VBCC NOVEMBER 2012 VOL 3 NO 8

NOVEMBER 2012 VOL 3 NO 8

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM www.ValueBasedCancerCare.com VBCC PERSPECTIVES

Delta Air Lines’ Approach to Patient Care: HighPerformance Cancer Networks Improving employees’ care while cutting costs

We Must Incorporate Value into Our Decision-Making Process

By John L. Marshall, MD Chief, Division of Hematology/Oncology, Director, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown University, Lombardi Comprehensive Cancer Center, Washington, DC

W

e should all read with great interest the New York Times opinion piece by Peter B. Bach, MD, and colleagues from Memorial Sloan-Kettering Cancer Center on their rationale for not including ziv-aflibercept (Zaltrap) in its formulary for patients with metastatic or advanced colorectal cancer (see article, page 19). Their argument is simple, they said: This new drug provides no additional benefit over existing medicines for the same

By Caroline Helwick

Houston, TX—Delta Air Lines has a commitment to preventive health and comprehensive cancer care for its 140,000 health plan members; the company is piloting a “high-performance cancer network,” said Lynn Zonakis, Managing Director of Health Strategy and Resources, Delta Air Lines, Atlanta, GA, at the 2012 Second Annual Conference of the Association for Value-Based Cancer Care. Ms Zonakis was part of the employers’ panel at the conference who presented perspectives from different employer groups related to cancer care.

Continued on page 27

Oncotype DX Score Predicts Residual Disease after Chemotherapy Expanded utility can also help clinical decision-making

By Audrey Andrews San Francisco, CA—The Oncotype DX Recurrence Score (the 21-gene) test can help identify patients with estrogen receptor (ER)-positive breast cancer with any number of positive lymph nodes who will have residual disease after adjuvant chemotherapy, and who may benefit from additional treatment, reported Eleftherios P. Mamounas, MD, Medical Director, Aultman Hospital Cancer Center,

Canton, OH, at the 2012 Breast Cancer Symposium.

This new retrospective analysis was conducted by investigators from the National Surgical Adjuvant Breast and Bowel Project (NSABP).

The Oncotype DX Recurrence Score has proved to have expanded utility in guiding treatment decisions. “We can identify patients with high residual Continued on page 11

©2012 Engage Healthcare Communications, LLC

type of cancer, yet it is significantly more expensive and has a higher toxicity profile.

[Editor’s note: Since this article was written, the company has indicated it would be cutting the cost of zivaflibercept. Please see additional information on this development on page 21.] As the authors note, anyone Continued on page 20

Stereotactic Body Radiation Therapy Cost-Saving, Convenient for Patients with Prostate Cancer

By Phoebe Starr Boston, MA—In the United States right now, intensity modulated radiation therapy (IMRT) has largely replaced 3-dimensional conformal radiation therapy as the technique of choice for most patients with organconfined prostate cancer that is being

treated with radiation as the primary therapy. Another technique in use is brachytherapy, and, at some centers, proton beam therapy is being studied.

Of all of these radiation technologies, stereotactic body radiation theraContinued on page 9

INSIDE FDA UPDATE . . . . . . . . . . . . . . . . . .4 Synribo approved for CML Abraxane for NSCLC

VBCC PERSPECTIVES . . . . . . . . .20 How will we pay for cancer treatment?

IN THE LITERATURE . . . . . . . . . . . .8 Statins improve survival in patients with cancer

PERSONALIZED MEDICINE . . . . .22 New personalized Rx decisionmaking system

ASTRO ANNUAL MEETING . . . . . . .9 Proton beam therapy more expensive, toxic than standard radiation

HEALTH POLICY . . . . . . . . . . . . . .26 CMS’s new value-based payment policies for 2013

ECONOMIC ISSUES . . . . . . . . . . . .19 A rational step to reducing costs in oncology

DRUG UPDATE . . . . . . . . . . . . . . .40 Abraxane gets new indication for NSCLC

The median age of patients in the VISTA† trial was 71 years (range: 48-91).

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

CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.

▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment.

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost IF YOU DEFINE VALUE AS AN OVERALL SURVIVAL ADVANTAGE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage At 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; 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 $1,506 per 3.5-mg vial as of July 2012 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers.

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

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

For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.

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. *Melphalan+prednisone. † VISTA TRIAL: 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 prespecified 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 analysis was performed.

FDA Update Synribo Approved for Chronic Myelogenous Leukemia The US Food and Drug Administration (FDA) approved omacetaxine mepesuccinate (Synribo; Teva Pharmaceutical) to treat adults with chronic myelogenous leukemia (CML), a he-

matologic disease. An estimated 5430 Americans will be diagnosed with CML in 2012, according to the National Institutes of Health.

“Today’s approval provides a new treatment option for patients who are resistant to or cannot tolerate other

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

VELCADE for Injection 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 (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.

WARNINGS AND PRECAUTIONS: 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 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% 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 require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. 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 8%.

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 Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, 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-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred 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, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.

Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES 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 PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.

Gastrointestinal Toxicity: 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. Interrupt VELCADE for severe symptoms.

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 bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.

Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy.

Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.

Monitor patients closely and take appropriate precautions.

Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

FDA-approved drugs for chronic or accelerated phases of CML,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products, noting that this is the second drug to be approved for CML in the past 2 months. In

Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 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) 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 (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).

A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).

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 reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%).

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 reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) 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. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, 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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September, bosutinib (Bosulif; Pfizer) received FDA approval for patients with chronic-, accelerated-, or blastphase Philadelphia chromosome– positive (Ph+) CML who are resistant to or who cannot tolerate other therapies.

Synribo is intended to be used in patients whose disease has progressed after treatment with ≥2 tyrosine kinase inhibitor (TKI) agents, currently the mainstay of therapy for CML. Omacetaxine mepesuccinate blocks certain proteins that promote the development of cancerous cells. It is injected subcutaneously twice daily for 14 consecutive days over a 28-day cycle, until hematologic response is observed. The drug is then administered twice daily for 7 consecutive days over a 28-day cycle, and continues to be used as long as the patient shows clinical benefit from this therapy.

The FDA approved omacetaxine mepesuccinate under the agency’s accelerated approval program, which allows the agency to approve a drug deemed necessary for a serious disease, based on data from clinical trials showing that the drug has an effect on a surrogate end point that is likely to predict a clinical benefit to patients, to accelerate the access of patients to this therapy until additional clinical evidence is available. In addition, this drug received an orphan drug designation, because it is designated for the treatment of CML, which is considered a relatively rare disease.

The effectiveness of omacetaxine mepesuccinate was evaluated using a combined cohort of patients whose disease progressed after previous treatment with ≥2 TKIs. All patients received omacetaxine mepesuccinate in this evaluation.

The drug’s effectiveness in chronicphase CML was demonstrated by a reduction in the percentage of cells expressing the Ph+ genetic mutation found in the majority of patients with CML. Of the 76 patients with chronicphase CML, 14 patients (18.4%) achieved a reduction in Ph+ expression in an average of 3.5 months. The median duration of the reduction was 12.5 months.

In patients with accelerated-phase CML, the effectiveness of omacetaxine mepesuccinate was determined by the number of patients whose white blood cell counts were normalized or who had a major hematologic response (ie, no evidence of CML). Among the 35 patients with this type of CML, 5 patients (14.3%) achieved a major hematologic response in an average of 2.3 months. The response lasted a median of 4.7 months.

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VALUE PROPOSITIONS Molecule P5091 Effective Against Drug-Resistant Myeloma Molecule P5091 shows effectiveness against drug-resistant myeloma, according to new research at Dana-Farber Cancer Institute that was in part funded by the National Institutes of Health. Findings show that this molecule, known as molecule P5091, can kill multiple myeloma cancer cells that are resistant to bortezomib (Velcade), a frontline therapy for the treatment of patients with multiple myeloma.

“While Velcade is successful in many patients with multiple myeloma, it often loses its effectiveness over time, which prompted us to seek other drug targets,” said lead investigator Dharminder Chauhan, JD, PhD, Senior Scientist at Dana-Farber, and Principal Associate in Medicine at Harvard Medical School.

“In laboratory cell cultures, P5091 resulted in the death of myeloma cells,” noted coinvestigator Kenneth C. Anderson, MD, Director of the Jerome Lipper Multiple Myeloma Center and the LeBow Institute for Myeloma Therapeutics at Dana-Farber. Dana-Farber Cancer Institute; September 10, 2012

Addressing Value a Key Objective of Michigan Oncology Medical Home Project The Michigan Oncology Medical Home Demonstration Project, which is among the first few oncology medical homes in the country, was initiated by ION Solutions and Physician Resource Management, in collaboration with Priority Health, a leading health plan in Michigan. This project aims at addressing and arresting the rising costs of cancer care, using an integrated approach to patient care.

“Our key objectives for this program are to address the public concern over the cost of cancer care therapy and to support oncologist payment for the breadth of services necessary to deliver care,” said John Fox, MD, Vice President, Medical Affairs, Priority Health.

By participating in this oncology medical home, “these practices are confirming their desire to improve upon the process of delivering care so that community oncology remains a viable option for patients desiring enhanced access to care, better outcomes, and reduced costs for care,” Dr Fox said.

The 3 groups intend to recruit additional community oncology practices to join this program in the future. ION Solutions/AmerisourceBergen Specialty Group; August 14, 2012

University, the Fred Hutchinson Cancer Research Center, Palo Alto Research Center, the University of Georgia Medical Center, and the University of Pittsburgh Medical Center. The team will be looking for the presence of carbohydrates in the bloodstream as a biomarker of pancreatic cancer.

“One of the most common features of pancreatic cancers is the increased abundance of a carbohydrate structure called the CA 19-9 antigen,” said Dr Haab. “This carbohydrate structure is attached to many different proteins, many of which are selected from the tumor into the blood circulation, making it available for detection as a biomarker.”

CA 19-9 blood samples are used to confirm the diagnosis of pancreatic cancer, but the test cannot be used in early stages of the disease, because 20% to 30% of incipient tumors produce low levels of CA 19-9. But new developments can now address these low levels, which will be the focus of the new research, with the goal of developing biomarkers for early diagnosis of this type of cancer to improve survival.

“We anticipate these new approaches advancing pancreatic cancer diagnostics, as well as benefiting other glycobiology research in cancer,” Dr Haab said. Van Andel Institute; October 18, 2012

Cancer Research UK Provides >£1 Million to Develop Simple Blood Test to Replace Mammography In a study funded by Cancer Research UK, a team of British scientists are looking for ways to use a simple blood test to detect the early signs of breast cancer more accurately than is done today with mammograms.

“This exciting research means we could one day have a blood test that detects the very early signs of cancer, meaning women could have an annual blood test rather than breast screening,” said principal investigator Jacqui Shaw, MD, University of Leicester, England.

Cancer Research UK has invested more than £1 million in this project.

Charles Coombes, MD, PhD, Coinvestigator and Cancer Research UK’s breast cancer expert from Imperial College, said, “This type of translational science is extremely promising, and the international scientific community is collaborating on its development. When a woman has breast cancer, we can tell by the DNA in their blood. But what we’re trying to find out in our study is how early the signs of breast cancer show up in a blood test….Our research team is only looking at breast cancer, but there are a number of other projects that are looking at using a blood test to detect other cancers, such as bowel and lung.” Cancer Research UK; October 2, 2012

NCI Launches a $2.3-Million Study to Develop Molecular Biomarkers for Pancreatic Cancer

Best Practices Focus of New Quality Program for Select Cancers

The National Cancer Institute (NCI) has awarded $2.3 million for a new research project to develop novel molecular biomarkers for pancreatic cancer. The program will be led by Brian Haab, PhD, Head of Van Andel Institute’s Laboratory of Cancer Immunodiagnostics in Grand Rapids, MI. Pancreatic cancer will affect >43,000 Americans and will kill >37,000 Americans in 2012, according to the NCI. This type of cancer is associated with especially poor prognosis, because it is usually diagnosed at advanced stages of the disease and because it is resistant to chemotherapy (see also page 7).

This 5-year project will include a team of researchers from Emory

A program launched by Blue Cross and Blue Shield of Louisiana in collaboration with Cardinal Health Specialty Solutions is designed to focus on applying clinical pathways to improve cancer treatment as a way to promote best practices.

Aimed at using clinical pathways to identify and promote best practices in the treatment of select types of cancer, “our goal with this joint program is to work with doctors to improve the consistency, quality, and cost-effectiveness of cancer treatment,” said David Carmouche, MD, Vice President and Chief Medical Officer, Blue Cross and Blue Shield of Louisiana.

Cardinal Health; October 22, 2012

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In This Issue

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Editor Lara J. Lorton lara@engagehc.com 732-992-1882 Associate Publisher American Health & Drug Benefits Maurice Nogueira maurice@engagehc.com 732-992-1895

FDA UPDATE

HEALTH POLICY

Synribo approved for CML Abraxane for NSCLC

CMS finalizes payment policies for 2013 More….

ASTRO ANNUAL MEETING

Associate Publisher Cristopher Pires cris@engagehc.com 732-992-1896 Associate Publisher Joe Chanley joe@greenhillhc.com Editorial Assistant Jennifer Brandt jbrandt@the-lynx-group.com 732-992-1536 National Accounts Manager Zach Ceretelle Director, Creative & Design Robyn Jacobs

Stereotactic body radiation therapy cost-saving in prostate cancer More….

Employers’ challenge: cut healthcare costs but not employees’ benefits More….

BREAST CANCER SYMPOSIUM

ECONOMIC ISSUES IN ONCOLOCY

Some staging studies unnecessary in early disease More….

A rational step to reducing cancer care costs More….

Abraxane receives a new indication for NSCLC

We must incorporate value into our decisionmaking process How will we pay for cancer treatment?

More….

ESMO CONFERENCE

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.

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 Past President, ACCC Past Chair, NCCN Board of Directors

Contact Information: For subscription information please contact: circulation@valuebasedcancercare.com Telephone: 732-992-1538 Fax: 732-992-1881

Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, NY

Permission requests to reprint all or part of any article published in this magazine should be addressed to editorial@valuebasedcancercare.com

Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA

Address all editorial queries to: editorial@valuebasedcancercare.com Telephone: 732-992-1536 Fax: 732-992-1881

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

Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 8 times a year by Engage Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2012 by Engage Healthcare Communications, LLC. All rights reserved.

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Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers Pittsburgh, PA Arlene A. Forastiere, MD Senior Vice President Medical Affairs eviti, Inc Philadelphia, PA

The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher.

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VALUE-BASED CANCER CARE

DRUG UPDATE

VBCC PERSPECTIVES

Bevacizumab plus chemotherapy improves survival in platinum-resistant ovarian cancer

VBCC Editorial Board

Quality Control Director Barbara Marino Business Manager Blanche Marchitto

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CONFERENCE

Tracy Gosselin, RN, MSN Duke University Medical Center Durham, NC Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute New York, NY

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Ira Klein, MD, MBA Aetna Hartford, CT

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

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

Denise K. Pierce DK Pierce & Associates Zionsville, IN

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Washington, DC Crystal Kuntz, MPA Astellas Pharma US Washington, DC John L. Marshall, MD Chief, Hematology and Oncology Director, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region Portland, OR

David Hom, MBA Solucia Farmington, CT

Ted Okon, BS, MBA Executive Director Community Oncology Alliance Washington, DC

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

Naimish Pandya, MD University of Maryland Baltimore, MD

NOVEMBER 2012

Jatin J. Shah, MD M.D. Anderson Cancer Center Houston, TX Jayson Slotnik, JD, MPH Partner Health Policy Strategies, LLC Washington, DC Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA 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 Chief Executive Officer OncoMed Onco360 Great Neck, NY

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FDA Update Synribo Approved for...

Continued from page 4

The most common side effects reported during clinical studies with omacetaxine mepesuccinate include thrombocytopenia, anemia, neutropenia (which may lead to febrile neutropenia), diarrhea, nausea, weakness and fatigue, injection site reaction, and lymphopenia. (October 26, 2012)

tein-bound particles in combination with carboplatin for NSCLC are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue.

Paclitaxel protein-bound is already approved for the treatment of patients

with metastatic breast cancer whose disease has progressed after therapy with or who did not respond to therapy with standard combination chemotherapy. In addition, in early results (released November 7) from a phase 3 clinical trial, paclitaxel pro-

tein-bound particles in combination with gemcitabine showed significant improvement in overall survival in patients with pancreatic cancer compared with gemcitabine alone; complete results are expected in January.

(October 11, 2012) ■

Abraxane Receives a New Indication for First-Line Therapy of NSCLC The FDA approved a new indication for paclitaxel protein-bound particles for injection (Abraxane; Celgene Corporation) for the first-line treatment of locally advanced or metastatic non–small-cell lung cancer (NSCLC), in combination with carboplatin, for patients who are not candidates for curative surgery or radiation therapy.

“Non–small cell is the most common type of lung cancer, the leading cause of cancer death in the United States,” said Mark A. Socinski, MD, Director, Lung Cancer Section, Division of Hematology/Oncology, University of Pittsburgh, and lead investigator of phase 2 and phase 3 clinical trials of paclitaxel proteinbound particles in patients with lung cancer. “The FDA approval of Abraxane…offers an important new treatment option for all types of non– small-cell lung cancer patients, in an area that has seen few treatment advancements in recent years.”

The FDA approval of this new indication for paclitaxel protein-bound particles is based on the results of a phase 3, multicenter, open-label study of patients with advanced NSCLC who were randomized to paclitaxel protein-bound particles 100 mg/m2 weekly plus carboplatin (area under the curve [AUC] = 6) every 3 weeks (n = 521) or to generic paclitaxel 200 mg/m2 every 3 weeks plus carboplatin (AUC = 6; n = 531). Overall response rate (ORR)—the primary end point— was significantly higher with proteinbound paclitaxel particles compared with generic paclitaxel (33% vs 25%, respectively).

In addition, paclitaxel proteinbound particles demonstrated a higher ORR for squamous-cell carcinoma compared with paclitaxel (41% vs 24%, respectively) and for large-cell carcinoma (33% vs 15%, respectively).

Paclitaxel protein-bound particles achieved ORR that was similar to generic paclitaxel in patients with carcinoma or adenocarcinoma (26% vs 27%, respectively).

The most common (≥20%) adverse reactions reported with paclitaxel pro-

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In The Literature Statin Therapy Improves Survival in Patients with Cancer It is well understood that cancer-cell proliferation encourages tumor growth and metastasis. It is also known that the use of statins blocks the production of cholesterol, and endogenous choles-

terol is crucial for human cell proliferation. Linking these 2 disparate mechanisms, researchers in Denmark set out to investigate whether statin therapy can help to reduce cancer-related mortality by limiting cancer-cell proliferation in patients who have used statins before they were diagnosed

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

with cancer (Nielsen SF, et al. N Engl J Med. 2012;367:1792-1802).

Using data from the Danish Cancer Registry between 1995 and 2007, which includes cancer data for the entire patient population in Denmark, the investigators compared mortality among patients with cancer (aged ≥40

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

65481-R1-V1

years) who had used statins before their cancer diagnosis and patients with cancer who had never used statin therapy. During the study period, 18,721 patients with cancer had used statins regularly before being diagnosed with cancer, and 277,204 patients with cancer had never used statins. The follow-up continued until the end of 2009 (median, 2.6 years; range, 0-15). Other national registries were also used to incorporate mortality data and the various causes of death.

During the 1,072,503 person-years of follow-up, a total of 195,594 patients died—162,067 from cancer, 14,489 from cardiovascular disease, and 19,038 from other causes. The multivariable-adjusted hazard ratios (HRs) for death from any cause for patients using statins compared with those who have never used statins were 0.85 (95% confidence interval [CI], 0.83-0.87; P <.001) and 0.85 (95% CI, 0.82-0.87; P <.001) for death from cancer.

Adjusted HRs for death from cancer according to the daily statin dose (the assumed average maintenance daily dose) were 0.83 (95% CI, 0.81-0.86; P <.001), for a defined daily dose of 0.01 to 0.75; 0.87 (95% CI, 0.83-0.91; P <.001), for a defined daily dose of 0.76 to 1.50; and 0.87 (95% CI, 0.81-0.92; P <.001), for a defined daily dose of 1.50.

This lack of a statin dose and cancerrelated mortality indicates that the use of any statin dose will help to reduce mortality in patients with cancer.

Furthermore, the reduction in cancer-related mortality was seen in all 13 types of cancer that were investigated.

These results are supported by evidence from previous studies showing a reduction in mortality in patients with advanced prostate cancer who have used statins and a reduced rate of cancer recurrence in patients with prostate or breast cancer who have used statins.

This new study clearly shows a need for clinical trials to investigate the potential role of statin therapy in patients with cancer. This study was not designed to investigate the role of statins for the prevention of cancer.

Survival Trends in Myelofibrosis Improving at a Slow Pace Primary myelofibrosis (PMF) is associated with a significant risk for mortality. Advances in the treatment of PMF have nevertheless failed to significantly affect survival, which remains a challenge, and life expectancy has not increased significantly in the Continued on page 16

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Stereotactic Body Radiation Therapy Cost-Saving... py (SBRT) delivered via the CyberKnife is potentially the most cost-effective and convenient for patients, while achieving at least equivalent efficacy in disease control, according to 2 retrospective studies reported at the 2012 American Society for Radiation Oncology annual meeting. Both studies have a median follow-up of approximately 3 years, and larger studies with longer follow-up are needed to verify these findings.

SBRT delivers precise high doses of radiation to the prostate using con-

at a glance ➤ Overall, IMRT has replaced 3-dimensional conformal radiation therapy for patients with organ-confined prostate cancer ➤ SBRT via CyberKnife is a cost-effective, convenient option for patients to achieve disease control ➤ SBRT typically requires 5 sessions versus the 40-45 sessions needed with IMRT; results are 5%-10% better with SBRT than with IMRT ➤ Medicare reimbursement for SBRT is a median of $22,000 versus $40,000-$45,000 per patient for IMRT

verging, finely collimated beams that target prostate tissue and spare normal tissue. The CyberKnife is a robotic technology used to deliver SBRT. A course of prostate radiation typically takes 5 sessions (or 1-2.5 weeks) compared with 40 to 45 sessions using IMRT. SBRT technology is now available at approximately 150 centers in the United States.

because Medicare reimbursement for SBRT is a median of $22,000 versus $40,000 to $45,000 per patient for IMRT. In addition, because SBRT is delivered over 1 to 2.5 weeks instead of the 8 weeks needed for IMRT, the cost-savings in healthcare utilization are significant, and the shorter duration offers greater convenience for patients.

Pooled Analysis of OrganConfined Prostate Cancer A pooled analysis of 1100 patients with organ-confined prostate cancer who were treated at 8 different centers between 2003 and 2010 with Cyberknife SBRT showed that the actuarial 5-year biochemical control was 95% for low-risk patients, 90% for intermediate-risk patients, and 80% for highrisk patients.

Similar results were found in 150 patients who were treated with androgen deprivation therapy and with different doses of SBRT, reported Alan J. Katz, MD, JD, a radiation oncologist at Flushing Radiation Oncology, NY. “These results are 5% to 10% better than those with standard IMRT, which takes 40 to 45 days to deliver. At this point, the statistics should encourage men with organ-confined prostate cancer to seek SBRT as an alternative to IMRT, brachytherapy, or prostate surgery,” Dr Katz stated.

Intermediate-Risk Prostate Cancer A second retrospective review, which was reported by Robert M. Meier, MD, a radiation oncologist at Swedish Radiosurgery Center, Seattle, WA, focused on 129 patients with intermediate-risk, organ-confined prostate cancer who were treated with CyberKnife SBRT at 21 different institutions between December 2007 and April 2010. The median follow-up was 3 years (range, 2.5-4 years).

The quality-of-life Expanded Prostate Cancer Index Composite scores showed that both urinary and bowel side effects were greater early in the course of treatment, but by 6 months, tended to approach baseline levels.

At 2 years after SBRT, quality-of-life scores were similar to baseline. Most urinary and bowel side effects were grades 1 and 2.

Biochemical control was achieved in 99.2% of patients; only 1 of 129 patients experienced a rise in prostatespecific antigen after a nadir achieved

by SBRT. Putting these preliminary results in

Significant Cost-Savings SBRT can achieve huge cost-savings,

Continued from cover

“These results are 5% to 10% better than those with standard IMRT, which takes 40 to 45 days to deliver. At this point, the statistics should encourage men with organ-confined prostate cancer to seek SBRT as an alternative to IMRT, brachytherapy, or prostate surgery.”

—Alan J. Katz, MD, JD

context, Dr Meier said that the typical rate of biochemical failure is 10% to 20% at 4 years with IMRT and proton beam therapy.

At a press conference, the President-Elect of ASTRO, Colleen Lawton, MD, Clinical Director of Radiation Oncology at the Medical College of Wisconsin, Milwaukee, said that these are exciting results, but longer followup is needed to establish SBRT as a standard of care. ■

Proton Beam Therapy: Similar Toxicity to Standard Radiation, at Much Higher Cost

By Phoebe Starr Boston, MA—The use of proton beam radiation therapy (PBRT) for the treatment of prostate cancer is increasing across the United States, but there is no evidence from randomized, controlled trials to suggest that PBRT is more effective than intensity modulated radiation therapy (IMRT), which is the current standard of care. A study presented at the 2012 American Society for Radiation Oncology annual meeting found few differences in toxicity between the 2 techniques, but demonstrated that PBRT was associated with a 57% increase in median cost per patient.

Similar Efficacy, Double the Cost “PBRT is an emerging treatment for

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“PBRT is an emerging treatment for men with prostate cancer, yet it is much more expensive than IMRT. The longer-term effects, costs, and other clinical and patientreported outcomes are needed to inform the adoption of PBRT for prostate cancer.”

—James B. Yu, MD

men with prostate cancer, yet it is much more expensive than IMRT,” said James B. Yu, MD, Assistant Professor of Therapeutic Radiology, Yale School of Medicine, New Haven,

CT. “We need a prospective large study comparing radiation techniques to justify widespread use of PBRT for prostate cancer,” he explained.

The population-based, retrospec-

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tive, observational study was based on 22,647 Medicare beneficiaries between the ages of 66 and 94 years who received PBRT or IMRT for prostate cancer in 2008 and 2009; 421 patients (2%) received PBRT and 27,226 patients (98%) received IMRT. The median Medicare reimbursement per patient is $32,428 for PBRT and $18,575 for IMRT, which represents a 57% difference.

PBRT was associated with a significant reduction in urinary toxicity at 6 months versus IMRT (6.1% vs 12%, respectively); however, by 1 year, there was no difference between groups for urinary toxicity (18.9% for PBRT vs Continued on page 10

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Proton Beam Therapy: Similar Toxicity to Standard...

21.9% for IMRT). No significant differences were observed at 6 months and at 1 year between the 2 groups in gastrointestinal (GI) or other toxicities.

“The longer-term effects, costs, and other clinical and patient-reported outcomes are needed to inform the adoption of PBRT for prostate cancer,” Dr Yu stated.

The study had several limitations, he continued. It is a retrospective study that is a claims-based analysis with no staging information and with no data on the extent or field of radiation.

Potential Differences in Side Effects A second study found minimal differences between PBRT, IMRT, and the older 3-dimensional conformal radiation therapy (3D-CRT).

The study included 153 patients treated with IMRT, 123 treated with 3D-CRT, and 94 patients treated with

“These findings are a unique addition to existing research…and suggest that PBRT may lead to fewer immediate side effects in prostate cancer patients.”

—Phillip Gray, MD

PBRT. Quality of life (QOL) was assessed by the Expanded Prostate Cancer Index Composite in the IMRT cohort and by the Prostate Cancer Symptom Index in the PBRT and 3DCRT cohorts.

The main difference in QOL scores in the GI domain was found 2 to 3 months posttreatment, when 3D-CRT and IMRT—but not PBRT—were asso-

ciated with a clinically meaningful decrement in QOL scores. Over 12 months, the 3 cohorts had similar QOL scores for GI effects.

For urinary irritation, all 3 groups had lower QOL scores at 2 to 3 months of follow-up, but this was clinically meaningful only for IMRT. Sexual function QOL scores were lower in all 3 groups at 24 months, but this was not clinically meaningful (defined in this study as scores exceeding half of the standard deviation of the baseline mean score).

“These findings are a unique addition to existing research in the field, and suggest that PBRT may lead to fewer immediate side effects in prostate cancer patients,” noted Phillip Gray, MD, a resident at Harvard Radiation Oncology Program, Boston.

He suggested that a prospective, randomized, controlled trial is needed to compare these technologies. ■

Continued from page 9

at a glance ➤ PBRT is an emerging treatment for men with prostate cancer, but is much more costly than IMRT ➤ There is no evidence to suggest that PBRT is more effective than IMRT ➤ Although treatment with PBRT showed a significant, almost 50% reduction in urinary toxicity at 6 months versus IMRT, after 1 year this difference disappeared ➤ Median Medicare reimbursement per patient is $32,428 for PBRT and $18,575 for IMRT ➤ More evidence is needed to compare the various treatment options to justify the use of PBRT in this patient population

Newer, More Costly Radiation Technologies Adopted in Elderly Patients with Breast Cancer

By Phoebe Starr Boston, MA—The patterns of use of radiotherapy have changed over time in elderly patients with stage I breast cancer, and these changes have financial implications for the healthcare system. In elderly patients with favorable-risk breast cancer, the use of intensity modulated radiation therapy (IMRT) and brachytherapy steadily increased from 2001 to 2007, while the use of standard external beam radiation therapy (EBRT) decreased.

Data are lacking on whether the newer technologies improve outcomes in this patient population. In a study of patients who were enrolled in the Surveillance, Epidemiology and End Results–Medicare database, these utilization patterns led to a cost increase of 63% per patient. The study’s results were reported at the 2012 American Society for Radiation Oncology annual meeting.

In 2007, 52% of patients with favorable-risk breast cancer received EBRT, and 24% received a newer form of therapy. The median cost of EBRT was $6000 per patient compared with $12,469 for IMRT and $13,981 for brachytherapy, said Kenneth B. Roberts, MD, Associate Professor of Therapeutic Radiology and Medical Director, Yale-New Haven Shoreline

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Medical Center, CT. “The incremental cost to our nation for new radiation therapy modalities in 2007 was $31 billion. We need to

When considering whether to omit radiation therapy in elderly patients with breast cancer, “the decision should encompass tumor characteristics, patient anxiety, and patient goals.”

—Meena S. Moran, MD determine if the benefit is commensurate with the increased cost,” stated Dr Roberts. “Further study is needed to explore radiation modalities in this low-risk population.”

The CALGB C9343 trial, which was published in 2004, included women aged ≥70 years who had clinical stage

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T1 cancer and negative nodes treated with lumpectomy with negative margins. The 10-year follow-up showed that the local recurrence rate was 2% for those treated with radiation versus 9% for those who did not receive radiation.

Dr Roberts coauthored a study showing that this trial had no effect on the use of radiation in favorable-risk patients. “Radiation use remained stable even in patients with low life expectancy,” he said.

Over the past decade, new treatments have been adopted—including accelerated partial-breast irradiation and brachytherapy—without much evidence to support their use, Dr Roberts noted. The present study was conducted to determine temporal trends in the use of technology and the associated costs in elderly patients with favorable-risk breast cancer.

This new study included 12,925 women (mean age, 77.7 years; range, 70-94 years) with stage I breast cancer who were undergoing lumpectomy.

Their tumor size was <2 cm, and all cancers were estrogen receptor positive. Of the total patients, 67% received some form of radiation therapy.

The utilization patterns changed over time. In 2007, 24% of the patients

received no radiotherapy, and progressive increases in brachytherapy (11.2%) and IMRT (12.4%) were seen.

The use of standard EBRT decreased from 76% in 2001 to 52% in 2007.

Fewer women aged ≥85 years received radiation therapy, but even in this group there were temporal changes; in 2008, 8.8% were treated with brachytherapy, 5.3% with IMRT, and 21.2% received standard EBRT. The study did not include data on quality of life and toxicity.

Meena S. Moran, MD, Associate Professor of Therapeutic Radiology and Assistant Clinical Professor of Nursing, Yale School of Medicine, and Medical Director, Radiation Oncology at William W. Backus Hospital, CT, commented that this study showed that the utilization of EBRT has decreased in older women, yet these patients are opting for costly newer technologies, with no data to show improved outcomes.

Dr Moran indicated that the real question is how to define “elderly.”

Also, it is not clear whether radiation should be omitted in elderly patients with favorable-risk breast cancer. “The decision should encompass tumor characteristics, patient anxiety, and patient goals,” she stated. ■

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Oncotype DX Score Predicts Residual Disease... risk in spite of receiving chemotherapy. We can try to find a better treatment for them or enroll them in a clinical trial. By contrast, patients with low residual risk may do well with less treatment,” said Dr Mamounas.

Such patients may be sufficiently treated with only 4 cycles of chemotherapy rather than a full course of 8 cycles, including a taxane, Dr Mamounas suggested.

The current analysis indicates that the extent of chemotherapy may be tailored according to the estimation of residual risk, he said.

at a glance ➤ The Oncotype DX Recurrence Score is approved for patients with ER-positive, node-negative breast cancer as a guide for adding chemotherapy to endocrine therapy ➤ A new study shows that it can also be used in patients with ER-positive, node-positive breast cancer who are treated with chemotherapy and with endocrine therapy ➤ The test was a significant predictor of DFS, distant recurrence–free interval, breast cancer–specific survival, and OS ➤ Low scores were associated with improved DFS and OS outcomes ➤ By identifying residual disease in this patient population, the test scores can help identify patients who would benefit from a different therapy or from less chemotherapy

The Oncotype DX Recurrence Score is currently approved for use in patients with ER-positive, node-negative breast cancer to estimate whether the addition of chemotherapy to endocrine therapy would be beneficial.

This new study shows that the Oncotype DX Recurrence Score can also be applied to patients with ERpositive, node-positive breast cancer who are treated with chemotherapy and with endocrine therapy. In this population, the Recurrence Score was prognostic across the spectrum of subgroups.

“This gene assay represents a biological tool that may be useful in the future in stratifying patients for clinical trials and in identifying candidates whose outcomes can be improved.”

“We can identify patients with high residual risk in spite of receiving chemotherapy. We can try to find a better treatment for them or enroll them in a clinical trial. By contrast, patients with low residual risk may do well with less treatment.”

—Eleftherios P. Mamounas, MD

—Andrew Seidman, MD

correlating them with outcomes. The median follow-up was 11.2 years.

The current analysis included 1065 patients who had been treated with adjuvant endocrine therapy and an anthracycline and cyclophosphamide combination, with or without paclitaxel, in the randomized NSABP B-28 clinical trial. Recurrence scores were calculated using tissue specimens from past breast surgeries and then

Robust Independent Predictor of Outcomes The Recurrence Score was low (<18) in 36% of patients, intermediate (1830) in 34% of patients, and high (≥31) in 30% of patients.

In a univariate analysis, the Recurrence Score was a significant predictor of disease-free survival (DFS), distant recurrence–free interval, breast cancer–specific survival, and overall

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survival (OS). In a multivariate analysis, the Recurrence Score provided independent prognostic information for DFS, distant recurrence–free interval, and OS beyond clinical and pathologic factors, including treatment, age, tumor size/grade, number of positive nodes, and type of surgery (P <.001).

Low scores on the test were associated with improved outcomes: • DFS was close to 76% among patients with a low score but dropped to 48% for those with a high score • OS was 90% for patients with a low score versus 63% for those with a high score.

The Recurrence Score was strongly related to the 10-year risk of recurrence, with events occurring in 54% of patients in the group with high Recurrence Scores versus in 17% of patients with low Recurrence Scores.

Breast cancer–specific deaths occurred in 33% of patients with high Recurrence Scores and in 2% of those with low Recurrence Scores.

By treatment assignment, outcomes were very similar between the treatment arms in patients with low Recurrence Scores, with the benefit of paclitaxel seen mainly in the groups with intermediate and high Recurrence Scores.

Andrew Seidman, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center, New York, commented that the study “highlights the fact that despite hormone receptor positivity and HER2 negativity, many patients will have a high risk of recurrence despite receiving chemotherapy and appropriate endocrine therapy. This gene assay represents a biological tool that may be useful in the future in stratifying patients for clinical trials and in identifying candidates whose outcomes can be improved.” ■

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11

Breast Cancer Symposium

Some Staging Studies Not Beneficial in Early Breast Cancer Work-Up Avoid extensive imaging in stage I or II disease

By Caroline Helwick San Francisco, CA—Three frequently used radiologic tests rarely detect metastases in patients with a new diagnosis of breast cancer and should not be routinely performed, according to a comprehensive literature review presented at the 2012 Breast Cancer Symposium.

Bone scan, liver ultrasound, and chest x-ray are often used as first-line screening modalities for potential metastases. However, no established protocol is available for such costly screening, and no solid evidence justifies its use—which now is often accompanied by computed tomography (CT), positron-emission tomography (PET), and magnetic resonance imaging (MRI), said Stuart-Allison Moffat Staley, MPH, a medical student at the University of North Carolina School of Medicine, Chapel Hill.

“These very low detection rates, particularly in stage I and II disease, make us question the utility of these 3 modalities for an adequate staging evaluation.”

—Stuart-Allison Moffat Staley, MPH “Our literature analysis suggests that these 3 tests are of little use in screening women for metastases, and likely result in a lot of false-negatives in early-stage disease,” Ms Staley said at a press briefing. “The relevant topic is cost containment. When you look at the cost of these 3 tests, they are significantly less expensive than other more advanced imaging options; however, when they

are used routinely in thousands of new breast cancer patients annually, collectively they become costly to the healthcare system,” she indicated.

Ms Staley noted that as a tertiary care center, her institution receives many referrals from community oncologists.

“Many patients do come in having had staging evaluations, and physicians are using chest x-ray and liver ultrasound in many cases,” she stated.

Test Outcomes Vary

by Disease Stage The investigators asked whether bone scan, liver ultrasound, and chest x-ray help to determine the extent of metastatic disease in asymptomatic, newly diagnosed patients with breast cancer. Using detection rate (defined as the number of patients with an abnormal test result divided by the total number of patients tested) as the primary outcome, 8 studies met the inclusion criteria.

The primary outcome measure ranged from <0.9% to approximately 4%. As expected, the rates were highest for patients with stage III disease.

By modality and by stage, the detection rates were: • Bone scan: 1.29% for stage I, 3.09% for stage II, and 12.5% for stage III, for an average of 4.18% • Ultrasound of the liver: 0.47% for stage I, 1.0% for stage II, and 4.2% for stage III, for an average of 1.46% • Chest x-ray: 0% for stage I, 0.42% for stage II, and 4.57% for stage III, for an average of 0.87%.

“These very low detection rates, particularly in stage I and II disease, make us question the utility of these 3 modalities for an adequate staging evaluation,” Ms Staley noted.

Detection rates of metastases were higher for women with stage III disease than for women with stage I or II breast cancers, particularly as detected by bone scans (12.5%), suggesting that this modality may still have a role in this subgroup.

“We are living in a time when we move quickly to embrace new, more sensitive technologies, but the elephants in the room are the false-positives.”

—Andrew Seidman, MD

However, the researchers suggested that these 3 particular imaging tests may be unnecessary even in these women, when the patients are also assessed with more sensitive imaging, such as PET, CT, or MRI scans.

Andrew Seidman, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center, New York, commented on the findings. “It strikes me that we are living in a time when we move quickly to embrace new, more sensitive technologies, but the elephants in the room are the false-positives. The ‘Choosing Wisely’ campaign, which ASCO [American Society of Clinical

at a glance ➤ Bone scans, liver ultrasounds, and chest x-rays result in a high rate of false-negatives in stage I or II breast cancer ➤ Although these tests are less expensive than newer imaging modalities, they become costly when used in thousands of women ➤ Detection rates are highest for stage III breast cancer but their utility is still not clear ➤ According to the “Choosing Wisely” campaign, extensive testing in low-risk patients can do more harm than good Oncology] participates in, recommends that we back off from examinations that are really not evidencebased and which, in many cases, do more harm than good.”

Extensive Testing Is Futile in Low-Risk Patients The results of this study are consistent with other findings suggesting that extensive testing is futile in patients with a very low risk of distant metastases, pointed out Dr Seidman.

“Doing extensive imaging, looking for something that has a very low yield and little impact on health, can lead to unnecessary procedures, biopsies, complications, and costs,” he noted.

The higher yield in patients with stage III disease probably exempts this group from such restrictions, Dr Seidman added. He said that for patients with stage I and II cancer, he does not order these imaging tests, nor does he order PET scans. “I reserve these for patients at high risk, which includes stage III breast cancer,” he said. ■

Costly Acute Care Episodes Are Common for Patients with Early Breast Cancer Physicians must anticipate, plan for these events San Francisco, CA—Acute care utilization, namely, emergency department visits and hospitalizations, are surprisingly common among patients with early breast cancer, according to a retrospective study using an administrative database in Ontario, Canada.

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The findings coincide with current efforts, at least in the United States, to reduce acute care utilization as a chief means of reducing the cost of treating cancer. In fact, keeping patients with cancer away from emergency departments and hospitals has become a

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quality measure in many healthcare systems.

“In clinical trial populations, serious adverse events resulting in hospitalization from adjuvant chemotherapy are uncommon, but in community populations there’s a lack of information re-

garding the frequency of these toxicities,” said Katherine A. Enright, MD, MPH, of the Carlo Fidani Peel Regional Cancer Centre in Mississauga, Ontario, who presented the study results at the 2012 Breast Cancer Symposium.

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Breast Cancer Symposium

No Increase in Leukemia or MDS with Adjuvant Chemotherapy for Breast Cancer

By Audrey Andrews

“The rates of AML/MDS were found to be low after adjuvant chemotherapy, and similar to those noted in nonchemotherapy-treated patients.”

Photo by © ASCO/Todd Buchanan 2012

San Francisco, CA—According to a study from the US Oncology Network, patients with breast cancer who are treated with adjuvant chemotherapy have no increased risk for acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), at least within the first 3 years of treatment.

“The rates of AML/MDS were found to be low after adjuvant chemotherapy, and similar to those noted in nonchemotherapy-treated patients,” reported Neelima Denduluri, MD, a medical oncologist at Virginia Cancer Specialists, Arlington, during the 2012 Breast Cancer Symposium.

Previous estimates have placed the risk for AML or MDS after breast cancer therapy at approximately 1%, with the greatest risk seen among older patients and patients who receive anthracyclines, higher cumulative doses of cyclophosphamide, or radiotherapy. It has not been established

—Neelima Denduluri, MD

whether granulocyte colony-stimulating factors are correlated with increased risk, and incidence rates with taxane combinations are not wellcharacterized.

Dr Denduluri and colleagues explored the oncology-specific electronic health record iKnowMed, which contains nearly 1.3 million patient records.

The base population included 20,900 patients with breast cancer, of whom 11,295 received chemotherapy.

At a median follow-up time of approximately 3 years, 12 cases of AML or of MDS were identified among chemotherapy recipients (0.106%); of these 12 patients, 8 were receiving anthracyclines and 11 were receiving peg-

Costly Acute Care Episodes Are Common...

“The objective of this study was to identify the frequency and type of serious chemotherapy-associated toxicities resulting in acute care utilization among women undergoing contemporary adjuvant chemotherapy for early breast cancer, and to com-

at a glance ➤ Acute care utilization for chemotherapy-related toxicities is common among patients with early breast cancer ➤ These events add significant cost to cancer therapy ➤ Fever, neutropenia, and infection are the most common and are greater with taxanebased therapy than with anthracycline therapy ➤ Consider safety when choosing a chemotherapy regimen in early breast cancer ➤ Because all regimens recommended by the NCCN for these patients contain a taxane, physicians must anticipate and plan for these events

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pare these rates to women with no history of cancer,” Dr Enright said.

More than 40% of Patients Seek Acute Care The study identified 4718 patients who received at least 1 cycle of chemotherapy and who were matched to controls without cancer. The study did not include patients who had received growth factor support or dose-dense chemotherapy.

“The use of taxane-based chemotherapy, a high comorbidity burden, and place of residence were all associated with increased odds of acute care utilization.”

—Katherine A. Enright, MD, MPH

The majority (57.9%) of patients received docetaxel-containing chemotherapy regimens, and a smaller proportion received paclitaxel (21.9%) or anthracyclines only (20%).

An acute care contact (an emergency department visit or hospitalization) was noted if the visit occurred within

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30 days of chemotherapy. At least 1 acute care visit occurred in 43% of the patients receiving adjuvant chemotherapy compared with 9% of the controls without cancer. In addition, 18% of patients receiving chemotherapy had multiple visits (range, 2-16) compared with 2% of the controls.

“Clinicians just have to anticipate these toxicities.”

—Krystyna D. Kiel, MD

Hospital admissions were significantly more frequent (44%) in those with breast cancer compared with the controls (25%; P <.001).

Fever, neutropenia, and infection were the most frequent (24%) chemotherapy-associated toxicities; these events were more common with the use of docetaxel (28%) or with paclitaxel (20%) than with anthracyclineonly chemotherapy regimens (16%).

“The use of taxane-based chemotherapy, a high comorbidity burden, and place of residence were all associated with increased odds of acute care utilization,” Dr Enright pointed out.

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filgrastim. The median time to onset of AML or MDS in chemotherapy recipients was 22 months. Among patients with breast cancer who were not receiving chemotherapy, 16 cases of AML or MDS (0.167%) were reported.

The risk was significantly increased, by 7-fold, among patients aged ≥70 years and nearly 4-fold among those who received anthracyclines. By contrast, the almost 3-fold increase with pegfilgrastim was numerically higher but not statistically significant, Dr Denduluri said.

“With the recent news that Robin Roberts with Good Morning America developed MDS after beating breast cancer, many of my patients were concerned about the risk,” Dr Denduluri said. “This study can reassure patients who receive adjuvant chemotherapy that their risk of a secondary AML/MDS is very low within the first 3 years.” ■

Krystyna D. Kiel, MD, Lecturer, Rush University Medical Center, Chicago, IL, commented that the findings are in line with those of a 2006 SEER (Surveillance, Epidemiology and End Results) database analysis. That analysis showed that 61% of patients with breast cancer receiving chemotherapy versus 42% of patients not receiving chemotherapy were seen in the emergency department or were hospitalized.

Dr Kiel found it noteworthy that 57% of the hospitalizations in the 2006 study were related to surgery for breast cancer. These episodes are very costly to the healthcare system, she indicated.

Dr Kiel said that the findings speak to the need for oncologists to choose treatment regimens based on efficacy, as well as on tolerability. For example, because taxanes were shown to be responsible for much of the toxicity leading to acute care utilization, their elimination might be appropriate in some patients, such as in patients with a low-risk disease, based on the Oncotype DX Recurrence Score (see article, page 1).

Dr Kiel added, however, that the regimens currently recommended by the National Comprehensive Cancer Network (NCCN) all contain a taxane.

“So, clinicians just have to anticipate these toxicities,” she said.—CH ■

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In Advanced Renal Cell Carcinoma (RCC)...

INDICATION VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

IMPORTANT SAFETY INFORMATION WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See â&#x20AC;&#x153;Warnings and Precautions,â&#x20AC;? Section 5.1, in complete Prescribing Information. s Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed.

Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions].

Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. s QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed.

s Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (0.6%). Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment).

Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. s Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. s Arterial Thrombotic Events: Arterial thrombotic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thrombotic event in the past 6 months. s Venous Thromboembolic Events: Venous thromboembolic events have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized RCC trial, venous thromboembolic events were reported

in 1% of patients treated with VOTRIENT and in 1% of patients treated with placebo. Monitor for signs and symptoms. s Gastrointestinal Perforation and Fistula: In RCC trials, gastrointestinal perforation or fistula were reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. s Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. s Hypertension: Hypertension, including hypertensive crisis, has occurred. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks).

Blood pressure should be well-controlled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than one week), and frequently thereafter. Treat increased blood pressure promptly with standard antihypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. s Wound Healing: VOTRIENT may impair wound healing.

Interruption of therapy is recommended in patients undergoing surgical procedures; treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence. s Hypothyroidism: Hypothyroidism was reported in 7% (19/290) of patients treated with VOTRIENT in the

Move Forward With VOTRIENT In a Phase 3, randomized, double-blind, placebo-controlled trial, VOTRIENT provided significant improvement in progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients with advanced RCC of clear cell or predominant clear cell histology1,2

All patients

Treatment-naïve patients

Cytokine-pretreated patients

9.2 months (95% CI, 7.4-12.9)

11.1 months (95% CI, 7.4-14.8)

7.4 months (95% CI, 5.6-12.9)

overall median PFS with VOTRIENT (n=290) vs 4.2 months (95% CI, 2.8-4.2) with placebo (n=145) (P<0.001) 1,3

median PFS with VOTRIENT (n=155) vs 2.8 months (95% CI, 1.9-5.6) with placebo (n=78) (P<0.001) 1,3

median PFS with VOTRIENT (n=135) vs 4.2 months (95% CI, 2.8-5.6) with placebo (n=67) (P<0.001) 1,3

NCCN Guidelines® Category 1 recommendation4 s As a first-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology. These Guidelines also include therapies other than pazopanib (VOTRIENT) as first-line treatment options

Once-daily oral dosing1

VOTRIENT: Adverse events profile included1:

s The recommended starting dose of VOTRIENT is 800 mg once daily without food (1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg s Do not crush tablets due to the potential for increased rate of absorption s If a dose is missed, it should not be taken if it is less than 12 hours until the next dose s In RCC, initial dose reduction should be 400 mg; additional dose decrease or increase should be in 200-mg steps based on individual tolerability s Dose modifications, interruptions, and discontinuations may be required in patients with hepatic impairment, drug interactions, and following adverse events

s Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended

s Forty-two percent of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose-reduced

randomized RCC trial and in no patients receiving placebo.

Monitoring of thyroid function tests is recommended. s Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. Monitor urine protein. Interrupt treatment for 24-hour urine protein *3 grams and discontinue for repeat episodes despite dose reductions.

s Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thrombotic events, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, and fetal harm s Most common adverse events (>20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting s See below and accompanying Brief Summary for additional Important Safety Information, including warnings and precautions

s Pneumothorax: Two of 290 patients treated with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax. s Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT. Avoid grapefruit and grapefruit juice.

s Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly.

Consider interruption or discontinuation of VOTRIENT.

Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers.

s Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized

by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events.

s Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. s Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. s Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients.

In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients.

Laboratory abnormalities occurring in >10% of patients and more commonly (*5%) in patients taking VOTRIENT versus placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%).

Please see Brief Summary of Prescribing Information for VOTRIENT, including BOXED WARNING, on adjacent pages.

References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2012. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Data on file, GlaxoSmithKline.

4. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.2.2012. ©National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed June 1, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. s Adverse Reactions in the Randomized RCC Trial: Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced.

The most common adverse reactions (>20%) for VOTRIENT versus placebo were diarrhea (52% vs 9%), hypertension (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%).

VOTRIENT.com

In The Literature Survival Trends in Myelofibrosis Improving...

Continued from page 8

past decades, in part because of a lack of breakthroughs in treatment.

Approximately 20% of patients with PMF progress to acute leukemia. A recent international study evaluated

the current survival status of patients with PMF in 4 countries in Europe (Cervantes F, et al. J Clin Oncol. 2012; 30:2981-2987).

Median survival of patients with PMF in the 1970s, 1980s, and early and mid-1990s ranged from 3.5 years to 5 years, with no evidence of improved

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information.

WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials.

Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).]

1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg.

Further dose reductions may be needed if adverse effects occur during therapy.

This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors [see Drug Interactions (7.1)]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided.

VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)].

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized RCC trial, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo. Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)].

Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.3)].

Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the RCC trials

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survival for patients who were diagnosed between 1985 and 1997 compared with those diagnosed in the previous decade (1970-1984). However, the landscape for patients with PMF may be incrementally changing in recent years.

This new study included data of 802

patients with PMF in France, Italy, Spain, and the United Kingdom who were divided into 2 groups based on the period of their PMF diagnosis— 434 patients were diagnosed between 1980 and 1995, and 368 patients were diagnosed between 1996 and May 2007. By the time of this analysis, 83%

of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy studies. In the randomized RCC trial, 1% (3/290) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. Blood pressure should be monitored and managed promptly using a combination of antihypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.9)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N=586), cerebral/intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thrombotic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thrombotic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have occurred. In the randomized RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.8 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances.

Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Discontinue VOTRIENT in patients developing RPLS. 5.9 Hypertension: Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well-controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.10 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.11 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial. No patients on the placebo arm had hypothyroidism.

In RCC trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) of patients. Proactive monitoring of thyroid function tests is recommended. 5.12 Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Baseline and periodic urinalysis

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In The Literature of patients from the earlier period and approximately 50% of the patients diagnosed in the later period had died.

A comparison of the survival patterns among the 2 period groups showed a survival increase of almost 2 years for patients diagnosed between 1996 and 2007 (median survival, 6.5

years; 95% CI, 5.5-7.4) compared with those diagnosed a decade earlier (median survival, 4.6 years; 95% CI, 4.0-5.1). Furthermore, the increase in survival persisted after applying the data from other survival studies and adjusting for increased life expectancy in the general population, as well as

during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.13 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection.

Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.14 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.15 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and wellcontrolled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thrombotic events, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.9, 5.13-5.14)]. Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.1) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC who Received VOTRIENT VOTRIENT

Placebo

(N=290)

(N=145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4

% % % % % % Adverse Reactions Diarrhea 52 3 <1 9 <1 0 Hypertension 40 4 0 10 <1 0 Hair color changes 38 <1 0 3 0 0 Nausea 26 <1 0 9 0 0 Anorexia 22 2 0 10 <1 0 Vomiting 21 2 <1 8 2 0 Fatigue 19 2 0 8 1 1 Asthenia 14 3 0 8 0 0 Abdominal pain 11 2 0 1 0 0 Headache 10 0 0 5 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).

Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.

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other demographic factors.

Of note, the increase in survival in the later decade compared with the early decade was greater among women (mean survival, 10.6 vs 4.7, respectively) compared with the survival among men (median survival, 5.3 vs 4.4, respectively).

Direct-to-Consumer Advertising Positively Affects Prescriptions for Breast Cancer Therapy It is safe to assume that direct-toconsumer advertising (DTCA) has a positive impact on increasing the Continued on page 18

Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo Placebo (N=145)

VOTRIENT (N=290)

Parameters

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % %

Hematologic 37 0 0 6 0 0 Leukopenia 34 1 <1 6 0 0 Neutropenia 32 <1 <1 5 0 <1 Thrombocytopenia 31 4 <1 24 1 0 Lymphocytopenia Chemistry ALT increased 53 10 2 22 1 0 53 7 <1 19 <1 0 AST increased Glucose 41 <1 0 33 1 0 increased Total bilirubin 3 <1 10 1 <1 36 increased Phosphorus 34 4 0 11 0 0 decreased Sodium 31 4 1 24 4 0 decreased Magnesium <1 1 14 0 0 26 decreased Glucose 17 0 <1 3 0 0 decreased a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact.

Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.8)].

7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Reduce the dose of VOTRIENT when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib.

CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)].

7.2 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction studies conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information].

Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.3 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin.

If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.

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number of prescriptions, which can be evidenced from the continuation of this practice by pharmaceutical companies. However, it has often been

suggested that DTCA might result in patients placing inappropriate pressure on physicians to prescribe therapies that may not always be appropriate for a particular patient. A new study has now shown that DTCA has a positive effect on the prescription patterns of aromatase inhibitors (AIs) for

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.15)].

VOTRIENT can cause fetal harm when administered to a pregnant woman.

There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of â&#x2030;Ľ3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossiďŹ cation. In addition, there was reduced fetal body weight, and preand post-implantation embryolethality in rats administered pazopanib at doses â&#x2030;Ľ3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses â&#x2030;Ľ30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses â&#x2030;Ľ100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses â&#x2030;Ľ3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug 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 VOTRIENT, 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. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses â&#x2030;Ľ3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at â&#x2030;Ľ30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged â&#x2030;Ľ65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identiďŹ ed differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin â&#x2030;¤1.5 X ULN and AST and ALT â&#x2030;¤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC (0-24) achieved at this dose was approximately 40% and 29%, respectively of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance â&#x2030;Ľ30 mL/min) were included in clinical studies for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to signiďŹ cantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/min) did not inďŹ&#x201A;uence clearance of pazopanib. Therefore, renal impairment is not expected to inďŹ&#x201A;uence pazopanib exposure, and dose adjustment is not necessary.

10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials.

Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no speciďŹ c antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not signiďŹ cantly renally excreted and is highly bound to plasma proteins.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may

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women with breast cancer, by increasing the number of appropriate prescriptions; surprisingly, the study has also shown that DTCA does not lead to an increase in inappropriate use of these agents for this patient population (Abel GA, et al. Cancer. 6 Nov 2012. Epub ahead of print).

impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages â&#x2030;Ľ30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses â&#x2030;Ľ10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given â&#x2030;Ľ100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given â&#x2030;Ľ300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses â&#x2030;Ľ3 mg/kg/day, epididymal sperm concentrations at doses â&#x2030;Ľ30 mg/kg/day, and sperm motility at â&#x2030;Ľ100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of â&#x2030;Ľ30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.

17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaďŹ&#x201A;et that accompanies the product. However, inform patients of the following: t 5IFSBQZ XJUI 7053*&/5 NBZ SFTVMU JO IFQBUPCJMJBSZ MBCPSBUPSZ BCOPSNBMJUJFT Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the ďŹ rst 4 months of treatment or as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. t 1SPMPOHFE 25 JOUFSWBMT BOE UPSTBEFT EF QPJOUFT IBWF CFFO PCTFSWFE 1BUJFOUT should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. t $BSEJBD EZTGVODUJPO TVDI BT $)' BOE -7&' EFDSFBTF IBT CFFO PCTFSWFE JO patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. t 4FSJPVT IFNPSSIBHJD FWFOUT IBWF CFFO SFQPSUFE 1BUJFOUT TIPVME CF BEWJTFE UP report unusual bleeding. t "SUFSJBM UISPNCPUJD FWFOUT IBWF CFFO SFQPSUFE 1BUJFOUT TIPVME CF BEWJTFE UP report signs or symptoms of an arterial thrombosis. t 3FQPSUT PG QOFVNPUIPSBY BOE WFOPVT UISPNCPFNCPMJD FWFOUT JODMVEJOH pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. t "EWJTF QBUJFOUT UP JOGPSN UIFJS EPDUPS JG UIFZ IBWF XPSTFOJOH PG OFVSPMPHJDBM function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). t )ZQFSUFOTJPO BOE IZQFSUFOTJWF DSJTJT IBWF CFFO SFQPSUFE 1BUJFOUT TIPVME CF advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. t (* QFSGPSBUJPO PS mTUVMB IBT PDDVSSFE "EWJTF QBUJFOUT UP SFQPSU TJHOT BOE symptoms of a GI perforation or ďŹ stula. t 7&('3 JOIJCJUPST TVDI BT 7053*&/5 NBZ JNQBJS XPVOE IFBMJOH "EWJTF QBUJFOUT to stop VOTRIENT at least 7 days prior to a scheduled surgery. t )ZQPUIZSPJEJTN BOE QSPUFJOVSJB IBWF CFFO SFQPSUFE "EWJTF QBUJFOUT UIBU UIZSPJE function testing and urinalysis will be performed during treatment. t 4FSJPVT JOGFDUJPOT JODMVEJOH TPNF XJUI GBUBM PVUDPNFT IBWF CFFO SFQPSUFE Advise patients to promptly report any signs or symptoms of infection. t 8PNFO PG DIJMECFBSJOH QPUFOUJBM TIPVME CF BEWJTFE PG UIF QPUFOUJBM IB[BSE UP UIF fetus and to avoid becoming pregnant. t (BTUSPJOUFTUJOBM BEWFSTF SFBDUJPOT TVDI BT EJBSSIFB OBVTFB BOE WPNJUJOH IBWF been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs t 1BUJFOUT TIPVME CF BEWJTFE UP JOGPSN UIFJS IFBMUIDBSF QSPWJEFST PG BMM concomitant medications, vitamins, or dietary and herbal supplements. t 1BUJFOUT TIPVME CF BEWJTFE UIBU EFQJHNFOUBUJPO PG UIF IBJS PS TLJO NBZ PDDVS during treatment with VOTRIENT. t 1BUJFOUT TIPVME CF BEWJTFE UP UBLF 7053*&/5 XJUIPVU GPPE BU MFBTU IPVS before or 2 hours after a meal).

VOTRIENT is a registered trademark of GlaxoSmithKline.

Š2012, GlaxoSmithKline. All rights reserved.

Revised 04/2012 VTR:7BRS Š2012 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. VOT319R0 August 2012

NOVEMBER 2012

Because AIs have been particularly targeted for DTCA, and because they are indicated only for postmenopausal women, the investigators believed that this drug class was a good way to investigate the cancer-related impact of DTCA, and that age was a surrogate marker of appropriate use.

They combined national data on DTCA spending (from TNS Media Intelligence) and prescription data for hormonal therapy use (from IMS Health) between October 2005 and September 2007. Prescriptions for women aged â&#x2030;¤40 years (assumed premenopausal) were considered inappropriate and for women aged â&#x2030;Ľ40 years, appropriate.

The main target of DTCA for AIs was in national magazines, and to a lesser degree in Sunday newspapers.

During the study period, the highest spending ($22,019,660) on AI-related DTCA was in October 2005 and the lowest ($118,600) was in January 2007, reflecting a great variation over time.

The results were also compared with a second analysis of the impact of AI advertising in the Journal of Clinical Oncology on physicians during the same period.

Overall, every $1 million spent on AI-related DTCA was associated with a 0.15% increase in new prescriptions for AI 3 months later for all ages (P <.001) and a 0.18% increase for women aged >60 years (P <.001), but with no significant change for women aged <40 years up to 6 months later.

This finding suggests that DTCA has a positive impact on the appropriate use of certain types of cancerrelated drugs and does not lead to increased inappropriate prescription use. It is not clear whether this conclusion can be extended to all drug classes, but it may suggest that, when it comes to cancer drugs, DTCA does not have a negative impact. â&#x2013;

Newâ&#x20AC;&#x2C6;Mechanismâ&#x20AC;&#x2C6;ofâ&#x20AC;&#x2C6;Action forâ&#x20AC;&#x2C6;PARPâ&#x20AC;&#x2C6;Inhibitorsâ&#x20AC;&#x2C6; Researchers have discovered a significant new mechanism of action for the poly (ADP-ribose) polymerase (PARP) inhibitors in their different ability to inhibit PARP enzyme activity, and significant differences in the toxicity level of the 3 PARP inhibitors currently in clinical trials (Yang ES, et al. Cancer Research. November 1, 2012.

Epub ahead of print). â&#x20AC;&#x153;We now know that they [PARP inhibitors] are not equivalent with respect to their potency to trap PARP,â&#x20AC;? said Yves Pommier, MD, PhD, of the National Cancer Institute Center for Cancer Research. (See more details in the January 2013 issue.)

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Economic Issues in Oncology

A Rational Step in Holding Down Costs in Cancer Care Pricing of cancer drug launches a national debate on value

See also VBCC Perspectives, pages 20-21

By Alice Goodman

T

he cost of cancer care matters; in fact, it matters so much that Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City has decided not to include in its formulary the newly approved drug ziv-aflibercept (Zaltrap), which was recently approved for use in patients with progressive metastatic colorectal cancer. The decision is based on considering cost versus benefit rather than on “newer is better.”

Peter B. Bach, MD, Leonard B. Saltz, MD, and Robert E. Wittes, MD, all from MSKCC, explain in an Op-Ed piece in the New York Times (October 15, 2012) that bevacizumab (Avastin) costs approximately $5000 per month, which is less than 50% of the cost of ziv-aflibercept. The side effects of both drugs are “roughly similar,” they say, and the survival benefit for both drugs is a median of 1.4 months. (The manufacturer of ziv-aflibercept has since announced it was cutting the cost by half, see page 21.)

They call the medical culture to task for unequivocally equating “new” with “better.”

“In most industries something that offers no advantage over its competitors and yet sells for twice the price would never even get on the market.

But that is not how things work for drugs. The Food and Drug Administration approves drugs once they are shown to be ‘safe and effective.’ It does not consider what the relative costs might be once the new medicine is marketed,” Dr Bach and colleagues write. US organizations and societies that set guidelines for physicians also rarely factor cost into their determinations, they note.

Ignoring costs, however, is “no longer tenable,” they urge. “Soaring spending has presented the medical community with a new obligation.”

Cost must be considered when choosing a specific therapy. “This is particularly the case with cancer, where the cost of drugs, and of care overall, has risen precipitously.”

In addition to the cost to society, the cost burden of cancer care is increasingly being borne by individual patients. Some patients with cancer report exhausting all of their savings

to pay for care, and some have been driven into bankruptcy by treatment costs. One of 10 patients with cancer now reports spending more than $18,000 out of pocket on cancer care.

“The Food and Drug Administration approves drugs once they are shown to be ‘safe and effective.’ It does not consider what the relative costs might be once the new medicine is marketed.”

—Peter B. Bach, MD, et al To put this particular issue in perspective, colorectal cancer is typically diagnosed in older people, many of whom live on Medicare and fixed incomes. Medicare requires copayment for drugs to treat cancer, so 20% of the cost of ziv-aflibercept, bevacizumab, and other cancer drugs is

passed on to supplemental insurance or to patients themselves. An older patient without gap insurance coverage would have to pay more than $2200 monthly for treatment with zivaflibercept, which is more than the monthly income of half of the Medicare recipients, the authors state.

The authors believe that the political climate has prevented presidential candidates from addressing the runaway costs of cancer therapies. They acknowledge that the step that MSKCC is taking regarding this particular drug will not halt the larger problem of out-of-control rising healthcare spending, “but it is a step in the right direction—one of many we need to take,” they warn.

“The current level of spending on health care, estimated to be $2.8 trillion this year, is already too high. The growth rate in health spending is unsustainable,” the authors state, challenging the US healthcare system to apply a value-based approach to care.

“The future of our health care system, and of cancer care, depends on our using our limited resources wisely.” ■

Cumulative Financial Impact of Skeletal-Related Events on Patients with Breast Cancer Is Significant

By Caroline Helwick San Francisco, CA—In patients with breast cancer with bone metastases, skeletal-related events (SREs) are associated with high treatment costs.

For example, the cumulative cost of treating 1 spinal cord compression exceeds $100,000, according to a new cost analysis presented at the 2012 Breast Cancer Symposium.

“Breast cancer patients with bone metastases are at risk for a variety of SREs. While a number of studies have described the impact of these SREs on cost, none has used an episode-of-care approach to examine the costs of unique SRE episodes in a typical clinical practice,” said May Hagiwara, PhD, Senior Economist, Policy Analysis Inc, Brookline, MA. The data for this study came from the Thomson MedStat MarketScan Commercial Claims and Encounters database of patients treated between October 2002 and June 2011. Patients with breast cancer were included if they had confirmed bone metastasis and at least 1 diagnosis or procedure

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related to an SRE during the followup period (beginning with the index date and ending with disenrollment from the health plan).

Unique SRE episodes were identified based on a gap of at least 90 days without an SRE claim. Each SRE episode was then classified by the type of the event—spinal cord compression, pathologic fracture, bone surgery, and bone radiotherapy.

Episodes were further classified as inpatient or outpatient. Treatment costs were calculated to calendar year 2010. The population included 5809 women who met the study criteria and had ≥1 SRE claims. Most of the women were insured through a preferred provider organization.

Cumulative Impact of Common SREs Is Costly A total of 7617 SRE episodes were identified during a mean follow-up of 17.2 months, and included 113 (1.5%) spinal cord compression episodes, 1390 (18%) pathologic fracture epi-

sodes, 191 (2.5%) bone surgery episodes, and 5923 (78%) radiotherapy episodes, Dr Hagiwara reported.

“Previous studies often looked, for example, at 1 inpatient admission, but the truth is that spinal cord compression may be preceded by a succession of other events. When you look at all events separately, you are not assessing the impact on the patient.”

—May Hagiwara, PhD

Spinal cord compressions were the most costly to treat, and pathologic fractures were the least costly. Bone surgery required involved an inpatient episode in 76% of patients com-

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pared with only 11% for those undergoing radiotherapy. The mean perepisode cost for the 4 types of events was: • Outpatient pathologic fracture episode: $10,700 • Outpatient episode: $11,080 • Inpatient episode: $55,229 • Inpatient spinal cord compression episode: $102,205.

The costs, especially for spinal cord compression, appear high, and this is largely because such episodes may be multifactorial. Including all components of an episode gives a more realistic picture of the disease and of its high associated costs, Dr Hagiwara explained.

“Previous studies often looked, for example, at 1 inpatient admission, but the truth is that spinal cord compression may be preceded by a succession of other events,” noted Dr Hagiwara.

“When you look at all events separately, you are not assessing the impact on the patient. Rather than look at a chunk here and a chunk there, we think this is probably the right way to assess this.” ■

www.ValueBasedCancerCare.com

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VBCC Perspectives

Payers’ Support of Clinical Decisions Allows Providers to Choose Most Effective, Cost-Saving Therapies

By Ira M. Klein, MD, MBA, FACP

See article on page 19

Chief of Staff to the Chief Medical Officer, Aetna

T

he cost of cancer care is staggering. Global sales of cancer drugs alone are forecast to grow at a rate of 12% to 15% annually, reaching $75 billion to $80 billion by the end of this year, according to IMS Health.1 Clinical leadership is one of the critical keys to controlling quality and costs in healthcare. Every other segment of the healthcare system also has a role to play. At Aetna, we work to influence the creation of safer, more effective, and more affordable healthcare through clinical evidence and unprecedented collaboration.

We look to medical evidence— published, peer-reviewed results that show which treatments and procedures have been scientifically proven to be effective—to create clinical policies, which form the basis of coverage policy.

Based on the current evidence, we consider ziv-aflibercept (Zaltrap) medically necessary for the treatment of patients with colorectal cancer. But being proved medically necessary for a broad condition does not mean that it is

the best treatment for every patient.

We look to doctors, such as Peter B. Bach, MD, and his team (see article, page 19), to constantly add to the body of knowledge for cancer care, especially experience that further clarifies the effectiveness of a therapy

all about. We applaud Dr Bach and his team for incorporating costs into their evaluation of the best treatment options. The oncology community is in the best position to help eliminate costs that do not bring additional value to patients.

Based on the current evidence, we consider ziv-aflibercept (Zaltrap) medically necessary for the treatment of patients with colorectal cancer. But being proved medically necessary for a broad condition does not mean that it is the best treatment for every patient.

based on specific characteristics of the patient. Oncologists can learn from the collective experience, which is what evidence-based pathways are

For our part, we help ensure that these evidence-based care standards can be quickly shared. Aetna enables technology and real-time clinical deci-

sion support to allow doctors and patients to decide together the most effective and cost-efficient treatments.

We are also developing new payment models to support evidence-based quality of care rather than quantity of care or drug costs.

A recent study by Aetna and US Oncology found that evidence-based care for patients with non–small-cell lung cancer resulted in an average cost-savings of 35% while demonstrating equivalent health outcomes.2 We know that collaborating with the oncology community to support highquality, evidence-based care can actually reduce costs and save patients, as well as the nation’s healthcare system, millions of dollars. ■ References 1. Gavel SJ. The oncology pipeline: maturing, competitive, and growing? http://imshealth.com/deployedfiles/imshealth/Global/Americas/North%20America/ United%20States/StaticFile/Oncology_Pipeline.pdf.

Accessed November 3, 2012.

2. Neubauer MA, Hoverman JR, Kolodziei M, et al.

Cost-effectiveness of evidence-based treatment guidelines for the treatment of non–small-cell lung cancer in the community setting. J Oncol Pract. 2010;6:12-18.

We Must Incorporate Value into Our Decision-Making... reviewing these facts would come to the conclusion that this medicine does not carry the necessary value to support the higher cost.

This development was inevitable.

Just as the tide rises, we have seen several new therapies that yield modest improvements in outcome but that also come with an ever-increasing price tag. Examples include sipuleucel-T (Provenge), a nearly $100,000 per year prostate cancer immunotherapy that adds 4 months of survival, and, now ziv-aflibercept, an anti–vascular endothelial growth factor therapy that offers a benefit similar to the existing therapy bevacizumab (Avastin), but with higher toxicity and a significantly higher price tag.

As we recognize that we can no longer simply expand the amount of money we are spending on healthcare, we increasingly have to make valuebased clinical decisions.

Although we are throwing stones at recent therapy pricing decisions, it is important to remember Susan Desmond-Hellman, MD, MPH, former president of product development at Genentech, defending the

20

price of bevacizumab, by stating that it was “what the market would bear.”

As long as there are third-party payers and providers, and as long as patients do not directly feel the impact of the cost of their therapies, we will continue to see ever-escalating drug costs. It may be that at this point, with the multiple external pressures being applied to the healthcare system, that the market will no longer bear highpriced medicines that bring little additional value to our patients and to patient care.

Our group at Georgetown’s Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers has been working in collaboration with other centers to develop a value metric for drug approvals for this very circumstance.

One could envision that drugs such as ziv-aflibercept would be useful in the treatment of certain patients with metastatic colorectal cancer, but not at double the price of its competitor.

If we were to apply a value metric for drug approval that links payers and the approval process, as is suggested by Bach and colleagues, this drug would not have gained US Food

VALUE-BASED CANCER CARE

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NOVEMBER 2012

John L. Marshall, MD

As we recognize that we can no longer simply expand the amount of money we are spending on healthcare, we increasingly have to make value-based clinical decisions. and Drug Administration approval, especially not at that price. However, the manufacturers could have made a decision to lower the price and enter the market as a less-expensive option, which would, in my opinion, have

Continued from cover

been a more appropriate strategy, and one that may be forced on Zaltrap and its makers in the future.

We clearly need a collaboration of payers, patients, employers, and providers to ensure transparency in healthcare. I am reminded of the book The Cost of Hope by Amanda Bennett, which is an outstanding review of a single patient’s course through cancer therapy. Ms Bennett reviews her husband’s treatments and emotional wellbeing through his battle with cancer, as well as the consumption of healthcare through the process. In one of the more striking examples, her husband underwent 76 separate computed tomography scans in the course of his care.

As we “pick on” our drugs as a high-cost item, we must also remember that we consume a great deal of resources as cancer care providers. As such, we need to look at our entire process, and assess it for the value it brings—not only to judge new approaches but also to evaluate our existing approaches, removing the ones that are not helping our patients’ outcomes or quality of life.

Continued on page 21

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VBCC Perspectives

How Will We Pay for Cancer Treatment?

By Ted Okon, BS, MBA Executive Director, Community Oncology Alliance, Washington, DC

W

ith the fanfare of a New York Times Op-Ed piece by Peter B. Bach, MD, and colleagues (see page 19), the announcement was made that Memorial Sloan-Kettering Cancer Center (MSKCC) would exclude the new colorectal cancer drug ziv-aflibercept (Zaltrap) from its formulary. Regardless of questions raised about the accuracy of the cost and the dosing comparisons and certain conflicts, the question is—Will the MSKCC decision influence community oncology clinics to consider a similar restriction?

Although the press around the MSKCC decision has caught the attention of community oncologists, I believe that they will not be unduly influenced by it. In this day and age, oncology clinics typically are basing treatment decisions on evidencebased guidelines that are evolving into specific treatment pathways.

These pathways incorporate national information on efficacy and cost, as well as the experiences of oncologists and practices. The realities of the increasing cost of cancer treatment have been on the radar screens of community oncologists for several years, as well as the effort required to

We Must Incorporate Value... Continued from page 20 In a way, we owe something to Zaltrap and its high price. I believe that this will be a turning point in cancer drug development, and that the pendulum will begin to swing back toward value. My concern is that the pharmaceutical industry will decide that the return on investment is not sufficient to support cancer drug development, particularly as we increasingly personalize our approach to therapy, which shrinks the overall drug market.

We are at a critical time; we must incorporate value into our decisionmaking. We must alter our drug approval process to enable rapid, efficient drug development in the era of personalized medicine. We must connect our payers, patients, employers, and providers so that the medicines of tomorrow will be measured by value and will be incorporated into daily practice based on safety and efficacy, as well as on their impact and magnitude of benefit for individual patients. ■

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ensure that all patients—including Medicare recipients and those with private insurance—have access to the optimal standard-of-care treatment.

So, most oncologists will weigh the facts and will make decisions in concert with their patients.

From a societal standpoint, the MSKCC decision begs the larger question of how we will pay for the rapidly escalating cost of cancer treatment and who the arbiter is.

Some would like to see a UK-type National Institute for Clinical Excellence–like board decide at a governmental level what cancer drugs get paid for, based on the calculated valueof-life extension from a specific medication. Others fear that our government regulatory and payment agencies are already moving in that direction, without legislative mandate. Some, presumably like MSKCC, believe that the institution must intervene, as in the

case of ziv-aflibercept. Yet others believe that individual physicians, who are familiar with specific efficacy and cost data, must make decisions in concert with their patients. My guess is that most physicians agree that the rapidly escalating cost of cancer treatment is unsustainable, and that something must be done, starting with the drug manufacturers.

From a policy perspective, I believe that we first need to substantially trim the regulations, inefficiencies, and costs that impede bringing effective, safe new cancer drugs to market, as well as ensure accessibility to low-cost generics, which are increasingly in short supply.

Competition will produce the best treatments with the optimal value propositions. Manufacturers with superior science and understanding of market needs will prosper. Oncologists will be able to focus on getting the optimal treatment to patients, based on the value equation—and patients with cancer will end up the

From a policy perspective, I believe that we first need to substantially trim the regulations, inefficiencies, and costs that impede bringing effective, safe new cancer drugs to market

ultimate winners.

Until we fix an increasingly dysfunctional cancer care landscape, it is unclear how we will pay for cancer treatment going forward. ■

Responding to Market Resistance, Sanofi Cuts Cost of Zaltrap by Half

T

he October 15, 2012, Op-Ed in the New York Times by Peter B. Bach, MD, Leonard B. Saltz, MD, and Robert E. Wittes, MD, of Memorial Sloan-Kettering Cancer Center (MSKCC) who discussed the rationale for MSKCC’s decision not to include ziv-aflibercept (Zaltrap) in its formulary (see page 19 in this issue) has sent shockwaves throughout the oncology community.

The following day, Sandra M. Swain, MD, President of the American Society of Clinical Oncology, published a letter in the New York Times, noting that MSKCC’s “decision to forgo an expensive new cancer drug reflects a much-needed willingness to address the elephant in the room: unsustainable costs in cancer care.”

A few days later, Harold J. Burstein, MD, PhD, Editor-in-Chief of the Journal of the National Comprehensive Cancer Network addressed this topic, noting that “the decision at MSKCC, and more particularly its public declaration, may serve as a ‘shot heard around the world’ for voluntary limits on the use of expensive oncology drugs” (J Natl Compr Canc Netw. 2012; 10:1315-1316).

Dr Burstein further makes an important point regarding conflicts of interest, “If institutional formulary or pathway committees are to have a larger

say in the treatment that patients receive, it becomes imperative to minimize conflicts of interest.”

In their Op-Ed piece, the authors acknowledge that Dr Bach and Dr Saltz are consultants to Genentech, the maker of the competitor drug bevacizumab (Avastin), which raises concerns for a potential bias. Indeed, the issue of conflicts of interest muddies the waters here and should be addressed as well, but the cost of the drug has taken on a life of its own.

Calling for a National Debate on Value The article by Dr Bach and colleagues has forced the oncology community to face the issue of value-based cancer care head on.

Lee Newcomer, MD, Senior Vice President for Oncology at UnitedHealthcare, told ValueBased Cancer Care, “I applaud the leaders at MSKCC for taking this stand. When physician leaders make these assessments, they will be taken far more seriously than when policymakers attempt the same effort.”

“UnitedHealthcare follows the NCCN recommendations to determine what drugs it will cover for cancer therapy. I hope that the MSKCC leaders can convince their peers at NCCN to begin

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making these same value assessments,” Dr Newcomer said.

Responding to comments from the oncology community, Sanofi initially tried to explain its position in discussions with The Cancer Letter (2012; 38:1-10), acknowledging how it priced ziv-aflibercept to match the 10-mg/kg dose of bevacizumab rather than the smaller, 5-mg/kg dose, which is also half the cost, but noting that the drug was appropriately priced and that its approval was expedited by the US Food and Drug Administration. Although some oncologists have said they only use the 5-mg/kg dose of bevacizumab, this issue requires further feedback from other sources.

On November 8, 2012, Sanofi issued a statement cited on that day in The Cancer Letter and in the New York Times, saying, “We believe that Zaltrap is priced competitively as used in real-world situations. However, we recognize that there was some market resistance to the perceived relative price of Zaltrap in the U.S.—especially in light of low awareness of Zaltrap in the U.S. market. As such, we are taking immediate action across the U.S. oncology community to reduce the net cost of Zaltrap.”

The company said the price was being cut by 50%, an unprecedented move. It remains to be seen if this step will set a new trend in oncology. ■

www.ValueBasedCancerCare.com

21

Personalized Medicine

A New Personalized Prescription Decision-Making System Translating pharmacogenomics into clinical practice

By Rosemary Frei, MSc Phoenix, AZ—Using the paradigm of individualizing drug therapy based on a patient’s genetics, a group of oncologists and genomic experts have designed a genomic prescribing system that they hope will significantly reduce the staggeringly high rate of adverse drug reactions associated with prescription drugs in the United States. Principal investigator Peter H. O’Donnell, MD, Assistant Professor, Department of Medicine, Section of Hematology/ Oncology, Genitourinary Oncology Program, Committee on Clinical Pharmacology and Pharmacogenomics, Center for Personalized Therapeutics, University of Chicago, IL, discussed the very early results of the 1200 Patients Project at the 2012 Society for Medical Decision Making annual meeting.

“Patients and providers see this as the future of how medicine will be practiced,” Dr O’Donnell told ValueBased Cancer Care (VBCC). “A key advantage of this approach is that all potentially desired pharmacogenomic information is obtained for the patient’s entire drug prescription lifetime, with one single test.”

The model attempts to circumvent the barriers to implementing personalized medicine resulting from the limited and high cost of genetic testing, the delay in their results, and the common disagreement regarding the interpretation of the results. Dr O’Donnell and his colleagues are hoping that this new venture will help to translate the benefits of pharmacogenomics, or personalized medicine, into clinical practice in oncology.

The 1200 Patients Project The project began in the spring of

2011 and involves preemptive and comprehensive pharmacogenomic genotyping of a large number of consenting patients—at a cost of less than $500 per person—and rapid and cheap elec-

“Patients and providers see this as the future of how medicine will be practiced. A key advantage of this approach is that all potentially desired pharmacogenomic information is obtained for the patient’s entire drug prescription lifetime, with one single test.”

—Peter H. O’Donnell, MD

tronic dissemination of geno-type information (http://cpt.uchicago. edu/page/1200-patients-project). It harnesses the discovery of genetic variants that govern appropriateness

of response to, and toxicity from, drugs, but which until now have not been incorporated into prescribing decisions.

In a recent article published in Clinical Pharmacology & Therapeutics, Dr O’Donnell and his team outlined the full scope of the project, which is designed to overcome barriers to the application of routine “pharmacogenomic prescribing” into clinical practice (O’Donnell PH, et al. Clin Pharmacol Ther. 2012;92:446-449). The software and the other technologies for the project were created by Dr O’Donnell’s team, in collaboration with the University of Chicago Center for Research Informatics.

Discussing the rationale for this project, the authors write, “We have carefully considered the alternative option of whole-genome sequencing.

Although whole-genome sequencing has the advantage of detecting rare variants…it has the disadvantage of requiring substantially greater costs in quality-control/bioinformatics analysis.” Funding is provided by the Conquer Cancer Foundation of the American Society for Clinical Oncology’s Translational Research Professorship and other institutional and philanthropic sources.

The 1200 patients being recruited for the study are receiving outpatient medical care from 1 of 12 physicians.

These include 4 general internists, 3 oncologists, 2 cardiologists, 1 pulmonologist, 1 hepatologist, and 1 gastroenterologist.

The patients undergo testing for a panel of genotypic variants that have been associated with a positive response to, or an adverse reaction to,

The Missing Perspective in Personalized Cancer Care

By Caroline Helwick Vienna, Austria—The identification of genetic mutations and tumor biomarkers to select the right drug for the right patient are not enough to satisfy the need for personalized cancer care, according to Kathy Redmond, MSc, RN, Editor of Cancer World magazine, a publication of the European School of Oncology and former president of the European Oncology Nursing Society, who addressed the topic of personalized medicine at the 2012

22

European Society for Medical Oncology Congress.

Ms Redmond maintains that genomic profiling does not go far enough to justify the concept of personalized care in cancer. “I use the term ‘personalized cancer care.’ I deliberately do not use the term ‘personalized medicine,’” she said.

“We maintain that personalized medicine will eventually be delivered to all cancer patients. There has been

VALUE-BASED CANCER CARE

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NOVEMBER 2012

so much hype around the term ‘personalized medicine’ that we lose sight of the fact that we should be focusing on the personalized care of the whole individual,” Ms Redmond argues.

Tailored treatment has been the standard for some time, she says, and this includes not just drugs but type and extent of surgery, radiotherapy, and the like. What is missing is more personalized psychosocial care.

Continued on page 26

frequently used medications. The drugs include those that the patients are currently taking and other drugs that they may receive in the future.

Newly discovered genetic and pharmacogenomic variants will be incorporated into the testing over time, once they have been confirmed to be clinically relevant.

“A full 674 drugs have been reviewed for inclusion in the genomic prescribing system, with patientspecific information being present when pharmacogenomic information exists,” said Dr O’Donnell.

The patient-specific testing results indicate: Whether the person’s genotypic profile suggests that the patient is likely (or not) to benefit from a particular drug • What the level of evidence is for this conclusion • What published studies support these findings.

These data are made available exclusively to the enrolling provider of the specific patient through a research web portal.

Overcoming Clinicians’ Knowledge Gap The ultimate goals of the project are to determine whether physicians are taking pharmacogenomic information into account during clinic visits, and whether this information alters prescribing to patients who are genetically at high risk for negative outcomes because of adverse drug reactions or for a nonresponse to the specific medication.

“Although a recent survey suggests that 98% of physicians believe ‘patient genetic profiles may influence drug therapy,’ only 13% had ordered a pharmacogenetic test, and only 10% had felt adequately informed about pharmacogenetics,” Dr O’Donnell and colleagues write in their published article.

Approximately 700 patients have been recruited to date, 400 of whom have received pharmacogenomic testing thus far. One physician began using the genomic prescribing system in October 2012, and the other 11 physicians will begin using it “soon,” Dr O’Donnell told VBCC. The physicians and patients who are involved in the project have expressed “significant enthusiasm,” Dr O’Donnell added. “Patients have little reservation about this type of testing, and physicians are very interested to see what medications have relevant information in our database.” ■

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A NE W I N D I C ATI O N

COMING SOON

Please see adjacent pages for current indication, Important Safety Information, and brief summary of full Prescribing Information.

Janssen Biotech, Inc. Š Janssen Biotech, Inc. 2012 8/12 08Z12244A

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI)—AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids, and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information).

Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Food Effect—ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid coadministration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution.

Use in Specific Populations—The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®.

www.zytiga.com Please see brief summary of full Prescribing Information on the following pages.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 8/12 08Z12244A

08Z11121R3

Adverse Reactions—The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castrationresistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.

CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter.

In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Food Effect: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess [see Warnings and Precautions].

Adrenocortical insufficiency [see Warnings and Precautions].

Hepatotoxicity [see Warnings and Precautions].

Food effect [see Warnings and Precautions].

Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The median duration of treatment with ZYTIGA was 8 months.

The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.

The most common adverse drug reactions that resulted in drug discontinuation were aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patients taking ZYTIGA).

Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention (edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA, grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of patients [see Warnings and Precautions].

Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute increase in frequency compared to placebo, or were events of special interest (mineralocorticoid excess, cardiac adverse reactions, and liver toxicities).

Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Prednisone (N=791) System/Organ Class All Grades1 Grade 3-4 Adverse reaction % % Musculoskeletal and connective tissue disorders 29.5 4.2 Joint swelling/discomfort2 26.2 3.0 Muscle discomfort3 General disorders 26.7 1.9 Edema4 Vascular disorders Hot flush 19.0 0.3 Hypertension 8.5 1.3 Gastrointestinal disorders Diarrhea 17.6 0.6 Dyspepsia 6.1 0 Infections and infestations Urinary tract infection 11.5 2.1 Upper respiratory tract infection 5.4 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 Nocturia 6.2 0 Injury, poisoning and procedural complications 5 5.9 1.4 Fractures Cardiac disorders 6 Arrhythmia 7.2 1.1 Chest pain or chest discomfort 7 3.8 0.5 8 Cardiac failure 2.3 1.9 1 2 3

Placebo with Prednisone (N=394) All Grades Grade 3-4 % % 23.4 23.1

4.1 2.3

18.3

0.8

16.8 6.9

0.3 0.3

13.5 3.3

1.3 0

7.1 2.5

0.5 0

7.6

0

5.1 4.1

0.3 0

2.3

0

4.6 2.8 1.0

1.0 0 0.3

Adverse events graded according to CTCAE version 3.0 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness

ZYTIGA® (abiraterone acetate) Tablets 4 5 6

Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema Includes all fractures with the exception of pathological fracture Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in 1 patient on both arms.

Hepatotoxicity: Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, liver function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ZYTIGA was withheld or discontinued. In two instances marked increases in liver function tests occurred [see Warnings and Precautions]. These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations.

In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver function tests developing in patients participating in clinical trials were managed by treatment interruption, dose modification and/or discontinuation [see Dosage and Administration (2.2) in full Prescribing Information and Warnings and Precautions]. Patients with elevations of ALT or AST > 20X ULN were not re-treated.

Other Adverse Reactions: Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 clinical trial (< 1%).

Laboratory Abnormalities of Interest: Table 2 shows laboratory values of interest from the phase 3 placebocontrolled clinical trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred more frequently in the ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Low Potassium 28.3 5.3 19.8 1.0 Low Phosphorus 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA was shown to inhibit the hepatic drug-metabolizing enzyme CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8.

Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo.

Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate 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 ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: ZYTIGA is not indicated in children.

Geriatric Use: Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years and over and 28% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily.

If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information].

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE: There have been no reports of overdose of ZYTIGA during clinical studies. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

Manufactured by: Patheon Inc. Mississauga, Canada

Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044

© Janssen Biotech, Inc. 2012

Revised: July 2012

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Health Policy

CMS Finalizes Payment Policies for 2013, Signaling a Shift toward Paying for Value

By Ross D. Margulies, JD, MPH, and Jayson Slotnik, JD, MPH Mr Margulies is an Associate at Foley Hoag, LLP, Washington, DC; Mr Slotnik is a Partner, Health Policy Strategies, LLC, Washington, DC

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n this article we address the final payment rules issued on November 1, 2012, by the Centers for Medicare & Medicaid Services (CMS), the Physician Fee Schedule (PFS), and the Hospital Outpatient Prospective Payment System. These annual updates to Medicare payment rates for physicians and hospitals can have a dramatic impact on reimbursement and incentives within the Medicare program, but they also tend to impact trends in the commercial insurance market.

You previously read our summary of CMS’s payment proposals in the September issue of Value-Based Cancer Care, and, by and large, the final rules come as no surprise. In possibly the biggest change in payment rules, CMS is increasing payment for primary care specialties (and therefore decreasing payments to select other specialties) as a result of several changes in the way CMS is calculating payments in 2013.

Specifically, in large part because of a new set of payment codes for transitional care management services in the month after a patient is being discharged from a hospital, family physicians will receive a 7% payment increase in 2013. In addition, payments to primary care specialties will increase as a result of redistributions from changes in payments for services that are furnished by other specialties.

Other healthcare professionals who provide primary care services, includ-

ing internal medicine physicians, would receive a 3% to 5% increase in pay. Of note, the new set of codes for

discharge from an acute care setting— with future medical decision-making, including communication with other

Ross D. Margulies

Jayson Slotnik

An oncologist who is involved in the treatment of a patient—postdischarge from an acute care setting—with future medical decision-making, including communication with other healthcare professionals and assistance in scheduling any required follow-up, may be eligible to bill for the new transitional care management codes.

transitional care management services may be billed by any physician who provides the relevant services, including oncologists (CMS specifically cited oncology as a specialty that may take advantage of the new codes in the final rule). An oncologist who is involved in the treatment of a patient—post-

healthcare professionals and assistance in scheduling any required follow-up, may be eligible to bill for the new transitional care management codes.

In our September summary of the proposed rule, we also noted CMS’s proposal in the 2013 PFS rule to reduce the payment for 2 radiation therapy

services by as much as 20%. In this proposed rule, CMS indicated that based on information that was obtained from patients’ experiences regarding the length of intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT), CMS would reduce the procedure time for both treatment modalities to more accurately take into account actual patient experiences.

In a half sigh of relief to the rational oncology community, CMS slightly retreated from its original proposal.

Although CMS will still cut payment rates for IMRT and SBRT services, the changes reflect an overall 7% reduction in payment for radiation oncology services and an overall 9% cut to radiation therapy centers, which is less than half of the 15% cuts for IMRT and 19% cuts for SBRT that were suggested in CMS’s original proposal.

Overall, both rules indicate a general shift in CMS’s policy toward paying for value. In particular, the new codes for transitional care management signal an increasing focus toward “whole patient” care. The oncology community can expect similar incentives to develop further in the commercial market in the wake of the current CMS decision.

Look for our analysis of the implications of the presidential elections for healthcare and oncologists in the next issue of this publication. ■

Personalized Medicine

The Missing Perspective in Personalized Cancer...

“We know all our patients differ in terms of their age, their tumors, their mutations, their baseline health status, and their access to care, and they come with different attitudes, values, and beliefs about cancer. Some live far distances away from treatment centers.

Some are retired….All these things influence their willingness to accept certain cancer treatments,” she says.

Rather, the focus should be on the total care of the patient, above and beyond what is considered “core medicine.”

Will Personalized Medicine Be Available to All? The landscape of cancer is becoming

26

“There has been so much hype around the term ‘personalized medicine’ that we lose sight of the fact that we should be focusing on the personalized care of the whole individual.”

—Kathy Redmond, MSc, RN

populated by a growing number of subtypes for every tumor, marked by

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multiple genetic mutations. “And on top of this we have hundreds of rare cancers, with many subtypes as well,” Ms Redmond says. More mutations will be found every day in different grades and stages of disease, she predicted.

“Some of these mutations will be druggable and others not,” she suggests. “In fact, mutation status may not be relevant for many cancers and many patients.” In addition, “the reality today is that there are very, very few targeted drugs on the market, and they are delivered effectively to very few cancer patients.”

“We are at an exciting moment in

Continued from page 22

time. We are starting to win the war on some cancers. But for the vast majority of patients, personalized medicine, that is, the effective use of targeted agents, is not delivering,” she maintains. “We need to be more careful of how we talk about personalized medicine, and we probably need to move the discussion to ‘personalized cancer care’ where we talk about the many aspects of the individual.”

“We often look at the cost of cancer to society, but not necessarily the cost to the patient,” she says. “At the end of the day, it’s the patients we should be focusing on, and putting them at the center of all that we do.” ■

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THE AFINITOR® (everolimus) TABLETS DUAL BENEFIT CO-PAY CARD FROM NOVARTIS PHARMACEUTICALS CORPORATION Designed to help make treatment more affordable for your eligible AFINITOR patients h The AFINITOR Dual Benefit Co-Pay Card With this co-pay assistance card, most eligible patients will pay $25 per 28-day prescription of AFINITOR® (everolimus) Tablets when they visit their pharmacy. The card also provides up to $50 off their co-pay for generic exemestane when prescribed with AFINITOR.

601341 RxBIN: OHCP RxPCN: RxGrp: [OHXXXXXXX] RxID: [000000000000] 01 Suf:

THE AFINITOR DUAL BENEFIT CO-PAY CARD

Novartis Pharmaceuticals Corporation will pay the balance of your eligible patient’s out-of-pocket expenses, up to a maximum of $1200 per month for the AFINITOR prescription and up to $50 per month for generic exemestane when prescribed with AFINITOR. Not valid for prescriptions for which payment may be made in whole or in part under federal or state healthcare programs, including, but not limited to, Medicare or Medicaid. The exemestane offer is not valid in Michigan. Patients can obtain the co-pay card at their physician’s office or at www.AFINITOR.com. This program will expire on June 30, 2014.

Helping make access to AFINITOR easier Novartis Oncology shares your commitment to helping patients living with cancer receive the medicines they need. Patient Assistance Now Oncology offers quick and easy access to information about the broad array of support and reimbursement programs available for patients.

For more information about AFINITOR access services, please visit www.AFINITOR.com.

Please see accompanying Important Safety Information and Brief Summary of Prescribing Information for AFINITOR on the following pages.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2012 Novartis

11/12

AFB-1053812

AFINITOR速 (everolimus) Tablets is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Important Safety Information AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis: Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively.

Fatal outcomes have been observed. If symptoms are moderate, patients should be managed with dose interruption until symptoms improve. The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve. For grade 3 cases, interrupt AFINITOR until resolution to grade )1. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose.

Infections: AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment. Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered.

Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment.

Oral Ulceration: Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 86% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients. In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed.

Renal Failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR. Geriatric Patients: In the randomized advanced hormone receptorpositive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients *65 years of age compared to 2% in patients <65 years of age. Adverse reactions leading to permanent discontinuation occurred in 33% of patients *65 years of age compared to 17% in patients <65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended.

Laboratory Tests and Monitoring: Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have been reported. Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine), blood glucose, lipids,

and hematologic parameters should be evaluated prior to treatment and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Drug-Drug Interactions: Avoid coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole). Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4 and/or PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). Avoid coadministration with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, increase the AFINITOR dose from 10 mg daily up to 20 mg daily, using 5-mg increments.

Hepatic Impairment: Exposure of everolimus was increased in patients with hepatic impairment. For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended.

Vaccinations: The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Embryo-Fetal Toxicity: Fetal harm can occur if AFINITOR is administered to a pregnant woman. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment.

Adverse Reactions: The most common adverse reactions (incidence *30%) were stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%) and decreased appetite (30%). The most common grade 3/4 adverse reactions (incidence *2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%), and diarrhea (2%).

Laboratory Abnormalities: The most common laboratory abnormalities (incidence *50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST) concentrations (69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT) concentrations (51%), and hypertriglyceridemia (50%). The most common grade 3/4 laboratory abnormalities (incidence *3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%).

Please see accompanying Brief Summary of Prescribing Information for AFINITOR on the following pages.

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009 Brief Summary of Prescribing Information. See full prescribing information for complete product information.

1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptorpositive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole.

4 CONTRAINDICATIONS Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients.

Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives.

5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information].

Fatal outcomes have been observed.

Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms.

Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis.

If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information].

For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose.

Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy.

Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-8% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions].

Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring].

Geriatric Patients In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations] .

Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter.

Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.

Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions].

A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions].

An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions].

Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B)

hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information].

For SEGA patients with severe hepatic impairment, AFINITOR is not recommended. For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed; however subsequent dosing should be individualized based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information].

Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

The timing of routine vaccinations in pediatric patients with SEGA should be considered prior to the start of everolimus therapy.

Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use an effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations].

6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone-receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia.

Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%).

Table 3 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo.

Table 3: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 19 4 0.2 0.4 0 0 Pneumonitisd Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 Median Duration of Treatmente 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration c Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo

Key observed laboratory abnormalities are presented in Table 4.

Table 4: Key Laboratory Abnormalities Reported in â&#x2030;Ľ 10% of Patients with Advanced HR+ BC Laboratory parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical Chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.

7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: O >8GB6BA4MB?8 4 FGEBA: 0) <A;<5<GBE 4A7 4 ):) <A;<5<GBE max 4A7 - <A6E84F87 5L 4A7

9B?7 E8FC86G<I8?L

O 8ELG;EB@L6<A 4 @B78E4G8 0) <A;<5<GBE 4A7 4 ):) <A;<5<GBE max 4A7 - <A6E84F87 5L

4A7

9B?7 E8FC86G<I8?L

O I8E4C4@<? 4 @B78E4G8 0) <A;<5<GBE 4A7 4 ):) <A;<5<GBE max 4A7 - <A6E84F87 5L 4A7

9B?7 E8FC86G<I8?L

Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Warnings and Precautions].

Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Warnings and Precautions].

Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers "A ;84?G;L FH5=86GF 6B 47@<A<FGE4G<BA B9 "'",(* J<G; E<94@C<A 4 FGEBA: <A7H68E B9 CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared GB 8I8EB?<@HF GE84G@8AG 4?BA8 BA F<78E 4 7BF8 <A6E84F8 B9 "'",(* J;8A 6B 47@<A<FG8E87 J<G; FGEBA: 0) <A7H68EF <9 4?G8EA4G<I8 treatment cannot be administered. St. Johnâ&#x20AC;&#x2122;s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information].

Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions 58GJ88A "'",(* 4A7 G;8 !& B E87H6G4F8 <A;<5<GBEF 4GBEI4FG4G<A 4 0) FH5FGE4G8 4A7 CE4I4 FG4G<A 4 ABA 0) FH5FGE4G8 4A7 CBCH?4G<BA C;4E@46B kinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. FGH7L <A ;84?G;L FH5=86GF 78@BAFGE4G87 G;4G 6B 47@<A<FGE4G<BA B9 4A BE4? 7BF8 B9 @<7 4MB?4@ F8AF<G<I8 0) FH5FGE4G8 J<G; 8I8EB?<@HF E8FH?G87 <A 4 <A6E84F8 <A @<7 4MB?4@ max and a 30% increase in @<74MB?4@ - <A9 .

Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%.

However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse 8I8AGF E8?4G87 GB 8K8@8FG4A8 J4F B5F8EI87 <A C4G<8AGF J<G; ;BE @BA8 E868CGBE CBF<G<I8 ! * A8:4G<I8 47I4A687 5E84FG 64A68E E868<I<A: G;8 6B@5<A4G<BA

Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. ,;8E8 4E8 AB 478DH4G8 4A7 J8?? 6BAGEB??87 FGH7<8F B9 "'",(* <A CE8:A4AG JB@8A ;BJ8I8E 54F87 BA the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman.

I8EB?<@HF 64HF87 8@5ELB 98G4? GBK<6<G<8F <A 4A<@4?F 4G @4G8EA4? 8KCBFHE8F G;4G J8E8 ?BJ8E G;4A ;H@4A exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the 7EH: G;8 C4G<8AG F;BH?7 58 4CCE<F87 B9 G;8 CBG8AG<4? ;4M4E7 GB 4 98GHF /B@8A B9 6;<?7584E<A: CBG8AG<4? should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment.

In animal reproductive studies, oral administration of everolimus to female rats before mating and G;EBH:; BE:4AB:8A8F<F <A7H687 8@5ELB 98G4? GBK<6<G<8F <A6?H7<A: <A6E84F87 E8FBECG<BA CE8 <@C?4AG4G<BA 4A7 CBFG <@C?4AG4G<BA ?BFF 786E84F87 AH@58EF B9 ?<I8 98GHF8F @4?9BE@4G<BA 8 : FG8EA4? 6?89G 4A7 retarded skeletal development. These eff86GF B66HEE87 <A G;8 45F8A68 B9 @4G8EA4? GBK<6<G<8F @5ELB 98G4? toxicities in rats occurred at doses â&#x2030;Ľ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC ;) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

"A 4 CE8 4A7 CBFG A4G4? 78I8?BC@8AG FGH7L <A E4GF 4A<@4?F J8E8 7BF87 9EB@ <@C?4AG4G<BA G;EBH:; ?46G4 tion. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or F<:AF B9 @4G8EA4? GBK<6<GL ;BJ8I8E G;8E8 J8E8 E87H6G<BAF <A 5B7L J8<:;G HC GB E87H6G<BA 9EB@ G;8 6BAGEB? 4A7 <A FHEI<I4? B9 B99FCE<A: N 7<87 BE @<FF<A: ,;8E8 J8E8 AB 7EH: E8?4G87 89986GF BA G;8 developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, 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 AFINITOR is recommended for use only in patients with SEGA who are aged â&#x2030;Ľ 3 years.

CEBFC86G<I8 BC8A ?458? F<A:?8 4E@ GE<4? J4F 6BA7H6G87 GB 8I4?H4G8 G;8 F498GL 4A7 899<646L B9 "'",(* <A C4G<8AGF J<G; + 4FFB6<4G87 J<G; ,+ "A GBG4? C4G<8AGF E868<I87 GE84G@8AG J<G; "'",(* @87<4A 4:8 J4F L84EF E4A:8 "'",(* ;4F ABG 588A FGH7<87 <A C4G<8AGF J<G; + L84EF B9 4:8

Geriatric Use "A G;8 E4A7B@<M87 47I4A687 ;BE@BA8 E868CGBE CBF<G<I8 ! * A8:4G<I8 5E84FG 64A68E FGH7L B9 "'",(* GE84G87 C4G<8AGF J8E8 â&#x2030;Ľ 65 years of age, while 15% were 75 and over. No overall differences in effectiveness were observed between elderly and younger subjects. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients â&#x2030;Ľ 65 years of age compared to 2% in C4G<8AGF L84EF B9 4:8 7I8EF8 E846G<BAF ?847<A: GB C8E@4A8AG GE84G@8AG 7<F6BAG<AH4G<BA B66HEE87 <A 33% of patients â&#x2030;Ľ L84EF B9 4:8 6B@C4E87 GB <A C4G<8AGF L84EF B9 4:8 [see Warnings and Precautions].

"A GJB BG;8E E4A7B@<M87 GE<4?F 47I4A687 E8A4? 68?? 64E6<AB@4 4A7 47I4A687 A8HEB8A7B6E<A8 GH@BEF B9 pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and LBHA:8E FH5=86GF "A G;8 E4A7B@<M87 47I4A687 * FGH7L B9 "'",(* GE84G87 C4G<8AGF J8E8 â&#x2030;Ľ 65 L84EF B9 4:8 J;<?8 J8E8 4A7 BI8E "A G;8 E4A7B@<M87 47I4A687 )' , FGH7L B9 "'",(* treated patients were â&#x2030;Ľ 65 years of age, while 7% were 75 and over.

Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out 1F88 ?<A<64? );4E macology (12.3) in the full prescribing information].

'B 7BF4:8 47=HFG@8AG <A <A<G<4? 7BF<A: <F E8DH<E87 <A 8?78E?L C4G<8AGF 5HG 6?BF8 @BA<GBE<A: 4A7 4CCEBCE< ate dose adjustments for adverse reactions is recommended. [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information].

Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal <@C4<E@8AG <F ABG 8KC86G87 GB <A9?H8A68 7EH: 8KCBFHE8 4A7 AB 7BF4:8 47=HFG@8AG B9 8I8EB?<@HF <F E86 ommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose FGH7L B9 8I8EB?<@HF <A FH5=86GF J<G; <@C4<E87 ;8C4G<6 9HA6G<BA E8?4G<I8 GB FH5=86GF J<G; ABE@4? ;8C4G<6 9HA6 tion. KCBFHE8 J4F <A6E84F87 <A C4G<8AGF J<G; @<?7 ;<?7 )H:; 6?4FF @B78E4G8 ;<?7 )H:; 6?4FF 4A7 F8I8E8 ;<?7 )H:; 6?4FF ;8C4G<6 <@C4<E@8AG 1F88 ?<A<64? );4E@46B?B:L <A G;8 9H?? CE8 scribing information].

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the E<F> BE C4G<8AGF J<G; @<?7 ;<?7 )H:; 6?4FF BE @B78E4G8 ;<?7 )H:; 6?4FF ;8C4G<6 <@C4<E@8AG 4 dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information].

BE + C4G<8AGF J<G; F8I8E8 ;8C4G<6 <@C4<E@8AG ;<?7 )H:; 6?4FF "'",(* <F ABG E86B@@8A787

BE + C4G<8AGF J<G; @<?7 ;<?7 )H:; 6?4FF BE @B78E4G8 ;<?7 )H:; 6?4FF ;8C4G<6 <@C4<E@8AG 47=HFG@8AG GB G;8 FG4EG<A: 7BF8 @4L ABG 58 A88787 ;BJ8I8E FH5F8DH8AG 7BF<A: F;BH?7 58 <A7<I<7H4? <M87 54F87 BA G;8E4C8HG<6 7EH: @BA<GBE<A: [see Dosage and Administration (2.4 <A G;8 9H?? CE8F6E<5 ing information].

10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test).

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

Manufactured by: Novartis Pharma Stein AG +G8<A +J<GM8E?4A7 Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 Š Novartis ,

July 2012

2012 Conference

Delta Air Lines’ Approach to Patient Care...

Delta contracts with 1 national insurance carrier—UnitedHealth Group— for multiple plan design options for active employees, retirees aged <65 years, and their dependents.

Cancer care accounts for 16% of Delta’s overall health plan costs, 25% of high-cost expenses associated with claims, and 20% of its pharmacy spending. Among the various tumor types, breast cancer is the most costly.

A Business Perspective on Best Practices Quality of care, economics, cost, and employee productivity are the key issues and concerns that make cancer management a top priority at Delta, Ms Zonakis said.

Elaborating on these issues, she noted that reducing variations in practice and pathology testing is important for high quality of care. With regard to cost, Delta is interested in monitoring trends, minimizing perverse incentives for providers (eg, reimbursement linked to drug use, use of futile therapy), and reducing off-label drug use.

Even from a business perspective, Ms Zonakis said, employee productivity suffers as patients or caregivers lose time from work, develop secondary depression, and have trouble navigating the medical system. Therefore, employers have a stake at providing employees access to the best care possible, including cancer care, at the lowest cost.

Delta’s Oncology Initiatives and Cancer Network Oncology management “starts with prevention,” she said. “Long before the Affordable Care Act, we began paying 100% for all preventive services that are recommended by the US Preventive Services Task Force, and in many cases we go beyond the recommendations.”

Care given at a National Comprehensive Cancer Network (NCCN)

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Oncology management “starts with prevention. Long before the Affordable Care Act, we began paying 100% for all preventive services that are recommended by the US Preventive Services Task Force, and in many cases we go beyond the recommendations.”

—Lynn Zonakis

Center of Excellence is covered 100% after the deductible is met, and Delta pays for travel and lodging expenses as well. “The Centers of Excellence are an important program of ours. There are rare cancers that call for specialized expertise, and we want to remove access barriers for our members. We have some great success stories from employees who have taken advantage of this.”

Delta also has comprehensive care management and cancer-specific care management programs that are staffed by dedicated oncology nurses; employee assistance and behavior health programs; and pharmacy benefit management strategies for oral agents, injectables, and infusions.

Ms Zonakis was most excited about

cancer programs that are under way at Delta, especially the “high-performance cancer networks,” which are being piloted in communities where most cancer care is delivered. The goals of these programs are to: • Supplement the NCCN Centers of Excellence, by identifying quality providers at the local and regional levels • Collect practice and outcomes data and measure results • Establish pay-for-performance (PFP) standards to reward providers for reaching various evidence-based goals.

“We must start solving the problems of lack of performance data and practice variation at the local and community levels,” Ms Zonakis said, and these networks should help to do that.

Management Support Delta’s cancer program will also include day 1 referrals into a cancer support program and access to NCCN patient resources. “We want the pro-

Continued from cover In addition, under way is a joint project of the National Business Group on Health and the NCCN that aims to identify ways to assist employers in cancer-related benefit design and to improve the second-opinion referral process.

Within this are efforts to enhance employee communications (to reinforce the importance of healthy behaviors and early detection and to offer tools to manage cancer care) encourage appropriate palliative treatment and use of hospice, and to use onsite primary care for prevention and early detection of cancer.

Pay-for-Performance Program in Oncology To participate in the PFP oncology program, providers must agree to be measured and evaluated, and they must strive to practice the best evidence-based medicine. The NCCN guidelines and compendium will be used, but the aim is to further refine these guidelines and encourage physi-

“The Centers of Excellence are an important program of ours. There are rare cancers that call for specialized expertise, and we want to remove access barriers for our members. We have some great success stories from employees who have taken advantage of this.”

—Lynn Zonakis

gram to have early referral for case management support before the patient’s course is set,” Ms Zonakis pointed out.

The initial rollout is in Atlanta, GA, and Minneapolis-St Paul, MN. If the program proves robust enough, Delta may establish a closed network of preferred oncology providers, Ms Zonakis noted.

NOVEMBER 2012

I

cians to “hone in on what works best,” she added.

A portion of physician reimbursement will be linked to evidencebased goals, and these goals will be revised annually. The initial focus is on overtreatment of bony metastasis and overuse of radiotherapy in patients with breast cancer, Ms Zonakis said. ■

www.ValueBasedCancerCare.com

31

2012 Conference

Employers’ Challenge: Cut Healthcare Costs Without Limiting Employees’ Benefits Clinical evidence supports prior authorization paradigm

By Caroline Helwick Houston, TX—Employers’ health plan managers must “balance members’ access to new treatments with the fiscal responsibility of managing the healthcare financial resources wisely,” said Bridget Eber, PharmD, Senior Consultant and Clinical Lead of Rx Group Purchasing, Towers Watson, at the 2012 Second Annual Association for Value-Based Cancer Care Conference. Towers Watson’s clients include 175 employers with self-funded benefits programs totaling $3 billion in annual drug spending.

“That means not wasting resources on unnecessary, unproven, and costly new treatments, while at the same time avoiding barriers for effective and potentially life-saving treatments,” said Dr Eber.

In the past, employers and health plans hesitated to manage oncology costs, because of political sensitivities around the issues. A good example is the use of high-dose chemotherapy, followed by autologous bone marrow transplant, which in the early 1990s was considered a promising therapy for breast cancer. Although the treatment was not proved effective, the legal and political climate at the time resulted in almost universal coverage of that approach by health plans. By the time published studies showed that this therapy was ineffective, more than 30,000 women had received bone marrow transplants, which shortened the lives and worsened the quality of life of many women.

“As a result of this compassionate coverage policy, the healthcare system incurred over $1.5 billion in costs,” Dr Eber noted. “This was the worst of all

Table

In the 1990s, despite lack of evidence for its efficacy, bone marrow transplant for breast cancer was covered by all health plans, and “the healthcare system incurred over $1.5 billion in costs.

This…is an example of how the obligation to make benefits available can generate some unwanted consequences.”

—Bridget Eber, PharmD

scenarios, and is an example of how the obligation to make benefits available can generate some unwanted consequences.”

Drug Utilization and Costs Of the $3 billion in total annual drug spending within Dr Eber’s clients’ health plans, approximately $70 million goes toward medications managed within the specialty pharmacy.

Where Should Employers Begin? Specialty Drug Coverage Checklist

Question

Correct answer

Does your specialty drug list contain <250 products?

√

Are you maximizing pharmacy benefit manager adjudication for self-administered specialty drugs?

√

Are your prices refreshed annually?

√

Is your clinical utilization management strategy comprehensive?

√

Are you taking advantage of high-performance network providers?

√

Does your plan design create incentives: preferred products and/or channels?

√

Are you coordinating care across providers?

√

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VALUE-BASED CANCER CARE

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Specialty pharmacy drugs represent less than 0.5% of all drug utilization in these plans, but these medications are associated with 19% of all covered charges.

Cancer-related drugs—the third highest driver of specialty pharmacy utilization (after autoimmune diseases and multiple sclerosis)—account for less than 0.05% of drug utilization, but are responsible for approximately 2.5% of covered charges within specialty pharmacy. Although these are relatively low utilization rates, specialty drugs are associated with exceptionally high costs, according to Dr Eber.

Cancer Drugs In each clinical area, a few medications drive most of the utilization and costs. In oncology, 50% of drug utilization and costs are for imatinib (Gleevec), leuprolide acetate for depot suspension (Lupron Depot), lenalidomide (Revlimid), and capecitabine (Xeloda). Overall, 10 cancer drugs represent approximately 80% of all drug utilization and 75% of all drug costs.

“Employers know the main drivers of utilization among their members, so when employers are looking for a core strategy or the most essential areas to focus upon, we try to help them recognize the low-hanging fruit,” said Dr Eber.

Critical Need for Data Clinical utilization data have been difficult to come by, creating a handicap for benefit consultants who design strategies for employers. However, data are increasingly becoming available, with better documentation of prior authorization, step therapy, and quantity limits. “We are getting some sense of activity, approval and denial rates, appeal rates, and reversal rates,” stated Dr Eber.

These data show that much of the cost-saving stems from using therapy only as indicated and denying coverage when treatment efficacy has not been established. The data also indicate that appeals often lead to reversals, probably because physicians provide more information or have direct contact with a representative.

Dr Eber noted that of a total of 120 appeals from providers in the Rx Collaborative program (an employer coalition for purchasing pharmacy benefit manager [PBM] services), 107 appeals were reversed, based on a recent analysis.

Employers Depend on Prior Authorization to Control Utilization In contrast with the historical paradigm of coverage decisions of not interfering with a physician’s choice, the current paradigm of many plans is to restrict access to treatments that are not proved, largely with the use of prior authorization.

Bevacizumab (Avastin) coverage denial several years ago is an example of this newer strategy, which prevented spending on unnecessary or unproved therapy. Based on safety and efficacy in several tumor sites, clinicians believed that bevacizumab could improve outcomes in patients with pancreatic cancer when added to a standard regimen, and wanted to use this approach.

The current paradigm of many plans is to restrict access to treatments that are not proved, largely with the use of prior authorization.

However, the drug’s high cost forced most PBMs to be rigorous with their prior authorization processes and to typically deny coverage for that approach, for lack of evidence for benefit. Then, in 2008, an efficacy study failed to show a survival advantage for bevacizumab in patients with pancreatic cancer.

“Approximately 40,000 new cases of pancreatic cancer occur each year, and if doctors had routinely added Avastin to standard regimens based solely on theories, the additional cost would have been $1 billion to $2 billion,” Dr Eber emphasized. Employers, however, recognize that evidence and strong rationale need to support prior authorization and coverage denials, she noted.

To ensure that employers are striking the right balance between advocating for their members and being fiscally responsible, she offers a checklist of issues for employers to consider before embarking on a specialty drug coverage program (Table). This list outlines the questions that are important to consider when looking for a benefit design for specialty drugs. ■

VOL. 3

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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.

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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.

To learn more, visit us at millennium.com. ©2012 Millennium Pharmaceuticals, Inc. All rights reserved.

2012 Conference

To Many Employers, Specialty Pharmacy Is a Vague Concept

By Caroline Helwick Houston, TX—Most employers do not understand biologics and specialty pharmacy well enough to use services appropriately and to take advantage of their benefits, said F. Randy Vogenberg, RPh, PhD, Principal, Institute for Integrated Healthcare, Sharon, MA, an employer benefit consulting company.

Speaking at the Second Annual Association for Value-Based Cancer Care Conference, Dr Vogenberg drew from a recent survey of employers to suggest actions that need to be taken to better integrate healthcare stakeholders.

In 2011, the Midwest Business Group on Health (MBGH), which evaluates issues from an employer point of view, saw a growing lack of understanding among employers regarding biologics and specialty pharmacy. A significant part of any health plan, biologics and specialty pharmacy currently account for approximately 25% of today’s spending but are projected to represent 50% by 2030; the average annual per-user cost today is $12,500.

With product growth within biologics and specialty pharmacy anticipated to be a top concern, MBGH partnered with Dr Vogenberg on research that would help employers to understand the role of biologics and specialty pharmacy, to prepare for challenges, to manage benefits through plan design innovation and partnering with specialty vendors in contracting and patient management, to better manage the at-risk population, and to more

effectively communicate specialty benefits to employees.

Part of the difficulty, said Dr Vogenberg, is the lack of a single, standard definition of biologics and specialty pharmacy. Additional challenges are posed by the existence of various delivery channels, sites of care, the US Food and Drug Administration requirements, and reimbursement schemes, and by innovations in formulations, drug delivery systems, and

“This linkage, taking traditional pharmacy management and applying it to specialty pharmacy, is the standard in the marketplace, and it is probably not the appropriate way to spend resources, time, and money in managing these categories.”

—F. Randy Vogenberg, RPh, PhD

companion diagnostics—all contributing to cost and to the dilemma of determining what benefits are appropriate for employees.

National Employer Survey on Biologics The MBGH’s National Employer Survey on biologics and specialty

Figure Level of Importance for Key Areas When Contracting with Biologics and Specialty Pharmacy Vendors Very important

Important

Somewhat important

Not important

100% 9

12

24

7

5

4

18

80%

60%

Don’t know

6 4 5

6 4 7

27

23

10

18 28 31

40%

25 58

60

45

20% 29

35

0% Special distribution requirements for biologics & specialty pharmacy

Utilization of a specialty pharmacy

Prior approval and/or step therapy edits for claim approval

Patient support and care management are provided

Copyright © 2011 Midwest Business Group on Health and IIH. Used with permission.

34

VALUE-BASED CANCER CARE

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NOVEMBER 2012

Vendor costs

“There is a need to close the knowledge gap regarding healthcare benefits coverage, spending, and costs, to identify potential improvements to benefit strategies, and to shift coverage decisions to better benefit employers and their employees.”

—F. Randy Vogenberg, RPh, PhD pharmacy, in which 120 national employers participated, revealed that: • In the past 5 years, specialty drug plan spending rose by more than 15%, several times more than the overall drug trend • Employers are unaware of their spending on biologics and whether that spending is effective • Employers are unsure how to design appropriate benefits regarding biologics, and how to effectively communicate this information to their employees.

More than 50% of the participating employers indicated that their level of understanding of specialty pharmacy is “low.” This low level of understanding was much more likely to be reported by very small companies (<500 employees), whereas the greatest understanding was observed among very large companies (>25,000 employees), possibly because large companies get more support from benefit advisors. “Still, we saw a significant lack of understanding of the whole area,” Dr Vogenberg said.

Based on this survey, more than 66% of employers offer case management services, disease management, or drug utilization management. Benefits and services provided around specialty pharmacy, for the most part, rely on pharmacy benefit managers (PBMs), he said. “This linkage, taking traditional pharmacy management and applying it to specialty pharmacy, is the standard in the marketplace, and it is probably not the appropriate way to spend resources, time, and money in managing these categories,” Dr Vogenberg suggested.

In addition, more than 50% of employers require that employees use specialty pharmacy to receive coverage, but 75% offer no incentives for doing so.

The survey also sought to determine what employers consider important when contracting with biologics and specialty pharmacy vendors (Figure).

The majority of respondents consider

vendor cost to be a critical factor.

“They said they could not differentiate between Plan A versus Plan B, or PBM A versus PBM B, based on performance, so they look at cost when making decisions,” Dr Vogenberg said about the employers who were surveyed.

“This survey suggests that employers have not moved away from traditional benefit designs to take advantage of the benefits that specialty pharmacy vendors could provide,” he observed.

“And it suggests there is a need to close the knowledge gap regarding healthcare benefits coverage, spending, and costs, to identify potential improvements to benefit strategies, and to shift coverage decisions to better benefit employers and their employees.”

Action Points Dr Vogenberg suggests “key themes for action” for tightening the distance between employers and the management of biologics and specialty pharmacy: • Fill in gaps in understanding cancer related benefit coverage, spending, and the total cost of healthcare for self-funded plans • Determine key areas of utilization trends that are important to an employer organization and the organization’s success as a business • Identify short- and longer-term opportunities for improving benefit strategies or the use of support resources as part of a holistic approach • Choose how best to optimize benefit spending based on technology trends • Use knowledge gained in cancer care to incrementally shift benefit decisions and press for changes, such as benefit design and insurance innovation.

“Cancer is a good opportunity and starting point for employers around biologics, and experience gained here can be leveraged into other therapeutic areas,” Dr Vogenberg said. ■

VOL. 3

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NO. 8

Serving Your Oncology Needs Our Generics Lineup Just Expanded—Again.

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CYTOSAFE is a registered trademark of Pfizer Inc, New York, NY. USI00227E-01

© 2011 Pfizer Inc.

All rights reserved.

July 2011

www.pfizerinjectables.com

Drug Update

Abraxane Receives New Indication for Locally Advanced or Metastatic Non–Small-Cell Lung Cancer, in Combination with Carboplatin, in Patients Who Are Not Candidates for Curative Surgery or Radiation Therapy

By Lynne Lederman, PhD, Medical Writer

F

or the purposes of treatment, lung cancer is classified as non– small cell, which accounts for approximately 85% of cases, or as small cell, representing 14% of cases.1 Non–small-cell lung cancer (NSCLC) is the leading cause of death worldwide.2 The greatest risk factor for lung cancer is cigarette smoking.

Other risk factors include smoking pipes or cigars and exposure to agents such as radon gas, secondhand smoke, asbestos, chromium, cadmium, arsenic, some organic chemicals, radiation, and air pollution. The rate of lung cancer may be increased in individuals with a history of tuberculosis or a genetic susceptibility to the disease.1,3

The Burden and Impact of Lung Cancer In 2012, the American Cancer Society estimated there would be 226,160 individuals with new cases of lung cancer, representing approximately 14% of all cancer diagnoses, and 160,340 deaths from lung cancer in the United States, which is approximately 28% of all cancer deaths.1 Lung cancer is the second leading cause of new cases of cancer (other than nonmelanoma skin cancer or noninvasive cancers other than bladder cancer) in both men and women in the United States, and the leading

Table 1

cause of death for both sexes.1 The likelihood of developing lung cancer increases with age.1 Although the rate of lung cancer has been decreasing in men over the past 20 years, it has only recently started decreasing in women. Sex differences in the incidence of lung cancer and in death rates are a result of historic rates of smoking and smoking cessation in men and women over the past 50 years.4

Lung cancer is usually diagnosed at later stages and is rarely cured. Symptoms can include persistent cough, blood-tinged sputum, chest pain, change in the voice, and recurrent pneumonia or bronchitis.

Lung cancer is usually diagnosed at later stages and is rarely cured.4 Symptoms can include persistent cough, blood-tinged sputum, chest pain, change in the voice, and recurrent pneumonia or bronchitis.1 Median age at diagnosis is age 70 years for men and age 71 years for women.5 Annual chest x-rays do not decrease

mortality from lung cancer. Although a screening trial using low-dose spiral computed tomography reduced the death rate by 20% for high-risk individuals (ie, current and former heavy smokers), it is not known if this technology is applicable for screening of those with less cigarette exposure. The risks of screening include cumulative radiation exposure and unnecessary biopsies and surgery.1 The 1-year relative survival for patients with lung cancer—which has been increasing over the past several decades as a result of better surgical techniques and combination therapies—was 43% in the period between 2003 and 2006.1 The 5-year survival rate for all stages of lung cancer combined is only 16%. Early detection at the localized stage results in a 5-year survival rate of 52%, but localized lung cancer represents only 15% of all cases.

The overall 5-year survival for NSCLC is 17%,1 but the 5-year survival rate for stage IV NSCLC is only 1%.6 Current Treatments for Lung Cancer The current treatments for lung cancer are based on the type and stage of the tumor, and include surgery, radiation therapy, chemotherapy, and targeted therapies, such as bevacizumab, erlotinib, or crizotinib.1,3 Surgery is the most common treatment choice for

Baseline Demographics and Disease Characteristics in the Phase 3 NSCLC Trial, ITT Population Abraxane (N = 521)

Paclitaxel (N = 531)

All patients (N = 1052)

Median age, yrs

60

60

60

Male, %

75

75

75

Female, %

25

25

25

15/2/80/2/<1

15/2/82/<1/<1

15/2/81/2/<1

Stage IIIB at random assignment, %

21

21

21

Stage IV at random assignment, %

79

79

79

Characteristic

Asian/black/white/Hispanic/other, %

Prior radiation/prior chemotherapy, %

7/3

9/2

8/3

Never smoked, %

26

27

27

Smoked and quit, %

32

29

30

Still smokes, %

41

44

43

ITT indicates intention-to-treat; NSCLC, non–small-cell lung cancer.

Source: Socinski MA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non–small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012;30:2055-2062.

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localized NSCLC (stage I or stage II).3 Chemotherapy after surgery usually improves survival. However, NSCLC is usually diagnosed at a more advanced stage, and treatment often includes radiation therapy and chemotherapy, which can be combined with surgery. Patients with advanced NSCLC usually receive chemotherapy, targeted therapy, or both.1 Platinumbased regimens are recommended for patients with stage IV NSCLC.3 Although many combinations of new agents have been tested in patients with advanced, inoperable NSCLC, their prognosis is still poor, suggesting a need for new therapeutic options.3 Abraxane Receives a New Indication for NSCLC On October 11, 2012, paclitaxel protein-bound particles for injectable suspension (Abraxane for Injectable Suspension), an albumin-bound form of paclitaxel, was approved for the first-line treatment of locally advanced or metastatic NSCLC in combination with carboplatin in patients who are not candidates for curative surgery or radiation therapy.7-9 Abraxane is a nanoparticle proteinbound paclitaxel, which may therefore also be referred to as nab-paclitaxel.6 Abraxane is already indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or for relapse within 6 months of adjuvant chemotherapy.

Prior therapy should have included an anthracycline unless clinically contraindicated.8 The new indication for NSCLC was based on a clinical trial comparing weekly infusions of Abraxane at a dose of 100 mg/m2 (ITT [intention to treat], n = 521) to infusions of paclitaxel every 3 weeks at a dose of 200 mg/m2 (ITT, n = 531). All patients also received carboplatin (AUC [area under the curve], 6 mg•min/mL) every 3 weeks.6,9 The study design and results are described in detail below.

Clinical Pharmacology: Development and Mechanism of Action Abraxane is an albumin-bound form of paclitaxel, the active component.

Continued on page 37

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Drug Update

Abraxane has a mean particle size of approximately 130 nm.8,10 Abraxane does not contain any solvents or ethanol. The 130-nm particle size will not obstruct capillaries when the agent is delivered by intravenous (IV) infusion.10 Abraxane was developed to avoid toxicities associated with the vehicle polyoxyethylated castor oil (Cremophor EL), which is used to deliver paclitaxel because of its poor solubility.10,11 Paclitaxel is contraindicated in patients with a history of hypersensitivity reactions to the drug itself or to other drugs formulated in polyoxyethylated castor oil. Patients receiving paclitaxel require pretreatment with corticosteroids, diphenhydramine, and H2 antagonists to avoid hypersensitivity reactions.12 Severe hypersensitivity reactions that required treatment occurred in 2% to 4% of patients receiving paclitaxel in clinical trials, and some of these reactions were fatal, despite premedication.12 Unlike paclitaxel, Abraxane does not require premedication and can be infused over a shorter period of time.8,12 Abraxane was also designed to increase intratumor concentrations of the active drug using endogenous albumin pathways.11 The mechanism of action of Abraxane is microtubule inhibition, the same as that of paclitaxel. Abraxane promotes the assembly of microtubules from tubulin dimers and stabilizes these microtubules, by preventing depolymerization. This stabilization prevents microtubules from reorganizing properly and from maintaining their normal structure during mitosis, thereby inhibiting cancer-cell division, motility, and intracellular transport.8,10

carboplatin as first-line systemic treatment in patients with locally advanced (stage IIIB) or metastatic (stage IV) NSCLC. A total of 1052 patients were randomly assigned in a 1:1 ratio to receive weekly 30-minute infusions of Abraxane 100 mg/m2 or 3-hour infusions of paclitaxel 200 mg/m2 after premedication every 3 weeks.

All patients also received IV carboplatin (AUC, 6 mg•min/mL) every 3 weeks after infusion with Abraxane or paclitaxel. The primary objective was ORR.6,8

Trial Design This randomized, multicenter, openlabel phase 3 trial compared the efficacy and safety of Abraxane plus carboplatin with that of solvent-based paclitaxel (paclitaxel injection) plus

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(≥10% incidence) for the patients receiving Abraxane plus carboplatin are listed in Table 2.8 These common adverse reactions occurred at a similar incidence in the paclitaxel injection plus carboplatin–treated patients.

Continued on page 38

Common (≥10% Incidence) Adverse Reactions in Patients Receiving Abraxane plus Carboplatin Incidence, % Adverse reaction (N = 514) Table 2

Alopecia

56

Nausea

27

Key baseline demographic and disease characteristics of the enrolled patients are listed in Table 1. The 2 treatment groups were well-balanced.6

Fatigue

25

Decreased appetite

17

Asthenia

16

Constipation

16

Safety Profile

Diarrhea

15

Adverse reactions (ie, safety) were assessed in the 514 patients who received Abraxane plus carboplatin, and in the 524 patients who received paclitaxel injection plus carboplatin.6,8 The median number of treatment

Vomiting

12

Dyspnea

12

Rash

10

Patient Population

Table 3

Source: Abraxane for Injectable Suspension [package insert]. Summit, NJ: Celgene Corporation; October 2012.

Selected Hematologic Toxicities between Treatment Groups Abraxane (100 mg/m2 weekly) plus carboplatin

Anemia

a,b

Neutropenia

a,c

Thrombocytopenia

a,c

Paclitaxel injection (200 mg/m2 every 3 weeks) plus carboplatin

Grades 1-4, %

Grades 3-4, %

Grades 1-4, %

Grades 3-4, %

98

28

91

7

85

47

83

58

68

18

55

9

a

508 patients assessed in the Abraxane plus carboplatin-treated group.

514 patients assessed in the paclitaxel injection plus carboplatin-treated group. c 513 patients assessed in the paclitaxel injection plus carboplatin-treated group.

Adapted from Abraxane for Injectable Suspension [package insert]. Summit, NJ: Celgene Corporation; October 2012. b

Table 4 Phase 3 Clinical Trial in Locally Advanced or Metastatic NSCLC The new indication for Abraxane as first-line treatment of locally advanced or metastatic NSCLC, in combination with carboplatin in patients who are not candidates for curative surgery or for radiation therapy, was approved on the basis of one phase 3 clinical trial, showing significantly improved overall response rates (ORRs) in all patients receiving Abraxane, regardless of histology results.6,7,9

cycles was 6 for each treatment group.

The doses and schedules for the 2 treatment groups were different; therefore, direct dose-dependent and schedule-dependent comparisons concerning safety cannot be made.8 The adverse reactions seen most frequently

Selected Nonhematologic Toxicities between Treatment Groups

System organ class

MedDRA v 12.1 preferred term

Abraxane (100 mg/m2 weekly) plus Paclitaxel injection (200 mg/m2 every carboplatin (N = 514) 3 weeks) plus carboplatin (N = 524) Grades 1-4, %

Grades 3-4, %

Grades 1-4, %

Grades 3-4, %

Peripheral neuropathya

48

3

64

12

General disorders, administration-site conditions

Edema, peripheral

10

0

4

<1

Respiratory thoracic and mediastinal disorders

Epistaxis

7

0

2

0

Arthralgia

13

<1

25

2

Myalgia

10

<1

19

2

Nervous system disorders

Musculoskeletal, connective-tissue disorders a

Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope).

Adapted from Abraxane for Injectable Suspension [package insert]. Summit, NJ: Celgene Corporation; October 2012.

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Drug Update

Abraxane Receives New Indication for Locally Advanced or Metastatic NSCLC...

Continued from page 37

The frequency and severity of hematologic abnormalities occurring with a difference of ≥5% for all grades (grades 1-4) or ≥2% for grade 3 and 4 toxicities for the 2 treatment groups are listed in Table 3.8 Only 1% of patients in each arm developed febrile neutropenia, and 1 treatment-related death was reported in each arm.6 Thrombocytopenia and anemia associated with Abraxane plus carboplatin were readily manageable.6 The frequency and severity of nonhematologic adverse reactions occurring with a difference of ≥5% for all grades (grades 1-4) or ≥2% for grade 3 and 4 toxicities between the 2 treatment groups are listed in Table 4.8 The incidences of severe neuropathy, myalgia, and arthralgia were lower in the Abraxane plus carboplatin group.6

Table 5

In the Abraxane plus carboplatin– treated group, 17 of 514 (3%) patients developed grade 3 peripheral neuropathy (PN), and none developed grade 4 PN. In 10 (59%) of these patients, the grade 3 neuropathy resolved or improved to grade 1 after interruption or discontinuation of Abraxane.8 Median time to improvement of grades 3 or 4 sensory neuropathy was shorter (38 days) for patients in the Abraxane plus carboplatin group than the median time (104 days) for those in the paclitaxel injection plus carboplatin group.6

spectively; P = .005). No significant difference was found in overall survival between the 2 treatment groups.8 The efficacy results are summarized in Table 5.

Dose Modifications

Unlike paclitaxel, Abraxane does not require premedication.

Dosing and Administration Unlike paclitaxel, Abraxane does not require premedication.8 The recommended dose of Abraxane for patients with NSCLC is 100 mg/m2, which is administered as an IV infusion over 30 minutes on days 1, 8, and 15 of each 21-day cycle. The recom-

Response The trial met its primary end point.9 The ORR was significantly higher in the Abraxane plus carboplatin group than in the paclitaxel injection plus carboplatin group (33% vs 25%, re-

Efficacy Results from the Phase 3 NSCLC Trial, ITT Population Abraxane (100 mg/m2 weekly) plus carboplatin (N = 521)

Paclitaxel injection (200 mg/m2 every 3 weeks) plus carboplatin (N = 531)

Confirmed complete or partial overall response, N (%)

170 (33)

132 (25)

95% CI

28.6-36.7

21.2-28.5

Overall response rate

P value (chi-square test)

.005

Median DoR in months (95% CI)

mended dose of carboplatin is AUC 6 mg•min/mL on day 1 only of each 21-day cycle, beginning immediately after administration of Abraxane is completed.8

6.9 (5.6-8.0)

6.0 (5.6-7.1)

Carcinoma/adenocarcinoma

66/254 (26%)

71/264 (27%)

Squamous-cell carcinoma

94/229 (41%)

54/221 (24%)

Large-cell carcinoma

3/9 (33%)

2/13 (15%)

Other

7/29 (24%)

5/33 (15%)

Overall response rate, by histology

CI indicates confidence interval; DoR, duration of response; ITT, intention-to-treat; NSCLC, non–small-cell lung cancer.

Adapted from Abraxane for Injectable Suspension [package insert]. Summit, NJ: Celgene Corporation; October 2012.

Dose modifications are not required for patients with mild hepatic impairment (AST [aspartate aminotransferase] <10 times the upper limit of normal [ULN], or bilirubin up to 1.25 times ULN). Abraxane should not be administered to patients with AST >10 times ULN or bilirubin >5 times ULN. The starting doses for patients with NSCLC who have moderate hepatic impairment (AST <10 times ULN and bilirubin 1.26-2 times ULN) or severe hepatic impairment (AST <10 times ULN and bilirubin 2.01-5 times ULN) should be reduced to 75 mg/m2 or to 50 mg/m2, respectively. Subsequent dose increases or adjustments should be based on individual tolerance.8 Patients with NSCLC should not receive Abraxane on day 1 of a cycle if they do not have an absolute neutrophil count (ANC) of ≥1500 cells/mm3 and platelet counts of ≥100,000 cells/ mm3.

Treatment should be withheld until counts reach these levels on day 1 or until ANC is ≥500 cells/mm3 and platelet counts are ≥50,000 cells/mm3 on days 8 and 15 of a cycle. Abraxane should be withheld for grades 3 or 4 PN. Permanent modifications to Abraxane and to carboplatin doses are required when treatment is resumed after neutropenia, neutropenic fever, thrombocytopenia, or PN.8 These dose reductions are summarized in Table 6.

Warnings and Precautions

Boxed Warning Table 6

Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC

Adverse drug reaction Neutropenic fever (ANC <500 cells/mm3 with fever >38°C) or delay of next cycle by >7 days for ANC <1500 cells/mm3 or ANC <500 cells/mm3 for >7 days

Occurrence

Weekly Abraxane dose, mg/m2

Every 3-week carboplatin dose, AUC mg•min/mL

First

75

4.5

Second

50

3

Third First

Platelet count <50,000/mm3

Discontinue treatment 75

Second

Severe sensory neuropathy, grade 3 or 4

4.5 Discontinue treatment

First

75

4.5

Second

50

3

Third

Discontinue treatment

ANC indicates absolute neutrophil count; AUC, area under the curve; NSCLC, non–small-cell lung cancer.

Adapted from Abraxane for Injectable Suspension [package insert]. Summit, NJ: Celgene Corporation; October 2012.

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The prescribing information for Abraxane contains a Boxed Warning concerning neutropenia. The Boxed Warning states the following8: • Do not administer Abraxane therapy to patients who have baseline neutrophil counts of <1500 cells/ mm3; to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and may result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving Abraxane • An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. Do NOT substitute for or with other paclitaxel formulations.

Continued on page 41

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NOW AVAILABLE

©2012 Onyx Pharmaceuticals, Inc., South San Francisco, CA 1111-CARF-147a July 2012 Printed in USA

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THIRD ANNUAL

Association for Value-Based Cancer Care Conference Influencing the Patient-Impact Factor May 2-5, 2013 • Westin Diplomat • Hollywood, Florida CONFERENCE CO-CHAIRS

AGENDA* THURSDAY, MAY 2, 2013 8:00 am - 5:00 pm

Registration

FRIDAY, MAY 3, 2013 7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

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Session 1: Welcome, Introductions, and Opening Remarks Conference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS

9:15 am - 10:15 am

Keynote Address

10:15 am - 10:30 am

Break

PROGRAM OVERVIEW

10:30 am - 11:45 am

Following on the success of our Second Annual Conference, AVBCC will be coming to Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise of leaders in these fields providing attendees with a thorough understanding of the evolution of the value equation as it relates to cancer therapies. Our goal is to be able to assist them in implementing, improving, and sustaining their organizations and institutions, while improving access for patients and ultimately quality patient care.

Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder Collaborations Roy A. Beveridge, MD; Michael Kolodziej, MD

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 2:00 pm

Session 3: Cost of Cure: When, How, and How Much?

John Fox, MD; John Hennessy

2:00 pm - 2:45 pm

Session 4: Where Is Oncology Care Headed in the Future?

Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD

Upon completion of this activity, the participant will be able to: • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery.

• Define the barriers associated with cost, quality, and access as they relate to healthcare reform and what solutions are currently being considered.

• Compare and contrast the different approaches/tools providers and payers are utilizing to manage and deliver care collaboratively.

• Examine the current trends in personalized care and companion diagnostics.

• Analyze the patient issues around cost, quality, and access to care.

2:45 pm - 3:30 pm

Session 5: What Will the Cancer Delivery System Look Like in 2015?

Linda Bosserman, MD, FACP; John D. Sprandio, MD

3:30 pm - 3:45 pm

Break

3:45 pm - 4:30 pm

Session 6: Employers and Oncology Care F. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman

4:30 pm - 5:15 pm

Session 7: The Role of Government in the Future of Oncology Care Jayson Slotnick, JD, MPH

TARGET AUDIENCE

5:15 pm - 5:45 pm

Summary/Wrap-Up of Day 1

This conference is intended for medical oncologists, practice managers/administrators, and managed care professionals. Stakeholders in a position to impact cancer patient care, such as advanced practice nurses, pharmacists, and medical directors, are also invited to join this exciting forum.

6:00 pm - 8:00 pm

Cocktail Reception in the Exhibit Hall

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

DESIGNATION OF CREDIT STATEMENTS

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 8: Advanced Care Directives: Palliative Care, Hospice, Ethics J. Russell Hoverman, MD, PhD Thomas J. Smith, MD, FACP, FASCO

9:15 am - 10:00 am

Session 9: Medicaid: A Healthcare Delivery System Review Matthew Brow

COMMERCIAL SUPPORT ACKNOWLEDGMENT

10:00 am - 10:15 am

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Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

10:15 am - 11:00 am

Session 10: Payer, Government, and Industry Insights: Balancing Cost and Quality

11:00 am - 11:45 am

Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence Issues Pat McKercher

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 3:00 pm

Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm

Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling, Genome Sequencing—The Impact on Cost, Treatment, and the Value Proposition Mark S. Boguski, MD, PhD

3:45 pm - 4:15 pm

Summary/Wrap-Up of Day 2

4:30 pm - 6:30 pm

Cocktail Reception in the Exhibit Hall

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

Gary M. Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS President and CEO OncoMed

LEARNING OBJECTIVES

SPONSORS This activity is jointly sponsored by Medical Learning Institute Inc, the Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

SATURDAY, MAY 4, 2013

PHYSICIAN CREDIT DESIGNATION The Medical Learning Institute Inc designates this live activity for a maximum of 17.25 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 through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

REGISTERED NURSE DESIGNATION Medical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.

SUNDAY, MAY 5, 2013 7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

REGISTERED PHARMACY DESIGNATION

8:15 am - 8:30 am

Opening Remarks

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 17.25 contact hours (1.725 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

8:30 am - 9:15 am

Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship Care Julie Silver, MD

9:15 am - 10:00 am

Session 15: Current and Future Considerations for the Oncology Practice Manager Dawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 16: Access to Drugs—Shortages, Biosimilars Douglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am

Session 17: Perspectives from Large Oncology Group Practices—Successes, Issues, and Challenges

11:45 am - 12:00 pm

Summary and Conclusion of Conference

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$375.00 until January 15, 2013 $475.00 until March 15, 2013 $675.00 after March 15, 2013

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*Agenda is subject to change. #'

Drug Update

Abraxane Receives New Indication for Locally Advanced or Metastatic NSCLC...

Continued from page 38

Other warnings, precautions, and contraindications for Abraxane include8: • Abraxane is contraindicated in patients with neutrophil counts of <1500 cells/mm3 • Patients who experience a severe hypersensitivity reaction to Abraxane should not be rechallenged with the drug • Abraxane causes myelosuppression; complete blood counts should be monitored and doses reduced as needed • Sensory neuropathy is a frequent adverse event and may require dose reduction or treatment interruption • Severe, fatal hypersensitivity reactions have been reported; do not rechallenge patients with Abraxane • Hepatic impairment can increase exposure and toxicity of paclitaxel; Abraxane should be administered with caution in patients with hepatic impairment • Abraxane contains albumin derived from human blood, which has a theoretical risk of viral transmission • Abraxane may cause fetal harm when administered to pregnant women; women of childbearing age should avoid becoming pregnant while receiving Abraxane • Men should be advised not to father a child while receiving Abraxane.

for the first-line treatment of advanced non-small cell lung cancer. October 12, 2012. http://ir.celgene.com/ phoenix.zhtml?c=111960&p=irol-newsArticle&ID= 1744792&highlight=. Accessed October 29, 2012.

8. Abraxane for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) [packet insert]. Summit, NJ: Celgene Corporation; October 2012.

RJ Health Systems — the pharmaceutical specialists that healthcare professionals have turned to since 1983 for their drug information.

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ReimbursementCodes.com incorporates the CMS HCPCS and AMA CPT Drug codes into a system that crosswalks each drug code with the drug’s NDC and brand/generic name.

Please visit www.rjhealthsystems.com to learn more about our products and services listed below:

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References

1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American Cancer Society; 2012. www. cancer.org/acs/groups/content/@epidemiology surveilance/documents/document/acspc-031941. pdf. Accessed October 29, 2012.

2. Chien C-R, Shih Y-C T. Economic evaluation of bevacizumab in the treatment of non-small cell lung cancer (NSCLC). Clinicoecon Outcomes Res. 2012;24:201-208.

3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non–smallcell lung cancer. Version 2.2012. www.nccn.org.

Accessed October 29, 2012.

4. Vera-Llonch M, Weycker D, Glass A, et al. Health care costs in patients with metastatic lung cancer receiving chemotherapy. BMC Health Serv Res. 2011;11:305-312.

5. American Cancer Society. Cancer Treatment and Survivorship Facts & Figures 2012-2013. Atlanta, GA: American Cancer Society; 2012.

6. Socinski MA, Bonderenko I, Karaseva NA, et al.

Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced nonsmall-cell lung cancer: final results of a phase III trial.

J Clin Oncol. 2012;30:2055-2062.

7. Celgene Corporation. FDA approves ABRAXANE®

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mophor-based paclitaxel. Clin Cancer Res. 2006;12: 1317-1324.

11. Green MR, Manikhas GM, Orlov S, et al. Abraxane, a novel Cremophor-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-smallcell lung cancer. Ann Oncol. 2006;17:1263-1268.

12. Taxol (paclitaxel) injection [packet insert]. Princeton, NJ: Bristol-Myers Squibb Corporation; April 2011.

RJ Health Systems The Creators of ReimbursementCodes.com

Conclusion NSCLC is the most common type of lung cancer, which is the leading cause of cancer-related mortality in the United States. There have not been many new treatment options approved for NSCLC. The approval of Abraxane for the treatment of NSCLC offers a new treatment option for all patients with this type of malignancy whose treatment options are limited, especially those who are not candidates for curative surgery or for radiation therapy. ■

VOL. 3

9. US Food and Drug Administration. Drugs. Paclitaxel (Abraxane). October 11, 2012. www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ ucm323668.htm. Accessed October 29, 2012.

10. Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albuminbound paclitaxel, ABI-007, compared with cre-

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

rjhealthsystems.com

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CONTINUING EDUCATION NOVEMBER 2012 • VOLUME 5 • NUMBER 4

5th Annual

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Retreatment Settings LETTER

FROM THE

EDITOR-IN-CHIEF

PUBLISHING STAFF

Over the past several years, significant progress has been made in the management of multiple myeloma (MM). This is due, in large part, to an accumulating knowledge of the biology of the disease, along with the development and clinical investigation of highly effective therapies. The shift in the paradigm of care for MM has resulted in revised criteria for diagnosing, staging, and risk-stratifying patients; new standards of care; and updated guidelines for the management of comorbidities and treatment-related toxicities. However, more progress is needed and many questions remain regarding the application and interpretation of recent clinical advances.

In this fifth annual “Considerations in Multiple Myeloma” newsletter series, we continue to address frequently asked questions related to the diagnosis and treatment of the disease. To provide an interprofessional perspective, questions are answered by physicians, nurses, and pharmacists from leading cancer institutions, who share their insight, knowledge, and professional experience regarding evidence-based care. In this fourth issue, experts from the University of California, San Francisco answer questions pertaining to the management of patients in the retreatment setting.

President & CEO Brian F. Tyburski

Chief Operating Officer Pam Rattananont Ferris

Editorial Director Susan Berry susan@coexm.com

Copyeditor Dana Delibovi

Sincerely, Director, Production and Manufacturing Alaina Pede

Sagar Lonial, MD Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA

Director, Creative and Design Robyn Jacobs

Quality Control Director Barbara Marino

Director, Digital and Media Anthony Romano

FACULTY

Web Coordinator Jose Valentin

Jeffrey Wolf, MD Clinical Professor Department of Medicine, UCSF Director, Myeloma Program UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA

Digital Content Specialist David Maldonado

Business Manager Blanche Marchitto

Bookkeeper Teresa Torgersen

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Jennifer Knoche, RN, BSN Lead Practice Nurse UCSF Hematology/BMT Ambulatory Care Center San Francisco, CA

Helen T. Wu, PharmD, BCOP Clinical Pharmacist Adult Hematology/Oncology and Health Sciences Associate Clinical Professor School of Pharmacy, UCSF San Francisco, CA

Supported by educational grants from Celgene Corporation and Millennium: The Takeda Oncology Company.

Circulation Department circulation@greenhillhc.com Center of Excellence Media, LLC 1249 South River Road Suite 202B Cranbury, NJ 08512

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VALUE-BASED CANCER CARE

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

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CONSIDERATIONS IN MULTIPLE MYELOMA Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Celgene Corporation and Millennium: The Takeda Oncology Company.

Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM).

Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. Physician Credit Designation The Medical Learning Institute Inc 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 through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

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

in the relapsed/refractory setting • Apply evidence-based retreatment strategies for MM, taking into consideration patient- and disease-related factors • Describe appropriate prophylactic measures for managing adverse events to optimize treatment efficacy 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 offlabel discussions. All identified conflicts of interest are thoroughly vetted

by Medical Learning Institute Inc 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.

Patricia A. Ensor, RPh, MBA, MLI Reviewer, has nothing to disclose.

Judith A. Bonomi, RN, MS, MSN, OCN, MLI Reviewer, has disclosed that her spouse is investigator on a study for Agenix, ImClone, and Lilly; on the data monitoring committee for Infinity; on the Advisory Committee for Boehringer Ingelheim; and on the data monitoring committee and principal investigator on a study for Pfizer.

Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 1.25 contact hours (0.125 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-12-030-H01-P.

Faculty Disclosures *Sagar Lonial, MD, is Consultant to Bristol-Myers Squibb, Celgene Corporation, Merck, Millennium: The Takeda Oncology Company, Novartis, and Onyx. *Jeffrey Wolf, MD, is on the speakers’ bureau for Celgene Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharmaceuticals, Inc. Helen T. Wu, PharmD, BCOP, has nothing to disclose.

Jennifer Knoche, RN, BSN, is on the speakers’ bureau for Celgene Corporation.

Learning Objectives Upon completion of this activity, the participant will be able to: • Review data from recent clinical trials evaluating novel agents for MM

*Content will include non–FDA-approved uses.

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/CPE/CE activity for any amount during the past 12 months.

Disclaimer The information provided in this CME/CPE/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.

Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/ CPE/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/P12028.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 Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org.

Estimated time to complete activity: 1.25 hours Date of initial release: November 13, 2012 Valid for CME/CPE/CE credit through: November 13, 2013

SCAN HERE to Download the PDF or Apply for Credit.

To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s Web browser, and select “Download” • Visit the app store for your smartphone

Making Treatment Decisions in Relapsed and Refractory Multiple Myeloma Jeffrey Wolf, MD Clinical Professor, Department of Medicine, UCSF Director, Myeloma Program UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA

Eligible patients advance to autologous stem cell transplantation (ASCT) following this therapy. More and more patients receive maintenance therapy, either with lenalidomide or bortezomib. Therefore, when patients relapse, they have already received quite a bit of therapy. The choice of treatment for relapsed MM must take into account the resultant toxicities and efficacy of prior drugs.

Introduction Novel agents and regimens have greatly improved the management of multiple myeloma (MM). However, the retreatment setting remains complex, since many patients have already received numerous therapies at the time of disease progression. The result can

The choice of treatment for relapsed MM must take into account the resultant toxicities and efficacy of prior drugs.

be resistance to specific agents and/or cumulative toxicities, which may influence the choice of therapy. In this article, Jeffrey Wolf, MD, discusses therapeutic decision-making in relapsed and refractory MM and the latest evidence on investigational drugs that may expand treatment options for the disease.

When a patient experiences a first relapse, what factors do you consider in choosing retreatment with previously used therapy versus treatment with different agents?

Because first-line therapy for MM often involves several different combinations,1 choosing second-line therapy can be a challenge. In the setting of initial treatment, we are using doublet and triplet combinations that may include bortezomib, lenalidomide, cyclophosphamide, or dexamethasone.

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For example, if a patient has progressed on lenalidomide maintenance, we would not choose lenalidomide as part of second-line therapy. However, if that same patient achieved a very good partial response (VGPR) or a complete response during induction with a bortezomib-based regimen, we might utilize bortezomib at relapse, provided that the patient did not have significant peripheral neuropathy (PN) or other adverse events (AEs) associated with treatment. Bortezomib-related AEs might suggest the use of an alkylator alone at the time of relapse in such a patient.

Another example is a patient who relapses after initial therapy with a combination of lenalidomide, bortezomib, and dexamethasone (RVD)2 but who has not undergone transplant or maintenance therapy. We could go back to RVD, which has been shown to be effective (Figure),3 or we may switch the patient to a regimen of cyclophosphamide, bortezomib, and dexametha-

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CONTINUING EDUCATION

who exhibited resistance earlier in the clinical course of the disease. In other words, â&#x20AC;&#x153;once resistant, always resistantâ&#x20AC;? may not be true.

Of course, one could argue that the best option for a patient resistant to bortezomib would be treatment with carfilzomib. That is an argument that will play out now that both agents are available. My point is that going back to a proteasome inhibitor makes sense, even if a patient had only a modest prior response to bortezomib.

Figure. Response rates with RVD in a phase 2 trial of relapsed/refractory MM (N=64).3

100 90

78%

Patients (%)

80 64%

70 60

Has the approval of carfilzomib impacted treatment approaches in the retreatment setting?

50 40 25%

30

22%

20 10 0 CR/near CR

PR

NR

ORR ( MR)

CR indicates complete response; MR, minimal response; NR, no response; ORR, overall response rate; PR, partial response; RVD, lenalidomide, bortezomib, and dexamethasone.

Table 1. Response to Bortezomib-Based Retreatment Following Response to Initial Bortezomib-Based Therapy (N=22)8 Response to Initial Therapy, n (%) Complete or partial response

No response

15 (68%)

7 (32%)

Response to Retreatment, n (%) Complete or partial response

9 (60%)

No response

6 (40%)

Complete or partial response

2 (29%)

No response

5 (71%)

sone.4,5 Both of these regimens yield a response rate of about 75% in the relapsed setting.3-5 We could consider ASCT as part of second-line therapy, usually with some initial therapy to get better control pretransplant. If the myeloma is particularly aggressive at relapse, we may use a combination such as bortezomib and dexamethasone with cisplatin, doxorubicin, cyclophosphamide, and etoposide (VD-PACE) and then go to transplant.6 If the patient has renal insufficiency, we will use modified HyperCVAD (cyclophosphamide, bortezomib, doxorubicin, and dexamethasone; with bortezomib in place of vincristine) instead of VD-PACE.7 How would you choose therapy for a patient who is resistant to initial treatment?

Drug resistance is a topic of ongoing investigation, and therapeutic choices in this setting require careful consideration. Recently, we had a patient who was treated with a 2-drug regimen of bortezomib and dexamethasone and attained only a partial response. We added lenalidomide, and his response improved to a VGPR. At the time of relapse, we might be disinclined to use bortezomib for such a patient, because of the modest initial response. There is a caveat here, however. Evidence suggests that, if you wait long enough, you can often go back to a drug such as bortezomib despite initial resistance (Table 1).8,9 We now believe that myeloma is made up of various clones with multiple sensitivity and resistance patterns to different drugs. Sometimes, if a patient has not received a drug for a period of time, the clone that may be relapsing most recently may be one that is sensitive to bortezomib. Therefore, it may be worth retrying this agent. Often we do see a response in patients

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The next-generation proteasome inhibitor carfilzomib is now available for use in the relapsed/refractory setting for MM, but it is approved by the US Food and Drug Administration only for patients who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent.10 Clinical trials have shown the efficacy of carfilzomib in this setting and have also indicated that carfilzomib is less likely than bortezomib to cause PN.11,12 Because we see many patients who have run through all of the other treatment options and have progressed on bortezomib-based therapies, our team has used carfilzomib frequently since its approval. However, in patients who received bortezomib with good response a long time ago, or in patients who progressed on bortezomib 2 to 5 years ago, retreatment with bortezomib could be considered at relapse. In such cases, the decision of which drug to use may be influenced by possible prior toxicities.

Drug resistance is a topic of ongoing investigation, and therapeutic choices in this setting require careful consideration.

For instance, in a patient who still has PN that developed during prior treatment with bortezomib, I would probably lean toward using carfilzomib.

Even though you can give bortezomib subcutaneously (SC) and possibly avoid making neuropathy worse,13 it may not be worth taking that chance. In contrast, if there is no neuropathy and the patient did not progress on bortezomib initially, I would lean toward bortezomib retreatment. Convenience is a consideration here. At the present time, carfilzomib is cumbersome to administer. It is given intravenously over 2 to 10 minutes 2 days in a row, weekly for 3 weeks followed by a 12-day rest period.10 Bortezomib, which can now be given SC twice a week,13 is more convenient.

For the patient with relapsed or refractory MM, what investigational therapies show the most promise?

The immunomodulator pomalidomide is the first agent that comes to mind, as it may be approved in the next 6 months. Clinical data support the efficacy of this agent when combined with weekly dexamethasone in the relapsed/refractory setting for MM, and it is fairly well tolerated. In 2 phase 2 trials of pomalidomide plus dexamethasone in patients refractory to bortezomib and lenalidomide, overall response rates were 43% to 49%.14 In an earlier report, this combination showed a 63% response rate in patients receiving 1 to 3 prior therapies; however, the incidence of grade 2 toxicities was high, including neutropenia, fatigue, leukopenia, and anemia (Table 2).15 Elotuzumab is an antibody that does not have a lot of activity on its own, but looks good when combined with lenalidomide and dexamethasone.16

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References Table 2. Toxicities Grade 2 with Pomalidomide Plus Dexamethasonea in a Phase 2 Trial (N=60)15 Toxicity

Patients, n (%)

Anemia

20 (33%)

Lymphopenia

4 (7%)

Neutropenia

30 (50%)

Thrombocytopenia

6 (10%)

Leukopenia

24 (40%)

Fatigue

27 (45%)

Nausea

1 (2%)

Diarrhea

5 (8%)

Constipation

11 (18%)

Pneumonia

6 (10%)

Hyperglycemia

10 (17%)

Confusion

5 (8%)

Insomnia

7 (12%)

Agitation

7 (12%)

Peripheral neuropathy

6 (10%)

Thrombosis

1 (2%)

a Patients also received aspirin 325 mg once daily for thromboprophylaxis. Patients were allowed to substitute full-dose anticoagulation with either low-molecular-weight heparin or warfarin at physician discretion.

There are also CD38 antibodies—daratumumab and SAR650984—in phase 1/2 trials that look promising.17,18 Additional drugs that are progressing through clinical trials include the Bruton’s tyrosine kinase inhibitor ibrutinib (PCI-32765)19 and the mammalian target of rapamycin inhibitor MLN0128.20 The histone deacetylase inhibitor vorinostat and the pan-deacetylase inhibitor panobinostat do not seem to have very good antimyeloma activity on their own. Vorinostat has provided a slight advantage in combination with bortezomib, but it appears to add quite a bit of toxicity.21 Panobinostat is in trials in combination with a proteasome inhibitor,22-24 but it is not yet clear if this drug will perform better than vorinostat.

Conclusion

Over the past decade, we have witnessed spectacular progress in the area of treating myeloma. Today, a majority of patients are alive and doing well at 5 years following initial treatment. It is becoming apparent that many patients can hope for very extended survival because of novel drugs and our ability to treat relapsed and refractory disease.

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1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. Version 1.2013. http://www.nccn.org. Accessed October 12, 2012.

2. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-686.

3. Richardson PG, Jagannath S, Jakubowiak AJ, et al. Phase II trial of lenalidomide, bortezomib, and dexamethasone in patients (pts) with relapsed and relapsed/refractory multiple myeloma (MM): updated efficacy and safety data after >2 years of follow-up. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 3049.

4. Davies FE, Wu P, Jenner M, Srikanth M, Saso R, Morgan GJ. The combination of cyclophosphamide, Velcade and dexamethasone (CVD) induces high response rates with comparable toxicity to Velcade alone (V) and Velcade plus dexamethasone (VD). Haematologica. 2007;92: 1149-1150.

5. Fu W, Delasalle K, Wang J, et al. Bortezomib-cyclophosphamide-dexamethasone for relapsing multiple myeloma [published online ahead of print June 18, 2011]. Am J Clin Oncol. doi:10.1097/COC.0b013e31822043f6.

6. Barlogie B, Anaissie E, van Rhee F, et al. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol. 2007;138:176-185.

7. Pegylated liposomal doxorubicin hydrochloride, bortezomib, cyclophosphamide, and dexamethasone in treating patients with multiple myeloma (NCT00849251). http://www.clinical trials.gov. Accessed October 22, 2012.

8. Wolf J, Richardson PG, Schuster M, LeBlanc A, Walters IB, Battleman DS. Utility of bortezomib retreatment in relapsed or refractory multiple myeloma patients: a multicenter case series. Clin Adv Hematol Oncol. 2008;6:755-760.

9. Sood R, Carloss H, Kerr R, et al. Retreatment with bortezomib alone or in combination for patients with multiple myeloma following an initial response to bortezomib. Am J Hematol.

2009;84:657-660.

10. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012.

11. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-2825.

12. Vij R, Siegel DS, Jagannath S, et al. An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol. 2012;158:739-748.

13. 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.

14. Lacy MQ, Allred JB, Gertz MA, et al. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dualrefractory disease. Blood. 2011;118:2970-2975.

15. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27:5008-5014.

16. Lonial S, Vij R, Harousseau JL, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012; 30:1953-1959.

17. Gimsing P, Plesner T, Nahi H, et al. A phase I/II, dose-escalation study of daratumumab, a CD38 Mab in patients with multiple myeloma—preliminary safety data. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 1873.

18. Dose escalation study of anti-CD38 monoclonal antibody in patients with selected CD38+ hematological malignancies (NCT01084252). http://www.clinicaltrials.gov. Accessed October 22, 2012.

19. Study of the Bruton’s tyrosine kinase inhibitor in subjects with relapsed or relapsed and refractory multiple myeloma (NCT01478581). http://www.clinicaltrials.gov. Accessed October 22, 2012.

20. Dose escalation study of MLN0128 in relapsed or refractory multiple myeloma or Waldenstrom macroglobulinemia (NCT01118689). http://www.clinicaltrials.gov. Accessed October 28, 2012.

21. Dimopoulos MA, Jagannath S, Yoon S-S, et al. Vantage 088: vorinostat in combination with bortezomib in patients with relapsed/refractory multiple myeloma: results of a global, randomized phase 3 trial. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 811.

22. San Miguel JF, Hungria VTM, Yoon S-S, et al. Update on a phase III study of panobinostat with bortezomib and dexamethasone in patients with relapsed multiple myeloma: PANORAMA 1. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 3976.

23. Richardson PG, Alsina M, Weber DM, et al. Phase II study if the pan-deacetylase inhibitor panobinostat in combination with bortezomib and dexamethasone in relapsed and bortezomibrefractory multiple myeloma (PANORAMA 2). Blood (ASH Annual Meeting Abstracts). 2011; 118:Abstract 814.

24. Carfilzomib plus panobinostat in relapsed/refractory multiple myeloma (MM) (NCT01301807). http://www.clinicaltrials.gov. Accessed October 22, 2012.

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Nursing Interventions in the Relapsed and Refractory Settings for Myeloma Jennifer Knoche, RN, BSN Lead Practice Nurse UCSF Hematology/BMT Ambulatory Care Center San Francisco, CA

laxation become important components of therapy, in addition to dose reduction. Fortunately, we now have the option of administering bortezomib subcutaneously (SC), which has been shown to help reduce the incidence and severity of PN.5 How has the recent approval of carfilzomib affected your approach to treating relapsed and/or refractory disease?

Introduction For patients with multiple myeloma (MM), prompt and effective nursing interventions can make a significant difference in care—from minimizing adverse events (AEs) to protecting bone health and alleviating pain. In this article, Jennifer Knoche, RN, BSN, examines key strategies for improving outcomes in the relapsed/refractory setting for myeloma, and discusses best practices for whole-patient care.

When patients are retreated with agents such as bortezomib or thalidomide, what strategies are effective for minimizing the risk of peripheral neuropathy (PN)?

The main strategy for minimizing this risk remains dose adjustment or treatment interruption. With thalidomide, which is administered orally, PN can be an especially challenging toxicity to manage. We often use thalidomide at a low dose in the relapsed/refractory setting; therefore, to reduce the amount even further may require patients to cut their pills in half or take their medication every other day—neither of which are ideal options. With intravenous (IV) bortezomib, reducing or holding the dose is easier. Recommended dose reductions for thalidomide- and bortezomib-based PN are shown in Tables 1 and 2.1,2 Of course, we cannot make an informed decision regarding dose adjustment without an accurate assessment of a patient’s condition. In the relapsed/refractory setting, we must look at current symptoms as well as treatment history. What drugs have been administered previously? Did the patient experience neuropathy with prior treatment, and if so, did dose reduction or discontinuation provide relief? Did supportive therapies help to reduce symptoms? Are there comorbid conditions associated with the existing PN? Is the patient taking any medications for comorbidities that may contribute to neuropathy? Answers to these questions help us to plan the schedule and dose of agents at the time of relapse.

Complementary therapies, such as alpha lipoic acid, L-carnitine, and vitamin B6 may be helpful.3 At our institution, we begin patients on these therapies prior to antimyeloma treatment to prevent or minimize PN. In those who already exhibit symptoms, we may add these therapies as supplements, to keep neuropathy from progressing. Some patients need a more robust medical intervention, in which case we may prescribe gabapentin, pregabalin, tricyclic antidepressants, or even nonopioid analgesics.3 Our goal is to do whatever works to manage pain, tingling, burning, and functional impairment to keep the patient on therapy.

PN may cause the nerves that control intestinal muscle contractions to malfunction, leading to gastrointestinal problems, including constipation.4 If this occurs, a good bowel regimen, proper diet, hydration, and exercise, and

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With the approval of carfilzomib, we now have another treatment option at our disposal, which is extremely important. Given the challenges patients face in the relapsed/refractory setting, including the fact that they have already been treated with so many therapies, it matters greatly to have one more way to attack the disease. In addition to demonstrating good efficacy, carfilzomib has been associated with low rates of PN (Figure).6 Anecdotally, we are not seeing this toxicity among patients receiving carfilzomib. However, since these individuals are on so many drugs, sequenced over time, it can be hard to determine whether AEs are related to past or current regimens. For instance, an agent may cause some degree of neu-

Table 1. Thalidomide Dose Modifications Based on Severity of Peripheral Neuropathy1 Severity of Peripheral Neuropathy

Modification of Dose and Regimen

Grade 1 (mild)

No action

Grade 1 with pain or grade 2

Intermittent symptoms: Continue therapy Continuous symptoms: Withhold thalidomide until toxicity resolves, then reduce dose

Grade 3

Withhold thalidomide until toxicity resolves, then restart at reduced dose

Grade 4 (permanent sensory loss that interferes with function)

Discontinue thalidomide

Table 2. Bortezomib Dose Modifications Based on Severity of Peripheral Neuropathy2 Severity of Peripheral Neuropathy

Modification of Dose and Regimen

Grade 1 (paresthesia or loss of reflex) without pain or loss of function

No action

Grade 1 with pain or grade 2 (interferes with function but not with activities of daily living)

Reduce bortezomib dose from 1.3 to 1.0 mg/m2

Grade 2 with pain or grade 3 (interferes with activities of daily living)

Withhold bortezomib until toxicity resolves, then reinitiate at a dose of 0.7 mg/m2 once weekly

Grade 4 (permanent sensory loss that interferes with function)

Discontinue bortezomib

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Figure. Carfilzomib-related, nonhematologic adverse events with an incidence 5% in a single-agent study of relapsed/refractory MM patients (N=266).6 40 35

Patients (%)

30 25 20 15 10 5 0

e igu Fat

a use Na

ea rrh Dia

ea spn Dy

e um ach ser ine ad He sed atin rea cre Inc

g tin mi Vo

ia ia thy rex tem pa Py ha uro ne osp ph ral o e p h Hy rip Pe

ropathy, but symptoms do not appear until later, after another therapy is given.

Administration of carfilzomibâ&#x20AC;&#x201D;2 days in a row intravenously, weekly for 3 weeks7â&#x20AC;&#x201D;is not as simple as administration of bortezomib, especially bortezomib SC. Some patients, depending on how far they live from the cancer center, may have to spend the night once a week to receive carfilzomib. The infusion time for this drug is longer than it is for IV bortezomib. Additionally, if you compare IV carfilzomib administration to the use of bortezomib SC,

Unfortunately, there is no road map to guide us in restarting or continuing bisphosphonates in a relapsed or refractory patient who has already had 2 years of therapy.

there is a big difference in convenience favoring bortezomib.

Dose adjustment schedules for carfilzomib-related PN are available, along with those for hematologic, cardiac, pulmonary, and hepatic toxicities. In some patients, we have noticed a decline in red blood cells with carfilzomib use, typically during the first cycle. As with any agent, careful monitoring of blood counts and vital organ functions are an essential part of nursing care.

How do you support bone health and manage skeletal-related events over the course of care in the relapsed/refractory setting?

Supporting bone health in this setting is essential but can be complex.

Many myeloma patients are older, with comorbidities such as osteoarthritis

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and osteoporosis. When treating a patient for osteoporosis, we need to assess his or her current bisphosphonate regimen and see how it dovetails with the need for myeloma bone support.

In a patient who has experienced a long clinical course and relapsed, prior bisphosphonate treatment is a given. Currently, the American Society of Clinical Oncology recommends 2 years of bisphosphonate therapy for myelomarelated bone disease. After that, treatment is at the discretion of the physician.8 Unfortunately, there is no road map to guide us in restarting or continuing bisphosphonates in a relapsed or refractory patient who has already had 2 years of therapy. Our biggest concern is the risk for osteonecrosis of the jaw, which increases with prolonged time on bisphosphonate therapy.9 As the myeloma disease process continues, and as patients age, they may need supportive devices, surgical care, and pain management strategies.

Functional limitations and pain can be improved with antimyeloma therapy and bisphosphonates, but for some individuals, canes, walkers, wheelchairs, or braces may be necessary. We may also refer patients with spine involvement for vertebroplasty or kyphoplasty, which can be very effective.10 Local irradiation is occasionally used for supportive care, especially if there is a plastocytoma. Bone pain often requires opioid analgesics, and we encourage our patients to accept such medications when necessary.11 Pain can delay healing and diminish quality of life and must therefore be minimized whenever possible.

Conclusion

Nurses need to carefully monitor relapsed and refractory MM patients, and be ready to intervene to ensure the continuation of treatment and the ability to perform activities of daily living. The detection and effective management of AEs, skeletal-related complications, and pain are essential components of evidence-based care, which will lead to better clinical outcomes.

References 1. Thalomid [package insert]. Summit, NJ: Celgene Corporation; 2012.

2. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc.; June 2012.

3. Tariman JD, Love G, McCullagh E, et al. Peripheral neuropathy associated with novel therapies in patients with multiple myeloma: Consensus statement of the IMF Nurse Leadership Board.

Clin J Oncol Nurs. 2008;12:29-36.

4. National Institute of Neurological Disorders and Stroke. Peripheral neuropathy fact sheet. http://www.ninds.nih.gov/disorders/peripheralneuropathy/detail_peripheralneuropathy.htm.

Accessed October 27, 2012.

5. 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.

6. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-2825.

7. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals Inc.; July 2012.

8. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol.

2007;25:2464-2472.

9. Badros A, Weikel D, Salama A, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol. 2006;24:945-952.

10. Berenson J, Pflugmacher R, Jarzem P, et al. Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial. Lancet Oncol. 2011;13:225-235.

11. Definitions related to the use of opioids for the treatment of pain: Consensus statement of the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine. www.asam.org. Accessed October 30, 2012.

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Pharmacologic Considerations in the Retreatment Setting for Multiple Myeloma Helen T. Wu, PharmD, BCOP Clinical Pharmacist Adult Hematology/Oncology and Health Sciences Associate Clinical Professor, School of Pharmacy, UCSF San Francisco, CA

Introduction In patients with relapsed/refractory multiple myeloma (MM), retreatment can contribute to longer survival and better quality of life,

mended in the NCCN guidelines for this indication.6 In the salvage setting, choosing therapies that are least likely to be toxic to the kidneys is a must. It is also important to remember that myeloma patients with renal dysfunction often have other comorbidities and poor performance status.7 Therefore, therapeutic benefit must be balanced with drug-related toxicities.

Although lenalidomide can be effective in the retreatment setting, this agent needs to be dose-adjusted for patients with varying degrees of renal dysfunction.8 Bortezomib and carfilzomib, which have also demonstrated efficacy as second-line therapies, do not require dosing adjustments in renally impaired patients.9,10

but can also pose a number of clinical challenges. When choosing therapies for this indication, it is necessary to consider numerous factors, including preexisting toxicities, patient preferences and perfor-

How has the approval of subcutaneous (SC) bortezomib impacted your approach to retreatment?

mance status, and agents used during initial therapy. In this article, Helen T. Wu, PharmD, BCOP, shares her perspective on these issues in both the transplant and nontransplant settings and discusses recent advances that may promote better patient outcomes.

How do comorbidities and other patient factors affect selection and administration of therapy in the retreatment setting?

An important issue to consider is how well a patient has tolerated a specific agent or regimen in the frontline setting, as this may affect administration and dosing at the time of retreatment. For example, if a patient did not experience serious adverse events (AEs) with frontline therapy, we can typically start retreatment at the standard, recommended dose of the same agent.

Conversely, if a patient did suffer significant toxicities, we may choose to retreat with an agent from a different class. However, studies have shown a therapeutic benefit when patients are retreated with agents they have received previously.1-5 Therefore, if a patient has achieved a good response to a specific agent as induction, we may try using dose modifications to reduce the incidence of AEs. For example, we can consider a patient with preexisting peripheral neuropathy (PN) who relapses after being treated with lenalidomide, bortezomib, and dexamethasone (RVD) and autologous stem cell transplantation (ASCT). According to the most recent National Comprehensive Cancer Network (NCCN) guidelines for the treatment of MM, RVD is a recommended primary therapy (category 2A) for transplant candidates.6 If relapse occurs at >6 months, the same primary regimen may be repeated. However, in a patient who has residual PN, clinicians may consider avoiding bortezomib and instead select a regimen that has less potential for neurotoxicity. In addition, because of previous ASCT and lenalidomide treatment, a regimen that has the least hematologic toxicity would be preferred. It would be necessary to look at which agents are available for salvage therapy, based on these factors.

In a different type of scenario, you may be treating a relapsing patient who is not eligible for transplant and who has renal impairment. Such a patient may have been treated initially with bortezomib, melphalan, and prednisone or lenalidomide plus low-dose dexamethasoneâ&#x20AC;&#x201D;regimens that are recom-

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In January 2012, the US Food and Drug Administration (FDA) approved SC administration of bortezomib for the treatment of MM. This mode of delivery has several advantages, as shown in a recent multicenter trial by Moreau and colleagues.11 These investigators compared the efficacy and safety of SC versus intravenous (IV) bortezomib in patients with relapsed MM who had received 3 previous lines of therapy. The end point was to show noninferiority of SC versus IV bortezomib in terms of overall response rate (ORR) following 4 treatment cycles. After these cycles, ORR was 42% in both groups, showing noninferiority (P=.002). After a median follow-up of 11.8 months in the SC group and 12.0 months in the IV group, there were no significant between-group differences in time to progression and 1-year overall survival. PN of any grade was significantly reduced with SC versus IV bortezomib (Figure). Grade 3 or higher AEs were reported in 57% of patients in the SC group versus 70% in the IV group; the most common were thrombocytopenia (13% vs 19%), neutropenia (18% vs 18%), and anemia (12% vs 8%), respectively.11

if a patient has achieved a good response to a specific agent as induction, we may try using dose modifications to reduce the incidence of AEs.

It is important for pharmacists to be aware of how to prepare SC bortezomib for administration. The concentration for IV infusion of bortezomib is 1 mg/mL, which is significantly different from the concentration for SC injection, which is 2.5 mg/mL.9 Pharmacists should be cautious when reconstituting this medication and calculating the volume to be administered.

However, the amount of work involved in preparing bortezomib for SC versus IV administration is really no different, and SC bortezomib appears to be a much-preferred route of administration for several reasons. For nurses, it simplifies care, since there is no need to obtain IV access, and the potential risks and complications of inserting IV lines are eliminated. In addition, it reduces chair time, allowing for a much quicker turnaround time for appointments. For patients, it is easier and generally less stressful to receive an SC injection compared with IV administration. Since there is no need

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Figure. Incidence of peripheral neuropathy in a phase 3 trial comparing SC versus IV bortezomib dosing in relapsed myeloma (N=222).11

60

P=.044

SC bortezomib

53% P=.012

50

IV bortezomib

Patients (%)

41% 40

38%

30

24%

P=.026

20

fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%).

The rate of treatment-related PN was 12.4%.

Our institution was one of the participating centers for clinical trials of carfilzomib prior to its FDA approval. Now, we are able to offer this agent to patients off study, and we make sure to follow the recommended dosing, reconstitution, and administration guidelines to ensure maximum benefit and safety. Although we rarely use carfilzomib in the inpatient setting, we do utilize it in patients who come in for emergent plasmapheresis after failing transplant, administering concomitant IV hydration to prevent tumor lysis syndrome. I think this agent is becoming an important retreatment option in MM.

16%

Conclusion 10

6%

0 Any grade

Grade 2

Grade 3

IV indicates intravenous; SC, subcutaneous.

to insert an IV line, wait time is much shorter, which can potentially improve quality of life.

Although MM remains an incurable disease, retreatment with novel agents is leading to higher response rates, prolonged survival, and better quality of life. An important goal in this setting is the prevention and management of AEs, which allows the cancer care team to maximize dose intensity and provide continuation of therapy. This requires careful consideration of comorbidities and other patient factors, as well as a thorough understanding of the doses, schedules, and modes of administration recommended for available agents.

References

How is the recently approved agent carfilzomib being used at your center in the retreatment setting?

On July 20, 2012, the FDA approved carfilzomib, a next-generation proteasome inhibitor, for the treatment of patients with MM who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and who have demonstrated disease progression on or within 60 days of therapy completion. Many patients who have relapsed/refractory MM are being treated with carfilzomib at our institution, given its proven efficacy and good safety profile. In a phase 2 study conducted by Siegel and colleagues, patients received single-agent IV carfilzomib for relapsed/refractory MM; all of these individuals were heavily pretreated.12 Of the evaluable patients in this study, 95% were refractory to their last therapy, and 80% were refractory to both bortezomib and lenalidomide. The treatment regimen was designed as IV carfilzomib 20 mg/m2 (cycle 1) followed by 27 mg/m2 (cycle 2), on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The ORR was 23.7%, median duration of response was 7.8 months, and median overall survival was 15.6 months. Reported AEs included

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1. Sood R, Carloss H, Kerr R, et al. Retreatment with bortezomib alone or in combination for patients with multiple myeloma following an initial response to bortezomib. Am J Hematol.

2009;84:657-660.

2. Berenson JR, Jagannath S, Barlogie B, et al. Safety of prolonged therapy with bortezomib in relapsed or refractory multiple myeloma. Cancer. 2005;104:2141-2148.

3. Hrusovsky I, Emmerich B, von Rohr A, et al. Bortezomib retreatment in relapsed multiple myelomaâ&#x20AC;&#x201D;results from a retrospective multicentre survey in Germany and Switzerland. Oncology.

2010;79:247-254.

4. Richardson PG, Weller E, Jagannath S, et al. Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol. 2009;27:5713-5719.

5. Madan S, Lacy MQ, Dispenzieri A, et al. Efficacy of retreatment with immunomodulatory drugs (IMiDs) in patients receiving IMiDs for initial therapy of newly diagnosed multiple myeloma.

Blood. 2011;118:1763-1765.

6. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncologyâ&#x201E;˘: Multiple Myeloma. Version 1.2013. http://www.nccn.org. Accessed October 24, 2012.

7. Glade J, Fernandez-Llama P, Bosch F, et al. Renal failure in multiple myeloma presenting features and predictors of outcome in a series of 94 patients from a single institution. Arch Intern Med. 1998;158:1889-1893.

8. Revlimid [package insert]. Summit, NJ: Celgene Corporation; 2012.

9. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc; June 2012.

10. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012.

11. 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.

12. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-2825.

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ESMO 2012 Conference

Platinum-Resistant Ovarian Cancer: Bevacizumab Improves Survival When Added to Chemotherapy

By Phoebe Starr Vienna, Austria—Adding bevacizumab (Avastin) to chemotherapy improves outcomes in patients with platinum-resistant recurrent ovarian cancer, according to results of the phase 3 clinical trial AURELIA, which was presented at the 2012 European Society for Medical Oncology Congress.

Bevacizumab improved progressionfree survival (PFS) and overall response rate (ORR) with any of the 3 chemotherapy regimens in the study, but adding bevacizumab to weekly paclitaxel was the most active combination in an exploratory analysis of the trial.

AURELIA is one of the only trials to show a positive outcome in patients with platinum-resistant ovarian cancer, said Nicoletta Colombo, MD, University of Milan-Bicocca, European Institute of Oncology, Milan, Italy.

In the overall trial, the median PFS was 6.7 months for bevacizumab plus chemotherapy versus 3 months for chemotherapy alone.

Investigators could choose chemo-

therapy from among weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan. When chemotherapy regimens were analyzed separately, the bevacizumab plus weekly paclitaxel regimen achieved the best results.

The median PFS durations for the different cohorts were: • 10.4 months with bevacizumab plus weekly paclitaxel versus 3.9 months with chemotherapy alone • 5.8 months with bevacizumab plus topotecan versus 2.1 months with chemotherapy alone • 5.4 months with bevacizumab plus pegylated liposomal doxorubicin versus 3.4 months with chemotherapy alone.

“Bevacizumab combined with chemotherapy should be considered a new standard option for platinum-resistant recurrent ovarian cancer,” stated lead author Andres M. Poveda, MD, Fundacion Instituto Valenciano de Oncologia, Valencia, Spain.

AURELIA randomized 361 patients

(median age, approximately 60 years) with platinum-resistant recurrent ovarian cancer whose disease progressed with up to 2 previous regimens to chemotherapy alone versus chemotherapy plus bevacizumab.

“Bevacizumab combined with chemotherapy should be considered a new standard option for platinum-resistant recurrent ovarian cancer.”

—Andres M. Poveda, MD Treatment was continued until unacceptable toxicity or progressive disease occurred.

Demographic and disease characteristics were well balanced at baseline between the treatment arms. Approximately 90% of the patients had

stage III/IV disease.

Response rates were superior for all 3 chemotherapy regimens with the addition of bevacizumab, with the highest rate seen with weekly paclitaxel plus bevacizumab—51.7% versus 28.8% for chemotherapy alone; the ORRs for bevacizumab plus pegylated liposomal doxorubicin were 18.3% and 7.9%, respectively, and 5.8% and 2.1%, respectively, for the topotecan cohort.

No new toxicity concerns emerged in the trial. Toxicities were similar in the 2 treatment arms. A higher rate of peripheral neuropathy was reported in the weekly paclitaxel cohort and a higher rate of hand-foot syndrome in the patients treated with pegylated liposomal doxorubicin.

Dr Colombo was particularly impressed by the results in the weekly paclitaxel plus bevacizumab cohort.

She stated that this combination should be explored earlier in the course of disease. ■

Cost-Effectiveness Comparison of First-Line Therapies for Advanced Non–Small-Cell Lung Cancer

By Caroline Helwick Vienna, Austria—Costs associated with first-line pemetrexed/cisplatin are significantly lower than those of carboplatin/paclitaxel/bevacizumab for the treatment of advanced non–small-cell lung cancer (NSCLC), according to an analysis presented at the 2012 European Society for Medical Oncology Congress.

“This is the first known study that used real-world, nontrial data to evaluate the outpatient care cost-effectiveness of pemetrexed/cisplatin relative to 2 other first-line regimens for pa tients with advanced nonsquamous NSCLC,” said Katherine B. Winfree, PhD, MPH, Research Scientist, Global Outcomes, Oncology, Eli Lilly and Company.

The study compared the incremental cost-effectiveness of outpatient management with these regimens in patients with advanced NSCLC. The data came from the International Oncology Network database, which documents care by 20 large US community oncology practices. The index date was the initiation of first-line therapy.

50

Of approximately 5000 patients, 234 (78 matched pairs per treatment type) were selected for the cost-effectiveness analysis. Costs included charges for chemotherapy, supportive care, and physician and nursing services.

Pemetrexed/Cisplatin Less Costly, More Effective than Triplet Incremental costs were measured as differences in costs during the progression-free survival (PFS) and overall survival (OS) periods for each matched pair.

Median PFS was 128 days in patients receiving pemetrexed/cisplatin versus 112 for patients receiving carboplatin/ paclitaxel/bevacizumab (P = .007) and 105 days in patients receiving carboplatin/paclitaxel (P = .004).

The median OS was 327 days in patients treated with pemetrexed/cisplatin, 279 days in patients treated with carboplatin/paclitaxel/bevacizumab, and 234 in patients treated with carboplatin/paclitaxel, a nonsignificant difference.

Considering the treatment costs, as

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well as the improvement in PFS, the costs associated with first-line therapy were significantly lower with pemetrexed/cisplatin than with carboplatin/ paclitaxel/bevacizumab; however, as expected, the costs were significantly higher with pemetrexed/cisplatin treatment than with carboplatin/paclitaxel—primarily a result of the underlying difference in the drug costs, Dr Winfree noted.

Mean PFS costs were approximately $43,000 for pemetrexed/cisplatin, $61,000 for carboplatin/paclitaxel/ bevacizumab, and $18,000 for carboplatin/paclitaxel. The overall costs of treatment were approximately $40,000, $58,000, and $14,000, respectively.

“Costs associated with first-line therapy with pemetrexed/cisplatin were significantly lower than those of carboplatin/paclitaxel/bevacizumab. Further evaluation is warranted to identify possible drivers of this difference, such as bevacizumab utilization (including maintenance), differences in number of cycles, and so forth,” Dr Winfree said.

“But patients treated with peme-

trexed/cisplatin experienced a significant PFS benefit and trended toward being more effective and less costly compared with carboplatin/paclitaxel/bevacizumab for both PFS and OS,” she said.

More Costly, but Improved PFS, versus Carboplatin/Paclitaxel The analysis also showed that pemetrexed/cisplatin was more costly than carboplatin/paclitaxel, but with a potential incremental clinical benefit, Dr Winfree emphasized. Patients treated with pemetrexed/cisplatin had a significant PFS benefit compared with carboplatin/paclitaxel/bevacizumab.

The doublet was more effective and less costly than carboplatin/paclitaxel/ bevacizumab for PFS and OS (although the differences were not significant).

“Therefore, depending on society’s or payers’ willingness to pay threshold, pemetrexed/cisplatin may be seen as cost-effective compared to carboplatin/paclitaxel, because it demonstrated greater effectiveness at a higher cost,” Dr Winfree concluded. ■

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NO. 8

“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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