto be reimbursed. How this will play out in drug for-

mularies in the United States remainsto be seen. �

“This is going to be the emerging treatment. We need to now consider the price tag. Patients will be pushing for this treatment.”

—Vincent C. Tam, MD

at a glance� The emerging regimen

FOLFIRINOX is more costly

than the current standard

therapy for metastatic

pancreatic cancer but has

shown a 3- to 4-month

survival benefit

� It can be expected that

this regimen will become a

treatment option for this

patient population

� The higher cost of this

regimen, however, is likely to

invoke a debate among

providers, payers, and patients

� Whether health plans will

reimburse for this new

combination regimen

remains to be seen

Table Cost and Clinical Outcomes: Gemcitabine versus FOLFIRINOX

GemcitabineGemcitabine +

capecitabineGemcitabine +

erlotinib FOLFIRINOX

Cost, $a 29,658 34,139 46,874 65,924

Life expectancy, yr 0.677 0.762 0.790 1.005

QALY 0.529 0.583 0.613 0.764

ICER vs gemcitabinealone, $a/QALY — 82,982 204,952 154,323

aCanadian $. FOLFIRINOX indicates oxaliplatin, irinotecan, fluorouracil, and leucovorin; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Chicago, IL—The “big news” in meta-static ovarian cancer presented atASCO 2011 involved the investigationalpoly (ADP-ribose) polymerase (PARP)inhibitor olaparib, which prolongedprogression-free survival (PFS) bynearly 4 months versus placebo. Theresults of this study were reported inthe June issue of VBCC.In addition, 2 other studies reported

in the meeting show that maintenancetherapy with bevacizumab (Avastin)reduced the risk of disease progres-sion, both in the metastatic setting andin early-stage disease.

The OCEANS Trial

The phase 3 randomized, double-blind, multicenter OCEANS trial eval-uated the use of bevacizumab pluscarboplatin (Paraplatin) and gemc-itabine (Gemzar) versus chemotherapyalone in 484 women with recurrentplatinum-sensitive ovarian cancer.After 6 cycles, those receiving the

bevacizumab-containing regimen con-tinued to receive bevacizumab aloneas maintenance therapy until diseaseprogression.Patients in the bevacizumab arm


Bevacizumab MaintenanceReduces Disease ProgressionRisk in Ovarian CancerPotential new option for recurrent platinum-sensitive disease By Audrey Andrews


ASCO ANNUAL MEETING


Chicago, IL—The potential of 2 novelagents still in clinical trials, and 1 drugthat was recently approved, offer newhope to patients with metastatic cas-trate-resistant prostate cancer (mCRPC),a disease with a dire prognosis and fewgood current treatment options.

First-in-Class R-223

One of the investigational agents,alpharadin (radium-223 chloride [R-223]), may have just earned a chancefor an expedited approval by the USFood and Drug Administration (FDA)because of its positive results.R-223 is a first-in-class alpha-emitter

radioisotope pharmaceutical, whichtargets bone metastases with its high-energy alpha radiation, thereby affect-ing prostate metastatic cells. However,because of its short-range effects, itspares the patient’s bone marrow. In 2 phase 2 clinical trials reported at

the 2011 ASCO Annual Meeting, R-223was tested in mCRPC patients withbone metastasis (N = 101). The com-bined aim of the trials was to deter-mine if normalization of levels of alka-line phosphatase (ALP), a marker of

bone metabolism, could be taken as asurrogate for R-223 efficacy. In both trials—one a randomized,

placebo-controlled study (N = 64) andthe other a dose escalation trial (N =117)—ALP normalization was stronglycorrelated with overall survival (OS). In both trials, the median survival

was 102 weeks in patients with ALP

normalization versus <58 weeks forthose without ALP. In the dose-escala-tion study, treatment response in -creased with the increasing dose. Of note, approximately 50% of

patients treated with R-223 did not

achieve ALP normalization, indicatingALP as a potentially good marker togauge patient response.

Phase 3 Trial Terminated Early

Within hours of these findingsbeing reported at the meeting, R-223manufacturer announced off-site thatan interim analysis of their R-223phase 3 trial in mCRPC (N = 922) pro-duced such impressive results that thetrial was immediately halted in accor-dance with the recommendation ofthe Independent Data MonitoringCom mittee.In patients with mCRPC and bone

metastases, R-223 treatment resulted inan OS of 14.0 months versus 11.2months for placebo. Lead investigator Chris Parker, MD,

of the Royal Marsden Hospital, said,“Approximately 90% of men withadvanced prostate cancer have bonemetastases, which are the main causeof disability and death in this disease.”Based on the observed survival bene-fits of these 3 trials, R-223 is expected tobecome an important treatment optionfor this patient population.

Surprising Results

with Cabozantinib

A second surprise was reported forthe novel agent cabozantinib, aninhibitor of tumor growth and metasta-sis signaling pathways involving METand vascular endothelial growth factorreceptor 2. In a phase 2 clinical trial,patients with mCRPC and progressivemeasurable disease received 100 mg ofcabozantinib daily; response wasassessed at 6 and 12 weeks.Although the trial was slated to

recruit up to 200 patients, accrual washalted at 168 patients, because of earlyobserved rates of robust clinical activi-ty. Interim analysis for cabozantinib-treated patients showed bone meta s -tases shrinking in 76% of subjects. Of the 108 patients evaluable for

bone scan, 21 demonstrated completeresolution of bone lesions and 61 hadpartial shrinkage—these lesions canlead to bone fractures, severe pain, andeventual death.Study investigators reported that,

“Cabozantinib showed clinical activi-ty regardless of prior treatment withdocetaxel,” indicating that patientswere still responsive to agents likecabozantinib.

Progress with Abiraterone

After an expedited 6-month review,

the novel agent abiraterone acetate(Zytiga) was approved by the FDA inApril 2011. Since then, physicians havebeen using the drug in patients whohave been previously treated withthe standard treatment ketoconazole(Nizoral), a molecule with a similarmechanism of action to abiraterone. As the transition from the old stan-

dard treatment to the one showingsuperior efficacy goes forward, thequestion is, would patients receivingketoconazole before treatment beresistant to abiraterone? (Patients tak-ing ketoconazole were excluded fromthe abiraterone registration trial.)An interim analysis for the first

14 ketoconazole-experienced patientswith mCRPC was reported at the meet-ing. Median follow-up was 13.1 weeks.Treatment response was defined aspercent decline in prostate-specificantigen (PSA) from baseline. Results showed that abiraterone

therapy induced a ≥50% decline in PSAat 12 weeks in 3 of 14 patients, and a≥30% decline in 6 of 14 patients. Of the patients without a ≥30% PSA

decline, 1 had developed ResponseEvaluation Criteria In Solid Tumors–defined disease progression at 12weeks and the remainder had stabledisease.Although accrual for this trial is

ongoing, results thus far are promising.Trial investigators did comment, how-ever, that the lower responses observedin this study compared with ketocona-zole-naïve patients with mCRPC sug-gests the potential for overlappingmechanisms of resistance. �

Impressive Results with New Drugs for Advanced Prostate CancerBy Neil Canavan

“Approximately 90% of men with advanced prostatecancer have bone metastases,which are the main cause of disability and death in this disease.”

—Chris Parker, MD

at a glance� Alpharadin (R-223) is a first-in-

class alpha-emitter radioisotope

pharmaceutical that targets

bone metastases but spares

the patient’s bone marrow

� Alkaline phosphatase (a

marker of bone metabolism)

normalization was strongly

correlated with overall survival

in patients with metastatic

castrate-resistant prostate

cancer (14.0 months vs 11.2

months for placebo)

� Interim analysis for

cabozantinib-treated patients

showed bone metastases

shrinking in 76% of subjects

� Abiraterone therapy induced

a ≥50% decline in PSA at 12

weeks in 3 of 14 patients, and a

≥30% decline in 6 of 14 patients

had a median PFS of 12.4 months com-pared with 8.4 months with chemo-therapy alone (P <.001), representing a52% reduction in the risk of progres-sion, said Carol Aghajanian, MD,Memorial Sloan-Kettering CancerCenter, New York.“OCEANS is a positive study. We

met our primary end point,” DrAghajanian said at a press briefing.“The safety data are also reassuringand consistent with the known sideeffect profile. We believe this regimenshould be considered a new option forrecurrent platinum-sensitive ovariancancer.”

ICON7 Updated

A second analysis presented at themeeting was the updated results fromthe ICON7 trial of 1528 women withearly- or advanced-stage ovarian can-cer who received carboplatin and pacli-taxel (Taxol), with or without beva-cizumab, for 6 cycles. In theexperimental arm, at the end of the 6cycles, bevacizumabmonotherapy was

continued as mainte-nance therapy for a total of 12 cycles.In this study, the PFS was 19.8

months in the bevacizumab arm and17.4 months with chemotherapyalone—a 13% reduction in progressionrisk (P = .039).In addition, a 15% reduction in risk

of death was also seen in this study, butthis was not statistically significant,reported Gunnar Kristensen, MD,Norwegian Radium Hospital in Oslo,Norway.Subgroup analysis showed that

patients deemed at highest risk for dis-ease recurrence—those with subopti-mally debulked stage III cancer—hadeven better outcomes, experiencing asignificant 36% reduction in the risk ofdeath (P = .002). Median overall sur-vival was 36.6 months in the beva-cizumab arm compared with 28.8months in the control arm.Dr Kristensen noted that the study

revealed a treatment effect that isgreater in high-risk patients, “and thismay be of clinical relevance.” �

Bevacizumab MaintenanceReduces Disease... Continued from page 12


3 ye

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Multipl

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www.VELCADE.com

If You Define Value as an Overall Survival Advantage:

If You Define Value as Medication Cost:

VELCADE Warnings, Precautions, and Adverse Events

Please see Brief Summary for VELCADE on the next page of this advertisement.

UPDATED VISTA* OVERALL SURVIVAL (OS) ANALYSIS: VcMP† vs MP(36.7-month median follow-up)

VELCADE+MP (n=344)MP (n=338)

% P

atie

nts

With

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In Previously Untreated Multiple MyelomaIMPORTANT 3-YEAR UPDATE- SUSTAINED BENEFIT

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INDICATIONS:

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphomawho have received at least 1 prior therapy.

CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use ofantineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment withVELCADE.

Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while beingtreated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and adecreased number of live fetuses.

Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory.However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients withpre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheralneuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment withVELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation,hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencingnew or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE.Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51%of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement inor resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. Thelong-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. Theseevents are observed throughout therapy. Caution should be used when treating patients with a history ofsyncope, patients receiving medications known to be associated with hypotension, and patients who aredehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensivemedications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset ofdecreased left ventricular ejection fraction have been reported, including reports in patients with no riskfactors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart diseaseshould be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively.The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure,cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causalityhas not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknownetiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory DistressSyndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial,the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicinand VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. Therehave been reports of pulmonary hypertension associated with VELCADE administration in the absence ofleft heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonarysymptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patientsreceiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure,hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances.Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patientsdeveloping RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previouslyexperiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, andvomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid andelectrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia thatfollow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recoveringprior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases andrecovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence ofcumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In therelapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar onboth the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to eachdose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and scheduleof VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association withVELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, thecomplications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those withhigh tumor burden prior to treatment. These patients should be monitored closely and appropriateprecautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitantmedications and with serious underlying medical conditions. Other reported hepatic events includeincreases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upondiscontinuation of VELCADE. There is limited re-challenge information in these patients.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure isincreased in patients with moderate or severe hepatic impairment. These patients should be treated withVELCADE at reduced starting doses and closely monitored for toxicities.

ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma(N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) andpreviously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, thesafety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (includingfatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheralneuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%),thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%),anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), coughand insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo);(each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension(each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia(each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) ofpatients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) andneutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies.The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%),and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination withmelphalan/prednisone is consistentwith the known safety profiles of both VELCADE and melphalan/prednisone.The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vsmelphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea(48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%),constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%),pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%),asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%),rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%),dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain(14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%),hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension(12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%),arthralgia (11% vs 15%) and pruritus (10% vs 5%).

DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib.Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposureof bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole,a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantlyreceiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closelymonitored for either toxicities or reduced efficacy.

USE IN SPECIFIC POPULATIONS:

Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs areexcreted in human milk and because of the potential for serious adverse reactions in nursing infants fromVELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking intoaccount the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 andyounger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renalimpairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency.Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysisprocedure. For information concerning dosing of melphalan in patients with renal impairment, seemanufacturer's prescribing information.

Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate andsevere hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabeticpatients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADEtreatment may require close monitoring of their blood glucose levels and adjustment of the dose of theirantidiabetic medication.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc.Other trademarks are property of their respective owners.Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Cambridge, MA 02139Copyright ©2009, Millennium Pharmaceuticals, Inc.

Brief Summary

All rights reserved. Printed in USA V1215 12/0910V-10-020410

Cambridge, MA 02139


ASCO ANNUAL MEETING


4 7

Chicago, IL—A series of studies pre-sented at this year’s ASCO annualmeeting suggest that the use of unwar-ranted high-cost imaging procedures,a surge in the use of innovative treat-ment technologies, and off-label use ofsupportive cancer agents are helpingto escalate Medicare costs, leadingresearchers to suggest that further reg-ulation may be needed to rein in un -necessary expenses.

The first study examined trends inthe use of advanced imaging tech-niques in elderly patients withmetastatic cancer. “Like all interven-tions in patients with metastatic solidtumors, imaging may contribute topalliation but is unlikely to lead tolong-term survival,” said investigatorYue-Yung Hu, MD, a surgical researchfellow at Brigham and Women’sHospital, Boston, MA. “We wanted todetermine pattern use, because costshave been rising so rapidly.”

Dr Hu and colleagues compared 2retrospective data sets from Sur veil -lance, Epidemiology and End Results(SEER)-Medicare claims dating from1999 to 2005. The first set accounted forthe use of high-cost imaging proce-dures—such as computed tomogra-phy, magnetic resonance imaging,positron-emission tomography, and

nuclear medicine—in elderly patientswith metastatic disease (stage IV; N =64,267); the second data set consisted oforders for imaging studies in patientswith early-stage disease (N = 127,827).

Excess High-Cost Imaging in

Late-Stage Disease

The results were striking: stage IVpatients underwent a mean of 2.4high-cost imaging procedures duringtheir first 60-day diagnostic periodcompared with 0.8 procedures inpatients with early-stage disease.

In addition, after the initial diagno-sis, elderly patients were imaged onaverage once every 43 days, and 41% ofthe terminally ill patients underwentan imaging procedure in the last monthof life (regardless of tumor type).

“We thought that the longer you’reexpected to live, the more imagingwould be done, but that was not thecase,” said Dr Hu. “It’s hard to sayexactly what all these scans were for.One of the things we’ll be looking at inthe future is if there was some changein management that happens aroundthe time of these scans that could justi-fy the procedure—but really, in the last

30 days of life, what useful informa-tion could be new?”

Trends in Prostate

Cancer Treatment

A second study looked at the escalat-ing use of intensity-modulated radia-tion therapy (IMRT) for the treatment ofprostate cancer compared with other,less costly standards of care. “In the lastdecade, a number of novel treatmentoptions have been developed, includ-ing minimally invasive radical prosta-tectomy and IMRT,” said coinvestigatorMichaela Dinan, Duke ClinicalResearch Institute, Durham, NC. MsDinan and colleagues were interestedin the financial implications of theavailability of these new technologies.

Based on Medicare records forpatients with prostate cancer from 1999to 2007 (N = 20,399), IMRT has replacedstandard 3-dimensional conformalradiation therapy (3D-CRT) as the mostcommon method of prostate radiother-apy, which was used in 66% of allMedicare patients with prostate cancerwho were receiving radiotherapy.

“With Medicare reimbursement forIMRT averaging $48,000 per benefici-ary versus $22,000 for 3D-CRT, thistrend has significant budgetary impli-cations,” stated Ms Dinan, especiallygiven the aging of the US populationand the inevitable increase in futureprostate cancers.

Prescribers of Off-Label Use

A third study examined prescribingtrends for the already well-known off-label use of erythropoiesis-stimulatingagents (ESAs), which are approved totreat debilitating anemia in chemo -therapy patients.

“These are drugs that are associatedwith significant costs to the overallhealthcare system,” said Jason D.Wright, MD, Columbia University,New York. “And we already know thatthese are drugs that are often utilizedin a way that’s different from whatthey were approved for by the FDA.”

Dr Wright and colleagues wonderedif it was possible to identify the physi-cian characteristics responsible for thevaried patterns of ESA misuse.

In a retrospective analysis of pre-scribing patterns using a SEER-Medicare data set dating back overthe past 10 years, records of 21,091patients with cancer were reviewed. Ofthese patients:• 5099 (24.2%) received ESAs for <1

week (misuse)• 1601 (7.6%) received ESAs for >14

weeks (prolonged use is often mis-use)

• 2876 (13.6%) patients received ESAswhile not actively receiving chemo -therapy (off-label).

In a multivariable analysis, ESA mis-use was associated with physicianswith an MD degree and greater num-ber of years since medical school grad-uation. Treatment by high-volumeoncologists, private-practice physi-cians, and oncologists who graduatedfrom US medical schools predictedprolonged duration of ESA use. ESAuse should be limited to times ofchemotherapy administration. Femaleoncologists were less likely to pre-scribe prolonged ESA use.

“This study further bolsters theargument that a lot of noncancer-relat-ed factors are driving how we pre-scribe ESAs,” said Dr Wright, althoughhe is quick to point out that off-labeluse is not by definition irresponsible.

“Each patient is a unique individual.There are circumstances where usebeyond the label is reasonable,” hesaid. The problem is not so muchunreasonable use as it is increasinglyuntenable expense. �

Off-Label Drug Use, Advanced Technologies Driving UpMedicare Cost of Cancer CareValue of aggressive utilization in late-stage cancer questionedBy Neil Canavan

at a glance� Use of unwarranted high-cost

imaging procedures, innovative

treatment technologies, and

off-label use of supportive

cancer agents are escalating

Medicare costs

� Patients with stage IV disease

underwent a mean of 2.4 high-

cost imaging procedures during

their first 60-day diagnostic

period compared with 0.8

procedures in patients with

early-stage disease

� After initial diagnosis,

terminally ill elderly patients were

imaged on average once every

43 days; 41% of these patients

underwent an imaging procedure

in the last month of life

� Intensity-modulated radiation

therapy has replaced standard

3D-CRT as the most common

prostate radiotherapy

“With Medicarereimbursement for IMRTaveraging $48,000 perbeneficiary versus $22,000for 3D-CRT, this trend hassignificant budgetaryimplications.”

—Michaela Dinan

“This study further bolstersthe argument that a lot ofnoncancer-related factors are driving how we prescribe ESAs.”

—Jason D. Wright, MD

“One of the things we’ll be looking at in the future is if there was some change in management that happens around the time of these scans that could justify theprocedure—but really, in the last 30 days of life, what useful information could be new?” —Yue-Yung Hu, MD



ASCO ANNUAL MEETING

Studies presented at the 2011annual meeting of the AmericanSociety of Clinical Oncology

(ASCO) suggest that patients withmetastatic mel anoma or with non–small-cell lung cancer (NSCLC)—2disease states with very high rates ofmortality—may soon have new treat-ment options.Other reports suggest the ongoing

promise of drugs in various stages ofdevelopment for the treatment ofmetastatic castration-resistant prostatecancer (mCRPC), as well as metastaticsarcoma, myelofibosis, and ovariancancer.Although it is by no means a com-

prehensive list of investigationalagents with positive data reported atASCO 2011, this summary representssome of the top highlights as indicatedby the opinions of clinical experts, theattention paid by financial analysts,and overall attendance at given ASCOpresentations.

Lung Cancer

“Truly brilliant,” said Nasser H.Hanna, MD, Associate Professor ofHematology/Oncology at IndianaUniversity, Indianapolis, commentingon the ongoing investigational resultspresented for crizotinib. Since enter-ing its first human trials, crizotinib hasgarnered considerable attention notonly for its observed activity inpatients with NSCLC, but also for its“adaptive” trial design.

Molecular targeting to the anaplasticlymphoma kinase (ALK) is key to theefficacy of crizotinib; the ALK onco-gene pathway is highly active in asmall subset of patients with NSCLC. “The striking activity of crizotinib in

ALK-positive lung cancer was apparentvery early in clinical development,” saidstudy investigator, D. Ross Camidge,MD, PhD, Associate Professor, Divisionof Medical Oncology, University ofColorado, Denver. Dr Camidge reported the results of a

phase 2 investigation, which looked atthe overall survival (OS) of patientswith ALK-positive lung cancer that

had been involved in 2 phase 1 trialswith crizotinib.The results of this analysis showed

that among the 82 patients with ALK-positive lung cancer treated withcrizotinib, the 1-year OS was 77% andthe 2-year OS was 64%, which com-pares highly favorably with historicalcontrols. In addition, when looking at pa -

tients by line of therapy, survival of 32patients treated with second- or third-line crizotinib was significantly longerthan that of 24 controls with ALK-pos-itive lung cancer (P = .004): 1-year OSwas 71% versus 46%, respectively, and2-year OS was 61% vs 9%, respectively.

Metastatic Melanoma

“Unprecedented” is how lead in -vestigator Paul Chapman, MD, ofMemorial Sloan-Kettering CancerCenter, New York, described the out-come of his clinical trial with vemu-rafenib in patients with metastaticmelanoma, a condition that is invari-ably fatal.Vemurafenib is a targeted agent,

specifically designed to inhibit thetumor-generating activity of a muta-tion in the BRAF signaling pathway,an error found in 60% of all mel -anomas. In Dr Chapman’s phase 3study, treatment with vemurafenibwas compared with that of the currentstandard, dacarbazine (DTIC) in 675metastatic melanoma patients with theBRAF mutation.The superior efficacy of vemurafenib

was observed almost immediately.“The survival curves separated veryearly,” said Dr Chapman at a press con-ference heralding the results. Althoughnot enough time had passed to calcu-late a median OS, the estimated 6-month survival for patients receivingvemurafenib was 84% compared with64% for those treated with dacarbazine. “That’s a 63% decrease in risk of

death—a huge difference,” said DrChapman. Large differences were alsoobserved for disease progression-freesurvival (PFS). (See full story in theJune 2011 issue of VBCC.)

Prostate Cancer

Cabozantinib, an inhibitor of tumorgrowth and metastasis signaling path-ways involving MET, and vascularendothelial growth factor 2 was shownto have impressive activity in a phase2 investigation—so impressive thatenrollment to the trial was suspendedbased on the results from an interimanalysis.

The interim results showed that inpatients with mCRPC, 76% of subjectsachieved shrinkage of their bonemetastases, including 21 patients whodemonstrated a complete resolution ofbone lesions, which are often the causeof severe pain and eventual death inpatients with mCRPC.The radioactive, bone-seeking com-

pound, radium-223, was also tested inpatients with mCRPC. The results ofthis investigation were so unexpectedlypositive that its manufacturer, AlgentaASA, in partnership with Bayer, imme-diately halted the trial following therecommendation of the IndependentData Monitoring Committee.

In a large trial with more than 900CRPC patients with bone metastases,treatment with radium-223 was able toextend OS to 14.0 months comparedwith 11.2 months for patients receivinga placebo. (See article on page 13.)

Sarcoma

The novel compound ridaforolimustargets the mTOR signaling pathway,which is activated in most sarcomas.In a phase 3 investigation of this

new agent, 711 patients with metastat-ic sarcoma were randomized to either

ridaforolimus or placebo as mainte-nance therapy following stable diseaseor better response to prior chemother-apy. The primary end point of thisstudy was PFS, with a secondary endpoint of OS and safety end points.Results showed that treatment with

ridaforolimus achieved median PFS of17.7 weeks versus 14.6 weeks for place-bo, an improvement of 21%. Althoughdata accrual for OS is ongoing, current-ly observed events indicate a trendfavoring ridaforolimus, with medianOS of 88.0 weeks for ridaforolimus ver-sus 78.7 weeks for placebo.The incidence of stomatitis was high

in the ridaforolimus cohort (52%), butthese levels are considered in linewith previous experience with othermTOR inhibitors.Commenting on these results, study

investigators stated, “The rapid pro-gression of metastatic sarcomas dem -onstrates the aggressive nature of thesemalignancies, and maintenance thera-py with ridaforolimus will provide anew option for patients.”

Ovarian Cancer

Poly (ADP-ribose) polymerase(PARP) inhibitors have previouslyshown impressive activity in animalstudies, capturing the attention of anumber of leading researchers. How -ever, after recent and very surprisingnegative results for the use of thePARP inhibitor iniparib in triple-nega-tive breast cancer patients, interestedparties have been on the lookout forother potential disease settings thatmay be more responsive to PARPinhibitors (which interferes with DNArepair in tumor cells). This interestconfirmed at ASCO where olaparibdata in ovarian cancer were presented. The first study presented was a

phase 2 trial where either olaparib orplacebo was used as a maintenancetreatment in 117 patients with plat-inum-sensitive ovarian cancer. Pa -tients were treated until their diseaseprogressed.Results showed that olaparib treat-

ment extended PFS to 8.4 months ver-sus 4.8 months for patients receivingplacebo—a significant improvement.In addition, the iniparib regimen waswell tolerated by patients. “This is thefirst study demonstrating a signifi-cant PFS benefit following mainte-nance treatment with a PARPinhibitor,” said lead investigator,Jonathan Ledermann, UniversityCollege, London, United Kingdom.

The Oncology Drug Pipeline Is PromisingBy Neil Canavan

“That’s a 63% decrease inrisk of death—a hugedifference.”

—Paul Chapman, MD

“The striking activity ofcrizotinib in ALK-positivelung cancer was apparentvery early in clinicaldevelopment.”

—D. Ross Camidge, MD, PhD

“The rapid progression ofmetastatic sarcomasdemonstrates the aggressivenature of these malignancies,and maintenance therapywith ridaforolimus willprovide a new option forpatients.”



bazine, and the estimated median pro-gression-free survival (PFS) was 5.3months and 1.6 months, respectively.Compared with dacarbazine, vemu-

rafenib was associated with a 63% rel-ative risk reduction for death and a74% risk reduction of either death ordisease progression.The response rate with vemurafenib

was 48% versus 5% with dacarbazine.The results show improved OS and

PFS with vemurafenib monotherapyin this patient population. Further -more, a survival benefit was observedin all subgroups of patients receivingvemurafenib, including those withstage M1c disease or an elevated lac-tate dehydrogenase level, conditionsassociated with an especially poorprognosis. The most common adverse events

associated with vemurafenib werearthralgia, rash, fatigue, alopecia, sec-ondary neoplasia (keratoacanthoma orsquamous-cell carcinoma), photosen-sitivity, nausea, and diarrhea. In allcases of secondary neoplasia (18%)associated with vemurafenib, thelesions were removed by simple exci-sion and no modifications in drugdose were necessary.

Intensified BEACOPP DoesNot Provide Long-TermAdvantage in HodgkinLymphomaFor patients with advanced Hodg-

kin lymphoma, an intensified initialregimen of bleomycin, etoposide,doxorubicin, cyclophosphamide, vin-cristine, procarbazine, and prednisone(BEACOPP) may provide better initialtumor control but not long-term clini-cal benefits than the standard regimenwith doxorubicin, bleomycin, vinblas-tine, and dacarbazine (ABVD), espe-cially in patients who require high-dose salvage therapy afterward(Viviani S, et al. N Engl J Med. 2011;365:203-212).Previously, the German Hodgkin

Lymphoma Group had advocated itsescalated BEACOPP regimen (whichincludes higher than standard doses ofetoposide, doxorubicin, and cyclo-phosphamide) as the preferred stan-dard treatment over ABVD in thetreatment of high-risk, advancedHodgkin lymphoma, based on datashowing better tumor control andlong-term OS.To determine whether these claims

applied to patients who require high-dose salvage therapy after the initialtreatment, Italian researchers com-pared the 2 regimens over a median 61

months in 331 patients with untreatedstage IIB, III, or IV Hodgkin lym-phoma from 3 centers.Patients were randomized to initial

therapy with 6 or 8 cycles of ABVD(N = 168) or 8 cycles (4 escalated, 4standard) of BEACOPP (N = 163), fol-lowed by radiotherapy, as needed.Those who demonstrated a less-than-

complete response or relapsed dis-ease received salvage chemotherapyconsisting of a standard ifosfamide-based reinduction regimen followedby 1 high-dose course of therapywith carmustine, etoposide, cytara-bine, and melphalan, supported byautologous hematopoietic stem-cellrescue.

The estimated 7-year rate of PFS, theprimary end point, was 85% withBEACOPP versus 73% with ABVD(P = .004). However, when discontinu-ation was calculated, that rate did notdiffer significantly. Neither did the rateof freedom from second progression orOS after salvage therapy in 65 patients.

IN THE LITERATURE


CHEMOTHERAPY FOUNDATION SYMPOSIUMINNOVATIVE CANCER THERAPY FOR TOMORROW®

November 8-12, 2011, New York City

Emerging Developments in Cancer TherapeuticsNew Agents, Clinical Trials, Personalized MedicinePractical Applications for the Practicing OncologistThe Changing Environment of Health Care Delivery

ScheduleNov. 8 Pediatric OncologyNov. 9 Hematology, GI CancersNov. 10 GYN, Thyroid, Head & Neck,

Breast CancersNov. 11 GU, Lung, Melanoma,

Novel Agents, Neuroendocrine, Melanoma, Practice Issues

Nov. 12 New Perspectives in Oncology Practice

Conference HighlightsWednesday, November 9Keynote Lecture: The Oncology Time WarpJames Holland, MDThursday, November 10Ezra M. Greenspan Memorial Lecture:Cure of Her2 Positive Breast Cancer with Noor Minimal Chemotherapy at the Door Step?Martine Piccart, MDFriday, November 11Judah Folkman Memorial Lecture: Anti-Angiogenesis: Paradise Lost?Norman Wolmark, PhD

A CME Oncology Conference presented by the

Mount Sinai School of Medicineand The Chemotherapy Foundation

Tuesday, November 8Pediatric Oncology

Therapeutic Advances in Cancers of Childhood

Saturday, November 12Oncology Nurses, Physician Assistants, Case Managers, Pharmacists

Therapeutic Advances, Treatment Related Complications,Supportive Care, Symptom Management, Targeted Therapies

Register on line at www.chemotherapyfoundationsymposium.orgContact: [email protected], (212) 866-2813

The Greenspan Meeting XXVIII

Complimentary Breakfasts, Lunches, Dinners





































































Vemurafenib ImprovesSurvival...Continued from page 9



Chicago, IL—Results from a phase 3clinical trial presented at a plenary ses-sion at ASCO 2011 could lead to pro-longed treatment with adjuvant ima-tinib for gastrointestinal stromaltumors (GIST).The extension of imatinib (Gleevec)

treatment to 3 years, compared withthe usual 1 year, resulted in a 54%reduced risk of recurrence and 55%reduced risk of death within 5 yearsfor patients with high-risk disease,reported Heikki Joensuu, MD,Helsinki University Central Hospital,Finland.“These data are pretty compelling,”

Dr Joensuu said. “I would not be sur-prised if the standard will be 3 years ofadjuvant imatinib in the near future.”Mark G. Kris, MD, who moderated

a press briefing and is Chair of theASCO Cancer Communications Com -mittee, agreed. “The entire oncologycommunity was extremely excitedwhen we saw the survival curve andthose numbers at 5 years. It’s one ofthe amazing stories in oncology, and itis the kind of data that change guide-lines,” he said.

Study Details

The Scandinavian Sarcoma Groupand Sarcoma Group of the AIO,Germany, conducted the SSGXVIII/AIO study, a phase 3 open-label clini-cal trial that evaluated 36 months ver-sus 12 months of adjuvant imatinib

administered after surgical resection to400 patients with GIST at high risk ofrecurrence.At a median follow-up of 54

months, recurrences or death occurredin 50 of 198 (25%) patients receiving 36months of imatinib compared with 84of 199 (42%) patients receiving only 12months of treatment. The recurrence-free survival rate was

86.6% at 3 years and 65.6% at 5 yearswith 36 months of treatment comparedwith 60.1% and 47.9%, respectively,with 12 months of treatment, represent-ing a significant 54% reduction in riskof recurrence (P <.001). Overall survival was 96.3% at 3

years and 92.0% at 5 years with 36months of treatment compared with94.0% and 81.7%, respectively, with 12months of imatinib, representing a55% mortality risk reduction (P = .019). However, grade 3 or 4 adverse

events were more common with longertreatment, and more patients discon-tinued GIST in the 36-month arm.

More May Be Better, Experts

Agreed

Charles D. Blanke, MD, Chief ofMedical Oncology, University of

British Columbia, Vancouver, com-mented on the study, noting that itsconclusions were “valid.” He suggest-ed that oncologists who typically initi-ate imatinib on relapse might want torethink this strategy. “If you have a patient who has

high-risk GIST, at least as defined bythe study, giving him or her 3 yearsof imatinib represents the new goldstandard,” he maintained. “The over-all survival benefit demonstrated withimmediate postoperative imatinibmeans it is no longer acceptable towithhold treatment in the adjuvantsetting, hoping to ‘catch up’ whena patient has recurrent metastaticdisease.”He acknowledged, however, contin-

uing treatment for 3 years could beproblematic for many patients, as sug-gested by a higher rate of side effectsand more than a doubling in thedropout rate among patients whoreceived imatinib for that long.Although it is possible that treatmenteven beyond 3 years could be evenmore beneficial, he noted, “Difficultieson the 3-year arm of SSGXVIII/AIOmay bode poorly for therapy lastingeven longer.” “For now, if I were a patient with a

resected GIST and I had a compliantoncologist, I would request more,” hesaid. “As a compliant oncologist, I per-sonally will offer patients treatment…indefinitely.” �

Prolonged Treatment with Imatinib for High-Risk GISTIncreases Survival, Reduces Recurrence Phase 3 clinical trial results will likely change standard of careBy Audrey Andrews

“The entire oncologycommunity was extremelyexcited when we saw the survival curve and thosenumbers at 5 years. It’s oneof the amazing stories inoncology, and it is the kindof data that changeguidelines.”

—Mark G. Kris, MD

“The overall survival benefitdemonstrated with im me -diate postoperative imatinibmeans it is no longer accept -able to withhold treatmentin the adjuvant setting,hoping to ‘catch up’ when apatient has recurrentmetastatic disease.”

—Charles D. Blanke, MD

ASCO ANNUAL MEETING


A second, much smaller study of 41patients suggested that iniparib mightbe beneficially partnered with the stan-dard chemotherapeutic agent gem-citabine. Results for the combinationdemonstrated an overall response of65% and a PFS of 9.5months in patientswith platinum-sensitive ovarian cancer.

Stomach Cancer

Targeting the ability of tumors togenerate a sufficient blood supply isthe mechanism behind the antiangio-genic agent telatinib.In a phase 2 investigation of 39 in-

operable metastatic stomach cancerpatients, results demonstrated a rapidand sustained tumor regression in 66%of patients when telatinib was com-bined with chemotherapy. (Antian-

giogenic drugs are not used as single-agent treatments.) These results wereobserved regardless of the tumor loca-tion or whether it had already spreadto the liver.The median PFS was 140 days, and

safety end points suggest that thechemotherapy combination with tela-tinib was well tolerated. “Antiangio-genic agents are an important class ofdrugs for the treatment of gastroin-testinal cancers,” said Jaffer A. Ajani,MD, Professor of Medicine at theUniversity of Texas M.D. AndersonCancer Center in Houston.The efficacy of telatinib without a

significant increase in side effects whencombined with chemotherapy sug-gests a potent new approach forpatients with stomach cancer. �

The Oncology Drug Pipeline...Continued from page 18

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ASCO ANNUAL MEETING


Center, examined some of the majortrials.

The only true “practice-changing”study, in her opinion, involvedtrastuzumab (Herceptin) as treatmentfor gastric cancer. The rationale isstrong, she said, based on the discov-ery that HER2 is overexpressed inmany gastric tumors. In the phase 3ToGA (Trastuzumab for GastricCancer) trial, trastuzumab added tocapecitabine (Xeloda) and cisplatin(Platinol) improved overall survival(OS) from 11.1 months to 13.8 monthswith chemotherapy alone, constituting

a 26% reduction in death. The effectwas robust in the subset that stronglyoverexpressed HER2.

In contrast, in pancreatic cancer, thepivotal National Cancer Institute ofCanada Clinical Trials Group PA.3 trialof erlotinib (Tarceva) plus gemcitabine(Gemzar) versus gemcitabine alone is“an example of a statistically signifi-cant phase 2 trial that has clinicallylimited therapeutic impact,” DrO’Reilly maintained. The median OSwas improved by <1 month, as wasprogression-free survival (PFS); butbecause these small differences werestatistically significant, the US Foodand Drug Administration approvederlotinib for pancreatic cancer basedon these results.

For pancreatic neuroendocrine tu -mors, “we don’t yet fully know” thetrue benefit of everolimus (Afinitor)and sunitinib (Sutent), which have ledto improvements in outcomes and rep-resent new options for a rare malig-nancy. Many questions remain, such asthe best time to initiate therapy withthese drugs, and how to sequence andcombine them with other treatments,Dr O’Reilly said.

“In the era of cost constraints, wemust recognize that all these agentsare palliative, all are expensive, and allhave added toxicity,” Dr O’Reilly said.Future investigations must be basedon strong biologic rationale, robustearly-phase results, and intelligenttrial design.

The Value of New Cancer Drugs

Neal J. Meropol, MD, AssociateDirector for Clinical Research, CaseWestern Reserve University, Cleve -

land, who investigates the economicsof cancer care, said he was “provid-ing perspective on how to interpretthese claims.” He ranked the clinicalbenefit of upper GI cancer treat-ments, largely based on the magni-tude of the statistical differences inPFS and OS compared with standardtreatment, and then assessed thevalue of the new upper GI cancer reg-imens, demonstrating that clinicalbenefit is often not parallel withvalue (Table).

Dr Meropol said the “trastuzumabstory” is informative regarding thefuture of oncology clinical trials andoncology care. He reminded the audi-ence that although trastuzumab hasbecome an important treatment in gas-tric cancer, its effect, compared withthe drug’s impact on breast cancer, isminimal. In metastatic breast cancer,trastuzumab prolonged median OS bynearly 5 months; in advanced gastriccancer, it added a median of 2.7months. In patients with highly over-expressed HER2, however, the addi-tional benefit exceeded 4 months, thusoffering somewhat higher value in thissubset, he acknowledged.

The “lessons,” according to DrMeropol, are that diagnostics develop-ment must begin early and in concertwith clinical development, that all can-

cers will be “rare” cancers once theirmolecular profile is understood, that“blockbuster drugs” will becomedinosaurs (ie, no one drug will fit all),that the bar must be set high early indrug development, and that treatmentbased on site of origin will be replacedby treatment based on phenotype.

Smaller patient populations willeventually become defined for essen-tially all tumor types, necessitatingever more targeted treatments as thenorm. The effect of this on drug devel-opment and cost control remainsunclear, according to Dr Meropol.

“Will this prolong drug develop-ment time and reduce the chances ofbringing drugs to market? Will thehigher value of the targeted approachbring even higher prices to make upfor smaller markets? The answers tothese questions are unknown,” hesaid.

Where We Need to Go

Dr Meropol offered some concretesuggestions for “where we need to go”in the future treatment of cancer. Hissuggestions included the following:• Reduce overutilization: eliminate

nonbeneficial interventions• Raise the bar for drug approval• Link payment to value via cost-

sharing• Authorize the Centers for Medicare

& Medicaid Services to negotiateprice

• Reduce incentives for developmentof marginal advances

• Improve the evidence base withcomparative effectiveness research.Value-based insurance design may

be a viable strategy for achieving someof these goals and is gaining traction,he noted. “Not all effective treatmentshave equivalent value. Cost-sharingcan be used to discourage low-valuetreatment and encourage high-valuetreatment, in contrast with currentplans that base coverage on cost,” hesaid. “There would be the potential fordifferent coverage based on the dis-ease and stage.”

“The low-hanging fruit is cost-sharing that is not based on the costof the intervention but its value,” hemaintained.

He emphasized that in the alloca-tion of finite resources, “the goal isto move from implicit decisionsabout allocation to explicit andtransparent ones,” adding that poli-tics will impact this process. “Weneed to weigh in as the oncologycommunity to advocate for ourpatients and for the development ofhigh-value treatments.” �

Upper GI Cancers: Are We Getting Value... Continued from cover

“In the era of costconstraints, we mustrecognize that all theseagents are palliative, all are expensive, and all have added toxicity.”

—Eileen Mary O’Reilly, MD

“Not all effective treatmentshave equivalent value. Cost-sharing can be used todiscourage low-valuetreatment and encouragehigh-value treatment….The low-hanging fruit is cost-sharing that is not based on the cost of theintervention but its value.”

—Neal J. Meropol, MD

Table Value of Upper GI Cancer Treatments

Cancer type/drug regimen

Clinical benefit New drug

Annual costof drug, $a Value

Pancreatic cancerGemcitabine/erlotinib Very low Erlotinib 53,954 Very low

Liver cancerSingle-agent sorafenib Modest Sorafenib 115,866 Low

Gastric cancerChemotherapy/trastuzumab

Modest Trastuzumab51,225(excluding loading dose)

Modest

Biliary cancerGemcitabine/cisplatin Modest Cisplatin 364 Higher

Neuroendocrine tumorSingle-agent sunitinib Higher Sunitinib 108,569 Higher

Neuroendocrine tumorSingle-agent everolimus Higher Everolimus 201,516 Modest

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


ASCO ANNUAL MEETING


Chicago, IL—Two agents are vying tobe the preferred option for bone protec-tion in patients with cancer—the block-buster drug zoledronic acid (ZA;Zometa, Reclast) and the newer drugdenosumab (Prolia), which was ap -proved last year for the prevention ofskeletal-related events (SREs) inpatients with cancer. Denosumab has proved more effec-

tive in preventing SREs than the stan-dard agent, ZA, in several cancer types,but its wholesale acquisition cost perinjection is $1650 compared with $886for ZA. Some oncologists have ques-tioned whether the benefit is worth thecost. At ASCO 2011, studies sponsoredby the 2 manufacturers addressed thedrugs’ value, but the “winner” is stillnot clear.

Treatment of Metastatic

Breast Cancer

Using a literature-based Markovmodel, investigators analyzed thesurvival, quality-adjusted life-years(QALYs), number and costs of SREs,and costs of the 2 drugs in patientswith metastatic breast cancer. The con-clusion was that denosumab’s cost perQALY far exceeds what is traditionallyconsidered good value.“This analysis raises questions about

the cost/benefit ratio of denosumab inmetastatic breast cancer,” said John A.Carter, research analyst, PharmeritNorth America, Bethesda, MD. Inputs were selected to reproduce

the phase 3 trial outcomes for as longas 28 months. QALYs were estimatedby assigning utilities to health states.SRE-related costs and utilities wereobtained from the literature; per-eventSRE costs ranged from $4039 (vertebral

fracture) to $20,734 (bone surgery). In asensitivity analysis, serious adverseevents (AEs) of $15,441 per patientwere included. Scenario analyses werealso assessed. All costs and outcomeswere discounted at 3% annually. Compared with ZA, denosumab

resulted in fewer SREs, more QALYs,and lower SRE-related costs, but high-er drug-related and total costs. Thisresulted in an incremental cost of$6884 per patient. The cost per QALYgained was $613,000 per QALY when

including serious AEs ($644,000 whenexcluding them). “Relative to ZA, the use of deno-

sumab for the prevention of SREs inmetastatic breast cancer is estimatedto reduce SRE-related costs over 28months of treatment. However, onemust invest more than $9000 in addi-tional drug costs and thus incur a netcost of $7000 over 28 months toachieve these benefits,” Mr Carterconcluded. “The resultant cost per QALY…is far

above what is traditionally consideredto be good value for a medical inter-vention in the US ($50,000-$100,000 perQALY),” he noted.

Treatment of Castration-Resistant

Prostate Cancer

Using the same study design as thebreast cancer study, Sonya J. Snedecor,Associate Director of Health Economics,Pharmerit North America, Bethesda,MD, similarly concluded that the costper QALY of denosumab in men withmetastatic castration-resistant prostatecancer (mCRPC) is “far higher thanwhat is considered in the US to be goodvalue for a medical intervention, thusraising questions about the value ofusing denosumab in mCRPC.”

The use of denosumab was predict-ed to result in an incremental cost perQALY gained of $1.25 million. The

high cost was attributed to denosumabbeing associated with higher drugacquisition costs, limited prevention ofSREs, and no additional overall sur-vival or disease progression benefitsversus ZA. The cost of drug administration and

monitoring was figured at $12,963 forZA and $20,277 for denosumab, DrSnedecor said.

Low Number Needed to Treat

Demonstrates Efficacy

However, in another analysis, inves-tigators found a low number needed totreat (NNT) to prevent 1 SRE. GaryRichardson, MD, of Cabrini Hospitalin Malvern, Australia, reported theresults of this international random-ized double-blind trial.In this study, denosumab was com-

pared with ZA in 1776 patients withcancer. Results showed that denosu -mab was superior to ZA in preventingSREs and bone metastases and wasnoninferior when patients with multi-ple myeloma (MM) were included. The NNT to prevent the first SRE and

the first and subsequent on-study SREswere determined based on data fromthe initial placebo-controlled trials.The NNT to prevent 1 additional

first SRE during 1 year was 7.8 fordenosumab versus ZA and only 3.0 fordenosumab versus placebo. For theanalysis of time to first and subsequentSREs (ie, multiple SREs), the NNT withdenosumab versus ZA was 6.5. Whenpatients with MM were included, theNNT was 9.9 versus ZA and 3.0 versusplacebo. “These low NNT values demon-

strate the therapeutic efficacy of deno-sumab,” Dr Richardson said. �

Comparing the Value of Denosumab versus ZoledronicAcid in Preventing Cancer-Related Skeletal EventsBy Caroline Helwick

“These low NNT valuesdemonstrate the therapeuticefficacy of denosumab.”

—Gary Richardson, MD

“The resultant cost perQALY…is far above what is traditionally considered to be good value for amedical intervention in the US ($50,000-$100,000 per QALY).”

—John A. Carter

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focused discussions on the quality and effectivenessof care, with the goal of improving the care forpatients with cancer.

Among the areas of high interest for the BestPractices Committee is quality assurance. The goalis to ensure that NCCN’s institutions, such as ourNorthwestern Robert H. Lurie ComprehensiveCancer Center, are following clinical guidelines forpatient management, and that we verify how con-cordant our institutions are in following clinicalguidelines and quality indicators that are based onthe guidelines.

Another very important aspect of best practices isthe integration of practice models to enhance com-prehensive cancer care delivery. Practice modelsinclude defining the role of different providers ofcare, such as the role of nurse practitioners in theoncology practice. This is a multifaceted concept thatencompasses the overall goal of providing the bestcomprehensive services possible for each individualpatient. It can also include other areas, such as look-ing at reimbursement patterns.

The way patient services are delivered can varysignificantly, depending on the type of practice andpractice location, for example.

Q: What are some of the unique featuresoffered at your Northwestern center, and whatmakes it one of the leading cancer centers inthe country?

Dr Benson: One significant advantage we have isa centralized clinical cancer center, which enables usto provide broad-based services. We have had todivide our clinical cancer center into 2 differentbuildings, principally because of our patient volumeand space limitations. The bulk of the clinical cancercenter is on one floor of our ambulatory care tower(the Galter Pavillion), where we provide a full rangeof services, including full infusion services.

Our clinical nurse specialists, who provide treat-ment to patients, also work closely with individual

physicians to develop areas of expertise in a giventumor type. For example, I have been working withthe same nurse clinician for 15 years, and she knowsgastrointestinal oncology inside out, which is alsomy area of expertise. She is an enormous resource forpatients undergoing treatment.

The same floor houses our surgical oncologists,hematologists, medical oncologists, the transplantteam, neuro-oncology, urologic oncology, interven-tional radiology, psychologists, dieticians, financialcounselors, and social workers. Such proximityoffers a great advantage that allows us to offer serv-ices in one place that cannot always be provided bysmaller centers.

Our second clinical cancer center is located inPrentice Women’s Hospital. The gynecologic oncolo-gy service clinicians have moved from our originalclinical cancer center to our Women’s Hospital.Patients with breast cancer are also seen in this loca-tion by the breast cancer oncologists, including thesurgeons and the medical oncologists. PrenticeWomen’s Hospital also has a radiation unit, sopatients undergoing radiation treatments can conve-niently take one elevator from the oncology servicedown to radiation oncology.

We have full laboratory services in both clinical can-cer center locations, as well as radiology services inboth buildings. Therefore, most patients have consoli-dated services all in one location.

To further support patients, we try to coordinatemultidisciplinary appointments, although withsome exceptions—we do not have multidiscipli-nary clinics as is the case in some centers. We try toset up various appointments for a patient so differ-ent providers end up seeing the patient on thesame day.

In addition, we have weekly multidisciplinarytumor conferences for the different diseases. Many ofour patients are presented at these conferences thatresult in a multidisciplinary opinion; we then take

that recommendation to our patients and schedulethe appropriate follow-up visits and interventionsbased on these conferences.

This centralization and ready availability of thevarious disciplines are important for patient care, asare our financial counselors, social workers, psychol-ogists, dieticians, and other important services thatare integrated within the same location.

We emphasize palliative care through our sup-portive oncology care team, which is a critical com-ponent of our comprehensive approach to cancercare.

Q: You have a huge advantage being in a bigcity, and you likely have good funding as well.Is this typical for most cancer centers?

Dr Benson: Large cities often offer a number ofdifferent cancer programs. There are hospital-basedcancer center programs that may not be NationalCancer Institute (NCI) comprehensive cancer cen-ters, as our center is, but they are in large hospitalsthat also try to offer comprehensive cancer care serv-ices. Regardless, there can be many differences inhow the care is delivered.

Overall, there are many permutations as to thestructure of cancer programs and a multitude ofchallenges. For example, when there is not one cen-ter location, where people may have to go to themedical oncologist’s office or to a separate infusioncenter, and they may even have to go to a separatecenter for imaging, and maybe yet another locationfor radiation oncology, coordination of care canbecome very complicated and challenging.

Another advantage we have at Northwestern isour complete electronic medical records (EMRs)system; we do not use paper records at all. An EMRsystem enhances care coordination, because therecords are computer-based and readily availableto all the medical staff at the center. Schedulingamong specialists can also be more readily coordi-nated, for example.

At Northwestern, we receive many outside refer-rals, so we have many outside medical records,which in turn are scanned into our own EMR system.For example, today I was referred a new patientwhom I scheduled to see tomorrow. The records andscans were sent to me on a disk and have beendownloaded into our system. I have already calledthe interventional radiology specialist and askedhim to look at this patient’s liver CT [computedtomography], to see what we might have to offer forthis individual patient. All of this was coordinatedbefore I am seeing the patient (tomorrow), thanks toour EMR system.

Q: Clearly your EMR system helps carecoordination for a patient with cancer. Butwhat if that patient was also diabetic—would you have access to medical records notrelated to the cancer?

Dr Benson: In addition to our cancer center, wehave immediate access to electronic patient recordsfrom Northwestern Memorial Hospital, as well as tothe outpatient records through the NorthwesternMedical Faculty Foundation. Our faculty membersuse the same EMR; therefore, if I am referring a dia-

Northwestern University Comprehensive Cancer Center... Continued from cover


at a glance� NCCN’s institutions must follow clinical

guidelines for patient management and be

concordant in following clinical guidelines

and quality indicators

� A significant advantage at Northwestern is

having a centralized clinical cancer center,

which facilitates delivery of a wide range of

services

� An EMR system enhances care

coordination, which is critical for optimal

cancer care

� A much more integrated comprehensive

program is required in this country to merge

all the components of what it takes to deliver

oncology care in a cooperative venture

� Participation in research programs by

clinicians and patients in far greater numbers

has to become the norm rather than the

exception

A very important aspect of bestpractices is the integration of practice

models to enhance comprehensivecancer care delivery.




betic patient (with cancer) to an endocrinologist, theendocrinologist has total access to our EMR, andvice versa.

The exception would be one that involved our pri-vate physicians, who are on the medical staff of thehospital, who many have offices that are off site.Their record system may therefore be totally differentfrom ours and may not be directly linked to the out-patient system, although the off-site physicians mayhave access to the hospital EMR system through theiroffice computers.

As faculty members, we have the advantage ofbeing able to go online to access the NorthwesternEMR system, do charting at home, and if a patientcalls when the faculty member is off site, we haveimmediate access to that patient’s records.

Q: Disparities of care is an important issuein cancer care. Does your centralized care helpto reduce disparities in care?

Dr Benson: Not exactly. No matter what systemwe have, we are going to face disparities for manyreasons—some are very obvious, such as lack ofinsurance and limited financial resources—and atruly big area is the underinsured. With complex can-cer services, there is a risk that all the required serv-ices may not be fully reimbursed.

In addition, high copayments may make it diffi-cult for some patients to receive all the medicationsthey need.

Our social and financial services try to assistpatients, including trying to arrange transportationor to find other assistance programs, but often thereare obstacles that make it difficult for patients toreceive the comprehensive care they require.

We have a big urban environment that covers avery large referral area, which, in addition toChicago, encompasses Indiana, Michigan, Wiscon -sin, and even Iowa, as well as the entire state ofIllinois. With such a geographically diverse popula-tion, some complex issues come up, and many of ourpatients, because of their geographic distance, alsoneed services closer to their home.

They may have oncologists closer to home, orthey may get some testing done closer to home;when that happens, it can result in disjointed care,which may not necessarily be health disparities, butit does fragment the care.

In addition, many patients have very limitedresources, and it becomes a challenge how to orches-trate a comprehensive program for these individualsto ensure that they can receive the care they need.

Q: Many oncologists today are urgingother oncologists to refer patients to clinicaltrials, especially those who have few or notherapeutic options. As one who is heavilyinvolved in clinical research, where doesclinical research fit within best practices in oncology?

Dr Benson: The philosophy is that clinical trialsrepresent a standard of care and are directly integrat-ed into the decision process in terms of therapeuticoptions, and this is also part of the best practices con-cept of using evidence-based medicine.

In gastrointestinal oncology, where we have avery vigorous clinical trials program, we actively dis-cuss clinical trials with our patients, and we get refer-rals requesting us to consider a patient for our clini-cal trials.

We certainly buy into this philosophy of clinicalresearch and integrated cancer care and try to pro-mote such an approach by our involvement with theNCCN guidelines, which actively promote clinicalresearch. As an NCI comprehensive cancer center,clinical research is an integral part of our mission.

Q: Does being an NCI cancer center implyparticipation in clinical trials?

Dr Benson: Absolutely. An NCI comprehensivecancer center must show significant funding andactivity in 3 big areas of research—clinical research,laboratory research, and what we often call “cancercontrol,” which is a very broad area that can encom-pass everything from screening, prevention, symp-tom management, and quality-of-life measures.

Q: Finally, what do you see as some of themajor challenges today for oncology practices?

Dr Benson: There is a laundry list of massive chal-lenges that revolve around the growing workforceshortage. It is clear that we are going to have insuffi-cient numbers of oncologists, including medical andradiation oncologists, and in particular a shortage ofoncology nurses and nurse practitioners.

When we project a growing population of individ-uals who will be faced with a cancer diagnosis, thereare very significant issues that will magnify our chal-lenges, including reimbursement of cancer care, theongoing struggle to deliver comprehensive care, andthe ability to afford these services.

Patients having access to treatment financially isgoing to continue to be a big problem. In addition, ifwe are going to more readily advance cancer careand take advantage of rapidly emerging technolo-gies as well as rapid development of new agents, wesimply have to have a far greater percentage ofpatients who are participating in clinical trials, par-ticularly trials that include tissue acquisition, so wecan continue to learn more about and develop astrategy centered around tumor biology.

This is where the concept of personalized medi-cine comes into play. We need to look at personalizedmedicine in providing overall comprehensive cancerservices to the individual patient, and to be able toselect appropriate treatment based on the host andthe tumor biology profiles. To be able to do this isgoing to take a concerted investment not only in thescience of cancer but also in supporting the infra-structure of clinical trials work.

So much of what we do now represents tremen-dously underfunded clinical trials and a dependenceon a voluntary effort, as well as institutional financialsupport to conduct these trials. With the economicpressures on institutions, and with the workforceshortage pressures, we have a mix of challenges thatcould directly impede our efforts to advance cancerresearch and, subsequently, cancer care.

We require a much more integrated comprehen-sive program in this country that will merge togetherall the components of what it takes to deliver oncol-ogy care in a cooperative venture, as well as to max-imally promote research. Advancements in researchwill require enhanced government support not onlyfrom the NCI but also from our regulatory agenciesin the government, reimbursement branches of gov-ernment, and for drug development, the pharmaceu-tical industry.

It is going to require integration of imaging, diag-nostics companies, and third-party carriers to at leasthelp support the standard care costs for patients onclinical research trials; future research endeavors willmandate interdisciplinary collaboration includingother critical people, such as surgeons, radiologists,and pathologists who have not been routinelyawarded appropriately for their clinical trials effortsand are too often underfunded and underrecognizedfor their work.

A societal commitment to the notion that scientificinnovation is of critical importance—and worth theinvestment in capital and people—is necessary if weare to improve cancer care and expected outcomes.Participation in these research programs by cliniciansand patients alike in far greater numbers will need tobecome the norm rather than the exception. �

One advantage we have atNorthwestern is our complete EMRssystem; we do not use paper vvrecords at all. An EMR system enhances care coordination and schedulingamong specialists.

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The Galter Pavilion, Northwestern Memorial Hospital


HEALTH POLICY


On August 2, 2011, PresidentObama signed the BudgetControl Act of 2011 into law,

the result of a month-long partisan bat-tle over raising the federal debt ceilingand, in the long-term, reducing the fed-eral deficit (Budget Control Act of 2011.Pub. L. No. 112-25). The Budget Control Act places an ini-

tial $917-billion cap on discretionaryspending over the next decade and setsup a new Joint Select Committee onDeficit Reduction tasked with recom-mending $1.2 trillion to $1.5 trillion inadditional deficit reduction by earlyDecember 2011.If the Joint Select Committee (or

“supercommittee,” as it has come to beknown) either fails to submit a reportto Congress or, as an alternative, ifCongress fails to pass the proposal, anautomatic sequestration is triggered. Under sequestration, Medicare pay-

ments to healthcare providers and tohealth insurance plans would be cutacross the board by 2% over the nextdecade—saving roughly $216 billion—starting in 2012. Medicaid and SocialSecurity are notably exempt under thisfail-safe measure, as are cuts toMedicare beneficiaries. Looking forward, the oncology

community is faced with 2 very differ-

ent paths—one to be shaped by theyet-to-be-named 12 members ofCongress and a lot of unknowns, andthe other a known fail-safe measurecertain to cause pain to healthcareproviders, manufacturers, and pa -tients. Which path is the worst of these2 evils for those involved in cancercare? Ultimately this answer comes down

to what the Joint Select Committeemay do to cut the federal deficit, andwhat would be the full impact of thisaction on the oncology community asa whole.

Path 1: The Joint Select

Committee Recommendation

The Joint Select Committee onDeficit Reduction, composed of 12bipartisan members, is empowered tolook for cost-savings and increasedrevenue everywhere it can, includingtax increases; tax reform; or cuts to themilitary, domestic programs, or enti-tlements. The following strategies arepotential proposals that the Joint SelectCommittee could consider that wouldhave a negative effect on many aspectsof cancer care delivery: • Reducing Medicare’s reimbursementrate for Part B drugs from averagesales price (ASP) + 6% to ASP + 4%or some lower amount. This propos-al would lower reimbursement forMedicare Part B drugs to a decreaseof ≥2% from the current ASP + 6%.

• Rolling Medicare Part B into PartD. By folding the Part B program fordrugs administered in the physi-cian’s office into the Part D program,advocates insist that increased pricecompetition would push down drugprices among similar drugs (ie, inthe same class or the same therapeu-

tic category). It is argued that thecost-savings could result fromincreased therapeutic substitutionbetween oral and injectable drugs.

• Allowing Medicare to negotiatePart B drug prices. Although in -creased attention has been paidto the proposal that allows theSecretary of Health and HumanServices to negotiate the price onPart D drugs, one possibility forcost-savings is also to allow the fed-eral government to negotiate lowercost with pharmaceutical manufac-turers when Medicare is the majorpurchaser of a specific Part B drug.

• Least costly alternative. Althoughprohibited since 2009, based on a USCourt of Appeals for the District ofColumbia circuit case, applying the“least costly alternative” approachwould allow the Centers forMedicare & Medicaid Services toinclude a cost-effectiveness calcula-tion in Medicare payment policy tolimit reimbursement on costly newtherapies (which would apply tomany new cancer drugs and diag-nostics), thereby limiting beneficiar-ies’ access to these potentially life-saving options.It is evident that the adoption of one

or some of these proposals could havea devastating impact on both oncologyproviders and on manufacturers in theoncology space. Most important, how-ever, these cuts could have a detrimen-tal impact on patients with cancer.

Path 2: Across-the-Board Cuts

Although the sequestration process,which guarantees cuts to Part D reim-bursement and Medicare providers,initially appears to be a losing proposi-tion, when compared with the alterna-

tives as discussed above, this may bethe better of 2 evils. Moreover, giventhe composition of the Joint SelectCommittee on Deficit Reduction (6Democrats, 6 Republicans) and thecurrent ultrapartisan atmosphere inCongress, the likelihood of the com-mittee actually coming to a “grandbargain” appears highly unlikely. As such, unless the committee is

able to beat the odds and reach a majorcompromise, or, in the alternative, ifCongress is able to amend the BudgetControl Act with a much larger deal(economists are still insisting that atleast $4 trillion in cuts are necessary toavert a crisis), across-the-board cutsappear the most likely result. Underthis scenario, it is still possible that theASP percentage would be reduced, butthe more sweeping policy changesmentioned above would not occur.

Regardless of which path is chosen,we have a classic example of bad factsmaking bad law. The resulting policychanges will not take place throughregular order, and will shut out manystakeholders and lawmakers. Is thisreally what the founders of our coun-try had in mind? �

Hanging in Limbo: What Does Deficit Reduction Mean for Oncology?By Jayson Slotnik and Ross MarguliesMr Slotnik is a Partner, Health Policy Strategies, LLC, Washington, DC; Mr Margulies is Health Policy Specialist, Foley Hoag, LLP

The oncology community isfaced with 2 very differentpaths—one to be shaped bythe yet-to-be-named 12members of Congress and alot of unknowns, and theother a known fail-safemeasure certain to causepain to healthcare providers.

at a glance� The Budget Control Act of2011 places an initial $917-billion cap on discretionaryspending over the next decade

� The act sets up a new JointSelect Committee tasked withrecommending $1.2 trillion to$1.5 trillion in additional deficitreduction by end of year

�The Joint Select Committee isempowered to look for cost-savings and increased revenueby tax increases; tax reform; orcuts to the military, domesticprograms, or entitlements

� Reducing Medicare’sreimbursement rate for Part Bdrugs, rolling Medicare Part Binto Part D, or reinstating theleast costly alternative wouldhave a devastating impact oncancer care as a whole,including oncologists andpatients with cancer

Jayson Slotnik Ross Margulies


HEALTH POLICY


Chicago, IL—Accountable care organi-zations (ACOs) are a prominent part ofthe Patient Protection and AffordableCare Act (ACA), better known as thehealthcare reform. ACOs are believedto hold the potential for addressingvariation in quality and costs of cancercare, but their impact will depend onbuy-in and leadership among oncolo-gists, according to David Miller, MD,MPH, a urologic surgeon and healthservices researcher at the University ofMichigan, Ann Arbor. He addressedthis topic during the recent annualmeeting of the American Society ofClinical Oncologists. “There is a lot of uncertainty on this

topic,” noted Dr Miller. “The story isyet to be told.” Section 3022 of theACA established a Medicare Shared-Savings Program that allows for ACOsto participate in Medicare. The pro-gram is slated to be implemented byJanuary 2012, but full details are justemerging.

Quality Measures Focus of ACOs

An ACO is a large group of pro -viders that accepts responsibility forthe quality and cost of care provided toa population of patients. This can be inthe form of physician group practices,networks of individual or group prac-

tices, joint ventures between physicianorganizations and hospitals, or hospi-tals that employ ACO physicians. The ACO has explicit mechanisms

for receiving and distributing sharedsavings, repaying shared losses, andperforming quality measurements.“This sounds like the HMO [healthmaintenance organization] of the‘90s,” Dr Miller observed, “but withquality measures and opportunitiesfor shared savings.” Of course, themechanisms for the proposed savingsare very complex, he added. There are 65 proposed measures for

reporting related to quality of care inthe following 5 domains:• Patient/caregiver experience• Care coordination• Patient safety• Preventive health• At-risk population and frail elderlyhealth. Breast and colorectal cancer screen-

ings have strong emphasis. Per for -mance is measured via claims, surveys,and the use of new data collection tools.

High Expectations

Approximately 75 to 150 ACOs areexpected to be in place over the next 3years. This means 1.5 million to 4 mil-lion Medicare beneficiaries will be cov-ered through ACOs, with a projectedsavings of $510 million over the 3-yearperiod, according to Dr Miller.“But, there are mixed emotions

about ACOs,” he added, as exempli-fied by 2 recent perspectives in theNew England Journal of Medicine

(Haywood TT, Kosel KC. N Engl J Med.2011;364:e27; Ginsburg PB. N Engl JMed. 2011;364:2085-2086) that describethe controversies and criticism, muchof it doubting the potential for cost-savings. “On the other hand, some say we

need to do even more,” Dr Milleracknowledged. This has led to a “vir-tual ACO economy” aimed at fine-tun-ing how the whole process will beengineered and fulfilled, he said.

ACOs May Curb Variation in Care

ACOs might be most useful, hemaintained, by reducing variation inquality and cost in the “3 big-ticketareas” of treatment decision-makingand therapeutic intervention, identifi-cation and management of side effects,and the delivery of end-of-life palliativecare. Studies have demonstrated signif-icant variation by specialty, geographicarea, hospital, and race/ethnicity. Variation in care is relevant to ACOs

for several reasons. Variation in quali-ty suggests basic problems with cancercare delivery: overtreatment, under-treatment, or both. It also suggests theneed for evidence-based medicine,quality measurements, and shareddecision-making.

Variation in costs suggests there is aplace for business in setting qualityand eliminating waste, for example, byimproving coordination across caresettings, Dr Miller said. ACOs are relevant in this setting, he

noted, because “both hospitals andphysicians would have ‘skin in thegame’ with respect to optimizing effi-ciency of cancer care,” but there is“major work ahead in defining opti-mally efficient practices,” he added. “We need to define what constitutes

efficient care in oncology, because a lotof money is at stake,” Dr Milleremphasized.

The Challenges of ACOs

for Oncology

The challenges in developing ACOsfor cancer care primarily reflect thatcancer is so complex, encompassinga variety of specialists (in separatesilos), surgeries, imaging, and med-ications. As such, cancer-related costsare substantial, especially in the ini-tial diagnostic period, but there arealso continuing costs pertaining todisease recurrence and end-of-lifepatient care. Although medical oncologists usu-

ally serve as the primary provider ofcare for cancer patients, primary careproviders (PCPs)—who are less in -formed about cancer—are sometimestapped for this role, at least after theinitial treatment period. “The challenge for PCPs to man-

age that care and ensure high qualityand low cost is monumental,” DrMiller suggested. “We feel the locusof control is best kept in the oncologyfield, he said.”There are other “pragmatic issues,”

he added. For example, oncologistsmay be unwilling to participate in anACO led by a small hospital or pri-mary care group. “The truth is, oncol-ogists are unlikely to participate in anACO voluntarily if it is led by a pri-mary care group or small hospital,” DrMiller said. “And if oncologists are not partici-

pating, there will be a huge cost centerleft outside of the scope of this policylever. It will be hard to achieve savingsgoals without the involvement of can-cer care.”

Questions for Oncologists

“There is no question that ACOshold some promise, and we should allbe considering how this and other pol-icy reforms could be used to improvepatient care,” Dr Miller said.However, he said, there are practical

issues to be resolved:• Can oncology specialists form theirown ACOs?

• Will oncologists and cancer hospi-tals function as “free agents” thatcompete for referrals based on costand quality?

• How can quality of cancer care bestbe measured within an ACO?

• Should oncologists be able to “leadwithin their ACOs,” will this trans-late into cost-savings? Dr Miller said that “it feels good, but

whether it achieves cost-savings isunknown.” �

Accountable Care Organizations: Implications for Cancer-Related Quality Care and SpendingBy Caroline Helwick

at a glance� As part of the PatientProtection and Affordable CareAct, ACOs hold the potential toaddress variation in quality andcosts of through treatmentdecision-making/ therapeuticintervention, identification/management of side effects, and delivery of end-of-lifepalliative care

� ACOs include 65 proposedmeasures for reporting related toquality of care in patient/caregiver experience, carecoordination, patient safety,preventive health, and at-riskpopulation/frail elderly health

� Approximately 75-150 ACOsare expected to be in place overthe next 3 years

� The ACO coverage slated for1.5 million-4 million Medicarebeneficiaries will result in aprojected savings of $510million over the 3-year period

“We need to define whatconstitutes efficient care inoncology, because a lot ofmoney is at stake.”

—David Miller, MD, MPH

“If oncologists are notparticipating [in ACOs], therewill be a huge cost centerleft outside of the scope ofthis policy lever. It will behard to achieve savings goalswithout the involvement of cancer care.”

—David Miller, MD, MPH


ONCOLOGY PHARMACY


Dose-Monitoring, Split-Fill Programs Reduce OralChemotherapy Waste, Save CostsBy Caroline Helwick

Dose-monitoring programs fororal chemotherapy drugs canreduce wastage and reduce the

risk of serious adverse effects associat-ed with these drugs. This translatesinto cost-savings for patients and forpayers of >$2500 per patient, suggestedresearchers from Walgreens SpecialtyPharmacy. The company developed an oral

chemotherapy cycle management pro-gram (CMP) that offers a “split-fill”option and close monitoring of pa -tients for adverse events. This is anoptional program, and payers can electto participate. The analysis of these programs was

simultaneously published in the Jour -nal of Oncology Practice (Khandelwal N,et al. J Oncol Pract. 2011;7:e255-e295)and The American Journal of ManagedCare (2011;17[5 Spec No]:e169-e173). “Due to high drop-off rates for pa -

tients on oral chemotherapy drugs,there is a significant likelihood of med-ication wastage. The split-fill programhas the potential to reduce wastage inmembers who discontinue mid-cycle.Our analysis showed that of thosepatients that discontinued therapy,34% would have experienced reducedwastage had they been on a split-fillmedication plan,” said lead authorNikhil Khandelwal, PhD, BPharm, ofWalgreens.Nearly 20% of patients using chemo -

therapy are prescribed an oral oncolyt-ic, and approximately 25% of antineo-plastic agents in development arebeing studied as oral formulations.Although patients indicate that they

prefer an oral rather than an intravenouschemotherapy, drug self-administrationresults in the transfer of responsibility tothe patient for identifying, monitoring,and managing toxicity. This is impor-tant, because risks associated with oraldrugs are insignificant. More than 90% of patients using so -

rafenib (Nexavar) or sunitinib (Sutent)experience adverse events; of these, asmany as 33% are grade 3 to 4 (based onthe 2010 package inserts for these 2drugs). In addition to risks to thepatient’s clinical outcomes, there is alsothe potential for a patient’s treatmentdiscontinuation without the providers’knowledge.

Walgreens Chemotherapy Cycle

Management Program

In 2008, Walgreens initiated pharma-cist- and nurse-facilitated clinical man-agement and support to patients who

were receiving sorafenib, sunitinib, orerlotinib (Tarceva) as part of their oralchemotherapy management. Throughthe CMP, patients receive intensiveeducation, close supervision, andcounseling at predetermined intervals. To minimize medication waste,

pharmacists can dispense partial-month supplies of oral chemotherapy(split-fill), followed by the balance ofthe monthly supply if the patientdemonstrates adherence and toler a bil -ity. The objectives of the CMP are toaddress factors that lead to patientnonadherence; to minimize drugwastage; to improve quality of care;and to maximize satisfaction of thepatient, payer, and provider, DrKhandelwal said.“The split-fill program reduces

wastage when therapy is discontinuedduring the first half of the month, sincethe remainder of the monthly supply iswithheld,” he explained.In a retrospective test-control study,

Dr Khandelwal and colleagues evalu-ated medication wastage and potentialcost-savings for 1069 patients enrolledin the CMP (June 2008-February 2010)and for 351 patients not enrolled (June2007-May 2008). Information camefrom prescription claims and surveyassessment data.

Eliminating Wastage for 33%

of Patients

Participation in the CMP resulted insignificantly lower wastage of medica-tions because of early treatment dis-continuation. In the first month oftreatment, 261 patients discontinuedtreatment and 20 (7.7%) could havesaved at least half of 1 cycle (14 days)had the payer used the split-fill pro-gram. Over the entire study period, 278(33.8%) of 823 patients could have pre-vented wasting oral medicationsthrough use of the split-fill program,the study found.On the basis of the prevailing aver-

age wholesale price of the drug at thetime of dispensing, the estimated totalpotential savings using split-fill dosingversus a full-month supply for the pro-

gram’s patients was $768,850 ($2765per patient). In addition, approximately 34% of

patients in the CMP group could havepotentially avoided medication wast -age if split-fill plans had been availableto them, which could have amountedto another realized savings of $934.20per patient. The reasons for drug wastage among

patients who discontinued treatmentearly were: • Death—21.9% • Physician decision—10.1%• Ineffective therapy—9.7%• Medication switch—9.0%• Adverse events—7.2%.The majority of discontinuations,

however, were recorded as “reasonunknown” or “other.”The researchers also analyzed hospi-

tal admissions resulting from adverseevents, showing that the CMP grouphad a 2.9% probability for fewer hospi-tal admissions (P <.05), resulting in ad -ditional savings of approximately $440per patient. “The combined savings from re -

duced wastage and fewer hospitaladmissions was $1374 per patient,” DrKhandelwal reported.“Our study suggests there is a poten-

tial for health plans and other payers toimprove quality and achieve significantcost-savings by participating in programsthat actively manage oral chemotherapypatients through monitoring programssuch as the CMP,” he said. �

at a glance� Dose-monitoring programs fororal chemotherapy drugs canreduce wastage and the risk ofassociated serious adverseeffects, which translates intocost-savings of >$2500 perpatient

� The Walgreens SpecialtyPharmacy initiated an oralchemotherapy cycle manage -ment program consisting of“split-fill” and close monitoringof patients for adverse events

� To minimize medication waste,pharmacists can dispensepartial-month supplies of oralchemotherapy, followed by thebalance of the monthly supply ifthe patient demonstratesadherence and tolerability

� The estimated total potentialsavings using split-fill dosingversus a full-month supply forpatients was $2765 per patient

“Due to high drop-off ratesfor patients on oralchemotherapy drugs, there isa significant likelihood ofmedication wastage….Thecombined savings fromreduced wastage and fewerhospital admissions was$1374 per patient.”

—Nikhil Khandelwal, PhD, BPharm

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5% decrease below institutional lower limit of normal)

� Myelosuppression may occur; frequently monitor complete blood count (including platelet count), at least prior to each dose of DOXIL®

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— In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL® and/or VELCADE

— Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage

— Sepsis occurring during neutropenia has resulted in discontinuation of treatment and in rare cases of death

� DOXIL® may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow

� Hand-foot syndrome (HFS) may occur during therapy with DOXIL®

— Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL® may be required

— HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier• The reaction was mild in most patients, resolving in 1 to 2 weeks• The reaction can be severe and debilitating in some patients, resulting in

discontinuation of therapy� DOXIL® is an irritant, not a vesicant; use precautions to avoid extravasation� DOXIL® can cause fetal harm when used during pregnancy� Recall reaction has occurred with DOXIL® administration after radiotherapy� DOXIL® may interact with drugs known to interact with the conventional formulation

of doxorubicin HCl� In patients with recurrent ovarian cancer, the most common all-grade adverse reactions

(ARs) 20% (DOXIL® vs topotecan, respectively) included: asthenia (40% vs 51%), fever (21% vs 31%), nausea (46% vs 63%), stomatitis (41% vs 15%), vomiting (33% vs 44%), diarrhea (21% vs 35%), anorexia (20% vs 22%), dyspnea (15% vs 23%), HFS (51% vs 1%), and rash (29% vs 12%)

— In addition, 19% vs 52.3% reported alopecia (all grades) — Grade 3/4 hematologic ARs reported in 5% (DOXIL® vs topotecan, respectively)

were neutropenia (12% vs 76%) and anemia (6% vs 29%)� In patients with multiple myeloma, the most common all-grade ARs 20% (DOXIL®

plus VELCADE vs VELCADE, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%), pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%)

— In addition, 19% vs <1% reported HFS

Please see brief summary of Prescribing Information, including Boxed WARNINGS, on adjacent pages.

VELCADE is a registered trademark of Millennium Pharmaceuticals, Inc.

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


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

INDICATIONS AND USAGE: Ovarian Cancer: DOXIL (doxorubicin HCl liposome injection) is indicated for thetreatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-basedchemotherapy. AIDS-Related Kaposi’s Sarcoma: DOXIL is indicated for the treatment of AIDS-related Kaposi’ssarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy. MultipleMyeloma: DOXIL in combination with bortezomib is indicated for the treatment of patients with multiple myelomawho have not previously received bortezomib and have received at least one prior therapy.

CONTRAINDICATIONS: DOXIL (doxorubicin HCl liposome injection) is contraindicated in patients who have ahistory of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of DOXIL[see Warnings and Precautions]. DOXIL is contraindicated in nursing mothers [see Full Prescribing Information].

WARNINGS AND PRECAUTIONS: Cardiac Toxicity: Special attention must be given to the risk of myocardialdamage from cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin,particularly in patients who have received a total cumulative dosage of doxorubicin exceeding the currentlyrecommended limit of 550 mg/m2. Lower (400 mg/m2) doses appear to cause heart failure in patients who havereceived radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agentssuch as cyclophosphamide. Prior use of other anthracyclines or anthracenodiones should be included incalculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered afterdiscontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should beadministered DOXIL only when the potential benefit of treatment outweighs the risk. Cardiac function should becarefully monitored in patients treated with DOXIL. The most definitive test for anthracycline myocardial injury isendomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have beenused to monitor cardiac function during anthracycline therapy. Any of these methods should be employed tomonitor potential cardiac toxicity in patients treated with DOXIL. If these test results indicate possible cardiacinjury associated with DOXIL therapy, the benefit of continued therapy must be carefully weighed against the riskof myocardial injury. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL atstarting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2, orbetween 500–550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. In this study,cardiotoxicity was defined as a decrease of >20% from baseline if the resting left ventricular ejection fraction(LVEF) remained in the normal range, or a decrease of >10% if the resting LVEF became abnormal (less than theinstitutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity andcongestive heart failure (CHF) are in the table below.

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

Patients who Developed Cardiotoxicity 10(LVEF Defined)

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

Patients With Signs and Symptoms of CHF Only 2

In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiacfailure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema andpulmonary edema) was similar in the DOXIL+bortezomib group and the bortezomib monotherapy group, 3% ineach group. LVEF decrease was defined as an absolute decrease of 15% over baseline or a 5% decreasebelow the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and42 patients in the DOXIL+bortezomib arm (13%) experienced a reduction in LVEF.

Infusion Reactions: Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL in therandomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms:flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest andthroat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. Inmost patients, these reactions resolve over the course of several hours to a day once the infusion is terminated.In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treatedwith DOXIL (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDS-related Kaposi’s sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL therapy because ofinfusion-related reactions. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusionreactions have been reported. Medications to treat such reactions, as well as emergency equipment, should beavailable for immediate use. The majority of infusion-related events occurred during the first infusion. Similarreactions have not been reported with conventional doxorubicin and they presumably represent a reaction to theDOXIL liposomes or one of its surface components. The initial rate of infusion should be 1 mg/min to help minimizethe risk of infusion reactions [see Full Prescribing Information].

Myelosuppression: Because of the potential for bone marrow suppression, careful hematologic monitoring isrequired during use of DOXIL, including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With therecommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reductionor delay or suspension of DOXIL therapy. Persistent severe myelosuppression may result in superinfection,neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted indiscontinuation of treatment and, in rare cases, death. DOXIL may potentiate the toxicity of other anticancertherapies. In particular, hematologic toxicity may be more severe when DOXIL is administered in combination withother agents that cause bone marrow suppression. In patients with relapsed ovarian cancer, myelosuppressionwas generally moderate and reversible. In the three single-arm studies, anemia was the most commonhematologic adverse reaction (52.6%), followed by leukopenia (WBC <4,000 mm3; 42.2%), thrombocytopenia(24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most commonhematologic adverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm3; 36.8%), neutropenia (ANC<1,000; 35.1%), and thrombocytopenia (13.0%) [see Adverse Reactions]. In patients with relapsed ovarian cancer,4.6% received G-CSF (or GM-CSF) to support their blood counts [see Full Prescribing Information]. For patientswith AIDS-related Kaposi’s sarcoma who often present with baseline myelosuppression due to such factors astheir HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse

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

Hand-Foot Syndrome (HFS): In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL at 50 mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling,pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of thepatients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skintoxicity. HFS toxicity grades are described in Dosage and Administration section [see Full PrescribingInformation]. Among 705 patients with AIDS-related Kaposi’s sarcoma treated with DOXIL at 20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing. In the randomized multiple myeloma study, 19% ofpatients treated with DOXIL at 30 mg/m2 every three weeks experienced HFS. HFS was generally observed after2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to twoweeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manageHFS [see Full Prescribing Information]. The reaction can be severe and debilitating in some patients and mayrequire discontinuation of treatment.

Radiation Recall Reaction: Recall reaction has occurred with DOXIL administration after radiotherapy.

Fetal Mortality: Pregnancy Category D: DOXIL can cause fetal harm when administered to a pregnant woman.There are no adequate and well-controlled studies in pregnant women. If DOXIL is to be used during pregnancy,or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to thefetus. If pregnancy occurs in the first few months following treatment with DOXIL, the prolonged half-life of thedrug must be considered. Women of childbearing potential should be advised to avoid pregnancy duringtreatment with Doxil. [see Full Prescribing Information].

Toxicity Potentiation: The doxorubicin in DOXIL may potentiate the toxicity of other anticancer therapies.Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-inducedtoxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration ofdoxorubicin HCl.

Monitoring: Laboratory Tests: Complete blood counts, including platelet counts, should be obtained frequentlyand at a minimum prior to each dose of DOXIL [see Warnings and Precautions].

ADVERSE REACTIONS: Overall Adverse Reactions Profile: The following adverse reactions are discussed in moredetail in other sections of the labeling. • Cardiac Toxicity [see Warnings and Precautions] • Infusion reactions [seeWarnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hand-Foot syndrome [seeWarnings and Precautions]

The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis,vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia andanemia. The most common serious adverse reactions observed with DOXIL are described in Section AdverseReactions in Clinical Trials. The safety data described below reflect exposure to DOXIL in 1310 patients including:239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma and 318 patients with multiplemyeloma.

Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, theadverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflectthe rates observed in clinical practice. The following tables present adverse reactions from clinical trials of DOXILin ovarian cancer, AIDS-Related Kaposi’s sarcoma, and multiple myeloma.

Patients With Ovarian Cancer: The safety data described below are from 239 patients with ovarian cancer treatedwith DOXIL (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in arandomized, multicenter, open-label study. In this study, patients received DOXIL for a median number of 98.0 days(range 1-785 days). The population studied was 27-87 years of age, 91% Caucasian, 6% Black and 3% Hispanicand other. Table 2 presents the hematologic adverse reactions from the randomized study of DOXIL compared to topotecan.

Table 2: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian CancerDOXIL Topotecan

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

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

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

Thrombocytopenia10,000 - <50,000/mm3 3 (1.3%) 40 (17.0%)<10,000/mm3 0 (0.0%) 40 (17.0%)

Table 3 presents a comparative profile of the non-hematologic adverse reactions from the randomized study ofDOXIL compared to topotecan.

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

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

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

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

Nervous Dizziness 4.2 0 10.2 0

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

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

WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTALSUBSTITUTION1. The use of DOXIL (doxorubicin HCl liposome injection) may lead to cardiac toxicity. Myocardial damage maylead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at a startingdose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2 or between 500-550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. Prior use of other anthracyclinesor anthracenediones should be included in calculations of total cumulative dosage. Cardiac toxicity may alsooccur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrentcyclophosphamide therapy [see Warnings and Precautions]. 2. Acute infusion-related reactions including, butnot limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in thechest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL. In mostpatients, these reactions resolve over the course of several hours to a day once the infusion is terminated. Insome patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treatsuch reactions, as well as emergency equipment, should be available for immediate use. DOXIL should beadministered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [see Warnings andPrecautions]. 3. Severe myelosuppression may occur [see Warnings and Precautions]. 4. Dosage should bereduced in patients with impaired hepatic function [see Full Prescribing Information]. 5. Accidentalsubstitution of DOXIL for doxorubicin HCl has resulted in severe side effects. DOXIL should not be substitutedfor doxorubicin HCl on a mg per mg basis [see Full Prescribing Information].


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

Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombo phlebitis, hypotension, cardiacarrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic andLymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia,hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia,sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash,exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. SpecialSenses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis.

Patients With AIDS-Related Kaposi’s Sarcoma: The safety data below is based on the experience reported in 753patients with AIDS-related Kaposi’s sarcoma enrolled in four studies. The median age of the population was 38.7years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2%Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL every two to three weeks. Themedian time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m2

and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2. Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immunesystem, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients’ median CD4 countwas 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count atstudy entry was approximately 3,000 cells/mm3. Patients received a variety of potentially myelotoxic drugs incombination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or moreantiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% onzalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) onsulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarilyfluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir,and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim)sometime during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patientswith AIDS related Kaposi’s sarcoma. Those that did so included bone marrow suppression, cardiac adversereactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis,progression of a non-KS tumor, allergy to penicillin, and unspecified reasons.

Table 4: Hematology Data Reported in Patients With AIDS-Related Kaposi’s SarcomaPatients With Total Patients

Refractory or Intolerant WithAIDS-Related AIDS-Related

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

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

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

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

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

Adverse Patients With Total PatientsReactions Refractory or Intolerant With

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

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

The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi’ssarcoma. Incidence 1% to 5%: Body as a Whole: headache, back pain, infection, allergic reaction, chills.Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouthulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia.Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1%: Body As A Whole: sepsis,moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block,congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic andNutritional Disorders: dehydration. Respiratory: cough increase, pharyngitis. Skin and Appendages:maculopapular rash, herpes zoster. Special Senses: taste perversion, conjunctivitis.

Patients With Multiple Myeloma: The safety data below are from 318 patients treated with DOXIL (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every threeweeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combinationgroup were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age,58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 6 lists adverse reactions reportedin 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma. Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple

myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRATerminology.

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

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

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

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

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

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

Infections and infestationsHerpes zoster 11 2 0 9 2 0Herpes simplex 10 0 0 6 1 0InvestigationsWeight decreased 12 0 0 4 0 0Metabolism and Nutritional disordersAnorexia 19 2 0 14 <1 0Nervous system disordersPeripheral Neuropathy* 42 7 <1 45 10 1Neuralgia 17 3 0 20 4 1Paresthesia/dysesthesia 13 <1 0 10 0 0Respiratory, thoracic and mediastinal disordersCough 18 0 0 12 0 0Skin and subcutaneous tissue disordersRash** 22 1 0 18 1 0Hand-foot syndrome 19 6 0 <1 0 0*Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathyperipheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS.

**Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular,rash pruritic, exfoliative rash, and rash generalized.

Post Marketing Experience: The following additional adverse reactions have been identified during post approvaluse of DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is notalways possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic andMediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders:Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whosetreatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interactwith drugs known to interact with the conventional formulation of doxorubicin HCl.

USE IN SPECIFIC POPULATIONS: Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients havenot been established.

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

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

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

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

TM

An ALZA STEALTH®

Technology Product


ELECTRONIC HEALTH RECORDS


Impact of EHRs on Oncology Practice: Enhancing the Value of Cancer Care By Gena Cook, Chief Executive Officer and Cofounder of Navigating Cancer

Widespread adoption of infor-mation technology (IT) isnow regarded as a pathway

to improving healthcare and achievingthe highly regarded goals for redesign-ing care. Achieving these goals willrequire new approaches to health sys-tem design, including continuousimprovement of relationships betweenphysicians and patients and tools thathelp providers have the right informa-tion at their fingertips to provide thebest care to patients and tools forpatients to actively participate in theirown care.

The Health Information Technologyfor Economic and Clinical Health(HITECH) Act provides new incen-tives for providers to digitize theirpractice. The act peaks in 2012 andstarts to penalize providers starting in2015 and beyond, if they have not metthe various stages of meaningful useobjectives. To qualify for the incen-tives, providers must incorporate certi-fied electronic health record (EHR)technology into their practices.

Where Are We Today?

As a result of the HITECH incen-tives, most providers are initiatingplans to qualify for the stimulus pay-ments, but few are ready. It is estimat-ed that of the 12,000 US oncologists,only approximately 25% (an estimatebased on oncology-specific EHR ven-dor-reported install base divided bythe number of US oncologists) haveeither implemented or signed up foran EHR. But only the oncologists whoare on a web-based platform are on aHITECH-certified version today.

Client server applications, which arethe leading oncology-specific EHRsimplemented in the marketplacetoday, are starting to schedule theirfirst upgrades this summer. It will taketime to upgrade their entire customerbase, and providers cannot certify forHITECH incentives until they haveupgraded to the certified version oftheir HER system. In April 2011, someoncologists received their first stimu-lus payments.

Because providers will not be penal-ized for waiting until 2012, manyoncology practices plan to certify in2012 to receive the maximum pay-ments. We are therefore seeing manypractices buy and adopt EHRs, planupgrades to the certified version if nec-essary, and start implementing patientportals so they can meet the patientobjectives.

In the next few years, the focus willbe on adopting the right technology,and then working within the practiceto meet the meaningful use objectives,which will continue to increase. In2014, stage 2 criteria will need to bemet, and in subsequent years, stage 3criteria will be announced.

Interoperability between informa-tion technologies will be a priority tominimize duplicate entry and workwithin the practice. As this evolves,the ability to implement new IT prod-ucts and features to reduce duplica-tion of efforts will become necessaryto continue to improve the cancer careparadigm.

Sharing Best PracticesThroughout this process, providers

still need to do their complex day job,which involves taking care of patientsin a broken and inefficient healthcaresystem. To implement these changes

effectively will require commitmentand participation from every staffmember, because many jobs will beadjusted with the use of IT.

Provider groups, state societies, andother support organizations shouldsupport providers in the effort to sharebest practices and work with the ITvendors to make changes that are notonly necessary to meet meaningful useobjectives but also to help practices dotheir jobs with as few keystrokes aspossible.

Self-Management ToolsPatients today have little to no

access to their healthcare data and tothe information needed to participatein their care. Although 86% of patientsgo online to look for healthcare infor-mation,1 they still have difficulty find-ing the information that is pertinent totheir specific condition, which is espe-cially problematic for patients withcancer.

With HITECH, patients have themost to gain, because providers will berequired to give them access to theirhealth information, information “pre-scriptions,” which include personal-ized disease-specific education andeventually securemessaging and otherself-management tools to participatein their own care.

The Transformed Healthcare

System of Tomorrow

With widespread adoption of infor-mation systems and interoperabilitywithin systems, it is conceivable thatthe healthcare system can be trans-formed. Providers and patients canenvision a system that can producebetter outcomes, higher quality, andlower costs than today.

With IT, providers can minimizewaste and duplication and providetransparency to patients and to otherproviders. Today, patients are trans-ported through the healthcare systemfrom appointment to appointment buthave very little transparency to theprocess. Other than showing up attheir appointment and adhering totheir prescribed medications (whichmany patients do not do), little isrequired of a patient.

In tomorrow’s system, patients willhave the ability to see parts of theirhealthcare record, understand theirlaboratory values in a longitudinalway, and receive more informationabout their health to minimize diseaseand actively manage it when diag-

nosed with cancer or other illnesses.Patients will be able to use technology,and most likely be required to managethe transactions of their care online,such as requesting prescriptions, ap -pointments, and laboratory testing.

IT and Personalized MedicineOncology providers, because of the

growing complexity of cancer care inthe era of targeted therapies, will havethe right data to provide personalizedcare to each patient. Providers will beable to easily view tests, laboratoryresults, and care that patients havealready received to avoid duplicationand make better decisions.

Oncologists will have decision sup-port tools to help guide their decision-making as cancer becomes more com-plex and personalized, as well astracking tools to eventually under-stand the outcomes of the variousoptions in clinic.

Because patients will have access totheir own health information, pro -viders will be able to give patients bet-ter instructions to manage and facili-tate better communication betweenface-to-face appointments. Providerswill be able to log in to their informa-tion systems to monitor patient med-ication adherence and side effects andprovide interventions as neededthroughout the care process, not justin the 15-minute time slots withpatients today. This enhanced com-munication will help patients under-stand the meaning of their data andfoster better postvisit adherence tomedical instructions.

IT EfficienciesMedical staff will enjoy the efficien-

cies of IT as well. Phone calls, faxmachines, and clipboards of informa-

With informationtechnology, providers canminimize waste andduplication and providetransparency to bothpatients and other providers.

It is estimated that of the 12,000 oncologists,approximately 25% haveeither implemented orsigned up for an EHR.


at a glance� The HITECH Act, which

provides new incentives for

providers to digitize their

practice, peaks in 2012 and

begins to take effect in 2015

� Providers, including

oncologists, will be required to

give patients access to their

health information, allowing them

to participate in their own care

and providing instructions to

facilitate better communication

between appointments

� Enacting EHRs will allow

practices to minimize waste and

duplication and provide

transparency to patients and

other providers involved in these

patients’ care

� Oncology practices must be

encouraged to share best

practices, and steadily improve

leveraging information systems


An analysis of payer and pro-vider responses to key clinicalinformation presented at the

ASCO 2011 annual meeting offers aglimpse of the oncology landscapeshared by oncologists and health plans. The research was conducted by

Xcenda (AmerisourceBergen Con-sulting Services), a specialty pharma-ceutical research and consulting firm.The full study, led by Loreen M.Brown, MSW, Vice President ofXcenda’s Access and ReimbursementConsultancy, was published online inthe Oncology Business Review (www.oncbiz.com; July 2011).“We wanted to draw connections

between the new data presented atASCO and the payer–provider respon s - es,” said Ms Brown, “to determine ifpayers and providers in the oncologyspace are congruent or divergent intheir thinking. ASCO is a great time tosee what oncologists are planning todo with new data and to see if payersare paying attention.”

Ms Brown and her team conductedan online survey of oncologists andhealth plan decision makers. The sur-vey included questions about theawareness of clinical trials and thechanging attitudes and behaviors ofoncologists, as well as views regardingincipient changes to coverage andtreatment policies.“By offering real-world insight into

what is important to 2 key stakehold-ers, our research provides an overviewof how emerging oncology data influ-ence treatment and coverage deci-sions, especially in the present contextof skyrocketing healthcare costs,” MsBrown told Value-Based Cancer Care.

Which Novel Agents Captured

Attention?

Oncologists reported high awarenessof clinical trial data for a number ofestablished biologics and several novelagents in late-stage development. Notsurprising, considering the amount ofpublicity of recent findings, ipilimumab

garnered the most notice (88%). Alsoreceiving high attention were new dataon bevacizumab (82%), erlotinib (75%),abiraterone acetate (75%), panitumum-ab (72%), and cetuximab (68%).Of note, despite the poly(ADP-

ribose) polymerase inhibitor’s high pro-file and the anxiously awaited phase 3data, iniparib was acknowledged byonly 62% of providers. And only 55% ofresponders had heard the vemurafenibdata for melanoma, which were pre-sented in the plenary session alongwith the ipilimumab study. More oncologists were unaware

than aware of findings related to theinvestigational drugs ponatinib, rux-olitinib, tivantinib, and MetMab.

Increasing Use of

Diagnostic Testing

Not surprising, given the wealth ofdata supporting targeted use of manybiologics, tissue-based molecular diag-nostic testing for genetic factors suchas epidermal growth factor receptorexpression and KRAS mutations isgoing to increase. More testing toguide treatment decisions is expectedfor lung cancer, melanoma, and colo -rectal cancer.Two thirds (67.5%) of oncologists

intend to increase their present use ofdiagnostic testing based on what theyheard at ASCO. Another 30% predicttheir use will remain stable, and only2.5% said they expected to use lessdiagnostic testing.Eighty percent of oncologists and

payer survey respondents plan on tar-geting surveillance testing or imagingto situations in which benefit has beenshown. “Anecdotally, from our con-

versations, we know that physiciansand payers are all for diagnostic test-ing, which could lead to cost-savingsby treating the right patient with theright drug at the right time,” MsBrown said. “But the issue at this timeis that the validity of the testingremains undetermined. Some tests,such as for HER2 expression, workbeautifully, whereas others are stillbeing evaluated. Payers and providersare on the same track—as long as thetests are reliable.”

Actionable Reimbursement

Strategies

Although treatment guidelines aimat optimizing patient care while keep-ing it cost-effective, approximately66% of oncologists do not alwaysadhere to guidelines in their plans orpractices as a means for reimburse-ment. Lung, breast, and colorectal can-cers are the tumors for which guide-lines are most likely to be adhered toand for which reimbursements aremost likely to be based.“Over the next year, however, based

on data presented at ASCO, new dis-ease states may be added to predeter-mined treatment contracts. More than20% of providers are considering theaddition of melanoma,” she noted,“and payers are considering the addi-tion of multiple myeloma, chronicmyeloid leukemia, and melanomaguidelines to this type of contractingarrangement.”Another reimbursement issue is the

policy discrepancy between infusedand oral oncolytics. Here, the surveyrevealed that many payers are un -aware of cost issues related to oraldrugs. “There is a striking distinction,”Ms Brown said. Only 50% of payersseem aware of the differences betweenthese types of agents (eg, the highercopays for patients).

Aligning Interests Regarding Costs

A recent article in the New EnglandJournal of Medicine (Smith TJ, et al. NEngl J Med. 2011;364:2060-2065) sug-gested that oncologists can helpreduce the cost of cancer care throughspecific behaviors and actions. Thisincluded reducing surveillance testingor imaging, using sequential mono -therapy instead of combination thera-py, limiting chemotherapy to patientswith good performance status, replac-ing the routine use of growth factorswith chemotherapy dose reductions in

ONCOLOGY REIMBURSEMENT


Post-ASCO Survey: Oncologists’ and Payers’ Treatment and Coverage Decisions By Caroline Helwick

tion will become obsolete, becauseonline tools will make the processmore effective for all. We are seeingthose changes in the airline industrytoday, where we check in online within24 hours of a flight or through a kioskat the airport. Today, we are alreadystarting to see this applied to medicalpractices in small ways as practicesand clinics implement kiosks andpatient portals and create interoper-ability between their current and newinformation systems.

Where Do We Go from Here?

A lot will be required to get to thedesired state. This transformation willtake time, and we are at a critical junc-ture within the healthcare system andin cancer care. Healthcare is now onthe national agenda, and HITECH pro-vides incentives for providers to digi-tize their practices before beginning topenalize those not compliant by 2015and beyond.Providers not meeting the objectives

by then will see decreases in theirMedicare fee schedule. Accountablecare organizations and medical homeswill require digitization to meet therequirements and establish new rela-tionships with patients, with unique

implications for cancer care.New payment models in oncology

are being piloted today, including tech-nology systems, with hopes of estab-lishing new models that better alignthe healthcare system to improve thequality and increased cost-effective-ness of cancer care.IT is a component of all these

changes, and the time is now for oncol-ogists to become vigilant aboutimproving efficiencies and reducingthe waste that exists with inefficientprocesses and systems. These invest-ments have steadily been made overthe past 10 years by thousands ofoncologists, but interoperability be-tween systems and broken processesstill continue to cause more adminis-trative burden than necessary.Oncology practices need to continue

on this path, sharing best practiceswith each other, and steadily improveleveraging information systems when-ever possible to provide the highest-quality cancer care for their patients. �

Reference1. Fox S. Looking for health information is the thirdmost popular online activity measured in our sur-veys. Health Topics. PewInternet. February 1, 2011.www.pewinternet.org/Reports/2011/HealthTopics/Summary-of-Findings/Looking-for-health-informa-tion.aspx. Accessed August 1, 2011.

Impact of EHRs on Oncology...Continued from page 32


“Over the next year…newdisease states may be addedto predetermined treatmentcontracts. More than 20% ofproviders are considering theaddition of melanoma, andpayers are considering theaddition of multiplemyeloma, chronic myeloidleukemia, and melanomaguidelines to this type ofcontracting arrangement.”

—Loreen M. Brown, MSW


metastatic solid tumors, enrollingpatients on clinical trials when chanceof success is minimal, and integratingpalliative care.“TheNew England Journal of Medicine

authors also wanted oncologists to rec-ognize that costs of care are driven bywhat they do and do not do and tohave more realistic expectations,” MsBrown said.Additional suggestions were to re-

align compensation for cognitive serv-ices to utilize cost-effectiveness analysisand to accept greater limits on care.The survey included questions

about the New England Journal ofMedicine article’s suggestions for costcontainment. The responses showedthat providers and payers generallyagreed that certain evidence-basedbehaviors and attitudes on the part ofoncologists would lower overall coststo the healthcare system (Figures 1and 2). For example, almost all of bothstakeholder groups believe that pallia-tive care should be integrated intooncology treatment.

However, “there were nuances tothe different payer perspectives,”according to Ms Brown.For example, >50% of the payers

argued that the routine use of growthfactors could be replaced by reduc-tions in chemotherapy dose in patientswith metastatic solid tumors. Only30% of providers, however, were ac-cepting of this strategy. Also, oncolo-gists desired reimbursement of cogni-tive services, which shows “adisconnect” between “what providersseek and what payers compensate,”she said. “Time spent talking topatients about the treatment plan, sideeffects, end-of-life care, and so forth istime that the oncologist is not paidfor.”Oncologists are also less agreeable

than providers to reducing chemother-apy among patients who do notrespond to 3 consecutive regimens(Figures 3 and 4).“The responses indicate that payers

work more keenly toward constrain-ing cancer costs,” Ms Brown said.

However, 85% of providers and payersstrongly agree that physicians’ andpatients’ expectations must be reset tobe more realistic.To align payers’ interest in cost con-

tainment with oncologists’ perceptionsof quality care, increased collaborationand improved communication withinthe payer–provider relationship arerequired.How might this be done? “Payers

and providers first need to understandthat they are on the same side,” MsBrown said. “Until recently, there hasbeen an ‘us versus them’ mentality. Thecontract negotiations were mostlyabout how much physicians were paidfor the drugs they used. Moving intothe new healthcare reform world, withepisode payments, bundling, and pay-ment for quality, there is a broader pic-ture of reimbursement. It is not justabout individual services. And bothgroups are amenable to that. The ques-tion is how to come upwith a system ofreimbursement that is episodic and thatmeets the needs of both parties.” �

ONCOLOGY REIMBURSEMENT


Figure 1 Payers’ Views on the Role of Oncologists’ Behavior on Healthcare Costs

0 20 40 60 80 100

Oncologists need to recognize that thecosts of care are driven by what we do and

what we do not do

Both doctors and patients need to havemore realistic expectations

Realign compensation to value cognitiveservices, rather than chemotherapy,

more highly

Better integrate palliative care into usualoncology care (concurrent care)

The need for cost-effectiveness analysisand for some limits on care must

be accepted

Figure 4 Oncologists’ Views on Patient Management Based on Emerging Evidence

0 20 40 60 80 100

UnawareNeutralAgree

Target surveillance testing or imaging to situations in which a benefit has been

shown

Limit second-line and third-line treatment for metastatic cancer to sequential

monotherapies for most solid tumors

Limit chemotherapy to patients with goodperformance status, with an exception for

highly responsive disease

Replace the routine use of white cell–stimulating factors with a reduction in the chemotherapy dose in metastatic

solid cancers

For patients not responding to 3 consecutive regimens, limit further

chemotherapy to clinical trials

Figure 3 Payers’ Views on Patient Management Issues Based on Emerging Evidence

0 20 40 60 80 100

UnawareNeutralAgree

Target surveillance testing or imaging to situations in which a benefit has been

shown

Limit second-line and third-line treatment for metastatic cancer to sequential

monotherapies for most solid tumors

Limit chemotherapy to patients with goodperformance status, with an exception for

highly responsive disease

Replace the routine use of white cell–stimulating factors with a reduction in the chemotherapy dose in metastatic

solid cancers

For patients not responding to 3 consecutive regimens, limit further

chemotherapy to clinical trials

Figure 2 Oncologists’ Views of Their Role in Controlling Costs

0 50 100 150

DisagreeNeutralAgree

Oncologists need to recognize that thecosts of care are driven by what we do and

what we do not do

Both doctors and patients need to havemore realistic expectations

Realign compensation to value cognitiveservices, rather than chemotherapy,

more highly

Better integrate palliative care into usualoncology care (concurrent care)

The need for cost-effectiveness analysisand for some limits on care must

be accepted

at a glance� Oncologists reported high

awareness of clinical trial data

for a number of established

biologics and several novel

agents in late-stage development

� More testing to guide treatment

decisions is expected within

lung cancer, melanoma, and

colorectal cancers

� 67.5% of oncologists intend to

increase their present use of

diagnostic testing based on what

they heard at ASCO and 30%

predict their use will remain

stable

� To align payers’ interest in cost

containment with oncologists’

perceptions of quality care,

increased collaboration and

improved communication within

the payer–provider relationship

are required

DisagreeNeutralAgree


IN THE LITERATURE


In addition, initial therapy withBEACOPP, compared with ABVD, ledto approximately 2 to 3 times higherrates of severe acute adverse eventsand death from toxic effects.These results, the investigators sug-

gest, indicate the importance of select-ing an initial chemotherapeutic regi-men not strictly according to its curerate but also in consideration of itstoxic effect profile and of the perform-ance of the secondary treatment. The author of an accompanying edi-

torial points out that since the 1990s,treatment strategies involving far lessintensive primary therapies haveachieved very high cure rates, whileavoiding the risk of infertility or sec-ondary leukemia. Almost all cases oflimited-stage Hodgkin lymphomatoday, for example, can be cured withonly 2 cycles of minimally toxic ABVDfollowed by involved-field, moderate-dose radiation therapy.

Whole-GenomeSequencing ProvidesTimely DiagnosisWhole-genome sequencing (WGS)

has traditionally been an importanttool in nonclinical research. Recently,however, the potential clinical value ofthe technique was demonstrated in apatient with acute promyelocyticleukemia (APL) that was hard to iden-tify (Welch JS, et al. JAMA. 2011;305:1577-1584).The patient, a 39-year-old woman

with acute myeloid leukemia (AML)in first remission after induction ther-apy with cytarabine, idarubicin, andetoposide, had been referred to theinvestigators for consideration of allo-geneic stem-cell transplantation. Abone marrow biopsy revealed nomorphologic evidence of AML, how-ever, and routine metaphase cytoge-netic testing and fluorescence in situhybridization failed to detect thepathogenic X-RARA fusion gene.Reverse transcription polymerasechain reaction testing also revealed noevidence of PML-RARA, the gene thatidentifies APL.Because timely diagnosis and treat-

ment are crucial to ensuring an optimaloutcome inAML, the investigators’ pri-mary goal was to establish an accuratediagnosis and administer appropriatetherapy—either consolidation therapywith chemotherapy or allogeneicstem-cell transplantation, dependingon the diagnosis—within a period of 6to 8 weeks.Within 7 weeks, using massively

parallel paired-end sequencing, theyhad detected and validated a novel

insertional fusion that created a classicPML-RARA bcr3 variant, thereby con-firming APL. The patient was thenadministered consolidation therapywith all-trans retinoic acid andremains in first remission 15 monthsafter her first presentation.Although other laboratory methods

are available for detecting potential

pathogenic RARA rearrangements,those are labor- and resource-inten-sive, say the investigators, and demon-strate success rates inadequate for clin-ical practice. The use of WGS identified the onco-

gene to facilitate a life-saving changeof therapy. For routine use for patientswith cancer, diagnostic WGS is cur-

rently cost-prohibitive ($40,000 foreach tumor per normal pair), althoughits cost has been decreasing rapidly inthe past several years. Because the cumulative costs of

molecular testing have been increas-ing, the decreasing cost of WGS maybe enough to encourage its use as adiagnostic and risk assessment tool. �

October 13 – 14, 2011 • Chicago, Illinois Palmer House Hilton Hotel

REGISTER NOW

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REGISTER BY JULY 15TH AND SAVE $200

Questions – Contact Jodi Brunner at [email protected]

Achieving Accountable Cancer Care

Introducing two new tracks:Hospital Track and Radiation Oncology Track

Keynote: Will ACOs Bundle Off Oncology?Peter Bach, M.D., MAPP, Memorial Sloan-Kettering Cancer Center

Luncheon Keynote: A Washington Perspective on Oncology Payment ReformKaren Ignagni, President and Chief Executive Officer, America’s Health Insurance Plans

CancerBusinessSummit.com

2011 Advisory BoardMichael J. Anderson, M.D., Commonwealth Hematology-OncologyRonald Barkley, M.S., J.D., Cancer Center Business Development GroupThomas R. Barr, MBA, Oncology Metrics, a division of Altos SolutionsAnthony M. Berson, M.D., Aptium OncologyDavid C. Beyer, M.D., Arizona Oncology ServicesMichael L. Blau, J.D., Foley & Lardner LLPBradford C. Burkett, Epsilon Securities, LLCStephanie Clayton, University of Texas Southwestern John V. Cox, D.O., American Society of Clinical OncologyAllison Cuff Shimooka, The Advisory Board CompanyBruce Cutter, M.D., MMM, Cutter Health Care ConsultingDaniel Dosoretz, M.D., 21st Century OncologyMeredith B. Feinberg, North Shore-LIJ Health SystemTeri U. Guidi, MBA, FAAMA, Oncology Management Consulting GroupKaren Hagerty, M.D., American Society of Clinical OncologyRichard J. Hall, Alliance OncologyJohn E. Hennessy, MBA, CMPE, Kansas City Cancer CenterDeborah D. Hood, MBA, Catholic Health InitiativesWilliam Jordan, D.O., The Center for Cancer & Blood DisordersMark Krasna, M.D., St. Joseph Medical Center / CHIPete Lawson, Health Management Associates, Inc.Kathleen G. Lokay, D3 Oncology SolutionsBarbara L. McAneny, M.D., New Mexico Oncology Hematology Consultants, Ltd.Barbara Miller, Wells Fargo Equipment Finance, Inc.Steve Newman, M.D., Hematology Oncology Associates of IllinoisKent Nicaud, Memorial Hospital at Gulfport Paul O’Dea, Aptium Oncology Inc.Gitesh Patel, Comprehensive Blood & Cancer CenterBarry Russo, The Center for Cancer and Blood DisordersMartin Shenk, CMPE, The Medical Oncology Group, P.A.Kelley D. Simpson, Oncology Solutions, LLCAmy Starling, Meridian Health System Elaine L. Towle, CMPE, Oncology Metrics, a division of Altos SolutionsJessica Turgon, ECG Management Consultants, Inc.Strode Weaver, University of Colorado Hospital

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21st Century Oncology • Accuray Incorporated • Alliance Oncology • AmeriPath, Inc • Aptium Oncology • athenahealth • Cancer CarePoint, Inc.CareCore National • Catholic Health Initiatives • D3 Oncology Solutions • e+ Cancer Care • Epsilon Securities, LLC • GenentechHealthCare Appraisers, Inc. • Integrated Healthcare Strategies • Integrated Oncology Network • IntrinsiQ, LLC • KEW Group, LLC

McKesson Specialty Care Solutions/US Oncology • Millennium: The Takeda Oncology Company • Oncology Business Review • Oncology Management Consulting GroupOncology Metrics, a division of Altos Solutions • Oncology Practice Management • Oncology Solutions, LLC • Oncology Supply/ION Solutions • OncoMed

Oncure Medical Corp. • PricewaterhouseCoopers, LLP • Proventys, Inc. • The Schwartz Center • Unlimited Systems • US Radiosurgery, LLC • VMG Health • Wells Fargo

CCBD GROUPCANCER CENTER BUSINESS DEVELOPMENT

Intensified BEACOPP...Continued from page 19


MCM0000417100 06/11

R

The VEGF ligand is one of the fi rst pro-angiogenic factors and is present throughout the tumor life cycle1,2,3

Avastin directly binds VEGF to inhibit angiogenesis4,5

Avastin is designed to directly bind to VEGF extracellularly to prevent interaction with VEGF receptors (VEGFR) on the surface of endothelial cells, thereby inhibiting its biologic activity5

Cessation of anti-VEGF treatment may diminish impact on tumors6,7,8

TO CONTACT YOUR ACCOUNT MANAGER FOR MORE INFORMATION ON AVASTIN VISIT: genentechmm.com

IndicationsAvastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Avastin is indicated for the fi rst-line treatment of unresectable, locally advanced, recurrent, or metastaticnon–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Avastin is indicated for the fi rst- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fl uorouracil–based chemotherapy.

The mechanism of action of anti-VEGF agents has been elucidated primarily in preclinical models. Its clinical signifi cance is unknown.

V E G F I N H I B I T I O N

THE PROPOSED EFFECTS OF

AVASTIN®

The VEGF ligand is one of the fi rst pro-angiogenic factors and is present throughout the tumor life cycle1,2,3

VEGF

VEGF Inhibition

Avastin

B


©2011 Genentech Inc., So. San Francisco, CA MCM0000417100 06/11

References: 1. Hanrahan V, Currie MJ, Gunningham SP, et al. J Pathol. 2003;200:183-194. 2. Fontanini G, Vignati S, Boldrini L, et al. Clin Cancer Res. 1997;3:861-865. 3. Rini BI, Small EJ. J Clin Oncol. 2005;23:1028-1043. 4. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027. 5. Avastin Prescribing Information. Genentech, Inc. February 2011. 6. Bagri A, Berry L, Gunter B, et al. Clin Cancer Res. 2010;16:3887-3900 [and supplemental appendix]. 7. Baluk P, Hashizume H, McDonald DM. Curr Opin Genet Dev. 2005;15:102-111. 8. Inai T, Mancuso M, Hashizume H, et al. Am J Pathol. 2004;165:35-52.

Boxed WARNINGS and additional important safety informationGastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation rangedfrom 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation

Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention

Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade 3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis ( 1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fi stula formation ( 0.3%), arterial thromboembolic events (grade 3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the fi rst dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Based on animal data, Avastin may cause fetal harm and may impair fertility. Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin. For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Please see the following brief summary of full Prescribing Information, including Boxed Warnings, for additional important safety information.


Solution for intravenous infusion Initial U.S. Approval: 2004

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGEGastrointestinal PerforationsThe incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]Surgery and Wound Healing ComplicationsThe incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), and Adverse Reactions (6.1).]HemorrhageSevere or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to �ve-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), and Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE1.1 Metastatic Colorectal Cancer (mCRC)Avastin is indicated for the �rst- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-�uorouracil–based chemotherapy.1.2 Non-Squamous Non–Small Cell Lung Cancer (NSCLC)Avastin is indicated for the �rst-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.1.3 Metastatic Breast Cancer (MBC)Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel.The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).]Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.1.4 GlioblastomaAvastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]1.5 Metastatic Renal Cell Carcinoma (mRCC)Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.4 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Gastrointestinal PerforationsSerious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and �stula formation. The majority of cases occurred within the �rst 50 days of initiation of Avastin.Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]5.2 Surgery and Wound Healing ComplicationsAvastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]5.3 HemorrhageAvastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to �ve-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%–5.93%).Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]5.4 Non-Gastrointestinal Fistula FormationSerious and sometimes fatal non-gastrointestinal �stula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤0.3% in clinical studies. Most events occurred within the �rst 6 months of Avastin therapy.Discontinue Avastin in patients with �stula formation involving an internal organ. [See Dosage and Administration (2.4).]5.5 Arterial Thromboembolic EventsSerious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]5.6 HypertensionThe incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%.Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuation of Avastin.Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to con�rm the diagnosis of RPLS.Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]5.8 ProteinuriaThe incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed �ndings consistent with thrombotic microangiopathy.Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]5.9 Infusion ReactionsInfusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the �rst dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the label:

Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Non-Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.6.1 Clinical Trial ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not re�ect the rates observed in practice.The data below re�ect exposure to Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin. [See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white. The population included 1089 �rst- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 �rst-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.Surgery and Wound Healing ComplicationsThe incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus-IFL plus Avastin as compared to 4% (1/25) of patients who received bolus-IFL alone.In Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal �uid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]HemorrhageThe incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL plus Avastin compared with patients receiving bolus-IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus-IFL plus Avastin when compared to those receiving bolus-IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]Venous Thromboembolic EventsThe incidence of Grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving chemotherapy alone. In Study 1, 53 patients (14%) on the bolus-IFL plus Avastin arm and 30 patients (8%) on the bolus-IFL plus placebo arm received full dose warfarin following a venous thromboembolic event. Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus-IFL plus Avastin and 3% (1/30) of patients receiving bolus-IFL alone.The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus-IFL plus Avastin and 13.6% in patients receiving bolus-IFL plus placebo. In Study 1, the incidence of the following Grade 3–4 venous thromboembolic events was higher in patients receiving bolus-IFL plus Avastin as compared to patients receiving bolus-IFL plus placebo: deep venous thrombosis (34 vs. 19 patients) and intra-abdominal venous thrombosis (10 vs. 5 patients).Neutropenia and InfectionThe incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the �rst 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%.ProteinuriaGrade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).] Congestive Heart FailureThe incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with MBC, the incidence of Grade 3-4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.Metastatic Colorectal Cancer (mCRC)The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving bolus-IFL plus Avastin as compared to bolus-IFL plus placebo, are presented in Table 1.

Table 1 NCI-CTC Grade 3−4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

Arm 1 Arm 2 IFL + Placebo IFL + Avastin (n = 396) (n = 392)

NCI-CTC Grade 3-4 Events 74% 87%Body as a Whole Asthenia 7% 10% Abdominal Pain 5% 8% Pain 5% 8%Cardiovascular Hypertension 2% 12% Deep Vein Thrombosis 5% 9% Intra-Abdominal Thrombosis 1% 3% Syncope 1% 3%Digestive Diarrhea 25% 34% Constipation 2% 4%Hemic/Lymphatic Leukopenia 31% 37% Neutropeniaa 14% 21%

a Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving bolus-IFL plus Avastin as compared to the bolus-IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the �rst approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Avastin) was discontinued.

Table 2 NCI-CTC Grade 1-4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL)

Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5-FU/LV + Avastin (n = 98) (n = 102) (n = 109)

Body as a Whole Pain 55% 61% 62% Abdominal Pain 55% 61% 50% Headache 19% 26% 26%Cardiovascular Hypertension 14% 23% 34% Hypotension 7% 15% 7% Deep Vein Thrombosis 3% 9% 6%Digestive Vomiting 47% 52% 47% Anorexia 30% 43% 35% Constipation 29% 40% 29% Stomatitis 18% 32% 30% Dyspepsia 15% 24% 17%

GI Hemorrhage 6% 24% 19% Weight Loss 10% 15% 16% Dry Mouth 2% 7% 4% Colitis 1% 6% 1%

Hemic/Lymphatic Thrombocytopenia 0% 5% 5%Nervous Dizziness 20% 26% 19%Respiratory Upper Respiratory Infection 39% 47% 40% Epistaxis 10% 35% 32% Dyspnea 15% 26% 25% Voice Alteration 2% 9% 6%Skin/Appendages Alopecia 26% 32% 6% Skin Ulcer 1% 6% 6%Special Senses Taste Disorder 9% 14% 21%Urogenital Proteinuria 24% 36% 36%

Avastin in Combination with FOLFOX4 in Second-line mCRCOnly Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2.Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC)Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary in�ltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).Metastatic Breast Cancer (MBC)Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs. 0.3%) and proteinuria (3% vs. 0%).Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm.Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2).Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC. The data below are presented to provide information on the overall safety pro�le of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3.

Table 3 NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

Capecitabine Capecitabine + Avastin (n = 215) (n = 229)

Body as a Whole Asthenia 47% 57% Headache 13% 33% Pain 25% 31%Cardiovascular Hypertension 2% 24%Digestive Stomatitis 19% 25%Metabolic/Nutrition Weight loss 4% 9%Musculoskeletal Myalgia 8% 14%Respiratory Dyspnea 18% 27% Epistaxis 1% 16%Skin/Appendages Exfoliative dermatitis 75% 84%Urogenital Albuminuria 7% 22%

GlioblastomaAll adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin-related adverse events (Grade 1– 4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).Metastatic Renal Cell Carcinoma (mRCC)All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN-α) plus Avastin compared to 304 patients receiving IFN-α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN-α plus Avastin compared to the IFN-α plus placebo arm are presented in Table 4.

Table 4 NCI-CTC Grades 1−5 Adverse Events in Study 9

(Occuring at Higher Incidence [≥ 5%] in IFN-α + Avastin vs. IFN-α + Placebo)

System Organ Class/ IFN-α + Placebo IFN-α + Avastin Preferred terma (n = 304) (n = 337)Gastrointestinal disorders Diarrhea 16% 21%General disorders and administration site conditions Fatigue 27% 33%Investigations Weight decreased 15% 20%Metabolism and nutrition disorders Anorexia 31% 36%Musculoskeletal and connective tissue disorders Myalgia 14% 19% Back pain 6% 12%Nervous system disorders Headache 16% 24%Renal and urinary disorders Proteinuria 3% 20%Respiratory, thoracic and mediastinal disorders Epistaxis 4% 27% Dysphonia 0% 5%Vascular disorders Hypertension 9% 28%

aAdverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Avastin arm compared to IFN-α alone and not represented in Table 4: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal re�ux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).6.2 ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected.Immunogenicity data are highly dependent on the sensitivity and speci�city of the assay. Additionally, the observed incidence of antibody positivity in an assay may be in�uenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.6.3 Postmarketing ExperienceThe following adverse reactions have been identi�ed during post-approval use of Avastin. 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.Body as a Whole: PolyserositisCardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusionEye disorders (reported from unapproved use for treatment of various ocular disorders): Endophthalmitis; Intraocular in�ammation such as iritis and vitritis; Retinal detachment; Other retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous �oaters; Visual disturbances; Ocular hyperemia; Ocular pain and/or discomfortGastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulcerationHemic and lymphatic: PancytopeniaRenal: Renal thrombotic microangiopathy (manifested as severe proteinuria)Respiratory: Nasal septum perforation, dysphonia7 DRUG INTERACTIONSA drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no signi�cant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CThere are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of speci�c gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Because of the observed teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential bene�t to the pregnant woman justi�es the potential risk to the fetus.8.3 Nursing MothersIt is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]8.4 Pediatric UseThe safety, effectiveness and pharmacokinetic pro�le of Avastin in pediatric patients have not been established.Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insuf�cient information to determine the safety and ef�cacy of Avastin in children with glioblastoma.Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.8.5 Geriatric UseIn Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]In Study 5, there were insuf�cient numbers of patients ≥ 65 years old to determine whether the overall adverse events pro�le was different in the elderly as compared with younger patients.Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.In an exploratory, pooled analysis of 1745 patients treated in �ve randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]10 OVERDOSAGEThe highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab)

02/11 AVA000030660010127309

Initial U.S.Approval: February 2004Code Revision Date: February 2011

Avastin® is a registered trademark of Genentech, Inc.

©2011 Genentech, Inc.

Avastin® (bevacizumab) Manufactured by:Genentech, Inc.A Member of the Roche Group1 DNA WaySouth San Francisco, CA94080-4990


SCREENING FOR CANCER


Ongoing efforts to screen asymp-tomatic persons for pancreaticcancer have been unsuccess-

ful, but targeting persons at high riskfor the disease appears to be clinicallyeffective as well as cost-effective. Researchers have combined the use

of a serum biomarker, CA 19-9, andendoscopic ultrasonography to createa screening protocol for persons at riskfor the malignancy on the basis of fam-ily history and age and reported theirresults in the July issue of Gastro -intestinal Endoscopy (Zubarik R, et al.Gastrointest Endosc. 2011;74:87-95).

High-Risk Characteristics

Serum CA 19-9 has performed poor-ly in several previous studies, but inthose studies participants were oftenyounger than age 50 years (an ageassociated with low risk for pancreaticcancer) or have been tested with insen-sitive imaging modalities.“Our hypothesis was that a high-

risk population identified by age andat least 1 first-degree relative withpancreatic cancer can be success -fully screened,” said lead investigatorRichard Zubarik, MD, AssociateProfessor of Medicine and Chief ofEndoscopy, University of Vermont,Burlington. “Our objective was to determine

whether early pancreatic neoplasia canbe detected in a high-risk population by

using tumor marker CA 19-9 followedby targeted endoscopic ultrasonogra-phy. We also sought to determinewhether this protocol was more likelyto detect early-stage pancreatic cancerthan standard means of detection.”This study enrolled 546 patients

aged ≥50 years with at least 1 first-degree relative with pancreatic cancer.Enrollment was initiated at age 45 if anindividual had 2 affected first-degreerelatives and at age 40 if the personhad a BRCA2 mutation or Peutz-Jeghers syndrome.

The BRCA2 mutation raises the riskof pancreatic cancer by 3.5- to 10-fold,whereas Peutz-Jeghers syndrome isassociated with a 132-fold increasedrisk, according to Marcia Canto, MD,Associate Professor of Medicine andOncology, Johns Hopkins UniversitySchool of Medicine, Baltimore, anexpert in the field who did not partici-pate in this study. Johns Hopkins Hospital conducts

high-risk screening using multipleimaging modalities that include notonly endoscopic ultrasonography butalso magnetic resonance imaging,magnetic resonance cholangiopancre-atographic imaging, and endoscopicretrograde cholangiopancreatographyin select cases.

Elevated Biomarkers Raised

Suspicion

In the current study, all patientsunderwent serum CA 19-9 level test-ing, and those with an elevated level(>37 U/mL) were referred for endo-scopic ultrasonography. For compari-son, the study included patients whowere diagnosed with pancreatic cancerat the University of Vermont duringthe same period but were not enrolledin this study.

Serum CA 19-9 was elevated in 27patients (4.9%). Neoplastic (potentiallypremalignant or malignant) findingswere detected in 5 patients (0.9%); 1(0.2%) of those lesions was identified asstage I adenocarcinoma of the pancreas.No additional cases of pancreatic can-cer were identified at 1-year follow-up. In the comparison group, pancreatic

cancer was diagnosed in 124 patientsduring the study period, and thetumors in 114 of these patients werestaged, revealing that: • 1 patient (0.9%) had stage I disease• 52 patients (45.6%) had stage II disease

• 20 patients (17.5%) had stage III disease

• 41 (36%) had stage IV disease.“The one patient detected in the

CA 19-9/endoscopic ultrasonographystudy had stage I disease, whereasdetection of stage I cancer in the com-parison group was rare (1 of 114patients),” according to Dr Zubarik. Among the 122 patients in the com-

parison group for whom survival datawere available, median overall sur-vival was only 7 months, and the 2-year survival rate was 10%. “The one patient found to have ade-

nocarcinoma of the pancreas by ourscreening protocol is still alive, with-out evidence of recurrence, 3 yearsafter surgical resection, and is thelongest survivor of pancreatic cancerdetected in a published screening pro-tocol,” Dr Zubarik noted.

Cost Implications

Potentially curable pancreatic can-

cer can be identified with CA 19-9 test-ing and targeted endoscopic ultra-sonography, and stage I disease ismore likely to be found using thisscreening protocol than through stan-dard means of detection, the investiga-tors maintain. The cost to detect pancreatic neo-

plasia was determined from Medi -care reimbursement data from 2010.The reimbursement for CA 19-9,physician, and facility fees for endo-scopic ultrasonography S, and cyto -pathology were considered, but sub-sequent therapy after detection of theneoplastic process and secondarycosts were not. The cost of detecting 1 pancreatic

neoplasm as part of the protocol wasapproximately $8430, whereas the costof identifying 1 pancreatic tumor was$41,133.For detecting neoplasia and adeno-

carcinoma, the respective breakdownof costs was $3249 and $16,276 for theCA 19-9 test; $3028 and $15,748 for theendoscopic ultrasonography facilityfee; $993 and $4469 for the endoscopicultrasonography professional fee; $795and $3182 for endoscopic ultrasonog-raphy/biopsy professional fee; and$364 and $1458 for cytopathology pro-fessional fees. This screening approach offers

“acceptable rates of disease diagnosisand exclusion as well as acceptablecosts,” Dr Zubarik suggested. “Earlypancreatic adenocarcinoma, associatedwith prolonged disease-free survival,can be detected as part of this pancre-atic screening protocol.” �

Screening for Pancreatic Cancer Is Effective, Has Value—at Least in High-Risk IndividualsBy Caroline Helwick

at a glance� Efforts to screen asympto -matic persons for pancreaticcancer have been unsuccessful

� Targeting persons at high riskis clinically effective, as well ascost-effective

� BRCA2 mutation raises therisk of pancreatic cancer by 3.5- to 10-fold

� Peutz-Jeghers syndrome isassociated with a 132-foldincreased risk

� Stage I disease is more likelyto be found using endoscopicultrasonography screeningprotocol than standard means

� The cost of detecting 1pancreatic neoplasm as part ofthe protocol is approximately$8430, whereas the cost ofidentifying 1 pancreatic tumorwas $41,133

“The one patient found tohave adenocarcinoma of thepancreas by our screeningprotocol is still alive, withoutevidence of recurrence, 3years after surgical resection,and is the longest survivor of pancreatic cancer detected in a publishedscreening protocol.”

—Richard Zubarik, MD

Most professional guidelinesnow recommend screeningfor hepatitis B virus (HBV)

infection in essentially all patientsreceiving chemotherapy, but it is sel-dom performed and is not cost-effec-tive in patients with solid (nonhema-tologic) tumors, according to studiespresented at ASCO 2011.Researchers at the University of

Texas M.D. Anderson Cancer Center,Houston, used their database to evalu-ate the prevalence of HBV infectionbefore chemotherapy and of reactiva-tion of the virus during treatment bycomparing patient and treatment char-acteristics in those with and withoutHBV reactivation.

Of the 10,729 patients who receivedchemotherapy, 1787 (17%) patientswere screened and 151 (8%) tested pos-itive for HBV surface antigen and/oranti-HBc (core antibody).Reactivation occurred in 73 of these

patients and was most commonamongAsians and patients with hema-tologic cancer.“Overall, we found low rates of

HBV screening prior to chemotherapy,and we found that preventable reacti-vation of HBV infection is common,”Jessica Hwang, MD, MPH, said.

Cost-Effectiveness Analysis

A study from Australian investiga-

HBV Screening Recommended withChemotherapy, but Not Cost-Effectivein Solid Tumors



Medicare may be paying formore screening colonos -copies than are warranted

for the prevention of colorectal cancer(CRC), according to a new study(Goodwin JS, et al. Arch Intern Med.2011 May 9 [Epub ahead of print]).

All relevant authorities recommendan interval of 10 years between normalscreening colonoscopies. Althoughmuch attention has been given to theunderuse of CRC screening, less atten-tion has been paid to possible overuse,according to James S. Goodwin,MD, George and Cynthia MitchellDistinguished Chair in GeriatricMedicine and Director, Sealy Centeron Aging, University of Texas MedicalBranch, Galveston.

Dr Goodwin led a study thatassessed the timing of repeatedcolonoscopies after a negative screen-ing colonoscopy finding in a pop -ulation-based sample of Medicarepatients. A 5% national sample ofMedicare enrollees from 2000 through2008 was used to identify average-risk patients undergoing screeningcolonoscopy between 2001 and 2003.

Colonoscopy was classified as anegative screening examination if noadditional indications appeared inclaims and if no biopsy or related pro-cedure was performed. The time torepeated colonoscopy was calculated.

Among 24,071 Medicare patientswith a negative screening examina-tion, 46.2% underwent a repeated

examination in less than 7 years. In42.5% of these patients (23.5% of theoverall sample), there was no clearindication for the early repeated exam-ination, the study found.

“The actual practice of colonoscopyin the community seems quite differ-ent from the assumptions made inassessing the cost-effectiveness of CRC

screening by colonoscopy,” main-tained Dr Goodwin.

He acknowledged, however, thatinvestigators lacked information onthe quality of the initial colonoscopy.Early repeated colonoscopies couldresult from incomplete or poor-qualityinitial examinations, he said, althoughthe study eliminated subjects withincomplete examinations. “Also, onewould expect repeated colonoscopiesto follow up on suspicious findings tooccur relatively soon after the initialcolonoscopy, which is not the temporalpattern we found,” he added.

Repeated colonoscopies were alsoaffected by the patient’s age. Amongpersons aged 75 to 79 years, 45.6%were screened within 7 years, as were32.9% of individuals aged ≥80 yearsat the time of the initial negativecolonoscopy result.

In multivariable analyses, male sex,presence of more comorbidities, per-formance of colonoscopy by a high-vol-ume colonoscopist, and performance ofthe test in an office setting were associ-ated with higher rates of early repeatedcolonoscopy without clear indication.

There were also marked geographicvariations, from less than 5% in somehealth referral regions to greater than40% in others.

Looking for the Reasons

The investigators concluded that, “Alarge proportion of Medicare pa tientswho undergo screening colonos copydo so more frequently than recom-mended.” Current Medi care regula-tions intending to limit reimbursementfor screening colonos copy to every 10years do not appear to be effective.

In an interview with Value-BasedCancer Care, Dr Goodwin noted,“Every authority (including theAmerican Gastroenterological As -socia tion [AGA], American CancerSociety, US Preventive Services TaskForce, and others) says that after a nor-mal screening colonoscopy, anotherexamination is not needed for 10 years,but surveys suggest that individualgastroenterologists often disagree.There is a strong opinion that theyshould be done more frequently. Thegastroenterologists are doing whatthey feel is the right thing, but no otherorganization that lacks direct involve-ment in this situation, including theAGA, agrees.”

Could there be a profit motive atwork? “The profit motive in American

medicine is like gravity. It’s a force thatwill always be there,” he responded.“Clearly, when you have the peoplewho are profiting from the procedurebeing the ones who decide when todo it, there will always be some forcetoward overuse. Yes, I think theprofit motive is partly responsiblefor the findings.”

Medicare regulations preclude reim-bursement for screening colonoscopywithin 10 years of a negative examina-tion result. However, Medicare deniedonly 2% of the claims for early repeat-ed colonoscopies without indicationin this study. The study showed thatan understanding of such cases, wherean indication was lacking, is compli-cated by the “seeming underuse ofthe screening code” in colonoscopiesbilled to Medicare.

“When we looked at the reasons forthese examinations, many were excep-tionally nebulous, and there was noevidence in prior billing that theseindications existed. For example, ifthey indicated a ‘change in bowelhabits,’ there was often no mention ofthis in previous billings. We thoughtthis was suggestive of some ‘creativecoding,’” he said.

Dr Goodwin elaborated that suchpractice has been ingrained for years.“You have to look historically. By 1990,colonoscopy had been shown to pre-vent cancer, detect it early, and reducemortality, but Medicare did not startreimbursing for screening colon -oscopy until 2001. So all during the1990s, physicians used creativity to dowhat they felt was the right thing—doscreening colonoscopy—and to bereimbursed for it from Medicare.

“Many, many examinations weredone throughout the 1990s, but theywere not called ‘screening colon -oscopy,’ because these were not re -imbursed,” he continued. “I thinkwhen Medicare finally started reim-bursing, the billing staff continued touse these codes.”

Fee-for-Service the Culprit?

Dr Goodwin reiterated that earlyrepeated colonoscopies without clearindication veer from national recom-mendations, compose a substantialproportion of the present endoscopist’sworkload, and represent “substantialMedicare expenditures,” he said. “Andfrom my personal experience as a pri-mary care provider, my gut feeling isthat this is not something unique toMedicare but could happen under anyfee-for-service program.” �

SCREENING FOR CANCER


Colonoscopy Overused in Medicare Recipients,Adding Unnecessary Expenditures Negative screening and current recommendations too often ignoredBy Caroline Helwick

“Every authority says thatafter a normal screeningcolonoscopy, anotherexamination is not neededfor 10 years, but surveyssuggest that individualgastroenterologists oftendisagree. There is a strongopinion that they should bedone more frequently.

—James S. Goodwin, MD

tors suggests universal screening is notcost-effective, at least in patients withsolid tumors.

According to Fiona L. Day, MD, ofPeter MacCallum Cancer Center,Melbourne, approximately 50% ofAustralian oncologists screen for HBV;only 19% screen every patient.

A decision-analytic model was usedto compare universal screening versusno screening in hypothetical patientcohorts, one consisting of patientsreceiving adjuvant chemotherapy forearly breast cancer (adjuvant cohort),one of patients receiving palliativechemotherapy for advanced non–small-cell lung cancer (palliativecohort), and one in which results fromall patients were pooled.

Using an incremental cost-effective-ness ratio (ICER) threshold of $50,000

Australian per life-year (LY) saved, uni-versal HBV screening was not cost-effective for patients who receivedadjuvant chemotherapy (ICER of$88,173/LY, 13% probability of beingcost-effective), patients who receivedpalliative chemotherapy (ICER >$1.3million/LY, 0% probability of beingcost-effective), or all pooled patientswith solid tumors (ICER of $149,771/LY, 1% probably of cost-effectiveness).

A sensitivity analysis showed thatscreening approached cost-effective-ness among patients receiving adju-vant chemotherapy who had the high-est rate (65%) of undiagnosed chronicHBV infection, for whom the ICERwas $51,979/LY, or the highest chanceof reactivation with chemotherapy(41%), for whom the ICER was$48,779/LY.—CH �

HBV Screening... Continued from page 39


METASTATIC MELANOMA


The development of ipilimumab(Yervoy) and its approval by theUS Food and Drug Admin -

istration (FDA) in March 2011 haveopened a new era in the treatment andmanagement of patients with metasta-tic melanoma. The continued innova-tion in cancer drug development hasbeen focused on a different mecha-nism of action that engages thepatient’s own immune system inattacking malignancy in contrast to themore traditional myelosuppressivedrugs that have been used in the pasthalf century to kill rapidly dividingcancer cells. The hallmark of successful therapy

for melanoma has always been surgi-cal excision. Although curative, thismethod does not necessarily reducethe likelihood of recurrence. To mini-mize this potentially lethal risk, inter-feron therapy has historically beeninstituted, administered as 1 month ofinduction therapy followed by 11months of injections; however, this isan intense regimen for patients, whotherefore benefit from a multidiscipli-nary approach to treatment that caninclude pharmacy management ofsymptoms. Even then, the disease canrecur and progress. As a result, bioim-munotherapy, a rudimentary type ofimmunotherapy, was developed in thelate 1990s.1 Like interferon therapy,however, bioimmunotherapy is in-tense and necessitates hospital servic-es, sometimes including the intensivecare unit.Despite these efforts, melanoma all

too often still claims a large number oflives. Although the cure rate is highfor patients whose disease is detect-ed early and surgically resected, the5-year survival rate is fairly low forthose with disease that has metasta-sized—less than 15% according to the2010 data from the American CancerSociety.2 In the United States alone, justunder 70,000 new cases of melanomawere diagnosed in 2010, and 8700deaths occurred, mostly from ad-vanced or metastatic disease.3

For some time now, researchershave focused on the development ofimmune stimulants and vaccinesdesigned to enlist a patient’s immunesystem to attack cancer cells, culminat-

ing with the March 25, 2011, FDAapproval of ipilimumab—the first T-cell–mediated therapy for unresectableor metastatic melaonoma.4 This drug isa monoclonal antibody that bindsCTLA-4 (cytotoxic T-lymphocyte anti-gen 4), thereby blocking its interactionwith the ligands CD80/CD86. Thisappears to result in T-cell overproduc-tion, which in turn stimulates an acti-vated immune response.4

My professional experience with 5patients provides a unique perspectivefor those who have not yet treated anypatients with this novel medication.My center is a multidisciplinary centerinvolved in a robust clinical trials pro-gram that includes active pharmacistparticipation in symptom manage-ment. In one of these trials, 3 of ourpatients were treated with ipilimumabbefore the FDA approval of the drug;in addition, 1 patient was in theexpanded access program created byBristol-Myers Squibb (BMS) whileawaiting final FDA approval for thedrug, and 1 patient had just begun toreceive it on April 11, 2011, the dayipilimumab became commerciallyavailable. Our experience with these 5 patients

shows that the drug indeed has anovel mechanism of action, and itquite simply “revs up” the immunesystem and then stands back. Therehave been many previous attempts todevelop vaccines and other productsto stimulate the immune system inpatients with melanoma by killing themelanoma-affected cells, but ipilim -umab is the first product to receiveFDA approval. Although the activity of ipilimumab

is impressive, it is also associated witha wide range of potential toxicities,which can manifest in almost any sys-tem in the body, including gastroin-testinal, liver, skin, neurologic, andendocrine toxicities that are highlight-ed in the Risk Evaluation and Mitiga -tion Strategy (REMS) program for thisagent. There is currently no way topredict the focus of any of the immunesystem’s responses. What is predictable is the response

to ipilimumab therapy, which is asso-ciated with a 34% risk of death.5 Unliketraditional chemotherapy, the goalwith ipilimumab is not to deliver asmuch drug as possible but rather tostimulate the immune system proper-ly—only 4 doses maximum can be

given, according to the FDAapproval.4

Also noteworthy is the agent’s cost,which has captured much mediaattention. The price is in the samerange as the prostate cancer drugsipuleucel-T (Provenge). Both drugshave a limited number of cycles (3administrations for sipuleucel-T and 4for ipilimumab).Ipilimumab will be distributed only

through the wholesaler McKesson andthe distributor Oncology Supply.Because ipilimumab is approved

with a REMS program, BMS hasdesigned a comprehensive plan thatemploys sales and medical scienceliaisons in coordinated teams to ensureclinicians are properly educated aboutthe risks and benefits of the drug. TheREMS program also includes a med-ication guide for patients. At its centeris a wallet card that a patient carries toalert any potential urgent care andemergency department physicians tothe possibility of immune-related toxi-city and the resultant need for steroids.The copious and early use of steroidshas been found to ameliorate manytoxicity-related problems, because thetoxic effects in this case are not frommyelosuppressive chemotherapy butrather from stimulated T lymphocytes.In addition, BMS has initiated a sur-

veillance and peer-to-peer educationprogram in which medical serviceliaisons will contact clinicians within avery tight window of a few days afterreceiving a new order for ipilimumabto provide educational services andfollow-up. As the Pharmacy Practice Editor of

the Journal of Hematology OncologyPharmacy, I urge those not experiencedwith this novel agent to accept anyoffer of education or assistance regard-ing its use. Despite the associated risksinvolved, this new therapy offers ben-efits beyond the standard myelosup-pressive agents or monoclonal anti-body drugs that we have becomeaccustomed to in the past decade anda half, when these therapies proliferat-ed on the oncology scene. It is certainly not my wish to deter

clinicians from using this drug, but itdoes involve many occasions forerrors, including the aggressive useof corticosteroids as the primaryresponse to almost any toxicity—which is counterintuitive for many cli-nicians. Getting the appropriate edu-cation about the use of this drug istherefore crucial for preventingadverse outcomes and potentiallydenying other patients the opportuni-ty for this therapeutic option. Al -though cost has become a major issue,nothing costs as much as a therapythat is not used successfully or safely.The FDA has been criticized for hav-

ing approved the fewest number ofnew drugs in decades, but theapproval of ipilimumab offers a novelagent with promising therapeutic out-comes in an area of oncology that hashad few worthwhile choices. �

References1. Elsevier/Gold Standard Clinical Pharmacologywebsite. Aldesleukin FDA approval date for MM.www.clinicalpharmacology-ip.com/Forms/Monograph/ monograph.aspx?cpnum=12&sec=mondesc.Accessed May 5, 2011. [Accessible through paid sub-scription.]2. American Cancer Society. Cancer facts and figures,2010. www.cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf. AccessedMay 21, 2011. 3. National Cancer Institute. General informationabout melanoma. www.cancer.gov/cancertopics/pdq/treatment/melanoma/HealthProfessional/page1#Reference1.1. Accessed May 19, 2011.4. US Food and Drug Administration. Ipilimumab.March 25, 2011. www.fda.gov/AboutFDA/CentersOffices/CDER/ucm248478.htm. Accessed May 23,2011. 5. Bristol-Myers Squibb. Yervoy (ipilimumab) website.Pivotal phase 3 study. Yervoy (ipilimumab) is the firstand only approved therapy to demonstrate an overallsurvival benefit. www.yervoy.com/hcp/phase-3-study/efficacy-study-safety.aspx. Accessed June 2,2011.

Ipilimumab: A New Era in Metastatic MelanomaManagement Timothy G. Tyler, PharmD, FCSHPDr Tyler is Director of Pharmacy Services, Comprehensive Cancer Center, Desert Regional Medical Center, Palm Springs, California

Despite the associated risksinvolved, this new therapyoffers benefits beyond thestandard myelosuppressiveagents or monoclonalantibody drugs that we havebecome accustomed to in thepast decade and a half, whenthese therapies proliferatedon the oncology scene.

Reprinted with permission from the Journal of Hematology Oncology Pharmacy. 2011, Vol 1, No 2.


CONTINUING EDUCATION


Presentations from the 2011Annual Meeting of theAmerican Society of Clinical

Oncology (ASCO) provide an idealforum for payers grappling withreimbursement issues and benefitdesign for patients with non–small-cell lung cancer (NSCLC) and forpharmacists who must understandemerging treatments.This article summarizes key clinical

studies and expert discussions thatdescribe current trends in the manage-ment of this increasingly complex andmutation-driven tumor and their costimplications. The shifting landscape inNSCLC management highlights the

need to align providers’ and payers’strategies to enhance high-quality,value-based patient care.

maintenance Therapy extends

Progression-free Survival by a

Slim margin

Two randomized phase 3 clinical tri-als showed a progression-free survival(PFS) benefit for maintenance therapywith pemetrexed and gefitinib inpatients with advanced NSCLC. Themagnitude of the benefit, however,was modest—a gain of just 1.3 to 2.2months in remission time, with nogain in overall survival (OS).These studies fail to answer an

important question: is maintenancetherapy superior to second-line treat-ment initiated once the disease pro-gresses?The maintenance strategy is based

on 2 observations: limited benefit from4 courses of chemotherapy and im-proved outcomes with second-linechemotherapy after disease progres-sion. Maintenance therapy can involvecontinued treatment with the samedrug, as with pemetrexed in thePARAMOUNT trial,1 or “switch”maintenance, as in the INFORM study,which initiated gefitinib after plat-inum-based induction.2

The PARAMOUNT trial enrolled 939

patients with advanced nonsquamousNSCLC after they received 4 standardcourses of treatment with pemetrexedand cisplatin.1 Of these, 539 patientsachieved stable disease and were ran-domly assigned tomaintenance therapywith pemetrexed or to placebo (and bestsupportive care). Maintenance peme-trexed resulted in a 38% reduction in therisk of disease progression.1

Median PFS in this group was 4.1months versus 2.8 months for patientsreceiving placebo (P = .006), and dis-ease control (ie, response plus stabledisease) was attained in 71.8% and59.6%, respectively, but maintenance

Cost Implications for Novel Therapies and Strategies in theTreatment of NSCLC: Perspectives and Clinical Updates from ASCO 2011Program

Initial Release Date: August 19, 2011 • Expiration Date: August 19, 2012.Estimated time to complete activity: 1 hour.

SPonSor

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

TargeT audience

This activity was developed for physician oncologists and oncology pharmacists.

Learning objecTiveS

At the end of this activity, participants will be able to:

• Explain the impact of clinical and health economic data presented at the 2011 ASCOmeeting on the care of patients with non–small-cell lung cancer (NSCLC)

• Describe how value-based cancer care is evolving in the changing US healthcare system

• Examine how all stakeholders can implement value-based care in the treatment ofNSCLC

commerciaL SuPPorT acknowLedgmenT

This activity is supported by an educational grant from Genentech.

inSTrucTionS for crediT

There is no fee for this activity. To receive credit, participants must read this CME/CE activity in its entirety and complete the posttest and evaluation. The posttest andevaluation can be completed online at www.mlicme.org/p11054.html. Upon

completion of the evaluation and scoring 70% or better on the posttest, you will immedi-ately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.For questions regarding the accreditation of this activity, please contact Medical LearningInstitute, Inc., at 609-333-1693 or [email protected].

PhySician crediT deSignaTion

The University of Cincinnati designates this enduring material for a maximum of1 AMA PRA Category 1 Credit™. The University of Cincinnati is accredited

by the Accreditation Council for Continuing Medical Education (ACCME) to provide continu-ing medical education for physicians. Physicians should only claim credit commensuratewith the extent of their participation in this activity.

regiSTered Pharmacy deSignaTion

Medical Learning Institute, Inc., is accredited by the Accreditation Council for Pharmacy Education(ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for1.0 contact hour (0.1 CEU) of continuing education credit. The universal activity number for thisactivity is 0468-9999-11-034-H01-P.

diScLoSureS

Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by University of Cincinnati and Medical Learning Institute, Inc., for fair balance, scientific objectivity ofstudies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.The associates of University of Cincinnati, Medical Learning Institute, Inc., and Center ofExcellence Media, LLC, do not have any financial relationships or relationships to productsor devices with any commercial interest related to the content of this CME/CE activity forany amount during the past 12 months. The planners and managers reported the following financial relationships or relationshipsto products or devices they or their spouse/life partner have with commercial interestsrelated to the content of this CME/CE activity.Name of Planner or Manager Company Reported Financial RelationshipTeresa Haile, RPh, MBA Reviewer for MLI Has nothing to disclosefaculty disclousures

Ira Klein, MD, has nothing to disclose.

Caroline Helwick, medical writer, has nothing to disclose. She intends to discuss investiga-tional medications for NSCLC.

diScLaimer

The information provided in this CME/CE activity is for continuing education purposes onlyand is not meant to substitute for the independent medical judgment of a healthcareprovider relative to diagnostic and treatment options of a specific patient’s medical condi-tion. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for the agent discussed in this program should be inferred.

Cost Implications for Novel Therapies and Strategies in the Treatment of NSCLC:Perspectives and Clinical Updates from ASCO 2011By Caroline Helwick, Independent Medical Writer





therapy did not confer a quality-of-lifebenefit.1

New findings from the PARA-MOUNT trial “suggest that patientscan still continue to benefit from theuse of the same drug rather than ‘useup’ an alternative early in the course oftreatment,” said lead investigator LuisPaz-Ares, MD, PhD, Seville UniversityHospital, Spain. “We believe the mag-nitude of benefit is clinically signifi-cant and may support the use of peme-trexed as maintenance therapy. Thiscould change the standard of care forthese patients, at least in terms ofmaintenance.” Similarly, in the phase 3 clinical

study INFORM, maintenance therapywith gefitinib (after 4 cycles of plat-inum-based chemotherapy) was asso-ciated with significantly superior PFScompared with placebo among 296Chinese patients, but no difference inOS was observed.2

At a median follow-up of 16.8months, median PFS was 4.8 monthswith gefitinib maintenance versus 2.6months with placebo (P <.001), repre-senting a 58% reduction in the risk ofdisease progression. Approximatelyone third of patients carried mutationsof the epidermal growth factor recep-tor (EGFR), and they derived the bestoutcomes from gefitinib.2

Despite both studies meeting theirprimary end points, study discussantMartin J. Edelman, MD, of the Uni-versity of Maryland GreenbaumCancer Center, Baltimore, commentedthat “maintenance therapy in NSCLCis an ever-contentious issue,” suggest-ing that “these studies raise morequestions than answers.”He pointed out that PFS “does not

necessarily predict overall survival,”and that when differences in PFS aresmall, quality-of-life (QOL) analysescan help define benefit. “But the quali-ty-of-life data from maintenance stud-ies is actually somewhat disappoint-ing.…No differences have beendemonstrated, which indicates thatmaintenance is not necessarily cost-free in terms of toxicity,” said DrEdelman.The PARAMOUNT study demon-

strated no improvement in QOL formaintenance therapy with peme-trexed.1 Along with increased toxicitywith continued treatment, the cost oftreatment also becomes a factor. “Wereally need a cost-effective analysis inthis era of follow-up strategies, of fre-quent visits and of scanning, with [astudy of] early institution of second-line therapy, versus the maintenanceapproach,” he said.What has been learned from PARA-

MOUNT, said Dr Edelman, is that“the drugs work in patients who

derive benefit from first-line chemo-therapy. To date, there is no evidencethat early introduction of therapy willimprove survival compared withintroducing second-line therapy atdisease progression.”

First-Line Erlotinib Superior to

Chemotherapy

Erlotinib, given as first-line treat-ment to patients with advancedNSCLC and EGFRmutations, substan-tially prolonged remissions in thephase 3 clinical trial EURTAC (Euro-pean Randomized Trial of Tarceva vsChemotherapy).3

“EGFR tyrosine kinase–activatingmutations are present in 10% to 26% ofNSCLC tumors and are associatedwith increased response to erlotiniband gefitinib. But little is known aboutthe efficacy and safety profile oferlotinib compared with chemothera-py in EGFR-mutant Caucasian pa-tients,” said Rafeal Rosell, MD, of theCatalan Institute of Oncology,Barcelona, Spain, who presented thefindings.3

The interim updated analysis of 173patients in the EURTAC trial showedsignificant efficacy for single-agenterlotinib over a standard platinum-based doublet in the up-front setting.Erlotinib reduced the risk for diseaseprogression or death by 63%, nearlydoubling the median PFS, which was9.7 months versus 5.2 months withchemotherapy (P <.001). Objectiveresponse rates were 58% with erlotiniband 15% with chemotherapy.3

The death rate was also reduced by20%, but this finding was not signifi-cant (P = .417),3 presumably because ofhigh crossover from chemotherapy toan EGFR inhibitor, and because the OSdata are not mature. Erlotinib was bet-

ter tolerated than chemotherapy, DrRosell reported.

New Class of Agents May Change

Treatment for 5% of Patients with

NSCLC

The novel agent crizotinib, whichtargets the EML4-ALK mutation that isfound in about 5% of patients withNSCLC, is positioned to become anintegral part of treatment for thisNSCLC subgroup. The oral agentcrizotinib is first in a class known asanaplastic lymphoma kinase (ALK)inhibitors; it targets tumors harboringrearrangements of the ALK gene,which is involved in growth and sur-vival of lung tumors.Ross Camidge, MD, PhD, of the

University of Colorado, Denver, re-marked in an interview, “Knowingthat ALK-positive patients respond tocrizotinib—you can take this to thebank.” He said that the data show a“consistency of message” and form thebasis for confirmatory registrationstudies that will compare crizotinibwith chemotherapy. These will “naildown where the drug fits in the treat-ment paradigm for what is essentiallya new disease—ALK-positive lungcancer,” he said.Crizotinib nearly doubled OS

among ALK-positive patients withNSCLC in an update of a phase 1study reported at ASCO 2011 byAlice T. Shaw, MD, PhD, of Massa-chusetts General Hospital, Boston.4

The study involved 82 heavily pre-treated patients with the ALK fusiongene who received crizotinib aftertumor progression.The objective response rate was

57%, the disease control rate was 87%,and more than 90% of the tumorsregressed in the ALK-positive group

who received crizotinib. The survivalrate was 74% at 1 year and 54% at 2years. Median OS has not yet beenreached, because more than half of the82 subjects are still alive. Side effectswith crizotinib were generally mildand transient, although unusual visualeffects were common.4

By comparison, the OS rate amongALK-positive control patients receiv-ing standard chemotherapy was 44%at 1 year and 12% at 2 years; medianOS was 6 months. The median OS wassimilar for ALK-positive patients whoreceived chemotherapy and for pa -tients lacking the ALK rearrangement,Dr Shaw reported.4

In a separate presentation, DrCamidge reported on a combinedanalysis of these 82 patients plus thefirst 19 ALK-positive patients whoreceived crizotinib.5 After a medianfollow-up of 11 months, median PFSwas 10 months and OS has not beenreached; 79% of the patients remainalive, yielding a survival probability of90% at 6 months and 81% at 1 year, DrCamidge said.5

Accelerated approval for crizotinib inALK-positive NSCLC has been soughtfrom the US Food and Drug Admin-istration in conjunction with the ongo-ing confirmatory phase 3 program.

Mutation Testing Poised for

Routine Use

Based on the results of mutationaltesting through the new Lung CancerMutation Consortium, RamaswamyGovindan, MD, Washington Uni-versity, St. Louis, said EGFR testing isready to be clinically applied in lungcancer and that EML4-ALK (the targetof crizotinib) fusion testing is not toofar behind.Dr Govindanwas the invited discus-

sant of a presentation by Mark G. Kris,MD, of Memorial Sloan-Kettering Can-cer Center, New York. The Consortiumevaluated 1234 patients with stage IVadenocarcinoma for 10 known muta-tions using standard multiplexedassays and fluorescence in situhybridization.6

Driver mutations were identified in54% of adenocarcinomas—most oftenKRAS (22%), EGFR (17%), and EML4-ALK rearrangement (7%). Less com-

Figure 1 Use of Erlotinib versus Platinum-Based Chemotherapy in EGFRmut NSCLC

EGFRmut indicates epithelial growth factor receptor mutation; Chemo, chemotherapy; NSCLC, non–small-cell lung cancer.Source: MDoutlook, powered by The Arcas Group, LLC. Used with permission.

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Crizotinib nearly doubled OS among ALK-positivepatients with NSCLC in aphase 1 study reported at ASCO 2011.




mon were alterations in BRAF,PIK3CA, HER2, Met amplification,MEK1, NRAS, and AKT1.6

“While an individual mutation maybe rare, having a mutation of somekind that is actionable is very commonin adenocarcinoma,” Dr Kris said.Mutation identification allowed EGFR-positive patients to be selected forerlotinib and patients with other muta-tions to be referred to clinical trials ofother targeted agents.The collaborative effort represents

the revolutionary changes taking placein the management of lung cancer andthe potential for personalized treat-ment, Dr Kris added.

Oncologists Plan to Use More

Targeted Agents

Oncologists who treat NSCLC planto rely more on erlotinib therapy andless on platinum-based chemotherapyin advanced disease, according toresults of a survey conducted im -mediately after ASCO 2011—theMDOutlook ASCO 2011 Quick Poll—facilitated by the Arcas Group.7

The survey showed that approxi-mately 50% of patients with mutationsof EGFR now receive erlotinib, andabout 45% receive chemotherapy.However, survey respondents antici-pated prescribing erlotinib for 65% oftheir patients in the next year andreducing the use of platinum-basedchemotherapy by 15% (Figure 1).7

The oncologists also indicated highinterest in crizotinib therapy forpatients with the EML4-ALK generearrangement. More than 55% of therespondents predicted that theywould“always” prescribe crizotinib to thismutation subgroup and 25% said theywould “often” prescribe the new drug(Figure 2).7 The respondents alsoexpected to start integrating c-Metinhibitors, especially in the setting ofNSCLC resistant to EGFR inhibitors.

Novel Agents Show

Encouraging Activity

New EGFR Inhibitor Comparablewith GefitinibIcotinib, an EGFR inhibitor manu-

factured in China, was found to be asactive and effective as gefitinib inpatients with advanced NSCLC andEGFR mutations who had receivedprevious treatment.8 In the noninferi-ority randomized ICOGEN trial of 395patients, icotinib was comparable togefitinib in PFS, OS, and QOL, but itwas better tolerated than gefitinib8.The median PFS was 137 days for

icotinib versus 102 days for gefitinib,and median OS was 419 days and 467

days, respectively. As expected,patients with EGFR mutations hadpreferential benefit over those withwild-type EGFR, with responsesobserved in more than 50% of thisgroup compared with 5% of patientswithout the mutation.8

Also showing promise was the Metinhibitor MetMAb (an antibody toc-Met) combined with erlotinib in astudy of 137 previously treated pa-tients.9 Met gene expression is associ-ated with a worse NSCLC prognosis.Among patients with the Met muta-

tion, the combination (compared witherlotinib alone) extended median PFSto 2.9 months compared with 1.5months with erlotinib alone (P = .04),and extended median OS to 12.6months versus 3.8 months (P = .002).A phase 3 trial of this combinationwill begin later in 2011.9

Second-Generation Hsp90 Inhibitorsin the PipelineGeoffrey Shapiro, MD, PhD, of Dana

Farber Cancer Institute, Boston,reported encouraging results for theheat shock protein 90 (Hsp90)inhibitor ganetespib from an open-label phase 2 trial of 96 patients whoreceived previous treatment foradvanced NSCLC. The median PFSwas 24.1% by week 16.10

Ganetespib provides potent Hsp90inhibition and better safety than first-generation compounds. The dose-lim-iting hepatic and ocular toxicity, whichhas complicated the development ofother Hsp90 inhibitors, is absent.“Ganetespib showed promising clini-cal activity as a single agent, especiallyin tumors harboring the ALK re-arrangement,” Dr Shapiro noted.

Surash S. Ramalingam, MD, ofEmory University, Atlanta, comment-ed on the Hsp90 inhibitor pipeline.Despite a strong biologic rationale forthese drugs, he said, there have beenmany hurdles in drug development,primarily involving formulation is-sues, dose-limiting hepatic toxicity,and less than robust efficacy. The sec-ond-generation compounds, includ-ing ganetespib, are structurally differ-ent and more potent than thefirst-generation agents and have afavorable safety profile that facilitatestheir use in combination.“Therefore, there is a resurgence of

interest in these compounds,” DrRamalingam said. More than a dozenare in various stages of development,of which the most active in solidtumors are ganetespib, retaspimycin,and AUY-922.

Ganetespib and retaspimycin haveproduced “robust anticancer effects,”with tumor regression or disease stabi-lization seen in almost allALK-positivepatients, Dr Ramalingam noted.“Hsp90 inhibitors have entered thetherapeutic algorithm for ALK-posi-tive disease,” he concluded. “In thehistorically disappointing develop-ment of Hsp90 inhibitors, it is mybelief that we have reached an impor-tant and exciting turning point.”

Chemoimmunotherapy with Toll-Like ReceptorsThe toll-like receptor (TLR)-2 agonist

mycobacterium w (Cadi-05) lookedpromising in a study presented byChandra Belani, MD, of Penn StateHershey Cancer Institute, Hershey, PA.Mycobacterium w works best whencombined with paclitaxel and cisplatinas chemoimmunotherapy; this regi-men was evaluated in 121 patients.11

Chemoimmunotherapy led to high-er response rates and disease controlrates than chemotherapy alone. Themedian PFS was 199 days with thecombination versus 97 days withchemotherapy alone, representing a31% risk reduction (P = .052). Al -though OS was similar at 208 days ver-sus 196 days, respectively, a survivalbenefit was observed among the sub-set of patients with squamous-cell car-cinoma: median OS was 229 days withchemoimmunotherapy versus 172days with chemotherapy, representinga 46% risk reduction (P = .031).11

In addition, in the analysis ofpatients who completed all 4 cycles,median PFS was 253 days withchemoimmunotherapy versus 157days with chemotherapy, a 57% riskreduction (P = .001), and OS was 299days versus 233 days, respectively, fora 36% risk reduction (P = .043). Forpatients with squamous-cell carcino-ma who completed 4 cycles, medianOS reached 364 days with chemoim-munotherapy versus 254 days withchemotherapy alone, representing a60% reduction in risk of dying (P =.041), Dr Belani reported.11

“The addition of Cadi-05 to paclitax-el and cisplatin improved OS and PFSin the prespecified subset of patientscompleting 4 cycles, and its efficacywas better in patients with squamous-cell carcinoma than with adenocar-cinoma,” Dr Belani concluded.Raffit Hassan, MD, of the National

Cancer Institute, said that several im-munotherapy approaches for NSCLCwere moving forward, including vac-cines and TLR agonists, such asmycobacterium w. “Hurdles remain,and no agent has been approved,” DrHasson said, “but recent randomizedphase 2 trials show hints of activity,leading to phase 3 trials.”The vaccines in phase 3 trials are

belagenpumatucel-L (Lucanix), L-BLP25 (Stimuvax), and the MAGE-A3vaccine, which showed OS benefits(or trends) in phase 2 trials.TLR agonists, by contrast, have been

disappointing in phase 3 trials, al-though mycobacterium w is showing


Cost Implications for Novel Therapies and Strategies... Continued from page 43

Ganetespib provides potentHsp90 inhibition and bettersafety than first-generationcompounds.

Figure 2 Frequency of Crizotinib Use in the Treatment of ALK-Positive NSCLC

NSCLC indicates non–small-cell lung cancer.Source: MDoutlook, powered by The Arcas Group, LLC. Used with permission.

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promise, he said.“The results of the ongoing phase 3

trials will be important to validateimmunotherapy as a valid option inlung cancer,” Dr Hassan concluded.

Future of Some Once-PromisingAgents Uncertain Several investigational agents, how-

ever, turned in disappointing results.One of these is motesanib, whichinhibits a number of tumors. Whencombined with chemotherapy in therandomized, placebo-controlled phase3 MONET (Motesanib NSCLC Efficacyand Tolerability) 1 clinical study of1090 patients with advanced nonsqua-mous NSCLC, motesanib—which wasonce considered a promising drug forNSCLC—did not improve OS overchemotherapy alone.12

The vascular-disrupting agent vad -imezan has also failed to improve effi-cacy versus chemotherapy alone in aglobal phase 3 clinical trial of front-linetreatment in 1299 patients.13

Aggressive Care at End of Life StillCommon, ExpensiveThe practice of overly aggressive

care at the end of life has been recog-nized as a concern. A study presentedat last year’s ASCO showed that OS inpatients with NSCLC was actuallycompromised, not improved, bychemotherapy administered in thefinal months.14 However, the messagethat aggressive end-of-life care isunwarranted is still falling on deafears, ASCO studies suggested.

One in 5 Patients ReceivesAggressive End-of-Life CareThis appears true even at institu-

tions of the National ComprehensiveCancer Network (NCCN). In an analy-sis of patients with metastatic NSCLCtreated at NCCN institutions, almost20% of patients received aggressiveend-of-life chemotherapy or treatmentin the intensive care unit (ICU).15

Investigators identified 1092 pa-tients with metastatic NSCLC whoreceived treatment at 8 NCCN insti-tutions between 2007 and 2010.Aggressive end-of-life care was

defined as (1) the initiation of a newchemotherapy regimen within 30days of death, (2) the receipt ofchemotherapy within 14 days ofdeath, or (3) any ICU admission with-in the last 30 days of life. The analysisrevealed that15:• 18.9% of patients received aggres-sive end-of-life chemotherapy orcare in an ICU

• 10.7% started a new chemotherapyregimen in the last 30 days of life

• 11.8% received chemotherapy dur-ing the last 14 days of life

• 3.2% were admitted to the ICU inthe last 30 days of life

• 43% of patients with poor perform-ance status received aggressive end-of-life chemotherapy

• 34% of patients receiving aggressivechemotherapy were starting theirfirst and only treatment line

• 37.5% of patients receiving an EGFRinhibitor as their final treatmentwere still using the drug 14 daysbefore death

• 48% of patients receiving chemo -therapy in the last 14 days of lifewere taking erlotinib.“This is a higher rate than I was

hoping for,” said lead authorKathleen Bickel, MD, from theUniversity of Michigan Compre -hensive Cancer Center, Ann Arbor.“And this is recent data. It’s notpatients treated 10 years ago.”

Early Palliative Care ReducesIntravenous, but Not Oral, Drug Use Early initiation of palliative care

resulted in a 2.7-month (30%) survivalbenefit and QOL improvements in therandomized study by Temel and col-leagues that was presented last year atASCO 2010.14 A secondary analysisexamined the reasons for this findingand was presented at ASCO 2011.16

“Palliative care services are tradi-tionally delivered late in the course ofdisease, when their benefits may belimited. Ideally, they should be inte-grated throughout the course of illnessand in tandem with life-prolongingtreatment,” said lead investigatorJoseph Greer, PhD, MassachusettsGeneral Hospital Cancer Center,Boston.Within 8 weeks of a metastatic

NSCLC diagnosis, 151 patients wereassigned to early palliative care inte-grated with standard oncology care(regularmeetingswith a palliative carespecialist) or to standard care (adhoc palliative care upon request).16

Although the early palliative careintervention did not result in less useof oral chemotherapy, other benefitswere obvious, he reported.Patients in the early palliative care

group were significantly less likely to

receive intravenous (IV) chemothera-py, and, although about 70% ofpatients in each arm entered hospice,the patients who received early pallia-tive care enrolled earlier and spentalmost 3 times as many days underhospice care (P = .004).16

IV chemotherapy was administeredwithin 60 days of death to 25% of thepalliative care group versus 45% ofpatients receiving standard care (P =.01); within 30 days of death in 10%versus 25%, respectively (P = .07); andwithin 14 days of death in 2% and 10%(P = .06). Less use of IV chemotherapyin the early palliative care arm had nodetrimental effect on survival.16

The use of oral agents, however, didnot differ between the 2 groups. Oralagents were prescribed within 60 daysof death to 28% of patients whoreceived early palliative care and 22%of the standard care group; within 30days in approximately 20% per arm;and within 14 days in 10% per arm.16

The more frequent use of oral drugsmight be the result of a “clinical com-promise” or may reflect that they canbe started while patients are enrollingin hospice, Dr Greer suggested, but thereasons for their frequent use in thepalliative care setting must be deter-mined.The bottom line is that early integra-

tion of palliative care means that thetiming of final chemotherapy willprobably bemore appropriate and thatpatients will access hospice servicessooner, he said, “which are key meas-ures of quality end-of-life care.”

End-of-Life Care More Expensivethan BiologicsAn analysis of the total cost of man-

aging patients with advanced NSCLCyielded a few surprises, showing thatthe most costly segment was end-of-life care, and targeted agents wereresponsible for only a modest portionof the active treatment costs.17

Investigators from the University ofTexas Health Science Center at SanAntonio used the PharMetrics claimsdatabase of 5847 patients to character-ize the direct cost of treating patientswith advanced NSCLC between 2000and 2009.They divided the study period into a

“preperiod” (2000-2002), “transitionperiod” (2003-2005), and “current peri-od” (2006-2009) to account for themove from standard chemotherapy tothe introduction of the newer agentspemetrexed, tyrosine kinase inhibitors(TKIs), and biologics.17

The mean costs of various segmentsof care over the study period were17:• Total cost: $162,134 per patient (for

≥5 months of therapy)• Cost per patient per month (PPPM):$10,284

• Cost related to diagnosis, PPPM:$9162

• Active mean treatment cost, PPPM:$10,141

• End-of-life cost, PPPM: $18,033 PPPM costs were similar in all 3

periods: $8662 in the preperiod,$10,578 the transition period, and$10,141 in the current period. Neweragents accounted for 16% of activetreatment, including pemetrexed (5%),TKIs (6%), and biologics (5%). In total,newer agents accounted for just 4% ofthe overall cost.17

Cost of Treatment Highly VariableResearchers from McKesson Spe-

cialty Care Solutions in South SanFrancisco, CA, evaluated adherence tonational treatment guidelines forNSCLC and chemotherapy costs in theadjuvant and first-line metastatic set-tings among community oncologypractices.18

A total of 811 adjuvant and 2761metastatic regimens were adminis-tered by 333 practices in 41 states.National guidelines recommended 26adjuvant and 67 metastatic regimens.The rate of guideline adherence wassignificantly higher with the metastat-ic regimen than with the adjuvant reg-imen. In both treatment settings, car-boplatin-containing regimens weregiven more often than cisplatin-con-taining regimens.18

Based on Medicare reimbursementrates for 3 months of treatment, thecosts varied for the top 5 regimens inthe adjuvant and metastatic settings. Astandard course of therapy in the adju-vant group ranged from $2803 (for car-boplatin and etoposide every 3 weeks)to $7362 (for carboplatin and paclitaxelevery 4 weeks).18

Metastatic regimens ranged from$3297 (for carboplatin and paclitaxelevery 3 weeks) to $29,322 (for carbo-platin, paclitaxel, and bevacizumabevery 3 weeks).18

“A large number of unique regi-Continued on page 46

OS in patients with NSCLCwas actually compromised,not improved, by chemo -therapy administered in the final months.

The most costly segment was end-of-life care, andtargeted agents wereresponsible for only a modest portion of the active treatment costs.




mens were administered in the meta -static group, and costs for the top 5regimens varied considerably,” theinvestigators observed. �

References1. Paz-Ares LG, De Marinis F, Dediu M, et al. PARA-MOUNT: phase III study of maintenance pemetrexed(pem) plus best supportive care (BSC) versus placeboplus BSC immediately following induction treatmentwith pemetrexed plus cisplatin for advanced non-squamous non-small cell lung cancer (NSCLC).Presented at the 47th Annual American Society ofClinical Oncology Meeting; Chicago, IL; June 3-7,2011. 2. Zhang L, Shenglin M, Song X, et al. Efficacy, tolera-bility and biomarker analyses from a phase III, ran-domized, placebo-controlled, parallel group study ofgefitinib as maintenance therapy in patients withlocally advanced or metastatic non-small cell cancer(NSCLC; INFORM; C-TONG 0804). Presented at the47th Annual American Society of Clinical OncologyMeeting; Chicago, IL; June 3-7, 2011. 3. Rosell R, Gervais R, Vergnenegre A, et al. Erlotinibversus chemotherapy (CT) in advanced non-small celllung cancer (NSCLC) patients (p) with epidermalgrowth factor receptor mutations: interim results ofthe European erlotinib versus chemotherapy (EUR-TAC) phase III randomized trial. Presented at the 47thAnnual American Society of Clinical OncologyMeeting; Chicago, IL; June 3-7, 2011.

4. Shaw AT, Yeap BY, Solomon BJ, et al. Impact ofcrizotinib on survival in patients with advanced, ALK-positive NSCLC compared with historical controls.Presented at the 47th Annual American Society ofClinical Oncology Meeting; Chicago, IL; June 3-7,2011. 5. Camidge DR, Bang Y, Kwak EL, et al. Progression-free survival (PFS) from a phase I study of crizotinib(PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC). Presented at the 47thAnnual American Society of Clinical OncologyMeeting; Chicago, IL; June 3-7, 2011. 6. Kris MG, Johnson BE, Kwiatkowski DJ, et al.Identification of driver mutations in tumor specimensfrom 1,000 patients with lung adenocarcinoma: theNCI’s Lung Cancer Mutation Consortium (LCMC).Presented at the 47th Annual American Society ofClinical Oncology Meeting; Chicago, IL; June 3-7,2011. 7. The Arcas Group website. MDOutlook, LLC. 2011ASCO Annual Meeting: Immediate Impact on ClinicalPractices. NSCLC. 2011 ASCO Quick Poll in NSCLC.http://thearcasgroup.com/sub/wp-content/uploads/2011/06/arcas_asco2011_nsclc_quickpoll_final.pdf.Accessed July 26, 2011.8. Sun Y, Shi Y, Zhang L, et al. A randomized, double-blind phase III study of icotinib versus gefitinib inpatients with advanced non-small cell lung cancerpreviously treated with chemotherapy (ICOGEN).Presented at the 47th Annual American Society ofClinical Oncology Meeting; Chicago, IL; June 3-7,2011. 9. Spigel DR, Ervin TJ, Ramlau R, et al. Final efficacyresults from OAM4558g, a randomized phase II study

evaluating MetMAb or placebo in combination witherlotinib in advanced NSCLC. Presented at the 47thAnnual American Society of Clinical OncologyMeeting; Chicago, IL; June 3-7, 2011. 10. Wong K, Koczywas M, Goldman JW, et al. Anopen-label phase II study of the Hsp90 inhibitorganetespib (STA-9090) as monotherapy in patientswith advanced non-small cell lung cancer (NSCLC).Presented at the 47th Annual American Society ofClinical Oncology Meeting; Chicago, IL; June 3-7,2011. 11. Belani CP, Desai D, Khamar BM, for the Cadi-05Investigators Study Group. Open-label, randomizedmulticenter phase II clinical trial of a toll-like receptor-2 (TLR2) agonist mycobacterium w (Cadi-05) in com-bination with paclitaxel plus cisplatin versus paclitax-el plus cisplatin in advanced non-small cell lungcancer (NSCLC). Presented at the 47th AnnualAmerican Society of Clinical Oncology Meeting;Chicago, IL; June 3-7, 2011. 12. Scagliotti G, Vynnychenko I, Ichinose Y, et al. Aninternational, randomized, placebo-controlled, dou-ble-blind phase III study (MONET1) of motesanibplus carboplatin/paclitaxel (C/P) in patients withadvanced nonsquamous non-small cell lung cancer(NSCLC). Presented at the 47th Annual AmericanSociety of Clinical Oncology Meeting; Chicago, IL;June 3-7, 2011. 13. Lara P, Douillard J, Nakagawa K, et al.Randomized phase III placebo-controlled trial of car-boplatin/paclitaxel (C/P) with or without the vas -cular disrupting agent vadimezan (ASA404) inadvanced non-small cell lung cancer (NSCLC).Presented at the 47th Annual American Society of

Clinical Oncology Meeting; Chicago, IL; June 3-7,2011.14. Temel JS, Greer J, Gallagher E, et al. Effect of earlypalliative care (PC) on quality of life (QOL), aggres-sive care at the end of life (EOL), and survival in stageIV NSCLC patients: results of a phase III randomizedtrial. Presented at the 46th Annual American Societyof Clinical Oncology Meeting; Chicago, IL; June 4-8,2010. 15. Bickel KE, Niland JC, Mamet R, et al. Aggressiveend-of-life (EOL) chemotherapy (CT) use in metastaticnon-small cell lung cancer (mNSCLC): a NationalComprehensive Cancer Network (NCCN) outcomesdatabase analysis. Presented at the 47th AnnualAmerican Society of Clinical Oncology Meeting;Chicago, IL; June 3-7, 2011. 16. Greer JA, Pirl WF, Jackson VA, et al. Effect of earlypalliative care on chemotherapy utilization and end-of-life care in patients with metastatic non-small celllung cancer (NSCLC). Presented at the 47th AnnualAmerican Society of Clinical Oncology Meeting;Chicago, IL; June 3-7, 2011. 17. Koeller JM, Bell A, Corral M, et al. Total direct andsegmented medical cost-of-care for stage IV (adv)non-small cell lung cancer (NSCLC) in a private insur-ance population. Presented at the 47th AnnualAmerican Society of Clinical Oncology Meeting;Chicago, IL; June 3-7, 2011. 18. Wang Z, Aksamit I, Tuscher L, et al. Guidelineadherence rates and costs of chemotherapy treatmentfor NSCLC patients treated in U.S. community oncol-ogist practices. Presented at the 47th AnnualAmerican Society of Clinical Oncology Meeting;Chicago, IL; June 3-7, 2011.

Cost Implications for Novel Therapies and Strategies... Continued from page 45

Evidence-based medicine and afocused clinical orientation arekey elements to delivering the

right care at the right time to the rightperson. The recent findings reported atthe 2011 American Society of ClinicalOncology annual meeting regardingthe use of novel therapies and strate-gies in the treatment of non–small-celllung cancer make achieving thesegoals harder than ever.Each year, treatment approaches

become more complex and variable,and translating protocols that demon-strate positive outcomes into dailycommunity practice seems more diffi-cult than ever.Beyond the waste and nonbeneficial

care for those not well-matched fortreatment, we face the additional prob-lem of sizing and comparing treatmentefficiencies within a disease state. Howwould experts in process control andquality improvement from otherindustries handle this issue?Oncology care in the United States

today reflects 2 dramatic contrasts.Although admirable in its applicationof molecular biology (the pinnacle ofscience), oncology care is still verynonsystematic and inconsistent in theway new discoveries and practices arebeing incorporated into the patientcare realm.If data are the drivers of quality

improvement, how do we collect andmeasure that quality information inreal-life cancer care? Auniversal oncol-

ogy care data repository does not existtoday. Without the regular applicationof agreed upon gold standard NationalComprehensive Cancer Network–derived pathways, the typical commu-nity oncology practice, even if verballyespousing commitment to best prac-tices, is practicing “mass inspection”for quality rather than building qualityinto the product in the first place.Academic oncology practices

should also not be given a pass on this

issue, because quality is more than aglossy advertising campaign.We are in dire need of decision sup-

port and data storage tools thataddress oncologists’ needs in real time.We also need reporting that helps usall learn what is the most effective andefficient care at an aggregate level.Without this, we will never know

whomight be better servedwithmain-tenance therapy, when to use erlotinib,and how we can apply companiondiagnostic testing (to detect mutationsin, for example, epithelial growth fac-tor receptor, EML4-ALK, heat shockprotein 90, and toll-like receptor 2) tothe right patients so that theymay ben-efit from more targeted agents.Finally, the application of aggressive

end-of-life care will surely declinewhen all treating oncologists havemore data-linked confidence in the“best care options.” When this hap-pens, we will have our “focused facto-ries,” and the gods of process controlwill be smiling down upon us. �

Addressing Cost and Quality Issues in Novel TreatmentStrategies for Non–Small-Cell Lung Cancer: Where Is OurFocused Factory?Ira M. Klein, MD, MBA, FACPSenior Medical Director, Clinical Consulting, Strategy and Analysis National Accounts, Aetna

COMMENTARY

We are in dire need of decisionsupport and data storage toolsthat address oncologists’ needs inreal time. We also need reportingthat helps us all learn what is the most effective and efficientcare at an aggregate level.


AVBCC is the fastest growing national specialty organization dedicated to improving the care of

cancer patients and their quality of life.

The organization was established to provide a network for payers and oncology healthcare professionals to interactand network in order to promote optimal care for patients

and their families.

2011 REGIONAL MEETINGS

Sponsorship Opportunities Available

www.AVBCConline.orgRegister online at

Past Sponsors:

September 24Chicago, IL



2012 NATIONAL MEETINGMarch 29-31, Houston, TX

��

September 24, 2011JW Marriott

151 West Adams Street Chicago, Illinois

Strategies for Optimizing Value in Cancer Care DeliveryThe Best of the Association for Value-Based Cancer Care Conference

October 1, 2011Marriott Marquis55 Fourth Street

San Francisco, California

November 19, 2011Marriott Waterside

700 South Florida AvenueTampa, Florida

PROGRAM OVERVIEWAs a result of the resounding success of our First AnnualConference, we have been asked to incorporate “The Bestof AVBCC” into three regional meetings. We continueto be guided by the expertise of leaders in these fields pro-viding attendees with a thorough understanding of theevolution of the value equation as it relates to cancer ther-apies and will be able to implement, improve, and sustaintheir companies and institutions, while improving accessfor patients and ultimately patient care.

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

CONTINUING EDUCATION INFORMATIONGoalThe Association for Value-Based Cancer Care will fosteran open dialogue between providers, payers, and/or othermembers of the oncology team in order for attendees togain a better understanding of various points of view regarding cost, quality, and access in cancer care.

Objectives• Examine the impact of healthcare reform on allstakeholders involved in the management of patientswith cancer

• Identify issues and potential solutions to challengeswith access and affordability of oncology therapeutics

• Determine the value equation of cost, quality, andaccess when evaluating the diagnosis, treatment, andoverall management of cancer patients

• Define appropriate comparative effectivenessresearch and clinical pathways as tools to evaluatecurrent recommendations for patient management

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

ACCREDITATION INFORMATIONPhysician AccreditationScience Care designates this activity for a maximum of5.25 AMA PRA Category 1 Credit(s)™. Science Care isaccredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuingmedical education for physicians. Physicians should onlyclaim credit commensurate with the extent of their par-ticipation in the activity.Registered Nurse DesignationMedical Learning Institute, Inc. (MLI)Provider approved by the California Board of RegisteredNursing, Provider Number 15106, for 5.25 contact hours.Registered Pharmacy Designation

Medical Learning Institute is accredited by theAccreditation Council for Pharmacy Education

(ACPE) as a provider of continuing pharmacy educa-tion. Completion of this activity provides for 5.25 con-tact hours (0.525 CEUs) of continuing education credit.The Universal Activity Number for all three regionalmeetings is 0468-9999-11-033-L01-P.September 24, 2011 – Chicago, ILOctober 1, 2011 – San Francisco, CANovember 19, 2011 – Tampa, FL

ChairGary Owens, MDPresident, Gary Owens Associates

Invited FacultyStephanie Akbari, MDDonald Balfour III, MDAdam Brufsky, MD, PhD, FACPCraig Deligdish, MDJohn Fox, MD Scott Gottlieb, MDGary Johnson, MD, MS, MBATed OkonWinston Wong, PharmD

8:00 – 9:00 am Registration & Breakfast9:00 – 9:15 am Welcome & Introduction9:15 – 10:45 am The Challenges of Personalized

Cancer Care10:45 – 11:30 am Community Oncology Crisis:

An Uncertain Future11:30 – 12:15 pm Improving Patient Care Through

Collaboration & Partnerships12:15 – 1:45 pm Lunch Symposium1:45 – 2:30 pm Regional Insurer’s Perspective

on Cancer Care2:30 – 3:15 pm The Impact of New Healthcare

Legislation3:15 – 3:30 pm Summary & Concluding Remarks

CONFERENCE REGISTRATION$125 Includes 1-year association membership

Registration InformationChicago, www.regonline.com/avbcc-chicago2011San Francisco, www.regonline.com/avbcc-sanfran2011Tampa, www.regonline.com/avbcc-tampa2011

CONTACT/SUPPORTIf you have any questions please contact:Association for Value-Based Cancer Care™241 Forsgate Drive, Suite 205B Monroe Township, NJ 08831Phone: 732-992-1040 [email protected]

PRELIMINARY AGENDA

COMMERCIAL SUPPORT ACKNOWLEDGEMENTThere is no commercial support for this activity.

� �� VBCC_Aug_11_2_Follow ASCO Tabloid 8/11/11 9:36 AM

©2011 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.

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.


AUGUST 2011 VOL 2 NO 5

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