VBCC JUNE 2012, VOL 3, NO 4 by Value-Based Cancer Care

JUNE 2012 VOL 3 NO 4

www.ValueBasedCancerCare.com ASCO ANNUAL MEETING

Pathways in Oncology: Implications for Providers, Payers, and Patients End-of-life issues key component

Houston, TX—At the Second Annual Association for Value-Based Cancer Care Conference on March 29-31, 2012, a panel of payers and providers considered the role of pathways in oncology practice and the potential implications for end-of-life concerns. Craig K. Deligdish, MD, Chief Medical Officer, Oncology Resource Networks of America, led the discussion and added his own comments. Participants included Winston Wong, PharmD, Associate Vice President of Continued on page 18

ACCC ANNUAL MEETING

Can Pathways Improve Quality of Care While Reducing Cost? By Neil Canavan Baltimore, MD—Changes are constant in cancer care—new technologies, new targets, and new treatments. But the associated spiraling costs are also constant. Not surprisingly, payers are pushing back, with an attempt to change the way business is being done in oncology. “Cancer is now more than 10% of payers’ spending,” said Kathleen G. Lokay, President and Chief Executive Officer of D3 Oncology Solutions, Pittsburgh, PA, at the 2012 Association of Community Cancer Centers

(ACCC) meeting, and the drivers of cost are coming from all sides. “It’s drugs, radiation, imaging, and specialty [pharmacy].” Payers use formularies, prior authorization, and treatment guidelines in the attempt to control costs. Can pathways help payers in addressing cost issues related to providers? “When you think about pathways, there’s a tendency to just think about drugs,” said Ms Lokay, “but we’re talking about addressing all of the difContinued on page 29

“Precision Medicine” the Theme of ASCO 2012 Molecular profiling driving cancer therapy By Caroline Helwick Chicago, IL—“Precision medicine” is the new catch phrase in oncology, and examples of it were evident across the vast halls of McCormick Place at the 2012 American Society of Clinical Oncology (ASCO) meeting. Precision medicine is the next iteration of “personalized medicine,” a moniker perhaps meant to convey the

increasing refinement of the molecular targets that underlie tumors. It has become evident that mutations that describe certain tumors—such as the epidermal growth factor receptor (EGFR) mutation in non–small-cell lung cancer (NSCLC)—may be present to some extent in a variety of apparentContinued on page 10

Regional Cancer Care Associates: Consolidating Small Practices into a Large Consortium Interview with Andrew Pecora, MD, FACP, CPE President, Regional Cancer Care Associates, LLP, NJ

alue-Based Cancer Care is focused on examining value within the context of healthcare stakeholder relations. Dr Pecora and his team at Regional Cancer Care Associates (RCCA) have changed the relationship between the practicing oncologist and the payer, which will have substantial effects on value. For years, the signs were clear that for oncologists to survive and be in a posi-

tion to implement the great advances in treatment, they would require a new business model, and Dr Pecora and RCCA have provided one. RCCA has consolidated independent small practices into a major consortium, redefining the balance of power between provider and payer, freeing the providers to focus on the individual patient. Continued on page 26

INSIDE FDA UPDATE

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Pertuzumab for metastatic HER2 breast cancer IN THE LITERATURE

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Patients willing to pay more for unproven but promising cancer therapies New reimbursement policies needed ASCO ANNUAL MEETING

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Novel T-DM1 prolongs remission in advanced breast cancer Abiraterone before chemotherapy a new standard in prostate cancer?

CONFERENCE . .17

Reimbursement must be patient-centered The value of level I pathways at US Oncology Personalized medicine enhances treatment decision CareFirst oncology management program HIT IN ONCOLOGy . . . . . . . . . . . . . . .28

Digital patient engagement in cancer care CONTINUING EDUCATION . . . . .36 Considerations in lymphoma

IV R FO AND D S ON E V OU TI O R NE TRA P AP UTA INIS C M B SU AD

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.

FDA Update FDA Expedites Approval of Pertuzumab for Metastatic HER2 Breast Cancer The US Food and Drug Administration (FDA) approved pertuzumab (Perjeta; Genentech) for intravenous use in patients with HER2-positive metastatic breast cancer. Pertuzumab, a humanized monoclonal antibody, is

approved for use in combination with the other anti-HER2 trastuzumab (Herceptin) and docetaxel (Taxotere) chemotherapy in patients with metastatic breast cancer who have not been treated previously with an antiHER2 therapy or with chemotherapy. The approval was done under the expedited review process.

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.

In a clinical trial designed to evaluate the safety and efficacy of pertuzumab, 808 patients with HER2-positive metastatic breast cancer were randomized to trastuzumab plus docetaxel combined with either pertuzumab or with placebo. The median progression-free survival was 18.5 months in patients receiving the pertuzumab combination

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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VALUE-BASED CANCER CARE

JUNE 2012

compared with 12.4 months with the placebo combination. The most common side effects in the pertuzumab combination group were diarrhea, hair loss, a decrease in white blood cells, nausea, fatigue, rash, and peripheral neuropathy. Pertuzumab works by targeting a different part of the HER2 protein than trastuzumab, which may explain the added benefits when these 2 antiHER2 drugs are administered together. Pertuzumab was approved with a boxed warning regarding the potential risk of death or severe effects in a fetus. Pregnancy status must be verified before the start of pertuzumab treatment. In addition, because of production issues that could affect the long-term supply of pertuzumab, the FDA approval was limited to drug product that has not been affected by those issues. “Given the need for additional treatments for metastatic breast cancer, we made the decision to approve this drug today and not to delay its availability to patients pending resolution of the production issues relating to future supply,” said Janet Woodcock, MD, Director of FDA’s Center for Drug Evaluation and Research. “Genentech is currently developing a plan to mitigate the effect on patients of any potential shortage of Perjeta.” (June 8, 2012)

Safety Warnings Added to Lenalidomide The FDA has added new safety information to the label and medication guide for lenalidomide (Revlimid; Celgene), noting that lenalidomide maintenance treatment in patients with newly diagnosed multiple myeloma is associated with an increased risk for developing new primary malignancies. The decision to include this information was based on data from postapproval clinical trials in patients who previously had undergone chemotherapy, either alone or with stem-cell transplantation, before starting maintenance treatment with lenalidomide or with placebo. Of these, 7.9% of lenalidomide recipients compared with 2.8% of placebo recipients were later diagnosed with a myelogenous leukemia, myelodysplastic syndromes, Hodgkin disease, or another new malignancy. The new cancers occurred within 2 years of starting maintenance therapy in half of the affected patients. However, lenalidomide-receiving patients had no increased risk for nonmelanoma skin cancers or solid tumors. The FDA advises providers to weigh lenalidomide risks and benefits as part of their treatment decisions. Providers need to monitor patients receiving lenalidomide for secondary malignancies. (May 7, 2012) ■

VOL. 3

NO. 4

In This Issue

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Publisher American Health & Drug Benefits Maurice Nogueira maurice@engagehc.com 732-992-1895 Associate Publisher Cristopher Pires cris@engagehc.com 732-992-1896 Director, Client Services Lou Lesperance, Jr. lou@engagehc.com Associate Editor Lara J. Lorton Editorial Assistant Jennifer Brandt jennifer@generaladminllc.com 732-992-1536 Sales Assistant Zach Ceretelle Director, Creative & Design Robyn Jacobs Quality Control Director Barbara Marino Business Manager Blanche Marchitto

Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments. This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care. Contact Information: For subscription information please contact: circulation@valuebasedcancercare.com Telephone: 732-992-1538 Fax: 732-992-1881 Permission requests to reprint all or part of any article published in this magazine should be addressed to editorial@valuebasedcancercare.com Address all editorial queries to: editorial@valuebasedcancercare.com Telephone: 732-992-1536 Fax: 732-992-1881 Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 7 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. Value-Based Cancer Care is a registered trademark 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. The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

VOL. 3

NO. 4

FDA UPDATE

NCCN ANNUAL CONFERENCE

Pertuzumab approved for metastatic HER2-positive breast cancer More….

Cancer and corporate America

CONFERENCE Reimbursement must be patient-centered Personalized medicine empowers treatment decisions CareFirst oncology management program More….

VALUE PROPOSITIONS Personalized medicine and drug development More….

IN THE LITERATURE ACCC ANNUAL MEETING

Patients willing to pay more for unproven, promising cancer therapies New reimbursement policies needed to align payment with cancer care outcomes More….

Tips for optimizing financial performance More….

CORRECTION Page 32

ASCO ANNUAL MEETING T-DM1 “the new hope” in breast cancer Biomarker identifies patients with brain cancer for chemotherapy plus radiation More….

CONTINUING EDUCATION Considerations in lymphoma

VBCC Editorial Board Al B. Benson III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University Chicago, IL Immediate Past President, ACCC Past Chair, NCCN Board of Directors Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, NY Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA Craig Deligdish, MD Florida Comprehensive Cancer Network, Melbourne, FL

Ira Klein, MD, MBA Aetna Hartford, CT

Jatin J. Shah, MD M. D. Anderson Cancer Center Houston, TX

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

Jayson Slotnik, JD, MPH Partner Health Policy Strategies, LLC Washington, DC

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance

Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA

Crystal Kuntz, MPA Astellas Pharma US Washington, DC Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT

Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers Pittsburgh, PA

Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN

Arlene A. Forastiere, MD Senior Vice President Medical Affairs, eviti, Inc

Lynn Nishida, RPh RegenceRX Portland, OR

Tracy Gosselin, RN, MSN Duke University Medical Center Durham, NC

Ted Okon, BS, MBA Executive Director Community Oncology Alliance

Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute New York, NY

Naimish Pandya, MD University of Maryland Baltimore, MD

G. Rhys Williams, ScD, MS Amgen Thousand Oaks, CA Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS BioPharma Partners, LLC New York, NY

David Hom, MBA Solucia Farmington, CT

Ed Pezalla, MD, MPH National Medical Director of Pharmacy Policy and Strategy Aetna, Hartford, CT

Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL

Denise K. Pierce DK Pierce & Associates Zionsville, IN

JUNE 2012

Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA

Section Editor Dawn Holcombe, FACMPE, MBA, ACHE President, DGH Consulting South Windsor, CT

www.ValueBasedCancerCare.com

VALUE PROPOSITIONS Personalized Medicine the “Crown Jewel” of Drug Development

Understanding Genes Is Crucial to Predicting Response to Breast Cancer Therapy

The recent trend in drug development of shifting away from one-sizefits-all cancer medications to targeted therapies, which is the key to personalized medicine, points to the value of and monetary benefits of developing drugs that target the molecular levels of cancer cells. Although personalized medicine may limit the number of patients who will benefit from a targeted drug, it can help the company in terms of reimbursement, despite the high price tag, because payers can feel confident that a drug will actually work in the patients specifically designated for that therapy, according to Barclays Capital analyst Tony Butler. Another aspect of this trend is that, once the drug is approved, drug manufacturers are then conducting new research in the attempt to expand the original US Food and Drug Administration (FDA) indication to new indications in the hope of increasing the drug’s market share. One such example, according to Mr Butler, involves the new studies conducted by Johnson & Johnson for its drug abiraterone acetate (Zytiga) for use before chemotherapy in men with localized, high-risk prostate cancer (see article, page 11). The drug was approved by the FDA last year for treatment of metastatic prostate cancer in men who had already undergone chemotherapy. If the FDA approves a new indication based on these latest results, it could push the sales for abiraterone acetate to >$2 billion in 2015, thereby doubling the projected sales of $1 billion for 2012, Mr Butler predicted. Numerous pharmaceutical companies are in the process of developing new targeted drugs for a variety of cancers, some of which will likely be accompanied by a companion diagnostic test, representing yet another revenue stream. Loftus P. Wall Street J. May 15, 2012.

A study funded by the National Cancer Institute, the National Institutes of Health, a Theodore N. Law Endowment for Scientific Achievement, and a Dodie P. Hawn Fellowship in Cancer Genetics Research surprisingly showed that the presence of normal p53, a tumor suppressor gene and not the mutated gene, was making chemotherapy with doxorubicin less effective in breast cancer; it is the mutated gene that actually enhances the benefit of the drug and not the reverse. This study moves us a step closer to personalized medicine for breast cancer. “It’s really important to understand the genetic defects a tumor cell has before we treat it,” says lead investigator Guillermina Lozano, PhD, Professor and Chair, Department of Genetics at M.D. Anderson. “What we learned here is the complete opposite of what we expected. We thought tumors would respond better to treatment if the p53 gene was normal. But the opposite was true.” The study showed that the nonmutated p53 gene stopped cell division, resulting in cell aging, which allows cells to survive, thus fueling relapse. By contrast, the mutated p53 gene cells proceed into cell division with broken chromosomes caused by the chemotherapy, which is “a signal for the cell to die,” according to Dr Lozano. The tumor suppressor p53 is mutated or inactivated in the majority of cancers, and approximately one third of breast cancers have this mutation. It has long been thought that normal p53 results in a better response to chemotherapy. “The response rates were mixed, and we never understood the difference. Now we understand that we need to know the p53 status to predict a response,” Dr Lozano stated. M.D. Anderson, news release, June 11, 2012.

In a Policy Reversal, FDA Concedes Value of Accelerating Approval of Early-Stage Breast Cancer Drugs The FDA has reversed its long-standing policy regarding breast cancer trials that could greatly reduce the time and cost of new drug development for early-stage breast cancer. Developed in collaboration with the Biomarkers Consortium, a partnership of public and private groups led by the Foundation for the National Institutes of Health, and intended to spur innovation in drug development, the FDA has released a new regulatory guidance that describes a novel pathway for accelerated approval of drugs based on data for certain types of localized, early-stage breast cancer showing complete response (or cure) with neoadjuvant therapy. Up to now, the FDA first reviewed breast cancer drugs for metastatic disease; only after such an indication was received would the drug become eligible to be tested for early-stage disease. This meant that patients with early disease would have to wait years for new and improved therapies to become available. “Better options for patients with high-risk breast cancer are urgently needed,” said Janet Woodcock, MD, Director of the Center for Drug Evaluation and Research. “The FDA guidance explains how a promising drug identified in trials such as the I-SPY 2 could be evaluated for FDA approval, so patients could have rapid access if the drug proved better than current treatments.” Foundation for the National Institutes of Health, press release, June 1, 2012.

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Radium-223 Offers New Hope for Patients with Bone Metastases At the 2012 annual meeting of the Society of Nuclear Medicine, researchers presented new results for the radioisotope therapy radium223 chloride, suggesting that these results represent a new treatment protocol for patients with advanced prostate cancer that has spread to the bone. This drug seeks out bone metastases with very potent alpha particles that are deadly to tumors. This drug has a short range of penetration, sparing healthy tissue and bone marrow. “This is a pivotal study of a new treatment that potentially offers a better standard of care for patients with advanced prostate cancer,” said Val Lewington, Professor of Clinical Therapeutic Nuclear Medicine at King’s College and Guy’s and St Thomas’ Hospital, London. “Radium-223 offers a new approach to the treatment of bone metastases. It systematically treats multiple sites of disease simultaneously and is usually very well tolerated.” Society of Nuclear Medicine press release, June 11, 2012.

Will Merger of 2 Major Diagnostic Centers Up Access to Molecular Imaging? Two of the largest diagnostic imaging centers in the country—Insight Imaging in California and Centers for Diagnostic Imaging (CDI) in Minneapolis—have announced that they are merging forces. The combined company will have 116 fixed centers in 25 states and 90 mobile MRI and PET/CT units. The combined company will be headquartered at CDI’s current offices, with CDI’s current CEO Tom Tomlinson becoming CEO of the new company. The merger is expected in July. TriMed Media Group, Inc, June 8, 2012.

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In The Literature Patients with Cancer Willing to Pay More for Unproven, but Promising, Therapies Assessments of the value of cancer therapies have been based on the assumption that stakeholders care most about average or median gain in survival or quality-adjusted survival. These assessments have ignored variability or spread around the average, or in more tangible terms, a chance (albeit possibly small) at a large and highly meaningful gain in survival. A recent survey investigated hypothetical scenarios to assess the value that patients place on promising, although unproven, cancer therapies (Lakdawalla DN, et al. Health Aff [Millwood]. 2012;31:676-682). The investigators surveyed 150 patients with cancer who were undergoing radiation, chemotherapy, or “watchful waiting.” The survey was conducted at 5 sites within a national network of community-based oncology practices. Survey questions involved “hopeful gamble” and “safe bet” hypothetical treatment scenarios, asking patients which treatment they would prefer, and how much they would be willing to pay for it. The hopeful gamble provides a chance of a bigger survival benefit, but also a worse potential downside. The safe bet offers similar survival duration but a reduced chance for a large gain. The results showed that 77% of the survey participants would prefer a hopeful, unproven therapy to a sure bet in the hope of a potentially greater benefit. These patients were willing to pay $54,362 for the hopeful therapy rather than the evidence-based alternative; the average patient would pay $36,305 for a 1-year increase in survival (standard deviation). The investigators acknowledged that these results would not necessarily be identical to real-world decisions in terms of how much patients would be willing or able to pay for such therapies; however, these results do point to the need to address the patient’s perspective and to consider long-term benefits in assessing the value of cancer therapies.

proposes new reimbursement strategies to align payments with out-comes as a way of achieving best possible outcomes at the lowest cost (Newcomer LN. Health Aff [Millwood]. 2012;31:780-785). Dr Newcomer describes how the “buy-and-bill” reimbursement approach encourages oncologists to use

expensive medications, which may explain why the projected total US cost for cancer drugs in 2020 is $173 billion (up from $104 billion in 2006). Implementing clinical pathways and bundled payments can cut drug costs without compromising quality of care. The use of pathways requires oncologists to follow predefined chemothera-

py regimens and, when 2 or more regimens are considered clinically equivalent, to select the lowest-cost option. In addition, incentives are used to encourage adherence to the predefined regimens. Several oncology groups have successfully used this approach to lower drug costs in cancer therapy. Continued on page 8

New Reimbursement Policies Needed to Align Payment with Cancer Care Outcomes Current reimbursement policies for cancer chemotherapies do not ensure that the value and cost of therapies are commensurate with outcomes. These policies also reward the use of the most expensive drugs, in that providers’ markups are larger for these drugs than for lower-cost therapies. Lee Newcomer, MD, Senior Vice President of Oncology Services, UnitedHealthcare,

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In The Literature New Reimbursement Policies... Continued from page 7

This approach requires coordinated care and efficient resource management to enhance profits. Providers can also increase their payments by improving patient outcomes. UnitedHealthcare launched its episode pay-

ment program in November 2010; results for the first year are expected this summer.

Inotuzumab Ozogamicin Shows High Response Rate in Refractory/Relapsed ALL In a single-arm, phase 2 study, ino-

patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% INDICATIONS AND USAGE Hispanic, 2% Black, and < 1% Asian, Native American or other. Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated malignancies receiving myelosuppressive anticancer drugs patients. associated with a clinically significant incidence of febrile Table 1. Adverse Reactions With ≥ 5% Higher Incidence neutropenia. Neulasta is not indicated for the mobilization of peripheral blood in Neulasta Patients Compared to Placebo in Study 3 progenitor cells for hematopoietic stem cell transplantation. System Organ Class Placebo Neulasta 6 mg CONTRAINDICATIONS Preferred Term (N = 461) SC on Day 2 Do not administer Neulasta to patients with a history of serious (N = 467) allergic reactions to pegfilgrastim or filgrastim. Musculoskeletal and connective tissue disorders WARNINGS AND PRECAUTIONS Bone pain 26% 31% Splenic Rupture Pain in extremity 4% 9% Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen Leukocytosis or splenic rupture in patients who report left upper abdominal In clinical studies, leukocytosis (WBC counts > 100 x 109/L) or shoulder pain after receiving Neulasta. was observed in less than 1% of 932 patients with nonmyeloid Acute Respiratory Distress Syndrome malignancies receiving Neulasta. No complications attributable Acute respiratory distress syndrome (ARDS) can occur in patients to leukocytosis were reported in clinical studies. receiving Neulasta. Evaluate patients who develop fever and Immunogenicity lung infiltrates or respiratory distress after receiving Neulasta, for As with all therapeutic proteins, there is a potential for ARDS. Discontinue Neulasta in patients with ARDS. immunogenicity. Binding antibodies to pegfilgrastim were Serious Allergic Reactions detected using a BIAcore assay. The approximate limit of Serious allergic reactions, including anaphylaxis, can occur in detection for this assay is 500 ng/mL. Pre-existing binding patients receiving Neulasta. The majority of reported events antibodies were detected in approximately 6% (51/849) occurred upon initial exposure. Allergic reactions, including of patients with metastatic breast cancer. Four of 521 anaphylaxis, can recur within days after the discontinuation of pegfilgrastim-treated subjects who were negative at baseline initial anti-allergic treatment. Permanently discontinue Neulasta developed binding antibodies to pegfilgrastim following in patients with serious allergic reactions. Do not administer treatment. None of these 4 patients had evidence of Neulasta to patients with a history of serious allergic reactions neutralizing antibodies detected using a cell-based bioassay. to pegfilgrastim or filgrastim. The detection of antibody formation is highly dependent on Use in Patients With Sickle Cell Disorders the sensitivity and specificity of the assay, and the observed Severe sickle cell crises can occur in patients with sickle cell incidence of antibody positivity in an assay may be influenced disorders receiving Neulasta. Severe and sometimes fatal sickle by several factors, including assay methodology, sample cell crises can occur in patients with sickle cell disorders handling, timing of sample collection, concomitant medications, receiving filgrastim, the parent compound of pegfilgrastim. and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence Potential for Tumor Growth Stimulatory Effects on of antibodies to other products may be misleading. Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor Postmarketing Experience through which pegfilgrastim and filgrastim act has been found The following adverse reactions have been identified during on tumor cell lines. The possibility that pegfilgrastim acts post approval use of Neulasta. Because these reactions are as a growth factor for any tumor type, including myeloid reported voluntarily from a population of uncertain size, it is not malignancies and myelodysplasia, diseases for which always possible to reliably estimate their frequency or establish pegfilgrastim is not approved, cannot be excluded. a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more ADVERSE REACTIONS of the following factors: (1) seriousness of the reaction, (2) The following serious adverse reactions are discussed in reported frequency of the reaction, or (3) strength of causal greater detail in other sections of the Brief Summary: relationship to Neulasta. • Splenic Rupture [See Warnings and Precautions] Gastro-intestinal disorders: Splenic rupture [see Warnings • Acute Respiratory Distress Syndrome [See Warnings and Precautions] and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] Blood and lymphatic system disorder: Sickle cell crisis [see Warnings and Precautions] • Use in Patients with Sickle Cell Disorders [See Warnings Hypersensitivity reactions: Allergic reactions/hypersensitivity, and Precautions] including anaphylaxis, skin rash, and urticaria, generalized • Potential for Tumor Growth Stimulatory Effects on Malignant erythema and flushing [see Warnings and Precautions] Cells [See Warnings and Precautions] Respiratory, thoracic, and mediastinal disorder: ARDS The most common adverse reactions occurring in ≥ 5% of [see Warnings and Precautions] patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: in the pegfilgrastim arm in placebo controlled clinical trials Injection site reactions are bone pain and pain in extremity. Skin and subcutaneous tissue disorders: Sweet’s syndrome, Clinical Trials Experience Cutaneous vasculitis Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials DRUG INTERACTIONS of a drug cannot be directly compared with rates in the clinical No formal drug interaction studies between Neulasta and other trials of another drug and may not reflect the rates observed in drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may clinical practice. Neulasta clinical trials safety data are based upon 932 patients result in transiently positive bone-imaging changes. Consider these findings when interpreting bone-imaging results. receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The USE IN SPECIFIC POPULATIONS ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and Pregnancy 1% Asian. Patients with breast (n = 823), lung and thoracic Pregnancy Category C tumors (n = 53) and lymphoma (n = 56) received Neulasta There are no adequate and well-controlled studies in pregnant after nonmyeloablative cytotoxic chemotherapy. Most patients women. Pegfilgrastim was embryotoxic and increased received a single 100 mcg/kg (n = 259) or a single 6 mg pregnancy loss in pregnant rabbits that received cumulative (n = 546) dose per chemotherapy cycle over 4 cycles. doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients occurred at these doses. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies with metastatic or non-metastatic breast cancer receiving the potential risk to the fetus. docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use

tuzumab ozogamicin, a CD22 monoclonal antibody conjugate, showed potential utility as a monotherapy that may improve the often poor prognosis for patients with refractory or relapsed acute lymphocytic leukemia (ALL; Kantarjian H, et al. Lancet Oncol. 2012;13:403-411).

In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman. Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed. NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product. This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2012 Amgen Inc. All rights reserved. www.neulastaHCP.com 1-800-77-AMGEN (1-800-772-6436) v 13.0

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This study conducted at M.D. Anderson Cancer Center, Houston, initially included adults with refractory or relapsed ALL of B-cell origin; younger patients (aged <16 years) were eligible to participate only after ≥1 course of the study medication was safely used in ≥10 adults. The primary end point was overall response. A total of 49 patients were treated. Of these patients, 9 had complete response, 19 had marrow complete response, 19 had resistant disease, and 2 died within 4 weeks of treatment onset. The overall response rate was 57%, and the median overall survival was 5.1 months. The most frequent adverse events (AEs) in the first course of treatment were fever (n = 29), hypotension (n = 13), increased bilirubin (n = 14), and increased aminotransferase concentration (n = 28). These AEs did not increase in frequency with subsequent treatment courses. The 57% response rate was much higher than rates reported in previous studies, but it was of short duration. The investigators are exploring a shorter, weekly schedule for the drug, which they hope will improve its efficacy and toxicity profile.

Phased Ipilimumab Improves PFS and OS in NSCLC Ipilimumab—added in a phased regimen to paclitaxel and carboplatin chemotherapy—increased progressionfree survival (PFS) and immune-related PFS in a randomized, double-blind, international, phase 2 study of previously untreated adult patients with non–small-cell lung cancer (NSCLC). However, a concurrent regimen of ipilimumab with the chemotherapy did not differ significantly from a control (placebo plus chemotherapy) regimen (Lynch TJ, et al. J Clin Oncol. 2012; 30:2046-2054. Epub 2012 Apr 30). Paclitaxel- and carboplatin-induced antigen release occurred before the addition of ipilimumab, which could have contributed to T-cell activation. To supplement each chemotherapy cycle, patients were randomized to a concurrent ipilimumab regimen (4 ipilimumab doses followed by 2 placebo doses), a phased ipilimumab regimen (2 placebo doses followed by 4 ipilimumab doses), or a control regimen (up to 6 doses of placebo). Ipilimumab or placebo, paclitaxel, and carboplatin were administered intravenously once every 3 weeks for up to 18 weeks, followed by ipilimumab or placebo once every 12 weeks until progression, intolerance, or death. The primary end point was immune-related PFS; PFS and overall survival (OS) periods were Continued on page 33

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ASCO Annual Meeting

EMILIA: Trastuzumab Emtansine Prolongs Remission in Advanced Breast Cancer Novel T-DM1 significantly extends PFS, reduces mortality By Audrey Andrews Chicago, IL—The novel antibodydrug conjugate trastuzumab emtansine (T-DM1) significantly extended progression-free survival (PFS) and was very well tolerated in the first results of the international EMILIA trial, which were presented at the 2012 American Society of Clinical Oncology (ASCO) meeting. “The drug worked. It was significantly better than a very effective approved therapy for HER2-overexpressing metastatic breast cancer,” said Kimberly L. Blackwell, MD, Associate Professor of Medicine in the Division of Hematology-Oncology at Duke Cancer Institute at Duke University, Winston-Salem, NC, at the ASCO plenary session. EMILIA randomized 991 HER2positive patients with advanced breast cancer who were previously treated with a taxane and trastuzumab. Patients received T-DM1 or capecitabine plus lapatinib (XL) every 3 weeks until progression. At a median follow-up time of approximately 12 months, patients receiving T-DM1 had a median PFS of 9.6 months compared with 6.4 months for XL, which was a 35% highly significant reduction in risk (P <.001), Dr Blackwell reported. The efficacy was consistent across all prespecified patient subgroups, and only in women aged ≥65 years was T-DM1 not superior to established treatment. Median overall survival (OS) was not reached with T-DM1 compared

“The drug worked. It was significantly better than a very effective approved therapy for HER2overexpressing metastatic breast cancer.” —Kimberly L. Blackwell, MD

with 23.3 months median OS with XL. This amounted to a 38% reduction in mortality risk (P = .005), although it did not meet the prespecified threshold for significance at the first analysis. Despite the lack of significant OS difference as prespecified, after 2 years in the trial, 65.4% of the patients receiving T-DM1 were alive compared with 47.5% of those receiving XL, Dr Blackwell noted, adding, “There is an apparent survival benefit with T-DM1.” Louis M. Weiner, MD, Director of

the Georgetown-Lombardi Cancer Center in Washington, DC, and the invited discussant of the presentation, agreed that a statistically significant OS benefit will eventually be observed with T-DM1. “This would be particularly notable, since effective palliative treatment has rarely been associated with improved survival in the metastatic setting,” he pointed out. T-DM1 also has the advantage of being very well tolerated. Dose reductions were required only for 16.3% of patients receiving T-DM1 compared with 53.4% for capecitabine and 27.3% for lapatinib. The most common grade 3 or higher adverse events for T-DM1 were thrombocytopenia and transient elevations in liver function tests. As expected, patients receiving XL experienced significantly more diarrhea, hand-foot syndrome, and vomiting.

“T-DM1 really works in this patient population. It is an important new weapon in the therapeutic armamentarium for breast cancer.” —Louis M. Weiner, MD

T-DM1 “Really Works” “Stated simply, T-DM1 really works in this patient population,” Dr Weiner said. “It is an important new weapon in the therapeutic armamentarium for breast cancer.” Future studies will need to validate the results and to elucidate the mechanisms of tumor control with this novel

at a glance ➤ T-DM1 significantly extended PFS and was very well tolerated in patients with advanced breast cancer ➤ After 2 years in the trial, 65.4% of patients receiving T-DM1 were alive compared with 47.5% of those receiving XL ➤ Median OS was not reached with T-DM1 compared with 23.3 months with XL; this amounted to a 38% reduction in mortality risk (P = .005) ➤ Dose reductions of T-DM1 were needed for only 16.3% of patients compared with 53.4% for capecitabine and 27.3% for lapatinib ➤ Other trials are in progress or are planned to further validate T-DM1 as treatment for HER2overexpressing metastatic disease

agent, he said. “But the very clean design and institution of this study, coupled with the compelling results, make it unlikely that additional studies will fail to confirm these important findings,” he suggested. “Needless to say, T-DM1 merits evaluation for previously untreat-ed HER2-overexpressing metastatic breast cancer and ultimately may find utility in adjuvant and neoadjuvant management, and perhaps in other HER2-overexpressing cancers,” Dr Weiner predicted. “Such trials are planned or are in progress.” ■

Biomarker Identifies Patients with Rare Brain Tumors Who Have a Survival Benefit from Chemotherapy plus Radiation By Phoebe Starr Chicago, IL—Patients with the relatively rare brain tumor anaplastic oligodendroglioma who were treated with adjuvant chemotherapy after standard radiation therapy had improved survival compared with radiation alone, especially if they had codeletion of chromosomes 1p/19q, according to long-term follow-up of the EORTC (European Organisation for Research and Treatment of Cancer) 2651 study reported at the

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2012 Annual Meeting of the American Society of Clinical Oncology (ASCO). The difference in survival between the 2 arms was not evident when results were first reported in 2006, at a median of 5 years’ follow-up. But the curves for the 2 arms separated with longer follow-up, and at a median of ≥10 years of follow-up, patients with the codeletion of 1p/19q who received chemotherapy and radiation were 44% more likely to live longer

than codeleted patients treated with radiation alone. “We have identified a subgroup of patients who benefit from adjuvant chemotherapy following radiation,” said lead author Martin J. Van Den Bent, MD, Professor of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands. The study randomized 368 patients to radiotherapy and 185 to adjuvant chemotherapy with procarbazine,

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lomustine, and vincristine (PCV), which was considered the best option in 1995, when the study was first initiated. By the 2012 ASCO meeting, updated results were presented 17 years after the study was begun. Median progression-free survival (PFS) and overall survival (OS) rates were significantly longer for the group treated with adjuvant PCV (P = .003 and P = .018, respectively); most of the Continued on page 10

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“Precision Medicine” the Theme of...

“It’s remarkable that this targeted oral medication [crizotinib] provided such a substantial benefit in these children with highly aggressive cancers, most of whom had already undergone every available therapy.” —Yael P. Mossé, MD Drugs that Are “Crossing Over” For several drugs that were considered breakthroughs in one tumor type, treatment niches are emerging in other cancers. A striking example is crizotinib, the ALK inhibitor that elicits robust responses (70%-80%) in the 5% of patients with NSCLC who have ALK gene abnormalities. Investigators reported at ASCO that crizotinib is also an active treatment for a phenotypically unrelated set of aggressive pediatric cancers. In a phase 1 study of 70 children, treatment with crizotinib led to complete responses in 88% of patients with anaplastic large-cell lymphoma and produced complete and partial responses in patients with other tumor types as well. Many of these young patients have maintained their responses to crizotinib for more than 2 years, reported Yael P. Mossé, MD, Assistant Professor, Perelman School of Medicine at the University of Pennsylvania, and an attending physician at the Children’s Hospital of Philadelphia. “It’s remarkable that this targeted oral medication provided such a substantial benefit in these children with highly aggressive cancers, most of

whom had already undergone every available therapy. Now that we know much more about the drivers of some pediatric cancers, we can target those changes and treat patients in a much smarter and potentially safer way,” Dr Mossé said. Photo by © ASCO/Scott Morgan 2012

ly unrelated cancers. This means that drugs targeted to one tumor type may be useful in small subsets of other types of cancers. This has implications for drug development, clinical trials, and the treatment of patients. “We now understand that it’s not sufficient to identify a tumor based on the histology or the organ of origin, as we did traditionally, but rather that tumors are heterogeneous. We need to understand the particular molecular driver of the tumor to select appropriate therapy,” said ASCO outgoing President Michael P. Link, MD, during a press briefing. As medicine has become “personalized” in recent years, molecular profiling of the patient has become a standard practice, at least for many tumors and in academic centers. But this is an expensive process, and sessions at ASCO 2012 were devoted to best practices in this area, at least for lung cancer, colorectal cancer, and neuro-oncology. In some instances, molecular profiling may be life-saving, said Nicholas J. Vogelzang, MD, Chair of ASCO’s Cancer Communications Committee and Chair and Medical Director, US Oncology Research, Houston, TX, and an oncologist at Comprehensive Cancer Centers of Nevada, Las Vegas. Dr Vogelzang pointed out that it is no longer uncommon for patients with disease refractory to established treatments to go hunting for unsuspected mutations that might be targeted by drugs that would otherwise never be considered. “It’s not intuitive,” he said. “Unusual tumors have these mutations, so you have to test them.”

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“We now understand that it’s not sufficient to identify a tumor based on the histology or the organ of origin…but rather that tumors are heterogeneous. We need to understand the particular molecular driver of the tumor to select appropriate therapy.” —Michael P. Link, MD Dr Vogelzang, who commented on the results, said he had also witnessed a dramatic response to crizotinib in an

adult with ALK-positive anaplastic large-cell lymphoma. “The patient was very, very ill. She achieved a complete response with crizotinib and was able to receive a transplant. So, this drug does have dramatic potential in older patients as well, and in patients with other tumors.” BRAF inhibitors may also have crossover appeal, because colorectal and lung cancers also harbor BRAF mutations. A “Blueprint” for Change In keeping with the rapidly emerging molecular landscape, ASCO is pushing for an accompanying paradigm shift in cancer research and drug development. In November 2011, ASCO issued a report, Accelerating Progress Against Cancer: ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research, that lays out its vision for transforming clinical and translational research to deliver more effective and personalized cancer therapies faster (www.asco.org/ ASCOv2/Department%20Content/ Cancer%20Policy%20and%20Clinical %20Affairs/Downloads/Blueprint.pdf). “Advances in cancer prevention, detection, and treatment have already extended the lives of millions of adults and children living with cancer—but the critical question is, ‘Where do we go from here?’” said Dr Link. “With the cancer burden growing rapidly around the globe, millions of future patients are depending on the answer. This report aims to set us on a path to deliver the new therapies that patients urgently need,” he said. ■

Biomarker Identifies Patients with Rare Brain Tumors... benefit was driven by patients with the 1p/19q codeletion. (Patients were prospectively stratified for presence of this codeletion after other investigators showed that the codeletion was associated with greater sensitivity to chemotherapy and radiation.) Looking at patients with the codeletion, PFS went from a median of 50 months with radiotherapy alone to 157 months for those who received adjuvant PCV (P = .002). Median OS was 112 months in the radiotherapyalone arm, but median OS had not yet been reached in the adjuvant PCV plus radiotherapy arm. These data are particularly impressive, because approximately 70% of

patients originally assigned to radiotherapy alone crossed over to the adjuvant PCV arm at progression, which could underestimate the survival difference, Dr Van Den Bent commented. A second study by Cairncross and colleagues reported at the meeting confirmed these results. The RTOG (Radiation Therapy Oncology Group) 9402 study showed that early PCV chemotherapy plus radiation improved survival in patients with anaplastic oligodendroglioma with the 1p/19q codeletion. “These 2 studies, led by cooperative groups, define a new standard of care for 1p/19q-deleted anaplastic

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“These 2 studies, led by cooperative groups, define a new standard of care for 1p/19q-deleted anaplastic oligodendroglioma.” —Martin J. Van Den Bent, MD

Continued from page 9

oligodendroglioma,” Dr Van Den Bent said. These studies are practice-changing, according to Mark Gilbert, MD, M.D. Anderson Cancer Center, Houston, TX. Both studies established that a predictive biomarker informs treatment decisions. Dr Gilbert emphasized the importance of collecting tumor samples in clinical studies and archiving them for future analysis when new markers are identified. “I commend the investigators for their perseverance and long-term follow-up,” Dr Gilbert said, noting that this led them to different conclusions from any initial results. ■

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ASCO Annual Meeting

In Head-to-Head Comparison, Continuous Beats Intermittent Hormonal Therapy for Metastatic Prostate Cancer By Wayne Kuznar Chicago, IL—In men with metastatic prostate cancer, especially those with minimal disease spread, continuous rather than intermittent hormonal therapy should be considered the preferred therapy, according to the results of a large multicenter phase 3 international trial. In these men, the difference in median survival favoring continuous therapy was approximately 2 years, said lead investigator Maha H. Hussain, MD, Professor of Medicine and Urology, University of Michigan Comprehensive Cancer Center, Ann Arbor, who presented the data at the 2012 meeting of the American Society of Clinical Oncology. Continuous androgen deprivation therapy has been the standard of care for men with metastatic hormonesensitive prostate cancer. In an effort to curb side effects from hormone therapy, such as loss of libido, weight gain, loss of muscle, and hot flashes, some oncologists have used intermittent hormone therapy with the belief that efficacy would not be affected. Early clinical trials showed that intermittent therapy was feasible and may be associated with an improvement in quality of life. Based on these trials, there was broad acceptance of intermittent therapy by patients, physicians, and insurers. But the present study’s findings “clearly demonstrate that intermittent hormonal therapy is not safe for all patients with metastatic prostate cancer,” said Dr Hussain. She noted that these data are practice changing. “This finding is striking

“This finding is striking and surprising, because it goes against the conventional belief based on all of the trials that have been done thus far.” —Maha H. Hussain, MD

and surprising, because it goes against the conventional belief based on all of the trials that have been done thus far,” she pointed out. The study, which was sponsored by the National Cancer Institute, included 1535 patients with newly diagnosed hormone-sensitive metastatic prostate cancer whose serum prostate-specific antigen level declined to ≤4 ng/mL after 7 months of continuous hormonal therapy with goserelin acetate in combination with bicalutamide. After stratifying them by disease extent, the patients were randomly assigned to receive intermittent hormonal therapy or continuous hormonal therapy.

“Prior underpowered studies suggested that there was no downside to intermittent therapy. This study demonstrates for the first time that there is a price to pay.” —Bruce J. Roth, MD

The median age of the patients was 70 years. Approximately 50% had extensive disease, and 50% had minimal disease. After a median follow-up of 9.2 years, median overall survival (OS) was 5.1 years in the group assigned to intermittent therapy versus 5.8 years for those assigned to continuous therapy, for a hazard ratio (HR) of 1.09. This HR did not meet the prespecified definition for noninferiority, because the upper confidence interval for the relative increase in the risk of death exceeded 20% (the trial was designed to show whether intermittent therapy was noninferior to continuous therapy). In the arm receiving continuous therapy, 42% of patients were still alive at 7 years compared with 38% of the arm randomized to intermittent therapy. For men with minimal disease spread, the difference in survival between the 2 groups was even greater. In this subset, median OS was 5.2 years in those receiving intermittent therapy versus 7.1 years for those who received continuous therapy. The HR for death with intermittent therapy was 1.23, which again did not meet the criterion for noninferiority.

at a glance ➤ There is broad acceptance of intermittent therapy by patients, physicians, and insurers, but it is not safe for all patients with metastatic prostate cancer ➤ Especially in men with minimal disease spread, continuous hormonal therapy should be the preferred therapy ➤ The difference in median survival favoring continuous therapy was approximately 2 years ➤ For men with minimal disease spread, median OS was 5.2 years in the intermittent therapy arm versus 7.1 years in the continuous therapy arm Among men with more extensive disease spread, median survival was similar in the 2 arms (5 years with intermittent vs 4.4 years with continuous therapy). There were no differences in the rate of grade 4 treatmentemergent adverse events. According to Bruce J. Roth, MD, Professor of Medicine in the Division of Oncology at Washington University, St Louis, “prior underpowered studies suggested that there was no downside to intermittent therapy. This study demonstrates for the first time that there is a price to pay.” He noted that patients with minimal disease are the ones who have been most likely to receive intermittent therapy. ■

Abiraterone Merits Consideration as New Standard Before Chemotherapy for Treatment of Prostate Cancer Chicago, IL—Abiraterone acetate (Zytiga) delays disease progression when used with prednisone before chemotherapy in men with metastatic castration-resistant prostate cancer, said Charles J. Ryan, MD, Associate Professor of Clinical Medicine, Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, who reported a planned interim analysis of a phase 3 study at the 2012 meeting of the American Society of Clinical Oncology. The finding represents a potential

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“These data merit consideration as providing a new standard approach in this highly prevalent population faced with an unmet medical need.” —Charles J. Ryan, MD

new use of abiraterone in prostate cancer; the drug is now approved only for men with metastatic castration-resistant prostate cancer in whom docetaxel (Taxotere) chemotherapy has failed.

“These data merit consideration as providing a new standard approach in this highly prevalent population faced with an unmet medical need,” said Dr Ryan. The trial included 1088 men with

JUNE 2012

metastatic castration-resistant prostate cancer that was no longer responsive to hormonal therapy. It was conducted in 151 centers in North America, Europe, and Australia. The men were randomized to abiraterone plus prednisone or to placebo plus prednisone. The trial was terminated early, with 43% of total events reported, given the favorable response on overall survival (OS) and progression-free survival (PFS) observed with abiraterone. At this point, the independent data moniContinued on page 12

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ASCO Annual Meeting

Abiraterone Merits Consideration as New Standard... toring committee recommended unblinding the study and offering the placebo recipients active treatment with abiraterone. The median survival in this study was 14.8 months, with an improvement of 3.9 months over the prednisone control arm, “thus reflecting the advanced clinical stage of the population tested,” said Dr Ryan. “A reality is that much of the life of a patient with metastatic castrationresistant prostate cancer is lived before chemotherapy, and, in fact, a large proportion of patients never receive it,” Dr Ryan stated in explaining the rationale for studying abiraterone in chemotherapy-naïve patients. There was a 57% improvement in radiographic PFS, a coprimary end

point, in men randomized to abiraterone. The median time to progres-

“A reality is that much of the life of a patient with metastatic castrationresistant prostate cancer is lived before chemotherapy, and, in fact, a large proportion of patients never receive it.” —Charles J. Ryan, MD

sion was 8.3 months in the control group, but the median time to PFS

had not yet been reached in the abiraterone group at the time the trial was suspended. “This represents an approximate doubling of the radiographic progression-free survival,” he said. The median survival in the prednisone control arm was 27.2 months, whereas the median survival had not yet been reached in the abiraterone arm, which conforms to a 25% improvement in survival, “a strong trend in favor of abiraterone,” Dr Ryan pointed out. This trend did not reach statistical significance because of the early termination of the trial. Some 60.3% of the prednisone control group required additional therapies for prostate cancer, including docetaxel (the most common subse-

Continued from page 11

quent treatment) compared with only 44.3% of the abiraterone arm. Abiraterone significantly delayed the time (by 31%) before patients needed opiates to control pain and the time (by 42%) to initiate chemotherapy. Susan Halabi, PhD, Associate Professor of Biostatistics and Bioinformatics at Duke University Medical Center, Durham, NC, said that although the study represents the first to show activity of abiraterone in chemotherapy-naïve patients, she questioned early termination of the trial, before the difference in OS observed with abiraterone could achieve statistical significance. Nevertheless, the survival benefit with abiraterone is most likely real, she said.—WK ■

BRAF and MEK Inhibitors Make News at ASCO Combined inhibition is highly active, less toxic By Audrey Andrews Chicago, IL—At the 2012 American Society of Clinical Oncology meeting, attendees flocked to sessions on the treatment of melanoma to hear about the next generation of agents that are building on the success achieved with the BRAF inhibitor vemurafenib (Zelboraf), and the immunotherapy drug ipilimumab (Yervoy), which have added new treatment options where, not long ago, none existed. In two phase 3 studies, the investigational BRAF inhibitor dabrafenib and the first-in-class MEK inhibitor trametinib, as single agents, led to encouraging outcomes in advanced disease. In a phase 1/2 dose-finding study, the combination of the 2 inhibitors was especially impressive. As Single Agents, Drugs Were Effective The global BREAK-3 trial of 250 previously untreated BRAF-positive patients showed median progressionfree survival (PFS) of 5.1 months with dabrafenib and 2.7 months with standard dacarbazine (DTIC) treatment, representing a 70% reduction in risk (P <.001), reported Axel Hauschild, MD, Professor of Dermatology, University Hospital in Kiel, Germany. In a related phase 2 study of dabrafenib in 172 patients with brain metastases, other investigators reported an unprecedented overall intracranial disease control rate of 81% in patients with no prior treatment and 89% for previously treated patients. In the METRIC study of 322 patients

previously treated with chemotherapy (but not vemurafenib), after treatment with the MEK inhibitor trametinib, the median PFS was 4.8 months with trametinib compared with 1.5 months with chemotherapy, a 55% reduction in risk (P <.001), reported Caroline Robert, MD, PhD, Professor of Dermatology at the Institut Gustave Roussy, Paris, France.

“The findings show that targeting the MEK molecular pathway is a viable strategy. Trametinib is likely to become another first-line treatment option for patients with advanced melanoma.” —Caroline Robert, MD, PhD

“This is the first in a new class of targeted drugs that could benefit patients with melanoma who have BRAF mutations. The findings show that targeting the MEK molecular pathway is a viable strategy. Trametinib is likely to become another first-line treatment option for patients with advanced melanoma,” Dr Robert said. Dual Inhibition May Work Even Better When both dabrafenib and trame-

VALUE-BASED CANCER CARE

JUNE 2012

tinib were combined to create dual inhibition of 2 related molecular pathways (MEK is downstream of BRAF), an even more powerful effect was observed, other investigators reported. The combination was tested in varying doses in 125 advanced melanoma patients with the BRAF mutation. The current efficacy analysis focused on 77 patients who had not received prior BRAF-targeted therapy and thus had demonstrated no resistance to vemurafenib. The results included complete responses in 8% of patients, partial responses in 49%, and stable disease in 38%, for an overall disease control rate of 95%. However, among the 24 patients who received twice-daily 150mg dabrafenib plus 2 mg/day of trametinib (assumed to be the optimal dose), 100% of patients achieved disease control or better, and no patients progressed on therapy, reported Jeffrey S. Weber, MD, PhD, Director, Donald A. Adam Comprehensive Research Center, Senior Member at Moffitt Cancer Center, Tampa, and Professor and Associate Chair, Department of Oncologic Sciences, University of South Florida. The median PFS was 7.4 months, which rose to 10.8 months in patients who were optimally dosed. It is important to note that these outcomes were achieved with far less dermatologic toxicity (14%) than is normally observed with single-agent vemurafenib or with either of the investigational agents alone, he said. “Certainly this is an impressive record by any assessment,” Dr Weber

suggested. “It’s fascinating to find such promising effects with this combination regimen.”

“Not only are the 2 drugs [dabrafenib and trametinib] causing shrinkage of the cancer, but we’re seeing that a second anticancer therapy may actually suppress the side effects of the first.” —Jeffrey S. Weber, MD, PhD “Not only are the 2 drugs causing shrinkage of the cancer, but we’re seeing that a second anticancer therapy may actually suppress the side effects of the first,” he explained. “There is a significant diminution of the dermatologic toxicities, such as just 3% squamous cell carcinomas, which can favorably be compared to 15% to 25% seen with this drug alone or other BRAF inhibitors.” In discussing the exciting new research, Michael B. Atkins, MD, Deputy Director of Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, said that BREAK-3 establishes dabrafenib as the second BRAF inhibitor with proven efficacy, and he suggested that “competition is good” in the field of oncology. “Despite recent advances, metastatic melanoma is still a bad disease,” he concluded. “We need to pause to celebrate, but then begin work to raise the bar higher.” ■

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NCCN Annual Conference

Cancer and Corporate America: Business as Usual? Increased attention to employees’ health is mired with economic concerns By Audrey Andrews Hollywood, FL—Is corporate America doing enough to promote optimal cancer care? The provision of insurance coverage alone is no longer sufficient for America’s workers. Advocates for persons with cancer contend that professional and emotional support should also be part of the “benefits package” that companies offer. At the 2012 Annual Conference of the National Comprehensive Cancer Network (NCCN), representatives of national and international corporations, oncologists, patient advocates, and government advisors convened to address the topic of corporate America’s responsibility toward those with cancer. A Healthy Employee Is Good Business Expressing the general sentiment of the panel, Robert W. Carlson, MD, of Stanford University Medical Center and Chair of the NCCN’s Breast Cancer Panel, said, “We need to make sure the system is configured so that employees can effectively fight their cancer and not waste their time fighting their insurance companies or being concerned about their employment.” Patients with cancer inevitably worry about how their diagnosis will affect their employment, he observed. “What businesses owe their employees is professional support—assurance that their careers will not be torpedoed by their diagnosis and that they will not be abandoned by their company during this process—coupled with emotional support,” Dr Carlson said. When companies do this, they are also helping themselves, some said. “The reality is that a healthy employee is a productive employee. A productive employee is an innovative employee. And an innovative employee creates products and services that are satisfying to the client or customer,” according to J. Randall MacDonald, Senior Vice President of Human Resources at IBM. Helen Darling, Chief Executive Officer of the National Business Group on Health, added, “Company executives want to do the right thing, but it’s also in their company’s best interest. They know that the way the employer responds [to illness] is a signal to everyone as to the culture of that company.” Commitment to cancer care (or any illness) is part of the “leadership DNA” in exemplary corporations, Ms Darling suggested. Such companies

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“We need to make sure the system is configured so that employees can effectively fight their cancer and not waste their time fighting their insurance companies or being concerned about their employment.” —Robert W. Carlson, MD

send the message, “We care about you,” and provide a variety of tools and resources for dealing with cancer, including help with physician referrals, patient navigators, employee assistance programs, and the like. One company that has gone the extra mile is Salesforce.com in San Francisco, CA, the leading cloud computing provider, represented on the panel by John Greene, Director of Engineering. When Mr Greene was diagnosed with acute myeloid leukemia in 2010, his company helped secure a consultation with a nationally recognized hematologist and began a bone marrow registry to help him find a donor. “This stuff just happens in my company. No questions asked,” Mr Greene said. Preventing Disease Is Good for Employers But the need is broader, the panelists maintained. “We know that a healthy employee is one who is going to contribute in meaningful ways,” said Sheri McCoy, Vice Chair of the Executive Committee at Johnson & Johnson, which aims to move from “disease care” to “preventive care,” she said. Her company promotes smoking cessation, healthy eating, and fitness, because disease prevention, she said, “is a good business proposition,” both for the company and the individual. Brent Pawlecki, MD, Chief Health Officer at Goodyear Tire & Rubber, agreed, suggesting that corporate America generally does a decent job providing coverage and support for cancer treatment, but tends to aban-

don workers toward the end of the cancer continuum. At Goodyear, he said, “the goals we have set are to prevent illness whenever possible, and when it is not, to get people into the right care at the right place at the right time and, when treatment is no longer possible, to assure a dignified and respectful exit. We need to help employees plan for the inevitable, whatever form it takes.” Mr MacDonald added, “We have to provide a sense of prevention, detection, and ultimately—in those unfortunate cases—end-of-life care, and to use evidence-based medicine to do these things effectively.” Carole Klase, PhD, a mental health specialist and cancer survivor, argued that psychosocial services should be part of comprehensive cancer care as well. “The psychological difficulties in dealing with cancer can be as staggering as the cancer itself, and perhaps more so,” said Dr Klase, who survived Merkel-cell carcinoma but found the financial burden of her treatment to be a great source of emotional stress.

“It’s mind boggling, the cost of my cancer to my own insurance plan. I have taken sunitinib for 5 years, at $60,000 a year. Employers want to do the right thing. They just want to be able to understand how we can control our business model in the end.” —J. Randall MacDonald

Cost Is the Obstacle The increasing recognition that patients with cancer need a wide range of services unfortunately coincides with the need to reign in healthcare spending, the panelists acknowledged. IBM spends $1.2 billion on healthcare for its US employees alone, approximately $110 million of which is for cancer. “We have very tough decisions to make,” said Mr MacDonald. “I like to think we err on the side of the employee, but I can’t say we do this every time.

JUNE 2012

In reality, we have to run a business.” Living with advanced renal-cell carcinoma himself, he can appreciate the problem. “It’s mind boggling, the cost of my cancer to my own insurance plan. I have taken sunitinib for 5 years, at $60,000 a year,” he said. “I think employers want to do the right thing. They just want to be able to understand how we can control our business model in the end.” From the provider’s point of view, “struggles with costs” are a daily occurrence, Dr Carlson added. The most troublesome are costs related to “structures that are overlaid on the medical system in order to try to control costs,” such as preauthorization procedures and those aimed at assuring compliance with evidence-based medicine. Although the companies themselves do not directly spawn these frustrations, they approve the benefits packages, he noted. “Fighting these battles takes literally hundreds of hours of staff time,” he said. The Potential Impact of the ACA The Patient Protection and Affordable Care Act (ACA) will clearly affect employers and employees alike. Kavita Patel, MD, Managing Director for Clinical Transformation and Delivery at the Brookings Institution’s Engelberg Center for Healthcare Reform and former Director of Policy for the White House Office of Intergovernmental Affairs and Public Engagement, helped draft the legislation. She said the ACA puts patients in a better position regarding insurance eligibility and coverage. “It’s definitely helping by putting private insurance regulations into place and by providing a more even playing field.” Ms Darling added that expanded coverage is not enough; it should involve not just more healthcare, but evidence-based care. Dr Patel noted that, “there still needs to be a system of checks and balances to make sure these things are executed. That is actually what the exemplary companies, such as those represented on this roundtable, can do.” Although the ACA contains “some phenomenally good things,” businesses fear that providing these benefits will be very costly. “It’s not the content of the law, it’s the unknown that is bothering us,” said Mr MacDonald. “We are not against healthcare. We are just trying to put it in the context of what we need to do to control our costs.” ■

www.ValueBasedCancerCare.com

Making

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

TAILORING a PRO tool for myelofibrosis

130T BSF BO JNQPSUBOU NFBOT UP EFNPOTUSBUF USFBUNFOU benefits in clinical trials. 6TF PG B 130 JOTUSVNFOU DBO evaluate symptoms best judged by the patient, whether caused by the disease or treatment toxicity. Assessment of symptom burden is important because it can be a major indicator of disease severity, progression or improvement. *ODPSQPSBUJOH 130T JOUP B DMJOJDBM USJBM QSPHSBN QSPWJEFT B means for evaluating the impact of therapy from the patientâ&#x20AC;&#x2122;s perspective and helps patients and clinicians make betterinformed decisions.

.ZFMPĂĽ CSPTJT .' JT B MJGF UISFBUFOJOH QSPHSFTTJWF EJTFBTF characterized by splenomegaly, debilitating symptoms and cytopenias.5-7 Measures to assess both the splenomegaly and core symptoms of MF were incorporated into the phase III, EPVCMF CMJOE QMBDFCP DPOUSPMMFE TUVEZ $0.'035 * GPS +BLBĂĽ 4QMFFO SFEVDUJPO BT NFBTVSFE CZ JNBHJOH .3* PS $5 was the primary and biologic endpoint, and a reduction in total TZNQUPN TDPSF 544 UIF 130 NFBTVSF XBT B LFZ TFDPOEBSZ endpoint.8,9 The TSS encompassed the following symptoms: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain.9 5P JODMVEF 130T JO UIF USJBM B OPWFM JOTUSVNFOU IBE UP CF specifically developed. After patient interviews, advice from clinical experts and extensive input from the FDA, the modified Myelofibrosis Symptom Assessment Form, version NPEJĂĽ FE .'4"' W XBT ĂĽ OBMJ[FE BT QBSU PG UIF 4QFDJBM 1SPUPDPM "TTFTTNFOU QSJPS UP UIF JOJUJBUJPO PG $0.'035 * Ultimately, Jakafi was approved by the FDA for the treatment of intermediate or high-risk MF.1,8 This became Incyteâ&#x20AC;&#x2122;s first approved drug and also the first oncology medicine approved with symptom data in its label since the FDAâ&#x20AC;&#x2122;s draft guidance on 130T XBT ĂĽ OBMJ[FE JO

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, postâ&#x20AC;&#x201C;polycythemia vera myelofibrosis and postâ&#x20AC;&#x201C;essential thrombocythemia myelofibrosis. Important Safety Information t 5SFBUNFOU XJUI +BLBĂĽ DBO DBVTF IFNBUPMPHJD BEWFSTF 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 t 5IF UISFF NPTU GSFRVFOU OPO IFNBUPMPHJD BEWFSTF reactions were bruising, dizziness and headache t 1BUJFOUT XJUI QMBUFMFU DPVOUT Â¨ 9/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 t 1BUJFOUT EFWFMPQJOH BOFNJB NBZ SFRVJSF CMPPE USBOTGVTJPOT Dose modifications of Jakafi for patients developing anemia may also be considered t /FVUSPQFOJB "/$ Â¨ 9/L) was generally reversible and was managed by temporarily withholding Jakafi t 1BUJFOUT TIPVME CF BTTFTTFE GPS UIF SJTL PG EFWFMPQJOH serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before TUBSUJOH +BLBĂĽ 1IZTJDJBOT TIPVME DBSFGVMMZ PCTFSWF QBUJFOUT receiving Jakafi for signs and symptoms of infection JODMVEJOH IFSQFT [PTUFS BOE JOJUJBUF BQQSPQSJBUF treatment promptly t " EPTF NPEJĂĽ DBUJPO JT SFDPNNFOEFE XIFO BENJOJTUFSJOH +BLBĂĽ XJUI TUSPOH $:1 " JOIJCJUPST PS JO QBUJFOUT XJUI

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

0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

0 -50

-100

Placebo (n = 153)

Each bar represents an individual patientâ&#x20AC;&#x2122;s response.

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 patientâ&#x20AC;&#x2122;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 MFâ&#x20AC;&#x201D;this is an important consideration when evaluating and treating patients.9 5IF '%" BQQSPWBM JODMVEFE QBUJFOUT XJUI JOUFSNFEJBUF SJTL BOE IJHI SJTL BT XFMM BT QBUJFOUT 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 BDBEFNJD FYQFSUT UP EFWFMPQ SFMFWBOU BOE WBMJEBUFE 130 JOTUSVNFOUT UIBU DBO CF JODPSQPSBUFE JOUP DMJOJDBM USJBMT 1,8 The approval PG +BLBĂĽ NBSLT B TJHOJĂĽ DBOU NJMFTUPOF JO XIJDI WBMJEBUFE 130 JOTUSVNFOUT DBO QSPWJEF TZNQUPN EBUB BOE EFNPOTUSBUF DMJOJDBM CFOFĂĽ U 5IF FYQFSJFODF XJUI +BLBĂĽ NBZ QSPWJEF B NPEFM GPS UIF GVUVSF VTF PG 130T JO NBSLFUJOH BQQMJDBUJPOT 8

renal or hepatic impairment [see Dosage and Administration]. 1BUJFOUT TIPVME CF DMPTFMZ NPOJUPSFE BOE UIF EPTF UJUSBUFE based on safety and efficacy t 5IFSF BSF OP BEFRVBUF BOE XFMM DPOUSPMMFE TUVEJFT PG +BLBĂĽ 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 t 8PNFO UBLJOH +BLBĂĽ TIPVME OPU CSFBTU GFFE %JTDPOUJOVF 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.

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 â&#x2030;Ľ35% 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 â&#x2030;Ľ50% 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 â&#x20AC;&#x153;absentâ&#x20AC;? and 10 representing â&#x20AC;&#x153;worst imaginableâ&#x20AC;? 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.

Health Policy

ObamaCare in Reverse

ne tragedy of the Affordable Care Act is that we already know what its regulations will do to insurance markets, because the states have been conducting policy experiments since the 1990s. But we

also know from the states that the damage is reversible, as shown by Maine’s emerging insurance turnaround. In 1993, Augusta passed coverage laws that resemble those that ObamaCare

is about to impose nationwide: insurers could only vary premiums within narrow bands regardless of age or health status, a regulation known as community rating. Four of Maine’s five insurers in the individual market stopped

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All b Grade 3 Grade 4 Grades Grade 3 Grade 4 Parameter 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)], Herpes Zosterf 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.

offering coverage and fled, and the state entered an insurance “death spiral” in which premiums don’t cover underlying medical costs. That leads to higher premiums, consumers dropping coverage as a result, and still higher premiums in turn. Then the 2010 electoral wave carried in Republican Governor Paul LePage and a GOP legislature, and they took modest steps to deregulate the insurance market. Insurers are now allowed to sell policies for premiums that range from 3 to 1 on the basis of age, rather than the prior 1.5 to 1, and to offer incentives or discounts for consumers to choose high-value providers. The state also created a reinsurance fund that taxes all health plans by $4 a month. If someone ends up requiring extremely expensive care, the fund picks up some of the costs, which means insurers can better manage their future liabilities and pass the savings on to individuals. The returns are now rolling in for the new coverage that can be offered starting on July 1, and premiums are falling by as much as 69% for Maine’s dominant insurer, Anthem. According to the Maine Bureau of Insurance, a married couple age 40 to 44 with one child will pay $1,919 a month for a policy with a $2,250 deductible in 2013 if they choose to re-up their current policy. If the same family switches to the new health plan, or buys the plan for the first time, their premium will fall to $920, a 52% decrease. A couple over 60 could buy the same policy for $1,290, down from $2,466 under the old system. Or a young adult 25 to 29 could buy a high $10,000 deductible plan for catastrophic expenses for $232, previously $665. The old and new products are not identical, so the comparison isn’t perfect. On top of the rule changes, the benefits are slightly different, such as separate deductibles for in- and out-ofnetwork services. And many of the year-over-year reductions are less dramatic, in the range of 10% to 20%, while a few older consumers will see rate increases. Still, any premium decrease is remarkable on the U.S. health cost escalator, which is being accelerated by ObamaCare. Maine consumers who choose to stay with their current policy (same benefits, old rules) will see an average premium rate increase of just 1.7% from 2012 to 2013—compared to an historical trend of about 10%. Some 46% of the existing book of business will see a rate decrease. Continued on page 17

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Reimbursement Strategies Must Be Patient-Centered Interview with Jennifer Malin, MD, PhD Medical Director of Oncology, WellPoint

n an interview with the Association for Value-Based Cancer Care (AVBCC), Jennifer Malin, MD, PhD, Medical Director of Oncology at WellPoint, emphasized that patients should remain the central focus in novel or innovative reimbursement models. AVBCC: Dr Malin, you have talked about the importance of keeping patient-centered care the focus of reimbursement strategies. How can this be done while still controlling cost? Dr Malin: There is so much talk about creating value, but achieving that goal in oncology care is complex. Oncology is a complicated field to address, because the stakes are so high. What payment models need to consider are the best ways to combine cost control with patient-centered medical care. Some standard payment models—the so-called “capitation episode-based payment model” for example—give physicians a lump sum to provide care for a population or for 1 patient throughout the course of care. Other models focus on episodebased payment. AVBCC: What is being done at WellPoint that you consider patientcentered? Dr Malin: For our oncology medical home, for which we have an ongoing

ObamaCare... Continued from page 16 The major irony is that Maine’s reform merely brings its community rating rules into compliance with ObamaCare, which is actually less restrictive than the rules the state passed in 1993. The new national health law will block a further Maine liberalization that is due for 2016. Maine learned the hard way that the most heavily regulated insurance markets are the most expensive. But the more ominous lesson out of Vacationland is for the 33 states that had the wit never to make the MaineObamaCare mistake. They’re the ones that are about to see premiums spike under the Affordable Care Act—perhaps by as much as 69%, and likely by far more. ■ Reprinted with permission from the Wall Street Journal (wsj.com), May 2012.

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Figure Implementing New Web-Based, Evidence-Based Tool for Precertification of Episode of Care Web portal

Clinical engine

Output

• Practice submits request for episode of treatment via web portal • Single request instead of multiple requests • Direct link to WellPoint medical policy and evidence-based treatment options

• Review against WellPoint medical policy • Compare against evidencebased recommendations and preferred treatment based on efficacy, toxicity, and cost

• Immediate approval if consistent with WellPoint medical policy and evidence-based treatment recommendations • Feedback regarding preferred regimens provided back to physician • Integrated with claims systems

• Builds on existing infrastructure of advanced infrastructure management, which currently provides preauthorization and guidance for diagnostic imaging • Phased approach to implementation starting with radiotherapy

pilot, we pay oncologists a disease management fee. We still pay for the drugs and the office visits, but we also give providers a fee for caring for the patient, for selecting the most appropriate evidence-based and guidelinebased care, for being value conscious, and for making sure patient care is well coordinated and that their symptoms are effectively managed so they do not have to turn to the emergency department unnecessarily. AVBCC: How do you verify that physicians are using the disease management fee appropriately? Dr Malin: We only have the oncology medical home pilot in 1 practice at the moment, but we hope it will be scalable. For this initial program, we are collaborating with the Wilshire Oncology group in Los Angeles, CA. The group has instituted a proactive program to reach out to patients who are receiving treatment and confirm that their symptoms are being addressed. We meet with the physicians and staff regularly, and they share their information with us, which we then compare with information that is available to us. In this way, we all know what cancer-directed and supportive treatments patients are receiving, and which patients had complications, were seen in the office or went to the emergency department, or needed to be admitted to the hospital. We have found that many times, patients who are seen in the emergency department could have received proper treatment outside of that setting, but they do not call the office when they have a problem. So, we are changing the protocols to have nurses remind patients regularly of the importance of calling the office. It is a labor-intensive process, but one that

we are passionate about and that we believe will reap benefits for patients. We need to be sure it does not look like the plan is interfering with patients obtaining emergency services, so we may need to revise it further. AVBCC: What other approaches at WellPoint are you taking to lower costs and not compromise quality? Dr Malin: In addition to our oncology medical home and our new webbased tools implemented to expedite preauthorization (Figure), we are also exploring ways to reimburse oncologists for the time they spend planning treatment and coordinating care using the newly approved S code linked to preauthorization for episodes of care. Over time, we will link this reimbursement to performance as well. AVBCC: How will you structure your performance measures? Dr Malin: Performance will be measured by adherence to evidencebased care, selection of treatment options that are value conscious, and quality of care. For this, we are working out the exact metrics, but they will be based on national standards such as the American Society of Clinical Oncology’s Quality Oncology Practice Initiative and the National Quality Forum’s quality measures. AVBCC: When do you expect stakeholders will agree on what is the best care for a patient with cancer? There are many ways to approach this, and there are many outcomes to consider. How will all of this come together? Dr Malin: In general, there is pretty good consensus on what the right care is when the evidence is strong. The area where there tends to be disagreement, especially in the context of value, is the use of technology, espe-

JUNE 2012

There is so much talk about creating value, but achieving that goal in cancer care is complex. Oncology is a complicated field to address, because the stakes are so high. cially high-cost technology, ahead of the evidence. We want to make sure that our health plan members have access to those technologies that have the potential to improve their quality of life. But we cannot provide patientcentered care if all healthcare dollars go to technology, especially expensive treatments that do not provide a meaningful improvement in patient outcomes, and leave nothing to compensate the dedicated clinicians who are there holding the hands of patients and their loved ones and standing beside them on this difficult journey. That means that we, as oncologists, need to rely on evidence-based medicine and continually refer to its efficacy, its latest progress, and the quality improvements it affords our members. ■

www.ValueBasedCancerCare.com

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Pathways in Oncology: Implications for Providers... Pharmacy Management with CareFirst BlueCross BlueShield in Maryland; Roy A. Beveridge, MD, Chief Medical Officer, US Oncology and McKesson Specialty Health, Fairfax, VA; and Peter G. Ellis, MD, Associate Clinical Professor of Medicine, University of Pittsburgh School of Medicine and Director, Medical Oncology Network, UPMC Cancer Centers in Pennsylvania. Dr Deligdish: What is happening with prior authorizations in relation to pathways? More specifically, if a practice agrees to a pathway approach, should you eliminate all prior authorizations? Dr Wong: Traditionally, health plans have emphasized prior authorizations, especially in the oncology world. One of the benefits to the practices that participated in our program at CareFirst BlueCross BlueShield was that, for the most part, all prior authorizations were eliminated. We were depending on the pathways and the judgment of the physician to use the drugs appropriately. The only thing we really did as a plan was to document that the pathways delineated by our steering committee were working. We as a plan did not drive the pathway process. Dr Deligdish: I understand the benefit of pathways to the payers and the benefit to the providers. Have you measured the benefit to the patient? Are pathways also improving patient satisfaction? Dr Beveridge: At McKesson Specialty Health/US Oncology Network, we have used our data analysis to determine that overall survival is the same or better using evidence-based medicine. That is a crucial acid test of overall efficacy. We found that our use of research has increased because of the associated logic tool, and our patient surveys indicate that an increased use of meaningful research is important to patients. We put 50,000 patients on studies last year, so we think that is important. In terms of “Have we measured quality-of-life improvements?” the answer is “no.” But we are implementing patient portals that connect to the electronic health record, the FACT-G (Functional Assessment of Cancer Therapy-General), for example, and they will get these out on a weekly/monthly basis. With these, I think we will be able to demonstrate over the next 2 years an improvement in quality of life from a patient standpoint. We do not have those data yet.

“At CareFirst BlueCross BlueShield, prior authorizations were eliminated. We were depending on the pathways and the judgment of the physician to use the drugs appropriately.” —Winston Wong, PharmD Dr Ellis: Indeed, the Institute of Medicine feels strongly that if you apply evidence-based care, the patient’s outcome will be better. Pathways guarantee that evidencebased care is being applied to the patient, and they guarantee personalized medicine where it is appropriate and measurable. The ability of pathways to also streamline practice mechanics—such as getting patients through the office faster; having more time with nurses who provide patient education with more standardized educational protocols; and reducing hospitalizations, emergency department visits, and toxicity—leads to better quality-of-life and better clinical outcomes. Also, the more we standardize care and the more we follow protocols, the fewer medical errors we see. We think that is an improvement in patient care. Dr Beveridge: We have also been able to demonstrate that nursing errors decrease when we are on standardized pathways, which is a good thing for patients. Dr Wong: We have also not measured patient satisfaction specifically, but at least under our first-generation oncology management program, we would have no reason to suspect that patient satisfaction would diminish; we are still encouraging physicians to practice in a manner that is in the best interest of that patient. That is why we did not set the threshold for pathway

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compliance to be 100%. We know there are individual patient situations where one-offs are going to be required. The second-generation program will be a lot more comprehensive, and there will be more monitoring of the patients. If anything, patient satisfaction should increase, because we are “touching” the patient. We are following back up with the patient within 24 to 48 hours of treatment. We are making sure that they are staying out of the hospital. Based on the key principles we followed in forming the pathways, we believe patient satisfaction should go up. Dr Deligdish: We should perhaps think of pathways as not just a pathway to a treatment, but as a pathway to the entire continuum from diagnosis to the end of life. Pathways that include advanced illness programs for patients who cannot be cured have been tested over the past decade. In randomized trials, they have clearly demonstrated improvements in quality of life and improvements in patient satisfaction. This is in part a result of some of the things we talked about, such as reductions in emergency department visits and in hospitalization, but also as measured in true quality-of-life param-

“The Institute of Medicine feels strongly that if you apply evidence-based care, the patient’s outcome will be better. Pathways guarantee that evidence-based care is being applied to the patient, and they guarantee personalized medicine, where it is appropriate and measurable.” —Peter G. Ellis, MD

Continued from cover

eters. We also know there is more satisfaction among the patients’ families, who are frequently burdened with the responsibility of caring for the family member with cancer. As we begin to incorporate in our second and third generations a more comprehensive approach to pathways that includes these programs, we will start to see benefits to patients and their families. Dr Beveridge: To emphasize this point, we have data in the community showing that the use of advanced-care planning, as built into various pathways, significantly reduces the number of patients who get chemotherapy within 14 days and 30 days of the end of life, and reduces the futility of care, namely the fourth- and fifth-line therapies. I think this is becoming increasingly well documented across the country, and that is where we are heading. Dr Deligdish: A 20% deviation from pathways seems to be typical of most programs. Are these variations mostly in the first-line or second-line setting, and what were the criteria for having these variations approved? Dr Beveridge: Our data suggest that most exceptions occur not in the adjuvant or first-line setting, and not in the second-line setting, but more in the third- and fourth-line settings. I think that the exception process is different, depending on geographic region. In our exception process, we have other members within that large practice— usually someone from the Pharmacy and Therapeutics Committee—review the exception within 24 hours. This person reviews the literature, and if the recommendation is within the compendia, there is a reasonable chance that it will be approved. Probably one third of our exceptions are for patients who have had second opinions in academic centers, such as “A major institution in Houston has suggested X, Y, and Z.” It is hard at that point not to apply X, Y, and Z. So that would be an exception that would be granted. Dr Ellis: In many pathway programs, including ours at the University of Pittsburgh, you have to put the reason you went off pathway. We currently have a review board for radiation oncology pathway requests, but we do not have this on the medical side. We just ask the doctor to tell us why, and then we collate those and Continued on page 20

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Pathways in Oncology: Implications for Providers... bring those back to the committee every quarter. Also, to Dr Beveridge’s point, we very rarely see off-pathway treatments in the adjuvant setting, but more in the metastatic setting and then rarely in the first- or second-line setting. We see it either because the patient is 52 years old and has young children, has good performance status, and is beyond second line, and we do not have the pathway for that. They go off pathway because there are extenuating circumstances. We also see the academic second opinion.

generally found that no one likes to have these end-of-life discussions. Physicians, nurse practitioners, and nurses do not like to do it. We need a powerful educational methodology, and then we need to build this into our information technology infrastructure so that providers cannot avoid it. Ideally, we need to have systems by which the responsibility is not just with the physician but with a manager within a practice or group. It is a true team approach. It is not just one conversation but multiple conversations, and it requires an attitude

“We have data in the community showing that the use of advanced-care planning, as built into various pathways, significantly reduces the number of patients who get chemotherapy within 14 days and 30 days of the end of life, and reduces the futility of care, namely the fourth- and fifth-line therapies.” —Roy A. Beveridge, MD Dr Beveridge: I think collating these exceptions is very important because (1) it tells us whether the evidencebased process is not keeping track with where clinical acumen is going, and (2) it serves not only as a check to ensure that our pathways are reasonable to clinicians, but it also sets up a system by which we can see what is happening within a practice. If a physician has a much greater number of exceptions, this may indicate a need for an educational intervention. Dr Deligdish: One of the biggest challenges in oncology is end-of-life care and limiting futile therapy. How do you engage physicians to talk to their patients about this? Are there any educational tools or scripts that can be used? Dr Beveridge: Changing physician behavior is challenging. We have

readjustment. In practices that successfully implement this, this will eventually change the global attitude of the environment where oncologists practice. Dr Deligdish: When do you first introduce the topic of end-of-life goals? Is it early on, or is it once you have exhausted all the options? Dr Ellis: Our Medical Oncology Network is no longer at University of Pittsburgh, but we are 110 doctors. So we face many of the same challenges, although on a smaller scale. We have 25 sites of service in western Pennsylvania, and the same thing applies. We too have been on a big educational program. I want to put a plug in also for a system like pathways, because you can educate but it still is not a pleasant thing. Reminders

Continued from page 18

“We should perhaps think of pathways as not just a pathway to a treatment, but as a pathway to the entire continuum from diagnosis to the end of life.” —Craig K. Deligdish, MD

and prodding are necessary to some degree. When you order a chemotherapy regimen, if you look at the Quality Oncology Practice Initiative guidelines, was it explained and documented that the patient is getting that chemotherapy regimen for curative intent or for palliative intent? That question begets the entire discussion of end of life. If you are getting chemotherapy for palliative intent, it begets the conversation of “Oh, you mean I am not going to be cured, doctor?” “No, that means that you are not going to be cured. You are going to live with your disease, and eventually you are going to die of your disease.” At least at the University of Pittsburgh Medical Center, whenever a patient with metastatic disease is placed on a chemotherapy regimen, that question is asked. Therefore the conversation is hopefully prompted. Dr Beveridge: We need to be careful as oncologists to say, “Hi, Mrs Smith. I am meeting you for the first time. I am going to talk to you about treatment. Now, let me talk to you about advanced-care planning.” One needs to be moderately sophisticated in determining on an individual basis when that conversation should occur. We believe that, in some of our pilots that we are doing and rollouts, that if one has stage IV pancreatic or non– small-cell lung cancer, you better have that conversation very early. We need to be rather careful with breast cancer, because women with metastatic breast cancer are living

years and years. Ditto with myeloma and a number of other cancers. So you have to choose when you are going to do that. Dr Deligdish: Let me just add on to that, that there really is no answer to that question. Because there are so many different issues involved, and we are hearing the answers from 2 people who have practiced oncology for decades. If we look at the greater issues in the United States about end of life, and how it is addressed, we have companies and organizations that have specially trained individuals to have those conversations. There is so much going on in an oncology practice at any given time that to sit down with somebody and to really have that conversation and devote the amount of time, that is really necessary. It has been stated that it is not one conversation, but it is a series of conversations. In general, with the exception of a patient with stage IV pancreatic cancer, a hepatoma, or a disease that is imminently terminal, it is not something that we can generally do in the span of 15 minutes, with just the patient or the patient’s family. So it is difficult, and it takes a lot of time. Those who expect that such conversations are going to happen only in the oncology office, when so much else is happening at the same time, are deluding themselves. It is something that has to be handled in a much more sophisticated way, by social workers and/or by nurses. It is a team approach, and it takes a lot of time. ■

“

The Association for Value-Based Cancer Care Conference provides a unique forum for all stakeholders to wrestle with the challenges confronting cancer care delivery and to share and discuss novel approaches to optimize quality and value in cancer care.

”

—Jennifer Malin, MD, PhD, Medical Director of Oncology, WellPoint

VALUE-BASED CANCER CARE

JUNE 2012

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2nd Conference

The Value of Level I Pathways at US Oncology By Caroline Helwick Houston, TX—The use of the Level I Pathways Program at McKesson Specialty Health/US Oncology Network over the past 5 years has reduced treatment variability and resulting costs, according to Roy A. Beveridge, MD, Chief Medical Officer, McKesson Specialty Health/US Oncology Network. “We fundamentally believe that the use of these pathways significantly reduces the variation in patient care, and we have been able to demonstrate this,” Dr Beveridge said at the Second Annual Conference of the Association for Value-Based Cancer Care. Level I pathways at McKesson/US Oncology have been used by more than 900 medical oncologists in 39 states for more than 5 years. They are based on US Oncology’s physiciancreated, evidence-based clinical guidelines, and provide a platform for standardization, outcomes measurement, and ongoing peer review. Currently, 20 medical oncology pathways and 17 radiation oncology pathways are used, including pathways for relatively rare cancers, such as mantle cell. Parlaying evidence-based medicine into a level I pathway design creates the opportunity to improve quality and value to key healthcare stakeholders, Dr Beveridge pointed out. These results reduce variation in patient care, promote evidence-based medicine, offer up-to-date clinical tools, and are fiscally responsible. Pathways also distinguish practices that use them by streamlining and improving efficiencies and validating quality through measurement outcomes and benchmarking. In short, level I pathways constitute a more precise approach to the delivery of patient care compared with the use of guidelines alone, he said (Table 1).

Table 1

The Particulars of Level I Pathways at McKesson/US Oncology The Level I Pathways Program at McKesson/US Oncology takes a stepwise approach to treatment, giving recommendations for drugs and modalities according to disease stage and line of therapy. The elimination of “futile therapy” is one of the aims, Dr Beveridge explained. “Apart from a research trial or hospice care, you do not find third- or fourth-line therapies in non–small-cell lung cancer or pan-

creatic cancer. Although we do have sixth-line therapies for metastatic breast cancer, because this actually works in some patients.” Some exceptions are allowed, based on the belief that a physician who always adheres to the written pathway without deviation may be practicing “cookbook medicine,” Dr Beveridge noted, “and we think exceptions are appropriate to a certain level.” McKesson/US Oncology also chose to include cost data in formulating the pathways. Where multiple regimens have equal efficacy, the choice should

Other guidelines/labels

Lines of therapy are limited

No limits in lines of therapy

Designed by community oncologists, for community oncologists, through a consensus process Costs to patients and payers are considered Structured with implementation tools and feedback mechanism to ensure consistent quality of care

Designed by academic/tertiary centers without a lot of input from community oncology practices Costs to patients and payers are not considered

NO. 4

12-month average cost On-pathway Off-pathway treatment treatment (N = 1095), $ (N = 314), $

Cost

General document without support framework to ensure quality care

Average cost-savings per patient (on vs off), $

Total medical oncology cost

18,042

27,737

–9695

Chemotherapy

11,839

18,762

–6923

Supportive care medications

4374

7198

–2824

Adapted from Neubauer MA, et al. J Oncol Pract. 2010;6:12-18.

—Roy A. Beveridge, MD

Regimens are generally recommend- General panel of options only. ed in step-wise sequences by lines of No sequence or preference among therapy options stated

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On-Pathway Cost Reductions

“We fundamentally believe that the use of these pathways significantly reduces the variation in patient care, and we have been able to demonstrate this. We found, on pathway, not only reductions in drug costs but reductions in emergency department visits and hospitalizations, because when pathways are followed, physicians are less likely to use futile therapies.”

Level I Pathways Development: A More Precise Approach to Therapy

Level I pathways

Table 2

be based on the one with the lowest toxicity; given a similar toxicity profile, the lowest-cost regimen would be preferred. Pathways Development “The critical elements on the form are actually quite few,” Dr Beveridge noted. “We built in the logic and the ability for an electronic health record or a web portal to assist physicians in terms of how to treat patients with particular lines of therapy,” with regimens being organized by line of treatment. The program incorporates the iKnowMed decision-support tool and Pathways Portal, a web-based clinical decision tool that recommends pathway treatment options based on patient-specific criteria (with literature references given). Data are fed back to the physician practices so that physicians can learn their rates of compliance with appropriate treatments for each cancer type and setting, which thereby increases adherence. “Physicians are pretty competitive, so if you rank where they are in the universe of their peers, and they are in the bottom third, they will want to rise to the upper third,” he commented. Proven Value of Pathways Recent peer-review data indicate

JUNE 2012

that treatment on pathway is costeffective and provides similar results to treatment off pathway, he said. Onpathway treatment versus off-pathway treatment results in lower costs for chemotherapy, lower overall healthcare costs, fewer hospitalizations, and equivalent or slightly improved survival. Dr Beveridge said he is able to satisfy payers’ concerns about survival. “Payers tell us, ‘Show us the overall survival curves. Show us that there is equivalence.’ And we have been able to do this now for multiple diseases,” he said. For example, the adjuvant treatment for colon cancer costs $103,000 on pathway but $156,000 off pathway, and survival at 5 years is improved on-pathway (Hoverman JR, et al. J Oncol Pract. 2011;7[3 suppl]:52s-59s). For patients with non–small-cell lung cancer, a similar pattern has been found, with on-pathway treatment being $18,000 compared with $28,000 for off-pathway treatment, with a total savings of $9695 per patient on pathway, a 35% reduction in overall medical cost, and a 37% reduction in chemotherapy cost (Table 2). Linking electronic health record data on 1400 patients with lung cancer with data from a major payer, McKesson/US Oncology has drilled down to find the source of spending. “We found, on pathway, not only reductions in drug costs but reductions in emergency department visits and hospitalizations, because when pathways are followed, physicians are less likely to use futile therapies. They are not using fourth, fifth, and sixth lines, which is where you see an increased use of supportive medications and an increase in emergency department visits,” Dr Beveridge pointed out. “The cost-savings do not necessarily come with up-front therapy, but later on with the global overall care of the patient.” ■

www.ValueBasedCancerCare.com

2nd Conference

Personalized Medicine Empowers Treatment Decisions Molecular diagnostics have a role in pathways By Caroline Helwick Houston, TX—“Personalized medicine can improve healthcare delivery, improve healthcare outcomes, and help manage healthcare costs and spending,” said Jeffrey Scott, MD, Senior Vice President, General Manager for P4 Healthcare/Cardinal Health Specialty Solutions, at the Second Annual Conference of the Association for Value-Based Cancer Care. Personalized medicine is integral to all healthcare stakeholders (Figure 1), Dr Scott suggests. Patients need individualized treatment based on their

specific diseases. Physicians need more accurate clinical predictors, and payers need better allocation of resources. However, Dr Scott notes, there are challenges to the broad adoption of personalized medicine, including: • Physicians and payers need education in the use and interpretation of new diagnostic tests that individualize treatment planning • Reimbursement has traditionally been cost-based rather than valuebased

“Personalized medicine can improve healthcare delivery, improve healthcare outcomes, and help manage healthcare costs and spending.” —Jeffrey Scott, MD

Figure 1 Personalized Medicine Relevant to All Stakeholders Patients Patients Need individualized treatment based on their specific disease

Physicians Physicians

Need more accurate clinical predictors

Personalized Medicine

• New individualized diagnostics and therapeutics are based on new technologies and innovative test concepts • Legacy regulatory frameworks must evolve to accommodate new diagnostic and therapeutic technologies. The number of potential molecular targets in just 1 solid tumor alone,

Payers

Need better allocation of resources

Figure 2 Molecular Targets in Non–Small-Cell Lung Cancer ErbB3

PDGFR / c–Kit c–Met

AZD2171 Sunitinib Dasatinib Imatinib BEZ235

Dasatinib Aggresome

HDAC

LBH589

BCRAB1 GSK3 a/b Waste Proteins

Crizotinib PF–04217903

Cetuximab

AZD2171 Sunitinib Dasatinib Imatinib

mTOR

Gefitinib Erlotinib PF–0299804 BIBW 2992 PF–0299804 BIBW 2992 Crizotinib PPI/Dasatinib

ALK RAS

RAD001

Jak

B-RAF

p70 S6K K P

ERK1/2 P

R CELL CYCLE

Chemotherapeutic agents (cisplatin/paclitaxel docetaxel/docetaxel + cisplatin)

Tumor cell

VALUE-BASED CANCER CARE

p38MAPK

ERK1/2 S

G1 G2

HDAC

HIF-1

17-AAG

LBH589

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VEGFR1 Bevacizumab

P P

VEGFR2 P

VEGFR3

Src P

p70 S6K P

Bevacizumab

AZD2171 Sunitinib

STAT1,2,3,5,6

Proteosome

bFGR

AZD2171 Sunitinib Sorafenib AZD2171 ZD6474 Sunitinib Sorafenib

PDF184352

p38MAPK

Predominant in endothelia

Figitumumab

STAT

Sorafenib

IGF–1R

AG1024/ PP1 SU5402

MEK

SUBSTRATE

Bortezomib

Src

P13K AKT

EGFR/HER1 HER2

AG490 ASA404

STAT1,2,3,5,6

VEGFs, bFGF

Blood vessel Bevacizumab Bevacizumab

bFGFR

VEGFR1

Endothelial cell

SU5402

AZD2171 sorafenib sunitinib

VEGFR1

VEGFR3

AZD2171 AZD2171 ZD6474 sunitinib sorafenib sunitinib

such as non–small-cell lung cancer (Figure 2), is overwhelming. If drugs in development improve outcomes, this is good news for the patient, but it adds to confusion for clinicians and payers. “Nevertheless, targeted therapy allows me to better understand how to treat a specific patient,” Dr Scott said. Accuracy and clinical relevance of genomic assays must be assured, Dr Scott emphasized. Ideally, this includes strong analytical performance (quantification of analyte is reliable and reproducible), clinical validity (test relates to the clinical outcome of interest), clinical utility (information contributes to and improves on current management), and economic value (cost-savings or cost-effectiveness can be assessed). These measures are interrelated. Analytic performance must be evaluated in the context of clinical use, and clinical validity must be assessed in the context of analytic performance, he noted. Role of Molecular Diagnostics in Evidence-Based Pathways Molecular diagnostics has a place in evidence-based pathways, because they can optimize patient care and can create value, Dr Scott said. Molecular diagnostic tests contribute to achieving the lowest total or “appropriate” costs of care, to optimization of therapeutic spend, and to providing a coordinated approach to diagnostics. Patients only receive the drugs from which they can benefit, and the lowest cost is achieved where there is no efficacy differential. The coordinated approach allows for more precise stratification to pathways, he said. Dr Scott suggested that even when molecular diagnostic tests are expensive up front, if test results drive more appropriate treatment, then cost becomes less important. Finally, when treatment decisions are based on biology and evidence relevant to the individual patient, disease prognosis and prediction of treatment benefit are improved and therefore outcomes are optimized, he concluded. “It is likely that within the next decade molecular diagnostics and therapeutics will play a role in the diagnosis and treatment of almost all cancers,” Dr Scott predicted, “and we will enter into a new realm of cancer prevention.” ■

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

One focus: discovering and delivering breakthrough medicines to combat cancer. Millennium: The Takeda Oncology Company is developing an extensive pipeline — among the top in oncology worldwide — with more than 17 compounds in development for a broad range of solid and hematological cancers. Our pipeline — rich in novel compounds — includes multiple candidates that target seven disease pathways: protein homeostasis, anti-angiogenesis, growth-signaling inhibition, cell-cycle inhibition, apoptosis, immunomodulators and hormone regulation. We are dedicated to a strong partnership with the oncology community. Together we can make a dramatic impact on cancer therapeutics over the next decade.

2nd Conference

CareFirst Oncology Management Program Aims to Manage the “Entire Oncology Patient” Physicians share in cost-savings By Caroline Helwick Houston, TX—The Oncology Management Program at CareFirst Blue Cross Blue Shield (BCBS) continues to evolve, producing nearly 10% in cost-savings over prepathways practice, and ensuring that patients get more appropriate care, said Winston Wong, PharmD, Associate Vice President of Pharmacy Management at CareFirst BCBS, who described the program at the Second Annual Conference of the Association for Value-Based Cancer Care. “With over 400 novel drugs in the oncology pipeline, most of which are expensive biologic/biotech formulations, the ability for payers to control oncology costs will become even more difficult,” Dr Wong said. CareFirst Oncology Management Program CareFirst developed its Oncology Management Program in 2008. The program is managed by P4 Healthcare and is based on compliance with pathways for breast, lung, colon, and prostate cancers; hematologic malignancies; and supportive care. Compliant parties receive the standard fee schedule plus a differential; noncompliant parties receive only the standard fee schedule. “We call it a ‘true P4’ program—pay for performance or pay for quality— because there is no detriment to a

Figure

physician or practice that does not participate; they simply get reimbursed at the standard fee,” Dr Wong said. “If practices participate (80% pathway compliance is expected), they are reimbursed at a higher rate. So in essence, we are taking some of the savings we projected and giving them back to the physician practices.” Over the first 2 years, net savings reached 9%, primarily through the reduced utilization of branded antineoplastics in breast, lung, and colon cancers (Figure). Two years of savings totaled more than $17 million, of which more than $12 million was in drug costs, nearly $4 million was in service costs and more than $1 million was in supportive care costs. The pathways program encourages the use of generics via a modified generic fee schedule that inflates reimbursement to average sales price plus 300%, Dr Wong said. “What we are trying to do is encourage the use of generics, trying to make up for some of the margin lost on the brand, but still have an overall lower cost than for the branded product.” The company figured that $2.3 million was saved by eliminating prepathways regimens. Of interest, 60% of the savings in antineoplastic spend are minimizing the use of bevacizumab-containing combinations.

“With over 400 novel drugs in the oncology pipeline, most of which are expensive biologic/biotech formulations, the ability for payers to control oncology costs will become even more difficult.” —Winston Wong, PharmD

The pathways program also has reduced variability by 10%, and this accounts for approximately 4% of the total cost-savings. In addition, there has been an absolute 3% reduction in the percentage of patients who visit the emergency department during a given line of therapy.

Brand Utilization

A decrease in brand treatment has been demonstrated in breast, lung, and colon cancers since the initiation of the pathways program Brand-based regimens have decreased since program inception in total lines of treatment

Percent of brand drug use in total lines of treatment

Brand 76

Total lines of treatment, %

Total lines of treatment, N

100 90 80 70 60

73% 67%

71%

84% 77% 63%

61%

54%

50 40 30 20 10 0

Baseline

83% 79% 72%

80%

First line

Second line

Prepathways

Third line Year 1

Fourth line+ Year 2

This analysis used patient line of therapy regimens during each period. “Prepathways” contains the 12 months before July 2009, “Year 1” contains the 12 months ending June 2010, and “Year 2” contains the 12 months ending July 2011. Limited to chemotherapy for breast, colon, and lung cancers in “after implementation” period. Data include all participating sites as of Year 2, regardless of site start date. Data do not include Medicare members.

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Second-Generation Program CareFirst began taking the next step in April 2011, implementing a comprehensive second-generation program that addresses the “entire oncology patient,” Dr Wong said, in the following manner: • Including treatment pathways, representing a balance of best treatment practices and cost-efficiency • Incorporating the management of nonmedication services, such as laboratory studies, radiology, and radiation oncology • Incorporating end-of-life and hospice services • Removing the potential influence of drug reimbursement by reimbursing for professional services only: treating physicians are reimbursed for cognitive services and a flat infusion fee is given for infusions. “We are taking the margin out of the drug and putting the margins into an inflated E/M [evaluation and management] code,” Dr Wong said. This minimizes the incentive to give chemotherapy because of drug margins. “And we are encouraging the physician to talk to the patient,” he added. “If we are paying the physician’s practice through the E/M codes, there is the possibility that they may use an oral drug. We are allowing the physician to truly make a clear and clean decision,” he emphasized. In general, as the “savings pool distribution” shifts from the current model to the proposed model, drug margins will be nominal (enough to cover processing, handling, and storage of drugs) and the bulk of the reimbursement will be for professional services. The second-generation Oncology Management Program will also include some of the features of their primary-care patient-centered medical home, such as ensuring patient followup within 24 to 48 hours of chemotherapy infusion and taking measures to keep patients out of the hospital. Onsite audits of charts will also occur, to establish that recommendations such as hospice referrals are being followed. Practices will receive feedback, with physicians compared with their practices and practices compared with the program. In addition, quality measures, such as the use of hospice care and administration of chemotherapy within 2 weeks of mortality, will be reviewed. ■

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Best Practices

Regional Cancer Care Associates: Consolidating Small... Value-Based Cancer Care (VBCC) asked Dr Pecora to describe how oncologists can survive and implement advances in cancer treatment through a new business model that is focused on patient outcomes, stakeholder viability, and value-based care. VBCC: What forces motivated the consolidation that RCCA provides, and what are the clinical and economic components contributing to the success of RCCA? Andrew Pecora, MD, FACP, CPE: We use a lot of buzz words. But at the end of the day, what do patients with cancer want? They want to live. They don’t want to die. They want to be offered the best possible therapy; cancer, in addition to causing much fear, is very inconvenient. Patients need convenience. Patients require access to care. That’s the first layer of developing a product. Let’s say that cancer care was a product that we wanted to develop. We know there is a market for it, although no one has ever seen it before, and here is what it needs to do. That was the approach advocated by the group of doctors who formed RCCA. When we looked at high-quality, cost-efficient cancer care, we believed that no one but us should be the ones developing it. This is what we were all trained to do, and what we have been doing for 30 or 40 years. Many of us are professors of medicine. We are well regarded in our opinions. We write book chapters, papers, and so on. Yet, everyone else was saying, “This is how we should do it, and this is why.” Given the power of economics, the power of scale, and the power of controlling the dollar, it just did not seem like there was any sensible way for the people who actually delivered the care to do it, other than coming together with the understanding that there needs to be a new product offering. Value-based cancer care cannot mean one thing to a payer, something else to a doctor, and a third thing to a patient. It has to mean the same thing to everybody. And we are going to drive that by having an entity that is of substantive size and scale, which will get attention in the marketplace. Then, if you have a good product, you need to be able to deliver on that product. We created RCCA based on the idea that like-minded physicians could come together in one entity. We are one practice. We are not a confederacy

If you take all of those dollars and can change the system even a little bit, and move the needle a little bit, there will be lots of money or resources available, so that you do not have to say to a person, “This drug can improve your survival by 4 months, but we cannot give it to you.” —Andrew Pecora, MD, FACP, CPE

of practices, and there is not a practice management model with everyone keeping their own entity. As one entity, we have assumed the responsibility of delivering what we consider to be a high-quality, cost-efficient product, which is cancer care for each type of cancer. VBCC: No field of medicine is more innovative than oncology. People have always been donating for cancer research. It has been driven into the American culture that overcoming cancer and doing research for its cure is an enormous priority. Are we now getting our wish? Dr Pecora: Yes, we are getting our wish, but ironically, we are being told that we cannot afford it. And then we are being told, “Don’t do it,” or we are asked, “Why are you keeping these people alive so long?” and, “Is it really worth it to give them this medication that only adds 4 months to their survival?” If you dissect these arguments to their natural conclusions, it would make for great comedy, or maybe tragedy, depending on your perspective. The National Cancer Act of 1972 set in motion, globally, a consequence that has transformed biology. Many

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of the discoveries in molecular biology come out of understanding cancer and its many positive consequences, and all of the wonderful new drugs. I can now offer patients with metastatic melanoma a drug that extends survival, but I have payers saying, “Yes, but it is only for 1 month,” and asking, “Is it really worth it?” The ultimate conflict for a physician is to go into a patient’s room. Do I wear my “I have to do what is good for society” hat and make sure that we are competitive in the global marketplace as a business and have proper healthcare margins? Do I wear my “doctor hat” and say, “You really want this drug, because it may extend your life,” or do I wear my “ethicist hat” and ask, “Did I discuss the value of that next 4 months enough with this person? Should I help the patient decide that hospice may be the better way to go?” I am going to have to do all of this in 10 minutes and 32 seconds, because I am reimbursed approximately $40 to do this, and I have to see 30 people a day just to keep my office open. This is the embodiment of what is going into a doctor ’s decision process. I do not mean to be glib, but that is the truth. VBCC: We all have to come to grips with the concept of value as a balance of cost and quality and understand how to implement it. If you become a cost zealot you are going to do so by reducing quality, access, or both. Conversely, if you come up with treatments that are profoundly helpful, but they consume the entire Gross National Product, you have not really done anyone a favor. Does there have to be some common sense on the part of researchers? Dr Pecora: Yes, but who adjudicates that in real time? You cannot adjudicate that outside of the bedside. Value is not for a group discussion. It is not for a committee. That is why they call it the “death panel” in the United States and NICE (the National Institute for Clinical Excellence) in Europe. NICE involves a small group of people deciding who lives, who dies, and how long you live or die. RCCA intends to show that you can save millions of dollars without adversely affecting quality of care, but you can only save millions of dollars if you are willing to recognize that millions of dollars are being spent around healthcare, enriching people around healthcare. Millions of dollars are being spent legislating

Continued from cover

healthcare. There is no business like it in America. If you take all of those dollars and can change the system even a little bit, and move the needle a little bit, there will be lots of money or resources available, so that you do not have to say to a person, “This drug can improve your survival by 4 months, but we cannot give it to you.” What RCCA and others like it need to do is assume our responsibility. We are the experts in cancer care delivery, the federal government is not. The Centers for Medicare & Medicaid Services is not; they do not provide cancer care. Blue Cross does not provide cancer care; they pay for it. How do we do that? Doctors were never trained to think this way, and they do not have the tools. Even if you have 2 or 3 doctors who do everything perfect, it does not move the needle. But now you put together a network of doctors like we have, who represent approximately 40% of all cancer in New Jersey, and if we start moving the needle, (1) it will be measurable, and (2) it will have an effect. We realize that, and that is why we are here—to assume the responsibility of providing high-quality, transparent cancer care. We have some ideas about how to do it, because this is what we do. VBCC: You have pointed out that the greatest dangers to the costs of care and oncology are the inefficiencies that come from legislation by people who really do not understand oncology, which is what you refer to as the cost of legislation in trying to systematize something that is inherently a personalized medicine process. What are the main problems with the inefficient financial aspects that plague oncology? Dr Pecora: In general terms, one is site of service. We have to move sites of service from expensive sites to less-expensive ones. Hospitals do not have to be the most expensive site of service, but they can be. You do not need to come to an office and spend time, money, and gas, and generate an office charge when something can be done at home. How do you do that at scale? How do you do it in a way that is not averse to the people who are actually doing it, so they are rewarded for doing it? That is one big area. The second large area is, do what is needed, but no more and no less. Continued on page 27

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Regional Cancer Care Associates: Consolidating Small... There are many examples where tests that are critical to help make a decision—do you go in direction A or B?—are not done. You either do not know, or you are getting too many tests. You are seeing all of the recent news on that. How do you systematize that in a way that is businessefficient? That is another. The third area is how to deliver personalized cancer care, down to the level of genomics, at scale in a business-efficient way. You can waste a lot of time and money giving a drug therapy that has no hope of working, if you only knew a certain gene was not in the right direction. How do you do that? That is what RCCA intends to do. We are already at scale, given our size and volume, and we know how we can do that. We believe we are going to be able to move the needle and demonstrate higher quality and more cost efficiency, and do it transparently. VBCC: Can you provide a brief summary of your protocol, your structure that provides for these services and output? Dr Pecora: We are all 1 business, 1 provider number, 1 corporation, 1 entity. It is not a management service company. That is unique. VBCC: In the past, what was preventing medical associations, such as the American Society of Clinical Oncology (ASCO), from solving the problem? Why did it require physicians in the trenches to realize and act on this? Dr Pecora: There are plenty of people who know what needs to be done, but there are fewer people who can actually execute it. We at RCCA can execute it. That is the difference. VBCC: There are a lot of guidelines in cancer care. How does your organizational process benefit from them? How much latitude do you have in determining which tests to perform? How does RCCA’s approach impact the process of care? Dr Pecora: Going back to the concept of a product, there are plenty of circumstances in cancer care where it is straightforward what you want the product to be. That is what we need to be able to do well, and we have to be able to demonstrate that we are doing a good job. It is not just the drugs we choose to give or the procedures, but it is also how we follow up with the person. You will see a lot more of that from RCCA in short order.

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The other side of it, however, is that sometimes you don’t know what you are trying to make, because you are not quite sure what the issues are. That is where the other arm of RCCA, being a major engine of discovery, is going to be important. We plan on working with the evolving genomic-based personalized medicine industry, so that we can look at a tumor in a way that we could not before, and make a specific decision to give or not to give a treatment, on an individual-patient basis, based on what the DNA of the tumor is telling you to do. That is not science fiction anymore, and it is coming pretty rapid. We need to be able to integrate that at scale—to offer patients high-quality, cost-efficient care in their local community so that access is not an issue, and to make certain that doctors are following preagreed guidelines. The consensus was there from the start. They have agreed on them, and they have said, “We’ve all agreed, and we have a methodology for how we do that. We all agree this is the right way to go, and if some new information comes in, we change what we do then, and we do it in real time.” But, also, they have formed this consensus to be part of this vanguard of better characterization of patients so that they may receive optimum care. What matters is that they can do that at a corporate scale level of RCCA. As I said before, if I do this in my office, and I am a 3-man practice, even if I were the best in the world at it, I would not be moving the needle at all. But if I do this at the scale of RCCA, I am going to move the needle and be rewarded for it, and that is like a feedback cycle. I do something, I get rewarded for doing something that brings value to the system, and I want to bring more value to the system. This is no different from any other entity: you do something, you get rewarded for it, you want to do more of it. VBCC: Are you able to leverage the advantages of biologics and of the personalized care that is out there? Dr Pecora: Yes, absolutely, through new efficiencies and removing the distractions. It is a huge distraction if you are an oncologist walking into that hypothetical room and one third of your brain is supposed to be an economist, one third is supposed to be an ethicist, and one third is supposed to be a brilliant biologist/clinician. You have to adjudicate all of these things we talked about, and then you step outside and

you realize you need a computed axial tomography scan for someone who just came in and is coughing up blood. You have to spend 20 minutes on the phone getting approval from a secretary in another state, because the system is not keying right. Now you are 30 minutes behind schedule, and the next 2 patients who were waiting for you are upset that you are behind. Your patient satisfaction scores are now dropping, and by the way, you did not get reimbursed from Medicare, and this is wrong, and that is wrong.

We plan on working with the evolving genomic-based personalized medicine industry, so that we can look at a tumor in a way that we could not before, and make a specific decision to give or not to give a treatment. —Andrew Pecora, MD, FACP, CPE

You are doing all of this by yourself, and now you are done with your day; it is 10:00 at night, you have not eaten lunch, and you are supposed to decide, “OK, what am I going to do that is good for society?” Instead of the threat of oncologist monopolies, how about taking as much off the plate as possible from these physicians so they are not worrying about negotiating their business contracts and their drug purchasing contracts, and they are not all one at a time dealing with payers, but rather all at once dealing with payers? You are setting up paradigms whereby they can be efficient clinical and business people bringing value to the system. VBCC: Do you view healthcare as a fundamentally flawed financial system that has lost its ability to keep the practicing oncologist financially viable because of an erratic and unsatisfactory revenue stream? Dr Pecora: That’s the subtext, but that is not what is driving this for me. What is driving this for me is the fear that we spent 30 years finally figuring out how to treat people effectively, and we are not going to be able to do it because the system implodes on itself.

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VBCC: Where are you seeing support for what you are doing, do you see it spreading, and what are the trends? Who is behind this, who is uncertain about it, and who is opposed to it, if anyone? Dr Pecora: I do not know that anyone is opposed to our efforts, because I am not sure these are fully appreciated for what they are. We are receiving a lot of support from hospitals and from physician groups that are very enamored with the idea of what we have done at RCCA. Even the payers have been so far supportive of it, because they believe this will provide them a conduit to achieve what they want, which is efficient care without wasteful spending. At least, that is what they have told me; so far it has been all good. VBCC: Purchasers, particularly large employers, are often leading the way toward wellness and the aggressive pursuit of innovation. Do they see the advantage of being proactive instead of reactive about RCCA? Dr Pecora: Absolutely. Part of what we need to prevent patients from coming back is the interplay between having had cancer and going back to good health, or counseling family members of the patient with cancer as well, so they can, where it is avoidable, avoid it. We, as a profession, have to step up and assume the responsibility of maintaining quality while controlling the cost of care. If we do that successfully, we will be ultimately rewarded in the marketplace. That is why we are very enthusiastic about what we have done, and you are going to be hearing a whole lot more from us, and about us, as time goes on. VBCC: Is ASCO in support of this, or for that matter, is the government? Dr Pecora: There is no word yet from ASCO, but it is early. We only came together on January 1, 2012. But we have had very positive praises from the American Cancer Society, and we have had private positive praises from the payers and from the industry. VBCC: Do you expect this to be growing to other states? Dr Pecora: We named it “regional” for a reason. We do not intend on staying limited to 1 state. My hope is that we can show a path that makes sense to people and get people excited. ■

www.ValueBasedCancerCare.com

HITECH in Oncology

Integrating Digital Patient Engagement into Your Care Model By Gena Cook, Founder and Chief Executive Officer, Navigating Cancer (gena@navigatingcancer.com)

he Health Information Technology for Economic and Clinical Health (HITECH) Act has set aside $19 billion in incentives to encourage healthcare providers to adopt and meaningfully use electronic medical record (EMR) technology in an effort to provide more patient-centered care. This unprecedented investment in health information technology (HIT) will digitize the medical industry and connect patients to their providers electronically for the first time so they (and their families) can be more engaged in their own care. Once connected, providers and patients can communicate using new technology in novel and exciting ways.

Patient Engagement Patient engagement in its current form is fractured and disconnected from the healthcare team. Patients go online to research their condition after receiving a diagnosis; join online communities with similar patients to learn first-hand experiences; use care management tools, such as online calendars and health trackers, to manage their care; and must enter their medical history into an online personal health record if they want to have their own electronic copy. This requires patients to visit numerous sites and manage multiple accounts, it is not a user-friendly or an efficient experience, and the patients are not connected to their healthcare team. With the implementation of EMRs and patient portal technology, practices can offer their patients all of these services under their own clinic’s brand. Once connected, providers and patients can communicate important health information to improve quality of care. HIT, and specifically a patient portal, will be mandated to meet HITECH requirements, new medical home models, and American College of Surgeons Commission on Cancer standards. It will be instrumental in helping practices become more efficient while providing quality care, which are fundamental objectives of accountable care organizations (ACOs) and alternative payment models. Patient portals also offer providers the ability to engage patients in their care and to improve patient satisfaction. For example, providers can deliver physician-approved patient education from trusted experts, saving patients time and anxiety searching for it online and ensuring that they receive

the right information. This service can be automated once a diagnosis is entered in the EMR, so there is no additional workload for practice staff. One of the primary goals of HITECH is to engage patients and their families to improve care coordination. HITECH is split into 3 stages. Stage 1 includes specific rules that map directly to meeting that objective: • Give patients an electronic copy of their health information on request • Provide patients with clinical summaries for each office visit • Give patients timely electronic access to updated health information • Use EMR technology to provide patient-specific education resources. Stage 1 is only the start, where 2 objectives are required (“core” set) and 2 objectives are part of a “menu” set that practices must choose from to meet 5 of 10 measures. In stage 2, all patient engagement requirements move to the “core” set and must be met. In addition, the requirements for meeting the objectives increase, and additional measures regarding patient engagement will be added. Although they have already been released, the rules and measures for stage 2 will be finalized in June 2012. Using Technology to Engage Patients in their Care Technology can enable patients to access their personal health information and provide feedback to their healthcare team, but it is what patients and providers do with that information that matters and will ultimately impact outcomes. Providers can encourage patients to track their treatment side effects in an online health journal so they can be alerted when issues arise and make interventions to reduce patient visits to the emergency department. This is an important element of emerging payer pilot programs to reduce overall healthcare costs through ACO and medical home models. In addition, by connecting patients to their support network and to similar patients through social media tools, providers can offer psychosocial support to keep patients engaged in their care throughout their journey from diagnosis of cancer to survivorship. HIT can enable this to occur under the clinic’s brand and to be connected to the healthcare team, so patients associate these positive experiences and robust support with the practice.

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A third example of how HIT can engage patients in their care is using automatic electronic messages to encourage treatment adherence. A 2011 study revealed how electronic messages (SMS, audio/visual, and pagers) improved adherence to medications for patients with a chronic illness.1 Certified HIT will also give patients online, timely access to their personal health information, another meaningful use objective to engage patients in their care. A 2008 study by the Deloitte Center for Health Solutions revealed that 70% of patients want to have online access to their medical records.2 Giving patients the ability to easily review their records for inconsistencies or mistakes can prevent costly errors. The Challenges To achieve the patient engagement objectives outlined in the meaningful use rules, practices will need to implement certified EMR and patient portal technologies that connect providers to their patients so they can communicate with them as their health information is updated. This release of patient information will need to be reviewed and triggered by the clinic’s staff, which will require new routines to be adopted as part of the daily workflow. At the same time, new technology will replace inefficient processes, such as printing and mailing copies of medical records and duplicate data entry. Although the initial adoption of new technology will require some time to become part of a new routine, the time and resources saved will outweigh the initial effort. To be able to release patient information from the EMR via a patient portal will require that disparate internal systems be connected so patient information can flow from one system to the other. Not only will internal systems need to integrate with each other, but key clinical information must also be exchanged among providers during transfer of care, as well as with different systems that are external to your practice (both meaningful use objectives). To truly engage patients, providers will need to integrate their practice management EMR and patient portal technologies so that data can be shared with patients as they are updated. In addition, the patient user interface will need to be simple and intuitive so patients can easily log on to their secure profile to access personal information and personalized resources.

Engaged Patients = Improved Outcomes A 2012 Navigating Cancer survey revealed that 72% of patients with cancer were interested in using online tools and resources to help manage their care and recovery.3 Patients want to be more engaged in their care; 77% of patients were interested in reading cancer education materials from expert sources, and 74% of patients were interested in having access to their medical records securely online, which was consistent with survey findings from the Deloitte Center for Health Solutions.2 Surveys have also revealed that more engaged patients have better outcomes. In a 2011 study, patients suffering from depression who participated in online messaging through an EMR with their healthcare team had higher rates of treatment adherence (81% vs 61%, respectively), lower overall depression scores, and greater satisfaction with treatment (53% vs 33%, respectively) compared with patients without online care management support.4 By digitizing personal health information, technology will enable providers to communicate with patients in new and exciting ways to encourage more patient engagement. Although technology can enable this connection and make it easier and more efficient to share critical information, it is the influence of individuals that will ultimately encourage patients to become more engaged. This can come from a patient’s care team, support network, or other patients/survivors, but to be effective, they must all be connected. When patients are engaged, they complete the feedback loop by communicating with their healthcare team and supporters, which can be as simple as reading patient education materials or as involved as tracking side effects in an online health journal. Technology can help engage patients and providers to communicate the right information at the right time, which will lead to better quality care, improved patient satisfaction, and, ultimately, to better outcomes. References 1. Vervloet M, Linn AJ, van Weert JC, et al. The effectiveness of interventions using electronic reminders to improve adherence to chronic medication. J Am Med Inform Assoc. 2012 Apr 25. [Epub ahead of print]. 2. Deloitte Center for Health Solutions. 2008 Survey of Health Care Consumers Executive Summary. www.deloitte.com/assets/Dcom-United States/Local%20Assets/Documents/us_chs_ConsumerSurveyExecutive Summary_200208.pdf. Accessed June 4, 2012. 3. Navigating Cancer Blog. Patient Engagement Survey Results. February 27, 2012. www.navigatingcancer.com/blog/patient-engagement-surveyresults/. Accessed June 4, 2012. 4. Simon GE, Ralston JD, Savarino J, et al. Randomized trial of depression follow-up care by online messaging. J Gen Intern Med. 2011;26:698-704.

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Can Pathways Improve Quality of Care... ferent aspects of care, with the goal of driving down variability and improving quality.” Meeting these goals will inevitably impact cost. If pathways reduce the payer’s costs, can practices share in the savings? “There is clearly internal practice value from pathways,” Ms Lokay noted. Beyond the ideal of providing the highest-quality care for patients, more specific aims can be achieved. Pathways can: • Ensure that all physicians are educated on the increasing complexity of cancer care options • Lower bad debt risk (staying on the pathway reduces risk of payer denials) • Create practice efficiencies through uniformity of care (increased staff productivity, lower inventory holding costs) • Reduce medical errors (common platforms for care reduce errors) • Increase accrual to clinical trials. Overall cost-savings are realized through lower drug spending, fewer emergency department visits, fewer

at a glance ➤ If providers are willing to work with payers cooperatively, a safer, more profitable pathway can possibly be found ➤ Pathways can ensure that all physicians are educated on cancer care options, lower bad debt risk, create practice efficiencies, reduce medical errors, and increase accrual to clinical trials ➤ Cost-savings from pathways are realized through lower drug spending and reduced hospital services utilization ➤ The use of pathways is inevitable; payers are starting to contract with third-party vendors for cancer management services

Continued from cover

“When you think about pathways, there’s a tendency to just think about drugs, but we’re talking about addressing all of the different aspects of care, with the goal of driving down variability and improving quality.” —Kathleen G. Lokay

hospital stays, and the elimination of redundant imaging. Why Should you Save the Payer Money? “In a perfect world, once you’ve made these adjustments, the payers should step up and share the savings,” said Ms Lokay, but that is largely not yet the case, and is a deterrent to pathway introduction. The reasons for payer hesitance include wanting proof of savings (difficult to show with a de novo program), a failure to understand how pathways can be scaled, a failure to comprehend what comprehensive cancer care means, and, according to Ms Lokay, “a general sense that oncologists already make too much money anyway.” What about a negotiated gain-sharing? “This makes sense on the surface, but what are we going to measure? Total costs, just drugs?” Ms Lokay questioned. There is also the matter of what to measure against. “In oncology, costs continue to rise due to technology,” Ms Lokay pointed out. “So you could have costs go up 3% last year and have it look like you failed, when in reality everyone else’s costs shot up 13%.” Any gain-sharing agreement would have to include a benchmark to measure against that reflects the overall market over time. “Even if you can bring the payer to the contracting table, the challenges are enormous.” Do you include all

cancer types, or only the most common? Do you include only patients receiving active treatment? How long do you measure? How many patients/procedures do you need for statistical validity? Implementing and Integrating Pathways into Practice The implementation and integration of a pathway creates relationships and reputations. “I look at it as having offensive and defensive benefits,” Ms Lokay maintained. Collaborating with the payer may lead to the extension of current favorable reimbursement rates or the elimination of prior authorizations. By contrast, you may avoid impending rate cuts, new prior authorization programs, or action by the payer to shift drugs from your practice to a specialty pharmacy or infusion center. Reputations will also likely extend beyond the payer/provider universe. “As other providers are coming on board with medical homes, or ACOs [accountable care organizations],” said Ms Lokay, “suddenly they are going to start thinking about where their patients are going for cancer care.” Referral patterns that have existed for years are going to be challenged. “If you can demonstrate tangibly what you do when patients come to your program, referrals will come your way.” Perhaps the best argument for the

use of pathways is inevitability. “Payers are starting to move forward with contracting with third-party vendors for cancer management services,” Ms Lokay reported. So, changes in workflow are coming; it is just a matter of whether changes are proposed from within or imposed from without. The Big Picture “A lot of times when we think about clinical pathways, we think about the diagnosis and treatment of cancer,” said Cheryl Corizzo, Cancer Center Director, St Tammany Parish Hospital, Covington, LA, commenting on Ms Lokay’s presentation. “But this got me thinking more about the bigger picture,” for example, an emphasis on research. “Why do we need to provide better access to clinical trials? It really fits in with being able to offer comprehensive quality care,” said Ms Corizzo. “Why is survivorship so important? Obviously, we have nearly 14 million survivors in the country.” Ms Corizzo noted that pathways are not exactly new, but that in her region of the country, the uptake of such broad-ranging initiatives has been slow. “I do think that private-physician oncology practices have worked

“Why is survivorship so important? Obviously, we have nearly 14 million survivors in the country.” —Cheryl Corizzo with pathways as a method to be able to reduce variation within their own practices,” Ms Corizzo said, adding that now may be the time for her center to create a pathway of its own. “To me, this brought together the whole realm of looking at clinical pathways, relative to the new Commission on Cancer standards, and how to look at and meet those new standards.” ■

More Revenue, Less Waste: Tips for Optimizing Financial Performance By Neil Canavan Baltimore, MD—Belt tightening is the order of the day. To succeed, you are going to need a stern resolve, a sturdy belt, and a steady pull—not just by the bean counters in the back office, but by everyone: administrators, doctors, and mid-level employees alike.

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At the 2012 Association of Community Cancer Centers meeting, several presenters offered practical tips to help in the new climate of healthcare reform. “As economic pressures mount, physicians have migrated to the safer harbors of integrated delivery sys-

tems,” said Malita Scott, MHA, Senior Manager at ECG Management Consultants, Arlington, VA. “Our focus today is on hospitals that have, over recent years, gotten into the business of employing physicians.” To make this new financial relationship

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work, these institutions need to develop different skill sets to ensure that every employee is on board and actively supporting the effort to minimize operating losses and maximize delivery revenue. Continued on page 30

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ACCC Annual Meeting

More Revenue, Less Waste: Tips for Optimizing... Revenue Opportunities Data capture. “What’s important here is to understand that it’s garbage in, garbage out,” Ms Scott said, further explaining that to support claims on the back end when it’s time for reimbursement, accurate data have to be captured on the front end at the time of service delivery. “And this is all about communication. We need real-time communication with our physicians so that, for instance, they understand the changes that necessarily must be made to a treatment plan in the event that a payer has certain requirements,” she added. Communication networks within the organization must be streamlined so that physicians are able to touch base in real time with the business office, the financial counselors, and even the person greeting the patient at check in. Once systems and individuals are talking, it is likely that organizational deficits become obvious. “There is a lot of low-hanging fruit available in the revenue cycle,” said Ms Scott, “and again, much of it is a matter of communication.” Consider the 8 critical components of the front end (the clinic) and the back end (the business office) of the revenue cycle, as identified by Ms Scott, and how each can be optimized. On the front end, these components include: • Appointment screening (reduce noshows with patient reminders) • Patient sign-in (get complete insurance information) • Time of service collections (get copays or self pays or firmly establish financial agreements) • Coding charge captures (physician hires need to pitch). On the back end, the components include: • Charge entry (adjust capitated charges) • Claims submissions (submit primary and secondary claims) • Payment posting (deposit the money today) • Account follow-up (follow up on denials and resubmit). Productivity. “We’re not just looking at work RVUs [relative value units] here,” Ms Scott noted. “We’re looking in total at the practice.” These analyses (performed by a consultant, such as ECG Management) help to inform practices about operational inefficiencies, as well as to give insight to potential discussions about a given clinical care model and how that is being carried out (or not) within the organization. “Most hospital-employed oncology groups have developed incentive-

“Most hospital-employed oncology groups have developed incentive-driven compensation plans with a focus on productivity. Often, however, these groups do not have robust tools for evaluating group and individual performance.” —Malita Scott, MHA driven compensation plans with a focus on productivity. Often, however, these groups do not have robust tools for evaluating group and individual performance,” Ms Scott pointed out. She identified the components of physician productivity as work rate, work hours, visit/procedure combination, and coding. Key productivity indicators that are captured from this include gross charges, net collections, RVUs, and overall visits. As for coding practices, evaluation and management coding analysis is advised. Having oncologists evaluate Current Procedural Terminology codes helps to identify the variations in coding and documentation patterns that ultimately drive inconsistencies in productivity. “We tend to downcode because it’s safe,” Ms Scott acknowledged, but with the advent of electronic health records, coding practices are more easily revealed. “It allows you to then measure a physician’s performance against [his or her] peers.” Commercial contracts. “You want to make sure that you’re at the table, [and] that there is a representative from the practice that understands the implications of the contract on the practice,” Ms Scott suggested. Commercial contracts are key levers for improving the bottom line. Negotiating small changes in financial and administrative terms can translate into significant margin gains. “This can be especially true for medical oncology practices,” she added. Costs Overhead expenses. “In general, when you think about expenses, there are 3 key considerations to take into account,” Ms Scott explained. First, there is the rate of consumption— how much of a given expense is being consumed; one example is the dollar amount of drugs purchased. Second, there is the type of expense, such as with the staff. Consider what type of support the physician is utilizing, be

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it consultative, mid-level, or other. “Each job title has different financial implications for the practice,” Ms Scott said. The third consideration is the rate of compensation. “Even within the same job title, like nurses, there can be a fairly wide range of salary,” she pointed out. In this regard, Scott strongly recommends “right-sizing,” meaning you do not want to find yourself paying a PhD to empty bedpans; compensate according to the duty performed. Optimize individual training to the task at hand. Part-time providers. “We’re seeing a significant uptick in this,” said Ms Scott. “So, it’s increasingly important that your organization has clearly defined policies addressing this issue.” For example, if you have a physician working at a full-time equivalent (FTE) of 0.75, it may be reasonable to prorate that individual’s benefits. Drug inventory. Closely tracking drug inventory in real time is critical. “Maximizing rebates and minimizing drug expenses are vital for sustained performance,” Ms Scott maintained. For many oncology practices, pharmaceutical supplies will account for 80% of the clinic’s expenses.

“This needs to be a component of physician contracts—making sure there is an adherence to clinical pathways.” —Brendan M. Fitzpatrick, MBA 340B Drug Pricing Program. Hospitals can increase their participation in 340B through partnerships with community oncologists. These arrangements generally yield incremental value to the hospital and physicians. “We’re seeing between 20% and 40% cost-savings for your pharmaceuticals with this program,” Ms Scott pointed out. “You might be looking at up to $500,000 in savings per physician FTE, assuming reasonable levels of production.” Infrastructure This is about having everyone on the same page. “It’s really important to understand that once you put these procedures in place, you have to have standardization across your practice sites. The staff needs to know what SOPs [standard operating procedures] are and have them documented and disseminated,” Ms Scott said. Performance monitoring and reporting. Implement reporting mechanisms

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that communicate practice performance to your physicians. “A dashboard of key metrics should be created to monitor the performance of employed oncology practices and to get the information out there,” Ms Scott advised. Let everybody know that the work stream is profitably flowing or that it’s been log-jammed. Efforts in this regard usually require information technology systems compatibility across the board. “Beyond that, the key is to get physicians engaged and provide them with a practice overview that clearly illustrates where problems lie,” she concluded. Physician compensation. “Oncology care really starts with the physician,” said Brendan M. Fitzpatrick, MBA, Executive Director of the Alamance Regional Cancer Center, Burlington, NC. “You have to have the physicians engaged. And to get them engaged, quite honestly, you must make sure that they are compensated appropriately. You want to make sure they know they are highly valued and that they are the pinnacle of the program.” So, how much should a pinnacle be paid? “Fair market value is actually very well established and publicized at this point, so it’s not too much of a wild card. I think we’ve achieved a nice correlation between production, our reimbursement, and their compensation,” Mr Fitzpatrick said. A Work in Progress Going forward, Mr Fitzpatrick would like to incorporate quality measures. “This needs to be a component of physician contracts—making sure there is an adherence to clinical pathways,” he said. “US Oncology was really ahead of the curve on this, but it’s not being mainstreamed in community cancer centers just yet.” Another adjustment to be made is to get his institution to grab more of the dollars being left on the table. “It has to do with drug cost-savings. I think in the past, programs have allowed physicians to order whatever they want, whenever they so choose,” Mr Fitzpatrick remarked. “But we need to be much more structured in our purchases, so that physicians know what the program is going to be reimbursed. Many of our drugs are under water, and, quite honestly, I don’t think administrators have done a great job articulating which drugs and which chemotherapy regimens are under water. We need to provide more information so that our physicians can make good value decisions for their patients.” ■

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“Managing patients with myeloma means staying current.”

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

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Radiation Breakdown: All That Glitters Is Not Gold By Neil Canavan Baltimore, MD—Radiation technologies rank as some of the most interesting new developments. However, the advantages of these new technologies in terms of patient outcomes are sometimes elusive, and the costs of acquiring radiologic facilities—and the revenue generated by them—are increasingly coming into question. “There’s a disconnect about how costs are going in one direction but reimbursement is going in another, and no one is really sure what to do about it,” said Andre Konski, MD, MBA, FACR, Professor and Chair, Department of Radiation Oncology, Wayne State University School of Medicine, Detroit, MI, at the 2012 Association of Community Cancer Centers meeting. The technologies in question include: • Intensity-modulated radiation therapy (IMRT). This technology allows for the sparing of critical anatomical structures, while at the same time facilitating the delivery of increased doses of radiation to the tumor • Image-guided radiation therapy. This allows for the real-time targeting of radioactive material (“seeds”) directly to the tumor site • Stereotactic body radiotherapy (SBRT). The use of SBRT allows for the compression of radiation treatments from as many as 6 weeks of therapy to 3 to 4 days of therapy. This technology can accurately deliver very high biologic doses, and has demonstrated high activity in some tumor types, particularly lung cancer • Proton therapy. This particle therapy using protons allows for targeting a confined dose within a given tumor volume. It is often used to treat prostate cancer and is considered a game changer for certain types of pediatric cancers. Is It Cost-Effective? All of these technologies are expensive (proton therapy facilities exceedingly so), but as expenses rise for facilities and machines, reimbursements for the related procedures decline. “As we are moving toward more hypofractionated regimens,” said Dr Konski, “we have to ask ourselves if it is really cost-effective.”

That the new technologies are more convenient for the patient is without question, having greatly reduced treatment times. However, are these new treatment modalities more effective?

“There’s a disconnect about how costs are going in one direction but reimbursement is going in another, and no one is really sure what to do about it.” —Andre Konski, MD, MBA, FACR

“Some research presented recently suggests that fewer fractions of radiation might be better for prostate cancer,” Dr Konski noted. “We’re talking about more than 30 fractions to potentially less than 5.” But the data may not necessarily translate to other tumor types, or, at the end of the day, make good business sense. Consider a recent analysis of the cost-effectiveness of modern radiotherapy techniques in patients with locally advanced pancreatic cancer (Cancer. 2012;118:1119-1129). “They did a modeling exercise comparing historical data for the use of single-fraction SBRT for pancreatic cancer to a study performed by ECOG [Eastern Cooperative Oncology Group study 4201].” In that study, the chemotherapy gemcitabine was compared with gemcitabine plus radiation versus gemcitabine alone, “and what they found was that there was no statistical difference in disease-free or overall survival at 36 months with the addition of SBRT,” Dr Konski said. The analysis then considered cost, which was calculated using the 2009 Medicare fee schedule. Results showed that the expected mean costs generated by the model were gemcitabine alone, $42,900; gemcitabine/ SBRT, $56,700; gemcitabine/radiotherapy, $59,900; and gemcitabine/IMRT, $69,500 (the current standard of care in many cancer centers). Quality-adjusted life-years (QALYs),

Correction

In the February 2012 issue, in the article titled, “Significant Cost of Treating Myeloproliferative Neoplasms” (page 24), the column headings in the Table could have been misleading. The correct headings in this chart convey the correct intention. We regret any potential errors.

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a measure increasingly used in costbenefit analysis, were highest for gemcitabine/SBRT at 0.77; however, this was not greatly improved from the other 2 modalities that rated an average QALY of 0.72. “So, over the lifetime of the patient, if you look at gemcitabine/IMRT versus gemcitabine/SBRT, that’s a $12,000 difference in revenue being generated by the cancer center,” observed Dr Konski. “That’s great for the insurance companies—they save money—but for every patient you treat with SBRT, your cancer center has just registered $12,000 in potential lost revenue.” And that is just one tumor type— pancreatic. It is likely that if you are using SBRT at all, it will be a part of the prescribed therapy for breast cancer and prostate cancer as well. How will that impact your cancer center? “We’ve shown that revenue is going to decline because of this technology,” Dr Konski said, but along with this, treatment time has been compressed. So, perhaps you are saving money on staffing? Actually, no. “You’re going to need the same dosimetrist to design the treatment plan,” Dr Konski pointed out. Short course, long course, IMRT, or SBRT—it does not matter. “And you are going to need the same physicist, because there is the same need for quality assurance. These are highly technical procedures that must be delivered correctly, and physicists do not come cheap.” That brings the question, is the reality of needing fewer therapists for fewer procedures a wash in terms of overall cost-savings? Consider the pressure that will come from payers when they realize how much money they can save. Medicare reimbursement for a full course of 40 treatments with IMRT for prostate cancer (technical component only) is $17,888; the reimbursement rate for 26 treatments of hypofractionated radiotherapy for prostate cancer is $11,627; and the rate for 5 courses of SBRT in the same disease setting is $12,992. Therefore, the saving to Medicare is a minimum of $4896 or a maximum of $6261, depending on which advanced modality you compare with standard IMRT.

at a glance ➤ Radiation treatments include IMRT, image-guided radiation therapy, SBRT, and proton therapy ➤Radiation technology is expensive, and reimbursements are decreasing for these procedures ➤Although insurance companies can benefit from the use of radiation therapies, cancer centers can experience loss of revenue from them ➤Those who have invested in novel radiation therapies should notify patients of the associated shorter treatment times; others are cautioned against adding new radiation technologies to their arsenal Implications for Cancer Centers And the reward for the provider in the middle of all this? Over a period of 1 year, “The potential loss of revenue to the cancer center is $325,580 for hypofractionated [radiotherapy] and $254,594 for SBRT [compared with IMRT] if 1 patient a week is treated with the alternative fractionation schedule,” Dr Konski said. Are cancer centers going to be able to make up that lost revenue? Not if everyone is doing it. “You’re not going to make it back on volume. These things are easy to set up (except for proton facilities). In some states, there is a Cyberknife on every corner,” Dr Konski stated. With that said, he urges those who have already made the investment in the technology to be sure to advertise the advantage of abbreviated treatment times to the patient. In almost any market, there are still centers where lengthy IMRT courses are the norm. Beyond that, however, Dr Konski urges cancer centers to think twice about buying into any additional new radiation technologies that can prove too costly. ■

Correct headings should be

Patients with MF only (no other cancer)

Matched controls (noncancer, non-MPN)

Patients with PV only (no other cancer)

Control group with PV

Patients with ET (on other cancer)

Matched controls (noncancer, non-MPN)

Headings provided in the article

Patients with cancer and MF

Control group with MF

Patients with cancer and PV

Control group with PV

Patients with cancer and ET

Control group with ET

JUNE 2012

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In The Literature Phased Ipilimumab... Continued from page 8

key secondary end points. A total of 204 patients were randomized to the concurrent, phased, or control regimens. Phased ipilimumab significantly improved immune-related PFS compared with the control regimen (P = .05). Phased ipilimumab also improved PFS (P = .02). The differences in favor of phased ipilimumab were greater in patients with squamous histology than in those with nonsquamous histology. The concurrent, phased, and control regimens were associated with median OS durations of 9.7, 12.2, and 8.3 months, respectively. Grades 3 and 4 immune-related adverse event rates were 20%, 15%, and 6% for the concurrent, phased, and control regimens, respectively.

Navitoclax Shows Limited Clinical Activity in SCLC, but Findings Point to Potential New Biomarkers When oral navitoclax (ABT-263) was evaluated in an open-label, phase 2 study in adult patients with recurrent and progressive small-cell lung cancer (SCLC) who had received at least 1 prior therapy, this Bcl-2 inhibitor showed only limited activity (Rudin CM, et al. Clin Cancer Res. 2012;18;1-7). Nevertheless, this study provided evidence that selected biomarkers may have prognostic value in clinical settings; for example, the biomarker plasma pro–gastrin-releasing peptide (pro-GRP) may have value in predicting a patient’s potential to benefit from Bcl-2–directed therapy. Efficacy end points included response rate, median progression-free survival (PFS), and median overall survival (OS). In addition, concentrations of several exploratory biomarkers, as well as tumor Bcl-2 gene copy numbers, were obtained in these patients and those from a related study. Baseline concentrations of the biomarkers correlated with median PFS and median OS values. In addition, a strong association was demonstrated between pro-GRP concentration and tumor Bcl-2 copy number. If confirmed, these study findings may have direct application to the implementation of future navitoclax studies, which the authors believe will focus on combination therapies.

Ipilimumab-GVAX Combination Safe for Metastatic CastrationResistant Prostate Cancer

label phase 1 study in men with metastatic castration-resistant prostate cancer (van den Eertwegh AJM, et al. Lancet Oncol. 2012;13:509-517). Based on the toxicity profile and clinical activity, the authors recommended further clinical evaluation of ipilimumab and tumor vaccines in combination. After a GVAX intradermal priming

dose, patients received additional doses every 2 weeks for 24 weeks, for a total of 13 injections. They received intravenous infusions of ipilimumab 0.3, 1.0, 3.0, or 5.0 mg/kg every 4 weeks, for a total of 6 infusions, each administered on the same day as a vaccination. The primary end point was the safety of GVAX.

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A combination of ipilimumab and the granulocyte-macrophage colonystimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) was feasible and tolerable in an open-

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No severe immune-related adverse events (AEs) were reported with the lowest 2 doses. The most common AEs were injection-site reactions, fatigue, and pyrexia. Clinical activity included durable prostate-specific antigen responses, bone scan improvements, and tumor regression. ■

rjhealthsystems.com JUNE 2012

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33 10:36 PM

AACR Annual Meeting

Brain, Breast, and Liver Cancers All Respond to Immunotherapy By Richard Hyer

Brain Tumors Survival has been extended in children with brain tumors, according to interim results of a pilot study of 22 patients with high-risk gliomas treated with peptide-based vaccine therapy. Their prognosis would typically be dismal, said Ian F. Pollack, MD, Chief of Pediatric Neurosurgery at Children’s Hospital of Pittsburgh, and Walter Dandy Professor of Neurosurgery at the University of Pittsburgh School of Medicine. Typical overall survival is barely 35%. These patients were treated with glioma-associated antigen (GAA)based immunotherapy using a “cocktail” of novel GAA peptides.

tients with breast cancer treated in a phase 2 trial of the novel AE37 HER2 peptide vaccine. The trial compares AE37 with granulocyte-macrophage colony-stimulating factor (GM-CSF) versus GM-CSF alone. “The goal of the vaccine is to prime the immune system to recognize and attack the HER2 protein that is found

“Do not be discouraged when you hear about moderate success. In the setting of advanced cancer, moderate success is great news.” —Olivera J. Finn, PhD So far, 19 of the 22 patients have had stable disease or have at least responded through 2 vaccine cycles. There have been 7 cases of pseudoprogression. Of all patients, 3 had partial response, 1 had a mixed response, and 1 had prolonged disease-free status postresection. Of 11 patients with adequate follow-up, 8 have survived beyond the historical medium of 10.5month survival. Breast Cancer Diane F. Hale, MD, a research resident in general surgery at Brooke Army Medical Center, Fort Sam, Houston, TX, described very encouraging immune responses from pa-

Chicago, IL—Immunotherapy is nontoxic, tumor-specific, long-term therapy with a long-term memory. The expectation is that once the patient has been treated with immunotherapy, the therapeutic effect will remain and safeguard the patient for life by provoking the immune system to attack any return of the cancer. There is progress in at least 4 areas: pediatric brain tumors, breast cancer, hepatocellular carcinoma, and generally advanced cancers, according to 4 current studies described at the 2012 American Association for Cancer Research meeting. “Do not be discouraged when you hear about moderate success,” said moderator Olivera J. Finn, PhD, Chairman of the Department of Immunology at the University of Pittsburgh. “In the setting of advanced cancer, moderate success is great news.”

“The goal of the vaccine is to prime the immune system to recognize and attack the HER2 protein that is found in breast cancer, and thus, if or when the patient has a recurrence, their immune system will recognize it and then take action.” —Diane F. Hale, MD

in breast cancer, and thus, if or when the patient has a recurrence, their immune system will recognize it and then take action,” said Dr Hale. The AE37 vaccine combines 2 pro-

teins to target HER2. Trastuzumab (Herceptin) also targets HER2, but it is available to only approximately 20% of patients in the adjuvant setting. AE37 can be used in 50% to 60% of patients expressing HER2. This small, randomized, controlled trial has already proved AE37 to be effective in stimulating the host immune system to recognize and kill cancer cells in the adjuvant setting. A benefit was demonstrated for all 217 patients at 22 months of followup, and a much greater benefit was shown for patients with low expression of HER2. Hepatocellular Carcinoma Ignacio Melero, MD, PhD, Department of Oncology and Professor and Senior Investigator in El Centro de Investigacion Medica Aplicada at the Universidad de Navarra, Pamplona, Spain, described a study of 21 patients treated with the humanized immunoglobulin G2 monoclonal antibody tremelimumab (CP675,206). Therapy produced an intense and persistent antiviral effect in more than 50% of the patients, Dr Melero reported. Francesco Recchia, MD, Director of Oncology at the Civilian Hospital in Avezzano, Italy, described a phase 2 study of maintenance immunotherapy with a combination of low-dose interleukin-2 and 13-cis retinoic acid in advanced cancer, which he said has produced a sustained improvement on natural killer cells, and a decrease of vascular endothelial growth factor. ■

Late-Breaking Clinical Trials: Potential New Therapies for Lymphoma, Prostate, and Other Cancers Chicago, IL—Several presentations featured at a news conference at the 2012 American Association for Cancer Research meeting highlighted new therapies showing promising results in the early stage of research, potentially charting new options for patients with cancer. Ibrutinib for B-Cell Lymphoma Diffuse large B-cell lymphoma (DLBCL) represents 40% of all nonHodgkin lymphoma. Some 23,000 new

cases are diagnosed and 10,000 deaths occur annually in the United States, with a 50% cure rate at best, using chemotherapy and radiation therapy. The B-cell receptor is required for survival of malignant cells in the activated B-cell–like (ABC) subgroup, which is 1 of 2 subgroups of DLBCL. The National Cancer Institute’s (NCI) Center for Cancer Research used geneexpression profiling to dissect this cancer into molecularly and clinically distinct subgroups.

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JUNE 2012

Ibrutinib showed rapid results for the treatment of patients with relapsed/refractory ABC DLBCL, a condition with low cure rate—1 patient showed complete response at 3 weeks, and 1 patient had sustained remission at 16 months. —Louis M. Staudt, MD, PhD

Preliminary results from a phase 2 trial in patients with relapsed/refractory ABC DLBCL showed that the drug

ibrutinib (PCI-32765) was effective for this patient population and well tolerated, according to principal investiga-

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AACR Annual Meeting

tor Louis M. Staudt, MD, PhD, a senior investigator with the NCI. The response was rapid and encouraging. One patient with primary refractory disease had nearcomplete response at week 3, as confirmed by computed tomography and positron-emission tomography scan. Another patient has had 16 months of sustained remission, without side effects. A third patient showed significant, but not complete, response. The trial is ongoing. New Developments in Prostate Cancer Anthony M. Joshua, MD, MBBS, medical oncologist, Princess Margaret Hospital, Toronto, Canada, described the ANIMATE trial, a phase 2 openlabel assessment of neoadjuvant intervention with metformin to interrupt tumor-expression signaling in patients with prostate cancer. The ANIMATE trial is based on the notion that metformin lowers blood insulin, stresses cancer cells, and inhibits the mTOR pathway, which regulates tumor-cell growth, proliferation, and survival. Analysis of tumor samples suggests that metformin is active in depressing prostate-specific antigen (PSA) levels. Results from ARMOR, a phase 1 trial of men with refractory, castrationresistant prostate cancer, were presented by R. Bruce Montgomery, MD, Associate Professor of Medical Oncology at the University of Washington School of Medicine, Seattle. The ARMOR trial is investigating the safety of galeterone (TOK-001), an oral, small-molecule drug with 3 mecha-

Late-Breaking Clinical Trials...

Results from the ANIMATE trial suggest that metformin, which is being investigated as a potential treatment for prostate cancer, is active in depressing elevated PSA levels. —Anthony M. Joshua, MD, MBBS

nisms of action. The study included 48 patients who were chemotherapynaïve; results showed a ≥30% decline in PSA levels and varying degrees of tumor reduction, without significant adverse events. A phase 2b trial is planned for this year. In yet another study, Reinhold Vieth, PhD, Professor, Department of Nutritional Sciences, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada, and Director, Bone and Mineral Laboratory, Pathology and Laboratory Medicine, Mount Sinai

Continued from page 34 such as myelosuppression, were a problem, but because of the drug’s efficacy, Dr Naing suggested managing the toxicity and keeping the patient on treatment. Finally, John H. Farley, MD, Professor, Division of Gynecologic Oncology, Creighton University School of Medicine at St Joseph’s Hospital and Medical Center,

Hospital, discussed his study investigating whether the rise in serum vitamin D depresses cellular proliferation of Ki67, a nuclear protein associated with cellular proliferation. It has been documented that vitamin D3 slows the rise in PSA levels in men with prostate cancer, and that this increase is also slower in the summer months, when sunlight affects levels of the vitamin. Interim results suggest that vitamin D is safe in this patient population, and that it raises levels of calcitriol, which is related to lower Ki67 levels. Rising levels of vitamin D were also associated with higher levels of tumor-suppressive microRNA. Dr Vieth noted that these early results justified a larger study to examine whether vitamin D may prolong survival of patients with cancer or possibly even prevent cancer.

In patients with prostate cancer, vitamin D3 raised levels of calcitriol, which is related to lower Ki67 levels, a nuclear protein associated with cell proliferation. Increased vitamin D levels were also associated with higher levels of tumorsuppressive microRNA.

Other New Therapies Refractory tumors of the Ewing sarcoma family (bone or soft tissue) in heavily pretreated patients were treated with a combination of the insulin-like growth factor-1 receptor antibody cixutumumab and the mTOR inhibitor temsirolimus, reported Aung Naing, MD, Assistant Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, M.D. Anderson Cancer Center, Houston, TX. In this trial, benefit was demonstrated in 29% of the patients, and 2 patients achieved complete remission. Most patients tolerated the treatment well and were able to maintain their performance status. Adverse events,

—Reinhold Vieth, PhD

Phoenix, AZ, described an openlabel phase 2 trial of selumetinib (AZD6244) in women with recurrent low-grade serous carcinoma of the ovary or peritoneum. This drug inhibits MAPK kinase 1/2, which is particularly active in this cancer. The trial that includes 52 patients suggests that selumetinib is active on tumors with minimal toxicity; a 15% response rate was observed. A randomized phase 3 trial has been proposed.—RH ■

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CONTINUING EDUCATION JUNE 2012 • VOLUME 4 • NUMBER 1

4th Annual

CONSIDERATIONS

Lymphoma

™

ASK THE EXPERTS: Mantle Cell Lymphoma LETTER PUBLISHING STAFF

FROM THE

EDITOR-IN-CHIEF

According to recent estimates from the American Cancer Society, approximately 70,130 individuals will be diagnosed with non-Hodgkin lymphoma (NHL) in 2012 and about 18,940 deaths will be attributed to the disease. There has been significant progress in the treatment of these hematologic malignancies, including the development and approval of new, highly effective therapies. However, more progress is needed and numerous questions remain unanswered regarding the application and interpretation of recent clinical advances. The goal of our 4th annual “Considerations in Lymphoma” newsletter series is to provide clinicians with the latest evidence-based strategies for managing NHL in the era of novel agents. To address the needs of key members of the interdisciplinary team, frequently asked questions have been posed to physicians, midlevel providers, and pharmacists from leading cancer centers specializing in the treatment of lymphoma. In this first issue, experts from Fox Chase Cancer Center discuss the effective management of mantle cell lymphoma. It is our hope that the insight, knowledge, and experience offered by these professionals will facilitate the optimal care of your patients with NHL.

President & CEO Brian F. Tyburski

Chief Operating Officer Pam Rattananont Ferris

Director, Medical & Scientific Services Linda M. Ritter, PhD linda@coexm.com

Editorial Director Susan Berry susan@coexm.com

Sincerely, Stephanie A. Gregory, MD The Elodia Kehm Chair of Hematology Professor of Medicine Director, Lymphoma Program Rush University Medical Center/Rush University Chicago, IL

Associate Director Elizabeth S. Cohen liz@coexm.com

Copyeditor Dana Delibovi

Director, Production and Manufacturing Alaina Pede

Director, Creative and Design Robyn Jacobs

FACULTY Mitchell R. Smith, MD, PhD Director, Lymphoma Service Fox Chase Cancer Center Philadelphia, PA

Quality Control Director Barbara Marino

Web Coordinator Jose Valentin

Barbara Rogers CRNP, MN, AOCN, ANP-BC Adult Hematology-Oncology Nurse Practitioner Fox Chase Cancer Center Philadelphia, PA

Dwight Kloth, PharmD, FCCP, BCOP Director of Pharmacy Fox Chase Cancer Center Philadelphia, PA

Business Manager Blanche Marchitto

Executive Administrator Jackie Luma

Supported by educational grants from Millennium: The Takeda Oncology Company and Spectrum Pharmaceuticals

Circulation Department circulation@greenhillhc.com Center of Excellence Media, LLC 241 Forsgate Drive Suite 205B Monroe Township, NJ 08831

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This activity is jointly sponsored by Medical Learning Institute, Inc., and Center of Excellence Media, LLC.

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CONSIDERATIONS IN LYMPHOMA Sponsor This activity is jointly sponsored by Medical Learning Institute, Inc., and Center of Excellence Media, LLC.

Learning Institute, Inc. and the Center of Excellence Media, LLC. The Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education for physicians.

Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with mantle cell lymphoma.

Registered Nurse Designation Medical Learning Institute, Inc. (MLI). Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.25 contact hours.

Educational Objectives Upon completion of this activity, the participant will be able to: • Analyze results of recent clinical trials investigating the incorporation of newer agents into mantle cell lymphoma (MCL) treatment • Discuss the safety and efficacy of adding radioimmunotherapy to chemotherapy regimens for patients with MCL • Summarize common toxicities associated with treatments for MCL, and identify current approaches to reduce or ameliorate these effects Commercial Support Acknowledgment This activity is supported by educational grants from Millennium: The Takeda Oncology Company and Spectrum Pharmaceuticals. Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P12030.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the Certificate for your records. For questions regarding the accreditation of this activity, please contact MLI at 609-333-1693 or cgusack@mlicme.org. Physician Credit Designation The Medical Learning Institute, Inc. (MLI) designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Medical

Barbara Rogers CRNP, MN, AOCN, ANP-BC, is on the advisory board for Celgene and Teva, and on the speakers bureau for Allos, Millennium: The Takeda Oncology Company, Spectrum Pharmaceuticals and Teva. *Dwight Kloth, PharmD, FCCP, BCOP, is the director of the pharmacy advisory board for Amgen, Celgene, Eisai, Hospira, and Prostrakan. *Content will include non-FDA-approved uses.

Registered Pharmacy Designation Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.25 contact hours (0.125 CEUs) of continuing education credit. The universal activity number for this activity is 04689999-12-014-H01-P. Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by MLI for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. Planners’ and Managers’ Disclosures Dana Delibovi, Medical Writer, has nothing to disclose. William J. Wong, MD, MLI Reviewer, has nothing to disclose. Ryan Sims, CRNA, MS, MLI Reviewer, has nothing to disclose. Shelley Chun, PharmD, MLI Reviewer, has nothing to disclose.

The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CE activity for any amount during the past 12 months. Disclaimer The information provided in this CME/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred. Agenda: 1.25 hours Articles/Commentaries: 60 minutes Evaluation/Posttest: 15 minutes Date of original release: June 11, 2012 Valid for CME/CE credit through: June 11, 2013

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Faculty Disclosures Stephanie A. Gregory, MD, is on the advisory board for Genentech/Roche, and Spectrum Pharmaceuticals, and on the data safety monitoring board for Genentech/Roche. Mitchell R. Smith, MD, PhD, is on the advisory board for Teva, and on the speaker’s bureau for Allos, Genentech, Millennium: The Takeda Oncology Company, and Spectrum Pharmaceuticals.

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Current and Emerging Treatment Strategies in Mantle Cell Lymphoma Mitchell R. Smith, MD, PhD Director, Lymphoma Service Fox Chase Cancer Center, Philadelphia, PA

ple, a minority of patients (about 5%-10%) have indolent disease.2-4 Therefore, it is important to factor in cell proliferation and other disease characteristics, in addition to age and performance status, to ensure that patients are not “overtreated.” MCL is essentially an incurable disease, and we do not want to subject individuals to severe drug-related toxicities that may shorten survival.

Introduction Mantle cell lymphoma (MCL) is an uncommon, clinically heterogeneous subtype of B-cell lymphoma. Although survival rates for patients

Which regimens can be used when an intensive approach to frontline treatment is necessary?

have improved over the past decade, the disease remains incurable. An individualized approach to treatment is essential, taking into account age, performance status, and whether a patient needs more or less aggressive therapy. In this article, Mitchell R. Smith, MD, PhD, answers questions related to the treatment of newly diagnosed and relapsed/refractory MCL and provides insights on recent developments that may lead to improved clinical outcomes.

Which factors need to be considered when choosing frontline therapy for patients with MCL?

Age, performance status, pace of disease, and goals of therapy are all important factors to consider when deciding on an approach to initial treatment. Older patients and individuals with compromised health status cannot tolerate some of the more intensive regimens used to treat MCL, such as those containing high-dose chemotherapy. Younger, more fit individuals can often endure these regimens1; however, this approach may not always be required. For exam-

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To date, the best published outcomes data have been observed with a regimen of rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HyperCVAD) alternating with rituximab plus high-dose methotrexate and cytarabine (R-MA).5,6 Investigators from MD Anderson Cancer Center recently published 10-year follow-up data on the safety and efficacy of this regimen, which they studied in an MCL population with no upper age limit. Survival was good, but toxicity was significant, especially in older patients.5,6 The Gruppo Italiano Studio Linfomi (GISL) reported that R-HyperCVAD/ R-MA was effective in patients 70 years, but only 22 of 60 patients could actually complete the 8 planned cycles.7 The Southwest Oncology Group (SWOG) also conducted a study that reached more or less the same conclusion: R-HyperCVAD/R-MA was difficult to complete, but the regimen provided reasonable results for those who could tolerate it.8 At our institution, we often use R-HyperCVAD/R-MA in patients who are 60 years of age or younger, and we ensure that patients near the cutoff age have good performance status before we decide to use this regimen.

JUNE 2012

www.ValueBasedCancerCare.com

CONTINUING EDUCATION

Figure. Response rates with VcR-CVAD plus rituximab maintenancea in MCL: interim results (n=76).18

100

96% 75%

Patients (%)

80 60 40

21% 20

results suggest applicability in select older patients. These regimens appear to be feasible therapeutic options, but longer follow-up is necessary. An emerging trend is to combine ASCT with shorter courses of R-HyperCVAD/R-MA. The upcoming US Intergroup S1106 trial will treat patients 65 years old with 2 rather than 4 cycles of R-HyperCVAD/R-MA, followed by consolidation therapy and ASCT.13 This strategy will allow patients to receive intensive cytoreduction before transplantation. In my opinion, ASCT is easier for patients to endure than the 4 additional rounds of RHyperCVAD/R-MA used in the traditional protocol. S1106 also has a comparative arm of less-intensive induction with bendamustine plus rituximab (BR), followed by ASCT. Hopefully, results from this trial will offer insight on how intensive cytoreduction really needs to be prior to transplantation.

Overall Response

Complete Response

Partial Response

Given to patients achieving stable disease, partial response, or complete response to VcR-CVAD. MCL indicates mantle cell lymphoma; VcR-CVAD: bortezomib, rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone.

Table. R-CHOP (4 cycles) Followed by RIT Consolidation With 90 Y-Ibritumomab Tiuxetan in MCL: Efficacy Results at 5-Year Follow-up (n=57)19 Endpoint

Result

PFS

31 months

➢ PFS in patients 65 years ➢ PFS in patients >65 years

32 months 25 monthsa

Overall response rate

82%

➢ CR/CRu ➢ PR

56% 26%

Number of patients in whom response improved after RIT Estimated median OS

23/44 76 month

➢ 5-year OS in patients 65 years ➢ 5-year OS in patients >65 years

No significant difference between age groups. Significant difference between age groups (P=.023). CR/Cru indicates complete response/complete response unspecified; MCL, mantle cell lymphoma; OS, overall survival; PFS, progression-free survival; PR, partial response; RCHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; RIT, radioimmunotherapy.

For patients aged 60 to 70 years who are diagnosed with aggressive disease, we often use rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP),9 followed by consolidation with myeloablative chemotherapy and autologous stem cell transplantation (ASCT). A randomized trial by the European MCL Network (MCL net) showed that, in MCL patients treated with CHOP or R-CHOP, myeloablative radiochemotherapy plus ASCT prolonged progression-free survival (PFS) compared with interferon maintenance.10 The MCL net also studied a variation in treatment: alternating courses of R-CHOP plus rituximab, dexamethasone, cytarabine, and cisplatin (RDHAP), followed by high-dose cytarabine-based myeloablation and ASCT.11 This regimen had acceptable toxicity compared with a regimen of R-CHOP followed by cyclophosphamide-based myeloablation and ASCT. Similarly, the Nordic Lymphoma Group reported favorable outcomes with dose-intensified R-CHOP alternating with R-A, followed by ASCT.12 Although neither of these trials included patients older than 65 years, the favorable toxicity

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R-CHOP remains a common choice for patients who cannot tolerate aggressive treatment. Responses to this regimen are good, but not durable, in MCL.14 As a result, researchers are searching for alternative therapies. In a phase 3 trial by the German Study Group Indolent Lymphomas (StiL), Rummel and colleagues showed that BR was more effective (with better tolerability) than R-CHOP in a population of lymphoma patients that included individuals with MCL.15 This study has been the genesis of many ongoing trials of regimens based on BR. For example, the US Intergroup E1411 trial, which is set to open in the next few months, will evaluate a regimen of BR with or without bortezomib as frontline therapy.16 Kahl and colleagues studied a modified R-HyperCVAD regimen, which omitted the alternating cycle of R-MA but included rituximab maintenance.17 The results were intriguing, so the approach was extended to the ECOG E1405 trial, which also added bortezomib.18 This study of VcRCVAD plus rituximab maintenance is now accrued and closed; interim results showed a high complete response (CR) rate (Figure), but we need longer follow-up to see whether this translates into better PFS and OS.

76 months 66 monthsb

Which regimens can be used when a less-intensive approach to frontline treatment is necessary?

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Hopefully, results from this trial will offer insight on how intensive cytoreduction really needs to be prior to transplantation. Our group conducted a separate ECOG trial (E1499), which evaluated RCHOP for 4 cycles (instead of the traditional 6 cycles), followed by a dose of radioimmunotherapy (RIT) with 90Y-ibritumomab tiuxetan.19 This is a brief regimen, applicable to the vast majority of MCL patients, which results in relatively good outcomes (Table). We are using R-CHOP followed by RIT more frequently, keeping in mind that we do not have the breadth of data on this regimen for MCL that we do for follicular lymphoma via the phase 3 First-Line Indolent Trial.20 It appears that BR, modified R-HyperCVAD (with or without bortezomib) followed by rituximab maintenance, and R-CHOP followed by RIT are all reasonable choices for patients who require less-intensive regimens. Two of these options include consolidation of response, which I think is an important consideration in MCL. In the studies of modified R-HyperCVAD, rituximab maintenance appeared to be helpful.17,18 We have learned more from an MCL net trial conducted in elderly patients, which compared R-CHOP versus rituximab, fludarabine, and cyclophosphamide (R-FC), after which patients were ran-

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domized a second time to rituximab maintenance versus interferon.21 Patients receiving R-CHOP followed by rituximab maintenance had an excellent outcome, much better than we usually see in MCL—4-year OS was 87%, although this was limited to R-CHOP responders. Results were not as good with R-CHOP followed by interferon maintenance or R-FC followed by either type of maintenance. Moreover, R-FC followed by rituximab maintenance produced the highest infection rate (50%) of any induction/maintenance combination in the trial. One of the lessons of this study is that R-FC is probably not a good regimen for initial treatment of elderly patients with MCL. Another lesson is that, when R-CHOP or a similar regimen is used for initial therapy, rituximab maintenance is clearly beneficial. Ongoing trials continue to refine the role of maintenance therapy in MCL. For instance, the E1411 trial discussed earlier will also compare rituximab maintenance with lenalidomide-rituximab maintenance.16 What investigational agents and regimens are showing promise in the treatment of MCL?

We are excited about drugs that target the B cell receptor signaling pathway, including the Bruton’s tyrosine kinase inhibitor ibrutinib (PCI-32765). Wang and colleagues recently presented data showing a high response rate with single-agent ibrutinib in the relapsed/refractory setting for MCL.22 The phosphatidylinositol 3-kinase (PI3K) inhibitor GS-1101 (formerly known as CAL-101) is also demonstrating good activity.23 Both ibrutinib and GS1101 are well-tolerated oral agents.22,23 BCL2 pathway inhibitors, such as obatoclax, navitoclax, and oblimersen, may also have a role in MCL.24 The mammalian target of rapamycin (mTOR) inhibitors, notably temsirolimus and everolimus, have clinical activity in MCL.25,26 Investigators are beginning to assess whether dual PI3K/mTOR inhibition may be effective in the treatment of the disease.27 Combining mTOR inhibition with something that targets B-cell receptor signaling allows us to hit 2 pathways. In principle, the cell will be less likely to have, or to develop, resistance to such a combination. There is also growing interest in the use of histone deacetylase inhibitors in combination with other agents for the treatment of MCL.28 A number of studies are combining investigational agents with chemotherapy or approved novel agents. One example is a trial of obatoclax plus bortezomib for the treatment of relapsed and refractory MCL.29 Trials like these reflect a useful strategy: combining a B-cell signaling agent and a pro-apoptotic agent, which may signal cells not to divide and at the same time to undergo cell death. Bortezomib is the only targeted agent approved by the US Food and Drug Administration for the treatment of relapsed MCL. Two groups recently evaluated bortezomib plus BR in trials of previously treated patients with lymphoma, including MCL.30,31 The results were interesting, and the combination was tolerable. While it may be advantageous to add these drugs together to treat patients with relapsed/refractory disease, it is not clear whether we should give bendamustine and bortezomib together or sequentially in this setting. Rituximab plus lenalidomide also has a role in the treatment of relapsed/refractory MCL. Given the clinical activity and tolerability of this combination,32 it is also being explored as maintenance therapy. Clearly, we have entered a very productive period of research in the treatment of the disease. Novel targeted agents and new combination regimens have the potential to prolong survival and improve clinical outcomes for patients diagnosed with MCL.◆ References 1. Ghielmini M, Zucca E. How I treat mantle cell lymphoma. Blood. 2009;114:1469-1476. 2. Ondrejka SL, Lai R, Smith SD, Hsi ED. Indolent mantle cell leukemia: a clinicopathological

variant characterized by isolated lymphocytosis, interstitial bone marrow involvement, kappa light chain restriction, and good prognosis. Haematologica. 2011;96:1121-1127. 3. Vizcarra E, Martínez-Climent JA, Benet I, et al. Identification of two subgroups of mantle cell leukemia with distinct and biological features. Hematol J. 2001;2:234-241. 4. Fernàndez V, Salamero O, Espinet B, et al. Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res. 2010;70:1408-1418. 5. Romaguera JE, Fayad L, Rodriquez MA, et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus Hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005;23:7013-7023. 6. Romaguera JE, Fayad LE, Feng L, et al. Ten-year follow-up after intense chemoimmunotherapy with Rituximab-HyperCVAD alternating with Rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma. Br J Haematol. 2010;150:200-208. 7. Merli F, Luminari S, Ilariucci F, et al. Rituximab plus HyperCVAD alternating with high dose cytarabine and methotrexate for the initial treatment of patients with mantle cell lymphoma, a multicentre trial from Gruppo Italiano Studio Linfomi. Br J Haematol. 2012;156:346-353. 8. Epner EM, Unger J, Miller T, et al. A multi center trial of hyperCVAD+Rituxan in patients with newly diagnosed mantle cell lymphoma. Blood (ASH Annual Meeting Abstracts). 2007;110: Abstract 387. 9. Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005;23:184-1992. 10. Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progressionfree survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. 2005;105:2677-2684. 11. Hermine O, Hoster E, Walewski J, et al. Alternating courses of 3x CHOP and 3x DHAP plus rituximab followed by a high dose ARA-C containing myeloablative regimen and autologous stem cell transplantation (ASCT) is superior to 6 courses CHOP plus rituximab followed by myeloablative radiochemotherapy and ASCT in mantle cell lymphoma: results of the MCL younger trial of the European Mantle Cell Lymphoma Network (MCL net). Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 110. 12. Geisler CH, Kolstad A, Laurell A, et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo–purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008;112: 2687-2693. 13. Bernstein S; Southwest Oncology Group (SWOG). Phase II randomized study of induction therapy comprising rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, dexamethasone, methotrexate, cytarabine, and leucovorin calcium versus rituximab and bendamustine hydrochloride followed by consolidation therapy and autologous stem cell transplantation in older patients with previously untreated mantle cell lymphoma (S1106). http://cancer.gov/clinicaltrials/search/view?cdrid=707601&version=healthprofessional. Accessed May 7, 2012. 14. Howard OM, Gribben JG, Neuberg DS, et al. Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival. J Clin Oncol. 2002;20:1288-1294. 15. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as firstline treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 405. 16. Smith MR; Eastern Cooperative Oncology Group (ECOG). Rituximab, bendamustine hydrochloride, and bortezomib followed by rituximab and lenalidomide in treating older patients with previously untreated mantle cell lymphoma (E1411). http://www.clinicaltrials.gov/ ct2/show/NCT01415752?term=E1411&rank=1. Accessed May 7, 2012. 17. Kahl BS, Longo WL, Eickoff JC, et al. Maintenance rituximab following induction chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: a pilot study from the Wisconsin Oncology Network. Ann Oncol. 2006;17:1418-1423. 18. Kahl BS, Li H, Smith MR, et al. The VcR-CVAD regimen produces a high complete response rate in untreated mantle cell lymphoma (MCL): first analysis of E1405—a phase II study of VcRCVAD with maintenance rituximab for MCL. Blood (ASH Annual Meeting Abstracts). 2009; 114:Abstract 1661. 19. Smith MR, Li H, Gordon L, et al. Phase II study of R-CHOP followed by 90Y-ibritumomab tiuxetan in untreated mantle cell lymphoma (MCL): 5 year follow-up of Eastern Cooperative Oncology Group E1499. Ann Oncol (ICML Annual Meeting Abstracts). 2011;22(suppl 4):Abstract 017. 20. Morschhauser F, Radford J, Van Hoof A, et al. Phase III trial of consolidation therapy with yttrium-90–ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008;26:5156-5164. 21. Kluin-Nelemans JC, Hoster E, Walewski J, et al. R-CHOP versus R-FC followed by maintenance with rituximab versus interferon-alfa: outcome of the first randomized trial for elderly patients with mantle cell lymphoma. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 439. 22. Wang L, Martin P, Blum KA, et al. The Bruton’s tyrosine kinase inhibitor PCI-32765 is highly active as single-agent therapy in previously-treated mantle cell lymphoma (MCL): preliminary results of a phase II trial. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 442. 23. Kahl B, Byrd JC, Flinn IW, et al. Clinical safety and activity in a phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110 , in patients with relapsed or refractory non-Hodgkin lymphoma. Blood (ASH Annual Meeting Abstracts). 2010;116: Abstract 1777. 24. Jares P, Colomer D, Campo E. Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. Nature Review Cancer. 2007;7:750-762. 25. Hess G, Herbrecht R, Romaguera J, et al. Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009;27:3822-3829. 26. Renner C, Zinzani PL, Gressin R, et al. A multi-center phase II study (SAKK 36/06) of single agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 2803. 27. Meadows SA, Kashishian A, Johnson D, et al. CAL-101 (GS-1101), a specific inhibitor of phosphatidylinositol-3-kinase-delta (PI3K ), disrupts signals from the microenvironment, induces apoptosis, and enhances the antitumor activity of everolimus (RAD001), an inhibitor of mam-

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Improving Patient Outcomes in Mantle Cell Lymphoma Barbara Rogers, CRNP, MN, AOCN, ANP-BC Adult Hematology-Oncology Nurse Practitioner Fox Chase Cancer Center Philadelphia, PA

Introduction The treatment of mantle cell lymphoma (MCL) continues to evolve with the development of newer, more effective therapies. However, treatment-related adverse events remain a significant source of concern, as they may negatively impact clinical outcomes and quality of life. In this article, Barbara Rogers, CRNP, MN, AOCN, ANP-BC, answers questions concerning specific toxicities that may occur during treatment, including infection, myelosuppression, and hypersensitivity reactions. She also discusses the importance of individualizing management strategies to provide optimal patient care.

What steps are necessary to minimize infection in patients with MCL who undergo stem cell transplantation?

The National Comprehensive Cancer Network (NCCN) suggests highdose therapy with autologous stem cell transplant (ASCT) as consolidation for patients receiving first-line therapy for MCL and high-dose therapy with allogeneic SCT (allo-SCT) for consolidation in the second-line setting.1 Both of these approaches are myelosuppressive, with allo-SCT being associated with a much higher infection risk than ASCT.1 This risk may be lessened to some degree if a patient is treated with a nonmyeloablative allo-SCT. This type of transplant administers chemo radiotherapy with the intent of allowing for donor cell engraftment, with less of an emphasis on dose intensity. Based on emerging safety and efficacy data,2,3 nonmyeloablative alloSCTs may become the preferred transplant modality for patients with relapsed/refractory MCL when suitable donors are available. Regardless of the type of transplant a patient receives, nurses should carefully monitor patients for signs and symptoms of infection during all phases of the process. Patients must receive prophylaxis for bacterial, viral, and fungal infections, in accordance with guidelines published by the Centers for Disease Control and Prevention, the Infectious Diseases Society of America, and the American Society of Blood and Marrow Transplantation.4 Patient education about infection precautions should include the importance of good hygiene (especially frequent hand washing), food safety, and strategies for avoiding or minimizing exposure to potentially infectious people and pets.4 Following transplant, patients must also be reimmunized with childhood vaccinations, because antibody titers to vaccine-preventable diseases decrease 1 to 4 years post-transplant. Guidelines suggest a schedule of reimmunization that begins 1 year after allo-SCT or ASCT.4 At our institution, we try to follow these recommendations as closely as possible. There are times, however, when we may need to alter the schedule due to specific medical situations, such as patients who are extremely immunocompromised after transplant.

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How do you minimize and manage infusion reactions associated with the use of rituximab?

Similar to other monoclonal antibodies, rituximab is associated with infusion reactions that are caused primarily by cytokine release, rather than true allergic reactions.5 The incidence of mild-to-moderate reactions is approximately 77% with the first infusion of rituximab and tends to decrease with subsequent infusions.5,6 Certain factors may increase the risk of a reaction, including having a hematologic malignancy such as MCL (Table 1).6 Patient education is the first step in the effective management of rituximab-related infusion reactions. We always inform patients of potential signs and symptoms that may occur during their first infusion. Common symptoms are fever, chills, and rigors; less frequent (and more severe) reactions include angioedema, bronchospasm, and dyspnea.5 All patients receiving rituximab must be premedicated with acetaminophen and diphenhydramine prior to each infusion. If we anticipate that a patient is at very high risk for a reaction,6 we will also administer a steroid such as dexamethasone. Risk factors for more significant infusion reactions are very high white blood cell (WBC) counts or untreated bulky disease.6 In patients with high counts, we may divide the dose of rituximab over 2 days. For example, we may administer 100 mg of the calculated dose on day 1 and the remainder of the dose on the following day. Alternatively, we may omit rituximab in the first cycle of treatment to allow for a decline of the WBC count, and add it during the second cycle instead. We start the rituximab infusion slowly and monitor vital signs every 30 minutes. If a reaction occurs, we stop the infusion, perhaps give more steroid

Table 1. Risk Factors for Hypersensitivity Reactions6 Asthma diagnosis Atopic patients (ie, patients who tend to react to specific allergens, such as hay fever, skin irritations, and asthma) Circulating lymphocyte counts 25,000 mm3 (lymphoma or leukemia) Concomitant -adrenergic blocker therapy Concurrent autoimmune disease Female gender Higher than standard drug doses Iodine or seafood allergies Newly diagnosed, untreated patients Older age Patients with hematologic malignancies such as mantle cell lymphoma and chronic or small lymphocytic leukemia Personal history of drug allergy or previous immediate reaction to a medication Preexisting cardiac or pulmonary dysfunction Previous exposure to the drug Vogel WH. Infusion reactions: diagnosis, assessment, and management. Clin J Oncol Nurs. 2010;14:E10-E21. Reproduced with permission of the Clinical Journal of Oncology Nursing.

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or diphenhydramine, and wait for recovery. A histamine-2 receptor antagonist may also be added as a precautionary measure. We then resume rituximab at a slower rate. When a patient has a severe, anaphylactic-like reaction, the infusion is usually discontinued and reinitiated on an alternate day. In rare situations, we may need to halt rituximab therapy permanently. What strategies can be used to manage hematologic toxicities associated with treatments for MCL?

Our approach to the management of neutropenia, anemia, and thrombocytopenia is dependent on the severity of the myelosuppression itself, as well as patient-specific factors. We always use pegfilgrastim when administering chemotherapy regimens that pose a high risk of neutropenia, such as rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HyperCVAD). For older patients, who are at higher risk of neutropenic fever, we give neutrophil growth factors starting with the first cycle of treatment, in accordance with guidelines from the American Society of Clinical Oncology.7 However, younger, fit patients and those who are being treated with less aggressive chemotherapy combinations usually do not receive growth-factor support unless we see a need for it during treatment. If a patient develops anemia, transfusion may be necessary. However, according to current NCCN recommendations, the decision to transfuse should not be based solely on red blood cell (RBC) count, but rather on patient-specific criteria.8 For example, patients with cardiac comorbidities are often transfused at a higher hemoglobin level than otherwise healthy individuals. We also use the erythropoiesis-stimulating agents (ESAs) epoetin alfa and darbepoetin alfa to treat anemia in some cases. Although these agents can be beneficial, as they help patients avoid transfusion, they are associated with serious risk, including increased mortality and tumor progression, thromboembolism, hypertension, and seizures.8 As a result, ESAs are contraindicated if the intention of treatment is to cure. Treatment with standard chemotherapy can cause a decline in platelet count. If a patient experiences severe thrombocytopenia (platelet count <10,000 platelets/mm3 without bleeding or 10,000 platelets/mm3 with bleeding),9 we initiate a platelet transfusion. Dose reductions of certain agents may be helpful for reducing a patient’s risk of experiencing severe thrombocytopenia in future cycles of therapy. In clinical practice, we have also learned that some drugs may be better tolerated if they are administered at a dose lower than what is listed in the package insert. For example, the approved dose of bendamustine for the management of non-Hodgkin lymphoma is 120 mg/m2.10 However, in a phase 3 trial of patients with mantle cell, indolent, and follicular lymphomas, Rummel and colleagues administered bendamustine at a dose of 90 mg/m2, in combination with rituximab (BR). This regimen was shown to be effective and well tolerated, with a reasonably good safety profile. As shown in Table 2, significant differences in grade 3/4 hematologic toxicities were observed between BR and a regimen of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).11 It is important to remember, however, that there are clinical scenarios in which dose-reducing bendamustine may not be the best course of action, and the full dose will be needed to obtain adequate response. The rate of recovery from hematologic toxicities varies, depending on the type of therapy the patient is receiving, as well as what he or she received in the past. With chemotherapy, the nadir occurs approximately 7 to 10 days after treatment. R-HyperCVAD/R-MA is associated with profound (grade 4) neutropenia and thrombocytopenia in spite of growth-factor support,12 and-

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Table 2. Grade 3/4 Myelosuppression in the Phase 3 StiL Trial of R-CHOP versus BR11 Toxicity

R-CHOP (N=253)

BR (N=260)

P Value

Neutropenia

46.5%

10.7%

<.0001

Leukocytopenia

38.2%

12.1%

<.0001

Use of G-CSF

20.0%

4.0%

<.0001

BR indicates bendamustine plus rituximab; G-CSF, granulocyte colony-stimulating factors; R-CHOP; rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

patients treated with this type of aggressive regimen are at greater risk of developing neutropenic fever. Hematologic toxicities seen with regimens such as BR and R-CHOP tend to be less severe, but still require careful monitoring and management strategies.11,13 With radioimmunotherapy, the rate of myelosuppression is usually delayed; blood cell and platelet counts typically do not decline until approximately 1 month after treatment. For example, following 90Y-ibritumomab tiuxetan therapy, nadir counts occur at about 7 to 9 weeks post treatment and last approximately 1 to 4 weeks before recovery begins.14 As a result, patients do not receive additional antilymphoma therapies for approximately 3 to 4 months following treatment. Conclusion

Although advances in the treatment of MCL have led to improved outcomes, individuals who receive treatment with novel agents, with or without transplant, can potentially experience significant toxicities that can lead to greater morbidity and mortality. Nurses must be aware of evidence-based preventative and supportive care strategies for these toxicities so that patients can be promptly treated and continue with their therapy. ◆ References 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™): Non-Hodgkin Lymphoma. Version 2.2012. http://www.nccn.org. Accessed May 14, 2012. 2. Khouri IF, Lee MS, Saliba RM, et al. Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma. J Clin Oncol. 2003;21:4407-4412. 3. Tam CS, Bassett R, Ledesma C, et al. Mature results of the M.D. Anderson Cancer Center riskadapted transplantation strategy in mantle cell lymphoma. Blood. 2009;113:4144-4152. 4. Centers for Disease Control and Prevention; Infectious Diseases Society of America; American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep. 2000;49:1-125. 5. Lenz H-J. Management and preparedness for infusion and hypersensitivity reactions. Oncologist. 2007;12:601-609. 6. Vogel WH. Infusion reactions: diagnosis, assessment, and management. Clin J Oncol Nurs. 2010;14:E10-E21. 7. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline. J Clin Oncol. 2006;24:3187-3205 8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™): Cancer- and Chemotherapy-Induced Anemia. Version 2.2012. http:// www.nccn.org. Accessed May 15, 2012. 9. Slichter SJ. Evidence-based platelet transfusion guidelines. Hematology Am Soc Hematol Educ Program. 2007:172-1788. Review. 10. Treanda [package insert]. Frazer, PA: Cephalon, Inc; 2008. 11. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 405. 12. Romaguera JE, Fayad L, Rodriquez MA, et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005;23: 7013-7023. 13. Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005;23:1984-1992. 14. Witzig TE, White CA, Gordon LI, et al. Safety of yttrium-90 ibritumomab tiuxetan radioimmunotherapy for relapsed low-grade, follicular, or transformed non-Hodgkin’s lymphoma. J Clin Oncol. 2003;21:1263-1270.

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Pharmacologic Considerations in the Treatment of Mantle Cell Lymphoma Dwight Kloth, PharmD, FCCP, BCOP Director of Pharmacy, Fox Chase Cancer Center Philadelphia, PA

Introduction Historically, the treatment of mantle cell lymphoma (MCL) has relied on conventional chemotherapeutic agents, which, unfortunately, are not curative. Patients eventually relapse following initial treatment, and overall survival rates have remained quite variable,

of therapy to prolong survival while minimizing side effects? It is important to have an open dialogue with patients in order to review their treatment history, establish priorities, and ascertain which therapies offer the best chance of meeting therapeutic goals. For instance, if a patient expresses a desire to continue working at a job that requires great mental acuity, it may be prudent to avoid lenalidomide-based treatment, as this drug can cause significant drowsiness.2 Similarly, a patient’s ability to perform certain work-related tasks may be impaired by bortezomib-induced peripheral neuropathy.1 Consequently, it is imperative to consider the toxicity profile of any agent as part of the decision algorithm.

with most patients succumbing to the disease. In recent years, a number of newer therapies have been developed for MCL, leading to more durable responses in both the frontline and relapsed/refractory

What special requirements are necessary to administer radioimmunotherapy (RIT) to patients with MCL?

settings. With an ever-increasing array of choices, treatment decisions have become more complex, requiring careful consideration of numerous patient- and drug-related factors. In this article, Dwight Kloth, PharmD, FCCP, BCOP, answers questions related to the use of novel agents for MCL and provides his clinical perspectives on future directions in the treatment of the disease.

What are some of the pharmacologic issues that must be considered when using novel drugs in the relapsed/refractory setting for MCL?

We are fortunate to have several novel therapies available to treat patients with relapsed/refractory MCL. If we try 1 agent and it is not well tolerated or does not appear to be effective, we can usually offer the patient an alternative treatment. When choosing among the different agents, we must consider several factors. For example, the novel agents we are using with the greatest frequency in MCL—bendamustine, bortezomib, lenalidomide, and rituximab—have varied routes of administration. Bendamustine and rituximab can only be given by intravenous (IV) infusion, which lasts 60 minutes or longer. Bortezomib has traditionally been used as an IV drug but is increasingly being administered subcutaneously (SC). This new approach is based on a study in multiple myeloma patients that showed reduced neurotoxicity and similar therapeutic benefit with SC dosing.1 Lenalidomide is taken orally, which increases convenience but also raises issues concerning the teratogenic risk associated with this drug.2 Patients must be advised that the risk management program for lenalidomide is not trivial. Prior to prescribing a high-cost oral agent, it is important to ascertain whether a patient has a prescription drug benefit plan, and what the tier level for the out-of-pocket copay will be, as reimbursement issues can have a significant impact on patients and their families. Individuals may have coverage for an IV drug administered by a healthcare provider (eg, Medicare Part B or a commercial insurer’s major medical plan), but not for an oral self-administered agent, and this may affect choice of therapy. Other considerations include the patients’ ability to travel to the clinic for IV infusions and how well they are able to comply with and adhere to an oral drug regimen. Goals of therapy are another factor to consider when selecting treatments. Are we trying to prepare the patient for stem cell transplantation? Is the aim

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Clinical data regarding the use of RIT in MCL are somewhat limited. However, 90Y-ibritumomab tiuxetan consolidation therapy after a regimen of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone improved the quality of response in 57 previously untreated patients with stage III/IV MCL.3 The mechanism of action of RIT—radiation combined with a monoclonal antibody carrier—provides an interesting and effective way to target treatment right to the malignancy. The antibody binds to receptor sites on the tumor cell, and the radiation hits the cell where it is targeted. Radiation also hits neighboring tumor cells that may be inaccessible to the antibody due to penetration barriers—a phenomenon called radioactive crossfire.4 However, logistics can be a challenge with RIT. The half-life of the radiolabeled combination product makes this therapy extremely time sensitive,5 so everything has to be carefully staged and choreographed. The antibody must be radiolabeled by a nuclear-certified pharmacy in close geographic proximity to the treatment site; this needs to be done immediately before the scheduled time of treatment to ensure that radiation does not decay excessively. In addition, patients must have the necessary bone marrow reserves and hematologic status to undergo RIT (Table).4-7 Careful follow-up is needed postRIT, to prepare for the nadir of blood counts several weeks later.8 These issues almost always make it impractical for a small oncology practice to provide RIT to their patients. The therapy is usually coordinated and given by a nuclear medicine department and its affiliated pharmacy. These clinicians have the expertise to give RIT efficiently and safely, and to maintain continuity of care as patients return home and back to their oncology team.

Table. Bone Marrow Reserves and Hematologic Criteria for the Administration of Radioimmunotherapy4-7 • Bone marrow: - < 25% bone marrow involvement with lymphoma, assessed via biopsy - No other evidence of bone marrow impairment • Blood counts: - Platelet count 100,000 cells/mm3 - Neutrophil count 1500 cells/mm3

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Figure. The central role of Btk in the B-cell fate.

apoptosis of non-Hodgkin lymphoma cell lines.11 The PI3-K pathway may have special relevance to MCL. It is part of a larger pathway—PI3K/Akt/mTOR (mammalian target of rapamycin)—involved in the transduction of signals from cell receptors to proteins that mediate cell cycling. These proteins include cyclin D1, which is overexpressed in MCL.12,13 Promising results with GS-1101 have been reported in a phase 1 study that included 16 heavily pretreated patients with relapsed/refractory MCL.11 ORR was 62%, with higher rates of response in the relapsed versus the refractory populations (73% and 40%, respectively). Median duration of response in MCL was 3 months (range, 1-8 months).11 Recent data show that GS-1101 is active in combination with the mTOR inhibitor everolimus, another agent that affects protein kinase pathways and interrupts translation of cyclin D1.12,13 Several investigative teams are now developing protocols with kinase inhibitors in combination with other drugs. These novel agents are an exciting development, because they are targeted to the B cell and to specific molecular pathways of MCL.9,12-14 The hope is that this kind of targeting will move us closer to our goal of prolonging survival in this difficult-to-treat population of patients. ◆

References Courtesy of Sabine Ponader, PhD.

Can you discuss the mechanism of action and clinical activity of the investigational agents ibrutinib (PCI-32765) and GS-1101 (formerly known as CAL-101)?

Ibrutinib (PCI-32765) is an inhibitor of Bruton’s tyrosine kinase (Btk), which is a key component of the B-cell receptor signaling pathway.9 This agent selectively and permanently inhibits Btk, which blocks B-cell activation and downstream signaling of the B-cell receptor (Figure). MCL cells are known to express Btk.9 Preliminary results of an ongoing phase 2 study of ibrutinib in MCL were recently reported.10 A total of 48 patients were enrolled, in cohorts of bortezomib-naive and bortezomib-exposed, with 24 patients evaluable for response. The objective response rate (ORR) for both cohorts was 67% (16/24); ORR was 58% (7/12) in the bortezomib-naive cohort and 75% (9/12) in the bortezomib-exposed cohort. Treatment was well-tolerated; the most frequent grade 1/2 toxicities included fatigue, diarrhea, and nausea. Grade >3 toxicities considered potentially related to ibrutinib were observed in 11% of patients.10 The expression of phosphatidylinositol 3-kinase (PI3-K) P110 in cells of hematopoietic origin influences B-cell proliferation and survival.11 GS-1101 is a selective inhibitor of PI3-K signaling and has been shown in vitro to induce

1. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440. 2. Revlimid [package insert]. Summit, NJ: Celgene Corporation. October 2011. 3. Smith MR, Li H, Gordon L, et al. Phase II study of R-CHOP immunochemotherapy followed by 90Y-ibritumomab tiuxetan in untreated mantle cell lymphoma: 5-year Eastern Cooperative Oncology Group Study E1499. J Clin Oncol. In press. 4. Rao AV, Akabani G, Rizzieri DA. Radioimmunotherapy for non-Hodgkin’s lymphoma. Clin Med Res. 2005;3:157-165. 5. Wagner HN Jr, Wiseman GA, Marcus CS, et al. Administration guidelines for radioimmunotherapy of non-Hodgkin’s lymphoma with 90Y-labeled anti-CD20 monoclonal antibody. J Nucl Med. 2002;43:267-272. 6. Zevalin [package insert]. Irvine, CA: Spectrum Pharmaceuticals, Inc. November 2011. 7. Bexxar [package insert]. Research Triangle Park, NC: GlaxoSmithKline. February 2012. 8. Wiztig TE, White CA, Gordon LI, et al. Safety of yttrium-90 ibritumomab tiuxetan radioimmunotherapy for relapsed low-grade, follicular, or transformed non-Hodgkin’s lymphoma. J Clin Oncol. 2003;21:1263-1270. 9. Ponader S, Balasubramanian S, Pham LV, et al. Activity of Bruton’s tyrosine kinase (Btk) inhibitor PCI-32765 in mantle cell lymphoma (MCL) identifies Btk as a novel therapeutic target. Blood (ASH Annual Meeting Abstracts). 2011;118. Abstract 3688 and Poster. 10. Wang L, Martin P, Blum KA, et al. The Bruton’s tyrosine kinase inhibitor PCI-32765 is highly active as single-agent therapy in previously-treated mantle cell lymphoma (MCL): preliminary results of a phase II trial. Blood (ASH Annual Meeting Abstracts). 2011;118. Abstract 442. 11. Kahl B, Byrd JC, Flinn IW, et al. Clinical safety and activity in a phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110 , in patients with relapsed or refractory non-Hodgkin lymphoma. Blood (ASH Annual Meeting Abstracts). 2010;116. Abstract 1777. 12. Meadows SA, Kashishian A, Johnson D, et al. CAL-101 (GS-1101), a specific inhibitor of phosphatidylinositol-3-kinase-delta (PI3K ), disrupts signals from the microenvironment, induces apoptosis, and enhances the antitumor activity of everolimus (RAD001), an inhibitor of mammalian target of rapamycin (mTOR), in mantle cell lymphoma (MCL). Blood (ASH Annual Meeting Abstracts). 2011;118. Abstract 3730. 13. O’Connor OA. Mantle cell lymphoma: identifying novel molecular targets in growth and survival pathways. ASH Education Book. 2007;2007:270-276. 14. Smith MR. Mantle cell lymphoma: advances in biology and therapy. Curr Opin Hematol. 2008;15:415-421.

Current and Emerging Treatment Strategies in Mantle Cell Lymphoma Continued from page 39 malian target of rapamycin (mTOR), in mantle cell lymphoma (MCL). Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 3730. 28. Goy A, Kahl B. Mantle cell lymphoma: the promise of new treatment options. Crit Rev Oncol Hematol. 2011;80:69-86. 29. Viallet J; Gemin X. Safety and efficacy of obatoclax mesylate (GX15-070MS) in combination with bortezomib for the treatment of relapsed or refractory mantle cell lymphoma (MCL). http://clinicaltrials.gov/ct2/show/NCT00407303. Accessed May 7, 2012. 30. Friedberg JW, Vose JM, Kelly JL, et al. The combination of bendamustine, bortezomib, and rit-

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uximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood. 2011;117:2807-2812. 31. Fowler N, Kahl BS, Matous JV, et al. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II vertical study. J Clin Oncol. 2011;29: 3389-3395. 32. Wang M, Fayad L, Wagner-Bartak N, et al. Oral lenalidomide plus 4 doses of rituximab induced prolonged remissions in relapsed/refractory mantle cell lymphoma: a completed phase I/II clinical trial. Ann Oncol. 2011;22(suppl 4):iv119. Abstract 109.

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