July 2012, Vol 5, No 4

INTRODUCTION

Cancer: Exploding Treatment and Diagnostic Pipeline, and Ever-Increasing CostsCraig K. Deligdish, MD

PERSPECTIVES

Defining Value in Cancer Care: AVBCC 2012 Steering Committee ReportGene Beed, MD; Al B. Benson, III, MD, FACP; Roy A. Beveridge, MD; Craig K. Deligdish, MD;John Fox, MD, MHA; Ira M. Klein, MD, MBA, FACP; Jennifer Malin, MD, PhD; Matthew Mitchell, PharmD, MBA; Lee N. Newcomer, MD; Gary M. Owens, MD; Samuel M. Silver, MD, PhD, FACP; John D. Sprandio, MD, FACP; F. Randy Vogenberg, RPh, PhD

CLINICAL

Diabetes Medications and Cancer Risk: Review of the LiteratureQuang T. Nguyen, DO, FACE; Lindsay Sanders, DO, MPH; Anu P. Michael, MD; Scott R. Anderson, MS IV; Loida D. Nguyen, PharmD, BCPS; Zackary A. Johnson, MS II

Stakeholder Perspective by Matthew Mitchell, PharmD, MBA

Chemotherapy-Induced Nausea and Vomiting: Optimizing Prevention and ManagementKamakshi V. Rao, PharmD, BCOP, CPP; Aimee Faso, PharmD, BCOP, CPP

Stakeholder Perspective by Robert Mancini, PharmD

BUSINESS

Emerging Trends in Cancer Care: Health Plans’ and Pharmacy BenefitManagers’ Perspectives on Changing Care ModelsRhonda Greenapple, MSPH Stakeholder Perspective by Gary M. Owens, MD

™

©2012 Engage Healthcare Communications, LLCwww.AHDBonline.com

JULY 2012 VOLUME 5, NUMBER 4

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

Hematology/Oncology Theme Issue

is a registered trademark of Incyte Corporation.©

05/12

Indications and UsageJaka� is indicated for treatment of patients with intermediate or high-risk myelo� brosis, including primary myelo� brosis, post–polycythemia vera myelo� brosis and post–essential thrombocythemia myelo� brosis.

Important Safety Information• Treatment with Jaka� can cause hematologic adverse

reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, withthe most frequent being thrombocytopenia and anemia.A complete blood count must be performed before initiating therapy with Jaka� . Complete blood counts should be monitored as clinically indicated and dosingadjusted as required

• The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache

• Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia

during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jaka� . If clinically indicated, platelet transfusions may be administered

• Patients developing anemia may require blood transfusions. Dose modi� cations of Jaka� for patients developing anemia may also be considered

• Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jaka�

• Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jaka� . Physicians should carefully observe patients receiving Jaka� for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly

• A dose modi� cation is recommended when administeringJaka� with strong CYP3A4 inhibitors or in patients with

a A

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group and

1

Prescribing Information. Incyte Corporation. November 2011. 1

T i during pregnancy is not r

W should not breast-feed. Discontinue n

is

p

has shown that with the right process, manufacturers can successfully collaborate with regulatory agencies and academic

e

m

may provide a model for the future use of PROs in marketing applications.8

How PROs were successfully integrated into the Jaka� ® (ruxolitinib) drug development program1

A novel approach to engage clinicians and FDA

PROs are an important means to demonstrate treatment

bene� ts in clinical trials.2,3 Use of a PRO instrument can

evaluate symptoms best judged by the patient, whether

caused by the disease or treatment toxicity. Assessment

of symptom burden is important because it can be a major

indicator of disease severity, progression or improvement.

Incorporating PROs into a clinical trial program provides a

means for evaluating the impact of therapy from the patient’s

perspective and helps patients and clinicians make better-

informed decisions.4

TAILORING a PRO tool for myelo� brosis

Myelo� brosis (MF) is a life-threatening, progressive disease

characterized by splenomegaly, debilitating symptoms and

cytopenias.5-7 Measures to assess both the splenomegaly

and core symptoms of MF were incorporated into the phase III,

double-blind placebo-controlled study, COMFORT-I, for Jaka� .

Spleen reduction, as measured by imaging (MRI or CT), was the

primary and biologic endpoint, and a reduction in total symptom

score (TSS), the PRO measure, was a key secondary endpoint.8,9

The TSS encompassed the following symptoms: abdominal

discomfort, pain under left ribs, early satiety, pruritus, night

sweats and bone/muscle pain.9

To include PROs in the trial, a novel instrument had to be

speci� cally developed. After patient interviews, advice from

clinical experts and extensive input from the FDA, the

modi� ed Myelo� brosis Symptom Assessment Form, version

2.0 (modi� ed MFSAF v2.0) was � nalized as part of the Special

Protocol Assessment prior to the initiation of COMFORT-I.

Ultimately, Jaka� was approved by the FDA for the treatment

of intermediate or high-risk MF.1,8 This became Incyte’s � rst

approved drug and also the � rst oncology medicine approved

with symptom data in its label since the FDA ’s draft guidance on

PROs was � nalized in 2009.2,4

gresswith patient-reported outcomes

Making

PRO

P

Placebo (n = 145)Jaka� (n = 145)

COMFORT-I: Percent Change in TSS in Individual Patients From Baseline to Week 24 or Last Observation9,a,b

150

100

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)

IMP

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50% Improvement

Upper 50th Percentile Upper 50th Percentile

Each bar represents an individual patient’s response. Worsening of TSS is truncated at 150%.

Placebo (n = 153)Jaka� (n = 155)

COMFORT-I: Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation9,a

Upper 50th Percentile Upper 50th Percentile

80

60

40

20

0

-20

-40

-60

-80

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)

IMP

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35% Reduction

Each bar represents an individual patient’s response.

Jaka� is a registered trademark of Incyte Corporation.© 2012, Incyte Corporation. All rights reserved.RUX-1130 05/12

I is indicated for treatment of patients with intermediate

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for patients developing anemia

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A dose modi�

a As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase IIIstudy with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume frombaseline to Week 24 as measured by MRI or computed tomography (CT). A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modi� ed MFSAF v2.0.9,10

b Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jaka� group and 16.5 in the placebo group.9,10

References: 1. McCallister E, et al. BioCentury. Reprint from December 5, 2011. 2. Haley S.The Pink Sheet. November 21, 2011;73:47. Symptom Measurement in Clinical Trials. 3. US Department of Health and Human Services Guidance for Industry: Patient-reported outcome measures: Use in medical product development to support labeling claims. December 2009. 4. Basch E, et al. Issue brief from Conference on ClinicalCancer Research, November 2011. 5. Cervantes F, et al. Blood. 2009;113:2895-2901.6. Mesa RA, et al. Leuk Res. 2009;33:1199-1203. 7. Verstovsek S, et al. N Engl J Med.2012;366:799-807. 8. Deisseroth AB, et al. Clin Cancer Res. 2012 Apr 27. (Epubahead of print). 9. Jaka� Prescribing Information. Incyte Corporation. November 2011. 10. Data on File, Incyte Corporation.

renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and ef� cacy

• There are no adequate and well-controlled studies of Jaka� in pregnant women. Use of Jaka� during pregnancy is not recommended and should only be used if the potential bene� t justi� es the potential risk to the fetus

• Women taking Jaka� should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

PROVIDING proof of patient bene� t

MF is progressive, and spleen size and symptoms can become increasingly burdensome to patients over time.5-7 Jaka� is

proven to decrease total symptom score in patients with intermediate or high-risk MF—this is an important consideration when

evaluating and treating patients.9 The FDA approval included patients with intermediate-2 risk and high risk, as well as patients

with intermediate-1 risk, since intermediate-1 patients may also have symptoms that require treatment. Clinical experience with

Jaka� has shown that with the right process, manufacturers can successfully collaborate with regulatory agencies and academic

experts to develop relevant and validated PRO instruments that can be incorporated into clinical trials.1,8 The approval of Jaka�

marks a signi� cant milestone in which validated PRO instruments can provide symptom data and demonstrate clinical bene� t.

The experience with Jaka� may provide a model for the future use of PROs in marketing applications.8

JAKAFI endpoints included both biologic and patient-reported outcomes8,9

T

Please see Brief Summary of Full PrescribingInformation on the following page.

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya

Jakafi Placebo (N=155) (N=151)Laboratory All All Parameter Gradesb Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0Anemia 96.1 34.2 11.0 86.8 15.9 3.3Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3

a Presented values are worst Grade values regardless of baselineb National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% ofpatients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine trans-aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3%Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treatedwith placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase(AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring orworsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% forJakafi with no Grade 3 or 4 cholesterol elevations.DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinibis predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinibincreased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was alsoprolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamicmarker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent admin-istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction isrecommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should beclosely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors:There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration(10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days,compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3inhibition was consistent with the corresponding exposure information. No dose adjustment is recommendedwhen Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration(50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone inhealthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmaco-dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered witha CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy.USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment withruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses.Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at dosesof 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of terato-genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest andmaternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 timesthe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weightsof approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. Ina pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implan-tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups forfertility indices or for maternal or embryofetal survival, growth and development parameters at the highestdose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or itsmetabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternalplasma. Because many drugs are excreted in human milk and because of the potential for serious adversereactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinuethe drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effec-tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number ofmyelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differ-ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. RenalImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)],moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8)additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmaco-kinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those withnormal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasingseverity of renal impairment. This was most marked in the subjects with end stage renal disease requiringhemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removalof some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients withmoderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet countbetween 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reductionis recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. HepaticImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], orsevere hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28%and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patientswith normal hepatic function. The terminal elimination half-life was prolonged in patients with hepaticimpairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmaco-dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposureexcept in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity wasmore prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) inFull Prescribing Information].

BRIEF SUMMARY: For Full Prescribing Information, see package insert.INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-riskmyelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis.CONTRAINDICATIONS None.WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatmentwith Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia.A complete blood count must be performed before initiating therapy with Jakafi [see Dosage andAdministration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/Lat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia wasgenerally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in FullPrescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans-fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia(ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi[see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosingadjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and AdverseReactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac-terial, fungal and viral infections. Active serious infections should have resolved before starting therapy withJakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection andinitiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signsand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see AdverseReactions].ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted underwidely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directlycompared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Thesafety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies,patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% ofpatients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred andeleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. Ina double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. Themost frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia,anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactionswere bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless ofcausality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo.Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return topretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon-tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen;however, it has not been established whether discontinuation of therapy contributed to the clinical course inthese patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of thedose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information].Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlledStudy During Randomized Treatment

Jakafi Placebo (N=155) (N=151)Adverse All All Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Bruisingb 23.2 0.6 0 14.6 0 0Dizzinessc 18.1 0.6 0 7.3 0 0Headache 14.8 0 0 5.3 0 0Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7Weight Gaine 7.1 0.6 0 1.3 0.7 0Flatulence 5.2 0 0 0.7 0 0Herpes Zosterf 1.9 0 0 0.7 0 0

a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site

hematoma, increased tendency to bruise, petechiae, purpurac includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitisd includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria

urine, bacteria urine identified, nitrite urine presente includes weight increased, abnormal weight gainf includes herpes zoster and post-herpetic neuralgiaDescription of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, mediantime to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%)discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobinreached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and thengradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This patternwas observed in patients regardless of whether they had received transfusions during therapy. In therandomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receivingplacebo received red blood cell transfusions during randomized treatment. Among transfused patients, themedian number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia wasgenerally reversible with dose reduction or dose interruption. The median time to recovery of platelet countsabove 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafiand to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo-cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens.Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency ofGrade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5%versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafibecause of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalitiesreported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Jakafi is a trademark of Incyte Corporation. All rights reserved.U.S. Patent No. 7,598,257© 2011 Incyte Corporation. All rights reserved.Issued: November 2011 RUX-1040

EDITORIAL BOARD

197www.AHDBonline.com l American Health & Drug Benefits lVol 5, No 4 l July 2012

EDITOR-IN-CHIEFDavid B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. GrandonProfessor, Jefferson School of Population HealthPhiladelphia, PA

DEPUTY EDITORSJoseph D. Jackson, PhDProgram Director, Applied Health Economics and Outcomes Research, Jefferson UniversitySchool of Population Health, Philadelphia, PALaura T. Pizzi, PharmD, MPH, RPhAssociate Professor, Department of PharmacyPractice, Jefferson School of PharmacyPhiladelphia, PA

AGING AND WELLNESSEric G. Tangalos, MD, FACP, AGSF, CMDProfessor of MedicineMayo Clinic, Rochester, MN

CANCER RESEARCHAl B. Benson, III, MD, FACPProfessor of Medicine, Associate Director for Clinical InvestigationsRobert H. Lurie Comprehensive Cancer CenterNorthwestern University, ILPast President, ACCCPast Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FASCOProfessor of Internal MedicineHematology/OncologyAssistant Dean for ResearchAssociate Director, Faculty Group PracticeUniversity of Michigan Medical School, MI

EMPLOYERSArthur F. Shinn, PharmD, FASCPPresident, Managed Pharmacy Consultants, LLC, Lake Worth, FLF. Randy Vogenberg, RPh, PhDPrincipal, Institute for Integrated Healthcare and Bentteligence, Sharon, MA

ENDOCRINOLOGY RESEARCHJames V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans AffairsMedical Center, Phoenix, AZ

EPIDEMIOLOGY RESEARCHJoshua N. Liberman, PhDExecutive Director, Research, Development & DisseminationSutter Health, Concord, CA

GOVERNMENTKevin B. “Kip” Piper, MA, FACHEPresident, Health Results Group, LLCWashington, DC

HEALTH INFORMATION TECHNOLOGY Kelly Huang, PhDPresident, HealthTronics, Inc.Austin, TX J. B. Jones, PhD, MBAResearch Investigator, Geisinger Health System, Danville, PAVictor J. Strecher, PhD, MPHProfessor and Director for Innovation and Social EntrepreneurshipUniversity of Michigan, School of Public Health and Medicine, Ann Arbor, MI

HEALTH OUTCOMES RESEARCH Diana Brixner, RPh, PhDProfessor and ChairDepartment of PharmacotherapyExecutive Director, Outcomes Research Center,Director of Outcomes Personalized Health CareProgram, University of UtahSalt Lake City, UT

Joseph Couto, PharmD, MBAClinical Program ManagerCigna Corporation, Bloomfield, CT Steve Miff, PhDSenior Vice PresidentVHA, Inc., Irving, TXKavita V. Nair, PhDAssociate Professor, School of PharmacyUniversity of Colorado at Denver, COGary M. Owens, MDPresident, Gary Owens AssociatesGlen Mills, PAAndrew M. Peterson, PharmD, PhDDean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia, PASarah A. Priddy, PhDDirector, Competitive Health AnalyticsHumana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPhExecutive Director, Strategic Accounts Xcenda, Palm Harbor, FLVincent J. Willey, PharmDAssociate Professor, Philadelphia School ofPharmacy, University of the SciencesPhiladelphia, PADavid W. Wright, MPHPresident, Institute for Interactive Patient CareBethesda, MD

HEALTH & VALUE PROMOTION Craig Deligdish, MDHematologist/OncologistOncology Resource Networks, Orlando, FLThomas G. McCarter, MD, FACPChief Clinical OfficerExecutive Health Resources, PAAlbert Tzeel, MD, MHSA, FACPENational Medical DirectorHumanaOne, Waukesha, WI

MANAGED MARKETS Jeffrey A. Bourret, RPh, MS, FASHPSenior Director, Medical Lead, Payer andSpecialty Channel Strategy, Medical AffairsPfizer Specialty Care Business Unit, PARichard B. Weininger, MDChairman, CareCore National, LLCBluffton, SC

PATIENT ADVOCACY William E. Fassett, BSPharm, MBA, PhD, FAPhAProfessor of Pharmacy Law & EthicsDept. of Pharmacotherapy, College of PharmacyWashington State University, Spokane, WAMike PucciSr VP Commercial Operations and BusinessDevelopment, PhytoChem PharmaceuticalsLake Gaston, NC

PERSONALIZED MEDICINEEmma Kurnat-Thoma, PhD, MS, RNDirector, Research ServicesURAC, Washington, DC

PHARMACOECONOMICSJosh FeldsteinPresident & CEOCAVA, The Center for Applied Value Analysis, Inc., Norwalk, CTJeff Jianfei Guo, BPharm, MS, PhDProfessor of Pharmacoeconomics& Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

PHARMACY BENEFIT DESIGN Joel V. Brill, MD, AGAF, CHCQMChief Medical Officer, Predictive Health, Phoenix, AZ

Teresa DeLuca, MD, MBASenior VP, PBM LeaderHumana Solutions, Louisville, KYLeslie S. Fish, PharmDVice President of Clinical ProgramsFallon Community Health Plan, MAJohn Hornberger, MD, MSCedar Associates, LLCCHP/PCOR Adjunct Associate, Menlo Park, CA Michael S. Jacobs, RPhVice President, National AccountsTruveris, Inc., New York, NYMatthew Mitchell, PharmD, MBAManager, Pharmacy ServicesSelectHealth, Salt Lake City, UTPaul Anthony Polansky, BSPharm, MBASenior Field Scientist, Health Outcomes andPharmacoEconomics (HOPE) Endo Health Solutions, Chadds Ford, PAChristina A. Stasiuk, DO, FACOISenior Medical DirectorCigna, Philadelphia, PA Scott R. Taylor, BSPharm, MBAExecutive Director, Industry RelationsGeisinger Health System, Danville, PA

POLICY & PUBLIC HEALTH Joseph R. Antos, PhDWilson H. Taylor Scholar in Health CareRetirement Policy, American Enterprise InstituteWashington, DCRobert W. Dubois, MD, PhDChief Science OfficerNational Pharmaceutical Council, Washington, DCJack E. Fincham, PhD, RPh Professor of Pharmacy, Practice and AdministrationSchool of Pharmacy, University of Missouri Kansas City, MOWalid F. Gellad, MD, MPHAssistant Professor of Medicine, University ofPittsburgh, Staff Physician, Pittsburgh VA MedicalCenter, Adjunct Scientist, RAND HealthPaul Pomerantz, MBAExecutive DirectorDrug Information Association, Horsham, PAJ. Warren Salmon, PhDProfessor of Health Policy & AdministrationSchool of Public HealthUniversity of Illinois at ChicagoRaymond L. Singer, MD, MMM, CPE, FACSChief, Division of Cardiothoracic SurgeryVice Chair, Department of Surgery for Quality &Patient Safety and OutreachLehigh Valley Health Network, PA

RESEARCH & DEVELOPMENT Frank Casty, MD, FACPChief Medical OfficerSenior VP, Clinical Development Medical ScienceEndo Pharmaceuticals, Chadds Ford, PAMichael F. Murphy, MD, PhDChief Medical Officer and Scientific Officer Worldwide Clinical TrialsKing of Prussia, PA

SPECIALTY PHARMACYAtheer A. Kaddis, PharmDSenior Vice PresidentManaged Markets/Clinical ServicesDiplomat Specialty Pharmacy Flint, MIJames T. Kenney, Jr, RPh, MBAPharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MAMichael KleinrockDirector, Research DevelopmentIMS Institute for Healthcare InformaticsCollegeville, PA

198 l American Health & Drug Benefits l www.AHDBonline.com July 2012 l Vol 5, No 4

TABLE OF CONTENTS

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INTRODUCTION

200 Cancer: Exploding Treatment and Diagnostic Pipeline, and Ever-Increasing CostsCraig K. Deligdish, MD

PERSPECTIVES

202 Defining Value in Cancer Care: AVBCC 2012 Steering Committee ReportGene Beed, MD; Al B. Benson, III, MD, FACP; Roy A. Beveridge, MD; Craig K. Deligdish,MD; John Fox, MD, MHA; Ira M. Klein, MD, MBA, FACP; Jennifer Malin, MD, PhD; Matthew Mitchell, PharmD, MBA; Lee N. Newcomer, MD; Gary M. Owens, MD; SamuelM. Silver, MD, PhD, FACP; John D. Sprandio, MD, FACP; F. Randy Vogenberg, RPh, PhD

CLINICAL

221 Diabetes Medications and Cancer Risk: Review of the LiteratureQuang T. Nguyen, DO, FACE; Lindsay Sanders, DO, MPH; Anu P. Michael, MD; Scott R. Anderson, MS IV; Loida D. Nguyen, PharmD, BCPS; Zackary A. Johnson, MS II

229 Stakeholder Perspective by Matthew Mitchell, PharmD, MBA

American Health & Drug Benefits is found-ed on the concept that health and drugbenefits have undergone a transforma-tion: the econo metric value of a drug isof equal importance to clinical outcomesas it is to serving as the basis for securingcoverage in formularies and benefitdesigns. Because benefit designs aregreatly affected by clinical, business, andpolicy conditions, this journal offers aforum for stakeholder integration andcollaboration toward the improvementof healthcare.This publication further provides benefitdesign de cision makers the integratedindustry information they require todevise formularies and benefit designsthat stand up to today’s special health-care delivery and business needs.

Mission Statement

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American Health & Drug Benefits, ISSN1942-2962 (print); ISSN 1942-2970(online), is published 8 times a year byEngage Healthcare Communications,LLC, 241 Forsgate Drive, Suite 205A,Monroe Township, NJ 08831. Copyright © 2012 by Engage HealthcareCommunications, LLC. All rightsreserved. American Health & Drug Benefitsand The Peer-Reviewed Forum for Evidencein Benefit Design are trademarks of EngageHealthcare Communications, LLC. Nopart of this publication may be repro-duced or transmitted in any form or byany means now or hereafter known, elec-tronic or mechanical, including photo-copy, recording, or any informationalstorage and retrieval system, without written permission from the Publisher.Printed in the United States of America.

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POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESSshould be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, 241 Forsgate Drive,Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year:$99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

CLINICAL

232 Chemotherapy-Induced Nausea and Vomiting: Optimizing Prevention andManagementKamakshi V. Rao, PharmD, BCOP, CPP; Aimee Faso, PharmD, BCOP, CPP

240 Stakeholder Perspective by Robert Mancini, PharmD

BUSINESS

242 Emerging Trends in Cancer Care: Health Plans’ and Pharmacy BenefitManagers’ Perspectives on Changing Care ModelsRhonda Greenapple, MSPH

252 Stakeholder Perspective by Gary M. Owens, MD

INTRODUCTION


Cancer has always been a devastating and deadlydisease. Unlike many other illnesses, it does notdiscriminate among populations, and it spares

neither young nor old. As our population ages, and themenu for diagnostic tools and treatments becomes moreexpansive and sophisticated, cancer has been evolving asan increasingly dominant disease for research and discus-sion. Only 30 years ago, our ability to differentiate sub-classes, subtypes, and even the stage of cancer was signif-icantly more limited than it is today. Our understandingof the etiology and pathogenesis, as well as the pathobi-ology of cancer, has dramatically increased. In addition,the investment by the industry and government in can-cer research and treatment has expanded dramaticallysince President Richard Nixon signed the NationalCancer Act of 1971, which expanded and providedadditional resources to battle this disease.We have witnessed significant progress in screen -

ing, diagnosis, and treatment since the “war” on cancerbegan. The reality, however, is that despite this progress,many of our new diagnostic modalities and treatments,although costly, provide only incremental benefit. Themore dramatic strides in the understanding of cancerbiology on a molecular level have been translated intomore effective treatments; however, with rare exception,the degree of progress that we have seen in the under-standing of cancer biology has lagged in the clinic. Many types of cancer remain incurable and, in many

cases, are diagnosed at a stage when treatment is limitedin its ability to prolong life. That being said, cancer rateshave decreased in recent years,1 and fewer people aredying from cancer in the United States compared withseveral decades ago.2 Specifically, an age-specific analysisof cancer mortality based on data from the SEER(Surveillance, Epidemiology, and End Results) programindicated a reduction in mortality during the past severaldecades in the United States.3 However, a significantcontribution to this decreased mortality can be attrib-uted to smoking cessation, a greater focus on cancerscreening efforts, and early detection of cancer.1A number of factors have impeded our ability to

improve our approaches to cancer screening, diagnosis,and treatment, as well as to finding a “cure” for cancer.Some of these factors include the level of biologic com-plexity and cellular and molecular heterogeneity of thedisease on a global level and on an individual patientlevel.4 The complexity of cellular interactions and cellsignaling within the tumor microenvironment, and thechallenges associated with testing new treatment modal-ities, have hampered our progress in the battle againstcancer. Despite these challenges, more patients are livingwith cancer and are surviving cancer than in the past. Improvements in our understanding of the disease

have led to dramatic strides in our ability to classify can-cer and prognosticate based on molecular diagnostictools. These tools have contributed to our ability toexpand the resources available to treat cancer. Theability to target therapy and personalize treatments hasbeen furthered by advances in our understanding of themolecular basis of the disease.The diversity of our diagnostic tools and treatments,

and the increasing cost of treating cancer care, have con-tributed to a focus on guidelines and pathways based onevidence-based medicine, with the goal of increasing theprevalence of an evidence-based approach to cancermanagement. More recently, the concept of “value” hasentered the discussion of treating cancer. This issue of American Health & Drug Benefits is repre-

sentative of the research and efforts in oncology in 3important areas—cancer epidemiology, the managementof treatment-related toxicity, and current and emergingtrends in the management of cancer in the United Statesfrom the perspective of payers who face increasing chal-lenges as a result of the mounting costs, not only for drugsbut also for other treatment modalities. Quang Nguyen, DO, FACE, and colleagues have

made an important contribution in their comprehensivereview of the literature, addressing the increasing evi-dence for the relationship between diabetes and cancerand the potential impact of antidiabetes medications oncancer risk. This is an important article, given the signif-icant increase in the prevalence of patients with diabetes

Cancer: Exploding Treatmentand Diagnostic Pipeline, andEver-Increasing CostsBy Craig K. Deligdish, MD

Hematologist/Oncologist, Oncology Resource Networks, Orlando, FL

INTRODUCTION


in the United States, and even more so, the increasingpublic health hazards associated with obesity, which por-tend an increasing prevalence of diabetes, further rein-forcing the importance of managing both of these dis-eases in the United States. Kamakshi V. Rao, PharmD, BCOP, CPP, and col-

leagues review the literature on chemotherapy-inducednausea and vomiting. In their critical review article, theauthors highlight the advances that have occurred in thetreatment of these toxicities, which are considered bymany oncologists to be one of the most significantadvances in the past 2 decades in the management oftreatment-related side effects in cancer.Recent estimates put the costs of cancer care at $100

billion annually, with projections that the cost couldrise up in excess of $200 billion by the end of thisdecade.5 Much of this cost is borne by government pro-grams, such as Medicare and Medicaid, and much ofthe remainder being paid for by commercial healthinsurance companies. Cancer care is an area ripe forcost-saving and quality-improvement interventions,because it is marked by high and rapidly escalatingcosts, suboptimal adherence to evidence-based guide-lines, and wide variations in pricing across regimensthat provide similar efficacy. Even in the absence ofincreasing unit costs for a treatment, the aging of theUS population alone will have profound effects on can-cer-related spending.Rhonda Greenapple, MSPH, has provided signifi-

cant insight into the emerging trends in the manage-ment of cancer-related costs and other strategies incor-porated or anticipated to be introduced by health plansand pharmacy benefit managers, given the dramaticincrease in oncology-related treatment options andcosts during the past 5 years and those that are expect-ed in the next 5 years. This important article providescompetitive insight into innovative approaches, as wellas state-of-the-art cancer cost management in light ofreimbursement challenges and the expected impact ofthe Affordable Care Act.

This issue of the journal also includes a discussion bythe Steering Committee of the 2nd Annual Conferenceof the Association for Value-Based Cancer Care, held onMarch 28-31, 2012, in Houston, TX, and attended bymore than 200 payers, providers, manufacturers, andother stakeholders associated with cancer care deliveryand oncology-focused research in the United States.

This panel of thought leaders addresses the challengesplaced on managing patients with cancer by the increas-ing cost of cancer treatment and discusses and debatesthe concepts and paths necessary to achieve a value-based approach to cancer care. We look forward to additional oncology/hematology-

focused peer-reviewed articles in future issues of thisjournal to assist providers, payers, and other stakeholderswho are actively involved in the battle against thisdevastating disease. ■

References1. Centers for Disease Control and Prevention. Many cancer rates continue todecline. Updated March 28, 2012. www.cdc.gov/Features/dsCancerAnnualReport/.Accessed July 1, 2012.2. Science Daily. US cancer death rates continue to decline. March 28, 2012.www.sciencedaily.com/releases/2012/03/120328172103.htm. Accessed July 1, 2012.3. Howlader N, Noone AM, Krapcho M, et al. eds. SEER Cancer Statistics Review,1975-2009 (Vintage 2009 Populations). National Cancer Institute. Bethesda, MD.http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER datasubmission, posted to the SEER website, April 2012. Accessed July 1, 2012.4.Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branchedevolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883-892.5.Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in theUnited States: 2012-2010. J Natl Cancer Inst. 2011;103:117-128. Epub January 12, 2011.

Cancer care is an area ripe for cost-savingand quality-improvement interventions,because it is marked by high and rapidlyescalating costs, suboptimal adherence toevidence-based guidelines, and widevariations in pricing across regimens thatprovide similar efficacy.


Al B. Benson, III, MD,FACPProfessor of MedicineAssociate Director forClinical InvestigationsRobert H. LurieComprehensive CancerCenter, Northwestern Univ.

Roy A. Beveridge, MDChief Medical OfficerMcKesson Specialty Health/The US OncologyNetworkThe Woodlands, TX

Craig K. Deligdish, MDHematologist/OncologistOncology ResourceNetworksOrlando, FL

John Fox, MD, MHAAssociate Vice President for Medical AffairsPriority HealthGrand Rapids, MI

Ira M. Klein, MD, MBA, FACPChief of Staff to the Chief Medical OfficerAetna Oncology StrategyHartford, CT

Jennifer Malin, MD, PhDManager and MedicalDirector of OncologyWellPoint Los Angeles, CA

Matthew Mitchell,PharmD, MBAManagerPharmacy ServicesSelectHealthSalt Lake City, UT

Lee N. Newcomer, MDSenior Vice President ofOncology ServicesUnitedHealthcareMinneapolis, MN

Samuel M. Silver, MD,PhD, FACPProfessor of InternalMedicineHematology/OncologyAssociate Director, FacultyGroup Practice, Universityof Michigan MedicalSchool, MI

John D. Sprandio, MD,FACPChief PhysicianConsultants in MedicalOncology and HematologyDrexel, PA

F. Randy Vogenberg, RPh,PhDPrincipal, Institute forIntegrated HealthcareCo-Founder, BentelligenceSharon, MA

STEERING COMMITTEE MEMBERS

CO-MODERATORS

2nd Annual Conference

AVBCC 2012 Steering Committee

Gene Beed, MDPresident and CEOHorses, Zebras, andUnicornsIrvine, CA

Gary M. Owens, MDPresidentGary Owens AssociatesGlen Mills, PA

Gary M. Owens, MD: The 2 target concepts we needto consider during this Steering Committee discussion are“value” and “action.” Our goal is to define what is value incancer care, and how is that value different for a payer, a cli-nician, and, of course, the patient. But we also must includeother stakeholders, such as employers and the government,who pay for the care. In addition, we want to develop con-cepts and ideas that are actionable, ones that we can ultimate-ly transfer into true action steps.One thing that complicates the approach to cancer is that

it is not a single disease but a collection of very different dis-eases. Heterogeneity is the hallmark of cancer. At the sametime, there are similarities in the issues that concern patientswith cancer, related to costs and outcomes. Currently, themost robust area in the drug pipeline is oncology. There arealmost twice as many specialty oncology agents in thepipeline as there are other specialty agents for all of the otherdiseases combined. So we are on this cusp of innovation.We are seeing innovation in cancer diagnostics, which par-allels the types of therapies being developed, and we are nowable to do testing to tailor treatment for certain geneticmutations and expression of genes.We need to mold that innovation into what it means for

patient care, what it means to those who pay for it, andwhat it means for those who provide that care. That is howwe are going to open the discussion for the Second AnnualAVBCC Conference.

Gene Beed, MD: We are going to discuss the changing

epidemiology of cancer toward patient-centered medicine.This means personalized medicine and the economics of can-cer care. For example, what does this mean in terms of inno-vation, or when cancer becomes a chronic disease? Our over-arching mission today is to focus on the issues that are mostimportant to promoting value-based cancer care—quality,costs, policy, regulation, and patient access.What is value in cancer care? I can say that it is quality

divided by cost, but those are not quantifiable terms that wecan all agree on. What is quality, and quality in the eyes ofwhom? If there are barriers related to cost, then the questionarises who will pay for the care. Are we just all going to paymore for healthcare, or spend less on other conditions? Arewe going to indebt the next generation, stifle innovation,ration care? What are our options?Perceptions of value differ throughout the healthcare in -

d ustry. For manufacturers, efficacy, total patient outcomes,and unmet medical needs determine value. This is in markedcontrast to how health insurance companies, employers, andregulators define value, which concerns longevity, quality oflife (QOL), and cost. Cost is a key part of the value equa-tion, regardless of what part of the healthcare industry isinvolved. Why is defining value in cancer care more challeng-ing than defining value in other areas of medicine?

John D. Sprandio, MD, FACP: Value in cancer careis challenging for 2 reasons. One reason is the clinicalsituations in which patients present, depending on theirstate and their variable frame of reference in terms of


Defining Value in Cancer Care: AVBCC2012 Steering Committee Report

Approximately 200 oncologists, payers, em -ployers, managed care executives, pharma-cy benefit managers, and other healthcare

stakeholders convened in Houston, TX, on March28-31, 2012, for the Second Annual Conferenceof the Association for Value-Based Cancer Care(AVBCC).

The mission of the conference was to align thevarious perspectives around the growing need ofdefining value in cancer care and developingstrategies to enhance patient outcomes. TheAVBCC conference presented a forum for the var-ious viewpoints from all the stakeholders across thecancer care continuum, featuring more than 20 ses-sions and symposia led by nearly 30 oncology lead-

ers. The discussions focused on current trends andchallenges in optimizing value in oncology byreducing or controlling cost while improving carequality and patient outcomes, introducing emerg-ing approaches to management and tools thatproviders and payers are using to enhance cancercare collaboratively.

The AVBCC Second Annual Conference wasopened by a Steering Committee discussion of 11panel members who attempted to define value incancer care and articulated action steps that can helpto implement value into cancer care delivery. Thefollowing summary represents highlights from theSteering Committee discussion, which was moderat-ed by Gene Beed, MD, and Gary M. Owens, MD.

their goals and their understanding of the situation. Andthe second reason is the cost of drugs. Cancer care isuniquely complex. This is not to say that in other areasof medicine cost is not complex, but cancer presents auniquely complex situation.

Samuel M. Silver, MD, PhD, FACP: I agree whole-heartedly that there are 2 issues here. One issue is indeedthe complexity of oncology. When I talk about quality-of-care issues to nononcology audiences, they say, “Sowhat is the problem? We talked to our cardiovascularcolleagues, and we have it down.” And, they partly haveit down. If you have to treat a myocardial infarction(MI), that involves a single organ. It does not make a dif-ference how the patient got the MI, only that thatpatient has MI. There are not 4 stages of the disease. Itis not estrogen receptor–positive or progesterone recep-tor–positive; it is not HER2-negative or HER2-positive.It is not all of these various silos. The science of canceris complex, with multiple diseases and with multiple pre-sentations of a single disease.

Second, because we have so many silos and our car-diovascular colleagues do not, they can have hundreds oreven thousands of patients in randomized trials lookingat a single point. In cancer, we do not have these num-bers of patients. Therefore, the science becomes moredifficult for comparative effectiveness analyses.

It is very difficult to determine the degree of improvedefficacy and total patient outcomes in oncology. It alsodepends on where and how we are looking. What doescost mean for the patient? Value is not about the totalcost of management, it is about the cost that we bear per-sonally. Some of us are only seeing a part of the costs,and some of us see more of them.

This also varies from patient to patient, depending ontheir insurance. The value equation changes dependingon the outlook of just that one variable.

Improved patient QOL—whether we define that interms of years of life or quality per se—is the metric thathas to be the most important. And the next is totalpatient outcomes.

Craig K. Deligdish, MD: For the purpose of this dis-cussion, I would disagree with my colleagues for a coupleof reasons. We have been treating cancer for many years.I think we must ask, “What has changed during thistime?” Why would the definitions of value, quality, oroutcomes be different today from what they were 10, 20,or even 30 years ago?

The difference today is in the cost of treatment. Thecost of treatment today is drastically different from whatit was 10, 20, or 30 years ago. By contrast, I do believethat we have made a dramatic impact on the survival ofpatients with cancer. At the end of the day, one of theimportant questions that a physician and a patient needto answer is, “Do I have a curable form of cancer? Canthe patient be cured?” And a second important questionis indeed about QOL, which is even more importantwhen the patient does not have a curable disease. Thatquestion must be answered in the context of defining“quality” and “value.”

Next we need to consider all of the treatment anddiagnostic tools that are available to us today, as com-pared with those that were available 10 or 20 years ago.What have they contributed in terms of value, quality,and cost? We also need to talk about how we define effi-cacy. We need to factor all of this information into whatultimately is the definition of value. Is a diagnostic tool ora treatment efficacious if it extends survival by 1 or 2months? Clearly, taking a pill that has few side effects andcures an otherwise terminal disease (eg, Gleevec) hashigh value, whereas a drug that costs $30,000 a monthand allows us to live 1 month longer has less value.

In terms of value, the definition is to some degreebased on whether value is being defined by the patientor by the payer. As we all know, it frequently is neitherthe provider nor the patient who is paying for treatment.Is the government paying, the employer, or the insur-ance company, or is the patient paying for the treatment?And this is tantamount to defining the issue of value.We must also consider whether it is going to result in animprovement in QOL, make the patient feel better, orcure the patient’s disease.

Al B. Benson, III, MD, FACP: I would agree thatin terms of value, the central focus must be on thepatient’s perspective. For patients whose disease couldbe cured, the goal is cure and living a long, productivelife. I think that is how most patients would definevalue. Financially, this is very difficult from a patient’sperspective, because in many cases the patient isdivorced from the outlay of funds that cover the truecost. Although we are talking about tremendous prob-lems with uninsured patients, copays, and so forth, overtime most patients with cancer end up in a situation

AVBCC 2012 Steering Committee Report


Value in cancer care ischallenging for 2reasons. One reason isthe clinical situationsin which patientspresent. And thesecond reason is thecost of drugs.John D. Sprandio

that they would not experience in any other aspect oftheir daily life in terms of potential catastrophic costsand life-threatening illness.

Normally, if you purchase any product, you have tocover that cost. Within the overall complexity of oncol-ogy, value is somehow distorted for many patients,because they are not paying the full cost of the service.Another fundamental problem with value is that overtime we are seeing significant technological advances inall aspects of care, whether it is in diagnosis, in imaging,or in treatments, that may not be optimally defined interms of utilization yet can drive up costs and at the sametime have the potential to extend life.

There is so much we do not understand about cancerbiology, and, as the technology advances, we have beenunable to study the technology at its maximum to trulydefine value. For example, for cancer surveillance, wenow talk about survivorship and how we monitorpatients over time. The literature is very sparse in termsof defining what is appropriate surveillance. In my areaof expertise, which includes colon cancer, there havebeen some meta-analyses done, but that is the exception.Overall, we need evidence to decide how to maximallyuse imaging, how to define risk, which patients are atrisk, and how to monitor patients over time. And if wediagnose a tumor recurrence, for example, what can wedo to help that patient further?

The same is true for drugs—the way we study mostdrugs now remains empiric. We do not have the selec-tion tools that we need to demonstrate true value. As wedevelop markers, we are certainly making some progress.We have seen this in diseases such as leukemia, breastcancer, and to some extent, colon cancer.

When we talk about value and cost, survival benefitdemonstrated in clinical trials shows proof of principle,that this given intervention works, but we cannot definehow it works maximally in each individual patient.Because of the way we design these large trials—in mostof them we are giving treatment to a large proportion ofpatients who will absolutely not benefit from that treat-ment—we cannot select out the patients who, in fact,truly benefit from the therapy, thereby reaching the ulti-mate goal for the individual patient.

Roy A. Beveridge, MD: The topic of adjuvant ther-apy versus palliative therapy is directly relevant here.The value for these types of therapy is different. I do notknow of many biopharmaceutical companies thatbelieve that improved longevity of a patient is not veryimportant, because everything related to drug designright now is related to making patients live longer. Interms of personalized medicine, identifying particularpatient populations is among the major goals.

By contrast, the US Food and Drug Administration(FDA) has indicated a lack of interest in QOL improve-ments. That may be something that the FDA may aspireto in the future, but this has not been relevant so far toany major drug development approvals.

Dr Beed: From the payer’s perspective, how do yourespond to what people have said so far about value, and howis it perhaps different from that of clinicians?

Dr Silver: Fundamentally, value relates to peopleagreeing that something has equivalent value; there is anexchange that goes on. But in cancer care, that equationdoes not work, because the consumer is not the payer. Imay not agree that this has the same value as somethingelse, but I am constrained, because I cannot set the prices.I cannot decide on the prices of treatment, and I amrestrained by state laws that force me to pay for some-thing, even though I do not think it has value. Therefore,we have a fundamental challenge in defining what valueis in cancer care.

We have a challenge defining value in all of medicine.For example, there are new transaortic valve replace-ments that cost $35,000 for a valve—$60,000 total com-pared with $8000 for a typical valve replacement. Thesenew valves provide an additional 18 months of life for apatient who has less than 1 year of life expectancy. Wehave the ability to negotiate those prices. But in cancercare, we do not have the ability to negotiate that,because there are typically monopolies, at least early on,with the release of a new drug and a new drug category.

There is hope that in the era of biomarkers therewould be enhanced value, because at least we would notbe spending money on drugs that were not going to ben-efit a patient. But with tumor biology that involves

Defining Value in Cancer Care


Within the overallcomplexity of oncology,value is somehowdistorted for manypatients, because theyare not paying the fullcost of the service.Another fundamental problem with value is that over time we areseeing significant technological advances inall aspects of care that may not be optimallydefined in terms of utilization.

Al B. Benson

escape mechanisms, it is not clear that it is going to pro-vide a long-term benefit. Even with the recent study thatwas published in the New England Journal of Medicineshowing that there is a lot of tumor heterogeneity, withinany given tumor there may be multiple tumor types. Wejust happened to pick one, because that is what we biop-sied. So even the role of biomarkers is now coming intoquestion, especially in relation to the current economy.

The challenge is that we do not compare the valuein producing 1 year of life or a QOL year in the sameway that we compare it to people with heart disease.We may pay $80,000 a year to a patient with multiplemyeloma, which is now a chronic disease, and that per-son may live for another 2, 3, or 4 years, but we do nothave discussions about this—what is 1 year of lifeworth? At the same time, we are making tradeoffs as asociety, because in the state of Michigan we are closingschools and are not paying for teachers. This is a chal-lenge for us as oncologists, because at the end of the daywe have to make choices on where we put our money,and we are not having a dialogue about where weshould spend those dollars.

Dr Beed: You raise a very good point. One way thatoncology is different from the rest of medicine is that just ageneration ago we did not even use the word “cancer” withour patients. This is very different from most diagnoses. We

did not talk about cancer, and we did not mention the diag-nosis. Now we want to talk about the value of 1 year of life,QOL, and what the patient’s out-of-pocket copay is.

Matthew Mitchell, PharmD, MBA: You asked whatmakes cancer different from other categories of manage-ment. From my perspective, some of the biggest issuesare the regulatory and government mandates in oncolo-gy. Nothing comes close to cancer care, and when we tiethat with the amount of money that is tied to oncolytics,that is where the difference is between oncology andother clinical areas.

Dr Beed: So cost has been the main change.

Dr Mitchell:Cost is what gets on the radar, but muchof this is semantics, that is, the way the question is asked.We have to ask what is efficacy, or what is the treatmenteffectiveness in real-world outcomes. I am surprised thatwe are not discussing adverse events or safety issues inrelation to value. From a management perspective, theseissues have to enter into the quality of care and the valueproposition. We may need to consider allowing cover-age of products within a certain regimen even if theexact regimen was not studied in a specific cancer type.One example may be allowing the substitution of cis-platin/carboplatin therapies into a regimen in whichboth products have demonstrated efficacy in separateregimens, but one may produce fewer adverse events,leading to better patient experience and lower cost withthe reduced adverse events.

Ira M. Klein, MD, MBA, FACP: My role at Aetnafor the past several years has been to be the clinicalleader for our oncology strategy, and in that position wehave wrestled with the issue of value. I would say thatthe standard definition of value is quality over cost. Ithink we can define value in many different ways, butthat is the basic premise.

Dr Beed: There is some disconnect between, “The valueof an extra month of life in a clinical study does not showwhat this drug can really do in the real world in my hands,”versus “It’s not a free market. There is no ability to negoti-ate.” What is the value for the cost that is being paid withsomeone else’s money?

Lee N. Newcomer, MD: By the time our 5-year-oldchildren graduate from college, their healthcare premi-um will be equal to the average US salary. Based on cur-rent cost trends, we are 1 generation away from spend-ing our entire salary to cover healthcare, if we do notchange something. We can have many discussions



We have to ask whatis efficacy, or what isthe treatment effectiveness in real-world outcomes. Wemay need to considerallowing coverage ofproducts within a

certain regimen even if the exact regimenwas not studied in a specific cancer type.

Matthew Mitchell

By the time our 5-year-old childrengraduate from college, their healthcarepremium will be equal to the average USsalary. Based on current cost trends, we are1 generation away from spending ourentire salary to cover healthcare, if we donot change something.

about how we ought to tweak this, but we have to makesome changes in the system, and they have to be madein the next 2 or 3 years.

We need to make some decisions about whether, as asociety, we can spend any time treating people withdrugs that get a 1- or 2-month response, until we find outhow those drugs work in a combination that gets us amuch more meaningful response, such as 4 to 6 monthsor 6 to 8 months. And we have to decide as a societyhow much those months are worth.

We know that England has done that. It came upwith the number of $40,000 per life-year. I do not knowif that is the right number for the United States, and atUnitedHealthcare I will not be making that decision,but as a society we have to do that, because we simplycannot afford to continue the way we are spendingtoday. It is not sustainable.

Dr Beed: In the Affordable Care Act, the discussionabout comparative effectiveness explicitly says that a calcula-tion of cost per quality-adjusted life-year shall not be used.

Dr Newcomer: Exactly, and the way that Medicarebalances its budget is by simply paying the physicianand the hospital less and less each year, because it is notbringing enough money in. Medicare simply lowers thereimbursement and tells providers that it is somethingthey have to accept. Very few people can walk awayfrom Medicare. But, we cannot take that all the waydown to zero.

I have just attended a hospital board meeting to dis-cuss reimbursement. Each year we have to find $30 mil-lion worth of new profits just to cover what Medicare isnot going to pay us, because their fee schedule wentdown. We have to do that year after year, and now we arelaying off people to get it done. That the government willnot address this tells us how difficult the discussion is, butwe cannot use their approach of down-pricing to zero.

Dr Beed: If the US government will not address it, whowill? Where is the area of agreement between clinicians whoare caring for patients with cancer and the payers who are try-ing to manage this pot of money?

Jennifer Malin, MD, PhD: My alma mater, the Uni -v ersity of California Los Angeles (UCLA) has the dubi-ous honor of being the most expensive academic centerin the country, according to the Dartmouth Group. Atthe same time, California is in a budget crisis. The 3primary state budget expenses are healthcare, educa-tion, and prisons. I do not see any efforts to try to reinin costs at UCLA, even though the educational mis-sion of the university is suffering—our faculty and the

entire staff have mandatory furloughs, essentially a 2-week salary cut per year. The cost of tuition hasincreased by 30% over the past year. Our public educa-tion system is in shambles.

Therefore, what we are talking about in a theoreticalway is actually very real. It is happening now: 1 in 3 ofus is going to get cancer, so what do we see as worthputting our money away for in terms of treatments?Realistically, being in the position of being able to nothave cancer, but thinking about ourselves as potentialpatients, what is a meaningful improvement in QOLand in length of life that is worth mortgaging our chil-dren’s future for?

F. Randy Vogenberg, RPh, PhD: There are so manydifferent perspectives in this issue. Looking at it fromthe perspective of the commercial payer, the self-fund-ed plan sponsor, whether it is an employer, a union, ora municipality, they are all feeling the squeeze as well.The research that I have been involved with recently isdemonstrating very clearly that employers in particularare very much engaged in this debate, more than manypeople realize. They are trying to grapple with thevalue question not only in economic terms but alsowith how the whole healthcare system that they arepaying for is performing to deliver outcomes.

As one of the biggest areas that is so visible to every-body, cancer is a very emotional disease. Everybody hasbeen touched one way or another by cancer, includingme. And there are many dollars involved. Employers areconcerned about cost, but their primary interest hasbeen performance. There is a big gap between what weare paying for today and the results or the performancethat we expect to see. It is not just about cost. Employersare looking for the performance that is related to the costof therapy, whether it is a drug or a diagnostic test,extending life, or curing disease.

We are now also dealing with severe drug shortages.Employers are very interested in more of a 360-degree



What we are talkingabout in a theoreticalway is actually veryreal. It is happeningnow: 1 in 3 of us isgoing to get cancer, sowhat do we see asworth putting our money away for in terms of treatments?

Jennifer Malin

view of what is happening with the dollars that they arespending. That is unlike what we see typically with theCenters for Medicare & Medicaid Services (CMS)because of some of the congressional budget rules thatCMS has to play by.

There are probably employers who are seeing this as anurgent issue. They are looking at a 2- to 3-year window, aswell as a time for very rapid innovation and change, to tryand shift not only the cost curve but also the performancecurve among all of the vendors that they are paying for.

Dr Beed: We were just talking about the meaning ofvalue and about how the demographics have changed.Personalized medicine, biomarkers, and resource allocationare where the rubber hits the road in many cases. Should wespend more money on cancer care going forward? Are wewilling to take money from other diseases and spend less onthem and more on cancer?

Dr Vogenberg: That is all part of the discussion.There’s a finite amount of financial resources.

Dr Sprandio: Cancer therapies are valuable if theyare potentially curative. In the metastatic setting, thereis value, and it is reasonable as a society to support 1 or2 lines of therapy. Regarding biologics, especially bio-markers, if we can convince patients that we are usingthe best drug from the beginning, and the second-bestdrug for the second round of chemotherapy, we wouldhave a much better chance of telling patients that thereis no sense in doing the second, third, fourth, or fifthlines of therapy. But today we cannot say that. We canjust say that based on a population and a probability, weare going to choose the best drug, but we do not knowwhat is best for the specific patient’s tumor.

No one would question that we should be investingmore in early detection when there is good evidencethat makes a difference in outcomes. In metastatic dis-ease, we have to ask questions about how long to treat.

Dr Klein: Because this is an epidemiologic discus-sion, we should point out that we do not have the gran-ular data that we know how to get to the answers weare seeking. Clearly there is a lead time bias. One of thereasons that we do not know whether we are doing bet-ter than we were doing 20 years ago (except in someselect diseases, such as chronic myelogenous leukemia)is that Medicare and most of the private payers do notcapture the elements that we need to figure outwhether we are comparing like to like. So we mighthave a diagnosis, but we do not have a stage. We do nothave tumor histology. We do not have biomarkers. Andwe do not have performance status. Until we get thatinformation, we cannot make an informed epidemio-logic decision. Once that information is available, Ithink we will be able to make much better decisionsregarding the value of treating a metastatic disease, andwho is getting the best chemotherapy.

And if we are comparing like to like, then we justeliminated the lead time bias, because we can get rid ofthe disease through our ability to granularly bucket dif-ferent patient categories.

Dr Beed: So when it comes to actionable things thatneed to happen in terms of value in cancer, I have heardabout watchful worrying and the early detection lead timebias. You point out that we need to have more robust infor-matics that look at cancer, and that may integrate clinicaltrial data, claims data, and other data to get some ideas ofwhat happens in the population. Dr Newcomer, what elsewould you add to this in terms of making value-based cancercare a reality, considering the increasing numbers of expen-sive therapies, better early detection, and better survivabilitythat may be real or may be related to lead time bias?

Dr Newcomer: I want to underscore the need forstarting to collect some registries, so we can truly findout whether your statements are true. One of the thingsI am struck with in my discussions with practicingoncologists is that they do not get the same responsethat was shown in the registration trials, because thepatients are different. Patients entered into a registra-tion trial have a performance status of zero. Thepatients we see in the office often cannot do half thethings as patients who are enrolled in clinical trials.

Only about 2% to 3% of all patients with cancerenter into clinical trials. If we are going to acceleratethe pace of making these kinds of value-based decisions



I want to underscorethe need for startingto collect someregistries, so we cantruly find out whetheryour statements aretrue. One of thethings I am struck with

in my discussions with practicing oncologistsis that they do not get the same responsethat was shown in the registration trials,because the patients are different.

Lee N. Newcomer

with cancer, we need registries. I think they are verypossible. At UnitedHealthcare, we have 35,000 patientsnow with breast, colon, and lung cancers, and we havethe data that were requested. We have information onstage, genetics, and current status—everything but per-formance status. We are starting to try to mine thatdata now to see if we can find what delivers value, andwhat does not.

Dr Beed: How do we apply these to individual patients?How do we make sure we are using the treatments that arereally of value? Is this just the art of medicine, or is theresomething more to it than that?

Dr Benson: This gets back to the point about howwe expand our knowledge base in terms of understand-ing how to use these drugs for appropriate people. It isgoing to take many shifts in what we do. Clinical trialsare designed to determine efficacy, to see whether thedrug works. They are critical in that regard, but whatwe are increasingly arguing now is that we have tochange the way we design clinical trials. Even if we donot have the correct biological profile, since we oftendo not know that at the beginning of the trial, we needto prepare an information database, including tumorbanking, so that in the future we could go back to thatdatabase and tissue to explore links encompassing bio-logical profiles, treatment, and outcome.

A good example of that is the KRAS marker incolon cancer. When some of the colon cancer trialswere designed and the researchers were looking atmarkers, KRAS was not even one of the markers in theoriginal design. But because the researchers had col-lected tissue, they had excellent clinical data andbanked tissue from which exploration of markers couldbe pursued. They had a methodology that was consis-tent with the need to test the marker. We were there-fore able to go back to the data and combine a numberof different trials to come up with a marker that trans-formed the treatment strategy.

These databases are going to be increasingly impor-tant, provided that we are putting the appropriateinformation in the databases. One reason that the data-base concept is especially attractive is that we are mov-ing away from an empiric approach to one looking forpatient selection based on more precise criteria. Wenow know that most malignant diseases, because oftumor heterogeneity, are a collection of different bio-logical profiles. And as we start subsetting, we are goingto need larger populations to look at these small popu-lation subsets. For example, in patients with lung can-cer, there is a marker that defines a 4% population thatwill benefit from a given intervention; in patients with

gastric cancer, there is a marker that identifies 20% ofthe gastric cancer population that will potentially ben-efit from a targeted therapy. If we are going to do com-parative effectiveness analyses in oncology with thesedatabases, we have to make sure, in an ongoing way,that we are populating these databases with ongoinginformation as it evolves, so that we can look at thesesubpopulations with meaningful data over time.

It is also going to require cultural shifts in trying toconvince more people to participate in clinical trials.These trials are going to be even more complex,because as the National Cancer Institute has recentlystated at the American Society of Clinical Oncology(ASCO) GI Symposium, “No tissue, no marker, nostudy.” The point is that if we are going to truly demon-strate marked improvement in efficacy, we have todefine the population that is most likely to respond toa given treatment. This changes the landscape in howwe conduct oncology clinical research. It changes thelandscape in real need for population-based databases.It asks less, “Does it work in the real world?” and asksmore, “Will this enable us to capture the subpopula-tions in sufficient numbers of patients that we couldactually show that there is efficacy and appropriateintervention for the subpopulation?”

Dr Sprandio: What we are getting at is that we aregoing to change the epidemiologic description of dis-ease from a histopathologic diagnosis to a genomic orepigenomic diagnosis. That will give us much morepotential, I think, to observe changes in outcomes.

Additional clinical studies that Dr Benson men-tioned are critical to driving guidelines, and it is theoncologist’s job to follow guidelines. The question ishow do we devise innovative practices to impact thechanging clinical and economic burdens of cancer?What can we control in terms of the economics? Wecan control unnecessary resource utilization. At thecore of what we have done in this model that is stillevolving is that we have minimized unnecessaryresource utilization on a consistent basis over the past6 years.

Consider the National Committee for QualityAssurance guidelines; each of the guidelines and



The question is how do we deviseinnovative practices to impact the changingclinical and economic burdens of cancer?What can we control in terms of the economics?

requirements include a quality of service and a valuecomponent. The guidelines help to focus on patients asa central target, streamlining the standardizing treat-ment, which is what we do as oncologists.

Dr Beed: In your oncology delivery system, how is myexperience as a patient going to be different from anothercenter or from the old way of care delivery?

Dr Sprandio: Patients notice improvement in serv-ice. They also recognize better coordination and com-munication, which are major concerns. The physiciansare different silos. That is noticeable in the patient’seyes. Access, engagement, and responsibility are impor-tant, and making patients understand that they have aresponsibility to communicate and report informationto their providers. The whole thing about patient-cen-tered medical homes (PCMHs) is tracking chronicallyill patients over time to be in a better position to avertthe acute exacerbations of their symptoms or issues,and then not only provide a decrease in resource uti-lization but also to improve their QOL.

The PCMH was geared and developed for primarycare, initially pediatrics, and then adopted by primarycare. It is a model that also fits very well for oncologycare. At my practice, we are now saving money deliv-ering care this way. I run a 9-man practice, and we haveshown that we were able to reduce our annual emer-gency department utilization per patient receivingchemotherapy by 68% since 2005. We have reducedour annual hospital rate for patients receivingchemotherapy by 51%, and we have reduced the lengthof hospital stay for admitted patients by 21%.

Dr Beed: Does that drive every insurer to your doorstep?

Dr Sprandio: Yes, it is starting to. We created manyefficiencies; for example, we went down from 8.3 full-time equivalents (FTEs) to 5.5 FTEs. There was a lot ofinternal infrastructure that we had to build, and thatwas costly. The programming was done by trial anderror. There was instruction and hand holding. It cost alot of money to develop this model, but now our prac-tice has stabilized—we are still independent, and weare hopeful.

Dr Beed: Have the capital expenditures been laid out,and are you going to start seeing a return on investment?

Dr Sprandio: If there is no return on investment, itmeans that there is no payer response to this. Reform -ing payment methodology is harder than reformingcare delivery.

Dr Beed: If somebody does something that decreasesemergency department use and other resource use, it savesmoney in terms of patients with cancer. They spend somemoney, they save some money, and they have an ongoingprocess that’s saving money in caring for cancer patients.Does that mean that we should then, as a system or as apayer, be spending less on patients with cancer going forwardand realizing those savings? Or does it mean that we shouldreward people for saving money and spend more on cancer,and then the ultimate burden on the system is negligible?

Dr Malin: One of the elephants in the room that wehave not talked about is how oncology care is paid for,and the fact that most of the revenue for oncology prac-tices comes from the margin on drugs. If we are going tomake the decisions about which treatments to use onwhich patients as cost-neutral to the practice, we have toreward those innovative practice models and start toreimburse providers for offering care that is patient-cen-tered and well-coordinated rather than reimbursingthem for selecting the most expensive, highest technol-ogy–based novel therapy, if that therapy is not going tohave a dramatic improvement in patient outcomes.

Dr Beed: What do you think about the way we payoncologists, and the incentives that are a part of it?

Dr Mitchell: I am unable to think of another special-ty that brings in revenue based on billing for drug thera-py to the degree that is done in oncology. Part of the ele-phant in the room is the potential for treatmentdecisions, and more specifically medication selection,based on potential clinic revenue. One possible solutionis to reevaluate the way cancer centers are reimbursed.One option would be allowing a management fee, simi-lar to a medical home but more comprehensive, becausethe sophisticated centers do have interdisciplinaryteams. Knowing that it costs more to deliver that type ofcare, this removes the revenue out of the drug side com-pletely, and puts it into a management fee.

Dr Beed: We have mentioned personalized medicine:what do payers think of this approach? Are they going to onlypay for people who have the biomarker? Does personalizedmedicine direct therapy, or do people just become a little more



One of the elephants in the room that wehave not talked about is how oncology careis paid for, and the fact that most of therevenue for oncology practices comes fromthe margin on drugs.

comfortable or a little less comfortable with what they havedecided they are going to do? If all we have done is add thecost of a test, that really did not change anything. Is person-alized medicine the Holy Grail? Are we going to test for bio-markers in everyone?

Dr Beveridge: One of the main problems is that withInternational Classification of Diseases, Ninth Edition(ICD-9) coding, the insurers do not know whether apatient with lung cancer had small-cell or non–small-celllung cancer, localized versus metastatic, first-line therapyor fifth-line therapy. Payers were in the dark. In the nextcouple of years, ICD-10 will address some of that.

The inability to compare groups throughout thecountry has been a fundamental problem in terms ofassessing quality in one area versus the other. Peter Ellis,MD, Kathy Lokay, and others first started using path-ways, and then the US Oncology Network andMcKesson Specialty Health have continued with path-ways in the past 7 years. I suspect that some of the criti-cism that Dr Ellis remembers is that we (the USOncology Network) were converting over to “cookbookmedicine,” that all people were being treated the same,and that the goals of pathways were to render the leastexpensive care. As we look at the evolution of pathwaysin the past 6 to 7 years, we recognize that it allows fortrue personalization of care. Because the treatment algo-rithm does specify, and probably all pathways in thecountry do now, whether this is for a patient with breastcancer who is HER2-positive, HER2-negative, estrogen-receptor–positive, triple-negative, and so on.

But this is not the “be all and end all” as far as wherewe need to go. In terms of truly personalized care, theanswer is more than just pathways. We need to begin totake into account radiation, which we have not yet dis-cussed. Today, radiation is a significant component ofour cancer care delivery system.

We keep talking about drugs, because most of us aremedical oncologists, but hospitalization and emergencydepartment rates are very important in terms of costs.

At some point we need to address the issues of endof life, corporate use of hospice, and futile therapy.These are all crucially important for the managementof the patient. That is what we should discuss when wetalk about true patient-centered principles and person-alized medicine.

Dr Vogenberg: I have recently had discussions withemployers about personalized medicine. One of thecommon responses I hear is, “If you cannot prove orshow me that what you are doing is better than what wedid before using a newer product versus an older prod-uct, then the only difference is cost.” All of these other

quality parameters we talk about are considered to beirrelevant by the true payer (ie, the employer as benefitspurchaser). We have seen this with CMS, and we areseeing it now with employers. I have never heard anemployer say, “I’m not willing to pay.” All employers arewilling to pay, but they want to see that this cost is mak-ing a difference. That value is going to be key to thefocus of personalized medicine.

We are increasingly moving toward personalized med-icine, which will be a large conundrum. A key issue willbe whether we can differentiate between the perform-ance of one product and all of the surrounding services.

Dr Sprandio:Ultimately we are going to get to a pointwhere we are using genomic diagnosis. But with tumorgenomics sequencing, any escape mechanism creates asignificant challenge for the oncologist in trying to decidehow to use that wealth of information to figure out whichtherapy is best. And there are probably going to be anumber of tumors for which no markers exist.

Dr Deligdish: Payers think there is value in informa-tion related to clinical utility, if that information helpsthe physician to decide on an optimal therapy. But if thisinformation does not help in the decision-makingprocess, then that information has limited value. Forexample, if the cost of tumor genome sequencing is inthe $2000 range in the next several years, and the costof treatment is between $5000 and $15,000 monthly, thecost of genome sequencing may be a good investment ifit impacts the decision-making process. However, ifsome patients can be cured by the information gleanedfrom this test, the value may be priceless.

We can most likely all accept that our current systemis not sustainable. If we look to the past, at least in thearea of cancer treatment, some fairly dramatic mistakes



At some point weneed to address theissues of end of life,corporate use ofhospice, and futiletherapy. These are allcrucially important forthe management of the patient. That is what we should discusswhen we talk about true patient-centeredprinciples and personalized medicine.

Roy A. Beveridge

were made when it came to value and cost; one exampleis the use of high-dose chemotherapy and autologousbone marrow transplantation for women with breast

cancer. That treatment was very popular and was evenperformed at tertiary medical centers and in the commu-nity setting. Indeed, billions of dollars were spent beforeit was recognized that the treatment had no true valueand was associated with significant morbidity and mor-tality. Similar examples occurred in the past couple ofyears, when treatments that were promoted withoutproven benefit were approved and implemented on afairly large scale. We cannot continue to make thesetypes of mistakes, but we continue to make them.

As we move toward healthcare reform, we continueto see consolidation in the number of providers and pay-ers. But as we continue with this consolidation, we arerealizing that it does not reduce cost and does not makethe system more efficient. Indeed, it makes the systemless efficient and more costly. Unless we, as a society, arewilling to address those issues, we will end up in a place

where there probably is only 1 payer, because no otherpayers will be able to afford to be in that space, andpatients may no longer be able to afford treatment.

We need to think about where we are going to be in5 years, because, as Dr Newcomer said, we cannot affordto be where we would end up in 10 years unless some ofthese issues are addressed.

Dr Beed: If we are going to spend more money on can-cer, how are we going to finance it? Are we going to spendless money on other diseases, hold down innovation, or bor-row from the next generation? What are the appropriatesteps, that could be accepted by providers, that we have totake as a society?

Dr Silver: I have heard at an oncology panel that wespend more money on testing now than we do onchemotherapy drugs and radiation.

Dr Newcomer: That is correct, and that is on genetictesting alone. However, genetic testing includes all dis-eases. When you do parse it down by cancer, it will comedown. But, the point is that when we look at spending,it is clear that we are enamored with genetic testing, andwe are spending large amounts of money on it. In fact,we are seeing significant spending for genetic testing inareas without evidence to support use yet.

Dr Silver: Hematologists have been working withthese kinds of advanced personalized medicine tests forthe past 20 years. These tests have been getting morespecific and more advanced. But, it is much easier toobtain tissue in hematologic malignancies than in solidtumors, which is why this has been in the forefront.

Overuse in the very expensive diagnostic testing forpersonalized medicine typically takes place for severalreasons. First, there are many perverse incentives finan-cially for doing this. Second is the lack of impedimentsfor use. For example, Oncotype DX for women withbreast cancer does decrease the amount of adjuvantchemotherapy when used appropriately. However, wehave reviewed cases when the Oncotype DX showed ahigh-risk score and the women did not receive adjuvantchemotherapy, or when women had a low-risk score andreceived adjuvant therapy.

One question that I cannot answer is who was order-ing the tests. We can have an 85-year-old woman whoshould never get adjuvant chemotherapy, but if the testis being ordered reflexively by a pathologist (who doesnot meet the woman), is that reasonable? We end upspending $5000 on a test that no one is going to look at.

We have excellent tests, but they have to be used inthe right context. We are ordering too many things,



Overuse in the veryexpensive diagnostictesting forpersonalized medicinetypically takes placefor several reasons.First, there are manyperverse incentives

financially for doing this. Second is the lackof impediments for use.

Samuel M. Silver

We can most likely allaccept that our currentsystem is notsustainable. If we lookto the past, at least inthe area of cancertreatment, some fairlydramatic mistakes were

made when it came to value and cost. Wecannot continue to make these types ofmistakes, but we continue to make them.

Craig K. Deligdish

because we can do it. There are certainly overuse issuesthat must be addressed.

Dr Beed: Does the PCMH model address the need tokeep the pathologists from ordering something when they havenever seen the patient?

Dr Sprandio: It does. Among the goals of the PCMHmodel is assuming complete control of everything relat-ed to cancer diagnosis, orchestrating the appropriateresponse, and coordinating patient care.

Dr Beed: With regard to negative consequences of per-sonalized medicine on drug innovation—should we continueto develop the same innovative products that only approxi-mately 4% of the population will benefit from?

Dr Benson: One of the hallmarks of selecting a mark-er to become a clinical test is that in the end it must ben-efit the patient. Part of the problem with technologicinnovations—whether it is a diagnostic test, an interven-tional radiology procedure, or now positron-emissiontomography (PET) or magnetic resonance imaging(MRI)—because of the way they are being developed andget reimbursed, they enter the marketplace without thetrue testing that is required to understand their clinicalbenefit. We have been talking about drugs, but if we lookat PET scans alone, the amount of money being spent onthem is mindboggling, and most of it is inappropriate use.

There are important clinical trials addressing the useof PET scans, but they are lagging behind in defining theoptimal use of this technology, which is also an evolvingtechnology. Because PET scanning is readily availableacross the country, it impedes the prospective collectionof the essential information needed to answer, “Does thiswork, or does it not work?”

Part of the perversity of our reimbursement system isthe way these products get on the market. They are paidfor before we clearly define the appropriate clinical use.We need to make a better investment and say, “We aregoing to order this test, but the only way the test is goingto get reimbursed is that it will be entered into a databaseor a prospective clinical trial, to try to define what thereal use should be.”

How to get around that is a major problem. Forexample, I was on the ASCO panel that was going tocreate a guideline for radiofrequency ablation use forpatients with colon cancer and liver metastasis. This isa procedure used every day around the world. It hasbeen used for years. In doing a systematic review, wefound that there was not even 1 prospective randomizedtrial on this. It was, therefore, impossible to create aguideline, and we were left defining a group of research

questions that are yet to be addressed. But there are cur-rently no incentives for these type of trials to be done;there are certainly no reimbursement disincentives.

Dr Beed: When a new diagnostic test or a new therapybecomes available, we would expect that the coverage willbe contingent on these data points, so that we get an answerand can revisit it with real data. Does that appeal to aninsurer? Is it doable?

Dr Klein: In many ways, CMS has punted on muchof this by saying, “We will give coverage with evidencedevelopment.” But the majority of coverage decisionsare made at the local or the regional level. Therefore,from a national perspective, CMS has not necessarilytaken the bull by the horns.

At Aetna, we have tried to approach some of themore egregious misuses of technology through clinicalpolicy bulletins and sometimes on claims table edits.Nobody likes to get a precertification for an MRI. Andyet, because we have collected systematic data, we knowthat radiology benefit management works and formularymanagement works. Benefit design changes do drivebehavior on the member side.

We have already been doing this, but not enough. Ifwe (ie, payers) are always being looked at as those whoare not doing something or are withholding something,then it is hard to get our message out that we are reallytrying to address overuse. As with the Oncotype DX, forexample, there is overuse, underuse, and misuse.

There are 2 ways we can reduce cost. First, we canmake the individual practices more efficient as entitiesthat have a product. Second, we can better connect thesystem with data. The discussion about overuse of genet-



At Aetna, we have triedto approach some ofthe more egregiousmisuses of technologythrough clinical policybulletins and sometimeson claims table edits.Nobody likes to get aprecertification for an MRI. And yet, becausewe have collected systematic data, we knowthat radiology benefit management worksand formulary management works.

Ira M. Klein

ic tests speaks to a fragmented system in which nobodytalks to one another. If we all talked to one another, wewould have much less misuse and overuse of testing,because the communication will solve these problems.Those are 2 areas where we may have a glimmer of hopein reducing the cost of cancer care.

Dr Beed: Do we have mechanisms to encourage collec-tion of data and connection of practices?

Dr Vogenberg: Yes, companies have gotten involvedvery rapidly, particularly the larger Fortune 500 compa-nies. They are looking at the sharing of information that

Dr Klein talked about, and are trying to promote betteruse of information technology, as well as linking it tobenefit design. From the employer’s perspective, all theycan do is look at changing some of the coverage param-eters through their benefit design. They are not going toget involved, and they are not going to “touch” patients.But they are trying to drive many types of behavior.

There are gaps in their success; up until a few yearsago, most employers did not pay attention to any of this,because drugs were cheap. Now that drugs are expensiveand are getting more expensive, employers are now look-ing at the cost of healthcare.

What they still do not see is the spending on diagnos-tics and devices, which is going to force even more inter-

est around the integration of information and a bettercoordination of care delivery. We are seeing that withsome of the larger employers.

Dr Beed:What will the reimbursement mechanism be foremployers who invest money and provide better care?

Dr Vogenberg: We are back to how employers per-ceive performance of their vendors—the health plansand other providers of services. It is rare to see a veryclearly differentiated performance, which is why I thinkwe keep going back to this cost issue. Some employersare trying to drive the discussion, as well as partner andcollaborate with their plans and with their other vendorsto encourage that kind of innovation. Employers arelooking to drive innovation with their partners.

What has changed is the cost. Whether it is thepatient or the employer as a payer, the dollars at staketoday are so significant that it makes it worth their while.

Dr Beed: How does cancer prevention fit into our value-based care discussion?

Dr Vogenberg: Employers have invested quite heav-ily in wellness and in preventive services. They are now“getting it,” and they are seeing the return on theirinvestment in employee satisfaction and in the differ-ence in employee performance and productivity as aresult of catching disease earlier.

Dr Beed: Are we going to prevent cancer? Is that some-thing we should be investing our money in?

Dr Beveridge: I do not think that medical oncolo-gists see patients early enough to prevent cancer. Thenumbers of my patients who start a “brown rice andbroccoli diet” after they have had colon cancer are quitea few, but they started it approximately 25 years too late.Breast cancer genetics programs are going to be increas-ingly widespread. I think we should continue to invest insome expensive tests in the relatives of our patients withbreast cancer as a preventive measure.

Dr Malin: I would not say that prevention focusedspecifically on cancer is how we are going to bend the costcurve; rather, the issue of obesity, and it is affecting notonly cancer prevalence rates but also all other diseases.

Dr Newcomer: I could come up with a list of 10things that we could get rid of without hurting thepatient. For example, 20% of our patients with stage Ibreast cancer get PET scans. Why? There is no reason todo that, as Dr Benson mentioned.



Employers haveinvested quite heavilyin wellness and inpreventive services.They are now “gettingit,” and they are seeingthe return on theirinvestment in

employee satisfaction and in the difference inemployee performance and productivity.

F. Randy Vogenberg

I could come up with a list of 10 things thatwe could get rid of without hurting thepatient. For example, 20% of our patientswith stage I breast cancer get PET scans.Why? There is no reason to do that, as Dr Benson mentioned.

I would look for that “list of 10,” and then try andmake sure that that is consistently applied throughoutmy entire practice, that every one of my partners signsoff on this list, and that we monitor it carefully.

We will pick our 10 habits, and get rid of them. Assoon as we are consistent on those 10 things, we willmove to the next 10 things. We have to start findingthings today that we are going to stop doing, so that wecould leave some funds for therapies that truly work. Thelast thing any of us wants to say to a patient with Hodgkinlymphoma is, “There’s not enough money in the system totreat you anymore.” That would be a travesty.

There is plenty of waste in the system that we couldand should start eliminating, and that budget could bevery viable.

Dr Owens: No matter where we went in our value dis-cussion, the elephant in the room remains cost. Every roadleads back to cost. So the reality is that value and costs areinextricably linked together. We cannot take them apart.But one of the things that we can do vis-à-vis action is takewaste out of the system. Another thing we can do is changethe way care is delivered. The only true mistake is to keepdoing the same thing we always did, and hope to get a dif-ferent outcome.

Dr Beveridge: It is worth noting that DartmouthCollege has a new institute, the Center for Health CareDelivery Science. Its goal is to change the way we thinkabout the importance of the actual execution of care. Thepresident of Dartmouth College has been quoted as say-ing that the real rocket science in medicine over the next10 years is in the delivery of, and in the execution of,care. This is true. It is one way of wringing out the waste.

Dr Owens: The other piece of this is certainly changingthe payment methodology. In oncology in particular, a lot isdriven by drug cost and the way we reimburse for drugs. Tochange the system, we have to change the way we pay for it.That is another action item. We cannot be afraid to experi-ment with new payment methodologies and truly change them.

John Fox, MD, MHA: One of the things that DrBeveridge brought up was the need to have processes foradvance care planning. The National ComprehensiveCancer Network (NCCN) guidelines and the ASCOguidelines document the importance of advance careplanning and trying to understand, through conversa-tions with patients, what their goals, preferences, andpriorities are for care at the end of life. Yet we don’t doadvance care planning, not because we do not think ithas value, but because it is uncomfortable, and we do notknow how to integrate it into practice. The hard work

this requires is not rocket science, just social science.Oncology practices need to achieve consensus amongthe oncologists, develop the competence to have thesediscussions, and implement them through a process intothe practice.

Waste, and often harm, occur when we provide treat-ments to patients that they would not have wanted hadthey known all their options. There is compelling evi-dence that having advance care planning discussionimproves the patient experience in the healthcare sys-tem, improves health outcomes, and reduces cost ofcare—not because of denied care, but because we haveprovided the care that patient truly wanted.

Dr Silver: My practice is an outlier, in that many ofthe patients I see have very low-prevalence diseases.Therefore there are no guidelines, and there are no ran-domized trials for these diseases. In addition, because Iam in Michigan, many of my patients work for ERISAcorporations, and their insurance company is an admin-istrator. Because the insurance says no, and becausethere is no evidence for the treatment, when I see apatient I call the human resources (HR) department ofthat patient’s company to check on insurance. We endup having a good conversation about their employee,about what the employee needs, and about this rare dis-ease. The HR department, the patient, and I feel goodabout the next step, but I think that is unusual.

Dr Newcomer: At UnitedHealthcare, we are pilot-ing a 6 medical group experiment that starts with anepisode payment. We have created an episode paymentthat covers all of the patient care involved. As the physi-cian group gets more effective in improving an outcomeor in reducing the total cost of care, their amount of theepisode payment will increase. And we are trying toreduce cost by having one third of the savings go to the



Waste, and oftenharm, occur when weprovide treatments topatients that theywould not have wantedhad they known alltheir options. There iscompelling evidence that having advance care planning discussionimproves health outcomes.

John Fox

group, roughly one third goes to UnitedHealthcare, andone third goes back to the employer in the form of alower premium.

By now we know that we can get enough data to startfiguring this out. The 6 groups just met recently. Welooked at 64 measures of cost, quality, and operationalefficiencies and came back with some projects that wethink will begin to reduce care in a number of areas. Thereason I mention this is that it is an example of a payersitting with 6 medical groups, and I never saw a fingerpointed at someone the entire day. The questions were,“I wonder how we can fix this. We saw this problem inthe data. Now, how can we solve it? What do you doover here? How did you get such good results? What areyou doing here that maybe makes you so variant, andhow can we bring it down?”

The point is that we are all going to have to roll upour sleeves and probably work together. I do not thinkany of us can do this alone. We need to start more of thelittle projects that we have heard all day about—literallya dozen different attempts at trying to do this, but weneed 100. Some of them will fail. A lot of them will suc-ceed. But we are going to have to start faster and beginto collaborate and look at each other as partners. Weneed to figure out how we can get it done.

Dr Beed: How do we integrate survivorship services intothe definition of value?

Dr Benson: This is a fundamental element of person-alized medicine. It is not just the markers. The NCCN,for example, has created a partnership in terms ofemployers. What are the fundamental aspects of a cancer

program that truly provide comprehensive care? Wehave talked about the absurd way drugs have been reim-bursed for oncologists, but that has created the margin sothat programs could integrate many of these other serv-ices that are otherwise not paid for. One of the enormouschallenges is how do we fairly reimburse these essentialservices that are hallmarks for appropriate care?

Another challenge is access. Someone who is in arural community, for example, may not even have anoncologist. How can we make these services available tomuch larger populations? It is one thing to be a patientat my cancer center, where we have all of these services

on the same floor, so the day patients are being seen,they can get insurance counseling, nutrition counseling,or psychosocial support, for example, if they need them.We can quickly get all of that integrated, but that is nottrue in many situations.

A free-standing practice may not be able to provideall of those services right in its own facility; this gets usinto the referral mechanisms. It is also an issue when wetalk about accountable care organizations and bundledpayments for care. Not everyone needs all of the serviceswe may have available, such as nutrition services or psy-chological support. But how do we make sure, whenwe are talking about episodic care reimbursement, thatwe are integrating all these other essential services thatwe now have to pay for, often in a way that comes fromphilanthropy or from other sources, but not because weare billing for these services?

Dr Beed: Is this just another sign of the toxicity of ourà-la-carte system of billing?

Dr Malin: This gets at the issue we were getting atearlier of early detection versus surveillance. When wetalk about survivorship care, we need to think about whoare the people at risk in the transition. It should not beone-size-fits-all survivorship care anymore than it shouldbe for active treatment. We need to think about when tointegrate people back into primary care, who are thepeople who truly need the extra support, and what arethe best models to deliver that kind of care.

Dr Sprandio: One of the things that would be veryhelpful is if we all agreed on a core set of services that areinherent to providing good patient-centered care thateveryone would reimburse. That is not restricted to can-cer only. Any patient who has a chronic disease wouldbenefit from that. There is no patient mechanism forthat today, because there are no margins on drugs.

That is one challenge, and I agree that when we lookat whole person care, there are a set of services that wecould all agree are important to that patient’s care butthat we do not pay for today.

Dr Beed: Can anybody argue that there are not signifi-cant dollars to be saved by removing futile care?

Dr Beveridge: We have had 9 pilot studies in the USOncology Network looking at end of life. We have pilot-ed putting palliative care physicians in practices. Wehave trained nurses in palliative care. We have trainednurse practitioners. We have a large number of palliativecare physicians in our 1400-physician network at thispoint. But the common theme is—when providers can



Another challenge is access. Someone whois in a rural community, for example, maynot even have an oncologist. How can wemake these services available to muchlarger populations?

speak to the patient with metastatic disease early, whichour data clearly support, there is a higher use of palliativecare; there is a greater use of appropriate hospice treat-ment; the days in hospice increase significantly; and thenumber of days using a drug therapy decrease.

The number of physicians trained in palliative care inthe country is so small that they cannot even begin totake up the slack. The average reimbursement for a pal-liative care physician across the country is less than$210,000, and on the East Coast, in Washington, DC, inparticular, the average compensation for a palliative carephysician is less than $145,000.

The other thing we have not talked about is the wastethat exists when we continue chemotherapy in the faceof progressive disease. I have had many oncologists say,“The patient wants to continue treatment, even thoughtheir disease has progressed.” Is that a waste, because weare not willing to have a conversation with the patient?

Therefore, not only do we need guidelines on diseasesurveillance and disease progression, but we also needclear guidelines on when to stop therapy, what to dowhen patients progress, and whether we should addfourth- or fifth-line therapy.

Dr Deligdish:We do not need guidelines about treat-ing or not treating a patient when a patient’s disease isprogressing. This is intuitively obvious, and it is a verysmall minority of oncologists, I hope, who are treatingpatients with the same treatment when a patient’s dis-ease is progressing. If we cannot accept that, then theproblem is that we do not have access to data that candemonstrate that either way.

We need to be very clear on this; we have talked a lotabout advanced illness programs and a little bit aboutpalliative care programs. It is very important to differen-tiate between these 2 entirely different approaches.

Advanced illness programs have been around formore than a decade. We have all heard about the num-ber of successful pilots that have been conducted.However, there are many examples in which payers have

adopted these programs, but they have failed to educatepatients or providers as to their availability. In these sit-uations, the programs are not utilized.

Palliative care is quite different. Palliative care canextend survival in patients with cancer, in addition toenhancing QOL.

Call to ActionIn closing, the amount ofinformation that we cov-ered is very impressive.We did our best to definevalue from the differentstakeholders’ points ofview, and we decided it isinextricably linked tocost and action.

Based on this discussion, I have formed the following 7 actionable steps neededto develop a highly valuable cancer care system:1. Get rid of waste2. Change the systems of care, and do not be afraid to

experiment with multiple new systems of care,because no one answer is going to be the right answer

3. Change the payment systems; ultimately, the paymentsystems have to be changed to reward value, howeverwe define it

4. Use new technology judiciously; we heard someexamples of where technology was not used wisely—newer is not always better, until it is proved better, butit is generally more expensive

5. Introduce data collection and data integration im -provements across the system, whether real-world orclinical trial data: ultimately we cannot manage a sys-tem that we cannot measure; that is almost axiomatic

6. Improve communication across all stakeholders7. Finally, do not be afraid to try new things and be will-

ing to try multiple things. ■



Gary M. Owens

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VELCADEHCP.COM

If you defi ne value as an overall survival advantage:VELCADE® (bortezomib) DELIVERED A >13-MONTH OVERALL SURVIVAL ADVANTAGE

At 5-year median follow-up, VELCADE (bortezomib)+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-085]; p<0.05)†

At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you defi ne value as defi ned length of therapy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

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VELCADE Indication and Important Safety InformationINDICATIONVELCADE is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONSVELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS Peripheral neuropathy, including severe cases, may occur — manage with dose modifi cation or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefi t assessment

Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated

Closely monitor patients with risk factors for, or existing heart disease

Acute diffuse infi ltrative pulmonary disease has been reported

Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fl uid replacement

Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment

Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus

Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONSMost commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported

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*Melphalan+prednisone.† VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the effi cacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specifi ed interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in signifi cantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analyses were performed.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.

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Brief Summary

INDICATIONS:VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE.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 with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone 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 in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-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%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, 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% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (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 daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving 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 patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. 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, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks 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) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety 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 (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy 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%), cough and 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%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (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 in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/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%).In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.USE IN SPECIFIC POPULATIONS:Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.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 and younger 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 renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc.All rights reserved. Printed in USA V-12-0095 6/12

2:18 PM

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Diabetes mellitus is one of the fastest growing epi-demics in the United States and worldwide.According to the International Diabetes

Federation atlas, there were approximately 366 millionpeople worldwide with diabetes in 2011, and this num-ber is expected to increase to 552 million by 2030.1Currently, the Centers for Disease Control andPrevention (CDC) estimates that more than 25.8 mil-lion Americans (8.3% of the population) have diabetes.2The CDC also estimates that approximately 7 million ofthese individuals are undiagnosed and are therefore

untreated.2 Type 2 diabetes (90%-95% of diagnosed dia-betes cases in the United States) has been largely attrib-uted to an increase in obesity.2,3 It is estimated thatapproximately one third of the US population is obese.3The rates of increase in obesity and diabetes have mir-rored each other over the past 2 decades.3 The complica-tions of diabetes, which include heart disease, kidneydisease, blindness, and increased risk for amputations,are as serious as they are diverse.2In general, diabetes has been shown to increase the risk

for heart disease by 2-fold4 and has been shown to carrythe same risk for myocardial infarction (MI) as for non -diabetic individuals who have previously had an MI.5Emerging data are now correlating diabetes with anincreased risk of certain types of cancer.6 With canceralready making a large impact on mortality in our popula-tion, and with type 2 diabetes on the rise, research specificto these 2 disease states is becoming even more important.

The Link between Cancer and DiabetesSeveral studies have revealed a relatively strong cor-

relation between some types of cancer and diabetes. Astudy conducted by Davila and colleagues looking at therisk of hepatocellular carcinoma in diabetic patients ver-

Review ARticle

Diabetes Medications and Cancer Risk:Review of the LiteratureQuang t. Nguyen, DO, FAce; lindsay Sanders, DO, MPH; Anu P. Michael, MD; Scott R. Anderson, MS iv;loida D. Nguyen, PharmD, BcPS; Zackary A. Johnson, MS ii

Background: Cancer and diabetes are major public health problems for the United States

and the world. Diabetes remains the leading cause of blindness, kidney failure, and nontrau-

matic lower limb amputation, whereas cancer continues to be a major cause of death,

accounting for approximately 1 of 4 deaths in the United States. Recently, a potential link

between diabetes and cancer has been suggested in the medical literature.

Objective: To review the current literature on any potential link between diabetes medications

and the risk for cancer.

Discussion: Increasing evidence suggests that diabetic patients are at increased risk of

developing cancer. The exact mechanism for the increased cancer risk in patients with dia-

betes is unknown. Because of a potential correlation between diabetes and cancer, studies

are emerging that evaluate the cancer risk of medications used to treat diabetes. This article

reviews the current data in the literature regarding the association between the various drug

classes indicated for the treatment of diabetes and cancer development or prevention.

Conclusion: Despite many studies showing a correlation between some medications for dia-

betes and the development of cancer, there is no clear evidence of a direct causation between

these drugs and cancer. Therefore, providers and patients should continue to use medications

to control diabetes as before, because the correlation between uncontrolled diabetes and

cancer is stronger than the correlation between medications for diabetes and cancer.

Am Health Drug Benefits.2012;5(4):221-229www.AHDBonline.com

Disclosures are at end of text

Stakeholder Perspective,page 229

Dr QT Nguyen is an Endocrinologist, Carson TahoePhysicians Clinic, Carson City, and Adjunct AssociateProfessor, Endocrinology and Internal Medicine, TouroUniversity Nevada, College of Osteopathic Medicine; Dr Sanders is a Senior Medical Resident, Internal MedicineProgram, University of Nevada, Reno; Dr Michael is aSenior Medical Resident, Internal Medicine Program,University of Nevada, Reno; Mr Anderson is a SeniorMedical Student, University of Nevada School of Medicine,Reno; Dr LD Nguyen is Clinical Pharmacy Specialist, VASierra Nevada Health Care System, Reno; and Mr Johnsonis a Sophomore Medical Student, University of NevadaSchool of Medicine, Reno.

Quang T. Nguyen

sus nondiabetic patients in the United States showed anincreased relative risk of 3.08 in those with diabetes.7 Astudy by Wang and colleagues showed an increased risk(odds ratio [OR], 1.5) of developing pancreatic cancer inpatients with type 2 diabetes among randomly selected

patients in the San Francisco Bay Area.8 There is also anincreased risk of developing several other types of can-cers, including kidney, endometrial, colorectal, non-Hodgkin lymphoma (NHL), bladder, and breast.9 Bycontrast, the risk for prostate cancer appears to bedecreased among diabetic patients.6

The presence of type 2 diabetes has also been shownto increase mortality in patients who already have can-cer.10 Data collected by more than 350 primary carephysicians on patients in the United Kingdom haveshown that patients with a diagnosis of breast cancerwho developed type 2 diabetes had a 1.32 increased mor-tality risk compared with patients with breast cancerwithout diabetes.10The Cancer Prevention Study-II evaluated more than

2200 patient records of those diagnosed with nonmeta -static colon or rectal cancer and showed a 1.53 increasedrisk of mortality among patients with type 2 diabetes.11Even with the decreased risk of prostate cancer in diabet-ic patients, they experience higher mortality rates.12Bladder cancer is the fourth most common cancer

and the ninth leading cause of cancer death among USmen.13,14 Bladder cancer is estimated to occur in approxi-mately 21 per 100,000 persons annually in the UnitedStates and is thought to be higher in diabetic patients.15Mechanisms involved in the association between dia-

betes mellitus and cancer are not completely understood,but they are likely associated with hyperinsulinemia,which is a result of insulin resistance characteristic oftype 2 diabetes. Insulin’s role in cell proliferation,through the action of insulin-like growth factor 1, as wellas inhibition of apoptosis, could play a significant role inthe development of cancerous tissues.3 Although thesesystemic responses are reasonably well understood, thecurrent literature does not adequately explain organ-spe-cific cancer risk. Despite the lack of a complete understanding of the

mechanisms, the correlation between diabetes and can-cer is strong, as suggested by the literature. Therefore, itis logical to inquire whether the treatment of diabetescan affect the risk of these patients developing cancer.Recently, studies have been emerging that evaluate therisk of developing cancer in diabetic patients who arebeing treated for their disease versus those who are notreceiving antidiabetes medications. There are currently 14 classes of drugs used in the treat-

ment of diabetes, as discussed below. This article reviewsthe mechanism of action and the effect on cancer risk ofeach class of medication for the treatment of diabetes.

Antidiabetic Drugs and Cancer RiskBiguanides (Metformin)Metformin’s mechanism of action in the treatment of

diabetes has been elucidated for quite some time; how -ever, all of its actions are not fully understood. Its maineffect is to improve hepatic insulin resistance via decreas-ing the hepatic glucose output. Metformin also improvesperipheral glucose uptake by sensitizing insulin receptorsin the muscles.16 Several studies in the past few years have

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KEY POINTS➤ Cancer and diabetes are major public healthproblems worldwide.

➤ Data are now emerging that link diabetes with anincreased risk for certain types of cancer.

➤ Although the mechanisms linking diabetes andcancer are not completely understood, they are likelyassociated with hyperinsulinemia.

➤ Ironically, of the many drug classes used to treatdiabetes, some have been linked to increased risk of cancer.

➤ By contrast, metformin has a negative relationshipwith cancer; increasing evidence shows it offersprotection against some types of cancers (eg, breastcancer) and prolongs the life of diabetic patientswith cancer.

➤ It is important to continue to control diabetes withappropriate medications, because the correlationbetween uncontrolled diabetes and cancer is strongerthan the correlation between medications fordiabetes and cancer, but it is also necessary tostrongly consider the possibility of cancer-related risk for some of these agents.

➤ All available evidence linking antidiabetes drugswith cancer risk is based on retrospective studies;therefore, prospective studies are needed to verifythis association.

Despite the lack of a completeunderstanding of the mechanisms, thecorrelation between diabetes and cancer isstrong, as suggested by the literature.Therefore, it is logical to inquire whetherthe treatment of diabetes can affect therisk of these patients developing cancer.

identified additional benefits of metformin, such as low-ering cancer risk and improving survival of those diag-nosed with cancer among the diabetic population. Libby and colleagues designed an observational

cohort study that compared 4000 subjects with diabeteswho had taken metformin with 4000 diabetic subjectswho had not received the drug.17 Cancer was diagnosedin 7.3% of metformin users compared with 11.6% ofthose who did not take the medication.17 In a nestedcase-control study conducted by Monami and col-leagues, 112 of 1340 diabetic patients (average follow-up, 75.9 months) developed cancer.18 Those who devel-oped cancer had less exposure to metformin comparedwith a control group of diabetic patients.18Jiralerspong and colleagues compared the pathologic

complete response (pCR) rates—pCR is the absence oftumor in tissue removed during surgery, and it correlateswith improved survival rates—between diabetic patientswith early-stage breast cancer who received neoadjuvanttherapy as well as metformin with diabetic patients withsimilar cancer characteristics but who were not takingmetformin.19 Of 2529 patients identified in the study withearly-stage breast cancer treated with neoadjuvant thera-py, 68 patients also had diabetes and were taking met-formin and 87 patients had diabetes but were not takingmetformin. The pCR rates in the metformin group were3 times (24%) higher compared with the nonmetformingroup. This finding suggests a protective factor of met-formin in diabetic patients who develop breast cancer.19In another case-control study, Li and colleagues

evaluated 973 patients with pancreatic adenocarcino-ma who were receiving antidiabetic therapy.20 Theinvestigators compared 259 diabetic patients and 109diabetic controls (who had no pancreatic adenocar -cinoma). The results showed that diabetic patientsreceiving metformin had a significantly lower risk forpancreatic cancer compared with those who had nottaken metformin (OR, 0.38; 95% confidence interval[CI], 0.22-0.69; P = .001), with adjustments for poten-tial confounders. Those who received metformin had a62% reduction in the risk for pancreatic cancer.20Wright and colleagues analyzed 1001 patients with

prostate cancer versus 942 controls for diabetes andcancer risk.21 Of these, 97 of the patients with cancerand 101 of the controls had diabetes. The use of met-formin was more frequent in the control group com-pared with the group of patients with cancer (4.8% vs4.0%, respectively). The investigators calculated thatprostate cancer risk was reduced by 44% with met-formin use.21 The results showed that the use of met-formin for >5 years reduced the risk for breast cancercompared with the use of metformin or any otherantidiabetic drugs for <5 years.22

Furthermore, He and colleagues reviewed therecords of 233 patients diagnosed with prostate cancerwho were taking antidiabetic medications.23 The inves-tigators concluded that treatment with metformin wasa positive predictor of improved survival time by nearlya year compared with those patients who did notreceive metformin.23Several of the studies cited above have suggested that

the anticancer properties of metformin are likely a resultof AMP-activated protein kinase (AMPK). AMPKphosphorylates proteins, which leads to inhibition of cellgrowth and possible reduction in cancer.24Based on the present review of the most recent liter-

ature, there appears to be a negative relationshipbetween metformin use and cancer. The mechanisms bywhich metformin decreases cancer risk and improves sur-vivability with cancer, possibly through decreased pro-tein synthesis or maintaining normal insulin levels, arenot clear. All of the clinical studies reviewed are retro-spective studies, which may be subject to bias and con-founding issues. Further research, especially prospectivestudies, should be conducted to better assess the relation-ship between metformin and cancer.

Second-Generation Sulfonylureas (Glyburide,Glipizide, Glimepiride)Sulfonylureas work by stimulating endogenous in -

sulin secretion through inhibition of potassium chan-nels in the pancreatic cells. They are most effective dur-ing the early stages of diabetes when insulin secretion isstill working.25Cancer risk associated with sulfonylureas has not

been extensively studied in comparison with otherantidiabetic drugs; however, the limited studies thathave been completed indicate that there may be a higherincidence of cancer among those who receive them. Thenested case-control study by Monami and colleaguesmentioned above included 1340 diabetic patients whowere followed up for an average of 75.9 months. The 112patients who developed cancer also had a greater length

Diabetes Medications and Cancer Risk


Based on the present review of the mostrecent literature, there appears to be anegative relationship between metforminuse and cancer. The mechanisms by whichmetformin decreases cancer risk and improvessurvivability with cancer, possibly throughdecreased protein synthesis or maintainingnormal insulin levels, are not clear.

of exposure to a sulfonylurea compared with the controlgroup of diabetic patients.18Similarly, in the case-control study by Li and col-

leagues, compared with the nondiabetic patients, therewas a nonsignificant increased risk for pancreatic cancerdetected among the patients with diabetes who wereusing a sulfonylurea.20 A cohort study by Bowker and col-leagues identified 10,309 new users of metformin or sul-fonylureas.26 The mean follow-up for the study wasapproximately 5 years. Its results showed that the cancer-related mortality for patients receiving sulfonylureas was4.9% compared with 3.5% for metformin.26 No controlgroup was used in this study, so it is unclear if this findingis a protective effect of metformin or a worsening effectassociated with the use of sulfonylureas.

A cohort study by Yang and colleagues involving6103 patients with type 2 diabetes identified a decreasedcancer risk among patients taking glibenclamide andgliclazide.27 Furthermore, the cancer risk reduction wasfound to be dose dependent with these 2 drugs. Of note,there was no benefit in terms of cancer risk with the useof glipizide.27 Finally, Chang and colleagues evaluatedthe use of insulin secretagogues among diabetic patientsin a retrospective study carried out in China.28 Of the108,920 subjects included in the study, 8194 cancercases were identified. Results showed significantlyincreased risk for liver and pancreatic cancers with theuse of first- and second-generation sulfonylureas, butnot with third-generation sulfonylureas. Chang and col-leagues do note that there was no dose-response mea -sured in evaluating the risk of cancer with the first- andsecond-generation drugs.28The increased risk of cancer seen with sulfonylureas

is concerning. These case-control studies support thehypothesis that increasing insulin levels has a positiveeffect on cancer development. Sulfonylureas, like otherantidiabetic drugs, have only been evaluated in a retro-spective manner, leading to incomplete assessments andinvalidated conclusions.

Meglitinides (Repaglinide, Nateglinide)Meglitinide is an insulin secretagogue that stimulates

insulin release by inhibiting potassium channels in thepancreas on a different site from sulfonylureas. These

medications work much faster than other secretagoguesand can be taken more effectively before meals. They canlower postprandial blood glucose levels and thus avoid therisk of hypoglycemia between mealtimes.29 Only 1 studywas found in a literature search that evaluated the effectof meglitinide on cancer risk. The retrospective study byChang and colleagues discussed earlier showed that anyuse of a meglitinide had a significantly increased risk fordeveloping cancer, but mainly liver cancer.28 As discussedwith sulfonylureas, elevated insulin levels can possiblyincrease cancer risk. A correlation between meglitinideuse and cancer risk cannot be determined at this time,because there was only 1 study evaluating this effect, andit was based on a retrospective analysis.

Glucosidase Inhibitors (Acarbose, Miglitol)Glucosidase inhibitors act by delaying the absorption

of complex carbohydrates from the digestive tract, there-fore reducing the body’s glucose load.30 It is used in con-junction with other antidiabetic medications to attainbetter blood glucose control.30 There are no current stud-ies evaluating glucosidase inhibitors and cancer.

Thiazolidinediones (Rosiglitazone, Pioglitazone)Thiazolidinediones (TZDs) improve metabolic con-

trol in patients with type 2 diabetes through theimprovement of peripheral tissue insulin sensitivity.TZDs activate a group of receptor molecules inside thecell nucleus known as peroxisome proliferator-activatedreceptors (PPARs), specifically PPARγ, to increaseperipheral insulin sensitivity and potentially reducehepatic gluconeogenesis. Although not all the actions ofTZDs are known, these agents still have the potential tobenefit the full “insulin resistance syndrome” that is asso-ciated with diabetes.31In June 2011, the US Food and Drug Administration

(FDA) issued a safety announcement that the use ofpioglitazone for more than 1 year may be associated withan increased risk of bladder cancer.32 This announce-ment was based on studies conducted by the drug manu-facturer, which included a 10-year, observational cohortstudy, as well as a nested case-control study in patientswith diabetes who are members of the KaiserPermanente Northern California (KPNC) health plan.This study included 193,099 patients in the KPNCDiabetes Registry who were aged ≥40 years. A planned5-year interim analysis was performed with data collect-ed from January 1, 1997, through April 30, 2008. Themedian duration of therapy among patients treated withpioglitazone was 2 years (range, 0.2-8.5 years).32 Theresults showed no significant increase in the risk for blad-der cancer in patients ever exposed to pioglitazone com-pared with those who were never exposed to pioglita-

CLINICAL


The increased risk of cancer seen withsulfonylureas is concerning. These case-control studies support the hypothesis thatincreasing insulin levels has a positive effecton cancer development.

zone (hazard ratio [HR], 1.2; 95% CI, 0.9-1.5). However,the risk for bladder cancer was greater with increasingdose and duration of pioglitazone use compared withnever being exposed to pioglitazone. In this study, theHRs were 0.8 for <1 year of pioglitazone treatment and1.4 for 1 to 2 years and for >2 years of therapy.32In a post hoc analysis, the HR was even higher for

those patients with >36 months of exposure and for thosewith >48 months of exposure, with a trend for increasingrisk with longer duration of exposure.33 The use of piogli-tazone therapy for 12 months was associated with a 40%increase in risk (HR, 1.4; 95% CI, 0.9-2.1), whereas theHR after >24 months of treatment with pioglitazone was1.4 (95% CI, 1.03-2.0). Based on these data, the FDAcalculated that duration of therapy >12 months was asso-ciated with 27.5 additional cases of bladder cancer per100,000 person-years of follow-up compared withpatients having never received pioglitazone.32In a retrospective cohort study using data from the

French National Health Insurance Plan, approximately1.5 million patients with diabetes who were aged 40 to 79years were followed for up to 42 months (2006-2009).32,34The study showed a statistically significant increase inthe risk of bladder cancer in patients exposed to pioglita-zone compared with patients exposed to other antidiabet-ic agents (HR, 1.22; 95% CI, 1.05-1.43). There was anincreased bladder cancer risk observed with a largercumulative dose of ≥28,000 mg (HR, 1.75; 95% CI, 1.22-2.50) and for longer duration of exposure between 12 to23 months (HR, 1.34; 95% CI, 1.02-1.75).32,34A cohort study of pioglitazone and cancer incidence

in patients with diabetes explored whether treatmentwith pioglitazone was associated with a risk of incidentcancer at the 10 most common sites (ie, prostate, femalebreast, lung/bronchus, endometrial, colon, NHL, pan-creas, kidney/renal pelvis, rectal, and melanoma).35 Thisstudy evaluated 252,467 patients aged ≥40 years fromthe KPNC Diabetes Registry. The HR for each cancerassociated with the ever-use of pioglitazone ranged from0.7 to 1.3, with all 95% CIs including 1.0. Increased risksof melanoma (HR, 1.3; 95% CI, 0.9-2.0) and NHL (HR,1.3; 95% CI, 1.0-1.8) were suggested, and a decreasedrisk of kidney/renal pelvis cancers (HR, 0.7; 95% CI,0.4-1.1) was associated with the ever-use of pioglitazone.These associations were not affected by increasing dose,duration, or time since first use. The power of the studywas somewhat limited, given the relatively small numberof cases for NHL, kidney/renal pelvis cancers, andmelanoma. There was no clear evidence of an associa-tion between the use of pioglitazone and the risk of inci-dent cancer at the sites examined. This study of relative-ly short-term use could miss effects that requirelonger-term exposure or follow-up to become evident.35

A recent retrospective cohort study using a nestedcase-control analysis was done to determine if the use ofpioglitazone is associated with an increased risk of inci-dent bladder cancer in patients with type 2 diabetes.36Azoulay and colleagues analyzed data from a large UKgeneral practice database from January 1988 to December2009. The cohort included 115,727 new users of oralhypoglycemic agents, with a mean patient age of 64 yearsand a mean follow-up duration of 4.6 years. A total of0.5% of patients were taking pioglitazone or rosiglitazoneas monotherapy, with a mean duration of use of approxi-mately 2.2 years. A total of 470 patients were diagnosedwith bladder cancer during follow-up (rate, 89.4 per100,000 person-years). The 376 cases of bladder cancerthat were diagnosed beyond 1 year of follow-up werematched to 6699 controls. Overall, the ever-use of piogli-tazone was associated with an increased rate of bladdercancer by 83% (rate ratio [RR], 1.83; 95% CI, 1.10-3.05).The rate of bladder cancer increased with longer use ofpioglitazone, with those taking the drug for >2 years hav-ing a 2-fold increase in risk (RR, 1.99; 95% CI, 1.14-3.45), and in those with a cumulative dosage >28,000 mg(RR, 2.54; 95% CI, 1.05-6.14). Rosiglitazone did nothave an elevated risk, even with duration of use andcumulative dosage (RR, 1.14; 95% CI, 0.78-1.68). Theauthors hypothesized that the possible mechanism for thebladder cancer risk is chronic irritation of the bladderfrom crystal formation, which needs further research.36,37Based on these studies, pioglitazone use for longer

duration and exposure to the highest cumulative dose areassociated with an increased risk of bladder cancer,whereas no increased risk was observed with rosiglita-zone. The potential for increasing melanoma or NHL riskand decreasing kidney/renal pelvis cancer risk associatedwith an ever-use of pioglitazone was observed in onestudy38; however, the power of the study was limited.38

Bromocriptine MesylateBromocriptine mesylate, an ergot derivative, is a sym-

patholytic dopamine D2 receptor agonist that can exertinhibitory effects on serotonin turnover in the centralnervous system. Bromocriptine mesylate was FDAapproved for type 2 diabetes in adults in 2009. It hasbeen proposed that bromocriptine can reverse many ofthe metabolic alterations associated with insulin resis -tance and obesity by resetting central (hypothalamic)circadian organization of monoamine neuronal activi-ties. Bromocriptine has been shown to reduce hemoglo-bin A1c levels (by 0.4-0.8), fasting and postprandial glu-cose, and fasting and postprandial triglycerides.39Bromocriptine is used in the treatment of pituitary

prolactinomas.40 In September 2000, a preliminary studyconducted in Italy showed that low-dose bromocriptine



is sufficient to acutely normalize prolactin in patientswith metastatic breast cancer and in those with prostatecarcinoma.40It is unknown whether bromocriptine affects cancer risk

in diabetic patients. On the other hand, it is used in thetreatment of prolactinomas and paraneoplastic processesof certain cancers where prolactin levels are elevated.

Colesevelam (Welchol)The mechanism by which colesevelam exerts its anti-

hyperglycemic effect is unknown; however, speculatedactions include enhanced meal-induced incretin secre-tion and/or altered farnesoid X receptor signaling.41Because of a lack of data regarding colesevelam and can-cer, its effect on cancer risk is unknown.

DPP-4 Inhibitors (Sitagliptin, Saxagliptin,Linagliptin)/GLP-1 Agonists (Exenatide, Liraglutide)Glucagon-like peptide (GLP)-1 is an incretin hor-

mone that is secreted by L-type endocrine cells in thedistal ileum when food is ingested.42 It acts by binding tocell membrane GLP receptors, which promotes stimula-tion of glucose-dependent insulin secretion, as well aspromotes beta-cell proliferation and survival.43,44 GLP-1agonists bind to GLP receptors to restore beta-cell sensi-tivity to glucose and to increase beta-cell mass.43 NativeGLP-1 is normally degraded by the enzyme dipeptidylpeptidase (DPP)-4. Drugs that inhibit DPP-4 have beendeveloped and are currently being used as treatment fortype 2 diabetes. Together, these 2 drug classes are knownas the incretin family.Type 2 diabetes and obesity are known risk factors for

chronic pancreatitis and pancreatic cancer. There were88 postmarketing cases of acute pancreatitis, including 2cases of necrotizing hemorrhagic pancreatitis, in patientsreceiving sitagliptin that were reported to the FDAbetween October 2006 and February 2009.45In 2007, the FDA released a safety alert, and subse-

quently the manufacturer updated exenatide’s prescribinginformation to include the precaution of acute pancrea -titis, based on postmarketing reports of pancreatitis inpatients taking exenatide.46 Because pancreatitis is aknown risk factor for pancreatic cancer, there is concernthat long-term use of a GLP-1 agonist increases pancreaticcancer risk. A study published in 2006 found that GLP-1receptor stimulation did not impact the growth or survivalof pancreatic cancer cells.44 However, in a study publishedby Elashoff and colleagues in 2011, the FDA database wasused to look for associations between GLP-1 agonist useand pancreatitis, pancreatic cancer, and thyroid cancer.They found that patients taking exenatide or sitagliptinhad a more than 6-fold higher event rate in pancreatitiscompared with patients receiving other treatment options

and a 2.9-fold higher event rate of pancreatic cancer inthose patients whose diabetes was treated with exenatidecompared with other therapies.42In addition to the FDA noting the suspected associa-

tion, the Drug Commission of the German MedicalAssociation has received 11 reports of pancreatic cancerassociated with the use of exenatide.47,48 The timebetween exposure and diagnosis was 2 to 33 months,which is contrary to the thought that the time betweentumor induction and diagnosis is usually >10 years.47,48 With regard to thyroid cancer, there is a known asso-

ciation with liraglutide use and medullary thyroid cancerin rodents.49 Elashoff and colleagues reviewed the FDAdata for association between exenatide use and thyroidcancer and found a greater than 4-fold increase in eventsin the exenatide therapy group.42There is also an association between colorectal cancer

and type 2 diabetes, especially in men.50 However, in anarticle published in 2011, Koehler and colleagues foundthat activation of the GLP-1 receptor actually decreasesthe growth of and increases apoptosis of colon cancercells.51 In addition, although there is a known associationbetween obesity, type 2 diabetes, and breast cancer, thereis evidence that stimulation of GLP-1 receptors leads toincreased apoptosis and reduced viability of breast can-cer cells without affecting noncancer cells.52GLP-1 agonists have the potential to reduce breast

cancer and colon cancer risk.51,52 Diabetes alone is a riskfactor for breast and colon cancers; therefore, this partic-ular treatment would be especially useful in diabeticindividuals with or at risk for these cancers. It wouldlikely be advisable to use caution in those patients withknown risk factors for pancreatic cancer, beyond dia-betes and obesity alone. The association with thyroidcancer is one that should be investigated further.At present, there is no direct evidence to support an

increase in pancreatic cancer with long-term DPP-4inhibitor use. Long-term prospective studies are needed.Meanwhile, caution should be used when prescribingDPP-4 inhibitors in patients who are obese and havetype 2 diabetes, as well as other known risk factors forpancreatic cancer.42

Insulin/Insulin AnaloguesSimilar to endogenous insulin, exogenous insulin

increases the uptake of glucose into the cells, stimulatesglycogen synthesis, and inhibits glucagon. It is altered invarious ways to change the onset and duration of action.For example, insulin aspart, a fast-acting insulin ana-logue, begins to work within minutes of administrationbut lasts only a few hours, whereas insulin glargine isstable enough for once-daily dosing.A German cohort study published in 2009 investigat-

CLINICAL


ed the association between cancer risk and insulin use.53Using malignancy diagnosis as a primary outcome, theauthors analyzed data from one of the national statutoryhealth insurance funds and included individuals withouta known malignancy who received first-time treatmentonly with human insulin, aspart, lispro, or glargine. Ofthe 127,031 patients included in the study, it was notedthat there was an association between incidence ofmalignancy and insulin dose for all insulin types; how -ever, in comparing aspart, lispro, and glargine to humaninsulin, only glargine was found to have a higher dose-dependent risk. Although the authors found thatglargine treatment involved a higher risk of the develop-ment of cancer, a specific type of cancer was not identi-fied in the study.In another analysis published the same year, an associ-

ation between insulin glargine use and cancer incidencewas not identified after evaluating 31 randomized clinicaltrials in a drug manufacturer’s database.54 The analyzedtrials included fewer total participants (N = 10,880), andthe length of the trials was, in general, approximately 6months, except for 1 study in which participants werefollowed for 5 years. Furthermore, only 20 of these trialscompared insulin glargine with neutral protamineHagedorn (NPH) insulin, whereas the others includedsuch treatments as lispro, pioglitazone, or dietary meas-ures. Because of the concerns surrounding glargine andcancer risk, Dejgaard and colleagues conducted a meta-analysis to study the effect of insulin detemir use ondiabetic patients; they found that among a group of8693 patients with diabetes, the incidence of malig-nancy in those using insulin detemir was lower than orno different from the incidence in patients treated withNPH insulin or with insulin glargine.55A French study published in 2012, using the national

healthcare insurance system database and data from2003 to 2010, found that there was no increase in cancerrisk with glargine use compared with human insulinuse.56 By contrast, using “possession rate”—which isdefined as “the ratio of the number of treatments dis-pensed during the insulin exposure period divided by thenumber of 28-day periods during the follow-up period”—the authors did find an association between cancer riskand increasing mean possession rate.56In another study published this year with similar con-

clusions, Ruiter and colleagues analyzed pharmacyrecords linked to hospital discharge records of 2.5 millionpatients in the Netherlands to determine the number offirst hospital admissions with a primary diagnosis of can-cer (main outcome) and to identify specific cancers.57 Ofthe 19,337 insulin users included in this study, 878patients developed cancer. Use of glargine was actuallyassociated with a lower risk of malignancy (HR, 0.75).

With regard to specific malignancies, glargine use wasassociated with a lower risk of colon cancer, but no othercancers, when compared with human insulin use (similarresults were true for other insulin analogues). However,glargine was associated with an increased risk of breastand prostate cancers (HRs, 1.58 and 2.76, respectively)in comparison with the use of human insulin. Glarginedose was not found to be related to diagnosis.57In another recently published study, Luo and col-

leagues identified an association between postmenopausalwomen with diabetes who were treated with insulin andlung cancer risk.58 Using data from the Women’s HealthInitiative, it was found that women who reported a diag-nosis of diabetes had a higher risk of lung cancer comparedwith women without diabetes (HR, 1.27). Furthermore,women who reported treatment with insulin had an evengreater risk of developing lung cancer (HR, 1.71). In addi-tion, the authors noted that an association between dia-betes duration and untreated diabetes was not found.58Although the concern regarding insulin use and can-

cer risk is worth noting, recent studies have not justifiedthis concern because of the lack of correlation. Furtherresearch on insulin use and cancer is warranted, andunless a patient has a high risk for malignancy, not uti-lizing insulin when needed would not be appropriate.Long-term prospective studies are needed.

AmylinomimeticsAmylin is a peptide hormone that is secreted with

insulin from pancreatic beta-cells, so it is therefore defi-cient in diabetic patients. It regulates postprandial spikesin blood glucose by slowing gastric emptying and diges-tion, promoting satiety, and inhibiting glucagon secre-tion.59 Pramlintide, an amylinomimetic, is utilized intype 1 and type 2 diabetic patients as an adjunctive ther-apy to insulin therapy, hence allowing patients to use lessinsulin. It has no known association with cancer.

ConclusionsNo conclusive data are currently available that link

the use of diabetes drugs to cancer development. Ofthe 14 diabetes drug classes currently available, thereare data suggesting a higher risk of cancer developmentwith insulin, pioglitazone, and insulin secretagogues.Metformin seems to be protective against some cancersin diabetic patients. It is important to note that all ofthese data are from retrospective studies and can onlysuggest association rather than direct cause. Prospectivestudies are needed to shed light on this topic.In the absence of clear correlation, practitioners and

patients should continue to feel comfortable utilizingmedications to control diabetes, because the correlationbetween uncontrolled diabetes and cancer is stronger



than the correlation between diabetic medications andcancer. In patients with other risk factors for malignancy(such as a strong family history or personal history ofcancer), providers may wish to be more thoughtful intheir selection of agents to manage diabetes by utilizingthe data provided in the studies mentioned. ■

Author Disclosure StatementDr QT Nguyen, Dr Sanders, Dr Michael, Mr Anderson,

Dr LD Nguyen, and Mr Johnson have reported no conflictsof interest.

References1.Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates ofthe prevalence of diabetes for 2011 and 2030. Res Clin Pract. 2011;94:311-321.2. Centers for Disease Control and Prevention. National diabetes fact sheet 2011.www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed July 2, 2012.3. Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence andproposed mechanisms. Nat Rev Cancer. 2004;4:579-591.4. Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose con-centration, and risk of vascular disease: a collaborative meta-analysis of 102 prospec-tive studies. Lancet. 2010;375:2215-2222.5. Schramm TK, Gislason GH, Kober L. Diabetes patients requiring glucose-lower-ing therapy and nondiabetics with a prior myocardial infarction carry the same car-diovascular risk: a population study of 3.3 million people. Circulation. 2008;117:1945-1954. 6. Cannata D, Fierz Y, Vijayakumar A, Le Roith D. Type 2 diabetes and cancer: whatis the connection? Mt Sinai J Med. 2010;77:197-213.7.Davila JA, Morgan RO, Shaib Y, et al. Diabetes increases the risk of hepatocellularcarcinoma in the United States: a population based case control study. GUT. 2005;54:533-539.8.Wang F, Gupta S, Holly EA. Diabetes mellitus and pancreatic cancer in a popula-tion-based case-control study in the San Francisco Bay Area, California. CancerEpidemiol Biomarkers Prev. 2006;15:1458-1463.9.McFarland MS, Cripps R. Diabetes mellitus and increased risk of cancer: focus onmetformin and the insulin analogs. Pharmacotherapy. 2010;30:1159-1178. 10. Currie CJ, Poole CD, Jenkins-Jones S, et al. Mortality after incident cancer inpeople with and without type 2 diabetes: impact of metformin on survival. DiabetesCare. 2012;35:299-304.11. Dehal AN, Newton CC, Jacobs EJ, et al. Impact of diabetes mellitus and insulinuse on survival after colorectal cancer diagnosis: the Cancer Prevention Study-IINutrition Cohort. J Clin Oncol. 2012;30:53-59.12. Vigneri P, Frasca F, Sciacca L, et al. Diabetes and cancer. Endocr Relat Cancer.2009;16:1103-1123.13. Baylor College of Medicine. Bladder cancer. www.bcm.edu/urology/index.cfm?pmid=4973. Accessed June 17, 2012.14. Piccinni C, Motola D, Marchesini G, Poluzzi E. Assessing the association ofpioglitazone use and bladder cancer through drug adverse event reporting. DiabetesCare. 2011;34:1369-1371.15. National Cancer Institute. SEER stat fact sheets: bladder. http://seer.cancer.gov/statfacts/html/urinb.html. Accessed June 17, 2012.16. Bosi E. Metformin—the gold standard in type 2 diabetes: what does the evidencetell us? Diabetes Obes Metab. 2009;11(suppl 2):3-8.17. Libby G, Donnelly LA, Donnan PT, et al. New users of metformin are at low riskof incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care.2009;32:1620-1625.18. Monami M, Colombi C, Balzi D, et al. Metformin and cancer occurrence ininsulin-treated type 2 diabetic patients. Diabetes Care. 2011;34:129-131.19. Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic completeresponses to neoadjuvant chemotherapy in diabetic patients with breast cancer.J Clin Oncol. 2009;27:3297-3302.20. Li D, Yeung SC, Hassan MM, et al. Antidiabetic therapies affect risk of pancre-atic cancer. Gastroenterology. 2009;137:482-488.21. Wright JL, Stanford JL. Metformin use and prostate cancer in Caucasian men:results from a population-based case-control study. Cancer Causes Control. 2009;20:1617-1622.22. Bodmer M, Meier C, Krähenbühl S, et al. Long-term metformin use is associatedwith decreased risk of breast cancer. Diabetes Care. 2010;33:1304-1308.23. He XX, Tu SM, Lee MH, Yeung SC. Thiazolidinediones and metformin associ-ated with improved survival of diabetic prostate cancer patients. Ann Oncol. 2011;22:2640-2645.24. Luo Z, Zang M, Guo W. AMPK as a metabolic tumor suppressor: control ofmetabolism and cell growth. Future Oncol. 2010;6:457-470.

25. Hanefeld M. Pioglitazone and sulfonylureas: effectively treating type 2 diabetes.Int J Clin Pract Suppl. 2007;61(suppl 153):20-27.26. Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-relatedmortality for patients with type 2 diabetes who use sulfonylureas or insulin. DiabetesCare. 2006;29:254-258.27. Yang X, So WY, Ma RC, et al. Use of sulphonylurea and cancer in type 2 dia-betes—The Hong Kong Diabetes Registry. Diabetes Res Clin Pract. 2010;90:343-351.28. Chang C, Lin J, Wu L, et al. Oral insulin secretagogues, insulin, and cancer riskin type 2 diabetes mellitus. J Clin Endocrin Metab. 2012 May 4. [Epub ahead of print.]29. Landgraf R. Meglitinide analogues in the treatment of type 2 diabetes mellitus.Drugs Aging. 2000;17:411-425.30. van de Laar FA. Alpha-glucosidase inhibitors in the early treatment of type 2 dia-betes. Vasc Health Risk Manag. 2008;4:1189-1195.31. Hauner H. The mode of action of thiazolidinediones. Diabetes Metab Res Rev.2002;18(suppl 2):S10-S15.32. US Food and Drug Administration. FDA Drug Safety Communication: update toongoing safety review of Actos (pioglitazone) and increased risk of bladder cancer. June5, 2011. www.fda.gov/Drugs/Drugsafety/ucm259150.htm. Accessed June 17, 2012.33. Lewis JD, Ferrara A, Peng T, et al. Risk of bladder cancer among diabetic patientstreated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care.2011;34:916-922.34. Neumann A, Weill A, Ricordeau P, et al. Pioglitazone and risk of bladder canceramong diabetic patients in France: a population-based cohort study. Diabetologia.2012;55:1953-1962.35. Ferrara A, Lewis JD, Quesenberry CP Jr, et al. Cohort study of pioglitazone andcancer incidence in patients with diabetes. Diabetes Care. 2011;34:923-929.36.Azoulay L, Yin H, Filion KB, et al. The use of pioglitazone and the risk of bladdercancer in people with type 2 diabetes: nested case-control study. BMJ. 2012;344:e3645. 37.Walsh N. Study affirms Actos bladder cancer risk. Med Page Today. May 31, 2012.www.medpagetoday.com/Endocrinology/Diabetes/33012. Accessed June 17, 2012.38. Ferrara A, Lewis JD, Quesenberry CP Jr, et al. Cohort study of pioglitazone andcancer incidence in patients with diabetes. Diabetes Care. 2011;34:923-929.39. Mikhail N. Quick-release bromocriptine for treatment of type 2 diabetes. CurrDrug Deliv. 2011;8:511-516.40. Iyer P, Molitch M. Positive prolactin response to bromocriptine in 2 patients withcabergoline-resistant prolactinomas. Endocr Pract. 2011;17:e55-e58.41. Younk LM, Davis SN. Evaluation of colesevelam hydrochloride for the treatmentof type 2 diabetes. Expert Opin Drug Metab Toxicol. 2012;8:515-525.42. Elashoff M, Matveyenko AV, Gier B, et al. Pancreatitis, pancreatic, and thyroid can-cer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141:150-156.43. Sun G, Kashyap SR. Cancer risk in type 2 diabetes mellitus: metabolic links andtherapeutic considerations. J Nutr Metab. 2011;2011:708183.44. Koehler JA, Drucker DJ. Activation of glucagon-like peptide-1 receptor signalingdoes not modify the growth or apoptosis of human pancreatic cancer cells. Diabetes.2006;55:1369-1379.45. US Food and Drug Administration. Sitagliptin (marketed as Januvia andJanumet)—acute pancreatitis. September 29, 2009. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm183800.htm.Accessed June 17, 2012.46. US Food and Drug Administration. Byetta (exenatide) October 2007. August18, 2008. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150839.htm. Accessed June 17, 2012.47. Spranger J, Gundert-Remy U, Stammschulte T. GLP-1-based therapies: thedilemma of uncertainty. Gastroenterology. 2011;141:20-23.48. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the geneticevolution of pancreatic cancer. Nature. 2010;467:1114-1117.49. Victoza (liraglutide [rDNA origin]) injection: REMS-risk of thyroid C-celltumors, acute pancreatitis. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258826.htm. Accessed June 17, 2012.50. Limburg PJ, Vierkant RA, Fredericksen ZS, et al. Clinically confirmed type 2 dia-betes mellitus and colorectal cancer risk: a population-based, retrospective cohortstudy. Am J Gastroenterol. 2006;101:1872-1879.51. Koehler JA, Kain T, Drucker DJ. Glucagon-like peptide-1 receptor activationinhibits growth and augments apoptosis in murine CT26 colon cancer cells.Endocrinology. 2011;152:3362-3372.52. Ligumsky H, Wolf I, Israeli S, et al. The peptide-hormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells. Breast Cancer Res Treat.2012;132:449-461.53.Hemkens LG, Grouven U, Bender R, et al. Risk of malignancies in patients withdiabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia.2009;52:1732-1744.54. Home PD, Lagarenne P. Combined randomised controlled trial experience ofmalignancies in studies using insulin glargine. Diabetologia. 2009;52:2499-2506.55. Dejgaard A, Lynggaard H, Råstam J, Krogsgaard Thomsen M. No evidence ofincreased risk of malignancies in patients with diabetes treated with insulin detemir:a meta-analysis. Diabetologia. 2009;52:2507-2512.56. Blin P, Lassalle R, Dureau-Pournin C, et al. Insulin glargine and risk of cancer: acohort study in the French National Healthcare Insurance Database. Diabetologia.2012;55:644-653.

CLINICAL




Cancer Risk Associated with Antidiabetes Medications: Implicationsfor Patients, Providers, and Payers

PATIENTS/PROVIDERS: A patient with dia-betes may find it difficult to watch television withoutnoticing advertisements from law offices addressingconcerns related to adverse events of antidiabetic med-ications. One of the most current advertisementsnationally relates to the US Food and Drug Adminis -tra tion’s warning that was added in 2011 to the labelof pioglitazone (Actos), associating this antidiabetesmedication with the risk for bladder cancer. Theseadvertisements, along with others that also targetpatients directly, may have a negative impact on thewillingness of patients to pay money out of pocket totake a medication or medications that have the poten-tial for significant harm. All patients must be made to understand that all

medications carry a risk for adverse events. However,the well-known complications of untreated or under-treated diabetes have well-defined risk factors. It is alsoknown that diet and exercise alone are often not suffi-cient for glucose control in many patients with type 2diabetes. Determining the most effective medicationthat is balanced by a favorable side-effect profile isimportant for ensuring appropriate medication adher-ence and adequate glucose control.

PAYERS/EMPLOYERS: In their present article,Dr Nguyen and colleagues do a great job outlining therisk for cancer associated with diabetes and antidiabetesmedications through a comprehensive review of avail-able retrospective analyses in the current literature. Diabetes is a significant focus area for payers for sev-

eral reasons. The cost of treatment for diabetes standsout among many other conditions as a result of thechronic and progressive nature of diabetes and its asso-ciated sequelae, as well as the associated comorbid con-ditions. Prevention of diabetes is a strong focus formany payers through incentives for, or educationaround, behavior modification. The other focus for

payers is trying to get their members to reach their goallevel of hemoglobin A1c, and then to maintain ade-quate glucose control. Diabetic control is also a focus for employer groups,

who like to see measurements similar to what is reflect-ed by the HEDIS (Healthcare Effectiveness Data andInforma tion Set) measures, to understand diabetic con-trol within their own employee population. One positive aspect revealed by this literature

review article concerns the data related to metformin,showing a potential protective benefit against somecancers. Metformin remains the most cost-effectivemedication available for type 2 diabetes. Metforminalso continues to be recommended as a first-line agentfor type 2 diabetes and is a mainstay of therapy accord-ing to the American Diabetes Association and theAmerican Association of Endocrinologists/AmericanCollege of Endocrinology guidelines. With an in -creased cancer risk associated with diabetes and a cor-related increased risk for medications used to treat dia-betes, having one medication that potentially offersprotection against some types of cancer is importantand further reaffirms its role as a first-line therapy forthis patient population. With several newer agents available for type 2 dia-

betes, and with several agents currently in the drugpipeline that will potentially become available withinthe next couple of years, data supporting any potentialcancer risk associated with antidiabetes medicationsmay not become immediately available. Currentlyavailable data can be used for formulary decisions toprovide coverage for medications that have demonstrat-ed the best efficacy and safety through available data.

Matthew Mitchell, PharmD, MBAManager, Pharmacy Services

SelectHealth, Salt Lake City, UT

STAKEHOLDER PERSPECTIVE

57. Ruiter R, Visser LE, van Herk-Sukel MP, et al. Risk of cancer in patients oninsulin glargine and other insulin analogues in comparison with those on humaninsulin: results from a large population-based follow-up study. Diabetologia. 2012;55:51-62.

58. Luo J, Chlebowski R, Wactawski-Wende J, et al. Diabetes and lung cancer amongpostmenopausal women. Diabetes Care. 2012;35:1485-1491.59. Symlin [prescribing information]. San Diego, CA: Amylin Pharmaceuticals; 2008.http://documents.symlin.com/SYMLIN_PI.pdf. Accessed June 17, 2012.


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CLINICAL


Nausea and vomiting are 2 serious and related sideeffects of cancer chemotherapy. These adverseeffects can cause significant negative impacts on

patients’ quality of life and on their ability to complywith therapy. Also, nausea and vomiting can result inanorexia, decreased performance status, metabolicimbalance, wound dehiscence, esophageal tears, andnutritional deficiency.1,2 Despite advances in the preven-tion and management of chemotherapy-induced nauseaand vomiting (CINV), these side effects remain amongthe most distressing for patients. The use of emergingantiemetic medications has reduced the incidence ofvomiting substantially, but evaluations show thatapproximately 30% to 60% of patients still experienceeither acute or delayed nausea after chemotherapy.3Serial evaluations throughout the 1980s and into the2000s show that, although vomiting has fallen furtherdown on the list of side effects that patients perceive asbeing their most severe, nausea remains either the first orsecond most severe side effect of chemotherapy.4-8Risk factors for CINV can be divided into patient-

specific and treatment-specific risk factors. Female sex

and history of motion or morning sickness are clear riskfactors for nausea and vomiting.5,6 Younger age has alsobeen correlated with increased risk, although this may beexplained by the more aggressive chemotherapy regi-mens that tend to be administered to younger patientswho have more aggressive diseases.5-7 Finally, alcoholintake tends to be inversely correlated with the risk ofdeveloping CINV. Many factors contribute to the treat-ment-specific risk, including (1) the emetogenicity ofthe agents being used, (2) the dose and schedule of eachagent, and (3) in the case of radiation-induced or post-operative nausea, the site of radiation or surgery.“Emetogenicity” refers to an agent’s tendency to cause

nausea and/or vomiting. Initially described in 1997, theemetogenicity scale, also known as the Hesketh scale,divided chemotherapy agents and doses into 5 levels,based on their likelihood to cause CINV.9 Since then,the American Society of Clinical Oncology (ASCO)and the National Comprehensive Cancer Network(NCCN) have modified this scale to be divided into thefollowing 4 categories10,11:• Highly emetogenic: medications or doses that causeCINV in >90% of patients

• Moderately emetogenic: medications that induce CINVin 30% to 90% of patients

• Low emetogenic: medications that are associated withCINV rates of 10% to 30%

CLINICAL

Review aRticle

Chemotherapy-Induced Nausea and Vomiting: Optimizing Prevention and ManagementKamakshi v. Rao, PharmD, BcOP, cPP; aimee Faso, PharmD, BcOP, cPP

Background: Nausea and vomiting are serious side effects of cancer chemotherapy that

can cause significant negative impacts on patients’ quality of life and on their ability to toler-

ate and comply with therapy. Despite advances in the prevention and management of

chemotherapy-induced nausea and vomiting (CINV), these side effects remain among the

most distressing for patients.

Objective: To discuss CINV and the current pharmacologic approaches to its management.

Discussion: This article outlines the mechanism of CINV, followed by a review of current

approaches to pharmacologic therapy and current practice guidelines from national cancer

organizations. This information will help providers and payers understand the optimal man-

agement of patients with CINV, including practical considerations and value-based decision-

making that considers cost issues.

Conclusion: Numerous preventive and treatment options are available to manage CINV.

Addressing antiemetic regimens requires ongoing patient evaluation to determine the best

approach for each individual patient.




Dr Rao is an oncology/BMT clinical pharmacist practitionerand Dr Faso is a hematology/oncology clinical pharmacistpractitioner, University of North Carolina Hospitals andClinics, Chapel Hill, NC.

Chemotherapy-Induced Nausea and Vomiting


• Minimally emetogenic: medications that cause CINVin <10% of patients.“CINV” is a broad term used to describe the many

types of nausea and vomiting that can occur in patientswith cancer. The major subtypes of nausea and vomitingassociated with chemotherapy are12-16:• Acute: onset of nausea and vomiting within minutesto hours after administration of chemotherapy andresolving within 24 hours

• Delayed: occurs 24 hours or later after administrationof chemotherapy

• Anticipatory: occurs before chemotherapy administra-tion; thought to be an indicator of previous poor con-trol of nausea and vomiting

• Breakthrough/refractory: nausea and vomiting thatoccur despite appropriate prophylaxis; requires theuse of rescue medications.Because there are so many independent and variable

risk factors that can influence the risk for CINV in anyparticular patient, it becomes paramount for providers toindividualize the approach to the prevention and treat-ment of CINV in every patient case.

Pathophysiology of Nausea and VomitingThe vomiting response is controlled centrally by the

emetic center, which lies in the reticular formation ofthe brain stem. The emetic center receives input from 3sources: the periphery, the cortex, and the chemorecep-tor trigger zone. Peripheral pathways are mediated main-ly by serotonin (5-hydroxytryptamine3 [5-HT3]) and neu-rokinin (NK). The cortical pathway, which is responsiblefor anticipatory emesis, is mediated by dopamine andhistamine. The chemoreceptor trigger zone, which is acollection of neurons at the base of the brain and isexposed to the body’s general circulation, mediates sig-nals through all of the above chemokines. Once theemetic center has been triggered, signals are then sent tothe salivatory, vasomotor, respiratory, and cranial centersto activate the organs involved with the vomiting reflex,namely the abdominal muscles, diaphragm, stomach,and esophagus.17

Pharmacologic Treatment Options for CINVAvailable AgentsBefore the 1980s, CINV was primarily managed

with dopamine receptor antagonists. Today, we have amultitude of options available, targeting the variouspathways of the process, to use in the prevention andmanagement of CINV.

5-HT3 receptor antagonists.Ondansetron was the firstUS Food and Drug Administration (FDA)-approved 5-HT3 antagonist in 1991. Early trials showed thatondansetron was an effective antiemetic for patients

receiving cisplatin-based regimens, and they subsequent-ly showed it to be superior to metoclopramide in patientsreceiving cisplatin and noncisplatin regimens.18-22Currently, four 5-HT3 receptor antagonists are availablein the United States—ondansetron, granisetron,dolasetron, and palonosetron. Palonosetron, the newestagent, was approved in 2003. These agents are believedto prevent CINV by antagonizing 5-HT3 receptors eitherperipherally on vagal nerve terminals and/or centrally inthe chemoreceptor trigger zone.23-27 Since their introduc-tion, 5-HT3 receptor antagonists have become part of thecornerstone for CINV prevention, thanks to their effec-tiveness and tolerable side-effect profile. The most com-mon adverse effects reported (in their respective packageinsert) with these agents are headache and constipation.Transient elevation of liver function enzymes and QTcprolongation have also been noted.

NK1 receptor antagonists.NK1 receptor antagonistsinhibit substance P in peripheral and central emeticpathways. Aprepitant was the first drug in this class tobe approved by the FDA in 2003. Aprepitant wasapproved at doses of 125 mg orally on day 1 and 80 mgorally on days 2 and 3 for the prevention of nausea andvomiting in patients receiving highly emetogenic or

KEY POINTS➤ Risk factors for CINV can be either patient-specificor treatment-specific.

➤ Treatment-specific risks include emetogenicity of theagents used, the dose and schedule of each agent,and, if applicable, the radiation or surgery site.

➤ Agents available to treat CINV include 5-HT3receptor antagonists, NK1 receptor antagonists, andcorticosteroids, as well as dopamine receptorantagonists, benzodiazepines, olanzapine, andcannabinoids.

➤ Guidelines from the NCCN and ASCO can helpproviders personalize the antiemetic regimens fortheir patients, but these are only starting points; a“value judgment” must also be made.

➤ The preferred status for palonosetron was derivedfrom data in 3 of 4 trials showing significant benefitsin the delayed setting; these trials had significantflaws in design, leading us to question this“preferred” status and suggest that all 5-HT3 receptorantagonists are equal if used at equivalent doses andschedules.

➤ Providers must consider clinical, logistic, safety, andcost factors when treating CINV, and antiemeticregimens for a particular patient must be evaluatedand then reevaluated at every treatment cycle.

CLINICAL


moderately emetogenic single-day chemotherapy.28Aprepitant was approved after 2 trials showed that thecombination of aprepitant, ondansetron, and dexa -methasone decreased emesis or decreased the use of res-cue medications for patients receiving highly emeto-genic chemotherapy during the acute and delayedphases.29,30 The most common adverse effects includefatigue, headache, anorexia, diarrhea, hiccups, andincreased transaminases.Aprepitant is primarily metabolized by cytochrome

(CY)P-450 3A4 with minor metabolism by CYP-1A2and CYP-2C9.28,31 Aprepitant has been shown to be aninhibitor of CYP-3A4 and an inducer of CYP-2A9.Coadministration with corticosteroids such as dexa -methasone, a CYP-3A4 substrate, causes an increase inplasma concentrations of dexamethasone. Therefore,when aprepitant is given with dexamethasone forCINV prevention, the dexamethasone dose should bereduced. Because aprepitant is a weak inducer of CYP-2C9, the metabolism of warfarin can be affected. Adecrease of international normalized ratio has beennoted with this combination, and patients should bemonitored, although no empiric dose adjustments forwarfarin are recommended.32Fosaprepitant, which was approved in 2008, is a

water-soluble prodrug of aprepitant that is administeredintravenously before chemotherapy.33 Fosaprepitant isused as an intravenous (IV) 150-mg dose on day 1 only.The one-time 150-mg IV dose has been shown to benoninferior to the 3-day oral aprepitant regimen.34

Corticosteroids. Corticosteroids were first shown tobe efficacious for CINV in the 1980s, and they are nowconsidered a mainstay of antiemetic regimens for theprevention of acute and delayed emesis.10,11,35 Althoughnot approved by the FDA for CINV, corticosteroidshave been found to be beneficial when used alone forthe prevention of nausea and vomiting in patientsreceiving low emetogenic chemotherapy and toimprove efficacy when combined with 5-HT3 receptorantagonists in patients receiving moderately or highlyemetogenic chemotherapies.36-39 Dexamethasone is therecommended corticosteroid according to currentguidelines, although no studies have been performedcomparing available corticosteroids.10,11The mechanism of action of corticosteroids as

antiemetic agents has not been elucidated, but it maybe related to activity in the peripheral nervous systemor in the central nervous system (CNS), and possiblyby antagonizing serotonin receptors.40-43 Tolerability tocorticosteroids can be a concern, because when used forthe prevention of delayed nausea and vomiting, com-mon adverse effects have included insomnia, epigastricdiscomfort, agitation, weight gain, and hyperglycemia.44

Additional OptionsDopamine receptor antagonists. Before the approval

of the 5-HT3 antagonists, dopamine receptor antagonistswere the primary antiemetics used for CINV. With thecurrent availability of more effective preventive agents,dopamine receptor antagonists are mostly used in themanagement of breakthrough or refractory emesis. Thedopamine antagonists are divided into phenothiazines(eg, prochlorperazine), butyrophenones (eg, haloperidol,droperidol), and substituted benzamides (eg, metoclo-pramide). These agents antagonize the dopamine (D2)receptor in the chemoreceptor trigger zone.45,46Metoclopramide antagonizes dopamine, but at high dosesit also has activity against the 5-HT3 receptor.47,48Common side effects of dopamine receptor antagonists,which include extrapyramidal symptoms, dystonia, anddrowsiness, make them more suitable for breakthroughnausea rather than for primary prophylaxis.

Benzodiazepines. These agents are anxiolytics thatare used in patients receiving chemotherapy. Benzodi -azepines are appropriate adjunct therapies to decreasetreatment-related anxiety, and they are the preferredagents to treat and prevent anticipatory nausea andvomiting.49-51 Lorazepam and alprazolam are the primaryagents used in this class, with sedation being the mostcommon adverse effect, based on our clinical practiceexperience.

Olanzapine. This atypical antipsychotic has antago-nist activity at adrenergic receptors, muscarinic recep-tors, and multiple dopamine (D1-4) and serotonin recep-tors (5-HT2A, 5-HT2C, 5-HT3, 5-HT6).52,53 Several trialshave shown that olanzapine safely and effectively pre-vents acute, delayed, and refractory CINV when com-bined with other antiemetics in patients receivingmoderately and highly emetogenic chemotherapy.54-56Adverse effects such as sedation, weight gain, orthostatichypotension, hyperglycemia, and a black box warningfor increased mortality in elderly patients with demen-tia-related psychosis limit its use.57

Cannabinoids. Dronabinol and nabilone are 2cannabinoids that are currently approved by the FDA forCINV in patients who have not adequately responded toconventional antiemetics. Cannabinoids are thought toprevent nausea and vomiting by antagonizing cannabi-noid receptor CB1 in the CNS and possibly CB2 recep-tors as well.58 Cannabinoids have been shown to be aseffective as or slightly more effective than dopaminereceptor antagonists.59,60 Only 1 trial has directly com-pared a cannabinoid with standard treatment.61Ondansetron with dexamethasone plus dronabinol wasfound to be equally efficacious to ondansetron, dexa -methasone, and placebo.61 This lack of added benefit haslimited the use of cannabinoids in the preventive set-



ting. In addition, vertigo, euphoria, and somnolence areadverse effects that limit the use of cannabinoids.

Current Practice GuidelinesPractice guidelines from the NCCN and ASCO are

available to help providers determine optimal prophylax-is and the treatment of CINV.10,11 The NCCN AntiemesisGuidelineTM, a consensus-based guideline that incorpo-rates evidence and expert opinion to make recommenda-tions, is revised annually.11 ASCO guidelines are purelyevidence-based guidelines and are updated periodically;the last update was in 2011.10 Table 1 summarizes specificrecommendations for antiemesis from the NCCN andfrom ASCO. For CINV, both guidelines outline primaryprophylaxis based on the emetogenicity of the patient’schemotherapy: high, moderate, low, and minimal.For patients receiving highly emetogenic chemother-

apy, both guidelines recommend a 3-drug combinationthat includes a 5-HT3 receptor antagonist, an NK1receptor antagonist, and dexamethasone to preventCINV. The NCCN specifies that the preferred 5-HT3receptor antagonist for highly emetogenic chemotherapyis palonosetron,11 whereas ASCO does not list a pre-ferred 5-HT3 receptor antagonist.For patients receiving moderately emetogenic

chemotherapy, the NCCN and ASCO recommend a 2-drug combination of a 5-HT3 receptor antagonist,preferably palonosetron, with dexamethasone. Dexa -m ethasone is recommended by both organizations forthe prevention of CINV in patients with low or minimalemetogenic potential. The NCCN also lists metoclo-pramide or prochlorperazine as possible alternatives. Forpatients receiving minimal-risk chemotherapy, no med-ications are recommended primarily as prophylaxis.For anticipatory nausea and vomiting (ANV), ASCO

and the NCCN recommend that prevention with opti-mal primary prophylaxis is the best approach.10,11 Both

organizations state that behavioral therapy, includingdesensitization, is recommended for treatment of ANV.The NCCN guidelines recommend the use of benzodi-azepines to treat ANV.For radiation-induced nausea and vomiting, 5-HT3

receptor antagonists are the preferred class of antiemetic.The NCCN divides types of radiation into high risk(eg, total body irradiation), moderate risk (eg, radiationto upper abdomen), and combined radiation withchemotherapy.11 For moderate- and high-risk radiation,granisetron or ondansetron before each radiation treat-ment, with or without dexamethasone, is recommended.Prophylaxis of nausea and vomiting with combinationchemotherapy and radiation is determined by the eme-togenic potential of the chemotherapy.ASCO categorizes emetogenic risk of radiation as

high (eg, total body irradiation), moderate (eg, upperabdomen), low (eg, head and neck), minimal (eg,breast), and combination of radiation and chemothera-py.10 For moderate- and high-risk radiation, a 5-HT3receptor antagonist before each radiation treatment,along with dexamethasone during fractions 1 to 5, arerecommended. Granisetron and ondansetron are pre-ferred 5-HT3 receptor antagonists in this setting, butdolasetron can be considered. Palonosetron is listed as anoption, although there are no trials to indicate appropri-ate dosing frequency. Patients receiving radiation with alow risk for nausea and vomiting can be offered a 5-HT3receptor antagonist or a dopamine receptor antagonist,such as metoclopramide or prochlorperazine, as a rescuetreatment. Prophylaxis for nausea and vomiting forpatients receiving a combination of chemotherapy andradiation is determined by the chemotherapy regimen,unless the radiation causes a higher risk.

Practical ConsiderationsEven with the current published guidelines, there are

Table 1 Recommended Antiemetic Regimens for CINV Prophylaxis

Emetic risk Treatment for acute phasea Treatment for delayed phase

High 3-drug combination treatment with an NK1 receptorantagonist, a 5-HT3 receptor antagonist, and dexamethasone

NK1 receptor antagonist if oralroute was used; dexamethasone

Moderate 2-drug combination treatment with a 5-HT3 receptorantagonist and dexamethasone

Dexamethasone

Low Dexamethasone

Minimal No routine prophylaxis recommendedaAll patients should have “as-needed” rescue medication available, which can include prochlorperazine, promethazine,or lorazepam, regardless of emetic risk level. 5-HT indicates serotonin; CINV, chemotherapy-induced nausea and vomiting; NK, neurokinin.

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unique challenges for clinicians who manage patientswith CINV or patients at risk of developing CINV. In thisarticle, we focus on the following 3 practical challenges.

1. Are all 5-HT3 receptor antagonists created equal?Currently, there are four 5-HT3 antagonists available inthe US market—dolasetron, granisetron, ondansetron,and palonosetron. Studies with these agents show rela-tively similar rates of success in the prevention of CINVin patients receiving cisplatin-based chemotherapy reg-imens. In addition, studies have established acceptableoral:IV conversions that result in similar levels of eme-sis control. Equivalent doses and pharmacokineticproperties of the agents are listed in Table 2 and Table3. When used in equivalent doses, ondansetron,granisetron, and dolasetron are considered similar for theprevention of nausea and vomiting.62,63 The pharmacoki-netics of ondansetron, granisetron, and dolasetron areslightly different, but not enough to result in any clini-cally significant differences.Palonosetron differs from the other 5-HT3 antagonists

by having increased binding affinity to the 5-HT3receptor, higher potency, and a longer half-life.64,65 Thehalf-life of palonosetron is approximately 40 hourscompared with the significantly lower half-lives of

ondansetron, granisetron, and dolasetron.64 This resultsin altered dosing recommendations for palonosetron,which is dosed once per cycle rather than on a daily basis.As discussed earlier, the NCCN and ASCO guide-

lines have stated a preference for palonosetron for theprevention of CINV. These recommendations are basedon data from 4 trials.66-69 In 3 of these trials, palonosetronwas compared with various other 5-HT3 receptor antag-onists to determine noninferiority.67-69 Only 1 trial wasdesigned to detect superiority in the comparison.66 All 4trials demonstrated similar success rates in preventingacute CINV between palonosetron and the comparator.The preferred status for palonosetron was derived fromthe data showing significant benefits for palonosetron inthe delayed setting in 3 of the 4 trials, including the trialsized to measure superiority.All of these trials, however, had significant flaws in

their design. Most notable, all of the trials compared asingle dose of palonosetron to a single dose of the com-parator 5-HT3 receptor antagonist. Given palonosetron’sextended half-life of 40 hours, compared with the half-lives of between 3 and 8 hours for other 5-HT3 receptorantagonists, comparisons at any time after 24 hours arepharmacokinetically irrelevant. In addition, only 1 of

Table 3 Pharmacokinetic Properties of 5-HT3 Receptor Antagonists

Agent Ondansetron Granisetron Dolasetron Palonosetron

Half-life (hrs) 3-4 7-9 7-8 40

Oral bioavailability, % 56 60 75 N/A

Renal elimination, % 5 12 67 42

Hepatic metabolism CYP-3A, CYP-1A, CYP-2D6, CYP-2E1

CYP-3A CYP-3A, CYP-2D6

CYP-3A4, CYP-2D6, CYP-1A2

5-HT indicates serotonin; CYP, cytochrome P; N/A, not applicable.

Antiemetic Dose

NK1 receptor antagonists

Fosaprepitant 150 mg IV

Aprepitant 125 mg oral on day 1and 80 mg oral ondays 2 and 3

5-HT3 receptor antagonists

Ondansetron 16-24 mg oral; 8 mg IV

Antiemetic Dose

Granisetron 2 mg oral or 1 mg oraltwice daily; 1 mg IV or0.01 mg/kg IV

Dolasetron 100 mg oral

Palonosetron 0.25 mg IV

Corticosteroid

Dexamethasone 8-20 mg oral IV

Table 2 Dosing Ranges for Antiemetics Used for Primary Prophylaxis of CINV

5-HT indicates serotonin; CINV, chemotherapy-induced nausea and vomiting; IV, intravenous; NK, neurokinin.



the trials mandated the use of corticosteroids, whichare the backbone of any combination antiemetic regi-men.69 Given these significant flaws in design, we callinto question the “preferred” status of palonosetron andinstead endorse the idea that all 5-HT3 receptor antag-onists are indeed equal if used at equivalent doses andschedules.

2. Multiday chemotherapy. Most data on the use of5-HT3 receptor antagonists, especially NK1 receptorantagonists, are in the setting of single-day chemothera-py. However, numerous malignancies are treated withmultiple sequential days of chemotherapy, often withvarious agents being given on different days. Currentguidelines recommend using the appropriate level ofprophylaxis, according to the emetogenicity of the regi-men, on each day of the regimen, and continuingdelayed prophylaxis for 2 to 3 days after the completionof chemotherapy.10,11 In patients receiving moderatelyemetogenic regimens, this is a relatively straightforwardapproach. In patients receiving highly emetogenic regi-mens, however, it becomes more difficult.The timing of the NK1 receptor antagonist dose or of

the frequency of palonosetron dosing in these regimensis poorly defined. Einhorn and colleagues evaluated theuse of every 2-day palonosetron in patients receiving thehighly emetogenic chemotherapeutic combination of

bleomycin, etoposide, and cisplatin for testicular cancerand showed favorable results.70 Another study evaluatedthe use of aprepitant in combination with granisetronand dexamethasone, in patients receiving multidayhighly emetogenic and moderately emetogenicchemotherapy. Aprepitant was administered as 125 mg,followed by 80 mg daily for the remainder of chemother-apy days, and continued for 2 more days, all along withdexamethasone. This study demonstrated a completeremission rate of almost 58% in highly emetogenic and73% in moderately emetogenic regimens.71

3. Breakthrough/refractory nausea and vomiting.Breakthrough/refractory nausea and vomiting are chal-lenging to treat. In particular, refractory nausea andvomiting may cause significant morbidity, includingweight loss, metabolic imbalances, and nutritional defi-ciency, and may result in the inability of patients toremain on their therapy schedule. The use of anti-dopaminergic and anticholinergic agents is very appro-priate in this setting. More important, however, is theneed to continually reassess the patient’s response totherapy with each cycle. In some cases, severe or refrac-tory nausea could be predicted, given a patient’s historyof poor tolerance of therapy, and adjustments could havebeen made to decrease the risk of nausea and vomiting.Also, regular reevaluation of risk factors can help to

Figure Proposed Value-Based Decision Algorithm for CINV

Appropriateselection of initialtherapy based onpatient- andtreatment-specific riskfactors

–Likelihood ofadherence

–Health literacy–Complexity ofregimen

Consideration ofadverse effects 5-HT3: QTcprolongation,headache,constipationSteroids:hyperglycemiaD2 antagonists:drowsiness,extrapyramidalsyndrome

–Cost per dose–Cost per cycle–Cost ofhospitalizationfor breakthrough

Guideline-basedtherapy

Incorporate value-based considerations

Clinical success Convenience Safety Cost

➤

➤ ➤➤➤

➤ ➤ ➤

Patient’soptimaltherapy

5-HT indicates serotonin; CINV, chemotherapy-induced nausea and vomiting.

CLINICAL


identify patients who may have an increased risk ofbreakthrough nausea and vomiting.

Proposal for a Value-Based Decision-Making AlgorithmIt must be emphasized that the currently available

guidelines are not meant to be clear-cut decisions on howto approach every patient. The guidelines are meant to beviewed as a starting point from which to build the case forevery individual’s antiemetic regimen. Along with theseguidelines, a “value judgment” must be made to deter-mine the most optimal regimen for any patient.Value, as it relates to CINV, may be determined based

on a number of factors. The most relevant factorsinclude (1) clinical factors (ie, freedom from nausea anddecreased use of rescue medications), (2) logistic factors(ie, convenience of a regimen and likelihood of adher-ence), (3) safety factors (ie, consideration of potentialadverse effects of agents in particular scenarios), and (4)cost factors (ie, affordability, coverage, and reimburse-ment). In many cases, treatment decisions must be madeconsidering whether the patient will be able to afford orcomply with the regimen that would technically be“ideal.” For example, clinicians may consider using IVNK1 receptor antagonists and/or IV palonosetron in apatient who either cannot afford to pay for continuedoral NK1 receptor antagonist or 5-HT3 receptor antago-nist therapy, or in a patient who will be unlikely toremember to take doses as scheduled for the days afterchemotherapy. A proposed algorithm for decision-making, including

considerations regarding the abovementioned valueconsiderations, is outlined in the Figure.

ConclusionsAntiemetic regimens for a particular patient must be

evaluated and then reevaluated at every treatment cycle.At every step of a patient’s care, clinicians must incorpo-rate clinical decision-making with value-based consider-ations to determine each patient’s individual, most opti-mal approach to treatment. With such an approach, wehope to continue to make progress in the prevention andmanagement of this troublesome and problematicadverse effect of chemotherapy, thereby helping toimprove the therapy experience and quality of life forour patients. ■

Author Disclosure StatementDr Rao and Dr Faso have reported no conflicts of interest.

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Emend (aprepitant) capsules [package insert]. Whitehouse Station, NJ: Merck;2006. www.merck.com/product/usa/pi_circulars/e/emend/emend_pi.pdf?WT.mc_id=N02N3. Accessed June 21, 2012.29. Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonistaprepitant for the prevention of chemotherapy-induced nausea and vomiting: amultinational, randomized, double-blind, placebo-controlled trial in patients receiv-ing high-dose cisplatin—the Aprepitant Protocol 052 Study Group. J Clin Oncol.2003;21:4112-4119.30. Schmoll HJ, Aapro MS, Poli-Bigelli S, et al. Comparison of an aprepitant regi-men with a multiple-day ondansetron regimen, both with dexamethasone, for



antiemetic efficacy in high-dose cisplatin treatment. Ann Oncol. 2006;17:1000-1006.31. Sanchez RI, Wang RW, Newton DJ, et al. Cytochrome P450 3A4 is the majorenzyme involved in the metabolism of the substance P receptor antagonist aprepi-tant. Drug Metab Dispos. 2004;32:1287-1292.32. Depré M, Van Hecken A, Oeyen M, et al. Effect of aprepitant on the pharmaco-kinetics and pharmacodynamics of warfarin. Eur J Clin Pharmacol. 2005;61:341-346.33. Emend (fosaprepitant dimeglumine) for injection [package insert]. WhitehouseStation, NJ: Merck; 2009. www.merck.com/product/usa/pi_circulars/e/emend_iv/emend_iv_pi.pdf. Accessed June 21, 2012.34.Grunberg S, Chua D, Maru A, et al. Single-dose fosaprepitant for the preventionof chemotherapy-induced nausea and vomiting associated with cisplatin therapy:randomized, double-blind study protocol—EASE. J Clin Oncol. 2011;29:1495-1501.35. Ioannidis JP, Hesketh PJ, Lau J. Contribution of dexamethasone to control ofchemotherapy-induced nausea and vomiting: a meta-analysis of randomized evi-dence. J Clin Oncol. 2000;18:3409-3422.36. The Italian Group for Antiemetic Research. Dexamethasone, granisetron, orboth for the prevention of nausea and vomiting during chemotherapy for cancer.N Engl J Med. 1995;332:1-5.37. Hesketh PJ, Harvey WH, Harker WG, et al. A randomized, double-blind com-parison of intravenous ondansetron alone and in combination with intravenous dexa -methasone in the prevention of high-dose cisplatin-induced emesis. J Clin Oncol.1994;12:596-600.38. Latreille J, Stewart D, Laberge F, et al. Dexamethasone improves the efficacy ofgranisetron in the first 24 h following high-dose cisplatin chemotherapy. SupportCare Cancer. 1995;3:307-312.39. Markman M, Sheidler V, Ettinger DS, et al. Antiemetic efficacy of dexametha-sone. Randomized, double-blind, crossover study with prochlorperazine in patientsreceiving cancer chemotherapy. N Engl J Med. 1984;311:549-552.40. Ho CM, Ho ST, Wang JJ, et al. Dexamethasone has a central antiemetic mech-anism in decerebrated cats. Anesth Analg. 2004;99:734-739.41.Mantovani G, Maccio A, Esu S, Lai P. Evidence that cisplatin induces serotoninrelease from human peripheral blood mononuclear cells and that methylprednisoloneinhibits this effect. Eur J Cancer. 1996;32A:1983-1985.42. Suzuki T, Sugimoto M, Koyama H, et al. Inhibitory effect of glucocorticoids onhuman-cloned 5-hydroxytryptamine3A receptor expressed in xenopus oocytes.Anesthesiology. 2004;101:660-665.43. Tanihata S, Oda S, Nakai S, Uchiyama T. Antiemetic effect of dexamethasoneon cisplatin-induced early and delayed emesis in the pigeon. Eur J Pharmacol. 2004;484:311-321.44. Vardy J, Chiew KS, Galica J, et al. Side effects associated with the use of dexa -methasone for prophylaxis of delayed emesis after moderately emetogenicchemotherapy. Br J Cancer. 2006;94:1011-1015.45. Edmonds-Seal J, Prys-Roberts C. Pharmacology of drugs used in neuroleptanal-gesia. Br J Anaesth. 1970;42:207-216.46. Wyant GM. A comparative study of eleven anti-emetic drugs in dogs. CanAnaesth Soc J. 1962;9:399-407.47. Bianchi C, Beani L, Crema C. Effects of metoclopramide on isolated guinea-pig colon. 2. Interference with ganglionic stimulant drugs. Eur J Pharmacol. 1970;12:332-341.48. Fontaine J, Reuse JJ. Pharmacological analysis of the effects of metoclopramideon the guinea-pig ileum in vitro. Arch Int Pharmacodyn Ther. 1973;204:293-305.49. Laszlo J, Clark RA, Hanson DC, et al. Lorazepam in cancer patients treated withcisplatin: a drug having antiemetic, amnesic, and anxiolytic effects. J Clin Oncol.1985;3:864-869.50. Malik IA, Khan WA, Qazilbash M, et al. Clinical efficacy of lorazepam in pro-phylaxis of anticipatory, acute, and delayed nausea and vomiting induced by highdoses of cisplatin. A prospective randomized trial. Am J Clin Oncol. 1995;18:170-175.51. Razavi D, Delvaux N, Farvacques C, et al. Prevention of adjustment disorders andanticipatory nausea secondary to adjuvant chemotherapy: a double-blind, placebo-

controlled study assessing the usefulness of alprazolam. J Clin Oncol. 1993;11:1384-1390.52. Bymaster FP, Calligaro DO, Falcone JF, et al. Radioreceptor binding profile of theatypical antipsychotic olanzapine. Neuropsychopharmacology. 1996;14:87-96.53. Bymaster FP, Falcone JF, Bauzon D, et al. Potent antagonism of 5-HT(3) and 5-HT(6) receptors by olanzapine. Eur J Pharmacol. 2001;430:341-349.54. Navari RM, Einhorn LH, Loehrer PJ Sr, et al. A phase II trial of olanzapine, dexa -methasone, and palonosetron for the prevention of chemotherapy-induced nausea andvomiting: a Hoosier Oncology Group study. Support Care Cancer. 2007;15:1285-1291.55. Navari RM, Einhorn LH, Passik SD, et al. A phase II trial of olanzapine for theprevention of chemotherapy-induced nausea and vomiting: a Hoosier OncologyGroup study. Support Care Cancer. 2005;13:529-534.56. Passik SD, Navari RM, Jung SH, et al. A phase I trial of olanzapine (Zyprexa) forthe prevention of delayed emesis in cancer patients: a Hoosier Oncology Groupstudy. Cancer Invest. 2004;22:383-388.57. Zyprexa Relprevv (olanzapine) [package insert]. Indianapolis, IN: Eli Lilly; 2011.58.Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treat-ment of cachexia, emesis, and pain. J Support Oncol. 2004;2:305-314; discussion 314-316.59. Herman TS, Einhorn LH, Jones SE, et al. Superiority of nabilone over prochlor-perazine as an antiemetic in patients receiving cancer chemotherapy. N Engl J Med.1979;300:1295-1297.60. Steele N, Gralla RJ, Braun DW Jr, Young CW. Double-blind comparison of theantiemetic effects of nabilone and prochlorperazine on chemotherapy-induced eme-sis. Cancer Treat Rep. 1980;64:219-224.61. Meiri E, Jhangiani H, Vredenburgh JJ, et al. Efficacy of dronabinol alone and incombination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr Med Res Opin. 2007;23:533-543.62. Billio A, Morello E, Clarke MJ. Serotonin receptor antagonists for highly eme-togenic chemotherapy in adults. Cochrane Database Syst Rev. 2010;CD006272.63. Jordan K, Hinke A, Grothey A, et al. A meta-analysis comparing the efficacy offour 5-HT3-receptor antagonists for acute chemotherapy-induced emesis. SupportCare Cancer. 2007;15:1023-1033.64. Rojas C, Stathis M, Thomas AG, et al. Palonosetron exhibits unique molecularinteractions with the 5-HT3 receptor. Anesth Analg. 2008;107:469-478.65. Rojas C, Thomas AG, Alt J, et al. Palonosetron triggers 5-HT(3) receptor inter-nalization and causes prolonged inhibition of receptor function. Eur J Pharmacol.2010;626:193-199.66. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, ran-domized trial of palonosetron compared with ondansetron in preventing chemother-apy-induced nausea and vomiting following highly emetogenic chemotherapy. AnnOncol. 2006;17:1441-1449.67. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moder-ately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, apharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dosetrial versus dolasetron. Cancer. 2003;98:2473-2482.68. Gralla R, Lichinitser M, Van Der Vegt S, et al. Palonosetron improves preven-tion of chemotherapy-induced nausea and vomiting following moderately emeto-genic chemotherapy: results of a double-blind randomized phase III trial comparingsingle doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577.69. Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versusgranisetron plus dexamethasone for prevention of nausea and vomiting duringchemotherapy: a double-blind, double-dummy, randomised, comparative phase IIItrial. Lancet Oncol. 2009;10:115-124.70. Einhorn LH, Brames MJ, Dreicer R, et al. Palonosetron plus dexamethasone forprevention of chemotherapy-induced nausea and vomiting in patients receiving mul-tiple-day cisplatin chemotherapy for germ cell cancer. Support Care Cancer. 2007;15:1293-1300.71. Jordan K, Kinitz I, Voigt W, et al. Safety and efficacy of a triple antiemetic com-bination with the NK-1 antagonist aprepitant in highly and moderately emetogenicmultiple-day chemotherapy. Eur J Cancer. 2009;45:1184-1187.

Stakeholder Perspective on next page



Selecting Best Therapies for Control of Chemotherapy-InducedNausea and Vomiting

PROVIDERS/PAYERS: In a world of guidelines,algorithms, and literature searches, we often forget tofocus on the patient. Nausea and vomiting are sideeffects that need to be evaluated differently from othereffects related to chemotherapy in patients with can-cer. Thoughtful evaluation to determine the patho-physiologic mechanisms that trigger nausea, asdescribed in the article by Dr Rao and Dr Faso, is keyto selecting the optimal antinausea medications.1When evaluating chemotherapy-induced nausea andvomiting (CINV), we automatically think of serotoninin peripheral receptors and dopamine in the chemo -receptor trigger zone as the primary culprits; however,we must also consider any underlying causes that maybe contributing factors.Direct interaction with and discussion of patients’

past experiences with nausea, their perception of nausea,and their day-to-day lives affect the choice of antiemet-ics for patients with cancer. Neurologic or visionchanges secondary to chemotherapy may contribute tovestibular changes, indicating a need for anticholiner-gics or antihistamines. Taste and smell changes second-ary to chemotherapy may require benzodiazepines or cor-ticosteroids to help control nausea. The main point isthat the patient must be evaluated beyond just the eme-togenic potential of the chemotherapy itself. As theauthors pointed out, clinical success is the first step inthe value-based decision algorithm.Comorbid conditions also affect the success of these

agents, and it is sometimes important to consider sideeffects as intended benefits of some of these drugs.Steroids may cause agitation or weight gain, but somepatients experience this as increased energy or moodboosts, which can be a dual benefit beyond the anti -nausea component. Sedation is a common side effectwith benzodiazepines, but patients with insomnia(especially secondary to their corticosteroid use) mayrealize dual benefit here as well. The key factors forthese patients are convenience and safety.A final consideration for healthcare providers is

the question of reimbursement, when the choice“does not fit with the guidelines.” The fact is that

guidelines are great in some cases, but value-basedconsiderations are essential to optimizing therapy inour patients. Without consideration of the whole per-son, the potential increased risk factors for CINV, andother comorbid conditions, payers may approve reim-bursement for whatever standard guidelines recom-mend, but this will not necessarily be getting the besttreatment for our patients. As providers, we have tomake sure that we drive the decision for antiemetictherapy based on patient-specific factors in additionto the chemotherapy itself.

PATIENTS: Nausea and vomiting remain the sideeffects of chemotherapy that patients with cancer fearthe most. Almost every patient has known someone orhad a family member who has “suffered” throughchemotherapy and has had horrendous issues withCINV. Patients report that they would rather be inpain than have CINV, because many can work throughthe pain, but nausea is completely debilitating. Thebest option is empowering patients to take control oftheir nausea through proper education, use of anti -emetics that are appropriate to their case, and throughcontinual follow-up and adjustment to their anti emeticregimens. Patients need to be given the opportunity tosit down with a nurse or a pharmacist to reiterate thecounseling provided by their physicians. Our experi-ence with this process has helped to improve monitor-ing and follow-up for patients with CINV. We must not only give patients the antiemetics

they need, but we must also provide them with theresources to be properly educated about these medica-tions. Therefore, to incorporate value-based consider-ations for optimal therapy, it is necessary to ensurethat a cohesive multidisciplinary approach is providedto the patient.

Robert Mancini, PharmDOncology Pharmacist

St. Luke’s Mountain States Tumor InstituteBoise, ID

1. Wood GJ, Shega JW, Lynch B, Von Roenn JH. Management of intractable nau-sea and vomiting in patients at the end of life. JAMA. 2007;298:1196-1207.


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Original article

Emerging Trends in Cancer Care: HealthPlans’ and Pharmacy Benefit Managers’Perspectives on Changing Care Modelsrhonda greenapple, MSPH

Background: Cancer care in the United States is being transformed by a number of medical

and economic trends, including rising drug costs, increasing availability of targeted therapies and

oral oncolytic agents, healthcare reform legislation, changing reimbursement practices, a growing

emphasis on comparative effectiveness research (CER), the emerging role of accountable care

organizations (ACOs), and the increased role of personalization of cancer care.

Objective: To examine the attitudes of health plan payers and pharmacy benefit managers

(PBMs) toward recent changes in cancer care, current cost-management strategies, and antic-

ipated changes in oncology practice during the next 5 years.

Methods: An online survey with approximately 200 questions was conducted by

Reimbursement Intelligence in 2011. The survey was completed by 24 medical directors and

31 pharmacy directors from US national and regional health plans and 8 PBMs. All respon-

dents are part of a proprietary panel of managed care decision makers and are members of

the Pharmacy and Therapeutics Committees of their respective plans, which together manage

more than 150 million lives. Survey respondents received an honorarium for completing the

survey. The survey included quantitative and qualitative questions about recent developments

in oncology management, such as the impact on their plans or PBMs of healthcare reform,

quality improvement initiatives, changes in reimbursement and financial incentives, use of tar-

geted and oral oncolytics, and personalized medicine. Respondents were treated as 1 group,

because there were no evident differences in responses between medical and pharmacy

directors or PBMs.

Results: Overall, survey respondents expressed interest in monitoring and controlling the

costs of cancer therapy, and they anticipated increased use of specialty pharmacy for oncol-

ogy drugs. When clinical outcomes are similar for oral oncolytics and injectable treatments,

93% prefer the oral agents, which are covered under the specialty tier by 59% of the plans.

The use of the National Comprehensive Cancer Network practice guidelines for coverage and

reimbursement of oncologic agents is reported as “very frequent” by 10% of survey respon-

dents, “frequent” by 21%, and “moderately frequent” by 7%. Most (66%) respondents believe

that it is probable and 3% believe it is highly probable that healthcare reform will help to control

oncology treatment costs, although 59% also predict an increase in utilization restrictions and

48% predict more stringent comparative effectiveness evidence requirements. The survey

reveals a considerable uncertainty among health plans and PBMs about the eventual impact

of ACOs on oncology care. Although 82% of those surveyed believe that measures such as

increasing adherence to evidence-based treatments will achieve cost-savings, nearly half

(48%) had no plans to use such measures.

Conclusions: Recent trends in healthcare legislation, rising drug costs, and changing reim-

bursement practices are poised to significantly alter conventional models of cancer care deliv-

ery and payment. The results of this survey indicate that health plans and PBMs anticipate

greater use of evidence-based management strategies, including CER, quality initiatives, and

biomarker testing for appropriate cancer therapy selection. In addition, they anticipate greater

focus on cost control, with a greater role for utilization management and increased patient

cost-sharing. Finally, there is a high level of uncertainty among plans and PBMs about the

eventual impact of ACOs and other aspects of healthcare reform on oncology practice.




Ms Greenapple is President, Reimbursement Intelligence, Madison, NJ.

Emerging Trends in Cancer Care


According to the American Cancer Society, morethan 1.6 million new cancer cases will be diag-nosed in 2012, and more than 577,000 Americans

are expected to die of cancer this year.1 Currently, claimsfor cancer care account for 10% of total healthcare costsbut for less than 1% of a typical commercially insured pop-ulation.2 Cancer drugs are the third most expensive cate-gory among specialty drugs, with an average cost per pre-scription of $3259.3 It has been estimated that with theaging of the US population, the annual number of newlydiagnosed cases of cancer will increase by approximately45%, to 2.3 million, by 2030.4 As a result of advances incancer diagnosis and treatment over the past severaldecades, the 5-year survival rate for all cancers increasedfrom 49% for patients diagnosed between 1975 and 1977,to 67% for those diagnosed between 2001 and 2007.1Several important trends are currently changing the

oncology management marketplace. Oral oncolytics,once uncommon, now account for approximately 25%of all drugs in the oncology pipeline.5 Healthcare reformlegislation has been introduced with the goal of improv-ing patient outcomes while reducing overall cost, andthis legislation is likely to significantly alter traditionalmodels of care delivery, assessment, and reimbursement.Advances in cellular and molecular biology have madeit possible to target a patient’s unique tumor biology, butthe new targeted agents are considerably more expen-sive than older cancer medications. For example, ananalysis of monthly Medicare costs for a typical patient(70 kg body weight or 1.7 m2 body surface area) showedthat costs exceeded $5000 per month for several target-ed agents, including sorafenib ($5097), nilotinib($6140), panitumumab ($7991), cetuximab ($9465),and alemtuzumab ($19,925).6 In contrast, the costs formost cytotoxic drugs introduced before 1995 were lessthan $1000 monthly.6Compared with older treatments, many newer

chemotherapy agents are much more expensive; thisincludes bendamustine ($7023 monthly), ixabepilone($6781 monthly), and nelarabine ($19,425 monthly).6In addition, many of these agents require histologic,genetic, or molecular tests to identify appropriatepatients for a specific cancer therapy, for example,HercepTest (Dako) or Ventana Pathway (Ventana),used to predict response to trastuzumab in patients withbreast cancer.7 Test costs may vary from approximately$350 to ≥$4000 per test.8The economic impact of targeted therapies may be

expected to grow as clinical trials continue to explorenew applications of these agents, including their use asfirst-line therapy and/or in combination with other high-cost targeted agents (eg, the combination of erlotiniband bevacizumab in patients with lung cancer, or

lenalidomide plus bortezomib in patients with multiplemyeloma). Newer diagnostic approaches, such asincreasing use of positron emission tomography, alsocontribute to increasing costs of cancer care.9The rising healthcare costs associated with more

recent cancer diagnostics and treatments are a signifi-cant concern for many health plans. To understand cur-rent oncology cost-management strategies, as well asexpectations about future practice patterns of healthcarepayers and pharmacy benefit managers (PBMs) inresponse to changes in oncology care, ReimbursementIntelligence conducted an online survey of health plansand PBMs to determine their attitudes and expectationsabout cancer management.

Survey MethodologyReimbursement Intelligence, a market research com-

pany, conducted an online survey of approximately 200questions in October 2011. The survey was completed by55 (of 57) medical and pharmacy directors (24 medical

KEY POINTS➤ Cancer care is undergoing changes related to newclinical and economic trends, including rising drugcosts of biologic therapies, changing reimbursementpractices, a growing emphasis on comparativeeffectiveness research, and potential changes relatedto healthcare reform.

➤ This survey of 55 health plans and PBMs exploredtheir perspectives on these emerging changes andtheir anticipated cost-management strategies inoncology.

➤ The survey findings indicate an increasing role forspecialty pharmacy for cancer drugs, a growing focuson cost-control efforts, and a significant impact ofnational practice guidelines on formulary andreimbursement decisions for cancer therapies.

➤ National guidelines serve as compendia forreimbursement purposes for approved and off-labeluses of cancer therapies.

➤ Quality initiatives are perceived as having thegreatest potential impact on breast cancer.

➤ Seventy-nine percent of health plans and PBMsparticipating in this survey do not have a specificprice threshold for placing drugs on the specialty tier.

➤ The decision to cover a particular cancer test issignificantly influenced by clinical practiceguidelines, according to 90% of survey respondents.

➤ These findings highlight important trends inoncology management and reimbursement thatreinforce the continuing efforts by payers to controlcosts while maintaining quality of care.

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directors and 31 pharmacy directors) from US nationaland regional health plans and 8 PBMs. Survey respon-dents were formulary decision makers for oncology cov-erage at health plans and PBMs, who together managemore than 151 million covered lives, including individ-uals enrolled in commercial, Medicare Advantage, andManaged Medicaid plans. The most frequent benefitdesign in these companies is a 3-tier open formulary,which was used by 48% of health plans and PBMs; a 3-tier closed design was used by 21%; a 4-tier design witha specialty pharmacy plan by 17%; a 2-tier design by 7%;and other benefit designs by 7%. All survey respondents are also part of a proprietary

panel of managed care decision makers and are mem-bers of the Pharmacy and Therapeutics Committees oftheir respective plans. Respondents received an hono-rarium for completing the survey. The survey includedquantitative and qualitative questions about severalaspects of oncology management, including the appli-cation of clinical practice guidelines in cancer care, thepotential impact of healthcare reform, quality improve-ment initiatives, and personalized medicine. Therespondents were treated as 1 group, because no differ-ences in responses were evident between medical andpharmacy directors or PBMs.

ResultsCost-Management Strategies for OncologyDrugs prescribed by oncologists currently account for

more than 40% of all Medicare drug spending.10According to the National Institutes of Health, the directcosts of cancer care in the United States are expected toincrease from approximately $124 billion annually in2010 to approximately $173 billion in 2020 (a 39%increase).11 Most cancer drugs approved since 2005 costmore than $4000 monthly, and a full course of treatmentwith some targeted therapies costs more than $80,000.6,12The rising cost of cancer care comes at a time when

legislative changes to Medicare reimbursement policieshave markedly decreased the reimbursement that physi-cians receive for prescribing many oncology drugs, insome cases leaving prescribers in debt for oncology drugsthat they must purchase.13Qualitative surveys and interviews of senior physician

executives at large managed care organizations (MCOs),which were conducted by the National ComprehensiveCancer Network (NCCN), identified several strategiesthat these MCOs were using to control costs and max-imize clinical benefit.9 These cost-control strategiesinclude aggressive contracting, new reimbursementmodels (eg, payments based on episodes of care ratherthan on oncologic drug costs), nursing-led case-manage-ment strategies focused on patients with the greatestmedical needs, the use of NCCN guidelines and otherresources to establish standards of treatment and reim-bursement, and the use of specialty pharmacy services forhigh-cost oral drugs. Cost-management strategies in current use by respon-

dents to the present survey, as well as strategies expectedto be initiated within the next 2 years, are summarized inTable 1. Participants were asked to rate each cost-man-agement tactic as either currently utilized, not currentlyutilized but likely to be utilized within the next 2 years,or not utilized and with no plans for utilization withinthe next 2 years. The use of clinical practice guidelinesfrom the NCCN or the American Society of ClinicalOncology (ASCO), as well as moving a drug from themedical benefit to the pharmacy, are the most frequentlyutilized management tactics (by 76% and 65%, respec-tively), whereas biomarker testing and the use of pre-ferred brands on the oncology formulary are the strate-gies most likely to be introduced in the next 2 years. Survey respondents report that oncologist responses

to declining reimbursement rates include consolidationof oncology clinics (35%), selecting more profitabletherapy options (35%), sending more patients for hospi-talization (31%), forming joint ventures or partnershipswith hospital groups (21%), and increasing practice effi-ciency (17%).

Table 1 Current and Anticipated Oncology Management Tactics

Management tactics

Not utilized, %

Currently utilized, %

Likely to be utilized in thenext 2 years, %

NCCN/ASCOguidelines

10 76 14

Pharmacy benefitclassification

21 65 14

ASP-based payments

21 58 21

Biomarker testingfor appropriatetherapy selection

10 52 38

Quality initiatives 28 41 31

Episode of carepayments

55 17 28

Oncology formulary with preferred brand

45 17 38

ASCO indicates American Society of Clinical Oncology; ASP, average sales price; NCCN, National ComprehensiveCancer Network.



In this survey, breast cancer was rated as the mostexpensive cancer type overall, followed by non–small-celllung cancer, prostate cancer, multiple myeloma, non-Hodgkin lymphoma (NHL), and metastatic melanoma.Techniques used to monitor oncology drug costs includeper-member per-month costs (by 69% of respondents);utilization review (41%); and analysis by cancer diagnosis(31%), episode of care (21%), disease type (21%), ortumor type (17%). Only 10% of respondents say that theirorganization does not monitor oncology costs. A recent trend in oncology care has been the growing

number of health plans that use a 4-tier pharmacy bene-fit structure, with specialty pharmacy coinsurance pay-ments of 10% to 25% of the drug costs.14 In this survey,copayments at tier 4 are reported as $21 to $40 by 5% ofplans/PBMs and >$40 by 26%, whereas 68% of plans/PBMs use coinsurance. Within the next 5 years, mostrespondents expect that between 11% and 40% of cancertherapies would go through specialty pharmacy. Most(79%) plans/PBMs in this survey do not have a specificprice threshold for placing drugs on the specialty tier. When clinical end points are similar, 93% of respon-

dents prefer oral agents to infused therapies, 7% are neu-tral, and none finds infused agents to be superior. Ofnote, although oral oncolytics offer greater patient con-venience, they are also associated with increased likeli-hood of nonadherence, resulting in adverse outcomes

and greater resource utilization.15 In fact, reported adher-ence rates have varied widely, from 16% to 100%.15 Incompanies included in this survey, oral oncolytic agentsare covered under the specialty drug tier by 59% ofplans/PBMs. In terms of the preferred type of trackingdata to assess patient adherence, 58% of respondentsprefer the medication possession ratio, and 42% preferclaim or refill information. A key distinction between oral and injectable cancer

medication coverage is that oral agents are covered byMedicare under the pharmacy benefit, which may meanhigher coinsurance or cost burden for patients, includingthe potential of falling into the Medicare coverage“doughnut hole.” In contrast, office-infused agents aregenerally covered by the medical benefit, with fewer out-of-pocket costs for patients. Although Medicare benefi-ciaries must pay a 20% copayment for drugs administeredunder the medical benefit, approximately 90% have sup-plemental insurance under Medicare part B, which cov-ers this amount.16 Physicians may take these factors intoaccount when making therapy decisions.

Role of Practice Guidelines in TreatmentSelection and Reimbursement ConsiderationsClinical practice guidelines from the NCCN and

ASCO use data from large, well-designed clinical trials,combined with supporting evidence from retrospective

Figure 1 Overall Survival and Progression-Free Survival the Most Important Efficacy End Points When EvaluatingCoverage of Cancer Therapies

Respondents, %

70

60

50

40

30

20

10

0 1 = Not important 2 3 4 5 = Very important

Rating

Question: Please rate each of the following efficacy end points in terms of their importanceand influence when evaluating cancer therapies for coverage and reimbursement.

Overall survivalProgression-free survival Duration of responseOverall response rateTime to symptom progressionTime to treatment failure

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62%

52%

48%

31%

21%

14%

10%

10%

3%

Elimination of exclusions for preexisting conditions

CER

Elimination of lifetime caps on coverage

Required coverage of Standard of Care for patients in clinical trials

340B hospital reimbursement

Closing of the Medicare coverage “doughnut hole” gap

Changes to the PQRI incentive payments

Changes to the SGR payment system

Other

Figure 2 Elimination of Exclusion for Preexisting Conditions and CER Are Expected to Have the Greatest Impact on Oncology Management

Question: What aspects of the healthcare reform legislation will have the most impact onyour approach to management of oncology therapies? Please choose all that apply.

Respondents, %0 20 40 60 80

CER indicates comparative effectiveness research; PQRI, Physician Quality Reporting Initiative; SGR, SustainableGrowth Rate.

studies and other data sources, to identify treatment reg-imens that produce the best possible clinical outcomesfor patients with different types of cancer. The guidelinesuse disease stage and other patient factors to identify pre-ferred and alternate regimens, which are continuallyrevised and updated as new data become available.These guidelines serve as standards of medical care andas compendia for reimbursement for approved and foroff-label uses of antitumor agents.17 For example, thecontinued use of bevacizumab for the treatment of breastcancer has been recommended by the NCCN guide-lines, even after the withdrawal of the US Food andDrug Administration indication for this purpose.18Participants were asked how frequently self-insured

employers or employee benefit consultants require theuse of NCCN guidelines when soliciting bids for oncolo-gy pharmacy management services. The use of clinicalpractice guidelines for coverage or reimbursement is “veryfrequent” (occurring in >75% of all requests for proposals[RFPs]) by 10% of respondents, “frequent” (51%-75% ofall RFPs) by 21% of respondents, “moderately frequent”(26%-50% of all RFPs) by 7%, and “used in someinstances” (10%-25% of all RFPs) by 14% of respon-dents. Only 14% say that clinical guidelines are not used

at all, and the remaining 34% consider the question notapplicable to their contracting practices. Data sourcesrequired for off-label reimbursement include NCCNguidelines (72%), compendia listings (66%), and peer-reviewed articles in the medical literature (66%). Otherrequirements for off-label treatment include failure of on-label therapy (52%), prior authorization (52%), and pre-scribing physician documentation (28%). Participants were also asked to rate the importance,

on a scale of 1 (not important) to 5 (very important), ofdifferent efficacy end points that they consider whenevaluating cancer therapies for reimbursement. Overallsurvival (OS) is the most important efficacy end point,with a rating of “very important” by 59%; progression-free survival (PFS) was rated as “very important” by28%; and duration of response by 24% (Figure 1).

Healthcare Reform and Comparative Effectiveness ResearchThe Patient Protection and Affordable Care Act

(ACA) was signed into law on March 23, 2010. Thegoals of the ACA include expanding access to healthinsurance coverage, improving affordability and sustain-ability for those with coverage, controlling healthcare



Figure 4 Randomized Controlled Trials and Population Studies Expected to Have the Most Impact on Cost of Care and Drug Utilization

Respondents, %

80

60

40

20

0Populationstudies,including

registries andadministrativeand claims data

Question: Which CER methodologies will have the greatest impact on cost-efficientcare and drug utilization? Please check all that apply.

Clinical decisionmodels,

including cost-effectivenessand cost-utility

analysis

Systematicreviews andmeta-analysis

Prognostic andpredictive associationstudies

Randomizedcontrolled trials

79%

CER indicates comparative effectiveness research; QOL, quality-of-life.

QOL studies,including

patient-reportedoutcomes

Quality-adjusted life-years

measurement

69%

59%

48%

21% 21% 21%

Figure 3 Healthcare Reform Expected to Lead to Greater Utilization Restrictions and More Stringent CER Requirements

Respondents, %

70

60

50

40

30

20

10

0More stringentcomparative

effectiveness evidencerequirements

Question: How will the healthcare reform legislation impact your management of oncology agents?Please check all that apply.

Increased patient cost-sharing throughuse of specialty tier

Narrower patientidentification for

appropriate utilization

OtherIncrease in utilizationrestrictions (eg, PAs,

step edits)

59%

48%

38%31%

10%

CER indicates comparative effectiveness research; PAs, prior authorizations.

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costs, and improving the quality of care.19 The ACA isexpected to standardize coverage by defining a numberof significant changes in oncology practice, includingelimination of exclusions for preexisting conditions orlifetime caps on coverage, coverage of routine care forpatients participating in clinical trials, changes in reim-bursement, and expanded access to the federal 340Bdrug discount pricing program.19-22 In addition, the USAmerican Reinvestment and Recovery Act of 2009promotes comparative effectiveness research (CER)through a separate $1.1 billion appropriation to fundclinical studies that will compare efficacy, safety, andother primarily clinical outcomes associated with 2 ormore treatments for the same medical problem.23

When asked to identify aspects of healthcare reformlegislation that will have the greatest impact on oncologymanagement, elimination of exclusions for preexistingconditions was selected by 62% of respondents, followedby the use of CER (52%), eliminating lifetime caps oncoverage (48%), required coverage for patients in clinicaltrials (31%), and increased number of hospitals eligiblefor the federal 340B drug discount (21%; Figure 2).

Regarding the impact of healthcare reform on themanagement of cancer drugs, most respondents (59%)expect that healthcare reform measures would lead togreater utilization restrictions, such as prior authoriza-tions or step edits; 48% anticipate the use of more strin-gent requirements for comparative effectiveness evi-dence; 38% anticipate greater patient cost-sharingthrough the use of a specialty pharmacy tier; and 31%expect narrower patient identification for appropriateutilization (Figure 3). CER methodologies that are expected to have the

greatest impact on cost of care and drug utilizationinclude randomized controlled clinical trials, populationstudies, and clinical decision models (Figure 4). In addi-tion, most respondents (66%) believe that it is probable,and 3% believe that it is highly probable, that CER willhelp control oncology costs and healthcare utilization;10% consider this outcome to be highly improbable orimprobable; and 21% are neutral on this question. CERis expected to help identify the most effective interven-tions to improve care by 76% of payers. None of the planssurveyed are currently involved in new CER models.

Accountable Care OrganizationsAccountable care organizations (ACOs) are affilia-

tions of healthcare providers that are held jointlyaccountable for improving care quality and reducingspending.24 ACOs are established by the ACA as a newpayment model under Medicare, Medicaid, and privateinsurance.25 They are intended to reduce fragmentationof care,26 although their precise implementation inoncology practice remains uncertain. Primary care physi-cians may join only 1 ACO; oncologists may join 2 ormore ACOs as independent physicians, but they are notpermitted to launch new ACOs.When asked to rate their overall impressions of

ACOs, 48% of surveyed respondents were neutral, 38%were favorable or highly favorable, and 14% were un -favorable or highly unfavorable. Those with negativeopinions of ACOs emphasize factors such as the resem-blance of ACOs to the “gatekeeper” role of HMOs,potential barriers to care for rural patients, and the diffi-culties involved in moving physicians from private prac-tice to employee status. Those with positive opinions ofACOs note the potential for improved care manage-ment and the use of incentives to align primary carephysicians, specialists, and hospitals. Participants view ACOs as moderately relevant

(52%), relevant (31%), or very relevant (7%) to oncol-ogy care; only 10% say that ACOs are not relevant tooncology. In addition, 24% believe that they would formor partner with an ACO within the next 2 years, andanother 41% say that such a move is possible. Of those

Table 2 Primary Drivers for Forming/Partnering with an ACO

Item Overall rank

Improve quality of care and performance standards

1

Increase lower-cost treatment alternative utilization

2

Improve outcomes data tracking 3

Improve overall spending tracking 4

Improve patient drug compliance 5

Improve physician adherence to the formulary

6

Implement pay-for-performance 6

Legislative requirement for Medicare beneficiaries

7

ACO indicates accountable care organization.

CER methodologies that are expected tohave the greatest impact on cost of careand drug utilization include randomizedcontrolled clinical trials, population studies, and clinical decision models.



indicating having plans to form or partner with anACO, 16% plan to address the Medicare population,26% the commercial population, and 58% both popula-tions. The primary drivers for forming or partnering withan ACO are shown in Table 2. Although the US Department of Health and

Human Services operates an ACO pilot program (thePioneer Accountable Care Organization Model pro-gram),27 only 31% of respondents expressed an interestin participating in that program. Lack of interest in apilot program, a perception of the program as overlycumbersome, or competition with other priorities werecited as reasons for nonparticipation in the PioneerACO pilot program.Most (76%) respondents believe that ACOs would

result in cost-savings of 1% to 30%; 18% believe thatACOs would yield no cost-savings, and 4% believe thatcost-savings would likely exceed 40%. They expect thatthe cost-savings would be generated primarily throughgreater adherence to evidence-based treatments, improve-ment in coordination of care, and greater use of low-costalternative treatment options. ACOs are considered mostlikely (83% of respondents) to yield cost-savings in thetreatment of breast cancer (Figure 5). Other cancer typesexpected to yield cost-savings include prostate cancer(identified by 58%), lung cancer (58%), metastaticmelanoma (29%), and hematologic malignancies (21%).

Quality InitiativesOver the past decade, several initiatives have been

developed to quantify and improve the quality of carereceived by patients with cancer. ASCO has sponsoredthe development and dissemination of the QualityOncology Practice Initiative (QOPI), a voluntary, physi-cian-led program that is designed to improve oncologypractice by identifying general performance measures, aswell as specific performance measures for breast, colon,lung, and rectal cancer, and NHL.28 The NCCN andASCO have also developed a simplified set of qualitymeasures for breast and colorectal cancer.29 ThePhysician Quality Reporting System (PQRS), formerlyknown as the Physician Quality Reporting Initiative(PQRI), was established by the Centers for Medicare &Medicaid Services as a voluntary reporting system that islinked to financial incentives for eligible healthcare pro-fessionals who provide care to Medicare recipients.30Health plans are experimenting with a variety of

approaches to manage costs associated with oncologycare, while also ensuring that patients receive care thatmeets evidence-based standards. For example, UnitedHealthcare has been evaluating the effects of a “bun-dled” payment pilot program in 5 oncology practices, inwhich these practices receive an up-front fee for the full

cost of care for each episode of cancer care rather thanpurchasing cancer medications and receiving reimburse-ment for these purchases. This approach is intended tostandardize cancer care and encourage greater adherenceto treatment guidelines, while separating evidence-basedmedication prescribing from drug reimbursement.31 Aquality improvement program led by the University ofMichigan, in coordination with Blue Cross Blue Shield,has been developed to increase the statewide use of breastcancer treatments that meet benchmarks recommendedby the NCCN, including appropriate use of endocrinetherapy, chemotherapy, and radiation therapy.32 In this present survey, nearly half (48%) of respon-

dents have no plans to implement quality initiatives,35% plan to implement quality measures created by theNCCN, 24% plan to implement the ASCO QOPI, 7%plan to implement the PQRS/PQRI measures, and 3%plan to implement other quality measures. Quality ini-tiatives are believed to have the greatest potentialimpact on breast cancer, with 83% agreeing that initia-tives would improve the care of patients with breast can-cer, followed by prostate cancer (48%), lung cancer(45%), hematologic malignancies (21%), and metastaticmelanoma (17%). In addition, 35% say that quality ini-

Figure 5 ACOs Expected to Generate the Greatest Cost-Savingsin the Treatment of Patients with Breast Cancer

Respondents, %

80

60

40

20

0Prostatecancer

Question: In which types of cancer indications do you expect tosee the biggest cost-savings to your plan as a result of your formation/partnership with an ACO? Please check all that apply.

Lung cancer Metastatic melanoma

Hematologic malignancies

Breast cancer

83%

ACO indicates accountable care organization.

58% 58%

29%

21%

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tiatives are unlikely to significantly affect any indication. Survey respondents believe that quality initiatives

have the potential to improve the use of evidence-basedtreatments (97%), including a reduction in the use ofimaging studies without compelling clinical evidence(52%) and an increase in patient–provider discussionsabout palliative care (35%). However, the respondentswere split on the types of incentives they would offer forparticipation in quality initiatives: 31% would offer apercentage of cost-savings, 7% would offer incentivesbased on quality achievements, 28% would not offerincentives, and 35% were unsure about the types ofincentives they would offer.

Personalized Medicine: The Role of Diagnosticsand Tumor MarkersTargeted therapies make it possible to modulate cellu-

lar signal transduction pathways that are important intumor growth and development, whereas new geneticand molecular tests make it possible to identify individualpatients who are most likely to benefit from a particulartreatment strategy and to predict toxicity reactions.33-35Greater individualization of therapy may also help toreduce overall costs by identifying patients who are notappropriate candidates for certain treatments. Examplesof biomarkers that are used in treatment selection includebiomarkers for the expression of epidermal growth factorreceptor mutations to predict response to erlotinib inpatients with advanced lung cancer,36 as well as biomark-ers for overexpression of the HER2 protein to predicttrastuzumab response in patients with breast cancer.37The decision to cover a particular oncology diagnos-

tic test is significantly influenced by published clinicalpractice guidelines, according to 90% of survey respon-dents. ASCO and NCCN guidelines are the most influ-ential in determining genetic test coverage, and bothare cited as important by 73% of those surveyed.Regarding the types of information that would be need-ed to increase the acceptance of genetic testing, proof ofgreater specificity/sensitivity was identified by 79% ofrespondents, cost-effectiveness data by 62%, identifica-tion of more clinically meaningful targets by 48%, andclinical trials with larger sample sizes by 35%. For reim-bursement, a majority (64%) of respondents agree that acompanion diagnostic test must produce an improvementin the overall treatment response rate between 11% and30% in the target population compared with untestedpatients (Figure 6). In addition, a companion diagnostictest must improve OS or PFS by 3 to 7 months in the tar-geted population for the test to be reimbursed (Figure 7).

DiscussionFew recent studies have surveyed managed care pro-

fessionals regarding their views on oncology cost-man-agement strategies and expectations for future trends.One recent study conducted by the NCCN was based oninterviews with physician executives at MCOs to identi-fy their perspectives on the oncology marketplace, andthe measures they used to address the cost and quality ofcancer care.9 Frequently used cost-control strategiesincluded aggressive contracting, new reimbursementmodels, case management, use of NCCN guidelines toestablish treatment standards, and the use of specialtypharmacy services.9

Figure 6 A Companion Diagnostic Test Must Improve ORR by 11% to 30% in the Targeted Population Compared with Untested Patients for Reimbursement Consideration

Respondents, %

30

20

10

06-10

Question: For your organization to reimburse a diagnostic test relevant to a targeted treatment, whatlevel of clinical benefit (such as ORR) does a diagnostic test need to show versus all-comers?

16-20 21-25 26-30<5

4%

ORR indicates overall response rate.

31-35 >4136-4011-15

4%

15%

4%

15%

9%

13%

27%

11%

Improved ORR with diagnostic test, %



Our survey has evaluated viewpoints of managed careprofessionals in the present, at a time when oncologymanagement costs are rising rapidly, and there is yet con-siderable uncertainty about the eventual impact ofhealthcare reform on oncology practice. Key insightsfrom this present survey include: • Health plans and PBMs expect to see increased use ofspecialty pharmacy services during the next 5 years

• When clinical outcomes are similar, respondentsoverwhelmingly prefer oral oncolytic agents toinjectable chemotherapy drugs

• Clinical guidelines are frequently used to establishcoverage and reimbursement criteria, including thosefor off-label uses; when evaluating different treat-ments, OS is considered the single most importantclinical end point

• Most respondents believe that healthcare reformefforts would help to control oncology costs, butthat these measures would also result in greater uti-lization restrictions

• Nearly all respondents view ACOs as relevant tooncology care; however, many have not yet formedan opinion about whether the impact of ACOs wouldlikely be positive or negative, and interest in partici-pating in pilot programs is generally low

• Quality improvement measures are perceived to havethe potential to improve cancer care and the use ofevidence-based treatments, yet nearly half of therespondents have no plans to use such measures

• Participants believe that ACOs and quality improve-ment measures have the greatest potential impact on

the treatment of breast cancer • ASCO and NCCN guidelines are important consider-ations in reimbursement decisions for genetic testing.

ConclusionThe survey findings highlight important emerging

trends in oncology management, as well as informing thecoordination of cost and clinical management ofpatients with cancer. In general, health plans and PBMsshow a great deal of interest in monitoring and control-ling costs of cancer therapy. Published guidelines fromASCO and the NCCN are central to payer views abouttreatment selection, reimbursement, off-label prescrib-ing, and genetic testing. CER is believed to help identifybetter treatment options and control costs, althoughmost respondents also believe that healthcare reformwould lead to more restrictions on the use of some can-cer therapies. ACOs generated the greatest uncertaintyamong the topics included in this survey; althoughrespondents expect ACOs to significantly affect oncolo-gy management over the next 2 years, most are not yetplanning to form or join such an organization, and theirattitudes in general toward ACOs remain largely neu-tral. In addition, there is a significant gap between pay-ers’ perceptions about the potential benefit of qualityimprovement measures and their plans to use such mea -sures at their own organizations. When considering therole of genetic testing, respondents expect to see measur-able improvements attributable to testing on clearlydefined clinical end points, such as overall response rateand duration of OS. ■

Figure 7 A Companion Diagnostic Test Must Improve OS or PFS by 3 to 7 Months in the Targeted Population over All-Comers for Reimbursement Considerations

Respondents, %

30

20

10

01-2

Question: For your organization to reimburse a diagnostic for a targeted treatment, what level ofclinical benefit (such as PFS or OS) does a diagnostic test need to show versus all-comers?

3-4 4-5 5-7<1

4% 4%2%

4%6% 7%

15%17%

22%

15%15%

20%22%

24%

15%13%

OS indicates overall survival; PFS, progression-free survival.

>107-102-3

Months (OS and PFS)

Overall survivalProgression-free survival

Continued

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Author Disclosure StatementMs Greenapple reported no conflicts of interest.

References1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: AmericanCancer Society; 2012.2. Fitch K, Pyenson B. Cancer patients receiving chemotherapy: opportunities forbetter management. http://publications.milliman.com/research/health-rr/pdfs/cancer-patients-receiving-chemotherapy.pdf. March 30, 2010. Accessed February 1, 2012.3. Express Scripts Research & New Solutions Lab. 2011 Drug Trend Report. April2012. www.drugtrendreport.com/docs/reports/Express_Scripts-Drug-Trend-Report.pdf.Accessed May 10, 2012.4. Smith BD, Smith GL, Hurria A, et al. Future of cancer incidence in the UnitedStates: burdens upon an aging, changing nation. J Clin Oncol. 2009;27:2758-2765.5. Campbell MC, Kaufman MB, Bendix J. Oral oncology drugs: navigating dispens-ing, billing, and reimbursement challenges is a daunting but not insurmountable task.Modern Medicine. 2009. www.modernmedicine.com/modernmedicine/Modern+Medicine+Now/Oral-oncology-drugs/ArticleStandard/Article/detail/578180.Accessed February 21, 2012. 6. Bach PB. Limits on Medicare’s ability to control rising spending on cancer drugs.N Engl J Med. 2009;360:626-633. www.nejm.org/doi/suppl/10.1056/NEJMhpr0807774/suppl_file/nejm_bach_626sa1.pdf. Accessed February 17, 2012.7. Diamandis M, White NMA, Yousef GM. Personalized medicine: marking a newepoch in cancer patient management. Mol Cancer Res. 2010;8:1175-1187.8. M.D. Anderson Cancer Center. Your first visit. www.mdanderson.org/education-and-research/departments-programs-and-labs/programs-centers-institutes/clinical-cancer-genetics/your-first-visit/index.html. Accessed May 2, 2012. 9. Danielson E, DeMartino J, Mullen JA. Managed care & medical oncology: thefocus is on value. J Natl Compr Canc Netw. 2010;8(suppl 7):S28-S37.10. Meropol NJ, Schulman KA. Cost of cancer care: issues and implications. J ClinOncol. 2007;25:180-186.11.Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care inthe United States: 2010-2020. J Natl Cancer Inst. 2011;103:117-128.12. Fojo T, Grady C. How much is life worth: cetuximab, non–small cell lung cancer,and the $440 billion question. J Natl Cancer Inst. 2009;101:1044-1048.13. Carroll J. Oncologists plead for fairer drug payments. Manag Care. 2008;17:32-34.14. Stern D, Reissman D. Specialty pharmacy cost management strategies of privatehealth care payers. J Manag Care Pharm. 2006;12:736-744.15. Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anti-cancer treatment. CA Cancer J Clin. 2009;59:56-66.16. Kaiser Family Foundation. Medicare at a glance. Publication #1066-14. IssuedNovember 2011. www.kff.org/medicare/upload/1066-14.pdf. Accessed February 24, 2012.17. Soares M. “Off-label” indications for oncology drug use and drug compendia: his-tory and current status. J Oncol Pract. 2005;1:102-105. 18. Bankhead C. NCCN backs Avastin for breast cancer. MedPage Today. July 27,2011. www.medpagetoday.com/HematologyOncology/BreastCancer/27772. AccessedJune 28, 2012.

19. Dalton WS, Sullivan DM, Yeatman TJ, Fenstermacher DA. The 2010 HealthCare Reform Act: a potential opportunity to advance cancer research by taking can-cer personally. Clin Cancer Res. 2010;16:5987-5996.20. Moy B, Polite BN, Halpern MT, et al. American Society of Clinical Oncologypolicy statement: opportunities in the Patient Protection and Affordable Care Act toreduce cancer care disparities. J Clin Oncol. 2011;29:3816-3824.21. Barlas S. Health care reform bill expands access to section 340B discounted drugsfor hospitals. PT. 2010;35:632-634.22. Jones EC, Amery M. Health care reform: what it may mean for your practice.Neurology. 2010;75(suppl 1):S52-S55.23. American Medical Association. H.R. 1, the “American Recovery and Reinvest -ment Act of 2009”: explanation of comparative effectiveness research (CER) provi-sions. www.ama-assn.org/ama1/pub/upload/mm/399/arra-cer-provisions.pdf. AccessedFebruary 11, 2012.24.Greaney TL. Accountable care organizations—the fork in the road. N Engl J Med.2011;364:e1.25. Piper K. The new accountable care organizations and Medicare gain-sharing pro-gram. Am Health Drug Benefits. 2010;3:261-262.26. Berwick DM. Launching accountable care organizations—the proposed rule forthe Medicare Shared Savings Program. N Engl J Med. 2011;364:e32.27.Centers for Medicare & Medicaid Services. Pioneer ACO model. http://innovations.cms.gov/initiatives/aco/pioneer/. Accessed February 22, 2012. 28. The Quality Oncology Practice Initiative. Program details presentation. January2012. http://qopi.asco.org/Documents/QOPIProgramDetailsPresentation-December2011.pdf. Accessed June 28, 2012.29. Desch CE, McNiff KK, Schneider EC, et al. American Society of ClinicalOncology/National Comprehensive Cancer Network quality measures. J Clin Oncol.2008;26:3631-3637.30. Centers for Medicare & Medicaid Services. Physician Quality ReportingInitiative (PQRI) and Electronic Prescribing Incentive Program (eRx) and MedicareAdvantage (MA) plans. September 2010. www.cms.gov/MLNProducts/downloads/wPQRIMAPlansTS.pdf. Accessed February 12, 2012. 31. Burns J. UnitedHealthcare’s bold effort to deal with cancer drug costs. ManagCare. 2011;20:12-14,16.32. Silver SM, Mehringer AM, Hayes A, et al. Michigan Breast Oncology QualityInitiative (MiBOQI): a state-wide multidisciplinary breast cancer quality initiative—concordance with quality measures. Poster presented at the American Society ofClinical Oncology Breast Cancer Symposium. October 8-10, 2009; San Francisco, CA. 33. Chiang A, Million RP. Personalized medicine in oncology: next generation. NatRev Drug Discov. 2011;10:895-896.34. Schilsky RL. Personalized medicine in oncology: the future is now. Nat Rev DrugDiscov. 2010;9:363-366.35. Duffy MJ, Crown J. A personalized approach to cancer treatment: how biomark-ers can help. Clin Chem. 2008;54:1770-1779.36.Huang CH, Powers BC. The evolving role of maintenance therapy using epidermalgrowth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in the management ofadvanced non-small-cell lung cancer. Clin Med Insights Oncol. 2012;6:137-147.37. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvantchemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-1672.

The Cost of Cancer Care: In Search of New SolutionsPATIENTS: The treatment of cancer and the asso-

ciated cost of cancer care is a topic of major importancefor patients and for health plans alike. According tothe American Cancer Society, more than 1.6 millionAmericans will be diagnosed with some form of cancerin 2012 (Table).1As a result of advances in cancer diagnosis and

treatment during the past several decades, the 5-yearsurvival rate for all cancer types increased from 49%for patients diagnosed between 1975 and 1977, to67% for those diagnosed between 2001 and 2007.1Although more than 577,000 Americans are expect-ed to die of cancer this year, the increased number ofpatients diagnosed with cancer and the improved

long-term survival rates mean that the number ofAmericans living with cancer will increase by nearly1 million in 2012. In addition, it has been estimated that with the

aging of the US population, the annual number ofnewly diagnosed cancers will increase by approxi-mately 45%, to 2.3 million, by 2030.2A recent analysis indicates that the overall US cost

of cancer care is approximately 10% of the totalhealthcare costs.3 According to a recent ExpressScripts report, cancer drugs are the third most expen-sive category among specialty drugs, with an averagecost of $3259 per prescription.4 Many of these drugsare biologics that have been available for some time;




for example, rituximab (Rituxan)was launched in 1997 and trastuzu -mab (Herceptin) in 1998. These 2drugs accounted for more than $4.5billion in US sales in 2011.5In addition, the cancer drug

pipeline is robust. A report by thePharmaceutical Research and Man -ufac turers of America reveals thatUS drug manufacturers are testing981 targeted medicines for cancer,including lung cancer (121 drugs),lymphoma (117 drugs), and breastcancer (111 drugs).6 The cost ofusing cancer drugs in the UnitedStates is expected to grow by 20%annually, to $173 million by 2020.7The annual cost of treatment perpatient could top $100,000 for thosereceiving combination cancer drugs.7MEDICAL/PHARMACY DIRECTORS: With

this as a backdrop, the survey data in Ms Greenapple’sarticle are very relevant, clearly showing that the costof oncology care—driven by increasing numbers ofpatients, greater survival rates, and the ever-growing costof care—is an area of major concern for all health plansand pharmacy benefit managers. It is unclear, however,how health plans will be able to effectively manage thiscost trend and maintain affordability. In an era of health-care reform that is enrolling more individuals into theinsured population, this issue is certain to grow in scope. Health plans must find new solutions to manage this

trend. This will require meaningful comparative effec-tiveness research, guideline and pathway managementthat keeps up with changing technologies, and pro -viders’ commitment to consider fiscal, as well as clini-cal, responsibility when managing patients with cancer.Current therapies are simply too expensive to ignorecost. It is hoped that new entities, such as accountablecare organizations, will bring new solutions to augmentthe efforts of health plans. Meanwhile, plans must con-tinue to look for new and better ways to manage thesepatients. Personalized medicine, gene-expression testing,

and other gene-based tests may provide help, but therole of such testing for effectively managing most cancersremains unclear. The next decade will bring manyimportant developments in cancer; health plans must bewilling to try new solutions to effectively manage thisarea of medical care.

1. American Cancer Society. Cancer Facts & Figures 2012. www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf.Accessed July 13, 2012.2. Smith BD, Smith GL, Hurria A, et al. Future of cancer incidence in the UnitedStates: burdens upon an aging, changing nation. J Clin Oncol. 2009;27:2758-2765.3. Fitch K, Pyenson B. Cancer patients receiving chemotherapy: opportunities forbetter management. March 30, 2010. http://publications.milliman.com/research/health-rr/pdfs/cancerpatients-receiving-chemotherapy.pdf. Accessed July 1, 2012.4. Express Scripts. 2011 Drug Trend Report. April 2012. www.drugtrendreport.com/docs/reports/Express_Scripts-Drug-Trend-Report.pdf. Accessed July 12, 2012.5. Stanton T. Top 10 best-selling cancer drugs. Fierce Pharma. May 15, 2012.www.fiercepharma.com/special-reports/top-10-best-selling-cancer-drugs/top-10-best-selling-cancer-drugs?utm_medium=nl&utm_source=internal. Accessed July 16, 2012.6. Grogan K. Nearly 1000 cancer drugs in development in USA. June 1, 2012.Pharma Times On-Line. www.pharmatimes.com/Article/12-06-01/Nearly_1_000_cancer_drugs_in_development_in_USA.aspx. Accessed July 1, 2012.7. Palmer E. With targeted cancer drugs, cost vs benefits gets more complicated.Fierce Pharma. June 15, 2012. www.fiercepharma.com/story/targeted-cancer-drugs-cost-vs-benefits-gets-more-complicated/2012-06-15?utm_medium=nl&utm_source=internal. Accessed July 12, 2012.

Gary M. Owens, MDPresident, Gary Owens Associates

Philadelphia, PA

STAKEHOLDER PERSPECTIVE (Continued)

Table Estimated Cancer Casesa in the United States, 2012

Cancer type in men (N = 848,170)

Estimated cases, %

Cancer type in women(N = 790,740)

Estimated cases, %

Prostate 29 Breast 29

Lung and bronchus 14 Lung and bronchus 14

Colon and rectum 9 Colon and rectum 9

Urinary bladder 7 Uterine corpus 6

Melanoma of skin 5 Thyroid 5

Kidney and renal pelvis 5 Melanoma of skin 4

Non-Hodgkin lymphoma 4 Non-Hodgkin lymphoma 4

Oral cavity 3 Kidney and renal pelvis 3

Leukemia 3 Ovary 3

Pancreas 3 Pancreas 3

All other sites 18 All other sites 20aExcludes basal and squamous skin cell cancers and in situ carcinomas, excepturinary bladder.Source: American Cancer Society. Cancer Facts & Figures 2012.


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One focus: a shared commitment to improve the lives of cancer patients everywhere.

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.

To make a dramatic impact on cancer therapeutics, we are dedicated to a strong partnership with

the oncology community.

©2012 Millennium Pharmaceuticals, Inc. All rights reserved.

To learn more, visit us at millennium.com.

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July 2012, Vol 5, No 4

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Transcript of July 2012, Vol 5, No 4