VBCC October Vol2 No6

Novel Agents ImproveOutcomes as MaintenanceTherapy for Multiple MyelomaBy Phoebe Starr

Therapy-AssociatedComplications SignificantlyIncrease Cost of Cancer CareBy Caroline Helwick

©2011 Engage Healthcare Communications, LLC

www.ValueBasedCancerCare.com

Stockholm, Sweden—With recognitionof common tumor mutations and apipeline full of biologic agents thattarget them, personalized medicineshould be all but a fait accompli. But oneexpert told attendees at the EuropeanSociety for Medical Oncology’s 2011European Multidisciplinary CancerCongress, “We may be overpromisingour patients.” Gordon Mills, MD, of the Zayed

Institute for Personalized CancerTherapy at the University of TexasM.D. Anderson Cancer Center,Houston, said, “We are coming closerto having a scientific underpinning forwhat we want to do, but integratingthis remains a challenge. Can weachieve personalized therapy? Is iteven doable?”

Personalized medicine—matchingthe right drug with the right patient—is “not the present, but it is clearly inour future,” but there are many chal-lenges, Dr Mills said. “The biggest problem is the ‘N of 1,’”

he emphasized, because each individ-ual patient has a unique genetic tumor

New York, NY—Maintenance therapyis now an option for the treatment ofmultiple myeloma in elderly patientsand in patients who have undergoneautologous stem-cell transplant(ASCT). Thalidomide (Thalomid), len -a lidomide (Revlimid), and bortezomib

(Velcade) have all shown benefit in themaintenance setting, said StevenDevine, MD, Professor of Medicineand Director of the Blood and MarrowTransplant Program, Ohio State Uni -versity Comprehensive Cancer Center,

Stockholm, Sweden—The cost of can-cer therapies is a growing concern notonly for patients but also for providersand payers. Addressing the cost bur-den for those involved in cancer care isbecoming a priority that cannot beavoided with the growing role of tar-geted therapies in oncology.

Cost Nearly Doubles in Metastatic

Breast Cancer

A study presented by MelissaBrammer, MD, Medical Director,Genentech, San Francisco, CA, showsthat complications associated withtreating cancer essentially double the

Continued on page 18

Continued on page 9


OCTOBER 2011 VOL 2 NO 6

VALUE PROPOSITIONS . . . . . . . . . . . 5Value of cost-effectiveness analyses

US patients get new cancer drugsfaster than in Europe

FDA UPDATES . . . . . . . . . . . . . . . . . . . . . 6Vemurafenib approved for metastaticmelanoma, with a test for BRAF V600E mutation

Crizotinib approved for NSCLC, with a test for ALK mutation

MEETINg HIgHLIgHTS

ESMO annual meeting . . . . . . . . . . . . . 8NCCN hematology congress . . . . 18Breast cancer symposium . . . . . . . 34VBCC PERSPECTIVE . . . . . . . . . . . . 16Novel biomarkers ushering in newapproaches to cancer therapy

HEALTH POLICY . . . . . . . . . . . . . . . . . 26USPSTF and the future of prostatecancer screening

I N S I D E

The Road to Personalized MedicineIs Strewn with Obstacles Individualizing treatment: promising and complex By Audrey Andrews

The First NCQA-RecognizedMedical Home in Oncology A new model for increasing value in cancer care Interview with John D. Sprandio, MDConsultants in Medical Oncology and Hematology, Drexel Hill, PA

ONCOLOGY BEST PRACTICES ESMO ANNUAL MEETING

NCCN HEMATOLOGY CONGRESS

The patient-centered medical home (PCMH) model of care has proved suc-cessful in overcoming some of the fragmentation of primary care. Dr Sprandioand his colleagues have now demonstrated the value of applying the princi-ples of the medical home to cancer care, with particular implications for oncol-ogists and for payers and unique reimbursement dilemmas.

Q: Your practice is the first oncology medical home to berecognized by the National Committee for Quality Assurance?

Dr Sprandio: Our hematology/oncology practice is the first, and still theonly, cancer center in the country to have gained recognition from the National


VBCC Perspective, page 16

Consultants in Medical Oncology & Hematology, P.C.

VBCC_Oct_11_2_6_Follow ASCO Tabloid 10/18/11 11:47 AM Page 1

N O W A P P R O V E D F O R

BRAFV600E MUTATION-POSITIVEMETASTATIC MELANOMA

©2011 Genentech Inc., So. San Francisco, CA BRF0000583300 08/11

Indication and UsageZELBORAF™ (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test.ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma.Important Safety InformationCutaneous squamous cell carcinoma, serious hypersensitivity reactions including anaphylaxis, serious dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, QT prolongation, liver laboratory abnormalities, photosensitivity, ophthalmologic reactions, and new primary malignant melanoma have all been observed or associated with ZELBORAF treatment.ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action.Confirmation of BRAFV600E mutation-positive melanoma as detected by an FDA-approved test is required for selection of patients appropriate for ZELBORAF therapy.The most common adverse reactions of any grade ( 30%) reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.

Please see brief summary of full Prescribing Information on the following page for additional important safety information or visit ZELBORAF.com for full Prescribing Information.

10:52 AM

VBCC_Oct_11_2_6_Follow ASCO Tabloid 10/17/11 3:34 PM Page 2

ZELBORAF™ (vemurafenib) tablet, oralInitial U.S. Approval: 2011This is a brief summary of information about TRADENAME. Before prescribing, please refer to the full Prescribing Information.1 INDICATIONS AND USAGEZELBORAF™ is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test.Limitation of Use: ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma.5 WARNINGS AND PRECAUTIONS5.1 Cutaneous Squamous Cell Carcinoma (cuSCC)Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. The incidence of cuSCC in ZELBORAF-treated patients in Trial 1 was 24%. CuSCC usually occurred early in the course of treatment with a median time to the �rst appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced > 1 occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC in ZELBORAF clinical studies included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In the clinical trials, cases of cuSCC were managed with excision, and patients were able to continue treatment without dose adjustment.It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and every two months while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per standard of care. Monitoring should be considered for 6 months following discontinuation of ZELBORAF.5.2 Hypersensitivity ReactionsSerious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, ZELBORAF treatment should be permanently discontinued.5.3 Dermatologic ReactionsSevere dermatologic reactions have been reported in patients receiving ZELBORAF, including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis in Trial 1. In patients who experience a severe dermatologic reaction, ZELBORAF treatment should be permanently discontinued.5.4 QT ProlongationExposure-dependent QT prolongation was observed in an uncontrolled, open-label Phase 2 QT sub-study in previously treated patients with BRAFV600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.3)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Treatment with ZELBORAF is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval.ECG and electrolytes, including potassium, magnesium, and calcium, should be monitored before treatment with ZELBORAF and after dose modi�cation. Monitoring of ECGs should occur 15 days after treatment initiation and then monthly during the �rst 3 months of treatment, followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with ZELBORAF is not recommended in patients with QTc > 500 ms. If during treatment the QTc exceeds 500 ms (CTC-AE ≥ Grade 3), ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms [see Dosage and Administration (2.2)]. Permanent discontinuation of ZELBORAF treatment is recommended if after correction of associated risk factors, the QTc increase meets values of both > 500 ms and > 60 ms change from pre-treatment values.5.5 Liver Laboratory AbnormalitiesLiver laboratory abnormalities have occurred with ZELBORAF (Table 3) [see Adverse Reactions (6.1)]. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Laboratory abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.2)].5.6 PhotosensitivityMild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials [see Adverse Reactions (6.1)]. All patients should be advised to avoid sun exposure while taking ZELBORAF. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn.For intolerable grade 2 (tender erythema covering 10 - 30% body surface area) or greater photosensitivity, dose modi�cations are recommended [see Dosage and Administration (2.2)].5.7 Ophthalmologic ReactionsIn Trial 1, �ve cases of uveitis have been reported in patients treated with ZELBORAF. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, there were �ve patients with blurry vision, �ve patients with iritis and six patients with photophobia. There was one case of retinal vein occlusion in Trial 2.5.8 New Primary Malignant MelanomaThere were eight skin lesions in seven patients reported as new primary malignant melanoma in Trial 1. Cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above [see Warnings and Precautions (5.1)].5.9 Use in PregnancyPregnancy Category DZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies 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 a fetus [see Use in Speci�c Populations (8.1)].5.10 BRAFV600E TestingCon�rmation of BRAFV600E mutation-positive melanoma as detected by an FDA-approved test is required for selection of patients for ZELBORAF therapy because these are the only patients studied and for whom bene�t has been shown. For patients in ZELBORAF clinical studies, including Trial 1 and Trial 2, all enrolled patients tested positive when their tumor tissue was assessed with the cobas® 4800 BRAF V600 Mutation Test [see Clinical Studies (14)]. This test is designed to detect BRAFV600E

mutations in DNA isolated from formalin-�xed, paraf�n-embedded

human melanoma tissue. The safety and ef�cacy of ZELBORAF have not been evaluated in patients whose melanoma tested negative by the cobas® 4800 BRAF V600 Mutation Test. Refer to the package inserts of FDA approved test kits,for detailed information.6 ADVERSE REACTIONS6.1 Clinical Trials ExperienceBecause clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.The adverse drug reactions (ADRs) described in this section were identi�ed from Trial 1 and Trial 2 [see Clinical Studies (14)]. In Trial 1, treatment naive patients with unresectable or metastatic melanoma (n=675) were allocated to ZELBORAF 960 mg orally twice daily or to dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, (n=132) patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Adverse reactions reported in at least 10% of patients treated with ZELBORAF are presented in Table 2. The most common adverse reactions of any grade (≥ 30% in either study) reported in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.

Table 2 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF*

Trial 1: Treatment Naive Patients Trial 2: Patients with Failure of at Least One Prior Systemic

TherapyZELBORAF

n= 336Dacarbazine

n= 287ZELBORAF

n= 132ADRs

All

Grades (%)

Grade 3

(%)

Grade 4

(%)

All Grades

(%)

Grade 3

(%)

Grade 4

(%)

All Grades

(%)

Grade 3

(%)

Grade 4

(%)Skin and subcutaneous tissue disordersRash 37 8 - 2 - - 52 7 -Photosensitivity reaction 33 3 - 4 - - 49 3 -

Alopecia 45 <1 - 2 - - 36 - -Pruritis 23 1 - 1 - - 30 2 -Hyperkeratosis 24 1 - <1 - - 28 - -Rash maculo-papular 9 2 - <1 - - 21 6 -

Actinic keratosis 8 - - 3 - - 17 - -Dry skin 19 - - 1 - - 16 - -Rash papular 5 <1 - - - - 13 - -Erythema 14 - - 2 - - 8 - -Musculoskeletal and connective tissue disordersArthralgia 53 4 - 3 <1 - 67 8 -Myalgia 13 <1 - 1 - - 24 <1 -Pain in extremity 18 <1 - 6 2 - 9 - -Musculoskeletal pain 8 - - 4 <1 - 11 - -

Back pain 8 <1 - 5 <1 - 11 <1 -General disorders and administration site conditionsFatigue 38 2 - 33 2 - 54 4 -Edema peripheral 17 <1 - 5 - - 23 - -Pyrexia 19 <1 - 9 <1 - 17 2 -Asthenia 11 <1 - 9 <1 - 2 - -Gastrointestinal disordersNausea 35 2 - 43 2 - 37 2 -Diarrhea 28 <1 - 13 <1 - 29 <1 -Vomiting 18 1 - 26 1 - 26 2 -Constipation 12 <1 - 24 - - 16 - -Nervous system disordersHeadache 23 <1 - 10 - - 27 - -Dysgeusia 14 - - 3 - - 11 - -Neoplasms benign, malignant and unspeci�ed (includes cysts and polyps)Skin papilloma 21 <1 - - - - 30 - -Cutaneous SCC†# 24 22 - <1 <1 - 24 24 -Seborrheic keratosis 10 <1 - 1 - - 14 - -

InvestigationsGamma- glutamyltransferase increased

5

3

<1

1

-

-

15

6

4

Metabolism and nutrition disordersDecreased appetite 18 - - 8 <1 - 21 - -Respiratory, thoracic and mediastinal disordersCough 8 - - 7 - - 12 - -Injury, poisoning and procedural complicationsSunburn 10 - - - - - 14 - -

* Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity.

† Includes both squamous cell carcinoma of the skin and keratoacanthoma.# All cases of cutaneous squamous cell carcinoma were to be reported as

Grade 3 per instructions to study investigators and no dose modi�cation or interruption was required.

Clinically relevant adverse events reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include:Skin and subcutaneous tissue disorders: palmar-plantar erythrodysaesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndromeMusculoskeletal and connective tissue disorders: arthritisNervous system disorders: dizziness, neuropathy peripheral, VIIth nerve paralysisNeoplasms benign, malignant and unspeci�ed (includes cysts and polyps): basal cell carcinomaInfections and infestations: folliculitisInvestigations: weight decreasedEye disorders: retinal vein occlusion, uveitisVascular disorders: vasculitisCardiac disorders: atrial �brillationTable 3 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4.

Table 3 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities*

Change From Baseline to Grade 3/4

Parameter ZELBORAF (%) Dacarbazine (%)GGT 11.5 8.6

AST 0.9 0.4

ALT 2.8 1.9

Alkaline phosphatase 2.9 0.4

Bilirubin 1.9 -

* For ALT, alkaline phosphatase and bilirubin, there were no patients with a change to grade 4 in either treatment arm.

7 DRUG INTERACTIONS7.1 Effects of Vemurafenib on Drug Metabolizing EnzymesResults from an in vivo drug-drug interaction study in patients with cancer demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak CYP2D6 inhibitor and a CYP3A4 inducer [see Clinical Pharmacology (12.3)].Concomitant use of ZELBORAF with agents with narrow therapeutic windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is not recommended as ZELBORAF may alter their concentrations. If coadministration cannot be avoided, exercise caution and consider a dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug.Coadministration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) [see Clinical Pharmacology (12.3)]. Exercise caution and consider additional INR monitoring when ZELBORAF is used concomitantly with warfarin.7.2 Drugs that Inhibit or Induce CYP3A4Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nel�navir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) should be used with caution when coadministered with ZELBORAF.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category D [see Warnings and Precautions (5.9)].ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action.There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.8.3 Nursing MothersIt is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, 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 UseSafety and ef�cacy in pediatric patients below the age of 18 have not been established.8.5 Geriatric UseNinety-four (28%) of 336 patients with unresectable or metastatic melanoma treated with ZELBORAF in Trial 1 were ≥ 65 years. Elderly patients (≥ 65 years) may be more likely to experience some adverse reactions, including cutaneous squamous cell carcinoma, nausea, decreased appetite, peripheral edema, keratoacanthoma and atrial �brillation. The effects of ZELBORAF on overall survival, progression-free survival and best overall response rate were similar in the elderly as compared to younger patients.8.6 GenderThe Grade 3 adverse events reported more frequently in females than males were rash, arthralgia, photosensitivity and increased creatinine. The Grade 3 adverse events reported more frequently in males than females were keratoacanthoma, increased alkaline phosphatase and increased total bilirubin.8.7 Hepatic ImpairmentNo adjustment to the starting dose is needed for patients with pre-existing mild and moderate hepatic impairment. ZELBORAF should be used with caution in patients with pre-existing severe hepatic impairment [see Clinical Pharmacology (12.3)].8.8 Renal ImpairmentNo adjustment to the starting dose is needed for patients with pre-existing mild and moderate renal impairment.ZELBORAF should be used with caution in patients with pre-existing severe renal impairment [see Clinical Pharmacology (12.3)].10 OVERDOSAGEThere is no speci�c antidote for overdosage of ZELBORAF. Patients who develop adverse reactions should receive appropriate symptomatic treatment. In case of suspected overdose, ZELBORAF should be withheld and supportive care instituted.

Manufactured by:Genentech, Inc.1 DNA Way BRF0000422000 South San Francisco, CA Initial U.S. Approval: August 2011 94080-4990 © 2011 Genentech, Inc

10:52 AM


4 I VALUE-BASED CANCER CARE I October 2011 VOL. 2 I NO. 6

IN THIS ISSUE

PublisherNicholas [email protected]

Associate PublisherMaurice [email protected]

Editorial DirectorDalia [email protected]

Associate EditorsBrett KaplanLara J. Lorton

Editorial AssistantJennifer [email protected]

Director, Client ServicesCristopher [email protected]

Director, Creative & DesignRobyn Jacobs

Quality Control Director Barbara Marino

Business ManagerBlanche Marchitto

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.

BPA Worldwide membership applied for August 2010.

Contact Information:For subscription information please contact: [email protected]: 732-992-1538 Fax: 732-992-1881

Permission requests to reprint all or part of any articlepublished in this magazine should be addressed to [email protected]

Address all editorial queries to: [email protected]: 732-992-1536 Fax: 732-992-1881

Value-Based Cancer Care, ISSN 2153-4888 (print);ISSN 2153-4896 (online), is published 7 times ayear by Engage Healthcare Communica tions, LLC,241 Forsgate Drive, Suite 205A, Monroe Township,NJ 08831. Copyright © 2011 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.

The ideas and opinions expressed in Value-BasedCancer Care do not necessarily reflect those of theeditorial board, the editors, or the publisher.Publication of an advertisement or other productmentioned in Value-Based Cancer Care should not beconstrued as an endorsement of the product or themanufacturer’s claims. Readers are encouraged tocontact the manufacturers about any features or limi-tations of products mentioned. Neither the editorsnor the publisher assume any responsibility for anyinjury and/or damage to persons or property arisingout of or related to any use of the material mentionedin this publication.Postmaster: Correspondence regarding subscriptionsor change of address should be directed to CIRCU-LATION DIRECTOR, Value-Based Cancer Care, 241 Forsgate Drive, Suite 205A, Monroe Township,NJ 08831. Fax: 732-992-1881. Yearly subscriptionrates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

VBCC Editorial Board

ONCOLOGY BEST PRACTICESThe first and only NCQA-recognized medicaloncology home

ESMO ANNUAL MEETINGNew bone-targeting compound extends survivalin metastatic prostate cancer

New analysis boosts value of bevacizumab in ovarian cancer

Everolimus-exemestane combination prolongsremission

More….

NCCN HEMATOLOGY CONGRESSNovel agents for multiple myeloma maintenanceAdvances in chronic lymphocytic leukemiaMore….

NOISE-CANCELING INFORMATIONSubmit your IT-related questions at www.valuebasedcancercare.com/submit-noise

HEALTH POLICY USPSTF and the future of prostate cancer screening

Recent ruling on genetic patents leaves many questions

More….

IN THE LITERATUREPARP inhibitor a promising therapy for ovarian cancer

Nilotinib sustains 24-month superiority to imatinib in CML

More….

BREAST CANCER SYMPOSIUM Targeted radiation therapy reduces treatment time

Novel HDAC inhibitor improves outcomes in estrogen-sensitive patients

Initial order of therapy approach has no impact on outcomes

More….

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

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

Mary KruczynskiDirector of Policy AnalysisCommunity Oncology Alliance

Ira Klein, MD, MBAAetnaHartford, CT

Crystal Kuntz, MPAAstellas Pharma USWashington, DC

Lee Newcomer, MD, MHAUnitedHealthcareMinnetonka, MN

Lynn Nishida, RPhRegence BlueCross BlueShield of OregonPortland, OR

Ted Okon, BS, MBAExecutive DirectorCommunity Oncology Alliance

Naimish Pandya, MDUniversity of MarylandBaltimore, MD

Ed Pezalla, MD, MPHAetna Pharmacy ManagementHartford, 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, FAAFPPrescription SolutionsIrvine, 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, BSBioPharma Partners, LLCNew York, NYSection EditorDawn Holcombe, FACMPE,MBA, ACHEPresident, DGH ConsultingSouth Windsor, CT

Al B. Benson III, MD, FACPProfessor of MedicineAssociate Director for ClinicalInvestigationsRobert H. Lurie ComprehensiveCancer Center of NorthwesternUniversity Chicago, ILImmediate Past 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, MDFlorida Comprehensive CancerNetwork, Melbourne, FL

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

Arlene A. Forastiere, MDITA PartnersPhiladelphia, 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

NEW


5VOL. 2 NO. 6 www.ValueBasedCancerCare.com I

VALUE PROPOSITIONS

Value of Cost-Effectiveness Analyses for ClinicalPractice Outlined by NICEThe National Institute for Health and Clinical Excellence (NICE) has

issued a report (Wonderling D, et al. Ann Intern Med. 2011;154:758-765)explaining the process and value of cost-effectiveness assessments and howthese inform recommendations and decisions regarding clinical questionsmade by the UK National Clinical Guidelines Centre. The report dispels thefollowing 3 myths regarding cost-effectiveness evaluations that furtherclarify the concept of value in medicine:

Myth 1: The aim of health economics is to save money. This is not the case,says NICE. Rather, the purpose of health economics is to promote as muchclinical value as possible for patients, based on available resources.

Myth 2: Expensive interventions are not cost-effective. This is not necessarilythe case. The cost of an expensive intervention may be fully or partly offsetby its ability to reduce side effects and their associated costs. In addition,an expensive intervention that offers significant health gains may oftenjustify its high cost.

Myth 3: The main goal of cost-effective analyses is to support the implementationof clinical practice. Instead, says NICE, the main goal of such analyses is todetermine which interventions are most cost-effective. This can mean that aclinically beneficial intervention may not be recommended if its benefit isnot sufficient to justify its cost. NICE suggests that these misconceptions can explain the reluctance of

providers to consider cost-effective analyses as not relevant to the clinicaldecision-making. Dispelling these misconceptions is therefore key to grasp-ing the true value and implications of this type of research methodologyfor clinical practice.

How to Assess the Value of Clinical InterventionsAnother report in the same issue of the Annals of Internal Medicine focuses

on the relevance of 3 concepts that can help in understanding the value ofclinical interventions for those involved in clinical decisions (Owens DK, etal. Ann Intern Med. 2011;154:174-180). The authors define value as “an assess-ment of the benefit of an intervention relative to expenditures.” The distinction between cost and value is crucial, the authors suggest:

interventions with high cost may nevertheless provide good value, becausethey provide a great clinical benefit. By contrast, inexpensive interventionsmay be tempting because of their low cost but may actually have littlevalue, because they offer no or only little clinical benefit. Differentiatingbetween cost and value is therefore important to clinical decision-making;supporting high-cost, high-value interventions may be justified even in acost-conscious healthcare system. The key to slowing the rate of cost escalation is not to avoid using high-

cost interventions: the challenge is to promote high-value and high-qualitypatient care, and this may include high-cost interventions. The first step toincreasing value in clinical care is to reduce or eliminate interventions thatprovide no benefit and may often be even harmful. Next, it is necessary topromote interventions with high value, that is, those that provide a clinicalbenefit that justifies the cost. Finally, when assessing the value of an inter-vention, it is critical to include not only the cost of the intervention itself butalso any additional cost that may be added or prevented to the total cost ofcare for that patient as a result of the original intervention (eg, cost or pre-vention of side effects, disease progression).

PET Imaging an Effective Tool for Tailoring Therapyin Advanced Lung Cancer Positron emission tomography (PET) is a promising approach for differ-

entiating which patients with inoperable lung cancer will and will not ben-efit from additional treatment after standard chemotherapy/radiation ther-apy. Lead investigator Mitch Machtay, MD, Chairman of RadiationOncology, Seidman Cancer Center, University Hospitals Case Western

Medical Center, presented these results at the 2011 annual meeting of theAmerican Society for Radiation Oncology (ASTRO), based on 251 patientswith stage III lung cancer at 60 cancer centers around the country.“Lung cancer remains the number 1 cancer killer in the United States.

These findings have the potential to give cancer physicians a new tool tomore effectively tailor treatments for patients with locally advanced lungcancer,” Dr Machtay said. “PET scans can show us which patients have themost aggressive tumors, potentially enabling us to intensify their treatment.”He noted that this was “one of the largest studies-of-its-kind to show thatPET scans have great potential in predicting the prognosis for patients withinoperable lung cancer. It supports the theory that PET scans add an impor-tant new dimension to a physician’s ability to determine which patients needadditional cancer therapies to best manage their disease.”

US Patients Get New Cancer Drugs Faster than in EuropeThe US Food and Drug Administration (FDA) is often criticized for delay-

ing treatments for patients, especially those with terminal illnesses such asadvanced cancer. However, a new drug-to-drug comparison (Roberts SH, etal. Health Aff [Millwood]. 2011;30:1375-1381) of the 35 new cancer drugsapproved by the FDA and the European Medicines Agency (EMA) between2003 and 2010 shows that: • Median time from submission to approval of a new cancer drug is 6months in the United States, 12 months in Europe

• Of the 35 oncology drugs approved either by the FDA or the EMA duringthat period, all the drugs approved by both agencies were available in theUnited States before in Europe

• The FDA approved 32 of the 35 new cancer drugs, the EMA approved 23.

Ginger Root Cost-Effective for Preventing Colon Cancer In a new study funded by the National Cancer Institute and the

University of Michigan Clinical Research Center, inexpensive ginger sup-plements reduced markers of colon inflammation, indicating that gingerroot may be beneficial in preventing colon cancer (Zick SM, et al. Cancer PrevRes [Phila]. 2011 Oct 11. Epub ahead of print). Colon inflammation is a pre-cursor of colon cancer. “Interest in this is only going to increase as people look for ways to pre-

vent cancer that are nontoxic, and improve their quality of life in a cost-effective way,” said Suzanna M. Zick, ND, MPH, a research assistant profes-sor at the University of Michigan Medical School and lead investigator. The study included 30 patients with colon inflammation who were ran-

domly assigned to 2 g of ginger root supplements daily or to placebo for 28days. Most of the standard measures of colon inflammation were significantlyreduced after 28 days with the ginger supplement compared with placebo;other inflammatory markers were trending toward significant reductions.

Diagnosing Melanoma Early May Soon Be Easier:MelaFind Gets Approvable Letter On September 26, 2011, the FDA issued an approvable letter to Mela

Sciences, the manufacturer of MelaFind, an investigational diagnostic devicefor early melanoma. This letter comes almost 1 year after the FDA rejectedthe device, requesting more clinical data. MelaFind is a noninvasive, multi-spectral computerized vision system that analyzes images of skin lesions. Itis designed to differentiate nonulcerated, nonbleeding cutaneous malignantmelanoma and high-grade lesions <2.2 cm from all other pigmented skinlesions. MelaFind showed 98.3% sensitivity and 9.9% specificity versus 3.7%specificity of standard diagnostic methods used by dermatologists.


Vemurafenib JoinsIpilimumab for TreatingMetastatic MelanomaThe US Food and Drug Admin -

istration (FDA) approved the targetedtherapy vemurafenib tablets (Zelboraf,Hoffmann-La Roche) for the treatmentof patients with unresectable ormetastatic mela noma with the BRAF

V600E gene mutation. The BRAF

V600Emutation occurs in 40% to 60%of patients with melanoma.Vemurafenib received accelerated

approval under the FDA’s priorityreview program, ahead of its October28, 2011, regulatory date. “This hasbeen an important year for patientswith late-stage melanoma. Zelboraf isthe second new cancer drug approvedthat demonstrates an improvement inoverall survival,” said Richard Pazdur,MD, Director of the Office of OncologyDrug Products in the FDA. In an international, randomized,

open-label trial, 675 patients withpreviously untreated metastatic orunresectable melanoma with theBRAF V600E mutation received eithervemurafenib 960 mg orally twice dailyor dacarbazine (DTIC) 1000 mg/m2

intravenously every 3 weeks. After a median follow-up of 6.2

months in the vemurafenib arm and4.5 months in the dacarbazine arm,the overall survival rate was signifi-cantly greater with vemurafenib thanwith dacarbazine (P <.001), as wasthe progression-free survival (PFS)rate (P <.001). The median survival of patients

receiving vemurafenib had not beenreached in the trial; it was 7.9 monthsfor those receiving dacarbazine; medi-an PFS rates were 5.3 months and 1.6months, respectively.The most common adverse effects

associated with vemurafenib werearthralgia, rash, alopecia, fatigue, pho-tosensitivity reaction, and nausea.Cutaneous squamous-cell carcinomas,including those of the skin and kera-toacanthomas, were reported in 24% ofpatients receiving vemurafenib. Otherreactions, sometimes severe, includedhypersensitivity, Stevens-Johnson syn-drome, toxic epidermal necrolysis,uveitis, QT prolongation, and liverenzyme laboratory abnormalities.The recommended dose is 960 mg,

taken every 12 hours, with or withouta meal. Vemurafenib is approved witha medication guide and is not indicat-ed for patients with the wild-typeBRAF (ie, no mutation) melanoma.(August 17, 2011)

Companion Diagnostic forBRAF V600E Mutation Along with vemurafenib the FDA

concurrently approved the companion

molecular diagnostic for this targetedtherapy—the cobas 4800 BRAF V600Mutation Test (Roche) for the diagno-sis of BRAF V600E mutation inpatients with melanoma. As a real-time polymerase chain-reaction test, itis 97.3% positive in detecting themutation. (August 17, 2011)

Brentuximab Indicated for 2 Types of LymphomasThe FDA expedited the approval of

brentuximab vedotin (Adcetris, SeattleGenetics) for the treatment of Hodgkinlymphoma, as well as for systemicanaplastic large-cell lymphoma(ALCL), a rare non-Hodgkin lym-

phoma that may manifest in severalparts of the body, including the lymphnodes, skin, bones, soft tissue, lungs,and liver. Brentuximab is the firstCD30-directed antibody-drug conju-gate approved for systemic ALCL; it isalso the first treatment ever approvedfor this rare disease.

FDA UPDATES


MC49941 06-10

MC49941 06-10


FDA UPDATES


Brentuximab is indicated for pa -tients with Hodgkin lymphoma thathas progressed after autologous stem-cell transplantation (ASCT) or after 2previous chemotherapy treatments. Brentuximab is also indicated for

patients with systemic ALCL whosedisease has progressed after 1 previ-

ous chemotherapy treatment. “Early clinical data suggest that

patients who received Adcetris forHodgkin lymphoma and systemicanaplastic lymphoma experienced asignificant response to the therapy,”said Dr Pazdur.The approval for Hodgkin lym-

phoma was based on a single-armtrial involving 102 patients, who hadan objective response rate to the drugof 73%, with 32% of patients showingcomplete remission and 40% show-ing partial remission; the medianresponse duration was 6.7 months. The approval for systemic ALCL

was based on a single-arm clinicaltrial in 58 patients; treatment withbrentuximab showed 86% objectiveresponse: 57% complete remissionand 29% partial remission. Themedian objective response durationwas 12.6 months.The recommended dosage is a 1.8-

mg/kg intravenous infusion adminis-tered over 30 minutes every 3 weeks.Treatment may continue up to 16cycles or until disease progression orunacceptable toxicity occurs. The most common adverse effects

associated with this drug include neu-tropenia, peripheral sensory neuropa-thy, fatigue, nausea, anemia, upperrespiratory infection, diarrhea, fever,cough, vomiting, and thrombocytope-nia. (August 19, 2011)

FDA Accelerates Approval ofCrizotinib for NSCLCUsing a priority review, the FDA

approved oral crizotinib (Xalkori,Pfizer) for the treatment of locallyadvanced or metastatic non–small-celllung cancer (NSCLC) in patients withthe anaplastic lymphoma kinase (ALK)genetic mutation, as detected bythe companion test concurrently ap -proved by the FDA. Approximately3% to 5% of patients with NSCLC areALK-positive.Crizotinib “represents a paradigm

shift in NSCLC treatment, where we’removing away from a one-size-fits-allapproach to biomarker-based treat-ment decisions,” said Paul A. Bunn, Jr,MD, the James Dudley Chair in CancerResearch, University of Colorado,Denver. Crizotinib was approvedabout 1 month ahead of its scheduledregulatory date. The approval was based on 2 multi-

center, single-arm trials involving 255ALK-positive patients with locallyadvanced or metastatic NSCLC. In thefirst study, the objective response was50%, with a median response durationof 42 weeks; in the second study, theobjective response rate was 61%, witha median response of 48 weeks.Complete responses were observed in1% of the patients. The most common adverse reac-

tions (≥25%) were vision disorders,nausea, diarrhea, vomiting, edema,and constipation. Grade 3 or 4 adversereactions (in ≥4% of patients) includedincreased alanine transaminase levelsand neutropenia. Life-threatening orfatal treatment-related pneumonitisoccur red in 1.6% of pa tients within 2months after the initiation of crizo-tinib therapy. The recommended dosage is 250 mg

orally twice daily. (August 26, 2011)

ADVERTISEMENT

* Crawford J, et al. J Natl Compr Canc Netw. 2008. Nationwide, prospective registry study conducted in 115 community-based, randomly selected, IRB-approved sites, evaluating the incidence and timing of neutropenia and neutropenic events in the first cycle and in cycles 2–3 across major tumor types.

References: 1. Crawford J, et al. J Natl Compr Canc Netw. 2008;6:109-118. 2. Kuderer N, et al. Cancer. 2006;106:2258-2266. 3. Lyman G, et al. J Clin Oncol. 2003;21:4524-4531. 4. Lyman G, et al. J Clin Oncol. 2004;22:4302-4311. 5. Lyman G, et al. J Natl Compr Canc Netw. 2009;7:99-108. 6. Link B, et al. Cancer. 2001;92:1354-1367. 7. Picozzi V, et al. Oncology. 2001;15:1295-1306.8. Bonadonna G, et al. N Engl J Med. 1995;332:901-906. 9. Bonadonna G, et al. BMJ. 2005;330:217-222. 10. Chirivella I, et al. Breast Cancer Res Treat. 2009;114:479-484. 11. Kwak L, et al. J Clin Oncol. 1990;8:963-977. 12. Bosly A, et al. Ann Hematol. 2008;87:277-283.

What happens to the patient caught in the complications of chemotherapy-induced neutropenia?

Figure. Overall survival by average relative dose intensity (ARDI)

0.0

0.4

0.6

0.7

0.8

Years post-chemotherapy

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ARDI: ≤ 85%

ARDI: 86% to ≤ 90%

ARDI: > 90%

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Retrospective chart data of overall survival in 210 patients treated with CHOP-21 according to average relative dose intensity (ARDI). CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone.

Adapted from Bosly A, et al. Ann Hematol. 2008.

For patients with NHL, age > 60 years, advanced disease stage and poor performance status were associated with relative dose intensity < 85%.4

You can intervene for your next patient A comprehensive risk assessment protocol is critical to helping you identify patients at risk for clinically significant febrile neutropenia.

C onsider the risk of the chemotherapy regimenie, chemotherapeutics administered, alone or in combination

A ssess patient risk factorseg, age ≥ 65 years, poor performance status

R isk increases with more comorbiditieseg, COPD, cardiovascular disease, diabetes mellitus

Evaluate each patient prior to every cycle

To request a febrile neutropenia Risk Assessment Checklist, email: [email protected].

Assess the risk.

Consider your last patient with neutropeniaDid your patient experience any consequences from severe or febrile neutropenia? According to a prospective registry study of 2,692 patients encompassing major tumor types, 29.3% overall were impacted by severe or febrile neutropenia in the first 3 cycles of chemotherapy, leaving a large opportunity for risk assessment intervention. This study also showed that the risk of severe or febrile neutropenia was greatest in the first cycle. That risk continued in subsequent cycles.*1

Febrile neutropenia–related hospitalization can lead to mortalityIn a retrospective database analysis (N = 41,779), the inpatient mortality rate for febrile neutropenia–related hospitalization was 9.5%. This inpatient mortality rate was directly related to the number of major comorbidities present at the time of admission. Major comorbidities were defined as any major organ dysfunction requiring diagnostic or therapeutic intervention. Inpatient mortality ranged from 2.6% (556/21,386) for patients with no comorbidities to over 50% (181/358) for those with 4 or more.2

Optimal chemotherapy delivery was shown to improve survival in some tumor typesRetrospective studies have shown that dose delays and reductions due to severe or febrile neutropenia may impact treatment plans and result in unfavorable outcomes for some diagnoses.3-7

While there are inherent risks associated with chemotherapy treatment, landmark studies in both non-Hodgkin’s lymphoma (NHL) and early-stage breast cancer have shown that closer adherence to standard doses is one factor that was associated with increased survival rates.8-11

A retrospective analysis demonstrated significantly longer median survival (7.08 years) for patients with NHL who received > 90% average relative dose intensity of CHOP-21 compared with those who received ≤ 90% (N = 210; P = 0.002) (see Figure).12

Multivariate analyses have identified several independent risk factors for reduced relative dose intensity. The risk factors for relative dose intensity < 85% among early-stage breast cancer patients included age, weight, and three-drug regimens (CAF or CMF).3

© 2010 Amgen. All rights reserved. MC49941 06-10

MC49941 06-10Continued on page 19


ESMO ANNUAL MEETING


Stockholm, Sweden—An investiga-tional alpha-pharmaceutical not onlyprevented skeletal-related events(SREs) in patients with prostate cancerwith bone metastases in a phase 3study presented at the 2011 EuropeanMultidisciplinary Cancer Congress,but it also improved overall survival. “This is the first drug targeted to

bone metastases in prostate cancer toimprove survival,” said lead investiga-tor Chris Parker, MD, Royal MarsdenHospital, London. “There are otherbone drugs used in prostate cancer, butthey help to minimize symptoms; theydon’t improve survival. In my opinion,radium-223 is likely to become a newstandard of treatment for advancedprostate cancer,” Dr Parker told jour-nalists at a press briefing.Jean-Charles Soria, MD, Institut

Gustave Roussy, Villejuif, France, whocochaired the meeting’s scientific pro-gram, agreed. “This is really practicechanging, and after regulatory approval,I think this is going to be a major player

in advanced prostate cancer.”A US coinvestigator of the trial,

Oliver Sartor, MD, Tulane University,New Orleans, LA, said the radiophar-

maceutical is far superior to prior com-pounds of the sort, and the studyresults were highly impressive.Radium-223 chloride (Alpharadin)

was recently granted a fast-track desig-nation by the US Food and DrugAdministration. The company plans tofile a new drug application in mid-2012.The Alpharadin in Symptomatic

Prostate Cancer (ALSYMPCA) trialwas a phase 3, randomized, double-blind, placebo-controlled internationalstudy that compared radium-223 chlo-ride plus current standard of care withplacebo plus current standard of carein 922 men with symptomatic castra-tion-resistant prostate cancer that hadspread to the bone. Patients had multi-ple skeletal metastases on bone scan

and were taking regular analgesics forbone pain.At a planned interim analysis, the

patients who received radium-223 hadthe following positive outcomes:• Median overall survival: 14 monthscompared with 11.2 months for theplacebo group, a 30% reduction inmortality (P = .00185)

• Time to first SREs: 13.6 months ver-sus 8.4 months, a 64% improvement(P = .00046)

• Total alkaline phosphatase (bonemarker) normalization: 33% versus1% (P <.001)

• Time to prostate-specific antigenprogression: 49% improvement(P = .00015).

Nonhematologic adverse events werenot significantly worse with radium-223versus placebo; the most commongrade 3-4 adverse events were bonepain (18% vs 23%, respectively). Otherserious toxicities were uncommon.Based on the interim analysis, the

data monitoring committee recom-mended the study be stopped andpatients in the placebo arm be offeredradium-223. �

Stockholm, Sweden—Two expensivedrugs may be better than 1 for mainte-nance treatment of advanced non–small-cell lung cancer (NSCLC),according to a study at the 2011European Multidisciplinary CancerCongress. Adding pemetrexed(Alimta) to bevacizumab (Avastin)maintenance therapy reduced the riskof disease progression in the phase 3AVAPERL trial.Pemetrexed is approved by the US

Food and Drug Administration for themaintenance treatment of nonsqua-mous, locally advanced or metastaticNSCLC that has not progressed after 4cycles of platinum-based chemo -therapy. AVAPERL was the first phase3 trial to investigate the combinationof pemetrexed plus bevacizumab asmaintenance therapy.Patients receiving the combination

had a median progression-free sur-vival (PFS) of 10.2 months from thestart of first-line induction therapyversus 6.6 months with single-agentbevacizumab maintenance, amount-ing to a 30% re duction in risk (P<.001), reported Fabrice Barlesi, MD,Assistance Publique Hôpitaux deMarseille, France.

Similarly, from study randomizationto maintenance therapy, median PFSwas doubled with the combination: 7.4months versus 3.7 months—a 52%reduction in risk (P <.001). Overall sur-vival from induction was 15.7 monthswith single-agent bevacizumab and

has not been reached with the combi-nation used for maintenance.“First-line cisplatin [Platinol], peme-

trexed, and bevacizumab followed bycontinuation maintenance with beva-cizumab and pemetrexed achieved apatient PFS benefit of unprecedentedmagnitude,” Dr Barlesi maintained.All the 376 patients enrolled in

AVAPERL received four 3-week

cycles of first-line induction withbevacizumab, pemetrexed, and cis-platin. After this treatment, patientswith a response or stable diseasewere randomized to continuationmaintenance with bevacizumab (N =125) or bevacizumab plus peme-trexed (N = 128). PFS was assessedfrom the beginning of induction ther-apy to progression or death.Notably, grade 3-5 hematologic ad -

verse events were greater with the beva-cizumab plus pemetrexed arm, 10% ver-sus 0% in the control arm. Grade 3-5nonhematologic events were noted for31% and 22%, respectively. —CH �

Pemetrexed Plus Bevacizumab Maintenance KeepsNSCLC at Bay Longer

“First-line cisplatin,pemetrexed, andbevacizumab followed bycontinuation maintenancewith bevacizumab andpemetrexed achieved apatient PFS benefit ofunprecedented magnitude.”

—Fabrice Barlesi, MD

New Bone-Targeting Compound Improves Survival in Metastatic Prostate CancerPotentially practice-changing drug By Caroline Helwick

at a glance� The investigational drug

radium-223 chloride is the

first agent targeted to bone

metastases in prostate cancer

that has shown improved survival

� It also prevented skeletal-

related events in this patient

population

� Based on these results, the

phase 3 study was stopped

early and those receiving

placebo were offered radium-223

� The company plans to file a

new drug application in mid-2012

� Experts suggest this new

therapy may be a “game changer”

“This isreallypracticechanging,and afterregulatoryapproval, I

think this is going to be amajor player in advancedprostate cancer.”

—Jean-Charles Soria, MD

New Warnings for Bevacizumab

On September 30, 2011, the USFood and Drug Administrationissued label changes for bevacizumab(Avastin), adding these 3 warnings:an increased risk for ovarian failurein premenopausal women who usethe drug in combination with themFOLFOX regimen; a risk for venousthromboembolism (VTE) and bleed-ing in patients using anticoagulationtherapy after a first VTE event whilereceiving bevacizumab; and a risk forosteonecrosis of the jaw.


ESMO ANNUAL MEETING


The Road to Personalized Medicine... Continued from cover

profile that requires a finely tuneddrug regimen. “Some subgroups willbe so small, it will be impossible toimplement clinical trials [to evaluatesuch regimens] with sufficient power,”he said.

Intratumor Heterogeneity

Emerging data further suggest thattumors within one patient may be het-erogeneous. Discordance between theprimary (initial, nonmetastatic) tumorand the recurrent or metastatic lesionhas been recently established. Althoughthis has been evaluated for estrogenreceptor and HER2 status, geneticmutations can also vary. Some discor-dance between primary and advanceddisease has been observed in as manyas 40% of patients in some studies, andthis presents a big clinical problem.“We found one patient with 2 metas-

tases, with 2 different mutations inPI3K, and the primary tumor wascalled a wild type [ie, lacking themutation]. If you treated according tothe primary tumor, you would notgive this patient a PI3K inhibitor. But itturns out there was heterogeneity inthe primary tumor,” Dr Mills said.“The mutations were there. If this isthe case, will we have to grind up thewhole tumor and look deeply? Yes, orwe will run the risk of treating thewrong disease. This is the future: biop-sy, biopsy, biopsy.” Better categorization will also be

required of the mutations that are dis-covered, in particular, distinguishingmutations that are “drivers” and “drug-gable” from those that are “passengers”and thus exert no harm. Tumors willneed to be sequenced in depth to cap-ture important subclones, he said.“We are finding hundreds, if not

thousands, of mutations, and not allare created equal. How will we inte-grate this information to find driversthat can be targeted for each patient?And for the actionable aberrations wehave a limited number of drugs,” DrMills pointed out.Even when the tumor is well

described, and a drug has been mar-keted to target the patient’s variousreceptors and mutations, resistanceultimately develops in metastatic dis-ease, and responses—which can bedramatic with some targeted agents—are not durable.“We have to figure out how to make

durable, combinatorial therapy to im -prove outcomes,” he said.

Pilot Study Results

Dr Mills and his colleagues at theZayed Institute for Personalized Cancer

Therapy “are finding actionable muta-tions and doing ‘N of 1’ clinical trials inan efficient manner to determine whichpopulations could benefit from a partic-ular drug,” he said.They are observing very high re -

sponses in many patients for whomthey are able to identify the “driver”mutations and match these to aneffective agent. But they have alsofound that in their first 1000 patients,only about 40% have genetic aberra-tions in the tumor, and only 25% have“actionable” mutations. This meansthat the pool of patients who willtruly be candidates for personalizedmedicine may be narrower than orig-inally believed.“There are still many patients who

will benefit, but in terms of delivering‘personalized medicine’ to all patients,we are way below the desired num-bers,” Dr Mills said.

Cost Considerations in

Personalized Cancer Therapy

The new era of personalized medi-cine in oncology raises economic con-cerns of the cost-benefit ratio. The useof molecular testing, some argue, isadding a significant burden to the totalcost of therapy. But others have shown,for example in relation to KRAS, thatalthough the cost of testing is consider-able, a true economic analysis showsthat genetic testing actually reducesthe total costs, by decreasing the num-ber of patients who receive a high-costtherapy that does not benefit them.

Dr Mills also discussed the potentialcost implications of genomic medicine. “The cost of implementing personal-

ized cancer therapy has added a mas-sive burden to healthcare costs at avery minor improvement in outcomesfor a small population,” said Dr Mills.He noted that although there has beenmodest success so far, there have been“spectacular failures” as well.“We are far from understanding the

challenges and overcoming the pitfallsto the implementation of personalizedcancer therapy,” he said, and one ofthese is the cost of technology andtreatment in this new era.“The cost of assessing molecular

markers such as genetic sequenc-ing and the cost of targeted therapies

that benefit only a few patients con -stitute incredible burdens on alreadystrained healthcare resources. Next-generation sequencing [NGS] approach -es are held as the next great step for-ward in implementing personalizedcancer therapy. Indeed, it is possibleto sequence a human genome forunder $10,000, and the costs continueto drop rapidly. However, NGS iscurrently fraught with major prob-lems,” Dr Mills maintained.“The cost of $10,000 for a human

genome is presupposed on a depth ofsequencing of 30- to 60-fold. Unfortu -nately, at this depth of sequencing,achieving a true-positive rate of 60%results in a false-positive rate ap -proaching 60%. Both of these areunacceptable for patient manage-

ment. Further, the $10,000 does notinclude the costs of bioinformaticsanalysis of data storage and handling.Indeed, it has been estimated thateven the eventual $1000 genome willcost $100,000 to manage and inter-pret,” he said.Accurate treatment calls for targeting

the specific tumor characteristics, andfor patients with metastatic disease thismeans rebiopsying, perhaps repeatedly,to reveal important subclones withineach tumor. “This would massivelyincrease the cost, as well as be associat-ed with the morbidity of repeat biop-sies. The goal of replacing biopsies withmolecular imaging or characterizationof circulating tumor cells or DNAremains an important dream, but adream nevertheless,” he said.Resistance to targeted therapies is

another challenge in recurrent dis-ease; therefore, combination regi-mens will be necessary to addresscompensatory signaling pathwaysand to help overcome resistance. “This is fraught with its own chal-

lenges of increased costs, increasedtoxicity, and difficulty in gettingmultiple companies to cooperate inclinical trials,” Dr Mills said. However, José Baselga, MD, PhD,

Co director of the MassachusettsGeneral Hospital Cancer Center, whois a clinician and a translational scien-tist, was more optimistic about the eco-nomics of this approach. He comment-ed that, “The cost of looking formutations should be far less than thecost of treating patients with expen-sive therapies that will not work inthem.” With a goal of advancing personal-

ized medicine over the next 10 years,Dr Baselga called for dedicated facili-ties to study the treatment of patientswith novel agents, expansion oftumor genotyping and next-genera-tion sequencing, creation of tumorbiomarker facilities, sharing of data,incorporation of novel technologicplatforms, innovative clinical trialdesign, and recruitment of “the bestpool of physician scientists into a cul-ture of team work.” �

“The cost of looking for mutationsshould be far less than the cost of treating patients with expensivetherapies that will not work in them.” —José Baselga, MD, PhD

Photo Courtesy © ASCO/Todd Buchanan 2007

“We are finding hundreds, if notthousands, of mutations, and not all are created equal. How will weintegrate this information to finddrivers that can be targeted for eachpatient? And for the actionableaberrations we have a limited number of drugs.”

—Gordon Mills, MD

Death rates for esophageal cancer,

1990-2006Women: Men:

0.2% 9.7%

2011 estimates Incidence: 16,980 Deaths: 14,710

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www.VELCADE.com

If You Define Value as an Overall Survival Advantage:

If You Define Value as Medication Cost:

VELCADE Warnings, Precautions, and Adverse Events

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

UPDATED VISTA* OVERALL SURVIVAL (OS) ANALYSIS: VcMP† vs MP(36.7-month median follow-up)

VELCADE+MP (n=344)MP (n=338)

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Months0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

HR 0.65 (95% CI, 0.51-0.84); P=0.00084

In Previously Untreated Multiple MyelomaIMPORTANT 3-YEAR UPDATE- SUSTAINED BENEFIT

Kaplan-Meier estimate.

MEDIAN OSNOT REACHEDFOR VcMP

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(36.7-month median follow-up)A* OVERAL TED VIST TA* OVERALL SURVIVAATED VISTUPD

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(36.7-month median follow-up)SIS: VcMYYSIS: VcMAL (OS) ANAL LY LL SURVIV VAL (OS) ANAL

AINE TE- SUST TAINED BENEFIT UPDA ATE- SUST

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INDICATIONS:

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphomawho have received at least 1 prior therapy.

CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use ofantineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment withVELCADE.

Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while beingtreated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and adecreased number of live fetuses.

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 withpre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheralneuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment withVELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation,hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencingnew or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE.Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51%of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement inor resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. Thelong-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. Theseevents are observed throughout therapy. Caution should be used when treating patients with a history ofsyncope, patients receiving medications known to be associated with hypotension, and patients who aredehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensivemedications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset ofdecreased left ventricular ejection fraction have been reported, including reports in patients with no riskfactors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart diseaseshould be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively.The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure,cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causalityhas not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknownetiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory DistressSyndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial,the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicinand VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. Therehave been reports of pulmonary hypertension associated with VELCADE administration in the absence ofleft heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonarysymptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patientsreceiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure,hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances.Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patientsdeveloping RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previouslyexperiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, andvomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid andelectrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia thatfollow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recoveringprior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases andrecovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence ofcumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In therelapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar onboth the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to eachdose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and scheduleof VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association withVELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, thecomplications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those withhigh tumor burden prior to treatment. These patients should be monitored closely and appropriateprecautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitantmedications and with serious underlying medical conditions. Other reported hepatic events includeincreases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upondiscontinuation of VELCADE. There is limited re-challenge information in these patients.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure isincreased in patients with moderate or severe hepatic impairment. These patients should be treated withVELCADE at reduced starting doses and closely monitored for toxicities.

ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma(N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) andpreviously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, thesafety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (includingfatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheralneuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%),thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%),anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), coughand insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo);(each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension(each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia(each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) ofpatients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) andneutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies.The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%),and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination withmelphalan/prednisone is consistentwith the known safety profiles of both VELCADE and melphalan/prednisone.The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vsmelphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea(48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%),constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%),pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%),asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%),rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%),dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain(14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%),hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension(12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%),arthralgia (11% vs 15%) and pruritus (10% vs 5%).

DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib.Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposureof bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole,a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantlyreceiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closelymonitored for either toxicities or reduced efficacy.

USE IN SPECIFIC POPULATIONS:

Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs areexcreted in human milk and because of the potential for serious adverse reactions in nursing infants fromVELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking intoaccount 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 andyounger 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 renalimpairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency.Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysisprocedure. For information concerning dosing of melphalan in patients with renal impairment, seemanufacturer's prescribing information.

Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate andsevere hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabeticpatients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADEtreatment may require close monitoring of their blood glucose levels and adjustment of the dose of theirantidiabetic medication.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc.Other trademarks are property of their respective owners.Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Cambridge, MA 02139Copyright ©2009, Millennium Pharmaceuticals, Inc.

Brief Summary

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5:02 PM


ESMO ANNUAL MEETING


4 9

Value of Bevacizumab in Ovarian Cancer Got a Boost in a New Analysis“Bevacizumab should be continued until disease progression”By Caroline Helwick

Stockholm, Sweden—The indefiniteuse of bevacizumab (Avastin) inpatients with re lapsed ovarian cancergot another boost at the 2011 EuropeanMulti disciplinary Cancer Congress,with a subanalysis of the phase 3OCEANS trial showing consistentbenefit across subgroups. The main finding of OCEANS,

which was reported earlier at the 2011American Society of Clinical Oncolo -gy annual meeting, was that the addi-tion of bevacizumab to carboplatin(Paraplatin)/gemcitabine (Gemzar) inpatients with advanced ovarian cancerreduced the risk of disease progress -ion by 52%. OCEANS enrolled 484 women with

a first recurrence of ovarian cancer andno prior treatment with bevacizumab.In the experimental arm, bevacizumab15 mg/kg was given concurrentlywith chemotherapy followed by beva-cizumab maintenance until diseaseprogression or unacceptable toxicityoccurred. Patients in the control armreceived chemotherapy plus placebo

and placebo maintenance. In Stockholm, OCEANS investiga-

tors reported a consistent effect acrossthe majority of clinically relevant sub-groups, including not only platinum-sensitive patients and those with lessbulky disease but also those with par-tially platinum-sensitive disease andbulky disease, who tend to fare poorly.

For patients with a platinum-freeinterval (PFI) of <24 months (indicat-ing platinum sensitivity), median pro-gression-free survival (PFS) was 16.6

months with bevacizumab and 11.6months with placebo, for a 38% reduc-tion in risk. For patients with a PFI of12 to 24 months (indicating partialplatinum sensitivity), median PFS was12.3 and 8.6 months, respectively, for a48% risk reduction. Patients with PFI<12 months, indicating less platinum-sensitive disease, had a median PFS of12.5 months and 7.4 months, respec-tively, for a 64% risk reduction, DrAghajanian reported. Overall survivaldata are not yet mature.“Bevacizumab plus chemotherapy

followed by bevacizumab until diseaseprogression should be considered anoption for recurrent ovarian cancer,”said Carol Aghajanian, MD, ofMemorial Sloan-Kettering CancerCenter, New York. Putting the results of OCEAN togeth-

er with those of 2 other key trials—ICON7 and Gynecologic OncologyGroup (GOG)-218—the study’s formaldiscussant, Stanley Kaye, MD, RoyalMarsden Hospital and Institute forCancer Research, London, commented

on the status of vascular endothelialgrowth factor inhibition in ovarian can-cer. “This is its finest hour,” he said. “Itseems that patients with a relativelypoor outlook have the most to gain. Akey message is that in recurrent disease,bevacizumab should be given withchemotherapy and continued until dis-ease progression.”

Quality of Life Not Worsened with

Frontline Bevacizumab

Additional studies analyzed quali-ty-of-life data in the ICON7 and GOGtrials, showing that incorporatingbevacizumab into frontline therapy ofpatients with ovarian cancer did notworsen, or improve, quality of life. Although the studies had somewhat

different designs and end points andused different doses of bevacizumab,together they provide “an unprece-dented database on quality of life inovarian cancer that will be valuable forfuture studies,” said Ate G. J. van derZee, MD, of University Medical Centerin Groningen, the Netherlands. �

“It seems that patients witha relatively poor outlookhave the most to gain. A keymessage is that in recurrentdisease, bevacizumab shouldbe given with chemotherapyand continued until diseaseprogression.”

—Stanley Kaye, MD

Positive Data Continue to Accrue for Crizotinib in ALK-Positive NSCLCVisual effects reported as transient, don’t affect dosing

Stockholm, Sweden—In patients withadvanced non–small-cell lung cancer(NSCLC) and anaplastic lymphomakinase (ALK) gene rearrangements,treatment with crizotinib (Xalkori)provided clinically meaningful antitu-mor activity, producing responses in51% of patients, in the multicenterphase 2 PROFILE 1005 study reportedat the 2011 European MultidisciplinaryCan cer Congress.Rearrangements in ALK (ie, activat-

ing ALK mutations or translocations)are seen in up to 5% of patients, andcrizotinib—a first-in-class, oral, potent,and selective small molecular entity—competitively inhibits ALK. The report was based on an ongoing

open-label phase 2 study of the first133 evaluable patients, who receivedcrizotinib 250 mg twice daily on a con-tinuous basis until progression. Ob -jective responses were observed in50.4% of patients, with 1 being a com-plete response. Stable disease wasobserved in another 33.8%, reported

Dong-Wan Kim, MD, Clinical Re -searcher, Seoul National UniversityHospital, South Korea.

Of all responders, 79.4% demon-strated a response within the first 8weeks of treatment and maintained itfor an average of 42 weeks. A total of32% of patients discontinued thestudy, but only 4.4% as a result ofadverse events. Treatment-relatedgrade 3-4 adverse events were report-ed in 26% of patients, mainly elevatedliver enzymes and neutropenia.

About half the patients completedpatient-reported outcomes for keysymptoms and global quality of life.Clinically meaningful improvements(change, ≥10 points) were reported forpain, dyspnea, and cough from asearly as cycle 2 and for fatigue fromcycle 5; these positive changes weremaintained through all subsequentcycles. Global quality of life was alsomaintained during treatment, withclinically meaningful improvementseen by cycle 7, Dr Kim reported.

Visual Effects Evaluated

One of the most frequently reportedside effects of crizotinib treatment isvisual events. These are described asimage carryover, flashing/trailinglights and floaters, and/or blurryvision, often occurring during lightadaptation. A patient-reported ques-tionnaire (Visual Symptom Assess -ment Questionnaire [VSAQ]) wasdeveloped to further characterizethese symptoms and their effect on

activities of daily living.Ben Solomon, MD, of the Peter

MacCallum Cancer Centre, located inMel bourne, Australia, reported a pre-liminary analysis of VSAQ findings in57 patients, showing that the visualeffects associated with crizotinib hadno or only minimal impact on patients’daily activities.“The majority of patients reported

that each visual effects event was tran-sient, lasting either 30 seconds or lessor between 30 and 60 seconds,” DrSolomon noted.Approximately 56% of patients at

cycle 2 and 50% at cycle 3 and cycle 4reported visual effects, but these didnot require dose alterations, he said.The frequency of visual effects variedduring cycles 2 to 4. Most patientssaid they were not bothered by thevisual effects events or found them“only a little bothersome,” Dr Sol -omon said. No clinically meaningfulchanges were noted on ophthal micexaminations. —CH �

“The majority of patientsreported that each visualeffects event was transient,lasting either 30 seconds orless or between 30 and 60 seconds.”

—Ben Solomon, MD


ESMO ANNUAL MEETING


Everolimus-Exemestane Combination Prolongs Remission by 4 Months in Metastatic Breast Cancer“The most important advance in breast cancer since trastuzumab”By Caroline Helwick

Stockholm, Sweden—The use of ever -olimus (Afinitor) together with thearomatase inhibitor exemestane(Aromasin) more than halved the riskfor disease progression in patientswith advanced breast cancer, addingan average of 4 disease-free months,investigators reported at the 2011European Society for Medical Oncol -ogy European Multidisciplinary Can -cer Congress.

Lead investigator José Baselga, MD,of Massachusetts General Hospital,Boston, predicted that this combina-tion “could represent a new therapeu-tic option” for postmenopausal wo -men who have received previoushormonal therapy.

The hypothesis is that the mTORinhibitor could reverse the resistanceto endocrine therapy that inevitablydevelops in hormone receptor–posi-tive patients, a concept based onstrong preclinical evidence.

Fabrice André, MD, PhD, of theInstitut Gustav Roussy, Villejuif,France, commented on the results,saying, “I would consider the efficacyof everolimus in the range of themost important advances in medicaloncology.”

BOLERO-2

The phase 3 trial BOLERO-2 washalted early after an interim analysisshowed a 57% reduced risk for pro-gression in postmenopausal patients

with estrogen receptor–positive, HER2-negative disease.

In earlier phase 2 trials, the mTORinhibitor everolimus—approved forthe treatment of renal-cell carcinoma—

was effective as monotherapy and incombination with hormonal therapy.A double-blind, placebo-controlledphase 3 trial then evaluated the combi-nation in women who had previouslyreceived letrozole (Femara) or anastro-zole (Arimidex) whose disease contin-ued to progress.

The 724 patients were randomizedto either everolimus 10 mg/day orplacebo; all patients also receivedexemestane daily.

At an interim analysis, investigatorsobserved significantly better progres-sion-free survival (PFS) for the com-bined treatment group versus placebo:median 6.9 months versus 2.8 months,respectively (P <.001), according tolocal investigator assessment. By cen-tral review, the benefit was evengreater, with median PFS, 10.6 monthsversus 4.1 months, respectively, a 64%risk reduction (P <.001).

Overall survival data are immature,but Dr Baselga said there had been 83deaths overall, including 13% in theplacebo arm and 10% in the combina-tion therapy arm.

Future analyses will determine theeffects on bone metabolism, becauseeverolimus is expected to counteractthe bone problems that have beenassociated with aromatase inhibitors.Numerically, there were more grade 3-4 side effects with the combination, butthese were very uncommon in botharms and did not worsen quality of life

for patients taking the 2 drugs, he said.“Our results could represent a

paradigm shift in the managementof patients with hormone receptor–positive breast cancer,” Dr Baselgaconcluded.

Dr André said the study was welldesigned, used an appropriate controlarm, and appeared to be molecularlyenriched for mTOR activation on thebasis of the subjects’ resistance toendocrine therapy. “Everolimus notonly improves outcomes but opensperspectives in the field of kinaseinhibitors in general. I think this is themost important advance in breast can-cer since trastuzumab [Herceptin].” �

“I would consider theefficacy of everolimus in therange of the most importantadvances in medicaloncology. Our results couldrepresent a paradigm shift inthe management of patientswith hormone receptor–positive breast cancer.”

—José Baselga, MD

at a glance� Everolimus plus exemestane

more than halved the risk for

disease progression in patients

with advanced breast cancer

� The combination of everolimus

plus the aromatase inhibitor

added an average of 4 months

of progression-free survival

� This combination could

represent a new therapeutic

option for postmenopausal

women who have received

previous hormonal therapy

� The efficacy of everolimus can

be considered one of the most

important advances in oncology

Photo Courtesy © ASCO/Todd Buchanan 2007

Therapy-Associated Complications... Continued from cover

cost of treating metastatic breast cancer. The treatment of metastatic breast

cancer varies from $3000 to $8000 perpatient per month, but treating thecomplications that are associated withthe cancer treatment adds another$3000 to $4000 to the total cost of ther-apy, according to Dr Brammer. She re -ported the results of her study at the2011 European Multidisciplinary Can -cer Congress.

“Incremental costs of treating ad -verse events should be considered inevaluating new therapies. There is aneed for treatments that are effective,but do not incur significant toxicities,”Dr Brammer suggested.

She and her coinvestigators usedthe PharMetrics Integrated Database(2004-2009) to select patients withmetastatic breast cancer who were

treated with chemotherapy and/oragents targeting HER2.

They identified episodes of treat-ment with single-agent or combinationtherapies for a course of at least 30days. They determined the complica-

tions associated with treatment, usingmedical claims with a diagnosis for oneof the following events of interest:anemia, alopecia, arthralgia, bilirubinelevation, dehydration, dyspnea, infec-

tion, leukopenia, and neutropenia. A total of 1551 patients with 3157 eli-

gible episodes of treatment met theinclusion criteria. The most commontreatment-associated complicationswere anemia, bilirubin elevations, and

leukopenia, with substantial variationacross type of regimen, Dr Brammerreported.

Anemia was the most commonevent with trastuzumab (Herceptin)/

vinorelbine (Navelbine) (70%), single-agent gemcitabine (Gemzar) (70%),and vinorelbine (65%); it was leastlikely with capecitabine (Xeloda).Bilirubin elevations were most com-mon with trastuzumab/vinorelbine(35%), tras tuzumab/docetaxel (Tax -otere) (31%), and single-agent paclitax-el (Taxol) (31%). Leukopenia was mostcommon with vinorelbine (46%) andtrastuzumab/vinorelbine (38%). Neu -tro penia was most common withvinorelbine (30%) and trastuzumab/vinorelbine (30%).

The average monthly cost per pa -tient for treating the most expensivechemotherapy-related complicationsincluded $3200 for anemia, $3820 fordehydration, $4217 for dyspnea, and$3453 for neutropenia. Similar costs

“Incremental costs of treating adverse events should beconsidered in evaluating new therapies. There is a need for treat ments that are effective but do not incur significant toxicities.” —Melissa Brammer, MD



ESMO ANNUAL MEETING


were incurred when these side effectsoccurred with anti-HER2 agents.The cost drivers associated with

anemia and neutropenia were drugex penses, whereas dyspnea anddehydration costs were driven most-ly by hospitalization expenses. Thetreatment-related costs in this studydid not capture out-of-claims costs,such as alopecia and fatigue; there-fore, the total cost of these complica-tions is actually even higher, DrBrammer noted.

Skeletal-Related Events Linked to

Heavy Resource Utilization

Skeletal-related events (SREs) canlead to lengthy hospitalizations andmany outpatient visits in patientswith bone metastases, suggestedHerbert Hoefeler, MD, of the For -

schungszentrum Rhur in Witten,Germany. He presented results from amulticenter prospective observationalstudy conducted in Europe, Canada,and the United States. The study estimated future resourc-

ing needs and assessed the value ofnew treatments to prevent SREs.Although studies have shown thatSREs increase health resource utiliza-tion and cost, “there is a lack ofrobust, prospective data” on which tobase decisions, Dr Hoefeler said.“This is the first study to examinehealth resource utilization associatedwith different types of SREsprospective ly in a large sample ofpatients in Europe.”The study included 478 European

patients who had bone metastases sec-ondary to breast cancer, prostate can-

cer, lung cancer, or multiple myeloma,and who had at least 1 SRE within 90days of study enrollment.

Across all tumor types and coun-tries, 21% to 48% of SREs required

inpatient stays, with an average dura-tion of 13 to 27 days. Outpatient visitswere required for 58% to 84% of SREs,with each SRE associated with a meanof 2.5 to 7.3 outpatient visits. Hospitalization rates were similar

across tumor types, but a trend towarda higher percentage was seen for lungcancer—29% to 49% (according tocountry) versus 20% to 29% for othertumor types. Fewer outpatient visits were report-

ed per SRE in the United Kingdom,which was primarily driven by greateruse of single-fraction radiation.“Preventing SREs occurring in all

individuals with cancer is importantto substantially reduce patient bur -den and rate of hospitalization,” DrHoefeler said. “This may reduce costlyhealth resource utilization.” �

New T-DM1 Reduces Disease Progression by 40% in AdvancedBreast Cancer, with Low ToxicityBy Caroline Helwick

Stockholm, Sweden—Trastuzumab em -tansine (T-DM1), a novel monoclonalantibody–guided therapy for HER2-positive metastatic breast cancer,achieved almost a 40% reduction in therisk of disease progression comparedwith standard treatment withtrastuzumab (Herceptin) and docetax-el (Taxotere), investigators reported atthe 2011 European MultidisciplinaryCancer Congress.Excitement over T-DM1 has been

steadily building since early resultswere presented several years ago. Theresults have been so encouragingthat the manufacturer has a numberof similar compounds in development,investigators said. T-DM1 is an antibody-drug conju-

gate that links a cytotoxic agent (may-tansine) to a monoclonal antibody. It isonly when the molecule binds to theHER2 receptor via the antibody and isabsorbed into the tumor cell that thechemotherapy is released, producing ahighly targeted blow and sparing nor-mal tissues, thus avoiding adverseeffects typically associated with chemo -therapy, explained Sara Hurvitz, MD,University of California, Los Angeles,who presented the findings of thephase 2 trial.The study included 137 women

with locally advanced or metastaticHER2-positive breast cancer and noprior treatment for advanced disease.They were randomized to 3.6 mg/kg

of T-DM1 or to the standard regimenof trastuzumab plus docetaxel.Progression-free survival (PFS) was

14.2 months with T-DM1 compared with9.2 months with standard therapy—a41% relative risk reduction (P = .035),Dr Hurvitz reported.Although response rates were simi-

lar, the median duration of responsewas markedly higher in the experimen-tal arm. Patients receiving standardtherapy were stable for 9.5 months, onaverage, but the median duration ofresponse had not been reached in theT-DM1 arm at the time of analysis. Thismeans the treatment “is probably verydurable,” Dr Hurvitz said.Patients receiving T-DM1 also were

able to remain on treatment muchlonger than those on standard therapy,primarily because of toxicities such asneuropathy, she pointed out.Overall toxicity was far lower with

T-DM1, which is a key reason for itsappeal, Dr Hurvitz suggested. Adverseevents were reported by 46.4% ofpatients taking T-DM1 versus 89.4% ofpatients receiving standard treatment;discontinuation occurred in 7.2% ver-sus 28.8%. Neutropenia, alopecia, diar-rhea, and edema were also substantial-ly less common with T-DM1.However, thrombocytopenia was

observed more often with T-DM1 thanwith placebo (30.4% vs 6.1%, respec-tively), and liver enzymes were in -creased (39.1% vs 6.1%); thrombocy-

topenia is likely tied to the drug’seffect on the bone marrow, Dr Hurvitzsuggested.The results of 2 ongoing phase 3 tri-

als—EMILIA/TDM4370g and MARI-ANNE—are expected in spring 2012.Martine Piccart-Gebhart, MD, PhD,

of the Jules Bordet Institute, Brussels,Belgium, cautioned that these areearly-phase results. Pending theresults from the phase 3 trials, howev-er, T-DM1 “hopefully will be availableto patients in the not-too-distantfuture,” she predicted. �

Overall toxicity was far lower with T-DM1, which is a keyreason for its appeal. Adverse events were reported by 46.4%of patients taking T-DM1 versus 89.4% of patients receivingstandard treatment. —Sara Hurvitz, MD

Therapy-Associated Complications... Continued from page 14

“Preventing SREs occurring in all individuals with cancer is important tosubstantially reduce patient burden and rate of hospitalization. This may reduce costly health resource utilization.”

—Herbert Hoefeler, MD


VBCC PERSPECTIVE


It is next to impossible for a day to goby without thinking about the con-tributions of personalized medicine

to the care of patients living with can-cer. Whether we are treating a newlydiagnosed patient with HER2/neu-positive breast cancer using trastuzu -mab, or using erlotinib in the manage-ment of a patient with non–small-celllung cancer (NSCLC) whose tumorharbors specific mutations in the epi-dermal growth factor receptor genes,individualizing therapy based onmolecular biology and genetic testinghas become commonplace in contem-porary oncology practice. Yet, as our knowledge of cancer biol-

ogy continues to increase exponential-ly, we now find ourselves on the brinkof where discovery and clinical prac-tice collide, permanently changing thefuture of cancer medicine by alteringthe way we think not only about can-cer therapy but also about cancer clas-sification. In August 2011, the US Food and

Drug Administration (FDA) approved3 novel targeted therapies for patientswith cancer. Although the availabilityof new drugs is often enough to gen -erate attention among healthcare pro -viders and patients with cancer alike,what is unique, in this case, is thesimultaneous approval of 2 of thesenew drugs—crizotinib (Xalkori) andvemurafenib (Zelboraf)—with com-panion molecular assays, representinga potential paradigm shift in the FDA’sapproach to new, niche, biomarker-guided therapies. The specificity ofeach of these drugs for discrete, andsomewhat uncommon, molecular tar-gets will undoubtedly change the waywe approach the management ofpatients for which these new therapiesmay be indicated.Crizotinib is a first-in-class oral

anaplastic lymphoma kinase (ALK)inhibitor indicated for the manage-ment of locally advanced or metastaticNSCLC. Mutations or translocationswithin the ALK gene, which are foundin only 3% to 5% of all NSCLCs, giverise to the overexpression of the fusionprotein EML4-ALK, ultimately result-ing in the constitutive activation of theRas/MAP kinase pathway. When aberrantly activated, this sig-

naling pathway is known to fuel can-

cer growth by promoting cell prolifer-ation and survival.1 Before prescrib -ing crizotinib therapy to a patient, pro -viders must first ensure that thepatient is ALK-positive by using theconcurrently approved molecularassay known as the Vysis ALK Break-Apart FISH Probe Kit. This test usesfluorescence in situ hybridization tech-nology to detect gene rearrangementswithin the 2p23 chromosome that indi-cate that a patient may derive benefitfrom treatment with crizotinib.

For the small percentage of patientswith NSCLC and the appropriate ALKmutations, the efficacy of crizotinibdemonstrated in clinical trials suggeststhat this drug may be a valuable addi-tion to our arsenal of available treat-ment options. The FDA granted crizo-tinib accelerated approval after thecompletion of 2 early-phase studies thatenrolled a total of 255 patients (94% hadreceived previous treatment).2

A phase 1 study demonstrated a 57%overall response rate (complete pluspartial responses) and a 72% progres-sion-free survival (PFS) at 6 months.3

Results from the phase 2 PROFILE1005 trial confirmed similar findings,with an objective response rate of 61%and median response duration of 48weeks.3 Furthermore, crizotinib ap -pears to be well tolerated, with visiondisorders (occurring in 62% of pa -tients), nausea (53%), diarrhea (43%),vomiting (40%), edema (28%), and con-stipation (27%) representing the mostcommon adverse events.4

In view of the poor prognosis ofpatients with metastatic melanomaand the relative lack of therapies offer-ing improved survival outcomes, theapproval of vemurafenib represents asignificant achievement for the role ofpersonalized medicine in this deadlydisease state. Mechanistically, vemu-rafenib is an inhibitor of the BRAFV600E mutation found in approxi-mately 40% to 60% of all patients withcutaneous melanomas.

Much like the ALK mutations inNSCLC, these BRAF V600E mutationsresult in the activation of the MAPkinase pathway, thereby promotingtumor growth. However, it should benoted that vemurafenib has no activityin patients with wild-type BRAF, sopatients must be screened by using thecompanion cobas 4800 BRAF V600Mutation Test, which was concurrent-ly approved by the FDA.The phase 3 BRAF Inhibitor in

Melanoma (BRIM) 3 trial compared

vemurafenib with dacarbazine, a stan-dard of care for patients with meta -static melanoma.5 With a primary endpoint of overall survival at 6 months,the BRIM 3 study demonstrated a sig-nificant improvement in favor ofvemurafenib (84% vs 64% with dacar-bazine). PFS was also more favorablewith vemurafenib than with dacar-bazine (5.3 months vs 1.6 months,respectively).5 Vemurafenib was welltolerated, with rash, arthralgia, andfatigue reported as the most commonadverse events.5

Undoubtedly, the availability ofvemurafenib and ipilimumab (aCTLA-4 targeted monoclonal antibodyapproved by the FDA in March 2011)represents a major stride in our under-standing of the molecular basis ofstage IV melanoma, for which themedian survival has historically beenonly 8 to 18 months.6

Brentuximab vedotin (Adcetris)—the third new drug approved inAugust—not only offers new hope topatients with Hodgkin lymphoma whohave previously failed autologousstem-cell transplant (ASCT) therapy orwho are not candidates for ASCT afterfailing previous Hodgkin lymphomatherapy, but it may also help to reignitea debate regarding a new way of classi-fying malignant diseases based onunderlying molecular abnormalitiesrather than the traditionally usedorgan-based system of origin.It has been well documented that

CD30 is expressed on a subset of Reed-Sternberg cells found in Hodgkin lym-phoma and anaplastic large-cell lym-phomas (which is also an FDA-approved indication for brentuximab),some T-cell lymphomas, and some B-cell non-Hodgkin lymphomas. Bren -tuxi mab vedotin combines a CD30-tar-geted monoclonal antibody with theantitubulin compound mono methylauristatin E to form a potent novel drugcapable of inducing apoptosis by inhibit-ing the cell cycle in the G2/M phase.7

In the Hodgkin lymphoma study,the overall response rate was 73%,with an astounding 32% of patientsachieving a complete response. Theseresults are especially significant inview of the historically poor prognosisobserved in patients with Hodgkinlymphoma who failed ASCT.8

A new clinical trial will attempt toscreen for CD30 positivity amongpatients with metastatic solid tumorswho are running out of treatmentoptions. Patients confirmed as CD30-positive will be treated with brentux-imab in the experimental setting toassess disease response.9

This idea of evaluating malignanciesfor commonly expressed molecularbiomarkers and treating those patientswith similar therapeutic approaches isnot new. In a 1999 article published inScience, Golub and colleagues attempt-ed to challenge our thinking of oncolo-gy practice by suggesting just such amolecular classification system.10

With 32 targeted therapies currentlyapproved by the FDA for patients withcancer, and with, arguably, hundredsmore in various stages of develop-ment, is it possible that we haveentered the era of molecular classifica-tion of cancer? Is it possible that thehistoric nomenclature of breast cancer,lung cancer, pancreatic cancer, and soon, has become an outdated system ofthinking that will be toppled by a newsystem in which malignancies will bethought about, classified, and treatedaccording to their biomarkers (eg,CD30, ALK, mTOR, KRAS)? It is reasonable to believe that the

onslaught of new knowledge of cancerbiology and the development of tar-geted therapies has begun a revolutionin cancer medicine that will ultimatelyresult in a totally new way of thinkingabout cancer and usher in a new era ofpersonalized cancer medicine. �

References available at www.valuebasedcancercare.com

The New Era of Personalized Medicine in Oncology: NovelBiomarkers Ushering in New Approaches to Cancer Therapy Steve Stricker, PharmD, MS, BCOPAssistant Professor of Pharmacy Practice, Samford University McWhorter School of Pharmacy, Birmingham, AL

Reprinted with permission from AmericanHealth & Drug Benefits. 2011;4:387-388.

The onslaught of new knowledge ofcancer biology and the development oftargeted therapies has begun a revolutionin cancer medicine that will ultimatelyresult in a totally new way of thinkingabout cancer and usher in a new era ofpersonalized cancer medicine.


N O WA P P R O V E D

Visit www.zytiga.com

Contact your Centocor Ortho Biotech Sales Representative for more information.

© Centocor Ortho Biotech Inc. 2011 4/11 08A11076C




Columbus, during the recent Na tion -al Com prehensive Cancer Net work(NCCN) 6th Congress on HematologicMalignancies.

Dr Devine defined maintenancetherapy as treatment designed to pre-vent relapse in patients who achievecomplete response (CR) or partialresponse with induction therapy.Maintenance therapy for myeloma isusually of relatively low intensity andlong duration, he said.

Maintenance therapy for myelomacontinues to evolve as new agentsbecome available. Selection of the bestdrug for particular patient groups isthe subject of ongoing trials. At pres-ent, NCCN guidelines recommendthalidomide, lenalidomide, andbortezomib for maintenance therapy.

For maintenance, thalidomide hascategory 1 recommendation and borte-zomib and lenalidomide have category2A recommendation, but thalidomidecarries a high risk for severe peripher-al neuropathy.

Lenalidomide is now included inthe NCCN guidelines as an option forpatients with active myeloma whorespond to induction therapy; thesepatients can either continue inductionchemotherapy to plateau or undergo

ASCT and then be treated with main-tenance therapy. Lenalidomide asmaintenance therapy is supported bytwo phase 3 trials (McCarthy PL, et al.Blood. 2010;116:abstr 37; Attal M, et al.Blood. 2010;116:abstr 310). Both studiesshowed that lenalidomide mainte-

nance therapy doubled progression-free survival (PFS) after ASCT fromapproximately 2 years to 4 years andnumerically improved survival. Len -alidomide was generally well tolerat-ed. Hematologic events were themost common side effects. A slightincrease in secondary malignancieswas reported in both studies, andpatients are being monitored withthis in mind.

“Evidence from these trials suggests

that in contrast to thalidomide, len -alidomide maintenance therapy atdoses of 5 to 15 mg/day is generallywell tolerated. The intent should be touse it for at least 1 year,” said KennethC. Anderson, MD, Chief, Division ofHematologic Neoplasia, Director of

the Jerome Lipper Multiple MyelomaCenter, and Vice Chair of the JointProgram in Transfusion Medicine, atthe Dana-Farber Cancer Institute.

Bortezomib maintenance therapyhas also been studied, but the dataare less mature. The HaematoOncology Foundation for Adults inthe Netherlands (HOVON) trial(Sonneveld P, et al. Blood. 2010;116:abstr 40) showed that bortezomibmaintenance improved CR, near-CR,

and partial response rates, as well asPFS and overall survival (OS) com-pared with thalidomide in newlydiagnosed ASCT candidates. In con-trast to lenalidomide, bortezomibappears to overcome poor-risk cytoge-netic abnormalities, including 13q and17p deletions.

For elderly patients who are trans-plant-ineligible, melphalan (Alkeran)/prednisone (Deltasone)/lenalidomide(MPR) followed by lenalidomidemaintenance is a good option. A phase3 study showed that MPR pluslenalidomide maintenance versusMPR alone or melphalan/prednisone(MP) improved PFS from 14 monthsand 13 months with MPR and MPalone, respectively, to 31 months. NoOS advantage has been reported yet. Alow rate of secondary malignancieswas seen in this trial.

Bortezomib-based induction thera-py is another good option for elderlypatients with newly diagnosed myelo-ma (Niesvizky R, et al. Blood. 2010;116:abstr 619). In this study, 3 differentbortezomib-based regimens wereactive, and bortezomib maintenancewas well tolerated with increasedrates of very good partial remission inall 3 arms. �

New York, NY—Evidence suggests thatmaintenance therapy, as well as initia-tion of therapy for newly diagnosed fol-licular lymphoma, can be delayed inasymptomatic patients with low tumorburden, according to Andrew Zelenetz,MD, Chief of Lymphoma Service,Memorial Sloan-Kettering CancerCenter, New York, NY.

Speaking at the National Compre -hensive Cancer Network 6th Congresson Hematologic Malig nancies, whichhe chaired, Dr Zelenetz said, “Thequality of life for follicular lymphomapatients who are asymptomatic andliving with their disease is similar tothat of patients in remission.”

Although studies show that initialtreatment and maintenance therapyimprove progression-free survival(PFS) in patients with follicular lym-phoma, no overall survival (OS)advantage has been reported.

The ability to delay therapy in thispatient population has economicimplications, because treatment withsingle-agent rituximab (Rituxan)costs approximately $36,000 annuallyper patient. Dr Zelenetz estimated

that a treatment that costs this muchbut has no impact on OS would costabout “tens of millions of dollars” perquality-adjusted life-year, which isclearly unacceptable.

“Currently we have the luxury ofusing therapy that doesn’t impact OS,but I can’t predict the future. It mightbe difficult to get paid for maintenancerituximab,” he said.

Follicular lymphoma is an indolentB-cell lymphoma with a median sur-vival of 12 to 16 years. Rituximab hasdramatically improved PFS, butpatients will eventually relapse. Thedecision to initiate therapy in anasymptomatic patient with follicularlymphoma rests on the patient’s pref-erence. Dr Zelenetz said patients fallinto 2 groups: those who want treat-ment for a disease they know theyhave, even if there are no symptoms,and those who are content to foregotreatment while feeling well, prefer-ring to receive treatment when theyneed it.

He cautioned against routine treat-ment for every newly diagnosed follic-ular lymphoma. Patients who require

immediate up-front treatment aresymptomatic and have a tumor >3 cm,cytopenia, concurrent disease transfor-mation, or compromised end-organfunction.

At least 4 different randomized clin-ical trials in patients with low tumorburden failed to show improvementin OS with any chemotherapy versusobservation, suggesting that treatment

can be delayed in these patients. Studies by the European Organ -

ization for Research and Treatment ofCancer and by the Swiss Group forClinical Cancer Research, along withthe PRIMA, RESORT, and FIT studies,have shown that several maintenanceregimens, including radioimmuno -therapy or rituximab dramaticallyimprove PFS in follicular lymphoma,but none of these regimens improvedOS. Dr Zelenetz noted that PFS is notan ideal end point and an OS benefitwould be more convincing.

Researchers at Memorial Sloan-Kettering Cancer Center are studyingdisease proliferation as a marker forthe timing of initial treatment of fol -licular lymphoma. Based on imageanalysis of MIB-1/Li-67 staining, theresearchers determined that the medi-an time to need for treatment was 5years in patients with disease prolifer-ation <30% versus 18 months in thosewith disease proliferation >30%.

They anticipate that markers such asdisease proliferation will help ensurethat available treatments are usedmore efficiently. �

Novel Agents Improve Outcomes as Maintenance... Continued from cover

Treatment Delay Feasible in Asymptomatic Follicular LymphomaHas significant economic implications By Phoebe Starr

“In contrast to thalidomide,lenalidomide maintenance therapy at doses of 5 to 15 mg/dayis generally well tolerated. The intent should be to use it for at least 1 year.”

—Kenneth C. Anderson, MD

“The quality of life forfollicular lymphoma patientswho are asymptomatic andliving with their disease issimilar to that of patients inremission. Currently we havethe luxury of using therapythat doesn’t impact OS, but I can’t predict the future. Itmight be difficult to get paidfor maintenance rituximab.”

—Andrew Zelenetz, MD


Genetic Diagnostic for ALK-Positive Status The FDA also approved the Vysis

ALK Break-Apart FISH Probe Kit(Abbott) as a companion diagnostictest for the diagnosis of the ALK genein patients with NSCLC to identifyappropriate candidates for crizotinibtherapy. The test uses fluorescence insitu hybridization to detect thoserearrangements on the 2p23 chromo-some. (August 26, 2011)

ODAC RecommendsAccelerated Approval for IronChelator Deferiprone The FDA’s Oncologic Drugs

Advisory Committee (ODAC) recom-mended accelerated approval of theiron chelator deferiprone (Ferriprox,ApoPharma) for patients with trans-fusional iron overload that is inade-quately treated with deferoxamine(Desferal), the standard chelationtherapy for patients with diseasessuch as thalassemia or sickle-cell dis-ease, who must undergo multipleblood transfusions to survive. Approximately 25% of patients

with thalassemia do not respond ade-quately to standard iron chelationtreatment. Clinical data show thatamong transfusion-dependent pa -tients who failed standard chela-tion therapy, 52% had successfultreatment with deferiprone. ODAC also recommended further

assessment of clinical efficacy andsafety, especially in patients with sick-le-cell disease. (September 14, 2011)

New Indications forDenosumab for IncreasingBone Density in Patients with CancerThe FDA approved 2 new indica-

tions for denosumab (Prolia, Amgen)for treating patients at high risk fortherapy-induced bone fracture. Thefirst indication is for increasing bonemineral density (BMD) in men receiv-ing an dro gen-deprivation therapy fornonmetastatic prostate cancer; the sec-ond is for increasing BMD in womenreceiving adjuvant aromatase inhibitortherapy for breast cancer. The approval was based on 2 in -

ternational randomized, placebo-con-trolled trials, one involving 1468 menwith prostate cancer, the other includ-ing 252 women with breast cancer. At 24 months, BMD in the lumbar

spine increased by 5.6% in men whoreceived denosumab but decreasedby 1% in those receiving placebo(P <.001). At 36 months, only 1.5% of

the men receiving denosumab hadnew vertebral fractures versus 3.9% inthe placebo group (P = .012).In the women’s study, at 12 months

lumbar spine BMD increased by 4.8%with denosumab and decreased by0.7% with placebo (P <.001).

In both studies, the most commonadverse events with denosumab werearthralgia and back pain. Extremity andmusculoskeletal pain were also ob -served. Hypocalcemia, associated onlywith denosumab, was reported in 2.4%of patients after 1 month of therapy.

Denosumab is already approved forthe treatment of osteoporosis in post-menopausal women at high risk forfracture and for the prevention ofskeletal-related events in patients withbone metastases from solid tumors.(September 16, 2011) �

FDA UPDATES


Continued from page 7

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New York, NY—Several advanceshave been made in the diagnosis andtreatment of chronic lymphocyticleukemia (CLL), according to SusanO’Brien, MD, Chief, Acute LeukemiaSection at M.D. Anderson CancerCenter, Houston. Treatment selectioncan now be guided by fluorescence insitu hybridization (FISH) testing forgenetic abnormalities, and 2 new treat-ments in early-stage developmenthold promise for patients with a poorprognostic cytogenetic profile.

FISH testing is used to identify 3cytogenetic abnormalities of interest inCLL: 13q deletions—a predictor ofgood prognosis—and deletions of 11qand 17p, predictors of poor prognosis.The presence of these markers canguide treatment selection. TheNational Comprehensive CancerNetwork (NCCN) guidelines are clearfor CLL patients with 13q deletions butnot with 11q and 17p deletions.

CLL with 11q deletions is associatedwith extensive lymphadenopathy, dis-ease progression, and shorter mediansurvival. Patients with CLL and thesedeletions, even if asymptomatic, willprogress within 2 years. “Treatment[for 11q deletions] is needed, and theregimen should include an alkylatingagent,” Dr O’Brien said.

Her preferred regimen is fludara-bine (Fludara), cyclophosphamide(Cytoxan), and rituximab (Rituxan)(FCR), which was developed at M.D.Anderson. “FCR is the only regimenshown to improve survival in CLL,”Dr O’Brien said.

A survival advantage for FCR overfludarabine and cyclophosphamide(FC), an older regimen, was demon-strated in the CLL8 trial: completeresponse rates were doubled withFCR versus FC, and 3-year survivalwas 87.2% with FCR versus 82.5%with FC. FCR is considered the stan-dard of care for asymptomatic pa -tients with CLL and 11q deletions,according to NCCN guidelines.

Reduced-dose FCR is also an optionfor elderly patients with good per-formance status; palliative care is rec-ommended for elderly patients whoare compromised.

The deletion of 17p predicts lowresponse rates to treatment and poor

prognosis in CLL. FCR is probablynot going to be effective in thisgroup of patients. “The NCCNguidelines list many choices for ther-apy, and whenever there are so

many choices, it means that none ofthe therapies are particularly effec-tive,” Dr O’Brien said.

Studies have failed to establish agood chemotherapy regimen for

CLL characterized by 17p deletions.“Alemtuzumab [Campath] is noteffective in patients with bulky dis-ease, but it may be a good optionfor patients with nonbulky disease,”

Advances in the Management of Chronic Lymphocytic LeukemiaBy Phoebe Starr



IndicationYERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.1

REFERENCES 1. 2.

3.

Announcing YERVOY™ (ipilimumab) HCPCS Code C9284

The accurate completion of reimbursement- or coverage-related documentation is the responsibility of the healthcare provider and patient. Bristol-Myers Squibb and its agents make no guarantee regarding reimbursement for any serviceor item. This coding guidance is not intended to provide specifi c directions on requesting prior authorization or submitting claims for YERVOY and does not provide a guarantee of receiving prior authorization or reimbursement. Coding forYERVOY is dependent on the insurer and the care setting in which the drug will be administered. Oncology practices need to make coding decisions based on the diagnosis and treatment of each patient and the specifi c insurer requirements.

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Important Safety Information

“FCR is the only regimenshown to improve survival in CLL.”

—Susan O’Brien, MD


she said. Bendamustine (Treanda)plus rituximab is also not recom-mended for CLL with 17p deletions.The best choice for patients with 17pdeletions is a clinical trial. Thosewho achieve a partial or completeremission with frontline therapyshould be considered for allogeneicstem-cell transplant.

New Drugs

Dr O’Brien was enthusiastic about 2new inhibitors of B-cell receptor sig-naling in early clinical trials thatincluded patients with poor prognos-tic factors: PCI-32765 and CAL-101.

“There is no question whether these2 drugs will be approved. The ques-tion is when,” she said.

PCI-32765 is a small-molecule inhib -itor of Bruton’s tyrosine kinase. Phase1 trials showed promising results,especially in patients with a poor cyto-genetic profile. The drug appears to bewell tolerated and is associated withno cumulative toxicity. PCI-32765 is inphase 2 trials for CLL and non-Hodgkin lymphoma.

CAL-101, an orally available small-molecule inhibitor of phosphoinosi-tide-3 kinase, achieved responses inthe lymph nodes of CLL patients,including those with 17p deletions.The lymph nodes were reduced by84% in volume, and hemoglobin andplatelets were increased in studies ofpatients with refractory CLL. �



Boxed WARNING regarding immune-mediated adverse reactions

Recommended Dose Modifi cations

Immune-mediated Enterocolitis:

Immune-mediated Hepatitis:

Immune-mediated Dermatitis:

Immune-mediated Neuropathies:

Immune-mediated Endocrinopathies:

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations:

Pregnancy & Nursing:

Common Adverse Reactions:

Important Safety Information (cont)


New York, NY—The era of personal-ized medicine is progressing. At theFred Hutchinson Cancer Center,Seattle, WA, and at other centers,patients with intermediate-risk acute

myeloid leukemia (AML) are nowbeing tested for 3 molecular markersthat predict prognosis. The goal is touse these markers for treatment selec-tion and for monitoring response.

As people age, they accumulatemore cytogenetic markers of poorprognosis, said Jerald Radich, MD,Fred Hutchinson Cancer Center, whospoke at the National Comprehensive

Cancer Network 6th Congress onHematologic Malignancies.

The 3 genetic mutations are FLT3-ITD, NPM1, and CEPBA. The FLT3-ITDmutation predicts poor prognosis,



YERVOY™ (ipilimumab) Injection, for intravenous infusion

Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONSYERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. [See Dosage and Administration (2.2) in Full Prescribing Information]

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. [See Warnings and Precautions]

INDICATIONS AND USAGE

YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Boxed Warning]

Immune-mediated Enterocolitis

In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3–5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis.

The median time to onset was 7.4 weeks (range 1.6–13.4) and 6.3 weeks (range 0.3–18.9) after the initiation of YERVOY for patients with Grade 3–5 enterocolitis and with Grade 2 enterocolitis, respectively.

Twenty-nine patients (85%) with Grade 3–5 enterocolitis were treated with high-dose (≥40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids.

Of the 34 patients with Grade 3–5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve.

Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms.

Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least one month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients.

Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than one week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Dosage and Administration (2.2) in Full Prescribing Information]

Immune-mediated Hepatitis

In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3–5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event.

Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.

Permanently discontinue YERVOY in patients with Grade 3–5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Dosage and Administration (2.2) in Full Prescribing Information]

Immune-mediated Dermatitis

In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) YERVOY-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis.

The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY (ipilimumab).

Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks.

Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement.

Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.

Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Dosage and Administration (2.2) in Full Prescribing Information]

For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week.

Immune-mediated Neuropathies

In Study 1, one case of fatal Guillain-Barré syndrome and one case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported.

Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Dosage and Administration (2.2) in Full Prescribing Information]

Immune-mediated Endocrinopathies

In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3–4) occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and one case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY.

Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13).

Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.

Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.

Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosage and Administration (2.2) in Full Prescribing Information]

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations

The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia.

Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis.

Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immune-mediated adverse reactions.

Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosage and Administration (2.2) in Full Prescribing Information]

ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling.

[see Warnings and Precautions].






Progress in Molecular Markers that Predict Prognosis in AMLBy Phoebe Starr


whereas NPM1 and CEPBAmutationspredict good prognosis. The presenceof NPM1 trumps FLT3-I, meaning thatNPM1 still predicts good prognosisdespite the presence of FLT3-I. Thepresence of all 3 mutations also pre-

dicts improved outcomes.These markers are used in addi-

tion to conventional risk factors forAML, which include age, clinical sta-tus, and cytogenetics (recurrentabnormal chromosomal aberrations).

Based on cytogenetics, a patient’sprognosis is classified as favorable,intermediate, or poor. Approximately 40% of patients

with AML have a normal cytogeneticprofile and are considered to have

intermediate risk, but molecularmarkers (such as FLT3-ITD, NPM1,and CEPBA) identified by gene muta-tional studies can further refine riskstratification for disease progressionwithin people with a normal cytoge-netic profile.Approximately 84% of patients with

intermediate risk and normal karyo -types will have mutations: of these,approximately 50% will have NPM1,31% will have FLT3-ITD, and 14% willhave CEPBA mutations, which canoverlap in the same patient. Patients with NPM1mutations have

a better clinical course, and those withboth NPM1 and FLT3-ITD mutationsfare the best. “They are driven fromintermediate risk to favorable risk,” DrRadich commented.

It is important to quantify theamount of FLT3-ITD that is present ina patient with AML: the greater theamount, the greater the risk for poorprognosis, Dr Radich said. Although a patient may have com-

plete remission on induction/consoli-dation therapy, detecting the presenceof minimal residual disease (MRD)predicts relapse. MRD is used beforeand after transplant to predict out-comes. Dr Radich cautioned that earlyidentification of MRD does not im -prove outcomes.“The best technique for quantifying

MRD is flow cytometry, because it isexquisitely sensitive to phenotype,” DrRadich noted. An important area of research is the

use of cytogenetics and molecular test-ing for risk stratification of enrolleesin clinical trials, but funding for thisresearch seems to be drying up, DrRadich commented. �



Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.

The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY (ipilimumab) 3 mg/kg for four doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14) in Full Prescribing Information] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range 1 to 4 doses). YERVOY was discontinued for adverse reactions in 10% of patients.

The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis.

Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3–5 events.

Table 1: Selected Adverse Reactions in Study 1

Percentage (%) of Patientsa

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100

n=380

gp100 n=132

System Organ Class/ Preferred Term

Any Grade

Grade3–5

Any Grade

Grade3–5

Any Grade

Grade 3–5

Gastrointestinal Disorders Diarrhea ColitisSkin and Subcutaneous Tissue Disorders Pruritus RashGeneral Disorders and Administration Site Conditions Fatigue

328

3129

41

55

02

7

375

2125

34

43

<12

5

202

118

31

10

00

3

a Incidences presented in this table are based on reports of adverse events regardless of causality.

Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1.

Table 2: Severe to Fatal Immune-mediated Adverse Reactions in Study 1

Percentage (%) of Patients

YERVOY3 mg/kgn=131

YERVOY3 mg/kg+gp100

n=380

Any Immune-mediated Adverse ReactionEnterocolitisa,b

Hepatotoxicitya

Dermatitisa

Neuropathya

Endocrinopathy Hypopituitarism Adrenal insufficiencyOther Pneumonitis Meningitis Nephritis Eosinophiliac

Pericarditisa,c

157121440

00110

12723

<1111

<1<100

<1

a Including fatal outcome. b Including intestinal perforation. c Underlying etiology not established.

Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.

Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.

Immunogenicity

In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.

Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.

Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS

No formal drug-drug interaction studies have been conducted with YERVOY (ipilimumab).

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In a combined study of embryo-fetal and peri-postnatal development, severe toxicities including increased incidences of third-trimester abortion, stillbirth, premature delivery, low birth weight, and infant mortality occurred following intravenous administration of ipilimumab to pregnant cynomolgus monkeys every 21 days from the onset of organogenesis through parturition at doses of 2.6 or 7.2 times the recommended human dose of 3 mg/kg (by AUC). [See Nonclinical Toxicology (13.2) in Full Prescribing Information]

In genetically engineered mice in which the gene for CTLA-4 has been deleted (a “knockout mouse”), offspring lacking CTLA-4 were born apparently healthy, but died within 3–4 weeks due to multi-organ infiltration and damage by lymphocytes.

Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus.

Nursing Mothers

It is not known whether ipilimumab is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother.

Pediatric Use

Safety and effectiveness of YERVOY have not been established in pediatric patients.

Geriatric Use

Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years).

Renal Impairment

No formal studies of YERVOY in patients with renal impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information]

Hepatic Impairment

No formal studies of YERVOY in patients with hepatic impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information]

OVERDOSAGE

There is no information on overdosage with YERVOY.

PATIENT COUNSELING INFORMATION

See MEDICATION GUIDE in Full Prescribing Information.

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA

1281558A2 IP-B0001A-03-11 Issued: March 2011

“The besttechnique forquantifying[minimumresidual

disease] is flow cytometry,because it is exquisitelysensitive to phenotype.”

—Jerald Radich, MD

An important area ofresearch is the use ofcytogenetics and moleculartesting for risk stratification,but funding for this researchseems to be drying up.


ONCOLOGY BEST PRACTICES


Committee for Quality Assurance(NCQA) as a Level 3 PCMH. Weobtained that recognition in April 2010after several years of preparations. In2005, we began to restructure ourprocesses of care. The idea of applyingfor the NCQA-PCMH recognitionevolved in late 2009, after realizing thatour reengineered processes met themajority of the criteria for Level 3recognition. The NCQA is now trying to deter-

mine the recognition process for othersubspecialty practices, possibly devel-oping criteria for medical home neigh-bor recognition. They will likely openup that process to other practices with-in the next 18 to 24 months. For a prac-tice to be recognized as a medicalhome, it must currently meet 13 essen-tial NCQA standards of patient-centriccare, which our practice has surpassed.When we applied there were only 9 cri-teria, and the additional 4 are exten-sions of some of those 9. Although other cancer programs

and practices are now using the term“medical home,” they have not yetattained an officially recognized med-ical home status. They are workingtoward that goal, in terms of diseasemanagement and utilization out-comes, to meet the criteria for anoncology PCMH designation.

Q: What was the impetus forlaunching your oncology medicalhome?

Dr Sprandio: I founded our prac-tice 23 years ago; we now have 9physicians and more than 6000 activepatients. We are in a very competitiveenvironment in the Philadelphia sub-urbs. Our culture and belief havebeen, from the outset, to provide thebest care and the highest level of serv-ice possible. To do that, we believe it isnecessary to measure our perform-ance on a consistent basis, to gainobjective data, and to fix what needsfixing. This constant cycle of processimprovement is also an NCQA re -quirement for a medical home. Wedeveloped this oncology medicalhome model because it was the rightthing to do for patients: we alsothought it would give us an advan-tage in a competitive marketplace. The article I published last Decem -

ber (Sprandio JD. Community Oncol.2010;7:565-572) has helped to spreadthe word that this model may havereal value. There is a growing under-standing about the value of this modelfor oncology. Community oncologypractice, as well as health systems thatemploy oncologists, are interested indifferentiating themselves in their

market by potentially following ourexample and using our toolkit; theyare engaging us to help them trans-form their practices to an oncologymedical home. We have a MedicaidHMO contract that has been working

very well for about 1 year and are cur-rently in negotiations with our largerpayers.

Q: What are some of thecharacteristics of the medicalhome in oncology?

Dr Sprandio: Studies have shownthat the medical home is a wonderfulmodel to enhance primary care deliv-ery. It coordinates and reduces thefragmentation that plagues medicalcare today. And when this model isapplied to an older, or more vulnera-ble, patient population with comor-bidities, the potential benefits are mul-tiplied. In cancer care, for example,because care is so expensive and thepatient population is very vulnerable,better coordination in care deliverycan lead to positive outcomes andfewer hospitalizations. The medical home was initially

proposed by pediatricians in 1967 forchildren with severe, chronic medicalconditions requiring ongoing, com pli -cated care. Applying this model to can-cer care is right in step with their orig-inal intentions.The oncology medical home model

requires a standardized mechanismfor providing enhanced patient com-munication and physician coordina-tion of care; increasing patient accessto care; monitoring preventive screen-ing; having a standardized way ofevaluating patients in the office; and areproducible, reliable method of datacollection and presentation to thephysicians. It is all about increasedcare coordination, whole-person ori-entation, always measuring potential-ly avoidable complications, and ad -dressing symptoms early—beforethey become major issues that canresult in an emergency department

visit or hospitalization. It also in -volves educating patients about self-management of common symptoms,and helping them to coordinate carebeyond the medical oncology officethrough patient navigators.

Q: How do you addresssymptoms earlier than in othercare models?

Dr Sprandio: It begins at the time ofthe patient’s orientation to the prac-tice. Our model truly engages ourpatients and their families. Patients areeducated from the beginning abouttheir responsibility to report symp-toms. They are also given access to atelephone triage service that is verypopular and well executed. We have about 30 different symp-

tom algorithms that our nurses follow.When patients call into our officeabout a symptom, they are immediate-ly connected to a nurse. She accessesall of their data and can quickly assessthe situation and provide standard-ized recommendations. We track theresult of every clinical call that comesto our practice. Last year we had 3900symptom-related calls from patients.Of these calls, 76% of cases were man-aged over the phone, 4.2% were sent tothe emergency department, about5.5% were brought into the office thatday, and another 4.5% were told tocome in the next morning. We focus on early symptoms of

potential complications, and ourpatients are indoctrinated to call earlyin the day. Our common phrase is, “Ifyou wake up at 8 AM and you thinkyou may have a problem, call us at 8:15AM, not 4:15 PM.” Patients are also toldthat if they call and utilize our service,they will avoid wasting 8 hours in anemergency department and potentiallyhaving unnecessary testing or beingadmitted inappropriately.

Q: Do patients actually call theoffice with early symptoms?

Dr Sprandio: The more we engagepatients in this model, the more calls

we have received. For example, 5 yearsago we only had 1200 or 1300 calls;last year we received 3900 calls. Ourpatients love it and never hesitate tocall. They know they will have a liveperson on the phone who is a well-trained oncology nurse, with access totheir complete data. Because theircomplete records are available in frontof the nurse taking the call, patientsknow there will not be unnecessaryquestions. We engage them and givethem access to prompt, accurate serv-ice that is painless and efficient.

Q: What role did electronicmedical records play in yourability to establish the medicalhome?

Dr Sprandio: An oncology-specificelectronic medical record (EMR) sys-tem is essential for ordering of drugsand other tasks. Most of the EMR sys-tems have not been developed toenhance information sharing. Weinstalled our EMR system in 2004, andquickly learned that it had major defi-ciencies. We ended up developing asoftware overlay to add data from theoncology-specific EMR, and this hasenabled us to standardize our commu-nication processes. For example, 2years ago the turnaround time for adocument to be completed and sent

The First NCQA-Recognized Medical Home... Continued from cover

at a glance� To be recognized as a medical

home, a practice must meet 13

essential NCQA standards of

patient-centric care

� Oncology medical home

is all about increased care

coordination, whole-person

orientation, measuring avoidable

complications, and addressing

symptoms early. It also involves

educating patients about self-

management of common

symptoms and patient

navigators

� Because cancer care is so

expensive and the patient

population is very vulnerable,

better coordination in care

delivery can lead to positive

outcomes and fewer

hospitalizations

� Our total annual office visits

per chemotherapy patient has

decreased by 12% in the past

2 years. Patients have fewer

visits, less inconvenience,

and fewer copayments

We have reduced emergencydepartment utilization by 65% forpatients receiving chemotherapyand hospitalizations by 43%. Theannual cost-savings to our payers is between $6.5 million and $10million from our practice alone, andin excess of $9500 to $12,000 perpatient receiving chemotherapy.

—John D. Sprandio, MD ([email protected])


ONCOLOGY BEST PRACTICES


from our office after a visit was 28days; the turnaround time now is <1day. We can communicate within 1day, or even within an afternoon, withother physicians who may be dealingwith a very complicated patient. Ourability to communicate and coordinatecare has increased exponentially,which is crucial when dealing withpatients who are this ill.We have contacted many of the

larger technology providers, but theyare preoccupied with the HITECHAct’s meaningful use requirementsand cannot address our needs rightnow. We did not create shortcuts for our

physicians to complete their docu-mentation; we created efficiencies:before we see a patient, all the datawe could possibly need for that visitare available to us in a formatted waythat we are used to, and that we uti-lize consistently. I saw 32 patientstoday: all my correspondence anddocumentation is not only done bynow (4 PM), but it has already beensent to all the referring doctors forthose 32 patients. In the past I wouldnot be finished with that until late atnight, the following day, or on theweekend. We have eliminated ourtranscription costs, streamlined thenumber of employees we have, andchanged the job description for a lotof employees.

Q: How do you perceive thevalue of the medical home?

Dr Sprandio: Value is in the eye ofthe beholder. Patients see very organ-ized, comprehensive, and consistentcare coming from our practice. Theylove to have access, the patient-cen-tered service, and they love the infor-mation they receive. We also have apatient portal, where they can pull uptheir progress notes. Regarding the cost value of this

model, if patients have fewer officevisits, they also have fewer copay-ments. We have generated data thatdemonstrate that our total number ofoffice visits per chemotherapy patientper year has decreased by 12% overthe past 2 years. Patients have fewervisits, less inconvenience, and fewercopayments. Payers see value in that we have

reduced emergency department uti-lization by 65% since 2005 for patientsreceiving chemotherapy, and reducedhospitalizations for chemotherapy by43% since 2007. The conservative esti-mate for the collective annual cost-sav-ings to our payers is between $6.5 mil-lion and $10 million from our practicealone, and in excess of $9500 to $12,000per patient receiving chemotherapy.

There is no doubt that followingchemotherapy pathways can save pay-ers money. However, an internationalconsulting firm interviewed us toassess the potential value of applyingthe medical home model to cancercare. They found that the savings fromthe pathways program is a finite num-ber between 1% and 3% of the totalcost of cancer care. They found that, byapplying all of the medical home prin-ciples to cancer care, an additional 7%to 10% savings could be realized. Thiswas using more conservative utiliza-tion targets than we had alreadyachieved. We are not restricting care to save

money; we are eliminating unneces-sary resource utilization by screeningpatients more carefully and by provid-ing better care. This saves money.Some people have asked about ourclinical outcomes, because our patientsspend less time in our offices, in thehospital, and in the emergency depart-

ment. Our survival data are as good,or better, than those of a NationalCancer Institute–designated Compre -hensive Cancer Center.

Q: Are there reimbursementissues unique to the oncologymedical home?

Dr Sprandio: Yes, and this is ratherinteresting. After standardizing andstreamlining many processes, webecame very efficient and our full-timeequivalent employee-to-physicianratio decreased from 8.4 to 5.5, whichsaved a fair amount of money. Thatwas great until about 18 months ago,when we noticed significant reduc-tions in revenue as a result of fewerhospitalizations and outpatient visits.We also realized reductions in chemo -therapy revenue because of more con-sistent, open, and honest discussionsregarding end-of-life care. So thismodel creates an interesting dilemmafor oncologists.Our model should only be attempt-

ed by other oncology practices thatcan find payers who will be workingwith them to develop a reimburse-ment contract that will pay them formanaging patients more efficiently.We have such a contract with a Phila -

delphia-area Medicaid HMO, and weare now working with a large nationalpayer on a broader contract platform.There is no incentive for a practice todo what we have done as long as theyare paid on a fee-for-service basis.They will get penalized for doingthings more efficiently.It has not been easy to convince pay-

ers about the value of this model inoncology, because they all have variousissues regarding their information sys-tems and their data analytics. Thismodel raises unique reimbursementissues. Everyone is very focused on thecost of drugs. The cost of chemothera-py drugs is only 26% of the total cost ofcancer care. We are willing to focus onthat cost, but we are also focusing moreintently on the other 74% of cancer carecosts, by keeping people out of the hos-pital and the emergency department,by keeping them healthier.Gradually, payers are beginning to

respond to us positively. The interest is

clearly growing from different healthplans and from Medicare. The Com -mun ity Oncology Alliance’s OncologyPatient-Centered Medical Home(OPCMH) demonstration project pro-posal submitted to the Center forMedicare and Medicaid Inno vation isbased on our practice’s experience.

Q: Do you offer help to practicesinterested in your model?

Dr Sprandio: We have developed atoolkit that is now available to otherpractices, and we have utilized thistoolkit to successfully initiate thispractice transformation in a similar-sized oncology practice in downtownPhiladelphia. We are showing that it isreproducible. In addition to the tool -kit, we offer an OPCMH practicereadiness assessment and gap analy-sis, and provide software and supporttools to aid in the transformation. Through Oncol ogy Management

Services, we provide consulting serv-ices for health systems, payers, andpractices working together, or payersalone. This is a step-by-step processthat is like trying to feel your waythrough the dark. It will be a lot easierwhen this model is embraced by pay-ers, and when we have a standardizedcontract with a national payer, whichwe expect to have in the next 6months. �

� We reduced unnecessaryresource utilization by screeningpatients more carefully and byproviding better care. Oursurvival rates are as good, orbetter than, those of a NationalCancer Institute–designatedComprehensive Cancer Center

� The annual savings to ourpayers is between $6.5 millionand $10 million from ourpractice alone, and in excess of$9500 to $12,000 per patientreceiving chemotherapy

� Our chemotherapy-relatedemergency departmentutilization has been reduced by 65% and hospitalizations by43%; however, this reducedutilization also means reducedrevenue: this model has uniqueimplications regardingreimbursement

� Our model should only be attempted by oncologypractices that can find payerswho will agree to develop areimbursement contract that will pay them for managingpatients more efficiently

Our employee-to-physician ratio decreased from 8.4 to 5.5,which saved a fair amount of money. But then we noticedsignificant reductions in revenue as a result of fewerhospitalizations and outpatient visits. We also realized reductions in chemotherapy revenue because of more honest discussions regarding end-of-life care. So this model creates an interesting dilemma for oncologists.

NCQA’s 9 KeyRequirements for a

Medical Home The following standards must

be met to attain Level 3 medicalhome recognition:• Enhanced patient access to careand greater communication

• A patient tracking and registrysystem with preventive screen-ings reminders

• Patient management and adher-ence based on nationally accept-ed, evidence-based treatmentstandards

• Strategies that ensure patientself-management and supportfor avoiding potential of treat-ment- and disease-related com-plications

• E-prescribing and physicians’ordering system

• Tracking of referrals • Tracking of tests and patientcompliance monitoring

• Continually reporting and im -proving performance

• An advanced electronic com-munications system that in -cludes a portal for patients andreferring physicians


HEALTH POLICY


The decision this month (October2011) by the US PreventiveServices Task Force (USPSTF) to

recommend against a prostate-specificantigen (PSA)-based screening forprostate cancer in healthy men1 hascaused quite a stir both in and outsideof medical circles, reminding manypeople of the task force’s 2009 recom-mendation against routine breast can-cer screenings for women under age 50years. The task force’s “D” rating for the

PSA test, which signifies that “there ismoderate or high certainty that theservice has no benefit or that the harmsoutweigh the benefits,”1 has no imme-diate effect on access to or coverage forthe PSA screening test. Medicare, thesingle largest payer of healthcare costsin the country, for example, currentlypays for 44% of preventive servicesreceiving a D rating by the task force,including prostate cancer screeningsfor men aged ≥75 years.2 Moreover, inthe Affordable Care Act, Congressoverrode the task force’s under-age-50mammography recommendation, in alegislation that was in a large part inresponse to the public backlash.3

Nevertheless, it would be short-sighted to assume that the task force’srecommendation carries no weight.What does the new rating ultimatelymean for patient access? In this age offiscal stress, will federal and privatepayers opt to cut a service that is esti-

mated to cost $3 billion annually?Preventive services were excluded

from Medicare coverage when it wascreated in 1965, and over the years,Congress has amended the SocialSecurity Act to add individual preven-tive services. Private payers have his-torically followed Medicare’s lead indeveloping their coverage policies,and therefore, any major changes toMedicare coverage of products orservices often has an industry-wideimpact. In the Balanced Budget Act of1997, for example, Congress mandatedcoverage for a number of preventiveser vices, including “prostate screening

tests.”4 Private payers were quick tofollow suit, if they were not alreadycovering the service.With the passage of the Medicare

Im provements for Patients and Pro -viders Act in 2008, Congress empow-ered the Department of Health andHuman Services to add preventiveservices to Medicare without congres-sional action.5 The law permits theSecretary of Health and HumanServices to authorize Medicare cover-age for services rated A or B by theUSPSTF. In enacting the AffordableCare Act in 2010, Congress extendedthe reach of the task force to privatehealth plans by requiring group healthplans to cover items receiving an A orB rating from the task force.As noted, the task force’s recom-

mendation has no immediate impacton coverage for and access to the PSAtest. Ultimately, however, both federaland private payers may eliminate cov-erage for the test. For example, theAffordable Care Act requires thatgroup health plans cover only servicesrated A and B by the task force. With a D rating, plans may very

well drop coverage for the screeningprocedure. Moreover, if Medicaredoes ultimately eliminate coverage forthe PSA test, private payers will likelyfollow suit.Critics of such a prediction argue

that legislation requires Medicare topay for the PSA test, and therefore, the

task force’s recommendation carriesno weight in coverage for the test.6

Nevertheless, it is possible that Con -gress, facing increasing budgetarypressure, could amend the languageto take into account the task force’sfinding. Indeed, Congress predictedchanges in coverage for prostate can-cer screening tests in the statute, grant-ing the Health and Human ServicesSecretary authority to cover other pro-cedures taking into account “effective-ness” and “costs.”7

What will ultimately happen to thecoverage of the PSA test remains to beseen. The draft RecommendationState ment is available for commentfrom October 11, 2011, until November8, 2011, at www.uspreventiveservicestaskforce.org/draftrec3.htm. �

References1. Chou R, Croswell JM, Dana T, et al. Screening for ProstateCancer: A Review of the Evidence for the U.S. PreventiveServices Task Force. AHRQ Publication No. 12-05160-EF-3.www.uspreventiveservicestaskforce.org/uspstf12/prostate/prostateart.htm. Published October 2011. Accessed October 10,2011. 2. Lesser LI, Krist AH, Kamerow DB, Bazemore AW.Comparison between US Preventive Services Task Force recom-mendations and Medicare coverage. Ann Fam Med. 2011;9:44-49.3. Patient Protection and Affordable Care Act §2713(a)(5), Pub LNo. 111-148, 124 Stat 132 (2010). www.gpo.gov/fdsys/pkg/PLAW-111publ148/pdf/PLAW-111publ148.pdf. Accessed Oct -ober 10, 2011. 4. Balanced Budget Act of 1997 §4103, Pub L No. 105-33, 111 Stat361 (1997). www.gpo.gov/fdsys/pkg/PLAW-105publ33/pdf/PLAW-105publ33.pdf. Accessed Octo ber 10, 2011. 5. Medicare Improvements for Patients and Providers Act of2008, Pub L No. 110-275 (2008). www.gpo.gov/fdsys/pkg/PLAW-110publ275/pdf/PLAW-110 publ275.pdf. Accessed Oct -ober 10, 2011. 6. Social Security Act §1861(s)(2)(P). www.ssa.gov/OP_Home/ssact/title18/1861.htm. Accessed October 10, 2011. 7. Social Security Act §1861(oo). www.ssa.gov/OP_Home/ssact/title18/1861.htm. Accessed October 10, 2011.

In September 2011, the AmericanAssociation of Cancer Research(AACR) issued a new report,

“AACR Cancer Progress Report 2011”(www.aacr.org/Uploads/Document Repository/2011CPR/2011_AACR_CPR_Text_web.pdf) on the current state ofcancer research and the implications ofrecent cuts in funding for the NationalInstitutes of Health (NIH) and theNational Cancer Institute (NCI). Thesecuts in NIH and NCI funding arealready adversely affecting theprogress made in cancer research inthe United States. The report highlights the many suc-

cesses and advances made in cancercare since the National Cancer Act of

1971 was signed into law, but warnsCongress that current trends in cuttingfunding for research could lead to seri-ous consequences. “The declining NIH and NCI budg-

ets are creating an environment whereresearchers face numerous disincen-tives to continue or even enter into re -search careers in the first place,” say theauthors of the report. “These disincen-tives are resulting in a loss of taxpayer-funded training and are ad verselyaffecting the nation’s ability to maintainan optimal workforce for cancer re -search and to generate innovative scien-tific ideas for future implementation.”The report, which is signed by many

cancer researchers and experts, states

that since 2003, “appropriations for theNIH and NCI budget have remainedessentially flat. Therefore, the NIH haslost about 13% of its purchasing powerover the last 8 years due to inflationand the increasing costs of researchand technology.”It is estimated that at least 50% of

cancers in the United States are pre-ventable, the report notes, whichunderscores the need for invigoratedresearch to improve prevention strate-gies and mitigate many of the prevent-able causes of cancer, such as exposureto environmental carcinogens, radia-tion exposure, and infectious diseases.As a result of previous scientific

research, “about 12 million cancer sur-

vivors are alive in the US today, and15% of these cancer survivors werediagnosed more than 20 years ago.” Tomaintain that level of scientific success-es in cancer, the AACR recommendsthat “Congress provide the NIH andNCI with annual budget increases of atleast 5% above the biomedical inflationrate.” Indeed, such level “of sustainedsupport will enable the future scientificadvances needed to seize today’s scien-tific momentum…save countless lives,and spur innovation.” Some of the current 32 cancer drugs

available in the United States havetransformed cancer “from a death sen-tence into a chronic condition,”according to the report. �

US Preventive Services Task Force and the Future of Prostate Cancer ScreeningRoss D. Margulies, JD, MPH (Cand), and Jayson Slotnik, JD, MPHMr Margulies is a Health Policy Specialist, Foley Hoag, LLP, Washington, DC; Mr Slotnik is a Partner at Health Policy Strategies, LLC, Washington, DC

AACR Urges Congress to Increase Funding for the NIH and NCI

With a D rating, plans mayvery well drop coverage forthe screening procedure.Moreover, if Medicare does ultimately eliminatecoverage for the PSA test,private payers will likelyfollow suit.


■ VELCADE+MP (n=344)■ MP (n=338)

% P

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Overall Survival Advantage Sustained at 3-Year Median Follow-upIn Previously Untreated Multiple Myeloma (MM)

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IN THE LITERATURE


PARP Inhibitor Olaparib aPromising Treatment forOvarian CancerIn phase 1 and 2 clinical trials, ola-

parib, a small-molecule poly(ADP-ribose) polymerase (PARP) inhibitor,has demonstrated objective responsesin women with breast or ovarian can-

cer and BRCA1 and BRCA2 mutations.Results of a new study show that ola-parib may be a promising therapy forwomen with aggressive ovarian can-cer (Gelmon KA, et al. Lancet Oncol.2011;12:852-861).In an open-label, nonrandomized

phase 2 clinical study conducted in 6

centers in Canada, a total of 91 women(aged ≥18 years) with advanced high-grade serous and/or undifferentiatedovarian carcinoma (N = 65) or triple-negative breast cancer (N = 26) wereenrolled and stratified according toBRCA mutation or lack of mutation; allof the patients received oral olaparib 400

mg twice daily. The primary end pointwas the objective complete or partialresponse rate, based on the ResponseEvaluation Criteria in Solid Tumors. Objective responses were not re -

ported for patients with breast cancer;of the 63 patients with ovarian can - cer who were evaluable, objectiveresponses were confirmed in 7 (41%)of the 17 women with BRCA muta-tions and in 11 (24%) of the 46 patientswithout a mutation. A total of 13 (20%) patients with

ovarian cancer discontinued the studyearly for different reasons, includingworsening disease, adverse events,and voluntary discontinuation. Atstudy end, 13 patients with ovariancancer and 26 of those with breast can-cer were still receiving olaparib. The most common adverse events

reported in both groups were fatigue,nausea, vomiting, and decreased ap -petite. Drug-related adverse eventswere reported in 88% of patients withovarian cancer.

Nilotinib Sustains 24-Month Superiority toImatinib in CML The BCR-ABL inhibitor nilotinib

(Tasigna) was developed as a selectivetreatment for patients with chronicmyeloid leukemia (CML) who are notresponding appropriately to imatinib(Gleevec) therapy. Previous resultsfrom the Evaluating Nilotinib Efficacyand Safety in Clinical Trials–NewlyDiagnosed Patients (ENESTnd) studyshowed 12-month superior efficacy fornilotinib over imatinib in patients withnewly diagnosed Philadelphia chro-mosome–positive (Ph+) CML in thechronic phase. New results for addi-tional 12-month follow-up show thatpatients treated with nilotinib sus-tained their molecular response for 24months (Kantarijian HM, et al. Lancet

Oncol. 2011;12:841-851). In this phase 3, multicenter, open-

label, randomized study, 847 adultpatients with chronic-phase Ph+ CMLwere randomized to oral therapy withnilotinib 300 mg twice daily (N = 282),nilotinib 400 mg twice daily (N = 281),or imatinib 400 mg once daily (N =283). The primary end point was majormolecular response at 12 months. At 24 months, a major molecular

response occurred in 71% of patientsreceiving nilotinib 300 mg twice daily,in 67% of patients receiving nilotinib400 mg twice daily, and in only 44% ofpatients receiving imatinib 400 mgonce daily (P <.001 for both compar-isons vs imatinib). In addition, a com-plete molecular response occurred sig-nificantly more often in the 2 nilotinibgroups (26% and 21%, respectively)

INDICATIONS:

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) 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 to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE.

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

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. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy.

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, the drug 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 VELCADE 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 www.VELCADE.com

Brief Summary

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 © 2011, Millennium Pharmaceuticals, Inc.All rights reserved. Printed in USA V-11-0041 04/11



TARGET AUDIENCEThis activity was developed for physicians, nurses, pharmacists, and managed care professionals who areinvolved in the care of patients with cancer.

CONFERENCE GOALThe Association for Value-Based Cancer Care will foster an open dialogue between providers, payers,and/or other members of the oncology team in order for attendees to gain a better understanding ofvarious points of view regarding cost, quality, and access in cancer care.

EDUCATIONAL OBJECTIVES• Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer caredelivery

• Define the barriers associated with cost, quality, and access as it relates to healthcare reform andwhat solutions are currently being considered

• Compare and contrast the different approaches/tools that 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

DESIGNATION OF CREDIT STATEMENTS

Physician AccreditationThe Medical Learning Institute designates this live activity for a maximum of 13.5 AMA PRA Category1 Credits™. Medical Learning Institute is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Physiciansshould claim only the credit commensurate with the extent of their participation in the activity.

Registered Nurse DesignationMedical Learning Institute, Inc. (MLI)Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 13.5contact hours.

Registered Pharmacy DesignationMedical Learning Institute (MLI) is accredited by the Accreditation Council for PharmacyEducation (ACPE) as a provider of continuing pharmacy education. Completion of this

activity provides for 13.5 contact hours (1.35 CEUs) of continuing education credit.

Gary Owens, MDPresident Gary Owens Associates

Burt Zweigenhaft, BSPresident, CEO OncoMed

CONFERENCE REGISTRATION

SAVE $100 off full conference Tuition

REGISTER TODAY FOR ONLY $275at www.regonline.com/avbcc2012

For more information, please visit www.avbcconline.org/2012 or

e-mail [email protected].

CONTACT/SUPPORTIf you have any questions please contact:

Association for Value-Based Cancer Care™241 Forsgate Drive, Suite 205B Monroe Township, NJ 08831

Phone: 732-992-1040 [email protected]

The One Conference You Can’t AFFORD to Miss!

Second Annual Association for Value-Based Cancer Care ConferenceStrategies for Optimizing Value in Cancer Care Delivery

REGISTER TODAY

SAVE $100

March 29-31, 2012 • JW Marriott • Houston, Texas

��

CONFERENCE CO-CHAIRS

This activity is jointly sponsored by Medical Learning Institute, Inc., and Association for Value-Based Cancer Care

�� VBCC_Oct_11_2_6_Follow ASCO Tabloid 10/18/11 11:24 AM Page 29

On July 29, 2011, a 3-judge panelfrom the US Court of Appealsfor the Federal Circuit invali-

dated some patents held by MyriadGenetics and the University of Utah

Research Foundation for methods ofanalyzing individuals’ gene sequencesfor the presence of BRCA1 and BRCA2

mutations, but upheld other relatedpatents in a reversal of a lower court

ruling. The decision has left the dooropen to many questions. The court ruled that Myriad’s

patents remain valid for the BRCA1

and BRCA2 sequences and for the

company’s methods of screening po -tential cancer therapies via changesin cell growth. However, experts sug-gest that this new ruling leaves thecompany open to new challenges,especially in light of the $3340 cost ofthe test that was developed morethan a decade ago. Newer techniquesfor DNA sequencing are less costlyand more efficient, but this decisiongives the company time to upgradeits technology.

“Testing labs, or potential competi-tors, for deep-sequencing all 20-plusgenes associated with breast or ovariancancer, for example, might be able todo their analysis without much risk ofinfringement liability,” Robert Cook-Deegan, MD, Director of the Institutefor Genome Sciences & Policy’s Centerfor Genome Ethics, Law & Policy, DukeUniversity, Durham, NC, told Value-

Based Cancer Care.Dr Cook-Deegan added that be -

cause 1 of the 3 judges sharply dissent-ed from the other 2 on the patentabilityof DNA sequences, “that would leaveMyriad only with claims on specificmutations and on PCR [polymerasechain reaction] primers. So, someonedoing a PCR-based gene sequencingmight infringe if reporting one of thepatented mutations, but there may besome space for alternative methods.”

The Controversy Continues

Commenting on the decision, PeterMeldrum, President and Chief Execu -tive Officer of Myriad Genetics, said,“We believe this decision is in thebest interests of the agriculture, bio -technology, and pharmaceutical indus-tries, as well as the hundreds of mil-lions of people whose lives arebettered by the products these indus-tries develop based on the promise ofstrong patent protection.” But groups that include the Am -

erican Civil Liberties Union, the PublicPatent Foundation, and other litigantsare decrying the decision, which maywell be appealed to the full Court ofAppeals or to the US Supreme Court.“Such appeals are at the discretion

of the courts, but this is a high-profilecase, and there is clearly disagreement

Recent Ruling on Genetic Patents Leaves Many QuestionsBy Rosemary Frei, MSc

HEALTH POLICY


��

April 20-22, 2012Le Westin MontrealMontreal, QC, Canada

For more information and to register, please visit www.cutaneousmalignancies.com

A Focus on Melanoma, Basal Cell Carcinoma, and Cutaneous T-Cell Lymphoma

You are invited to join us at this multiday forum designed to inform, educate, and exchange clinically relevant ideas in the field of cutaneous malignancies.

PLEASE SAVE THE DATE!

CONFERENCE CHAIRKim A. Margolin, MD

Professor, Department of Medical OncologyUniversity of Washington School of Medicine

Seattle Cancer Care AllianceSeattle, WA

��

��

��

� ��

“There is clearly disagree mentto be resolved about whetherDNA sequences found innature can be patented.”

—Robert Cook-Deegan, MD



to be resolved about whether DNAsequences found in nature can bepatented,” noted Dr Cook-Deegan. The dissenting judge said that patents

on the BRCA1 and BRCA2 genes shouldbe invalid. “Extracting a gene is akin tosnapping a leaf from a tree,” Judge

William C. Bryson wrote. “Like a gene,a leaf has a natural starting and stop-ping point. It buds during spring fromthe same place that it breaks off and fallsduring autumn. Yet prematurely pluck-ing the leaf would not turn it into ahuman-made invention.”

Daniel B. Ravicher, Executive Direc -tor of the Public Patents Foundation andcounsel for plaintiffs in the lawsuit, said,“No one ‘invents’ genes. Inventions arethings like new genetic tools or drugs,all of which can be patented becausethey are not genes themselves.”

The first 2 acts of this real-life oncol-ogy drama have taken place, the pro-tagonists have made their positionsclear, and now it remains to be seenwhether the curtain will fall or theaction will continue for the foreseeablefuture. �

HEALTH POLICY


STARTS STRONG. LASTS LONG.

IndicationALOXI® (palonosetron HCl) injection 0.25 mg is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.


of its components

include headache (9%) and constipation (5%)

Please see the brief summary of the Full Prescribing Information on the adjacent page.

References: 1. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 2. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 3. Data on file. Eisai Inc., Woodcliff Lake, NJ. 4. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-1449.

Help support your patients’ chemotherapy treatment goals Powerful CINV prevention in the first 24 hours and up to 5 days following

moderately emetogenic chemotherapy1,2

Lasts long against nausea following moderately emetogenic chemotherapy

Powerful acute CINV prevention following highly emetogenic chemotherapy4

ALOXI® provides powerful CINV prevention that can’t be ignored.

pr®ALOXI

ovides powerful pr

t be ignorcan’evention thatCINV pr

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andomized trial of palonosetron compared with ondansetron in preventing chemother Data on file3. 2003;98:2473-2482.CancerCancer. single-dose trial versus dolasetron.

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apy-induced nausea and vomiting following highly emetogenic chemotherandomized trial of palonosetron compared with ondansetron in preventing chemother Grunberg SM,,Aapro MS4.. NJ,eoodcliff LakW Eisai Inc.,. Data on file

a pharmacologically novel 5-HTapy-induced nausea and vomiting with palonosetron, 2003;14:1570-1577.Ann Oncol.andomized phase III trial comparing single doses of palonosetron with ondansetron.

apy-induced nausea and vomiting following moderalonosetron improves prevention of chemother

escribing Information on the adjacent page.Please see the brief summary of the Full Pr


Ann Oncol. .apyapy-induced nausea and vomiting following highly emetogenic chemotherA phase III, et al. Manikhas GM, Grunberg SM,

results receptor antagonist:3 a pharmacologically novel 5-HT,adillo J Figueroa-V, Eisenberg P P,2. 2003;14:1570-1577.

ately emetogenic apy-induced nausea and vomiting following moder

escribing Information on the adjacent page.

®ALOXI


Ask the HIT Expert

Noise-CancelingInformation New discoveries in diagnosis, treat-

ment, and prevention of cancerabound, but what is just “noise”?What is in oncology that is interesting,intriguing, inspiring, yet still just“noise,” because the path to action“here and now” is missing, or notobvious?If biology is a system of information,1

the practice of medicine is an ever-growing struggle of making sense ofthat information. With exponentialgrowth in scope and diversity of rawinformation, processed knowledge,and predictive hypotheses, making theright decision and acting on it in oncol-ogy feels ever more elusive. And if leveraging information sys-

tems to provide the best-quality can-cer care is not that easy,2 where does itleave us?

Value-Based Cancer Care teamed upwith Ron Ribitzky, MD, to facilitate anoise-canceling journey on this sub-ject. The goal is to collaborate withyou, the reader, to identify topics ofinterest and diversified points of view.This new column aims to respond toyour queries in the pages of this jour-nal and in an online forum.Submit your questions or sugges-

tions for a topic of your interest at www.valuebasedcancercare.com/submit-noise.

References1. Maureen Cronin, PhD. Personalized MedicineWorld Conference. June 2010; Herzeliya, Isreal.2. Cook G. Impact of EHRs on oncology practice:enhancing the value of cancer care. Value-Based Cancer

Care. 2011;2(5):32-33.

Dr Ribitzky (www.linkedin.com/in/ronribitzky) is a former clinicianwho converted to informatics, withmore than 20 years of worldwideexperience in the science and practiceof information technology in health-care and life-sciences informatics.


than in the imatinib group (10%). Furthermore, BCR-ABL transcript

levels were decreased below thethreshold of 0.1% about 12 months ear-lier with nilotinib than with imatinib,and emerging BCR-ABL mutations inthe nilotinib groups were 50% less

than in the imatinib group.Progression to accelerated or blast-

phase CML during treatment, includingclonal evolution, occurred in 7 patientsin the nilotinib groups and in 17 patientsin the imatinib group. At 24 months, sur-vival was comparable in all treatmentgroups, but CML-related death occurredless often with nilotinib (8 patients) than

with imatinib (10 patients). The only grade 3 or 4 adverse effects

occurring more frequently with nilo-tinib were headache and rash. How -ever, in the second 12-month follow-upstudy, 8 additional serious adverseevents occurred—7 in the nilotinibgroup and 1 in the imatinib group. The investigators believe that as a

result of nilotinib’s faster, and moredurable responses and significantlylower associated risk of progression,the drug should be considered a first-line therapy for CML in chronic phase.

Concurrent Chemotherapyand Radiation TherapyExtends Survival in NSCLC The concurrent use of chemothera-

py and thoracic radiotherapy (TRT)confers a greater survival benefit inpatients with stage III non–small-celllung cancer (NSCLC) than a sequentialuse of these therapies, based on resultsfrom a phase 3 clinical study (CurranWJ, et al. J Natl Cancer Inst. 2011;103:1452-1460).This study compared standard ther-

apy (ie, chemotherapy followed byradiation) with 2 regimens of concur-rent chemoradiation in 610 patientswith inoperable stage II or III NSCLCenrolled from 153 centers in the UnitedStates and Canada. Patients were randomized to 1 of 3

treatment groups. Groups 1 (N = 203)and 2 (N = 204) received vincristine(Oncovin) administered once weeklyfor 5 weeks and cisplatin (Platinol)administered on days 1 and 29. Group1 also received TRT once daily for 7weeks, beginning on day 50, at the endof the vincristine/cisplatin regimen;group 2 received TRT once daily con-currently with the vincris tine/cisplatinregimen for 7 weeks. Group 3 (N = 203)received 10 weeks of chemotherapywith cisplatin/etoposide (Toposar)concurrent with 6 weeks of TRT twicedaily beginning on day 1.At a median follow-up of 11 years,

the primary end point of 5-year overallsurvival was 16% in those receiving theconcurrent regimen once daily (mediansurvival, 17 months), 13% among thosewho received TRT twice daily concur-rently (median survival, 15.6 months),and 10% among those who receivedTRT sequentially after chemotherapy(median survival, 14.6 months)—a sig-nificant difference favoring the once-daily concurrent regimen. Patients receiving concurrent chemo -

therapy plus TRT once daily and twicedaily had a higher rate of acuteesophagitis (22% and 45%, respective-ly) than those receiving sequentialtherapy (4%), but the long-term rates(ranging from 1%-4%), along with therates of other, late-occurring grade 3-5toxic effects, did not differ significantlybetween any of the groups. The investigators acknowledge that

unlike the patients included in theirstudy, most patients with stage IIINSCLC will have a poorer functionalstatus and suffer from comorbid con-ditions that would limit their tolerabil-ity to adverse effects such as severeesophagitis. �

IN THE LITERATURE




BREAST CANCER SYMPOSIUM


Novel HDAC Inhibitor Improves Outcomes in Patientswith Estrogen-Sensitive Breast CancerEntinostat plus exemestane combo doubles time to progressionBy Audrey Andrews

San Francisco, CA—A novel histonedeacetylase (HDAC) inhibitor, whenadded to the aromatase inhibitorexemestane (Aromasin), appears torestore sensitivity to the endocrineagent by significantly delaying recur-rences and creating an increased sur-vival trend.

The findings come from the Enti -nostat Combinations OvercomingResistance (ENCORE 301) study pre-sented at the 2011 Breast CancerSymposium by Denise Yardley, MD,Sarah Cannon Research Institute andTennessee Oncology, Nashville.

“This combination may allow pa -tients to remain on hormonal therapylonger, delaying the need for chemo -therapy,” Dr Yardley suggested.

ENCORE 301 was a phase 2 trial ofexemestane with and without entinos-tat in postmenopausal women withestrogen receptor–positive advancedbreast cancer that had progressed dur-

ing previous nonsteroidal aromataseinhibitor therapy. A total of 114 pa -tients were randomized to exemestaneplus placebo or weekly entinostat.

The median progression-free sur-vival (PFS) was 4.28 months with enti-

nostat/exemestane versus 2.27 monthswith exemestane alone, a significant,27% reduction in risk.

At a median follow-up of 18months, the median overall survival(OS) was 26.9 months with the combi-nation versus 20.3 months with exe -

mestane alone—a 54% reduction inrisk for mortality. “We saw a trend foran OS benefit. This is an exploratoryend point with data that are stillmaturing,” Dr Yardley said. The regi-men was well tolerated.

Pharmacodynamic Analysis Shows

Strong Benefit in Subgroup

In a biomarker analysis of a sub-group of 49 patients, those who demon-strated hyperacetylation (a chemicalprocess) in blood samples derived thegreatest benefit from the combination

therapy. The mechanism of action ofHDAC inhibitors involves inducinghyperacetylation of lysines on histonesand a number of other proteins.

The risk of disease progression wasreduced by 77% in this subgroup ofpatients: the median PFS was 8.54months with the combination thera-py versus 1.92 months with exemes-tane alone.

“This suggests that entinostat-induced hyperacetylation tracked withimproved outcomes and may be apotential marker of benefit,” DrYardley said.

Joyce O’Shaughnessy, MD, BaylorSammons Cancer Center, Dallas, TX,who moderated the symposium wherethese results were presented, calledthe use of entinostat in advanced hor-monally sensitive breast cancer “very,very promising.” A phase 3 globalstudy will begin enrolling patients inearly 2012. �

“This combination may allow patients to remain onhormonal therapy longer, delaying the need forchemotherapy. We saw a trend for an OS benefit. This is an exploratory end point with data that are still maturing.” —Denise Yardley, MD

San Francisco, CA—Several studiespresented at the 2011 Breast CancerSymposium shed light on the qualityof breast cancer care received bywomen who are uninsured or receiv-ing Medicaid.

In a study conducted at RollinsSchool of Public Health of EmoryUniversity, Atlanta, researchers inves-tigated the quality of breast cancertreatment in patients enrolled underMedicaid and the Breast and CervicalCancer Prevention and Treatment Act(BCCPTA) of 2000 in Georgia.

The BCCPTA allows states to coverwomen diagnosed with breast or cer-vical cancer or those with precancer-ous cervical conditions under Med -icaid at the time of diagnosis and whilethey receive treatment. Women mustnot be eligible for Medicaid underanother mandatory covered group andmust not have other health insurance.

The study included 2048 Medicaidenrollees, of whom 1046 were coveredunder the BCCPTA, 674 were dis-abled, and 328 had “other” types ofMedicaid eligibility. The researcherscalculated the odds of receiving vari-ous types of treatment according tothese various groups.

After controlling for covariates,BCCPTA-covered women were morelikely to receive any treatment (oddsratio [OR], 4.71), any drug regimen(OR, 3.58), any radiation therapy (OR,1.61), or any definitive surgery (OR,2.52) than other eligibility groups; dis-abled patients were more likely toreceive recommended treatments than“other” patients.

For example, treatment with “anydrug” was given to 90% of patientscovered under the BCCPTA and 83%of disabled patients versus 67% of“other” patients. Radiation therapywas administered to 61%, 50%, and45% of patients, respectively, accord-ing to E. Kathleen Adams, PhD,Associate Professor of Health Policy

and Management, Rollins School ofPublic Health.

No significant differences werefound in the use of a lumpectomy ver-sus a mastectomy based on an eligibil-ity group, but women covered underthe BCCPTA were more likely toreceive adjuvant treatment.

“The BCCPTA program in Georgiaappears to create a quicker pathway for

previously low-income uninsuredwomen with breast cancer to accessservices and, in turn, receive more treat-ment than women enrolled in more tra-ditional Medicaid eligibility groups,”Dr Adams said. “Yet the overall rate ofadjuvant therapy, whether radiation orhormonal or chemotherapy, appears tofall short of national criteria.”

Worse Outcomes in Uninsured/

Medicaid Patients

In a study from Michigan StateUniversity in Flint, 632 patients withbreast cancer were analyzed accord-ing to race and insurance status.Patients with Medicaid or no insur-ance had a significantly lower overallsurvival rate at 5 years than patientswith private insurance (P <.001) orwho re ceived Medicare disabilitybenefits (P = .006).

At 5 years, 76% of patients withprivate insurance and 75% of thosewith Medicare disability were alivecompared with only 49% of thosewith Medicaid or no insurance, asreported by Mohammad Omaira,MD, a hematology/oncology fellowat Michigan State University, andcolleagues.

Although black patients were sig-nificantly more likely to present at anadvanced stage of disease, this findinglost statistical significance after adjust-ment for insurance status.

“Not all segments of the US popula-tion have experienced equal benefitsfrom the major advances in early diag-nosis and treatment of breast cancer,”the authors noted. —AA �

“The BCCPTA program in Georgia appears to create a quicker pathway for previously low-income uninsured women with breast cancer to access services and, in turn, receive more treatment than women enrolled in more traditional Medicaid eligibility groups.” —E. Kathleen Adams, PhD

Breast Cancer Treatment Still Under Par for Patients Covered by Medicaid




Targeted Radiation Therapy Gaining MomentumDecreased treatment time, lower dose to uninvolved tissueBy Caroline Helwick

San Francisco, CA—Accelerated par-tial breast irradiation using brachy -therapy (APBIb) for breast cancer hasbeen rapidly adopted in the UnitedStates, although its use varies byregion, race, and ethnicity. Jona A.Hattangadi, MD, Harvard RadiationOncology Program, Boston, reportedthe findings at the 2011 ASCO BreastCancer Symposium, which was spon-sored by 6 breast, oncology, and surgi-cal societies.APBIb, a new alternative to whole

breast irradiation (WBI), delivers radi-ation only to tissue within a few cen-timeters of the excision cavity (the areaat highest risk for cancer recurrence). Ithas the advantage of decreased treat-ment time and lower radiation doseto uninvolved tissues. The concern is, however, that occult

foci of cancer may exist elsewhere inthe breast and are thus not well treat-ed. The lack of long-term data and thepossible expense of the approach arealso of concern, Dr Hattangadi said. Dr Hattangadi and colleagues eval-

uated radiation therapy patterns in138,815 patients with breast cancerusing the Surveillance, Epidemiologyand End Results (SEER) database. Patients received APBIb or WBI

after lumpectomy from 2000 to 2007and were classified as “suitable,” “cau-tionary,” or “unsuitable” for APBIbbased on the 2009 guidelines of the

American Society for RadiationOncology. Unsuitable patients, accord-ing to these guidelines, are those withtumors >3 cm, extensive lymphovas-cular invasion, and no lymph nodesurgery.The current analysis showed a

steadily rising trend for APBIb use; by2007, 7% of the patients in the SEERdatabase were treated with thisapproach overall. The use of APBIbrose steeply after 2002, when balloonbrachytherapy received US Food andDrug Administration approval, andagain in 2004, when Medicare beganreimbursing for this treatment. Therise in use was seen across all 3 patientcategories, with the steepest increaseamong suitable patients.

Disparities in APBIb Use

Significant differences in the use ofAPBIb exist, the study shows. Non -white patients are 20% to 50% less like-ly to receive APBIb than whitepatients, as are persons living outsideof or adjacent to metropolitan areasversus those living in metropolitanareas. Patients aged ≥60 years are morelikely to receive APBIb than youngerpatients.Geographical variation is common,

with the highest rates of APBIb usein Atlanta, rural Georgia, Louisiana,Utah, and Kentucky. Patients inAtlanta were almost 13 times morelikely to receive APBIb than patients inHawaii and were 22 times more likelyto receive APBIb if they fell into theunsuitable category. These same high-use regions had

increased rates of APBIb use amongunsuitable patients, Dr Hattangadisaid, adding, “The odds ratio for useincreased as the appropriateness of usedecreased.”From 2006 to 2007, the use of APBIb

increased 15-fold compared with the

period between 2000 and 2002.Patients with larger tumor size andinvasiveness, worse histologic grade,and positive lymph nodes were up to50% less likely to receive APBIb.

Oncologists’ Perspectives

Robert Kuske, MD, Arizona BreastCancer Specialists, Phoenix, AZ,who pioneered the brachytherapyapproach years ago, commented onthese findings to Value-Based Cancer

Care, pointing out that the use ofAPBIb in unsuitable patients shouldnot be considered out of line.“The APBIb movement started in

Louisiana [where he practiced at thetime] and is now being done all overthe world. When I started it, andbefore guidelines were established, Iwanted to be inclusive, not exclusive,in patient selection for my trials, todetermine if APBIb was as good as,

better than, or worse than WBI inaggressive cancers. Therefore, Iincluded all different subtypes of thedisease. I argued that dose-dense radi-ation, which you get with APBIb,might actually be more effective forthe worst cancers. Some of my col-leagues were skeptical and reserved itfor the best of the best of cancers,” DrKuske said. “Since I am the only investigator

who included the unfavorable subset,

and the guidelines were establishedbased on the amount of evidence inpatient groups, the unsuitable catego-ry is not based on negative data but ona paucity of data,” Dr Kuske said. Rakesh Patel, MD, Western Radi -

ation Oncology, El Camino, CA, alsocommented on ths study. He agreedthat the terms “suitable” and “unsuit-able” are “difficult to interpret bypatients and physicians,” adding that“it only takes 1 feature to ratchetpatients” to a higher-risk category.“There are no data to suggest that

cautionary or unsuitable patients doworse,” Dr Patel said. “We have to becareful when we look at the guidelinesand interpret them as right or wrong.We have to look at the complexity ofpatients.” After a 6-year period of follow-up in

the MammoSite registry trial, no dif-ferences in outcomes have emergedbetween the unsuitable and the suit-able/cautionary guideline groups,said Dr Patel. “We should treat thepatient, not the guidelines.”In doing so, it is possible to observe

cost-savings. “This is not more expen-sive, although it used to be. Thingshave changed. In fact, it’s less expen-sive,” Dr Patel added, describing datafrom his practice area (Table).“APBIb also has value when taking

into account less time spent away fromwork and family and the other param-eters that go into complex decision-making,” he added. �

at a glance� Accelerated partial breast

irradiation using brachytherapy

is gaining popularity as an

alternative to whole breast

irradiation

� This approach offers several

advantages, including focused

radiation to tissue within a few

centimeters of the excision

cavity only; decreased treatment

time; and lower radiation dose

to uninvolved tissues

� National guidelines indicate

that patients with tumors >3 cm,

extensive lymphovascular

invasion, and no lymph node

surgery are not suitable for this

treatment, but data are lacking

to show worse outcomes

� Although partial irradiation

was initially more expensive

than whole breast treatment,

this trend has now reversed

APBIb delivers radiation onlyto tissue within a fewcentimeters of the excisioncavity and has the advantageof decreased treatment timeand lower radiation dose touninvolved tissues. Cost may become a concern.

—Jona A. Hattangadi, MD

“APBIb also has value when taking into accountless time spent away fromwork and family, and theother parameters that gointo complex decision-making.”

—Rakesh Patel, MD

Table Cost of Whole Breast Irradiation versus Accelerated Partial Breast IrradiationUsing Brachytherapy in a California Region

Health plan coverage

Cost of whole breast irradiation, 33 treatments

in 33 days, $

Cost of partial breastbrachytherapy, 10

treatments in 5 days, $

Medicare allowable, 2010 14,808 11,542

Medicare allowable, 2011 15,724 11,915

Blue Cross 11,436 9475

Source: Rakesh Patel, MD.

Death rates for Hodgkin lymphoma,

1990-2006

Women: Men:0.5% 34.7%

2011 estimates Incidence: 8830 Deaths: 1300

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Nucleus

PTCH

SMO

GLI

GLIs travel to the nucleus to trigger tumor cell growth and proliferation

2

Once at the cell surface, SMO activates the GLI family of transcription factors

1

Following mutation in SMO or PTCH, SMO is translocated to the cell surface

Nucleus

3

The Hedgehog pathway plays an important role in regulating cell growth and differentiation during normal human embryonic development but remains inactive in most adult tissues. Mutations in the Hedgehog pathway can occur and may lead to different types of cancer.2 Most notably, Hedgehog pathway mutations are known to occur in BCC, medulloblastoma, and BCC in Gorlin syndrome.3,4

Key components of the Hedgehog pathway include Smoothened (SMO), which enables the signaling cascade, and Patched (PTCH), which normally suppresses the activity of SMO. In preclinical models, mutations in SMO or PTCH render the pathway constitutively active, triggering the activation of GLI transcription factors. GLI, in turn, mediates the expression of genes involved in tumor cell growth, differentiation, and proliferation.1,5-7

The Hedgehog pathway plays an important role in regulating cell growth and The Hedgehog pathway plays an important role in regulating cell growth and differentiation during normal human embryonic development but remains inactive

Mutations in the Hedgehog pathway are implicated in over 90% of basal cell carcinomas (BCCs)1

Genentech is actively researching the potential

of Hedgehog pathway inhibition and how it may fi t

into the therapeutic paradigms of various malignancies.

For more information about the Hedgehog pathway

and its components, please visit:

www.ResearchHedgehog.com

Demonstrating the Value of InnovationA Member of the Roche Group

©2011 Genentech, Inc., So. San Francisco, CA HED0000596500 09/11

References: 1. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8:743-754. 2. Scales SJ, de Sauvage FJ. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci. 2009;30:303-312. 3. Unden AB, Holm-berg E, Lundh-Rozell B, et al. Mutations in the human homologue of Drosophila patched (PTCH) in basal cell carcinomas and the Gorlin syndrome: different in vivo mechanisms of PTCH inactivation. Cancer Res. 1996;56:4562-4565. 4. Pietsch T, Waha A, Koch A, et al. Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res. 1997;57:2085-2088. 5. Stone DM, Hynes M, Armanini M, et al. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature. 1996;384:129-134. 6. Rohatgi R, Milenkovic L, Scott MP. Patched1 regulates Hedgehog signaling at the primary cilium. Science. 2007;317:372-376. 7. Wang B, Fallon JF, Beachy PA. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell. 2000;100:423-434.

The Hedgehog Pathway:

A critical factor in cancer development




San Francisco, CA—The debate overthe clinical significance of occultmicrometastases in the lymph nodes ofpatients with breast cancer continues.

NSABP B-32 Trial: No Effect on

Overall Survival

Investigators from the NationalSurgical Adjuvant Breast and BowelProject (NSABP) B-32 trial have report-ed very small but significant differ-ences in outcomes for patients withoccult metastases. However, in a fol-low-up analysis, they reported that sur-vival is not improved if these patientsundergo full lymph node dissection.

Thomas B. Julian, MD, AlleghenyGeneral Hospital, Pittsburgh, PA,reported the study results at the 2011Breast Cancer Symposium.

Previous investigators found a 1.2%improvement in survival and a 2.8%improvement in disease-free survival(DFS) among patients lacking occultmetastases; however, overall survival(OS) at 5 years was excellent in bothgroups: 94.6% with occult metastasesand 95.8% without.

“So our question was, if there is adifference according to the presence ofoccult metastases, did the addition ofaxillary dissection factor into this?” DrJulian said. “We found no effect oftreatment on OS and DFS.”

In the subanalysis, nearly 16% ofclinically node-negative patients werefound to have occult metastases on

more detailed assessment of the sen-tinel nodes. Among the 3986 patientswith clinically and hematoxylin andeosin–negative sentinel nodes, occultmetastases were identified in 616patients: 316 in the axillary lymphnode dissection (ALND) arm and 300in the sentinel node dissection (SND)arm (for 51 per arm, occult metastasesstatus remained unknown).

The clinical outcomes of the patientswere similar, whether they underwentSND or ALND, Dr Julian reported.“The clinical importance of immuno-histochemistry-detected occult metas-tases is questionable,” he said.

Among patients with occult nodalmetastases, complete ALND did notsignificantly improve OS (hazard ratio[HR], 0.89; P = .62) or DFS (HR, 0.79;P = .16). The actual differences in out-comes were less than 3%.

Similar Findings in ACOSOG Z0011

The results support previous find-ings from the American College ofSurgeons Oncology Group (ACOSOG)Z0011 study, which found no survivalbenefit from complete ALND com-pared with SND only. In Z0011, moreextensive dissection revealed that 27%of patients had positive nodes beyondthe sentinel nodes, said Armando E.Giuliano, MD, of Cedars-Sinai Medical

Center, Los Angeles, who was theprincipal investigator of Z0011.

“About 27% of patients with SND-only had unresected cancer remainingin the axilla,” he noted. “We as sur-geons affect survival by achievinglocal-regional control, and both ap -proaches did that. There was no differ-ence in survival.”

Taken together, the 2 studies—NSABP B-32 and ACOSOG Z0011—suggest that aggressive approaches tosurgically remove occult metastasesare not necessary.

Diminishing Returns, Increased

Expense

Donald L. Weaver, MD, Universityof Vermont College of Medicine,Burlington, who served as the NSABPB-32 protocol pathologist, agreed thatthe 2 studies have important implica-tions; namely, they argue against inten-sively looking for small metastases thatwill not make a difference in outcome.

“The more you look, the more youfind,” Dr Weaver acknowledged, butthis results in diminishing returns andadditional work and is of questionablevalue to the patient, he suggested.“Occult metastases are not discrimina-tory predictors of outcome.”

“If additional treatment was givenbased exclusively on the presence ofoccult metastases, 90% of these pa -tients would be overtreated,” he said.Dr Weaver calculated that thisamounts to $44.8 million in healthcaredollars spent annually to account for a1.2% difference in outcome.

His recommendation is that pathol-ogists should continue to examine 2-mm sections, one from each block,without requiring levels or immuno-histochemistry. �

“About 27% of patients withSND-only had unresectedcancer remaining in the axilla.We as surgeons affect survivalby achieving local-regionalcontrol, and both approachesdid that. There was nodifference in survival.”

—Armando E. Giuliano, MD

at a glance� The clinical importance ofoccult metastases in breastcancer remains questionable

� Two new analyses found smallbut significant differences inoutcomes, but these did notaffect overall survival

� “The more you look, the moreyou find,” suggests one expert;occult metastases are not goodpredictors of outcome

� If additional treatment is given based exclusively on thepresence of occult metastases,90% of these patients would be overtreated, which wouldamount to $44.8 million

� Pathologists should continueto examine 2-mm sections, one from each block, without requiring levels orimmunohistochemistry

Pho

to C

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y © ASCO/C

hris Salata 20

10

Order of Initial Breast Cancer Treatment Does Not Affect OutcomesSan Francisco, CA—Whether womenreceive chemotherapy or surgery firstas their initial treatment for breast can-cer does not affect long-term local-regional recurrence, according to alarge case series from the University ofTexas M.D. Anderson Cancer Center,Houston, that was presented at the2011 Breast Cancer Symposium.

“A woman can have chemotherapyor surgery first, and the choice willnot affect her outcome,” said Eli -zabeth Ann Mittendorf, MD, a surgi-cal oncologist at M.D. Anderson. “The

molecular characteristics of the tumorand other factors have an impact ontreatment success, but not the order inwhich chemotherapy and surgery isgiven.”

Their retrospective evaluation in -cluded 2984 women treated between1987 and 2005 with segmental mastec-tomy and whole breast irradiation,including 78% who underwent sur-gery before chemotherapy and 22%who had neoadjuvant chemotherapythen surgery.

Dr Mittendorf reported that therates of local-regional recurrence-freesurvival were excellent for bothgroups: at 5 years, 97% for the surgery-first group and 93% for the neoadju-vant chemotherapy group; at 10 years,94% and 90%, respectively.

Even in patients who had ≥1adverse features, such as later diseasestage and higher tumor grade or estro-gen-receptor–negative status, no sur-vival differences were observed.

Neoadjuvant chemotherapy resultedin downgrading of tumor stage inalmost half the patients, and thereforemade breast-conserving therapy (ie,lumpectomy) possible in these women.Lumpectomy was performed in 69% ofpatients with stage II breast cancer whounderwent neoadjuvant chemothera-py compared with 19% who had sur-gery first, and in 24% and 1%, respec-tively, of stage III patients (P <.001).

“Even women who present withclinical stage II or III disease mayhave good results with breast-con-serving therapy after chemotherapyand not need a mastectomy,” Dr Mit -tendorf said.

Barbara Fowble, MD, of the Uni -versity of California School ofMedicine, San Francisco, the inviteddiscussant of the abstract, said thestudy supports what has already beenestablished by randomized controlledtrials: the 2 approaches lead to compa-rable outcomes. —AA �

“A woman can havechemotherapy or surgeryfirst, and the choice will notaffect her outcome.”

—Elizabeth Ann Mittendorf, MD

Occult Metastases Do Not Warrant Axillary Dissection in Breast CancerBy Audrey Andrews


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Hope S. Rugo, MD Professor of Medicine

Director, Breast Oncology and Clinical Trials Education

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California

Rüdiger Hehlmann, MD Chief and Professor of Medicine

University of Heidelberg Coordinator, German CML Study Group

Mannheim, Germany

About the Global Biomarkers Consortium Annual ConferenceThis is the first global meeting dedicated to advancing the understand-ing of value and clinical impact of biomarker research in oncology.Guided by the expertise of leaders in this field, participants will receivea thorough understanding of the current and future landscape of therelevance of tumor biomarkers and how to effectively personalize can-cer care in the clinical setting. An international audience of approxi-mately 250 oncologists/hematologists, pathologists, advanced practicenurses, research nurses, and clinical oncology pharmacists is expected.

Who should attend All healthcare professionals who are involved in the management of patients with cancer are invited to join this exciting forum. Specifically, this conference is intended for:

• Medical Oncologists and Hematologists • Pathologists • Geneticists • Advanced Practice Oncology Nurses • Research Nurses • Clinical Oncology Pharmacists • Genetic Counselors

involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of moleculartumor biomarkers to help optimize patient care.Personalized Medicine in Oncology

is the official journal of the Global Biomarkers Consortium.

PERSONALIZEDMEDICINE INONCOLOGYM

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SURVIVORSHIP CARE


The population of cancer sur-vivors is rapidly growing. Morethan 12 million Americans are

alive after a cancer diagnosis: most areliving at least 5 years and 16% are alive20 years after diagnosis.

This growing population of cancersurvivors is at risk for many comor-bidities, especially as they age. A studyof 10,397 childhood cancer survivorsshowed that group is 8 times morelikely to have a severe or life-threat -ening condition than their siblings(Oeffinger K, et al. N Engl J Med. 2006;355:1572-1582).

Survivorship care, therefore, hasbecome a topic of interest as oncolo-gists aim to determine the best wayto attend to patients’ long-term needs.One session at the recent annual meet-ing of the American Society of ClinicalOncology (ASCO) was devoted to sur-vivorship care.

“Patients report feeling abandonedat the end of their cancer treatment,and many complete treatment withpersistent problems. Planning forrecovery is important,” said JuliaRowland, PhD, of the National CancerInstitute.

Personalized Care

Dr Rowland cited several lessonslearned recently about survivors andtheir need for personalized care: • The posttreatment survivorship

phase brings its own set of uniqueneeds and challenges—physical andmedical, psychological, social, andexistential/spiritual

• Intervening early, when problemsarise, leads to better outcomes

• For many individuals, cancer pro-vides “a teachable moment”

• It’s not only healthcare providerswho are concerned, but patientsthemselves are asking how they canreduce their risk of cancer recurrenceand live healthier lives; it is impor-tant for healthcare providers to beprepared to answer their questions

• The Institute of Medicine (IOM) hasrecommended that survivors receivea summary record that includesimportant disease characteristicsand the treatments they received,and that they be provided with a fol-low-up care plan that incorporatesevidence-based standards of care. ASCO has adopted this as a quality

initiative, “but we have little informa-tion as to how this is being done andits impact in real practice,” Dr

Rowland said. What care should beprovided and to whom? Who shouldprovide this care, and where and whenshould it be given? What impact doesthis care-planning have on patientbehavior, physician behavior, practicecosts, payer investments, and patienthealth outcomes? All these questionsremain to be answered, she noted.

Whose Job Is It?

A much debated issue is determin-ing which healthcare provider shouldbe in charge of survivorship care: theoncologist or the patient’s primarycare physician (PCP).

Paul Han, MD, of Maine MedicalResearch Institute, in Scarborough,discussed the early findings of theSurvey of Physician Attitudes Re -garding the Care of Cancer Survivors(SPARCCS). One survey was adminis-tered to 1100 PCPs and a second one to1100 oncologists, showing that the pri-mary care model may not be preferred.

“We wanted to examine the atti-tudes, knowledge, and practices ofPCPs and oncologists regarding thecare of cancer survivors,” Dr Han said.“We focused on breast and colon can-cer survivors, and we looked at howphysicians perceived their roles andresponsibilities in the care of cancersurvivors vis-à-vis one another.”

PCPs rated their skills for caring forcancer survivors as low, and oncolo-gists agreed. “These data could haveimplications, considering that manygroups have argued that we shouldmove toward a system of shared carebetween PCPs and oncologists, withPCPs demonstrating greater respon -sibility for cancer survivor care,” DrHan suggested.

Neither PCPs nor oncologists select-ed a PCP-led model as the ideal modelfor survivorship care. In addition,although oncologists said they providetreatment summaries or care plans toPCPs most of the time, PCPs reportedthey rarely receive these. Oncologistsalso reported frequent communicationwith other physicians to clarify theirrespective roles in follow-up care, but

PCPs reported that this communica-tion occurred infrequently. Both spe-cialties tended to overuse surveillancetesting, especially PCPs.

“We need to explore models wherethere is greater sharing of care withPCPs, yet these findings show thatPCPs have very low confidence, andoncologists also rate PCPs’ skills andknowledge as very low. It suggests wehave a long way to go before physiciansare comfortable with the proposedshared-care model,” Dr Han said.

Cost-Effectiveness Questioned

Survivorship programs are well-meaning, but do they really improvehealth outcomes and are they cost-effective? A research team fromCanada concluded that the survivor-ship care plan adopted by their centerhad no impact on patient outcomes oradherence to follow-up guidelines andwas not a cost-effective use of “scarcehealth care resources.”

In accordance with the IOM’s rec-ommendation for providing cancersurvivors with a formal survivorshipcare plan (SCP), the multicenter studyassessed the effect of such a programand its cost-effectiveness.

A randomized trial enrolled 408patients with early-stage breast cancerwho had completed treatment at a ter-tiary cancer center. In the interventiongroup, 200 patients received an SCPconsisting of a treatment summary, apatient’s version of the follow-upguidelines, and brochures and infor-mation about local relevant supportivecare resources. These were compiledinto a binder and reviewed with thepatient in a nurse-led 30-minute edu-cational session.

The family physicians received acopy of all documents plus the fullguideline and a reminder table of rec-ommended follow-up visits and tests.

The control group of 208 patientsreceived a discharge visit and theirphysicians received a discharge letter,according to usual practice.

The primary outcome was psy-chosocial adjustment 12 months afterintervention. The secondary outcomeswere continuity of care, health-relatedquality of life, patient satisfaction, andadherence to guidelines. A short-termstudy cannot adequately assess clinicaloutcomes, the investigators noted.

Despite having received a formalSCP, the intervention group demon-strated no additional improvement inpsychosocial adjustment or in anyof the secondary outcomes studied,reported Eva Grunfeld, MD, of theUniversity of Toronto.

Costs included physician visits, diag-nostic tests, patient travel costs, lostproductivity, and cost of recurrence.

In the SCP analysis, costs includedthe cost of developing and, wherenecessary, revising the plan, whichincluded labor, administrative sup-port, materials, and postage, totalingapproximately $60 per patient.

In the cost-effectiveness analysis, thebase cost was $736.23 for the standardof care and $788.63 for the SCP. Theanalysis was performed from variousperspectives, such as the healthcaresystem perspective, with inclusion andexclusion of lost productivity, and withexclusion and inclusion of recurrences.

Standard care remained dominantover the SCP when costs and benefitswere not discounted, when the analy-sis adopted the healthcare system per-spective, when lost productivity wasexcluded, and when estimates of thecosts were included, according toDoug Coyle, PhD, of the University ofOttawa, Canada.

In the probabilistic analysis, themost likely finding was that standardcare was more effective and less costly.For all threshold values of a quality-adjusted life-year <$100,000, the prob-ability that the SCP was cost-effectivewas <30%.

“The results of this study clearlysuggest that the SCP adopted was nota cost-effective use of scarce health-care resources,” Dr Coyle suggested.“Given the 22,500 new incident casesof breast cancer per year [in Canada],implementation of the SCP to allbreast cancer patients would cost inexcess of $1.3 million per year, with noevidence of improved health-relatedoutcomes.” �

“We have a long way to go before physicians arecomfortable with theproposed shared-care model.” —Paul Han, MD

“The SCP adopted was notcost-effective….Implemen -tation of the SCP to allbreast cancer patients wouldcost in excess of $1.3 millionper year, with no evidence ofimproved health-relatedoutcomes.”

—Doug Coyle, PhD

Survivorship Programs an Emerging Need, but Are TheyCost-Effective? Patients feel abandoned at end of treatmentBy Caroline Helwick


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VBCC October Vol2 No6