August Volume 4, No 5

©2011 Green Hill Healthcare Communications, LLC

AUGUST 2011 www.TheOncologyPharmacist.com VOL 4, NO 5

Robin Mower, PharmD, consults with a patient and his wife to help manage his pain.

Porter Cancer Care CenterOncology Pharmacists Manage Patients’ Pain

By Dawn Lagrosa

Clinical oncology pharmacists evaluate and treat pain through painmanagement consultations at Porter Cancer Care Center. Aspart of the comprehensive cancer treatment program at Porter

Adventist Hospital in Denver, Colorado, Robin Mower, PharmD, andcolleagues provide one-on-one pain evaluation consults to enhance thequality of life of patients with cancer. Fortunately, Colorado allows col-laborative drug therapy management (CDTM) between physicians andpharmacists, allowing the clinical pharmacists at Porter AdventistHospital to provide pain management under the CDTM protocol. Inaddition to inpatient oncology pain management consults, the clinicalpharmacists provide pain management for outpatients in radiationoncology and the outpatient medical oncology clinics. Furthermore,

CANCER CENTER PROFILE

Continued on page 21

Complimentary Ce . . . . . . . . . . . 16The Evolving Role of Outcomes andEnd Points in Evaluating Therapy forHematologic Malignancies

ConferenCe news . . . . . . . . . . 14Decitabine Improve Overall Survivalin Older AML Patients

Flaxseed No More Effective ThanPlacebo for Hot Flashes

Optimal Length of Treatment of Non-Hodgkin Lymphoma Debated

pharmaCoeConomiCs . . . . . 24Upper GI Cancers: Are We Getting

Value for the Money?

I N S I D E

CHICAGO—The phase 3 ACT-1 trialsuggests that amrubicin may have someadvantages over topotecan as second-line treatment for small-cell lung cancer(SCLC). Both drugs achieved similaroverall survival (OS) as second-linetreatment, but amrubicin improvedresponse rates, improved progression-free survival (PFS), and improved con-trol of lung cancer–associated symp-

toms, where as topotecan worsened thosesymptoms. Prespecified subgroup analy-sis suggested that amrubicin achieved amodest improvement in OS comparedwith topotecan in patients who wererefractory at baseline.

This study suggests some benefit foramrubicin in the second-line setting,said lead author Robert Jotte, MD, PhD,

Amrubicin Better ThanTopotecan for Second-LineTherapy of SCLC?Amrubicin Offers Similar OS Plus Improves

Response Rates and PFS


Paclitaxel and docetaxel areamong the most active chemo -therapy options for metastatic

breast cancer.1,2 Use of these agentscontinues to evolve, as evidenced bytheir increasing use in early breast can-cer and the emergence of a Cremophor

EL–free formulation of paclitaxel(nanoparticle albumin-bound paclitax-el), which exhibits im proved efficacyand tolerability profiles. Use of tax-anes, however, almost always leads totaxane resistance at some point, which

BREAST CANCER

Differences and Similarities AmongIxabepilone and the Taxanes inMetastatic Breast CancerBy Teresa Davis, RN, OCNClinical Trials Coordinator, Jackson Oncology Associates, PLLC, Jackson, Mississippi

CHICAGO—Results from an importantphase 3 trial presented at the plenary ses-sion could lead to prolonged treatmentwith adjuvant imatinib for gastrointesti-nal stromal tumors (GIST).

The extension of imatinib treatment

to 3 years, compared with the usual 1year, resulted in a 54% reduced risk ofrecurrence and 55% reduced risk ofdeath within 5 years for patients withhigh-risk disease, reported Heikki

CONFERENCE NEWS: ASCO

Prolonged Treatment withImatinib Recommended for High-Risk GIST3-Year Treatment Reduces Risk of Recurrence

By Audrey Andrews

Continued on page 8


From the Beginning

NewFeatureNewFeature

Koeller’s CornerShooting from the Hip

Specialization in Oncology

Page 33

TOP_August 2011_v7_TOP 8/18/11 12:57 PM Page 1

TOP_August 2011_FINAL_TOP 8/18/11 4:15 PM Page 2

EDITOR-IN-CHIEFPatrick Medina,PharmD, BCOPOklahoma UniversityCollege of PharmacyTulsa, OK

John F. Aforismo,BSc Pharm, RPh,FASCPRJ Health SystemsInternational, LLCWethersfield, CT

David Baribeault,RPh, BCOPBoston Medical CenterBoston, MA

Betty M. Chan,PharmD, BCOPUSC/Norris CancerHospitalLos Angeles, CA

Steven L.D’Amato, RPh,BCOPMaine Center for CancerMedicineScarborough, ME

Anjana Elefante,PharmD, BSc,BSc Pharm, RPhRoswell Park CancerInstituteBuffalo, NY

Beth Faiman, RN,MSN, APRN,BC, AOCN Cleveland Clinic TaussigCancer InstituteCleveland, OH

ChristopherFausel, PharmDIndiana University Simon Cancer CenterIndianapolis, IN

Rebecca S. Finley,PharmD, MSJefferson School ofPharmacyPhiladelphia, PA

David C.Gammon, BSPhOncologyPharmacist.net Warwick, RI

Lew Iacovelli, BS,PharmD, BCOP,CPP Moses H. Cone HealthSystemGreensboro, NC

Dwight Kloth,PharmD, FCCP,BCOPFox Chase Cancer CenterPhiladelphia, PA

Jim Koeller, MSUniversity of Texas atAustinSan Antonio, TX

Christopher J.Lowe, PharmDIndiana UniversityHospitalIndianapolis, IN

Emily Mackler,PharmD, BCOPUniversity of MichiganHealth System & Collegeof PharmacyAnn Arbor, MI

Laura BoehnkeMichaud,PharmD, BCOP,FASHPThe University of TexasM. D. Anderson CancerCenterHouston, TX

LeAnn BestNorris, PharmD,BCPS, BCOPSouth Carolina College ofPharmacyColumbia, SC

Steve Stricker,PharmD, MS,BCOPSamford UniversityMcWhorter School ofPharmacyBirmingham, AL

Timothy G. Tyler,PharmD, FCSHPDesert Regional MedicalCenterPalm Springs, CA

John M. Valgus,PharmD, BCOPUniversity of NorthCarolina Hospitals andClinicsChapel Hill, NC

Gary C. Yee,PharmD, FCCP,BCOPUniversity of NebraskaCollege of PharmacyOmaha, NE

Burt Zweigenhaft,BSBioPharma Partners LLCNew York, NY

Marlo Blazer, RPh, PharmDJames Cancer Hospital & Solove ResearchInstituteColumbus, OH

Heidi D. Gunderson, PharmD,BCOPMayo Clinic Cancer CenterRochester, MN

Kamakshi V. Rao, PharmD,BCOPUniversity of North Carolina Hospitals and ClinicsChapel Hill, NC

Editorial Board

www.theOncologyPharmacist.com August 2011 I VOL 4, NO 5 3


PUBLISHING STAFFSenior Vice President, Sales & Marketing

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The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN1944-9593 (online) is published 8 times a year by GreenHill Healthcare Communications, LLC, 241 ForsgateDrive, Suite 205C, Monroe Twp, NJ 08831. Telephone:732.656.7935. Fax: 732.656.7938. Copyright ©2011 byGreen Hill Healthcare Communications LLC. All rightsreserved. The Oncology Pharmacist® logo is a registeredtrademark of Green Hill Healthcare Com munications,LLC. No part of this publication may be reproduced ortransmitted in any form or by any means now or hereafterknown, electronic or mechanical, including photocopy,recording, or any informational storage and retrieval sys-tem, without written permission from the Publisher.Printed in the United States of America.

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4 AugusT 2011 I VOL 4, NO 5 www.TheOncologyPharmacist.com

With the release of the new edition of the DrugInformation Handbook for

Oncology: A Complete Guide toCombination Chemotherapy Regimens(Lexi-Comp, Inc; July/August 2011),I am reminded of the ever-evolvingdynamic of our profession. Since lastyear, this handbook has added 18new drug monographs and 38 newchemotherapy regimens for a total of304 monographs and 378 combina-tion regimens. And this does nottake into account myriad supportive

care and palliative care treatments.This is why I am proud that The Oncology Pharmacist

helps keep you up to date not only on new drugs and drugcombinations but also on practice processes to enhancepatient care. At the American Society of ClinicalOncology (ASCO) annual meeting, we gleaned new sur-vival benefits for imatinib, amrubicin, and decitabine,among others. Plus, at more specialized ASCO meetings,

we discovered new targeted treatments for prostate andcolorectal cancer. In addition, “the whole patient” needsto be considered. Our new column describes, comorbidi-ties can both affect cancer treatments and result from can-cer care. The transition from bench to bedside, however, can be

confusing for practicing pharmacists. To help, Ms Davisbrings clarity to the pros and cons of the epothilones andthe taxanes. And value, an integral part of drug purchas-ing, is also an integral part of pharmacy practice. Newstudies on cost-effectiveness offer priceless data on whichproducts proffer the most benefits with the least toxicitiesat a reasonable cost. Finally, with this issue, we introduce Koeller’s Corner.

Jim Koeller, an oncology pharmacist well-known by manyof us, provides a forum to discuss issues in our field. Ourhope is that his insights into the everyday aspects of prac-ticing oncology pharmacy will assist you in caring for yourpatients and his openness to readers’ comments will createa dialogue among pharmacists. As always, we welcome your comments and look for-

ward to your feedback. �

Patrick Medina,PharmD, BCOPEditor-in-Chief

From the Editor

What inspired you to enterthe oncology field?

It takes a very special personto become an oncologypharmacist. All of us at

The Oncology Pharmacist areinspired by the dedication andcompassion we routinelyobserve from our reading com-munity. As part of our readerpolls, and in recognition of theimportant work you do, we’d like to invite you to share your inspiration for working inthis field.

Please log on to www.TheOncologyPharmacist.com to share your story.

©iS

tockphoto

.com

/die

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erv

o


www.BioOncology.com

© 2011 Genentech USA, Inc. All rights reserved. BIO0000330901 Printed in USA.

At Genentech BioOncology, not only are we leading the fight against cancer with innovative science, but we’re also dedicated to supporting patients and others within the oncology community.

A commitment to patients — We created Genentech BioOncology™

Access Solutions®, a single source for all access and reimbursementissues, so healthcare providers can remain focused on patient care.

Reducing barriers to treatment — We help make treatment possiblefor patients in financial need through our BioOncology Co-pay Card Program and ongoing charitable donations to various independent, nonprofit organizations in support of co-pay assistance.

A commitment to care — Our first product was approved in 1985, and since then we have donated approximately $2.3 billion in medicine to uninsured patients through the Genentech® Access to Care Foundation and other donation programs.

Our goal is to fundamentally change the way that cancer is treated by personalizing solutions to patient care.

Taking a broader view —char ting a unique course in cancer care



Noteworthy Numbers

INoteworthy Numbers

ncreased awareness, earlier detection through screening, and advances in treatment have led to a decline in breast cancer

death rates in the United States since 1990. Sadly, breast cancer continues to claim more women’s lives than any other cancer,

besides lung cancer. For more statistical data on this prevalent disease, let’s take a look at breast cancer by the numbers.

About 1 in 8 (12%)women in the UnitedStates will develop invasive breast cancerover the course of herlifetime.

In 2010, an estimated207,090 new cases ofinvasive breast cancerwere expected to be

diagnosed in women in the United States,along with 54,010 newcases of noninvasivebreast cancer.

About 1970 new cases of invasive breast cancer were expected to be diagnosed in men in 2010…

Less than 1% of all newbreast cancer casesoccur in men.

From 1999 to 2006,breast cancer incidencerates in the UnitedStates decreased byabout 2% per year…

Besides skin cancer,breast cancer is the

most commonly dia gnosed canceramong US women…

More than 1 in 4 (about28%) cancers in womenare breast cancer.

Compared with African-American women, whitewomen are slightly morelikely to develop breast


cancer, but less likely todie of it.

A woman’s risk of breastcancer approximatelydoubles if she has afirst-degree relative whohas been diagnosed withbreast cancer…

About 20% to 30% ofwomen diagnosed withbreast cancer have thisfamily history althoughsome are attributed tochance.

About 5% to 10% ofbreast cancers can belinked to gene mutations inherited fromone’s mother or father…

Mutations of the BRCA1and BRCA2 genes are themost common…

Women with thesemutations have up to an 80% risk of developing breast cancerduring their lifetime,and they are more likelyto be diagnosed at ayounger age…

An increased ovariancancer risk also is associated with thesegenetic mutations.

In men, about 1 in 10breast cancers arebelieved to be associatedwith BRCA2 mutation.

About 70% to 80% ofbreast cancers occur inwomen who have nofamily history of breastcancer.

The most significant riskfactors for breast cancerare gender (being awoman) and age (growing older).

In 2010, there were morethan 2.5 million breastcancer survivors in theUnited States.Source: BreastCancer.org

Noteworthy Numbers


ERBITUX IndicationsHead and Neck Cancer� ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally

advanced squamous cell carcinoma of the head and neck

� ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed

Colorectal Cancer� ERBITUX, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer after failure of

both irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens

� ERBITUX, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of ERBITUX in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with ERBITUX in combination with irinotecan for the treatment of EGFR-expressing metastatic colorectal carcinoma

� Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations

ERBITUX Boxed WARNINGS� Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients

in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions

� Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX

EGFR=epidermal growth factor receptor; RT=radiation therapy.

ERBITUX Increased Overall Survival in Both:

Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

EGFR-Expressing Recurrent Metastatic Colorectal Cancer (mCRC) after Irinotecan and Oxaliplatin Failure

as a Single Agent

Squamous Cell Carcinoma of the Head and Neck (SCCHN)

in Combination With RT in Locoregionally Advanced Disease


Joensuu, MD, of Helsinki UniversityCentral Hospital in Finland.“These data are pretty compelling,”

Joensuu commented. “I would not be sur-prised if the standard will be 3 years ofadjuvant imatinib in the near future.”

Mark G. Kris, MD, who moderated apress briefing and is chair of the ASCOCancer Communications Committee,

agreed. “The entire oncology commu-nity was extremely excited when wesaw the survival curve and those num-

Conference News


ERBITUX (cetuximab) + RT vs RT alone(n=211) (n=213)

Median overall survival49.0 months vs 29.3 months HR: 0.74; 95% CI: 0.57-0.97; P=0.03

3-year overall survival rate55% vs 45%P=0.05

Survival in Combination With RT (N=424)*1,2

RT=radiation therapy; HR=hazard ratio; CI=confi dence interval.* A multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration

of locoregional control. Secondary endpoints included overall survival.1,2

Median follow-up=54 months.2

� Primary endpoint: ERBITUX + RT (n=211) significantly improved median duration of locoregional control by 9.5 months (24.4 vs 14.9 months) vs RT alone (n=213) (log-rank P value=0.005; HR: 0.68 [95% CI: 0.52-0.89])1

ERBITUX Safety Information for SCCHN

� The most serious adverse reactions associated with ERBITUX® (cetuximab) across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus

� The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%)

� ERBITUX Plus Radiation Therapy and Cisplatin: The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

� Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

19.7month

improvement BSC=best supportive care. †

The most

The most

The most frequent adverse events seen in patients with metastatic colorectal cancer (n=354) t

ERBITUX Signifi cantly Increased

SCCHNin Combination With RT

in Locoregionally Advanced Disease

9:31 AM

The following articles are based on presentations at the 2011 Annual Meeting of theAmerican Society of Clinical Oncology held June 3-7, in Chicago, Illinois.

Prolonged Treatment with Imatinib... Continued from cover


Conference News


6.14 months vs 4.57 monthsERBITUX + BSC BSC alone(n=287) (n=285) HR: 0.77; 95% CI: 0.64-0.92; P=0.0046

T

The most f

E

L

BSC=best supportive care. † NCIC CTG CO.17 was a multicenter, open-label, randomized (1:1) clinical trial conducted with ERBITUX plus BSC or BSC alone. The main outcome measure of the trial was overall survival.1

� The data presented above include patients with K-ras mutations because K-ras mutational status was not assessed at the time the study was conducted

� Use of ERBITUX is not recommended for the treatment of colorectal cancer with K-ras mutations in codon 12 or 13 because retrospective subset analyses have not shown a treatment benefit for ERBITUX in these patients1

ERBITUX Safety Information for EGFR-Expressing Recurrent mCRC

� The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus

� The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%)

� The most frequent adverse events seen in patients with metastatic colorectal cancer (n=354) treated with ERBITUX plus irinotecan in clinical trials (incidence ≥50%) were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse events (≥ 10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%)

References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company; March 2011. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.

Median Overall Survival, All Patients (N=572)†1

34%improvement

Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

Overall Survival in Both:EGFR-Expressing Recurrent mCRC after Irinotecan and Oxaliplatin Failure

as a Single Agent

bers at 5 years. It’s one of the amazingstories in oncology, and it is the kind ofdata that change guidelines,” he said.

Study DetailsThe SSGXVIII/AIO study, which wasconducted by the Scandinavian SarcomaGroup and Sarcoma Group of the AIO,

Germany, was an open-label phase 3study that evaluated 36 months versus12 months of adjuvant imatinib admin-istered after surgical resection to 400GIST patients considered to have ahigh risk of recurrence.At a median follow-up of 54 months,

recurrences or death were observed in 50

of 198 (25%) patients receiving36 months of imatinib comparedwith 84 of 199 (42%) patientsreceiving 12 months of treatment.The recurrence-free survival ratewas 86.6% at 3 years and 65.6% at5 years with 36 months of treat-ment compared with 60.1% and

47.9%, respectively, with 12months of treatment. This rep-resented a 54% reduction inrisk of recurrence that washighly significant (P <.0001),Joensuu reported.Overall survival was 96.3%

at 3 years and 92.0% at 5 yearsMark G. Kris, MD

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Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8

Replete electrolytes as necessary

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Important Safety Information Including Boxed WARNINGS

Infusion Reactions� Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in

clinical trials, with fatal outcome reported in less than 1 in 1000

— Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest

— Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions

� Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines

— Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions

— Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions

Cardiopulmonary Arrest� Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma

of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In three patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX.

� Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks— Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after

ERBITUX therapy

Pulmonary Toxicity� Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving

ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed

Dermatologic Toxicities� In clinical studies of ERBITUX, dermatologic toxicities, including acneiform rash, skin drying and fissuring,

paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneiform rash occurred in 1-17% of patients

— Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days

— Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae

— Sun exposure may exacerbate these effects

ERBITUX Plus Radiation Therapy and Cisplatin� The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established

— Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck

— Two of 21 patients died, one as a result of pneumonia and one of an unknown cause

— Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

6/11

9:31 AM

with 36 months of treatment comparedwith 94.0% and 81.7%, respectively, with12 months of imatinib, representing a55% mortality risk reduction (P = .019). Grade 3 or 4 adverse events were more

common with longer treatment, andmore patients discontinued treatment inthe 36-month arm.

More May Be Better, DiscussantAgreedCharles D. Blanke, MD, chief of med-ical oncology, University of BritishColumbia, Vancouver, critiqued theSSGXVIII/AIO study, noting that itsconclusions were “valid.” He suggestedthat oncologists who typically initiate

imatinib on relapse might want torethink this strategy. “If you have a patient who has

high-risk GIST, at least as defined bythe study, giving him or her 3 years ofimatinib represents the new goldstandard,” he maintained. “The over-all survival benefit demonstrated

with immediate postoperative ima-tinib means it is no longer acceptableto withhold treatment in the adju-vant setting, hoping to ‘catch up’when a patient has recurrent meta staticdisease.”He acknowledged, however, stay-

ing on treatment for 3 years could be

www.theOncologyPharmacist.com10 August 2011 I VOL 4, NO 5

Conference News


Electrolyte Depletion� Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe

(NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy

— Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy

— Replete electrolytes as necessary

Late Radiation Toxicities� The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation

therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and

the ERBITUX plus radiation therapy arms

Pregnancy and Nursing� In women of childbearing potential, appropriate contraceptive measures must be used during treatment with

ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus

� It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

Adverse Events� The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions,

cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus

� The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection

� The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%)

� The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%)

� The most frequent adverse events seen in patients with metastatic colorectal cancer (n=354) treated with ERBITUX plus irinotecan in clinical trials (incidence ≥50%) were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse events (≥10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%)

— Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of E

Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions

� Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite p

Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first s

Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and o

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Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and c

Two of 21 patients died, one as a result of pneumonia and one of an unknown cause

— Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to c

©2011 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company.

693US11AB15201 6/11

Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

problematic for many patients, as sug-gested by a higher rate of side effectsand more than a doubling in thedropout rate among patients whoreceived imatinib for that long.Although it is possible that treatmenteven beyond 3 years could be even morebeneficial, he noted, “Difficulties on the

3-year arm of SSGXVIII/AIO may bodepoorly for therapy lasting even longer.”

“For now, if I were a patient with aresected GIST and I had a compliantoncologist, I would request more,” hesaid. “As a compliant oncologist, I per-sonally will offer patients treatment toeternity, meaning indefinitely.” �

“The entire oncology community was extremely excitedwhen we saw the survival curve and those numbers at5 years. It’s one of the amazing stories in oncology,and it is the kind of data that changes guidelines.”

—Mark G. Kris, MD

AugusT 2011 I VOL 4, NO 5 11www.TheOncologyPharmacist.com

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ERBITUX® (cetuximab)injection, for intravenous infusionBrief Summary of Prescribing Information. For complete prescribing information consult official package insert.

INDICATIONS AND USAGESquamous Cell Carcinoma of the Head and Neck (SCCHN)Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally orregionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in FullPrescribing Information.]Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cellcarcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1)in Full Prescribing Information.]Colorectal CancerErbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressingmetastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a singleagent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who areintolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warningsand Precautions.]Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectalcarcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux incombination with irinotecan is based on objective response rates. Currently, no data are available thatdemonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combinationwith irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies(14.2) in Full Prescribing Information and Warnings and Precautions.]Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatmentbenefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is notrecommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) andClinical Pharmacology (12.1) in Full Prescribing Information].

CONTRAINDICATIONSNone.

WARNINGS AND PRECAUTIONSInfusion ReactionsSerious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux,included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss ofconsciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactionsoccurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient. Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication withantihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agentsnecessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators,and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusionreactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See BoxedWarning and Dosage and Administration (2.4) in Full Prescribing Information.]Cardiopulmonary ArrestCardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapyand Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlledtrial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, withmyocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one hadcongestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with noprior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use ofErbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary arterydisease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes,including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning andWarnings and Precautions.]Pulmonary ToxicityInterstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux inclinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinueErbitux for confirmed ILD. Dermatologic ToxicityDermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectioussequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis,cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88%of 1373 patients receiving Erbitux in clinical trials. Severe acneiform rash occurred in 1–17%of patients. Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patientsafter cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patientsreceiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposureduring Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.]Use of Erbitux in Combination With Radiation and CisplatinThe safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death andserious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin(100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumoniaand one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of thesediscontinuations were due to cardiac events.Hypomagnesemia and Electrolyte AbnormalitiesIn patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receivingErbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanyingelectrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients forhypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion ofErbitux. Replete electrolytes as necessary.

Epidermal Growth Factor Receptor (EGFR) Expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in thehead and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumorexpression prior to study entry.Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidenceof EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomationEGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR andintensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentageof positive cells or the intensity of EGFR expression.

ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in other sections of the label:• Infusion reactions [See Boxed Warning and Warnings and Precautions.]• Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.]• Pulmonary toxicity [See Warnings and Precautions.]• Dermatologic toxicity [See Warnings and Precautions.]• Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.]The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologictoxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may notreflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomizedPhase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedulefor a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.]Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm,angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbituxfor locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose andschedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions(range 1–11).

Table 1: Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally AdvancedSCCHN

Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212)

Body System Grades Grades Grades GradesPreferred Term 1–4 3 and 4 1–4 3 and 4

% of PatientsBody as a WholeAsthenia 56 4 49 5Fever1 29 1 13 1Headache 19 <1 8 <1Infusion Reaction2 15 3 2 0Infection 13 1 9 1Chills1 16 0 5 0DigestiveNausea 49 2 37 2Emesis 29 2 23 4Diarrhea 19 2 13 1Dyspepsia 14 0 9 1Metabolic/NutritionalWeight Loss 84 11 72 7Dehydration 25 6 19 8Alanine Transaminase, high3 43 2 21 1Aspartate Transaminase, high3 38 1 24 1Alkaline Phosphatase, high3 33 <1 24 0RespiratoryPharyngitis 26 3 19 4Skin/AppendagesAcneiform Rash4 87 17 10 1Radiation Dermatitis 86 23 90 18Application Site Reaction 18 0 12 1Pruritus 16 0 4 0

1 Includes cases also reported as infusion reaction. 2 Infusion reaction is defined as any event described at any time during the clinical study as “allergic

reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as“allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”.

3 Based on laboratory measurements, not on reported adverse events, the number of subjects with testedsamples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.

4 Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustularrash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation ToxicityThe overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiationtherapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%),esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicitieswas similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARRESTInfusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings andPrecautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion forserious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in FullPrescribing Information.]Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients withsquamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitorserum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [SeeWarnings and Precautions.]

9:31 AM

director of thoracic oncology, RockyMountain Cancer Center, USOncology, Denver, Colorado. “Topo -tecan is too difficult to use and is not agood option for our patients,” he notedduring his presentation of study results.

SCLC has a dismal prognosis, with a5-year survival of about 6%, and moreeffective treatments are a pressingneed, he told the audience. The ACT-1 investigators compared 2 drugs to see if outcomes could be improved.

Topotecan is approved in the UnitedStates and Europe as second-line treat-ment of SCLC, and amrubicin, apotent topoisomerase II inhibitor, isapproved in Japan for SCLC and non-SCLC.

The study randomized 637 patients ina 2:1 ratio to amrubicin 40 mg/m2 intra-venously (IV) on days 1 to 3 or topote-can 1.5 mg/m2 IV on days 1 to 5 withgrowth factors given in the last third ofthe trial. Baseline characteristics were

Amrubicin Better Than Topotecan... Continued from cover


well match ed between the groups.Median age was 62 years, about 58% weremen, and groups were well matched forsensitive patients and refractory patients(who progressed after first-line therapy)and for extensive and limited disease atdiagnosis. One prior line of chemothera-py was allowed for enrollment.

Both arms received a median of 4cycles of chemotherapy. More patientsreceived full-dose chemotherapy in theamrubicin arm: 92.7% versus 86.9%,respectively. More than three quarters ofthe amrubicin patients did not requiredose reductions compared with 55.3% ofthe topotecan-treated patients.

OS was not significantly or numerical-ly different between the 2 groups; medianOS was 7.5 months in the amrubicin armcompared with 7.8 months in the topote-can arm. The hazard ratio of 0.880, how-ever, suggested that amrubicin achievedsome improvement over topotecan after6 months, Jotte said.

Looking at OS in sensitive versusrefractory patients, amrubicin appearsto have a modest advantage in refrac-tory patients (median OS, 6.2 monthsvs 5.7 months, respectively), but notin sensitive patients (median OS, 9.2months vs 9.9 months, respectively).Jotte noted that the hazard ratio of0.766 for refractory patients suggestedthat amrubicin improved survival after6 months in this subgroup.

Overall response rates significantlyfavored amrubicin: 31.1% comparedwith 16.9% for topotecan (P = .0001),and time to PFS also favored amru-bicin: 4.1 months compared with 3.5months for topotecan (P = .0182). Amrubicin achieved better control of

SCLC symptoms, with improved ap -petite, cough, and dyspnea, whereas thesesymptoms worsened on topotecan. Bothtreatments caused fatigue, but fatigue wasabout 3 times greater in the topotecanarm. There were more infections (13.2%vs 8.6% with topotecan) but fewer trans-fusions needed (31.8% vs 52.8% withtopotecan) in the amrubicin arm. Moreanemia, neutropenia, and thrombocy-topenia were reported on the topotecanarm. About 11% of patients in both armsdied on treatment. Although there wasconcern about cardiotoxicity with amru-bicin, with cumulative dosing, no differ-ence in left ventricular ejection fractionwas reported between the 2 arms. During the question-and-answer ses-

sion, Steven Vogel, MD, a communityoncologist in New York City, said thatthere are other available second-lineoptions for this poor-risk population,some of whom will respond to etoposideand cisplatin. Vogel said that in his prac-tice, whether he uses amrubicin willdepend on cost. �

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Colorectal CancerTable 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or withErbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at therecommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly).

Table 2: Incidence of Selected Adverse Events Occurring in ≥10% of Patients with AdvancedColorectal Carcinoma1 Treated with Erbitux Monotherapy

Erbitux plus BSC BSC alone(n=288) (n=274)

Body System Any Grades Any GradesPreferred Term Grades2 3 and 4 Grades 3 and 4

% of Patients

DermatologyRash/Desquamation 89 12 16 <1Dry Skin 49 0 11 0Pruritus 40 2 8 0Other-Dermatology 27 1 6 1Nail Changes 21 0 4 0Body as a WholeFatigue 89 33 76 26Fever 30 1 18 <1Infusion Reactions3 20 5Rigors, Chills 13 <1 4 0PainAbdominal Pain 59 14 52 16Pain-Other 51 16 34 7Headache 33 4 11 0Bone Pain 15 3 7 2PulmonaryDyspnea 48 16 43 12Cough 29 2 19 1GastrointestinalConstipation 46 4 38 5Diarrhea 39 2 20 2Vomiting 37 6 29 6Stomatitis 25 1 10 <1Other-Gastrointestinal 23 10 18 8Mouth Dryness 11 0 4 0InfectionInfection without neutropenia 35 13 17 6NeurologyInsomnia 30 1 15 1Confusion 15 6 9 2Anxiety 14 2 8 1Depression 13 1 6 <1

1 Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls.2 Adverse events were graded using the NCI CTC, V 2.0. 3 Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest

tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus,sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusion-related.

BSC = best supportive care

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trialswere acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most commonGrades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiformrash (14%).

ImmunogenicityAs with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximabwere assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assayperformance and sampling timing, the incidence of antibody development in patients receiving Erbitux has notbeen adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) ofevaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may beinfluenced by several factors including assay methodology, sample handling, timing of sample collection,concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodiesto Erbitux with the incidence of antibodies to other products may be misleading.

Postmarketing ExperienceThe following adverse reaction has been identified during post-approval use of Erbitux. Because this reactionwas reported from a population of uncertain size, it was not always possible to reliably estimate its frequency orestablish a causal relationship to drug exposure.

• Aseptic meningitis

DRUG INTERACTIONSA drug interaction study was performed in which Erbitux was administered in combination with irinotecan. Therewas no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category CThere are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animalmodels, EGFR has been implicated in the control of prenatal development and may be essential for normalorganogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross theplacental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has thepotential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancyonly if the potential benefit justifies the potential risk to the fetus.

Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose ofcetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48).Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetalmalformations or other teratogenic effects occurred in offspring. However, significant increases inembryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human doseof cetuximab (based on total body surface area).

Nursing MothersIt is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted inhuman milk. Because many drugs are excreted in human milk and because of the potential for serious adversereactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or todiscontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted,based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information],nursing should not be resumed earlier than 60 days following the last dose of Erbitux.

Pediatric UseThe safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab betweenthe two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distributionappeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single doseof 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group(1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.

Geriatric UseOf the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advancedcolorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy wereobserved between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number ofsubjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years ofage or older.

OVERDOSAGEThe maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events werereported for this patient.

NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityLong-term animal studies have not been performed to test cetuximab for carcinogenic potential, and nomutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assayor in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receivingweekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area).Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to controlanimals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured malefertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) ascompared to control male monkeys. It is not known if cetuximab can impair fertility in humans.

Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weeklyhuman exposure (based on total body surface area), resulted in dermatologic findings, including inflammation atthe injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosaof the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renaltubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highestdose level beginning after approximately 13 weeks of treatment.

PATIENT COUNSELING INFORMATIONAdvise patients:

• To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.

• Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequatecontraception in both males and females during and for 6 months following the last dose of Erbitux therapy.

• That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy.

• To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last doseof Erbitux.

Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company.

Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA

Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA

Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

Copyright © 2004–2011 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved.

1236886A8 ER-B0001A-03-11 Rev March 2011

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“The hazard ratio of 0.766for refractory patientssuggested that amrubicinimproved survival after 6months in this [sensitivepatients] subgroup.”

—Robert Jotte, MD, PhD


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CHICAGO—Flaxseed failed to have asignificant effect on reducing hot flash-es in women compared with placebo,according to results of a randomized,placebo-controlled trial supported bythe North Central Cancer TreatmentGroup. The study included breast can-cer survivors as well as women who hadnever had breast cancer who experi-enced frequent hot flashes throughoutthe day and night.

These results were disappointing, saidlead investigator Sandhya Pruthi, MD,Mayo Clinic, Rochester, Minnesota.“Hot flashes are bothersome, andalthough there are effective therapies,these have side effects. We need to bal-ance side effects with efficacy. Althoughthe present study was disappointing, weneed to continue to try to identify com-plementary treatments [with fewer sideeffects] that can relieve hot flashes,” shesaid at a presentation.

Hot flashes compromise quality oflife. They can be socially awkward aswell as interfere with sleep. At present,there are 2 effective options for treat-ment of hot flashes—venlafaxine and

gabapentin—but both have side effectsthat may not be acceptable. After hear-ing anecdotal evidence that flaxseedcontrolled hot flashes, Pruthi and col-leagues conducted a pilot study in 30women with hot flashes, and resultsshowed that flaxseed decreased boththe severity and frequency of hot flash-

es. That pilot trial led to the random-ized, placebo-controlled trial.

The current study enrolled 188 partic-ipants who experienced >28 hot flashesper week at baseline; 75% were aged 50years and older; 51% had a history ofbreast cancer. Among women with abreast cancer history, 15% were taking

an aromatase inhibitor and 25% weretaking tamoxifen. Patients were random-ized to 1 flaxseed bar per day containing410 mg lignans and fiber or to 1 placebobar per day with 2 g protein and fiber;treatment was continued for 6 weeks.

The flaxseed bars achieved a 33%decrease in hot flash score from baselinecompared with a 29% decrease forplacebo bars. Mean hot flash scoreswere reduced by 4.9 units in theflaxseed group and 3.5 units in theplacebo group. This difference betweentreatment arms was not significant,Pruthi said. In both groups, about onethird of the women received a 50%reduction in their hot flashes.

No significant differences in toxicitywere observed between the 2 arms.Abdominal distension, gas, and diarrheawere common in both arms, presumablyas a result of fiber content, she said.

“As oncologists, we need to deal withthe rollercoaster effects of our research.[Some trials appear promising and thenpan out not to have efficacy.] Hot flasheshave a negative impact on quality of life,and we need to find the most effectivetreatment. There are some effectivetreatments for hot flashes. Patientsshould discuss treatment options withtheir doctors,” said Mark G. Kris, MD,chief of Thoracic Oncology Service atMemorial Sloan-Kettering CancerCenter in New York City, who moderat-ed the press conference where Pruthipresented the results. �

Flaxseed No More Effective ThanPlacebo for Hot FlashesHunt Continues for Complementary Treatments for Reduction

By Bonnie Gillis

CHICAGO—Decitabine extends overall survival and improves responserates compared with standard therapiesin the treatment of older patients withnewly diagnosed acute myelogenousleukemia (AML), said Xavier G.Thomas, MD, PhD.

The treatment options for olderpatients with AML are limited. Intensivechemotherapy is generally poorly tolerat-ed in this group, the initial mortality rateis high (exceeding 30% at 8 weeks), theresponse rate to chemotherapy is poor,and relapse rates are high.

Recently, DNA hypermethylationhas been demonstrated in the promoterregion in AML. Hypomethylating agentsmay affect tumor suppression genes andhave been shown to be beneficial inAML cell lines, said Thomas, who iswith the department of hematology,Edouard-Herriot Hospital, Lyon, France.

Among the hypomethylating agents,

decitabine has been approved forpatients with myelodysplastic syndrome,and has demonstrated activity in a previ-ous phase 2 trial of patients older than 60years with AML.

Based on these results, a phase 3 mul-ticenter, controlled, open-label trial wasdesigned to compare decitabine withpatients’ choice of treatment on overallsurvival in patients 65 years and older

with newly diagnosed de novo or sec-ondary AML and poor- or intermediate-risk cytogenetics. The 485 patientsenrolled were randomized to decitabine,20 mg/m2 as a 1-hour intravenous infu-sion once daily for 5 consecutive days,every 4 weeks, or treatment of choice.Patients assigned to treatment of choicecould select low-dose cytarabine, 20-mg/m2 subcutaneous injection once dailyfor 10 days, every 4 weeks (n = 243), orsupportive care (n = 28).

Patients assigned to decitabine had amedian duration of treatment of 4.4months compared with 2.4 months forthose on the treatment-of-choice arm.

The protocol-specified final analysis(after 396 deaths) showed a nonsignifi-cant but favorable trend for increasedoverall survival for patients treated withdecitabine, with a median survival of 7.7months compared with 5.0 months inthe treatment-of-choice arm (P = .10).

Seventy-five patients received dis-ease-modifying therapy after treatmentfailure following randomization. Whenthese 75 patients were censored fromthe analysis, median overall survivalimproved to 8.5 months in thedecitabine group and 5.3 months inthe treatment-of-choice arm, corre-sponding to a 20% reduction in therisk of mortality in the decitabine arm,and the difference became statisticallysignificant (P = .044).

An updated unplanned overall analy-sis was performed with 446 deaths, orapproximately an additional year ofpatient follow-up. This updated analysisshowed the same median survival in the2 groups (7.7 vs 5.0 months) but theeffect became significant (nominal P =.037). “This analysis increases thestrength and validity of the first clinicalcutoff,” said Thomas.

The secondary end point of com-plete remission with incompleteplatelet recovery or complete remis-sion with incomplete blood countrecovery was achieved by 17.8% of thedecitabine arm compared with 7.8%on treatment of choice.

Adverse event rates were consistentwith the known decitabine safety profileand without major differences betweenthe treatment arms. �

Decitabine Improves Overall Survival inOlder AML PatientsPhase 3 Trial Also Finds 20% Reduction in the Risk of Mortality By Wayne Kuznar

The protocol-specifiedfinal analysis (after 396deaths) showed anonsignificant butfavorable trend forincreased overall survivalfor patients treated withdecitabine.

©iStockphoto.com/Koshtu



Conference News

ORLANDO—Oncology pharmacistscan stick with the approved dosing forsunitinib in the treatment of advancedrenal cell carcinoma (RCC), accordingto a study by New York investigators.A dosing schedule of 50 mg daily for 4

weeks, followed by 2 weeks off treatment(4/2) of sunitinib appears to be the opti-mal dosing schedule as first-line treat-ment of advanced RCC. In a phase 2study, researchers compared differentdosing schedules of this vascularendothelial growth factor inhibitor andfound that patients treated with a 37.5-mg continuous daily dose (CDD) regi-men had similar overall response rates(ORRs) and overall survival (OS) topatients receiving 4/2 dosing. However,there was a trend toward inferior time totumor progression (TTP) with the CDDregimen.“The median time to progression for

the 4/2 schedule was 9.9 months com-pared with 7.1 months with continuousdosing. Although there wasn’t a statisti-cally significant difference, there was atrend toward superiority with the 4/2

schedule,” said lead study investigatorRobert Motzer, MD, who is an attendingphysician at Memorial Sloan-KetteringCancer Center, New York, New York.“We felt that this study was important todo because there has been a lot of inter-est in looking at alternative dosing.”

Motzer, who presented the study find-ings at the 2011 Genitourinary CancersSymposium, said these findings areimportant because they add to the

growing body of evidence supportingthe approved dosing schedule of suni-tinib in advanced RCC. An oral agent,sunitinib is a receptor protein-tyrosinekinase inhibitor that has been shown ina randomized phase 3 trial to providesuperior progression-free survival tointerferon-alfa (11 vs 5 months) as first-line metastatic RCC therapy. Previousstudies have suggested that continuousdosing of sunitinib 37.5 mg has antitumor activity with a manageable safetyprofile in first- and second-line treat-ment for metastatic RCC.Motzer and his colleagues conducted a

study comparing the CDD regimen tothe 4/2 schedule in 292 patients who hadclear cell, locally recurrent, or metastaticdisease. Sunitinib was continued untildisease progression, unacceptable toxici-ty, or up to 2 years. The primary endpoint was TTP, and secondary end pointswere ORR, OS, and adverse events.All the patients were randomized (146

patients in each arm) between January2007 and June 2008. As of October2010, 289 patients had received suni-

tinib, and all patients were off therapy.The median age of the patients was 62years, and 65% were men.In addition to the increase in TTP,

the researchers found that ORR was32.2% for the 4/2 dosing schedule com-pared with 28.1% for the CDD regi-men. Median OS was 23.1% for the 4/2dosing group compared with 23.5% forthe CDD group.“We looked at patient-reported out-

comes, and we found no difference inquality of life between the 2 dosingschedules, but we found in anotheranalysis of time to progression and timeto death that there was a statisticallysignificant improvement with the stan-dard 4/2 schedule compared with con-tinuous dosing,” said Motzer in an inter-view with The Oncology Pharmacist.He said the most common drug-

related adverse events were fatigue(62% in both arms), nausea (56% forthe 4/2 dosing group vs 49% for theCDD group), and diarrhea (56% forthe 4/2 dosing group vs 64% for theCDD group). �

KIDNEY CANCER

Approved Sunitinib Dosing Recommended for Metastatic Renal Cell CarcinomaBy John Schieszer

A dosing schedule of 50 mg daily for 4 weeks,followed by 2 weeks offtreatment (4/2) of sunitinibappears to be the optimaldosing schedule as first-line treatment ofadvanced RCC.

CHICAGO—Seve ra lstudies addressed key ques-tions in the treatment ofnon-Hodgkin lymphoma(NHL). One evaluated ashorter, more intense ritux-imab-based regimen, andanother evaluated the ben-efit of autologous stem-celltransplantation (ASCT) inhigh-risk patients. The 21-day regimenof rituximab plus cyclophosphamide,doxorubicin, vincristine, and pred-nisolone (R-CHOP) is still the standardof care for this paient population.Rituximab revolutionized the care of

NHL and is essentially part of the treat-ment for all patients with this disease,but researchers continue to evaluate var-ious schedules for delivering the drug. One debate during ASCO 2011

focused on whether the standard 21-dayregimen can be shortened to 14 days;however, investigators from the UnitedKingdom reported no advantage withthe 14-day regimen.

This randomized phase 3trial involved 1080 patientswith diffuse large B-cell NHL,all of whom were to receiveR-CHOP. The Treatment-naïve patients were randomlyas signed to receive either 8cycles of R-CHOP for 21 daysor 6 cycles of R-CHOP for 14days plus granulocyte colony-

stimulating factors, succeeded by 2cycles of single-agent rituximab.After a median follow-up of 37

months, the rates of overall survival(OS) and progression-free survival(PFS) were similar, as were objectiveresponse rates. No subgroup appeared to derive a

greater benefit from accelerated R-CHOP, reported David Cunningham,MD, of the Royal Marsden Hospital,who presented the results for the UKNational Cancer Research InstituteLymphoma Clinical Study Group. Neutropenia and febrile neutrope-

nia were more frequent in patients

receiving the 21-day regimen, probablybecause the 14-day group receivedgrowth factors, although thrombocy-topenia was more frequent with R-CHOP-14, probably because of greaterdose intensity. According to Cunningham, the re -

sults do not support a shift in clinicalpractice from R-CHOP-21 to R-CHOP-14.

Transplant ImprovesOutcomes in High-GradeAggressive NHL Julie M. Vose, MD, of theUniversity of Nebraska MedicalCenter, Omaha, discussed theUK trial’s findings and agreed.But she added that in youngerpatients at high risk for recur-rence, R-CHOP-21, followed by autol-ogous transplantation of peripheralstem cells, should be offered as a stan-dard of care.This strategy was shown to be effec-

tive in the phase 3 intergroup SWOG

S9704 trial of 253 patients with NHLthat was presented at the meeting byPatrick J. Stiff, MD, of LoyolaUniversity Medical Center, Chicago.ASCT after CHOP-based induction

therapy improved PFS in patients whohad an aggressive form of the disease,as indicated by their high or high-intermediate International PrognosticIndex score. Patients responding to CHOP, with

or without rituximab, had a 2-year PFSrate of 69% with ASCT comparedwith 56% with the induction therapyalone, which translates to a 72%increase in PFS (P = .005).

The 2-year OS rateswere similar between the2 groups, at 74% and71%, respectively; howev-er, many patients in thecontrol arm underwent asalvage transplant, whichmay have confused thisanalysis, Stiff pointed out.The survival benefit

was most apparent in pa -tients with high International PrognosticIndex score; in this subgroup, the 2-yearPFS rate was 75% with transplant com-pared with 41% with standard care, andthe 2-year OS rates were 82% and 64%,respectively. �

Optimal Length of Treatment of Non-Hodgkin Lymphoma DebatedBy Caroline Helwick

David Cunningham, MD

Julie M. Vose, MD


While healthcare reform is onthe horizon, the pipeline fornew cancer therapies contin-

ues to grow and cancer care costs are onthe rise. More than 90% of the anti-cancer agents approved by the US Foodand Drug Admin istration (FDA)between 2004 and 2008 cost more than$20,000 for a 12-week course of treat-ment.1 The practice of managed carepharmacy frequently involves makingdecisions about whether a given drug ora regimen is covered under a patient’spharmacy benefit or health insuranceplan. The question that managed carepayers are asking is, will the health out-comes produced by these expensivetherapies justify the increased cost?Payers are increasingly insisting thatnewly introduced agents and regimensdemonstrate improvement in patientoutcomes before their cost will be fullyreimbursed.

End Point versus Outcome: What Isthe Difference?Avedis Donabedian, MD, MPH, publichealth pioneer, defined outcomes as the“consequences to the health and wel-fare of individuals and of society.”2 Henoted that “outcomes, by and large,remain the ultimate validation of theeffectiveness and quality of medical

care.”2 Ultimately, cure is the desiredoutcome for patients with any disease.However, this is not currently a realisticgoal for most patients with cancer whoare undergoing the therapies availabletoday. As advances are made in ourunderstanding of molecular oncologyand new targeted therapies are devel-oped, many malignancies are beingtreated as chronic diseases, and patientsdiagnosed today may expect to livelonger than patients diagnosed in yearspast. A patient’s quality of life and free-dom from disease progression maybecome more important outcomes thansurvival if differences in overall survival(OS) are not apparent when comparingtherapies and regimens.The economic evaluations involved

in making managed care decisions oftenconsider the likely costs and outcomesof new therapies over time, based pri-marily on safety and efficacy end pointdata from the clinical trials that led tothe approval. A clinical trial will usual-ly define or specify a primary end pointas an objective measure that will indi-cate the success of the therapy beinginvestigated. A trial may also define 1 ormore secondary end points that will bemeasured and are expected to be met. Some of these end points may be sur-

rogate end points, which are biomarkers

that may correlate with a real clinicaloutcome but do not necessarily have aguaranteed relationship. In addition, aprimary end point that supports efficacyin previous and ongoing clinical trialsmay be different from the primary endpoint in subsequent trials, making it dif-ficult to compare agents and regimensand their effect on the desired outcome. Although an improvement in OS

had historically been the gold standardend point for a new oncology drugapproval, 68% of the regular approvalsand 100% of the accelerated approvalsfor oncology drugs between 1990 and2002 were based on clinical trial endpoints other than survival, includingthe objective response rate, progression-free survival (PFS), disease-free survival(DFS), and time to progression (TTP).3In 2003, the FDA began a project to

evaluate potential end points for cancerdrug approval.4 End points were exam-ined for the most common cancers dur-ing public workshops, important issueswere identified, and these issues werediscussed in meetings of the OncologicDrugs Advisory Com mit tee. Sub -sequently, a guidance document waspublished in 2007, describing the FDA’scurrent thinking on end points for can-cer drug approval.5 Although the FDAstill regarded OS as the preferred end

point in a cancer trial, FDA membersfound a clear disadvantage in the neces-sity of a long observation period. During this same period (2001 to pres-ent), the targeted therapies for multiplemyeloma (MM), non-Hodgkin lym-phoma (NHL), and chronic myeloidleukemia (CML) that are in commonuse today entered the clinical arena.

Multiple MyelomaMM is the second most frequently diagnosed hematologic malignancy.6 Al -though MM remains incurable, out-comes have significantly improved inrecent years with the introduction ofnovel agents, such as the immun o modu-latory drugs thalidomide and lenalido-mide and the proteasome inhibitorbortezomib, and with advancements insupportive care (Table). The early intro-duction of effective management strate-gies that include ≥1 of these novel agentshave improved survival for patients withMM. In fact, between 1975 and 1979, apatient receiving a diagnosis of MM hadonly a 53% probability of surviving 2years.7 In comparison, 2-year survivalrates for patients diagnosed within thepast few years have been reported as highas 88%, and the 5-year survival rate hasincreased to more than 40% for patientsdiagnosed in 2003.7

The Evolving Role of Outcomes and End Points in EvaluatingTherapy for Hematologic Malignancies: Value-Driven BenefitDesign and Utilization Management Strategies

PROGRAM P11067E • RELEASE DATE: JULY 15, 2011 • EXPIRATION DATE: JULY 15, 2012

ESTIMATED TIME TO COMPLETE: 1.0 HOUR • COMPLETE THE POSTTEST AT WWW.THEONCOLOGYPHARMACIST.COM

TARGET AUDIENCE

This activity was developed for health-systempharmacists and oncology pharmacists.

LEARNING OBJECTIVES

After completing this activity, the reader should beable to:• Compare and contrast the primary end pointsused in pivotal clinical trials for hemato logicmalignancies

• Determine which end points are the most appro-priate and clinically relevant for assessing theefficacy of novel targeted agents for multiplemyeloma, chronic myeloid leukemia, and non-Hodgkin lymphoma

• Evaluate surrogate end points as they relate tooptimal long-term outcomes for patients withhematologic malignancies

• Analyze the results from clinical trials toassess the justification of incorporating noveltargeted agents into standards of care andeffective benefit design and utilization man-agement approaches

SPONSOR

This activity is jointly sponsored by MedicalLearning Institute, Inc. (MLI), a nonprofit medicalaccreditation company, and Center of ExcellenceMedia, LLC.

INSTRUCTIONS fOR CREDIT

1. Read the article in its entirety2. Log on to www.TheOncologyPharmacist.com3. Select “Continuing Education”4. Click on this article’s title from the listshown

5. Select “Click here to complete the posttestand obtain a CE certificate online”

6. Complete and submit the CE posttest and CEActivity Evaluation

7. Print your Statement of Completion

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of continuing pharmacy education. Com pletionof this activity provides for 1.0 contact hour (0.1CEU) of continuing education credit. The univer-sal activity number for this activity is 0468-9999-10-059-H01-P.

This activity is provided free of charge to partici-pants. Upon completion of the evaluation and scor-ing 70% or better on the posttest, you will imme-diately receive your certificate online. If you do notachieve a score of 70% or better on the posttest,you will be asked to take it again. Please retain acopy of the certificate for your records.

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Before the activity, all faculty and anyone who isin a position to have control over the content ofthis activity and their spouse/life partner will dis-close the existence of any financial interestand/or relationship(s) they might have with anycommercial interest producing healthcaregoods/services to be discussed during their pres-entation(s): honoraria, expenses, grants, consult-ing roles, speakers’ bureau membership, stockownership, or other special relationships. Pre -senters will inform participants of any off-labeldiscussions. All identified conflicts of interest arethoroughly vetted by Medical Learning Institute,Inc., for fair balance, scientific objectivity of stud-ies mentioned in the materials or used as thebasis for content, and appropriateness of patientcare recommendations.

Shelly Chun, PharmD, a reviewer for MLI, hasnothing to disclose.

Linda Ritter, PhD, Center of Excellence Media,has nothing to disclose.

Chair James T. Kenney Jr, RPh, MBA, has nothing todisclose.

Faculty Michael Mauro, MD, receives research grants fromNovartis Oncology and Bristol-Myers Squibb.

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The associates of Medical Learning Institute,Inc., the accredited provider for this activity, andCenter of Excellence Media, LLC, do not haveany financial relationships or relationships toproducts or devices with any commercial inter-est related to the content of this CE activity forany amount during the past 12 months.

DISCLAImER

The information provided in this CE activity is forcontinuing education purposes only and is notmeant to substitute for the independent medicaljudgment of a healthcare provider relative todiagnostic and treatment options of a specificpatient’s medical condition. Re commendationsfor the use of particular therapeutic agents arebased on the best available scientific evidenceand current clinical guidelines. No bias towardor promotion for the agent discussed in this pro-gram should be inferred.

COmmERCIAL SUPPORT

ACkNOwLEDGmENT

This activity is supported by educational grantsfrom Millennium Pharmaceuticals and NovartisPharmaceuticals.

CONTINUING EDUCATION


TOP_August 2011_FINAL_TOP 8/19/11 11:50 AM Page 16

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Consistency in the conduct of clini-cal trials and in the analysis andreporting of results is essential toensuring valid and reliable results thatcan be compared with those of othertrials. Early in 2011, the InternationalMyeloma Workshop Consensus Panel1 recommended PFS as the primaryend point for clinical trials in lieu oflong-term OS data.8 An analysis ofPFS includes all patients and is calcu-lated from the beginning of treatmentto disease progression or death fromany cause. TTP has also been used asthe primary end point in clinical trialsfor MM. An analysis of TTP is essen-tially the same as that for PFS, butdeaths that are not directly related tothe disease are not counted in TTP.However, as data from trials initiatedin the past decade mature, a PFS orTTP trial end point benefit does notalways translate into an OS benefit.

Transplant-ineligible patientsThe combination of melphalan andprednisone (MP) had historicallybeen the regimen of choice for newlydiagnosed MM in patients who werenot eligible for autologous stem-celltransplant (ASCT). In 2008, theFDA approved bortezomib “for thetreatment of patients with multiplemyeloma.” This approval was basedon the VISTA (Velcade as InitialStandard Therapy in MultipleMyeloma) trial, in which the combi-nation of bortezomib, melphalan, andprednisone (VMP) was comparedwith MP in 682 patients with newlydiagnosed MM who were ineligible forASCT.9 The median TTP—the pri-mary efficacy end point in the study—was 24.0 months in the VMP groupcompared with 16.6 months in theMP group (P <.001).

In December 2009, survival benefitwas added to the VMP label after furtheranalysis of the VISTA trial demonstrat-ed that OS continued to improve signif-icantly in the VMP arm during a medi-an follow-up of 36.7 months despitesubsequent therapies, including bor -tezomib-based regimens.10 Median OSwas not reached with VMP versus 43.1months with MP (P <.001); after 3years, the OS rates were 68.5% versus54.0%, respectively.9Several phase 3 trials have compared

the use of melphalan, prednisone, andthalidomide (MPT) with that of MP forthe treatment of newly diagnosed MMin patients who were not eligible forASCT,11-15 showing mixed results.Although these trials have consistentlyshown better re sponse rates with MPTthan with MP, only 4 of the 5 trialsshowed a significant improvement inPFS, and only 2 showed a significantimprovement in OS (P <.05). A meta-analysis of these 5 trials (N = 1568)showed a pooled hazard ratio (HR) of0.68 for PFS (P <.001; 95% confidenceinterval [CI], 0.55-0.82) and 0.80 for OS(P = .07; 95% CI, 0.63-1.02) in favor of MPT.16 Although the addition ofthalidomide to MP results in significant-ly improved PFS, MP alone demon-strates only a nonsignificant improve-ment in OS, with the additional burdenof significantly increased toxicity.Recently, data were reported from a

phase 3 trial comparing the combina-tion of lenalidomide plus MP (MPR)with MP in patients aged ≥65 years whowere ineligible for ASCT (N = 459).17Patients were randomized to receiveeither MP alone, MPR (fixed dose sched-ule), or MPR followed by continuouslenalidomide maintenance (MPR-R). Ata median follow-up of 25 months,patients who received MPR-R demon-

strated a significant im provementin PFS (31 months) comparedwith patients who received MPR(14 months) or MP (13 months; P<.001). How ever, the significantPFS advantage did not apply topatients aged >75 years (MPR-R vsMPR; P = .118). Although a medianOS has not been reached among anyof the 3 arms, there is currently no sig-nificant difference be tween the armsin the estimated 1-year and 2-year OSrates.

Transplant-eligible patientsThe quality of posttransplantation re -sponse, especially the achievement ofcomplete response (CR), is now wellestablished as a prognostic indicator ofimproved long-term survival for previ-ously untreated MM in patients who re -ceive high-dose therapy and ASCT.18,19In a retrospective analysis of 344 pa -tients with MM who underwent trans-plantation between 1989 and 1998,after a median follow-up of 12.75 years,the OS rate at 12 years was 35% forpatients achieving CR, 22% for thosedemonstrating near CR (nCR), and

16% for those achieving very good par-tial response (VGPR).20 Significant dif-ferences in OS and PFS were foundbetween the CR and nCR groups (P =.01 and P = .002, respectively), as well asbetween CR and VGPR (P = .0001 and.003). A plateau in OS was ob servedafter 11 years; 35% of patients achievingCR are alive at 17 years. For patients who are transplant-eligi-

ble, recent clinical trials have evaluatedcombined modality induction regimenswith the novel agents in an attempt to increase the rate of response to induc-tion therapy to improve the quality of response to transplanta tion. In theHOVON-65/GMMG-HD4 (Dutch-Bel gian Hemato-Oncology/GermanCoop erative Groups) trial, patients wererandomized to induction therapy withbortezomib, doxo rubicin, and dexa meth a-sone (PAD) or with vincristine, doxo ru-bicin, and dexamethasone (VAD).21After undergoing high-dose therapy andASCT, patients who were randomizedto PAD received bortezomib as mainte-nance therapy for as long as 2 years, andthose randomized to VAD receivedthalidomide. The postinduction re -sponse rate of VGPR or bet ter was 42%in patients receiving PAD and 15% inthose receiving VAD (P <.001). Theresponse rates improved to 61% and36%, respectively, posttransplantationand to 76% and 55% during mainte-nance. Patients receiving PAD induc-tion with bortezomib maintenanceshowed significantly improved PFS(HR = 0.75; P = .005) and OS (HR =0.73; P = .02).In the phase 3 GIMEMA (Gruppo

Italiano Malattie Ematologiche dell’Adulto) trial, the safety and efficacy ofinduction therapy and consolidationwith thalidomide plus dexamethasone(TD) is being compared with that ofbortezomib, thalidomide, and dexa -methaone (VTD) in combination withdouble ASCT and dexamethasonemaintenance.22 The addition of bortez -omib to TD significantly im proved theCR rate after induction, first transplan-tation, second transplantation, andconsolidation. Treatment with VTDresulted in a significant 37% reductionin the relative risk for progression ordeath (HR = 0.63; P = .0061), but at amedian follow-up of 36 months, no dif-ference in OS has been seen (HR =0.76; P = .3071).Two additional promising novel

To Receive cRediT, compleTe The posTTesT aTTheOncologyPharmacist.com

aThalomid [package insert]. Summit, NJ: Celgene; 2010.bRevlimid [package insert]. Summit, NJ: Celgene; 2010.cVelcade [package insert]. Cambridge, MA: Millennium; 2010.

LD indicates lenalidomide/dexamethasone (high-dose); MM, multiple myeloma; MP, melphalan/prednisone; ORR, overall response rate; TD, thalidomide/dexamethasone (high-dose); TTP, time to progression; VMP, bortezomib/melphalan/prednisone.

Table Label Indication and Registration Trial Information for Thalidomide, Lenalidomide, and Bortezomib

Registration trial

Drug Indication Design/patientsPrimary end point Result

Thalidomidea In combination with dexamethasonefor the treatment of patients withnewly diagnosed MM

Newly diagnosed patients with MMN = 207TD vs high-dose dexamethasone

ORR, % 51.5 vs 35.6

Lenalidomideb In combination with dexamethasonefor the treatment of patients withMM who have received at least 1previous therapy

Relapsed/refractory MM(at least 1 previous treatment)Study 1: N = 353Study 2: N = 351LD vs high-dose dexamethasone

Median TTP, mo

Study 1: 13.9 vs 4.7 P <.001Study 2: 12.1 vs 4.7 P <.001

Bortezomibc Treatment of patients with MM Newly diagnosed patients with MMN = 682VMP vs MP

Median TTP, mo

20.7 vs 15.0 P <.0001

Relapsed/refractory MM (after 1-3 previous therapies)N = 669Bortezomib vs high-dose dexamethasone

Median TTP, mo

6.2 vs 3.5 P <.0001

The postinductionresponse rate of VGPR orbet ter was 42% in patientsreceiving bortezomib,doxorubicin, anddexamethasone and 15%in those receivingvincristine, doxorubicin,and dexamethasone.


combination regimens in phase 2 stud-ies have reported high rates of CR afterinduction. One is the combination ofbortezomib, lenalidomide, and dexa -methasone (VRD), and the other is thatof bortezomib, dexamethasone, andcyclo phos phamide (VDC).23,24 VRDshowed a VGPR rate of 74%, and VDC(modified to add an additional dose ofcyclophosphamide at day 15) showed aVGPR rate of 53%. In addition, untilmore data and longer follow-ups areavailable, consolidation and mainte-nance therapy with novel agents mayimprove posttransplant responses andprovide patients with a significant sur-vival advantage.

Chronic Myeloid LeukemiaApproximately 0.6 to 2.0 cases ofPhiladelphia chromosome-positive(Ph+) CML are diagnosed globally per100,000 persons each year. Approx -imately 1.5 cases per 100,000 personsare diagnosed each year in the UnitedStates.7,25 Historically, chemotherapywith alkylating agents and hydroxy ureaprovided a median survival of only 3 to4 years.26 Median survival improved to 6to 7 years in the early 1980s with theadvent of interferon-alpha, but the 10-year survival rate was still only 30% to40%, and patients had few options afterthe failure of first-line therapy.27

Before 2000, survival was the primarygoal of therapy for patients with CML inchronic phase (CML-CP). The intro-duction of the tyrosine kinase inhibitor(TKI) imatinib in 2001 has revolution-ized management strategies, refocusingthe outcome on prevention of progres-sion rather than on survival. The annualmortality rate has decreased to approxi-mately 1% to 2%, and the estimated 5-year survival rate has increased toapproximately 90%.7 This translates toan increasing prevalence that mayexceed 200,000 cases in the UnitedStates within the next 20 years.26

The importance of early optimalresponseIt was established that patients withCML had prolonged survival afterachieving a cytogenetic response (CyR)to interferon-alpha.28 In 2001, imatinibwas approved for newly diagnosed CML-CP based on the surrogate end points ofmajor CyR and complete CyR(CCyR).29 Since then, much has beenlearned regarding the accepted mile-stones for response to first-line therapyand the timing of those responses.Patients with suboptimal or poorresponse within the first 6 months oftherapy are far more likely to experienceearly disease progression to advancedphase or blast crisis, in which long-termresponses to TKIs are unlikely to occurand overall healthcare costs are muchhigher.

In a study comparing patients with asuboptimal response or failure within 6months of initiating imatinib therapyand those who responded during thatsame period, the likelihood of achievingCCyR was 39% versus 96%, respective-ly (P <.0001), the rate of PFS was 87%versus 98% (P = .04), and the rate ofOS was 70% versus 92% (P = .001).30In the IRIS (Insulin Resistance In -tervention after Stroke) trial, patientswho achieved a CCyR had a lowerannual incidence of events (loss ofresponse, transformation to advancedphase or blast crisis, or death) than theoverall group after 5 years of follow-up.31In addition, 100% of patients in theimatinib arm of the IRIS trial who hadachieved both a CCyR and a majormolecular response (MMR) by 12months were free from progression toadvanced phase or blast crisis at 8 years,and the achievement of CCyR by 12months was associated with improvedsurvival.32

Second-generation TKIsSecond-generation TKIs (nilotinib,dasatinib, and bosutinib) are beingcompared with imatinib in clinical trialsin patients with newly diagnosed CML-CP. Nilotinib (300 mg twice daily)received FDA approval in June 2010 forthe treatment of newly diagnosed CML,based on results from the ENESTnd(Evaluating Nilotinib Ef ficacy andSafety in Clinical Trials—NewlyDiagnosed Patients) trial. The primaryend point in this trial is the MMR rateat 12 months. After a median follow-upof 18.5 months, the rate of MMR fornilotinib at 12 months (44%) was twice(22%) that for imatinib (P <.0001).33By 12 months, the rate of CCyR wasalso significantly higher among patientsreceiving nilotinib (80%) than amongthose receiving imatinib (65%; P<.001). The Kaplan-Meier estimate ofthe median time to MMR was shorter

(8.6 months) for patients receivingnilotinib than for those receiving ima-tinib (median not yet achieved).

An updated analysis of data coveringa median follow-up of 24 months waspresented at the 2010 AmericanSociety of Hematology’s (ASH) annualmeeting.34 At 24 months, the MMRrate was 62% for nilotinib versus 37%for imatinib (P <.0001) and the CCyRrates were 87% versus 77%, respective-ly (P = .0018). In addition, significantlyfewer patients receiving nilotinib(0.7%) than those receiving imatinib(4.2%) had progressed to advancedphase or blast crisis or had died (P =.0059). Fewer patients receiving nilo-tinib discontinued therapy because ofadverse events.

Dasatinib received FDA approval fornewly diagnosed CML-CP in October2010 based on results from the DASI-SION (Dasatinib versus Imatinib Studyin Treatment-Naïve CML Patients)trial, which compared dasatinib withimatinib. The primary end point wasthe rate of confirmed CCyR at 12months.35 After a median follow-upperiod of 14 months, the rate of con-firmed CCyR at 12 months was signifi-cantly higher in patients receivingdasatinib (77%) than in those receiv-ing imatinib (66%; P = .007). In addi-tion, the rate of MMR at any time was

significantly higher among patientsreceiving dasatinib (52%) than amongpatients receiving imatinib (34%; P <.0001). Among patients whoachieved an MMR, the median time toMMR was 8.3 months for dasatiniband 11.8 months for imatinib. Fewerpatients receiving dasatinib (1.9%)than those receiving imatinib (3.5%)had progressed to advanced phase orblast crisis. The rates of discontinua-tion as a result of adverse events weresimilar for dasatinib and imatinib. Anupdated analysis of data covering amedian follow-up of 18 months waspresented at ASH 2010.36

First-line second-generation TKIsprovide optimal outcomesIn January 2011, nilotinib and dasatinibwere added to the National Compre -hensive Cancer Network (NCCN)treatment guidelines as category 1options for the primary treatment ofPh+ or BCR-ABL+ CML. With 3FDA-approved and NCCN-recom-mended therapies, what will drive thechoice of treatment? Should the highercost of the second-generation TKIs be afactor? A recent study examined theassociation between adherence to ima-tinib therapy and direct healthcare costsand resource utilization in a large group(N = 592) of privately insured patientswith CML.37 Patients with CML whodo not adhere to treatment may havesuboptimal outcomes and higher ratesof progression to advanced phase orblast crisis. In this study, patients withlow adherence had more all-cause inpa-tient visits (4.1) compared with thosewho demonstrated higher adherence(0.4; P <.001) and more all-cause inpa-tient days (14.8 days vs 1.8 days, respec-tively; P <.001).

In regression models, non-imatinibcosts were 283% higher in the nonad-herent group ($324) than in the adher-ent group ($56; P <.001). Therapy fail-ure occurred in approximately 22% ofpatients receiving first-line imatinibtherapy (the vast majority of failuresbeing early events) compared withapproximately 4% of patients receivingfirst-line therapy with a second-genera-tion TKI.

One may ask, “Why not wait untilpatients have a suboptimal response toimatinib or fail treatment before pre-scribing a higher-priced second-genera-tion TKI?” This may be too risky, and,in the long run, incur higher costs.Treatment at suboptimal response orfailure is salvage therapy. In such cases,the likelihood that the patient hasdeveloped drug-resistant mutations hasincreased, requiring the use of a third-generation TKI or a very expensivestem-cell transplant.

The 8-year analysis of the IRIS trialdemonstrated that imatinib was effec-

Figure Kinetics of Resistance to Imatinib in the IRIS Trial

AP/BC indicates advanced phase/blast crisis; CHR, complete hematologic response; IRIS, Insulin Resistance Interventionafter Stroke; MCyR, major cytogenetic response.Source: Deininger M, et al. Blood. 2009;114(suppl):462. Abstract 1126.

10

9

8

7

6

5

4

3

2

1

01 2 3 4 5 6 7 8

Event

Loss of CHRLoss of MCyRAP/BCDeath

AP/BC

Year

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nt rat

e or pat

ient

s at

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In January 2011, nilotiniband dasatinib were addedto the NCCN treatmentguidelines as category 1 options for the primarytreatment of Ph+ or BCR-ABL+ CML.




augusT 2011 I vol 4, No 5 19www.Theoncologypharmacist.com

tive in preventing prospective eventsbut not the loss of response or progres-sion events that occur early (Figure).32

The ENESTnd and DASISION trialssuggest that frontline therapy withsecond-generation TKIs produceshigher rates of CCyR and MMR thanthe standard-dose imatinib, and theseresponses are achieved at earlier timepoints. On the basis of data derivedfrom the IRIS trial that highlightedthe prognostic importance of achiev-ing early CCyR and MMR, it is rea-sonable to expect that the use of nilo-tinib or dasatinib in the frontlinesetting might render higher rates ofevent-free survival and transforma-tion-free survival and may thereforeoffset the high costs associated withprogression.

Non-Hodgkin LymphomaNHL is a highly heterogeneous group ofcancers affecting the lymph system, withvariable cytogenetic, cellular, and clini-cal features and natural histories thatrange from indolent to very aggressive.38NHL is the most common hematologicmalignancy in the United States.6 It isestimated that 65,540 Americans werediagnosed with various forms of NHL in2010, and 20,210 deaths were attributedto the disease. The prevalence of NHLin the United States is approximately440,000 patients.7 Most patients withNHL have a B-cell subtype: 31% ofpatients with NHL have diffuse large B-cell lymphoma (DLBCL), 22% have fol-licular lymphoma, 5% to 10% have mar-ginal zone lymphoma (MZL), and 6%have mantle-cell lymphoma (MCL).39T-cell lymphomas comprise about 15%of NHL cases.40

Indolent versus aggressive: desiredoutcomes of therapyBoth B-cell and T-cell lymphomas arecategorized into indolent and aggressivetypes. DLBCL, MCL, per iph eral T-celllymphoma, and anaplastic large-celllymphoma (ALCL) are consideredaggressive lymphomas. The goal of treat-ment is to cure an aggressive lymphoma;this may be achieved in 30% to 60% ofpatients for some subtypes.41 DLBCLcan be cured in a significant proportionof pa tients,42 but MCL cannot.43 The re -sponse rate and OS are often the endpoints in clinical trials for aggressivelymphomas that are curable, whereasresponse rate and duration of responseand PFS are end points in trials for thosethat are not.

For aggressive lymphomas that can-not be consistently cured at this time,the search continues for treatment thatcan become a curative standard of care.The lack of cure along with treatmentfailure exacts an enormous socioeco-nomic toll. For example, the mean costof treatment failure in aggressive NHL

has been reported to be as high as$14,174 monthly and reaches $85,934over a period of <2 years (in 1999-2000dollars).44

In contrast, indolent lymphomas arecharacterized by long, slowly pro gressiveclinical courses; examples include follic-ular lymphoma, MZL, Waldenstrom’smacroglobulinemia, and the cutaneousT-cell lymphoma mycosis fungoides.The goal of treatment is often long-termmanagement, as indolent lymphomas arerarely cured unless diagnosed when stilllocalized. The response rate, DFS, event-free survival, duration of response, andPFS are often the primary end points inclinical trials for indolent lymphomas.

Clinical trials have attempted toimprove on the best available acceptedtherapy by adding an additional agentor substituting one active agent foranother; therefore, there is a virtual“alphabet soup” of therapeutic regi-mens available to treat this group ofcancers. In the past decade, the treat-ment of NHL has changed dramatical-ly, with the advent of molecularly tar-geted anticancer therapies. Forexample, the development of the CD20monoclonal antibody rituximab haschanged the treatment paradigm for B-cell lymphomas and, in some subtypesof the disease, has markedly improvedprognosis.

Bortezomib, lenalidomide, bendamus-tine, alemtuzumab, and other novelagents have also demonstrated clinicalbenefit in B-cell lymphomas. T-cell sub-types and ALCL are being treated witha number of approved and investigation-al targeted agents, including romidepsin,pralatrexate, brentuximab vedotin,denileukin diftitox, and vorinostat. Theuse of targeted therapies for NHL, com-bined with refinements in cytotoxicchemotherapy and stem-cell transplan-tation, continue to alter the therapeuticlandscape at a rapid pace.

Indolent versus aggressive: clinicaltrial end pointsIn 1999, an international working groupof clinicians, radiologists, and patholo-gists with expertise in the evaluationand management of patients with NHLpublished guidelines for response assess-ment and outcomes measurement.45

These were revised in 2007, when inter-observer and intraobserver variationswere identified and recommended tech-nologies were no longer consideredstate-of-the-art.46 In addition to definingresponse criteria and making recom-mendations for disease evaluation, thisgroup proposed that the major endpoints of clinical trials should reflect thehistology, clinical situation, and objec-tives of the study and be defined consis-tently across clinical trials.

Response rates as a trial end point are greatly influenced by the defined

response criteria used. In addi-tion, response rates do not neces-sarily influence other measures ofoverall clinical benefit or outcomein patients with NHL. OS is theleast ambiguous of the trial endpoints, but it is not optimal for use in anindolent or incurable aggressive lym-phoma trial. PFS is often considered thepreferred end point in lymphoma clini-cal trials, especially those involvingincurable subtypes (indolent and aggres-sive). Event-free survival is generallynot encouraged by the FDA, because itcombines efficacy, toxicity, and patientwithdrawal. However, it may be usefulin the evaluation of novel agents thatmay be highly toxic and have a highrisk-benefit ratio. Duration of response,if associated with measures of clinicalbenefit, may also be an important andrelevant end point in lymphoma trials.

One of the most important outcomesfor patients with NHL has been evi-dence of clinical benefit. Clinical bene-fit may reflect improvement in quality oflife or a reduction in symptoms, transfu-sion requirements, frequent infections,or other parameters. As the symptomsassociated with lymphoma can greatlyimpact a patient’s quality of life, time toreappearance or progression of lym-phoma-related symptoms may also be animportant measure, especially for incur-able lymphomas.

Rituximab was first approved by theFDA in 1997 for the treatment ofrelapsed or refractory low-grade or follic-ular, B-cell NHL as a single agent basedon the overall response rate.47 Since thattime, rituximab has received 5 addition-al indications as a single agent or as partof a chemotherapeutic regimen. TheAppendix (available at www.theonclogypharmacist.com/P10067E) lists someof the targeted agents and new therapiesapproved within the past decade for var-ious subtypes of NHL and the primaryand secondary end points used in theregistration trials. Care must be takenwhen making cross-trial comparisons toensure that the patient populations arecomparable and that defined end pointsand response criteria have been usedconsistently.

Evolving Outcomes and End Pointsand Value-Based CareAs progress is made in the treatment ofMM, CML, and NHL, as with any can-cer, the ultimate outcome of therapy forpatients also evolves. Although OSremains the optimal outcome forpatients with MM, surrogate end pointsused in clinical trials do not always trans-late into a survival benefit as long-termdata mature. The use of TKIs for CML-CP has drastically changed the naturalhistory of this disease. Freedom fromtreatment failure and from progression toadvanced phase or blast crisis is the pre-ferred outcome. Early and durable CCyRand MMR are reliable surrogate endpoints for this outcome. For patientswith some subtypes of aggressive NHL, acure is possible and OS is both the trialend point and the desired outcome.However, for patients with indolent andincurable-aggressive NHL, an extendedperiod without progression that may becompounded by lymphoma-associatedsymptoms is preferred. PFS and durationof response are acceptable surrogate endpoints for this outcome. �

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To Receive cRediT, compleTe The posTTesT aTTheOncologyPharmacist.com

The mean cost oftreatment failure inaggressive NHL has beenreported to be as high as$14,174 monthly andreaches $85,934 over a period of <2 years (in 1999-2000 dollars).


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19. van de Velde H, Liu X, Chen G, et al. Completeresponse correlates with long-term survival and progres-sion-free survival in high-dose therapy in multiplemyeloma. Haematologica. 2007;92:1399-1406.20. Martinez-Lopez J, Blade J, Mateos MV, et al. Long-term prognostic significance of response in multiplemyeloma after stem cell transplantation. Blood. 2011Apr 11. Epub ahead of print.21. Sonneveld P, Schmidt-Wolf I, van der Holt B, et al.HOVON-65/GMMGHD4 randomized phase III trialcomparing bortezomib, doxorubicin, dexamethasone(PAD) vs VAD followed by high-dose melphalan(HDM) and maintenance with bortezomib or thalido-mide in patients with newly diagnosed multiple myeloma(MM). Presented at the 52nd American Society ofHematology Annual Meeting; Orlando, FL; December 4-7, 2010. Abstract 40. http://ash.confex.com/ash/2010/webprogram/Paper29306.html. Accessed June 28, 2011.22. Cavo M, Perrone G, Buttignol S, et al. Bortezomib-thalidomide-dexamethasone compared with thalido-mide-dexamethasone as induction and consolidationtherapy before and after double autologous transplanta-tion in newly diagnosed multiple myeloma: results froma randomized phase 3 study. Presented at the 52ndAmerican Society of Hematology Annual Meeting;Orlando, FL; December 4-7, 2010. Abstract 42. 23. Richardson PG, Weller E, Lonial S, et al.Lenalidomide, bortezomib, and dexamethasone combi-nation therapy in patients with newly diagnosed multi-ple myeloma. Blood. 2010;116:679-686.24. Kumar S, Flinn IW, Richardson PG, et al. Novelthree- and four-drug combination regimens of bor tezomib,dexamethasone, cyclophosphamide, and lenalidomide, forpreviously untreated multiple myeloma: results from themulti-center, randomized, phase 2 EVOLUTION Study.Presented at the 52nd American Society of HematologyAnnual Meeting; Orlando, FL; December 4-7, 2010.Abstract 621. 25. Rohrbacher M, Hasford J. Epidemiology of chronicmyeloid leukaemia (CML). Best Pract Res Clin Haematol.2009;22:295-302.26. Kantarjian H, O’Brien S, Cortes J, et al. Therapeuticadvances in leukemia and myelodysplastic syndrome

over the past 40 years. Cancer. 2008;113(7 suppl):1933-1952.27. Faderl S, Talpaz M, Estrov Z, Kantarjian HM.Chronic myelogenous leukemia: biology and therapy.Ann Intern Med. 1999;131:207-219.28. Kantarjian H, Smith TL, O’Brien S, et al. Prolongedsurvival in chronic myelogenous leukemia after cytoge-netic response to interferon-a. The Leukemia Service.Ann Intern Med. 1995;122:254-261.29. O’Brien SG, Guilhot F, Larson RA, et al. Imatinibcompared with interferon and low dose cytarabine fornewly diagnosed chronic-phase chronic myeloidleukemia. N Engl J Med. 2003;348:994-1004.30. Marin D, Milojkovic D, Olavarria E, et al. EuropeanLeukemiaNet criteria for failure or suboptimal responsereliably identify patients with CML in early chronicphase treated with imatinib whose eventual outcome ispoor. Blood. 2008;112:4437-4444.31. Druker BJ, Guilhot F, O’Brien SG, et al. Five-yearfollow-up of patients receiving imatinib for chronicmyeloid leukemia. N Engl J Med. 2006;355:2408-2417.32. Deininger M, O’Brien SG, Guilhot F, et al.International randomized study of interferon vs STI571(IRIS) 8-year follow up: sustained survival and low riskfor progression or events in patients with newly diag-nosed chronic myeloid leukemia in chronic phase(CMLCP) treated with imatinib. Presented at the 51stAmerican Society of Hematology Annual Meeting; NewOrleans, LA; December 5-8, 2009. Abstract 1126. 33. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib ver-sus imatinib for newly diagnosed chronic myeloidleukemia. N Engl J Med. 2010;362:2251-2259. 34. Hughes TP, Hochhaus A, Saglio G, et al. ENESTndupdate: continued superiority of nilotinib versus imatinibin patients with newly diagnosed chronic myeloidleukemia in chronic phase (CML-CP). Presented at the52nd American Society of Hematology Annual Meeting;Orlando, FL; December 4-7, 2010. Abstract 207. 35. Kantarjian H, Shah NP, Hochhaus A, et al.Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med.2010;362:2260-2270. 36. Shah N, Kantarjina H, Hochhaus A, et al. Dasatinibversus imatinib in patients with newly diagnosed chron-ic myeloid leukemia in chronic phase (CML-CP) in the

DASISION Trial: 18-month follow-up. Pre sented at the52nd American Society of Hematology Annual Meeting;Orlando, FL; December 4-7, 2010. Abstract 206. 37. Wu EQ, Johnson S, Beaulieu N, et al. Healthcareresource utilization and costs associated with non-adher-ence to imatinib treatment in chronic myeloid leukemiapatients. Curr Med Res Opin. 2010;26:61-69. 38. National Comprehensive Cancer Network. Non-Hodgkin’s Lymphoma. V.2.2009. www.nccn.org. Acces-sed June 23, 2011.39. Fauci AS, Braunwald E, Kasper DL, et al, eds.Harrison’s Principles of Internal Medicine. 17th ed. NewYork: McGraw-Hill; 2008. 40. Portlock C, Vose JM, Cheson BD. T-cell lympho -mas. www.lymphoma.org/atf/cf/%7B0363CDD6-51B5-427B-BE48-E6AF871ACEC9%7D/T-CELL%20LYM-PHOMAS.PDF. Accessed June 23, 2011.41. PDQ (Physician Data Query) Modification of REALClassification of Lymphoproliferative Diseases. NationalCancer Institute of the National Institutes of Health.www.cancer.gov/cancertopics/pdq/treat ment/adult-non-hodgkins/healthprofessional/allpages#Section_31.Accessed June 28, 2011.42. Coiffier B. Standard treatment of advanced-stagediffuse large B-cell lymphoma. Semin Hematol. 2006;43:213-220. 43. Witzig TE. Current treatment approaches for man-tle-cell lymphoma. J Clin Oncol. 2005;23:6409-6414.44. Kutikova L, Bowman L, Chang S, et al. Medicalcosts associated with non-Hodgkin’s lymphoma in theUnited States during the first two years of treatment.Leuk Lymphoma. 2006;47:1535-1544.45. Cheson BD, Horning SJ, Coiffier B, et al. Report ofan international workshop to standardize response crite-ria for non-Hodgkin’s lymphomas. NCI Spon soredInternational Working Group. J Clin Oncol. 1999;17:1244.46. Cheson BD, Pfistner B, Juweid ME, et al. Revisedresponse criteria for malignant lymphoma. J Clin Oncol.2007;25:579-586.47. [email protected]. Drug details. Rituximab. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed June 28,2011.

COMMENTARY

New End Points Create Novel Challenges forHealth Plans in Oncology Drug Management By James T. Kenney Jr, RPh, MBAMr Kenney is Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA

The management of complexoncology drugs in pharmacyand in medical benefits presents

unique challenges for all parties whoseek cost-effective, positive clinicaloutcomes for patients with cancer.New therapies are offering the excitingprospect of improved outcomes, pro-longed life, and, in some cases, a curefor specific diseases. Targeted oncolyt-ics and pharmacogenomics, whichcarry the promise of improved likeli-hood of successful treatment, havebecome welcome additions to the cur-rent standards of care. The concept ofcancer as a chronic disease is becomingaccepted in pharmacy oncology man-agement. Targeted therapies are nowstandard treatments for multiple myelo-ma (MM), non-Hodgkin lymphoma(NHL), and chronic myelogenousleukemia (CML).Recent trials in MM have used time

to progression and progression-free survival as primary end points (as rec-ommended by the InternationalMyeloma Workshop Consensus Panel1). The use of different end points inclinical trials for the same disease,however, has complicated the analysisand evaluation process for the phar-macy and therapeutics (P & T) com-mittees of health plans in comparingcompeting therapies to select themost efficacious and cost-effectivetreatment options for their members.The ability to diagnose cancer earlierin the disease process and to beginlife-saving treatments sooner placeadditional strain on pharmacy man-agers to maximize the value from alltherapies in the treatment algorithmof a particular cancer type.The tyrosine kinase inhibitors

(TKIs) have revolutionized the treat-ment of CML by extending survival.

It is now possible to achieve long-term success with these agents if treat-ment is initiated early enough in thecourse of disease, and a positive earlyresponse can be a good predictor oflong-term survival. As clinical studiesare able to demonstrate clinicallymeaningful differentiations betweenfirst- and second-generation TKIs,health plans can consider promotingspecific treatment pathways to maxi-mize cost-savings and outcomes.NHL affects a diverse population of

patients with various disease subtypesthat require careful diagnosis to bematched with specific drug treatmentprotocols. The International WorkingGroup has attempted to define appro-priate clinical trial end points andresponse criteria to effectively differ-entiate treatments. This process iscritical for managed care plans tomanage specific therapies effectively

and control costs in the treatment ofNHL and other cancer types.It is clear that in the near-term,

overall survival will remain the goldstandard for P & T committees intheir assessment of drug efficacy.However, other end points will con-tinue to be assessed as clinical trialresults become available. The devel-opment of pharmaceuticals with biomarkers can increasingly giveproviders and health plans the confi-dence that patients will have a greaterlikelihood of response. This new trendalso has the potential to decreasewaste and the risk of untoward sideeffects in patients who are not goodcandidates for a particular treatment.As health plans progress in the man-agement of oncology drugs, the abilityto target patients, predict outcomes,and reduce costs will drive the mostsuccessful programs. �




pain consults at Porter Adventist Hos -pital are not limited to oncology; theclinical pharmacists also help any hospi-tal inpatient who suffers from acuteand/or chronic pain. Located on the oncology floor, the

program grew out of a need to focus onthis aspect of cancer care. By havingpharmacists involved in the manage-ment of pain, the program uses their spe-cialized medication knowledge to opti-mize treatment. Mem bers of the cancercare team have found that this servicehelps them with time management,allowing physicians and nurses to focuson other aspects of their patients’ care.

How It Works“The physicians can write for a ‘phar-macist pain consult,’ and the clinicalpharmacists provide pain managementservices. Under CDTM protocols, thephysicians allow us to write orders forpain medications in addition to painmedication side-effect management,such as bowel regimens for treatmentof opioid-induced constipation,” Mowertells The Oncology Pharmacist. “Wemeet with the patients to assess andevaluate their pain. We check to seewhere the pain is located, what type ofpain it is, how the patients rate thepain, what makes it better, what makesit worse, and what have they tried inthe past. We also discuss what thepatients’ pain goals are and work onrealistic goals together. We decidewhat medications might be best basedon their history and comorbid condi-tions, and are able to write an order forthe pain medications.”Follow-up is very important. Mower

sees patients regularly to ensure theirpain is controlled. “For example, in the

radiation oncology clinic, many pa -tients visit every day and I can there-fore meet with them every couple ofdays face-to-face; occasionally it mightbe a phone contact,” she illustrates.“The nurses play a crucial role in iden-tifying patients that may need a painconsult by the pharmacist. We workclosely together. If they feel like apatient isn’t getting his or her pain con-trolled, they will talk to the physiciansand suggest they get a clinical pharma-cist involved. I would say that we havea close working relationship with thephysicians and that 99% of the timethey take the recommendation and anorder for a pain consult begins.” For pain management issues that are

not amenable to treatment by medica-tions alone, Porter Cancer CareCenter has a palliative care team towhich the pharmacists can refer apatient. This team comprises a medicaldirector, an advanced practice nurse, acase manager, a social worker, and achaplain, and it has access to anesthe-siologists and psychiatrists.

Patient-Focused CareTen years ago, when Mower began atPorter Adventist Hospital, there were nopain management consults. Pain wastreated by the physicians, along with allof the other aspects of cancer care.“When I came here, the nurses were ask-ing, ‘I am giving quite a bit of hydromor-phone to this patient, what can we dodifferently?’ or ‘This pain is not con-trolled well, what can we do?’” ToMower, the solution seemed clear: Sheshould offer her services for pain consul-tations. With her residency in hematol-ogy/oncology and her focus on pain man-agement during undergraduate study anddoctoral training, Mower did just that. From there, the program grew, now

encompassing not only oncology inpa-tients and outpatients but also inpa-tients from all units of the hospital.Mower trained the hospital’s other clin-ical pharmacists to provide the service aswell, so all patients in need can havehelp with their pain.With this success, Mower has been

able to focus all of her time on clinical

pharmacy, with other pharmacists in themain hospital pharmacy performingorder entry. “My office is on the oncolo-gy floor in the inpatient unit. For theoutpatients, it is a short walk to the out-patient clinic and I can provide servicesthere,” she explains. “Since my office islocated on the inpatient nursing unit, itenhances the care patients receive inthat I am readily available for questionsby nurses or physicians. In addition, wehave multidisciplinary rounds whichhelp identify patients who may benefitfrom a pharmacist pain consult.”

Future GoalsWith all of their success, one goal stilleludes the pharmacists offering painmanagement—reimbursement for theirservices. “Right now, our services arefree,” Mower notes. Given the improvedpain relief experienced by the patientsand the cost-savings associated with suchtailored drug therapy, she is working onit. “That is something I am looking into;I haven’t had success just yet.” She isexploring the possibility of setting up atrue clinic similar to the hospital’s anti-coagulation clinic, which might allowthe pharmacists to bill for their servicesin pain management. The oncology pharmacists are re -

warded in other ways. “The physiciansseem satisfied with the service. Theydon’t have to worry about pain manage-ment so they can focus on somethingelse. The patients seem satisfied becausethey have somebody focusing on thepain, which is one of the biggest com-plaints of oncology patients, and forthat matter all patients. Knowing that Ihave personally helped relieve one ofthe most traumatic symptoms of a dis-ease is reward in itself.” �

Porter Cancer Care Center... Continued from cover

“We meet with the patients toassess and evaluate their pain.We check to see where thepain is located, what type ofpain it is, how the patients ratethe pain, what makes it better,what makes it worse, and whathave they tried in the past.”

—Robin Mower, PharmD

ORLANDO—Interim results of a ran-domized, controlled, phase 3 trial showedthat abiraterone acetate significantlyprolonged overall survival (OS) inpatients with metastatic castration-resistant prostate cancer (CRPC) whoprogressed after docetaxel-based chemo -therapy. The survival benefit was con-sistent across all prespecified sub-groups. Lead author Howard Scher,MD, Memorial Sloan-KetteringCancer Center, New York, said abira -terone is poised to become a new stan-dard of care during his presentation atthe 2011 Genitourinary CancersSymposium.The study enrolled 1200 patients

with metastatic CRPC who failed on

docetaxel and ≤1 additional chemo -therapy regimen. Patients were ran-domized to abiraterone and prednisoneor prednisone and placebo. Groupswere well balanced for demographicand disease characteristics.Patients on abiraterone achieved

significantly superior median OS ver-sus placebo (14.8 months vs 10.9months; P <.001), representing a 35%reduction in the relative risk of mortal-ity. Pre planned analyses found survivalbenefit consistent across all subgroups,regardless of prior chemotherapy lines,performance status, pain scores, andradiographic progression-free survival.The abiraterone group also had higherrates of total and confirmed responses

according to prostate-specific antigen(PSA) testing. Rates of overall and seri-ous adverse events were similar betweenboth groups and considered manageable. Oliver Sartor, MD, Tulane Uni -

versity School of Medicine, New

Orleans, Louisiana, moderated theprostate cancer session. “This is agame-changer. To me this will changepractice,” he said.

Positive 42-month data were alsopresented for MDV3100, a novel, triple-

acting, oral androgen-receptor antago-nist for CRPC. In a phase 1/2 study,MDV3100 demonstrated durable antitumor activity, based on median times toPSA and radiographic progression.Celestia S. Higano, MD, and associ-

ates enrolled 140 men with progressivedisease resistant to standard antiandro-gen treatments. As of the meeting, 18men remained on active treatment.Median time to PSA progression was316 days in the postchemotherapygroup and not yet reached in thechemotherapy-naïve cohort. Mediantime to radio graphic progression was392 days versus 175 days, respectively.Circulating tumor cell counts re -mained favorable for 91% of patientswith favorable counts at baseline. MDV3100 is currently being studied

in the randomized phase 3 AFFIRMand PREVAIL trials. Both trials areactively recruiting patients. �

PROSTATE CANCER

Novel Drugs in Prostate CancerBy Alice Goodman

MDV3100 demonstrateddurable anti tumor activity,based on median times toPSA and radiographicprogression.

Cancer Center Profile



ORLANDO—Novel dosing regimensof rasburicase can prevent tumor lysissyndrome (TLS) at costs that are muchlower than conventional dosing,according to studies presented at the2010 American Society of HematologyAnnual Meeting & Exposition.Rasburicase is a recombinant urate

oxidase approved for the prevention ofTLS, an oncologic emergency that pro-duces metabolic disturbances and thepotential for acute renal failure anddeath. Currently, rasburicase is US Food

and Drug Administration (FDA)-approved for prevention. In adults, therecommended dose is 0.2 mg/kg intra-venous (IV) per day up to 5 days, whichtranslates into more than $5100 fortreatment of a 75-kg person.

Low Dose versus Standard DoseInvestigators from the Mayo Clinic inRochester, Minnesota, evaluated theeffectiveness of the 0.1-mg/kg dose ascompared with the recommended dosein the prevention of TLS among 125

PHARMACOECONOMICS

Novel Dosing of Rasburicase Reduces Cost of PreventionTable Cost of Single-Dose versus Weight-Based Rasburicase

Dosing Cost per patientTotal cost

(30 events) Total savings

Single 4.5-mg dose regimen

$1919 $53,549

$906,1065-day regimen $31,988 $959,655

Cost was calculated using August 2010 AmeriSourceBergen Bluebook Average Wholesale Price.One 1.5-mg vial of rasburicase costs $639.77. For a 75-kg patient dosed at 0.2 mg/kg, the costwould be approximately $6397 and $31,988 for a 1-dose and 5-day therapy, respectively.


SAN FRANCISCO—For patients withcolorectal cancer (CRC), advances inmolecular profiling have led to an ex -plosion in novel agents specific for tar-gets above and beyond the epidermalgrowth factor receptor (EGFR). JosephTabernero, MD, director of clinical re -search at Vall d’Hebron Institute ofOncology in Barcelona, Spain, pre-viewed the future of treatment for CRCat the 2011 Gastrointestinal CancersSymposium.“The good news is there are lots of

new compounds. The challenge will beto profile patients accurately and to iden-tify the gene signatures of those who willbenefit from the individual drugs andcombinations,” said Tabernero.

EGFR Remains a TargetMany patients with CRC are resistantto the currently approved EGFRinhibitors cetuximab and panitumu -mab. The KRAS gene has been identi-fied as playing an important role, withconstitutive mutations of KRAS servingas predictors of resistance to anti-EGFRmonoclonal antibodies.

Researchers are examining the role ofgenetic mutations associated with othersignal transducer proteins, includingmutations in BRAF, NRAS, PIK3CA,AKT, PTEN, and TP53. Tabernero saidany of these might prove to be a useful“on/off” biomarker for EGFR expressionin metastatic CRC. “More effective monoclonal antibod-

ies are coming,” Tabernero promised.Encouraging results have been observedwith the investigational compoundsGA201 and SYM004, including seem-ingly durable responses. “Objectiveresponse rates have been achieved invery refractory patients,” he noted. HER3 is a new target in CRC. It has

been implicated as a potential mecha-nism of resistance to EGFR inhibitors. Ahandful of anti-HER3 compounds are indevelopment, including the monoclonalantibody MEHD7945A (a dual anti-EGFR and HER3 inhibitor), MM121,and U3-1287-AMG888.

Other Targets Under StudyResearchers are developing monoclonalantibodies specific for receptors otherthan EGFR. One target is insulin-likegrowth factor-1 receptor (IGF-1R) pro-tein, which is expressed in 90% of coloncancers but not found at all in normalmucosa. Expression levels correspondwith proliferation and tumor stage.Overexpression of IGF-1R, ob served in~50% of patients, is an independentprognostic factor for worse survival. Research into therapeutics for this

novel target took a step back when a ran-domized phase 2 clinical trial of IMC-A12, an investigative inhibitor of IGF-1R, failed to improve outcomes inpatients with CRC refractory to EGFRinhibitors. Ongoing studies are attempt-ing to refine the gene signature anddevelop effective agents. Two possible new targets are the li -

gand of the c-MET receptor and hepato-cyte growth factor (HGF) receptor.Both have been implicated in tumorinvasiveness, metastasis, and prolifera-tion; angiogenesis; and resistance totreatment. The HGF inhibitor rilotu-mumab (AMG102) showed promisingefficacy in metastatic CRC when com-bined with panitumumab. Eric VanCutsem, MD, University of Leuven,Belgium, presented data from an inter-national, randomized, phase 1/2 trialinvolving 142 patients that comparedpanitumumab alone; rilotumumab plus panitumumab; and ganitumumab(AMG479), a novel IGF-IR inhibitor,plus panitumumab. Van Cutsem saidthe doublet of rilotumumab and pani-tumumab was promising, producing anoverall response rate (ORR) of 31%compared with an ORR of 22% in theganitumumab arm and 21% in thepanitumumab monotherapy group.Median progression-free survival was5.2 months with rilotumumab pluspanitumumab, 5.3 months with theganitumumab combination, and 3.7months with panitumumab alone.Another avenue being pursued in -

volves the tumor necrosis factor–relat-ed apoptosis-inducing ligand (TRAIL)and its receptors. TRAIL inhibits thegrowth of colon cancer cells, andTRAIL-R1 expression correlates withimproved disease-free survival. Con -atumumab (AMG655) is a monoclon-al antibody that binds to TRAIL-R2and has produced partial responses inearly trials. It is also being studied incombination with standard chemo -therapy regimens.

Looking at Downstream PathwaysSome researchers are looking intoinhibiting critical downstream pathways,such as the mitogen-activated proteinkinase (MAPK)/extracellular signal-reg-

ulated kinase (ERK) pathway. Proteinkinases along this pathway regulate cellproliferation, differentiation, and sur-vival and respond to external stimuli.Tabernero said investigators have identi-fied at least 2 therapeutic targets in theMAPK/ERK pathway, namely RAF andMEK. Already more than a dozeninhibitors are in development.In 50% of patients with advanced

disease, PIK3CA is dysregulated.PIK3CA activation triggers a signaltransduction cascade that promotescell growth and survival. Druggabletargets in this pathway includePIK3CA, AKT, mTOR, TORC 1/2,and pS6K. Nearly 20 relevant com-pounds are being investigated, includ-ing some multikinase inhibitors. It is thought that many novel agents

might be most effective when com-bined. Promising marriages are be -tween 2 ERK pathway inhibitors (ie, aRAF inhibitor and a MEK in hibitor);2 PIK3CA pathway in hibitors (ie, adual PIK3CA inhibitor and a TORC1/2 inhibitor); 1 ERK pathway in -hibitor and 1 PI3K pathway inhibitor(ie, a MEK inhibitor with either anAKT, TORC 1/2, or PIK3CA in -hibitor). Any of these agents couldpotentially be combined with a cyto-toxic agent, as well.Despite an apparent plethora of oppor-

tunities for arresting proliferation ofCRC cells, Tabernero cautioned thathuge challenges lie ahead. The molecu-lar profile of a specific cancer cell influ-ences its behavior, and cancer cells oper-ate under “plastic and evolutivephenomena” that extend to the genelevel (expression, mutation, amplifica-tion/deletion, etc) and the proteomiclevel (activation, phosphorylation).“Cells change under the pressure ofstress,” he said, noting that treatmentinduces stress. �

A Wealth of Targets Identified in Colorectal CancerBy Caroline Helwick

Novel Strategiesfor Treating CRC• More efficient anti-EGFRmonoclonal antibodies

• Monoclonal antibodies directed toother members of the EGFR/HERfamily

• Monoclonal antibodies directed toother receptors (c-MET, IGF-1R)

• Inhibitors of downstream effectors(MAPK/ERK)

• Rationally based combinations• Identification of populationslikely to benefit from specifictherapies

Colorectal Cancer


cancer patients receiving rasburicase onthe first day of chemotherapy. The drugwas dosed at either 0.1 mg/kg (lowdose) or 0.2 mg/kg (standard dose), perclinician discretion, and was repeatedas necessary. Additional doses wererequired in 14.6% of the low-dosepatients and in 21.4% of the standard-dose patients, which was not a signifi-cant difference.Although reduction in uric acid, the

intended effect, was higher with thestandard dose (97.1% vs 88.7%; P =.002), renal outcomes were similar, re -ported Alfonso Eirin, MD.“The low-dose patients received an

average of 6 mg per dose versus 12 mg inthe standard group. This represents asavings of $2601 per patient,” he said.Treatment of a 75-kg patient with

the standard dose costs $6504, whichis lowered to just $3252 using thelower dose.Only the standard-dose patients ex -

perienced renal insufficiency (7.4%).Rates of dialysis were numericallyhigher with the standard dose but notsignificantly different (18.6%) com-pared with 7.3% with the low dose(P = .07). Dialysis often was initiatedfor hyperkalemia and hyperphos-phatemia. Only 12.5% of doses were started for elevations in serumcreatinine.“Our results suggest that low-dose

rasburicase may be as effective as 0.2mg/kg. While high-dose rasburicasewas more effective at reducing uricacid, it did not reduce the need fordialysis because dialysis was often pre-cipitated for hyperkalemia and hyper-phosphatemia, which rasburicase doesnot affect,” Eirin ex plained. “Despitebias, our results suggest low-dose ras-buricase may be a viable alternativeand the potential savings could beenormous.”

Single-Dose Approach Effectiveand Less ExpensiveSince rasburicase came to market, var-ious studies have examined singledoses (3 mg and 6 mg) in the adultpopulation, in an effort to find a dosingregimen that is as effective as theFDA-approved dose but less expensive.A single-center study evaluated a 4.5-mg dose for its ability to lower uric acidlevels versus the conventional weight-based approach and to determine itscost-effectiveness. The results werereported by Barbara Yim, PharmD,BCOP, of the John H. Stroger Jr.Hospital of Cook County, Chicago.“The cost of rasburicase is a problem

for us. We found that using a singledose could save our hospital a lot ofmoney,” Yim commented (Table).The retrospective study included 25

patients with hematologic malignan-cies receiving chemotherapy or plan-ning to initiate chemotherapy within

24 hours of rasburicase administra-tion. Patients at low risk for TLS wereexcluded.There were 30 hyperuricemic

events, and 93% were successfullymanaged with the single dose of ras-buricase. Re sponders were defined aspatients achieving more than a 50%reduction in the uric acid level at 24hours, 48 hours, or 96 hours. Threepatients required a second dose toachieve response. � —CH


Pharmacoeconomics

CHEMOTHERAPY FOUNDATION SYMPOSIUMINNOVATIVE CANCER THERAPY FOR TOMORROW®

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CHICAGO—At the ASCO session“Moving the Bar in Upper GI Mal -ignancies,” 2 speakers examined whetherrecent trials of targeted agents are clini-cally meaningful or just statistically posi-tive, and whether value is being gainedfor the enormous amount of moneybeing spent in treating noncolo rectalgastrointestinal (GI) cancer.

Eileen Mary O’Reilly, MD, of Mem -orial Sloan-Kettering Cancer Center,weighed in by examining the bottomline of the major trials.

The only true “practice-changing”study, in her opinion, involved trastuz -umab as treatment for gastric cancer.The rationale is strong, she noted,based on the discovery that humanepidermal growth factor receptor(HER) 2 is overexpressed in many gas-tric tumors. In the phase 3 Trastuz -umab for Gastric Cancer (ToGA) trial,trastuzumab added to capecitabine andcisplatin improved overall survival(OS) from 11.1 months to 13.8months with chemotherapy alone,constituting a 26% reduction in death.The effect was robust in the subset whostrongly overexpressed HER2.

In contrast, in pancreatic cancer,the pivotal National Cancer Instituteof Canada Clinical Trials Group PA.3trial of erlotinib plus gemcitabineversus gemcitabine alone is “an ex -ample of a statistically significantphase 2 trial that has clinically limit-ed therapeutic impact,” O’Reillymaintained. The median OS wasimproved by <1 month, as was pro-gression-free survival (PFS); howev-er, these small differences were statis-tically significant, and the US Foodand Drug Administration approvederlotinib for pancreatic cancer basedon these results.

For pancreatic neuroendocrinetumors, “we don’t yet fully know” thetrue benefit of everolimus and sunitinib,which have led to improvements in out-comes and represent new options for arare malignancy. Many questions remain,such as the best time to initiate therapywith these drugs and how to sequenceand combine them with other treat-ments, O’Reilly said.

“In the era of cost constraints, wemust recognize that all these agents arepalliative, all are expensive, and allhave added toxicity,” she concluded.Future investigations must be based onstrong biologic rationale, robust early-phase results, and intelligent trialdesign, she added.

Neal J. Meropol, MD, of CaseWestern Reserve University inCleveland, who speaks often about theeconomics of cancer care, said he was

“providing perspective on how to inter-pret these claims.”

His ranking of the clinical benefit ofupper GI cancer treatment, largelybased on the magnitude of the statisti-cally significant differences in PFS andOS, compared with standard treatmentwas as follows:

• Very low benefit: erlotinib in pan-creatic cancer

• Modest benefit: sorafenib in livercancer, trastuzumab in gastric can-cer, and gemcitabine/cisplatin inbiliary cancer

• Higher benefit: sunitinib in neu-roendocrine tumor, everolimus inneuroendocrine tumor.

Meropol then assessed the value of thenew upper GI cancer regimens, demon-strating that clinical benefit is often notparallel with value (Table 1).

Lessons Learned from TrastuzumabMeropol said the “trastuzumab story” isinformative regarding the future ofoncology clinical trials and oncologycare. He reminded the audience thatalthough trastuzumab has become animportant treatment in gastric cancer, itseffect, compared with the drug’s impact

on breast cancer, is minimal. In meta -static breast cancer, trastuzumab pro-longed median OS by nearly 5 months;in advanced gastric cancer, it added amedian of 2.7 months. In patients withhighly overexpressed HER2, however,the additional benefit exceeded 4months, thus offering somewhat highervalue in this subset, he acknowledged.

The “lessons,” according to Meropol,are that diagnostics development mustbegin early and in concert with clinicaldevelopment, that all cancers will be“rare” cancers once their molecular pro-file is understood, that “blockbusterdrugs” will become dinosaurs (ie, no onedrug will fit all), that the bar must be sethigh early in drug development, and thattreatment based on site of origin will bereplaced by treatment based on pheno-type.

Ever-Greater Targeting Will Be theNormSmaller patient populations will even-tually become defined for essentially alltumor types, necessitating ever moretargeted treatments as the norm. Theeffect of this on drug development andcost control remains unclear (Table 2).

“Will this prolong drug developmenttime and reduce the chances of bring-ing drugs to market? Will the highervalue of the targeted approach bringeven higher prices to make up forsmaller markets? The answers to thesequestions are unknown,” he said.

Where We Need to GoMeropol offered some concrete sugges-tions for “where we need to go” in thefuture treatment of cancer. His sugges-tions included the following:

• Reduce overutilization: eliminatenonbeneficial interventions

• Raise the bar for drug approval• Link payment to value via cost-

sharing• Authorize the Centers for Med -

icare & Medicaid Services tonegotiate price

• Reduce incentives for develop-ment of marginal advances

• Improve the evidence base withcomparative effectiveness research.

Value-based insurance design maybe a viable strategy for achieving someof these goals and is gaining traction,he noted. “Not all effective treatmentshave equivalent value. Cost-sharingcan be used to discourage low-valuetreatment and encourage high-valuetreatment, in contrast with currentplans that base coverage on cost,” hesaid. “There would be the potential fordifferent coverage based on the diseaseand stage.”

“The low-hanging fruit is cost-sharingthat is not based on the cost of the inter-vention but its value,” he maintained.

Finally, he emphasized that in theallocation of finite resources “the goalis to move from implicit decisionsabout allocation to explicit and trans-parent ones,” adding that politics willimpact this process. �

Upper GI Cancers: Are We Getting Value for the Money?By Caroline Helwick

Table 1 Value of Upper GI Cancer Treatments

Cancer type, regimen Clinical benefit New drug Annual cost of drug, $a Value

PancreaticGemcitabine/erlotinib

Very low Erlotinib 53,954 Very low

Liver cancerSingle-agent sorafenib

Modest Sorafenib 115,866 Low

GastricChemotherapy/trastuzumab

Modest Trastuzumab 51,225 (excluding loading dose)

Modest

BiliaryGemcitabine/cisplatin

Modest Cisplatin 364 Higher

Neuroendocrine tumorSingle-agent sunitinib

Higher Sunitinib 108,569 Higher

Neuroendocrine tumorSingle-agent everolimus

Higher Everolimus 201,516 Modest

aBased on average wholesale price for oral drugs, average sale price for intravenous drugs.GI indicates gastrointestinal.

Table 2 Impact of Personalized Medicine on Pharma

Clear advantagesLonger treatment durationPotential new indications, new marketsCompetitive advantage with “personalized” approachComarketing of diagnostic tests, necessary to define treatment population

Clear disadvantagesReduced market size

Uncertain consequencesDevelopment time of new therapeuticSuccess in bringing pipeline therapeutic to marketImpact of higher-value therapeutic on pricing/willingness to pay

Adapted from Peppercorn J, et al. Lancet Oncol. In press.

Pharmacoeconomics




Breast Cancer


limits their clinical efficacy and application.Ixabepilone is the first of a new class

of cytotoxic agents: the epothilones.This relatively newly approved agentmay still be unfamiliar to many oncolo-gy nurses; they may equate ixabepiloneto taxanes because both are micro-tubule-stabilizing agents. Ixabepilone,however, is highly active in severaltumor types and is less susceptible tomany of the cellular resistance mecha-nisms that affect the use of taxanes.3 Inpreclinical models of taxane-resistantcancer, for example, ixabepilone hashigher anticancer activity than the tax-anes in cell lines that overexpress drugefflux pump proteins, presumably be -cause ixabepilone is less susceptiblethan taxanes to binding and removalfrom the cell by this mechanism.4 Inaddition, although taxanes and ixabepi-lone both bind to β-tubulin to mediatetheir cytotoxic activity, ixabepilonemaintains efficacy in cancer cells thathave high levels of class III β-tubulin, aform of β-tubulin to which taxanes can-not bind effectively.4This preclinical efficacy has translat-

ed into clinical benefit for patients withtaxane-pretreated breast cancer, as thisarticle will discuss.5-7 Currently, ixabepi-lone is indicated for use in combination

with capecitabine in patients withmetastatic or locally advanced breastcancer after failure of an anthracyclineand a taxane (or following taxane fail-ure when further anthracycline therapyis contraindicated).5 Ixabepilone also isindicated as monotherapy in metastaticor locally advanced breast cancer afterfailure of an anthracycline, a taxane,and capecitabine.5 Although ixabepi-lone is similar to the taxanes in manyways, oncology nurses should be awareof important differences in their clini-cal response and tolerability profiles(Table 1).

Clinical Efficacy Taxanes are one of the many approvedtherapies for metastatic breast cancer,

either alone or in combination withanthracyclines or other agents, such ascapecitabine and gemcitabine. Taxanesare of particular value when patientshave already been treated with anthra-cyclines.2 Regimens combining taxaneswith anthracyclines or other agentssuch as capecitabine and gemcitabineproduce response rates of about 40% to60%, median progression-free survival(PFS) of 6 to 9 months, and medianoverall survival of 15 to 22 months.11-14To explore the clinical benefits of

ixabepilone, 2 clinical trials involvingnearly 2000 patients combined assessedthe efficacy of ixabepilone plus cap -ecitabine in patients with locallyadvanced or metastatic breast cancerwho had been pretreated with an

anthracycline and a taxane.6,7 In thefirst trial, all patients met strict resis -tance criteria for taxanes and anthracy-clines.6 In the subsequent confirmatorytrial, all patients had been pretreatedwith a taxane and an anthracycline, butonly about half met the strict definitionof resistance used in the original trial.7In both trials, patients received 21-daycycles of either intravenous ixabepilone40 mg/m2 on day 1 plus oral cap -ecitabine 2000 mg/m2/day on days 1through 14, or oral capecitabine 2500mg/m2/day alone on days 1 through 14.The combination of ixabepilone plus

capecitabine showed superior efficacyon a range of outcome measures. In theoriginal and confirmatory trials, respec-tively, the median PFS was 5.3 monthsand 6.2 months with ixabepilone pluscapecitabine, respectively, approxi-mately 1.5 months longer than withcapecitabine alone. In addition, re -sponse rates associated with ixabepiloneplus capecitabine were approximately40%, more than 1.5-fold greater thanwith capecitabine alone.6,7Direct comparisons of ixabepilone

with taxane therapy currently are underway in multiple stages of breast cancer,mostly in sequence or combination witha variety of other agents (Table 2, page28). Interim data from a 3-arm phase 2

Differences and Similarities Among Ixabepilone... Continued from cover

Table 1 Comparison of Ixabepilone with Paclitaxel and DocetaxelPaclitaxel nab-paclitaxel Docetaxel Ixabepilone

Class Taxane Taxane Taxane EpothiloneMechanism of action Microtubule stabilizer Microtubule stabilizer Microtubule stabilizer Microtubule stabilizerMost common severe adverse effects

Nonhematologica Myalgia/arthralgia, peripheralneuropathy, alopecia

Peripheral neuropathy,fatigue/asthenia,myalgia/arthralgia, alopecia

Fatigue/asthenia,myalgia/arthralgia,stomatitis/mucositis, peripheral neuropathy, cutaneous reactions, diarrhea,alopecia, fluid retentionb

Peripheral neuropathy,fatigue/asthenia,myalgia/arthralgia,stomatitis/mucositis, hand-footsyndrome,c diarrheac

Hematologicd Neutropenia Neutropenia Neutropenia, leukopenia,febrile neutropeniab

Neutropenia, leukopenia

Contraindications Neutrophils <1500/mm3; previous hypersensitivity reaction to paclitaxel orCremophor EL

Neutrophils <1500/mm3 Hepatic impairment,eneutrophils <1500/mm3; previous severe hypersensitivityreaction to docetaxel orpolysorbate 80

Moderate/severe hepaticimpairment,fneutrophils <1500/mm3,platelets <100,000/mm3; previous severe hypersensitivityreaction to Cremophor EL

aGrade 3/4 severity and affecting ≥5% of patients, with the exception of alopecia, which was not graded for severity. Alopecia is included because of its significance for patients and high incidence (≥75% ofpatients). Listed in order of incidence.bDose-dependent. Incidence ≥5% with docetaxel 100 mg/m2, but less common with 60 mg/m2.cIxabepilone in combination with capecitabine.dSevere (grade 3/4) in ≥40% of patients.eNot defined as a contraindication, but labeling carries a boxed warning that docetaxel should generally not be given to patients with bilirubin levels above the ULN, or to patients with AST and/or ALT >1.5 xULN concomitant with ALP >2.5 x ULN.fThe use of ixabepilone in combination with capecitabine is contraindicated in patients with AST or ALT levels >2.5 x ULN or bilirubin levels above the ULN.

ALP indicates alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; nab, nanoparticle albumin-bound; ULN, upper limit of normal.

Sources: References 5, 8-10.

Ixabepilone is highly active inseveral tumor types and is lesssusceptible to many of the cellularresistance mechanisms thataffect the use of taxanes.

—Teresa Davis, RN, OCN


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FACULTYRegina Cunningham, PhD, RN, AOCNSenior Director, Oncology The Tisch Cancer InstituteMount Sinai Medical CenterNew York, NY

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Breast Cancer


trial comparing ixabepilone (Arm A: 16mg/m2 weekly; Arm B: 40 mg/m2 every3 weeks) with paclitaxel (Arm C: 90mg/m2 weekly), each in combinationwith the antiangiogenic agent beva-cizumab (10 mg/kg every 2 weeks inArms A and C; 15 mg/kg every 3 weeksin Arm B), reveal equivalent responserates and 24-week PFS for all 3 arms,suggesting that ixabepilone producedresults that were comparable with week-ly paclitaxel in this setting.15

TolerabilityOverall, ixabepilone and the taxanesexhibit fairly similar tolerability pro-files, because both ixabepilone and thetaxanes operate by inhibiting the func-tion of microtubules within cancercells. However, because ixabepilone ischemically unrelated to taxanes andinteracts with microtubules in a differ-ent manner, it does have a distinctadverse event profile. In patients withadvanced breast cancer, these adverseevents are generally predictable andmanageable with supportive care, dosereductions, and treatment delays.

Nonhematologic adverse events.Whether used alone or with cap e -citabine, one of the most commonadverse effects with ixabepilone is sen-sory chemotherapy-induced peripheralneuropathy (CIPN). CIPN affectsapproximately 60% of patients treatedwith ixabepilone and is severe (grade3/4) in about 15% to 25% of pa -tients.6,16,17 CIPN is also a common ad -verse effect with taxanes, with reportedincidence of severe CIPN more vari-able and highly dependent on thecumulative and per-cycle dose.18Incidence rates range from 2% to 32%with conventional paclitaxel to 4% to11% with nab-paclitaxel to 0% to 17%with docetaxel. For ixabepilone-induced CIPN,

even grade 3/4 events are responsive to dose reduction or delays,6,17,18 andguidelines for managing dose reductionbased on the severity of symptomshave been established (Table 3).Notably, in the original ixabepilonetrial, patients with grade 1 neuropathywere able to receive the same amountof therapy as the general population.6Also in this trial, the onset of grade 3/4neuropathy occurred after a median of4 cycles.6 These events are reversible inmost patients after discontinuation ofixabepilone, with a median time to res-olution to baseline or grade 1 of 5 to 6weeks,6,16,17 which is more rapid thanthat reported with conventional tax-anes.19 Ixabepilone should be used withcaution in patients with diabetes melli-tus or preexisting moderate-to-severeneuropathy, both of whom may be atincreased risk for CIPN.5,17,19There are no proven agents or inter-

ventions that prevent or eliminateCIPN more effectively than early

detection by routine clinical assess-ment of neurologic function. TheNational Comprehensive CancerNetwork (NCCN) Task Force forManagement of Neuropathy in Cancerstrongly recommends that patients bequestioned directly regarding commonsigns and symptoms of neuropathy,because patients may tend to bucketneuropathic symptoms together withother forms of cancer pain when self-reporting. Patients also should be givenneurologic assessments before initialtreatment, to establish a baseline, andperiodically thereafter. For a moreextensive review of commonly usedgrading scales, critical questions to askpatients, and functional assessments,please refer to the recently publishedNCCN Task Force report.19Several of the main themes of sup-

portive care in patients receivingixabepilone therapy have parallels inthe taxane drug class, and experiencewith taxanes will be useful in managingixabepilone-treated patients. In addi-tion to neuropathy, both taxanes andixabepilone are associated with a pre-dictable assortment of other nonhema-tologic adverse events, such as fatigue/asthenia, myalgia/arthralgia, stomati-tis/mucositis, nausea and vomiting, anddiarrhea.8-10 Although not mandatory, a20% reduction in the dose of ixabepi-lone is an option for mitigating tran-sient grade 3 fatigue.5 Patients withsymptoms of fatigue may benefit fromreducing activity levels overall, plan-ning activities around times when ener-gy levels tend to be highest, and struc-tured routines; nurses should beprepared to provide guidance in theseareas. Nurses also should consideraddressing underlying contributors tofatigue, such as inadequate nutrition or

nighttime sleep, anemia, or stress,should symptoms occur.20 Alopecia occurs as well, but is notably

more common with taxanes than withixabepilone, affecting 75% to 90% ofpatients treated with taxanes8-10 com-pared with 48% of patients treated withixabepilone monotherapy and 31% ofpatients treated with ixabepilone pluscapecitabine.5 Although the risk is lower,nurses should prepare their patients forthe possible onset of alopecia duringixabepilone therapy and discuss poten-tial coping mechanisms when relevant.As a general rule, the dose of ixabepi-

lone should be reduced by 20% for per-sistent grade 3 nonhematologic reac-tions, including transient fatigue ifnecessary, and treatment should bestopped for grade 4 reactions (refer toprescribing information). Resumption oftreatment may be considered if toxicitiesresolve or improve to grade 1 (mild).

Hematologic adverse events. Atleast 90% of patients treated withixabepilone alone or in combinationwith capecitabine will experience somehematologic toxicity.6,16 As with thetaxanes, myelosuppression is the mostcommon dose-limiting toxicity withixabepilone. Common toxicities in thiscategory include anemia and thrombo-cytopenia (mild to moderate in most

cases), severe (grade 3/4) neutropenia(affecting approximately 50% to 70% ofpatients), and severe leukopenia (affect-ing approximately 50% to 60% ofpatients). Despite the high incidence ofneutropenia, the incidence of ixabepi-lone-related serious febrile neutropeniais low, approximately 3% to 5%.6,16 Moderate or transient hematologic

toxicity and febrile neutropenia gener-ally can be managed by reducing theixabepilone dose by 20%. In addition,although not required, hematopoieticgrowth factor support (ie, colony-stim-ulating factors) may be provided.Patients should not begin a new treat-ment cycle with ixabepilone until neu-trophil counts are ≥1500 cells/mm3. To help ensure that neutropenia is

managed promptly, patients treatedwith ixabepilone should receive com-plete blood counts before treatmentbegins to establish a baseline, and peri-odically thereafter. Patients should becounseled in the areas of hygiene, pro-tecting themselves from infections, andrecognizing early signs of an infection.

Hepatic impairment. The risk of tox-icity and neutropenia-related deathassociated with the ixabepilone pluscapecitabine combination regimen isincreased in patients with significantbaseline hepatic impairment.6 Thus,

Table 2 Clinical Trials Comparing Ixabepilone with Taxanes in Breast Cancer

Clinical trial identifier Phase Patients Study designNCT00490646 2 Locally advanced and/or metastatic • Ixabepilone 40 mg/m² vs docetaxel 100 mg/m²

(day 1 every 21 days)

• Each with trastuzumab 2 mg/kg (loading dose,4 mg/kg; day 1 every 21 days)

NCT00789581 3 Triple-negative, early stage • Ixabepilone 40 mg/m² (day 1 every 21 days)vs paclitaxel 80 mg/m² (weekly)

• Each following cyclophosphamide 600 mg/m²and doxorubicin 60 mg/m² (day 1 every 21 days)

NCT00630032a 3 • Ixabepilone vs docetaxel

• Following combination chemotherapy(tamoxifen, aromatase inhibition, anthracyclines)

NCT00785291a 3 Locally recurrent stage IIIB or IV • Ixabepilone vs nab-paclitaxel vs paclitaxel(days 1, 8, and 15 every 28 days)

• Each with bevacizumab (days 1 and 15 every28 days)

aDosing and/or schedule not provided.

Table 3 Dose-Adjustment Guidelines for Ixabepilone in Chemotherapy-InducedPeripheral Neuropathy

Grade Dosage adjustment

Grade 2 (moderate) lasting ≥7 days Decrease by 20%

Grade 3 (severe) lasting <7 days Decrease by 20%

Grade 3 (severe) lasting ≥7 days Discontinue treatment

Grade 4 or disabling Discontinue treatmentSource: Reference 5.


�� Editor in ChiefSagar Lonial, MDAssociate Professor of Hematology and Oncology Emory University School of Medicine

Editor in ChiefStephanie A. Gregory, MDThe Elodia Kehm Chair of Hematology Professor of MedicineDirector, Section of HematologyRush University Medical Center/Rush University

Topics include:• Newly Diagnosed Patients• Maintenance Therapy• Transplant-Eligible Patients• Retreatment• Transplant-Ineligible Patients• Cytogenetics• Side-Effect Management• Bone Health

Newsletter Series

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Topics include:• Hodgkin Lymphoma• Follicular Lymphoma• Mantle Cell Lymphoma• Waldenstrom’s Macroglobulinemia• Diffuse Large B-Cell Lymphoma• T-Cell Lymphoma

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AccreditationThis activity has been approved for 1.0 AMA PRA Category 1 Credit™ (a total of 14.0 credit hours will be issued for completion of all activities). Nursing and Pharmacy credit hours will also be provided.For complete learning objectives and accreditation information, please refer to each activity.

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Breast Cancer


this regimen is contraindicated inpatients with preexisting moderate andsevere hepatic impairment; specifically,those with aspartate aminotransferase(AST) or alanine aminotransferase(ALT) levels that exceed 2.5 x the upperlimit of normal (ULN), or those withbilirubin levels that exceed ULN.Ixabepilone mono therapy can be usedcautiously, at a lower dose, in patientswith mild-to-moderate baseline hepaticimpairment. If a patient’s AST and ALTlevels do not exceed 2.5 x ULN andbilirubin does not exceed ULN, she mayreceive the full dose of ixabepilonemonotherapy, 40 mg/m2. As long as apatient’s AST and ALT levels do notexceed 10 x ULN and if bilirubin lev-els do not exceed 1.5 x ULN, she mayreceive ixabepilone at 32 mg/m2, or sheshould receive between 20 mg/m2 and30 mg/m2 if her bilirubin levels exceed1.5 times ULN but do not exceed 3 xULN (refer to the prescribing informa-tion for details).5

Hypersensitivity reactions. There is arisk of hypersensitivity reactions to thesolvents used in ixabepilone preparationsand in the conventional formulations ofthe taxanes. Standard paclitaxel (con-taining Cremophor EL) and docetaxel(containing polysorbate 80) may causesevere hypersensitivity in 2% to 4% ofpatients, necessitating a recommenda-tion for standard premedication withcorticosteroids and H1/H2 antagonists(nab-paclitaxel is solvent-free and doesnot need premedication).8-10 The inci-dence of severe hypersensitivity reac-tions (including anaphylaxis) is lowerwith ixabepilone, which contains

Cremophor EL but less than standardpaclitaxel—about 1%. H1/H2 antagonistpremedication is required (eg, oraldiphenhydramine 50 mg and oral raniti-dine 150 mg to 300 mg, or equivalent).Unlike taxanes, however, corticosteroidpremedication is required only in cases ofa history of hypersensitivity to ixabepi-lone.5 As with taxanes, if a severe hyper-sensitivity reaction occurs, ixabepilonemust be stopped immediately andaggressive supportive care started.Patients should not receive ixabepi-lone if any previous reaction to aCremophor EL–containing agent wassevere. Because of the risk of hypersen-sitivity to ixabepilone, patients shouldbe monitored for signs of hypersensitiv-ity, such as hives, itching (pruritus),rash, flushing, swelling, or difficultybreathing or swallowing, either duringor shortly after treatment.

ConclusionsLike the taxanes, ixabepilone killstumor cells by inhibiting the functionof microtubules. It is associated, there-fore, with a similar spectrum of adverseevents. Ixabepilone is chemically unre-lated to the taxanes, however, whichyields clinical benefit in patientswhose disease has progressed after tax-anes fail, as well as unique features ofits adverse event profile. CIPN associ-ated with ixabepilone is more likely tobe reversible, generally resolving tograde 1 or baseline in a median time of5 to 6 weeks.Like the taxanes (with the excep-

tion of nab-paclitaxel), ixabepilone isgiven intravenously and carries the riskof hypersensitivity reactions to itspolyethoxylated diluent. Most patientsreceiving ixabepilone, however, needonly receive prophylactic H1/H2 antag-onists to prevent hypersensitivity reac-tions, and corticosteroid premedica-tion is needed only in patients with ahistory of hypersensitivity reactions toixabepilone.As yet, no randomized comparative

data are available from head-to-head tri-als comparing ixabepilone and the tax-anes in breast cancer patients, but sever-al trials are ongoing. In addition, severalother trials are evaluating ixabepilone,either as a single agent or as part ofsequential or combination therapy, inearlier lines of breast cancer therapy. Asthe patients in these trials are less heavi-ly pretreated than the patients in the reg-istrational trials, it is expected thatixabepilone may show promising results.

AcknowledgmentThe author takes full responsibility forthe content of this publication and con-firms that it reflects her viewpoint andmedical expertise. She also wishes toacknowledge StemScientific, funded byBristol-Myers Squibb, for providingwriting and editing support. NeitherBristol-Myers Squibb nor StemSci -entific influenced the content of themanuscript, nor did the author receivefinancial compensation for authoringthe manuscript. �

References1. O’Shaughnessy J. Extending survival with chemo -therapy in metastatic breast cancer. Oncologist. 2005;10(suppl 3):20-29.2. O’Shaughnessy J, Twelves C, Aapro M. Treatment foranthracycline-pretreated metastatic breast cancer.Oncologist. 2002;7(suppl 6):4-12.3. Lee FY, Borzilleri R, Fairchild CR, et al. Preclinicaldiscovery of ixabepilone, a highly active antineoplasticagent. Cancer Chemother Pharmacol. 2008;63:157-166.4. Lee FY, Smykla R, Johnston K, et al. Preclinical effi-cacy spectrum and pharmacokinetics of ixabepilone.Cancer Chemother Pharmacol. 2009;63:201-212.5. Ixempra kit (ixabepilone) for injection [packageinsert]. Princeton, NJ: Bristol-Myers Squibb Company;2010.6. Thomas ES, Gomez HL, Li RK, et al. Ixabepilone pluscapecitabine for metastatic breast cancer progressingafter anthracycline and taxane treatment. J Clin Oncol.2007;25:5210-5217.7. Hortobagyi G, Perez E, Vrdoljak E, et al. Analysis ofoverall survival among patients with metastatic breastcancer receiving either ixabepilone plus capecitabine orcapecitabine alone and a review of results from two ran-domized phase III trials. Presented at: American Societyof Clinical Oncology Breast Cancer Symposium.September 5-7, 2008; Washington, DC:Abstract 186.8. Abraxane for injectable suspension (paclitaxel pro-tein-bound particles for injectable suspension) [packageinsert]. Bridgewater, NJ: Abraxis BioScience; 2010.9. Taxol (paclitaxel) injection [package insert].Princeton, NJ: Bristol-Myers Squibb Company; 2011.10. Taxotere (docetaxel) injection [package insert].Bridgewater, NJ: sanofi; 2010.11. Piccart-Gebhart MJ, Burzykowski T, Buyse M, et al.Taxanes alone or in combination with anthracyclines asfirst-line therapy of patients with metastatic breast can-cer. J Clin Oncol. 2008;26:1980-1986.12. Nabholtz JM, Falkson C, Campos D, et al; for theTAX 306 Study Group. Docetaxel and doxorubicincompared with doxorubicin and cyclophosphamide asfirst-line chemotherapy for metastatic breast cancer:results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003;21:968-975.13.O’Shaughnessy J, Miles D, Vukelja S, et al. Superiorsurvival with capecitabine plus docetaxel combinationtherapy in anthracycline-pretreated patients withadvanced breast cancer: phase III trial results. J ClinOncol. 2002;20:2812-2823.14. Albain KS, Nag SM, Calderillo-Ruiz G, et al.Gemcitabine plus paclitaxel versus paclitaxel mono -therapy in patients with metastatic breast cancer andprior anthracycline treatment. J Clin Oncol. 2008;26:3950-3957.15. Rugo HS, Campone M, Amadori D, et al.Randomized phase II study of weekly versus every-3-week ixabepilone plus bevacizumab (ixa/bev) versuspaclitaxel plus bev (pac/bev) as first-line therapy formetastatic breast cancer (MBC). J Clin Oncol.2009;27(15S):Abstract 1029.16. Perez EA, Lerzo G, Pivot X, et al. Efficacy and safe-ty of ixabepilone (BMS-247550) in a phase II study ofpatients with advanced breast cancer resistant to ananthracycline, a taxane, and capecitabine. J Clin Oncol.2007;25:3407-3414.17. Perez EA, Pivot X, Vrdoljak E, et al. A prospectivecharacterization of the resolution of ixabepiloneinduced peripheral neuropathy: data from a large regis-trational program in patients with metastatic breast can-cer. Cancer Res. 2009;69(suppl):Abstract 6140.18. Swain SM, Arezzo JC. Neuropathy associated withmicrotubule inhibitors: diagnosis, incidence, and man-agement. Clin Adv Hematol Oncol. 2008;6:455-467.19. Stubblefield MD, Burstein HJ, Burton A, et al.NCCN Task Force Report: management of neuropathyin cancer. J Natl Compr Canc Netw. 2009;7(suppl 5):S1-S28.20. National Comprehensive Cancer Network. ClinicalPractice Guidelines in Oncology: Cancer-Related Fatigue.V.1.2011. www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf. Accessed June 20, 2011.

For breast cancer patients aged 66years and older, nurses should con-sider comorbidities when discussing

prognosis, according to an analysis ofSurveillance, Epidemiology and End Re -sults–Medicare data.In a US population of 64,034 patients

diagnosed with breast cancer at a medi-an age of 75 years, Patnaik and col-leagues identified 13 comorbid condi-tions associated with decreased overallsurvival and increased all-cause mortal-ity (Table). Among the study popula-tion, 58% had none of the selectedcomorbidities, 28.0% had 1 comorbidi-ty, 8.8% had 2 comorbidities, and 4.9%

had ≥3 of the conditions. Kaplan-Meier survival curves showed

that comorbidities are associated withsurvival, meaning that for a patientwith comorbid conditions diagnosed atan early stage, that patient had similaror worse survival than a patient with nocomorbid conditions diagnosed at alater stage. The investigators concluded that their

findings suggest that “careful attention tothe effective management of comorbidconditions, as well as to the managementof a patient’s cancer, may result in longeroverall survival for older breast cancerpatients.” �

13 Comorbid Conditions DecreaseSurvival, Increase Mortality in ElderlyBreast Cancer PatientsBy Dawn Lagrosa

Table Comorbid Conditions Associated with Decreased Survival

Comorbid condition Patients, %Hazard ratio

(95% confidence interval)Previous cancer 16.3 1.27 (1.23-1.30)Diabetes 13.0 1.41 (1.36-1.45)Chronic obstructive pulmonary disease

8.8 1.52 (1.47-1.58)

Congestive heart failure 6.7 1.70 (1.64-1.76)Stroke 4.3 1.35 (1.28-1.42)Liver disease 0.3 2.32 (1.97-2.73)Myocardial infarction 1.7 1.11 (1.03-1.19)Peripheral vascular disease 2.6 1.36 (1.28-1.44)Dementia 1.4 1.96 (1.82-2.10)Paralysis 0.6 1.23 (1.09-1.38)Chronic renal failure 0.9 2.20 (2.02-2.41)Stomach ulcer 1.1 1.12 (1.02-1.23)Rheumatoid arthritis 2.0 1.27 (1.18-1.37)Source: Patnaik JL, Byers T, DiGuiseppi G, et al. The influence of comorbidities on overall survival among older women diagnosed with breast cancer. J Natl Cancer Inst. 2011;103:1101-1111.

Most patients receiving ixabepilone, however, need onlyreceive prophylactic H1/H2 antagonists to preventhypersensitivity reactions.


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SAN DIEGO—Current or recenttamoxifen therapy was associated withan increased risk of developing type 2diabetes in women older than 65 yearswho survived invasive breast cancer. Noassociation was found between aro-matase inhibitors (AIs) and develop-ment of type 2 diabetes, but the numbersof women on AIs was small. These find-ings of a population-based, case-controlstudy in Toronto, Ontario, Canada, werepresented at the 71st Scientific Sessionsof the American Diabetes Association.“To our knowledge, this is the first

study to examine the associationbetween tamoxifen and risk of type 2diabetes. We found a modest odds ratiofor the association, and this suggeststhat tamoxifen may exacerbate anunderlying risk of diabetes in suscepti-ble women. Further studies are neededto explore this association,” saidLorraine L. Lipscombe, MD, Women’sCollege Research Institute, Universityof Toronto, Canada.

Lipscombe explained that type 2 dia-betes is increased in women with breastcancer and it portends a worse progno-sis. “The reverse also may be true; thatis, that breast cancer patients may be atincreased risk of diabetes,” she noted.“For some time, the association be -tween estrogen and diabetes has beenknown. Tamoxifen is an estrogen recep-tor antagonist, and case reports suggestan increased risk of factors associatedwith diabetes in patients on tamoxifen,such as hypertriglyceridemia, steatohep-atitis, and visceral fat.”The study was based on a cohort of

14,360 women with invasive breastcancer diagnosed between 1996 and2008 identified in the large OntarioCancer Registry and physicians’ claimsand hospital abstracts. Exclusions weremetastasis, known diabetes, previouscancer, surgery, and expected survival ofless than 1 year. In total, 1445 cases ofincident diabetes diagnosed during thatperiod were matched with up to 5 con-trols, who did not have diabetes, for ageand date of breast cancer diagnosis (n =7220).Of the cases of type 2 diabetes identi-

fied, 531 (37%) were prescribed tamox-

ifen, and 127 (9%) were prescribed anAI. Tamoxifen use was defined as fillingat least 2 prescriptions. Cases and con-trols were stratified according to cur-rent/recent (within 6 months) tamoxifenusers and previous users (stopped 6months ago or more). Current/recent tamoxifen use was

associated with a significant increase inrisk of type 2 diabetes (adjusted oddsratio, 1.24 [95% confidence interval,1.08-1.41]; P = .0027). The risk began toincrease at years 2 and 3 of tamoxifenuse. Previous tamoxifen use and AI usewere not associated with an increasedrisk of diabetes.Lipscombe cited several limitations of

the study, including incomplete cancerdata, and no data on risk factors such asbody mass index, metabolic factors, fam-ily history, or ethnicity. “We cannotexclude bias from this observationalstudy, but this is the first report of thisassociation and it is hypothesis-generat-ing,” she told listeners. �

Tamoxifen Associated with Increased Risk of Type 2 DiabetesBy Alice Goodman

SAN DIEGO—Use of prandial insulin(ie, insulin given at mealtimes) appearsto be linked to cancer risk, according toa substudy of the large randomizedAction to Control Cardiovascular Riskin Diabetes (ACCORD) trial presentedat the 71st Scientific Sessions of theAmerican Diabetes Association. Otherfactors associated with development of cancer in this substudy includedincreasing body mass index (BMI),older age, and smoking. “Insulin exposure has been proposed

as a possible risk factor for the increasedrisk of cancer in patients with type 2diabetes. Although we found no associ-ation with insulin, basal insulin, orinsulin glargine, there was an associa-tion with use of prandial insulin. This ishypothesis-generating and needs to bestudied further,” stated presentingauthor Marwan Hamaty, MD, anendocrinologist at the Cleveland Clinicin Ohio.ACCORD was a large randomized,

double 2 × 2 factorial designed trial of10,251 patients with type 2 diabetes.All patients were randomized to receiveeither intensive or standard glycemictherapy. Those with moderate levels ofdyslipidemia (n = 5518) were furtherrandomized to either intensive or stan-dard lipid-lowering therapy. The re -maining 4733 patients were randomized

to achieve intensive or standardblood pressure targets. The substudypresented focused on the glycemiatherapy arm; 5076 patients were ran-domized to intensive glycemia con-trol and 5070 to standard glycemiacontrol.Among these patients, there were

304 cancer events: hospitalizationfor cancer but no deaths in 101patients and cancer-related deaths in203. The incidence of cancer wasnot affected by gender, but as wouldbe expected, was higher in cigaretteand tobacco smokers and lower innever-smokers. Also, cancer inci-dence was higher in patients olderthan 70 years, and in patients withincreased BMI. No association wasfound between alcohol use andinsulin use at baseline.Increasing hemoglobin A1c was

associated with risk of cancer. “Forevery 1% increase in A1c, cancer riskincreased by 30%, even after adjust-ment for the glycemia intervention,”Hamaty told listeners. After adjusting for a number of

covariates (baseline age, sex, BMI,insulin use, tobacco use, alcohol use,history of cardiovascular events, as -signment to glycemia treatment group,intensive versus standard blood pres-sure, and lipid lowering), a significant

association was found between prandi-al insulin and cancer risk, with a haz-ard ratio (HR) of 2.30 (95% confi-dence interval [CI], 1.08-4.90; P =.03). This association remained signifi-cant even after correction for basalinsulin exposure (HR, 2.41 [95% CI,1.05-5.49]; P = .03).The study had several limitations,

Hamaty noted. It was a post-hoc analy-sis, not a prespecified one, and therewere a relatively small number of can-cer-related events. Also, the use ofconcomitant medications was notaccounted for and might have influ-enced results. Nevertheless, these find-ings suggest that further study is need-ed, he said. � —AG

Prandial Insulin May Be Associated with Cancer Risk

“We found a modest odds ratio for the association, andthis suggests that tamoxifen may exacerbate anunderlying risk of diabetes in susceptible women.”

—Lorraine L. Lipscombe, MD

The Whole Patient


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Iwould like to welcome everyone tothe inaugural edition of “Koeller’sCorner.” The intent is for this to

be a regular column for The OncologyPharm acist. For this introductory edi-tion, I would like to introduce myself tothe readers and describe the intent ofmy column as we move forward.First, my name is Jim Koeller, and I

am currently a full professor at theUniversity of Texas at Austin College ofPharmacy and an adjoint professor ofmedicine and oncology at the Uni -versity of Texas Health Science Centerin San Antonio. Some have affectionately referred to

me as one of the old-timers in oncologypharmacy. And my 32-year career as anoncology pharmacy specialist has beenan interesting journey so far. I hope to share some of that perspective, re-flection, commentary, and, hopefully,thought-provoking discussion with you.I may not always have the answers, butfor those who know me, I always havesomething to say. I can tell you that Iam not exactly sure what direction thiscolumn will take. I have not been givenany marching orders or guidelines as towhat to say or how to say it, so we willhave to see where this goes.… I do readthe Hematology/Oncology PharmacyAssociation (HOPA) listserv religiously,and some topics will come from thosediscussions; other topics will just bethings I think we need to talk about.

Our PastMuch of what exists today in oncologytraining, continuing education, andlicensure have their roots from thoseearly days when others like me werelooking to create a forum for our special-ty. Many of the formal oncology interestgroups, residencies, and fellowships werecreated in the early 1980s.Back when I started in this business,

specialty pharmacy practice was in its

infancy, so with little direction a group ofus forged a path ahead for oncology phar-macy practice. Our specialty arose out of an American Society of Health-System Pharmacists’ (ASHP) specialinterest group. In 1986, I headed agroup from across the country, spon-sored by ASHP, who were responsibleto create a petition for oncology as aspecialty that would go to the Board ofPharmaceutical Specialties (BPS).This turned out to be a 7-year odyssey.That first submission was denied byBPS. This was quite a setback andalmost doomed the recognition of ourspecialty. But a handful of us perse-vered and, 2 years later, submitted a pro-posal that was accepted. A group of uswere asked to serve on the first BPSSpecial Council on Oncology Pharmacy,which created the inaugural specialtyexamination in 1995. A successful spe-cialist now could be a Board CertifiedOncology Pharmacist (BCOP).With an identified specialty, the next

issue was continuing education thatfocused on oncology pharmacy practice.Neither ASHP nor the AmericanCollege of Clinical Pharmacy offeredadequate oncology specialty content tosatisfy annual BCOP requirements orthe overall needs of specialists. TheAmerican Society of Clinical Oncologyannual meeting was an option, but notall oncology pharmacists were able toattend. In addition, the only stand-alone oncology pharmacy program wasthe M. D. Anderson Cancer Con -ference, but that was primarily an M. D.Anderson –created event using M. D.Anderson staff.During this same timeframe, a group of

oncology specialists formed ONC, a sub-group of a medical education companythat specifically created oncology phar-macy continuing education. From thisgroup, the second stand-alone oncologypharmacy national conference was

formed: Making a Difference. This meet-ing was a success, but following the salesof the medical education company, theMaking a Difference conference wasidled. Phil Johnson and a handful of oth-ers, however, resurrected the conference,ultimately becoming the HOPA annualmeeting when the organization launchedin 2005.

Our FutureI thought a little look backward to howour specialty came to be, would inter-est some of the younger oncology phar-macy specialists. Today, there are morethan 1000 identified oncology special-ty pharmacists. As the old VirginiaSlims TV commercial once said,“we’ve come a long way baby.”I was just looking through my desk

drawer for a pen, and do you think Icould find one? Not one, no drug-labeled pens, nada. Where have all thepens and sticky pads gone? I rememberwhen pens and sticky pads were as com-mon as fire ants in a Texas yard. Now,because I’m not trusted to make anunbiased drug assessment, all thoseenticements have been revoked. Nomore trips or junkets. Believe me, thingshave not stopped there. Most healthscience centers and health system rulescurrently outlaw the taking of any itemfrom a drug company—and I mean any-

thing. And if that’s not bad enough, ata rescent drug company lecture I gave,pharmacists were not allowed to attendunless they paid for their own dinner.Now employers are telling you what youcan do on your own time.Are we really so sleazy that we can

be bought with a pen, pad, or dinner?Maybe the answer is yes for some, butwhat heresy do these varmints speak (I am speaking about those of us whospeak for pharmaceutical companies)that is so toxic? The industry is so reg-ulated and monitored now that toclear the numerous legal internal hur-dles that exist, a company-sponsoredlecture is so cleansed and squeakyclean, it basically mirrors the packageinsert. Don’t get me wrong, I appreci-ate the continuing medical education(CME)-designated lectures I get achance to hear from time to time, butthe rules for CME have become quitetedious and not always reasonable forevery lecture.With all this being said, my question

is still: How do we get good, up-to-dateinformation on cancer drugs and treat-ment to us in practice in a reasonableand timely fashion, without having tospend thousands of dollars to go to anational meeting? I do realize there is web-based programming available.However, much us this is limited andmany times does not deal with the dis-ease or treatment of interest at the time. I’m not sure what the answer is, but

I do understand the ethics surroundingreceiving gifts for using a specific prod-uct and how that could taint the deci-sion process. When I look back at howwe made decisions and used drugs inthe ‘80s and ‘90s and how we do thingsnow, I really don’t see a big difference.Is it just me, or is my sight failing me inmy old age?If you don’t agree, let me know

where I’m off base or just wrong. �


Would you like straight-shooter Jim Koeller to respond to a particular topic? E-mail your ideas to [email protected].

Specialization in OncologyFrom the Beginning

Shooting from the Hip

Koeller’s Corner

Back when I started inthis business, specialtypharmacy practice wasin its infancy, so withlittle direction a group of us forged a pathahead for oncologypharmacy practice.


BRIEF SUMMARYGEMCITABINEFOR INJECTION, USP1 INDICATIONS AND USAGE

1.1 Ovarian Cancer 1.2 Breast Cancer1.3 Non-Small Cell Lung Cancer1.4 Pancreatic Cancer

2 DOSAGE AND ADMINISTRATION2.1 Ovarian Cancer2.2 Breast Cancer2.3 Non-Small Cell Lung Cancer2.4 Pancreatic Cancer2.5 Preparation and Administration Precautions2.6 Preparation for Intravenous Infusion Administration

3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS

5.1 Infusion Time5.2 Hematology5.3 Pulmonary5.4 Renal5.5 Hepatic5.6 Pregnancy5.7 Laboratory Tests5.8 Radiation Therapy

6 ADVERSE REACTIONS6.1 Clinical Trials Experience 6.2 Post-Marketing Experience

7 DRUG INTERACTIONS8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Renal8.7 Hepatic8.8 Gender

10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES14.1 Ovarian Cancer14.2 Breast Cancer14.3 Non-Small Cell Lung Cancer (NSCLC)14.4 Pancreatic Cancer14.5 Other Clinical Studies

15 REFERENCES16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied16.2 Storage and Handling

17 PATIENT COUNSELING INFORMATION17.1 Low Blood Cell Counts17.2 Pregnancy17.3 Nursing Mothers

* Sections or subsections omitted from the full prescribing information are not listed.1 INDICATIONS AND USAGE1.1 Ovarian Cancer

Gemcitabine for Injection in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.

1.2 Breast Cancer Gemcitabine for Injection in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.

1.3 Non-Small Cell Lung Cancer Gemcitabine for Injection is indicated in combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer.

1.4 Pancreatic Cancer Gemcitabine for Injection is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemcitabine is indicated for patients previously treated with 5-FU.

2 DOSAGE AND ADMINISTRATION Gemcitabine for Injection is for intravenous use only. Gemcitabine may be administered on an outpatient basis.

2.1 Ovarian Cancer Gemcitabine for Injection should be administered intravenously at a dose of 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Carboplatin AUC 4 should be administered intravenously on Day 1 after gemcitabine for injection administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count ≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle.Dose Modifications Gemcitabine for Injection dosage adjustment for hematological toxicity within a cycle of treatment is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, gemcitabine for injection dosage should be modified according to guidelines in Table 1.

Table 1: Day 8 Dosage Reduction Guidelines for Gemcitabine for Injection in Combination with Carboplatin

Absolutegranulocyte count Platelet count % of

(x 106/L) (x 106/L) full dose≥1500 And ≥100,000 100

1000 to 1499 and/or 75,000 to 99,999 50<1000 and/or <75,000 Hold

In general, for severe (Grade 3 or 4) non-hematological toxicity, except nausea/vomiting, therapy with gemcitabine for injection should be held or decreased by 50% depending on the judgment of the treating physician. For carboplatin dosage adjustment, see manufacturer’s prescribing information. Dose adjustment for gemcitabine for injection in combination with carboplatin for subsequent cycles is based upon observed toxicity. The dose of gemcitabine for injection in subsequent cycles should be reduced to 800 mg/m2 on Days 1 and 8 in case of any of the following hematologic toxicities: • Absolute granulocyte count <500 x 106/L for more than 5 days • Absolute granulocyte count <100 x 106/L for more than 3 days • Febrile neutropenia • Platelets <25,000 x 106/L • Cycle delay of more than one week due to toxicity If any of the above toxicities recur after the initial dose reduction, for the subsequent cycle, gemcitabine for injection should be given on Day 1 only at 800 mg/m2.

2.2 Breast Cancer Gemcitabine for Injection should be administered intravenously at a dose of 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3-hour intravenous infusion before gemcitabine administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count ≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle.Dose Modifications Gemcitabine dosage adjustments for hematological toxicity is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, gemcitabine dosage should be modified according to the guidelines in Table 2.

Table 2: Day 8 Dosage Reduction Guidelines for Gemcitabine in Combination with Paclitaxel

Absolutegranulocyte count Platelet count % of

(x 106/L) (x 106/L) full dose≥1200 And >75,000 100

1000 to 1199 Or 50,000 to 75,000 75700 to 999 And ≥50,000 50

<700 Or <50,000 Hold In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with gemcitabine should be held or decreased by 50% depending on the judgment of the treating physician. For paclitaxel dosage adjustment, see manufacturer’s prescribing information.

2.3 Non-Small Cell Lung Cancer Dose Modifi cations

Dosage adjustments for hematologic toxicity may be required for gemcitabine and

for cisplatin. Gemcitabine dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on the day of therapy. Patients receiving gemcitabine should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet counts. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3. For cisplatin dosage adjustment, see manufacturer’s prescribing information.

In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with gemcitabine plus cisplatin should be held or decreased by 50% depending on the judgment of the treating physician. During combination therapy with cisplatin, serum creatinine, serum potassium, serum calcium, and serum magnesium should be carefully monitored (Grade 3/4 serum creatinine toxicity for gemcitabine plus cisplatin was 5% versus 2% for cisplatin alone).

2.4 Pancreatic Cancer Dose Modifications Dosage adjustment is based upon the degree of hematologic toxicity experienced by

the patient [see Warnings and Precautions (5.2)]. Clearance in women and the elderly is reduced and women were somewhat less able to progress to subsequent cycles [see Warnings and Precautions (5.2) and Clinical Pharmacology(12.3)].

Patients receiving gemcitabine should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3.

Table 3: Dosage Reduction GuidelinesAbsolute

granulocyte count Platelet count % of (x 106/L) (x 106/L) full dose≥1000 And ≥100,000 100

500 to 999 Or 50,000 to 99,999 75<500 Or <50,000 Hold

Laboratory evaluation of renal and hepatic function, including transaminases and serum creatinine, should be performed prior to initiation of therapy and periodically thereafter. Gemcitabine for Injection should be administered with caution in patients with evidence of significant renal or hepatic impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations.

Patients treated with gemcitabine who complete an entire cycle of therapy may have the dose for subsequent cycles increased by 25%, provided that the absolute granulocyte count (AGC) and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and if non-hematologic toxicity has not been greater than WHO Grade 1. If patients tolerate the subsequent course of gemcitabine at the increased dose, the dose for the next cycle can be further increased by 20%, provided again that the AGC and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and that non-hematologic toxicity has not been greater than WHO Grade 1.

4 CONTRAINDICATIONS Gemcitabine is contraindicated in those patients with a known hypersensitivity to the

drug.5 WARNINGS AND PRECAUTIONS Patients receiving therapy with gemcitabine should be monitored closely by a physician

experienced in the use of cancer chemotherapeutic agents.5.1 Infusion Time Caution – Prolongation of the infusion time beyond 60 minutes and more frequent than

weekly dosing have been shown to increase toxicity [see Clinical Studies (14.5)].5.2 Hematology Gemcitabine can suppress bone marrow function as manifested by leukopenia,

thrombocytopenia, and anemia [see Adverse Reactions (6.1)], and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].

5.3 Pulmonary Pulmonary toxicity has been reported with the use of gemcitabine. In cases of severe

lung toxicity, gemcitabine therapy should be discontinued immediately and appropriate supportive care measures instituted [see Adverse Reactions (6.1 and 6.2)].

5.4 Renal Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following

one or more doses of gemcitabine. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been reported. The majority of the cases of renal failure leading to death were due to HUS [see Adverse Reactions (6.1 and 6.2)].

Gemcitabine should be used with caution in patients with preexisting renal impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations [see Use In Specific Populations (8.6)].

5.5 Hepatic Serious hepatotoxicity, including liver failure and death, has been reported in patients

receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.1 and 6.2)].

Gemcitabine should be used with caution in patients with preexisting hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of gemcitabine in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency [see Use In Specific Populations (8.7)].

5.6 Pregnancy Gemcitabine can cause fetal harm when administered to a pregnant woman. In pre-

clinical studies in mice and rabbits, gemcitabine was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of gemcitabine in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use In Specific Populations (8.1)].

5.7 Laboratory Tests Patients receiving gemcitabine should be monitored prior to each dose with a complete

blood count (CBC), including differential and platelet count. Suspension or modification of therapy should be considered when marrow suppression is detected [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].

Laboratory evaluation of renal and hepatic function should be performed prior to initiation of therapy and periodically thereafter [see Dosage and Administration (2.4)].

5.8 Radiation Therapy A pattern of tissue injury typically associated with radiation toxicity has been reported in

association with concurrent and non-concurrent use of gemcitabine. Non-concurrent (given >7 days apart) – Analysis of the data does not indicate enhanced

toxicity when gemcitabine is administered more than 7 days before or after radiation, other than radiation recall. Data suggest that gemcitabine can be started after the acute effects of radiation have resolved or at least one week after radiation.

Concurrent (given together or ≤7 days apart) – Preclinical and clinical studies have shown that gemcitabine has radiosensitizing activity. Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of gemcitabine, frequency of gemcitabine administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. In a single trial, where gemcitabine at a dose of 1000 mg/m2 was administered concurrently for up to 6 consecutive weeks with therapeutic thoracic radiation to patients with non-small cell lung cancer, significant toxicity in the form of severe, and potentially life-threatening mucositis, especially esophagitis and pneumonitis was observed, particularly in patients receiving large volumes of radiotherapy [median treatment volumes 4795 cm3]. Subsequent studies have been reported and suggest that gemcitabine administered at lower doses with concurrent radiotherapy has predictable and less severe toxicity. However, the optimum regimen for safe administration of gemcitabine with therapeutic doses of radiation has not yet been determined in all tumor types.

6 ADVERSE REACTIONS6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction

rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced.

Gemcitabine has been used in a wide variety of malignancies, both as a single-agent and in combination with other cytotoxic drugs.

Single-Agent Use: Myelosuppression is the principal dose-limiting toxicity with gemcitabine therapy.

Dosage adjustments for hematologic toxicity are frequently needed [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].

The data in Table 4 are based on 979 patients receiving gemcitabine as a single-agent administered weekly as a 30-minute infusion for treatment of a wide variety of malignancies. The gemcitabine starting doses ranged from 800 to 1250 mg/m2. Data are also shown for the subset of patients with pancreatic cancer treated in 5 clinical studies. The frequency of all grades and severe (WHO Grade 3 or 4) adverse reactions were generally similar in the single-agent safety database of 979 patients and the subset of patients with pancreatic cancer. Adverse reactions reported in the single-agent safety database resulted in discontinuation of gemcitabine therapy in about 10% of patients. In the comparative trial in pancreatic cancer, the discontinuation rate for adverse reactions was 14.3% for the gemcitabine arm and 4.8% for the 5-FU arm. All WHO-graded laboratory adverse reactions are listed in Table 4, regardless of causality. Non-laboratory adverse reactions listed in Table 4 or discussed below were those reported, regardless of causality, for at least 10% of all patients, except the categories of Extravasation, Allergic, and Cardiovascular and certain specific adverse reactions under the Renal, Pulmonary, and Infection categories.

Hematologic – In studies in pancreatic cancer myelosuppression is the dose-limiting toxicity with gemcitabine, but <1% of patients discontinued therapy for either anemia, leukopenia, or thrombocytopenia. Red blood cell transfusions were required by 19% of patients. The incidence of sepsis was less than 1%. Petechiae or mild blood loss (hemorrhage), from any cause, was reported in 16% of patients; less than 1% of patients required platelet transfusions. Patients should be monitored for myelosuppression during gemcitabine therapy and dosage modified or suspended according to the degree of hematologic toxicity [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].

Gastrointestinal – Nausea and vomiting were commonly reported (69%) but were usually

of mild to moderate severity. Severe nausea and vomiting (WHO Grade 3/4) occurred in <15% of patients. Diarrhea was reported by 19% of patients, and stomatitis by 11% of patients.

Hepatic – In clinical trials, gemcitabine was associated with transient elevations of one or both serum transaminases in approximately 70% of patients, but there was no evidence of increasing hepatic toxicity with either longer duration of exposure to gemcitabine or with greater total cumulative dose. Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.2)].

Renal – In clinical trials, mild proteinuria and hematuria were commonly reported. Clinical findings consistent with the Hemolytic Uremic Syndrome (HUS) were reported in 6 of 2429 patients (0.25%) receiving gemcitabine in clinical trials. Four patients developed HUS on gemcitabine therapy, 2 immediately post-therapy. The diagnosis of HUS should be considered if the patient develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, reticulocytosis, severe thrombocytopenia, and/or evidence of renal failure (elevation of serum creatinine or BUN). Gemcitabine therapy should be discontinued immediately. Renal failure may not be reversible even with discontinuation of therapy and dialysis may be required [see Adverse Reactions (6.2)].

Fever – The overall incidence of fever was 41%. This is in contrast to the incidence of infection (16%) and indicates that gemcitabine may cause fever in the absence of clinical infection. Fever was frequently associated with other flu-like symptoms and was usually mild and clinically manageable.

Rash – Rash was reported in 30% of patients. The rash was typically a macular or finely granular maculopapular pruritic eruption of mild to moderate severity involving the trunk and extremities. Pruritus was reported for 13% of patients.

Pulmonary – In clinical trials, dyspnea, unrelated to underlying disease, has been reported in association with gemcitabine therapy. Dyspnea was occasionally accompanied by bronchospasm. Pulmonary toxicity has been reported with the use of gemcitabine [see Adverse Reactions (6.2)]. The etiology of these effects is unknown. If such effects develop, gemcitabine should be discontinued. Early use of supportive care measures may help ameliorate these conditions.

Edema – Edema (13%), peripheral edema (20%), and generalized edema (<1%) were reported. Less than 1% of patients discontinued due to edema.

Flu-like Symptoms – “Flu syndrome” was reported for 19% of patients. Individual symptoms of fever, asthenia, anorexia, headache, cough, chills, and myalgia were commonly reported. Fever and asthenia were also reported frequently as isolated symptoms. Insomnia, rhinitis, sweating, and malaise were reported infrequently. Less than 1% of patients discontinued due to flu-like symptoms.

Infection – Infections were reported for 16% of patients. Sepsis was rarely reported (<1%).

Alopecia – Hair loss, usually minimal, was reported by 15% of patients. Neurotoxicity – There was a 10% incidence of mild paresthesias and a <1% rate of severe

paresthesias. Extravasation – Injection-site related events were reported for 4% of patients. There were

no reports of injection site necrosis. Gemcitabine is not a vesicant. Allergic – Bronchospasm was reported for less than 2% of patients. Anaphylactoid

reaction has been reported rarely. Gemcitabine should not be administered to patients with a known hypersensitivity to this drug [see Contraindications (4)].

Cardiovascular – During clinical trials, 2% of patients discontinued therapy with gemcitabine due to cardiovascular events such as myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension. Many of these patients had a prior history of cardiovascular disease [see Adverse Reactions (6.2)].

Combination Use in Non-Small Cell Lung Cancer: In the gemcitabine plus cisplatin versus cisplatin study, dose adjustments occurred with

35% of gemcitabine injections and 17% of cisplatin injections on the combination arm, versus 6% on the cisplatin-only arm. Dose adjustments were required in greater than 90% of patients on the combination, versus 16% on cisplatin. Study discontinuations for possibly drug-related adverse reactions occurred in 15% of patients on the combination arm and 8% of patients on the cisplatin arm. With a median of 4 cycles of gemcitabine plus cisplatin treatment, 94 of 262 patients (36%) experienced a total of 149 hospitalizations due to possibly treatment-related adverse reactions. With a median of 2 cycles of cisplatin treatment, 61 of 260 patients (23%) experienced 78 hospitalizations due to possibly treatment-related adverse reactions.

In the gemcitabine plus cisplatin versus etoposide plus cisplatin study, dose adjustments occurred with 20% of gemcitabine injections and 16% of cisplatin injections in the gemcitabine plus cisplatin arm compared with 20% of etoposide injections and 15% of cisplatin injections in the etoposide plus cisplatin arm. With a median of 5 cycles of gemcitabine plus cisplatin treatment, 15 of 69 patients (22%) experienced 15 hospitalizations due to possibly treatment-related adverse reactions. With a median of 4 cycles of etoposide plus cisplatin treatment, 18 of 66 patients (27%) experienced 22 hospitalizations due to possibly treatment-related adverse reactions. In patients who completed more than one cycle, dose adjustments were reported in 81% of the gemcitabine plus cisplatin patients, compared with 68% on the etoposide plus cisplatin arm. Study discontinuations for possibly drug-related adverse reactions occurred in 14% of patients on the gemcitabine plus cisplatin arm and in 8% of patients on the etoposide plus cisplatin arm. The incidence of myelosuppression was increased in frequency with gemcitabine plus cisplatin treatment (~90%) compared to that with the gemcitabine monotherapy (~60%). With combination therapy gemcitabine dosage adjustments for hematologic toxicity were required more often while cisplatin dose adjustments were less frequently required.

Table 5 presents the safety data from the gemcitabine plus cisplatin versus cisplatin study in non-small cell lung cancer. The NCI Common Toxicity Criteria (CTC) were used. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm. Nine cases of febrile neutropenia were reported on the combination therapy arm compared to 2 on the cisplatin arm. More patients required RBC and platelet transfusions on the gemcitabine plus cisplatin arm.

Myelosuppression occurred more frequently on the combination arm, and in 4 possibly treatment-related deaths myelosuppression was observed. Sepsis was reported in 4% of patients on the gemcitabine plus cisplatin arm compared to 1% on the cisplatin arm. Platelet transfusions were required in 21% of patients on the combination arm and <1% of patients on the cisplatin arm. Hemorrhagic events occurred in 14% of patients on the combination arm and 4% on the cisplatin arm. However, severe hemorrhagic events were rare. Red blood cell transfusions were required in 39% of the patients on the gemcitabine plus cisplatin arm, versus 13% on the cisplatin arm. The data suggest cumulative anemia with continued gemcitabine plus cisplatin use.

Nausea and vomiting despite the use of antiemetics occurred more often with gemcitabine plus cisplatin therapy (78%) than with cisplatin alone (71%). In studies with single-agent gemcitabine, a lower incidence of nausea and vomiting (58% to 69%) was reported. Renal function abnormalities, hypomagnesemia, neuromotor, neurocortical, and neurocerebellar toxicity occurred more often with gemcitabine plus cisplatin than with cisplatin monotherapy. Neurohearing toxicity was similar on both arms.

Cardiac dysrhythmias of Grade 3 or greater were reported in 7 (3%) patients treated with gemcitabine plus cisplatin compared to one (<1%) Grade 3 dysrhythmia reported with cisplatin therapy. Hypomagnesemia and hypokalemia were associated with one Grade 4 arrhythmia on the gemcitabine plus cisplatin combination arm.

Table 4: Selected WHO-Graded Adverse Reactions in Patients Receiving Single-Agent Gemcitabine WHO Grades (% incidence)a

Pancreatic Cancer DiscontinuationsAll Patientsb Patientsc (%)d

All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 All PatientsLaboratorye

HematologicAnemia 68 7 1 73 8 2 <1Leukopenia 62 9 <1 64 8 1 <1Neutropenia 63 19 6 61 17 7 -Thrombocytopenia 24 4 1 36 7 <1 <1

Hepatic <1ALT 68 8 2 72 10 1AST 67 6 2 78 12 5Alkaline Phosphatase 55 7 2 77 16 4Bilirubin 13 2 <1 26 6 2

Renal <1Proteinuria 45 <1 0 32 <1 0Hematuria 35 <1 0 23 0 0BUN 16 0 0 15 0 0Creatinine 8 <1 0 6 0 0

Non-laboratoryf

Nausea and Vomiting 69 13 1 71 10 2 <1Fever 41 2 0 38 2 0 <1Rash 30 <1 0 28 <1 0 <1Dyspnea 23 3 <1 10 0 <1 <1Diarrhea 19 1 0 30 3 0 0Hemorrhage 17 <1 <1 4 2 <1 <1Infection 16 1 <1 10 2 <1 <1Alopecia 15 <1 0 16 0 0 0Stomatitis 11 <1 0 10 <1 0 <1Somnolence 11 <1 <1 11 2 <1 <1Paresthesias 10 <1 0 10 <1 0 0

a

b

c

d

e

f ≥

Table 6 presents data from the randomized study of gemcitabine plus cisplatin versus etoposide plus cisplatin in 135 patients with NSCLC. One death (1.5%) was reported on the gemcitabine plus cisplatin arm due to febrile neutropenia associated with renal failure which was possibly treatment-related. No deaths related to treatment occurred on the etoposide plus cisplatin arm. The overall incidence of Grade 4 neutropenia on the gemcitabine plus cisplatin arm was less than on the etoposide plus cisplatin arm (28% versus 56%). Sepsis was experienced by 2% of patients on both treatment arms. Grade 3 anemia and Grade 3/4 thrombocytopenia were more common on the gemcitabine plus cisplatin arm. RBC transfusions were given to 29% of the patients who received gemcitabine plus cisplatin versus 21% of patients who received etoposide plus cisplatin. Platelet transfusions were given to 3% of the patients who received gemcitabine plus cisplatin versus 8% of patients who received etoposide plus cisplatin. Grade 3/4 nausea and vomiting were also more common on the gemcitabine plus cisplatin arm. On the gemcitabine plus cisplatin arm, 7% of participants were hospitalized due to febrile neutropenia compared to 12% on the etoposide plus cisplatin arm. More than twice as many patients had dose reductions or omissions of a scheduled dose of gemcitabine as


compared to etoposide, which may explain the differences in the incidence of neutropenia and febrile neutropenia between treatment arms. Flu syndrome was reported by 3% of patients on the gemcitabine plus cisplatin arm with none reported on the comparator arm. Eight patients (12%) on the gemcitabine plus cisplatin arm reported edema compared to one patient (2%) on the etoposide plus cisplatin arm.

Combination Use in Breast Cancer: In the gemcitabine plus paclitaxel versus paclitaxel study, dose reductions occurred with

8% of gemcitabine injections and 5% of paclitaxel injections on the combination arm, versus 2% on the paclitaxel arm. On the combination arm, 7% of gemcitabine doses were omitted and <1% of paclitaxel doses were omitted, compared to <1% of paclitaxel doses on the paclitaxel arm. A total of 18 patients (7%) on the gemcitabine plus paclitaxel arm and 12 (5%) on the paclitaxel arm discontinued the study because of adverse reactions. There were two deaths on study or within 30 days after study drug discontinuation that were possibly drug-related, one on each arm.

Table 7 presents the safety data occurrences of ≥10% (all grades) from the gemcitabine plus paclitaxel versus paclitaxel study in breast cancer.

The following are the clinically relevant adverse reactions that occurred in >1% and <10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse reactions (gemcitabine plus paclitaxel versus paclitaxel): febrile neutropenia (5% versus 1.2%), infection (0.8% versus 0.8%), dyspnea (1.9% versus 0), and allergic reaction/hypersensitivity (0 versus 0.8%).

No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65.

Combination Use in Ovarian Cancer: In the gemcitabine plus carboplatin versus carboplatin study, dose reductions occurred with

10.4% of gemcitabine injections and 1.8% of carboplatin injections on the combination arm, versus 3.8% on the carboplatin alone arm. On the combination arm, 13.7% of gemcitabine doses were omitted and 0.2% of carboplatin doses were omitted, compared to 0% of carboplatin doses on the carboplatin alone arm. There were no differences in discontinuations due to adverse reactions between arms (10.9% versus 9.8%, respectively).

Table 8 presents the adverse reactions (all grades) occurring in ≥10% of patients in the ovarian cancer study.

In addition to blood product transfusions as listed in Table 8, myelosuppression was also managed with hematopoietic agents. These agents were administered more frequently with combination therapy than with monotherapy (granulocyte growth factors: 23.6% and 10.1%, respectively; erythropoietic agents: 7.3% and 3.9%, respectively).

The following are the clinically relevant adverse reactions, regardless of causality, that occurred in >1% and <10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse reactions (gemcitabine plus carboplatin versus carboplatin): AST or ALT elevation (0 versus 1.2%), dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1%), hypersensitivity reaction (2.3% versus 2.9%), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0).

No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65.

6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of

gemcitabine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These adverse reactions have occurred after gemcitabine single-agent use and gemcitabine in combination with other cytotoxic agents. Decisions to include these events are based on the seriousness of the event, frequency of reporting, or potential causal connection to gemcitabine.

Cardiovascular – Congestive heart failure and myocardial infarction have been reported very rarely with the use of gemcitabine. Arrhythmias, predominantly supraventricular in nature, have been reported very rarely.

Vascular Disorders – Clinical signs of peripheral vasculitis and gangrene have been reported very rarely.

Skin – Cellulitis and non-serious injection site reactions in the absence of extravasation have been rarely reported. Severe skin reactions, including desquamation and bullous skin eruptions, have been reported very rarely.

Hepatic – Increased liver function tests including elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, and bilirubin levels have been reported rarely. Serious hepatotoxicity including liver failure and death has been reported very rarely in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs. Hepatic veno-occlusive disease has been reported.

Pulmonary – Parenchymal toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported rarely following one or more doses of gemcitabine administered to patients with various malignancies. Some patients experienced the onset of pulmonary symptoms up to 2 weeks after the last gemcitabine dose. Respiratory failure and death occurred very rarely in some patients despite discontinuation of therapy.

Renal – Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of gemcitabine. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS.

Injury, Poisoning, and Procedural Complications – Radiation recall reactions have been reported [see Warnings and Precautions (5.8)].

7 DRUG INTERACTIONS No specific drug interaction studies have been conducted. Information is available on the

pharmacodynamics and pharmacokinetics of gemcitabine in combination with cisplatin, paclitaxel, or carboplatin [see Clinical Pharmacology (12.2 and 12.3)].

Table 5: Selected CTC-Graded Adverse Reactions From Comparative Trial of Gemcitabine Plus Cisplatin Versus Single-Agent Cisplatin in NSCLC

CTC Grades (% incidence)a

Gemcitabine plus Cisplatinb Cisplatinc

All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4Laboratoryd

HematologicAnemia 89 22 3 67 6 1RBC Transfusione 39 13Leukopenia 82 35 11 25 2 1Neutropenia 79 22 35 20 3 1Thrombocytopenia 85 25 25 13 3 1Platelet Transfusionse 21 <1Lymphocytes 75 25 18 51 12 5

HepaticTransaminase 22 2 1 10 1 0Alkaline Phosphatase 19 1 0 13 0 0

RenalProteinuria 23 0 0 18 0 0Hematuria 15 0 0 13 0 0Creatinine 38 4 <1 31 2 <1

Other LaboratoryHyperglycemia 30 4 0 23 3 0Hypomagnesemia 30 4 3 17 2 0Hypocalcemia 18 2 0 7 0 <1

Non-laboratoryf

Nausea 93 25 2 87 20 <1Vomiting 78 11 12 71 10 9Alopecia 53 1 0 33 0 0Neuro Motor 35 12 0 15 3 0Neuro Hearing 25 6 0 21 6 0Diarrhea 24 2 2 13 0 0Neuro Sensory 23 1 0 18 1 0Infection 18 3 2 12 1 0Fever 16 0 0 5 0 0Neuro Cortical 16 3 1 9 1 0Neuro Mood 16 1 0 10 1 0Local 15 0 0 6 0 0Neuro Headache 14 0 0 7 0 0Stomatitis 14 1 0 5 0 0Hemorrhage 14 1 0 4 0 0Dyspnea 12 4 3 11 3 2Hypotension 12 1 0 7 1 0Rash 11 0 0 3 0 0

a ≥b

cdef

Table 6: Selected WHO-Graded Adverse Reactions From Comparative Trial of Gemcitabine Plus Cisplatin Versus Etoposide Plus Cisplatin in NSCLC

WHO Grades (% incidence)a

Gemcitabine plus Cisplatinb Etoposide plus Cisplatinc

All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4Laboratoryd

HematologicAnemia 88 22 0 77 13 2RBC Transfusionse 29 21Leukopenia 86 26 3 87 36 7Neutropenia 88 36 28 87 20 56Thrombocytopenia 81 39 16 45 8 5Platelet Transfusionse 3 8

HepaticALT 6 0 0 12 0 0AST 3 0 0 11 0 0Alkaline Phosphatase 16 0 0 11 0 0Bilirubin 0 0 0 0 0 0

RenalProteinuria 12 0 0 5 0 0Hematuria 22 0 0 10 0 0BUN 6 0 0 4 0 0Creatinine 2 0 0 2 0 0

Non-laboratoryf, g

Nausea and Vomiting 96 35 4 86 19 7Fever 6 0 0 3 0 0Rash 10 0 0 3 0 0Dyspnea 1 0 1 3 0 0Diarrhea 14 1 1 13 0 2Hemorrhage 9 0 3 3 0 3Infection 28 3 1 21 8 0Alopecia 77 13 0 92 51 0Stomatitis 20 4 0 18 2 0Somnolence 3 0 0 3 2 0Paresthesias 38 0 0 16 2 0

ab

c -

d e f

Table 7: Adverse Reactions From Comparative Trial of Gemcitabine Plus Paclitaxel Versus Single-Agent Paclitaxel in Breast Cancera

CTC Grades (% incidence)Gemcitabine plus Paclitaxel (N=262) Paclitaxel (N=259)

All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4Laboratoryb

HematologicAnemia 69 6 1 51 3 <1Neutropenia 69 31 17 31 4 7Thrombocytopenia 26 5 <1 7 <1 <1Leukopenia 21 10 1 12 2 0

HepatobiliaryALT 18 5 <1 6 <1 0AST 16 2 0 5 <1 0

Non-laboratoryc

Alopecia 90 14 4 92 19 3Neuropathy-sensory 64 5 <1 58 3 0Nausea 50 1 0 31 2 0Fatigue 40 6 <1 28 1 <1Myalgia 33 4 0 33 3 <1Vomiting 29 2 0 15 2 0Arthralgia 24 3 0 22 2 <1Diarrhea 20 3 0 13 2 0Anorexia 17 0 0 12 <1 0Neuropathy-motor 15 2 <1 10 <1 0Stomatitis/pharyngitis 13 1 <1 8 <1 0Fever 13 <1 0 3 0 0Rash/desquamation 11 <1 <1 5 0 0

a ≥bc

Table 8: Adverse Reactions From Comparative Trial of Gemcitabine Plus Carboplatin Versus Single-Agent Carboplatin in Ovarian Cancera

CTC Grades (% incidence)Gemcitabine plus Carboplatin (N=175) Carboplatin (N=174)

All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4Laboratoryb

HematologicNeutropenia 90 42 29 58 11 1Anemia 86 22 6 75 9 2Leukopenia 86 48 5 70 6 <1Thrombocytopenia 78 30 5 57 10 1RBC Transfusionsc 38 15Platelet Transfusionsc 9 3

Non-laboratoryb

Nausea 69 6 0 61 3 0Alopecia 49 0 0 17 0 0Vomiting 46 6 0 36 2 <1Constipation 42 6 1 37 3 0Fatigue 40 3 <1 32 5 0Neuropathy-sensory 29 1 0 27 2 0Diarrhea 25 3 0 14 <1 0Stomatitis/pharyngitis 22 <1 0 13 0 0Anorexia 16 1 0 13 0 0

a ≥b

c

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Pregnancy Category D. See ‘Warnings and Precautions’ section. Gemcitabine can cause fetal harm when administered to a pregnant woman. Based on its

mechanism of action, gemcitabine is expected to result in adverse reproductive effects. There are no adequate and well-controlled studies of gemcitabine in pregnant women. Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 1/200 the recommended human dose on a mg/m2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 1/600 the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.6)].

8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are

excreted in human milk and because of the potential for serious adverse reactions in nursing infants from gemcitabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of gemcitabine in pediatric patients has not been established.

Gemcitabine was evaluated in a Phase 1 trial in pediatric patients with refractory leukemia and determined that the maximum tolerated dose was 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. Gemcitabine was also evaluated in a Phase 2 trial in patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) using 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation, which were similar to those reported in adults. No meaningful clinical activity was observed in this Phase 2 trial.

8.5 Geriatric Use Gemcitabine clearance is affected by age [see Clinical Pharmacology (12.3)]. There is no

evidence, however, that unusual dose adjustments [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)] are necessary in patients over 65, and in general, adverse reaction rates in the single-agent safety database of 979 patients were similar in patients above and below 65. Grade 3/4 thrombocytopenia was more common in the elderly. In the randomized clinical trial of gemcitabine in combination with carboplatin for recurrent ovarian cancer [see Clinical Studies (14.1)], 125 women treated with gemcitabine plus carboplatin were <65 years and 50 were ≥ 65 years. Similar effectiveness was observed between older and younger women. There was significantly higher Grade 3/4 neutropenia in women 65 years of age or older. Overall, there were no other substantial differences in toxicity profile of gemcitabine plus carboplatin based on age.

8.6 Renal Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following

one or more doses of gemcitabine. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been reported. The majority of the cases of renal failure leading to death were due to HUS [see Adverse Reactions (6.1 and 6.2)].

Gemcitabine should be used with caution in patients with preexisting renal impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations [see Warnings and Precautions (5.4)].

8.7 Hepatic Serious hepatotoxicity, including liver failure and death, has been reported in patients

receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.1 and 6.2)].

Gemcitabine should be used with caution in patients with preexisting hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of gemcitabine in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency [see Warnings and Precautions (5.5)].

8.8 Gender Gemcitabine clearance is affected by gender [see Clinical Pharmacology (12.3)]. In

the single-agent safety database (N=979 patients), however, there is no evidence that unusual dose adjustments [see Dosage and Administration (2)] are necessary in women. In general, in single-agent studies of gemcitabine, adverse reaction rates were similar in men and women, but women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia. There was a greater tendency in women, especially older women, not to proceed to the next cycle.

12 CLINICAL PHARMACOLOGY12.2 Pharmacodynamics Gemcitabine demonstrated dose-dependent synergistic activity with cisplatin in vitro.

No effect of cisplatin on gemcitabine triphosphate accumulation or DNA double-strand breaks was observed. In vivo, gemcitabine showed activity in combination with cisplatin against the LX-1 and CALU-6 human lung xenografts, but minimal activity was seen with the NCI-H460 or NCI-H520 xenografts. Gemcitabine was synergistic with cisplatin in the Lewis lung murine xenograft. Sequential exposure to gemcitabine 4 hours before cisplatin produced the greatest interaction.

12.3 Pharmacokinetics Absorption and Distribution The volume of distribution was increased with infusion length. Volume of distribution of

gemcitabine was 50 L/m2 following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m2.

Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and gender. Gemcitabine plasma protein binding is negligible.

Excretion Clearance of gemcitabine was affected by age and gender. The lower clearance in women

and the elderly results in higher concentrations of gemcitabine for any given dose. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations. Table 9 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and gender.

Table 9: Gemcitabine Clearance and Half-Life for the “Typical” Patient

Age Clearance Clearance Half-Lifea Half-Lifea Men Women Men Women (L/hr/m2) (L/hr/m2) (min) (min)

29 92.2 69.4 42 4945 75.7 57 48 5765 55.1 41.5 61 7379 40.7 30.7 79 94

a Half-life for patients receiving a short infusion (<70 min). Gemcitabine half-life for short infusions ranged from 42 to 94 minutes, and the value for

long infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer infusions.

Drug Interactions

When gemcitabine (1250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m2 on Day 1) were administered in NSCLC patients, the clearance of gemcitabine on Day 1 was 128 L/hr/m2 and on Day 8 was 107 L/hr/m2. The clearance of cisplatin in the same study was reported to be 3.94 mL/min/m2 with a corresponding half-life of 134 hours [see Drug Interactions (7)]. Analysis of data from metastatic breast cancer patients shows that, on average, gemcitabine has little or no effect on the pharmacokinetics (clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of gemcitabine. Data from NSCLC patients demonstrate that gemcitabine and carboplatin given in combination does not alter the pharmacokinetics of gemcitabine or carboplatin compared to administration of either single-agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed.

14 CLINICAL STUDIES14.1 Ovarian Cancer Gemcitabine was studied in a randomized Phase 3 study of 356 patients with advanced

ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either gemcitabine 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after gemcitabine on Day 1 of each cycle or single-agent carboplatin AUC 5 administered on Day 1 of each 21-day cycle as the control arm. The primary endpoint of this study was progression free survival (PFS).

Patient characteristics are shown in Table 10. The addition of gemcitabine to carboplatin resulted in statistically significant improvement in PFS and overall response rate as shown in Table 11 and Figure 1. Approximately 75% of patients in each arm received poststudy chemotherapy. Only 13 of 120 patients with documented poststudy chemotherapy regimen in the carboplatin arm received gemcitabine after progression. There was not a significant difference in overall survival between arms.

Table 10: Gemcitabine Plus Carboplatin Versus Carboplatin in Ovarian Cancer – Baseline Demographics and Clinical

Characteristics

Gemcitabine/ Carboplatin Carboplatin Number of randomized patients 178 178 Median age, years 59 58 Range 36 to 78 21 to 81 Baseline ECOG

performance status 0-1a

94% 95% Disease Status Evaluable 7.9% 2.8% Bidimensionally measurable 91.6% 95.5% Platinum-free intervalb 6 to 12 months 39.9% 39.9% >12 months 59% 59.6% First-line therapy Platinum-taxane combination 70.2% 71.3% Platinum-non-taxane combination 28.7% 27.5% Platinum monotherapy 1.1% 1.1%

a Nine patients (5 on the gemcitabine plus carboplatin arm and 4 on the carboplatin arm) did not have baseline Eastern Cooperative Oncology Group (ECOG) performance status recorded.

b Three patients (2 on the gemcitabine plus carboplatin arm and 1 on the carboplatin arm) had a platinum-free interval of less than 6 months.

Table 11: Gemcitabine Plus Carboplatin Versus Carboplatin in Ovarian Cancer – Results of

Efficacy AnalysisGemcitabine/Carboplatin Carboplatin

(N=178) (N=178)PFS Median (95%, C.I.) months 8.6 (8, 9.7) 5.8 (5.2, 7.1) p=0.0038d

Hazard Ratio (95%, C.I.) 0.72 (0.57, 0.9)Overall Survival Median (95%, C.I.) months 18 (16.2, 20.3) 17.3 (15.2, 19.3) p=0.8977d

Hazard Ratio (95%, C.I.) 0.98 (0.78, 1.24)Adjusteda Hazard Ratio (95%, C.I.) 0.86 (0.67, 1.1)Investigator Reviewed Overall Response Rate 47.2% 30.9% p=0.0016

e

CR 14.6% 6.2% PR + PRNMb 32.6% 24.7%Independently ReviewedOverall Response Ratec, f 46.3% 35.6% p=0.11

e

CR 9.1% 4% PR + PRNM 37.2% 31.7%

a Treatment adjusted for performance status, tumor area, and platinum-free interval.b Partial response non-measurable diseasec Independent reviewers could not evaluate disease demonstrated by sonography or

physical exam.d Log Rank, unadjustede Chi Squaref Independently reviewed cohort – Gemcitabine/ Carboplatin N=121, Carboplatin

N=101

Figure 1: Kaplan-Meier Curve of Progression Free Survival in Gemcitabine Plus Carboplatin Versus Carboplatin in Ovarian Cancer (N=356)

14.5 Other Clinical Studies When gemcitabine was administered more frequently than once weekly or with infusions

longer than 60 minutes, increased toxicity was observed. Results of a Phase 1 study of gemcitabine to assess the maximum tolerated dose (MTD) on a daily x 5 schedule showed that patients developed significant hypotension and severe flu-like symptoms that were intolerable at doses above 10 mg/m2. The incidence and severity of these events were dose-related. Other Phase 1 studies using a twice-weekly schedule reached MTDs of only 65 mg/m2 (30-minute infusion) and 150 mg/m2 (5-minute bolus). The dose-limiting toxicities were thrombocytopenia and flu-like symptoms, particularly asthenia. In a Phase 1 study to assess the maximum tolerated infusion time, clinically significant toxicity, defined as myelosuppression, was seen with weekly doses of 300 mg/m2 at or above a 270-minute infusion time. The half-life of gemcitabine is influenced by the length of the infusion [see Clinical Pharmacology (12.3)] and the toxicity appears to be increased if gemcitabine is administered more frequently than once weekly or with infusions longer than 60 minutes [see Warnings and Precautions (5.1)].

17 PATIENT COUNSELING INFORMATION17.1 Low Blood Cell Counts Patients should be adequately informed of the risk of low blood cell counts and instructed

to immediately contact their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur [see Warnings and Precautions (5.2)].

17.2 Pregnancy There are no adequate and well-controlled studies of gemcitabine in pregnant women.

Based on animal studies gemcitabine can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the risks to the fetus need to be discussed with their physician [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)].

Manufactured by:APP Pharmaceuticals, LLC

Schaumburg, IL 60173Manufactured For:

Teva Parenteral Medicines, Inc.Irvine, CA 92618

451249Issued: May 2011


Please see brief summary of prescribing information on adjacent page.

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