July 2012, Vol 5, No 4 by Dalia Buffery

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ JULY 2012

VOLUME 5, NUMBER 4

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

Hematology/Oncology Theme Issue INTRODUCTION

Cancer: Exploding Treatment and Diagnostic Pipeline, and Ever-Increasing Costs Craig K. Deligdish, MD PERSPECTIVES

Defining Value in Cancer Care: AVBCC 2012 Steering Committee Report ™

Gene 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 Literature Quang 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 Management Kamakshi 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 Benefit Managers’ Perspectives on Changing Care Models Rhonda Greenapple, MSPH Stakeholder Perspective by Gary M. Owens, MD

Making

PRO gress with patient-reported outcomes How PROs were successfully integrated into the Jakafi® (ruxolitinib) drug development program1 A novel approach to engage clinicians and FDA

TAILORING a PRO tool for myelofibrosis

PROs are an important means to demonstrate treatment

Myelofibrosis (MF) is a life-threatening, progressive disease

2,3

Use of a PRO instrument can

characterized by splenomegaly, debilitating symptoms and

evaluate symptoms best judged by the patient, whether

cytopenias.5-7 Measures to assess both the splenomegaly

caused by the disease or treatment toxicity. Assessment

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

of symptom burden is important because it can be a major

double-blind placebo-controlled study, COMFORT-I, for Jakafi.

indicator of disease severity, progression or improvement.

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

Incorporating PROs into a clinical trial program provides a

primary and biologic endpoint, and a reduction in total symptom

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

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

perspective and helps patients and clinicians make better-

The TSS encompassed the following symptoms: abdominal

benefits in clinical trials.

informed decisions.

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 specifically developed. After patient interviews, advice from clinical experts and extensive input from the FDA, the modified Myelofibrosis Symptom Assessment Form, version 2.0 (modified MFSAF v2.0) was finalized as part of the Special Protocol Assessment prior to the initiation of COMFORT-I. Ultimately, Jakafi was approved by the FDA for the treatment of intermediate or high-risk MF.1,8 This became Incyte’s first approved drug and also the first oncology medicine approved with symptom data in its label since the FDA’s draft guidance on PROs was finalized in 2009.2,4

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted 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 Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions. Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with

JAKAFI endpoints included both biologic and patient-reported outcomes8,9 COMFORT-I: Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation9,a

COMFORT-I: Percent Change in TSS in Individual Patients From Baseline to Week 24 or Last Observation9,a,b 150

-20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

Placebo (n = 153)

Each bar represents an individual patient’s response.

50 0 -50

-100

WORSENING

100

IMPROVEMENT

Change From Baseline (%)

WORSENING

IMPROVEMENT

Change From Baseline (%)

50% Improvement

Upper 50th Percentile

Jakafi (n = 145)

Upper 50th Percentile

Placebo (n = 145)

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

PROVIDING proof of patient benefit MF is progressive, and spleen size and symptoms can become increasingly burdensome to patients over time.5-7 Jakafi 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 Jakafi 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 Jakafi marks a significant milestone in which validated PRO instruments can provide symptom data and demonstrate clinical benefit. The experience with Jakafi may provide a model for the future use of PROs in marketing applications.8

renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother 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: Patientreported outcome measures: Use in medical product development to support labeling claims. December 2009. 4. Basch E, et al. Issue brief from Conference on Clinical Cancer 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. (Epub ahead of print). 9. Jakafi Prescribing Information. Incyte Corporation. November 2011. 10. Data on File, Incyte Corporation.

a As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III

study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline 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 modified 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 Jakafi group and 16.5 in the placebo group.9,10

Please see Brief Summary of Full Prescribing Information on the following page.

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All b Parameter Grade 3 Grade 4 Grades Grade 3 Grade 4 Grades BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with 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 and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was 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 treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], f Herpes Zoster 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information]. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved. Issued: November 2011 RUX-1040 reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

EDITORIAL BOARD EDITOR-IN-CHIEF

David B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health Philadelphia, PA DEPUTY EDITORS

Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Jefferson University School of Population Health, Philadelphia, PA Laura T. Pizzi, PharmD, MPH, RPh Associate Professor, Department of Pharmacy Practice, Jefferson School of Pharmacy Philadelphia, PA AGING AND WELLNESS

Eric G. Tangalos, MD, FACP, AGSF, CMD Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Al B. Benson, III, MD, FACP Professor of Medicine, Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University, IL Past President, ACCC Past Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FASCO Professor of Internal Medicine Hematology/Oncology Assistant Dean for Research Associate Director, Faculty Group Practice University of Michigan Medical School, MI Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, LLC, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare and Bentteligence, Sharon, MA ENDOCRINOLOGY RESEARCH

MANAGED MARKETS

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ EPIDEMIOLOGY RESEARCH

Joshua N. Liberman, PhD Executive Director, Research, Development & Dissemination Sutter Health, Concord, CA GOVERNMENT

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group, LLC Washington, DC HEALTH INFORMATION TECHNOLOGY Kelly Huang, PhD President, HealthTronics, Inc. Austin, TX J. B. Jones, PhD, MBA Research Investigator, Geisinger Health System, Danville, PA Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship University of Michigan, School of Public Health and Medicine, Ann Arbor, MI HEALTH OUTCOMES RESEARCH

Diana Brixner, RPh, PhD Professor and Chair Department of Pharmacotherapy Executive Director, Outcomes Research Center, Director of Outcomes Personalized Health Care Program, University of Utah Salt Lake City, UT

Vol 5, No 4

July 2012

POLICY & PUBLIC HEALTH

HEALTH & VALUE PROMOTION

Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks, Orlando, FL Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA Albert Tzeel, MD, MHSA, FACPE National Medical Director HumanaOne, Waukesha, WI

EMPLOYERS

Teresa DeLuca, MD, MBA Senior VP, PBM Leader Humana Solutions, Louisville, KY Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate, Menlo Park, CA Michael S. Jacobs, RPh Vice President, National Accounts Truveris, Inc., New York, NY Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Paul Anthony Polansky, BSPharm, MBA Senior Field Scientist, Health Outcomes and PharmacoEconomics (HOPE) Endo Health Solutions, Chadds Ford, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA Scott R. Taylor, BSPharm, MBA Executive Director, Industry Relations Geisinger Health System, Danville, PA

Joseph Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT Steve Miff, PhD Senior Vice President VHA, Inc., Irving, TX Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver, CO Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia, PA Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, Philadelphia School of Pharmacy, University of the Sciences Philadelphia, PA David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD

Jeffrey A. Bourret, RPh, MS, FASHP Senior Director, Medical Lead, Payer and Specialty Channel Strategy, Medical Affairs Pfizer Specialty Care Business Unit, PA Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC PATIENT ADVOCACY

William E. Fassett, BSPharm, MBA, PhD, FAPhA Professor of Pharmacy Law & Ethics Dept. of Pharmacotherapy, College of Pharmacy Washington State University, Spokane, WA Mike Pucci Sr VP Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC PERSONALIZED MEDICINE

Emma Kurnat-Thoma, PhD, MS, RN Director, Research Services URAC, Washington, DC PHARMACOECONOMICS

Josh Feldstein President & CEO CAVA, The Center for Applied Value Analysis, Inc., Norwalk, CT Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

RESEARCH & DEVELOPMENT

Frank Casty, MD, FACP Chief Medical Officer Senior VP, Clinical Development Medical Science Endo Pharmaceuticals, Chadds Ford, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA SPECIALTY PHARMACY

Atheer A. Kaddis, PharmD Senior Vice President Managed Markets/Clinical Services Diplomat Specialty Pharmacy Flint, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA Michael Kleinrock Director, Research Development IMS Institute for Healthcare Informatics Collegeville, PA

PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ

www.AHDBonline.com

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise Institute Washington, DC Robert W. Dubois, MD, PhD Chief Science Officer National Pharmaceutical Council, Washington, DC Jack E. Fincham, PhD, RPh Professor of Pharmacy, Practice and Administration School of Pharmacy, University of Missouri Kansas City, MO Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Adjunct Scientist, RAND Health Paul Pomerantz, MBA Executive Director Drug Information Association, Horsham, PA J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA

American Health & Drug Benefits

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JULY 2012

VOLUME 5, NUMBER 4 THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS INTRODUCTION

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

PERSPECTIVES

202 Defining Value in Cancer Care: AVBCC 2012 Steering Committee Report Gene 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

221 Diabetes Medications and Cancer Risk: Review of the Literature Quang 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 Continued

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American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the improvement of healthcare. This publication further provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs.

July 2012

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JULY 2012

VOLUME 5, NUMBER 4 THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

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FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS

(Continued) American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 8 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2012 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

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232 Chemotherapy-Induced Nausea and Vomiting: Optimizing Prevention and Management Kamakshi 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 Benefit Managers’ Perspectives on Changing Care Models Rhonda Greenapple, MSPH

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252 Stakeholder Perspective by Gary M. Owens, MD

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INTRODUCTION

Cancer: Exploding Treatment and Diagnostic Pipeline, and Ever-Increasing Costs By Craig K. Deligdish, MD Hematologist/Oncologist, Oncology Resource Networks, Orlando, FL

ancer has always been a devastating and deadly disease. Unlike many other illnesses, it does not discriminate among populations, and it spares neither young nor old. As our population ages, and the menu for diagnostic tools and treatments becomes more expansive and sophisticated, cancer has been evolving as an increasingly dominant disease for research and discussion. Only 30 years ago, our ability to differentiate subclasses, subtypes, and even the stage of cancer was significantly more limited than it is today. Our understanding of the etiology and pathogenesis, as well as the pathobiology of cancer, has dramatically increased. In addition, the investment by the industry and government in cancer research and treatment has expanded dramatically since President Richard Nixon signed the National Cancer Act of 1971, which expanded and provided additional resources to battle this disease. We have witnessed significant progress in screening, diagnosis, and treatment since the “war” on cancer began. The reality, however, is that despite this progress, many of our new diagnostic modalities and treatments, although costly, provide only incremental benefit. The more dramatic strides in the understanding of cancer biology on a molecular level have been translated into more effective treatments; however, with rare exception, the degree of progress that we have seen in the understanding 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 limited in its ability to prolong life. That being said, cancer rates have decreased in recent years,1 and fewer people are dying from cancer in the United States compared with several decades ago.2 Specifically, an age-specific analysis of cancer mortality based on data from the SEER (Surveillance, Epidemiology, and End Results) program indicated a reduction in mortality during the past several decades in the United States.3 However, a significant contribution to this decreased mortality can be attributed to smoking cessation, a greater focus on cancer screening efforts, and early detection of cancer.1 A number of factors have impeded our ability to

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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 complexity and cellular and molecular heterogeneity of the disease on a global level and on an individual patient level.4 The complexity of cellular interactions and cell signaling within the tumor microenvironment, and the challenges associated with testing new treatment modalities, have hampered our progress in the battle against cancer. Despite these challenges, more patients are living with 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 cancer and prognosticate based on molecular diagnostic tools. These tools have contributed to our ability to expand the resources available to treat cancer. The ability to target therapy and personalize treatments has been furthered by advances in our understanding of the molecular basis of the disease. The diversity of our diagnostic tools and treatments, and the increasing cost of treating cancer care, have contributed to a focus on guidelines and pathways based on evidence-based medicine, with the goal of increasing the prevalence of an evidence-based approach to cancer management. More recently, the concept of “value” has entered the discussion of treating cancer. This issue of American Health & Drug Benefits is representative of the research and efforts in oncology in 3 important areas—cancer epidemiology, the management of treatment-related toxicity, and current and emerging trends in the management of cancer in the United States from the perspective of payers who face increasing challenges as a result of the mounting costs, not only for drugs but also for other treatment modalities. Quang Nguyen, DO, FACE, and colleagues have made an important contribution in their comprehensive review of the literature, addressing the increasing evidence for the relationship between diabetes and cancer and the potential impact of antidiabetes medications on cancer risk. This is an important article, given the significant increase in the prevalence of patients with diabetes

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in the United States, and even more so, the increasing public health hazards associated with obesity, which portend an increasing prevalence of diabetes, further reinforcing the importance of managing both of these diseases in the United States. Kamakshi V. Rao, PharmD, BCOP, CPP, and colleagues review the literature on chemotherapy-induced nausea and vomiting. In their critical review article, the authors highlight the advances that have occurred in the treatment of these toxicities, which are considered by many oncologists to be one of the most significant advances in the past 2 decades in the management of treatment-related side effects in cancer. Recent estimates put the costs of cancer care at $100 billion annually, with projections that the cost could rise up in excess of $200 billion by the end of this decade.5 Much of this cost is borne by government programs, such as Medicare and Medicaid, and much of the remainder being paid for by commercial health insurance companies. Cancer care is an area ripe for cost-saving and quality-improvement interventions, because it is marked by high and rapidly escalating costs, suboptimal adherence to evidence-based guidelines, and wide variations in pricing across regimens that provide similar efficacy. Even in the absence of increasing unit costs for a treatment, the aging of the US population alone will have profound effects on cancer-related spending. Rhonda Greenapple, MSPH, has provided significant insight into the emerging trends in the management of cancer-related costs and other strategies incorporated or anticipated to be introduced by health plans and pharmacy benefit managers, given the dramatic increase in oncology-related treatment options and costs during the past 5 years and those that are expected in the next 5 years. This important article provides competitive insight into innovative approaches, as well as state-of-the-art cancer cost management in light of reimbursement challenges and the expected impact of the Affordable Care Act.

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This issue of the journal also includes a discussion by the Steering Committee of the 2nd Annual Conference of the Association for Value-Based Cancer Care, held on March 28-31, 2012, in Houston, TX, and attended by more than 200 payers, providers, manufacturers, and other stakeholders associated with cancer care delivery and oncology-focused research in the United States.

Cancer care is an area ripe for cost-saving and quality-improvement interventions, because it is marked by high and rapidly escalating costs, suboptimal adherence to evidence-based guidelines, and wide variations in pricing across regimens that provide similar efficacy. This panel of thought leaders addresses the challenges placed on managing patients with cancer by the increasing cost of cancer treatment and discusses and debates the concepts and paths necessary to achieve a valuebased approach to cancer care. We look forward to additional oncology/hematologyfocused peer-reviewed articles in future issues of this journal to assist providers, payers, and other stakeholders who are actively involved in the battle against this devastating disease. â&#x2013;

References 1. Centers for Disease Control and Prevention. Many cancer rates continue to decline. 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 data submission, posted to the SEER website, April 2012. Accessed July 1, 2012. 4. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution 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 the United States: 2012-2010. J Natl Cancer Inst. 2011;103:117-128. Epub January 12, 2011.

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2nd Annual Conference AVBCC 2012 Steering Committee CO-MODERATORS Gene Beed, MD President and CEO Horses, Zebras, and Unicorns Irvine, CA

Gary M. Owens, MD President Gary Owens Associates Glen Mills, PA

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Al B. Benson, III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center, Northwestern Univ.

Ira M. Klein, MD, MBA, FACP Chief of Staff to the Chief Medical Officer Aetna Oncology Strategy Hartford, CT

Samuel M. Silver, MD, PhD, FACP Professor of Internal Medicine Hematology/Oncology Associate Director, Faculty Group Practice, University of Michigan Medical School, MI

Roy A. Beveridge, MD Chief Medical Officer McKesson Specialty Health/The US Oncology Network The Woodlands, TX

Jennifer Malin, MD, PhD Manager and Medical Director of Oncology WellPoint Los Angeles, CA

John D. Sprandio, MD, FACP Chief Physician Consultants in Medical Oncology and Hematology Drexel, PA

Craig K. Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL

Matthew Mitchell, PharmD, MBA Manager Pharmacy Services SelectHealth Salt Lake City, UT

F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare Co-Founder, Bentelligence Sharon, MA

John Fox, MD, MHA Associate Vice President for Medical Affairs Priority Health Grand Rapids, MI

Lee N. Newcomer, MD Senior Vice President of Oncology Services UnitedHealthcare Minneapolis, MN

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Defining Value in Cancer Care: AVBCC 2012 Steering Committee Report

pproximately 200 oncologists, payers, employers, managed care executives, pharmacy benefit managers, and other healthcare stakeholders convened in Houston, TX, on March 28-31, 2012, for the Second Annual Conference of the Association for Value-Based Cancer Care (AVBCC). The mission of the conference was to align the various perspectives around the growing need of defining value in cancer care and developing strategies to enhance patient outcomes. The AVBCC conference presented a forum for the various viewpoints from all the stakeholders across the cancer care continuum, featuring more than 20 sessions and symposia led by nearly 30 oncology lead-

Gary M. Owens, MD: The 2 target concepts we need to consider during this Steering Committee discussion are “value” and “action.” Our goal is to define what is value in cancer care, and how is that value different for a payer, a clinician, and, of course, the patient. But we also must include other stakeholders, such as employers and the government, who pay for the care. In addition, we want to develop concepts and ideas that are actionable, ones that we can ultimately 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 diseases. Heterogeneity is the hallmark of cancer. At the same time, there are similarities in the issues that concern patients with cancer, related to costs and outcomes. Currently, the most robust area in the drug pipeline is oncology. There are almost twice as many specialty oncology agents in the pipeline as there are other specialty agents for all of the other diseases combined. So we are on this cusp of innovation. We are seeing innovation in cancer diagnostics, which parallels the types of therapies being developed, and we are now able to do testing to tailor treatment for certain genetic mutations 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, and what it means for those who provide that care. That is how we are going to open the discussion for the Second Annual AVBCC Conference. Gene Beed, MD: We are going to discuss the changing

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ers. The discussions focused on current trends and challenges in optimizing value in oncology by reducing or controlling cost while improving care quality and patient outcomes, introducing emerging approaches to management and tools that providers and payers are using to enhance cancer care collaboratively. The AVBCC Second Annual Conference was opened by a Steering Committee discussion of 11 panel members who attempted to define value in cancer care and articulated action steps that can help to implement value into cancer care delivery. The following summary represents highlights from the Steering Committee discussion, which was moderated by Gene Beed, MD, and Gary M. Owens, MD.

epidemiology of cancer toward patient-centered medicine. This means personalized medicine and the economics of cancer care. For example, what does this mean in terms of innovation, or when cancer becomes a chronic disease? Our overarching mission today is to focus on the issues that are most important 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 we can all agree on. What is quality, and quality in the eyes of whom? If there are barriers related to cost, then the question arises who will pay for the care. Are we just all going to pay more for healthcare, or spend less on other conditions? Are we going to indebt the next generation, stifle innovation, ration care? What are our options? Perceptions of value differ throughout the healthcare industry. For manufacturers, efficacy, total patient outcomes, and unmet medical needs determine value. This is in marked contrast to how health insurance companies, employers, and regulators define value, which concerns longevity, quality of life (QOL), and cost. Cost is a key part of the value equation, regardless of what part of the healthcare industry is involved. Why is defining value in cancer care more challenging than defining value in other areas of medicine? John D. Sprandio, MD, FACP: Value in cancer care is challenging for 2 reasons. One reason is the clinical situations in which patients present, depending on their state and their variable frame of reference in terms of

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their goals and their understanding of the situation. And the second reason is the cost of drugs. Cancer care is uniquely complex. This is not to say that in other areas of medicine cost is not complex, but cancer presents a uniquely complex situation.

John D. Sprandio

Value in cancer care is challenging for 2 reasons. One reason is the clinical situations in which patients present. And the second reason is the cost of drugs.

Samuel M. Silver, MD, PhD, FACP: I agree wholeheartedly that there are 2 issues here. One issue is indeed the complexity of oncology. When I talk about qualityof-care issues to nononcology audiences, they say, “So what is the problem? We talked to our cardiovascular colleagues, and we have it down.” And, they partly have it down. If you have to treat a myocardial infarction (MI), that involves a single organ. It does not make a difference how the patient got the MI, only that that patient has MI. There are not 4 stages of the disease. It is not estrogen receptor–positive or progesterone receptor–positive; it is not HER2-negative or HER2-positive. It is not all of these various silos. The science of cancer is complex, with multiple diseases and with multiple presentations of a single disease. Second, because we have so many silos and our cardiovascular colleagues do not, they can have hundreds or even thousands of patients in randomized trials looking at a single point. In cancer, we do not have these numbers of patients. Therefore, the science becomes more difficult for comparative effectiveness analyses. It is very difficult to determine the degree of improved efficacy and total patient outcomes in oncology. It also depends on where and how we are looking. What does cost mean for the patient? Value is not about the total cost of management, it is about the cost that we bear personally. 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 on their insurance. The value equation changes depending on the outlook of just that one variable. Improved patient QOL—whether we define that in terms of years of life or quality per se—is the metric that has to be the most important. And the next is total patient outcomes.

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Craig K. Deligdish, MD: For the purpose of this discussion, I would disagree with my colleagues for a couple of reasons. We have been treating cancer for many years. I think we must ask, “What has changed during this time?” Why would the definitions of value, quality, or outcomes be different today from what they were 10, 20, or even 30 years ago? The difference today is in the cost of treatment. The cost of treatment today is drastically different from what it was 10, 20, or 30 years ago. By contrast, I do believe that we have made a dramatic impact on the survival of patients with cancer. At the end of the day, one of the important questions that a physician and a patient need to answer is, “Do I have a curable form of cancer? Can the patient be cured?” And a second important question is indeed about QOL, which is even more important when the patient does not have a curable disease. That question must be answered in the context of defining “quality” and “value.” Next we need to consider all of the treatment and diagnostic tools that are available to us today, as compared 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 efficacy. We need to factor all of this information into what ultimately is the definition of value. Is a diagnostic tool or a treatment efficacious if it extends survival by 1 or 2 months? Clearly, taking a pill that has few side effects and cures an otherwise terminal disease (eg, Gleevec) has high value, whereas a drug that costs $30,000 a month and allows us to live 1 month longer has less value. In terms of value, the definition is to some degree based on whether value is being defined by the patient or by the payer. As we all know, it frequently is neither the provider nor the patient who is paying for treatment. Is the government paying, the employer, or the insurance 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 an improvement in QOL, make the patient feel better, or cure the patient’s disease. Al B. Benson, III, MD, FACP: I would agree that in terms of value, the central focus must be on the patient’s perspective. For patients whose disease could be cured, the goal is cure and living a long, productive life. I think that is how most patients would define value. Financially, this is very difficult from a patient’s perspective, because in many cases the patient is divorced from the outlay of funds that cover the true cost. Although we are talking about tremendous problems with uninsured patients, copays, and so forth, over time most patients with cancer end up in a situation

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that they would not experience in any other aspect of their daily life in terms of potential catastrophic costs and life-threatening illness. Normally, if you purchase any product, you have to cover that cost. Within the overall complexity of oncology, 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 over time we are seeing significant technological advances in all aspects of care, whether it is in diagnosis, in imaging, or in treatments, that may not be optimally defined in terms of utilization yet can drive up costs and at the same time have the potential to extend life. There is so much we do not understand about cancer biology, and, as the technology advances, we have been unable to study the technology at its maximum to truly define value. For example, for cancer surveillance, we now talk about survivorship and how we monitor patients over time. The literature is very sparse in terms of defining what is appropriate surveillance. In my area of expertise, which includes colon cancer, there have been some meta-analyses done, but that is the exception. Overall, we need evidence to decide how to maximally use imaging, how to define risk, which patients are at risk, and how to monitor patients over time. And if we diagnose a tumor recurrence, for example, what can we do to help that patient further? The same is true for drugs—the way we study most drugs now remains empiric. We do not have the selection tools that we need to demonstrate true value. As we develop markers, we are certainly making some progress. We have seen this in diseases such as leukemia, breast cancer, and to some extent, colon cancer. When we talk about value and cost, survival benefit demonstrated in clinical trials shows proof of principle, that this given intervention works, but we cannot define how it works maximally in each individual patient. Because of the way we design these large trials—in most of them we are giving treatment to a large proportion of patients who will absolutely not benefit from that treatment—we cannot select out the patients who, in fact, truly benefit from the therapy, thereby reaching the ultimate goal for the individual patient. Roy A. Beveridge, MD: The topic of adjuvant therapy versus palliative therapy is directly relevant here. The value for these types of therapy is different. I do not know of many biopharmaceutical companies that believe that improved longevity of a patient is not very important, because everything related to drug design right now is related to making patients live longer. In terms of personalized medicine, identifying particular patient populations is among the major goals.

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

Within the overall complexity of oncology, value is somehow distorted for many patients, because they are not paying the full cost of the service. Al B. Benson Another fundamental problem with value is that over time we are seeing significant technological advances in all aspects of care that may not be optimally defined in terms of utilization. Dr Beed: From the payer’s perspective, how do you respond to what people have said so far about value, and how is it perhaps different from that of clinicians? Dr Silver: Fundamentally, value relates to people agreeing that something has equivalent value; there is an exchange that goes on. But in cancer care, that equation does not work, because the consumer is not the payer. I may not agree that this has the same value as something else, but I am constrained, because I cannot set the prices. I cannot decide on the prices of treatment, and I am restrained by state laws that force me to pay for something, even though I do not think it has value. Therefore, we have a fundamental challenge in defining what value is in cancer care. We have a challenge defining value in all of medicine. For example, there are new transaortic valve replacements that cost $35,000 for a valve—$60,000 total compared with $8000 for a typical valve replacement. These new valves provide an additional 18 months of life for a patient who has less than 1 year of life expectancy. We have the ability to negotiate those prices. But in cancer care, 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 there would be enhanced value, because at least we would not be spending money on drugs that were not going to benefit a patient. But with tumor biology that involves

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escape mechanisms, it is not clear that it is going to provide a long-term benefit. Even with the recent study that was published in the New England Journal of Medicine showing that there is a lot of tumor heterogeneity, within any given tumor there may be multiple tumor types. We just happened to pick one, because that is what we biopsied. So even the role of biomarkers is now coming into question, especially in relation to the current economy.

We have to ask what is efficacy, or what is the treatment effectiveness in realworld outcomes. We may need to consider allowing coverage of Matthew Mitchell products within a certain regimen even if the exact regimen was not studied in a specific cancer type. The challenge is that we do not compare the value in producing 1 year of life or a QOL year in the same way that we compare it to people with heart disease. We may pay $80,000 a year to a patient with multiple myeloma, which is now a chronic disease, and that person may live for another 2, 3, or 4 years, but we do not have discussions about this—what is 1 year of life worth? At the same time, we are making tradeoffs as a society, because in the state of Michigan we are closing schools and are not paying for teachers. This is a challenge for us as oncologists, because at the end of the day we have to make choices on where we put our money, and we are not having a dialogue about where we should spend those dollars.

By the time our 5-year-old children graduate from college, their healthcare premium will be equal to the average US salary. Based on current cost trends, we are 1 generation away from spending our entire salary to cover healthcare, if we do not change something. Dr Beed: You raise a very good point. One way that oncology is different from the rest of medicine is that just a generation ago we did not even use the word “cancer” with our patients. This is very different from most diagnoses. We

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did not talk about cancer, and we did not mention the diagnosis. 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 what makes cancer different from other categories of management. From my perspective, some of the biggest issues are the regulatory and government mandates in oncology. Nothing comes close to cancer care, and when we tie that with the amount of money that is tied to oncolytics, that is where the difference is between oncology and other clinical areas. Dr Beed: So cost has been the main change. Dr Mitchell: Cost is what gets on the radar, but much of this is semantics, that is, the way the question is asked. We have to ask what is efficacy, or what is the treatment effectiveness in real-world outcomes. I am surprised that we are not discussing adverse events or safety issues in relation to value. From a management perspective, these issues have to enter into the quality of care and the value proposition. We may need to consider allowing coverage of products within a certain regimen even if the exact regimen was not studied in a specific cancer type. One example may be allowing the substitution of cisplatin/carboplatin therapies into a regimen in which both products have demonstrated efficacy in separate regimens, but one may produce fewer adverse events, leading to better patient experience and lower cost with the reduced adverse events. Ira M. Klein, MD, MBA, FACP: My role at Aetna for the past several years has been to be the clinical leader for our oncology strategy, and in that position we have wrestled with the issue of value. I would say that the standard definition of value is quality over cost. I think we can define value in many different ways, but that is the basic premise. Dr Beed: There is some disconnect between, “The value of an extra month of life in a clinical study does not show what this drug can really do in the real world in my hands,” versus “It’s not a free market. There is no ability to negotiate.” What is the value for the cost that is being paid with someone else’s money? Lee N. Newcomer, MD: By the time our 5-year-old children graduate from college, their healthcare premium will be equal to the average US salary. Based on current cost trends, we are 1 generation away from spending our entire salary to cover healthcare, if we do not change something. We can have many discussions

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about how we ought to tweak this, but we have to make some changes in the system, and they have to be made in the next 2 or 3 years. We need to make some decisions about whether, as a society, we can spend any time treating people with drugs that get a 1- or 2-month response, until we find out how those drugs work in a combination that gets us a much more meaningful response, such as 4 to 6 months or 6 to 8 months. And we have to decide as a society how much those months are worth. We know that England has done that. It came up with the number of $40,000 per life-year. I do not know if that is the right number for the United States, and at UnitedHealthcare I will not be making that decision, but as a society we have to do that, because we simply cannot afford to continue the way we are spending today. It is not sustainable. Dr Beed: In the Affordable Care Act, the discussion about comparative effectiveness explicitly says that a calculation of cost per quality-adjusted life-year shall not be used. Dr Newcomer: Exactly, and the way that Medicare balances its budget is by simply paying the physician and the hospital less and less each year, because it is not bringing enough money in. Medicare simply lowers the reimbursement and tells providers that it is something they have to accept. Very few people can walk away from Medicare. But, we cannot take that all the way down to zero. I have just attended a hospital board meeting to discuss reimbursement. Each year we have to find $30 million worth of new profits just to cover what Medicare is not going to pay us, because their fee schedule went down. We have to do that year after year, and now we are laying off people to get it done. That the government will not address this tells us how difficult the discussion is, but we cannot use their approach of down-pricing to zero. Dr Beed: If the US government will not address it, who will? Where is the area of agreement between clinicians who are caring for patients with cancer and the payers who are trying to manage this pot of money? Jennifer Malin, MD, PhD: My alma mater, the University of California Los Angeles (UCLA) has the dubious honor of being the most expensive academic center in the country, according to the Dartmouth Group. At the same time, California is in a budget crisis. The 3 primary state budget expenses are healthcare, education, and prisons. I do not see any efforts to try to rein in costs at UCLA, even though the educational mission of the university is sufferingâ&#x20AC;&#x201D;our faculty and the

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

What we are talking about in a theoretical way is actually very real. It is happening now: 1 in 3 of us is going to get cancer, so what do we see as Jennifer Malin worth putting our money away for in terms of treatments? Therefore, what we are talking about in a theoretical way is actually very real. It is happening now: 1 in 3 of us is going to get cancer, so what do we see as worth putting our money away for in terms of treatments? Realistically, being in the position of being able to not have cancer, but thinking about ourselves as potential patients, what is a meaningful improvement in QOL and in length of life that is worth mortgaging our childrenâ&#x20AC;&#x2122;s future for? F. Randy Vogenberg, RPh, PhD: There are so many different perspectives in this issue. Looking at it from the perspective of the commercial payer, the self-funded plan sponsor, whether it is an employer, a union, or a municipality, they are all feeling the squeeze as well. The research that I have been involved with recently is demonstrating very clearly that employers in particular are very much engaged in this debate, more than many people realize. They are trying to grapple with the value question not only in economic terms but also with how the whole healthcare system that they are paying for is performing to deliver outcomes. As one of the biggest areas that is so visible to everybody, cancer is a very emotional disease. Everybody has been touched one way or another by cancer, including me. And there are many dollars involved. Employers are concerned about cost, but their primary interest has been performance. There is a big gap between what we are paying for today and the results or the performance that we expect to see. It is not just about cost. Employers are looking for the performance that is related to the cost of 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

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view of what is happening with the dollars that they are spending. That is unlike what we see typically with the Centers for Medicare & Medicaid Services (CMS) because of some of the congressional budget rules that CMS has to play by. There are probably employers who are seeing this as an urgent issue. They are looking at a 2- to 3-year window, as well as a time for very rapid innovation and change, to try and shift not only the cost curve but also the performance curve among all of the vendors that they are paying for.

I want to underscore the need for starting to collect some registries, so we can truly find out whether your statements are true. One of the Lee N. Newcomer things I am struck with in my discussions with practicing oncologists is that they do not get the same response that was shown in the registration trials, because the patients are different.

Dr Klein: Because this is an epidemiologic discussion, we should point out that we do not have the granular data that we know how to get to the answers we are seeking. Clearly there is a lead time bias. One of the reasons that we do not know whether we are doing better than we were doing 20 years ago (except in some select diseases, such as chronic myelogenous leukemia) is that Medicare and most of the private payers do not capture the elements that we need to figure out whether we are comparing like to like. So we might have a diagnosis, but we do not have a stage. We do not have tumor histology. We do not have biomarkers. And we do not have performance status. Until we get that information, we cannot make an informed epidemiologic decision. Once that information is available, I think we will be able to make much better decisions regarding the value of treating a metastatic disease, and who is getting the best chemotherapy. And if we are comparing like to like, then we just eliminated the lead time bias, because we can get rid of the disease through our ability to granularly bucket different patient categories.

Dr Vogenberg: That is all part of the discussion. Thereâ&#x20AC;&#x2122;s a finite amount of financial resources.

Dr Beed: So when it comes to actionable things that need to happen in terms of value in cancer, I have heard about watchful worrying and the early detection lead time bias. You point out that we need to have more robust informatics that look at cancer, and that may integrate clinical trial data, claims data, and other data to get some ideas of what happens in the population. Dr Newcomer, what else would you add to this in terms of making value-based cancer care a reality, considering the increasing numbers of expensive therapies, better early detection, and better survivability that may be real or may be related to lead time bias?

Dr Sprandio: Cancer therapies are valuable if they are potentially curative. In the metastatic setting, there is value, and it is reasonable as a society to support 1 or 2 lines of therapy. Regarding biologics, especially biomarkers, if we can convince patients that we are using the best drug from the beginning, and the second-best drug for the second round of chemotherapy, we would have a much better chance of telling patients that there is no sense in doing the second, third, fourth, or fifth lines of therapy. But today we cannot say that. We can just say that based on a population and a probability, we are going to choose the best drug, but we do not know what is best for the specific patientâ&#x20AC;&#x2122;s tumor.

Dr Newcomer: I want to underscore the need for starting to collect some registries, so we can truly find out whether your statements are true. One of the things I am struck with in my discussions with practicing oncologists is that they do not get the same response that was shown in the registration trials, because the patients are different. Patients entered into a registration trial have a performance status of zero. The patients we see in the office often cannot do half the things as patients who are enrolled in clinical trials. Only about 2% to 3% of all patients with cancer enter into clinical trials. If we are going to accelerate the pace of making these kinds of value-based decisions

Dr Beed: We were just talking about the meaning of value and about how the demographics have changed. Personalized medicine, biomarkers, and resource allocation are where the rubber hits the road in many cases. Should we spend more money on cancer care going forward? Are we willing to take money from other diseases and spend less on them and more on cancer?

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No one would question that we should be investing more in early detection when there is good evidence that makes a difference in outcomes. In metastatic disease, we have to ask questions about how long to treat.

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with cancer, we need registries. I think they are very possible. At UnitedHealthcare, we have 35,000 patients now with breast, colon, and lung cancers, and we have the data that were requested. We have information on stage, genetics, and current status—everything but performance status. We are starting to try to mine that data now to see if we can find what delivers value, and what does not. Dr Beed: How do we apply these to individual patients? How do we make sure we are using the treatments that are really of value? Is this just the art of medicine, or is there something more to it than that? Dr Benson: This gets back to the point about how we expand our knowledge base in terms of understanding how to use these drugs for appropriate people. It is going to take many shifts in what we do. Clinical trials are designed to determine efficacy, to see whether the drug works. They are critical in that regard, but what we are increasingly arguing now is that we have to change the way we design clinical trials. Even if we do not have the correct biological profile, since we often do not know that at the beginning of the trial, we need to prepare an information database, including tumor banking, so that in the future we could go back to that database and tissue to explore links encompassing biological profiles, treatment, and outcome. A good example of that is the KRAS marker in colon cancer. When some of the colon cancer trials were designed and the researchers were looking at markers, KRAS was not even one of the markers in the original design. But because the researchers had collected tissue, they had excellent clinical data and banked tissue from which exploration of markers could be pursued. They had a methodology that was consistent with the need to test the marker. We were therefore able to go back to the data and combine a number of different trials to come up with a marker that transformed the treatment strategy. These databases are going to be increasingly important, provided that we are putting the appropriate information in the databases. One reason that the database concept is especially attractive is that we are moving away from an empiric approach to one looking for patient selection based on more precise criteria. We now know that most malignant diseases, because of tumor heterogeneity, are a collection of different biological profiles. And as we start subsetting, we are going to need larger populations to look at these small population subsets. For example, in patients with lung cancer, there is a marker that defines a 4% population that will benefit from a given intervention; in patients with

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gastric cancer, there is a marker that identifies 20% of the gastric cancer population that will potentially benefit from a targeted therapy. If we are going to do comparative effectiveness analyses in oncology with these databases, we have to make sure, in an ongoing way, that we are populating these databases with ongoing information as it evolves, so that we can look at these subpopulations with meaningful data over time. It is also going to require cultural shifts in trying to convince more people to participate in clinical trials. These trials are going to be even more complex, because as the National Cancer Institute has recently stated at the American Society of Clinical Oncology (ASCO) GI Symposium, “No tissue, no marker, no study.” The point is that if we are going to truly demonstrate marked improvement in efficacy, we have to define the population that is most likely to respond to a given treatment. This changes the landscape in how we conduct oncology clinical research. It changes the landscape in real need for population-based databases. It asks less, “Does it work in the real world?” and asks more, “Will this enable us to capture the subpopulations in sufficient numbers of patients that we could actually show that there is efficacy and appropriate intervention for the subpopulation?” Dr Sprandio: What we are getting at is that we are going to change the epidemiologic description of disease from a histopathologic diagnosis to a genomic or epigenomic diagnosis. That will give us much more potential, I think, to observe changes in outcomes.

The question is how do we devise innovative practices to impact the changing clinical and economic burdens of cancer? What can we control in terms of the economics? Additional clinical studies that Dr Benson mentioned are critical to driving guidelines, and it is the oncologist’s job to follow guidelines. The question is how do we devise innovative practices to impact the changing clinical and economic burdens of cancer? What can we control in terms of the economics? We can control unnecessary resource utilization. At the core of what we have done in this model that is still evolving is that we have minimized unnecessary resource utilization on a consistent basis over the past 6 years. Consider the National Committee for Quality Assurance guidelines; each of the guidelines and

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requirements include a quality of service and a value component. The guidelines help to focus on patients as a central target, streamlining the standardizing treatment, which is what we do as oncologists.

One of the elephants in the room that we have not talked about is how oncology care is paid for, and the fact that most of the revenue for oncology practices comes from the margin on drugs. Dr Beed: In your oncology delivery system, how is my experience as a patient going to be different from another center or from the old way of care delivery? Dr Sprandio: Patients notice improvement in service. They also recognize better coordination and communication, which are major concerns. The physicians are different silos. That is noticeable in the patient’s eyes. Access, engagement, and responsibility are important, and making patients understand that they have a responsibility to communicate and report information to their providers. The whole thing about patient-centered medical homes (PCMHs) is tracking chronically ill patients over time to be in a better position to avert the acute exacerbations of their symptoms or issues, and then not only provide a decrease in resource utilization but also to improve their QOL. The PCMH was geared and developed for primary care, initially pediatrics, and then adopted by primary care. It is a model that also fits very well for oncology care. At my practice, we are now saving money delivering care this way. I run a 9-man practice, and we have shown that we were able to reduce our annual emergency department utilization per patient receiving chemotherapy by 68% since 2005. We have reduced our annual hospital rate for patients receiving chemotherapy by 51%, and we have reduced the length of 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 many efficiencies; for example, we went down from 8.3 fulltime equivalents (FTEs) to 5.5 FTEs. There was a lot of internal infrastructure that we had to build, and that was costly. The programming was done by trial and error. There was instruction and hand holding. It cost a lot of money to develop this model, but now our practice has stabilized—we are still independent, and we are hopeful.

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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, it means that there is no payer response to this. Reforming payment methodology is harder than reforming care delivery. Dr Beed: If somebody does something that decreases emergency department use and other resource use, it saves money in terms of patients with cancer. They spend some money, they save some money, and they have an ongoing process that’s saving money in caring for cancer patients. Does that mean that we should then, as a system or as a payer, be spending less on patients with cancer going forward and realizing those savings? Or does it mean that we should reward 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 we have not talked about is how oncology care is paid for, and the fact that most of the revenue for oncology practices comes from the margin on drugs. If we are going to make the decisions about which treatments to use on which patients as cost-neutral to the practice, we have to reward those innovative practice models and start to reimburse providers for offering care that is patient-centered and well-coordinated rather than reimbursing them for selecting the most expensive, highest technology–based novel therapy, if that therapy is not going to have a dramatic improvement in patient outcomes. Dr Beed: What do you think about the way we pay oncologists, and the incentives that are a part of it? Dr Mitchell: I am unable to think of another specialty that brings in revenue based on billing for drug therapy to the degree that is done in oncology. Part of the elephant in the room is the potential for treatment decisions, and more specifically medication selection, based on potential clinic revenue. One possible solution is to reevaluate the way cancer centers are reimbursed. One option would be allowing a management fee, similar to a medical home but more comprehensive, because the sophisticated centers do have interdisciplinary teams. Knowing that it costs more to deliver that type of care, this removes the revenue out of the drug side completely, 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 only pay for people who have the biomarker? Does personalized medicine direct therapy, or do people just become a little more

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comfortable or a little less comfortable with what they have decided they are going to do? If all we have done is add the cost of a test, that really did not change anything. Is personalized medicine the Holy Grail? Are we going to test for biomarkers in everyone? Dr Beveridge: One of the main problems is that with International Classification of Diseases, Ninth Edition (ICD-9) coding, the insurers do not know whether a patient with lung cancer had small-cell or non–small-cell lung cancer, localized versus metastatic, first-line therapy or fifth-line therapy. Payers were in the dark. In the next couple of years, ICD-10 will address some of that. The inability to compare groups throughout the country has been a fundamental problem in terms of assessing quality in one area versus the other. Peter Ellis, MD, Kathy Lokay, and others first started using pathways, and then the US Oncology Network and McKesson Specialty Health have continued with pathways in the past 7 years. I suspect that some of the criticism that Dr Ellis remembers is that we (the US Oncology Network) were converting over to “cookbook medicine,” that all people were being treated the same, and that the goals of pathways were to render the least expensive care. As we look at the evolution of pathways in the past 6 to 7 years, we recognize that it allows for true personalization of care. Because the treatment algorithm does specify, and probably all pathways in the country do now, whether this is for a patient with breast cancer who is HER2-positive, HER2-negative, estrogenreceptor–positive, triple-negative, and so on. But this is not the “be all and end all” as far as where we need to go. In terms of truly personalized care, the answer is more than just pathways. We need to begin to take into account radiation, which we have not yet discussed. Today, radiation is a significant component of our cancer care delivery system. We keep talking about drugs, because most of us are medical oncologists, but hospitalization and emergency department rates are very important in terms of costs. At some point we need to address the issues of end of life, corporate use of hospice, and futile therapy. These are all crucially important for the management of the patient. That is what we should discuss when we talk about true patient-centered principles and personalized medicine. Dr Vogenberg: I have recently had discussions with employers about personalized medicine. One of the common responses I hear is, “If you cannot prove or show me that what you are doing is better than what we did before using a newer product versus an older product, then the only difference is cost.” All of these other

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quality parameters we talk about are considered to be irrelevant by the true payer (ie, the employer as benefits purchaser). We have seen this with CMS, and we are seeing it now with employers. I have never heard an employer say, “I’m not willing to pay.” All employers are willing to pay, but they want to see that this cost is making a difference. That value is going to be key to the focus of personalized medicine. We are increasingly moving toward personalized medicine, which will be a large conundrum. A key issue will be whether we can differentiate between the performance of one product and all of the surrounding services.

At some point we need to address the issues of end of life, corporate use of hospice, and futile therapy. These are all crucially important for Roy A. Beveridge the management of the patient. That is what we should discuss when we talk about true patient-centered principles and personalized medicine. Dr Sprandio: Ultimately we are going to get to a point where we are using genomic diagnosis. But with tumor genomics sequencing, any escape mechanism creates a significant challenge for the oncologist in trying to decide how to use that wealth of information to figure out which therapy is best. And there are probably going to be a number of tumors for which no markers exist. Dr Deligdish: Payers think there is value in information related to clinical utility, if that information helps the physician to decide on an optimal therapy. But if this information does not help in the decision-making process, then that information has limited value. For example, if the cost of tumor genome sequencing is in the $2000 range in the next several years, and the cost of treatment is between $5000 and $15,000 monthly, the cost of genome sequencing may be a good investment if it impacts the decision-making process. However, if some patients can be cured by the information gleaned from this test, the value may be priceless. We can most likely all accept that our current system is not sustainable. If we look to the past, at least in the area of cancer treatment, some fairly dramatic mistakes

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

We can most likely all accept that our current system is not sustainable. If we look to the past, at least in the area of cancer treatment, some fairly Craig K. Deligdish dramatic mistakes were made when it came to value and cost. We cannot continue to make these types of mistakes, but we continue to make them. cancer. That treatment was very popular and was even performed at tertiary medical centers and in the community setting. Indeed, billions of dollars were spent before it was recognized that the treatment had no true value and was associated with significant morbidity and mortality. Similar examples occurred in the past couple of years, when treatments that were promoted without proven benefit were approved and implemented on a fairly large scale. We cannot continue to make these types of mistakes, but we continue to make them.

Overuse in the very expensive diagnostic testing for personalized medicine typically takes place for several reasons. First, there are many Samuel M. Silver perverse incentives financially for doing this. Second is the lack of impediments for use. As we move toward healthcare reform, we continue to see consolidation in the number of providers and payers. But as we continue with this consolidation, we are realizing that it does not reduce cost and does not make the system more efficient. Indeed, it makes the system less efficient and more costly. Unless we, as a society, are willing to address those issues, we will end up in a place

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where there probably is only 1 payer, because no other payers will be able to afford to be in that space, and patients may no longer be able to afford treatment. We need to think about where we are going to be in 5 years, because, as Dr Newcomer said, we cannot afford to be where we would end up in 10 years unless some of these issues are addressed. Dr Beed: If we are going to spend more money on cancer, how are we going to finance it? Are we going to spend less money on other diseases, hold down innovation, or borrow from the next generation? What are the appropriate steps, that could be accepted by providers, that we have to take as a society? Dr Silver: I have heard at an oncology panel that we spend more money on testing now than we do on chemotherapy drugs and radiation. Dr Newcomer: That is correct, and that is on genetic testing alone. However, genetic testing includes all diseases. When you do parse it down by cancer, it will come down. But, the point is that when we look at spending, it is clear that we are enamored with genetic testing, and we are spending large amounts of money on it. In fact, we are seeing significant spending for genetic testing in areas without evidence to support use yet. Dr Silver: Hematologists have been working with these kinds of advanced personalized medicine tests for the past 20 years. These tests have been getting more specific and more advanced. But, it is much easier to obtain tissue in hematologic malignancies than in solid tumors, which is why this has been in the forefront. Overuse in the very expensive diagnostic testing for personalized medicine typically takes place for several reasons. First, there are many perverse incentives financially for doing this. Second is the lack of impediments for use. For example, Oncotype DX for women with breast cancer does decrease the amount of adjuvant chemotherapy when used appropriately. However, we have reviewed cases when the Oncotype DX showed a high-risk score and the women did not receive adjuvant chemotherapy, or when women had a low-risk score and received adjuvant therapy. One question that I cannot answer is who was ordering the tests. We can have an 85-year-old woman who should never get adjuvant chemotherapy, but if the test is being ordered reflexively by a pathologist (who does not meet the woman), is that reasonable? We end up spending $5000 on a test that no one is going to look at. We have excellent tests, but they have to be used in the right context. We are ordering too many things,

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because we can do it. There are certainly overuse issues that must be addressed. Dr Beed: Does the PCMH model address the need to keep the pathologists from ordering something when they have never seen the patient? Dr Sprandio: It does. Among the goals of the PCMH model is assuming complete control of everything related to cancer diagnosis, orchestrating the appropriate response, and coordinating patient care. Dr Beed: With regard to negative consequences of personalized medicine on drug innovation—should we continue to develop the same innovative products that only approximately 4% of the population will benefit from? Dr Benson: One of the hallmarks of selecting a marker to become a clinical test is that in the end it must benefit the patient. Part of the problem with technologic innovations—whether it is a diagnostic test, an interventional radiology procedure, or now positron-emission tomography (PET) or magnetic resonance imaging (MRI)—because of the way they are being developed and get reimbursed, they enter the marketplace without the true testing that is required to understand their clinical benefit. We have been talking about drugs, but if we look at PET scans alone, the amount of money being spent on them is mindboggling, and most of it is inappropriate use. There are important clinical trials addressing the use of PET scans, but they are lagging behind in defining the optimal use of this technology, which is also an evolving technology. Because PET scanning is readily available across the country, it impedes the prospective collection of the essential information needed to answer, “Does this work, or does it not work?” Part of the perversity of our reimbursement system is the way these products get on the market. They are paid for before we clearly define the appropriate clinical use. We need to make a better investment and say, “We are going to order this test, but the only way the test is going to get reimbursed is that it will be entered into a database or a prospective clinical trial, to try to define what the real use should be.” How to get around that is a major problem. For example, I was on the ASCO panel that was going to create a guideline for radiofrequency ablation use for patients with colon cancer and liver metastasis. This is a procedure used every day around the world. It has been used for years. In doing a systematic review, we found that there was not even 1 prospective randomized trial on this. It was, therefore, impossible to create a guideline, and we were left defining a group of research

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questions that are yet to be addressed. But there are currently 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 therapy becomes available, we would expect that the coverage will be contingent on these data points, so that we get an answer and can revisit it with real data. Does that appeal to an insurer? Is it doable? Dr Klein: In many ways, CMS has punted on much of this by saying, “We will give coverage with evidence development.” But the majority of coverage decisions are made at the local or the regional level. Therefore, from a national perspective, CMS has not necessarily taken the bull by the horns.

At Aetna, we have tried to approach some of the more egregious misuses of technology through clinical policy bulletins and sometimes on claims table edits. Ira M. Klein Nobody likes to get a precertification for an MRI. And yet, because we have collected systematic data, we know that radiology benefit management works and formulary management works. At Aetna, we have tried to approach some of the more egregious misuses of technology through clinical policy bulletins and sometimes on claims table edits. Nobody likes to get a precertification for an MRI. And yet, because we have collected systematic data, we know that radiology benefit management works and formulary management works. Benefit design changes do drive behavior on the member side. We have already been doing this, but not enough. If we (ie, payers) are always being looked at as those who are not doing something or are withholding something, then it is hard to get our message out that we are really trying to address overuse. As with the Oncotype DX, for example, there is overuse, underuse, and misuse. There are 2 ways we can reduce cost. First, we can make the individual practices more efficient as entities that have a product. Second, we can better connect the system with data. The discussion about overuse of genet-

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ic tests speaks to a fragmented system in which nobody talks to one another. If we all talked to one another, we would 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 hope in reducing the cost of cancer care. Dr Beed: Do we have mechanisms to encourage collection of data and connection of practices? Dr Vogenberg: Yes, companies have gotten involved very rapidly, particularly the larger Fortune 500 companies. They are looking at the sharing of information that

Employers have invested quite heavily in wellness and in preventive services. They are now “getting it,” and they are seeing the return on their F. Randy Vogenberg investment in employee satisfaction and in the difference in employee performance and productivity. Dr Klein talked about, and are trying to promote better use of information technology, as well as linking it to benefit design. From the employer’s perspective, all they can do is look at changing some of the coverage parameters through their benefit design. They are not going to get involved, and they are not going to “touch” patients. But they are trying to drive many types of behavior.

I could come up with a list of 10 things that we could get rid of without hurting the patient. For example, 20% of our patients with stage I breast cancer get PET scans. Why? There is no reason to do that, as Dr Benson mentioned. There are gaps in their success; up until a few years ago, most employers did not pay attention to any of this, because drugs were cheap. Now that drugs are expensive and are getting more expensive, employers are now looking at the cost of healthcare. What they still do not see is the spending on diagnostics and devices, which is going to force even more inter-

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est around the integration of information and a better coordination of care delivery. We are seeing that with some of the larger employers. Dr Beed: What will the reimbursement mechanism be for employers who invest money and provide better care? Dr Vogenberg: We are back to how employers perceive performance of their vendors—the health plans and other providers of services. It is rare to see a very clearly differentiated performance, which is why I think we keep going back to this cost issue. Some employers are trying to drive the discussion, as well as partner and collaborate with their plans and with their other vendors to encourage that kind of innovation. Employers are looking to drive innovation with their partners. What has changed is the cost. Whether it is the patient or the employer as a payer, the dollars at stake today are so significant that it makes it worth their while. Dr Beed: How does cancer prevention fit into our valuebased care discussion? Dr Vogenberg: Employers have invested quite heavily in wellness and in preventive services. They are now “getting it,” and they are seeing the return on their investment in employee satisfaction and in the difference in employee performance and productivity as a result of catching disease earlier. Dr Beed: Are we going to prevent cancer? Is that something we should be investing our money in? Dr Beveridge: I do not think that medical oncologists see patients early enough to prevent cancer. The numbers of my patients who start a “brown rice and broccoli diet” after they have had colon cancer are quite a few, but they started it approximately 25 years too late. Breast cancer genetics programs are going to be increasingly widespread. I think we should continue to invest in some expensive tests in the relatives of our patients with breast cancer as a preventive measure. Dr Malin: I would not say that prevention focused specifically on cancer is how we are going to bend the cost curve; rather, the issue of obesity, and it is affecting not only cancer prevalence rates but also all other diseases. Dr Newcomer: I could come up with a list of 10 things that we could get rid of without hurting the patient. For example, 20% of our patients with stage I breast cancer get PET scans. Why? There is no reason to do that, as Dr Benson mentioned.

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I would look for that “list of 10,” and then try and make sure that that is consistently applied throughout my entire practice, that every one of my partners signs off on this list, and that we monitor it carefully. We will pick our 10 habits, and get rid of them. As soon as we are consistent on those 10 things, we will move to the next 10 things. We have to start finding things today that we are going to stop doing, so that we could leave some funds for therapies that truly work. The last thing any of us wants to say to a patient with Hodgkin lymphoma is, “There’s not enough money in the system to treat you anymore.” That would be a travesty. There is plenty of waste in the system that we could and should start eliminating, and that budget could be very viable. Dr Owens: No matter where we went in our value discussion, the elephant in the room remains cost. Every road leads back to cost. So the reality is that value and costs are inextricably linked together. We cannot take them apart. But one of the things that we can do vis-à-vis action is take waste out of the system. Another thing we can do is change the way care is delivered. The only true mistake is to keep doing the same thing we always did, and hope to get a different outcome. Dr Beveridge: It is worth noting that Dartmouth College has a new institute, the Center for Health Care Delivery Science. Its goal is to change the way we think about the importance of the actual execution of care. The president of Dartmouth College has been quoted as saying that the real rocket science in medicine over the next 10 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 changing the payment methodology. In oncology in particular, a lot is driven by drug cost and the way we reimburse for drugs. To change the system, we have to change the way we pay for it. That is another action item. We cannot be afraid to experiment with new payment methodologies and truly change them. John Fox, MD, MHA: One of the things that Dr Beveridge brought up was the need to have processes for advance care planning. The National Comprehensive Cancer Network (NCCN) guidelines and the ASCO guidelines document the importance of advance care planning and trying to understand, through conversations with patients, what their goals, preferences, and priorities are for care at the end of life. Yet we don’t do advance care planning, not because we do not think it has value, but because it is uncomfortable, and we do not know how to integrate it into practice. The hard work

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

Waste, and often harm, occur when we provide treatments to patients that they would not have wanted had they known all their options. There is John Fox compelling evidence that having advance care planning discussion improves health outcomes. Waste, and often harm, occur when we provide treatments to patients that they would not have wanted had they known all their options. There is compelling evidence that having advance care planning discussion improves the patient experience in the healthcare system, improves health outcomes, and reduces cost of care—not because of denied care, but because we have provided the care that patient truly wanted. Dr Silver: My practice is an outlier, in that many of the patients I see have very low-prevalence diseases. Therefore there are no guidelines, and there are no randomized trials for these diseases. In addition, because I am in Michigan, many of my patients work for ERISA corporations, and their insurance company is an administrator. Because the insurance says no, and because there is no evidence for the treatment, when I see a patient I call the human resources (HR) department of that patient’s company to check on insurance. We end up having a good conversation about their employee, about what the employee needs, and about this rare disease. The HR department, the patient, and I feel good about the next step, but I think that is unusual. Dr Newcomer: At UnitedHealthcare, we are piloting a 6 medical group experiment that starts with an episode payment. We have created an episode payment that covers all of the patient care involved. As the physician group gets more effective in improving an outcome or in reducing the total cost of care, their amount of the episode payment will increase. And we are trying to reduce cost by having one third of the savings go to the

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group, roughly one third goes to UnitedHealthcare, and one third goes back to the employer in the form of a lower premium. By now we know that we can get enough data to start figuring this out. The 6 groups just met recently. We looked at 64 measures of cost, quality, and operational efficiencies and came back with some projects that we think will begin to reduce care in a number of areas. The reason I mention this is that it is an example of a payer sitting with 6 medical groups, and I never saw a finger pointed at someone the entire day. The questions were, “I wonder how we can fix this. We saw this problem in the data. Now, how can we solve it? What do you do over here? How did you get such good results? What are you doing here that maybe makes you so variant, and how can we bring it down?” The point is that we are all going to have to roll up our sleeves and probably work together. I do not think any of us can do this alone. We need to start more of the little projects that we have heard all day about—literally a dozen different attempts at trying to do this, but we need 100. Some of them will fail. A lot of them will succeed. But we are going to have to start faster and begin to collaborate and look at each other as partners. We need to figure out how we can get it done. Dr Beed: How do we integrate survivorship services into the definition of value? Dr Benson: This is a fundamental element of personalized medicine. It is not just the markers. The NCCN, for example, has created a partnership in terms of employers. What are the fundamental aspects of a cancer

Another challenge is access. Someone who is in a rural community, for example, may not even have an oncologist. How can we make these services available to much larger populations? program that truly provide comprehensive care? We have talked about the absurd way drugs have been reimbursed for oncologists, but that has created the margin so that programs could integrate many of these other services that are otherwise not paid for. One of the enormous challenges is how do we fairly reimburse these essential services that are hallmarks for appropriate care? Another challenge is access. Someone who is in a rural community, for example, may not even have an oncologist. How can we make these services available to much larger populations? It is one thing to be a patient at my cancer center, where we have all of these services

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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 not true in many situations. A free-standing practice may not be able to provide all of those services right in its own facility; this gets us into the referral mechanisms. It is also an issue when we talk about accountable care organizations and bundled payments for care. Not everyone needs all of the services we may have available, such as nutrition services or psychological support. But how do we make sure, when we are talking about episodic care reimbursement, that we are integrating all these other essential services that we now have to pay for, often in a way that comes from philanthropy or from other sources, but not because we are billing for these services? Dr Beed: Is this just another sign of the toxicity of our à-la-carte system of billing? Dr Malin: This gets at the issue we were getting at earlier of early detection versus surveillance. When we talk about survivorship care, we need to think about who are the people at risk in the transition. It should not be one-size-fits-all survivorship care anymore than it should be for active treatment. We need to think about when to integrate people back into primary care, who are the people who truly need the extra support, and what are the best models to deliver that kind of care. Dr Sprandio: One of the things that would be very helpful is if we all agreed on a core set of services that are inherent to providing good patient-centered care that everyone would reimburse. That is not restricted to cancer only. Any patient who has a chronic disease would benefit from that. There is no patient mechanism for that today, because there are no margins on drugs. That is one challenge, and I agree that when we look at whole person care, there are a set of services that we could all agree are important to that patient’s care but that we do not pay for today. Dr Beed: Can anybody argue that there are not significant dollars to be saved by removing futile care? Dr Beveridge: We have had 9 pilot studies in the US Oncology Network looking at end of life. We have piloted putting palliative care physicians in practices. We have trained nurses in palliative care. We have trained nurse practitioners. We have a large number of palliative care physicians in our 1400-physician network at this point. But the common theme is—when providers can

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July 2012

Vol 5, No 4

Defining Value in Cancer Care

speak to the patient with metastatic disease early, which our data clearly support, there is a higher use of palliative care; there is a greater use of appropriate hospice treatment; the days in hospice increase significantly; and the number of days using a drug therapy decrease. The number of physicians trained in palliative care in the country is so small that they cannot even begin to take up the slack. The average reimbursement for a palliative care physician across the country is less than $210,000, and on the East Coast, in Washington, DC, in particular, the average compensation for a palliative care physician is less than $145,000. The other thing we have not talked about is the waste that exists when we continue chemotherapy in the face of progressive disease. I have had many oncologists say, “The patient wants to continue treatment, even though their disease has progressed.” Is that a waste, because we are not willing to have a conversation with the patient? Therefore, not only do we need guidelines on disease surveillance and disease progression, but we also need clear guidelines on when to stop therapy, what to do when patients progress, and whether we should add fourth- or fifth-line therapy. Dr Deligdish: We do not need guidelines about treating or not treating a patient when a patient’s disease is progressing. This is intuitively obvious, and it is a very small minority of oncologists, I hope, who are treating patients with the same treatment when a patient’s disease is progressing. If we cannot accept that, then the problem is that we do not have access to data that can demonstrate that either way. We need to be very clear on this; we have talked a lot about advanced illness programs and a little bit about palliative care programs. It is very important to differentiate between these 2 entirely different approaches. Advanced illness programs have been around for more than a decade. We have all heard about the number of successful pilots that have been conducted. However, there are many examples in which payers have

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adopted these programs, but they have failed to educate patients or providers as to their availability. In these situations, the programs are not utilized. Palliative care is quite different. Palliative care can extend survival in patients with cancer, in addition to enhancing QOL.

Call to Action In closing, the amount of information that we covered is very impressive. We did our best to define value from the different stakeholders’ points of view, and we decided it is inextricably linked to cost and action. Gary M. Owens Based on this discussion, I have formed the following 7 actionable steps needed to develop a highly valuable cancer care system: 1. Get rid of waste 2. 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 payment systems have to be changed to reward value, however we define it 4. Use new technology judiciously; we heard some examples of where technology was not used wisely— newer is not always better, until it is proved better, but it is generally more expensive 5. Introduce data collection and data integration improvements across the system, whether real-world or clinical trial data: ultimately we cannot manage a system that we cannot measure; that is almost axiomatic 6. Improve communication across all stakeholders 7. Finally, do not be afraid to try new things and be willing to try multiple things. ■

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R D IV O F AN D E US ION V O EO AT R P AN STR P A UT INI BC DM U S A

VELCADEHCP.COM

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

If you define value as medication cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,471 per 3.5-mg vial as of January 2012 Health plans should consider medication cost, length of therapy, and dosing regimens when determining the value of a prescription drug regimen. This list of considerations is not meant to be all-inclusive; there are multiple other factors to consider when determining value for a given regimen

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

CONTRAINDICATIONS VELCADE 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 modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit 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 infiltrative pulmonary disease has been reported Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid 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 REACTIONS Most 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 Please see Brief Summary for VELCADE on the next page of this advertisement. To contact a reimbursement specialist: Please call 1-866-VELCADE, Option 2 (1-866-835-2233). *Melphalan+prednisone. † VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy 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-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly 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.

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

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Diabetes Medications and Cancer Risk: Review of the Literature Quang 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 nontraumatic 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 diabetes 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 diabetes 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.

iabetes mellitus is one of the fastest growing epidemics in the United States and worldwide. According to the International Diabetes Federation atlas, there were approximately 366 million people worldwide with diabetes in 2011, and this number is expected to increase to 552 million by 2030.1 Currently, the Centers for Disease Control and Prevention (CDC) estimates that more than 25.8 million Americans (8.3% of the population) have diabetes.2 The CDC also estimates that approximately 7 million of these individuals are undiagnosed and are therefore

Dr QT Nguyen is an Endocrinologist, Carson Tahoe Physicians Clinic, Carson City, and Adjunct Associate Professor, Endocrinology and Internal Medicine, Touro University Nevada, College of Osteopathic Medicine; Dr Sanders is a Senior Medical Resident, Internal Medicine Program, University of Nevada, Reno; Dr Michael is a Senior Medical Resident, Internal Medicine Program, University of Nevada, Reno; Mr Anderson is a Senior Medical Student, University of Nevada School of Medicine, Reno; Dr LD Nguyen is Clinical Pharmacy Specialist, VA Sierra Nevada Health Care System, Reno; and Mr Johnson is a Sophomore Medical Student, University of Nevada School of Medicine, Reno.

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July 2012

Quang T. Nguyen

Stakeholder Perspective, page 229

Am Health Drug Benefits. 2012;5(4):221-229 www.AHDBonline.com Disclosures are at end of text

untreated.2 Type 2 diabetes (90%-95% of diagnosed diabetes cases in the United States) has been largely attributed to an increase in obesity.2,3 It is estimated that approximately one third of the US population is obese.3 The rates of increase in obesity and diabetes have mirrored each other over the past 2 decades.3 The complications of diabetes, which include heart disease, kidney disease, blindness, and increased risk for amputations, are as serious as they are diverse.2 In general, diabetes has been shown to increase the risk for heart disease by 2-fold4 and has been shown to carry the same risk for myocardial infarction (MI) as for nondiabetic individuals who have previously had an MI.5 Emerging data are now correlating diabetes with an increased risk of certain types of cancer.6 With cancer already making a large impact on mortality in our population, and with type 2 diabetes on the rise, research specific to these 2 disease states is becoming even more important.

The Link between Cancer and Diabetes Several studies have revealed a relatively strong correlation between some types of cancer and diabetes. A study conducted by Davila and colleagues looking at the risk of hepatocellular carcinoma in diabetic patients ver-

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KEY POINTS ➤

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Cancer and diabetes are major public health problems worldwide. Data are now emerging that link diabetes with an increased risk for certain types of cancer. Although the mechanisms linking diabetes and cancer are not completely understood, they are likely associated with hyperinsulinemia. Ironically, of the many drug classes used to treat diabetes, some have been linked to increased risk of cancer. By contrast, metformin has a negative relationship with cancer; increasing evidence shows it offers protection against some types of cancers (eg, breast cancer) and prolongs the life of diabetic patients with cancer. It is important to continue to control diabetes with appropriate medications, because the correlation between uncontrolled diabetes and cancer is stronger than the correlation between medications for diabetes and cancer, but it is also necessary to strongly consider the possibility of cancer-related risk for some of these agents. All available evidence linking antidiabetes drugs with cancer risk is based on retrospective studies; therefore, prospective studies are needed to verify this association.

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

Despite the lack of a complete understanding of the mechanisms, the correlation between diabetes and cancer is strong, as suggested by the literature. Therefore, it is logical to inquire whether the treatment of diabetes can affect the risk of these patients developing cancer. patients in the San Francisco Bay Area.8 There is also an increased risk of developing several other types of cancers, including kidney, endometrial, colorectal, nonHodgkin lymphoma (NHL), bladder, and breast.9 By contrast, the risk for prostate cancer appears to be decreased among diabetic patients.6

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The presence of type 2 diabetes has also been shown to increase mortality in patients who already have cancer.10 Data collected by more than 350 primary care physicians on patients in the United Kingdom have shown that patients with a diagnosis of breast cancer who developed type 2 diabetes had a 1.32 increased mortality risk compared with patients with breast cancer without diabetes.10 The Cancer Prevention Study-II evaluated more than 2200 patient records of those diagnosed with nonmetastatic colon or rectal cancer and showed a 1.53 increased risk of mortality among patients with type 2 diabetes.11 Even with the decreased risk of prostate cancer in diabetic patients, they experience higher mortality rates.12 Bladder cancer is the fourth most common cancer and the ninth leading cause of cancer death among US men.13,14 Bladder cancer is estimated to occur in approximately 21 per 100,000 persons annually in the United States and is thought to be higher in diabetic patients.15 Mechanisms involved in the association between diabetes mellitus and cancer are not completely understood, but they are likely associated with hyperinsulinemia, which is a result of insulin resistance characteristic of type 2 diabetes. Insulin’s role in cell proliferation, through the action of insulin-like growth factor 1, as well as inhibition of apoptosis, could play a significant role in the development of cancerous tissues.3 Although these systemic responses are reasonably well understood, the current literature does not adequately explain organ-specific cancer risk. Despite the lack of a complete understanding of the mechanisms, the correlation between diabetes and cancer is strong, as suggested by the literature. Therefore, it is logical to inquire whether the treatment of diabetes can affect the risk of these patients developing cancer. Recently, studies have been emerging that evaluate the risk of developing cancer in diabetic patients who are being treated for their disease versus those who are not receiving antidiabetes medications. There are currently 14 classes of drugs used in the treatment of diabetes, as discussed below. This article reviews the mechanism of action and the effect on cancer risk of each class of medication for the treatment of diabetes.

Antidiabetic Drugs and Cancer Risk Biguanides (Metformin) Metformin’s mechanism of action in the treatment of diabetes has been elucidated for quite some time; however, all of its actions are not fully understood. Its main effect is to improve hepatic insulin resistance via decreasing the hepatic glucose output. Metformin also improves peripheral glucose uptake by sensitizing insulin receptors in the muscles.16 Several studies in the past few years have

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identified additional benefits of metformin, such as lowering cancer risk and improving survival of those diagnosed with cancer among the diabetic population. Libby and colleagues designed an observational cohort study that compared 4000 subjects with diabetes who had taken metformin with 4000 diabetic subjects who had not received the drug.17 Cancer was diagnosed in 7.3% of metformin users compared with 11.6% of those who did not take the medication.17 In a nested case-control study conducted by Monami and colleagues, 112 of 1340 diabetic patients (average followup, 75.9 months) developed cancer.18 Those who developed cancer had less exposure to metformin compared with a control group of diabetic patients.18 Jiralerspong and colleagues compared the pathologic complete response (pCR) ratesâ&#x20AC;&#x201D;pCR is the absence of tumor in tissue removed during surgery, and it correlates with improved survival ratesâ&#x20AC;&#x201D;between diabetic patients with early-stage breast cancer who received neoadjuvant therapy as well as metformin with diabetic patients with similar cancer characteristics but who were not taking metformin.19 Of 2529 patients identified in the study with early-stage breast cancer treated with neoadjuvant therapy, 68 patients also had diabetes and were taking metformin and 87 patients had diabetes but were not taking metformin. The pCR rates in the metformin group were 3 times (24%) higher compared with the nonmetformin group. This finding suggests a protective factor of metformin in diabetic patients who develop breast cancer.19 In another case-control study, Li and colleagues evaluated 973 patients with pancreatic adenocarcinoma who were receiving antidiabetic therapy.20 The investigators compared 259 diabetic patients and 109 diabetic controls (who had no pancreatic adenocarcinoma). The results showed that diabetic patients receiving metformin had a significantly lower risk for pancreatic cancer compared with those who had not taken metformin (OR, 0.38; 95% confidence interval [CI], 0.22-0.69; P = .001), with adjustments for potential confounders. Those who received metformin had a 62% reduction in the risk for pancreatic cancer.20 Wright and colleagues analyzed 1001 patients with prostate cancer versus 942 controls for diabetes and cancer risk.21 Of these, 97 of the patients with cancer and 101 of the controls had diabetes. The use of metformin was more frequent in the control group compared with the group of patients with cancer (4.8% vs 4.0%, respectively). The investigators calculated that prostate cancer risk was reduced by 44% with metformin use.21 The results showed that the use of metformin for >5 years reduced the risk for breast cancer compared with the use of metformin or any other antidiabetic drugs for <5 years.22

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Furthermore, He and colleagues reviewed the records of 233 patients diagnosed with prostate cancer who were taking antidiabetic medications.23 The investigators concluded that treatment with metformin was a positive predictor of improved survival time by nearly a year compared with those patients who did not receive metformin.23 Several of the studies cited above have suggested that the anticancer properties of metformin are likely a result of AMP-activated protein kinase (AMPK). AMPK phosphorylates proteins, which leads to inhibition of cell growth and possible reduction in cancer.24 Based on the present review of the most recent literature, there appears to be a negative relationship between metformin use and cancer. The mechanisms by which metformin decreases cancer risk and improves survivability with cancer, possibly through decreased protein synthesis or maintaining normal insulin levels, are not clear. All of the clinical studies reviewed are retrospective studies, which may be subject to bias and confounding issues. Further research, especially prospective studies, should be conducted to better assess the relationship between metformin and cancer.

Based on the present review of the most recent literature, there appears to be a negative relationship between metformin use and cancer. The mechanisms by which metformin decreases cancer risk and improves survivability with cancer, possibly through decreased protein synthesis or maintaining normal insulin levels, are not clear. Second-Generation Sulfonylureas (Glyburide, Glipizide, Glimepiride) Sulfonylureas work by stimulating endogenous insulin secretion through inhibition of potassium channels in the pancreatic cells. They are most effective during the early stages of diabetes when insulin secretion is still working.25 Cancer risk associated with sulfonylureas has not been extensively studied in comparison with other antidiabetic drugs; however, the limited studies that have been completed indicate that there may be a higher incidence of cancer among those who receive them. The nested case-control study by Monami and colleagues mentioned above included 1340 diabetic patients who were followed up for an average of 75.9 months. The 112 patients who developed cancer also had a greater length

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of exposure to a sulfonylurea compared with the control group of diabetic patients.18 Similarly, in the case-control study by Li and colleagues, compared with the nondiabetic patients, there was a nonsignificant increased risk for pancreatic cancer detected among the patients with diabetes who were using a sulfonylurea.20 A cohort study by Bowker and colleagues identified 10,309 new users of metformin or sulfonylureas.26 The mean follow-up for the study was approximately 5 years. Its results showed that the cancerrelated mortality for patients receiving sulfonylureas was 4.9% compared with 3.5% for metformin.26 No control group was used in this study, so it is unclear if this finding is a protective effect of metformin or a worsening effect associated with the use of sulfonylureas.

The increased risk of cancer seen with sulfonylureas is concerning. These casecontrol studies support the hypothesis that increasing insulin levels has a positive effect on cancer development. A cohort study by Yang and colleagues involving 6103 patients with type 2 diabetes identified a decreased cancer risk among patients taking glibenclamide and gliclazide.27 Furthermore, the cancer risk reduction was found to be dose dependent with these 2 drugs. Of note, there was no benefit in terms of cancer risk with the use of glipizide.27 Finally, Chang and colleagues evaluated the use of insulin secretagogues among diabetic patients in a retrospective study carried out in China.28 Of the 108,920 subjects included in the study, 8194 cancer cases were identified. Results showed significantly increased risk for liver and pancreatic cancers with the use of first- and second-generation sulfonylureas, but not with third-generation sulfonylureas. Chang and colleagues do note that there was no dose-response measured in evaluating the risk of cancer with the first- and second-generation drugs.28 The increased risk of cancer seen with sulfonylureas is concerning. These case-control studies support the hypothesis that increasing insulin levels has a positive effect on cancer development. Sulfonylureas, like other antidiabetic drugs, have only been evaluated in a retrospective manner, leading to incomplete assessments and invalidated conclusions.

Meglitinides (Repaglinide, Nateglinide) Meglitinide is an insulin secretagogue that stimulates insulin release by inhibiting potassium channels in the pancreas on a different site from sulfonylureas. These

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medications work much faster than other secretagogues and can be taken more effectively before meals. They can lower postprandial blood glucose levels and thus avoid the risk of hypoglycemia between mealtimes.29 Only 1 study was found in a literature search that evaluated the effect of meglitinide on cancer risk. The retrospective study by Chang and colleagues discussed earlier showed that any use of a meglitinide had a significantly increased risk for developing cancer, but mainly liver cancer.28 As discussed with sulfonylureas, elevated insulin levels can possibly increase cancer risk. A correlation between meglitinide use and cancer risk cannot be determined at this time, because there was only 1 study evaluating this effect, and it was based on a retrospective analysis.

Glucosidase Inhibitors (Acarbose, Miglitol) Glucosidase inhibitors act by delaying the absorption of complex carbohydrates from the digestive tract, therefore reducing the body’s glucose load.30 It is used in conjunction with other antidiabetic medications to attain better blood glucose control.30 There are no current studies evaluating glucosidase inhibitors and cancer. Thiazolidinediones (Rosiglitazone, Pioglitazone) Thiazolidinediones (TZDs) improve metabolic control in patients with type 2 diabetes through the improvement of peripheral tissue insulin sensitivity. TZDs activate a group of receptor molecules inside the cell nucleus known as peroxisome proliferator-activated receptors (PPARs), specifically PPARγ, to increase peripheral insulin sensitivity and potentially reduce hepatic gluconeogenesis. Although not all the actions of TZDs are known, these agents still have the potential to benefit the full “insulin resistance syndrome” that is associated with diabetes.31 In June 2011, the US Food and Drug Administration (FDA) issued a safety announcement that the use of pioglitazone for more than 1 year may be associated with an increased risk of bladder cancer.32 This announcement was based on studies conducted by the drug manufacturer, which included a 10-year, observational cohort study, as well as a nested case-control study in patients with diabetes who are members of the Kaiser Permanente Northern California (KPNC) health plan. This study included 193,099 patients in the KPNC Diabetes Registry who were aged ≥40 years. A planned 5-year interim analysis was performed with data collected from January 1, 1997, through April 30, 2008. The median duration of therapy among patients treated with pioglitazone was 2 years (range, 0.2-8.5 years).32 The results showed no significant increase in the risk for bladder cancer in patients ever exposed to pioglitazone compared with those who were never exposed to pioglita-

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zone (hazard ratio [HR], 1.2; 95% CI, 0.9-1.5). However, the risk for bladder cancer was greater with increasing dose and duration of pioglitazone use compared with never being exposed to pioglitazone. In this study, the HRs were 0.8 for <1 year of pioglitazone treatment and 1.4 for 1 to 2 years and for >2 years of therapy.32 In a post hoc analysis, the HR was even higher for those patients with >36 months of exposure and for those with >48 months of exposure, with a trend for increasing risk with longer duration of exposure.33 The use of pioglitazone therapy for 12 months was associated with a 40% increase in risk (HR, 1.4; 95% CI, 0.9-2.1), whereas the HR after >24 months of treatment with pioglitazone was 1.4 (95% CI, 1.03-2.0). Based on these data, the FDA calculated that duration of therapy >12 months was associated with 27.5 additional cases of bladder cancer per 100,000 person-years of follow-up compared with patients having never received pioglitazone.32 In a retrospective cohort study using data from the French National Health Insurance Plan, approximately 1.5 million patients with diabetes who were aged 40 to 79 years were followed for up to 42 months (2006-2009).32,34 The study showed a statistically significant increase in the risk of bladder cancer in patients exposed to pioglitazone compared with patients exposed to other antidiabetic agents (HR, 1.22; 95% CI, 1.05-1.43). There was an increased bladder cancer risk observed with a larger cumulative dose of â&#x2030;Ľ28,000 mg (HR, 1.75; 95% CI, 1.222.50) and for longer duration of exposure between 12 to 23 months (HR, 1.34; 95% CI, 1.02-1.75).32,34 A cohort study of pioglitazone and cancer incidence in patients with diabetes explored whether treatment with pioglitazone was associated with a risk of incident cancer at the 10 most common sites (ie, prostate, female breast, lung/bronchus, endometrial, colon, NHL, pancreas, kidney/renal pelvis, rectal, and melanoma).35 This study evaluated 252,467 patients aged â&#x2030;Ľ40 years from the KPNC Diabetes Registry. The HR for each cancer associated with the ever-use of pioglitazone ranged from 0.7 to 1.3, with all 95% CIs including 1.0. Increased risks of 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 decreased risk 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 study was somewhat limited, given the relatively small number of cases for NHL, kidney/renal pelvis cancers, and melanoma. There was no clear evidence of an association between the use of pioglitazone and the risk of incident cancer at the sites examined. This study of relatively short-term use could miss effects that require longer-term exposure or follow-up to become evident.35

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A recent retrospective cohort study using a nested case-control analysis was done to determine if the use of pioglitazone is associated with an increased risk of incident bladder cancer in patients with type 2 diabetes.36 Azoulay and colleagues analyzed data from a large UK general practice database from January 1988 to December 2009. The cohort included 115,727 new users of oral hypoglycemic agents, with a mean patient age of 64 years and a mean follow-up duration of 4.6 years. A total of 0.5% of patients were taking pioglitazone or rosiglitazone as monotherapy, with a mean duration of use of approximately 2.2 years. A total of 470 patients were diagnosed with bladder cancer during follow-up (rate, 89.4 per 100,000 person-years). The 376 cases of bladder cancer that were diagnosed beyond 1 year of follow-up were matched to 6699 controls. Overall, the ever-use of pioglitazone was associated with an increased rate of bladder cancer by 83% (rate ratio [RR], 1.83; 95% CI, 1.10-3.05). The rate of bladder cancer increased with longer use of pioglitazone, with those taking the drug for >2 years having a 2-fold increase in risk (RR, 1.99; 95% CI, 1.143.45), and in those with a cumulative dosage >28,000 mg (RR, 2.54; 95% CI, 1.05-6.14). Rosiglitazone did not have an elevated risk, even with duration of use and cumulative dosage (RR, 1.14; 95% CI, 0.78-1.68). The authors hypothesized that the possible mechanism for the bladder cancer risk is chronic irritation of the bladder from crystal formation, which needs further research.36,37 Based on these studies, pioglitazone use for longer duration and exposure to the highest cumulative dose are associated with an increased risk of bladder cancer, whereas no increased risk was observed with rosiglitazone. The potential for increasing melanoma or NHL risk and decreasing kidney/renal pelvis cancer risk associated with an ever-use of pioglitazone was observed in one study38; however, the power of the study was limited.38

Bromocriptine Mesylate Bromocriptine mesylate, an ergot derivative, is a sympatholytic dopamine D2 receptor agonist that can exert inhibitory effects on serotonin turnover in the central nervous system. Bromocriptine mesylate was FDA approved for type 2 diabetes in adults in 2009. It has been proposed that bromocriptine can reverse many of the metabolic alterations associated with insulin resistance and obesity by resetting central (hypothalamic) circadian organization of monoamine neuronal activities. Bromocriptine has been shown to reduce hemoglobin A1c levels (by 0.4-0.8), fasting and postprandial glucose, and fasting and postprandial triglycerides.39 Bromocriptine is used in the treatment of pituitary prolactinomas.40 In September 2000, a preliminary study conducted in Italy showed that low-dose bromocriptine

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is sufficient to acutely normalize prolactin in patients with metastatic breast cancer and in those with prostate carcinoma.40 It is unknown whether bromocriptine affects cancer risk in diabetic patients. On the other hand, it is used in the treatment of prolactinomas and paraneoplastic processes of certain cancers where prolactin levels are elevated.

Colesevelam (Welchol) The mechanism by which colesevelam exerts its antihyperglycemic effect is unknown; however, speculated actions include enhanced meal-induced incretin secretion and/or altered farnesoid X receptor signaling.41 Because of a lack of data regarding colesevelam and cancer, 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 hormone that is secreted by L-type endocrine cells in the distal ileum when food is ingested.42 It acts by binding to cell membrane GLP receptors, which promotes stimulation of glucose-dependent insulin secretion, as well as promotes beta-cell proliferation and survival.43,44 GLP-1 agonists bind to GLP receptors to restore beta-cell sensitivity to glucose and to increase beta-cell mass.43 Native GLP-1 is normally degraded by the enzyme dipeptidyl peptidase (DPP)-4. Drugs that inhibit DPP-4 have been developed and are currently being used as treatment for type 2 diabetes. Together, these 2 drug classes are known as the incretin family. Type 2 diabetes and obesity are known risk factors for chronic pancreatitis and pancreatic cancer. There were 88 postmarketing cases of acute pancreatitis, including 2 cases of necrotizing hemorrhagic pancreatitis, in patients receiving sitagliptin that were reported to the FDA between October 2006 and February 2009.45 In 2007, the FDA released a safety alert, and subsequently the manufacturer updated exenatideâ&#x20AC;&#x2122;s prescribing information to include the precaution of acute pancreatitis, based on postmarketing reports of pancreatitis in patients taking exenatide.46 Because pancreatitis is a known risk factor for pancreatic cancer, there is concern that long-term use of a GLP-1 agonist increases pancreatic cancer risk. A study published in 2006 found that GLP-1 receptor stimulation did not impact the growth or survival of pancreatic cancer cells.44 However, in a study published by Elashoff and colleagues in 2011, the FDA database was used to look for associations between GLP-1 agonist use and pancreatitis, pancreatic cancer, and thyroid cancer. They found that patients taking exenatide or sitagliptin had a more than 6-fold higher event rate in pancreatitis compared with patients receiving other treatment options

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and a 2.9-fold higher event rate of pancreatic cancer in those patients whose diabetes was treated with exenatide compared with other therapies.42 In addition to the FDA noting the suspected association, the Drug Commission of the German Medical Association has received 11 reports of pancreatic cancer associated with the use of exenatide.47,48 The time between exposure and diagnosis was 2 to 33 months, which is contrary to the thought that the time between tumor induction and diagnosis is usually >10 years.47,48 With regard to thyroid cancer, there is a known association with liraglutide use and medullary thyroid cancer in rodents.49 Elashoff and colleagues reviewed the FDA data for association between exenatide use and thyroid cancer and found a greater than 4-fold increase in events in the exenatide therapy group.42 There is also an association between colorectal cancer and type 2 diabetes, especially in men.50 However, in an article published in 2011, Koehler and colleagues found that activation of the GLP-1 receptor actually decreases the growth of and increases apoptosis of colon cancer cells.51 In addition, although there is a known association between obesity, type 2 diabetes, and breast cancer, there is evidence that stimulation of GLP-1 receptors leads to increased apoptosis and reduced viability of breast cancer cells without affecting noncancer cells.52 GLP-1 agonists have the potential to reduce breast cancer and colon cancer risk.51,52 Diabetes alone is a risk factor for breast and colon cancers; therefore, this particular treatment would be especially useful in diabetic individuals with or at risk for these cancers. It would likely be advisable to use caution in those patients with known risk factors for pancreatic cancer, beyond diabetes and obesity alone. The association with thyroid cancer 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-4 inhibitor use. Long-term prospective studies are needed. Meanwhile, caution should be used when prescribing DPP-4 inhibitors in patients who are obese and have type 2 diabetes, as well as other known risk factors for pancreatic cancer.42

Insulin/Insulin Analogues Similar to endogenous insulin, exogenous insulin increases the uptake of glucose into the cells, stimulates glycogen synthesis, and inhibits glucagon. It is altered in various ways to change the onset and duration of action. For example, insulin aspart, a fast-acting insulin analogue, begins to work within minutes of administration but lasts only a few hours, whereas insulin glargine is stable enough for once-daily dosing. A German cohort study published in 2009 investigat-

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ed the association between cancer risk and insulin use.53 Using malignancy diagnosis as a primary outcome, the authors analyzed data from one of the national statutory health insurance funds and included individuals without a known malignancy who received first-time treatment only with human insulin, aspart, lispro, or glargine. Of the 127,031 patients included in the study, it was noted that there was an association between incidence of malignancy and insulin dose for all insulin types; however, in comparing aspart, lispro, and glargine to human insulin, only glargine was found to have a higher dosedependent risk. Although the authors found that glargine treatment involved a higher risk of the development of cancer, a specific type of cancer was not identified in the study. In another analysis published the same year, an association between insulin glargine use and cancer incidence was not identified after evaluating 31 randomized clinical trials in a drug manufacturer’s database.54 The analyzed trials included fewer total participants (N = 10,880), and the length of the trials was, in general, approximately 6 months, except for 1 study in which participants were followed for 5 years. Furthermore, only 20 of these trials compared insulin glargine with neutral protamine Hagedorn (NPH) insulin, whereas the others included such treatments as lispro, pioglitazone, or dietary measures. Because of the concerns surrounding glargine and cancer risk, Dejgaard and colleagues conducted a metaanalysis to study the effect of insulin detemir use on diabetic patients; they found that among a group of 8693 patients with diabetes, the incidence of malignancy in those using insulin detemir was lower than or no different from the incidence in patients treated with NPH insulin or with insulin glargine.55 A French study published in 2012, using the national healthcare insurance system database and data from 2003 to 2010, found that there was no increase in cancer risk with glargine use compared with human insulin use.56 By contrast, using “possession rate”—which is defined as “the ratio of the number of treatments dispensed during the insulin exposure period divided by the number of 28-day periods during the follow-up period”— the authors did find an association between cancer risk and increasing mean possession rate.56 In another study published this year with similar conclusions, Ruiter and colleagues analyzed pharmacy records linked to hospital discharge records of 2.5 million patients in the Netherlands to determine the number of first hospital admissions with a primary diagnosis of cancer (main outcome) and to identify specific cancers.57 Of the 19,337 insulin users included in this study, 878 patients developed cancer. Use of glargine was actually associated with a lower risk of malignancy (HR, 0.75).

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With regard to specific malignancies, glargine use was associated with a lower risk of colon cancer, but no other cancers, when compared with human insulin use (similar results were true for other insulin analogues). However, glargine was associated with an increased risk of breast and prostate cancers (HRs, 1.58 and 2.76, respectively) in comparison with the use of human insulin. Glargine dose was not found to be related to diagnosis.57 In another recently published study, Luo and colleagues identified an association between postmenopausal women with diabetes who were treated with insulin and lung cancer risk.58 Using data from the Women’s Health Initiative, it was found that women who reported a diagnosis of diabetes had a higher risk of lung cancer compared with women without diabetes (HR, 1.27). Furthermore, women who reported treatment with insulin had an even greater risk of developing lung cancer (HR, 1.71). In addition, the authors noted that an association between diabetes duration and untreated diabetes was not found.58 Although the concern regarding insulin use and cancer risk is worth noting, recent studies have not justified this concern because of the lack of correlation. Further research on insulin use and cancer is warranted, and unless a patient has a high risk for malignancy, not utilizing insulin when needed would not be appropriate. Long-term prospective studies are needed.

Amylinomimetics Amylin is a peptide hormone that is secreted with insulin from pancreatic beta-cells, so it is therefore deficient in diabetic patients. It regulates postprandial spikes in blood glucose by slowing gastric emptying and digestion, promoting satiety, and inhibiting glucagon secretion.59 Pramlintide, an amylinomimetic, is utilized in type 1 and type 2 diabetic patients as an adjunctive therapy to insulin therapy, hence allowing patients to use less insulin. It has no known association with cancer. Conclusions No conclusive data are currently available that link the use of diabetes drugs to cancer development. Of the 14 diabetes drug classes currently available, there are data suggesting a higher risk of cancer development with insulin, pioglitazone, and insulin secretagogues. Metformin seems to be protective against some cancers in diabetic patients. It is important to note that all of these data are from retrospective studies and can only suggest association rather than direct cause. Prospective studies are needed to shed light on this topic. In the absence of clear correlation, practitioners and patients should continue to feel comfortable utilizing medications to control diabetes, because the correlation between uncontrolled diabetes and cancer is stronger

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than the correlation between diabetic medications and cancer. In patients with other risk factors for malignancy (such as a strong family history or personal history of cancer), providers may wish to be more thoughtful in their selection of agents to manage diabetes by utilizing the data provided in the studies mentioned. ■ Author Disclosure Statement Dr QT Nguyen, Dr Sanders, Dr Michael, Mr Anderson, Dr LD Nguyen, and Mr Johnson have reported no conflicts of interest.

References 1. Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the 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 and proposed mechanisms. Nat Rev Cancer. 2004;4:579-591. 4. Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215-2222. 5. Schramm TK, Gislason GH, Kober L. Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular 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: what is the connection? Mt Sinai J Med. 2010;77:197-213. 7. Davila JA, Morgan RO, Shaib Y, et al. Diabetes increases the risk of hepatocellular carcinoma 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 population-based case-control study in the San Francisco Bay Area, California. Cancer Epidemiol Biomarkers Prev. 2006;15:1458-1463. 9. McFarland MS, Cripps R. Diabetes mellitus and increased risk of cancer: focus on metformin and the insulin analogs. Pharmacotherapy. 2010;30:1159-1178. 10. Currie CJ, Poole CD, Jenkins-Jones S, et al. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35:299-304. 11. Dehal AN, Newton CC, Jacobs EJ, et al. Impact of diabetes mellitus and insulin use on survival after colorectal cancer diagnosis: the Cancer Prevention Study-II Nutrition 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 of pioglitazone use and bladder cancer through drug adverse event reporting. Diabetes Care. 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 evidence tell 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 risk of 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 in insulin-treated type 2 diabetic patients. Diabetes Care. 2011;34:129-131. 19. Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic complete responses 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 pancreatic 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 associated with decreased risk of breast cancer. Diabetes Care. 2010;33:1304-1308. 23. He XX, Tu SM, Lee MH, Yeung SC. Thiazolidinediones and metformin associated 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 of metabolism and cell growth. Future Oncol. 2010;6:457-470.

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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-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care. 2006;29:254-258. 27. Yang X, So WY, Ma RC, et al. Use of sulphonylurea and cancer in type 2 diabetes—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 risk in 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 diabetes. 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 to ongoing safety review of Actos (pioglitazone) and increased risk of bladder cancer. June 5, 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 patients treated 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 cancer among 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 and cancer 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 bladder cancer 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 and cancer incidence in patients with diabetes. Diabetes Care. 2011;34:923-929. 39. Mikhail N. Quick-release bromocriptine for treatment of type 2 diabetes. Curr Drug Deliv. 2011;8:511-516. 40. Iyer P, Molitch M. Positive prolactin response to bromocriptine in 2 patients with cabergoline-resistant prolactinomas. Endocr Pract. 2011;17:e55-e58. 41. Younk LM, Davis SN. Evaluation of colesevelam hydrochloride for the treatment of 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 cancer 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 and therapeutic considerations. J Nutr Metab. 2011;2011:708183. 44. Koehler JA, Drucker DJ. Activation of glucagon-like peptide-1 receptor signaling does 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 and Janumet)—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. August 18, 2008. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHuman MedicalProducts/ucm150839.htm. Accessed June 17, 2012. 47. Spranger J, Gundert-Remy U, Stammschulte T. GLP-1-based therapies: the dilemma of uncertainty. Gastroenterology. 2011;141:20-23. 48. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467:1114-1117. 49. Victoza (liraglutide [rDNA origin]) injection: REMS-risk of thyroid C-cell tumors, 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 diabetes mellitus and colorectal cancer risk: a population-based, retrospective cohort study. Am J Gastroenterol. 2006;101:1872-1879. 51. Koehler JA, Kain T, Drucker DJ. Glucagon-like peptide-1 receptor activation inhibits 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 peptide1 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 with diabetes 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 of malignancies in studies using insulin glargine. Diabetologia. 2009;52:2499-2506. 55. Dejgaard A, Lynggaard H, Råstam J, Krogsgaard Thomsen M. No evidence of increased 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: a cohort study in the French National Healthcare Insurance Database. Diabetologia. 2012;55:644-653.

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57. Ruiter R, Visser LE, van Herk-Sukel MP, et al. Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: 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 among postmenopausal 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.

STAKEHOLDER PERSPECTIVE Cancer Risk Associated with Antidiabetes Medications: Implications for Patients, Providers, and Payers PATIENTS/PROVIDERS: A patient with diabetes may find it difficult to watch television without noticing advertisements from law offices addressing concerns related to adverse events of antidiabetic medications. One of the most current advertisements nationally relates to the US Food and Drug Administrationâ&#x20AC;&#x2122;s warning that was added in 2011 to the label of pioglitazone (Actos), associating this antidiabetes medication with the risk for bladder cancer. These advertisements, along with others that also target patients directly, may have a negative impact on the willingness of patients to pay money out of pocket to take a medication or medications that have the potential 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 undertreated diabetes have well-defined risk factors. It is also known that diet and exercise alone are often not sufficient for glucose control in many patients with type 2 diabetes. Determining the most effective medication that is balanced by a favorable side-effect profile is important for ensuring appropriate medication adherence and adequate glucose control. PAYERS/EMPLOYERS: In their present article, Dr Nguyen and colleagues do a great job outlining the risk for cancer associated with diabetes and antidiabetes medications through a comprehensive review of available retrospective analyses in the current literature. Diabetes is a significant focus area for payers for several reasons. The cost of treatment for diabetes stands out among many other conditions as a result of the chronic and progressive nature of diabetes and its associated sequelae, as well as the associated comorbid conditions. Prevention of diabetes is a strong focus for many payers through incentives for, or education around, behavior modification. The other focus for

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payers is trying to get their members to reach their goal level of hemoglobin A1c, and then to maintain adequate glucose control. Diabetic control is also a focus for employer groups, who like to see measurements similar to what is reflected by the HEDIS (Healthcare Effectiveness Data and Information Set) measures, to understand diabetic control 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 some cancers. Metformin remains the most cost-effective medication available for type 2 diabetes. Metformin also continues to be recommended as a first-line agent for type 2 diabetes and is a mainstay of therapy according to the American Diabetes Association and the American Association of Endocrinologists/American College of Endocrinology guidelines. With an increased cancer risk associated with diabetes and a correlated increased risk for medications used to treat diabetes, having one medication that potentially offers protection against some types of cancer is important and further reaffirms its role as a first-line therapy for this patient population. With several newer agents available for type 2 diabetes, and with several agents currently in the drug pipeline that will potentially become available within the next couple of years, data supporting any potential cancer risk associated with antidiabetes medications may not become immediately available. Currently available data can be used for formulary decisions to provide coverage for medications that have demonstrated the best efficacy and safety through available data.

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Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT

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CALL FOR PAPERS American Health & Drug Benefits offers an open forum for all healthcare participants to exchange ideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Manufacturers, Patients, Payers, Providers, Purchasers, Regulators, and Researchers. Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being while reducing or controlling costs, enhancing the health of communities and patient populations, as well as other topics relevant to benefit design with specific implications to policymakers, payers, and employers.

Areas of High Interest: • Health Economics Research • Health Plan Initiatives • Health Information Technology • Industry Trends • Innovations in Healthcare • Literature Reviews • Medicare/Medicaid • Patient Advocacy/Patient Care

• Adherence Concerns • Benefit Design • Case Studies • Comorbidities and Cost Issues • Comparative Effectiveness Research • Cost Analyses • Decision-Making Tools • Ethics in Medicine

• Pharmacoeconomics • Policy Issues • Prevention Initiatives • Reimbursement Strategies • Social Media and Health • Survey Results • Value-Based Healthcare • Wellness Programs

Clinical Topics of High Interest: AGING/DEMENTIA—With the aging of the US population there is a growing need for early implementation of outcomesbased preventive and therapeutic strategies for older people. ALLERGIES—Allergies, such as allergic or seasonal rhinitis, affect millions of Americans daily, resulting in a significant economic burden and human cost. Undertreatment and lack of adherence are common obstacles to patient management. ARTHRITIS—Musculoskeletal conditions are on the increase, yet many patients are undiagnosed and untreated. Comparing new and emerging therapies is a key target for improving patient outcomes and reducing costs. CANCER CARE—The growing focus on biologic agents dictates an enhanced study of these therapeutic options, including reimbursement policies and cost management. CARDIOVASCULAR DISEASE—Original, outcomesbased research on appropriate therapies, cost comparisons, emerging prevention strategies, and comparative effectiveness of best practices will enhance readers’ decision-making.

DIABETES, OBESITY—The increasing comorbid epidemics of these twin conditions mandates a thorough examination of best therapies, adherence issues, access, and prevention strategies. We invite articles that will address how to improve patient outcomes and best patient care. GASTROINTESTINAL CONDITIONS—Recognizing GI conditions, such as hepatitis C, Crohn’s disease, or inflammatory bowel disorder, remains a challenge. INFECTIOUS DISEASES—The spread of common and emerging pathogens within the hospital and in the community remains a major concern requiring increased vigilance. MENTAL DISORDERS—Depression, bipolar disorder, and schizophrenia exert a huge financial and human burden on individuals, employers, and payers. Topics of interest include comparative effectiveness analyses, best practices, and reimbursement.

PAIN MANAGEMENT—Chronic pain is associated with a slew of complicated medical disorders and an enormous economic burden, yet pain medications are still underused.

Manuscripts should follow the Manuscript Instructions for Authors (available at www.AHDBonline.com). Submit articles to editorial@engagehc.com. For more information, call 732-992-1892.

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RJ Health Systems The Creators of ReimbursementCodes.com

RJ Health Systems â&#x20AC;&#x201D; the pharmaceutical specialists that healthcare professionals have turned to since 1983 for their drug information. We work with over 170 Payor organizations that touch approximately 110 million lives. RJ Health Systems has established and continuously maintains a Library of Drug Intelligence that provides the most comprehensive, trusted, and up-to-date coding and reimbursement information in the industry. ReimbursementCodes.com incorporates the CMS HCPCS and AMA CPT Drug codes into a system that crosswalks each drug code with the drugâ&#x20AC;&#x2122;s NDC and brand/generic name. Please visit www.rjhealthsystems.com to learn more about our products and services listed below:

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ReimbursementCodes.com Drug Diagnosis Coding CMAC PartBorPartD.com NDC Conversion Database Min/Max Dosing Advisories Notations Clinical Consulting

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Review aRticle

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

Stakeholder Perspective, page 240

Am Health Drug Benefits. 2012;5(4):232-240 www.AHDBonline.com Disclosures are at end of text

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 tolerate 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 management of patients with CINV, including practical considerations and value-based decisionmaking 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.

ausea and vomiting are 2 serious and related side effects of cancer chemotherapy. These adverse effects can cause significant negative impacts on patients’ quality of life and on their ability to comply with therapy. Also, nausea and vomiting can result in anorexia, decreased performance status, metabolic imbalance, wound dehiscence, esophageal tears, and nutritional deficiency.1,2 Despite advances in the prevention and management of chemotherapy-induced nausea and vomiting (CINV), these side effects remain among the most distressing for patients. The use of emerging antiemetic medications has reduced the incidence of vomiting substantially, but evaluations show that approximately 30% to 60% of patients still experience either acute or delayed nausea after chemotherapy.3 Serial evaluations throughout the 1980s and into the 2000s show that, although vomiting has fallen further down on the list of side effects that patients perceive as being their most severe, nausea remains either the first or second most severe side effect of chemotherapy.4-8 Risk factors for CINV can be divided into patientspecific and treatment-specific risk factors. Female sex Dr Rao is an oncology/BMT clinical pharmacist practitioner and Dr Faso is a hematology/oncology clinical pharmacist practitioner, University of North Carolina Hospitals and Clinics, Chapel Hill, NC.

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and history of motion or morning sickness are clear risk factors for nausea and vomiting.5,6 Younger age has also been correlated with increased risk, although this may be explained by the more aggressive chemotherapy regimens that tend to be administered to younger patients who have more aggressive diseases.5-7 Finally, alcohol intake tends to be inversely correlated with the risk of developing CINV. Many factors contribute to the treatment-specific risk, including (1) the emetogenicity of the agents being used, (2) the dose and schedule of each agent, and (3) in the case of radiation-induced or postoperative nausea, the site of radiation or surgery. “Emetogenicity” refers to an agent’s tendency to cause nausea and/or vomiting. Initially described in 1997, the emetogenicity 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 the following 4 categories10,11: • Highly emetogenic: medications or doses that cause CINV in >90% of patients • Moderately emetogenic: medications that induce CINV in 30% to 90% of patients • Low emetogenic: medications that are associated with CINV rates of 10% to 30%

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• Minimally emetogenic: medications that cause CINV in <10% of patients. “CINV” is a broad term used to describe the many types of nausea and vomiting that can occur in patients with cancer. The major subtypes of nausea and vomiting associated with chemotherapy are12-16: • Acute: onset of nausea and vomiting within minutes to hours after administration of chemotherapy and resolving within 24 hours • Delayed: occurs 24 hours or later after administration of chemotherapy • Anticipatory: occurs before chemotherapy administration; thought to be an indicator of previous poor control of nausea and vomiting • Breakthrough/refractory: nausea and vomiting that occur despite appropriate prophylaxis; requires the use of rescue medications. Because there are so many independent and variable risk factors that can influence the risk for CINV in any particular patient, it becomes paramount for providers to individualize the approach to the prevention and treatment of CINV in every patient case.

KEY POINTS ➤

➤

Pathophysiology of Nausea and Vomiting The vomiting response is controlled centrally by the emetic center, which lies in the reticular formation of the brain stem. The emetic center receives input from 3 sources: the periphery, the cortex, and the chemoreceptor trigger zone. Peripheral pathways are mediated mainly by serotonin (5-hydroxytryptamine3 [5-HT3]) and neurokinin (NK). The cortical pathway, which is responsible for anticipatory emesis, is mediated by dopamine and histamine. The chemoreceptor trigger zone, which is a collection of neurons at the base of the brain and is exposed to the body’s general circulation, mediates signals through all of the above chemokines. Once the emetic center has been triggered, signals are then sent to the salivatory, vasomotor, respiratory, and cranial centers to activate the organs involved with the vomiting reflex, namely the abdominal muscles, diaphragm, stomach, and esophagus.17 Pharmacologic Treatment Options for CINV Available Agents Before the 1980s, CINV was primarily managed with dopamine receptor antagonists. Today, we have a multitude of options available, targeting the various pathways of the process, to use in the prevention and management of CINV. 5-HT3 receptor antagonists. Ondansetron was the first US Food and Drug Administration (FDA)-approved 5HT3 antagonist in 1991. Early trials showed that ondansetron was an effective antiemetic for patients

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Risk factors for CINV can be either patient-specific or treatment-specific. Treatment-specific risks include emetogenicity of the agents used, the dose and schedule of each agent, and, if applicable, the radiation or surgery site. Agents available to treat CINV include 5-HT3 receptor antagonists, NK1 receptor antagonists, and corticosteroids, as well as dopamine receptor antagonists, benzodiazepines, olanzapine, and cannabinoids. Guidelines from the NCCN and ASCO can help providers personalize the antiemetic regimens for their patients, but these are only starting points; a “value judgment” must also be made. The preferred status for palonosetron was derived from data in 3 of 4 trials showing significant benefits in the delayed setting; these trials had significant flaws in design, leading us to question this “preferred” status and suggest that all 5-HT3 receptor antagonists are equal if used at equivalent doses and schedules. Providers must consider clinical, logistic, safety, and cost factors when treating CINV, and antiemetic regimens for a particular patient must be evaluated and then reevaluated at every treatment cycle.

receiving cisplatin-based regimens, and they subsequently showed it to be superior to metoclopramide in patients receiving cisplatin and noncisplatin regimens.18-22 Currently, four 5-HT3 receptor antagonists are available in the United States—ondansetron, granisetron, dolasetron, and palonosetron. Palonosetron, the newest agent, was approved in 2003. These agents are believed to prevent CINV by antagonizing 5-HT3 receptors either peripherally on vagal nerve terminals and/or centrally in the chemoreceptor trigger zone.23-27 Since their introduction, 5-HT3 receptor antagonists have become part of the cornerstone for CINV prevention, thanks to their effectiveness and tolerable side-effect profile. The most common adverse effects reported (in their respective package insert) with these agents are headache and constipation. Transient elevation of liver function enzymes and QTc prolongation have also been noted. NK1 receptor antagonists. NK1 receptor antagonists inhibit substance P in peripheral and central emetic pathways. Aprepitant was the first drug in this class to be approved by the FDA in 2003. Aprepitant was approved at doses of 125 mg orally on day 1 and 80 mg orally on days 2 and 3 for the prevention of nausea and vomiting in patients receiving highly emetogenic or

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moderately emetogenic single-day chemotherapy.28 Aprepitant was approved after 2 trials showed that the combination of aprepitant, ondansetron, and dexamethasone decreased emesis or decreased the use of rescue medications for patients receiving highly emetogenic chemotherapy during the acute and delayed phases.29,30 The most common adverse effects include fatigue, headache, anorexia, diarrhea, hiccups, and increased transaminases. Aprepitant is primarily metabolized by cytochrome (CY)P-450 3A4 with minor metabolism by CYP-1A2 and CYP-2C9.28,31 Aprepitant has been shown to be an inhibitor of CYP-3A4 and an inducer of CYP-2A9. Coadministration with corticosteroids such as dexamethasone, a CYP-3A4 substrate, causes an increase in plasma concentrations of dexamethasone. Therefore, when aprepitant is given with dexamethasone for CINV prevention, the dexamethasone dose should be reduced. Because aprepitant is a weak inducer of CYP2C9, the metabolism of warfarin can be affected. A decrease of international normalized ratio has been noted with this combination, and patients should be monitored, although no empiric dose adjustments for warfarin are recommended.32 Fosaprepitant, which was approved in 2008, is a water-soluble prodrug of aprepitant that is administered intravenously before chemotherapy.33 Fosaprepitant is used as an intravenous (IV) 150-mg dose on day 1 only. The one-time 150-mg IV dose has been shown to be noninferior to the 3-day oral aprepitant regimen.34 Corticosteroids. Corticosteroids were first shown to be efficacious for CINV in the 1980s, and they are now considered a mainstay of antiemetic regimens for the prevention of acute and delayed emesis.10,11,35 Although not approved by the FDA for CINV, corticosteroids have been found to be beneficial when used alone for the prevention of nausea and vomiting in patients receiving low emetogenic chemotherapy and to improve efficacy when combined with 5-HT3 receptor antagonists in patients receiving moderately or highly emetogenic chemotherapies.36-39 Dexamethasone is the recommended corticosteroid according to current guidelines, although no studies have been performed comparing available corticosteroids.10,11 The mechanism of action of corticosteroids as antiemetic agents has not been elucidated, but it may be related to activity in the peripheral nervous system or in the central nervous system (CNS), and possibly by antagonizing serotonin receptors.40-43 Tolerability to corticosteroids can be a concern, because when used for the prevention of delayed nausea and vomiting, common adverse effects have included insomnia, epigastric discomfort, agitation, weight gain, and hyperglycemia.44

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Additional Options Dopamine receptor antagonists. Before the approval of the 5-HT3 antagonists, dopamine receptor antagonists were the primary antiemetics used for CINV. With the current availability of more effective preventive agents, dopamine receptor antagonists are mostly used in the management of breakthrough or refractory emesis. The dopamine antagonists are divided into phenothiazines (eg, prochlorperazine), butyrophenones (eg, haloperidol, droperidol), and substituted benzamides (eg, metoclopramide). These agents antagonize the dopamine (D2) receptor in the chemoreceptor trigger zone.45,46 Metoclopramide antagonizes dopamine, but at high doses it also has activity against the 5-HT3 receptor.47,48 Common side effects of dopamine receptor antagonists, which include extrapyramidal symptoms, dystonia, and drowsiness, make them more suitable for breakthrough nausea rather than for primary prophylaxis. Benzodiazepines. These agents are anxiolytics that are used in patients receiving chemotherapy. Benzodiazepines are appropriate adjunct therapies to decrease treatment-related anxiety, and they are the preferred agents to treat and prevent anticipatory nausea and vomiting.49-51 Lorazepam and alprazolam are the primary agents used in this class, with sedation being the most common adverse effect, based on our clinical practice experience. Olanzapine. This atypical antipsychotic has antagonist activity at adrenergic receptors, muscarinic receptors, and multiple dopamine (D1-4) and serotonin receptors (5-HT2A, 5-HT2C, 5-HT3, 5-HT6).52,53 Several trials have shown that olanzapine safely and effectively prevents acute, delayed, and refractory CINV when combined with other antiemetics in patients receiving moderately and highly emetogenic chemotherapy.54-56 Adverse effects such as sedation, weight gain, orthostatic hypotension, hyperglycemia, and a black box warning for increased mortality in elderly patients with dementia-related psychosis limit its use.57 Cannabinoids. Dronabinol and nabilone are 2 cannabinoids that are currently approved by the FDA for CINV in patients who have not adequately responded to conventional antiemetics. Cannabinoids are thought to prevent nausea and vomiting by antagonizing cannabinoid receptor CB1 in the CNS and possibly CB2 receptors as well.58 Cannabinoids have been shown to be as effective as or slightly more effective than dopamine receptor antagonists.59,60 Only 1 trial has directly compared a cannabinoid with standard treatment.61 Ondansetron with dexamethasone plus dronabinol was found to be equally efficacious to ondansetron, dexamethasone, and placebo.61 This lack of added benefit has limited the use of cannabinoids in the preventive set-

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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 receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone

NK1 receptor antagonist if oral route was used; dexamethasone

Moderate

2-drug combination treatment with a 5-HT3 receptor antagonist and dexamethasone

Dexamethasone

Low

Dexamethasone

Minimal

No routine prophylaxis recommended

All patients should have â&#x20AC;&#x153;as-neededâ&#x20AC;? 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.

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

Current Practice Guidelines Practice guidelines from the NCCN and ASCO are available to help providers determine optimal prophylaxis and the treatment of CINV.10,11 The NCCN Antiemesis GuidelineTM, a consensus-based guideline that incorporates evidence and expert opinion to make recommendations, is revised annually.11 ASCO guidelines are purely evidence-based guidelines and are updated periodically; the last update was in 2011.10 Table 1 summarizes specific recommendations for antiemesis from the NCCN and from ASCO. For CINV, both guidelines outline primary prophylaxis based on the emetogenicity of the patientâ&#x20AC;&#x2122;s chemotherapy: high, moderate, low, and minimal. For patients receiving highly emetogenic chemotherapy, both guidelines recommend a 3-drug combination that includes a 5-HT3 receptor antagonist, an NK1 receptor antagonist, and dexamethasone to prevent CINV. The NCCN specifies that the preferred 5-HT3 receptor antagonist for highly emetogenic chemotherapy is palonosetron,11 whereas ASCO does not list a preferred 5-HT3 receptor antagonist. For patients receiving moderately emetogenic chemotherapy, the NCCN and ASCO recommend a 2drug combination of a 5-HT3 receptor antagonist, preferably palonosetron, with dexamethasone. Dexamethasone is recommended by both organizations for the prevention of CINV in patients with low or minimal emetogenic potential. The NCCN also lists metoclopramide or prochlorperazine as possible alternatives. For patients receiving minimal-risk chemotherapy, no medications are recommended primarily as prophylaxis. For anticipatory nausea and vomiting (ANV), ASCO and the NCCN recommend that prevention with optimal primary prophylaxis is the best approach.10,11 Both

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organizations state that behavioral therapy, including desensitization, is recommended for treatment of ANV. The NCCN guidelines recommend the use of benzodiazepines 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, radiation to upper abdomen), and combined radiation with chemotherapy.11 For moderate- and high-risk radiation, granisetron or ondansetron before each radiation treatment, with or without dexamethasone, is recommended. Prophylaxis of nausea and vomiting with combination chemotherapy and radiation is determined by the emetogenic potential of the chemotherapy. ASCO categorizes emetogenic risk of radiation as high (eg, total body irradiation), moderate (eg, upper abdomen), low (eg, head and neck), minimal (eg, breast), and combination of radiation and chemotherapy.10 For moderate- and high-risk radiation, a 5-HT3 receptor antagonist before each radiation treatment, along with dexamethasone during fractions 1 to 5, are recommended. Granisetron and ondansetron are preferred 5-HT3 receptor antagonists in this setting, but dolasetron can be considered. Palonosetron is listed as an option, although there are no trials to indicate appropriate dosing frequency. Patients receiving radiation with a low risk for nausea and vomiting can be offered a 5-HT3 receptor antagonist or a dopamine receptor antagonist, such as metoclopramide or prochlorperazine, as a rescue treatment. Prophylaxis for nausea and vomiting for patients receiving a combination of chemotherapy and radiation is determined by the chemotherapy regimen, unless the radiation causes a higher risk.

Practical Considerations Even with the current published guidelines, there are

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

Dose

Antiemetic

NK1 receptor antagonists

Granisetron

Fosaprepitant Aprepitant

2 mg oral or 1 mg oral twice daily; 1 mg IV or 0.01 mg/kg IV

150 mg IV 125 mg oral on day 1 and 80 mg oral on days 2 and 3

5-HT3 receptor antagonists Ondansetron

Dose

Dolasetron

100 mg oral

Palonosetron

0.25 mg IV

Corticosteroid 16-24 mg oral; 8 mg IV

Dexamethasone

8-20 mg oral IV

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

Table 3 Pharmacokinetic Properties of 5-HT3 Receptor Antagonists Agent

Ondansetron

Granisetron

Dolasetron

Palonosetron

Half-life (hrs)

3-4

7-9

7-8

Oral bioavailability, %

N/A

Renal elimination, %

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

CYP-3A

CYP-3A, CYP-2D6

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

Hepatic metabolism

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

unique challenges for clinicians who manage patients with CINV or patients at risk of developing CINV. In this article, 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 in the US marketâ&#x20AC;&#x201D;dolasetron, granisetron, ondansetron, and palonosetron. Studies with these agents show relatively similar rates of success in the prevention of CINV in patients receiving cisplatin-based chemotherapy regimens. In addition, studies have established acceptable oral:IV conversions that result in similar levels of emesis control. Equivalent doses and pharmacokinetic properties of the agents are listed in Table 2 and Table 3. When used in equivalent doses, ondansetron, granisetron, and dolasetron are considered similar for the prevention of nausea and vomiting.62,63 The pharmacokinetics of ondansetron, granisetron, and dolasetron are slightly different, but not enough to result in any clinically significant differences. Palonosetron differs from the other 5-HT3 antagonists by having increased binding affinity to the 5-HT3 receptor, higher potency, and a longer half-life.64,65 The half-life of palonosetron is approximately 40 hours compared with the significantly lower half-lives of

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ondansetron, granisetron, and dolasetron.64 This results in altered dosing recommendations for palonosetron, which is dosed once per cycle rather than on a daily basis. As discussed earlier, the NCCN and ASCO guidelines have stated a preference for palonosetron for the prevention of CINV. These recommendations are based on data from 4 trials.66-69 In 3 of these trials, palonosetron was compared with various other 5-HT3 receptor antagonists to determine noninferiority.67-69 Only 1 trial was designed to detect superiority in the comparison.66 All 4 trials demonstrated similar success rates in preventing acute CINV between palonosetron and the comparator. The preferred status for palonosetron was derived from the data showing significant benefits for palonosetron in the delayed setting in 3 of the 4 trials, including the trial sized to measure superiority. All of these trials, however, had significant flaws in their design. Most notable, all of the trials compared a single dose of palonosetron to a single dose of the comparator 5-HT3 receptor antagonist. Given palonosetronâ&#x20AC;&#x2122;s extended half-life of 40 hours, compared with the halflives of between 3 and 8 hours for other 5-HT3 receptor antagonists, comparisons at any time after 24 hours are pharmacokinetically irrelevant. In addition, only 1 of

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Figure Proposed Value-Based Decision Algorithm for CINV

Clinical success

Cost

➤

Consideration of adverse effects 5-HT3: QTc prolongation, headache, constipation Steroids: hyperglycemia D2 antagonists: drowsiness, extrapyramidal syndrome

–Cost per dose –Cost per cycle –Cost of hospitalization for breakthrough

➤

–Likelihood of adherence –Health literacy –Complexity of regimen

➤

Guidelinebased therapy

Safety

➤

Appropriate selection of initial therapy based on patient- and treatmentspecific risk factors

Convenience

Patient’s optimal therapy

Incorporate value-based considerations

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

the trials mandated the use of corticosteroids, which are the backbone of any combination antiemetic regimen.69 Given these significant flaws in design, we call into question the “preferred” status of palonosetron and instead endorse the idea that all 5-HT3 receptor antagonists are indeed equal if used at equivalent doses and schedules. 2. Multiday chemotherapy. Most data on the use of 5-HT3 receptor antagonists, especially NK1 receptor antagonists, are in the setting of single-day chemotherapy. However, numerous malignancies are treated with multiple sequential days of chemotherapy, often with various agents being given on different days. Current guidelines recommend using the appropriate level of prophylaxis, according to the emetogenicity of the regimen, on each day of the regimen, and continuing delayed prophylaxis for 2 to 3 days after the completion of chemotherapy.10,11 In patients receiving moderately emetogenic regimens, this is a relatively straightforward approach. In patients receiving highly emetogenic regimens, however, it becomes more difficult. The timing of the NK1 receptor antagonist dose or of the frequency of palonosetron dosing in these regimens is poorly defined. Einhorn and colleagues evaluated the use of every 2-day palonosetron in patients receiving the highly emetogenic chemotherapeutic combination of

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bleomycin, etoposide, and cisplatin for testicular cancer and showed favorable results.70 Another study evaluated the use of aprepitant in combination with granisetron and dexamethasone, in patients receiving multiday highly emetogenic and moderately emetogenic chemotherapy. Aprepitant was administered as 125 mg, followed by 80 mg daily for the remainder of chemotherapy days, and continued for 2 more days, all along with dexamethasone. This study demonstrated a complete remission rate of almost 58% in highly emetogenic and 73% in moderately emetogenic regimens.71 3. Breakthrough/refractory nausea and vomiting. Breakthrough/refractory nausea and vomiting are challenging to treat. In particular, refractory nausea and vomiting may cause significant morbidity, including weight loss, metabolic imbalances, and nutritional deficiency, and may result in the inability of patients to remain on their therapy schedule. The use of antidopaminergic and anticholinergic agents is very appropriate in this setting. More important, however, is the need to continually reassess the patient’s response to therapy with each cycle. In some cases, severe or refractory nausea could be predicted, given a patient’s history of poor tolerance of therapy, and adjustments could have been made to decrease the risk of nausea and vomiting. Also, regular reevaluation of risk factors can help to

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

Proposal for a Value-Based Decision-Making Algorithm It must be emphasized that the currently available guidelines are not meant to be clear-cut decisions on how to approach every patient. The guidelines are meant to be viewed as a starting point from which to build the case for every individual’s antiemetic regimen. Along with these guidelines, a “value judgment” must be made to determine 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 factors include (1) clinical factors (ie, freedom from nausea and decreased use of rescue medications), (2) logistic factors (ie, convenience of a regimen and likelihood of adherence), (3) safety factors (ie, consideration of potential adverse effects of agents in particular scenarios), and (4) cost factors (ie, affordability, coverage, and reimbursement). In many cases, treatment decisions must be made considering whether the patient will be able to afford or comply with the regimen that would technically be “ideal.” For example, clinicians may consider using IV NK1 receptor antagonists and/or IV palonosetron in a patient who either cannot afford to pay for continued oral NK1 receptor antagonist or 5-HT3 receptor antagonist therapy, or in a patient who will be unlikely to remember to take doses as scheduled for the days after chemotherapy. A proposed algorithm for decision-making, including considerations regarding the abovementioned value considerations, is outlined in the Figure. Conclusions Antiemetic 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 incorporate clinical decision-making with value-based considerations to determine each patient’s individual, most optimal approach to treatment. With such an approach, we hope to continue to make progress in the prevention and management of this troublesome and problematic adverse effect of chemotherapy, thereby helping to improve the therapy experience and quality of life for our patients. ■ Author Disclosure Statement Dr Rao and Dr Faso have reported no conflicts of interest.

References 1. Laszlo J. Antiemetics and cancer chemotherapy. Baltimore, MD: Williams & Wilkins; 1983. 2. Fernández-Ortega P, Caloto MT, Chirveches E, et al. Chemotherapy-induced nau-

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sea and vomiting in clinical practice: impact on patients’ quality of life. Support Care Cancer. [Epub ahead of print Mar 31 2012]. 3. Cohen L, de Moor CA, Eisenberg P, et al. Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497-503. 4. Coates A, Abraham S, Kaye SB, et al. On the receiving end—patient perception of the side-effects of cancer chemotherapy. Eur J Cancer Clin Oncol. 1983;19:203-208. 5. de Boer-Dennert M, de Wit R, Schmitz PI, et al. Patient perceptions of the sideeffects of chemotherapy: the influence of 5HT3 antagonists. Br J Cancer. 1997;76: 1055-1061. 6. Griffin AM, Butow PN, Coates AS, et al. On the receiving end. V: Patient perceptions of the side effects of cancer chemotherapy in 1993. Ann Oncol. 1996;7:189-195. 7. Hofman M, Morrow GR, Roscoe JA, et al. Cancer patients’ expectations of experiencing treatment-related side effects: a University of Rochester Cancer Center— Community Clinical Oncology Program study of 938 patients from community practices. Cancer. 2004;101:851-857. 8. Lindley C, McCune JS, Thomason TE, et al. Perception of chemotherapy side effects cancer versus noncancer patients. Cancer Pract. 1999;7:59-65. 9. Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol. 1997;15:103-109. 10. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29:4189-4198. 11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Antiemesis.Version 1.2012. www.nccn.org/professionals/physician_gls/ pdf/antiemesis.pdf. Accessed June 20, 2012. 12. Jacobsen PB, Redd WH. The development and management of chemotherapyrelated anticipatory nausea and vomiting. Cancer Invest. 1988;6:329-336. 13. Kris MG, Gralla RJ, Clark RA, et al. Consecutive dose-finding trials adding lorazepam to the combination of metoclopramide plus dexamethasone: improved subjective effectiveness over the combination of diphenhydramine plus metoclopramide plus dexamethasone. Cancer Treat Rep. 1985;69:1257-1262. 14. Moher D, Arthur AZ, Pater JL. Anticipatory nausea and/or vomiting. Cancer Treat Rev. 1984;11:257-264. 15. Morrow GR. Clinical characteristics associated with the development of anticipatory nausea and vomiting in cancer patients undergoing chemotherapy treatment. J Clin Oncol. 1984;2:1170-1176. 16. Roila F, Boschetti E, Tonato M, et al. Predictive factors of delayed emesis in cisplatin-treated patients and antiemetic activity and tolerability of metoclopramide or dexamethasone. A randomized single-blind study. Am J Clin Oncol. 1991;14:238-242. 17. Allan SG. Mechanisms and management of chemotherapy-induced nausea and vomiting. Blood Rev. 1987;1:50-57. 18. Bonneterre J, Chevallier B, Metz R, et al. A randomized double-blind comparison of ondansetron and metoclopramide in the prophylaxis of emesis induced by cyclophosphamide, fluorouracil, and doxorubicin or epirubicin chemotherapy. J Clin Oncol. 1990;8:1063-1069. 19. Grunberg SM, Stevenson LL, Russell CA, McDermed JE. Dose ranging phase I study of the serotonin antagonist GR38032F for prevention of cisplatin-induced nausea and vomiting. J Clin Oncol. 1989;7:1137-1141. 20. Hainsworth J, Harvey W, Pendergrass K, et al. A single-blind comparison of intravenous ondansetron, a selective serotonin antagonist, with intravenous metoclopramide in the prevention of nausea and vomiting associated with high-dose cisplatin chemotherapy. J Clin Oncol. 1991;9:721-728. 21. Kris MG, Gralla RJ, Clark RA, Tyson LB. Dose-ranging evaluation of the serotonin antagonist GR-C507/75 (GR38032F) when used as an antiemetic in patients receiving anticancer chemotherapy. J Clin Oncol. 1988;6:659-662. 22. Marty M, Pouillart P, Scholl S, et al. Comparison of the 5-hydroxytryptamine3 (serotonin) antagonist ondansetron (GR 38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. N Engl J Med. 1990;322:816-821. 23. Endo T, Minami M, Hirafuji M, et al. Neurochemistry and neuropharmacology of emesis—the role of serotonin. Toxicology. 2000;153:189-201. 24. Fozard JR. Neuronal 5-HT receptors in the periphery. Neuropharmacology. 1984; 23:1473-1486. 25. Fukui H, Yamamoto M, Sato S. Vagal afferent fibers and peripheral 5-HT3 receptors mediate cisplatin-induced emesis in dogs. Jpn J Pharmacol. 1992;59:221-226. 26. Kilpatrick GJ, Jones BJ, Tyers MB. Binding of the 5-HT3 ligand, [3H]GR65630, to rat area postrema, vagus nerve and the brains of several species. Eur J Pharmacol. 1989;159:157-164. 27. Miner WD, Sanger GJ, Turner DH. Evidence that 5-hydroxytryptamine3 receptors mediate cytotoxic drug and radiation-evoked emesis. Br J Cancer. 1987;56:159-162. 28. 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 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving 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 regimen with a multiple-day ondansetron regimen, both with dexamethasone, for

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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 major enzyme involved in the metabolism of the substance P receptor antagonist aprepitant. Drug Metab Dispos. 2004;32:1287-1292. 32. DeprĂŠ M, Van Hecken A, Oeyen M, et al. Effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin. Eur J Clin Pharmacol. 2005;61:341-346. 33. Emend (fosaprepitant dimeglumine) for injection [package insert]. Whitehouse Station, 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 prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocolâ&#x20AC;&#x201D;EASE. J Clin Oncol. 2011;29:1495-1501. 35. Ioannidis JP, Hesketh PJ, Lau J. Contribution of dexamethasone to control of chemotherapy-induced nausea and vomiting: a meta-analysis of randomized evidence. J Clin Oncol. 2000;18:3409-3422. 36. The Italian Group for Antiemetic Research. Dexamethasone, granisetron, or both 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 comparison of intravenous ondansetron alone and in combination with intravenous dexamethasone 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 of granisetron in the first 24 h following high-dose cisplatin chemotherapy. Support Care Cancer. 1995;3:307-312. 39. Markman M, Sheidler V, Ettinger DS, et al. Antiemetic efficacy of dexamethasone. Randomized, double-blind, crossover study with prochlorperazine in patients receiving cancer chemotherapy. N Engl J Med. 1984;311:549-552. 40. Ho CM, Ho ST, Wang JJ, et al. Dexamethasone has a central antiemetic mechanism in decerebrated cats. Anesth Analg. 2004;99:734-739. 41. Mantovani G, Maccio A, Esu S, Lai P. Evidence that cisplatin induces serotonin release from human peripheral blood mononuclear cells and that methylprednisolone inhibits this effect. Eur J Cancer. 1996;32A:1983-1985. 42. Suzuki T, Sugimoto M, Koyama H, et al. Inhibitory effect of glucocorticoids on human-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 dexamethasone on 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 dexamethasone for prophylaxis of delayed emesis after moderately emetogenic chemotherapy. Br J Cancer. 2006;94:1011-1015. 45. Edmonds-Seal J, Prys-Roberts C. Pharmacology of drugs used in neuroleptanalgesia. Br J Anaesth. 1970;42:207-216. 46. Wyant GM. A comparative study of eleven anti-emetic drugs in dogs. Can Anaesth Soc J. 1962;9:399-407. 47. Bianchi C, Beani L, Crema C. Effects of metoclopramide on isolated guineapig 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 metoclopramide on 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 with cisplatin: 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 prophylaxis of anticipatory, acute, and delayed nausea and vomiting induced by high doses 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 and anticipatory 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 the atypical antipsychotic olanzapine. Neuropsychopharmacology. 1996;14:87-96. 53. Bymaster FP, Falcone JF, Bauzon D, et al. Potent antagonism of 5-HT(3) and 5HT(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, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: 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 the prevention of chemotherapy-induced nausea and vomiting: a Hoosier Oncology Group study. Support Care Cancer. 2005;13:529-534. 56. Passik SD, Navari RM, Jung SH, et al. A phase I trial of olanzapine (Zyprexa) for the prevention of delayed emesis in cancer patients: a Hoosier Oncology Group study. 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 treatment 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 prochlorperazine 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 the antiemetic effects of nabilone and prochlorperazine on chemotherapy-induced emesis. Cancer Treat Rep. 1980;64:219-224. 61. Meiri E, Jhangiani H, Vredenburgh JJ, et al. Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapyinduced nausea and vomiting. Curr Med Res Opin. 2007;23:533-543. 62. Billio A, Morello E, Clarke MJ. Serotonin receptor antagonists for highly emetogenic chemotherapy in adults. Cochrane Database Syst Rev. 2010;CD006272. 63. Jordan K, Hinke A, Grothey A, et al. A meta-analysis comparing the efficacy of four 5-HT3-receptor antagonists for acute chemotherapy-induced emesis. Support Care Cancer. 2007;15:1023-1033. 64. Rojas C, Stathis M, Thomas AG, et al. Palonosetron exhibits unique molecular interactions 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 internalization 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, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-1449. 67. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 68. Gralla R, Lichinitser M, Van Der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 69. Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial. Lancet Oncol. 2009;10:115-124. 70. Einhorn LH, Brames MJ, Dreicer R, et al. Palonosetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-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 combination with the NK-1 antagonist aprepitant in highly and moderately emetogenic multiple-day chemotherapy. Eur J Cancer. 2009;45:1184-1187.

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STAKEHOLDER PERSPECTIVE Selecting Best Therapies for Control of Chemotherapy-Induced Nausea and Vomiting PROVIDERS/PAYERS: In a world of guidelines, algorithms, and literature searches, we often forget to focus on the patient. Nausea and vomiting are side effects that need to be evaluated differently from other effects related to chemotherapy in patients with cancer. Thoughtful evaluation to determine the pathophysiologic mechanisms that trigger nausea, as described in the article by Dr Rao and Dr Faso, is key to selecting the optimal antinausea medications.1 When evaluating chemotherapy-induced nausea and vomiting (CINV), we automatically think of serotonin in peripheral receptors and dopamine in the chemoreceptor trigger zone as the primary culprits; however, we must also consider any underlying causes that may be 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 antiemetics for patients with cancer. Neurologic or vision changes secondary to chemotherapy may contribute to vestibular changes, indicating a need for anticholinergics or antihistamines. Taste and smell changes secondary to chemotherapy may require benzodiazepines or corticosteroids to help control nausea. The main point is that the patient must be evaluated beyond just the emetogenic potential of the chemotherapy itself. As the authors pointed out, clinical success is the first step in the value-based decision algorithm. Comorbid conditions also affect the success of these agents, and it is sometimes important to consider side effects as intended benefits of some of these drugs. Steroids may cause agitation or weight gain, but some patients experience this as increased energy or mood boosts, which can be a dual benefit beyond the antinausea component. Sedation is a common side effect with benzodiazepines, but patients with insomnia (especially secondary to their corticosteroid use) may realize dual benefit here as well. The key factors for these 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

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guidelines are great in some cases, but value-based considerations are essential to optimizing therapy in our patients. Without consideration of the whole person, the potential increased risk factors for CINV, and other comorbid conditions, payers may approve reimbursement for whatever standard guidelines recommend, but this will not necessarily be getting the best treatment for our patients. As providers, we have to make sure that we drive the decision for antiemetic therapy based on patient-specific factors in addition to the chemotherapy itself. PATIENTS: Nausea and vomiting remain the side effects of chemotherapy that patients with cancer fear the most. Almost every patient has known someone or had a family member who has “suffered” through chemotherapy and has had horrendous issues with CINV. Patients report that they would rather be in pain than have CINV, because many can work through the pain, but nausea is completely debilitating. The best option is empowering patients to take control of their nausea through proper education, use of antiemetics that are appropriate to their case, and through continual follow-up and adjustment to their antiemetic regimens. Patients need to be given the opportunity to sit down with a nurse or a pharmacist to reiterate the counseling provided by their physicians. Our experience with this process has helped to improve monitoring and follow-up for patients with CINV. We must not only give patients the antiemetics they need, but we must also provide them with the resources to be properly educated about these medications. Therefore, to incorporate value-based considerations for optimal therapy, it is necessary to ensure that a cohesive multidisciplinary approach is provided to the patient. Robert Mancini, PharmD Oncology Pharmacist St. Luke’s Mountain States Tumor Institute Boise, ID 1. Wood GJ, Shega JW, Lynch B, Von Roenn JH. Management of intractable nausea 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: Health Plans’ and Pharmacy Benefit Managers’ Perspectives on Changing Care Models rhonda greenapple, MSPH

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Am Health Drug Benefits. 2012;5(4):242-253 www.AHDBonline.com Disclosures are at end of text

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 anticipated 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 respondents 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 targeted 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 oncology 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 respondents, “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 reimbursement practices are poised to significantly alter conventional models of cancer care delivery 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.

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ccording to the American Cancer Society, more than 1.6 million new cancer cases will be diagnosed in 2012, and more than 577,000 Americans are expected to die of cancer this year.1 Currently, claims for cancer care account for 10% of total healthcare costs but for less than 1% of a typical commercially insured population.2 Cancer drugs are the third most expensive category among specialty drugs, with an average cost per prescription of $3259.3 It has been estimated that with the aging of the US population, the annual number of newly diagnosed cases of cancer will increase by approximately 45%, to 2.3 million, by 2030.4 As a result of advances in cancer diagnosis and treatment over the past several decades, the 5-year survival rate for all cancers increased from 49% for patients diagnosed between 1975 and 1977, to 67% for those diagnosed between 2001 and 2007.1 Several 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 reform legislation has been introduced with the goal of improving patient outcomes while reducing overall cost, and this legislation is likely to significantly alter traditional models of care delivery, assessment, and reimbursement. Advances in cellular and molecular biology have made it possible to target a patient’s unique tumor biology, but the new targeted agents are considerably more expensive than older cancer medications. For example, an analysis of monthly Medicare costs for a typical patient (70 kg body weight or 1.7 m2 body surface area) showed that costs exceeded $5000 per month for several targeted agents, including sorafenib ($5097), nilotinib ($6140), panitumumab ($7991), cetuximab ($9465), and alemtuzumab ($19,925).6 In contrast, the costs for most cytotoxic drugs introduced before 1995 were less than $1000 monthly.6 Compared with older treatments, many newer chemotherapy agents are much more expensive; this includes bendamustine ($7023 monthly), ixabepilone ($6781 monthly), and nelarabine ($19,425 monthly).6 In addition, many of these agents require histologic, genetic, or molecular tests to identify appropriate patients for a specific cancer therapy, for example, HercepTest (Dako) or Ventana Pathway (Ventana), used to predict response to trastuzumab in patients with breast cancer.7 Test costs may vary from approximately $350 to ≥$4000 per test.8 The economic impact of targeted therapies may be expected to grow as clinical trials continue to explore new applications of these agents, including their use as first-line therapy and/or in combination with other highcost targeted agents (eg, the combination of erlotinib and bevacizumab in patients with lung cancer, or

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KEY POINTS ➤

➤

Cancer care is undergoing changes related to new clinical and economic trends, including rising drug costs of biologic therapies, changing reimbursement practices, a growing emphasis on comparative effectiveness research, and potential changes related to healthcare reform. This survey of 55 health plans and PBMs explored their perspectives on these emerging changes and their anticipated cost-management strategies in oncology. The survey findings indicate an increasing role for specialty pharmacy for cancer drugs, a growing focus on cost-control efforts, and a significant impact of national practice guidelines on formulary and reimbursement decisions for cancer therapies. National guidelines serve as compendia for reimbursement purposes for approved and off-label uses of cancer therapies. Quality initiatives are perceived as having the greatest potential impact on breast cancer. Seventy-nine percent of health plans and PBMs participating in this survey do not have a specific price threshold for placing drugs on the specialty tier. The decision to cover a particular cancer test is significantly influenced by clinical practice guidelines, according to 90% of survey respondents. These findings highlight important trends in oncology management and reimbursement that reinforce the continuing efforts by payers to control costs while maintaining quality of care.

lenalidomide plus bortezomib in patients with multiple myeloma). Newer diagnostic approaches, such as increasing use of positron emission tomography, also contribute to increasing costs of cancer care.9 The rising healthcare costs associated with more recent cancer diagnostics and treatments are a significant concern for many health plans. To understand current oncology cost-management strategies, as well as expectations about future practice patterns of healthcare payers and pharmacy benefit managers (PBMs) in response to changes in oncology care, Reimbursement Intelligence conducted an online survey of health plans and PBMs to determine their attitudes and expectations about cancer management.

Survey Methodology Reimbursement Intelligence, a market research company, conducted an online survey of approximately 200 questions in October 2011. The survey was completed by 55 (of 57) medical and pharmacy directors (24 medical

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Table 1 Current and Anticipated Oncology Management Tactics Management tactics

Likely to be Not Currently utilized in the utilized, % utilized, % next 2 years, %

NCCN/ASCO guidelines

Pharmacy benefit classification

ASP-based payments

Biomarker testing for appropriate therapy selection

Quality initiatives

Episode of care payments

Oncology formulary with preferred brand

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

directors and 31 pharmacy directors) from US national and regional health plans and 8 PBMs. Survey respondents were formulary decision makers for oncology coverage at health plans and PBMs, who together manage more than 151 million covered lives, including individuals enrolled in commercial, Medicare Advantage, and Managed Medicaid plans. The most frequent benefit design in these companies is a 3-tier open formulary, which was used by 48% of health plans and PBMs; a 3tier closed design was used by 21%; a 4-tier design with a 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 members of the Pharmacy and Therapeutics Committees of their respective plans. Respondents received an honorarium for completing the survey. The survey included quantitative and qualitative questions about several aspects of oncology management, including the application of clinical practice guidelines in cancer care, the potential impact of healthcare reform, quality improvement initiatives, and personalized medicine. The respondents were treated as 1 group, because no differences in responses were evident between medical and pharmacy directors or PBMs.

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Results Cost-Management Strategies for Oncology Drugs prescribed by oncologists currently account for more than 40% of all Medicare drug spending.10 According to the National Institutes of Health, the direct costs of cancer care in the United States are expected to increase from approximately $124 billion annually in 2010 to approximately $173 billion in 2020 (a 39% increase).11 Most cancer drugs approved since 2005 cost more than $4000 monthly, and a full course of treatment with some targeted therapies costs more than $80,000.6,12 The rising cost of cancer care comes at a time when legislative changes to Medicare reimbursement policies have markedly decreased the reimbursement that physicians receive for prescribing many oncology drugs, in some cases leaving prescribers in debt for oncology drugs that they must purchase.13 Qualitative surveys and interviews of senior physician executives at large managed care organizations (MCOs), which were conducted by the National Comprehensive Cancer Network (NCCN), identified several strategies that these MCOs were using to control costs and maximize clinical benefit.9 These cost-control strategies include aggressive contracting, new reimbursement models (eg, payments based on episodes of care rather than on oncologic drug costs), nursing-led case-management strategies focused on patients with the greatest medical needs, the use of NCCN guidelines and other resources to establish standards of treatment and reimbursement, and the use of specialty pharmacy services for high-cost oral drugs. Cost-management strategies in current use by respondents to the present survey, as well as strategies expected to be initiated within the next 2 years, are summarized in Table 1. Participants were asked to rate each cost-management tactic as either currently utilized, not currently utilized but likely to be utilized within the next 2 years, or not utilized and with no plans for utilization within the next 2 years. The use of clinical practice guidelines from the NCCN or the American Society of Clinical Oncology (ASCO), as well as moving a drug from the medical benefit to the pharmacy, are the most frequently utilized management tactics (by 76% and 65%, respectively), whereas biomarker testing and the use of preferred brands on the oncology formulary are the strategies most likely to be introduced in the next 2 years. Survey respondents report that oncologist responses to declining reimbursement rates include consolidation of oncology clinics (35%), selecting more profitable therapy options (35%), sending more patients for hospitalization (31%), forming joint ventures or partnerships with hospital groups (21%), and increasing practice efficiency (17%).

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Vol 5, No 4

Emerging Trends in Cancer Care

Figure 1 Overall Survival and Progression-Free Survival the Most Important Efficacy End Points When Evaluating Coverage of Cancer Therapies Question: Please rate each of the following efficacy end points in terms of their importance and influence when evaluating cancer therapies for coverage and reimbursement. Overall survival Progression-free survival Duration of response Overall response rate Time to symptom progression Time to treatment failure

70 60

Respondents, %

50 40 30 20 10 0

1 = Not important

5 = Very important

Rating

In this survey, breast cancer was rated as the most expensive cancer type overall, followed by nonâ&#x20AC;&#x201C;small-cell lung cancer, prostate cancer, multiple myeloma, nonHodgkin lymphoma (NHL), and metastatic melanoma. Techniques used to monitor oncology drug costs include per-member per-month costs (by 69% of respondents); utilization review (41%); and analysis by cancer diagnosis (31%), episode of care (21%), disease type (21%), or tumor type (17%). Only 10% of respondents say that their organization 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 benefit structure, with specialty pharmacy coinsurance payments of 10% to 25% of the drug costs.14 In this survey, copayments at tier 4 are reported as $21 to $40 by 5% of plans/PBMs and >$40 by 26%, whereas 68% of plans/ PBMs use coinsurance. Within the next 5 years, most respondents expect that between 11% and 40% of cancer therapies would go through specialty pharmacy. Most (79%) plans/PBMs in this survey do not have a specific price threshold for placing drugs on the specialty tier. When clinical end points are similar, 93% of respondents prefer oral agents to infused therapies, 7% are neutral, and none finds infused agents to be superior. Of note, although oral oncolytics offer greater patient convenience, they are also associated with increased likelihood of nonadherence, resulting in adverse outcomes

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and greater resource utilization.15 In fact, reported adherence rates have varied widely, from 16% to 100%.15 In companies included in this survey, oral oncolytic agents are covered under the specialty drug tier by 59% of plans/PBMs. In terms of the preferred type of tracking data to assess patient adherence, 58% of respondents prefer the medication possession ratio, and 42% prefer claim or refill information. A key distinction between oral and injectable cancer medication coverage is that oral agents are covered by Medicare under the pharmacy benefit, which may mean higher coinsurance or cost burden for patients, including the potential of falling into the Medicare coverage â&#x20AC;&#x153;doughnut hole.â&#x20AC;? In contrast, office-infused agents are generally covered by the medical benefit, with fewer outof-pocket costs for patients. Although Medicare beneficiaries must pay a 20% copayment for drugs administered under the medical benefit, approximately 90% have supplemental insurance under Medicare part B, which covers this amount.16 Physicians may take these factors into account when making therapy decisions.

Role of Practice Guidelines in Treatment Selection and Reimbursement Considerations Clinical practice guidelines from the NCCN and ASCO use data from large, well-designed clinical trials, combined with supporting evidence from retrospective

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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 on your approach to management of oncology therapies? Please choose all that apply. Elimination of exclusions for preexisting conditions

62%

CER

52%

Elimination of lifetime caps on coverage

48%

Required coverage of Standard of Care for patients in clinical trials

31%

340B hospital reimbursement

21%

Closing of the Medicare coverage “doughnut hole” gap

14%

Changes to the PQRI incentive payments

10%

Changes to the SGR payment system

10%

Other

3% 0

Respondents, %

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

studies and other data sources, to identify treatment regimens that produce the best possible clinical outcomes for patients with different types of cancer. The guidelines use disease stage and other patient factors to identify preferred and alternate regimens, which are continually revised and updated as new data become available. These guidelines serve as standards of medical care and as compendia for reimbursement for approved and for off-label uses of antitumor agents.17 For example, the continued use of bevacizumab for the treatment of breast cancer has been recommended by the NCCN guidelines, even after the withdrawal of the US Food and Drug Administration indication for this purpose.18 Participants were asked how frequently self-insured employers or employee benefit consultants require the use of NCCN guidelines when soliciting bids for oncology pharmacy management services. The use of clinical practice guidelines for coverage or reimbursement is “very frequent” (occurring in >75% of all requests for proposals [RFPs]) by 10% of respondents, “frequent” (51%-75% of all RFPs) by 21% of respondents, “moderately frequent” (26%-50% of all RFPs) by 7%, and “used in some instances” (10%-25% of all RFPs) by 14% of respondents. Only 14% say that clinical guidelines are not used

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at all, and the remaining 34% consider the question not applicable to their contracting practices. Data sources required for off-label reimbursement include NCCN guidelines (72%), compendia listings (66%), and peerreviewed articles in the medical literature (66%). Other requirements for off-label treatment include failure of onlabel therapy (52%), prior authorization (52%), and prescribing physician documentation (28%). Participants were also asked to rate the importance, on a scale of 1 (not important) to 5 (very important), of different efficacy end points that they consider when evaluating cancer therapies for reimbursement. Overall survival (OS) is the most important efficacy end point, with a rating of “very important” by 59%; progressionfree survival (PFS) was rated as “very important” by 28%; and duration of response by 24% (Figure 1).

Healthcare Reform and Comparative Effectiveness Research The Patient Protection and Affordable Care Act (ACA) was signed into law on March 23, 2010. The goals of the ACA include expanding access to health insurance coverage, improving affordability and sustainability for those with coverage, controlling healthcare

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Vol 5, No 4

Emerging Trends in Cancer Care

Figure 3 Healthcare Reform Expected to Lead to Greater Utilization Restrictions and More Stringent CER Requirements Question: How will the healthcare reform legislation impact your management of oncology agents? Please check all that apply. 70

59%

Respondents, %

48%

38%

31% 30 20

10%

10 0 Increase in utilization restrictions (eg, PAs, step edits)

More stringent comparative effectiveness evidence requirements

Increased patient cost-sharing through use of specialty tier

Other

Narrower patient identification for appropriate utilization

CER indicates comparative effectiveness research; PAs, prior authorizations.

Figure 4 Randomized Controlled Trials and Population Studies Expected to Have the Most Impact on Cost of Care and Drug Utilization Question: Which CER methodologies will have the greatest impact on cost-efficient care and drug utilization? Please check all that apply. 80

79% 69% 59%

Respondents, %

48% 40

21%

Prognostic and predictive association studies

QOL studies, including patient-reported outcomes

Qualityadjusted life-years measurement

0 Randomized controlled trials

Population studies, including registries and administrative and claims data

Clinical decision models, including costeffectiveness and cost-utility analysis

Systematic reviews and meta-analysis

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

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Table 2 Primary Drivers for Forming/Partnering with an ACO Item

Overall rank

Improve quality of care and performance standards

Increase lower-cost treatment alternative utilization

Improve outcomes data tracking

Improve overall spending tracking

Improve patient drug compliance

Improve physician adherence to the formulary

Implement pay-for-performance

Legislative requirement for Medicare beneficiaries

ACO indicates accountable care organization.

costs, and improving the quality of care.19 The ACA is expected to standardize coverage by defining a number of significant changes in oncology practice, including elimination of exclusions for preexisting conditions or lifetime caps on coverage, coverage of routine care for patients participating in clinical trials, changes in reimbursement, and expanded access to the federal 340B drug discount pricing program.19-22 In addition, the US American Reinvestment and Recovery Act of 2009 promotes comparative effectiveness research (CER) through a separate $1.1 billion appropriation to fund clinical studies that will compare efficacy, safety, and other primarily clinical outcomes associated with 2 or more treatments for the same medical problem.23

CER methodologies that are expected to have the greatest impact on cost of care and drug utilization include randomized controlled clinical trials, population studies, and clinical decision models. When asked to identify aspects of healthcare reform legislation that will have the greatest impact on oncology management, elimination of exclusions for preexisting conditions was selected by 62% of respondents, followed by the use of CER (52%), eliminating lifetime caps on coverage (48%), required coverage for patients in clinical trials (31%), and increased number of hospitals eligible for the federal 340B drug discount (21%; Figure 2).

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Regarding the impact of healthcare reform on the management of cancer drugs, most respondents (59%) expect that healthcare reform measures would lead to greater utilization restrictions, such as prior authorizations or step edits; 48% anticipate the use of more stringent requirements for comparative effectiveness evidence; 38% anticipate greater patient cost-sharing through the use of a specialty pharmacy tier; and 31% expect narrower patient identification for appropriate utilization (Figure 3). CER methodologies that are expected to have the greatest impact on cost of care and drug utilization include randomized controlled clinical trials, population studies, and clinical decision models (Figure 4). In addition, most respondents (66%) believe that it is probable, and 3% believe that it is highly probable, that CER will help control oncology costs and healthcare utilization; 10% consider this outcome to be highly improbable or improbable; and 21% are neutral on this question. CER is expected to help identify the most effective interventions to improve care by 76% of payers. None of the plans surveyed are currently involved in new CER models.

Accountable Care Organizations Accountable care organizations (ACOs) are affiliations of healthcare providers that are held jointly accountable for improving care quality and reducing spending.24 ACOs are established by the ACA as a new payment model under Medicare, Medicaid, and private insurance.25 They are intended to reduce fragmentation of care,26 although their precise implementation in oncology practice remains uncertain. Primary care physicians may join only 1 ACO; oncologists may join 2 or more ACOs as independent physicians, but they are not permitted 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 unfavorable or highly unfavorable. Those with negative opinions of ACOs emphasize factors such as the resemblance of ACOs to the â&#x20AC;&#x153;gatekeeperâ&#x20AC;? role of HMOs, potential barriers to care for rural patients, and the difficulties involved in moving physicians from private practice to employee status. Those with positive opinions of ACOs note the potential for improved care management and the use of incentives to align primary care physicians, specialists, and hospitals. Participants view ACOs as moderately relevant (52%), relevant (31%), or very relevant (7%) to oncology care; only 10% say that ACOs are not relevant to oncology. In addition, 24% believe that they would form or partner with an ACO within the next 2 years, and another 41% say that such a move is possible. Of those

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Vol 5, No 4

Emerging Trends in Cancer Care

Quality Initiatives Over the past decade, several initiatives have been developed to quantify and improve the quality of care received by patients with cancer. ASCO has sponsored the development and dissemination of the Quality Oncology Practice Initiative (QOPI), a voluntary, physician-led program that is designed to improve oncology practice by identifying general performance measures, as well as specific performance measures for breast, colon, lung, and rectal cancer, and NHL.28 The NCCN and ASCO have also developed a simplified set of quality measures for breast and colorectal cancer.29 The Physician Quality Reporting System (PQRS), formerly known as the Physician Quality Reporting Initiative (PQRI), was established by the Centers for Medicare & Medicaid Services as a voluntary reporting system that is linked to financial incentives for eligible healthcare professionals who provide care to Medicare recipients.30 Health plans are experimenting with a variety of approaches to manage costs associated with oncology care, while also ensuring that patients receive care that meets evidence-based standards. For example, United Healthcare has been evaluating the effects of a â&#x20AC;&#x153;bundledâ&#x20AC;? payment pilot program in 5 oncology practices, in which these practices receive an up-front fee for the full

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Figure 5 ACOs Expected to Generate the Greatest Cost-Savings in the Treatment of Patients with Breast Cancer Question: In which types of cancer indications do you expect to see the biggest cost-savings to your plan as a result of your formation/partnership with an ACO? Please check all that apply.

83% 80

Respondents, %

indicating having plans to form or partner with an ACO, 16% plan to address the Medicare population, 26% the commercial population, and 58% both populations. The primary drivers for forming or partnering with an ACO are shown in Table 2. Although the US Department of Health and Human Services operates an ACO pilot program (the Pioneer Accountable Care Organization Model program),27 only 31% of respondents expressed an interest in participating in that program. Lack of interest in a pilot program, a perception of the program as overly cumbersome, or competition with other priorities were cited as reasons for nonparticipation in the Pioneer ACO pilot program. Most (76%) respondents believe that ACOs would result in cost-savings of 1% to 30%; 18% believe that ACOs would yield no cost-savings, and 4% believe that cost-savings would likely exceed 40%. They expect that the cost-savings would be generated primarily through greater adherence to evidence-based treatments, improvement in coordination of care, and greater use of low-cost alternative treatment options. ACOs are considered most likely (83% of respondents) to yield cost-savings in the treatment of breast cancer (Figure 5). Other cancer types expected to yield cost-savings include prostate cancer (identified by 58%), lung cancer (58%), metastatic melanoma (29%), and hematologic malignancies (21%).

58%

29% 21% 20

Breast cancer

Prostate cancer

Lung cancer

Metastatic melanoma

Hematologic malignancies

ACO indicates accountable care organization.

cost of care for each episode of cancer care rather than purchasing cancer medications and receiving reimbursement for these purchases. This approach is intended to standardize cancer care and encourage greater adherence to treatment guidelines, while separating evidence-based medication prescribing from drug reimbursement.31 A quality improvement program led by the University of Michigan, in coordination with Blue Cross Blue Shield, has been developed to increase the statewide use of breast cancer treatments that meet benchmarks recommended by the NCCN, including appropriate use of endocrine therapy, chemotherapy, and radiation therapy.32 In this present survey, nearly half (48%) of respondents have no plans to implement quality initiatives, 35% plan to implement quality measures created by the NCCN, 24% plan to implement the ASCO QOPI, 7% plan to implement the PQRS/PQRI measures, and 3% plan to implement other quality measures. Quality initiatives are believed to have the greatest potential impact on breast cancer, with 83% agreeing that initiatives would improve the care of patients with breast cancer, followed by prostate cancer (48%), lung cancer (45%), hematologic malignancies (21%), and metastatic melanoma (17%). In addition, 35% say that quality ini-

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Figure 6 A Companion Diagnostic Test Must Improve ORR by 11% to 30% in the Targeted Population Compared with Untested Patients for Reimbursement Consideration Question: For your organization to reimburse a diagnostic test relevant to a targeted treatment, what level of clinical benefit (such as ORR) does a diagnostic test need to show versus all-comers?

Respondents, %

27%

15%

13%

11%

6-10

0 11-15

16-20

21-25

26-30

31-35

36-40

>41

Improved ORR with diagnostic test, %

ORR indicates overall response rate.

tiatives are unlikely to significantly affect any indication. Survey respondents believe that quality initiatives have the potential to improve the use of evidence-based treatments (97%), including a reduction in the use of imaging studies without compelling clinical evidence (52%) and an increase in patientâ&#x20AC;&#x201C;provider discussions about palliative care (35%). However, the respondents were split on the types of incentives they would offer for participation in quality initiatives: 31% would offer a percentage of cost-savings, 7% would offer incentives based on quality achievements, 28% would not offer incentives, and 35% were unsure about the types of incentives they would offer.

Personalized Medicine: The Role of Diagnostics and Tumor Markers Targeted therapies make it possible to modulate cellular signal transduction pathways that are important in tumor growth and development, whereas new genetic and molecular tests make it possible to identify individual patients who are most likely to benefit from a particular treatment strategy and to predict toxicity reactions.33-35 Greater individualization of therapy may also help to reduce overall costs by identifying patients who are not appropriate candidates for certain treatments. Examples of biomarkers that are used in treatment selection include biomarkers for the expression of epidermal growth factor receptor mutations to predict response to erlotinib in patients with advanced lung cancer,36 as well as biomarkers for overexpression of the HER2 protein to predict trastuzumab response in patients with breast cancer.37 The decision to cover a particular oncology diagnos-

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tic test is significantly influenced by published clinical practice guidelines, according to 90% of survey respondents. ASCO and NCCN guidelines are the most influential in determining genetic test coverage, and both are cited as important by 73% of those surveyed. Regarding the types of information that would be needed to increase the acceptance of genetic testing, proof of greater specificity/sensitivity was identified by 79% of respondents, cost-effectiveness data by 62%, identification of more clinically meaningful targets by 48%, and clinical trials with larger sample sizes by 35%. For reimbursement, a majority (64%) of respondents agree that a companion diagnostic test must produce an improvement in the overall treatment response rate between 11% and 30% in the target population compared with untested patients (Figure 6). In addition, a companion diagnostic test must improve OS or PFS by 3 to 7 months in the targeted population for the test to be reimbursed (Figure 7).

Discussion Few recent studies have surveyed managed care professionals regarding their views on oncology cost-management strategies and expectations for future trends. One recent study conducted by the NCCN was based on interviews with physician executives at MCOs to identify their perspectives on the oncology marketplace, and the measures they used to address the cost and quality of cancer care.9 Frequently used cost-control strategies included aggressive contracting, new reimbursement models, case management, use of NCCN guidelines to establish treatment standards, and the use of specialty pharmacy services.9

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Emerging Trends in Cancer Care

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

Respondents, %

24%

22% 20

17%

4% 4%

20%

22%

15%

13%

15% 15%

6% 7%

0 <1

1-2

2-3

3-4

4-5

5-7

7-10

>10

Months (OS and PFS)

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

Our survey has evaluated viewpoints of managed care professionals in the present, at a time when oncology management costs are rising rapidly, and there is yet considerable uncertainty about the eventual impact of healthcare reform on oncology practice. Key insights from this present survey include: • Health plans and PBMs expect to see increased use of specialty pharmacy services during the next 5 years • When clinical outcomes are similar, respondents overwhelmingly prefer oral oncolytic agents to injectable chemotherapy drugs • Clinical guidelines are frequently used to establish coverage and reimbursement criteria, including those for off-label uses; when evaluating different treatments, OS is considered the single most important clinical end point • Most respondents believe that healthcare reform efforts would help to control oncology costs, but that these measures would also result in greater utilization restrictions • Nearly all respondents view ACOs as relevant to oncology care; however, many have not yet formed an opinion about whether the impact of ACOs would likely be positive or negative, and interest in participating in pilot programs is generally low • Quality improvement measures are perceived to have the potential to improve cancer care and the use of evidence-based treatments, yet nearly half of the respondents have no plans to use such measures • Participants believe that ACOs and quality improvement measures have the greatest potential impact on

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

Conclusion The survey findings highlight important emerging trends in oncology management, as well as informing the coordination of cost and clinical management of patients with cancer. In general, health plans and PBMs show a great deal of interest in monitoring and controlling costs of cancer therapy. Published guidelines from ASCO and the NCCN are central to payer views about treatment selection, reimbursement, off-label prescribing, and genetic testing. CER is believed to help identify better treatment options and control costs, although most respondents also believe that healthcare reform would lead to more restrictions on the use of some cancer therapies. ACOs generated the greatest uncertainty among the topics included in this survey; although respondents expect ACOs to significantly affect oncology management over the next 2 years, most are not yet planning to form or join such an organization, and their attitudes in general toward ACOs remain largely neutral. In addition, there is a significant gap between payers’ perceptions about the potential benefit of quality improvement measures and their plans to use such measures at their own organizations. When considering the role of genetic testing, respondents expect to see measurable improvements attributable to testing on clearly defined clinical end points, such as overall response rate and duration of OS. ■ Continued

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Author Disclosure Statement Ms Greenapple reported no conflicts of interest.

References 1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012. 2. Fitch K, Pyenson B. Cancer patients receiving chemotherapy: opportunities for better management. http://publications.milliman.com/research/health-rr/pdfs/cancerpatients-receiving-chemotherapy.pdf. March 30, 2010. Accessed February 1, 2012. 3. Express Scripts Research & New Solutions Lab. 2011 Drug Trend Report. April 2012. 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 United States: burdens upon an aging, changing nation. J Clin Oncol. 2009;27:2758-2765. 5. Campbell MC, Kaufman MB, Bendix J. Oral oncology drugs: navigating dispensing, 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 new epoch in cancer patient management. Mol Cancer Res. 2010;8:1175-1187. 8. M.D. Anderson Cancer Center. Your first visit. www.mdanderson.org/educationand-research/departments-programs-and-labs/programs-centers-institutes/clinicalcancer-genetics/your-first-visit/index.html. Accessed May 2, 2012. 9. Danielson E, DeMartino J, Mullen JA. Managed care & medical oncology: the focus 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 Clin Oncol. 2007;25:180-186. 11. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the 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 private health care payers. J Manag Care Pharm. 2006;12:736-744. 15. Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anticancer treatment. CA Cancer J Clin. 2009;59:56-66. 16. Kaiser Family Foundation. Medicare at a glance. Publication #1066-14. Issued November 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: history 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. Accessed June 28, 2012.

19. Dalton WS, Sullivan DM, Yeatman TJ, Fenstermacher DA. The 2010 Health Care Reform Act: a potential opportunity to advance cancer research by taking cancer personally. Clin Cancer Res. 2010;16:5987-5996. 20. Moy B, Polite BN, Halpern MT, et al. American Society of Clinical Oncology policy statement: opportunities in the Patient Protection and Affordable Care Act to reduce cancer care disparities. J Clin Oncol. 2011;29:3816-3824. 21. Barlas S. Health care reform bill expands access to section 340B discounted drugs for 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 Reinvestment Act of 2009”: explanation of comparative effectiveness research (CER) provisions. www.ama-assn.org/ama1/pub/upload/mm/399/arra-cer-provisions.pdf. Accessed February 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 program. Am Health Drug Benefits. 2010;3:261-262. 26. Berwick DM. Launching accountable care organizations—the proposed rule for the 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. January 2012. http://qopi.asco.org/Documents/QOPIProgramDetailsPresentation-December 2011.pdf. Accessed June 28, 2012. 29. Desch CE, McNiff KK, Schneider EC, et al. American Society of Clinical Oncology/National Comprehensive Cancer Network quality measures. J Clin Oncol. 2008;26:3631-3637. 30. Centers for Medicare & Medicaid Services. Physician Quality Reporting Initiative (PQRI) and Electronic Prescribing Incentive Program (eRx) and Medicare Advantage (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. Manag Care. 2011;20:12-14,16. 32. Silver SM, Mehringer AM, Hayes A, et al. Michigan Breast Oncology Quality Initiative (MiBOQI): a state-wide multidisciplinary breast cancer quality initiative— concordance with quality measures. Poster presented at the American Society of Clinical Oncology Breast Cancer Symposium. October 8-10, 2009; San Francisco, CA. 33. Chiang A, Million RP. Personalized medicine in oncology: next generation. Nat Rev Drug Discov. 2011;10:895-896. 34. Schilsky RL. Personalized medicine in oncology: the future is now. Nat Rev Drug Discov. 2010;9:363-366. 35. Duffy MJ, Crown J. A personalized approach to cancer treatment: how biomarkers can help. Clin Chem. 2008;54:1770-1779. 36. Huang CH, Powers BC. The evolving role of maintenance therapy using epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in the management of advanced 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 adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-1672.

STAKEHOLDER PERSPECTIVE The Cost of Cancer Care: In Search of New Solutions PATIENTS: The treatment of cancer and the associated cost of cancer care is a topic of major importance for patients and for health plans alike. According to the American Cancer Society, more than 1.6 million Americans will be diagnosed with some form of cancer in 2012 (Table).1 As a result of advances in cancer diagnosis and treatment during the past several decades, the 5-year survival rate for all cancer types increased from 49% for patients diagnosed between 1975 and 1977, to 67% for those diagnosed between 2001 and 2007.1 Although more than 577,000 Americans are expected to die of cancer this year, the increased number of patients diagnosed with cancer and the improved

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long-term survival rates mean that the number of Americans living with cancer will increase by nearly 1 million in 2012. In addition, it has been estimated that with the aging of the US population, the annual number of newly diagnosed cancers will increase by approximately 45%, to 2.3 million, by 2030.2 A recent analysis indicates that the overall US cost of cancer care is approximately 10% of the total healthcare costs.3 According to a recent Express Scripts report, cancer drugs are the third most expensive category among specialty drugs, with an average cost of $3259 per prescription.4 Many of these drugs are biologics that have been available for some time;

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STAKEHOLDER PERSPECTIVE (Continued) for example, rituximab (Rituxan) Table Estimated Cancer Casesa in the United States, 2012 was launched in 1997 and trastuzuCancer type in men Estimated Cancer type in women Estimated mab (Herceptin) in 1998. These 2 (N = 848,170) cases, % (N = 790,740) cases, % drugs accounted for more than $4.5 29 29 Prostate Breast billion in US sales in 2011.5 14 14 Lung and bronchus Lung and bronchus In addition, the cancer drug 9 9 Colon and rectum Colon and rectum pipeline is robust. A report by the 7 6 Urinary bladder Uterine corpus Pharmaceutical Research and Man5 5 ufacturers of America reveals that Melanoma of skin Thyroid US drug manufacturers are testing 5 4 Kidney and renal pelvis Melanoma of skin 981 targeted medicines for cancer, 4 4 Non-Hodgkin lymphoma Non-Hodgkin lymphoma including lung cancer (121 drugs), 3 3 Oral cavity Kidney and renal pelvis lymphoma (117 drugs), and breast 3 3 Leukemia Ovary cancer (111 drugs).6 The cost of 3 3 Pancreas Pancreas using cancer drugs in the United 18 20 All other sites All other sites States is expected to grow by 20% a annually, to $173 million by 2020.7 Excludes basal and squamous skin cell cancers and in situ carcinomas, except urinary bladder. The annual cost of treatment per Source: American Cancer Society. Cancer Facts & Figures 2012. patient could top $100,000 for those 7 receiving combination cancer drugs. MEDICAL/PHARMACY DIRECTORS: With and other gene-based tests may provide help, but the this as a backdrop, the survey data in Ms Greenapple’s role of such testing for effectively managing most cancers article are very relevant, clearly showing that the cost remains unclear. The next decade will bring many of oncology care—driven by increasing numbers of important developments in cancer; health plans must be patients, greater survival rates, and the ever-growing cost willing to try new solutions to effectively manage this of care—is an area of major concern for all health plans area of medical care. and pharmacy benefit managers. It is unclear, however, 1. American Cancer Society. Cancer Facts & Figures 2012. www.cancer.org/acs/ how health plans will be able to effectively manage this groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf. July 13, 2012. cost trend and maintain affordability. In an era of health- Accessed 2. Smith BD, Smith GL, Hurria A, et al. Future of cancer incidence in the United care reform that is enrolling more individuals into the States: burdens upon an aging, changing nation. J Clin Oncol. 2009;27:2758-2765. Fitch K, Pyenson B. Cancer patients receiving chemotherapy: opportunities for insured population, this issue is certain to grow in scope. 3.better management. March 30, 2010. http://publications.milliman.com/research/ Health plans must find new solutions to manage this health-rr/pdfs/cancerpatients-receiving-chemotherapy.pdf. Accessed July 1, 2012. Express Scripts. 2011 Drug Trend Report. April 2012. www.drugtrendreport. trend. This will require meaningful comparative effec- 4.com/docs/reports/Express_Scripts-Drug-Trend-Report.pdf. Accessed July 12, 2012. tiveness research, guideline and pathway management 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-bestthat keeps up with changing technologies, and pro- selling-cancer-drugs?utm_medium=nl&utm_source=internal. Accessed July 16, 2012. viders’ commitment to consider fiscal, as well as clini- 6. Grogan K. Nearly 1000 cancer drugs in development in USA. June 1, 2012. Times On-Line. www.pharmatimes.com/Article/12-06-01/Nearly_1_000_ cal, responsibility when managing patients with cancer. Pharma cancer_drugs_in_development_in_USA.aspx. Accessed July 1, 2012. Current therapies are simply too expensive to ignore 7. Palmer E. With targeted cancer drugs, cost vs benefits gets more complicated. Pharma. June 15, 2012. www.fiercepharma.com/story/targeted-cancer-drugscost. It is hoped that new entities, such as accountable Fierce cost-vs-benefits-gets-more-complicated/2012-06-15?utm_medium=nl&utm_ care organizations, will bring new solutions to augment source=internal. Accessed July 12, 2012. the efforts of health plans. Meanwhile, plans must conGary M. Owens, MD tinue to look for new and better ways to manage these President, Gary Owens Associates patients. Personalized medicine, gene-expression testing, Philadelphia, PA

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JOIN AHDB PEER REVIEW American Health & Drug Benefits (AHDB) is looking for medical and pharmacy directors, P & T Committee members, and other healthcare experts who are interested in joining our peer reviewers and assist in maintaining the high quality of articles published in the journal. You will be asked to review at least 1 or 2 articles per year in your area of expertise. Reviewersâ&#x20AC;&#x2122; names will be published online at the end of the year. Please indicate at least 1 area of expertise in a health-related field for which they feel qualified to assess the content and quality of manuscripts submitted to AHDB.

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â&#x20AC;&#x153;Better informed teams provide better care.â&#x20AC;? Matthew P. Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth Salt Lake City, UT

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