vbcc november 2012 vol 3 no 8

Houston, TX—Delta Air Lines has a commitment to preventive health andcomprehensive cancer care for its 140,000 health plan members; the compa-ny is pi loting 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 forValue-Based Cancer Care. Ms Zonakis was part of the employers’ panel atthe conference who presented perspectives from different employer groupsrelated to cancer care.

San Francisco, CA—The Oncotype DXRecurrence Score (the 21-gene) test canhelp identify patients with estrogenreceptor (ER)-positive breast cancerwith any number of positive lymphnodes who will have residual diseaseafter adjuvant chemotherapy, andwho may benefit from additionaltreatment, reported Eleftherios P.Mamounas, MD, Medical Director,Aultman Hospital Cancer Center,

Canton, OH, at the 2012 Breast CancerSymposium.

This new retrospective analysis wasconducted by investigators from theNational Surgical Adjuvant Breast andBowel Project (NSABP).

The Oncotype DX Recurrence Scorehas proved to have expanded utility inguiding treatment decisions. “We canidentify patients with high residual

Oncotype DX Score PredictsResidual Disease after ChemotherapyExpanded utility can also help clinical decision-makingBy Audrey Andrews

©2012 Engage Healthcare Communications, LLC

www.ValueBasedCancerCare.com

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM

Continued on page 11

NOVEMBER 2012 VOL 3 NO 8

FDA UPDATE . . . . . . . . . . . . . . . . . .4Synribo approved for CML

Abraxane for NSCLC

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

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

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

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

PERSONALIZED MEDICINE . . . . .22New personalized Rx decision-making system

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

DRUG UPDATE . . . . . . . . . . . . . . .40Abraxane gets new indication forNSCLC

I N S I D E

Delta Air Lines’ Approach to Patient Care: High-Performance Cancer NetworksImproving employees’ care while cutting costs By Caroline Helwick

VBCC PERSPECTIVES


Stereotactic Body Radiation TherapyCost-Saving, Convenient for Patientswith Prostate CancerBy Phoebe Starr

Boston, MA—In the United Statesright now, intensity modulated radia-tion therapy (IMRT) has largelyreplaced 3-dimensional conformalradiation therapy as the technique ofchoice for most patients with organ-confined prostate cancer that is being

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

Of all of these radiation technolo-gies, stereotactic body radiation thera-

Continued on page 9

We should all read with greatinterest the New York Timesopinion piece by Peter B.

Bach, MD, and colleagues fromMemorial Sloan-Kettering CancerCenter on their rationale for notincluding ziv-aflibercept (Zaltrap) inits formulary for patients withmetastatic or advanced colorectal can-cer (see article, page 19). Their argu-ment is simple, they said: This newdrug provides no additional benefitover existing medicines for the same

type of cancer, yetit is significantlymore expensiveand has a highertoxicity profile.[Editor’s note:Since this ar ticlewas written, the company has indicat-ed it would be cutting the cost of ziv-aflibercept. Please see additional infor-mation on this development on page21.] As the au thors note, anyone

We Must Incorporate Value intoOur Decision-Making ProcessBy John L. Marshall, MDChief, Division of Hematology/Oncology, Director, Otto J. Ruesch Center forthe Cure of Gastrointestinal Cancers, Georgetown University, LombardiComprehensive Cancer Center, Washington, DC


A

R

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

Indication and Important Safety Information for VELCADE® (bortezomib) INDICATIONVELCADE (bortezomib) is indicated for the treatment ofpatients 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 modi� cation

or discontinuation. Patients with preexisting severeneuropathy should be treated with VELCADE only aftercareful risk-bene� t assessment.

▼ Hypotension: Use caution when treating patientstaking 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▼ De� ned 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 REACTIONSMost 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 ef� cacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespeci� ed interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in signi� cantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.

1-2 1

Synribo Approved for ChronicMyelogenous Leukemia

The US Food and Drug Admini s -tration (FDA) approved omacetaxinemepesuccinate (Synribo; Teva Phar -ma ceutical) to treat adults with chron -ic myelogenous leukemia (CML), a he -

matologic disease. An estimated 5430Americans will be diagnosed withCML in 2012, according to the Na -tional Institutes of Health.

“Today’s approval provides a newtreatment option for patients who areresistant to or cannot tolerate other

FDA-approved drugs for chronic oraccelerated phases of CML,” saidRichard Pazdur, MD, Director of theFDA’s Office of Hematology andOncology Products, noting that this isthe second drug to be approved forCML in the past 2 months. In

September, bosutinib (Bosulif; Pfizer)received FDA approval for patientswith chronic-, accelerated-, or blast-phase Philadelphia chromosome–positive (Ph+) CML who are resistant toor who cannot tolerate other therapies.

Synribo is intended to be used inpatients whose disease has progressedafter treatment with ≥2 tyrosine kinaseinhibitor (TKI) agents, currently themainstay of therapy for CML.

Omacetaxine mepesuccinate blockscertain proteins that promote thedevelopment of cancerous cells. It isinjected subcutaneously twice dailyfor 14 consecutive days over a 28-daycycle, until hematologic response isobserved. The drug is then adminis-tered twice daily for 7 consecutivedays over a 28-day cycle, and contin-ues to be used as long as the patientshows clinical benefit from this therapy.

The FDA approved omacetaxinemepesuccinate under the agency’saccelerated approval program, whichallows the agency to approve a drugdeemed necessary for a serious dis-ease, based on data from clinical trialsshowing that the drug has an effect ona surrogate end point that is likely topredict a clinical benefit to patients, toaccelerate the access of patients to thistherapy until additional clinical evi-dence is available. In addition, thisdrug received an orphan drug desig-nation, because it is designated for thetreatment of CML, which is considereda relatively rare disease.

The effectiveness of omacetaxinemepesuccinate was evaluated using acombined cohort of patients whosedisease progressed after previoustreatment with ≥2 TKIs. All patients re -ceived omacetaxine mepesuccinate inthis evaluation.

The drug’s effectiveness in chronic-phase CML was demonstrated by areduction in the percentage of cellsexpressing the Ph+ genetic mutationfound in the majority of patients withCML. Of the 76 patients with chronic-phase CML, 14 patients (18.4%)achieved a reduction in Ph+ expres-sion in an average of 3.5 months. Themedian duration of the reduction was12.5 months.

In patients with accelerated-phaseCML, the effectiveness of omacetaxinemepesuccinate was determined by thenumber of patients whose white bloodcell counts were normalized or whohad a major hematologic response (ie,no evidence of CML). Among the 35patients with this type of CML, 5patients (14.3%) achieved a majorhematologic response in an average of2.3 months. The response lasted amedian of 4.7 months.

4 VALUE-BASED CANCER CARE I NOVEMBER 2012 VOL. 3 I NO. 8

Continued on page 7

FDA Update

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

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.

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.

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5VOL. 3 I NO. 8 NOVEMBER 2012 I www.ValueBasedCancerCare.com

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 inpart funded by the National Institutes of Health. Findings show that thismolecule, known as molecule P5091, can kill multiple myeloma cancercells that are resistant to bortezomib (Velcade), a frontline therapy for thetreatment 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 otherdrug targets,” said lead investigator Dharminder Chauhan, JD, PhD,Senior Scientist at Dana-Farber, and Principal Associate in Medicine atHarvard Medical School.

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

Addressing Value a Key Objective of MichiganOncology Medical Home Project

The Michigan Oncology Medical Home Demonstration Project, whichis among the first few oncology medical homes in the country, was initi-ated by ION Solutions and Physician Resource Management, in collabo-ration with Priority Health, a leading health plan in Michigan. This proj-ect aims at addressing and arresting the rising costs of cancer care, usingan integrated approach to patient care.

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

By participating in this oncology medical home, “thesepractices are confirming their desire to improve upon the process of deliv-ering care so that community oncology remains a viable option forpatients desiring enhanced access to care, better outcomes, and reducedcosts for care,” Dr Fox said.

The 3 groups intend to recruit additional community oncology prac-tices to join this program in the future. ION Solutions/AmerisourceBergenSpecialty Group; August 14, 2012

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

The National Cancer Institute (NCI) has awarded $2.3 million for anew research project to develop novel molecular biomarkers for pancre-atic cancer. The program will be led by Brian Haab, PhD, Head of VanAndel Institute’s Laboratory of Cancer Immunodiagnostics in GrandRapids, MI. Pancreatic cancer will affect >43,000 Americans and will kill>37,000 Americans in 2012, according to the NCI. This type of cancer isassociated with especially poor prognosis, because it is usually diagnosedat advanced stages of the disease and because it is resistant to chemothera-py (see also page 7).

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

University, the Fred Hutchinson Cancer Research Center, Palo Alto Re -search Center, the University of Georgia Medical Center, and theUniversity of Pittsburgh Medical Center. The team will be looking for thepresence of carbohydrates in the bloodstream as a biomarker of pancreat-ic cancer.

“One of the most common features of pancreatic cancers is theincreased abundance of a carbohydrate structure called the CA 19-9 anti-gen,” said Dr Haab. “This carbohydrate structure is attached to many dif-ferent proteins, many of which are selected from the tumor into the bloodcirculation, making it available for detection as a biomarker.”

CA 19-9 blood samples are used to confirm the diagnosis of pancreaticcancer, but the test cannot be used in early stages of the disease, because20% to 30% of incipient tumors produce low levels of CA 19-9. But newdevelopments can now address these low levels, which will be the focusof the new research, with the goal of developing biomarkers for earlydiagnosis of this type of cancer to improve survival.

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

Cancer Research UK Provides >£1 Million toDevelop Simple Blood Test to ReplaceMammography

In a study funded by Cancer Research UK, a team of British scientistsare looking for ways to use a simple blood test to detect the early signs ofbreast cancer more accurately than is done today with mammograms.

“This exciting research means we could one day have a blood test thatdetects the very early signs of cancer, meaning women could have anannual blood test rather than breast screening,” said principal investigatorJacqui 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’sbreast cancer expert from Imperial College, said, “This type of transla-tional science is extremely promising, and the international scientificcommunity is collaborating on its development. When a woman hasbreast cancer, we can tell by the DNA in their blood. But what we’re try-ing to find out in our study is how early the signs of breast cancer showup 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 bloodtest to detect other cancers, such as bowel and lung.” Cancer ResearchUK; October 2, 2012

Best Practices Focus of New Quality Program for Select Cancers

A program launched by Blue Cross and Blue Shield of Louisiana in col-laboration with Cardinal Health Specialty Solutions is designed to focuson applying clinical pathways to improve cancer treatment as a way topromote best practices.

Aimed at using clinical pathways to identify and promote best practicesin the treatment of select types of cancer, “our goal with this joint programis to work with doctors to improve the consistency, quality, and cost-effec-tiveness of cancer treatment,” said David Carmouche, MD, Vice Presidentand Chief Medical Officer, Blue Cross and Blue Shield of Louisiana.Cardinal Health; October 22, 2012


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Mission StatementValue-Based Cancer Care provides a forum for payers,providers, and the entire oncology team to considerthe cost-value issues particular to cancer treatments.This unique focus is achieved through news coveragefrom major hematology/oncology meetings and thecancer literature, supplemented with commentariesand perspectives from those involved in evaluatingtherapies, treating patients, and paying for care.

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Value-Based Cancer Care, ISSN 2153-4888 (print);ISSN 2153-4896 (online), is published 8 times ayear by Engage Healthcare Communica tions, LLC,1249 South River Road, Suite 202A, Cranbury, NJ08512. Copyright © 2012 by Engage HealthcareCommunications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark ofEngage Health care Communi cations, LLC. No partof this publication may be reproduced or transmittedin any form or by any means now or hereafter known,electronic or mechanical, including photocopy,recording, or any informational storage and retrievalsystem, without written permission from the publish-er. Printed in the United States of America.

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FDA UPDATESynribo approved for CML Abraxane for NSCLC

ASTRO ANNUAL MEETINGStereotactic body radiation therapy cost-savingin prostate cancerMore….

BREAST CANCER SYMPOSIUMSome staging studies unnecessary in early diseaseMore….

VBCC PERSPECTIVESWe must incorporate value into our decision-making processHow will we pay for cancer treatment?More….

HEALTH POLICYCMS finalizes payment policies for 2013More….

CONFERENCEEmployers’ challenge: cut healthcare costs butnot employees’ benefitsMore….

ECONOMIC ISSUES IN ONCOLOCYA rational step to reducing cancer care costsMore….

DRUG UPDATEAbraxane receives a new indication for NSCLC

ESMO CONFERENCEBevacizumab plus chemotherapy improves survival in platinum-resistant ovarian cancer

Ed Pezalla, MD, MPHNational Medical Director ofPharmacy Policy and StrategyAetna, Hartford, CT

Denise K. PierceDK Pierce & AssociatesZionsville, IN

Jatin J. Shah, MDM.D. Anderson Cancer CenterHouston, TX

Jayson Slotnik, JD, MPHPartnerHealth Policy Strategies, LLCWashington, DC

Brian K. Solow, MD, FAAFPChief Medical Officer Prescription Solutions/OptumRxIrvine, CA

Timothy Tyler, PharmD, FCSHPDirector of Pharmacy ServicesComprehensive Cancer CenterDesert Regional Medical CenterPalm Springs, CA

G. Rhys Williams, ScD, MSAmgenThousand Oaks, CA

Winston Wong, PharmD CareFirst BlueCross BlueShieldBaltimore, MD

Yu-Ning Wong, MD, MSCEFox Chase Cancer CenterPhiladelphia, PA

Burt Zweigenhaft, BSChief Executive OfficerOncoMed Onco360Great Neck, NY

VBCC Editorial BoardIra Klein, MD, MBAAetnaHartford, CT

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

Mary KruczynskiDirector of Policy AnalysisCommunity Oncology AllianceWashington, DC

Crystal Kuntz, MPAAstellas Pharma USWashington, DC

John L. Marshall, MDChief, Hematology and OncologyDirector, Otto J. Ruesch Center for the Cure of Gastrointestinal CancersLombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashington, DC

Matthew Mitchell, PharmD, MBAManager, Pharmacy ServicesSelectHealth, Salt Lake City, UT

Lee Newcomer, MD, MHAUnitedHealthcareMinnetonka, MN

Lynn Nishida, RPhDirector, Clinical ServicesCatamaran Center of Excellence Northwest Region Portland, OR

Ted Okon, BS, MBAExecutive DirectorCommunity Oncology AllianceWashington, DC

Naimish Pandya, MDUniversity of MarylandBaltimore, MD

Al B. Benson III, MD, FACPProfessor of MedicineAssociate Director for ClinicalInvestigationsRobert H. Lurie Comprehensive CancerCenter of Northwestern UniversityChicago, ILPast President, ACCCPast Chair, NCCN Board of Directors

Scott Breidbart, MDChief Medical OfficerEmpire BlueCross BlueShield, NY

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

Craig Deligdish, MDHematologist/OncologistOncology Resource NetworksOrlando, FL

Peter G. Ellis, MDUniversity of Pittsburgh School ofMedicine and UPMC Cancer CentersPittsburgh, PA

Arlene A. Forastiere, MDSenior Vice PresidentMedical Affairs eviti, IncPhiladelphia, PA

Tracy Gosselin, RN, MSNDuke University Medical CenterDurham, NC

Scott Gottlieb, MDMount Sinai Medical Center and American Enterprise InstituteNew York, NY

David Hom, MBASoluciaFarmington, CT

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

In This Issue

The most common side effectsreported during clinical studies withomacetaxine mepesuccinate includethrombocytopenia, anemia, neutrope-nia (which may lead to febrile neu-tropenia), diarrhea, nausea, weaknessand fatigue, injection site reaction, andlymphopenia. (October 26, 2012)

Abraxane Receives a NewIndication for First-LineTherapy of NSCLC

The FDA approved a new indicationfor paclitaxel protein-bound particlesfor injection (Abraxane; CelgeneCorporation) for the first-line treat-ment of locally advanced or metastaticnon–small-cell lung cancer (NSCLC),in combination with carboplatin, forpatients who are not candidates forcurative surgery or radiation therapy.

“Non–small cell is the most com-mon type of lung cancer, the leadingcause of cancer death in the UnitedStates,” said Mark A. Socinski, MD,Director, Lung Cancer Section,Division of Hematology/Oncology,University of Pittsburgh, and leadinvestigator of phase 2 and phase 3clinical trials of paclitaxel protein-bound particles in patients with lungcancer. “The FDA approval ofAbraxane…offers an important newtreatment option for all types of non–small-cell lung cancer patients, in anarea that has seen few treatmentadvancements in recent years.”

The FDA approval of this new indi-cation for paclitaxel protein-boundparticles is based on the results of aphase 3, multicenter, open-label studyof patients with advanced NSCLCwho were randomized to paclitaxelprotein-bound particles 100 mg/m2

weekly plus carboplatin (area underthe curve [AUC] = 6) every 3 weeks (n = 521) or to generic paclitaxel 200mg/m2 every 3 weeks plus carboplatin(AUC = 6; n = 531). Overall responserate (ORR)—the primary end point—was significantly higher with protein-bound paclitaxel particles comparedwith generic paclitaxel (33% vs 25%,respectively).

In addition, paclitaxel protein-bound particles demonstrated a higherORR for squamous-cell carcinomacompared with paclitaxel (41% vs 24%,respectively) and for large-cell carcino-ma (33% vs 15%, respectively).

Paclitaxel protein-bound particlesachieved ORR that was similar togeneric paclitaxel in patients with car-cinoma or adenocarcinoma (26% vs27%, respectively).

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

tein-bound particles in combinationwith carboplatin for NSCLC are ane-mia, neutropenia, thrombocytopenia,alopecia, peripheral neuropathy, nau-sea, and fatigue.

Paclitaxel protein-bound is alreadyapproved for the treatment of patients

with metastatic breast cancer whosedisease has progressed after therapywith or who did not respond to thera-py with standard combination che -mo therapy. In addition, in earlyresults (released November 7) from aphase 3 clinical trial, paclitaxel pro-

tein-bound particles in combinationwith gemcitabine showed significantimprovement in overall survival inpatients with pancreatic cancer com-pared with gemcitabine alone; com-plete results are expected in January.(October 11, 2012) �


FDA Update

Synribo Approved for...Continued from page 4

Statin Therapy ImprovesSurvival in Patients with Cancer

It is well understood that cancer-cellproliferation encourages tumor growthand metastasis. It is also known thatthe use of statins blocks the productionof cholesterol, and endogenous choles-

terol is crucial for human cell prolifer-ation. Linking these 2 disparate mech-anisms, researchers in Denmark setout to investigate whether statin thera-py can help to reduce cancer-relatedmortality by limiting cancer-cell prolif-eration in patients who have usedstatins before they were diagnosed

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

Using data from the Danish CancerRegistry between 1995 and 2007,which includes cancer data for the en -tire patient population in Denmark,the investigators compared mortalityamong patients with cancer (aged ≥40

years) who had used statins beforetheir cancer diagnosis and patientswith cancer who had never used statintherapy. During the study period,18,721 patients with cancer had usedstatins regularly before being diag-nosed with cancer, and 277,204patients with cancer had never usedstatins. The follow-up continued untilthe end of 2009 (median, 2.6 years;range, 0-15). Other national registrieswere also used to incorporate mortal -ity data and the various causes ofdeath.

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

Adjusted HRs for death from canceraccording to the daily statin dose (theassumed average maintenance dailydose) were 0.83 (95% CI, 0.81-0.86; P <.001), for a defined daily dose of 0.01to 0.75; 0.87 (95% CI, 0.83-0.91; P <.001), for a defined daily dose of 0.76to 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 cancer-related mortality indicates that the useof any statin dose will help to reducemortality in patients with cancer.

Furthermore, the reduction in can-cer-related mortality was seen in all 13types of cancer that were investigated.These results are supported by evi-dence from previous studies showinga reduction in mortality in patientswith advanced prostate cancer whohave used statins and a reduced rateof cancer recurrence in patients withprostate or breast cancer who haveused statins.

This new study clearly shows aneed for clinical trials to investigatethe potential role of statin therapy inpatients with cancer. This study wasnot designed to investigate the role ofstatins for the prevention of cancer.

Survival Trends inMyelofibrosis Improving at a Slow Pace

Primary myelofibrosis (PMF) isassociated with a significant risk formortality. Advances in the treatmentof PMF have nevertheless failed to significantly affect survival, which re -mains a challenge, and life expectancyhas not increased significantly in the


In The Literature


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

INDICATIONS AND USAGENeulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

CONTRAINDICATIONSDo not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

WARNINGS AND PRECAUTIONSSplenic RuptureSplenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta.

Acute Respiratory Distress SyndromeAcute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS.

Serious Allergic ReactionsSerious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta in patients with serious allergic reactions. Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

Use in Patients With Sickle Cell DisordersSevere sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim.

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

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

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

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

Cells [See Warnings and Precautions ]The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher in the pegfilgrastim arm in placebo controlled clinical trials are bone pain and pain in extremity.Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Neulasta clinical trials safety data are based upon 932 patients receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma (n = 56) received Neulasta after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles.The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928

patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and < 1% Asian, Native American or other.Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients.

Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3

System Organ Class Preferred Term

Placebo (N = 461)

Neulasta 6 mg SC on Day 2

(N = 467)

Musculoskeletal and connective tissue disordersBone pain 26% 31%Pain in extremity 4% 9%

LeukocytosisIn clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies.

ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay.The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading.

Postmarketing ExperienceThe following adverse reactions have been identified during post approval use of Neulasta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal relationship to Neulasta.Gastro-intestinal disorders: Splenic rupture [see Warnings and Precautions ]Blood and lymphatic system disorder: Sickle cell crisis [see Warnings and Precautions ]Hypersensitivity reactions: Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, and urticaria, generalized erythema and flushing [see Warnings and Precautions ]Respiratory, thoracic, and mediastinal disorder: ARDS [see Warnings and Precautions ]General disorders and administration site conditions: Injection site reactionsSkin and subcutaneous tissue disorders: Sweet’s syndrome, Cutaneous vasculitis

DRUG INTERACTIONSNo formal drug interaction studies between Neulasta and other drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider these findings when interpreting bone-imaging results.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category CThere are no adequate and well-controlled studies in pregnant women. Pegfilgrastim was embryotoxic and increased pregnancy loss in pregnant rabbits that received cumulative doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity occurred at these doses. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

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 MothersIt 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 UseSafety 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 (AUC

0-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 UseOf the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

Renal ImpairmentIn a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary.

DOSAGE AND ADMINISTRATIONThe recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy.Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed.NOTE: The needle cover on the single-use 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

Boston, MA—The use of proton beamradiation therapy (PBRT) for the treat-ment of prostate cancer is increasingacross the United States, but there is noevidence from randomized, controlledtrials to suggest that PBRT is more effec-tive than intensity modulated radiationtherapy (IMRT), which is the currentstandard of care. A study presented atthe 2012 American Society for RadiationOncology annual meeting found fewdifferences in toxicity between the 2techniques, but demonstrated thatPBRT was associated with a 57%increase in median cost per patient.

Similar Efficacy, Double the Cost

“PBRT is an emerging treatment for

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

CT. “We need a prospective largestudy comparing radiation techniquesto justify widespread use of PBRT forprostate cancer,” he explained.

The population-based, retrospec-

tive, observational study was based on22,647 Medicare beneficiaries betweenthe ages of 66 and 94 years whoreceived PBRT or IMRT for prostatecancer in 2008 and 2009; 421 patients(2%) received PBRT and 27,226 pa -tients (98%) received IMRT.

The median Medicare reimburse-ment per patient is $32,428 for PBRTand $18,575 for IMRT, which repre-sents a 57% difference.

PBRT was associated with a signifi-cant reduction in urinary toxicity at 6months versus IMRT (6.1% vs 12%,respectively); however, by 1 year, therewas no difference between groups forurinary toxicity (18.9% for PBRT vs


ASTRO Annual Meeting

Stereotactic Body Radiation Therapy Cost-Saving... Continued from cover


py (SBRT) delivered via the Cyber -Knife is potentially the most cost-effec-tive and convenient for patients, whileachieving at least equivalent efficacyin disease control, according to 2 retro-spective studies reported at the 2012American Society for RadiationOncology annual meeting. Both stud-ies have a median follow-up ofapproximately 3 years, and largerstudies with longer follow-up areneeded to verify these findings.

SBRT delivers precise high doses ofradiation to the prostate using con-

verging, finely collimated beams thattarget prostate tissue and spare normaltissue. The CyberKnife is a robotictechnology used to deliver SBRT. Acourse of prostate radiation typicallytakes 5 sessions (or 1-2.5 weeks) com-pared with 40 to 45 sessions usingIMRT. SBRT technology is now avail-able at approximately 150 centers inthe United States.

Pooled Analysis of Organ-

Confined Prostate Cancer

A pooled analysis of 1100 patientswith organ-confined prostate cancerwho were treated at 8 different centersbetween 2003 and 2010 with Cyber -knife SBRT showed that the actuarial5-year biochemical control was 95%for low-risk patients, 90% for interme-diate-risk patients, and 80% for high-risk patients.

Similar results were found in 150patients who were treated with andro-gen deprivation therapy and with dif-ferent doses of SBRT, reported Alan J.Katz, MD, JD, a radiation oncologist atFlushing Radiation Oncology, NY.

“These results are 5% to 10% betterthan those with standard IMRT, whichtakes 40 to 45 days to deliver. At thispoint, the statistics should encouragemen with organ-confined prostate can-cer to seek SBRT as an alternative toIMRT, brachytherapy, or prostate sur-gery,” Dr Katz stated.

Significant Cost-Savings

SBRT can achieve huge cost-savings,

because Medicare reimbursement forSBRT is a median of $22,000 versus$40,000 to $45,000 per patient forIMRT.

In addition, because SBRT is deliv-ered over 1 to 2.5 weeks instead of the8 weeks needed for IMRT, the cost-sav-ings in healthcare utilization are signif-icant, and the shorter duration offersgreater convenience for patients.

Intermediate-Risk Prostate Cancer

A second retrospective review,which was reported by Robert M.Meier, MD, a radiation oncologist atSwedish Radiosurgery Center, Seattle,WA, focused on 129 patients withintermediate-risk, organ-confined pros -tate cancer who were treated withCyberKnife SBRT at 21 different insti-tutions between December 2007 andApril 2010. The median follow-up was3 years (range, 2.5-4 years).

The quality-of-life Expanded Pros -tate Cancer Index Composite scoresshowed that both urinary and bowelside effects were greater early in thecourse of treatment, but by 6 months,tended to approach baseline levels.

At 2 years after SBRT, quality-of-lifescores were similar to baseline. Mosturinary and bowel side effects weregrades 1 and 2.

Biochemical control was achieved in99.2% of patients; only 1 of 129patients experienced a rise in prostate-specific antigen after a nadir achievedby SBRT.

Putting these preliminary results in

context, Dr Meier said that the typicalrate of biochemical failure is 10% to20% at 4 years with IMRT and protonbeam therapy.

At a press conference, the Presi - dent-Elect of ASTRO, Colleen Lawton,MD, Clinical Director of Radiation On -cology at the Medical College ofWisconsin, Milwaukee, said that theseare exciting results, but longer follow-up is needed to establish SBRT as astandard of care. �

at a glance� Overall, IMRT has replaced 3-dimensional conformalradiation therapy for patientswith organ-confined prostatecancer

� SBRT via CyberKnife is acost-effective, convenient optionfor patients to achieve diseasecontrol

� SBRT typically requires 5sessions versus the 40-45sessions needed with IMRT;results are 5%-10% better withSBRT than with IMRT

� Medicare reimbursement forSBRT is a median of $22,000versus $40,000-$45,000 perpatient for IMRT

Proton Beam Therapy: Similar Toxicity to StandardRadiation, at Much Higher CostBy Phoebe Starr

“Theseresults are5% to 10%better thanthose withstandardIMRT,which takes

40 to 45 days to deliver. Atthis point, the statisticsshould encourage men withorgan-confined prostatecancer to seek SBRT as analternative to IMRT,brachytherapy, or prostatesurgery.”

—Alan J. Katz, MD, JD

“PBRT is an emerging treatment for menwith prostate cancer, yet it is much moreexpensive than IMRT. The longer-termeffects, costs, and other clinical and patient-reported outcomes are needed to informthe adoption of PBRT for prostate cancer.”

—James B. Yu, MD

21.9% for IMRT). No significant differ-ences were observed at 6 months andat 1 year between the 2 groups in gas-trointestinal (GI) or other toxicities.

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

The study had several limitations, hecontinued. It is a retrospective studythat is a claims-based analysis with nostaging information and with no dataon the extent or field of radiation.

Potential Differences in

Side Effects

A second study found minimal dif-ferences between PBRT, IMRT, and theolder 3-dimensional conformal radia-tion therapy (3D-CRT).

The study included 153 patientstreated with IMRT, 123 treated with3D-CRT, and 94 patients treated with

PBRT. Quality of life (QOL) wasassessed by the Expanded ProstateCancer Index Composite in the IMRTcohort and by the Prostate CancerSymptom Index in the PBRT and 3D-CRT cohorts.

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

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

For urinary irritation, all 3 groupshad lower QOL scores at 2 to 3 monthsof follow-up, but this was clinicallymeaningful only for IMRT. Sexualfunction QOL scores were lower in all3 groups at 24 months, but this was notclinically meaningful (defined in thisstudy as scores exceeding half of thestandard deviation of the baselinemean score).

“These findings are a unique addi-tion to existing research in the field,and suggest that PBRT may lead tofewer immediate side effects inprostate cancer patients,” noted PhillipGray, MD, a resident at HarvardRadiation Oncology Program, Boston.He suggested that a prospective, ran-domized, controlled trial is needed tocompare these technologies. �


ASTRO Annual Meeting

at a glance� PBRT is an emergingtreatment for men with prostatecancer, but is much more costlythan IMRT

� There is no evidence tosuggest that PBRT is moreeffective than IMRT

� Although treatment with PBRTshowed a significant, almost50% reduction in urinary toxicityat 6 months versus IMRT, after 1year this difference disappeared

� Median Medicarereimbursement per patient is$32,428 for PBRT and $18,575for IMRT

� More evidence is needed tocompare the various treatmentoptions to justify the use ofPBRT in this patient population

Proton Beam Therapy: Similar Toxicity to Standard... Continued from page 9

Boston, MA—The patterns of use ofradiotherapy have changed over timein elderly patients with stage I breastcancer, and these changes have finan-cial implications for the healthcaresystem. In elderly patients with favor-able-risk breast cancer, the use ofintensity modulated radiation thera-py (IMRT) and brachytherapy steadi-ly increased from 2001 to 2007, whilethe use of standard external beamradiation therapy (EBRT) decreased.Data are lacking on whether the new -er technologies improve outcomes inthis patient population. In a study ofpatients who were enrolled in theSurveillance, Epi demiology and EndResults–Medi care database, these uti-lization patterns led to a cost increaseof 63% per pa tient. The study’s resultswere reported at the 2012 AmericanSociety for Radiation Oncology annu-al meeting.

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

Medical Center, CT.“The incremental cost to our nation

for new radiation therapy modalitiesin 2007 was $31 billion. We need to

determine if the benefit is commensu-rate with the increased cost,” stated DrRoberts. “Further study is needed toexplore radiation modalities in thislow-risk population.”

The CALGB C9343 trial, which waspublished in 2004, included womenaged ≥70 years who had clinical stage

T1 cancer and negative nodes treatedwith lumpectomy with negative mar-gins. The 10-year follow-up showedthat the local recurrence rate was 2%for those treated with radiation ver-sus 9% for those who did not receiveradiation.

Dr Roberts coauthored a studyshowing that this trial had no effect onthe use of radiation in favorable-riskpatients. “Radiation use remained sta-ble even in patients with low lifeexpectancy,” he said.

Over the past decade, new treat-ments have been adopted—includingaccelerated partial-breast irradiationand brachytherapy—without muchevidence to support their use, DrRoberts noted. The present study wasconducted to determine temporaltrends in the use of technology and theassociated costs in elderly patientswith favorable-risk breast cancer.

This new study included 12,925women (mean age, 77.7 years; range,70-94 years) with stage I breast cancerwho were undergoing lumpectomy.Their tumor size was <2 cm, and allcancers were estrogen receptor posi-tive. Of the total patients, 67% receivedsome form of radiation therapy.

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

received no radiotherapy, and pro -gressive increases in brachytherapy(11.2%) and IMRT (12.4%) were seen.The use of standard EBRT decreasedfrom 76% in 2001 to 52% in 2007.

Fewer women aged ≥85 yearsreceived radiation therapy, but even in this group there were temporalchanges; in 2008, 8.8% were treatedwith brachytherapy, 5.3% with IMRT,and 21.2% received standard EBRT.The study did not include data onquality of life and toxicity.

Meena S. Moran, MD, AssociateProfessor of Therapeutic Radiologyand Assistant Clinical Professor ofNursing, Yale School of Medicine, andMedical Director, Radiation Oncologyat William W. Backus Hospital, CT,commented that this study showedthat the utilization of EBRT has de -creased in older women, yet these pa -tients are opting for costly newer technologies, with no data to show im - proved outcomes.

Dr Moran indicated that the realquestion is how to define “elderly.”Also, it is not clear whether radiationshould be omitted in elderly patientswith favorable-risk breast cancer. “Thedecision should encompass tumorcharacteristics, patient anxiety, andpatient goals,” she stated. �

Newer, More Costly Radiation Technologies Adopted in Elderly Patients with Breast CancerBy Phoebe Starr

Whenconsideringwhether toomitradiationtherapy inelderlypatients

with breast cancer, “thedecision should encompasstumor characteristics, patientanxiety, and patient goals.”

—Meena S. Moran, MD

“These findings are a uniqueaddition to existingresearch…and suggest thatPBRT may lead to fewerimmediate side effects inprostate cancer patients.”

—Phillip Gray, MD


Breast Cancer Symposium

Oncotype DX Score Predicts Residual Disease... Continued from cover

risk in spite of receiving chemothera-py. We can try to find a better treat-ment for them or enroll them in a clin-ical trial. By contrast, patients withlow residual risk may do well withless treatment,” said Dr Mamounas.

Such patients may be sufficientlytreated with only 4 cycles ofchemotherapy rather than a fullcourse of 8 cycles, including a taxane,Dr Mamounas suggested.

The current analysis indicates thatthe extent of chemotherapy may betailored according to the estimation ofresidual risk, he said.

The Oncotype DX Recurrence Scoreis currently approved for use inpatients with ER-positive, node-nega-tive breast cancer to estimate whetherthe addition of chemotherapy to endo -crine therapy would be beneficial.This new study shows that theOncotype DX Recurrence Score canalso be applied to patients with ER-positive, node-positive breast cancerwho are treated with chemotherapyand with endocrine therapy. In thispopulation, the Recurrence Score wasprognostic across the spectrum of subgroups.

The current analysis included 1065patients who had been treated withadjuvant endocrine therapy and ananthracycline and cyclophosphamidecombination, with or without paclitax-el, in the randomized NSABP B-28clinical trial. Recurrence scores werecalculated using tissue specimensfrom past breast surgeries and then

correlating them with outcomes. Themedian follow-up was 11.2 years.

Robust Independent Predictor

of Outcomes

The Recurrence Score was low (<18)in 36% of patients, intermediate (18-30) in 34% of patients, and high (≥31)in 30% of patients.

In a univariate analysis, the Re -currence Score was a significant pre-dictor of disease-free survival (DFS),distant recurrence–free interval, breastcancer–specific survival, and overall

survival (OS). In a multivariate analy-sis, the Recurrence Score providedindependent prognostic informationfor DFS, distant recurrence–free inter-val, and OS beyond clinical and patho-logic factors, including treatment, age,tumor size/grade, number of positivenodes, and type of surgery (P <.001).

Low scores on the test were associ-ated with improved outcomes: • DFS was close to 76% among pa -

tients with a low score but droppedto 48% for those with a high score

• OS was 90% for patients with a lowscore versus 63% for those with ahigh score. The Recurrence Score was strongly

related to the 10-year risk of recur-rence, with events occurring in 54% ofpatients in the group with high Re -currence Scores versus in 17% ofpatients with low Recurrence Scores.

Breast cancer–specific deaths oc -curred in 33% of patients with highRecurrence Scores and in 2% of thosewith low Recurrence Scores.

By treatment assignment, outcomeswere very similar between the treat-ment arms in patients with low Recur -rence Scores, with the benefit of pacli-taxel seen mainly in the groups withintermediate and high RecurrenceScores.

Andrew Seidman, MD, a medical on - cologist at Memorial Sloan-KetteringCancer Center, New York, commentedthat the study “highlights the fact thatdespite hormone receptor positivityand HER2 negativity, many patientswill have a high risk of recurrencedespite receiving chemotherapy andappropriate endocrine therapy. Thisgene assay represents a biological toolthat may be useful in the future instratifying patients for clinical trialsand in identifying candidates whoseoutcomes can be improved.” �

“This geneassayrepresents abiologicaltool thatmay beuseful in

the future in stratifyingpatients for clinical trials andin identifying candidateswhose outcomes can beimproved.”

—Andrew Seidman, MD

“We can identify patientswith high residual risk in spite of receivingchemotherapy. We can try to find a better treatmentfor them or enroll them in a clinical trial. By contrast,patients with low residualrisk may do well with lesstreatment.”

—Eleftherios P. Mamounas, MD

at a glance� The Oncotype DX RecurrenceScore is approved for patientswith ER-positive, node-negativebreast cancer as a guide foradding chemotherapy toendocrine therapy

� A new study shows that it canalso be used in patients withER-positive, node-positivebreast cancer who are treatedwith chemotherapy and withendocrine therapy

� The test was a significantpredictor of DFS, distantrecurrence–free interval, breastcancer–specific survival, and OS

� Low scores were associatedwith improved DFS and OSoutcomes

� By identifying residual diseasein this patient population, thetest scores can help identifypatients who would benefit froma different therapy or from lesschemotherapy

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San Francisco, CA—Three frequentlyused radiologic tests rarely detectmetastases in patients with a newdiagnosis of breast cancer and shouldnot be routinely performed, accordingto a comprehensive literature reviewpresented at the 2012 Breast CancerSymposium.

Bone scan, liver ultrasound, andchest x-ray are often used as first-linescreening modalities for potentialmetastases. However, no establishedprotocol is available for such costlyscreening, and no solid evidence jus -tifies its use—which now is oftenaccompanied by computed tomogra-phy (CT), positron-emission tomogra-phy (PET), and magnetic resonanceimaging (MRI), said Stuart-AllisonMoffat Staley, MPH, a medical studentat the University of North CarolinaSchool of Medicine, Chapel Hill.

“Our literature analysis suggests thatthese 3 tests are of little use in screeningwomen for metastases, and likely resultin a lot of false-negatives in early-stagedisease,” Ms Staley said at a press brief-ing. “The relevant topic is cost contain-ment. When you look at the cost ofthese 3 tests, they are significantly lessexpensive than other more advancedimaging options; however, when they

are used routinely in thousands of newbreast cancer patients annually, collec-tively they become costly to the health-care system,” she indicated.

Ms Staley noted that as a tertiary carecenter, her institution receives manyreferrals from community oncologists.“Many patients do come in having hadstaging evaluations, and physicians areusing chest x-ray and liver ultrasoundin many cases,” she stated.

Test Outcomes Vary

by Disease Stage

The investigators asked whetherbone scan, liver ultrasound, and chestx-ray help to determine the extent ofmetastatic disease in asymptomatic,newly diagnosed patients with breastcancer. Using detection rate (definedas the number of patients with anabnormal test result divided by thetotal number of patients tested) as theprimary outcome, 8 studies met theinclusion criteria.

The primary outcome measureranged from <0.9% to approximately4%. As expected, the rates were high-est for patients with stage III disease.By modality and by stage, the detec-tion 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% forstage 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% forstage II, and 4.57% for stage III, foran 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 stagingevaluation,” Ms Staley noted.

Detection rates of metastases werehigher for women with stage III dis-ease than for women with stage I or IIbreast cancers, particularly as detectedby bone scans (12.5%), suggesting thatthis modality may still have a role inthis subgroup.

However, the researchers suggestedthat these 3 particular imaging testsmay be unnecessary even in thesewomen, when the patients are alsoassessed with more sensitive imaging,such as PET, CT, or MRI scans.

Andrew Seidman, MD, a medical on -cologist at Memorial Sloan-KetteringCancer Center, New York, commentedon the findings. “It strikes me that weare living in a time when we movequickly to embrace new, more sensi-tive technologies, but the elephants inthe room are the false-positives. The‘Choosing Wisely’ campaign, whichASCO [American Society of Clinical

Oncology] participates in, recom-mends that we back off from examina-tions that are really not evidence-based and which, in many cases, domore harm than good.”

Extensive Testing Is Futile in

Low-Risk Patients

The results of this study are consis-tent with other findings suggestingthat extensive testing is futile inpatients with a very low risk of distantmetastases, pointed out Dr Seidman.“Doing extensive imaging, looking forsomething that has a very low yieldand little impact on health, can lead to unnecessary procedures, biopsies,complications, and costs,” he noted.

The higher yield in patients withstage III disease probably exempts thisgroup from such restrictions, DrSeidman added. He said that forpatients with stage I and II cancer, hedoes not order these imaging tests, nordoes he order PET scans. “I reservethese for patients at high risk, whichincludes stage III breast cancer,” hesaid. �

“We are living in a timewhen we move quickly toembrace new, more sensitivetechnologies, but theelephants in the room arethe false-positives.”

—Andrew Seidman, MD

at a glance� Bone scans, liver ultrasounds,and chest x-rays result in a highrate of false-negatives in stage Ior II breast cancer

� Although these tests are lessexpensive than newer imagingmodalities, they become costlywhen used in thousands ofwomen

� Detection rates are highest forstage III breast cancer but theirutility is still not clear

� According to the “ChoosingWisely” campaign, extensivetesting in low-risk patients cando more harm than good

“These very low detectionrates, particularly in stage Iand II disease, make usquestion the utility of these3 modalities for an adequatestaging evaluation.”

—Stuart-Allison Moffat Staley, MPH

Costly Acute Care Episodes Are Common for Patients with Early Breast Cancer Physicians must anticipate, plan for these events

San Francisco, CA—Acute care uti-lization, namely, emergency depart-ment visits and hospitalizations, aresurprisingly common among patientswith early breast cancer, according toa retrospective study using an admin-istrative database in Ontario, Canada.

The findings coincide with currentefforts, at least in the United States, toreduce acute care utilization as a chiefmeans of reducing the cost of treatingcancer. In fact, keeping patients withcancer away from emergency depart-ments and hospitals has become a

quality measure in many healthcaresystems.

“In clinical trial populations, seriousadverse events resulting in hospitaliza-tion from adjuvant chemotherapy areuncommon, but in community popula-tions there’s a lack of information re -

garding the frequency of these toxici-ties,” said Katherine A. Enright, MD,MPH, of the Carlo Fidani Peel RegionalCancer Centre in Missis sauga, Ontario,who presented the study results at the2012 Breast Cancer Symposium.


Some Staging Studies Not Beneficial in Early Breast Cancer Work-UpAvoid extensive imaging in stage I or II disease By Caroline Helwick



“The objective of this study was toidentify the frequency and type ofserious chemotherapy-associated tox-icities resulting in acute care utiliza-tion among women undergoing con-temporary adjuvant chemotherapyfor early breast cancer, and to com-

pare these rates to women with nohistory of cancer,” Dr Enright said.

More than 40% of Patients

Seek Acute Care

The study identified 4718 patientswho received at least 1 cycle ofchemotherapy and who were matchedto controls without cancer. The studydid not include patients who hadreceived growth factor support ordose-dense chemotherapy.

The majority (57.9%) of patientsreceived docetaxel-containing chemo -therapy regimens, and a smaller pro-portion received paclitaxel (21.9%) oranthracyclines only (20%).

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

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

Hospital admissions were signifi-cantly more frequent (44%) in thosewith breast cancer compared with thecontrols (25%; P <.001).

Fever, neutropenia, and infectionwere the most frequent (24%) chemo -therapy-associated toxicities; theseevents were more common with theuse of docetaxel (28%) or with pacli-taxel (20%) than with anthracycline-only chemotherapy regimens (16%).

“The use of taxane-based chemo -therapy, a high comorbidity burden,and place of residence were all associ-ated with increased odds of acute careutilization,” Dr Enright pointed out.

Krystyna D. Kiel, MD, Lecturer,Rush University Medical Center,Chica go, IL, commented that the find-ings are in line with those of a 2006SEER (Surveillance, Epidemiology andEnd Results) database analysis. Thatanalysis showed that 61% of patientswith breast cancer receiving chemo -therapy versus 42% of patients notreceiving chemotherapy were seen inthe emergency department or werehospitalized.

Dr Kiel found it noteworthy that57% of the hospitalizations in the 2006study were related to surgery for breastcancer. These episodes are very costlyto the healthcare system, she indicated.

Dr Kiel said that the findings speak tothe need for oncologists to choose treat-ment regimens based on efficacy, as wellas on tolerability. For example, becausetaxanes were shown to be responsiblefor much of the toxicity leading to acutecare utilization, their elimination mightbe appropriate in some patients, such asin patients with a low-risk disease,based on the Oncotype DX RecurrenceScore (see article, page 1).

Dr Kiel added, however, that theregimens currently recommended bythe National Comprehensive CancerNetwork (NCCN) all contain a taxane.“So, clinicians just have to anticipatethese toxicities,” she said.—CH �

Costly Acute Care Episodes Are Common... Continued from page 12

No Increase in Leukemia or MDS with AdjuvantChemotherapy for Breast CancerBy Audrey Andrews

San Francisco, CA—According to astudy from the US Oncology Network,patients with breast cancer who aretreated with adjuvant chemotherapyhave no increased risk for acutemyeloid leukemia (AML) or myelo -dysplastic syndromes (MDS), at leastwithin the first 3 years of treatment.

“The rates of AML/MDS werefound to be low after adjuvantchemotherapy, and similar to thosenoted in nonchemotherapy-treated pa -tients,” reported Neelima Denduluri,MD, a medical oncologist at VirginiaCancer Specialists, Arlington, duringthe 2012 Breast Cancer Symposium.

Previous estimates have placed therisk for AML or MDS after breast can-cer therapy at approximately 1%, withthe greatest risk seen among olderpatients and patients who receiveanthracyclines, higher cumulativedoses of cyclophosphamide, or radio-therapy. It has not been established

whether granulocyte colony-stimulat-ing factors are correlated withincreased risk, and incidence rateswith taxane combinations are not well-characterized.

Dr Denduluri and colleagues ex -plored the oncology-specific electronichealth record iKnowMed, which con-tains nearly 1.3 million patient records.

The base population included 20,900patients with breast cancer, of whom11,295 received chemotherapy.

At a median follow-up time of ap -proxi mately 3 years, 12 cases of AMLor of MDS were identified amongchemotherapy recipients (0.106%); ofthese 12 patients, 8 were receiving an -thracyclines and 11 were receiving peg -

filgrastim. The median time to onset ofAML or MDS in chemotherapy recipi-ents was 22 months. Among patientswith breast cancer who were notreceiving chemotherapy, 16 cases ofAML or MDS (0.167%) were reported.

The risk was significantly increased,by 7-fold, among patients aged ≥70years and nearly 4-fold among thosewho received anthracyclines. By con-trast, the almost 3-fold increase withpegfilgrastim was numerically higherbut not statistically significant, DrDenduluri said.

“With the recent news that RobinRoberts with Good Morning Americadeveloped MDS after beating breastcancer, many of my patients were con-cerned about the risk,” Dr Dendulurisaid. “This study can reassure patientswho receive adjuvant chemotherapythat their risk of a secondaryAML/MDS is very low within the first 3 years.” �

“The rates of AML/MDS were found to be low afteradjuvant chemotherapy, and similar to those noted in nonchemotherapy-treatedpatients.”

—Neelima Denduluri, MD

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at a glance� Acute care utilization forchemotherapy-related toxicitiesis common among patients withearly breast cancer

� These events add significantcost to cancer therapy

� Fever, neutropenia, andinfection are the most commonand are greater with taxane-based therapy than with anthracycline therapy

� Consider safety whenchoosing a chemotherapyregimen in early breast cancer

� Because all regimensrecommended by the NCCN for these patients contain ataxane, physicians mustanticipate and plan for these events

“Clinicians just have to anticipate thesetoxicities.”

—Krystyna D. Kiel, MD“The use of taxane-basedchemotherapy, a highcomorbidity burden, andplace of residence were allassociated with increasedodds of acute care utilization.”

—Katherine A. Enright, MD, MPH

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

IMPORTANT SAFETY INFORMATION

WARNING: HEPATOTOXICITYSevere and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information.

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 fi rst 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.

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.

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 modifi cation 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.

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 signifi cant gastrointestinal hemorrhage in the past 6 months.

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.

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.

Gastrointestinal Perforation and Fistula: In RCC trials, gastrointestinal perforation or fi stula 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.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS.

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 fi rst 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 anti-hypertensive 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.

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.

Hypothyroidism: Hypothyroidism was reported in 7% (19/290) of patients treated with VOTRIENT in the

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randomized RCC trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended.

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.

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.

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.

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.

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.

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.

Pneumothorax: Two of 290 patients treated with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax.

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.

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.

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.

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 insuffi cient data to assess the risk of concomitant administration of alternative statins and VOTRIENT.

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%).

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 fi le, 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.

Once-daily oral dosing1

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

Do not crush tablets due to the potential for increased rate of absorption

If a dose is missed, it should not be taken if it is less than 12 hours until the next dose

In RCC, initial dose reduction should be 400 mg; additional dose decrease or increase should be in 200-mg steps based on individual tolerability

Dose modifi cations, interruptions, and discontinuations may be required in patients with hepatic impairment, drug interactions, and following adverse events

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

VOTRIENT: Adverse events profi le included1: Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended

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 fi stula, reversible posterior leukoencephalopathy syndrome, hypertension, wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, and fetal harm

Most common adverse events (>20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting

See below and accompanying Brief Summary for additional Important Safety Information, including warnings and precautions

NCCN Guidelines® Category 1 recommendation4

As a fi rst-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology. These Guidelines also include therapies other than pazopanib (VOTRIENT) as fi rst-line treatment options

Move Forward With VOTRIENTIn a Phase 3, randomized, double-blind, placebo-controlled trial, VOTRIENT provided signifi cant 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 patients9.2 months

(95% CI, 7.4-12.9) 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

Treatment-naïve patients

11.1 months (95% CI, 7.4-14.8)

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

Cytokine-pretreated patients

7.4 months(95% CI, 5.6-12.9)

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


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

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 anti-hypertensive 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

past decades, in part because of a lackof breakthroughs in treatment.Approx imately 20% of patients withPMF progress to acute leukemia. Arecent international study evaluated

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

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

survival for patients who were diag-nosed between 1985 and 1997 com-pared with those diagnosed in the pre-vious decade (1970-1984). However,the landscape for patients with PMFmay be incrementally changing inrecent years.

This new study included data of 802

patients with PMF in France, Italy,Spain, and the United Kingdom whowere divided into 2 groups based onthe period of their PMF diagnosis—434 patients were diagnosed between1980 and 1995, and 368 patients werediagnosed between 1996 and May2007. By the time of this analysis, 83%

Survival Trends inMyelofibrosis Improving...Continued from page 8

of patients from the earlier period andapproximately 50% of the patientsdiagnosed in the later period had died.

A comparison of the survival pat-terns among the 2 period groupsshowed a survival increase of almost 2years for patients diagnosed between1996 and 2007 (median survival, 6.5

years; 95% CI, 5.5-7.4) compared withthose diagnosed a decade earlier(median survival, 4.6 years; 95% CI,4.0-5.1). Furthermore, the increase insurvival persisted after applying thedata from other survival studies andadjusting for increased life expectancyin the general population, as well as

other demographic factors. Of note, the increase in survival in

the later decade compared with theearly decade was greater amongwomen (mean survival, 10.6 vs 4.7,respectively) compared with the sur-vival among men (median survival, 5.3vs 4.4, respectively).

Direct-to-ConsumerAdvertising Positively AffectsPrescriptions for BreastCancer Therapy

It is safe to assume that direct-to-consumer advertising (DTCA) has apositive impact on increasing the

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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 well-controlled 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)

Adverse Reactions

All Gradesa Grade 3 Grade 4


% % % % % %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 0a 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.

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

VOTRIENT(N=290)

Placebo(N=145)

Parameters



% % % % % % Hematologic

Leukopenia 37 0 0 6 0 0

Neutropenia 34 1 <1 6 0 0

Thrombocytopenia 32 <1 <1 5 0 <1

Lymphocytopenia 31 4 <1 24 1 0

ChemistryALT increased 53 10 2 22 1 0

AST increased 53 7 <1 19 <1 0Glucose increased 41 <1 0 33 1 0

Total bilirubin increased 36 3 <1 10 1 <1

Phosphorus decreased 34 4 0 11 0 0

Sodium decreased 31 4 1 24 4 0

Magnesium decreased 26 <1 1 14 0 0

Glucose decreased 17 0 <1 3 0 0

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.

In The Literature



number of prescriptions, which can beevidenced from the continuation ofthis practice by pharmaceutical com-panies. How ever, it has often been

suggested that DTCA might result inpatients placing inappropriate pres-sure on physicians to prescribe thera-pies that may not always be appropri-ate for a particular patient. A newstudy has now shown that DTCA has apositive effect on the prescription pat-terns of aromatase inhib itors (AIs) for

women with breast cancer, by increas-ing the number of appropriate pre-scriptions; surprisingly, the study hasalso shown that DTCA does not lead toan increase in inappropriate use ofthese agents for this patient popula-tion (Abel GA, et al. Cancer. 6 Nov2012. Epub ahead of print).

Because AIs have been particularlytargeted for DTCA, and because theyare indicated only for postmeno pausalwomen, the investigators believed thatthis drug class was a good way toinvestigate the cancer-related impactof DTCA, and that age was a surrogatemarker of appropriate use.

They combined national data onDTCA spending (from TNS MediaIntelli gence) and prescription data forhormonal therapy use (from IMSHealth) between October 2005 andSeptember 2007. Prescriptions forwomen aged ≤40 years (assumed pre-menopausal) were considered inap-propriate and for women aged ≥40years, appropriate.

The main target of DTCA for AIswas in national magazines, and to alesser degree in Sunday newspapers.During the study period, the highestspending ($22,019,660) on AI-relatedDTCA was in October 2005 and thelowest ($118,600) was in January 2007,reflecting a great variation over time.The results were also compared with asecond analysis of the impact of AIadvertising in the Journal of ClinicalOncology on physicians during thesame period.

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

This finding suggests that DTCAhas a positive impact on the appro -priate use of certain types of cancer-related drugs and does not lead toincreased inappropriate prescriptionuse. It is not clear whether this conclu-sion can be extended to all drug class-es, but it may suggest that, when itcomes to cancer drugs, DTCA doesnot have a negative impact. �


In The Literature

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 ≥3 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 ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 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 ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 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 ≥3 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 ≥30 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 ≥65 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 identified 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 ≤1.5 X ULN and AST and ALT ≤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 ≥30 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 significantly 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 influence clearance of pazopanib. Therefore, renal impairment is not expected to influence 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 specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly 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

impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 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 ≥10 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 ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 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 ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 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 ≥30 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 leaflet that accompanies the product. However, inform patients of the following:

Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the first 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.

should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications.

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.

report unusual bleeding.

report signs or symptoms of an arterial thrombosis.

pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs.

function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances).

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.

symptoms of a GI perforation or fistula.

to stop VOTRIENT at least 7 days prior to a scheduled surgery.

function testing and urinalysis will be performed during treatment.

Advise patients to promptly report any signs or symptoms of infection.

fetus and to avoid becoming pregnant.

been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs

concomitant medications, vitamins, or dietary and herbal supplements.

during treatment with VOTRIENT.

before or 2 hours after a meal).

VOTRIENT is a registered trademark of GlaxoSmithKline.

©2012, GlaxoSmithKline. All rights reserved. Revised 04/2012 VTR:7BRS

©2012 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. VOT319R0 August 2012

Direct-to-ConsumerAdvertising Positively AffectsPrescriptions...Continued from page 17

New Mechanism of Actionfor PARP Inhibitors

Researchers have discovered a sig-nificant new mechanism of action forthe poly (ADP-ribose) polymerase(PARP) inhibitors in their differentability to inhibit PARP enzyme activ-ity, and significant differences in thetoxicity level of the 3 PARP inhibitorscurrently in clinical trials (Yang ES, etal. Cancer Research. Novem ber 1, 2012.Epub ahead of print).

“We now know that they [PARPinhibitors] are not equivalent withre spect to their potency to trapPARP,” said Yves Pommier, MD,PhD, of the National Cancer InstituteCenter for Cancer Research. (See moredetails in the January 2013 issue.)

The cost of cancer care matters; in fact, it matters so much thatMemorial Sloan-Kettering Can -

cer Center (MSKCC) in New York Cityhas decided not to include in its for-mulary the newly approved drug ziv-aflibercept (Zaltrap), which wasre cently approved for use in patientswith progressive metastatic colorectalcancer. The decision is based on con-sidering cost versus benefit ratherthan on “newer is better.”

Peter B. Bach, MD, Leonard B. Saltz,MD, and Robert E. Wittes, MD, allfrom MSKCC, explain in an Op-Edpiece in the New York Times (October15, 2012) that bevacizumab (Avastin)costs approximately $5000 per month,which is less than 50% of the cost ofziv-aflibercept. The side effects of bothdrugs are “roughly similar,” they say,and the survival benefit for both drugsis a median of 1.4 months. (The manu -facturer of ziv-aflibercept has sinceannounced it was cutting the cost byhalf, see page 21.)

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

“In most industries something thatoffers no advantage over its competi-tors and yet sells for twice the pricewould never even get on the market.But that is not how things work fordrugs. The Food and Drug Admin -istration approves drugs once they areshown to be ‘safe and effective.’ Itdoes not consider what the relativecosts might be once the new medicineis marketed,” Dr Bach and colleagueswrite. US organizations and societiesthat set guidelines for physicians alsorarely factor cost into their determina-tions, they note.

Ignoring costs, however, is “nolonger tenable,” they urge. “Soaringspending has presented the medicalcommunity with a new obligation.”Cost must be considered when choos-ing a specific therapy. “This is particu-larly the case with cancer, where thecost of drugs, and of care overall, hasrisen precipitously.”

In addition to the cost to society, thecost burden of cancer care is increas-ingly being borne by individual pa -tients. Some patients with cancerreport exhausting all of their savings

to pay for care, and some have beendriven into bankruptcy by treatmentcosts. One of 10 patients with cancernow reports spending more than$18,000 out of pocket on cancer care.

To put this particular issue in per-spective, colorectal cancer is typicallydiagnosed in older people, many ofwhom live on Medicare and fixedincomes. Medicare requires copay-ment for drugs to treat cancer, so 20%of the cost of ziv-aflibercept, beva-cizumab, and other cancer drugs is

passed on to supplemental insuranceor to patients themselves. An olderpatient without gap insurance cover-age would have to pay more than$2200 monthly for treatment with ziv-aflibercept, which is more than themonthly income of half of theMedicare recipients, the authors state.

The authors believe that the politi-cal climate has prevented presidentialcandidates from addressing the run-away costs of cancer therapies. Theyacknowledge that the step thatMSKCC is taking regarding this par-ticular drug will not halt the largerproblem of out-of-control risinghealthcare spending, “but it is a stepin the right direction—one of manywe need to take,” they warn.

“The current level of spending onhealth care, estimated to be $2.8 trillionthis year, is already too high. Thegrowth rate in health spending isunsustainable,” the authors state, chal-lenging the US healthcare system toapply a value-based approach to care.“The future of our health care system,and of cancer care, depends on ourusing our limited resources wisely.” �

A Rational Step in Holding Down Costs in Cancer CarePricing of cancer drug launches a national debate on value By Alice Goodman

Economic Issues in Oncology

“The Food and DrugAdministration approvesdrugs once they are shownto be ‘safe and effective.’ Itdoes not consider what therelative costs might be oncethe new medicine ismarketed.”

—Peter B. Bach, MD, et al

San Francisco, CA—In patients withbreast cancer with bone metastases,skeletal-related events (SREs) areassociated with high treatment costs.For example, the cumulative cost oftreating 1 spinal cord compressionexceeds $100,000, according to a newcost analysis presented at the 2012Breast Cancer Symposium.

“Breast cancer patients with bonemetastases are at risk for a variety ofSREs. While a number of studies havedescribed the impact of these SREs oncost, none has used an episode-of-careapproach to examine the costs ofunique SRE episodes in a typical clin-ical practice,” said May Hagiwara,PhD, Senior Economist, Policy Analy -sis Inc, Brookline, MA.

The data for this study came fromthe Thomson MedStat MarketScanCommercial Claims and Encountersdatabase of patients treated betweenOctober 2002 and June 2011. Patientswith breast cancer were included ifthey had confirmed bone metastasisand at least 1 diagnosis or procedure

related to an SRE during the follow-up period (beginning with the indexdate and ending with disenrollmentfrom the health plan).

Unique SRE episodes were identi-fied based on a gap of at least 90 dayswithout an SRE claim. Each SRE epi -sode was then classified by the type ofthe event—spinal cord compression,pathologic fracture, bone surgery, andbone radiotherapy.

Episodes were further classified asinpatient or outpatient. Treatmentcosts were calculated to calendar year2010. The population included 5809women who met the study criteriaand had ≥1 SRE claims. Most of thewomen were insured through a pre-ferred provider organization.

Cumulative Impact of Common

SREs Is Costly

A total of 7617 SRE episodes wereidentified during a mean follow-up of17.2 months, and included 113 (1.5%)spinal cord compression episodes,1390 (18%) pathologic fracture epi -

sodes, 191 (2.5%) bone surgeryepisodes, and 5923 (78%) radiothera-py episodes, Dr Hagiwara reported.

Spinal cord compressions were themost costly to treat, and pathologicfractures were the least costly. Bonesurgery required involved an inpa-tient episode in 76% of patients com-

pared with only 11% for those under-going radiotherapy. The mean per-episode cost for the 4 types of eventswas: • Outpatient pathologic fracture epi -

sode: $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 islargely because such episodes may bemultifactorial. Including all componentsof an episode gives a more realistic pic-ture of the disease and of its high associ-ated costs, Dr Hagiwara explained.

“Previous studies often looked, forexample, at 1 inpatient admission, butthe truth is that spinal cord compressionmay be preceded by a succession ofother events,” noted Dr Hagiwara.“When you look at all events separately,you are not assessing the impact on thepatient. Rather than look at a chunkhere and a chunk there, we think this isprobably the right way to assess this.” �

Cumulative Financial Impact of Skeletal-Related Events onPatients with Breast Cancer Is Significant By Caroline Helwick

“Previous studies oftenlooked, for example, at 1inpatient admission, but thetruth is that spinal cordcompression may bepreceded by a succession ofother events. When you lookat all events separately, youare not assessing the impacton the patient.”

—May Hagiwara, PhD


See also VBCC Perspectives, pages 20-21

VBCC Perspectives


The cost of cancer care is stagger-ing. Global sales of cancer drugsalone are forecast to grow at a

rate of 12% to 15% annually, reaching$75 billion to $80 billion by the end ofthis year, according to IMS Health.1

Clinical leadership is one of the crit-ical keys to controlling quality andcosts in healthcare. Every other seg-ment of the healthcare system also hasa role to play. At Aetna, we work toinfluence the creation of safer, moreeffective, and more affordable health-care through clinical evidence andunprecedented collaboration.

We look to medical evidence— published, peer-reviewed results thatshow which treatments and procedureshave been scientifically proven to beeffective—to create clinical policies,which form the basis of coverage policy.

Based on the current evidence, weconsider ziv-aflibercept (Zaltrap) med-ically necessary for the treatment ofpatients with colorectal cancer. Butbeing proved medically necessary for abroad 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 thebody of knowledge for cancer care,especially experience that furtherclarifies the effectiveness of a therapy

based on specific characteristics ofthe patient. Oncologists can learnfrom the collective experience, whichis what evidence-based pathways are

all about. We applaud Dr Bach andhis team for incorporating costs intotheir evaluation of the best treatmentop tions. The oncology community isin the best position to help eliminatecosts that do not bring additionalvalue to patients.

For our part, we help ensure thatthese evidence-based care standardscan be quickly shared. Aetna enablestechnology and real-time clinical deci-

sion support to allow doctors andpatients to decide together the mosteffective and cost-efficient treatments.We are also developing new paymentmodels to support evidence-basedquality of care rather than quantity ofcare or drug costs.

A recent study by Aetna and USOncology found that evidence-basedcare for patients with non–small-celllung cancer resulted in an averagecost-savings of 35% while demonstrat-ing equivalent health outcomes.2 Weknow that collaborating with the on -cology community to support high-quality, evidence-based care can actu-ally reduce costs and save patients, aswell as the nation’s healthcare system,millions of dollars. �

References1. Gavel SJ. The oncology pipeline: maturing, competi-tive, and growing? http://imshealth.com/deployed-files/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 guide-lines for the treatment of non–small-cell lung cancer inthe community setting. J Oncol Pract. 2010;6:12-18.

Payers’ Support of Clinical Decisions Allows Providers toChoose Most Effective, Cost-Saving TherapiesBy Ira M. Klein, MD, MBA, FACPChief of Staff to the Chief Medical Officer, Aetna

reviewing these facts would come tothe conclusion that this medicine doesnot carry the necessary value to sup-port the higher cost.

This development was inevitable.Just as the tide rises, we have seen sev-eral new therapies that yield modestimprovements in outcome but thatalso come with an ever-increasingprice tag. Examples include sipuleu-cel-T (Provenge), a nearly $100,000 peryear prostate cancer immunotherapythat adds 4 months of survival, and,now ziv-aflibercept, an anti–vascularendothelial growth factor therapy thatoffers a benefit similar to the existingtherapy bevacizumab (Avastin), butwith higher toxicity and a significant-ly higher price tag.

As we recognize that we can nolonger simply expand the amount ofmoney we are spending on healthcare,we increasingly have to make value-based clinical decisions.

Although we are throwing stones at recent therapy pricing decisions, itis important to remember SusanDesmond-Hellman, MD, MPH, for-mer president of product develop-ment at Genentech, defending the

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

As long as there are third-party pay-ers and providers, and as long aspatients do not directly feel the impactof the cost of their therapies, we willcontinue to see ever-escalating drugcosts. It may be that at this point, withthe multiple external pressures beingapplied to the healthcare system, thatthe market will no longer bear high-priced medicines that bring little addi-tional value to our patients and topatient care.

Our group at Georgetown’s Otto J.Ruesch Center for the Cure of Gastro -intestinal Cancers has been workingin collaboration with other centers todevelop a value metric for drugapprovals for this very circumstance.One could envision that drugs such asziv-aflibercept would be useful in thetreatment of certain patients withmetastatic colorectal cancer, but not atdouble the price of its competitor.

If we were to apply a value metricfor drug approval that links payersand the approval process, as is sug-gested by Bach and colleagues, thisdrug would not have gained US Food

and Drug Administration approval,especially not at that price. However,the manufacturers could have made adecision to lower the price and enterthe market as a less-expensive option,which would, in my opinion, have

been a more appropriate strategy, andone that may be forced on Zaltrap andits makers in the future.

We clearly need a collaboration ofpayers, patients, employers, and pro -viders to ensure transparency inhealthcare. I am reminded of the bookThe Cost of Hope by Amanda Bennett,which is an outstanding review of asingle patient’s course through cancertherapy. Ms Bennett reviews her hus-band’s treatments and emotional well-being through his battle with cancer, aswell as the consumption of healthcarethrough the process. In one of the morestriking examples, her husband under-went 76 separate computed tomogra-phy scans in the course of his care.

As we “pick on” our drugs as ahigh-cost item, we must also remem-ber that we consume a great deal ofresources as cancer care providers. Assuch, we need to look at our entireprocess, and assess it for the value itbrings—not only to judge new ap -proaches but also to evaluate ourexisting approaches, removing theones that are not helping our patients’outcomes or quality of life.

We Must Incorporate Value into Our Decision-Making... Continued from cover

As we recognize that we canno longer simply expand theamount of money we arespending on healthcare, weincreasingly have to makevalue-based clinical decisions.

Based on the current evidence, we consider ziv-aflibercept (Zaltrap)medically necessary for thetreatment of patients with colorectalcancer. But being proved medicallynecessary for a broad condition doesnot mean that it is the besttreatment for every patient.


John L. Marshall, MD

See article on page 19

With the fanfare of a New YorkTimes Op-Ed piece by PeterB. Bach, MD, and colleagues

(see page 19), the announcement wasmade that Memorial Sloan-KetteringCancer Center (MSKCC) would ex -clude the new colorectal cancer drugziv-aflibercept (Zaltrap) from its for-mulary. Regardless of questions raisedabout the accuracy of the cost and thedosing comparisons and certain con-flicts, the question is—Will theMSKCC decision influence communi-ty oncology clinics to consider a simi-lar restriction?

Although the press around theMSKCC decision has caught the at -tention of community oncologists, Ibelieve that they will not be undulyinfluenced by it. In this day and age,oncology clinics typically are basingtreatment decisions on evidence-based guidelines that are evolvinginto specific treatment pathways.These pathways incorporate nationalinformation on efficacy and cost, aswell as the experiences of oncologistsand practices. The realities of theincreasing cost of cancer treatmenthave been on the radar screens ofcommunity oncologists for severalyears, as well as the effort required to

ensure that all patients—includingMedicare recipients and those withprivate insurance—have access to theoptimal standard-of-care treatment.So, most oncologists will weigh thefacts and will make decisions in con-cert with their patients.

From a societal standpoint, theMSKCC decision begs the larger ques-tion of how we will pay for the rapidlyescalating cost of cancer treatmentand who the arbiter is.

Some would like to see a UK-typeNational Institute for Clinical Ex -cellence–like board decide at a govern-mental level what cancer drugs getpaid for, based on the calculated value-of-life extension from a specific med-ication. Others fear that our govern-ment regulatory and payment agenciesare already moving in that direction,without legislative mandate. Some,presumably like MSKCC, believe thatthe institution must intervene, as in the

case of ziv-aflibercept. Yet others be -lieve that individual physicians, whoare familiar with specific efficacy andcost data, must make decisions in con-cert with their patients. My guess isthat most physicians agree that the rap-idly escalating cost of cancer treatmentis unsustainable, and that somethingmust be done, starting with the drugmanufacturers.

From a policy perspective, I believethat we first need to substantially trimthe regulations, inefficiencies, andcosts that impede bringing effective,safe new cancer drugs to market, aswell as ensure accessibility to low-costgenerics, which are increasingly inshort supply.

Competition will produce the besttreatments with the optimal valuepropositions. Manufacturers with su -perior science and understanding ofmarket needs will prosper. On -cologists will be able to focus on get-ting the optimal treatment to patients,based on the value equation—andpatients with cancer will end up the

ultimate winners. Until we fix an increasingly dys-

functional cancer care landscape, it isunclear how we will pay for cancertreatment going forward. �

VBCC Perspectives


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

In a way, we owe something toZaltrap and its high price. I believethat this will be a turning point in can-cer drug development, and that thependulum will begin to swing backtoward value. My concern is that thepharmaceutical industry will decidethat the return on investment is notsufficient to support cancer drugdevelopment, particularly as we in -creasingly personalize our approachto therapy, which shrinks the overalldrug market.

We are at a critical time; we mustincorporate value into our decision-making. We must alter our drugapproval process to enable rapid, effi-cient drug development in the era ofpersonalized medicine. We must con-nect our payers, patients, employers,and providers so that the medicinesof tomorrow will be measured byvalue and will be incorporated intodaily practice based on safety andefficacy, as well as on their impact andmagnitude of benefit for individualpatients. �

We Must IncorporateValue... Continued from page 20

The October 15, 2012, Op-Ed inthe New York Times by Peter B.Bach, MD, Leonard B. Saltz, MD,

and Robert E. Wittes, MD, of Memori -al Sloan-Kettering Cancer Center(MSKCC) who discussed the rationalefor MSKCC’s decision not to includeziv-aflibercept (Zaltrap) in its formu -lary (see page 19 in this issue) has sentshockwaves throughout the oncologycommunity.

The following day, Sandra M.Swain, MD, President of the AmericanSociety of Clinical Oncology, pub-lished a letter in the New York Times,noting that MSKCC’s “decision toforgo an expensive new cancer drugreflects a much-needed willingness toaddress the elephant in the room:unsustainable costs in cancer care.”

A few days later, Harold J. Burstein,MD, PhD, Editor-in-Chief of theJournal of the National Compre hensiveCancer Network addressed this topic,noting that “the decision at MSKCC,and more particularly its public decla-ration, may serve as a ‘shot heardaround the world’ for voluntary limitson the use of expensive oncologydrugs” (J Natl Compr Canc Netw. 2012;10:1315-1316).

Dr Burstein further makes an impor-tant point regarding conflicts of inter-est, “If institutional formulary or path-way committees are to have a larger

say in the treatment that patientsreceive, it becomes imperative to min-imize conflicts of interest.”

In their Op-Ed piece, the authorsacknowledge that Dr Bach and DrSaltz are consultants to Genentech, themaker of the competitor drug beva-cizumab (Avastin), which raises con-cerns for a potential bias. Indeed, theissue of conflicts of interest muddiesthe waters here and should be ad -dressed as well, but the cost of thedrug has taken on a life of its own.

Calling for a National

Debate on Value

The article by Dr Bach and col-leagues has forced the oncology com-munity to face the issue of value-basedcancer care head on.

Lee Newcomer, MD,Senior Vice Pres ident forOncology at United -Health care, told Value-Based Cancer Care, “Iapplaud the leaders at MSKCC for tak-ing this stand. When physician leadersmake these assessments, they will betaken far more seriously than whenpolicymakers attempt the same effort.”

“UnitedHealthcare follows the NCCNrecommendations to determine whatdrugs it will cover for cancer therapy. Ihope that the MSKCC leaders can con-vince their peers at NCCN to begin

making these same value assessments,”Dr Newcomer said.

Responding to comments from theoncology community, Sanofi initiallytried to explain its position in discus-sions with The Cancer Letter (2012;38:1-10), acknowledging how it pricedziv-aflibercept to match the 10-mg/kgdose of bevacizumab rather than thesmaller, 5-mg/kg dose, which is alsohalf the cost, but noting that the drugwas appropriately priced and that itsapproval was expedited by the USFood and Drug Administration. Al -though some oncologists have saidthey only use the 5-mg/kg dose ofbevacizumab, this issue requires fur-ther feedback from other sources.

On November 8, 2012, Sanofi issued astatement cited on that day in The CancerLetter and in the New York Times, saying,“We believe that Zaltrap is priced com-petitively as used in real-world situa-tions. However, we recognize that therewas some market resis tance to the per-ceived relative price of Zaltrap in theU.S.—especially in light of low aware-ness of Zaltrap in the U.S. market. Assuch, we are taking immediate actionacross the U.S. oncology community toreduce the net cost of Zaltrap.”

The company said the price wasbeing cut by 50%, an unprecedentedmove. It remains to be seen if this stepwill set a new trend in oncology. �

From a policy perspective, Ibelieve that we first need tosubstantially trim theregulations, inefficiencies,and costs that impedebringing effective, safe newcancer drugs to market

How Will We Pay for Cancer Treatment?By Ted Okon, BS, MBAExecutive Director, Community Oncology Alliance, Washington, DC


Personalized Medicine

Phoenix, AZ—Using the paradigm ofindividualizing drug therapy based ona patient’s genetics, a group of oncolo-gists and genomic experts have de -signed a genomic prescribing systemthat they hope will significantly reducethe staggeringly high rate of adversedrug reactions associated with prescrip-tion drugs in the United States. Prin -cipal investigator Peter H. O’Donnell,MD, Assistant Professor, De partment ofMedicine, Section of Hematol ogy/Oncology, Genitouri nary Oncol ogy Pro -gram, Committee on Clin ical Pharma -cology and Phar ma cogen om ics, Centerfor Person alized Thera peu tics, Univer -sity of Chicago, IL, dis cussed the veryearly results of the 1200 Patients Projectat the 2012 Society for Med ical DecisionMaking annual meeting.

“Patients and providers see this asthe future of how medicine will bepracticed,” Dr O’Donnell told Value-Based Cancer Care (VBCC). “A keyadvantage of this approach is that allpotentially desired pharmacogenomicinformation is obtained for the pa -tient’s entire drug prescription lifetime,with one single test.”

The model attempts to circumventthe barriers to implementing personal-ized medicine resulting from the limit-ed and high cost of genetic testing, thedelay in their results, and the commondisagreement regarding the interpreta-tion of the results. Dr O’Donnell andhis colleagues are hoping that this newventure will help to translate the bene-fits of pharmacogenomics, or person-alized medicine, into clinical practicein oncology.

The 1200 Patients Project

The project began in the spring of

2011 and involves preemptive andcomprehensive pharmacogenomic geno -typing of a large number of consent -ing patients—at a cost of less than $500per person—and rapid and cheap elec-

tronic dissemination of geno -typeinformation (http://cpt.uchicago.edu/page/1200-patients-project). Itharnesses the discovery of geneticvariants that govern appropriateness

of response to, and toxicity from,drugs, but which until now have notbeen incorporated into prescribingdecisions.

In a recent article published inClinical Pharmacology & Thera peutics,Dr O’Donnell and his team outlinedthe full scope of the project, which isdesigned to overcome barriers to theapplication of routine “pharma co -genomic prescribing” into clinicalprac tice (O’Donnell PH, et al. ClinPharmacol Ther. 2012;92:446-449). Thesoftware and the other technologiesfor the project were created by DrO’Donnell’s team, in collaborationwith the University of Chicago Centerfor Research Informatics.

Discussing the rationale for thisproject, the authors write, “We havecarefully considered the alternativeoption of whole-genome sequencing.Although whole-genome sequencinghas the advantage of detecting rarevariants…it has the disadvantage ofrequiring substantially greater costs inquality-control/bioinformatics analy-sis.” Funding is provided by theConquer Cancer Foundation of theAmerican Society for Clinical Oncol -ogy’s Translational Research Profes -sorship and other institutional andphilanthropic sources.

The 1200 patients being recruited forthe study are receiving outpatientmedical care from 1 of 12 physicians.These include 4 general internists, 3oncologists, 2 cardiologists, 1 pulmo-nologist, 1 hepatologist, and 1 gastro -enterologist.

The patients undergo testing for apanel of genotypic variants that havebeen associated with a positiveresponse to, or an adverse reaction to,

frequently used medications. Thedrugs include those that the patientsare currently taking and other drugsthat they may receive in the future.Newly discovered genetic and phar-macogenomic variants will be incor-porated into the testing over time,once they have been confirmed to beclinically relevant.

“A full 674 drugs have beenreviewed for inclusion in the genomicprescribing system, with patient-specific information being presentwhen pharmacogenomic informationexists,” said Dr O’Donnell.

The patient-specific testing resultsindicate: Whether the person’s geno-typic profile suggests that the patientis likely (or not) to benefit from a par-ticular drug• What the level of evidence is for this

conclusion• What published studies support

these findings. These data are made available exclu-

sively to the enrolling provider of thespecific patient through a researchweb portal.

Overcoming Clinicians’

Knowledge Gap

The ultimate goals of the project areto determine whether physicians aretaking pharmacogenomic informationinto account during clinic visits, andwhether this information alters pre-scribing to patients who are genetical-ly at high risk for negative outcomesbecause of adverse drug reactions or for a nonresponse to the specificmedication.

“Although a recent survey suggeststhat 98% of physicians believe ‘patientgenetic profiles may influence drugtherapy,’ only 13% had ordered a phar-macogenetic test, and only 10% hadfelt adequately informed about phar-macogenetics,” Dr O’Donnell and col-leagues write in their published article.

Approximately 700 patients havebeen recruited to date, 400 of whomhave received pharmacogenomic test-ing thus far. One physician beganusing the genomic prescribing systemin October 2012, and the other 11physicians will begin using it “soon,”Dr O’Donnell told VBCC.

The physicians and patients who are involved in the project haveexpressed “significant enthusiasm,”Dr O’Donnell added. “Patients havelittle reservation about this type oftesting, and physicians are very inter-ested to see what medications have rel-evant information in our database.” �

“Patients and providers seethis as the future of howmedicine will be practiced. Akey advantage of thisapproach is that all potentiallydesired pharmacogenomicinformation is obtained forthe patient’s entire drugprescription lifetime, withone single test.”

—Peter H. O’Donnell, MD

A New Personalized Prescription Decision-Making SystemTranslating pharmacogenomics into clinical practice By Rosemary Frei, MSc

The Missing Perspective in Personalized Cancer Care By Caroline Helwick

Vienna, Austria—The identification ofgenetic mutations and tumor biomark-ers to select the right drug for the rightpatient are not enough to satisfy theneed for personalized cancer care,according to Kathy Redmond, MSc,RN, Editor of Cancer World magazine,a publication of the European Schoolof Oncology and former president ofthe European Oncology NursingSociety, who addressed the topic ofpersonalized medicine at the 2012

European Society for Medical Oncol -ogy Congress.

Ms Redmond maintains thatgenomic profiling does not go farenough to justify the concept of per-sonalized care in cancer. “I use theterm ‘personalized cancer care.’ Ideliberately do not use the term ‘per-sonalized medicine,’” she said.

“We maintain that personalizedmedicine will eventually be deliveredto all cancer patients. There has been

so much hype around the term ‘per-sonalized medicine’ that we lose sightof the fact that we should be focusingon the personalized care of the wholeindividual,” Ms Redmond argues.

Tailored treatment has been thestandard for some time, she says, andthis includes not just drugs but typeand extent of surgery, radiotherapy,and the like. What is missing is morepersonalized psychosocial care.


A N E W I N D I C AT I O N

COMINGSOON

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

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

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

Janssen Biotech, Inc.

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.

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.

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.

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ZYTIGA® (abiraterone acetate) TabletsBrief Summary of Prescribing Information.INDICATIONS AND USAGEZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.CONTRAINDICATIONSPregnancy: 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 REACTIONSThe 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 ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not 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 Placebo with Prednisone (N=791) (N=394)System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % %Musculoskeletal and connective tissue disorders Joint swelling/discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3General disorders Edema4 26.7 1.9 18.3 0.8Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.31 Adverse events graded according to CTCAE version 3.02 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal

stiffness

4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema5 Includes all fractures with the exception of pathological fracture6 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 placebo-controlled 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 0High AST 30.6 2.1 36.3 1.5Low Potassium 28.3 5.3 19.8 1.0Low Phosphorus 23.8 7.2 15.7 5.8High ALT 11.1 1.4 10.4 0.8High Total Bilirubin 6.6 0.1 4.6 0

DRUG INTERACTIONSEffects 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 POPULATIONSPregnancy: 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: Manufactured for:Patheon Inc. Janssen Biotech, Inc.Mississauga, Canada Horsham, PA 19044

©Janssen Biotech, Inc. 2012 Revised: July 2012 08Z12237B

ZYTIGA® (abiraterone acetate) Tablets

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In this article we address the finalpayment rules issued on November1, 2012, by the Centers for Medicare

& Medicaid Services (CMS), thePhysician Fee Schedule (PFS), and theHospital Outpatient Prospective Pay -ment System. These annual updates toMedicare payment rates for physiciansand hospitals can have a dramaticimpact on reimbursement and incen-tives within the Medicare program, butthey also tend to impact trends in thecommercial insurance market.

You previously read our summaryof CMS’s payment proposals in theSeptember issue of Value-Based CancerCare, and, by and large, the final rulescome as no surprise. In possibly thebiggest change in payment rules, CMSis increasing payment for primary carespecialties (and therefore decreasingpayments to select other specialties) asa result of several changes in the wayCMS is calculating payments in 2013.

Specifically, in large part because ofa new set of payment codes for transi-tional care management services in themonth after a patient is being dis-charged from a hospital, family physi-cians will receive a 7% paymentincrease in 2013. In addition, paymentsto primary care specialties will in -crease as a result of redistributionsfrom changes in payments for servicesthat are furnished by other specialties.Other healthcare professionals whoprovide primary care services, includ-

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

transitional care management servicesmay be billed by any physician whoprovides the relevant services, includ-ing oncologists (CMS specifically citedoncology as a specialty that may takeadvantage of the new codes in the finalrule). An oncologist who is involved in the treatment of a patient—post -

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

healthcare professionals and assistancein scheduling any required follow-up,may be eligible to bill for the new tran-sitional care management codes.

In our September summary of theproposed rule, we also noted CMS’sproposal in the 2013 PFS rule to reducethe payment for 2 radiation therapy

services by as much as 20%. In thisproposed rule, CMS indicated thatbased on information that wasobtained from patients’ experiencesregarding the length of intensity-mod-ulated radiation therapy (IMRT) andstereotactic body radiation therapy(SBRT), CMS would reduce the proce-dure time for both treatment modali-ties to more accurately take intoaccount actual patient experiences.

In a half sigh of relief to the rationaloncology community, CMS slightlyretreated from its original proposal.Although CMS will still cut paymentrates for IMRT and SBRT services, thechanges reflect an overall 7% reduc-tion in payment for radiation oncologyservices and an overall 9% cut to radi-ation therapy centers, which is lessthan half of the 15% cuts for IMRT and19% cuts for SBRT that were suggestedin CMS’s original proposal.

Overall, both rules indicate a gener-al shift in CMS’s policy toward payingfor value. In particular, the new codesfor transitional care management sig-nal an increasing focus toward “wholepatient” care. The oncology communi-ty can expect similar incentives todevelop further in the commercialmarket in the wake of the current CMSdecision.

Look for our analysis of the implica-tions of the presidential elections forhealthcare and oncologists in the nextissue of this publication. �


“We know all our patients differ interms of their age, their tumors, theirmutations, their baseline health status,and their access to care, and they comewith different attitudes, values, andbeliefs about cancer. Some live far dis-tances away from treatment centers.Some are retired….All these thingsinfluence their willingness to acceptcertain cancer treatments,” she says.Rather, the focus should be on the totalcare of the patient, above and beyondwhat is considered “core medicine.”

Will Personalized Medicine

Be Available to All?

The landscape of cancer is becomingpopulated by a growing number ofsubtypes for every tumor, marked by

multiple genetic mutations. “And ontop of this we have hundreds of rarecancers, with many subtypes as well,”Ms Redmond says. More mutationswill be found every day in differentgrades and stages of disease, she predicted.

“Some of these mutations will bedruggable and others not,” she sug-gests. “In fact, mutation status maynot be relevant for many cancers andmany patients.” In addition, “the reality today is that there are very,very few targeted drugs on the mar-ket, and they are delivered effectivelyto very few cancer patients.”

“We are at an exciting moment in

time. We are starting to win the war onsome cancers. But for the vast majorityof patients, personalized medicine,that is, the effective use of targetedagents, is not delivering,” she main-tains. “We need to be more careful ofhow we talk about personalized medi-cine, and we probably need to movethe discussion to ‘personalized cancercare’ where we talk about the manyaspects of the individual.”

“We often look at the cost of cancerto society, but not necessarily the costto the patient,” she says. “At the end ofthe day, it’s the patients we should befocusing on, and putting them at thecenter of all that we do.” �

The Missing Perspective in Personalized Cancer... Continued from page 22

Health Policy

“There has been so muchhype around the term‘personalized medicine’ thatwe lose sight of the fact thatwe should be focusing onthe personalized care of thewhole individual.”

—Kathy Redmond, MSc, RN

An oncologist who is involved in the treatment of apatient—postdischarge from an acute care setting—withfuture medical decision-making, including communicationwith other healthcare professionals and assistance inscheduling any required follow-up, may be eligible to bill forthe new transitional care management codes.

Personalized Medicine

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

Jayson SlotnikRoss D. Margulies

THE AFINITOR DUAL BENEFIT CO-PAY CARD

RxBIN:RxPCN:RxGrp:RxID:Suf:

601341OHCP

[OHXXXXXXX][000000000000]

01

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.

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 offi ce or at www.AFINITOR.com. This program will expire on June 30, 2014.

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

The AFINITOR Dual Benefi t Co-Pay Card

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

Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936-1080 © 2012 Novartis 11/12 AFB-1053812

Helping make access to AFINITOR easier

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

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.

S

AFINITOR® (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 non-infectious 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 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 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.

S

AFINITOR (everolimus) tablets for oral administrationInitial U.S. Approval: 2009Brief 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 receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failureof treatment with letrozole or anastrozole.

4 CONTRAINDICATIONSHypersensitivity 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 respiratoryimpairment) have been observed with everolimus and other rapamycin derivatives.

5 WARNINGS AND PRECAUTIONSNon-infectious PneumonitisNon-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectiouspneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidenceof Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and upto 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 respiratorysigns and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neo-plastic, and other causes have been excluded by means of appropriate investigations. Advise patients toreport promptly any new or worsening respiratory symptoms.Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or nosymptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate theincidence of clinical pneumonitis.If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of cortico -steroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower thanthe dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribinginformation].For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Cortico steroids may be indicateduntil clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR untilresolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately50% 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 atgrade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported evenat a reduced dose.InfectionsAFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, orprotozoal 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 pneumo-nia, mycobac terial infections, other bacterial infections, invasive fungal infections, such as aspergillosisor candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patientstaking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic fail-ure) 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 ismade, 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 appro-priate antifungal therapy.Oral UlcerationMouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an inci-dence 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]. Insuch cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashesshould be avoided as they may exacerbate the condition. Antifungal agents should not be used unlessfungal 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 inpatients treated with AFINITOR [see Laboratory Tests and Monitoring].Geriatric PatientsIn the randomized advanced hormone receptor positive, HER2-negative breast cancer study, the incidenceof deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years ofage compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatmentdiscontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 yearsof 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 MonitoringRenal FunctionElevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reac-tions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, includingmeasurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended priorto the start of AFINITOR therapy and periodically thereafter.Blood Glucose and LipidsHyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [seeAdverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fastingserum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodicallythereafter. When possible, optimal glucose and lipid control should be achieved before starting a patienton AFINITOR.Hematologic ParametersDecreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [seeAdverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of completeblood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.Drug-drug InteractionsDue to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitorsshould be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information and DrugInteractions].A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4and/or PgP inhibitor [see Dosage and Administration (2.2, 2.4) in the full prescribing information andDrug 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 ImpairmentExposure 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 withsevere hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desiredbenefit 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 ClinicalPharmacology (12.3) in the full prescribing information].For SEGA patients with severe hepatic impairment, AFINITOR is not recommended. For SEGA patientswith mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to thestarting dose may not be needed; however subsequent dosing should be individualized based on thera-peutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information].VaccinationsThe use of live vaccines and close contact with those who have received live vaccines should be avoidedduring 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 startof everolimus therapy.Embryo-fetal ToxicityThere are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based onthe mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities inanimals at maternal exposures that were lower than human exposures. If this drug is used during preg-nancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of thepotential hazard to a fetus. Women of childbearing potential should be advised to use an effectivemethod of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use inSpecific Populations].

6 ADVERSE REACTIONSThe efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placeboplus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients withadvanced or metastatic hormone-receptor-positive, HER2-negative breast cancer. The median age ofpatients 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, diar-rhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) werestomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most commonlaboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST,anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The mostcommon grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, ane-mia, 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-emergentadverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemes-tane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions orreductions) were more frequent among patients in the AFINITOR plus exemestane arm than in theplacebo 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=238All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

% % % % % %Any adverse reaction 100 41 9 90 22 5Gastrointestinal disorders

Stomatitisb 67 8 0 11 0.8 0Diarrhea 33 2 0.2 18 0.8 0Nausea 29 0.2 0.2 28 1 0Vomiting 17 0.8 0.2 12 0.8 0Constipation 14 0.4 0 13 0.4 0Dry mouth 11 0 0 7 0 0

General disorders and administration site conditionsFatigue 36 4 0.4 27 1 0Edema peripheral 19 1 0 6 0.4 0Pyrexia 15 0.2 0 7 0.4 0Asthenia 13 2 0.2 4 0 0

Infections and infestationsInfectionsc 50 4 1 25 2 0

InvestigationsWeight decreased 25 1 0 6 0 0

Metabolism and nutrition disordersDecreased appetite 30 1 0 12 0.4 0Hyperglycemia 14 5 0.4 2 0.4 0

Musculoskeletal and connective tissue disordersArthralgia 20 0.8 0 17 0 0Back pain 14 0.2 0 10 0.8 0Pain in extremity 9 0.4 0 11 2 0

Nervous system disordersDysgeusia 22 0.2 0 6 0 0Headache 21 0.4 0 14 0 0

Psychiatric disordersInsomnia 13 0.2 0 8 0 0

Respiratory, thoracic and mediastinal disordersCough 24 0.6 0 12 0 0Dyspnea 21 4 0.2 11 0.8 0.4Epistaxis 17 0 0 1 0 0Pneumonitisd 19 4 0.2 0.4 0 0

Skin and subcutaneous tissue disordersRash 39 1 0 6 0 0Pruritus 13 0.2 0 5 0 0Alopecia 10 0 0 5 0 0

Vascular disordersHot flush 6 0 0 14 0 0Median 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 ulcerationc 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%), pneu-monia (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 fibrosise Exposure to AFINITOR or placebo

Key observed laboratory abnormalities are presented in Table 4. Table 4: Key Laboratory Abnormalities Reported in ≥ 10% of

Patients with Advanced HR+ BCLaboratory parameter AFINITOR (10 mg/day) Placebo

+ exemestanea + exemestanea

N=482 N=238All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

% % % % % %Hematologyb

Hemoglobin decreased 68 6 0.6 40 0.8 0.4WBC decreased 58 1 0 28 5 0.8Platelets decreased 54 3 0.2 5 0 0.4Lymphocytes decreased 54 11 0.6 37 5 0.8Neutrophils decreased 31 2 0 11 0.8 0.8Clinical ChemistryGlucose increased 69 9 0.4 44 0.8 0.4Cholesterol increased 70 0.6 0.2 38 0.8 0.8Aspartate transaminase (AST)

increased 69 4 0.2 45 3 0.4Alanine transaminase (ALT)increased 51 4 0.2 29 5 0

Triglycerides increased 50 0.8 0 26 0 0Albumin decreased 33 0.8 0 16 0.8 0Potassium decreased 29 4 0.2 7 1 0Creatinine increased 24 2 0.2 13 0 0CTCAE Version 3.0a 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 INTERACTIONSEverolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multi drug effluxpump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.Agents that may Increase Everolimus Blood ConcentrationsCYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases ineverolimus exposure when AFINITOR was coadministered with:

max

max

max

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. Ifalternative 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 ConcentrationsCYP3A4 Inducers

CYP3A4, decreasedeverolimus AUC and Cmax by 63% and 58% respectively, compared

treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably andshould be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information].Agents whose Plasma Concentrations may be Altered by EverolimusStudies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions

kinetic analyses also detected no influence ofsimvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.

max and a 30% increase in.

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 twotreatment arms. No increase in adverse

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].

the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman.

exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the

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

retarded skeletal development. These efftoxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately4% 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 toSEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternaltoxicities.

tion. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or

developmental parameters (morphological development, motor activity, learning, or fertility assessment)in the offspring.Nursing MothersIt is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passedinto the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because manydrugs are excreted in human milk and because of the potential for serious adverse reactions in nursinginfants from everolimus, a decision should be made whether to discontinue nursing or to discontinue thedrug, taking into account the importance of the drug to the mother.Pediatric UseAFINITOR is recommended for use only in patients with SEGA who are aged ≥ 3 years.

Geriatric Use

≥ 65 years of age, while 15% were 75 and over. No overall differences ineffectiveness were observed between elderly and younger subjects. The incidence of deaths due to anycause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in

33% of patients ≥ [see Warnings andPrecautions].

pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and≥ 65

treated patients were ≥ 65 years of age, while 7% were 75 and over. Other reported clinical experience has not identified differences in response between the elderly andyounger patients, but greater sensitivity of some older individuals cannot be ruled out macology (12.3) in the full prescribing information].

ate dose adjustments for adverse reactions is recommended. [see Dosage and Administration (2.2),Clinical Pharmacology (12.3) in the full prescribing information].Renal ImpairmentNo clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal

ommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribinginformation].Hepatic ImpairmentThe safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose

tion.

scribing information].For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients withsevere hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the

dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information].

[see Dosage and Administration (2.4ing information].

10 OVERDOSAGEIn animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity wereobserved 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 beenadministered. 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

Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936© Novartis

July 2012


2012 Conference

Delta Air Lines’ Approach to Patient Care... Continued from cover

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

Cancer care accounts for 16% ofDelta’s overall health plan costs, 25%of high-cost expenses associated withclaims, and 20% of its pharmacyspending. Among the various tumortypes, breast cancer is the most costly.

A Business Perspective

on Best Practices

Quality of care, economics, cost, andemployee productivity are the keyissues and concerns that make cancermanagement a top priority at Delta,Ms Zonakis said.

Elaborating on these issues, shenoted that reducing variations in prac-tice and pathology testing is importantfor high quality of care. With regard tocost, Delta is interested in monitoringtrends, minimizing perverse incen-tives for providers (eg, reimbursementlinked to drug use, use of futile thera-py), and reducing off-label drug use.

Even from a business perspective,Ms Zonakis said, employee productiv-ity suffers as patients or caregivers losetime from work, develop secondarydepression, and have trouble navigat-ing the medical system. Therefore,employers have a stake at providingemployees access to the best care pos-sible, including cancer care, at the low-est cost.

Delta’s Oncology Initiatives

and Cancer Network

Oncology management “starts withprevention,” she said. “Long beforethe Affordable Care Act, we beganpaying 100% for all preventive servic-es that are recommended by the USPreventive Services Task Force, and inmany cases we go beyond the recom-mendations.”

Care given at a National Compre -hensive Cancer Network (NCCN)

Center of Excellence is covered 100%after the deductible is met, and Deltapays for travel and lodging expenses aswell. “The Centers of Excellence are animportant program of ours. There arerare cancers that call for specializedexpertise, and we want to removeaccess barriers for our members. Wehave some great success stories fromemployees who have taken advantageof this.”

Delta also has comprehensive caremanagement and cancer-specific caremanagement programs that are staffedby dedicated oncology nurses; em -ployee assistance and behavior healthprograms; and pharmacy benefit man-agement strategies for oral agents,injectables, and infusions.

Ms Zonakis was most excited about

cancer programs that are under way at Delta, especially the “high-perfor-mance cancer networks,” which arebeing piloted in communities wheremost cancer care is delivered. Thegoals of these programs are to:• Supplement the NCCN Centers of

Excellence, by identifying qualityproviders at the local and regionallevels

• Collect practice and outcomes dataand measure results

• Establish pay-for-performance (PFP)standards to reward providers forreaching various evidence-basedgoals.“We must start solving the problems

of lack of performance data and prac-tice variation at the local and commu-nity levels,” Ms Zonakis said, andthese networks should help to do that.

Management Support

Delta’s cancer program will alsoinclude day 1 referrals into a cancersupport program and access to NCCNpatient resources. “We want the pro-

gram to have early referral for casemanagement support before thepatient’s course is set,” Ms Zonakispointed out.

The initial rollout is in Atlanta, GA,and Minneapolis-St Paul, MN. If theprogram proves robust enough, Deltamay establish a closed network of preferred oncology providers, MsZonakis noted.

In addition, under way is a jointproject of the National Business Groupon Health and the NCCN that aims toidentify ways to assist employers incancer-related benefit design and toimprove the second-opinion referralprocess.

Within this are efforts to enhanceemployee communications (to rein-force the importance of healthy behav-iors and early detection and to offertools to manage cancer care) encour-age appropriate palliative treatmentand use of hospice, and to use onsiteprimary care for prevention and earlydetection of cancer.

Pay-for-Performance Program

in Oncology

To participate in the PFP oncologyprogram, providers must agree to bemeasured and evaluated, and theymust strive to practice the best evi-dence-based medicine. The NCCNguidelines and compendium will beused, but the aim is to further refinethese guidelines and encourage physi-

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

A portion of physician reimburse-ment will be linked to evidence-based goals, and these goals will berevised annually. The initial focus ison overtreatment of bony metastasisand overuse of radiotherapy inpatients with breast cancer, MsZonakis said. �

Oncology management“starts with prevention. Longbefore the Affordable CareAct, we began paying 100%for all preventive servicesthat are recommended bythe US Preventive ServicesTask Force, and in many cases we go beyond therecommendations.”

—Lynn Zonakis

“The Centers of Excellence are an importantprogram of ours. There are rare cancers thatcall for specialized expertise, and we want toremove access barriers for our members. Wehave some great success stories from

employees who have taken advantage of this.”—Lynn Zonakis


2012 Conference

Houston, TX—Employers’ health planmanagers must “balance members’access to new treatments with the fis-cal responsibility of managing thehealthcare financial resources wisely,”said Bridget Eber, PharmD, SeniorConsultant and Clinical Lead of RxGroup Purchasing, Towers Watson, atthe 2012 Second Annual Associationfor Value-Based Cancer Care Con -ference. Towers Watson’s clients in -clude 175 employers with self-fundedbenefits programs totaling $3 billion inannual drug spending.

“That means not wasting resourceson unnecessary, unproven, and costlynew treatments, while at the sametime avoiding barriers for effectiveand potentially life-saving treat-ments,” said Dr Eber.

In the past, employers and healthplans hesitated to manage oncologycosts, because of political sensitivitiesaround the issues. A good example isthe use of high-dose chemotherapy,followed by autologous bone marrowtransplant, which in the early 1990swas considered a promising therapyfor breast cancer. Although the treat-ment was not proved effective, thelegal and political climate at the timeresulted in almost universal coverageof that approach by health plans. Bythe time published studies showedthat this therapy was ineffective, morethan 30,000 women had received bonemarrow transplants, which shortenedthe lives and worsened the quality oflife of many women.

“As a result of this compassionatecoverage policy, the healthcare systemincurred over $1.5 billion in costs,” DrEber noted. “This was the worst of all

scenarios, and is an example of howthe obligation to make benefits avail-able can generate some unwanted consequences.”

Drug Utilization and Costs

Of the $3 billion in total annual drugspending within Dr Eber’s clients’health plans, approximately $70 mil-lion goes toward medications man-aged within the specialty pharmacy.

Specialty pharmacy drugs representless than 0.5% of all drug utilization inthese plans, but these medications areassociated with 19% of all coveredcharges.

Cancer-related drugs—the thirdhighest driver of specialty pharmacyutilization (after autoimmune diseasesand multiple sclerosis)—account forless than 0.05% of drug utilization, butare responsible for approximately2.5% of covered charges within spe-cialty pharmacy. Although these arerelatively low utilization rates, special-ty drugs are associated with exception-ally high costs, according to Dr Eber.

Cancer Drugs

In each clinical area, a few medica-tions drive most of the utili zation andcosts. In oncology, 50% of drug utili -zation and costs are for imatinib(Gleevec), leuprolide acetate for depotsuspension (Lupron Depot), lenalido-mide (Revlimid), and capecitabine(Xeloda). Overall, 10 cancer drugs rep-resent approximately 80% of all drugutilization and 75% of all drug costs.

“Employers know the main driversof utilization among their members, sowhen employers are looking for a corestrategy or the most essential areas tofocus upon, we try to help them recog-nize the low-hanging fruit,” said Dr Eber.

Critical Need for Data

Clinical utilization data have beendifficult to come by, creating a handi-cap for benefit consultants who designstrategies for employers. However,data are increasingly becoming avail-able, with better documentation ofprior authorization, step therapy, andquantity limits. “We are getting somesense of activity, approval and denialrates, appeal rates, and reversal rates,”stated Dr Eber.

These data show that much of thecost-saving stems from using therapyonly as indicated and denying cover-age when treatment efficacy has notbeen established. The data also indi-cate that appeals often lead to rever-sals, probably because physicians pro-vide more information or have directcontact with a representative.

Dr Eber noted that of a total of 120appeals from providers in the RxCollaborative program (an employercoalition for purchasing pharmacybenefit manager [PBM] services), 107appeals were reversed, based on arecent analysis.

Employers Depend on Prior

Authorization to Control Utilization

In contrast with the historical para-digm of coverage decisions of notinterfering with a physician’s choice,the current paradigm of many plans isto restrict access to treatments that arenot proved, largely with the use ofprior authorization.

Bevacizumab (Avastin) coveragedenial several years ago is an exampleof this newer strategy, which prevent-ed spending on unnecessary or un -proved therapy. Based on safety andefficacy in several tumor sites, clini-cians believed that bevacizumab couldimprove outcomes in patients withpancreatic cancer when added to astandard regimen, and wanted to usethis approach.

However, the drug’s high costforced most PBMs to be rigorous withtheir prior authorization processes andto typically deny coverage for thatapproach, for lack of evidence for ben-efit. Then, in 2008, an efficacy studyfailed to show a survival advantage forbevacizumab in patients with pancre-atic cancer.

“Approximately 40,000 new cases ofpancreatic cancer occur each year, andif doctors had routinely added Avastinto standard regimens based solely ontheories, the additional cost wouldhave been $1 billion to $2 billion,” DrEber emphasized. Employers, how -ever, recognize that evidence andstrong rationale need to support priorauthorization and coverage denials,she noted.

To ensure that employers are strik-ing the right balance between advocat-ing for their members and being fiscal-ly responsible, she offers a checklist ofissues for employers to consider beforeembarking on a specialty drug cover-age program (Table). This list outlinesthe questions that are important toconsider when looking for a benefitdesign for specialty drugs. �

Table 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? √

The current paradigm of many plans is to restrict access to treatmentsthat are not proved, largelywith the use of priorauthorization.

In the 1990s, despite lack ofevidence for its efficacy,bone marrow transplant forbreast cancer was covered byall health plans, and “thehealthcare system incurredover $1.5 billion in costs.This…is an example of howthe obligation to makebenefits available cangenerate some unwantedconsequences.”

—Bridget Eber, PharmD

Employers’ Challenge: Cut Healthcare CostsWithout Limiting Employees’ BenefitsClinical evidence supports prior authorization paradigm By Caroline Helwick

©2012 Millennium Pharmaceuticals, Inc. All rights reserved.

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2012 Conference


Houston, TX—Most employers donot understand biologics and special-ty pharmacy well enough to use ser -vices appropriately and to takeadvantage of their benefits, said F.Randy Vogenberg, RPh, PhD,Principal, Insti tute for IntegratedHealthcare, Sharon, MA, an employerbenefit consulting company.

Speaking at the Second AnnualAssociation for Value-Based CancerCare Conference, Dr Vogenberg drewfrom a recent survey of employers tosuggest actions that need to be taken tobetter integrate healthcare stakeholders.

In 2011, the Midwest BusinessGroup on Health (MBGH), whichevaluates issues from an employerpoint of view, saw a growing lack of understanding among employersregarding biologics and specialtypharmacy. A significant part of anyhealth plan, biologics and specialtypharmacy currently account for ap -proximately 25% of today’s spendingbut are projected to represent 50% by2030; the average annual per-user costtoday is $12,500.

With product growth within biolog-ics and specialty pharmacy anticipatedto be a top concern, MBGH partneredwith Dr Vogenberg on research thatwould help employers to understandthe role of biologics and specialtypharmacy, to prepare for challenges, tomanage benefits through plan designinnovation and partnering with spe-cialty vendors in contracting andpatient management, to better managethe at-risk population, and to more

effectively communicate specialty ben-efits to employees.

Part of the difficulty, said DrVogenberg, is the lack of a single, stan-dard definition of biologics and spe-cialty pharmacy. Additional challengesare posed by the existence of variousdelivery channels, sites of care, the US Food and Drug Administrationrequirements, and reimbursementschemes, and by innovations in formu-lations, drug delivery systems, and

companion diagnostics—all contribut-ing to cost and to the dilemma ofdetermining what benefits are appro-priate for employees.

National Employer Survey

on Biologics

The MBGH’s National EmployerSurvey on biologics and specialty

pharmacy, in which 120 nationalemployers participated, revealed that: • In the past 5 years, specialty drug

plan spending rose by more than15%, several times more than theoverall drug trend

• Employers are unaware of theirspending on biologics and whetherthat spending is effective

• Employers are unsure how todesign appropriate benefits regard-ing biologics, and how to effectivelycommunicate this information totheir employees.More than 50% of the participating

employers indicated that their level ofunderstanding of specialty pharmacyis “low.” This low level of understand-ing was much more likely to be report-ed by very small companies (<500employees), whereas the greatestunderstanding was observed amongvery large companies (>25,000 em -ployees), possibly because large com-panies get more support from benefitadvisors. “Still, we saw a significantlack of understanding of the wholearea,” Dr Vogenberg said.

Based on this survey, more than 66%of employers offer case managementservices, disease management, or drugutilization management. Benefits andservices provided around specialtypharmacy, for the most part, rely onpharmacy benefit managers (PBMs),he said. “This linkage, taking tradi-tional pharmacy management andapplying it to specialty pharmacy, isthe standard in the marketplace, and itis probably not the appropriate way to spend resources, time, and moneyin managing these categories,” DrVogenberg suggested.

In addition, more than 50% of em -ployers require that employees use spe-cialty pharmacy to receive coverage, but75% offer no incentives for doing so.

The survey also sought to determinewhat employers consider importantwhen contracting with biologics andspecialty pharmacy vendors (Figure).The majority of respondents consider

vendor cost to be a critical factor.“They said they could not differen-

tiate between Plan A versus Plan B, orPBM A versus PBM B, based on per-formance, so they look at cost whenmaking decisions,” Dr Vogenbergsaid about the employers who weresurveyed.

“This survey suggests that employ-ers have not moved away from tradi-tional benefit designs to take advantageof the benefits that specialty pharmacyvendors could provide,” he observed.“And it suggests there is a need to closethe knowledge gap regarding health-care benefits coverage, spending, andcosts, to identify potential improve-ments to benefit strategies, and to shiftcoverage decisions to better benefitemployers and their employees.”

Action Points

Dr Vogenberg suggests “key themesfor action” for tightening the dis -tance between employers and themanagement of biologics and special-ty pharmacy: • Fill in gaps in understanding cancer

related benefit coverage, spending,and the total cost of healthcare forself-funded plans

• Determine key areas of utilizationtrends that are important to anemployer organization and theorganization’s success as a business

• Identify short- and longer-term op -portunities for improving benefitstrategies or the use of support re -sources as part of a holistic approach

• Choose how best to optimize bene-fit spending based on technologytrends

• Use knowledge gained in cancercare to incrementally shift benefitdecisions and press for changes,such as benefit design and insur-ance innovation.“Cancer is a good opportunity and

starting point for employers aroundbiologics, and experience gained herecan be leveraged into other therapeu-tic areas,” Dr Vogenberg said. �

Level of Importance for Key Areas When Contracting with Biologics andSpecialty Pharmacy Vendors

Figure

“This linkage, takingtraditional pharmacymanagement and applying itto specialty pharmacy, is thestandard in the marketplace,and it is probably not theappropriate way to spendresources, time, and moneyin managing thesecategories.”

—F. Randy Vogenberg, RPh, PhD

Very important Important Somewhat important Not important Don’t know

100%

80%

60%

40%

20%

0%Special

distributionrequirementsfor biologics &

specialty pharmacy

Utilization of aspecialty pharmacy

Prior approvaland/or steptherapy editsfor claimapproval

Patient supportand care

managementare provided

Vendor costs

2935

45

6058

25

31

18

24

4 18

7

9 12

5

10

28

2327

45

47

66

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

“There is a need to close the knowledgegap regarding healthcare benefitscoverage, spending, and costs, toidentify potential improvements tobenefit strategies, and to shift coveragedecisions to better benefit employersand their employees.”

—F. Randy Vogenberg, RPh, PhD

To Many Employers, Specialty Pharmacy Is a Vague ConceptBy Caroline Helwick

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T Check

M

Drug Update

Abraxane Receives New Indication for Locally Advancedor Metastatic Non–Small-Cell Lung Cancer, inCombination with Carboplatin, in Patients Who Are NotCandidates for Curative Surgery or Radiation TherapyBy Lynne Lederman, PhD, Medical Writer


For the purposes of treatment,lung cancer is classified as non–small cell, which accounts for

approximately 85% of cases, or assmall cell, representing 14% of cases.1

Non–small-cell lung cancer (NSCLC)is the leading cause of death world-wide.2 The greatest risk factor forlung cancer is cigarette smoking.Other risk factors include smokingpipes or cigars and exposure to agentssuch as radon gas, secondhandsmoke, asbes tos, chromium, cadmi-um, arsenic, some organic chemicals,radiation, and air pollution. The rateof lung cancer may be increased inindividuals with a history of tubercu-losis or a genetic susceptibility to the disease.1,3

The Burden and Impact

of Lung Cancer

In 2012, the American CancerSociety estimated there would be226,160 individuals with new cases oflung cancer, representing approxi-mately 14% of all cancer diagnoses,and 160,340 deaths from lung cancer inthe United States, which is approxi-mately 28% of all cancer deaths.1

Lung cancer is the second leadingcause of new cases of cancer (otherthan nonmelanoma skin cancer ornoninvasive cancers other than blad-der cancer) in both men and women inthe United States, and the leading

cause of death for both sexes.1

The likelihood of developing lungcancer increases with age.1 Althoughthe rate of lung cancer has beendecreasing in men over the past 20years, it has only recently starteddecreasing in women. Sex differencesin the incidence of lung cancer and indeath rates are a result of historic ratesof smoking and smoking cessation inmen and women over the past 50years.4

Lung cancer is usually diagnosed atlater stages and is rarely cured.4

Symptoms can include persistentcough, blood-tinged sputum, chestpain, change in the voice, and recur-rent pneumonia or bronchitis.1 Medianage at diagnosis is age 70 years formen and age 71 years for women.5

Annual chest x-rays do not decrease

mortality from lung cancer. Althougha screening trial using low-dose spiralcomputed tomography reduced thedeath rate by 20% for high-risk indi-viduals (ie, current and former heavysmokers), it is not known if this tech-nology is applicable for screening ofthose with less cigarette exposure. Therisks of screening include cumulativeradiation exposure and unnecessarybiopsies and surgery.1

The 1-year relative survival forpatients with lung cancer—which hasbeen increasing over the past severaldecades as a result of better surgicaltechniques and combination thera-pies—was 43% in the period between2003 and 2006.1 The 5-year survivalrate for all stages of lung cancer com-bined is only 16%. Early detection atthe localized stage results in a 5-yearsurvival rate of 52%, but localized lungcancer represents only 15% of all cases.The overall 5-year survival for NSCLCis 17%,1 but the 5-year survival rate forstage IV NSCLC is only 1%.6

Current Treatments for

Lung Cancer

The current treatments for lung can-cer are based on the type and stage ofthe tumor, and include surgery, radia-tion therapy, chemotherapy, and tar-geted therapies, such as bevacizumab,erlotinib, or crizotinib.1,3 Surgery is themost common treatment choice for

localized NSCLC (stage I or stage II).3

Chemotherapy after surgery usuallyimproves survival. However, NSCLCis usually diagnosed at a more ad -vanced stage, and treatment often in -cludes radiation therapy and chemo -therapy, which can be combined with sur gery. Patients with advancedNSCLC usually receive chemotherapy,targeted therapy, or both.1 Platinum-based regimens are recommended forpatients with stage IV NSCLC.3 Al -though many combinations of newagents have been tested in patientswith advanced, inoperable NSCLC,their prognosis is still poor, suggestinga need for new therapeutic options.3

Abraxane Receives a New

Indication for NSCLC

On October 11, 2012, paclitaxel pro-tein-bound particles for injectable sus-pension (Abraxane for InjectableSuspension), an albumin-bound formof paclitaxel, was approved for thefirst-line treatment of locally advancedor metastatic NSCLC in combinationwith carboplatin in patients who arenot candidates for curative surgery orradiation therapy.7-9

Abraxane is a nanoparticle protein-bound paclitaxel, which may thereforealso be referred to as nab-paclitaxel.6

Abraxane is already indicated forthe treatment of breast cancer after fail-ure of combination chemotherapy formetastatic disease or for relapse within6 months of adjuvant chemotherapy.Prior therapy should have included an anthracycline unless clinically contraindicated.8

The new indication for NSCLC wasbased on a clinical trial comparingweekly infusions of Abraxane at adose of 100 mg/m2 (ITT [intention totreat], n = 521) to infusions of paclitax-el every 3 weeks at a dose of 200mg/m2 (ITT, n = 531). All patients alsoreceived carboplatin (AUC [areaunder the curve], 6 mg•min/mL)every 3 weeks.6,9 The study design andresults are described in detail below.

Clinical Pharmacology:

Development and Mechanism

of Action

Abraxane is an albumin-bound formof paclitaxel, the active component.

Table 1 Baseline Demographics and Disease Characteristics in the Phase 3 NSCLC Trial, ITT Population

CharacteristicAbraxane(N = 521)

Paclitaxel(N = 531)

All patients(N = 1052)

Median age, yrs 60 60 60

Male, % 75 75 75

Female, % 25 25 25

Asian/black/white/Hispanic/other, % 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

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 paclitaxelplus 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.


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

Drug Update


Abraxane has a mean particle size ofapproximately 130 nm.8,10 Abraxanedoes not contain any solvents orethanol. The 130-nm particle size willnot obstruct capillaries when the agentis delivered by intravenous (IV) infu-sion.10 Abraxane was developed toavoid toxicities associated with thevehicle polyoxyethylated castor oil(Cremophor EL), which is used todeliver paclitaxel because of its poorsolubility.10,11

Paclitaxel is contraindicated in pa -tients with a history of hypersensitivi-ty reactions to the drug itself or toother drugs formulated in polyoxy -ethylated castor oil. Patients receivingpaclitaxel require pretreatment withcor ticosteroids, diphenhydramine, andH2 antagonists to avoid hypersensitiv-ity reactions.12 Severe hypersensitivityreactions that re quired treatmentoccurred in 2% to 4% of patientsreceiving paclitaxel in clinical trials,and some of these reactions were fatal,despite premedication.12

Unlike paclitaxel, Abraxane doesnot require premedication and can beinfused over a shorter period oftime.8,12 Abraxane was also designed toincrease intratumor concentrations ofthe active drug using endogenousalbumin pathways.11

The mechanism of action of Abrax -ane is microtubule inhibition, the sameas that of paclitaxel. Abraxane pro-motes the assembly of microtubulesfrom tubulin dimers and stabilizesthese microtubules, by preventingdepolymerization. This stabilizationprevents microtubules from reorganiz-ing properly and from maintainingtheir normal structure during mitosis,thereby inhibiting cancer-cell division,motility, and intracellular transport.8,10

Phase 3 Clinical Trial in Locally

Advanced or Metastatic NSCLC

The new indication for Abraxane asfirst-line treatment of locally advancedor metastatic NSCLC, in combinationwith carboplatin in patients who arenot candidates for curative surgery orfor radiation therapy, was approvedon the basis of one phase 3 clinicaltrial, showing significantly improvedoverall response rates (ORRs) in allpatients receiving Abraxane, regard-less of histology results.6,7,9

Trial DesignThis randomized, multicenter, open-

label phase 3 trial compared the effica-cy and safety of Abraxane plus carbo-platin with that of solvent-basedpaclitaxel (paclitaxel injection) plus

carboplatin as first-line systemic treat-ment in patients with locally advanced(stage IIIB) or metastatic (stage IV)NSCLC. A total of 1052 patients wererandomly assigned in a 1:1 ratio toreceive weekly 30-minute infusions of Abraxane 100 mg/m2 or 3-hourinfusions of paclitaxel 200 mg/m2

after premedication every 3 weeks. All patients also received IV carbo-platin (AUC, 6 mg•min/mL) every 3weeks after infusion with Abraxane orpaclitaxel. The primary objective wasORR.6,8

Patient Population Key baseline demographic and dis-

ease characteristics of the enrolledpatients are listed in Table 1. The 2treatment groups were well-balanced.6

Safety ProfileAdverse reactions (ie, safety) were

assessed in the 514 patients whoreceived Abraxane plus carboplatin,and in the 524 patients who receivedpaclitaxel injection plus carboplatin.6,8

The median number of treatment

cycles was 6 for each treatment group.The doses and schedules for the 2treatment groups were different; therefore, direct dose-dependent andschedule-dependent comparisons con-cerning safety cannot be made.8 Thead verse reactions seen most frequently

(≥10% incidence) for the patients re -ceiving Abraxane plus carboplatin arelisted in Table 2.8 These commonadverse reactions occurred at a similarincidence in the paclitaxel injectionplus carboplatin–treated patients.

Common (≥10% Incidence) Adverse Reactions in Patients ReceivingAbraxane plus Carboplatin

Adverse reactionIncidence, %(N = 514)

Alopecia 56

Nausea 27

Fatigue 25

Decreased appetite 17

Asthenia 16

Constipation 16

Diarrhea 15

Vomiting 12

Dyspnea 12

Rash 10

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

Table 2

Table 3 Selected Hematologic Toxicities between Treatment Groups

Abraxane (100 mg/m2 weekly)plus carboplatin

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

Grades 1-4, % Grades 3-4, % Grades 1-4, % Grades 3-4, %

Anemiaa,b 98 28 91 7

Neutropeniaa,c 85 47 83 58

Thrombocytopeniaa,c 68 18 55 9

a508 patients assessed in the Abraxane plus carboplatin-treated group.b514 patients assessed in the paclitaxel injection plus carboplatin-treated group.c513 patients assessed in the paclitaxel injection plus carboplatin-treated group.Adapted from Abraxane for Injectable Suspension [package insert]. Summit, NJ: Celgene Corporation; October 2012.

Table 4 Selected Nonhematologic Toxicities between Treatment Groups

System organ class

MedDRA v 12.1preferred term

Abraxane (100 mg/m2 weekly) pluscarboplatin (N = 514)

Paclitaxel injection (200 mg/m2 every3 weeks) plus carboplatin (N = 524)

Grades 1-4, % Grades 3-4, % Grades 1-4, % Grades 3-4, %

Nervous systemdisorders

Peripheral neuropathya 48 3 64 12

General disorders,administration-siteconditions

Edema, peripheral

10 0 4 <1

Respiratory thoracic and medi-astinal disorders

Epistaxis 7 0 2 0

Musculoskeletal,connective-tissuedisorders

Arthralgia 13 <1 25 2

Myalgia 10 <1 19 2

aPeripheral 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.


Drug Update


Abraxane Receives New Indication for Locally Advanced orMetastatic NSCLC... Continued from page 37

The frequency and severity of hema-tologic abnormalities occurring with adifference of ≥5% for all grades (grades1-4) or ≥2% for grade 3 and 4 toxicitiesfor the 2 treatment groups are listed inTable 3.8 Only 1% of patients in eacharm developed febrile neutropenia,and 1 treatment-related death wasreported in each arm.6 Thrombo -cytopenia and anemia associated withAbraxane plus carboplatin were readi-ly manageable.6

The frequency and severity of non-hematologic adverse reactions occur-ring with a difference of ≥5% for allgrades (grades 1-4) or ≥2% for grade 3and 4 toxicities between the 2 treat-ment groups are listed in Table 4.8 Theincidences of severe neuropathy, myal-gia, and arthralgia were lower in theAbraxane plus carboplatin group.6

In the Abraxane plus carboplatin–treated group, 17 of 514 (3%) patientsdeveloped grade 3 peripheral neuropa-thy (PN), and none developed grade 4PN. In 10 (59%) of these patients, thegrade 3 neuropathy resolved orimproved to grade 1 after interruptionor discontinuation of Abraxane.8

Median time to improvement of grades3 or 4 sensory neuropathy was shorter(38 days) for patients in the Abraxaneplus carboplatin group than the mediantime (104 days) for those in the paclitax-el injection plus carboplatin group.6

ResponseThe trial met its primary end point.9

The ORR was significantly higher inthe Abraxane plus carboplatin groupthan in the paclitaxel injection pluscarboplatin group (33% vs 25%, re -

spectively; P = .005). No significant dif-ference was found in overall survivalbetween the 2 treatment groups.8 Theefficacy results are summarized inTable 5.

Dosing and Administration

Unlike paclitaxel, Abraxane doesnot require premedication.8 The rec-ommended dose of Abraxane forpatients with NSCLC is 100 mg/m2,which is administered as an IV infu-sion over 30 minutes on days 1, 8, and15 of each 21-day cycle. The recom-

mended dose of carboplatin is AUC 6 mg•min/mL on day 1 only of each21-day cycle, beginning immediatelyafter administration of Abraxane iscompleted.8

Dose ModificationsDose modifications are not required

for patients with mild hepatic impair-ment (AST [aspartate aminotrans-ferase] <10 times the upper limit ofnormal [ULN], or bilirubin up to 1.25times ULN). Abraxane should not beadministered to patients with AST >10times ULN or bilirubin >5 times ULN.The starting doses for patients withNSCLC who have moderate hepaticimpairment (AST <10 times ULN andbilirubin 1.26-2 times ULN) or severehepatic impairment (AST <10 timesULN and bilirubin 2.01-5 times ULN)should be reduced to 75 mg/m2 or to50 mg/m2, respectively. Subsequent doseincreases or adjustments should bebased on individual tolerance.8

Patients with NSCLC should notreceive Abraxane on day 1 of a cycle ifthey do not have an absolute neutro philcount (ANC) of ≥1500 cells/mm3 andplatelet counts of ≥100,000 cells/ mm3.Treatment should be withheld untilcounts reach these levels on day 1 oruntil ANC is ≥500 cells/mm3 andplatelet counts are ≥50,000 cells/mm3

on days 8 and 15 of a cycle. Abraxaneshould be withheld for grades 3 or 4 PN.

Permanent modifications to Abrax -ane and to carboplatin doses arerequired when treatment is resumedafter neutropenia, neutropenic fever,thrombocytopenia, or PN.8 These dosereductions are summarized in Table 6.

Warnings and Precautions

Boxed WarningThe prescribing information for

Abraxane contains a Boxed Warningconcerning neutropenia. The BoxedWarning states the following8:• Do not administer Abraxane thera-

py to patients who have baselineneutrophil counts of <1500 cells/mm3; to monitor the occurrence ofbone marrow suppression, primari-ly neutropenia, which may be severeand may result in infection, it is rec-ommended that frequent peripheralblood cell counts be performed onall patients receiving Abraxane

• An albumin form of paclitaxel maysubstantially affect a drug’s func-tional properties relative to thoseof drug in solution. Do NOT sub-stitute for or with other paclitaxelformulations.

Table 5 Efficacy Results from the Phase 3 NSCLC Trial, ITT Population

Abraxane (100 mg/m2 weekly) pluscarboplatin (N = 521)

Paclitaxel injection (200 mg/m2 every3 weeks) plus carboplatin (N = 531)

Overall response rate

Confirmed complete or partial overall response, N (%)

170 (33) 132 (25)

95% CI 28.6-36.7 21.2-28.5

P value (chi-square test) .005

Median DoR in months (95% CI) 6.9 (5.6-8.0) 6.0 (5.6-7.1)

Overall response rate, by histology

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%)

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.

Table 6 Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC

Adverse drug reaction OccurrenceWeekly Abraxane dose,

mg/m2Every 3-week carboplatindose, AUC mg•min/mL

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

First 75 4.5

Second 50 3

Third Discontinue treatment

Platelet count <50,000/mm3First 75 4.5

Second Discontinue treatment

Severe sensory neuropathy, grade 3or 4

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.

Unlike paclitaxel, Abraxane does not require premedication.


NOWAVAILABLE

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

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CONFERENCE CO-CHAIRS

May 2-5, 2013 • Westin Diplomat • Hollywood, Florida

Craig K. Deligdish, MDHematologist/OncologistOncology Resource Networks

Gary M. Owens, MDPresidentGary Owens Associates

Burt Zweigenhaft, BSPresident and CEOOncoMed

THURSDAY, MAY 2, 20138:00 am - 5:00 pm Registration

FRIDAY, MAY 3, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am Session 1: Welcome, Introductions, and Opening RemarksConference 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

10:30 am - 11:45 am Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder CollaborationsRoy 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

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 CareF. 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 CareJayson Slotnick, JD, MPH

5:15 pm - 5:45 pm Summary/Wrap-Up of Day 1

6:00 pm - 8:00 pm Cocktail Reception in the Exhibit Hall

SATURDAY, MAY 4, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 8:30 am Opening Remarks

8:30 am - 9:15 am Session 8: Advanced Care Directives: Palliative Care, Hospice, EthicsJ. Russell Hoverman, MD, PhDThomas J. Smith, MD, FACP, FASCO

9:15 am - 10:00 am Session 9: Medicaid: A Healthcare Delivery System ReviewMatthew Brow

10:00 am - 10:15 am Break

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 IssuesPat 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 PropositionMark 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

SUNDAY, MAY 5, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 8:30 am Opening Remarks

8:30 am - 9:15 am Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship CareJulie Silver, MD

9:15 am - 10:00 am Session 15: Current and Future Considerations for the Oncology Practice ManagerDawn 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, BiosimilarsDouglas 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

*Agenda is subject to change.

PROGRAM OVERVIEWFollowing on the success of our Second Annual Conference, AVBCC will be comingto Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise ofleaders in these fields providing at tendees with a thorough understanding of the evo-lution of the value equation as it relates to cancer therapies. Our goal is to be able toassist them in implementing, improving, and sustaining their organizations and institu-tions, while improving access for patients and ultimately quality patient care.

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

SPONSORSThis activity is jointly sponsored by Medical Learning Institute Inc, the Association forValue-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core PrincipleSolutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENTGrant requests are currently being reviewed by numerous supporters. Support will beacknowledged prior to the start of the educational activities.

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

REGISTERED PHARMACY DESIGNATIONThe Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Comple-tion 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 activityis (To be determined).

PHYSICIAN CREDIT DESIGNATIONThe Medical Learning Institute Inc designates this live activity for a maximum of 17.25AMA PRA Category 1 Credits™. Physicians should claim only the credit commensuratewith the extent of their participation in the activity. This activity has been planned andimplemented in accordance with the Essential Areas and policies of the AccreditationCouncil for Continuing Medical Education through the joint sponsorship of the MedicalLearning Institute Inc and the Center of Excellence Media, LLC. The Medical LearningInstitute Inc is accredited by the Accreditation Council for Continuing Medical Educa-tion to provide continuing medical education for physicians.

DESIGNATION OF CREDIT STATEMENTS

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

• Define the barriers associated with cost, quality, and access as they relate to health-care 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.

CONFERENCE REGISTRATIONDiscounted Pricing Available!

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

Influencing the Patient-Impact Factor

THIRD ANNUALAssociation for Value-Based Cancer Care Conference

www.regonline.com/avbcc2013REGISTER TODAY AT

AGENDA*

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Drug Update


Abraxane Receives New Indication for Locally Advanced orMetastatic NSCLC... Continued from page 38

Other warnings, precautions, and con-traindications for Abraxane in clude8: • Abraxane is contraindicated in

patients with neutrophil counts of<1500 cells/mm3

• Patients who experience a severehy persensitivity reaction to Abrax -ane should not be rechallenged withthe drug

• Abraxane causes myelosuppression;complete blood counts should be mon -itored and doses reduced as needed

• Sensory neuropathy is a frequentadverse event and may require dosereduction or treatment interruption

• Severe, fatal hypersensitivity reac-tions have been reported; do notrechallenge patients with Abraxane

• Hepatic impairment can increaseexposure and toxicity of paclitaxel;Abraxane should be administeredwith caution in patients with hepaticimpairment

• Abraxane contains albumin derivedfrom human blood, which has a the-oretical risk of viral transmission

• Abraxane may cause fetal harmwhen administered to pregnantwomen; women of childbearing ageshould avoid becoming pregnantwhile receiving Abraxane

• Men should be advised not to fathera child while receiving Abraxane.

Conclusion

NSCLC is the most common type oflung cancer, which is the leading causeof cancer-related mortality in theUnited States. There have not beenmany new treatment options ap -proved for NSCLC. The approval ofAbraxane for the treatment of NSCLCoffers a new treatment option for allpatients with this type of malignancywhose treatment options are limited,especially those who are not candi-dates for curative surgery or for radia-tion therapy. �

References1. American Cancer Society. Cancer Facts & Figures2012. 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 beva -cizumab in the treatment of non-small cell lung cancer(NSCLC). Clinicoecon Outcomes Res. 2012;24:201-208.3. National Comprehensive Cancer Network. NCCNClinical Practice Guidelines in Oncology. Non–small-cell lung cancer. Version 2.2012. www.nccn.org.Accessed October 29, 2012.4.Vera-Llonch M, Weycker D, Glass A, et al. Health carecosts in patients with metastatic lung cancer re ceivingchemotherapy. BMC Health Serv Res. 2011;11:305-312.5.American Cancer Society. Cancer Treatment and Sur -vivorship Facts & Figures 2012-2013. Atlanta, GA:American Cancer Society; 2012.6. Socinski MA, Bonderenko I, Karaseva NA, et al.Week ly nab-paclitaxel in combination with carbo-platin versus solvent-based paclitaxel plus carboplatinas first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial.J Clin Oncol. 2012;30:2055-2062.7. Celgene Corporation. FDA approves ABRAXANE®

for the first-line treatment of advanced non-small celllung 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 pro-tein-bound particles for injectable suspension) (albu-min-bound) [packet insert]. Summit, NJ: CelgeneCorporation; October 2012.

9. US Food and Drug Administration. Drugs. Pac -litaxel (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 antitumoractivity, intratumor paclitaxel concentrations, andendothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cre-

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 formof paclitaxel for the treatment of advanced non-small-cell lung cancer. Ann Oncol. 2006;17:1263-1268.12. Taxol (paclitaxel) injection [packet insert]. Prince -ton, NJ: Bristol-Myers Squibb Corporation; April 2011.

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1 Session 11: National Coalition for Cancer Survivorship: Medication N

Summary and Conclusion of Conference

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CONTINUING EDUCATION

CONSIDERATIONS inMultiple Myeloma™5th Annual

ASK THE EXPERTS: Retreatment Settings

Jeffrey Wolf, MDClinical ProfessorDepartment of Medicine, UCSFDirector, Myeloma Program UCSF Helen DillerFamily Comprehensive Cancer CenterSan Francisco, CA

Jennifer Knoche, RN, BSNLead Practice NurseUCSF Hematology/BMT AmbulatoryCare CenterSan Francisco, CA

Helen T. Wu, PharmD, BCOPClinical PharmacistAdult Hematology/Oncology and Health SciencesAssociate Clinical Professor School of Pharmacy, UCSFSan Francisco, CA

Supported by educational grants from Celgene Corporation andMillennium: The Takeda Oncology Company.

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LETTER FROM THE EDITOR-IN-CHIEF

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

In this fifth annual “Considerations in Multiple Myeloma” newsletter series, we continue to address frequently askedquestions related to the diagnosis and treatment of the disease. To provide an interprofessional perspective, questionsare answered by physicians, nurses, and pharmacists from leading cancer institutions, who share their insight, knowl-edge, and professional experience regarding evidence-based care. In this fourth issue, experts from the University ofCalifornia, San Francisco answer questions pertaining to the management of patients in the retreatment setting.

Sincerely,

Sagar Lonial, MDProfessorVice Chair of Clinical AffairsDepartment of Hematology and Medical OncologyWinship Cancer InstituteEmory University School of MedicineAtlanta, GA

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

FACULTY

NOVEMBER 2012 • VOLUME 5 • NUMBER 4

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CONSIDERATIONS IN MULTIPLE MYELOMA

IntroductionNovel agents and regimens have greatly improved the manage-

ment of multiple myeloma (MM). However, the retreatment setting

remains complex, since many patients have already received nu -

merous therapies at the time of disease progression. The result can

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 youconsider in choosing retreatment with previously used therapyversus treatment with different agents?

Because first-line therapy for MM often involves several different combi-nations,1 choosing second-line therapy can be a challenge. In the setting ofinitial treatment, we are using doublet and triplet combinations that mayinclude bortezomib, lenalidomide, cyclophosphamide, or dexamethasone.

Eligible patients advance to autologous stem cell transplantation (ASCT)following this therapy. More and more patients receive maintenance thera-py, either with lenalidomide or bortez omib. Therefore, when patients re -lapse, they have already re ceived quite a bit of therapy. The choice of treat-ment for relapsed MM must take into account the resultant toxicities andefficacy of prior drugs.

For example, if a patient has progressed on lenalidomide maintenance, wewould not choose lenalidomide as part of second-line therapy. However, ifthat same patient achieved a very good partial response (VGPR) or a com-plete response during induction with a bortezomib-based regimen, we mightutilize bortezomib at relapse, provided that the patient did not have signifi-cant peripheral neuropathy (PN) or other adverse events (AEs) associatedwith treatment. Bortezomib-related AEs might suggest the use of an alkylatoralone at the time of relapse in such a patient. Another example is a patient who relapses after initial therapy with a com-

bination of lenalidomide, bortezomib, and dexamethasone (RVD)2 but whohas not undergone transplant or maintenance therapy. We could go back toRVD, which has been shown to be effective (Figure),3 or we may switch thepatient to a regimen of cyclophosphamide, bortezomib, and dexametha-

Making Treatment Decisions in Relapsed andRefractory Multiple Myeloma

Jeffrey Wolf, MDClinical Professor, Department of Medicine, UCSFDirector, Myeloma ProgramUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, CA

SponsorsThis activity is jointly sponsored by Medical Learning Institute Inc andCenter of Excellence Media, LLC.

Commercial Support AcknowledgmentThis activity is supported by educational grants from Celgene Corporationand Millennium: The Takeda Oncology Company.

Target AudienceThe activity was developed for physicians, nurses, and pharmacists in -volved in the treatment of patients with multiple myeloma (MM).

Purpose StatementThe purpose of this activity is to enhance competence of physicians, nurs-es, and pharmacists concerning the treatment of MM.

Physician Credit DesignationThe Medical Learning Institute Inc designates this enduring material for a max-imum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim onlythe credit commensurate with the extent of their participation in the activity.This activity has been planned and implemented in accordance with theEssential Areas and policies of the Accreditation Council for ContinuingMedical Education through the joint sponsorship of the Medical LearningInstitute Inc and the Center of Excellence Media, LLC. The Medical LearningInstitute Inc is accredited by the Accreditation Council for ContinuingMedical Education to provide continuing medical education for physicians.

Registered Nurse DesignationMedical Learning Institute IncProvider approved by the California Board of Registered Nursing, Pro viderNumber 15106, for 1.25 contact hours.

Registered Pharmacy DesignationThe Medical Learning Institute Inc is accredited by the Accredi -tation Council for Pharmacy Education as a provider of continu-

ing pharmacy education. Completion of this knowledge-based activityprovides for 1.25 contact hours (0.125 CEUs) of continuing pharmacyeducation credit. The Universal Activity Number for this activity is0468-9999-12-030-H01-P.

Learning ObjectivesUpon completion of this activity, the participant will be able to:• Review data from recent clinical trials evaluating novel agents for MM

in the relapsed/refractory setting • Apply evidence-based retreatment strategies for MM, taking into con-

sideration patient- and disease-related factors • Describe appropriate prophylactic measures for managing adverse

events to optimize treatment efficacy

DisclosuresBefore the activity, all faculty and anyone who is in a position to have con-trol over the content of this activity and their spouse/life partner will dis-close the existence of any financial interest and/or relationship(s) theymight 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, orother special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vettedby Medical Learning Institute Inc for fair balance, scientific objectivity ofstudies mentioned in the materials or used as the basis for content, andappropriateness of patient care recommendations.

Planners’ and Managers’ DisclosuresDana 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 disclosedthat her spouse is investigator on a study for Agenix, ImClone, and Lilly;on the data monitoring committee for Infinity; on the Advisory Com -mittee for Boehringer Ingelheim; and on the data monitoring committeeand principal investigator on a study for Pfizer.

Faculty Disclosures*Sagar Lonial, MD, is Consultant to Bristol-Myers Squibb, CelgeneCorporation, 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 OnyxPharmaceuticals, Inc.Helen T. Wu, PharmD, BCOP, has nothing to disclose.Jennifer Knoche, RN, BSN, is on the speakers’ bureau for CelgeneCorporation.

*Content will include non–FDA-approved uses.The associates of Medical Learning Institute Inc, the accredited providerfor this activity, and Center of Excellence Media, LLC, do not have any

financial relationships or relationships to products or devices with anycommercial interest related to the content of this CME/CPE/CE activityfor any amount during the past 12 months.

Disclaimer The information provided in this CME/CPE/CE activity is for continuingeducation purposes only and is not meant to substitute for the indepen -dent medical judgment of a healthcare provider relative to diagnostic andtreatment options of a specific patient’s medical condition. Recommenda -tions for the use of particular therapeutic agents are based on the best availablescientific evidence and current clinical guidelines. No bias towards or promotionfor 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 com-pleted online at www.mlicme.org/P12028.html. Upon completion of theevaluation and scoring 70% or better on the posttest, you will immediatelyreceive your certificate online. If you do not achieve a score of 70% or bet-ter on the posttest, you will be asked to take it again. Please retain a copyof the Certificate for your records.

For questions regarding the accreditation of this activity, please contactMedical Learning Institute Inc at 609-333-1693 or [email protected].

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The choice of treatment for relapsed MM must take into account the resultant toxicities and efficacy of prior drugs.

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sone.4,5 Both of these regimens yield a response rate of about 75% in therelapsed setting.3-5 We could consider ASCT as part of second-line therapy,usually with some initial therapy to get better control pretransplant. If themyeloma is particularly aggressive at relapse, we may use a combination suchas bortezomib and dexamethasone with cisplatin, doxorubicin, cyclophos-phamide, and etoposide (VD-PACE) and then go to transplant.6 If thepatient has renal insufficiency, we will use modified HyperCVAD(cyclophosphamide, bortezomib, doxorubicin, and dexamethasone; withbortezomib in place of vincristine) instead of VD-PACE.7

How would you choose therapy for a patient who is resistant toinitial treatment?

Drug resistance is a topic of ongoing investigation, and therapeutic choicesin this setting require careful consideration. Recently, we had a patient whowas treated with a 2-drug regimen of bortezomib and dexamethasone andattained only a partial response. We added lenalidomide, and his responseimproved to a VGPR. At the time of relapse, we might be disinclined to usebortezomib for such a patient, because of the modest initial response. Thereis 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 withmultiple sensitivity and resistance patterns to different drugs. Sometimes, if apatient has not received a drug for a period of time, the clone that may berelapsing 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

who exhibited resistance earlier in the clinical course of the disease. In otherwords, “once resistant, always resistant” 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 thatwill play out now that both agents are available. My point is that going backto a proteasome inhibitor makes sense, even if a patient had only a modestprior response to bortezomib.

Has the approval of carfilzomib impacted treatment approachesin the retreatment setting?

The next-generation proteasome inhibitor carfilzomib is now availablefor use in the relapsed/refractory setting for MM, but it is approved by theUS Food and Drug Administration only for patients who have re ceived atleast 2 prior therapies including bortezomib and an immuno modulatoryagent.10 Clinical trials have shown the efficacy of carfilzomib in this set-ting and have also indicated that carfilzomib is less likely than bortezomibto cause PN.11,12

Because we see many patients who have run through all of the other treat-ment options and have progressed on bortezomib-based therapies, our teamhas used carfilzomib frequently since its approval. However, in patients whoreceived bortezomib with good response a long time ago, or in patients whoprogressed on bortezomib 2 to 5 years ago, retreatment with bortezomib couldbe considered at relapse. In such cases, the decision of which drug to use maybe influenced by possible prior toxicities.

For instance, in a patient who still has PN that developed during priortreatment with bortezomib, I would probably lean toward using carfilzomib.Even though you can give bortezomib subcutaneously (SC) and possiblyavoid making neuropathy worse,13 it may not be worth taking that chance. Incontrast, if there is no neuropathy and the patient did not progress on bor -tezomib initially, I would lean toward bortezomib retreatment. Convenienceis a consideration here. At the present time, carfilzomib is cumbersome toadminister. 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 cannow be given SC twice a week,13 is more convenient.

For the patient with relapsed or refractory MM, what investigationaltherapies show the most promise?

The immunomodulator pomalidomide is the first agent that comes tomind, as it may be approved in the next 6 months. Clinical data support theefficacy of this agent when combined with weekly dexamethasone in therelapsed/refractory setting for MM, and it is fairly well tolerated. In 2 phase 2trials of pomalidomide plus dexamethasone in patients refractory to bortez -omib and lenalidomide, overall response rates were 43% to 49%.14 In an ear-lier report, this combination showed a 63% response rate in patients receiv-ing 1 to 3 prior therapies; however, the incidence of grade �2 toxicities washigh, 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

Figure. Response rates with RVD in a phase 2 trial ofrelapsed/refractory MM (N=64).3

Pati

ents

(%

)

100

90

80

70

60

50

40

30

20

10

0

CR indicates complete response; MR, minimal response; NR, no response; ORR, overall responserate; PR, partial response; RVD, lenalidomide, bortezomib, and dexamethasone.

CR/near CR PR NR ORR (��MR)

25%

64%

22%

78%

Table 1. Response to Bortezomib-Based Retreatment FollowingResponse to Initial Bortezomib-Based Therapy (N=22)8

Response to Initial Therapy, n (%) Response to Retreatment, n (%)

Complete orpartial response

No response

15 (68%)

7 (32%)

Complete or partial response

No response

Complete or partial response

No response

9 (60%)

6 (40%)

2 (29%)

5 (71%)

Drug resistance is a topic of ongoing investigation,and therapeutic choices in this setting require careful consideration.

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There are also CD38 antibodies—daratumumab and SAR650984—inphase 1/2 trials that look promising.17,18

Additional drugs that are progressing through clinical trials include theBruton’s tyrosine kinase inhibitor ibrutinib (PCI-32765)19 and the mam-malian target of rapamycin inhibitor MLN0128.20 The histone deacetylaseinhibitor vorinostat and the pan-deacetylase inhibitor panobinostat do notseem to have very good antimyeloma activity on their own. Vorinostat hasprovided a slight advantage in combination with bortezomib, but it appearsto add quite a bit of toxicity.21 Panobinostat is in trials in combination witha proteasome inhibitor,22-24 but it is not yet clear if this drug will perform bet-ter than vorinostat.

ConclusionOver the past decade, we have witnessed spectacular progress in the area

of treating myeloma. Today, a majority of patients are alive and doing wellat 5 years following initial treatment. It is becoming apparent that manypatients can hope for very extended survival because of novel drugs and ourability to treat relapsed and refractory disease. �

References1. 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 com-

bination 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 MeetingAbstracts). 2010;116:Abstract 3049.

4. Davies FE, Wu P, Jenner M, Srikanth M, Saso R, Morgan GJ. The combination of cyclophos-phamide, Velcade and dexamethasone (CVD) induces high response rates with comparabletoxicity 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 relapsingmultiple 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 formultiple myeloma: early results of total therapy 3. Br J Haematol. 2007;138:176-185.

7. Pegylated liposomal doxorubicin hydrochloride, bortezomib, cyclophosphamide, and dexa -methasone in treating patients with multiple myeloma (NCT00849251). http://www.clinicaltrials.gov. Accessed October 22, 2012.

8. Wolf J, Richardson PG, Schuster M, LeBlanc A, Walters IB, Battleman DS. Utility of bor -tezomib retreatment in relapsed or refractory multiple myeloma patients: a multicenter caseseries. Clin Adv Hematol Oncol. 2008;6:755-760.

9. Sood R, Carloss H, Kerr R, et al. Retreatment with bortezomib alone or in combination forpatients 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-171-003-

A1) 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 previ-ously treated with bortezomib. Br J Haematol. 2012;158:739-748.

13. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration ofbortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferioritystudy. Lancet Oncol. 2011;12:431-440.

14. Lacy MQ, Allred JB, Gertz MA, et al. Pomalidomide plus low-dose dexamethasone in myelomarefractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011;118:2970-2975.

15. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexametha-sone 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 andlow-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, aCD38 Mab in patients with multiple myeloma—preliminary safety data. Blood (ASH AnnualMeeting 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 October22, 2012.

19. Study of the Bruton’s tyrosine kinase inhibitor in subjects with relapsed or relapsed and refractorymultiple myeloma (NCT01478581). http://www.clinicaltrials.gov. Accessed October 22, 2012.

20. Dose escalation study of MLN0128 in relapsed or refractory multiple myeloma or Waldenstrommacroglobulinemia (NCT01118689). http://www.clinicaltrials.gov. Accessed October 28, 2012.

21. Dimopoulos MA, Jagannath S, Yoon S-S, et al. Vantage 088: vorinostat in combination withbortezomib in patients with relapsed/refractory multiple myeloma: results of a global, random-ized 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 panobinostatwith bortezomib and dexamethasone in patients with relapsed multiple myeloma: PANORA-MA 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 inhibitorpanobinostat in combination with bortezomib and dexamethasone in relapsed and bortezomib-refractory 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.

Table 2. Toxicities Grade ��2 with Pomalidomide PlusDexamethasonea 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%)

aPatients also received aspirin 325 mg once daily for thromboprophylaxis. Patients wereallowed to substitute full-dose anticoagulation with either low-molecular-weight heparinor warfarin at physician discretion.

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Nursing Interventions in the Relapsed andRefractory Settings for Myeloma

IntroductionFor 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 alle-

viating 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 orthalidomide, what strategies are effective for minimizing the risk ofperipheral neuropathy (PN)?

The main strategy for minimizing this risk remains dose adjustment ortreatment interruption. With thalidomide, which is administered orally, PNcan be an especially challenging toxicity to manage. We often use thalido-mide at a low dose in the relapsed/refractory setting; therefore, to reduce theamount even further may require patients to cut their pills in half or taketheir medication every other day—neither of which are ideal options. Withintravenous (IV) bortezomib, reducing or holding the dose is easier. Rec -ommended dose reductions for thalidomide- and bortezomib-based PN areshown in Tables 1 and 2.1,2

Of course, we cannot make an informed decision regarding dose adjust-ment without an accurate assessment of a patient’s condition. In therelapsed/refractory setting, we must look at current symptoms as well as treat-ment history. What drugs have been administered previously? Did thepatient experience neuropathy with prior treatment, and if so, did dosereduction or discontinuation provide relief? Did supportive therapies help toreduce symptoms? Are there comorbid conditions associated with the exist-ing PN? Is the patient taking any medications for comorbidities that maycontribute to neuropathy? Answers to these questions help us to plan theschedule and dose of agents at the time of relapse.Complementary therapies, such as alpha lipoic acid, L-carnitine, and vita-

min B6 may be helpful.3 At our institution, we begin patients on these ther-apies prior to antimyeloma treatment to prevent or minimize PN. In thosewho already exhibit symptoms, we may add these therapies as supplements,to keep neuropathy from progressing. Some patients need a more robust med-ical intervention, in which case we may prescribe gabapentin, pregabalin, tri-cyclic antidepressants, or even nonopioid analgesics.3 Our goal is to do what-ever works to manage pain, tingling, burning, and functional impairment tokeep the patient on therapy.PN may cause the nerves that control intestinal muscle contractions to

malfunction, leading to gastrointestinal problems, including constipation.4 Ifthis occurs, a good bowel regimen, proper diet, hydration, and exercise, and

laxation become important components of therapy, in addition to dosereduction. Fortunately, we now have the option of administering bortezomibsubcutaneously (SC), which has been shown to help reduce the incidenceand severity of PN.5

How has the recent approval of carfilzomib affected yourapproach to treating relapsed and/or refractory disease?

With the approval of carfilzomib, we now have another treatment optionat our disposal, which is extremely important. Given the challenges pa -tients face in the relapsed/refractory setting, including the fact that theyhave already been treated with so many therapies, it matters greatly to haveone more way to attack the disease. In addition to demonstrating good effi-cacy, carfilzomib has been associated with low rates of PN (Figure).6

Anecdotally, we are not seeing this toxicity among patients receiving carfil-zomib. How ever, since these individuals are on so many drugs, sequencedover time, it can be hard to determine whether AEs are related to past orcurrent regimens. For instance, an agent may cause some degree of neu-

Jennifer Knoche, RN, BSNLead Practice NurseUCSF Hematology/BMT Ambulatory Care CenterSan Francisco, CA

Table 1. Thalidomide Dose Modifications Based on Severity ofPeripheral Neuropathy1

Severity of Peripheral Neuropathy Modification of Dose and Regimen

Grade 1 (mild)

Grade 1 with pain or grade 2

Grade 3

Grade 4 (permanent sensory loss that interferes with function)

No action

Intermittent symptoms:Continue therapy

Continuous symptoms:Withhold thalidomide until toxicity resolves, then reduce dose

Withhold thalidomide until toxicity resolves, then restart at reduced dose

Discontinue thalidomide

Table 2. Bortezomib Dose Modifications Based on Severity ofPeripheral Neuropathy2

Severity of Peripheral Neuropathy Modification of Dose and Regimen

Grade 1 (paresthesia or loss of reflex) without pain or loss of function

Grade 1 with pain or grade 2 (interferes with function but not with activities of daily living)

Grade 2 with pain or grade 3 (interferes with activities of daily living)

Grade 4 (permanent sensory loss that interferes with function)

No action

Reduce bortezomib dose from 1.3 to 1.0 mg/m2

Withhold bortezomib until toxicity resolves, then reinitiate at a dose of 0.7 mg/m2 once weekly

Discontinue bortezomib

��



ropathy, but symptoms do not appear until later, after another therapy isgiven.Administration of carfilzomib—2 days in a row intravenously, weekly for 3

weeks7—is not as simple as administration of bortezomib, especially borte-zomib SC. Some patients, depending on how far they live from the cancercenter, may have to spend the night once a week to receive carfilzomib. Theinfusion 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,

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. Insome patients, we have noticed a decline in red blood cells with carfilzomibuse, typically during the first cycle. As with any agent, careful monitoring ofblood counts and vital organ functions are an essential part of nursing care.

How do you support bone health and manage skeletal-relatedevents 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

and osteoporosis. When treating a patient for osteoporosis, we need to assesshis or her current bisphosphonate regimen and see how it dovetails with theneed 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 Clin -ical Oncology recommends 2 years of bisphosphonate therapy for myeloma-related 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 bis-phosphonates in a relapsed or refractory patient who has already had 2 years oftherapy. Our biggest concern is the risk for osteonecrosis of the jaw, whichincreases with prolonged time on bisphosphonate therapy.9

As the myeloma disease process continues, and as patients age, they mayneed supportive devices, surgical care, and pain management strategies.Functional limitations and pain can be improved with antimyeloma thera-py and bisphosphonates, but for some individuals, canes, walkers, wheel-chairs, or braces may be necessary. We may also refer patients with spineinvolvement for vertebroplasty or kyphoplasty, which can be very effec-tive.10 Local irradiation is occasionally used for supportive care, especiallyif there is a plastocytoma. Bone pain often requires opioid analgesics, andwe encourage our patients to accept such medications when necessary.11

Pain can delay healing and diminish quality of life and must therefore beminimized whenever possible.

ConclusionNurses need to carefully monitor relapsed and refractory MM patients, and

be ready to intervene to ensure the continuation of treatment and the abilityto perform activities of daily living. The detection and effective managementof AEs, skeletal-related complications, and pain are essential components ofevidence-based care, which will lead to better clinical outcomes. �

References1. 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 ofbortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferioritystudy. Lancet Oncol. 2011;12:431-440.

6. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) 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 man-agement 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 theAmerican Academy of Pain Medicine, the American Pain Society, and the American Society ofAddiction Medicine. www.asam.org. Accessed October 30, 2012.

Figure. Carfilzomib-related, nonhematologic adverse eventswith an incidence ��5% in a single-agent study ofrelapsed/refractory MM patients (N=266).6

Patients (%)

40

35

30

25

20

15

10

5

0Fat

igue

Nausea

Diarrh

ea

Dyspne

a

Headac

he

Increa

sed serum

creatin

ine Vomitin

gPyr

exia

Periph

eral ne

uropat

hy

Hypoph

osphat

emia

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.

� ��



Pharmacologic Considerations in theRetreatment Setting for Multiple Myeloma

IntroductionIn patients with relapsed/refractory multiple myeloma (MM), re -

treatment can contribute to longer survival and better quality of life,

but can also pose a number of clinical challenges. When choosing

therapies for this indication, it is necessary to consider numerous fac-

tors, including preexisting toxicities, patient preferences and perfor -

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 selectionand administration of therapy in the retreatment setting?

An important issue to consider is how well a patient has tolerated a specif-ic agent or regimen in the frontline setting, as this may affect administrationand dosing at the time of retreatment. For example, if a patient did not expe-rience serious adverse events (AEs) with frontline therapy, we can typicallystart retreatment at the standard, recommended dose of the same agent.Conversely, if a patient did suffer significant toxicities, we may choose toretreat with an agent from a different class. However, studies have shown atherapeutic benefit when patients are retreated with agents they have re -ceived previously.1-5 Therefore, if a patient has achieved a good response to aspecific agent as induction, we may try using dose modifications to reduce theincidence of AEs.For example, we can consider a patient with preexisting peripheral neu-

ropathy (PN) who relapses after being treated with lenalidomide, bortez -omib, and dexamethasone (RVD) and autologous stem cell transplantation(ASCT). According to the most recent National Comprehensive CancerNetwork (NCCN) guidelines for the treatment of MM, RVD is a recom-mended primary therapy (category 2A) for transplant candidates.6 If relapseoccurs at >6 months, the same primary regimen may be repeated. However,in a patient who has residual PN, clinicians may consider avoiding bortez -omib and instead select a regimen that has less potential for neurotoxicity. Inaddition, because of previous ASCT and lenalidomide treatment, a regimenthat has the least hematologic toxicity would be preferred. It would be nec-essary to look at which agents are available for salvage therapy, based onthese 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 patientmay have been treated initially with bortezomib, melphalan, and prednisoneor lenalidomide plus low-dose dexamethasone—regimens that are recom-

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. Itis also important to remember that myeloma patients with renal dysfunctionoften 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 dys-function.8 Bortezomib and carfilzomib, which have also demonstrated effi -cacy as second-line therapies, do not require dosing adjustments in renallyimpaired patients.9,10

How has the approval of subcutaneous (SC) bortezomib impactedyour approach to retreatment?

In January 2012, the US Food and Drug Administration (FDA) approvedSC administration of bortezomib for the treatment of MM. This mode ofdelivery has several advantages, as shown in a recent multicenter trial byMoreau and colleagues.11 These investigators compared the efficacy and safe-ty of SC versus intravenous (IV) bortezomib in patients with relapsed MMwho had received �3 previous lines of therapy. The end point was to shownoninferiority of SC versus IV bortezomib in terms of overall response rate(ORR) following 4 treatment cycles. After these cycles, ORR was 42% inboth groups, showing noninferiority (P=.002). After a median follow-up of11.8 months in the SC group and 12.0 months in the IV group, there wereno significant between-group differences in time to progression and 1-yearoverall survival. PN of any grade was significantly reduced with SC versus IVbortezomib (Figure). Grade 3 or higher AEs were reported in 57% of patientsin the SC group versus 70% in the IV group; the most common were throm-bocytopenia (13% vs 19%), neutropenia (18% vs 18%), and anemia (12%vs 8%), respectively.11

It is important for pharmacists to be aware of how to prepare SC bortez -omib for administration. The concentration for IV infusion of bortezomib is1 mg/mL, which is significantly different from the concentration for SCinjection, which is 2.5 mg/mL.9 Pharmacists should be cautious when recon-stituting this medication and calculating the volume to be administered.However, the amount of work involved in preparing bortezomib for SC ver-sus IV administration is really no different, and SC bortezomib appears to bea much-preferred route of administration for several reasons. For nurses, itsimplifies care, since there is no need to obtain IV access, and the potentialrisks and complications of inserting IV lines are eliminated. In addition, itreduces chair time, allowing for a much quicker turnaround time forappointments. For patients, it is easier and generally less stressful to receivean SC injection compared with IV administration. Since there is no need

Helen T. Wu, PharmD, BCOPClinical PharmacistAdult Hematology/Oncology and Health SciencesAssociate Clinical Professor, School of Pharmacy, UCSFSan Francisco, CA

if a patient has achieved a good response to a specific agent as induction, we may try using dosemodifications to reduce the incidence of AEs.

� ��



to insert an IV line, wait time is much shorter, which can potentially im -prove quality of life.

How is the recently approved agent carfilzomib being used at yourcenter in the retreatment setting?

On July 20, 2012, the FDA approved carfilzomib, a next-generation pro-teasome inhibitor, for the treatment of patients with MM who havereceived at least 2 prior therapies, including bortezomib and an immuno -modulatory agent, and who have demonstrated disease progression on orwithin 60 days of therapy completion. Many patients who have re -lapsed/refractory MM are being treated with carfilzomib at our institution,given its proven efficacy and good safety profile. In a phase 2 study conduct-ed by Siegel and colleagues, patients received single-agent IV carfilzomib forrelapsed/refractory MM; all of these individuals were heavily pretreated.12

Of the evaluable patients in this study, 95% were refractory to their lasttherapy, and 80% were refractory to both bortezomib and lenalidomide. Thetreatment regimen was designed as IV carfilzomib 20 mg/m2 (cycle 1) fol-lowed by 27 mg/m2 (cycle �2), on days 1, 2, 8, 9, 15, and 16 of each 28-daycycle. The ORR was 23.7%, median duration of response was 7.8 months,and median overall survival was 15.6 months. Reported AEs included

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 agentto patients off study, and we make sure to follow the recommended dosing,reconstitution, and administration guidelines to ensure maximum benefitand safety. Although we rarely use carfilzomib in the inpatient setting, wedo utilize it in patients who come in for emergent plasmapheresis after fail-ing transplant, administering concomitant IV hydration to prevent tumorlysis syndrome. I think this agent is becoming an important retreatmentoption in MM.

ConclusionAlthough MM remains an incurable disease, retreatment with novel

agents is leading to higher response rates, prolonged survival, and better qual-ity of life. An important goal in this setting is the prevention and manage-ment of AEs, which allows the cancer care team to maximize dose intensityand provide continuation of therapy. This requires careful consideration ofcomorbidities and other patient factors, as well as a thorough understandingof the doses, schedules, and modes of administration recommended for avail-able agents. �

References1. 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 inrelapsed or refractory multiple myeloma. Cancer. 2005;104:2141-2148.

3. Hrusovsky I, Emmerich B, von Rohr A, et al. Bortezomib retreatment in relapsed multiple myelo-ma—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 oflenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J ClinOncol. 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 inOncology™: 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 featuresand 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-inferioritystudy. Lancet Oncol. 2011;12:431-440.

12. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-2825.

Figure. Incidence of peripheral neuropathy in a phase 3 trialcomparing SC versus IV bortezomib dosing in relapsedmyeloma (N=222).11

Patients (%)

60

50

40

30

20

10

0

IV indicates intravenous; SC, subcutaneous.

Any grade �Grade 2 �Grade 3

SC bortezomib

IV bortezomib

38%

53%

24%

41%

6%

16%

P=.044

P=.012

P=.026

��


ESMO 2012 Conference

Platinum-Resistant Ovarian Cancer: BevacizumabImproves Survival When Added to Chemotherapy By Phoebe Starr

Vienna, Austria—Adding bevacizu -mab (Avastin) to chemotherapy im -proves outcomes in patients with plat-inum-resistant recurrent ovariancan cer, ac cording to results of the phase3 clinical trial AURELIA, which waspresented at the 2012 European Societyfor Medical Oncology Con gress.Bevacizumab im proved progression-free survival (PFS) and overall responserate (ORR) with any of the 3 chemother-apy regimens in the study, but addingbevacizumab to weekly paclitaxel wasthe most active combination in anexploratory analysis of the trial.

AURELIA is one of the only trials to show a positive outcome in patientswith platinum-resistant ovarian can-cer, said Nicoletta Colombo, MD,University of Milan-Bicocca, EuropeanInstitute of Oncology, Milan, Italy.

In the overall trial, the median PFSwas 6.7 months for bevacizumab pluschemotherapy versus 3 months forche mo therapy alone.

Investigators could choose chemo -

therapy from among weekly paclitax-el, pegylated liposomal doxorubicin,or topotecan. When chemotherapyregimens were analyzed separately,the bevacizumab plus weekly paclitax-el regimen achieved the best results.The median PFS durations for the dif-ferent cohorts were:• 10.4 months with bevacizumab plus

weekly paclitaxel versus 3.9 monthswith chemotherapy alone

• 5.8 months with bevacizumab plustopotecan versus 2.1 months withchemotherapy alone

• 5.4 months with bevacizumab pluspegylated liposomal doxorubicinversus 3.4 months with chemother-apy alone.“Bevacizumab combined with chemo -

therapy should be considered a newstandard option for platinum-re sis tantrecurrent ovarian cancer,” stated leadauthor Andres M. Poveda, MD, Fun -dacion Instituto Valenciano de Onco -logia, Valencia, Spain.

AURELIA randomized 361 patients

(median age, approximately 60 years)with platinum-resistant recurrentovarian cancer whose disease pro-gressed with up to 2 previous regi-mens to chemotherapy alone versuschemotherapy plus bevacizumab.

Treatment was continued until unac-ceptable toxicity or progressive dis-ease occurred.

Demographic and disease charac -teristics were well balanced at base linebetween the treatment arms. Ap -proximately 90% of the patients had

stage III/IV disease.Response rates were superior for all

3 chemotherapy regimens with theaddition of bevacizumab, with thehighest rate seen with weekly paclitax-el plus bevacizumab—51.7% versus28.8% for chemotherapy alone; theORRs for bevacizumab plus pegylatedliposomal doxorubicin were 18.3%and 7.9%, respectively, and 5.8% and2.1%, respectively, for the topotecancohort.

No new toxicity concerns emergedin the trial. Toxicities were similar inthe 2 treatment arms. A higher rate ofperipheral neuropathy was reportedin the weekly paclitaxel cohort and ahigher rate of hand-foot syndrome inthe patients treated with pegylatedliposomal doxorubicin.

Dr Colombo was particularly im -pressed by the results in the weeklypaclitaxel plus bevacizumab cohort.She stated that this combinationshould be explored earlier in thecourse of disease. �

Cost-Effectiveness Comparison of First-Line Therapies forAdvanced Non–Small-Cell Lung CancerBy Caroline Helwick

Vienna, Austria—Costs associated withfirst-line pemetrexed/cisplatin are sig-nificantly lower than those of carbo-platin/paclitaxel/bevacizumab for thetreatment of advanced non–small-celllung cancer (NSCLC), according to an anal ysis presented at the 2012 Euro -pean Society for Medical Oncol ogyCongress.

“This is the first known study thatused real-world, nontrial data to eval -uate the outpatient care cost-effec-tiveness of pemetrexed/cisplatin rel-ative to 2 other first-line regimens forpa tients with advanced nonsqua-mous NSCLC,” said Katherine B.Winfree, PhD, MPH, ResearchScientist, Global Outcomes, Oncol -ogy, Eli Lilly and Company.

The study compared the incrementalcost-effectiveness of outpatient man-agement with these regimens inpatients with advanced NSCLC. Thedata came from the InternationalOncology Network database, whichdocuments care by 20 large US commu-nity oncology practices. The index datewas the initiation of first-line therapy.

Of approximately 5000 patients, 234(78 matched pairs per treatment type)were selected for the cost-effectivenessanalysis. Costs included charges forchemotherapy, supportive care, andphysician and nursing services.

Pemetrexed/Cisplatin Less Costly,

More Effective than Triplet

Incremental costs were measured as differences in costs during the pro-gression-free survival (PFS) and over-all survival (OS) periods for eachmatched pair.

Median PFS was 128 days in patientsreceiving pemetrexed/cisplatin versus112 for patients receiving carboplatin/paclitaxel/bevacizumab (P = .007) and105 days in patients receiving carbo-platin/paclitaxel (P = .004).

The median OS was 327 days inpatients treated with pemetrexed/cis-platin, 279 days in patients treated withcarboplatin/paclitaxel/bevacizumab,and 234 in patients treated with car -boplatin/paclitaxel, a nonsignificantdifference.

Considering the treatment costs, as

well as the improvement in PFS, thecosts associated with first-line therapywere significantly lower with peme-trexed/cisplatin than with carboplatin/paclitaxel/bevacizumab; however, asex pected, the costs were significantlyhigh er with pemetrexed/cisplatin treat - ment than with carboplatin/paclitax-el—primarily a result of the underly -ing difference in the drug costs, DrWinfree noted.

Mean PFS costs were approximate ly$43,000 for pemetrexed/cisplatin,$61,000 for carboplatin/paclitaxel/bevacizumab, and $18,000 for carbo-platin/paclitaxel. The overall costs oftreatment were approximately $40,000,$58,000, and $14,000, respectively.

“Costs associated with first-line ther-apy with pemetrexed/cisplatin weresignificantly lower than those of carbo-platin/paclitaxel/bevacizumab. Fur -ther evaluation is warranted to identifypossible drivers of this difference, suchas bevacizumab utilization (includingmaintenance), differences in number ofcycles, and so forth,” Dr Winfree said.

“But patients treated with peme-

trexed/cisplatin experienced a signifi-cant PFS benefit and trended towardbeing more effective and less costlycom pared with carboplatin/paclitax-el/bevacizumab for both PFS and OS,”she said.

More Costly, but Improved PFS,

versus Carboplatin/Paclitaxel

The analysis also showed that peme-trexed/cisplatin was more costly thancarboplatin/paclitaxel, but with apotential incremental clinical benefit,Dr Winfree emphasized. Patients treat-ed with pemetrexed/cisplatin had asignificant PFS benefit compared withcarboplatin/paclitaxel/bevacizumab.The doublet was more effective and lesscostly than carboplatin/paclitaxel/bevacizumab for PFS and OS (althoughthe differences were not significant).

“Therefore, depending on society’sor payers’ willingness to pay threshold,pemetrexed/cisplatin may be seen ascost-effective compared to carboplat -in/paclitaxel, because it demonstrat edgreater effectiveness at a higher cost,”Dr Winfree concluded. �

“Bevacizumab combinedwith chemotherapy shouldbe considered a newstandard option forplatinum-resistant recurrentovarian cancer.”

—Andres M. Poveda, MD

“Managing patients with myeloma means staying current.”

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Ira Klein, MD, MBA, FACPChief of Staff to the Chief Medical OfficerAetnaHartford, CT

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Get connected to the perspectives of 100 stakeholders who manage 143 million covered livesConnecting you with relevant information is part of our commitment to you. That’s why Lilly commissioned the publication of a report based on the Managed Care Oncology Index.* This study surveyed managed care executives, practicing oncologists, and oncology practice managers who shared their views on interesting oncology topics such as:

The publication, Trend Report on Oncology Management, is just one example of how Lilly Oncology can connect you with important information to assist your organization in managing members with cancer. To get your copy of the trend report, simply call 1-800-247-7832 and a Lilly Account Manager–Oncology Payer Services will contact you to arrange delivery of your copy and answer any questions you might have about other available services.

ON74961 12/11 PRINTED IN USA © 2011, Lilly USA, LLC. ALL RIGHTS RESERVED.

Visit www.lillyoncology.com. | Creating better connections.

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vbcc november 2012 vol 3 no 8

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