C ritical thinking—like the phrase “evidence-

based”—has become a rather overused mantra in clinical medicine. As an unfortunate result, this concept has lost much of its meaning and its impact on how we evaluate study results and ultimately consider their use in the non-trial setting.

Yet the idea can serve as a power-ful counterbalance to those “experts” who suggest they simply know the answer to important clinical

Critical thinking:

Meaningful Responses To ‘We-Know-the-Answer’ Syndrome

San Antonio—A new HER-target-ed antibody, pertuzumab (Omnitarg, Roche), is poised to alter the treatment landscape of patients with HER2-pos-itive metastatic breast cancer (MBC).

Adding pertuzumab to trastuzumab (Herceptin, Genentech) and docetax-el in this patient population improved progression-free survival (PFS) by six months, according to results from the CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) trial. The Phase III, double-blind trial was presented at the recent San Antonio

Pertuzumab: Practice-Changing for HER2+ MBC New antibody makes big splash at SABCS

Don’t be surprised if one of these days a patient with metastatic disease

shows up in your office toting a package from a North Carolina company and asks you to test his or her blood for circulat-ing tumor cells.

In November, the College of American Pathologists accredited North Carolina–based BioCytics for its CTC Enumeration assay using Veridex’s CellSearch and CellTracks platform. Patients can now order their own BioCytics Circulating

Tumor Cell Kit directly from the compa-ny and bring it to their oncologist’s office for a blood draw.

BioCytics is just one of dozens of com-panies putting significant development into assays for circulating tumor cells (CTCs), the isolated cells that have broken off from the main disease site and gone sailing throughout the bloodstream in numbers so small that searching for them invites comparison to counting grains of

San Diego—Transplant-ing growth factor–mobi-lized peripheral blood stem cells (PBSC) rath-er than bone marrow in patients with hematolog-ic malignancies increas-es the risk for chronic graft-versus-host dis-ease (GVHD) without providing a survival advantage, according to a major prospec-tive, multicenter trial.

In the United States, 75% of unrelated donor grafts in adults are now performed using PBSC and the study’s results, presented at the 2011 American Society of Hematology (ASH)

annual meeting, were unexpected. “We should perhaps ask our-

selves whether the shift to greater use of PBSC over the past 10 years is justi-fied in light of these results,” said Claudio

PBSCs Raise Risk For Chronic Graft-Versus-Host DiseaseBone marrow transplants preferable for most patients with unrelated donors

Circulating Tumor Cells: The Ultimate Assay?

see CLEOPATRA, page 22

see STEM CELLS, page 30

see RESPONSES, page 28 see CTC, page 10

FDA NEWS

4 Avastin revoked for breast cancer.

PRN

9 Clinical Conundrums: A quiz for the practicing oncologist.

18 Money for Drugs: Part I of an ongoing series on physicians and the pharmaceutical industry.

HEMATOLOGIC DISEASE

26 Nilotinib durable to 24 months for CML.

29 Oral Arsenic Trioxide as maintenance for APL.

Maurie Markman, MD

SOLID TUMORS

12 Oncologists need longer perspective with breast cancer treatments.

14 Europe pulls ahead of U.S. in colorectal cancer trials.

EDUCATIONAL REVIEW

Therapeutic Advances in Metastatic Colorectal Cancer

Between pages 16 and 17

To order cancer therapeutic

regimens or agents pocket guides,

go to http://www.clinicaloncology.com/

PocketGuides

Rationale and Relevance of Risk Assessment in Advanced Renal Cell Carcinoma: A Review for Community Oncologists

See page 6

FDA News

Erwinase (EUSA Pharma)

approved for acute lymphoblastic

leukemia.

See page 5.

Independent News on Advances in Cancer Care

ClINICAloNColoGy.CoM • January 2012 • Vol. 7, No. 1

Hematology/Oncology Edition

Approved in 3 indications

©2011 Novartis 09/11 AFI-1031818

MCCON472.indd 1 12/16/11 4:28 PM

CliniCal OnCOlOgy news • JanUaRy 2012 3CLINICAL ONCOLOGY NEWS

Solid TumorsBone Metastases

Allan lipton, MD Milton S. Hershey Medical Center, Penn State University Hershey, PA

Breast Cancer

Andrew Seidman, MDMemorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Maura N. Dickler, MDMemorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer

Edward Chu, MDUniversity of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Cathy Eng, MDUniversity of Texas, MD Anderson Cancer Center Houston, TX

leonard Saltz, MDMemorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer and Sarcoma

Ephraim Casper, MDMemorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Genitourinary Cancer

Ronald M. Bukowski, MDTaussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic Cancer

Maurie Markman, MDCancer Treatment Centers of America Philadelphia, PA

Lung, and Head and Neck Cancers

Edward S. Kim, MDUniversity of Texas, MD Anderson Cancer Center Houston, TX

Lung Cancer, Emesis

Richard J. Gralla, MDHofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center Lake Success, NY

Prostate Cancer

Michael A. Carducci, MDAEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD

Hematologic MalignanciesJennifer R. Brown, MD, PhDDana-Farber Cancer Institute, Harvard Medical School Boston, MA

Harry Erba, MD, PhDUniversity of Michigan Ann Arbor, MI

Shaji Kumar, MDMayo Clinic Rochester, MN

Richard Stone, MDDana-Farber Cancer Institute, Harvard Medical School Boston, MA

Community OncologyJohn W. Finnie, MDMercy Medical Center St. Louis, MO

Michael J. Fisch, MD, MPHUniversity of Texas, MD Anderson Cancer Center Houston, TX

Steven Vogl, MDMedical Oncologist New York, NY

Symptom Control and Palliative Care

William S. Breitbart, MDMemorial Sloan-Kettering Cancer Center New York, NY

Steven D. Passik, PhDVanderbilt University Medical Center Nashville, TN

Joseph V. Pergolizzi Jr., MDJohns Hopkins University School of Medicine Baltimore, MD

Russell K. Portenoy, MDBeth Israel Medical Center New York, NY

Charles F. von Gunten, MDUniversity of California, San Diego, CA

Infection Control

Susan K. Seo, MDMemorial Sloan-Kettering Cancer Center New York, NY

Oncology Nursing

Betty Ferrell, RN, PhDCity of Hope National Medical Center Duarte, CA

Pharmacy

Cindy o’Bryant, PharmDUniversity of Colorado Cancer Center Denver, CO

Sara S. Kim, PharmDThe Mount Sinai Medical Center New York, NY

Bioethics

Joseph P. DeMarco, PhDCleveland State University Cleveland, OH

Paul J. Ford, PhDCleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Policy and Management

Mary lou Bowers, MBAThe Pritchard Group Rockville, MD

Rhonda M. Gold, RN, MSNThe Pritchard Group Rockville, MD

EDITORIAL BOARD

Editorial Philosophy

The editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. a significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the asCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published. Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print.

additionally, all news articles that appear in Clinical Oncology news are sent to the sources quoted in each article to review and verify the accuracy of the article’s content.

educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

Mission Statement

The mission of Clinical Oncology News is to be an independent source of unbiased, accurate and reliable news combined with in-depth expert analysis about the

issues that oncologists and hematologists care about most. we strive to be a valuable source for oncologists and hematologists in providing the best possible care for their patients.

The move by FDA Commissioner Margaret Hamburg, MD, was

widely expected after the agency’s Oncologic Drugs Advisory Committee (ODAC) voted unanimously to with-draw the approved indication during a two-day hearing in June. (See “What Happened at the FDA Avastin Meet-ing?”, Clinical Oncology News August 2011, page 6, for complete coverage.)

Dr. Hamburg outlined her decision in a 69-page report. The principal rea-son, she said, was that the confirmato-ry studies by the drug’s manufactur-er, Genentech, did not demonstrate a clinical benefit for patients with met-astatic breast cancer (MBC) and that in light of this, the drug’s risks were too severe. The risks included high

blood pressure, bleeding and hemor-rhaging, heart attack or heart failure and development of a variety of tissue perforations.

“It is clear that women who take Avas-tin for MBC risk potentially life-threat-ening side effects without proof that the use of Avastin will provide a benefit,”

Dr. Hamburg said in a statement.The drug was approved for MBC in

February 2008 under the FDA’s accel-erated drug approval program, which provides patients access to a drug

while confirmatory clinical trials are being completed. Following submis-sion of this additional data in 2009 and 2010, ODAC voted, in July 2010, to remove the MBC indication for Avas-tin, based in part on presentations by the FDA’s Center for Drug Evaluation and Research. Genentech requested

a hearing to dispute the withdrawal. The hearing was held in late June, at which time ODAC unanimously agreed that Avastin did not demonstrate clin-ical benefits for patients and that the

risk–benefit profile was unacceptable.Following the hearing, Dr. Ham-

burg made her final decision as FDA commissioner and accepted ODAC’s recommendations.

Genentech has indicated it will be starting a new clinical trial of Avastin plus paclitaxel to identify a potential

biomarker for a subset of patients with MBC who might benefit more signifi-cantly from the drug.

—Gabriel Miller

Avastin Breast Cancer Indication RevokedFDA commissioner cites safety concerns, no clinical benefit

The FDA revoked Avastin’s indication for breast cancer on Nov. 18.

Letter From the Editors

Dear Reader:

This issue of Clinical Oncology News

heralds the arrival of two new

editors—group Publication editor

Kevin Horty and Managing editor

gabriel Miller.

as the editors responsible for the stra-

tegic vision and day-to-day operation

of the magazine, respectively, we plan

to make Clinical Oncology News the

best-read publication in oncology and

hematology.

we are planning to develop Clinical Oncology News in a number of ways.

while Clinical Oncology News will always

provide timely coverage of important

research at national meetings, we will be

adding more in-depth coverage of issues

outside of clinical research that really

matter to you and the treatment of your

patients. we want Clinical Oncology News to be a voice for oncologists and

hematologists from all walks of medi-

cine, from the large academic center to

the solo practitioner.

we also are adding a forum for discus-

sion and debate of controversial issues

in the field, which kicks off in this issue

with the first of a three-part series on

the relationship between trial investi-

gators and pharmaceutical companies.

(see “Money for Drugs,” page 18.)

we also plan to grow the magazine’s

digital presence significantly. Oncol-

ogy and hematology are among the fast-

est moving specialties in medicine, with

constant updates and advances in clin-

ical care, and oncologists and hematol-

ogists are among the most widely read

and digitally savvy physicians. we plan

to make Clinical Oncology News more

accessible via smartphones and social

media as well as expand on important

issues being discussed in the magazine

through online forums.

we also plan to broaden our coverage

of the shifting health policy and prac-

tice management landscape affecting

all physicians. as a profession, medicine

is facing the most significant changes in

decades. From the top down, the fed-

eral government and insurance pay-

ers are dictating change in a number of

far-reaching ways; from the bottom up,

a new generation of physicians is chal-

lenging old notions about the profes-

sion, as well as adapting to changes in

the business environment in new and

exciting ways.

Most importantly, we want to hear

from you. Reader feedback is the

lifeblood of Clinical Oncology News and

reader comments are the best way for

us to improve and adapt as a magazine.

we always welcome comments and

feedback from readers and may be

reached at khorty@mcmahonmed.com

and gmiller@mcmahonmed.com.

sincerely,

Kevin Horty and gabriel Miller

‘It is clear that women who take Avastin for metastatic breast cancer risk

potentially life-threatening side effects without proof that the use

of Avastin will provide a benefit.’

—FDA Commissioner Margaret Hamburg, MD

Kevin Horty, Group Publication Editor

Gabriel Miller, Managing Editor

4 CliniCal OnCOlOgy news • JanUaRy 2012

McMahon Publishing is a 40-year-old, family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications.

Clinical Oncology news (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Copyright© 2012 McMahon Publishing, New York, NY. All rights reserved.

POSTMASTER: Please send address changes to Clinical Oncology news, 545 W. 45th St., 8th Floor, New York, NY 10036.

www.mcmahonmed.com

Editorial Staff

Kevin Horty, Group Publication Editor khorty@mcmahonmed.com

Gabriel Miller, Managing Editor gmiller@mcmahonmed.com

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

James Prudden, Group Editorial Director

David Bronstein, Editorial Director

Robin B. Weisberg, Manager, Editorial Services

Elizabeth Zhong, Associate Copy Chief

SalES Staff

Julianna Dawson, Publication Director jdawson@mcmahonmed.com

Marlena McMahon, Associate Publication Director marlena@mcmahonmed.com

Jessica Pichardo, Junior Account Manager jpichardo@mcmahonmed.com

Nancy Parker, Executive Manager/Classified Advertising, nparker@mcmahonmed.com

art and Production Staff

Michele McMahon Velle, Creative Director, MAX Graphics

Frank Tagarello, Senior Art Director/ Managing Director, MAX Graphics

Dan Radebaugh, Director of Production and Technical operations

Brandy Wilson, Circulation Coordinator

Mark Neufeld, Associate Director, Project Management

McMahon PubliShing

Raymond E. McMahon, Publisher & CEo, Managing Partner

Van Velle, President, Partner

Matthew McMahon, General Manager, Partner

lauren Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

CLINICAL ONCOLOGY NEWS

SOLID TUMORS

Breast

TM

Asparaginase and pegaspargase are both commonly used as part of remis-sion induction regimens in patients with ALL. However, about 15% to 20% of these patients develop hypersensitivity to E. coli–derived asparaginase, according to EUSA Pharma, the drug’s manufacturer. Erwinia chrysanthemi is a close relative of E. coli, but the asparaginase enzyme produced by Erwinia chrysanthemi is

immunologically distinct.ALL cells are unable to synthesize

the asparagine; by removing aspara-gine from the bloodstream, asparaginase inhibits the growth of ALL cells.

Normal cells produce enough aspara-gine through biosynthesis and are not af- fected by Erwinase, according to the FDA.

The agency approved the drug based on a clinical trial in 58 patients. The

trial measured patients’ sustained asparaginase activity levels, an end point correlating with bet-ter leukemia control and survival. At 48 to 72 hours after dosing, all 58 patients had reached the prespecified end point, the FDA said.

Erwinase is injected directly into the

muscle three times a week. Side effects of the drug include ana-

phylaxis, pancreatitis, and abnormal trans-aminases, coagulation

abnormalities includ-ing thrombosis and hem-

orrhage, nausea, vomiting and hyperglycemia.

The drug was approved via the FDA’s program for orphan drugs; approx-imately 450 to 600 children in the United States each year will likely ben-efit from the approval, according to EUSA Pharma.

Erwinase Approved for Acute Lymphoblastic LeukemiaErwinase (asparaginase Erwinia chrysanthemi) has been approved by the FDA for patients with acute lymphoblastic leukemia (ALL) who develop an allergy to Escherichia coli–derived asparaginase and pegaspargase chemotherapy drugs.

From Lancet Oncology

Sequential administration of the cyto-toxic agents fluorouracil (5-FU),

leucovorin (LV), oxaliplatin (Eloxa-tin, Sanofi-aventis) and irinotecan in the treatment of advanced colorectal cancer (CRC) has similar efficacy, and less toxicity, than front-loaded combi-nation therapy using the same drugs, a new study has revealed.

This Phase III study (Lancet Oncol 2011;12:1032-1044, PMID: 21903473), conducted by a French team headed by Michel Ducreux, MD, was designed to determine the optimum use of cytotoxic agents in the treatment of advanced CRC, a disease for which prognosis has typically been poor. Historically, ther-apies have focused not on cure but rather on extending life, with mixed

results—although this may change with the recent introduction of new options, including bevacizumab (Avas-tin, Genentech).

For this open-label trial, 410 patients were randomized to receive either sequential therapy (n=205)—which included first-line treatment with bolus (400 mg/m2) and infusional (2,400 mg/m2) 5-FU plus leucovorin (400 mg/m2) (simplified LV5FU2 regimen), sec-ond-line LV5FU2 plus oxaliplatin (100 mg/m2) (FOLFOX6) and third-line LV5FU2 plus irinotecan (180 mg/m2) (FOLFIRI)—or combination therapy (n=205) with first-line FOLFOX6 and second-line FOLFIRI regimens. Che-motherapy was administered every two weeks; second- and third-line thera-pies were administered only if patients were deemed suitably fit based on World

Health Organization (WHO) criteria. The study was funded by Sanofi-aventis, which manufactures oxaliplatin.

Efficacy was similar in both treat-ment groups. Median progression-free survival (PFS; the primary end point) was 10.5 months in the sequential ther-apy group and 10.3 months in the com-bination-therapy group. Additionally, 161 patients in each group (79%) died during the course of the study. How-ever, all six of the deaths attributed to the toxic effects of treatment were reported in the combination group. During first-line chemotherapy, sig-nificantly fewer severe (grade 3 or 4) hematologic adverse events (AEs) occurred in the sequential group than in the combination group (12 vs 83; P<0.0001). Similarly, there also were fewer non-hematologic AEs reported

in the sequential group compared with the combination-therapy group (26 vs 186; P<0.0001).

The authors concluded that “the sur-vival benefit recorded with combina-tion chemotherapy in previous Phase III studies might have been overes-timated because of the insufficient use of salvage treatments in the con-trol group.” They also acknowledged the approval of bevacizumab for the treatment of advanced CRC indirectly presented a limitation to their study, in that it forced them to halt patient enrollment prematurely at 410 as a result of a lack of volunteers. Nonethe-less, the study did suggest that a less-intensive first-line chemotherapeutic regimen does not impart a reduction in survival and should be an option for patients.

Less Toxicity, Similar Efficacy for Sequential CRC Therapy

Colorectal cancer is a major public health problem, with nearly 800,000 new cases diagnosed each year, result-ing in approximately 500,000 deaths. In the United States, it is the sec-ond leading cause of cancer mortali-ty, with nearly 60,000 deaths annually. When diagnosed as an advanced, met-astatic disease, CRC is associated with five-year survival rates in the range of 5% to 8%; the actual survival rate has

remained unchanged over the past 35 to 40 years. However, during the past five years, significant advances have been made in chemotherapy treat-ment options, such that improvements in two-year survival are now being reported, with median survival of 21 to 24 months in patients with metastat-ic disease.

Chemotherapy has been the main-stay approach for patients with advanced CRC. For more than 40 years, the main drug has been 5-FU. In general, the clinical efficacy of 5-FU as monotherapy has been modest, with overall response rates (RRs) at 10% to 15% and median overall survival (OS) on the order of six to eight months. Over the past 10 years, significant advances have been made with respect to the approval of more anticancer agents for metastatic CRC, including irinotecan, oxaliplatin and the oral

fluoropyrimidine capecitabine. Addi-tionally, three novel biologic agents were approved by the FDA: the anti–epidermal growth factor receptor anti-bodies cetuximab and panitumum-ab, and the anti–vascular endothelial growth factor bevacizumab.

When combined with 5-FU/leucovo-rin (LV), both irinotecan and oxalipla-tin have shown significantly improved RRs, time-to-tumor progression and median survival. When combined with 5-FU/LV, 5-FU/LV plus irinotecan (i.e., IFL) or oxaliplatin-based chemother-apy, bevacizumab has shown marked-ly improved RRs and OS when used as first-line therapy for metastatic CRC. Cetuximab alone or in combination with chemotherapy and panitumum-ab alone are presently approved for refractory disease, but recent clini-cal studies have demonstrated impres-sive activity when combined with

chemotherapy in the first-line setting.1

In the present study, Ducreux et al investigate the difference in sequen-tial versus combination administra-tion of the same drugs in patients with advanced CRC. The researchers per-formed an open-label, randomized, Phase III trial that assigned patients (in a 1:1 ratio) with advanced, measur-able, nonresectable CRC and WHO performance status of 0 to 2. The pri-mary end point was PFS after two lines of treatment. Analyses were by inten-tion to treat.2

Sequential therapy was adminis-tered to 205 patients, while the com-bination treatment was administered to another 205. The authors concluded that the use of up-front combination chemotherapy is more toxic and is no more effective than the sequential use of the same cytotoxic drugs in patients

see CRC, page 20

Wasif Saif, MDProfessor of Clinical MedicineColumbia University College of Physicians and SurgeonsMedical Director, Pancreas Center NewYork-Presbyterian/Columbia

EXPERT INSIGHT

CliniCal OnCOlOgy news • JanUaRy 2012 5SOLID TUMORS

Colorectal

Myelofibrosis/Leukemia

HEMATOLOGIC DISEASE

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

6 CLINICAL ONCOLOGY NEWS • JANUARY 2012

Rationale and Relevance of Risk Assessment in Advanced Renal Cell Carcinoma:A Review for Community Oncologists

IntroductionIn 2010, cancer involving the kidney

afflicted more than 58,000 patients in the United States and resulted in more than 13,000 deaths.1 Most of these patients had renal cell carcinoma (RCC) of the clear cell type and were diagnosed with localized disease.2 Although surgical resection can be curative for localized disease, a risk for recurrence and distant spread is present with all stages of localized disease. Once RCC has metastasized it is considered incurable for the vast majority of patients3; however, several systemic agents that can affect clinical outcomes have been intro-duced during the past 5 years.2,4-8

Several risk-scoring systems have been formulated to help determine prognosis for patients who have developed metastatic dis-ease. These validated risk measurement tools are important for the community oncologist to employ since they can aid with prognos-tic discussions and may help formulate treat-ment decisions. In the case of metastatic RCC, community oncologists should be mindful of the fact that performance status is just one factor in assessing risk; in addition, age is not a prognostic factor and should not alter treat-ment options when considered by itself. A discussion of various criteria and prognostic factors is offered below, as well as ways to incorporate them into routine clinical prac-tice in the community setting.

Evaluating PrognosisIn Metastatic RCC

Prognostic Risk Factors Based On Memorial Sloan-Kettering Cancer Center Data

Despite many recent additions to the therapeutic armamentarium for metastatic

RCC, the development of this stage of the disease is almost uniformly fatal. However, patients with metastatic RCC can fol-low a variety of clinical paths, with some patients receiving single or multiple treat-ment courses, or even none at all. A set of prognostic risk factors based on data from Memorial Sloan-Kettering Cancer Center (MSKCC) was developed to help determine the prognosis of subsets of metastatic RCC patients and to aid in patient selection for clinical trials.9 These original MSKCC data identified patient factors that contribute to outcome, such as elevated lactate dehydro-genase (LDH; >1.5 x upper limit of normal), elevated corrected calcium (>10 mg/dL), poor performance status (Karnofsky Per-formance Status <80%), anemia (below lower limit of normal), and absence of prior nephrectomy.9 If present at initial diagno-sis, these factors each held negative prog-nostic significance. Patients with no risk factors were deemed to have good risk, 1 to 2 risk factors have intermediate risk, and 3 or more risk factors indicate poor risk.9

Median survival for patients with good-, intermediate-, and poor-risk RCC was 19.9, 10.3, and 3.9 months, respectively.9

After the original MSKCC data were published, 2 Phase III randomized trials highlighted the importance of primary tumor removal (debulking nephrectomy) in the outcomes of patients with sys-temic therapy.10,11 A longer survival time in patients after undergoing nephrectomy was found to be linked to a disease-free interval in those patients who had under-gone surgical resection for a localized tumor and then had relapsed. This prompted a review of the model of prognostic assess-ment from the original MSKCC data, with the presumption that most patients would undergo debulking nephrectomy prior to systemic interferon or other cytokine ther-apy.12 This led to a revised set of prognos-tic risk factors, commonly referred to as the Motzer criteria, which included ele-vated LDH; elevated calcium; anemia; poor performance status; and an interval of less than one year from initial RCC diagnosis to initiation of systemic therapy.12 With these updated criteria, patients in good-, inter-mediate-, and poor-risk categories had 29.6, 13.8, and 4.9 months median survival with interferon systemic therapy.12

External validation of these extended criteria was performed by Mekhail et al at the Cleveland Clinic Foundation, in which all risk factors held up under multivariate analysis with one exception: performance status.13 Additionally, 2 other prognostic

risk factors were found to be significant: number of sites of metastasis (≥2), and history of radiotherapy (Table).13

Clinical Application of Motzer And Mekhail Criteria

Although the Motzer criteria and the extended Mekhail criteria were devel-oped in the cytokine era, the pivotal Phase III trials evaluating vascular endothelial growth factor (VEGF) and mammalian tar-get of rapamycin (mTOR) inhibitors used one of these risk assessment schema in selecting patients for enrollment in their clinical trials.4-7 Most trials limited enroll-ment to patients with good or interme-diate risk, as per these criteria. Based on Phase III trial data, level 1 evidence exists for use of targeted therapeutics in certain RCC patients depending on their risk status and history of prior therapies; however, the optimal sequence and drug selection for patients remain to be defined.14 Patients with metastatic clear cell RCC and ade-quate organ function can be considered for high-dose interleukin-2 therapy, although in a recent prospective multicenter study no single pretreatment clinical factor was associated with improved outcome.15

The recently approved VEGF or

mTOR-targeted agents were almost exclu-sively studied in the clear cell RCC popula-tion in their registrational trials.2 However, data have been collected on non–clear cell RCC patients showing some activity for both classes of agents in this popula-tion.16-18 However, these patients should still be referred to a clinical trial when possi-ble since the optimal management of non–clear cell RCC remains to be defined.

Other Features Commonly Considered in RCC Management

In another evaluation of prognostic fac-tors that correlate with survival, Heng and colleagues examined the outcomes of 645 patients treated with VEGF pathway inhibi-tors.19 In this study, 4 prognostic risk fac-tors based on the published MSKCC data were found to be associated with poorer outcomes: anemia, hypercalcemia, elevated LDH, and performance status. In addition, neutrophilia (> upper limit of normal) and thrombophilia (> upper limit of normal) also were found to be important prognostic risk factors.19 Although neutrophilia and throm-bophilia may be signs of more aggressive disease, currently these findings should not affect treatment decision-making as they have not been prospectively validated.

C. Lance Cowey, MD

Genitourinary Oncology and Melanoma ProgramsBaylor Charles A. Sammons Cancer CenterTexas Oncology, PADallas, Texas

Thomas E. Hutson, DO, PharmD

Director, Genitourinary Oncology ProgramProfessor of Medicine and Co-Chair, GU ResearchUS OncologyBaylor Charles A. Sammons Cancer CenterTexas Oncology, PADallas, Texas

TABLE. Prognostic Factors Among Validated Prognostic Scoring Systems for Metastatic RCC

Original Published MSKCC Data

Modified MSKCC (Motzer Criteria)

Extended Criteria (Mekhail)

Karnofsky Performance Status score (<80)

X X

Corrected calcium (>10 mg/dL) X X X

LDH level (>1.5 times upper limit of normal)

X X X

Hemoglobin level (<lower limit of normal)

X X X

Absence of prior nephrectomy X

Time from diagnosis to systemic Rx (<1 year)

X X

Sites of metastasis (≥2) X

History of radiotherapy X

LDH, lactate dehydrogenase; MSKCC, Memorial Sloan-Kettering Cancer Center; RCC, renal cell carcinoma

Based on references 9, 12, and 13.

CLINICAL ONCOLOGY NEWS • JANUARY 2012 7

Supported by

Implementing Risk Assessment In the Community Setting

Prognostic risk scoring, specifically with the validated Motzer criteria, should play an important role in the medical oncolo-gist’s evaluation of patients with meta-static RCC. It is important to recognize that patients were selected for the recent Phase III trials based on this prognostic scoring system and it still applies to patients today. The Motzer risk scoring evaluation is simple and consists of laboratory assessment—including measurement of complete blood cell count (CBC), LDH, and serum calcium—and a clinical history to assess performance status, nephrectomy status, and interval from diagnosis to initiation of systemic therapy. These assessments should be con-sidered standard of care, so fortunately no additional costs are incurred.

It is important to recognize that using performance status alone does not equate to a proper assessment in terms of prognos-tic impact. Each finding (low hemoglobin, elevated LDH, elevated calcium, poor per-formance status, time from diagnosis to sys-temic therapy <12 months) is assigned one point in the Motzer risk factor scoring sys-tem, with zero total risk factors considered good risk, 1 or 2 total risk factors considered intermediate risk, and 3 or more total risk factors considered poor risk.

As with any clinical risk score, comfort

comes with frequency of clinical use. Prac-tical employment of clinical risk evaluation may include memorization of the risk scor-ing system, creation of a clinical worksheet for nursing staff to help complete, or use of an online tool. After receiving a proper risk assessment, patients can then get appro-priate therapy for their metastatic RCC.

ConclusionThe prognostic risk factors based on the

Motzer criteria and the extended criteria (the Mekhail criteria) remain clinically rel-evant in the modern era of targeted ther-apies. These risk factors include anemia, hypercalcemia, elevated LDH, poor perfor-mance status, and time from nephrectomy to initiation of systemic therapy within 12 months. Additionally, the number of sites of metastasis and absence of nephrectomy may also be prognostic risk factors. Also of clinical interest are histology and a review of comorbidities, outlined in the sidebar.

Regularly using these risk factors helps determine the clinical course and is a use-ful guide to the art of drug selection for these patients. Although level 1 evidence exists for the management of patients with good or intermediate prognostic risk fac-tors as well as those with poor prognostic risk, many treatment options are available and optimal sequencing of agents is still being determined.

Proper risk evaluation in the community

setting is simple: It should include patient history, including comorbidities, and physi-cal exam; laboratory assessment, including CBC, LDH, and calcium; and radiographic evaluation—such as CT imaging—to assess for location of metastatic sites. Physicians should also take into account RCC histology, as the clinical course can vary given the par-ticular histologic subtype.

Performance status is, by itself, never a surrogate for a formal risk assessment. Patients should be considered for cytore-ductive nephrectomy when appropriate, given the available data supporting improved outcomes with systemic therapy. And finally, proper risk factor assessment is important for clinical studies, which must be undertaken in order to continue to improve clinical outcomes in RCC.

AcknowledgmentsThis review was developed under the

direction of Drs. Cowey and Hutson, with support from Pfizer Inc.

References1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics,

2010. CA Cancer J Clin. 2010;60(5):277-300.

2. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271-2281.

3. Bracarda S. Metastatic renal cell carcinoma: pathogenesis and the current medical landscape. Euro Urol Suppl. 2009;8(10):787-792.

4. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125-134.

5. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115-124.

6. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449-456.

7. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treat-ment of metastatic renal cell carcinoma: a ran-domised, double-blind phase III trial. Lancet. 2007;370(9605):2103-2111.

8. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carci-noma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061-1068.

9. Motzer RJ, Mazumdar M, Bacik J, Berg W, Amster-dam A, Ferrara J. Survival and prognostic strati-fication of 670 patients with advanced renal cell carcinoma. J Clin Oncol. 1999;17(8):2530-2540.

10. Flanigan RC, Salmon SE, Blumenstein BA, et al.Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345(23):1655-1659.

11. Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R. Radical nephrectomy plus inter-feron-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001; 358(9286):966-970.

12. Motzer RJ, Bacik J, Murphy BA, Russo P, Mazum-dar M. Interferon-alfa as a comparative treat-ment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002; 20(1):289-296.

13. Mekhail TM, Abou-Jawde RM, Boumerhi G, et al. Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol. 2005;23(4):832-841.

14. Hudes GR, Carducci MA, Choueiri TK, et al. NCCN Task Force report: optimizing treatment of advanced renal cell carcinoma with molecular tar-geted therapy. J Natl Compr Canc Netw. 2011;9 (suppl 1):S1-S29.

15. McDermott DF, Ghebremichael MS, Signoretti S, et al. The high-dose aldesleukin (HD IL-2) “SELECT” trial in patients with metastatic renal cell car-cinoma (mRCC). J Clin Oncol. 2010;28(suppl 1): Abstract 4514.

16. Choueiri TK, Plantade A, Elson P, et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol. 2008;26(1):127-131.

17. Gore ME, Szczylik C, Porta C, et al. Safety and effi-cacy of sunitinib for metastatic renal-cell carci-noma: an expanded-access trial. Lancet Oncol. 2009;10(8):757-763.

18. Molina AM, Feldman DR, Ginsberg MS, et al. Phase II trial of sunitinib in patients with metastatic non-clear cell renal cell carcinoma. Invest New Drugs. 2010. [Epub ahead of print]

19. Heng DY, Xie W, Regan MM, et al. Prognostic fac-tors for overall survival in patients with meta-static renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009; 27(34):5794-5799. BB

1130

Additional Clinical ConsiderationsHistology

While the Motzer criteria were designed for clear cell RCC patients,1 it is important to note that the histologic subtype of RCC also plays an important role in risk assessment. RCC is a het-erogeneous group of tumors with different genetic defects and clinical courses. The most common RCC subtype is clear cell RCC, which makes up 75% to 80% of cases. Non–clear cell papillary RCC (types 1 and 2) make up the next most common type, occur-ring in about 15% to 20% of RCC cases, with the papillary type 2 variant having a more aggressive course than type 1. Chromo-phobe RCC accounts for about 5% of all cases and has an excel-lent prognosis. Less common are renal oncocytoma (benign neoplasms) and renal medullary carcinoma (very aggressive). Although renal pelvis carcinoma is often lumped in with RCC in epidemiologic tabulations, these cancers are more histologi-cally similar to urothelial cell carcinomas, such as bladder cancer.

Several studies have shown that clear cell RCCs portend a slightly worse outcome for patients than non–clear cell RCCs.2,3 Sarcomatoid dedifferentiation (which can occur in any histologic subtype), medullary, and Xp11.2 translocation carcinomas all tend to have the worst outcomes.4

ComorbiditiesAlthough it is logical to consider comorbidities when plan-

ning treatment, no specific comorbidities have been associated with prognosis. While VEGF inhibitors can cause hypertension and cardiac-related events, and mTOR inhibitors can lead to hyperglycemia and hyperlipidemia, these agents may safely be administered to patients with these pre-existing conditions in conjunction with careful monitoring and vigilant side-effect management.

References1. Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a

comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20(1):289-296.

2. Teloken PE, Thompson RH, Tickoo SK, et al. Prognostic impact of histological subtype on surgically treated localized renal cell carcinoma. J Urol. 2009; 182(5):2132-2136.

3. Leibovich BC, Lohse CM, Crispen PL, et al. Histological subtype is an independent predictor of outcome for patients with renal cell carcinoma. J Urol. 2010;183(4):1309-1315.

4. Prasad SR, Humphrey PA, Catena JR, et al. Common and uncommon histologic subtypes of renal cell carcinoma: imaging spectrum with pathologic correlation. Radiographics. 2006;26(6):1795-1806; discussion 1806-1810.

From Lancet Oncology

Polymorphisms in the genes VEGFR3 and CYP3A5*1 may influence the

pharmacodynamics and pharmacokinet-ics, respectively, of the tyrosine kinase inhibitor sunitinib (Sutent, Pfizer) and thus affect its efficacy and safety in the treatment of renal cell carcinoma (RCC), a new study has found.

The observational, prospective study by Jesus Garcia-Donas, MD, and col-leagues, which was published in Lancet Oncology (2011;12:1143-1150, PMID: 22015057), sought to identify potential biomarkers that can be used to predict treatment failure in adults with clear cell RCC prior to the initiation of first-line therapy. Earlier studies already

demonstrated that the study drug suni-tinib is generally safe and effective in the treatment of RCC; however, the drug has been found to be ineffective as first-line therapy in as many as 20% of patients who develop early progression of disease. Given other options avail-able for the treatment of kidney cancer as well as novel agents in development, the identification of potential predic-tors for treatment response is seen as crucial to the success of first-line suni-tinib therapy.

The study, which was funded by Pfizer, enrolled 101 treatment-naive adult patients with clear cell RCC from 15 hospital centers belonging to the Spanish Oncology Genitourinary Group in Spain. Patients in the study received

treatment with sunitinib according to currently accepted European guide-lines and were assessed for RECIST (Response Evaluation Criteria in Solid Tumors), progression-free survival (PFS), overall survival and drug tox-icity as well as for the presence of one or more of 16 previously identi-fied single nucleotide polymorphisms (SNPs) involving nine genes: VEGFR2 (rs2305948 and rs1870377), VEGFR3 (rs307826, rs448012 and rs307821), PDGFR-α (rs35597368), VEGF-A (rs2010963, rs699947 and rs1570360), IL8 (rs1126647), CYP3A4 (rs2740574), CYP3A5 (rs776746), ABCB1 (rs1045642, rs1128503 and rs2032582) and ABCB2 (rs2231142). In all, 95 patients enrolled in the study were eligible for inclusion

in the toxicity analyses; 89 were eligible for the efficacy analyses.

Among these patients, the authors found that two VEGFR3 missense poly-morphisms—rs307826 and rs307821—were associated with reduced PFS in patients receiving sunitinib, and that patients who possessed the CYP3A5*1 (rs776746) high-metabolizing allele required dose reductions (from the rec-ommended starting dose of 50 mg per day for four weeks, followed by two weeks off ) as a result of toxic effects.

The authors concluded that their findings highlight the potential use of these SNPs in the identification of RCC patients who might benefit from alter-native therapies to sunitinib, but further study of these biomarkers is needed.

Polymorphisms Affecting First-Line Sunitinib RCC Therapy Identified

Responses to the same anti-tumor therapy vary widely from patient to patient: Some tumors respond, oth-ers are insensitive; some patients develop toxicity, others do not. Some of these differences may be stochas-tic and unpredictable. Nonetheless, the fundamental premise of person-alized therapy holds that we will one day learn to select therapy based on the patient’s characteristics. Differ-ences in efficacy are easier to explain: Each tumor has a distinct origin and mutation profile. However, to

look for predictors of toxicity, one has to examine normal tissue char-acteristics, such as germline poly-morphisms, and in particular those that result in amino acid changes or altered protein levels. Even predic-tors of efficacy can be gleaned from studying germline polymorphisms, when the agent in question targets tumor stroma rather than malignant tumor cells.

For this reason, Garcia-Donas and colleagues examined germline poly-morphisms, rather than tumor genetic makeup, to identify predictors of effi-cacy and toxicity in patients receiv-ing sunitinib as first-line therapy for advanced clear cell RCC. Remark-ably for a relatively small study, can-didate predictors of both efficacy and toxicity were identified. How-ever the search for predictive mark-ers is fraught with challenges, as this study illustrates, and as is outlined in an accompanying editorial.

First, if a marker correlates with

survival, as the authors show for two VEGFR3 polymorphisms, it could be due to either differential benefit from sunitinib or difference in baseline dis-ease characteristics, or both. This is impossible to discern without a con-trol arm. In contrast, predictors of objective response can be identified in a single-arm study (although none reached significance in this study), but tumor shrinkage is a poor surro-gate for overall benefit.

Second, the more candidate mark-ers one begins with, even prospective-ly defined (as this study has done), the more will seem predictive by chance alone. Various statistical methods exist to adjust for this problem, the Bonferroni correction—used in this study—being one of them. But none is perfect, and there is no substitute for retesting in another population, espe-cially before adopting a marker for clinical use.

Third, a unique challenge in the analysis of polymorphisms is linkage

disequilibrium. Our genes are a stack of cards that has not been well shuf-fled, and some alleles stay togeth-er for generations. In this study, two VEGFR3 SNPs turned out to be in disequilibrium (i.e., often seen together), making it difficult to see which is the predictor and which is the bystander. Or could it be another SNP nearby?

Fourth, how does a SNP predict tox-icity? Is it by increasing drug levels or making tissues more susceptible or both? In this study, for example, a CYP3A5 polymorphism was predictive for needing a dose reduction. Pharma-cokinetic assessments are necessary to distinguish these possibilities, but were not performed in this study.

Despite the challenges, the study is provocative in demonstrating that perhaps someday genetic testing not just of the tumor, but also of a germ-line sample, will help us select the most effective and least toxic therapy for our patients.

Let Us Visit Your Practice Please consider inviting the staff of Clinical Oncology News to visit your practice.

We want to meet you and your colleagues, listen to your concerns, and observe the physical site of your practice.

You can help us improve Clinical Oncology News and fulfill our mission—to provide evidence-based, clinically relevant information that you can use to benefit

your patients and practice.

If you are interested, please contact Gabriel Miller, managing editor, at (212) 957-5300 ext. 265 or via e-mail at gmiller@mcmahonmed.com

Alex Morozov, MD, PhDInstructor of MedicineWeill Cornell Medical CollegeAssistant Attending PhysicianNewYork-Presbyterian/ Weill CornellSenior Medical Director ImClone Systems Bridgewater, NJ

EXPERT INSIGHT

8 CliniCal OnCOlOgy news • JanUaRy 2012SOLID TUMORS

Renal

QUESTIONS

1. A 35-year-old man presents with three weeks of cough and a

right testicular mass. The laboratory data demonstrate lactate dehydroge-nase (LDH) of 600, human chorionic gonadotropin (hCG) of 5,000 mIu/mL and normal alpha-fetoprotein (AFP). Computed tomography scans show a 5-cm retroperitoneal mass and multi-ple pulmonary nodules. Brain magnet-ic resonance imaging and bone scans are unremarkable. Lung biopsy is con-sistent with a diagnosis of semino-ma. According to International Germ Cell Cancer Collaborative Group (IGCCCG) classification, this patient belongs to which of the following risk categories?a. Good prognosisb. Intermediate prognosisc. Poor prognosis

2. Which of the following is the best treatment strategy for the patient

described in Question 1?a. Three cycles of bleomycin, etoposide

and cisplatin (BEP)b. Four cycles of BEPc. Three cycles of etoposide and

cisplatin (EP)

3. All of the following statements about serologic tumor markers in

germ cell tumors are correct except:a. hCG can be elevated in both semino-

ma and non-seminoma.b. AFP levels can be elevated in

non-seminoma.c. The half-life of hCG is

approximately five to seven days.d. The half-life of AFP is approximately

five to seven days.

e. Use of marijuana can cause a spurious rise in hCG.

4. All of the following statements about germ

cell tumors are true except:a. Family history confers a four- to

10-fold increase in risk. b. Testicular seminoma occurs with

an increased frequency in men with HIV.

c. The incidence is decreasing worldwide.

d. Primary mediastinal germ cell tumors are not associated with tes-ticular involvement.

e. In a good majority of patients, the therapeutic objective is cure, which requires an integrated multidisci-plinary approach.

5. All of the following diseases and chromosomes are related except:

a. Von Hippel-Lindau (VHL) disease and chromosome 3

b. Germ cell tumor and chromosome 13

c. Li-Fraumeni syndrome and chromo-some 17

d. Ataxia-telangiectasia and chromo-some 11

6. A 54-year-old man is started on a cisplatin and etoposide regimen

for extensive-stage small cell lung can-cer. Unfortunately, following comple-tion of day 1 IV therapy, a family emer-gency requires his immediate presence out of state for four days. He is motivat-ed to continue therapy but has to depart for an airline flight in a few hours. What would be the best management strategy for this patient?a. He will have to make a choice

between staying to complete IV ther-apy for the next two days or leave without further therapy and return in three weeks for cycle 2.

b. Commence oral etoposide at a dose twice the IV formulation for the next two days.

c. Commence oral etoposide at a dose similar to the IV formulation for the next two days.

d. Commence oral etoposide at a dose similar to the IV formulation for the next four days.

7. A 35-year-old woman is diagnosed with stage III rectal cancer. She is

an only child and has one child who is 5 years old. She denies family histo-ry for any cancers. Her oncologist rec-ommends genetic testing for hereditary nonpolyposis colon cancer (HNPCC).

Which of the following statements about testing for HNPCC in this patient is correct?a. The patient is offered the test

because she meets the revised Amsterdam criteria.

b. The patient is offered the test because she meets the revised Bethesda criteria.

c. All of the above.

8. True or false: The HNPCC-relat-ed tumors include but are not lim-

ited to colorectal, ovarian and endome-trial cancers.a. Trueb. False

9. True or false: A screening test is considered beneficial if it is able to

detect a large number of patients with a specific cancer at a very early stage.a. Trueb. False

10.One hundred patients are screened for cancer using a newly

developed test with the following results:• four results are truly positive• two results are falsely positive• two results are falsely negative• 90 results are truly negativeWhich of the following formulas is used to determine the specificity of the test?a. 90 divided by (2 + 90)b. 8 divided by (90 + 2)c. 90 divided by (90 + 4)d. 8 divided by (8 + 2)

Clinical ConundrumsA quiz for the community oncologist

Not receiving Clinical Oncology News? Like to?Clinical Oncology News is distributed free of charge to selected oncology physicians. We use addresses provided by the AMA and AOA.

You don’t need to be a member of these organizations, but they need to have your address and specialty information. To be sure this information is up-to-date, please call the AMA at (800) 262-3211 or AOA at (800) 621-1773. You can tell them whether you prefer to have Clinical Oncology News mailed to you at your office or at home.

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Independent News for the Oncologist and Hematologist/Oncologist

see CONUNDRUMS, page 11

Prepared by

Syed A. Abutalib, MD

assistant Director Hematology & stem Cell

Transplantation Program

Cancer Treatment Centers of america

Zion, illinois

CliniCal OnCOlOgy news • JanUaRy 2012 9PRN

Community Oncology

‘You have to wait a couple

of months to see changes on CT.

Using circulating tumor cells, we have the

potential to make the call earlier and prevent

longer durations of therapies that are not effective and

instead switch to something that is more effective.’

–David Tsai Ting, MD

sand on a beach.To date, there’s only one assay

approved for clinical use in actual-ly determining a prognosis for cancer patients with metastatic disease via CTC analysis—Veridex’s CellSearch, which so far has garnered the FDA’s stamp of approval for breast, colorectal and prostate cancers (with more indica-tions in the pipeline).

But CellSearch is unlikely to be alone for long. If “targeted therapies” was the buzzword in oncology over the last decade, a strong case could be made for “circulating tumor cells” to take the title during the next one. And ideally the two will go together because the only way to “target” a targeted therapy is to accurately identify which patients will respond to it, and the biomarker provid-ed by CTC assays might offer one viable option for doing that.

The Numbers Game

Fairly consistent data suggest that simply counting CTCs represents a useful prognostic tool for certain can-cers. One of the first published papers in the field, by renowned breast cancer researcher Massimo Cristofanilli, MD, now at Fox Chase Cancer Center in Philadelphia, found that between 60% and 70% of patients with metastatic breast cancer (MBC) have at least two CTCs per 7.5 mL of blood, while such cells could rarely be found in healthy controls. A minimum of just five CTCs per 7.5 mL of blood predicted poor-er progression-free survival (PFS) and overall survival (OS) compared with those who had fewer.

With varying thresholds, researchers have found CTC levels to provide sim-ilar prognostic value in prostate and colorectal cancers—hence the expand-ed approval for the Veridex assay.

But simply being able to predict who will do better and who will do worse is of little value to the patient, other than knowing who needs to get their affairs

in order more quick-ly. Clinical utility depends on actually being able to shape treatment choices based on the infor-mation provided in an assay.

C a n C T C s d o t h a t ? M a y b e . I t seems clear that they can accurately mea-sure response to treatment in the cancer types for which they’ve been validated—again, breast, colorectal and prostate. Studies by Dr. Cristofanilli’s team and others have found that in patients with nonmea-surable disease, a decrease in CTC lev-els two to five weeks after starting sys-temic therapy correlates with improved PFS and OS. In the recent Phase III CAIRO (Capecitabine, Irinotecan, and Oxaliplatin in Advanced Colorectal Cancer) study, patients with three or more CTCs per 7.5 mL at baseline had a 1.5-fold increased risk for progression (P=0.0003) and a 2.2-fold increased risk for death (P<0.0001) compared with those with low counts.

There are other ways of monitor-ing response to treatment, of course, but some studies have found that CTC analysis may be more accurate than these existing options, such as imaging in breast cancer and prostate-specif-ic antigen analysis for prostate cancer. And it may be much more responsive.

“CTC levels may change faster than responses we see on a CT [comput-ed tomography] scan,” said David Tsai Ting, MD, a medical oncologist at Massachusetts General Hospital in Boston. “You have to wait a couple of months to see changes on CT. Using cir-culating tumor cells, we have the poten-tial to make the call earlier and pre-vent longer durations of therapies that are not effective and instead switch to something that is more effective.”

Dr. Ting is a member of the team that has created one of the rivals to CellSearch, the CTC-Chip, a high-throughput microfluidic device for CTC

detection. Last January, Johnson & Johnson,

Veridex’s parent com-pany, put $30 mil-lion into a deal with the MGH group to commercialize the assay.

Although Dr. Ting’s area of research is

p a n c r e a t i c c a n c e r, he and his colleagues at

MGH, including renowned Tu r k i s h b i o m e d i c a l e n g i n e e r

Mehmet Toner, PhD, who designed the CTC-Chip, also are working on pros-tate, breast and lung cancers as well as melanoma and glioblastoma.

Translating Prognostic Value Into Survival

But say that you find out, after only a couple of weeks, that your patient with MBC is not responding to pacli-taxel and you elect to switch her to an anthracycline-based chemothera-py instead. Will that lead to improved OS? Have you bought her more weeks or months or even years?

The answer remains to be seen. The Southwest Oncology Group (SWOG) is currently trying to answer that ques-tion with a prospective Phase III study (SWOG 0500) involving 500 women with MBC. Enrolled patients will have their CTC levels evaluated at baseline and after one cycle of first-line chemo-therapy; patients who have an elevated CTC count will be switched to a new chemotherapy regimen. Those with persistent elevated CTC counts will be randomized to either continue initial therapy until clinical or radiograph-ic evidence of disease progression or switch to a different chemotherapeu-tic agent.

The genetic or proteomic makeup of CTCs also might suggest an altogether different line of therapy than the prima-ry tumor. There are cases in which, for example, a primary breast tumor shows no evidence of HER2/neu amplifica-tion, but the CTCs, by contrast, overex-press HER2/neu.

“In my mind, it might be more important to treat what’s circulating in the bloodstream rather than the pri-mary tumor for patients in whom the two results are discordant,” said Kevin Halling, MD, PhD, a cancer geneti-cist and pathologist at Mayo Clinic in Rochester, Minn.

Clinicians may be underutilizing the test, Dr. Halling added. “I think that clinicians are waiting for the results of studies such as the SWOG study to know whether treatment changes they make based on CTC results really do have an impact on survival.”

Although the CTC assay’s clinical promise—getting early evidence of a therapy’s effectiveness and potentially improving response by changing strate-gies—is a tantalizing prospect, it repre-sents only a small piece of what scien-tists hope to do with these nanoscopic sentinels of disease.

A Key to Metastasis

“The cells that we are seeing in the blood are presumably the ones that have the ability to metastasize, and metastasis is what ultimately leads to making patients incurable,” said Dr. Ting. “Understanding that process, and developing new drugs to stop that pro-cess, would be a very interesting way to improve our ability to cure patients up front.”

Although the work is still unpub-lished, Dr. Ting said that his group has been studying gene expression signa-tures to better understand the unique properties of CTCs. “We’ve identified some interesting genes that appear to be important for metastasis,” he said.

Peter Kuhn, PhD, a professor of cell biology at Scripps Research Institute in La Jolla, Calif., has called circulat-ing tumor cells “the messenger and the message of metastasis.”

“If we can understand CTCs, we can understand metastasis,” he said.

Dr. Kuhn, a biophysicist by train-ing, has taken a different approach to characterizing CTCs. His team’s “flu-id biopsy” involves spreading a layer of all nucleated cells found in the blood on a glass surface, adding fluorescent antibodies to cytokeratin, an essen-tial component of CTCs, and scan-ning the slide for sites of fluorescence. After some high-performance compu-tation that weighs the cellular param-eters, cellular pathologists then do an in-depth analysis of each marked cell to see if a CTC lurks there.

Dr. Kuhn’s group has licensed the technology to California’s Epic Sciences and is collaborating with Microsoft’s high-performance computing team to manage the vast trove of data a fluid biopsy generates. They are now being validated in observational studies at nearly a dozen clinical sites around the country and although Dr. Kuhn said he

CTCcontinued from page 1

10 CliniCal OnCOlOgy news • JanUaRy 2012SOLID TUMORS

Prognosis

ANSWERS

1. Answer: a. According to IGCCCG consensus classification, seminoma

has only two risk categories, good and intermediate prognosis. In advanced seminoma, metastatic disease confined to the lungs is classified as good progno-sis category, regardless of tumor mark-er levels. Metastatic disease outside of the lungs is classified as intermediate prognosis.

International Germ Cell Consensus Classifica-tion: a prognostic factor based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol. 1997;15(2):594-603, PMID: 9053482.

2. Answer: a. A majority of patients with advanced seminoma will be

classified as having good prognosis and are ideal candidates for three cycles of BEP chemotherapy, which has dem-onstrated remarkable five-year surviv-al rates. In certain circumstances bleo-mycin may be omitted and four cycles of EP is also a reasonable option compared with three cycles of BEP.

Williams SD, Birch R, Einhorn LH, et al. Treat-ment of disseminated germ-cell tumors with cis-platin, bleomycin and either vinblastine or etopo-side. N Engl J Med. 1987;316(23):1435-1440, PMID: 2437455.

Loehrer PJ, Johnson D, Elson P, et al. Impor-tance of bleomycin in favorable-prognosis dissem-inated germ cell tumors: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 1995;13(2):470-476, PMID: 7531223.

Kondagunta GV, Bacik J, Bajorin D, et al. Eto-poside and cisplatin chemotherapy for meta-static good-risk germ cell tumors. J Clin Oncol. 2005;23(36):9290-9294, PMID: 16361627.

Einhorn LH, Foster RS. Bleomycin, etopo-side, and cisplatin for three cycles compared with

etoposide and cisplatin for four cycles in good risk germ cell tumors: is there a preferred regimen? J Clin Oncol. 2006;24(16):2597-2598; author reply 2598-2599, PMID: 16735718.

3. Answer: c. The half-life of hCG

is approximately one to three days.

Gilligan TD et al. American Soci-ety of Clinical Oncology Clinical Prac-tice Guideline on uses of serum tumor markers in adult males with germ cell tumors. J Clin Oncol. 2010;28(20):3388, PMID: 20530278.

National Comprehensive Cancer Network (NCCN) guidelines. www.nccn.org. Accessed November 30, 2011.

Garnick MB. Spurious rise in human cho-rionic gonadotropin induced by marihuana in patients with testicular cancer. N Engl J Med. 1980;303(20):1177, PMID: 7421935.

4. Answer: c. The incidence of germ cell tumors is increasing worldwide.

Jemal A, Siegel R, Ward E, et al. Cancer statis-tics, 2006. CA Cancer J Clin. 2006;56(2):106-130, PMID: 16514137.

Powles T, Bower M, Daugaard G, et al. Multi-center study of human immunodeficiency virus-related germ cell tumors. J Clin Oncol. 2003; 21(10):1922-1927, PMID: 12743144.

Lutke Holzik MF, Rapley EA, Hoekstra HJ, et al. Genetic predisposition to testicular germ-cell tumors. Lancet Oncol. 2004;5(6):363-371, PMID: 15172357.

5. Answer: b. An isochromosome of the short arm of chromosome 12

is present in the majority of germ cell tumors, including extragonadal tumors. This cytogenetic abnormality can be a useful clinical tool to determine the

histogenesis in some patients with poorly

differentiated carcino-mas of unknown pri-mary location.

Latif F, Tory K, Gnar-ra J, et al. Identification of the von Hippel-Lindau dis-

ease tumor suppressor gene. Science. 1993;260(5112):1317,

PMID: 8493574.

Malkin D. Li-Fraumeni syn-drome. Genes Cancer. 2011;2(4):475,

PMID: 21779515.

Gatti RA, Berkel I, Boder E, et al. Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature. 1988;336(6199):577-580, PMID: 3200306.

6. Answer: b. The IV-to-oral con-version is approximately 1:2 for

etoposide.DeVita VT, Lawrence TS, Rosenberg SA.

DePinho RA, Weinberg RA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.

7. Answer: b. She meets revised Bethesda criteria for HNPCC

genetic testing. There are several benefits of HNPCC genetic testing in this patient, including predicting the risk for her child and other relatives, determining her future risk for other cancers and allowing the implementation of preventive and early detection practices.

Wakefield CE, Meiser B, Homewood J, et al. Randomized trial of a decision aid for indi-viduals considering genetic testing for heredi-tary nonpolyposis colorectal cancer risk. Cancer. 2008;113(5):956-965, PMID: 18618513.

8. Answer: a. The HNPCC-related tumors include colorectal, ovarian,

endometrial, gastric, small bowel, pancreas, biliary, ureter, renal pelvis and brain (usually glioblastoma as seen in Turcot syndrome). They also include sebaceous gland adenomas and keratocanthom as in Muir-Torre syndrome.

Lindor NM, Petersen GM, Hadley DW, et al. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA. 2006;296(12):1507-1517, PMID: 17003399.

National Comprehensive Cancer Network (NCCN) guidelines. www.nccn.org. Accessed November 30, 2011.

9. Answer: b. It is considered ben-eficial if it is able to decrease the

cause-specific mortality for those in the screened arm compared with those in the control arm of a randomized clinical trial.

Kramer BS, Brawley OW. Cancer screening. Hematol Oncol Clin North Am. 2000;14:831-848, PMID: 10949776.

10. Answer: a. Specificity is the number of patients who have a

negative test and do not have the disease divided by the number of patients who do not have the disease.

DeVita VT, Lawrence TS, Rosenberg SA. DePinho RA, Weinberg RA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.

Dr. S. Mustafa assisted in preparing this manuscript.

would like to see it FDA-ready by 2014, he recognizes the hurdles involved.

Freely admitting a bias for his team’s approach, Dr. Kuhn suggested that the CellSearch assay is limited in its utili-ty. According to Quest Diagnostics, a medical testing service, antibodies used

in the CellSearch assay are targeted at EpCAM and cytokeratins 8, 18 and 19, cell markers expressed by adenocarci-nomas. CTCs that do not express these markers will not be detected by the assay, while circulating epithelial tumor cells from malignancies other than met-astatic breast, colorectal or prostate cancer may be detected.

“What we need is a test with true

predictive value, a true drug stratifi-cation test,” he said. “And we need to develop this test for each and every drug. Nobody is quite there yet, but we are all working on that goal.”

The Tipping Point?

Unlike others in the field, Dr. Kuhn believes that CTCs can be identified in the bloodstreams of patients with virtually any type of cancer, once the right technology is developed and the right assays are applied. “We have a ‘no cell left behind’ approach—we’re not enriching for a particular cell,” he said. “Most people are enriching for partic-ular cells, so that becomes a selection process, and you will only find that par-ticular subtype.”

For Dr. Kuhn—and many others—the real value of the fluid biopsy goes beyond predicting prognosis or even effectively changing treatment strate-gies midstream.

“The ultimate utility for the bio-markers we identify in these cells is the predictive power for a specific drug

molecule,” he said. “After ASCO 2011, with the success of Pfizer’s crizotinib and Plexxikon’s vemurafenib, I would argue that we are now looking back at the tipping point of personalized cancer care. It is here to stay, and overlaying it with the fluid biopsy will be one way that we can accurately identify patients for these new agents. Will there be one test that will do it all? No. We need to understand how the fluid biopsy pro-vides us insight into each subtype of disease. That’s not going to fall out of the sky. We need serious clinical stud-ies that ask very specific clinical utility questions with validated approaches.”

—Gina Shaw

Dr. Halling has no relevant disclosures. Dr. Kuhn is the founder of and a

shareholder in Epic Sciences. Dr. Ting has a commercial interest in the development of the CTC-Chip. His group at Massachusetts General is also involved in a collaborative agreement with Veridex LLC, to establish a center of excellence in

research on CTC technologies.

CONUNDRUMS, continued from page 9

‘If we can understand

CTCs, we can understand

metastasis.’

—Peter Kuhn, PhD

VISIT US ONLINE AT

WWW. CLINICALONCOLOGY.COM

CliniCal OnCOlOgy news • JanUaRy 2012 11PRN

Community Oncology

There is a small advantage with an AI over tamoxifen in the first five years—in the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial, anastrozole (ANA) improved distant recurrence-free surviv-al by only 1.3% at five years and 2.6% at 10 years (Table). In addition, AIs do not cause venous clots or endometrial cancer. Alas, there are no data yet on safe or effec-tive therapy after five years of an AI as ini-tial hormonal therapy (although many physicians have recommended more AIs and many patients have taken them).

An initial thought was to give a slightly inferior therapy (tamoxifen) for the first five years, take the small “hit” of reduced efficacy, then give a very effective therapy (an AI) for an additional five years. This probably is not necessary. Randomized tri-als have suggested that giving two to three years of tamoxifen followed by two to three years of an AI is identical in efficacy to five years of an AI (the TEAM [Tamox-ifen and Exemestane Adjuvant Multina-tional] trial using exemestane) or perhaps minimally and nonsignificantly inferior (the BIG 1-98 trial). Although a switch to five years of an AI was not done in these trials, MA.17 has shown that five years of letrozole is both safe and very effec-tive after tamoxifen therapy. Thus, we can proceed to follow a regimen of giving five years of an AI after two to three years of tamoxifen (as I have been doing since the publication of MA.17). This gets us to 7.5 or eight years of adjuvant hormonal therapy.

A Caveat

We need to be somewhat cautious in interpreting the long-term results of the ATAC, BIG 1-98 and IES (Inter-group Exemestane Study) that looked

at tamoxifen versus AI versus “early” switching strategies. Certainly for the BIG 1-98,3 and probably for the others, thera-py was not specified or recorded after the first five years. This means that we really do not know what the patients took, and interpretation of long-term recurrence and survival data could be confounded by unrecorded therapy. This is probably a minor issue for the ATAC trial because it was completed early in the study of adju-vant AIs, but it is probably a major issue for the more recent studies like TEAM, IES and BIG 1-98.

Period After Five Years Is Important

How important is the period after the first five years of adjuvant therapy? The classic statement is that there are as many distant relapses between years 5 and 15 as occur in the first five years.4 I believe the answer depends on the characteris-tics of the patient population. When the ATAC trial was first published, I was struck by the mean age of 64 years. Never before had there been an adjuvant trial in breast cancer with such an aged popula-tion! If one starts with such an advanced age, and includes many women with less ominous breast cancers (node-negative and smaller primaries, high levels of hor-mone receptors and low rates of prolifer-ation, defined either by Ki67 immunohis-tochemistry or low oncotype score) and includes women with substantial comor-bidities, then many more of the late events will be related to vascular disease and other cancers compared with the incidence of death from metastases orig-inating from the primary breast cancer.

Such analyses recently have been done for the ATAC and MA.17 trials. In the MA.17 trial, breast cancer accounted for only 40% of deaths with a median follow-up of 3.9 years from the entry point (which was five years after starting adjuvant hor-monal therapy with tamoxifen).5 This is probably an underestimate of the breast cancer death rate because of short follow-up so soon after recruitment. Because it takes a median of two to three years to die from metastatic breast cancer, and because none of the women entering the MA.17 tri-al had metastatic breast cancer when they entered (they were eligible only if they had not relapsed), one would expect very few first relapses to end in death in the first two years, so most of the early deaths would not be from breast cancer regard-less of the efficacy of the treatment.

The ATAC trialists recently reported

a sophisticated analysis out to 10 years from diagnosis showing high rates of deaths without any recurrence of breast cancer, especially among older node-neg-ative patients with high comorbidities.6 This particular analysis probably slight-ly overestimates deaths from breast can-cer because it counted as breast cancer deaths any death after any breast cancer recurrence, not just from distant metas-tases. It turns out this was done to cor-respond to the definitions used by the Oxford overview Early Breast Cancer Trialists’ Collaborative Group, which had reviewed many studies in which distant metastases were not separately recorded.7

Therapy After Five Years of Initial AI

The alternative to 2.5 to three years of tamoxifen followed by an AI is to give five years of an AI followed by more hormonal therapy. Four trials are currently in prog-ress looking at this issue; each uses an AI for another five years, although one looks at giving an AI intermittently in the hope that rising and falling estrogen levels will induce waves of apoptosis (the SOLE [Study of Letrozole Extension] trial of the International Breast Cancer Study Group [IBCSG]). The National Surgical Adju-vant Breast and Bowel Project (NSABP) finished about two years ago recruiting 4,000 patients with either five years of an AI or five years of tamoxifen switched to five more years of an AI or placebo.8 The MA.17R trial has also completed accru-al and expects to report initial results in about one year.9

Although AIs are wonderful drugs, I think it worthwhile to look at alterna-tives that might even prove superior. The first is tamoxifen after five years of an AI. The second is tamoxifen plus everolimus, reported more effective than tamoxifen alone in a small Phase II trial in metastat-ic breast cancer.10 Everolimus improves response rate, time to progression and probably survival when added to anastro-zole for metastatic breast cancer.11 Evero-limus is moderately toxic and very expen-sive (about $10,000 per month), and is probably not yet ready for use as extended adjuvant therapy, but might be after trials as an induction therapy before surgery and some large Phase II trials as an adjuvant.

Other options include megesterol and fulvestrant (neither ever studied as an adjuvant, to my knowledge). Fulvestrant was superior to anastrozole for metastat-ic breast cancer as first hormonal thera-py in a trial of 205 patients.12 Fulvestrant

requires parenteral monthly administra-tion—an advantage in monitoring com-pliance and a disadvantage because it is somewhat painful and inconvenient. It is also very expensive compared with AIs or tamoxifen (all now generic in the United States), although it is approximately 20% the cost of everolimus. Recent data from the Southwest Oncology Group suggest that fulvestrant plus an AI is superior to an AI alone for metastatic breast cancer, but mostly among patients without prior adju-vant tamoxifen.13 Jonas Bergh, MD, found no benefit for the combination of fulves-trant and anastrozole in a similar study called FACT, although his patient pop-ulation had more prior adjuvant tamox-ifen (65% vs. 40%) and more prior adju-vant chemotherapy (46% vs. 33%).14 The SWOG results, though contradicted by the earlier FACT study, make the combination of AI and fulvestrant of great interest for initial hormonal therapy, but not so much for the second five years of therapy after five years of an AI or tamoxifen.

Megesterol has the advantage of oral administration, but causes weight gain and thrombosis, may lead to more new primary breast cancers and will cause vaginal bleeding among patients who retain their uteri if they fail to continue the medication.

Kathryn Ruddy, MD, MPH, at Dana-Farber Cancer Institute in Boston have started a small study looking at extend-ed adjuvant therapy for premenopaus-al women after five years of tamoxifen with letrozole and Lupron (leuprolide)—a logical extension of the dramatic ben-efits reported by Goss in 2009 among younger women who had reached meno-pause by the end of tamoxifen therapy.

How should we go forward? We need to define a population in which a 10- to 15-year horizon is reasonable by age, hab-its and comorbid conditions. A 65-year-old woman who is a nonsmoker and who has never been sick is an excellent can-didate. A 70-year-old diabetic who is a two-pack per day smoker, who has had two myocardial infarctions, gets dyspneic

Breast cancer adjuvant hormonal therapy:

Oncologists Need Long-Term PerspectiveOncologists have a problem: There is a big advantage for aromatase inhibitor (AI) therapy over observation after five years of tamoxifen therapy as shown in MA.17—a 43% to 50% reduction in events1—rising to 75% for those patients who were premenopausal at diagnosis.2

Table. Distant Recurrence-Free Interval After 5 Years of Initial Adjuvant Hormonal Therapya

5 Years

8 Years

10 Years

BIG 1-98 b

letrozole 92.3% 87.9%

Tamoxifen 89.6% 85.1%

ATACc

Anastrozole 92.1% 84.9%

Tamoxifen 90.8% 82.3%

a This term is taken from the Big 1-98 analysis reported by Regan et al., and is 100% minus the incidence of distant metastases, with intercur-rent deaths without metastases censored.

b Regan M, et al. Lancet Oncol. 2011 Oct 21. [epub ahead of print]

c aTaC: arimidex, Tamoxifen, alone or in Combination. Cuzick J, et al. Lancet Oncol. 2010;11:1135-1141.

Clinical Oncology Newswelcomes letters to the editor.

Do you have thoughts on Dr. Vogl’s commentary?

Please send comments to

gmiller@mcmahonmed.com

What are your thoughts?

Steven Vogl, MDMedical Oncologist, new york City

EDITORIAL BOARD COMMENTARY

12 CliniCal OnCOlOgy news • JanUaRy 2012SOLID TUMORS

Breast

when walking one block and has no pulse in her feet is probably best served by weighting immediate benefits over those that will accrue late. Younger women who become postmenopausal after diag-nosis are excellent candidates for lat-er hormonal control of occult metastat-ic breast cancer. The only study to look at this reported a huge benefit of 75%.15

Recent data suggest that simple avail-able tests may identify an estrogen receptor–positive population that does not benefit from adjuvant tamoxifen. Low levels of ESR1 mRNA measured in the Oncotype DX test correlated with no discernible benefit from tamoxifen in a retrospective subset analysis of NSABP B-14.16 Any study of new extended adju-vant hormonal therapy should look at gene expression profiles at diagnosis. If low ESR1 mRNA levels indeed define a group of patients resistant to hormonal intervention, we not only will spare them toxicity, expense and inconvenience, we may enter them into trials seeking effec-tive therapy for them.

Data presented at the San Antonio Breast Cancer Symposium in 2011 suggest that gene expression profiles differ in patients who relapse after five years compared with those who relapse earlier while on tamoxifen.17 These differences are some-what difficult to interpret because some may be beneficial in that they are associat-ed with delay of early relapse, rather than being deleterious by favoring late relapse as compared with no relapse. Other poten-tial ways to choose patients for extend-ed adjuvant endocrine therapy were sug-gested by Eric Winer, MD, director of the Breast Oncology Center at the Dana-Far-ber Cancer Institute in Boston, in a superb lecture in San Antonio in December 2011, including bone marrow tumor cells and circulating tumor cells measured at diag-nosis or at possible crossover.

The proper end point of late adjuvant therapy is prevention of distant metas-tases or death (distant metastasis–free survival). This is the end point most important to the patient because distant metastases inevitably lead to death after an interval of several years, and attribu-tion of cause of death after occurrence of distant metastases is problematic. Inci-dence of distant metastases is of inter-est, but ignoring rates of intercurrent death could lead to a situation in which a therapy is favored that kills some of the patients before relapse. Overall survival should always be a secondary end point. Although ipsilateral recurrence and new contralateral primaries are annoying and distressing, they lack the implication of impending death of distant metastases.

An unfortunate corollary of drug com-pany funding has been that many trials have mixed more and less ominous end points, allowing more events to accumu-late and thus allowing the drug compa-nies to get their results more quickly and get more years of FDA approval before

the patent expires. All three AIs are now available as generics. The bad news is that drug company money has dried up. The good news is that studies using these drugs can now be designed with the best end points and statistical considerations appropriate to the end point of distant relapse–free survival.

Studies should specify therapy for the duration of follow-up, and the lat-ter should be very long. Protocols should have defined reasons for the discontin-uation of adjuvant hormone therapy in the setting of major intercurrent illness. The thresholds for closing the studies and

unblinding and allowing crossover should be set high. These studies are very impor-tant, very hard to do and often impossi-ble to do again. If we close a trial for a small observed difference in recurrenc-es, only a fraction of which lead to fatal consequences, we lose forever the abili-ty to evaluate the study for the magnitude of real end points—metastatic cancer and death. Until the statisticians tell us that there is a likely absolute detriment of greater than 3% in distant metastases or mortality, the study should remain blind-ed and open to allow full analysis with-out need for the imaginative, creative and

very difficult statistical contortions Mer-edith Regan, ScD, had to perform to try to estimate the real consequences of the treatment programs studied in BIG 1-98.18

The gains of the past 10 years of extend-ed adjuvant hormonal therapy mean that more patients are living longer lives without the pain and disability of recur-rent breast cancer. We need to refine and extend these achievements.

References

1. Goss P, Mamounas E, Jakesz R, et al. Cancer Res. 2009;69(24 Suppl): Abstract nr 4081.

see PERSPECTIVE, page 28

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2 Additional requirements must be met by the practice in order to qualify.© 2012 McKesson Specialty Health. All rights reserved.

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Breast

Table. Clinical Trials Presented by European Researchers at the Esteemed Oral Abstract Sessions at the American Society of Clinical Oncology Meeting 2011

Capecitabine versus 5-fluorouracil–based neoadjuvant chemoradiotherapy for locally advanced rectal cancer—Germany.

Preoperative chemoradiotherapy and postoperative chemotherapy with 5-fluorouracil and oxaliplatin versus 5-fluorouracil alone in locally advanced rectal cancer: First results of the CAo/ARo/AIo-04 randomized phase III trial—Germany.

An analysis of preoperative chemoradiotherapy with 5FU/leucovorin for T3-4 rectal cancer on survival in a pooled analysis of EoRTC 22921 and FFCD 9203 trials—France.

Subgroup analyses from the AVANT trial—a multinational trial, but led by European investigators.

Final results from PRIME: Randomized phase III study of panitumumab with FolFoX4 for firstline metastatic colorectal cancer—France.

Influence of KRAS G13D mutations on outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab—Germany and Belgium.

Only two of the seven studies present-ed—the results of the NSABP C-08 trial assessing bevacizumab (Avastin, Genen-tech) in stage II and III colon cancer, and an analysis of four NSABP trials to determine the efficacy of oxaliplatin when added to 5-fluorouracil-leucovo-rin in stage II colon cancer—were con-ducted by U.S. investigators (Table).

This session wasn’t a one-time aberra-tion. “There is one very important large trial now going on in the U.S. through CALGB [Cancer and Leukemia Group B], involving patients with a wild type K-ras gene. They receive FOLFOX or FOLFIRI, dealer’s choice, with a ran-domization to cetuximab [Erbitux, Merck] or bevacizumab,” said Rich-ard M. Goldberg, MD, professor of medicine at The Ohio State Universi-ty and physician-in-chief of the Ohio State University Comprehensive Can-cer Center-James Cancer Hospi-tal and Richard J. Solove Research Institute in Columbus, Ohio. “And then there were two recent large trials in adjuvant therapy that just reported out—both negative tri-als, one of FOLFOX plus or minus cetuximab and an NSABP trial of the same regimen plus or minus

bevacizumab. Both of those were nega-tive trials, as it turns out.”

But with those few exceptions, Dr. Goldberg notes, “There aren’t a lot of other large trials in colorectal can-cer being done in the United States. When you go to the ASCO meet-ings and listen to the podi-um presentations of the year’s best research in colorectal cancer, the

E u r o p e -ans are stepping

up to the

stage much more often than the Amer-icans are. It’s a trend that’s been devel-

oping over the past five to 10 years, and while it’s a credit to the Europeans, it’s also a concern

for many of us who run—or try to run—

large trials in colorectal cancer

in the U.S.”

And it’s not just colorectal cancer, he adds. “I know colorectal best, but I also know gastric and pancreatic and GIST [gastrointestinal stromal tumor] and all of that. While I would say that there are more novel drug trials going on in the U.S. in other diseases, still the balance of presentations in the upper GI section at ASCO is in favor of Europe.”

If it were up to the United States alone, many cancer therapies might have pro-ceeded along a much slower time line, said Edward Chu, MD, deputy direc-tor of the Yale Cancer Center in New Haven, Conn. “Were it not for the folks in Europe and Merck KGaA, for exam-ple, cetuximab would probably not have been approved as quickly as it was.”

The Gazelle Versus the Elephant

So, why have so many of the pivot-al Phase III and later Phase II trials in colorectal cancer begun to migrate wholesale away from the United States? Leading investigators in the field say it

has to do with several interdependent factors: speed, efficiency, regulato-ry barriers and the ability to accrue patients.“Drug companies who own the

agents of most interest define success as getting new indications and improving outcomes. When they look at where to place their studies, they consider three things: speed, regulatory success and cost,” said Dr. Goldberg. “And because time is money in the business world, speed is their primary interest. They’re looking for rapid consensus on what a study should look like, rapid activation and accrual, and rapid analysis.”

That’s something they are not getting from the primary agent of major cancer clinical trials in the United States: the 12 cooperative groups. Originally estab-lished in 1955, the National Cancer Insti-tute’s (NCI) Clinical Trials Cooperative Group Program is intended “to promote and support clinical trials … of new can-cer treatments, explore methods of can-cer prevention and early detection, and study quality-of-life issues and rehabili-tation during and after treatment.”

They’ve been called “a national trea-sure,” but some in the field believe that the cooperative groups are beginning to pose an impediment to research advanc-es through their sheer size and bureau-cracy. Consent forms are the size of a small city phone book, and folders con-taining all the paperwork for trial pro-tocols would probably break a toe if one was dropped on your foot. “Rapid is not our middle name,” said Dr. Goldberg. “Gazelles are nimble, elephants are pon-derous, and we’re getting to look a lot more like elephants than gazelles.”

That’s borne out by data from the NCI’s Cancer Therapy Evaluation Pro-gram—cooperative group Phase III trials

Europe Dominates Colorectal Cancer Trial EffortsIf you attended the oral abstract session on colorectal cancer at the last annual meeting of the American Society for Clinical Oncology (ASCO), you might have noticed something about the trial results presented: The large majority of them were conducted by European researchers.

14 CliniCal OnCOlOgy news • JanUaRy 2012SOLID TUMORS

Colorectal

now take a median of 830 days to acti-vate—more than two years.

What’s more, Dr. Goldberg notes, the cooperative groups are now in the mid-dle of a process of consolidation—part of an effort to reinvigorate the groups’ system that has been undertaken in response to an Institute of Medicine report on the Cooperative Group Pro-gram issued in April 2010. “Making the groups bigger is not likely to make them more efficient,” Dr. Goldberg said. “My opinion is that we in the cooperative groups ought to be focusing on how we can interact with industry in a way that brings the best drugs to our American patients before they’re ready for regula-tory consideration.”

The European Model

Unlike the United States, there’s no NCI in Europe. Instead, many differ-ent countries work together through groups like the European Organisation for Research and Treatment of Cancer, but there’s not the same sort of funding that’s offered by the NCI. “We should have a real advantage with this infra-structure,” said Dr. Goldberg. “If you look at cost as an issue for drug compa-nies, much of the cost of running a U.S. trial and providing the care is borne by the NCI and insurance companies. So, conducting trials here should be very attractive, but because we don’t focus on being nimble, we end up at a disad-vantage in a system that should provide us with overwhelming advantages.”

Another factor is the American pay-ment system, said Dr. Chu, pointing to bevacizumab as a prime example. “Avas-tin has been used like water here ever since it was approved in 2004. Physi-cians here in the U.S. have been able to use Avastin pretty much whenever they want, in combination with chemo-therapy in the treatment of metastatic colorectal cancer.”

That’s not the case in Europe or Asia. “They look at cost and efficacy and see that the benefits of these drugs, while statistically significant, may be arguable in terms of clinical relevance,” said Dr. Chu. “So if someone is covered by the nationalized health care system, they may not have access to newer drugs and the only way they can get access to the

newer antibodies and small molecule agents is to go on a clinical trial.”

Thus, there are more patients in Europe with a vested interest in join-ing clinical trials in the first place. It’s also much harder, ethically speaking, to

randomize U.S. patients to certain regi-mens. “If you’re developing an angiogen-esis inhibitor and want to run a study of FOLFOX plus or minus your drug, that’s hard to do in the U.S., because FOLF-OX or FOLFIRI plus bevacizumab is the standard of care,” said Dr. Goldberg. “But because regulatory agencies like NICE [National Institute for Health and Clin-ical Excellence] in the United Kingdom and EMEA [European Medicines Agen-cy] in Europe have decided its benefit is marginal, an oncologist there can ran-domize patients to chemotherapy alone versus chemo plus agent X.”

That’s probably a big reason for the disparity in trial enrollment between the United States and Europe. Studies have found that trials take approximate-ly twice as long to accrue their minimum number of patients in the United States as in Europe—if they manage to accrue at all. According to a recent study from the Cancer Therapy Evaluation Program, only 26.6% of all cancer clinical trials ever accrued more than two patients.

Trial by Committee

Most oncologists would not argue in favor of making important new biologi-cal agents less available to U.S. patients in order to make trial accrual easier. But bloated trial bureaucracy is a far bigger impediment to cancer research in the United States, Dr. Goldberg said.

“Let’s say that I’m intrigued by drug X and approach company Y, saying that I want to run a trial of this standard che-motherapy regimen plus their mono-clonal antibody,” he said. “If we then go to the cooperative groups, first it has to go to the GI committee, then the execu-tive committee, then the NCI Task Force and its steering committees and then

the NCI. By the time something’s been approved, up to 150 people have had an opportunity to look at it. Most nimble organizations don’t need 150 people to look at and respond to something before going forward.”

According to Jordan Berlin, MD, clin-ical director of the GI oncology pro-gram at Vanderbilt University School of Medicine, Nashville, one idea that died a death by committee recently was for a trial of whether or not to continue beva-cizumab after the progression of disease in metastatic colorectal cancer. “It was an outstanding idea, but the NCI and the cooperative groups kept modifying it,” he said. “It was very slow to open, and when it finally did open it had been modified to the point of being far less interesting, among other problems that caused difficulties with the trial down the line. It was not even able to accrue patients, so it closed.”

Even when trials are able to open within the cooperative group system, they’re often not funded well enough to pay for the many required regulatory amendments. Dr. Berlin reports that he has several trials for which the patients are all now off study—some, of course, given the disease, are deceased—and the NCI still wants the investigators to make amendments to the original protocols based on new toxicity crite-ria. “That is pointless,” he said. “And of course, somebody has to do the work, which costs money. It takes approx-imately an hour to do work like that at my institution. Now, there are 50 institutions on the protocol, so that’s 50 man-hours of work for a pointless amendment—but if we don’t do it, we get in trouble when we get audited.”

A Broken System?

The Operational Efficiency Work-ing Group of the NCI Clinical Trials and Translational Research Advisory Com-mittee (CTAC) has put forth a number of recommendations to speed up trial

activation, calling for action plans and time lines, and rewards for meeting those time lines. CTAC also has established targets for trial activation: 300 days for Phase III, 210 days for Phase II, and 90 days for investigator-initiated trials.

If the U.S. cancer research communi-ty doesn’t take action, the day may come when literally all significant Phase III trials are conducted outside the United States. “We’ve gotten fat and slow, and we’ve lost our competitive edge. We have to become competitive again,” Dr. Chu said.

Dr. Berlin believes that efforts to improve the cooperative group system haven’t gotten at the heart of the matter. “There are a lot of useless steps at insti-tutions and in the groups that don’t add to science or the safety of patients, but just add work and cost,” he said. “None of those things are being eliminated. There’s no streamlining of the process, no elimination of steps, no fast tracking or regulatory improvements. The peo-ple at the NCI are good people—their goals are not to impede but to improve research—but the saying is that all of us are far dumber than any one of us by ourselves. What comes out of commit-tees and large groups is cumbersome and not very effective.”

Is Dr. Berlin saying what it sounds like he’s saying? Yes. He proposes a much more radical solution than con-solidating, restructuring or reconfigur-ing. “The cooperative group system is broken,” he said. “We can’t make Band-Aid changes. We have to break it down and start again from the beginning. If it’s to be made more effective, it has to be completely rethought.”

Dr. Goldberg might not go quite that far, but he agrees that the solutions proposed to date don’t go far enough. “We need to go back to the fundamen-tal principles that we as physicians and researchers have a responsibility to improve patient outcomes, as quick-ly and as painlessly as we possibly can. Process can be the enemy of this. I’m not arguing that all process should dis-appear, but streamlining is important to success and competing in a global mar-ket for access to these new agents.”

—Gina Shaw

‘We’ve gotten fat and slow, and we’ve lost our competitive edge.’

—Edward Chu, MD

If you missed any recent issues of Clinical Oncology News, visit www.clinicaloncology.com.

CliniCal OnCOlOgy news • JanUaRy 2012 15SOLID TUMORS

Colorectal

example:After a staging biopsy, 68-year-old

Robert Tolland is diagnosed with stage IV non-small cell lung cancer with metastasis to the brain. His oncologist, Dr. Sutherland, delivered the bad news to Mr. Tolland in a previous visit, and now the patient has returned to discuss potential therapeutic approaches. Giv-en the patient’s past medical history and general weakened condition, Dr. Suther-land has a sinking feeling that the patient will decompensate soon. Mr. Tolland tells the doctor that his granddaughter is getting married in 18 months and asks: “Am I going to make it to the wedding?” Dr. Sutherland pauses, deciding how to balance protecting Mr. Tolland and his loving family members from emotional distress and delivering an honest answer.

The Object of Hope

The moral and legal obligation to pro-vide adequate information to patients is well established and is based on the patient’s right to informed consent. When a patient is near death, frank prog-nostications are part of the informed con-sent obligation. Unfortunately, this is fre-quently easier said than done. Physicians report that they often simply avoid giv-ing prognostic details, and even at times purposefully provide false information. In one study, only 37% of physicians reported giving frank assessments. The remaining physicians reported giving no information, deliberately overesti-mating or underestimating survival.2 Added to this problem is the fact that oncologists, especially those who have established a relationship with patients, tend to overestimate likely survival. Even without the optimistic tenden-cy when predicting, prognostication, at best, involves inaccuracy. The belief that predictions come with an under-tone of uncertainty adds to the reluc-tance to provide adequate and appropri-ate information.

Another factor that compounds the problem is the belief that by being frank a patient may lose hope, with all the attendant drawbacks, including a poten-tial negative impact on health. Howev-er, this natural intuition is misguided in many instances. Patients desire good information, and providing such infor-mation typically does not lead to a loss

of all hope. “Hope” is not meaningful unless we know what a person is hop-ing for. Doctors are sometimes mistak-enly under the impression that patients are left without hope when given bad news. However, it may be that patients simply change what it is they hope for. Rather than hoping to live many more years, they might hope to be comfort-able enough to enjoy visits with their grandchildren in the time they have left. A grim prognosis may only require a shift in what is hoped for, not a complete elimination of hope.

With this in mind, it is important to emphasize that appropriate information may help a patient seek palliative med-icine, including hospice care, at times when it can be maximally beneficial. This could lead to a better and less pain-ful end-of-life experience. Unfortunate-ly, the length of stay in hospice has con-tinued to decrease. In a retrospective study of 240 cancer patients at the Uni-versity of Texas MD Anderson Cancer Center in Houston, the median length of time from diagnoses of advanced dis-ease and death was 9.4 months, where-as the interval between palliative care referral and death was 1.9 months.3

The Surprise QuestionWe turn to the problem of uncertain-

ty and its impact on providing informa-tion. Recently, investigators have studied the “surprise” question, an interest-ing approach to making better survival predictions. The approach is somewhat ironic because although the question is subjective in nature, it tends to produce a good objective response. When physi-cians are asked to judge survival time, they tend to be inaccurate even when using the best prognostication informa-tion, including comorbidities, staging, advance directive status and whether the cancer has metastasized. However, a recent study revealed that physicians are more accurate when they answer the surprise question: “Would I be surprised if this patient died in the next year?” A negative answer indicates an expecta-tion of death within a year, whereas an affirmative answer indicates the physi-cian’s gut response that the patient is highly likely to be alive within a year.1 In a study of 826 cancer patients, an affirmative answer proved “correct” in 97% of the responses; almost all of the patients with a “yes” response to the question were alive within a year.

Although patients with a “no” response had a highly statistically sig-nificant (P<0.001) seven times great-er hazard of death within the year, only 41% of these patients died with-in the year, still indicating large predic-tive error. However, in a paper by Lew-is M. Cohen et al, the surprise ques-tion was coupled with relatively elab-orate actuarial estimations for the sur-vival of dialysis patients.4 The surprise question alone accu-rately predicted six-month survival at 55%. When the surprise question was combined with empiri-cal data, overall accura-cy reached 87%. This nephrology study indicates the

Would You Be ‘Surprised’: Ethical Progress in PrognosticationOncologists have a moral and legal obligation to frankly and adequately inform their patients about their prognosis. The logistics of prognosis disclosure are tempered by a desire to be kind and offer hope, coupled with a responsibility to be accurate. In this article, we explore the concept of hope and a new psychological approach in prognostication called the “surprise” question.1

Consider the following case as an

Doctors are sometimes mistakenly under the impression that

patients are left without ‘hope’ when given bad news. However, it

may be that patients simply change what it is they hope for.

Joseph P. DeMarco, PhDProfessor emeritus of Philosophy, Department of Philosophy, Cleveland state University, Cleveland, Ohio

EDITORIAL BOARD COMMENTARY

Paul J. Ford, PhDDirector of the neuroethics Program, The Cleveland Clinic Foundation; associate Professor, Cleveland Clinic Foundation lerner College of Medicine of Case western Reserve University Cleveland, Ohio

EDITORIAL BOARD COMMENTARYWould I be surprised if this patient died in the next year?

16 CliniCal OnCOlOgy news • JanUaRy 2012PRN

Ethics

Therapeutic Advances in Metastatic Colorectal Cancer

SHAHAB AHMED, MDSenior Coordinator, Research Data

Department of Gastrointestinal Medical OncologyThe University of Texas MD Anderson Cancer Center

Houston, Texas

CATHY ENG, MD, FACPAssociate Professor

Department of Gastrointestinal Medical OncologyThe University of Texas MD Anderson Cancer Center

Houston, Texas

As the continuum of the previously published

“Overview of Frontline Therapy for

Metastatic Colorectal

Cancer,” this review provides an

update on the development of some

promising agents (both targeted

and cytotoxic) and recent reports on

already available agents in combination

with chemotherapy for metastatic colorectal cancer (mCRC).

Newer agents are emerging with the promise of improving the expected duration of survival to up to 32 months for patients with nonresectable mCRC.1

Treatment NaiveCETUXIMAB

At the 2011 annual meeting of the American Society of Clinical Oncology (ASCO), Tejpar et al. revealed infor-mation about a novel biomarker for use in clinical prac-tice.2 It had been thought that patients with KRAS-mutant colorectal cancer tumors would not benefit from anti-epidermal growth factor receptor (EGFR) monoclo-nal antibodies (mAbs), but recently this was challenged by a retrospective analysis of pooled data from patients treated with cetuximab (Erbitux, Bristol-Myers Squibb) after 5-fluorouracil (5-FU) plus irinotecan (FOLFIRI) or 5-FU plus oxaliplatin (FOLFOX). In this subanalysis—based on recent analysis by De Roock et al.3 from the CRYSTAL (Cetuximab combined with irinotecan in first line therapy for metastatic colorectal cancer) and OPUS trials—patients with KRAS G13D-mutant mCRC appeared to derive benefit from the addition of cetuximab to first-line combination therapy. In brief, these recent avail-able findings indicate that 1) not all KRAS mutations are the same and they do not have the same biologic

implications, 2) clinical documentation should capture and document the specific KRAS mutation detected, and 3) EGFR antibodies can be considered a potential treat-ment option in patients with a codon 13 KRAS mutation if the patient does not have access to a clinical trial.4

The results of the NORDIC VII study, which were presented at the 2010 European Society for Medical Oncology (ESMO) Congress, showed that adding cetux-imab to FLOX (5-FU, folinic acid, and oxaliplatin) did not improve response rate, progression-free survival (PFS), or overall survival (OS).5 Patients were random-ized to 1 of 3 arms: group A—FLOX, group B—FLOX plus cetuximab until progression, or group C—inter-mittent FLOX plus continuous cetuximab. For patients with wild-type KRAS, the median OS was 22 months for group A, 20.1 months for group B, and 21.4 months for group C (hazard ratio [HR], 1.14; 95% confidence interval [CI], 0.80-1.61; P=0.66 for group B vs group A) and PFS was 8.7 and 7.9 months for groups A and B, respectively (HR, 1.07; 95% CI, 0.79-1.45; P=0.66).

Adding cetuximab to FOLFIRINOX (oxaliplatin, irino-tecan, 5-FU, and folinate) for unresectable mCRC may have some promise. According to a recent Phase II trial, in which the primary end point was complete response (CR), 12% of patients achieved a CR with a median

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duration of 23.1 months with the ERBIRINOX (cetuximab plus FOLFIRINOX) regimen.6 The overall response rate (ORR) was an impressive 81%, with a median OS and PFS of 24.7 months (95% CI, 22.6 months-not reached) and 9.5 months (95% CI, 7.6-10.4 months), respectively. The most frequent grade 3/4 adverse events (AEs) were diarrhea (52%), neutropenia (38%), and asthenia (32%). Further development is under way specifically in surgi-cally resectable patients.

The Phase III MRC (Medical Research Council)/COIN (Combination Chemotherapy With or Without Cetuximab as First-Line Therapy in Treating Patients With Metastatic Colorectal Cancer) trial did not confirm favorable out-comes when cetuximab was added to oxaliplatin-based chemotherapy for mCRC.7 In this randomized controlled trial, patients with treatment-naive advanced colorectal cancer were randomly assigned to oxaliplatin and fluo-ropyrimidine chemotherapy (arm A), the same combi-nation plus cetuximab (arm B), or intermittent chemo-therapy (arm C). In patients with KRAS wild-type tumors (arm A, n=367; arm B, n=362), the median OS did not dif-fer between treatment arms (median OS, 17.9 months in the control group vs 17.0 months in the cetuximab group; HR, 1.04; 95% CI, 0.87-1.23; P=0.67). Similarly, there was no PFS benefit (8.6 months in the control group vs 8.6 months in the cetuximab group; HR, 0.96; 95% CI, 0.82-1.12; P=0.60). The ORR increased from 57% with chemo-therapy alone (n=209) to 64% with the addition of cetux-imab (P=0.049; n=232). Grade 3 and higher skin and gas-trointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97, respectively).

Second Line/After Initial ProgressionBEVACIZUMAB

The addition of bevacizumab (Avastin, Genentech) for second-line chemotherapy in bevacizumab-naive patients appears to be well tolerated and effective.8 During the Phase II AVASARI trial, the ORR was 32% (90% CI, 17.0%-50.4%), with 8 patients with partial responses, 15 with stable disease, and 2 with disease progression. Median PFS was 11.6 months (95% CI, 6.9-16.4). Median OS was 21.4 months (95% CI, 12.0-30.8). The grade 3/4 AEs with treatment were neutropenia (64%), leucopenia (16%), diarrhea (8%), anorexia (8%), and febrile neutrope-nia (8%). The most common bevacizumab-related grade 3/4 AE was hypertension, observed in 12% of patients.

The Phase II BEVACOLOR study also demonstrated favorable outcomes with bevacizumab in the setting of second-line therapy for mCRC.9 The study demon-strated an ORR of 32% (95% CI, 19%-46%), median PFS of 6.5 months (95% CI, 5.8-7.8 months), and median OS of 19.3 months (95% CI, 14.2-25.1 months).

Following the BRiTE (The Bevacizumab Regimens’ Investigation of Treatment Effects) and ARIES (Avastin Registry: Investigation of Effectiveness and Safety) tri-als of continuation of bevacizumab after progression with first-line therapy, the randomized Phase III TML (The ML18147) trial has completed enrollment and is estimated to be completed in March 2012.10,11

PANITUMUMAB

The STEPP (Skin Toxicity Evaluation Protocol with Panitumumab) study illustrates that panitumumab (Vectibix, Amgen) in combination with irinotecan-based chemotherapy has an acceptable toxicity profile as sec-ond-line therapy for mCRC.12 Patients received either panitumumab 6 mg/kg plus FOLFIRI every 2 weeks or panitumumab 9 mg/kg plus irinotecan every 3 weeks. The ORR was 16% and 8% for patients with KRAS wild-type and mutant tumors, respectively, with the empiric use of oral and topical antibiotics on initiation of anti-EGFR therapy. The most commonly observed AEs included dermatitis acneform and pruritus.

In a randomized Phase III study of panitumumab with FOLFIRI compared with FOLFIRI alone as second-line treatment in patients with mCRC (the 181 trial), the addi-tion of panitumumab resulted in a significant improve-ment in PFS (5.9 vs 3.9 months; HR, 0.73; 95% CI, 0.59-0.90; P=0.004) and increased the response rate to 35%.13

The multicenter randomized controlled PICCOLO (Panitumumab, Irinotecan & Cyclosporin in COLOrectal Cancer Therapy) trial was amended in June 2008 to include prospective KRAS testing to evaluate the addition of panitumumab to single-agent irinotecan as second- or subsequent-line therapy for KRAS wild-type mCRC. An abstract from ASCO 2011 showed that the PICCOLO study had not met its primary end point of improved OS with panitumumab in KRAS wild-type mCRC (median OS for irinotecan plus panitumumab was 10.4 vs 10.5 months for irinotecan only; HR, 0.91; 95% CI, 0.73-1.14; P=0.44), but a trend was seen toward survival benefit after 12 months, especially in KRAS/BRAF wild-type patients.14 Conversely, panitumumab was significantly detrimental in patients with BRAF-mutant tumors. Further analysis pre-sented at ESMO 2011 showed that the benefit of panitu-mumab was confined to patients whose tumors also were wild-type for BRAF, NRAS, PIK3CA, and KRAS codon 146, suggesting that close to one-third of patients being given EGFR therapies based on standard KRAS tests may be gaining no benefit or even being harmed.15

AFLIBERCEPT

Results of a large, multinational Phase III trial in the second-line treatment of mCRC was presented for the first time at the 2011 ESMO World Congress on Gastrointestinal Cancer.16 With a median follow-up of 22.3 months, the group treated with aflibercept (VEGF Trap, Regeneron) fulfilled its primary end point of OS (13.5 vs 12.06 months; HR, 0.817; P=0.0032) and PFS (6.9 vs 4.67 months; HR, 0.758; P=0.00007). The cohort of patients with prior bevacizumab therapy demonstrated an attenuated benefit for aflibercept, as was subse-quently presented at 2011 European Multidisciplinary Cancer Congress.17

RILOTUMUMAB Rilotumumab (AMG 102) is a mAb that binds to the

hepatocyte growth factor (HGF) and thereby blocks sig-naling in the c-Met pathway. In a randomized Phase II

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trial presented at ASCO 2011, Eng et al. compared pani-tumumab plus placebo (arm 1), with panitumumab plus rilotumumab, a mAb against the HGF (arm 2), and panitumumab plus the insulin-like growth factor-1 anti-body ganitumab (AMG 479; arm 3).18 Although gani-tumab failed to generate any benefit in this randomized trial, the arm with the HGF antibody fulfilled its primary objective of a superior response rate (31% vs 21%, odds ratio relative to arm 1: 0.93 vs 0.63, in KRAS wild-type colorectal cancer). The median PFS was 3.7 (2.5-5.3), 5.2 (3.6-5.4), and 5.3 (2.7-5.7) months for arms 1, 2, and 3, respectively.

Third Line and BeyondPERIFOSINE

Perifosine (Keryx) is an oral alkylophospholipid that inhibits AKT (also known as protein kinase B) and nuclear factor-κB that activates an apoptotic pathway via c-jun-N-terminal kinase.19 In a previous randomized Phase II placebo-controlled trial with capecitabine, the median total time to progress (TTP) (27.5 vs 10.1 weeks; P<0.001) and median OS (17.7 vs 7.6 months; P=0.0052) were improved in patients receiving P-CAP (perifosine plus capecitabine) versus CAP (placebo plus capecitabine). The ORR was 20% versus 7% in the P-CAP and CAP groups, respectively; one patient in the P-CAP group had a complete response. A subset anal-ysis of 5-FU–refractory patients showed a median TTP of 17.6 versus 9.0 weeks (P<0.001) and median OS of 15.1 versus 6.5 months (P=0.0061).20

A Phase III randomized placebo-controlled trial of capecitabine with or without perifosine, X-PECT

(Xeloda and Perifosine Evaluation in Colorectal cancer Treatment), has recently completed enrollment.21 Final data is expected to be presented in 2012.22

REGORAFENIB

On Oct. 26, 2011, Bayer Health Care announced that the Phase III CORRECT (patients with metastatic COlorectal cancer treated with REgorafenib or plaCebo after failure of standard Therapy) trial of regorafenib in mCRC met the primary end point of improving OS com-pared with best supportive care.23 A planned interim data analysis has shown that in comparison with pla-cebo, regorafenib completed its primary end point of a statistically significant OS improvement. The results are to be presented shortly.

TAS-102TAS-102 (Taiho) is a novel oral nucleoside antitu-

mor agent (cytotoxic) that inhibits the degradation of trifluorothymidine.24,25 A Phase II trial conducted in 20 medical institutions in Japan indicated that TAS-102 significantly improved OS compared with placebo (9.0 vs 6.6 months) and significantly reduced the risk for mortality (HR, 0.56; P=0.0011).26 Mutation test-ing revealed that TAS-102 offers a significant survival advantage for KRAS-mutant patients. KRAS mutation-positive patients treated with TAS-102 had a median OS of 13.0 months, compared with 6.9 months for those in the placebo group (HR, 0.44; P=0.006), and a PFS of 2.8 months versus 1.0 month in the placebo group (HR, 0.34; P<0.0001). The results were not favorable for the KRAS wild-type subset.

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Table. Phase III Trials of Novel Targeted Agents

Agent Mode of Action SettingSample Size, N Enrollment NCT Identifier

Aflibercept Angiogenesis: VEGF decoy Second-line + FOLFIRI ± aflibercept after first-line failure with oxaliplatin-based therapy

1,200 Active, not recruiting

NCT00561470 (VELOUR)

Ramucirumab Angiogenesis: monoclonal antibody against VEGFR-2

Second-line + FOLFIRI vs placebo

1,050 Recruitinga NCT01183780

Regorafenib Angiogenesis:RTKI for VEGF, TIE2Tumor cell growth:RTKI for RAF, RET, c-KIT

Second-line/third-line vsplacebo

690 Active, not recruiting

NCT01103323 (CORRECT)

Brivanib RTKI for VEGF, FGF signaling

Second-/third line + cetuximab vs placebo KRAS WT

750 Active, not recruiting

NCT00640471

Perifosine Tumor cell growth:AKT inhibitor (PI3K path-way); JNK activation

Second- or third-line vs placebo + capecitabine

430 Active, not recruiting

NCT01097018(X-PECT)

FGF, fibroblast growth factor; FOLFIRI, 5-fluorouracil, leucovorin, irinotecan; JNK, c-jun-N-terminal kinase; NCT, National Clinical Trial; RTKI, receptor tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; WT, wild typea Enrollment as of Dec. 16, 2011. Based on reference 27.

A Phase III trial is needed to confirm the promising results of TAS-102 in patients with mCRC.

Key Points• There is some potential efficacy for cetuximab in KRAS

13 codon-mutated mCRC tumors, but this requires further validation. EGFR inhibition remains largely reserved for KRAS wild-type colorectal cancers.

• Continuous favorable data may support the addition of bevacizumab in bevacizumab-naive patients after disease progression following first-line therapy for mCRC. Data is pending regarding the benefit of con-tinuing bevacizumab beyond progression in second-line therapy.

• The Phase III trial of aflibercept in combination with FOLFIRI shows that the combination significantly improves OS and PFS in patients previously treated with an oxaliplatin-containing regimen for mCRC.

• The Table lists details on several ongoing and com-pleted trials of novel targeted therapies for mCRC.27

References

1. Ga llagher DJ, Kemeny N. Metastatic colorectal cancer: from improved survival to potential cure. Oncology. 2010;78(3-4):237-248, PMID: 20523084.

2. T ejpar S. Influence of KRAS G13D mutations on outcome in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy with or without cetuximab. J Clin Oncol. 2011; 29(suppl): Abstract 3511.

3. D e Roock W, Jonker DJ, Di Nicolantonio F, et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA. 2010;304(16):1812-1820, PMID: 20978259.

4. G rothey A. Advanced colorectal cancer from the 2011 Annual Oncology Meeting. OncoFacts. http://oncofacts.com/archives/2011-annual-oncology-meeting-advanced-colorectal-cancer/. Accessed December 14, 2011.

5. T veit K, Guren B, Glimelius P, et al. Randomized Phase III study of 5-fluorouracil/folinate/oxaliplatin given continuously or intermit-tently with or without cetuximab, as first-line treatment of meta-static colorectal cancer: the NORDIC VII study (NCT00145314), by the NORDIC Colorectal Cancer Biomodulation group. Ann Oncol. 21(suppl 8): Abstract LBA20.

6. Assenat E, Desseigne F, Thezenas S, et al. Cetuximab plus FOLFIRINOX (ERBIRINOX) as first-line treatment for unresect-able metastatic colorectal cancer: a Phase II trial. Oncologist. 2011;16(11):1557-1564, PMID: 22016477.

7. M aughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised Phase 3 MRC COIN trial. Lancet. 2011;377(9783):2103-2014, PMID: 21641636.

8. H orita Y, Yamada Y, Kato K, et al. Phase II clinical trial of second-line FOLFIRI plus bevacizumab for patients with metastatic colorectal cancer: AVASIRI trial. Int J Clin Oncol. 2011 Oct 15. [Epub ahead of print], PMID: 22002492.

9. B ennouna J, Borg C, Delord JP, et al. Bevacizumab combined with chemotherapy in the second-line treatment of metastatic colorectal cancer: results from the Phase II BEVACOLOR Study. Clin Colorectal Cancer. 2011 Jul 28. [Epub ahead of print], PMID: 21803002.

10. C assidy J. Current role of biological agents in colorectal cancer. J Hong Kong Col Radiol. 2010;13(suppl):S3-S9.

11. C linicalTrials.gov. A Study of Avastin (bevacizumab) plus crossover fluoropyrimidine-based chemotherapy in patients with metastatic colorectal cancer. http://clinicaltrials.gov/ct2/show/NCT00700102?term=ML18147&rank=1. Accessed December 16, 2011.

12. Mitchell EP, Piperdi B, Lacouture ME, et al. The efficacy and safety of panitumumab administered concomitantly with FOLFIRI or irino-tecan in second-line therapy for metastatic colorectal cancer: the secondary analysis from STEPP (Skin Toxicity Evaluation Protocol With Panitumumab) by KRAS status. Clin Colorectal Cancer. 2011;10(4):333-339, PMID: 22000810.

13. P eeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinote-can (FOLFIRI) compared with FOLFIRI alone as second-line treat-ment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28(31):4706-4713, PMID: 20921462.

14. S eymour MT, Brown SR, Richman S, et al. Addition of panitumumab to irinotecan: results of PICCOLO, a randomized controlled trial in advanced colorectal cancer (aCRC). J Clin Oncol. 2011;29(suppl): Abstract 3523.

15. Seymour MT, Brown SR, Richman S, et al. Panitumumab in combi-nation with irinotecan for chemoresistant advanced colorectal can-cer: results of PICCOLO, a large, randomized trial with prospec-tive molecular marker stratification. 2011 European Multidisciplinary Cancer Congress. Abstract 6007.

16. v an Cutsem E. Intravenous (IV) aflibercept versus placebo in com-bination with irinotecan/5-FU (FOLFIRI) for second-line treatment of metastatic colorectal cancer (MCRC): results of a multinational Phase 3 trial (EFC10262-VELOUR). Ann Oncol. 2011;2 2(suppl 5): Abstract O-0024.

17. Tabernero J, Van Cutsem E, Lakomy R, et al: Results from VELOUR, a phase 3 study of aflibercept versus placebo in combination with FOLFIRI for the treatment of patients with previously treated meta-static colorectal cancer. Ann Oncol. 2011(suppl): Abstract 6LBA.

18. Eng C. A randomized, phase Ib/II trial of rilotumumab (AMG 102; ril) or ganitumab (AMG 479; gan) with panitumumab (pmab) versus pmab alone in patients (pts) with wild-type (WT) KRAS metastatic colorectal cancer (mCRC): primary and biomarker analyses. J Clin Oncol. 2011;29(suppl): Abstract 3500.

19. R ichards DA, Nemunaitis JJ, Vukelja SJ, et al. Final results of a randomized phase II study of perifosine in combination with capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients (pts) with second- or third-line metastatic colorectal cancer (mCRC). J Clin Oncol. 2010;28(15 suppl): Abstract 3531.

20. B endell JC, Nemunaitis J, Vukelja SJ, et al. Randomized placebo-controlled phase II trial of perifosine plus capecitabine as second- or third-line therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2011;29(33):4394-4400, PMID: 21969495.

21. D avies JM, Goldberg RM. Treatment of metastatic colorectal cancer. Semin Oncol. 2011;38(4):552-560, PMID: 21810514.

22. C linicalTrials.gov. Perifosine plus capecitabine versus placebo plus capecitabine in patients with refractory advanced colorectal cancer (X-PECT). http://clinicaltrials.gov/ct2/show/NCT00700102?term=ML18147&rank=1. Accessed December 16, 2011.

23. Bayer. Phase III trial of regorafenib in metastatic colorectal cancer meets primary endpoint of improving overall survival. 2011 (press release, October 26, 2011.) http://www.bayer.com/en/news-detail.aspx?newsid=15124. Accessed December 16, 2011.

24. H offland P. Results of a randomized, Phase II clinical trial for the novel oral nucleoside antitumor agent TAS-102 under development by Taiho Pharmaceutical Co., Ltd for metastatic colorectal cancer were presented at the 9th Annual Meeting of the Japanese Society of Medical Oncology held in Yokohama. 2011. Abstract 10428.

25. W endling P. Novel drug TAS-102 makes headway in refractory colorectal cancer. The Oncology Report. http://www.oncologyre-port.com/news/clinical/single-article/novel-drug-tas-102-makes-headway-in-refractory-colorectal-cancer/baf9bff605.html. Accessed December 16, 2011.

26. S hintani M, Urano M, Takakuwa Y, et al. Immunohistochemical char-acterization of pyrimidine synthetic enzymes, thymidine kinase-1 and thymidylate synthase, in various types of cancer. Oncol Rep. 2010;23(5):1345-1350, PMID: 20372850.

27. Chu E. An update on the current and emerging targeted agents in metastatic colorectal cancer. Clin Colorectal Cancer. 2011 Jul 11. [Epub ahead of print], PMID: 21752724.

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potential power of the surprise ques-tion when it is combined with the best empirical evidence. It is possi-ble that this strategy could also work in oncology.

We take predictive uncertainty seri-ously. A “yes” answer to the surprise question clearly indicates that the patient is very likely to be alive with-in a year. (Remember the question is: “Would I be surprised if this patient died in the next year?”) A “no” answer offers a predictive accuracy that the patient will die within the year of approximately 40%, which may be sub-stantially improved when coupled with other hard data. The “no” response is a relatively poor prognostication.

Nevertheless, if the answer to this question is “no,” oncologists are eth-ically required to inform the patient that the chance of survival is not good. Providing adequate warning to a patient can also produce superior pal-liative care consultations. The impor-tance of good end-of-life care cannot be understated.

Physicians should, however, keep two things in mind. First, the accura-cy level studied is only at the one-year mark and it makes sense that during the following year, many more patients will die making a clear majority who

live less than two years. Second, the ini-tial warning should be revisited when-ever there is a significant change in the patient’s condition—the initial warn-ing is not the final word. A change in circumstance could entail a different answer to the question.

The surprise question is subjective and probabilistic in nature, but it pro-vides an important heuristic device that helps clinicians reflect on patient outcomes and appears to help sharp-en clinician accuracy. This question can help oncologists avoid either act-

ing unreflectively from emotion or from pure scientific detach-

ment. Human brains have great potential to iden-

tify complex patterns derived from expe-rience and care-ful deliberation. If oncologists run this question through their minds, they have an opportu-nity to refocus and

deliberately evalu-ate the situation for

their patients. If the hard data about sur-

vival is consistent with an oncologist’s response

that he or she wouldn’t be surprised if the patient were

dead in a year, then disclosing this to the patient is ethically

obligatory. As with all ethical guidance, there are exceptions, but these should be few and have strong and obvious support. If there is a significant risk for death, then helping a patient refo-cus hope on a new goal will offset the idea of a life-limiting prognosis as one devoid of all hope.

The patient should be told that such estimations involve uncertainties and may be wrong. Care should be tak-en, however, not to provide unrealis-tic expectations. Although it is easiest to concentrate on last-chance efforts for treatment or enrollment in a new clinical trial in order to preserve the patient’s “hope” for a return to health and longevity, refocusing is most important.

Standard Default

An oncologist may believe that if the patient does not broach the ques-tion about survival, then it is ethical-ly acceptable to avoid the issue. It is true that a patient has a moral right to reject information. But the standard default should be to offer the informa-tion. Rejection of information should not be merely implicit. Even though a patient fails to raise the issue, the eth-ical obligation is to ask what types of information the patient desires. This respects the patient’s attainment of the best support and services, such as palliative care, hospice or some other style of care, as he or she enters a more

active dying phase. In a previous Clinical Oncology News

article, we explored ethically appropri-ate ways to provide dire information to patients (see QR code below). This includes taking into account the best physical setting and words to avoid and words that can be used.

Having discussed these points, the case of Mr. Tolland can now be bet-ter analyzed. In this case, the oncol-ogist, Dr. Sutherland, might ask her-self the surprise question and per-haps ask a colleague to review the case and give an opinion. Assume that both reach a negative answer—it would not surprise them if the patient died in a year. The objective data available also support the likelihood of the patient dying within the next year. Because the patient has expressed a desire to see his granddaughter get married in 18 months, Dr. Sutherland is reluc-tant to tell the patient her frank judg-ment about prognosis. Nevertheless, Dr. Sutherland is obligated to inform the patient of the significant likelihood of his passing before 18 months elapse. She assures the patient that he still has significant options in care regard-ing goals of living life as well as possi-ble in the time he has. Although this is the most ethical response, Dr. Suther-land still finds it emotionally difficult to deliver the news.

— Joseph P. DeMarco, PhD, Paul J. Ford, PhD

References

1. Moss AH, Lunney JR, Culp S, et al. Prognostic significance of the “surprise” question in cancer patients. J Palliat Med. 2010;13:837-840, PMID: 20636154.

2. Lamont EB, Christakis NA. Prognostic disclosure to patients with cancer near the end of life. Ann Intern Med. 2001;134:1096-1105, PMID: 11412049.

3. Cheng WW, Willey J, Palmer JL. Interval between palliative care referral and death among patients treated at a comprehensive cancer center. J Palliat Med. 2005;8:1025-1032, PMID: 16238515.

4. Cohen LM, Ruthazer R, Moss AH. Predicting six-month mortality for patients who are on maintenance hemodialysis. Clin J Am Soc Nephrol. 2010;5(1):72-79, PMID: 19965531.

CliniCal OnCOlOgy news • JanUaRy 2012 17PRN

Ethics

By Dr. DeMarco and Dr. Ford

Scan for Other Bioethics Articles

End-of-life Care: Examining Ethics

Sleeping Unto Death: Palliative

Sedation

What Is Success?Ethics and Disparate Patient Expectations

Yes, Physicians Must Interact With Pharma

The Cause of the Day for many pun-dits and academics is the terri-

ble wrongness of physicians taking any sort of payment from pharmaceuti-cal companies. Drug companies, other-wise known as Big Pharma, have been demonized by the media, academia and politicians. They make too much money;

charge too much; market too aggres-sively. We’ve all heard the litany of com-plaints. But, are they really evil? Are we really wrong to interact with them?

We are having a national discussion over the propriety of physician relation-ships with industry. The tone of that dis-cussion is hostile to both physicians and industry. The discussion is being large-ly conducted within medical journals, which themselves are partly support-ed by drug company advertising, and reported by news media that also prof-it from commercial advertising. Two of the most popular books on the sub-ject were written by former editors of a journal that accepts drug advertising, and charges a lot for it.1,2 Should we have different ethical standards for medical journals than we do for individuals? Per-haps so. But that argument is not being made. There is a whiff of hypoc-risy about the whole discussion.

It would be well to define some common assumptions. First, physicians can, and should, be paid for their time. The ethical position that physi-cians should work for nothing may be valid, but it pretty much closes off this discussion. Second, it is unethical for physicians to sell their opinions to

the highest bidder. We should not go out and urge other physicians to use a giv-en product simply because we are paid to do so.

This is, contrary to what many believe, a complex issue. To begin, is it ethical to work on drug development and clini-cal investigation? Most of us would say yes. How can it be otherwise? If physi-cians cannot ethically be paid to develop and test new drugs, then who is to car-ry out this vital work? Non-physicians? Employees of the drug companies? Con-gress and the media?

Suppose a physician serves on an advisory panel for, let us say, the devel-opment of a new cardiac drug. That

involves time and travel, perhaps oth-er expenses. If physicians cannot par-ticipate, I ask again: Who is going to do it? It is in society’s interest that the best clinicians advise the companies. Can it seriously be claimed that the compa-nies should develop drugs without input from physician clinicians?

Most drug studies are funded by contracts with institutions, although some are with individual physicians or groups. Does it make an ethical

No, Physicians Must Remain Independent of Pharma

One perception of the classic oath of Hippocrates is, “We hold those who

teach us and those who we teach to give knowledge without fee or covenant.”

Presentations by physicians that are sponsored by pharma ceutical compa-nies at expensive restaurants may be tainted by commercialism. The speak-

ers are chosen by the pharmaceutical company to speak favorably about the company’s product. Frequently, the PowerPoint presentations contain the same information found in drug infor-mation inserts or the Physicians Desk Reference. The new PhRMA Code developed by the pharmaceutical industry is the current guide for inter-acting with doctors.1

The new PhRMA Code of the phar-maceutical companies requires speakers to limit their discussion only to what is contained in the drug insert information. Open discussion

usually follows. Local

physician speakers often are given an honorarium ranging from $500 to $1,000. The American Medical Asso-ciation Code of Ethics 8.061—“Gifts from Industry to Physicians”—states that honorariums should be reason-able. I believe that “local” speakers, certainly those who are not recog-nized as experts in their field, should not receive any honorariums or com-pensation. It is their duty under the oath of Hippocrates to “teach to give knowledge without fee or covenant.”

Out-of-town speakers should have their travel expenses covered, but should only receive a small honorari-um for educational purposes and not be

motivated by profit. Frequently, a grant by a pharmaceutical company is given to a university department, and then the university chooses the appropriate speaker. Despite peer-group discussion and interaction among colleagues, the presentations certainly can be biased.2 In order to obtain a more unbiased view, it would be preferable to read the literature and attend university and hospital conferences.

There has been much written about conflict of interest of physicians, phar-maceutical companies, royalties and medical device companies in the lay literature such as The Wall Street Jour-nal, St. Louis Post-Dispatch, and The Kansas City Star.3-5 Movies such as “The Fugitive” and the “Constant Gar-dener” have highlighted this conflict. It is estimated that $8,000 to $13,000 is spent yearly by the pharmaceutical industry on each physician to promote their products.6

The federal government is establish-ing rules and regulations to minimize these conflicts requiring listing on the Internet of all monies given to physi-cians from pharmaceutical companies as a matter of public record. The Depart-ment of Health and Human Services published a draft proposal of new rules

Money for DrugsShould Physicians Be Paid for Pharmaceutical Development

and Clinical Investigations?

Editor’s Note: The following article was originally published in Missouri Medicine, september/October 2011;108:18-22.

Part 1 of a Three-Part Series

If physicians cannot ethically be paid to develop and test new drugs, then who is to carry out this vital work? Non-physicians? Employees of drug companies? Congress and the media?

Physicians should not receive even fully disclosed money from drug companies and medical device makers for research, consultation, royalties, lectures or CME efforts.

George Bohigian, MDProfessor of Clinical OphthalmologyDepartment of Ophthalmol-ogy and Visual Sciences Washington University St. Louis

Charles Van Way III, MD Professor of Surgery and The Sosland/Missouri Endowed Chair of Trauma Services The University of Missouri Kansas City

18 CliniCal OnCOlOgy news • JanUaRy 2012PRN

Pro/Con

difference whether the money goes directly to a physician or indirectly through the salary from a university? Surely not. Otherwise, anything could be justified by simply laundering the money through some conve-nient institution. One may argue that certain institutions, like universities and hospitals, have such high ethical standards that it is inconceivable that they are influenced by mere money. One may argue that, but one is unlikely to be believed.

Consider a quotation from Dr. Gor-don Gee, president of The Ohio State University. Now, Time magazine named Dr. Gee the best college president in the country in 2009, so he must be pret-ty well up in the profession. Recent-ly, Ohio State football coach Jim Tres-sel was caught in a particularly flagrant alleged violation of the NCAA rules. When asked whether he would fire the coach, he responded, “No. Are you kid-ding? I’m just hoping the coach doesn’t dismiss me.”3 Perhaps he was making a joke. A medical school dean once told me, many years ago, “Charlie, there is no such thing as dirty money.” In short, as much as universities would like to believe otherwise, there is little justifi-cation for handing the ethical decision making to them.

Perhaps the most troubling facet of this issue is represented by speakers’ bureaus. We all benefit from experts traveling about the country and teach-ing the rest of us. Most frequently, that teaching is at medical meetings, but it also occurs at universities or in hos-pitals. Funding comes from a variety of sources. Leading universities fund such activities out of their endow-ments, but other universities and most hospitals find the money where they can. Frequently, the money comes from

the pharmaceutical industry, directly or indirectly. Med-ical societies receive dues from members, but also grants from drug companies.

For some, it may feel good to say that no such money should

ever be accepted. But we would be the poorer if these activities were to be curtailed.

Indeed, we regard it as virtuous that physicians seek out continuing medi-cal education, and our licensing agen-cies even require it. We should real-ize that some physicians are abusing the system. We have a few colleagues going around the country making hun-dreds of thousands a year advocat-ing this or that particular treatment. Many others don’t make as much mon-ey, but are nevertheless shills for one company or another. Sure, they prob-ably believe in the treatment they are promoting. They may use it them-selves. But if you were in their audi-ences, knowing how much they were paid would influence how much cred-ibility they might be accorded.

We need more transparency. Put the information out there, and let every-one see. A number of states, such as Minnesota and Maine, have enact-ed reporting laws. Several companies, including Pfizer, Merck, Eli Lilly and GlaxoSmithKline, report their finan-cial transactions with physicians.4 There is also a public database that reports such monies.5

The Health Care Reform law, the Patient Protection and Affordable Care Act, mandates a national database. Spe-cifically, drug and device companies must report all payments to doctors and teaching hospitals. Companies must post the information. The Department of Health and Human Services will also post data, beginning in 2013, and there

are serious fines for failure to report.5

Our profession exists in symbiosis with the pharmaceutical industry. It is in society’s interest for us to work with drug companies to ensure that they develop the drugs we and our patients need. But we are not their apologists. It is strongly in our interest to see that we and they behave in an ethical man-ner. If that causes us distress and soul-searching over the next few years, so much the better.

Make no mistake. There have been problems, and they are our collective responsibility. We should not toler-ate the “bad apples” in our midst. We should assist in efforts to make the pro-cess as transparent as possible. More-over, we should educate policymak-ers and the public on the complexities of our interaction with those who pro-duce the drugs and devices on which we all depend.

Let us not be seduced by the argu-ments of people who are not our friends. We cannot practice medicine without pharmaceuticals. But we can practice medicine just fine without politicians or the media. They are not our friends; nor are they unbiased. They have unques-tionably hurt the medical profession over the past two decades. Neither the U.S. Senate nor The New York Times can make drugs or develop new ones. Yet they are generating a demand for an unrealistic ethical purity law, prohib-iting all paid constructive contact with drug companies. Their arguments are that physicians are greedy, foolish and easily manipulated by drug companies. But there is neither merit nor reality in that specious assertion.

Most physicians are actually fair-ly hard to manipulate. Ask anyone who has to deal with us. Most physicians are ethical. Greed is a characteristic of politicians far more than of physicians.

The public trusts physicians much more than they trust journalists.

To counter these arguments, we can advance the principles of autonomy, individual responsibility and profession-alism. These are often brushed aside. Yet it is our professionalism, judgment, and responsibility as physicians that make us of value to our patients. With-out these, we become simple health care workers, cogs in the machine. There are certainly problems in our relationships with Big Pharma, and we must repair them. But barring all contact would be a poor answer.

Ultimately, we serve our patients, and through them, society at large. We owe them our best judgment, and we owe them our professionalism. We will not accomplish either by adhering to a mindless prohibition, as appealing as that may appear to the moralist in all of us.

References

1. Angell M. The Truth About the Drug Companies: How They Deceive Us and What to Do About It. New York: Random House, 2005.

2. Kassirer J. On the Take: How Medicine’s Complicity with Big Business Can Endanger Your Health. Oxford: Oxford University Press, 2005.

3. Waiting For Next Year (WBNY). http://www.waitingfornextyear.com/2011/03/the-gee-comment-no-im-not-talkin-alonzo. Accessed March 29, 2011.

4. ProPublica. Dollars for Docs. http://projects.propublica.org/docdollars. Accessed April 3, 2011.

5. Weintraub A. New Health Law Will Require Industry To Disclose Payments To Physicians. Kaiser Health News, April 26, 2010. http://www. kaiserhealthnews.org/Stories/2010/April/26/physician-payment-disclosures.aspx. Accessed April 5, 2011.

Dr. Van Way reported no relevant conflicts of interest.

that relate to financial conflict of interest, which includes dis-closure by either the company or the institution. This is part of the Sunshine laws, section 6002, in the new Patient Pro-tection and Affordable Care Act passed by Congress.7 Currently, the pub-lic has access to how much a physician in Missouri and other states receives from the top eight pharmaceutical com-panies in honorariums and compensa-tion by searching the site Pro Publica, an independent nonprofit organization that was awarded the 2010 Pulitzer Prize for investigative reporting.8

Research money by the medical indus-try may be given to the researcher but it has been demonstrated that industry-supported research is considerably more biased than grants from the National Institutes of Health.9 It is unethical for

a physician to have a financial interest in the company from which he or she is seeking the funding, for example, if he or she has a paid consulting rela-

tionship with the company, is a co-founder of the company or

otherwise holds equity in the company, and so on. An example of this type of pol-icy can be seen in the Washington Uni-versity in St. Louis Conflict of Interest Guidelines.10

The physician-researcher should remain independent of the pharmaceu-tical company sponsoring the project and be able to publish the results both positive and negative in any journal he or she wishes. All information should be transparent and honest with the pharmaceutical companies. Keeping the best interest of the patient in mind should be our guiding principle. We

need to keep the trust of our patients and the public sacred.

References

1. Glover T. PM 360, The full spectrum of product management, Jan 2009. http://www.inventivhealth.com/about_us/down-loads/pm360_2009-01.pdf.

2. Roseman M, et al. Reporting of con-flicts of interest in meta-analysis of tri-als of pharmacological treatments. JAMA. 2011;305(10):1008-1017.

3. Gregorian C. Doctors Talk about Drug Firm Payments. St. Louis Post Dispatch, Novem-ber 28, 2010. http://www.stltoday.com/lifestyles/health-med-fit/fitness/ article_ff1fe84a-671b-5ed7-9ae8-1944bb62e8ef.html.

4. Gregorian C. Database has payment to 17,000 Doctors. St.Louis Post Dispatch, November 29, 2010. http://www.stlto-day.com/lifestyles/health-med-fit/fit-ness/article_0cd2662c-970e-5311-ad0f-61418464cb33.html.

5. Carreyrou J. Top Spine Surgeons Reap Royalties, Medicare Bounty. Wall Street

Journal. December 20, 2010. http://online.wsj.com/article/SB1000142405274870 3395204576024023361023138.html.

6. Wazana A. Physicians and the pharmaceuti-cal industry: is a gift ever just a gift? JAMA. 2000;283:373-380.

7. Congressional Record Office of the Legisla-tive Counsel Patient Protection and Afford-able Care Act. Section 6002 June 9, 2010 p 624. http://docs.house.gov/energycom-merce/ppacacon.pdf.

8. Ornstein C. What drug companies are pay-ing your doctor. Dec 10, 2010. Pro Publica. http://projects.propublica.org/docdollars/.

9. Benkelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA. 2003;289(4):454-465.

10. Washington University Guidelines on Con-flict of Interests. http://research.wustl.edu/ComplianceAreas/COI/Pages/COI.aspx.

Dr. Bohigian reported no relevant conflicts of interest.

CliniCal OnCOlOgy news • JanUaRy 2012 19PRN

Pro/Con

with advanced, nonresectable CRC.Previously, a study by Tournigand et

al was one of the first to address the issue of whether there might be an optimal sequence of combination regi-mens.3 Based on this study, there does not appear to be an optimal sequence with respect to the use of combina-tion regimens. Two intriguing studies, CAIRO4 (CApecitabine, IRinotecan, and Oxaliplatin in advanced colorec-tal cancer) and MRC FOCUS5 (Medical Research Council Fluorouracil, Oxali-platin, and CPT11[Irinotecan]—Use and Sequencing), have addressed the important issue of whether combina-tion chemotherapy is superior to the sequential use of individual drugs and/or combination regimens for the treat-ment of advanced CRC.

The results of the current study by Ducreux et al are not much different from the findings from these previous studies: 1. The CAIRO study randomized

820 patients to sequential ther-apy (first-line capecitabine, sec-ond-line irinotecan and third-line capecitabine/oxaliplatin [arm A]) or combination treatment (first-line capecitabine/irinotecan, and second-line capecitabine/oxaliplatin [arm B]). The primary end point was OS, and secondary objectives included PFS, RR and toxicity profile. Medi-an OS in the sequential treatment arm was 16.3 months and in the com-bination arm 17.4 months (P=0.328). Progression-free survival 2 (for sec-ond-line treatment) and PFS3 (third-line treatment) were not significant-ly different in the two arms. Not surprisingly, the overall RR in the first-line treatment was significant-ly better in the combination arm than with sequential therapy (41% vs. 20%; P<0.0001). As anticipat-ed, toxicity rates were higher in the combination arm in first-line thera-py, including grade 3 nausea, vomit-ing, diarrhea, neutropenia and febrile neutropenia.4

2. The FOCUS trial enrolled 2,135 previ-ously untreated patients and random-ized them to three treatment strat-egies. Strategy A was single-agent 5-FU with leucovorin until failure, followed by single-agent irinotecan. Strategy B began with single-agent 5-FU until failure, followed by com-bination chemotherapy (5-FU/irino-tecan or 5-FU/oxaliplatin). Strate-gy C was combination therapy in the first line (5-FU/irinotecan or 5-FU/oxaliplatin). Within arm A, 35% of patients were unable to receive sec-ond-line chemotherapy. Only 56% of patients received the planned sec-ond-line therapy in arm B. Also of note, 55% of patients in arm C were able to receive salvage chemotherapy versus 43% of patients in arms A and B. Median survival was 13.9 months in arm A and ranged from 15 to 16.7 months in arms B and C. No signifi-cant difference was observed in OS between irinotecan and oxaliplatin in first- or second-line combination treatment arms.5

Neither of these trials showed improvement in OS with combination or sequential therapy in a prospec-tive, randomized fashion, leading the authors to conclude that sequential therapy might be equally efficacious as combination treatment.

Results from a trial that compared sequential FOLFOX or FOLFIRI with FOLFOXIRI in the first-line setting conclude that combination chemother-apy may be the preferred treatment for those patients who may become eligible for curative resection.6 This view was taken by the FOCUS investigators, lead-ing them to exclude this patient popula-tion in that study.

Just like the FOCUS and CAIRO stud-ies, Ducreux et al did not include bio-logic agents in their treatment plat-forms. As we have seen from data from Hurwitz et al7 and the TREE8 (Three Regimens of Eloxatin [oxali-platin]) and BICC9 (Bolus, Infusion-al, or Capecitabine with Camptosar-Celecoxib) trials, among others, adding

targeted therapy to conventional agents improves outcomes.1 It is difficult to predict which patients might have more aggressive disease or a poorer perfor-mance status later on and thus might not be able to receive additional treat-ment after first progression. Because exposure to all active agents appears to be a key feature in maximizing OS, com-bination therapy would increase this probability.

As we take stock of what is now avail-able, we need to clarify how these agents will be used to maximize out-comes. This might include optimizing RRs with at least three agents when curative resection is the goal, or main-taining quality of life with sequential therapy if exposure to all agents is a rea-sonable expectation. Sequential mono-therapy starting with capecitabine or 5-FU/LV with or without bevacizumab and then proceeding to either oxalipla-tin- or irinotecan-based chemotherapy as second-line therapy may be consid-ered in patients who are asymptomatic, in those with relatively slow-growing disease and/or in those with multi-ple sites of disease that are deemed to be unresectable. This is in line with National Comprehensive Cancer Net-work guidelines. Additionally, mono-therapy may be more appropriate in elderly patients and in those with sig-nificant comorbidities. In contrast, ini-tiation with combination therapy is more appropriate in patients who have excellent performance status and clin-ically aggressive disease, in those with significant symptoms and/or in those who may be considered for salvage via surgical resection.

From the available data, the current standard of care for the vast majority of patients remains combination che-motherapy with a biologic agent in the untreated mCRC setting. It is expect-ed that prognostic and predictive fac-tors and pharmacogenomic data will be refined in such a way that we can bet-ter recognize subcategories of CRC and individual variability in drug processing that will be useful in helping physicians

and their patients make more informed choices among the various options.

References

1. Saif MW, Kang SP, Chu E. Treatment of metastatic colorectal cancer: from cytotox-ic agents to molecular agents and multitar-geted strategies. Oncology (Williston Park). 2006;20(14 suppl 10):11-19.

2. Ducreux M, Malka D, Mendiboure J, Eti-enne PL, et al., for the Fédération Franco-phone de Cancérologie Digestive (FFCD) 2000–05 Collaborative Group. Sequen-tial versus combination chemothera-py for the treatment of advanced colorec-tal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol. 2011;12(11):1032-1044.

3. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22(2):229-237.

4. Koopman M, Antonini NF, Douma J, et al. Sequential versus combination chemothera-py with capecitabine, irinotecan, and oxali-platin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007;370(9582):135-142.

5. Seymour MT, Maughan TS, Ledermann JA, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled tri-al. Lancet. 2007;370 (9582):143-152.

6. Souglakos J, et al.: FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinote-can) vs FOLFIRI (folinic acid, 5-fluoroura-cil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a mul-ticentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006;94(6):798-805.

7. Hurwitz HI, Fehrenbacher L, Hainsworth JD, et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regi-men for first-line metastatic colorectal can-cer. J Clin Oncol. 2005;23(15):3502-3508.

8. Hochster HS, Hart LL, Ramanathan RK, et al.: Safety and efficacy of oxaliplatin/fluoro-pyrimidine regimens with or without bev-acizumab as first-line treatment of met-astatic colorectal cancer (mCRC): final analysis of the TREE Study. J Clin Oncol. 2006;24:148s(suppl, abstr 3510).

9. Fuchs CS, Marshall J, Barrueco J. Random-ized, controlled trial of irinotecan plus infu-sional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorec-tal cancer: updated results from the BICC-C study. J Clin Oncol. 2008;26(4):689-690.

From the Journal of Clinical Oncology

A “wait-and-see” policy after chemo-radiotherapy appears to be a safe

and feasible approach for some patients with rectal cancer.

The study, published in the Jour-nal of Clinical Oncology (2011;29:4633-4640, PMID: 22067400) found that patients with rectal cancer who have achieved a clinical complete response (cCR) after neoadjuvant chemoradio-therapy experience outcomes similar

to those who undergo surgery. Patients were judged to have cCR based on find-ings from magnetic resonance imaging (MRI), nodal evaluation and endosco-pies with biopsy.

Of the 21 patients treated with neoad-juvant chemoradiotherapy but no sur-gery, all but one remained alive with-out disease after a mean follow-up of 25 months (±19 months). One patient devel-oped a small endoluminal local recur-rence without nodal recurrence after 22 months of follow-up. The patient

eventually underwent transanal endo-scopic microsurgery, which resulted in complete resection of the recurrence.

A control group of 20 patients who achieved pathologic complete response (pCR) after chemoradiother-apy and went on to have a total meso-rectal excision (TME) had a mean fol-low-up of 35 months (±23 months). Two control patients died, one from metastatic disease (diagnosed after three years of follow-up) and the other from surgical complications associated

with colostomy closure. None of the control patients experienced local recurrence.

In the wait-and-see group, the cumu-lative probability for two-year disease-free survival was 89% and 100% for two-year overall survival. In the control group, these probabilities were 93% and 91%, respectively; the difference in sur-vival rates was not significant.

“A wait-and-see policy for clinical complete responses after chemoradio-therapy for rectal cancer with strict

‘Wait and See’ an Attractive Alternative in Some Rectal Cancers

continued from page 5

continued on page 21

20 CliniCal OnCOlOgy news • JanUaRy 2012SOLID TUMORS

Colorectal

selection criteria and follow-up with up-to-date imaging techniques is feasi-ble and safe,” concluded the investiga-tors, from Maastricht University Med-ical Center, The Netherlands. “Out-come is at least comparable with that of patients with a pathologic complete response after surgery.”

In an accompanying editorial (J Clin Oncol 2011;29:4604-4606, PMID: 22067395), Joel E. Tepper, MD, and Bert H. O’Neil, MD, from the University of North Carolina Lineberger Comprehen-sive Cancer Center in Chapel Hill, wrote that “results have been impressive,” despite the limited length of follow-up.

The editorial noted that the results were achieved with less toxicity and better short-term bowel function in the observed patients compared with those who underwent surgical resection. The authors added that these results sup-port and enhance previous research, and raise the possibility that this approach

could be generalized to a larger portion of the patient population.

Dr. Maas and colleagues noted that patients with cCR showed a strong pref-erence for the wait-and-see approach over resection primarily because it offered the possibility of avoiding major surgery and a permanent colostomy.

From the Journal of Clinical Oncology

The prognosis of a patient with glio-blastoma multiforme (GBM) who

has survived for three years may be as good or even better than the prognosis for a newly diagnosed patient, accord-ing to a probability analysis of survival in these patients.

Disease outcome for patients with cancer is typically described in terms of estimated survival rates that are based on the Kaplan-Meier statistical meth-od. But these estimates, which are cal-culated with respect to the time of ini-tial diagnosis, may not be pertinent to patients with GBM who have already survived for a period of time and want to know their remaining life expectancy.

Conditional probability—the probabili-ty of surviving a certain number of years post-diagnosis, after having already sur-vived a given number of years—offers more relevant information for survivors of GBM, according to researchers led by Mei-Yin C. Polley, PhD, of the National Cancer Institute in Rockville, Md.

The researchers reported condition-al survival probabilities on the basis of 498 patients with newly diagnosed GBM who received radiation therapy and che-motherapy and were enrolled in sev-en Phase II clinical trials (J Clin Oncol 2011;29:4175-4180, PMID: 21969507). The Cox proportional hazards mod-el was used to evaluate the prognostic values of age, Karnofsky performance score (KPS) and prior progression one

year post-diagnosis. The constant haz-ard assumption also was assessed.

The results show the probabilities of surviving an additional year given sur-vival to one, two, three or four years: 35%, 49%, 69% and 93%, respectively. For patients who survived for one year, lower KPS and progression were signifi-cantly predictive of shorter survival, but age was not.

“The data suggested that the surviv-al probabilities decreased most rapid-ly in the first two years after diagnosis and leveled off in subsequent years,” the investigators reported. “This sug-gests a nonconstant hazard of death over time and indicates that the prog-nosis of patients with GBM surviving the first two years after diagnosis may

be more optimistic.”As expected, the survival estimates

were “discouraging”: one-, two-, three-, and four-year estimates were 58%, 20%, 10% and 7%, respectively. “However, the conditional probability of surviv-ing an additional year after survival to three years post-diagnosis exceeds the one-year survival rate,” the investigators wrote. Therefore, a patient who has sur-vived for three years may have a progno-sis similar to a newly diagnosed patient.

The authors concluded that “condi-tional probabilities provide encourag-ing information regarding life expectan-cy to survivors of GBM. For single-arm trials, we advise using individual patient data from historical data sets for effica-cy comparisons.”

GBM: After Two Years Survival Rises Dramatically

Glioblastoma is the most common tumor of the brain and is a highly

malignant neoplasm with an average survival of one to two years. How-ever, Polley and colleagues recent-ly analyzed the conditional survival of about 500 patients treated in one of several prospective clinical trials. They demonstrated that the likeli-hood of surviving an additional year increased for every year alive. For example, among patients living one year after diagnosis, 35% remained alive after two years (one year later).

This increased over time, so that 49% of patients alive after two years were still alive after three years; 93% of those alive after four years were alive after five.

Individual predictors were diffi- cult to identify. These results echo a landmark Phase III study (Lan-cet Oncol 2009;10:459-466, PMID: 19269895) in which long-term fol-low-up showed that almost 30% of patients in the most favorable

prognostic group—under age 50 at diagnosis, minimally sympto- matic and complete surgical resec-tion—survived five years from diag-nosis when treated aggressively. Together, these results clearly dem-onstrate that long-term survival from glioblastoma is possible. With additional translational research, the field may achieve the elusive goal of durable disease control in most if not all patients.

Is a “wait-and-see” approach fol-lowing a cCR to preoperative chemo-radiotherapy in localized rectal can-cer feasible?

This is an important question that is unlikely to be answered in a ran-dom-assignment clinical trial. The appeal of not having a colostomy pro-vides adequate motivation for some patients with low rectal cancers to not have surgery following completion of

chemoradiation for localized rectal cancer. However, the risk for local or distant recurrence that could have been avoided with a standard resection must be balanced against the prospect of life with a permanent colostomy in these patients. The decision is no doubt dif-ficult for many.

The article by Maas et al provides prospective data that may help guide this difficult decision in some patients. Specifically, in a cohort of 192 patients with locally advanced rectal cancer, 21 patients met strict prespecified crite-ria for achieving a cCR. These patients were offered participation in a clinical study in which they did not undergo TME surgery, as would be our standard approach. The cohort of patients who agreed to clinical trial participation and did not pursue resection was compared with a cohort of 20 patients who under-went TME surgery and were found to

have a patholog-ic CR. Notably, the two groups either were not random-ly assigned to sur-gery or had no surgery. Instead, the two groups were dissimi-lar in an impor-tant way—namely, there was a clear difference in that 75% of the pCR cohort proceeded to sur-gery because they had suspicious radio-graphic findings of persistent disease.

Nonetheless, the study did demon-strate that patients who did not under-go TME surgery following cCR had superior bowel function—including less incontinence and fewer postoper-ative complications—than the cohort that proceeded with standard TME surgery. Although the sample size is

small, these data lay the foundation for a possible wait-and-see approach for patients who have a cCR following stan-dard chemoradio-therapy for local-ized rectal cancer. Importantly, the cri-teria for selection

of patients who might be eligible for such an approach was carefully pre-specified and involved highly spe-cialized imaging, such as pelvic MRI enhanced with either miniature supermagnetic particles of iron oxide or gadofosveset trisodium, as well as diffusion-weighted MRI used to dif-ferentiate tumor from normal rectum. Such an approach of watchful wait-ing would therefore not be routinely advised, at least not yet.

Andrew B. Lassman, MDAssociate Professor of MedicineColumbia University College of Physicians and SurgeonsChief of Neuro-OncologyNewYork-Presbyterian/Columbia, New York City

EXPERT INSIGHT

Manish A. Shah, MDAssistant Professor of MedicineWeill Cornell Medical CollegeDirector, Gastrointestinal Oncology Program,Division of Hematology and Medical OncologyNewYork-Presbyterian/Weill CornellNew York City

EXPERT INSIGHT

CliniCal OnCOlOgy news • JanUaRy 2012 21SOLID TUMORS

Brain

Breast Cancer Symposium (SABCS; abstract S5-1), where it was received as the biggest news coming out of the meeting, and simultaneously published in The New England Journal of Medicine.

“The magnitude of this effect is unprecedented. This is the most posi-tive trial in the history of patients with HER2-positive advanced disease and for that matter in patients with advanced breast cancer,” said José Baselga, MD, associate director of the Massachusetts General Hospital Cancer Center in Bos-ton, who presented the results.

Other experts in the field are simi-larly enthusiastic about the drug. “For patients meeting the eligibility criteria, pertuzumab may be a new standard,” said Kent Osborne, MD, the director of the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston, during discussion of the trial at SABCS.

However, cost is a concern for many oncologists. At press time, Roche had applied for approval, and a company spokesperson said a price had not yet been decided.

The combination of pertuzumab and trastuzumab works because the drugs have complementary mechanisms of action. The HER signaling pathway is a complex, redundant, evolvable, lay-ered network that includes four mem-brane receptors—HER1 to HER4 and 11 ligands. The pathway can be acti-vated in a variety of ways, but the most predominant is ligand binding. “When these ligands bind to receptors on the membrane, they induce receptor homodimerization, where two of the same kind of receptor bind to each oth-er, or heterodimerization, where one type of receptor can bind with another family member,” Dr. Osborne said.

Trastuzumab works predominantly by inducing antibody-dependent cell-mediated cytotoxicity (ADCC), pre-venting HER2 extracellular domain shedding and inhibiting signaling of HER2 homodimers; it interferes only slightly with HER1/HER2 and HER2/HER3 heterodimers. Pertuzumab acti-vates ADCC and inhibits HER1/HER2 and HER2/HER3 heterodimer signal-ing, thus providing a more complete blockade of the HER signaling pathway.

“The two agents, when given together, provide a more comprehensive block-ade of HER2 signaling and result in greater anti-tumor activity than either agent alone,” said Dr. Baselga.

CLEOPATRA included 808 patients with HER2-positive, locally recurrent, unresectable or metastatic breast can-cer with measurable or nonmeasurable disease. Eligibility criteria included left ventricular ejection fraction (LVEF) of at least 50% at baseline, no more than

one hormonal regimen for MBC prior to randomization and no history of con-gestive heart failure or LVEF decline to less than 50% during or after pri-or trastuzumab therapy. Prior neoad-juvant systemic chemotherapy, includ-ing trastuzumab and/or taxanes, was allowed if followed by a disease-free interval of at least 12 months. The medi-an age was 54 years.

Patients were randomized to receive docetaxel, trastuzumab and

pertuzumab or docetaxel, trastuzum-ab and placebo (Figure 2). The tri-al arms were well balanced in terms of performance status and prior thera-py with anthracyclines, hormones, tax-anes and trastuzumab. “About 50% of patients were ER- and/or PR-positive,” Dr. Baselga said.

Independently assessed median PFS, the primary end point, was 18.5 months in patients receiving pertuzumab and 12.4 months in the control arm (hazard

ratio [HR], 0.62; 95% confidence inter-val, 0.51-0.75; P<0.0001). Improvement was seen in all subgroups. The interim analysis of overall survival (OS) did not cross the prespecified stopping bound-ary for statistical significance, according to Dr. Baselga, but looked very promis-ing with an HR of 0.64 (P=0.0053). An exploratory statistical analysis showed that pertuzumab also improved objec-tive response rate (80.2% vs. 69.3%), complete response rate (5.5% vs. 4.2%) and partial response rate (74.6% vs. 65.2%) (P=0.0011).

Adverse events (AEs), including diar-rhea, rash, mucosal inflammation and febrile neutropenia, were more com-mon in the experimental arm. These primarily grade 1-2 AEs occurred dur-ing docetaxel therapy and were char-acterized by Dr. Baselga as manage-able (Figure 1). No cardiac AEs were identified.

“CLEOPATRA met its primary end point and demonstrated a statistical-ly significant and clinically meaning-ful improvement in PFS,” Dr. Baselga said. “This new regimen may be prac-tice-changing in HER2-positive first-line metastatic breast cancer.”

Dr. Osborne said the well-conduct-ed study provided convincing data that adding pertuzumab to the regimen of trastuzumab and docetaxel increased PFS, OS and response rate. He point-ed out that 90% of patients had not received prior trastuzumab and out-comes likely would be worse in patients who had.

However, Dr. Baselga had present-ed an analysis of 88 patients who had received prior trastuzumab and showed a PFS HR of 0.62 in favor of pertuzum-ab. This was similar to the HR of 0.60 in favor of pertuzumab in an analy-sis of 288 similar patients who had not received trastuzumab.

Dr. Osborne also pointed out that the improved outcomes were less dramat-ic in ER-positive patients than in ER-negative patients (HR, 0.72 vs. 0.55). Similar to many other clinical trials in this patient population, he said, “Even though ER was present, it was not tar-geted. I suppose this is because we think that tamoxifen is antagonistic with chemotherapy, so we don’t com-bine them together, but I would point out that we know very little about com-bining chemotherapy with estrogen-deprivation therapy.”

A trial adding an aromatase inhibitor into the mix might yield better results. “This is something that does need to be studied,” Dr. Osborne said.

—Kate O’Rourke

Dr. Baselga disclosed that he is a consultant for Roche. Dr. Osborne disclosed that

he is a consultant for AstraZeneca, Novartis and Genentech.

CLEOPATRAcontinued from page 1

‘This is the most positive trial in the history of patients with

HER2-positive advanced disease and for that matter in patients

with advanced breast cancer.’ —José Baselga, MD

Figure 2. Design of CLEOPATRA trial. less than 6 cycles allowed for unacceptable toxicity or disease progression; more than 6 cycles allowed at investigator discretion.

Pertuzumab plus trastuzumab until disease progression

Placebo plus trastuzumab until disease progression

Docetaxel, ≥6 cycles recommended

Docetaxel, ≥6 cycles recommended

Arm A: 406 patients

Arm B: 402 patients

Pertuzumab: 840 mg loading dose, 420 mg maintenance

Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance

Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated

80

70

60

50

40

30

20

10

0

Incid

en

ce, %

Pertuzumab,trastuzumab, docetaxel

Placebo,trastuzumab, docetaxel

Diarrhea Rash Mucosal Febrile inflammation neutropenia

66.8

46.3

33.7

24.227.8

19.9

13.8

7.6

Figure 1. Comparison of key adverse events (all grades).

22 CliniCal OnCOlOgy news • JanUaRy 2012SOLID TUMORS

Breast

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1-800-813-HOPE (4673)

www.cancercare.org

Help and Hope

Researchers say the PHP technique could be used to treat other tumors that cause liver metastases, such as neuro-endocrine or colon, if trials yield pos-itive results. This news comes from a study reported by investigators from the University of Pittsburgh at the 2011 European Multidisciplinary Cancer Congress (EMCC).

“This is the first treatment to show a clinical benefit in patients with liv-er metastases from ocular melano-ma,” said lead investigator James Pingpank, MD, professor of surgery at the University of Pittsburgh School of Medicine and a surgical oncologist with UPMC Cancer Centers.

The Phase III trial randomized 93 patients to receive PHP or best alternative care (BAC), which could involve interleu-kin-2, ipilimumab (Yervoy, Bristol-Myers Squibb), transcatheter arterial chemo-embolization, systemic chemotherapy or inclusion in a clinical trial.

Patients in the PHP arm received high doses of melphalan, 3 mg/kg via a 30-minute hepatic artery infusion, using specially designed catheters, every four to five weeks for up to four cycles.

In the experimental arm of the trial, reported at the annual meeting of the American Society for Clinical Oncology, patients in the PHP arm had a median PFS of 6.1 months compared with just 1.6 months with BAC—a reduction in risk of 64% (P≤0.001).

The new data presented at EMCC indicate that the PFS benefit contin-ues, and even extends to patients who crossed over from the BAC arm at the conclusion of the experimental phase. Median PFS in the crossover group was 6.5 months overall. The difference was even more significant in patients with metastases confined to the liver: Median PFS in the BAC group was 1.6 months, compared with eight months in the PHP group (P≤0.0001).

Ocular melanoma, the most common primary cancer of the eye in adults, is diagnosed in about 2,500 adults annual-ly in the United States. Approximately half of these patients will develop liver metastases, for which life expectancy typically ranges between six and nine months.

However, the improvement in PFS did not appear to extend to overall survival (OS), which at 12 months was 26% with BAC and 29% with PHP. Median survival was 9.9 versus 11.4 months, respectively.

Overall survival is almost certainly confounded by the fact that so many of the BAC arm—more than half—crossed over to the experimental therapy, Dr. Pingpank said, especially because some

patients randomized to the experimen-tal arm actually progressed in their dis-ease between randomization and ther-apy, and ultimately went on to become among the trial’s earliest deaths.

“Still, the conclusions would have been much stronger if an overall surviv-al benefit had been demonstrated,” said Nikhil Khushalani, MD, section chief for soft tissue and melanoma medicine at Roswell Park Cancer Institute in Buffalo, N.Y. “This finding makes us question whether local control (in the liver) trans-lates into superior survival at all. Maybe PHP should be limited to patients with ‘liver-only’ metastases.”

But how absolutely can one state that disease is confined to the liver? “With the resolution on the scans we have, you’re always going to see a shadow on a node here or a single bone met,” said Dr. Pingpank. “But in the presence of significant liver disease, those patients will die of liver failure before you can ever document that that bone met is or isn’t real. Ideally, yes, you would nev-er treat someone with a local therapy unless they had purely liver disease, and when you have other therapeu-tic options, you don’t—but the reality of this disease is that we don’t have those options.”

Although the rate of adverse events was higher in the PHP arm than the BAC arm, Dr. Pingpank noted that side effects were primarily short-lived. “Side effects were predominantly neutropenia and thrombocytopenia. The majority of patients were able to undergo multiple treatments in the PHP arm, as toxicity resolved, whereas the major toxicity in the control arm was liver failure and/or death on treatment from disease pro-gression,” he said. “Most patients retain 80% or more of their daily functional

status, and return to full performance once therapy is completed.”

Nonetheless, there are some toxicity concerns, Dr. Khushalani noted. “There was undoubtedly some systemic absorp-

tion of melphalan as more than half the patients on PHP developed low white cell counts and platelet counts,” he said. “And there were three deaths in this treatment arm, two of which were related to low white cell counts and infection.”

Although ocular melanoma is rela-tively rare, the PHP technique could be applied to other tumors with liver metastases. Dr. Pingpank’s team also presented encouraging Phase II data in neuroendocrine tumors. “They’ve defi-nitely demonstrated efficacy in a Phase II setting for patients with metastat-ic neuroendocrine cancers,” said Paula Novelli, MD, a clinical assistant profes-sor of Vascular Interventional Radiology at the University of Michigan’s Comprehensive Cancer Center, Ann Arbor, who specializes in liver-directed oncologic therapies. “This technology could also be expanded to other tumor types. For example, melphalan has pre-viously demonstrated efficacy at high doses, using a different delivery system, in metastatic colorectal cancer, so that would be another area for study.”

In fact, the PHP infusion device, manufactured by Delcath Systems, has already been approved in Europe for the treatment of all liver tumors. But in February, citing safety concerns, the FDA held up Delcath’s new drug appli-cation for the system. Now that the Phase III trial is completed, no other tri-als of the device are currently ongoing in the United States, so the therapy remains unavailable here.

“We were startled that approval didn’t occur,” said Dr. Novelli, whose institu-tion was one of those providing BAC to patients in the trial who did not random-ize to PHP. “I expect that they will resub-mit soon, and I understand that they will be opening up several smaller trials this

year. We hope to be one of those sites.”Dr. Novelli acknowledged that the

procedure is not without its challenges. Most patients become hypotensive dur-ing the procedure on pressor medica-tions; some stay in the intensive care unit for several days post-procedure. “I think this procedure will have to be targeted to a younger, healthier population,” she said. “Ocular melanoma is the perfect population for this, because we have a lot of young patients in their late 20s or ear-ly 30s, without any systemic comorbidi-ty. Patients with neuroendocrine tumors also tend to be quite healthy other than the disease itself, so that is another ide-al indication.”

PHP is costly; its use may be limited to centers of expertise, Dr. Khushalani noted. “With the caveat that cross-comparisons with other treatments are difficult, using hepatic arterial chemoembolization (HACE) is proba-bly simpler and potentially equieffica-cious, although only a randomized tri-al between the two procedures will be able to tell us that,” he added. “Maybe some combination of local therapy, such as HACE or PHP, plus systemic thera-py to tackle liver and extrahepatic dis-ease concurrently, will be the next step.”

—Gina Shaw

The study was sponsored by the National Cancer Institute and Delcath Systems, the

manufacturer of the perfusion device. Dr. Pingpank reported that he personally

receives no payment or reimbursement from Delcath. Dr. Khushalani has consulting

relationships with Elekta and Prometheus. Dr. Novelli had no disclosures.

Novel Technique Shows Promise for Ocular Melanoma Percutaneous hepatic perfusion could be useful for colon, neuroendocrine cancers

Stockholm—Mature data from an ongoing trial of percutaneous hepatic perfusion (PHP)— a novel technique in which chemotherapy is infused directly into the liver—continue to show improved progression-free survival (PFS) for patients with liver metastases from ocular melanoma.

‘We were startled that approval didn’t occur. I expect that they

will resubmit soon, and I understand that they will be opening up

several smaller trials this year. We hope to be one of those sites.’

—Paula Novelli, MD

Variably pigmented, mushroom-shaped choroidal tumor has ruptured the Bruch membrane and grown into the subretinal space.

24 CliniCal OnCOlOgy news • JanUaRy 2012SOLID TUMORS

Melanoma

New Phase II and III Clinical TrialsThe studies listed below are actively recruiting trials that were added to the National Cancer Institute’s list of U.S. clinical trials in the 30 days before Dec. 28, 2011. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials/search, and enter the protocol ID.

Protocol Type Age Protocol ID Trial Sites

So

lid

Tu

mo

rs

A Study Combining mFolFoX6 With Tivozanib or Bevacizumab in Patients With Metastatic Colorectal Cancer as First-line Therapy, Phase II

18 and over 4130-Cl-0201 AZ, CA, Fl, IN, oH, oK, UT

Efficacy and Safety of GS-6624 With FolFIRI as Second-line Treatment in Colorectal Adenocarcinoma, Phase II 18 and over GS-US-295-0203

CA, Co

ABT-888 With Modified FolFoX6 in Patients With Metastatic Pancreatic Cancer, Phase I/II 18 and over lCCC 2009-608

DC

Gemcitabine Plus Nab-paclitaxel and FolFIRINoX and Molecular Profiling for Patients With Advanced Pancreatic Cancer, Phase I/II

18 and over PCRT 11-002 CA, MN

Study of MM-398 Versus 5-Fluorouracil and leucovorin in Patients With Metastatic Pancreatic Cancer, Phase III 18 and over MM-398-07-03-01

AZ, oH

Short Course Radiation Therapy With Proton Beam Capecitabine and Hydroxychloroquine for Resectable Pancreatic Cancer, Phase II

18 and over 11-073 MA

Evaluation of Prostate-specific Membrane Antigen-Based PET Imaging of Primary Prostate Cancer, Phase I/II 18 to 90 J1191 MD

l-BlP25 (Stimuvax) in Prostate Cancer, Phase II 18 and over EMR 63325-015

MA

Efficacy and Safety Study of NeuVax Vaccine to Prevent Breast Cancer Recurrence, Phase III 18 and over NeuVax PH3-01

TX

The BEACoN Study (Breast Cancer outcomes With NKTR-102), Phase III 18 and over 11-PIR-11 CA, Fl, TX

A Study of oral Rucaparib in Patients With gBRCA Mutation Breast Cancer or Other Solid Tumor, Phase I/II 18 and over Co-338-010 MI, TN

Neoadjuvant Trial of Eribulin Followed by Dose Dense Doxorubicin and Cyclophosphamide for Her2-negative, Locally Advanced Breast Cancer, Phase II

18 and over WCI1937-10 GA

GRN1005 Alone or in Combination With Trastuzumab in Breast Cancer Patients With Brain Metastases, Phase II 18 and over CP1005B016 Fl, GA, Il, MI, TN

Doxorubicin + BIBF 1120 in Patients With Ovarian Cancer, Phase I/II 18 ad over GyN10-149 IN

Dasatinib in Advanced Squamous Cell Lung Cancer, Phase II 18 and over 11-142 MA

Bronchoscopic Intratumoral Chemotherapy for Small-cell Lung Cancer, Phase III Not specified SClC Fl

KD019 Versus Erlotinib in Subjects With Stage IIIB/IV Non-small Cell Lung Cancer With Progression After First- or Second-line Chemotherapy, Phase III

18 and over KD019-301 NM

Short-incubation levulan Photodynamic Therapy Versus Vehicle for Face/Scalp Actinic Keratosis, Phase II 18 and over CP0105 Il, IN, TX

Melanoma Treatment With White Blood Cells That Destroy MART Expressing Tumor Cells, Phase II 18 and over 120045 MD

Cetuximab and Dasatinib in Recurrent Squamous Cell Carcinoma, Phase II 18 and over 08-034 PA

Pomalidomide for Kaposi Sarcoma in People With or Without HIV, Phase I/II 18 and over 120047 MD

Safety and Efficacy Study of TPI-287 in Neuroblastoma and Medulloblastoma, Phase I/II over 12 months to 30 years

NMTRC 004 MI

Cyclophosphamide, Topotecan, and Bevacizumab in Patients With Relapsed/Refractory Ewing’s Sarcoma and Neuroblastoma, Phase II

0 to 21 11-183 Ny

A Study of Rindopepimut/GM-CSF in Patients With Relapsed EGFRvIII-Positive Glioblastoma, Phase II 18 and over CDX110-06

Study of Rindopepimut/GM-CSF in Patients With Newly Diagnosed Glioblastoma, Phase III 18 and over CDX110-04 Fl, Ny

Vinorelbine for Children With Progressive or Recurrent Low-grade Gliomas, Phase II Under 18 CNMC-VRl DC

Safety Study of VAl-083 in Patients With Recurrent Malignant Glioma, Phase I/II 18 and over DlM-10-001 TN

Impact of Roux-En-y Pouch Reconstruction Compared With Conventional Roux-En-y Reconstruction on Health-Related Quality of life in Patients Undergoing Total Gastrectomy for Adenocarcinoma, Phase III

18 and over 11-070 Ny

He

mato

log

ic

Tl32711 in Elderly Acute Myelogenous Leukemia, Phase I/II 60 and over UPCC 15411 PA

Umbilical Cord Transplantation for the Elderly Population (leukemia, lymphoma), Phase II 55 to 73 202041 Il

A Phase III open label Randomized Study to Compare the Efficacy and Safety of Rituximab Plus lenalidomide (CC-5013) Versus Rituximab Plus Chemotherapy Followed by Rituximab in Subjects With Previously Untreated Follicular Lymphoma, Phase III

18 and over RV-Fol-GElARC-0683C

NJ

Brentuximab Vedotin and Combination Chemotherapy in Treating older Patients With Previously Untreated Stage II-IV Hodgkin Lymphoma, Phase II

60 and over NU 11H01 Il

Table continues on page 26

CliniCal OnCOlOgy news • JanUaRy 2012 25CLINICAL TRIALS

From Lancet Oncology

Nilotinib continues at 24 months to protect patients with chronic

myeloid leukemia (CML) from the development of emerging mutations and progression to advanced disease.

In the 24-month update of the ENESTnd (Evaluating Nilotinib Effica-cy and Safety in clinical Trials of new-ly diagnosed) trial of patients with Phil-adelphia chromosome–positive CML (Lancet Oncol 2011;12:841-851, PMID: 21856226), nilotinib (Tasigna, Novar-tis) demonstrated superior efficacy and significantly reduced rates of progres-sion to accelerated phase/blast crisis (AP/BC) over imatinib. The 846 patients with chronic phase CML (CML-CP)

were randomized to receive nilotinib 300 mg twice daily (n=282), nilotinib 400 mg twice daily (n=281) or imatinib 400 mg once daily (n=283). Seventeen patients progressed to AP/BC: two in the nilotinib 300 mg twice-daily group, three in the nilotinib 400 mg twice-dai-ly group and 12 in the imatinib 400 mg group. The researchers, who were fund-ed by Novartis and led by Hagop M. Kan-tarjian, MD, of the University of Texas MD Anderson Cancer Center in Hous-ton, found that more patients had new-ly detectable mutations on treatment with imatinib (n=20) than with nilotinib (300 mg twice daily, n=10; 400 mg twice daily, n=8). The majority of mutations were found in patients with high Sokal risk. Progressions were more frequent

in imatinib-treated patients, and more than 60% of progressions were associat-ed with the presence of mutations.

More patients achieved a major molecular response (MMR) with nilo-tinib (300 mg twice daily, 71%; 400 mg twice daily, 67%) than with imatinib (44%). Similarly, more patients achieved a complete molecular response (CMR; defined as BCR-ABL levels lowered to ≤0.0032%) on either of the nilotinib dosages. Patients were more likely to achieve complete cytogenetic response (cCR) at various time points in either of the nilotinib-treatment groups than the imatinib group.

The emergence of T315I mutations and the number of patients with multiple mutations were similar across treatment

arms (three patients in the nilotinib 300 mg twice-daily arm, two in the nilotinib 400 mg twice-daily arm and three in the imatinib arm).

Overall survival was comparable in all three treatment groups, but there were fewer CML-related deaths in the nilo-tinib groups (300 mg twice daily, n=5; 400 mg twice daily, n=3) than in the ima-tinib group (n=10).

“With longer follow-up, nilotinib continues to maintain an advantage in terms of the proportion of patients achieving MMR,” the authors report-ed. “Results from ENESTnd suggest that first-line nilotinib therapy might allow more patients to achieve these deep levels of response more rapidly than with imatinib.”

For CML, Nilotinib Superior to Imatinib at 24 Months

The introduction of the BCR-ABL kinase inhibitor imatinib substan-tially improved outcomes of patients with CML and was a major milestone in the treatment of cancer. Despite its positive effects, nearly 20% of patients treated with imatinib do not have a cCR and are at risk for disease progression and decreased overall survival.

Nilotinib is a BCR-ABL kinase devel-oped for patients resistant or intolerant

to imatinib and is a more potent and selective drug. The ENESTnd tri-al was a Phase III, multicenter, open-label randomized trial comparing the use of nilotinib at two dose lev-els (300 mg twice daily and 400 mg twice daily) with imatinib (400 mg once daily) in newly diagnosed patients with CML-CP; the end point was the rate of MMR at 12 months. There were 846 patients enrolled in the trial; the data were reported in The New England Journal of Medicine (2010;362:2251-2259, PMID: 20525993).

At 12 months, the rate of MMR for nilotinib (300 mg dose, 44%; 400-mg dose, 43%) was nearly twice that of imatinib (22%; P<0.0001 for both

comparisons) and sup-ported nilotinib as a first-line treatment option for patients with CML-CP.

Last fall, an update of the ENESTnd tri-al was published with follow-up data at 24 months. At lon-ger follow-up, signif-icantly more patients treated with nilotinib at either dose level

had an MMR (300 mg dose, 71%; 400 mg dose, 67%) in comparison with imatinib (44%; P<0.0001). Signifi-cantly more patients had achieved cCR by 24 months in the 300 and 400 mg nilotinib groups (87% and 85%, respectively; imatinib, 77%). Newly detectable mutations were identified in 10 patients in the nilotinib 300 mg group, eight patients in the nilotinib 400 mg group and 20 patients in the

imatinib group. Mutations known to be insensitive to nilotinib occurred in five patients in the nilotinib 300 mg group and six in the nilotinib 400 mg group, whereas mutations conferring resistance to imatinib occurred in 17 patients in the ima-tinib group. Seventeen patients pro-gressed to AP or BC on treatment: two in the nilotinib 300 mg group, three in the nilotinib 400 mg group and 12 in the imatinib group.

Since the 12-month follow-up, no new progressions were reported in the nilotinib 300 mg group. Two were reported in the nilotinib 400 mg group and one in the imatinib group. The significant difference in cumula-tive MMR achievement with nilotinib was maintained between months 12 and 24. At longer follow-up, nilotinib therapy continued to show superi-ority to imatinib with more durable molecular responses and decreased risk for progression.

Protocol Type Age Protocol ID Trial Sites

He

mato

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ic

IIT CTI Bendamustine, Rituximab, Pixantrone in Relapsed/Refractory B Cell Non-Hodgkin’s Lymphoma, Phase I/II 18 and over 00030834 NC

Carfilzomib for Relapsed and Unresponsive Multiple Myeloma, Phase II 18 and over 120043 MD

Bendamustine, Wkly Bortezomib, lenalidomide and Dexamethasone for Multiple Myeloma, Phase I/II 18 and over 203145 Il

Sequential Chemo-Radioimmunotherapy Followed by Autologous Transplantation for Patients With Untreated Advanced Stage Mantle Cell Lymphoma, Phase I/II

18 to 70 11-095 Ny

Therapeutic Effects of Epstein-Barr Virus Immune T-lymphocytes Derived From a Normal HlA-Compatible or Partially-Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies, Phase II

Any age 11-130 Ny

Su

pp

ort

ive

Care

Safety & Efficacy of Atorvastatin for Prophylaxis of Acute Graft Versus Host Disease in Patients With Hematological Malignancies HlA-Donor Hematopoietic Stem Cell Transplantation, Phase II

18 to 75 oSU-11004 oH

Alkaline Water in Reducing Skin Toxicity in Women With Breast Cancer Undergoing Radiation Therapy, Phase II 18 and over CASE2109 oH

Fluocinonide Cream in Treating Symptoms of Vaginal Dryness and Painful Sexual Intercourse In Patients With Breast Cancer Undergoing Hormone Therapy, Phase II

18 and over 7265 oR

VoICE: Cancer Communication Study, Phase II 21 and over 35388 Ny

Table continued from page 25

Ellen K. Ritchie, MDAssistant Professor of MedicineWeill Cornell Medical CollegeMedical Oncologist, Leukemia ProgramNewYork-Presbyterian/Weill CornellNew York City

EXPERT INSIGHT

26 CliniCal OnCOlOgy news • JanUaRy 2012HEMATOLOGIC DISEASE

CML

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questions—“conventional wisdom”—without thoroughly and objectively analyzing the basic foundation of their opinions. It is normal for “experts” to reject the suggestion that it is actually necessary to conduct rigorous trials to confirm the validity of their beliefs.

The following three examples, all drawn from the field of epithelial ovar-ian cancer management, illustrate the dangers of simply accepting convention-al wisdom, and in my opinion, serve as excellent examples of the importance of critical thinking when evaluating this type of proclamation.

1. There is no need to directly com-pare the utility of specific platinum dou-blets in the second-line management of ovarian cancer since combination plat-inum-based cytotoxic therapy has been shown to be equivalent in primary disease management.

This profound oversimplification of the natural history of ovarian cancer led some investigative leaders in the United States to strongly oppose the examina-tion of this very clinically relevant issue in a randomized cooperative group tri-al. Fortunately, others refused to simply accept this “belief” as objective fact and initiated a trial that ultimately revealed both the superiority (improved time-to-disease progression) and reduced tox-icity (substantially lower risk for seri-ous platinum-induced hypersensitivity reactions) associated with the delivery of a carboplatin plus pegylated liposo-mal doxorubicin combination compared with carboplatin plus paclitaxel in the treatment of recurrent, and potentially platinum-sensitive, ovarian cancer.1

2. Primary cytoreductive surgery is supe-rior to chemotherapy followed by surgery—the so-called neoadjuvant approach—based on extensive reported retrospective examinations of nonrandomized experi-ences of the two strategies.

Accepting this conventional wisdom prevented members of the U.S. gyneco-logic cancer research community from initiating a direct comparative trial to document the fundamental validity of

their beliefs. But the results of a land-mark, randomized Phase III trial con-ducted outside the United States have now revealed the essential therapeutic equivalence (progression-free and over-all survival) of the two approaches, with substantially reduced treatment-related morbidity (and mortality) observed with the neoadjuvant strategy.2 Although these data absolutely do not rule out the performance of primary surgical cytore-duction, they unquestionably reveal the absence of a negative impact associated with an alternative, and in selected cas-es clearly superior, approach. It remains to be seen if these strongly evidence-based trial results influence long-stand-ing clinical practice.

3. Intraperitoneal chemotherapy should only be employed in patients with micro-scopic or small-volume macroscopic dis-ease (<0.5-1 cm in maximal diameter) fol-lowing primary surgical cytoreduction because it is known that the depth of drug penetration/diffusion directly into tumor tissue is very limited.

This conclusion was based on both preclinical and clinical experience with second-line regional treatment strate-gies in ovarian cancer.3,4 Yet in the initial Phase III trial that examined intraperi-toneal versus systemic platinum admin-istration in the primary management of ovarian cancer, patients whose max-imum diameter of disease was great-er than 0.5 to 2 cm at the completion of surgical cytoreduction experienced an even greater relative benefit from deliv-ery of the regional program compared with individuals who began treatment with smaller tumor volumes (micro-

scopic disease only or largest mass lesion <0.5 cm maximum diameter).5 It can rea-sonably be hypothesized—and it must be emphasized that this is only a hypothe-sis—that this observation results from the fact that with each successive platinum treatment cycle and delivery of platinum to the cancer via direct uptake and deliv-ery by capillary flow following entry into the systemic compartment, the size of the residual tumor bulk will be reduced, per-haps substantially. This reduction may permit the higher concentrations of plat-inum (10- to 20-fold greater) achievable within the peritoneal cavity following regional delivery to exert their favorable impact on the clinical outcome.

Similar examples can be found in all areas of clinical oncology where con-ventional wisdom and “expert opin-ion” have inappropriately trumped the essential process of critical thinking. Unfortunately, this is not surprising: Critical thinking often is quite difficult, particularly when the outcome rejects a strong belief in some particular conven-tional wisdom that has been passed on by “senior leaders” or “experts in a field.”

Stressing the dangers of nonrigorous-ly tested, overly simplistic or nonbiolog-ically based beliefs often is not the way to win popularity contests among your peers (or within professional organiza-tions), who may accept the convention-al wisdom as being factually correct. But for those who appropriately, and even courageously, refuse to be swept up by the superficial allure and comfort of conventional wisdom, who understand that genuine progress in oncologic out-comes demands constant inquiry into our

existing interpretations of biological sys-tems and current medical practice, it is important to remember it is our patients who are the beneficiaries of our efforts.

References

1. Pujade-Lauraine E, Wagner U, Aavall- Lundqvist E, et al. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol. 2010;28:3323-3329, PMID: 20498395.

2. Vergote I, Trope CG, Amant F, et al. Neo-adjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363:943-953, PMID: 20818904.

3. Ozols RF, Locker GY, Doroshow JH, et al. Pharmacokinetics of adriamycin and tissue penetration in murine ovarian cancer. Can-cer Res. 1979;39:3209-3214, PMID: 455305.

4. Markman M, Reichman B, Hakes T, et al. Responses to second-line cisplatin-based intraperitoneal therapy in ovarian cancer: influence of a prior response to intravenous cisplatin. J Clin Oncol. 1991;9:1801-1805, PMID: 1919630.

5. Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cis-platin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335:1950-1955, PMID: 8960474.

2. Goss P, Ingle J, Martino S, et al. Cancer Res. 2009;69(24 Suppl): Abstract nr 13.

3. Regan M. Personal communication.

4. Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol. 1996;14(10):2738-2746, PMID: 8874335.

5. Chapman JA, Meng D, Shepherd L, et al. Competing causes of death from a random-ized trial of extended adjuvant endocrine therapy for breast cancer. J Natl Cancer Inst.

2008;100:252-260, PMID: 18270335.

6. Ring A, Sestak I, Baum M, et al. Influence of comorbidities and age on risk of death with-out recurrence: a retrospective analysis of the Arimidex, Tamoxifen Alone or in Combi-nation trial. J Clin Oncol. 2011;29:4266-4272, PMID: 21990403.

7. Ring A. Personal communication.

8. Mamounas E. Personal communication.

9. Goss P. Personal communication.

10. Bachelot T, Bourgier C, Cropet C, et al. TAMRAD: A GINECO randomized Phase II trial of everolimus in combination with tamoxifen versus tamoxifen alone in patients (pts) with hormone-recep-tor positive, HER2 negative metastatic

breast cancer (MBC) with prior exposure to aromatase inhibitors (AI). Cancer Res. 2010;70(24 Suppl):Abstract nr S1-6.

11. Baselga J, Cortés J, Kim SB, et al. Pertuzum-ab plus trastuzumab plus docetaxel for meta-static breast cancer. N Engl J Med. 2011 Dec 7 [Epub ahead of print], PMID: 22149875.

12. Robertson JF, Llombart-Cussac A, Rolski J, et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast can-cer: results from the FIRST study. J Clin Oncol. 2009;27(27):4530-4535. PMID: 19704066.

13. Mehta RS. Cancer Res 2010;71(24 supp):95s.

14. Bergh J, Jönsson PE, Lidbrink E, et al. San

Antonio Breast Cancer Symposium, 2009: Abstract 23.

15. Goss P, Ingle J, Martino S, et al. Cancer Res. 2009;69(24 Suppl):Abstract nr 13.

16. Kim C, Tang G, Pogue-Geile KL, et al. Estro-gen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer. J Clin Oncol. 2011;29(31):4160-4167, PMID: 21947828.

17. Liu MC, Dixon JM, Xuan JJ, et al. Molecu-lar signaling distinguishes early ER positive breast cancer recurrences despite adjuvant tamoxifen. San Antonio Breast Cancer Sym-posium, 2011: Abstract S1-8.

18. Regan M, et al. Lancet Oncol. 2011;12:1101-1108, PMID: 22018631.

RESPONSEScontinued from page 1

Clinical Oncology Newswelcomes letters to the editor.

Do you have thoughts on Dr. Markman’s commentary?

Please send comments to

gmiller@mcmahonmed.com

What are your thoughts?

PERSPECTIVEcontinued from page 13

Maurie Markman, MDsenior Vice President of Clinical affairs and national Director for Medical Oncology, Cancer Treatment Centers of america, Philadelphia

EDITORIAL BOARD COMMENTARY

28 CliniCal OnCOlOgy news • JanUaRy 2012CLINICAL TRIALS

Treatment Strategies

From the Journal of Clinical Oncology

Ashkenazi Jewish women with a BRCA1 gene mutation are signifi-

cantly more likely to be diagnosed with triple-negative breast cancers (TNBCs) than non-Ashkenazi Jewish women.

TNBC denotes tumors with lit-tle or no expression of estrogen recep-tor, progesterone receptor and HER-2; it is more common in women carry-ing the BRCA1 gene mutation. The aim of this National Cancer Institute–funded study (J Clin Oncol 2011;29:4373-4380, PMID: 22010008), which was headed by Eunjung Lee, MD, of the Keck School of Medicine in Los Angeles, was to identify additional potential distinguishing char-acteristics of TNBC after BRCA1 muta-tion has been established.

To do so, investigators enrolled a pop-ulation-based sample of 1,469 patients from Los Angeles County between the ages of 20 and 49 years who had been diagnosed with and treated for inci-dent breast cancer; tumor receptor sta-tus was available in 1,167 women. They sequenced BRCA1 and BRCA2 genes in the study population, and compared the participants across subgroups defined by BRCA1 mutation status and triple-negative receptor status for clinical,

pathologic and hormone-related life-style characteristics.

The authors found that 48% of the patients carrying BRCA1 gene mutations had TNBC compared with 12% of non-carriers. Triple-negative receptor sta-tus in both populations was associated with younger age at diagnosis and high-er tumor grade. Among women who did not have a BRCA1 mutation, the authors observed that women with TNBC had a higher premenopausal body mass index and had their first full-term pregnan-cy at an earlier age than those who did not have TNBC. By contrast, age at men-arche was not associated with triple-negative status.

Additionally, the authors found that Ashkenazi Jewish women with BRCA1 mutations were more likely to have TNBC (69%) than BRCA1 muta-tion carriers in other ethnic and reli-gious groups (39%; P=0.044 after adjust-ing for age at time of diagnosis). The authors acknowledged that the finding might be due to chance given the small number (n=13) of BRCA1 mutation car-riers of Ashkenazi Jewish origin in the study. However, they also noted that the BRCA1 mutations in Ashkenazi Jewish women enrolled in the study were pre-dominantly 185delAG and 5382InsC,

which are “located at opposite ends of the gene” (exons 2 and 20). Conversely, the BRCA1 mutations in non-Ashkenazi

Jewish women were spread throughout the gene. They believe this finding mer-its further study.

From Blood

Maintenance therapy using oral arsenic trioxide (As203) is effec-

tive and more practical than the more complex and toxic chemotherapeutic regimens currently employed for the prevention of relapse in patients with acute promyelocytic leukemia (APL), according to a study published in Blood.

Although APL may be a curable form of leukemia—existing therapies have been shown to achieve complete remis-sion (CR) rates as high as 90%—the spec-ter of relapse remains an ongoing issue in the management of this disease. The cur-rent study (2011;118:6535-6543, PMID: 21998212), led by Wing-Yan Au, MD, dem-onstrated that three different regimens of oral As203-based maintenance therapy are similarly effective in preventing relapse in patients who have achieved a first CR.

The study, by a team of researchers from Hong Kong and performed at the city’s Queen May Hospital and Princess Margaret Hospital, enrolled 76 patients with APL. The patients, all in their first

CR, received one of three oral As203 regi-mens—20 received oral As203 monothera-py (10 mg per day, regimen A); 19 received oral As203 plus all-trans retinoic acid (ATRA; 45 mg/m2 per day, regimen AA); and 37 received oral As203 plus ATRA plus ascorbic acid (1,000 mg per day, reg-imen AAA). Each regimen was given for two weeks every two months for a peri-od of two years and initiated at a median of 25 days after the participants’ final che-motherapy treatment. Median age of the study population was 44 years.

At median follow-up of 24 months, there were eight reported relapses in the study population: five bone marrow, one central nervous system (CNS), one bone marrow plus CNS and one molec-ular. Seven of the relapses occurred in male patients, with the molecular relapse occurring in the only female patient. The median time to relapse was 18 months from the first CR. However, only four of the patients relapsed while undergoing maintenance therapy, and three were in the regimen A group. All eight patients achieved a second CR after restarting

oral As203-based maintenance therapy, with no detectable PML-RARA (promy-elocytic leukemia–retinoic acid recep-tor-α) translocation, which is diagnos-tic for APL. Three of these patients sub-sequently developed a second relapse, but even in these cases the AAA regi-men proved effective, with two of these patients achieving a third CR. There were no reports of therapy-associated acute myeloid leukemia or myelodysplasia.

For all three oral As203–based regi-mens, three-year leukemia-free survival, event-free survival and overall survival were 87.7%, 83.7% and 90.6%, respective-ly. Adverse events observed during main-tenance therapy on all three regimens included headache, dyspepsia, reversible liver function derangement and herpes zoster reactivation. The researchers con-cluded that As203 therapy is “feasible, safe and beneficial.”

Oral Arsenic Trioxide Effective Maintenance Therapy for APL

Triple-Negative Breast Cancers Associated With Ashkenazi Origin

The article provides ample evidence that a simple regimen of oral As203-based maintenance therapy is at least

as good as IV arsenic and better than intensive chemotherapy–based main-tenance therapy for APL. The three-year leukemia-free survival was 87.7% for a cohort of 76 patients. Further-more, conventional risk factors such as age, high white blood cell count and low platelets were not found to be significant in this study. Although the number is small, the trial lays the groundwork for further study empha-sizing simplifying the treatment for APL and avoiding chemotherapy, at least in the maintenance phase.

TNBCs remain a therapeutic chal-lenge. This study is consistent with prior studies demonstrating that TNBCs are diagnosed at a young-er age and at a higher tumor grade and stage than non-TNBCs (observed among both BRCA1 carriers and noncarriers). This also is consis-tent with prior work indicating that approximately 50% of BRCA1 mutation carriers have TNBC. With-in the BRCA1 mutation carrier group, Ashkenazi Jewish women were found to be five times more likely to have TNBC than non-Ashkenazi

Jewish women. This study is important because

novel therapeutic agents are under investigation for TNBC and it is becoming increasingly evident that genetic factors impact response. Poly(ADP-ribose)polymerase inhibi-tors, which impair DNA single-strand break repair, are of particular benefit to those patients who have deficits in BRCA1 and BRCA2 genes. As tumor characteristics among different eth-nic, racial and genetic traits are bet-ter defined, targeted treatment can be further optimized.

Usama Gergis, MDAssistant Professor of MedicineWeill Cornell Medical CollegeAssistant Attending Physician, Leukemia ServiceNewYork-Presbyterian/Weill Cornell New York City

EXPERT INSIGHT

Preya Ananthakrishnan, MDAssistant Professor of Clinical SurgeryColumbia University College of Physicians and SurgeonsBreast Cancer SurgeonNewYork-Presbyterian/ColumbiaNew York City

EXPERT INSIGHT

CliniCal OnCOlOgy news • JanUaRy 2012 29HEMATOLOGIC DISEASE

Leukemia

SOLID TUMORS

Breast Cancer

Anasetti, MD, chair of Blood and Mar-row Transplant at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla., and the study’s lead author.

There was faster engraftment of neu-trophils and platelets with PBSC, Dr. Anasetti reported, but the greater risk for chronic GVHD meant that fewer patients were off immunosuppressants two years after their procedure.

In the open-label study, which was the first prospective, randomized Phase III comparison of strategies for stem cell transplants from unrelated donors, 278 patients were randomized at 48 par-ticipating centers in the United States and Canada to receive filgrastim-mobi-lized PBSC or bone marrow transplants (BMTs). The primary end point was two-year survival employing an intent-to-treat (ITT) analysis.

The most common reason for trans-plant was acute myeloid leukemia, which was the diagnosis in nearly half of patients. None of the baseline char-acteristics, particularly those most closely associated with prognosis, dif-fered significantly between the groups. More patients assigned to BMT crossed

over to PBSC than the reverse (4.3% vs. 0.4%) and a few patients were nev-er transplanted, but more than 90% of patients in both arms received trans-plant in their assigned study arm.

In the ITT analysis, survival was 51% for those receiving PBSC versus 46% for those receiving BMT (P=0.288). The difference remained nonsignificant on a modified ITT analysis that exclud-ed those who were never transplanted. There was no study arm interaction in a review of patient age, the donor HLA match, the underlying cancer diagnosis or the prognostic factors for the under-lying cancer.

However, there were important dif-ferences between treatments. The neu-trophil engraftment by the definition used in this study occurred five days earlier (P<0.001) in those transplanted with PBSC than in those receiving BMT. Similarly, the platelet engraftment was seven days earlier (P<0.001) with PBSC transplant. Graft failure rate also was higher in the BMT group whether pri-mary or secondary (9% vs. 3%), but acute low- and high-grade GVHD rates were very similar.

The rate of chronic GVHD (40% vs. 53%; P=0.02), which was higher in the PBSC group, was the most significant difference in overall outcome. This

included chronic extensive GVHD, sig-nifying multisystem involvement (32% vs. 48%; P<0.001).

“Of the patients alive at two years, 57% in the bone marrow arm were off immune suppression compared with 37% of the PBSC arm, which was also a significant difference [P=0.026],” Dr. Anasetti reported.

The primary cause of death was also different in the study arms. “Graft fail-ure was higher in the marrow arm, while chronic GVHD was higher in the PBSC arm,” Dr. Anasetti said. Neverthe-less, “acute and chronic GVHD taken together were the predominant causes of nonrelapse death in both arms of the study,” he added.

Prior to this study it had been recog-nized that chronic GVHD appeared to occur more frequently after PBSC trans-plant, but it was presumed that over-all outcomes with PBSC transplant for unrelated donors were better. This pre-sumption was derived in large part from previous studies performed in well-matched HLA siblings, where there has been an advantage for PBSC trans-plant for patients with high-risk malig-nancies. However, at ASH, William Fib-be, MD, PhD, professor of hematology and stem cell biology at the Leiden Uni-versity Medical Center in Leiden, The

Netherlands, said recent data had chal-lenged this presumption. The current tri-al, he said, finally addresses the question with an evidence-based approach.

In remarks to the press at ASH, Steph-anie Lee, MD, transplant specialist at the Fred Hutchinson Cancer Research Cen-ter in Seattle, agreed. She said the results challenge current assumptions and will likely lead to a reassessment of trans-plant practices at many centers. Like Dr. Fibbe, Dr. Lee noted that the current pref-erence for PBSC transplants for unrelated donors had developed from extrapolation of data based on related donors, and these new results are compelling.

In clinical practice, Dr. Anasetti con-cluded that both PBSC and BMTs can be considered acceptable, but he suggested that on the basis of this study, which was funded in part by the National Institutes of Health and run by the Blood and Mar-row Transplant Clinical Trials Network (BMT CTN), PBSC might be preferable for high-risk subgroups.

“PBSC may be preferred for some patients who are at high risk for graft failure or those with serious infection and may benefit from faster or more robust engraftment. Marrow should be employed in all others,” Dr. Anasetti said.

—Ted Bosworth

STEM CELLScontinued from page 1

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30 CliniCal OnCOlOgy news • JanUaRy 2012HEMATOLOGIC DISEASE

Leukemia

BRIEF SUMMARY OF PRESCRIBING INFORMATIONWARNING: QT PROLONGATION FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided [see Warnings and Precautions].INDICATIONS AND USAGEFARESTON® is an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.DOSAGE AND ADMINISTRATIONThe dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed.DOSAGE FORMS AND STRENGTHSTablet is 60 mg, round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side.CONTRAINDICATIONS Hypersensitivity to the Drug FARESTON is contraindicated in patients with known hypersensitivity to the drug.QT Prolongation, Hypokalemia, HypomagnesemiaToremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia.WARNINGS AND PRECAUTIONS Prolongation of the QT Interval Toremifene has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death.Toremifene should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated [see Drug Interactions and Clinical Pharmacology].Hypercalcemia and Tumor FlareAs with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and, if hypercalcemia is severe, FARESTON treatment should be discontinued.TumorigenicitySince most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene [see Nonclinical Toxicology].GeneralPatients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment [see Warnings and Precautions]. Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia.Laboratory TestsPeriodic complete blood counts, calcium levels, and liver function tests should be obtained.Use in PregnancyBased on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. 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].Women of Childbearing PotentialFARESTON is indicated only in postmenopausal women. However, premenopausal women prescribed FARESTON should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur.ADVERSE REACTIONSBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Clinical Trials ExperienceAdverse drug reactions are principally due to the antiestrogenic actions of FARESTON and typically occur at the beginning of treatment.The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related.

North American Study

FAR60 TAM20 n = 221 n = 215

Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4%Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction).Serious adverse reactions occurring in at least 1% of patients receiving FARESTON in the three major trials are listed in the table below.Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively [see Clinical Studies].

Adverse Reactions North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%)CardiacCardiac Failure Myocardial Infarction Arrhythmia Angina Pectoris Ocular*Cataracts Dry Eyes Abnormal Visual Fields Corneal Keratopathy Glaucoma Abnormal Vision/Diplopia ThromboembolicPulmonary Embolism Thrombophlebitis Thrombosis CVA/TIA Elevated Liver Tests**AST Alkaline Phosphatase Bilirubin Hypercalcemia

* Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual ophthalmic examinations were performed. No cases of retinopathy were observed in any arm.** Elevated defined as follows: North American Study: AST >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: AST, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal).

Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors.The incidence of AST elevations was greater in the 200 and 240 mg FARESTON dose arms than in the tamoxifen arms. Higher doses of FARESTON were also associated with an increase in nausea.Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor.Post-marketing ExperienceThe following adverse reactions were identified during post approval use of FARESTON. 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.Adverse reactions reported during post approval use of FARESTON have been consistent with clinical trial experience. The most frequently reported adverse reactions related to FARESTON use since market introduction include hot flash, sweating, nausea, and vaginal discharge.DRUG INTERACTIONSDrugs that Decrease Renal Calcium Excretion Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON.Agents that Prolong QTThe administration of FARESTON with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated [see Boxed Warning and Warnings and Precautions].Effect of Strong CYP3A4 Inducers on ToremifeneStrong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s Wort, lower the steady-state concentration of toremifene in serum.Effect of Strong CYP3A4 Inhibitors on ToremifeneIn a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene Cmax and AUC by 1.4- and 2.9-fold, respectively. N-demethyltoremifene Cmax and AUC were reduced by 56% and 20%, respectively.The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning and Warnings and Precautions].Effect of Toremifene on CYP3A4 SubstratesIn a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and -hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and

-hydroxymidazolam Cmax and AUC were reduced by less than 20%.Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely.Effect of Toremifene on CYP2C9 SubstratesIn a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide Cmax and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide Cmax and AUC.Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with FARESTON should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure).USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. 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.In animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies. Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo-fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly.Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits.In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis). Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol in utero.Nursing MothersIt is not known if toremifene is excreted in human milk. Toremifene is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FARESTON, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.Pediatric UseThere is no indication for use of FARESTON in pediatric patients.Geriatric UseThe pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC.The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.Renal ImpairmentThe pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function.Hepatic ImpairmentThe mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.RaceThe pharmacokinetics of toremifene in patients of different races has not been studied.Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in FARESTON effectiveness or safety were noted. OVERDOSAGELethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement.Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient.Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

CLINICALPHARMACOLOGY Mechanism of Action Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mammary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, i.e., its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor.PharmacodynamicsToremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH).Effects on Cardiac ElectrophysiologyThe effect of 20 mg, 80 mg, and 300 mg of toremifene on QT interval was evaluated in a double-blind, randomized study in healthy male subjects aged 18 to 45 years. The QT interval was measured at steady state of toremifene (Day 5 of dosing), including the time of peak plasma concentration (Tmax), at 13 time points (4 ECGs/time point) over 24 hours post dose in a time matched analysis. The 300 mg dose of toremifene (approximately five times the highest recommended dose 60 mg) was chosen because this dose produces exposure to toremifene that will cover the expected exposures that may result from potential drug interactions and hepatic impairment [see Drug Interactions].Dose and concentration-related increases in the QTc interval and T wave changes were observed (see Table 1). These effects are believed to be caused by toremifene and N-demethyltoremifene. Toremifene had no effects on heart rate, PR and QRS interval duration [see Boxed Warning and Warnings and Precautions].Table 1: QTc Prolongation in Healthy Male Volunteers

Pharmacokinetics Absorption – Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady state concentrations were reached in about 4-6 weeks.Distribution – Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly albumin.Metabolism – Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state.Following multiple dosing with toremifene in 20 healthy volunteers, plasma toremifene exposure was lower on Day 17 compared to Day 5 by approximately 14%. N-demethyltoremifene exposure was higher on Day 17 compared to Day 5 by approximately 80%. Based on these data and an in vitro induction study in human hepatocytes, auto- induction of CYP3A4 by toremifene is likely. The effect of auto-induction on efficacy was likely captured following prolonged dosing in the clinical studies.Elimination – The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (Deaminohydroxy) toremifene, were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5 L/h. Toremifene is eliminated as metabolites primarily in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation.Renal insufficiency – The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and patients with impaired kidney function.Hepatic insufficiency – The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.Geriatric patients – The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.Food – The rate and extent of absorption of FARESTON are not influenced by food; thus FARESTON may be taken with or without food.Race – The pharmacokinetics of toremifene in patients of different races has not been studied. Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in FARESTON effectiveness or safety were noted.NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (approximately 1/50 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (approximately 1/15 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human estrogen agonists/antagonists that have primarily estrogenic activity in mice. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (approximately 1/3 and 1.4 times, respectively, the daily maximum recommended human dose of 60 mg, on a mg/m2 basis).Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests). Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes).Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (approximately 4 times and 1/50 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (approximately 1.5 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/3 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 52 weeks.PATIENT COUNSELING INFORMATIONVaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs.FARESTON may harm the fetus and increase the risk for pregnancy loss [see Warnings and Precautions and Use in Specific Populations].Premenopausal women using FARESTON should use nonhormonal contraception during treatment and should be apprised of the potential hazard to the fetus should pregnancy occur [see Warnings and Precautions].Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur.Patients who must take medications known to prolong the QT interval, or potent CYP3A4 inhibitors, should be informed of the effect of toremifene on QT interval. Toremifene has been shown to prolong the QTc interval in a dose-related manner [see Boxed Warning, Warnings and Precautions, and Clinical Pharmacology].Specific interactions with foods that inhibit CYP3A4, including grapefruit juice, have not been studied but may increase toremifene concentrations. Patients should avoid grapefruit products and other foods that are known to inhibit CYP3A4 during FARESTON treatment.Certain other medicines, including over-the-counter medications or herbal supplements (such as St. John’s Wort) and toremifene, can reduce concentrations of coadministered drugs [see Drug Interactions].

Distributed by GTx, Inc. Memphis, TN 38103, USA Product covered by Orion Product Patents and related patent numbers. © 2011 GTx, Inc. All rights reserved.

2E Rev. 03/2011

Treatment Arm

Toremifene 20 mg (N = 47)Toremifene 80 mg (N = 47)Toremifene 300 mg (N = 48)

Mean (90% CI) ΔΔQTc, ms

7 (0.9, 13.6)26 (21.1, 31.2)65 (60.1, 69.2)

ΔQTc > 60 ms (n, %)

02 (4.3%)

43 (89.6%)

QTc > 500 ms (n, %)

00

5 (10.4%)

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MCCON469.indd 1 10/29/11 12:52 PM

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FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. FARESTON is contraindicated in patients with known hypersensitivity to the drug. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor flare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively.References: FARESTON® Prescribing Information, 2011. Data on file, GTx, Inc.

Important safety information:

MCCON468.indd 1 10/29/11 12:51 PM