clinical oncology news - january 2010 - digital edition

Rosemont, Ill.—Results from a national survey indicate that many hospi-tals are not properly managing a drug pricing tool, which may lead to inadequate reimburse-ment. In a national survey, more than one-half of hos-pitals said they reviewed and changed line-item drug prod-ucts on their pricing lists quar-terly or less often. Nearly one-third (28%) reported reviewing the list only once annually. Lax updating of the

list, known as a hospital pharmacy charge master, can result in reduced reim-

bursement that not only hurts health-systems individually, but can also trigger artificial-ly low national pay rates set by the Centers for Medicare & Medicaid Services (CMS),

according to lead investigator Christine A. Pierce, a partner

in The Resource Group, a reim-bursement consulting firm based

New York—Despite a previously pub-lished pilot study that had positive outcomes, an alternative medicine for mucositis called traumeel was shown to be ineffective in children in a mul-ticenter, double-blind trial conduct-ed by the Children’s Oncology Group (COG). The study was a rare effort to subject alternative medicines, which are now widely used by cancer patients, to the same rigorous, evidence-based examination used for conventional treatments.

According to Edward Chu, MD, chief of medical oncology and direc-tor of clinical research at Yale Cancer

Promising Homeopathy For Mucositis Fails TrialAlternative Medicine Trials Fraught With Challenges

New Orleans—A large, Phase III multi-center study has revealed that the com-bination of bendamustine (Treanda, Cephalon) and rituximab (Rituxan, Bio-gen Idec/Genentech) is better tolerated and more effective than the current stan-dard of CHOP-R (cyclophosphamide, hydroxydaunorubicin, vincristine and prednisone plus rituximab) for the treat-ment of indolent lymphomas and mantle cell lymphoma. The greater efficacy was somewhat unexpected; the researchers had anticipated similar efficacy with greater tolerability.

“These promising results suggest that the combination of bendamustine and rituximab [bendamustine-R] has the potential to become the new standard, first-line treatment option for patients with these non-Hodgkin’s lymphoma

San Antonio—The combination therapy of trastuzumab (Herceptin, Genentech) and lapatinib (Tykerb, GlaxoSmithKline) improves overall survival by 20 weeks compared with lapatinib alone in women with

HER2-posi-tive metastatic breast cancer (MBC) who have progressed on therapy with trastuzumab. Survival was roughly 60 weeks in the com-bination arm and 40 weeks in the lapatinib- only arm. This news comes from a study

reported at the recent San Antonio Breast Cancer Symposium (SABCS; abstract 61).

“This is the first time that someone has shown that continuing Herceptin through

progression and adding a second type of anti-HER2 therapy

leads to a sur-vival improve-

ment compared with just moving to another drug and eliminating the tras-tuzumab, so it really validates the concept that trastuzumab is an important drug to

Hospitals May Be Letting Crucial Drug Pricing Tool Rust

Trastuzumab Plus Lapatinib Lands Strong One-Two Punch

For Indolent Lymphomas\MCL:

Bendamustine-R Is Potential New Standard

see MUCOSITIS, page 6 �

see BENDAMUSTINE-RITUXAN, page 16 �

see ONE-TWO PUNCH, page 24 �

POLICY & MANAGEMENT

see DRUG PRICING, page 30 �

McMahon Publishing

Advances in Cancer CareCLINICALONCOLOGY.COM • JANUARY 2010 • Vol. 5, No. 1

PRSRT STDU.S. POSTAGE

PAIDEASTON, PAPERMIT #117

SOLID TUMORS

17 Cathy Eng, MD, discusses practice-changing colon cancer news from recent international meeting.

25 Adding sorafenib to chemotherapy improves PFS in metastatic breast cancer.

26 TS biomarker ready for routine clinical application in NSCLC.

FDA NEWS

28 FDA approves Arzerra for CLL, Istodax for CTCL and Elitek for plasma uric acid control.

WWW.CMEZONE.COM

EDUCATIONAL REVIEW

GastrointestinalStromal TumorsWhat Oncologists Need To Know About the Treatment of Localized and Advanced Disease

After page 24.

SUPPORTIVE CARE

5 ESA restrictions may be pushing up transfusion rates.

Istodax approved for

CTCL.

See page 28.

New Product

HEMATOLOGIC DISEASE

10 Jennifer Brown, MD, highlights news from the ASH meeting.

IMPORTANT SAFETY INFORMATIONBOXED WARNINGSCardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution◗ The use of DOXIL may lead to cardiac toxicity. Myocardial

damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2

— Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose

— Cardiac toxicity may also occur at lower cumulative doses (400 mg/m2) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy

◗ Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate— Serious and sometimes life-threatening or fatal allergic/

anaphylactoid-like infusion reactions have occurred. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use

— The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions

◗ Severe myelosuppression may occur◗ DOXIL dosage should be reduced in patients with impaired

hepatic function ◗ Accidental substitution has resulted in severe side effects.

Do not substitute for doxorubicin HCl on a mg per mg basis

Contraindications◗ Patients with a history of hypersensitivity reactions to a

conventional doxorubicin formulation or the components of DOXIL

◗ Nursing mothers

Additional Safety Information ◗ Cardiac function should be carefully monitored

— Congestive heart failure or cardiomyopathy may occur after discontinuation of anthracycline therapy

— For patients with a history of cardiovascular disease, or if the results of cardiac monitoring indicate possible cardiac injury, the benefit of therapy must be weighed against the risk of myocardial injury

— In the randomized multiple myeloma study, 25 patients (8%) in the VELCADE for Injection arm and 42 patients (13%) in the VELCADE plus DOXIL arm experienced left ventricular ejection fraction decrease (defined as absolute decrease ≥15% over baseline or a ≥5% decrease below institutional lower limit of normal)

Additional Safety Information, Continued ◗ Myelosuppression may occur; frequently monitor complete

blood count (including platelet count), at least prior to each dose of DOXIL

— In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL and/or VELCADE

— Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage

— Sepsis occurring during neutropenia has resulted in discontinuation of treatment and in rare cases of death

◗ DOXIL may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow

◗ Hand-foot syndrome (HFS) may occur during therapy with DOXIL

— Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL may be required

— HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier

• The reaction was mild in most patients, resolving in 1 to 2 weeks

• The reaction can be severe and debilitating in some patients, resulting in discontinuation of therapy

◗ DOXIL is an irritant, not a vesicant; use precautions to avoid extravasation

◗ DOXIL can cause fetal harm when used during pregnancy◗ Recall reaction has occurred with DOXIL administration

after radiotherapy◗ DOXIL may interact with drugs known to interact with the

conventional formulation of doxorubicin HCl◗ In patients with multiple myeloma, the most common

all-grade adverse reactions ≥20% (VELCADE plus DOXIL vs VELCADE, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%), pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%)

— In addition, 19% vs <1% reported HFS

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, on adjacent pages.

Distributed by: Centocor Ortho Biotech Products, L.P., Horsham, Pennsylvania 19044-3607© Centocor Ortho Biotech Products, L.P. 2009 Printed in U.S.A. 10/09 08DM09002 405041

45042ALT_Tabloid_v1 1-2 10/13/09 1:54 PM

A 43% increase in median TTP when DOXIL was combined with VELCADE—a statistically signifi cant increase (P<.0001)

100

90

80

70

60

50

40

30

20

10

06.5 9.3

0 4 8 12 15

N=646P<.0001b

HR=0.55c

95% CI 0.43 to 0.71

VELCADE(n=322)

VELCADE + DOXIL (n=324)

Perc

enta

ge o

f Pa

tient

s Pr

ogre

ssio

n-Fr

ee

Turn to VELCADE With DOXILFor a Statistically Signifi cant Increase in Time to Progression vs VELCADE Alone

Study DesignRandomized, open-label, international, multicenter study (N=646) of patients with multiple myeloma who had not previously received VELCADE and whose disease progressed during or after at least 1 prior therapy. The primary endpoint was time to progression (TTP). Patients were randomized (1:1 ratio) to receive either DOXIL (30 mg/m2 as a 1-hour IV infusion) administered on Day 4 following VELCADE (1.3 mg/m2 IV bolus on Days 1, 4, 8, and 11) or VELCADE alone (1.3 mg/m2 IV bolus on Days 1, 4, 8, and 11). Treatment was administered every 3 weeks. Patients were treated for up to 8 cycles until disease progression or the occurrence of unacceptable toxicity. Patients who maintained a response were allowed to receive further treatment. The median number of cycles in each treatment arm was 5 (range, 1–18).

Please see Important Safety Information, including Boxed WARNINGS, on previous page.

VELCADE6.5 Months Median TTPa

(95% CI: 5.6, 7.1) (n=322)

VELCADE + DOXIL9.3 Months Median TTPa

(95% CI: 8.2, 11.1) (n=324)

In Multiple Myeloma*...

* DOXIL in combination with VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma who have not previously received VELCADE and have received at least one prior therapy.

a Kaplan-Meier estimate.b Stratified log-rank test.c HR based on stratified Cox proportional-hazards regression. An HR <1 indicates an advantage for VELCADE + DOXIL.

Number of Subjects at Risk

VELCADE + DOXIL 324 301 269 201 170 127 97 70 56 38 19 13 6 4 2 0 VELCADE 322 290 253 189 150 112 84 56 35 25 14 9 2 1 1 0

TTP (Months)

45042ALT_Tabloid_v1 1-2 10/13/09 1:54 PM

43351ALT_DOX MM_v1 3 12/17/08 10:37:56 AM

CLINICAL ONCOLOGY NEWS • JANUARY 2010 5

According to the studies presented at the recent American Society of Health-System Pharmacists meeting, centers in Maryland and New Jersey have seen increases in the rates of blood transfusions in can-cer patients with anemia ever since label changes and reimbursement cutbacks were implemented for ESAs. Investigators at these and other centers fear that the full effect of the 2007 ESA restrictions on transfusion rates has not yet been seen and that centers need to take a closer look at their own rates.

In Maryland, John DiBona, PharmD, corporate direc-tor of pharmacy at Life bridge Health, Sinai Hospital of Baltimore, conducted a retrospective study of transfu-sion rates in cancer patients before and after implemen-tation of the August 2007 Medicare National Coverage Determination (NCD) restricting coverage for ESAs. The study focused on inpatient and outpatient visit and billing data and laboratory results for all cancer patients treated from Aug. 1, 2005 through Aug. 31, 2008, at the hospital. The researchers assessed chemotherapy epi-sodes for two pre-NCD periods as well as one post-NCD period. Outcome measures included ESA use and num-ber of blood transfusions.

The results showed that ESA restrictions had a signif-icant effect on the use of the growth factors: In the two time periods studied before the restrictions were put in place, ESAs were given to 75.4% and 80.9% of patients

undergoing chemotherapy. After the restrictions took effect, only slightly more than half (50.4%) of patients were prescribed ESAs, the investigators reported (P<0.0001).

Additionally, with the decrease in ESA rates came a corresponding increase in the rate of transfusions (21% before the NCD vs. 31% after-ward; P<0.05).

The increase from 21% to 31% “is not a huge jump, but if you look at it in relative terms, it is almost one-third,” Dr. DiBona said. He acknowl-edged that the data are limited to his center and he doesn’t know for sure “whether [the results are] externally valid.” But he expressed concern that if the data were in fact generalizable, “and you extrapolated the one-third increase across the country, that is a huge amount of blood use.”

Dr. DiBona further speculated that his study may underestimate the impact of the NCD on transfusion rates because, in the wake of the same adverse events related to increased hematocrits that led to the NCD, prescribers may have become “a little bit skittish about bringing hematocrits up.” That hesitation may have

persisted even regarding patients undergoing trans-fusions instead of ESA therapy, he noted. If that is the case, Dr. DiBona said, the one-third increase in the rate of blood transfusions would be even more significant in light of the downward effect that a possible increased

clinical threshold for transfusions would have exerted on the transfusion rate.

At the New Jersey center, investigators conducted a study focused on the NCD’s influence on the use of the ESA darbepoetin alfa (Aranesp, Amgen). Robert T. Adamson, PharmD, and his colleagues at Saint Barnabas Health Care System, in South Plainfield, ret-

rospectively evaluated patients who were admitted as inpatients during Nov. 1, 2006

through Jan. 31, 2008, and had received a dose of darbepoetin for chemothera-

py-induced anemia as outpatients four weeks or less before hospitalization. End points for the study included inpatient

and outpatient darbepoetin utilization patterns. The investigators evaluat-

ed darbepoetin use before and after four darbepoetin-related events occurred between March and July 2007: Darbepoetin labeling was changed to include a black box warning; a medication reconcilia-tion program was initiated at Saint Barnabas; the FDA’s Oncology Drug Advisory Committee reviewed the drug; and the NCD was implemented.

The investigators reviewed the hospital database and found 726 patients who fit the inclusion criteria and were included in the analysis. Whereas there was a

ESA Restrictions May Be Pushing Up Transfusion RatesRosemont, Ill.—Recent restrictions on erythropoietin-stimulating agents (ESAs) may be increasing blood transfusion rates, according to two recent studies.

ADVISORY BOARD

BioethicsJoseph P. DeMarco, PhD

Paul J. Ford, PhD

Community OncologyMichael J. Fisch, MD, MPH

John W. Finnie, MD

Hematologic MalignanciesJennifer R. Brown, MD, PhD

Agnes Y.Y. Lee, MSc, MD

Richard Stone, MD

Oncology Nursing Betty Ferrell, RN, PhD

PharmacyPolly E. Kintzel, PharmD

Melvin E. Liter, MS, PharmD

Policy and ManagementMary Lou Bowers, MBA

Barbara Constable, RN, MBA

Rhonda M. Gold, RN, MSN

Solid Tumors Bone Metastases

Allan Lipton, MD

Breast Cancer

Andrew Seidman, MD

Maura N. Dickler, MD

Gastrointestinal Cancer

Edward Chu, MD

Cathy Eng, MD

Leonard Saltz, MD

Gastrointestinal Cancer and Sarcoma

Ephraim Casper, MD

Genitourinary Cancer

Ronald M. Bukowski, MD

Gynecologic Cancer

Maurie Markman, MD

Lung, and Head and Neck Cancers

Edward S. Kim, MD

Lung Cancer, Emesis

Richard J. Gralla, MD

Infection ControlSusan K. Seo, MD, Director

Symptom Control and Palliative CareWilliam S. Breitbart, MD

Steven D. Passik, PhD

Joseph V. Pergolizzi Jr., MD

Russell K. Portenoy, MD

Charles F. von Gunten, MD

EDITORIAL STAFF

Kate O’Rourke, [email protected]

Sarah Tilyou, Senior [email protected]

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Elizabeth Zhong, Associate Copy Chief

SALES STAFF

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ART AND PRODUCTION STAFF

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MCMAHON PUBLISHING

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Van Velle, President, Partner

Thomas Ciriacks, Vice President, Medical Education

Matthew McMahon, General Manager, Partner

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

McMahon Publishing is a 38-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.

Copyright © 2010 by McMahon Publishing, New York, NY 10036. All rights reserved. Clinical Oncology News (ISSN 1933-0677) is published monthly for $70.00 per year by McMahon Publishing. Postage paid at New York, NY, and at additional mailing offices.

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TM

SUPPORTIVE CARE

Anemia

see RESTRICTIONS, page 15 �

6 CLINICAL ONCOLOGY NEWS • JANUARY 2010

Center, New Haven, Conn., research groups that want to test botanical herbal medicines in clinical trials face unique challenges because many of these medicines are complex agents. Generally, standard Western anti-cancer therapies consist of a single active agent that must be titrated into a therapeutic window in which the agent is both tolerable and active. In contrast, the large majority of therapies derived from botanicals are made up of multiple components for which the com-position ratio may be critical.

“The agent in the study conducted by the COG has at least 14 different ingredients that may be important for the activity of the agent. In approaching these agents, ensuring the consistency of the source and prepara-tion is challenging but essential for an adequate test of clinical efficacy,” said Dr. Chu, who was not involved with the study. He said one explana-tion for the highly positive pilot study and the negative multicenter study is that the second study used a version of traumeel that was in fact quite different from the original.

Rigorous Testing of Homeopathies

Although the lack of benefit from traumeel was a disappointing first attempt by COG to validate com-plementary therapies in oncology, the fact that COG even conducted a clinical trial with the agent is a big thing in itself. “With lots of scientific soul searching, COG did agree that it should become involved in test-ing alternative medicines, not least because so many patients are taking them,” said Susan F. Sencer, MD, medical director of Hematology/Oncology at Chil-dren’s Hospitals and Clinics of Minnesota in Minne-apolis, who led the study of traumeel. Presenting the results of the study at the recent annual meeting of the Society for Integrative Medicine in New York City, Dr. Sencer reported that traumeel was a reasonable candidate for study in a large multicenter trial because there was abundant evidence that the drug is safe; there was preliminary evidence of efficacy from a con-trolled pilot study; and current treatments of mucosi-tis offer little benefit.

Traumeel is considered a complex homeopathic agent, because it is a combination of defined and mea-surable ingredients that are believed to act together to exert its effect. This therapy has been widely used by homeopathists to treat a variety of indications, particularly inflammatory diseases. A controlled tri-al demonstrating the efficacy of traumeel in mucosi-tis was published in a peer-reviewed journal in 2001 (Cancer 2001;92:684-690, PMID: 11505416). Although this study randomized only 32 patients, it was dou-ble-blinded and used an objective scoring system to compare efficacy of the homeopathy with placebo. In the study, traumeel reduced the risk for mucositis by almost 30% (67% vs. 93%) and prevented the likeli-hood that those who had mucositis would develop a more severe case by roughly 50% (47% vs. 93%).

The interest in traumeel after this study was pub-lished led the National Cancer Institute (NCI) to fund the COG study to see if these results could be repli-cated. Although Dr. Sencer acknowledged that she was not initially receptive to the idea of conducting a study of an alternative medicine, she and others par-ticipating in COG have accepted that such therapies, now used in up to 90% of cancer patients, deserve to be studied when there is at least some existing sup-port for efficacy and safety. The published evidence

of benefit in mucositis, for which no therapy has been particularly effective, provided the justification for a large study of traumeel.

Study Details

In the COG study, 190 patients at 26 participat-ing centers in several countries were randomized to receive either traumeel or placebo. Patients between the ages of 3 and 25 years receiving a myeloablative regimen for stem cell transplantation were eligible. The primary outcome was the severity of mucositis as measured with the World Health Organization (WHO) scoring system, which was used in the previous trial, and with a scoring system developed by the COG. Sec-ondary outcomes included narcotic use and need for total parenteral nutrition. On their assigned therapy, patients were required to rinse their mouth vigorous-ly for 30 seconds before swallowing. This was repeat-ed five times per day, and patients were told to avoid food or drink for 30 minutes after each dose.

Although Dr. Sencer noted that the trial had one of the most rapid accruals in the history of COG, pre-sumably because of interest in alternative therapies for mucositis, compliance with the regimen proved to be difficult; 66 patients dropped out before the study was completed. Dropouts occurred as frequently on

placebo as on active treatment. Although the patients remaining in the study provided adequate power to detect a difference, none was found. This was true of both the primary and secondary end points except for a small and nonsignificant trend for reduced narcotic use in the traumeel group. Post-hoc analyses in which patients were stratified by varying levels of compli-ance also failed to show any advantage of traumeel. “We looked at the data at all angles and really did not find any difference,” Dr. Sencer said.

Trials Are Complicated

According to Dr. Chu, testing homeopathies in clin-ical trials is more complicated than testing standard drugs. “The importance of the complexity of botanical and traditional medicines is not very well understood by those used to working with standard pharmaceuti-cals,” said Dr. Chu, who has been active in evaluating traditional Chinese medicines for cancer care. Ensur-ing the composition of a homeopathy is difficult. He

emphasized that quality control is a major issue, but he and others have had success in establish-ing highly sophisticated chemical and biolog-

ic fingerprint profiling methodologies to ensure consistency across batches. With his colleagues at

Yale Cancer Center, Dr. Chu has conducted a series of pilot studies with a particular Chinese herbal medicine called PHY906, and they have demonstrated promis-ing efficacy as a modulator of chemotherapy-induced toxicities in several gastrointestinal cancers.

“I think the FDA feels uncomfortable with agents that have more than six active components. At our center, we are looking at a Chinese herbal medicine that is made up of four main herbs. However, using a very sensitive LC-MS [liquid chromatography-mass spectrometry] method, we have now identified at least 64 individual molecules contained within these four main herbs, which highlights the complexity of these herbal medicines,” Dr. Chu said. He believes the FDA may come to accept the complex composition of alter-native agents, but he still expects the agency to insist on a rigorous analysis capable of providing character-ization of the herbal formulation to ensure that it is reproducible. Dr. Chu believes these drugs should be subjected to the same types of rigorous clinical trials that have established the safety and efficacy of tradi-tional Western therapies.

Because of the difficulties of compliance and inad-equate information about appropriate dose, traumeel was not proven inactive in the COG study. Instead, the study conclusion was that it cannot be considered an evidence-based therapy for mucositis in children, according to Dr. Sencer. However, despite these disap-pointing results, Dr. Sencer said that COG will under-take clinical studies of other alternative agents if pilot studies provide an expectation of efficacy and safety.

“COG is committed to the study of any therapy that will improve management of pediatric cancer,” said Dr. Sencer, who characterized the large, controlled stud-ies as “the final common pathway” for establishing the clinical viability of treatments in cancer. Dr. Chu did not disagree, but he suggested that lack of understand-ing of the nature of these therapies combined with baseline skepticism increases the likelihood of failed trials. He suggested that the study of these botanical medicines requires a different approach that places an emphasis on recognizing and preserving the active ingredients. He believes this field is highly promising, but consistent results across trials require that the quality and consistency of the study agent be initial-ly established.

—Ted Bosworth

MUCOSITIScontinued from page 1 �

SUPPORTIVE CARE

Mucositis

The trial had one of the most rapid accruals in the history of COG, presumably because of interest in alternative therapies for mucositis.

One explanation for the highly positive pilot study and the negative multicenter study is that the second study used a version of traumeel that was in fact quite different from the original.

Raising the survival standardas observed in pivotal Phase III trials1-4

IndicationsAvastin, in combination with carboplatin and paclitaxel, is indicated for first-line treatment of patients with unresectable, locally advanced, recurrentor metastatic non-squamous, non-small cell lung cancer.Avastin, in combination with intravenous 5-fluorouracil–based chemotherapy, is indicated for first- or second-line treatment of patients withmetastatic carcinoma of the colon or rectum.Boxed WARNINGS and additional important safety informationGastrointestinal (GI) perforation: Avastin administration can result in the development of GI perforation, in some cases resulting in fatality. GI perforation, sometimes associated with intra-abdominal abscess, occurred throughout treatment with Avastin. Permanently discontinue Avastintherapy in patients with GI perforation.Wound healing complication: Avastin administration can result in the development of wound dehiscence, in some instances resulting in fatality.Permanently discontinue Avastin therapy in patients with wound dehiscence requiring medical intervention. The appropriate interval between termination of Avastin and subsequent elective surgery has not been determined.Hemorrhage: Severe, and in some cases fatal, pulmonary hemorrhage can occur in patients with NSCLC treated with chemotherapy and Avastin.Do not administer Avastin to patients with recent hemoptysis (≥1/2 tsp of red blood). Permanently discontinue Avastin in patients with serious hemorrhage and initiate aggressive medical management.Additional serious adverse events included non-GI fistula formation, arterial thromboembolic events, hypertensive crisis, reversible posteriorleukoencephalopathy syndrome, neutropenia and infection, nephrotic syndrome, and congestive heart failure. The most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events that may have occurred in Avastin indications (first-line NSCLC, first- and second-line MCRC) included neutropenia, fatigue, hypertension, infection, hemorrhage, asthenia, abdominal pain, pain, deep veinthrombosis, intra-abdominal thrombosis, syncope, diarrhea, constipation, leukopenia, nausea, vomiting, dehydration, ileus, neuropathy–sensory,neurologic–other, and headache.

Please see following brief summary of Prescribing Information, including Boxed WARNINGS, for additional safety information.

©2008 Genentech, Inc. All rights reserved. 9146400 Printed in USA. www.avastin.com

References: 1. Avastin Prescribing Information. Genentech, Inc. March 2008. 2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550. 3. Hurwitz H,Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 4. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544. 5. The NCCN Colon CancerClinical Practice Guidelines in Oncology (Version 1.2008). ©2007 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org. Accessed February 8, 2008. To view the most recent and complete version of the guideline, go online to www.nccn.org. 6. The NCCN Non-Small Cell Lung Cancer Clinical Practice Guidelines in Oncology(Version 2.2008). ©2008 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org. Accessed February 8, 2008. To view the most recent and complete version of the guideline, go online to www.nccn.org.

APPROVED for first-line metastatic NSCLC and first- and second-line MCRC

Primary Endpoint: OS

First-line

MCRC

vsmonths

Chemotherapy*

15.6months

Avastin +chemotherapy*

20.3

increase†

P<0.001Study 2107

30%


Second-line

MCRC

months Chemotherapy*

vs10.8months


13.0

P=0.001Study E3200

20%


First-line

NSCLC

increase†

P=0.013Study E4599

19%

vs

Chemotherapy*months10.3

months12.3


increase†

Avastin is recognized by the NCCN‡

as a standard of care for appropriate patient types in combination with first-line IV chemotherapy5,6

*Chemotherapy regimens with Avastin-based therapy: Study E4599, paclitaxel/carboplatin; Study 2107, IFL; Study E3200, FOLFOX4.†Difference statistically significant. Hazard ratios (HRs) for survival: Study E4599, HR=0.80; Study 2107, HR=0.66; Study E3200, HR=0.75.‡National Comprehensive Cancer Network.

Solution for intravenous infusion Initial U.S. Approval: 2004

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGEGastrointestinal PerforationsThe incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosageand Administration (2.4), Warnings and Precautions (5.1).]Surgery and Wound Healing ComplicationsThe incidence of wound healing and surgical complications,including serious and fatal complications, is increased inAvastin-treated patients. Discontinue Avastin in patients withwound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgeryrequired to reduce the risks of impaired wound healing/wounddehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for atleast 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions(5.2), and Adverse Reactions (6.1).]HemorrhageSevere or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4),Warnings and Precautions (5.3), and Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE1.1 Metastatic Colorectal Cancer (mCRC)Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.1.2 Non-Squamous Non–Small Cell Lung Cancer (NSCLC)Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.1.3 Metastatic Breast Cancer (MBC)Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel.The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).]Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.1.4 GlioblastomaAvastin is indicated for the treatment of glioblastoma with progressive disease following prior therapy as a single agent.The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival withAvastin. [See Clinical Studies (14.4).]1.5 Metastatic Renal Cell Carcinoma (mRCC)Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

4 CONTRAINDICATIONSNone.

5 WARNINGS AND PRECAUTIONS5.1 Gastrointestinal PerforationsSerious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]The typical presentation may include abdominal pain, nausea, emesis,constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]5.2 Surgery and Wound Healing ComplicationsAvastin impairs wound healing in animal models. [See NonclinicalToxicology (13.2).] In clinical trials, administration of Avastin was notallowed until at least 28 days after surgery. In a controlled clinical trial,the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients whodid not receive Avastin, was 4%. [See Adverse Reactions (6.1).]Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning,Dosage and Administration (2.4).]5.3 HemorrhageAvastin can result in two distinct patterns of bleeding: minor hemorrhage,most commonly Grade 1 epistaxis; and serious, and in some cases fatal,hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis,gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patientsreceiving Avastin compared to patients receiving only chemotherapy.Acrossindications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging,symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%–5.93%).Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]5.4 Non-Gastrointestinal Fistula FormationSerious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]5.5 Arterial Thromboembolic EventsSerious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina,and a variety of otherATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]5.6 HypertensionThe incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%.Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuation of Avastin.Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache,seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magneticresonance imaging (MRI) is necessary to confirm the diagnosis of RPLS.Discontinue Avastin in patients developing RPLS. Symptoms usually resolve orimprove within days,although some patients have experienced ongoing neurologicsequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]5.8 ProteinuriaThe incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidneybiopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy.Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours andresume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety studyshowed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57).[See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]5.9 Infusion ReactionsInfusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated withneurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinicalstudies, infusion reactions with the first dose of Avastin were uncommon(< 3%) and severe reactions occurred in 0.2% of patients.Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the label:

[See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

[See Boxed Warning,Dosage and Administration (2.4), Warnings and Precautions (5.2).]

[See Boxed Warning, Dosage and Administration (2.4),Warnings and Precautions (5.3).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.4).]





The most common adverse reactions observed in Avastin patients at a rate> 10% and at least twice the control arm rate, are epistaxis, headache,hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal

hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

6.1 Clinical Trial ExperienceBecause clinical trials are conducted under widely varying conditions,adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug andmay not reflect the rates observed in practice.The data below reflect exposure to Avastin in 2661 patients with mCRC,non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin.[See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white.The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin,480 first-line metastatic NSCLC patients who received a median of 8 dosesof Avastin, 592 MBC patients who had not received chemotherapy formetastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.Surgery and Wound Healing ComplicationsThe incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared topatients receiving only chemotherapy.Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding

In Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred inpatients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4),Warnings and Precautions (5.2).]HemorrhageThe incidence of epistaxis was higher (35% vs. 10%) in patients with

and resolved without medical intervention. Grade 1 or 2 hemorrhagic

gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0),and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]Venous Thromboembolic EventsThe incidence of Grade 3–4 venous thromboembolic events was higher inpatients with mCRC or NSCLC receiving Avastin with chemotherapy as comparedto those receiving chemotherapy alone. The risk of developing a secondsubsequent thromboembolic event in mCRC patients receiving Avastin andchemotherapy was increased compared to patients receiving chemotherapy

following a venous thromboembolic event.Among these patients, an additional

The overall incidence of Grade 3–4 venous thromboembolic events in

following Grade 3–4 venous thromboembolic events was higher in

intra-abdominal venous thrombosis (10 vs. 5 patients).Neutropenia and InfectionThe incidences of neutropenia and febrile neutropenia are increased in patientsreceiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1,the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients

Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patientsreceiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients

plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9(2%) neutropenic infections in patients receiving PC alone, of which none werefatal. During the first 6 cycles of treatment, the incidence of serious infectionsincluding pneumonia, febrile neutropenia, catheter infections and wound infectionswas increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PCalone arm [29 patients (6.6%)].In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%.ProteinuriaGrade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).] Congestive Heart FailureThe incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In

increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC,

patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.Metastatic Colorectal Cancer (mCRC)The data in Table 1 and Table 2 were obtained in Study 1, a randomized,double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving

presented in Table 1.

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab)

9

Curious about how much the National Institutes of Health is

spending this year on cancer research in Arkansas? Until now, finding out would have involved searching a litany of difficult-to-navigate databases scat-tered across the agency’s 27 institutes and centers.

No longer. The NIH has launched a new Web site, RePORTER (projectreporter.nih.gov), that offers visitors a single access point for data on the agen-cy’s spending. Users can search by keyword, institute, investigator name, dollar amount, Congressional dis-trict—handy for see-ing which legislators are best able to bring home the biomedi-cal bacon—and other cat-egories. The site also links to PubMed, PubMed Central and the U.S. Patent & Trademark Office, so users can look up the published findings of particular projects they have searched for.

“With the addition of RePORTER, we have taken a big step toward providing NIH’s broad community of stakehold-ers—including biomedical researchers, research administrators, science poli-cy makers and members of the general public—with richer information, acces-sible in a form designed to meet their diverse set of needs,” said Sally Rockey, PhD, acting deputy director of extramu-ral research for NIH, in a statement.

The site is housed on the NIH’s RePORT Web site (www.report.nih.gov), which in September replaced the agen-cy’s previous repository of grant infor-mation, CRISP.

NIH Streamlines Net Searches for Funding, Other Data

PRN

Research Funding

Where do you go?✪ If you recall seeing an in-depth

review of a topic but no longer have a hard copy?

✪ If you heard about an interesting piece from a colleague?

✪ If you see an installment from a multipart series but wish to see the other parts?

Clinicaloncology.com

Table 1NCI-CTC Grade 3−4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

Arm 1 Arm 2

(n = 396) (n = 392)NCI-CTC Grade 3-4 Events 74% 87%

Asthenia 7% 10%Abdominal Pain 5% 8%Pain 5% 8%

CardiovascularHypertension 2% 12%Deep Vein Thrombosis 5% 9%Intra-Abdominal Thrombosis 1% 3%Syncope 1% 3%

DigestiveDiarrhea 25% 34%Constipation 2% 4%

Hemic/LymphaticLeukopenia 31% 37%Neutropeniaa 14% 21%

aCentral laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in

placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who

Table 2NCI-CTC Grade 1-4 Adverse Events in Study 1

Arm 1 Arm 2 Arm 3

(n = 98) (n = 102) (n = 109)

Pain 55% 61% 62%Abdominal Pain 55% 61% 50%Headache 19% 26% 26%

CardiovascularHypertension 14% 23% 34%Hypotension 7% 15% 7%Deep Vein Thrombosis 3% 9% 6%

DigestiveVomiting 47% 52% 47%Anorexia 30% 43% 35%Constipation 29% 40% 29%Stomatitis 18% 32% 30%Dyspepsia 15% 24% 17%GI Hemorrhage 6% 24% 19%

Dry Mouth 2% 7% 4%Colitis 1% 6% 1%

Hemic/LymphaticThrombocytopenia 0% 5% 5%

NervousDizziness 20% 26% 19%

RespiratoryUpper Respiratory Infection 39% 47% 40%Epistaxis 10% 35% 32%Dyspnea 15% 26% 25%Voice Alteration 2% 9% 6%

Skin/AppendagesAlopecia 26% 32% 6%Skin Ulcer 1% 6% 6%

Special SensesTaste Disorder 9% 14% 21%

UrogenitalProteinuria 24% 36% 36%

Avastin in Combination with FOLFOX4 in Second-line mCRCOnly Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related totreatment were collected in Study 2. The most frequent adverse events (selectedGrade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at

13%), sensory neuropathy (17% vs. 9%),nausea (12% vs. 5%), vomiting (11% vs. 4%),dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%),hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) andheadache (3% vs. 0%). These data are likely to under-estimate the true adverse eventrates due to the reporting mechanisms used in Study 2.Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC)Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events werecollected in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverseevents (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastincompared with 441 patients receiving PC alone were neutropenia (27% vs.17%), fatigue(16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%),venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%),hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).Metastatic Breast Cancer (MBC)Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events werecollected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%)in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receivingpaclitaxel alone were sensory neuropathy (24% vs.18%),hypertension (16% vs.1%),fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs.3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache(4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration(3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs.0.3%) and proteinuria (3% vs. 0%).Sensory neuropathy,hypertension,and fatigue were reported at a ≥ 5% higher absoluteincidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm.

plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2).Avastin is not approved for use in combination with capecitabine or for use in secondor third line treatment of MBC.The data below are presented to provide information onthe overall safety profile of Avastin in women with breast cancer since Study 6 is theonly randomized, controlled study in which all adverse events were collected for all

patients. All patients in Study 6 received prior anthracycline and taxane therapy in theadjuvant setting or for metastatic disease.Grade 1– 4 events which occurred at a higherincidence (≥5%) in patients receiving capecitabine plus Avastin compared to thecapecitabine alone arm are presented in Table 3.

Table 3NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

CapecitabineCapecitabine + Avastin

(n = 215) (n = 229)

Asthenia 47% 57%Headache 13% 33%Pain 25% 31%

CardiovascularHypertension 2% 24%

DigestiveStomatitis 19% 25%

Metabolic/Nutrition

MusculoskeletalMyalgia 8% 14%

RespiratoryDyspnea 18% 27%Epistaxis 1% 16%

Skin/AppendagesExfoliative dermatitis 75% 84%

UrogenitalAlbuminuria 7% 22%

GlioblastomaAll adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every2 weeks alone or in combination with irinotecan.Avastin was discontinued dueto adverse events in 4.8% of patients treated with Avastin alone.In patients receiving Avastin alone (N=84), the most frequently reported adverseevents of any grade were infection (55%), fatigue (45%), headache (37%),hypertension (30%),epistaxis (19%) and diarrhea (21%).Of these, the incidenceof Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%),hypertension (8%) and diarrhea (1%).Two deaths on study were possibly relatedto Avastin: one retroperitoneal hemorrhage and one neutropenic infection.In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin-related adverse events (Grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension(32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinalperforation (2%), and RPLS (1%).The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%),hypertension (5%), venous thromboembolic event (7%), arterialthromboembolic event (3%),wound-healing complications (3%),proteinuria (1%), and gastrointestinal perforation (2%).Metastatic Renal Cell Carcinoma (mRCC)All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving

α) plus Avastin compared to 304 patients receivingα plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%),

proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis,small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage,gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving

α α plus placebo arm are presented in Table 4.

Table 4NCI-CTC Grades 1−5 Adverse Events in Study 9

α α + Placebo)

α α + AvastinPreferred term* (n = 304) (n = 337)

Gastrointestinal disordersDiarrhea 16% 21%

General disorders and administration site conditions

Investigations

Metabolism and nutrition disordersAnorexia 31% 36%

Musculoskeletal and connective tissue disorders

Myalgia 14% 19%Back pain 6% 12%

Nervous system disordersHeadache 16% 24%

Renal and urinary disordersProteinuria 3% 20%

Respiratory, thoracic and mediastinal disorders

Epistaxis 4% 27%Dysphonia 0% 5%

Vascular disordersHypertension 9% 28%

*Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5-fold greater incidence in theα α alone and not represented in Table 4:

gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0);gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1);tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0);gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).6.2 ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity.The incidenceof antibody development in patients receiving Avastin has not been adequatelydetermined because the assay sensitivity was inadequate to reliably detect lowertiters. Enzyme-linked immunosorbent assays (ELISAs) were performed on sera fromapproximately 500 patients treated with Avastin, primarily in combination withchemotherapy. High titer human anti-Avastin antibodies were not detected.Immunogenicity data are highly dependent on the sensitivity and specificity ofthe assay.Additionally, the observed incidence of antibody positivity in an assay

may be influenced by several factors, including sample handling, timing of

reasons, comparison of the incidence of antibodies to Avastin with theincidence of antibodies to other products may be misleading.6.3 Postmarketing ExperienceThe following adverse reactions have been identified during post-approvaluse of Avastin. 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.Body as a Whole: PolyserositisCardiovascular: Pulmonary hypertension, RPLSDigestive: Intestinal necrosis, mesenteric venous occlusion, anastomotic ulcerationHemic and lymphatic: PancytopeniaRenal: Renal thrombotic microangiopathy (manifested as severe proteinuria)Respiratory: Nasal septum perforation, dysphonia

7 DRUG INTERACTIONSA drug interaction study was performed in which irinotecan was

results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.In a randomized study in 99 patients with NSCLC,based on limited data, there didnot appear to be a difference in the mean exposure of either carboplatin orpaclitaxel when each was administered alone or in combination with Avastin.However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin hadsubstantially lower paclitaxel exposure after four cycles of treatment (at Day 63)than those at Day 0, while patients receiving paclitaxel/carboplatin withoutAvastin had a greater paclitaxel exposure at Day 63 than at Day 0.In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CThere are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]Human IgG is known to cross the placental barrier; therefore, bevacizumab may betransmitted from the mother to the developing fetus, and has the potential to causefetal harm when administered to pregnant women. Because of the observedteratogenic effects of known inhibitors of angiogenesis in humans, bevacizumabshould be used during pregnancy only if the potential benefit to the pregnant womanjustifies the potential risk to the fetus.8.3 Nursing MothersIt is not known whether Avastin is secreted in human milk, but human IgG isexcreted in human milk. Published data suggest that breast milk antibodies do notenter the neonatal and infant circulation in substantial amounts. Because manydrugs are secreted in human milk and because of the potential for serious adversereactions in nursing infants from bevacizumab, a decision should be made whetherto discontinue nursing or discontinue drug, taking into account the half-life of thebevacizumab (approximately 20 days [range 11–50 days]) and the importance ofthe drug to the mother. [See Clinical Pharmacology (12.3).]8.4 Pediatric UseThe safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasiafollowing 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose(based on mg/kg and exposure). The incidence and severity of physeal dysplasiawere dose-related and were partially reversible upon cessation of treatment.8.5 Geriatric UseIn Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patientsaged ≥65 years as compared to younger patients were asthenia, sepsis, deepthrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heartfailure,diarrhea, constipation,anorexia, leukopenia,anemia,dehydration,hypokalemia,and hyponatremia. The effect of Avastin on overall survival was similar in elderlypatients as compared to younger patients.

greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]In Study 5, there were insufficient numbers of patients ≥ 65 years old to determinewhether the overall adverse events profile was different in the elderly as comparedwith younger patients.Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis,increased cough, and voice alteration.In an exploratory, pooled analysis of 1745 patients treated in five randomized,controlled studies, there were 618 (35%) patients aged ≥65 years and 1127patients <65 years of age.The overall incidence of arterial thromboembolic events wasincreased in all patients receiving Avastin with chemotherapy as compared to thosereceiving chemotherapy alone, regardless of age. However, the increase in arterialthromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs.2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

10 OVERDOSAGEThe highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab)

Manufactured by: 7453214Genentech, Inc. 4835706

94080-4990 © 2009 Genentech, Inc


Hodgkin’s Lymphoma

Combined Modality Versus Chemo Alone

Results from the German Hodgkin Study Group HD10 trial demonstrated that two cycles of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) followed by 20 Gy involved-field radia-tion therapy (IFRT) is a highly effective therapy for patients with early-stage, favorable HL (abstract 716).

In recent years, clinicians contin-ue to debate the best therapy for early-stage favorable HL, in particular the role of combined modality therapy compared with chemotherapy alone. The HD10 trial, reported at this year’s ASH meeting, attempted to shed light on this matter. The study randomized 1,370 patients to two versus four cycles of ABVD followed by 20 versus 30 Gy IFRT. Disease features were well bal-anced between the arms.

Expected toxicities were greater with four cycles of ABVD compared with two cycles, and with 30 rather than 20 Gy radiation. With a median follow-up of 79 to 91 months, there was no signif-icant difference between two and four cycles of ABVD in terms of overall sur-vival (OS) at five years (four cycles, 97.1%; two cycles, 96.6%), freedom from treat-ment failure (FFTF; 93.0% vs. 91.1%) and progression-free survival (PFS; 93.5% vs. 91.2%). For the radiotherapy question, there also were no significant differenc-es between patients receiving 30 and 20 Gy IFRT in terms of OS (97.6% vs. 97.5%), FFTF (93.4% vs. 92.9%) and PFS (93.7% vs. 93.2%).

Dose-Dense/Dose-Intense ABVD Examined

Results of a Phase II study revealed that the activity of intensified ABVD is significantly higher than the activity of standard ABVD in patients with inter-mediate- or advanced-stage HL. Inten-sified ABVD increased rates of complete response (CR) and event-free survival (EFS) while maintaining a low-toxicity profile (abstract 715).

In the study, the intercycle period was shortened from 28 to 21 days, and for the dose-intense schedule, adriamycin was escalated to 70 mg/m2 for cycles 1 through 4. Early CR calculated by pos-itron emission tomography occurred in 95% of patients; by the end of six cycles, the CR rate was 98.6%. The EFS rates

were 95.8% for intermediate-disease patients and 91.3% for advanced-disease patients, with a minimum follow-up of 12 months, which is significantly better than expected with standard ABVD.

Treatment for Relapsed HLInterim results from a trial showed

that bendamustine (Treanda, Cepha-lon) is highly active in heavily pretreat-ed patients with relapsed/refractory HL,

and the use of the drug enables a signif-icant portion of eligible patients to be

Expert Highlights Hematology News From ASH MeetingBelow, Jennifer R. Brown, MD, PhD, highlights news from the recent annual meeting

of the American Society of Hematology (ASH) regarding Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). Dr. Brown is an attending physician with the CLL & Lymphoma Program, Dana-Farber Cancer Institute, and an assistant professor of medicine at Harvard Medical School, both in Boston.

HEMATOLOGIC DISEASE

Multiple Cancers

Interim results from a trial showed that bendamustine (Treanda, Cephalon) is highly active in heavily pretreated patients with relapsed/refractory HL.

References: 1. TYKERB Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; 2008. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V.1.2010. www.nccn.org. Accessed October 20, 2009.

DOSE MODIFICATION GUIDELINESFor dose modifi cation guidelines, please see Brief Summary of Prescribing Information on following pages.

IMPORTANT SAFETY INFORMATIONDecreased Left Ventricular Ejection Fraction—TYKERB has been reported to decrease LVEF. Caution should be taken if TYKERB is to be administered to patients with preexisting cardiac conditions, including uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure. Confi rm normal LVEF before starting TYKERB, and continue evaluations during treatment.

Patients With Severe Hepatic Impairment—If TYKERB is to be administered to patients with severe hepatic impairment, dose reduction should be considered.

Diarrhea—Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB and was the most common adverse reaction resulting in discontinuation of TYKERB therapy. Proactive management of diarrhea with antidiarrheal agents is important, and severe cases of diarrhea may require administration of oral or intravenous electrolytes and fl uids and interruption or discontinuation of therapy with TYKERB.

Interstitial Lung Disease/Pneumonitis—TYKERB has been associated with interstitial lung disease and pneumonitis. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis and if symptoms are ≥grade 3 (NCI CTCAE), TYKERB should be discontinued.

QT Prolongation—TYKERB prolongs the QT interval in some patients. TYKERB should be administered with caution to patients who have or may develop prolongation of QTc. Hypokalemia or hypomagnesemia should be corrected prior to TYKERB administration. Baseline and on-treatment electrocardiograms with QT measurement should be considered.

Pregnancy—Pregnancy Category D: TYKERB can cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant when taking TYKERB. 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.

Adverse Reactions—The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (65%, 40%), nausea (44%, 43%), vomiting (26%, 21%), palmar-plantar erythrodysesthesia (53%, 51%), rash (28%, 14%), and fatigue (46%, 47%).

The most common grade 3 and 4 adverse reactions (NCI CTCAE v3) with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (14%, 10%) and palmar-plantar erythrodysesthesia (12%, 14%).

BOXED WARNING: HEPATOTOXICITYTYKERB has been associated with hepatotoxicity. Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >1.5 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity mayoccur days to several months after initiation of treatment. Liver function tests should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with TYKERB should be discontinued and patients should not be re-treated with TYKERB.

www.TYKERB.com 1-866-4-TYKERB 1-866-489-5372

MCONCS644.indd 1 11/11/09 5:00:44 PM


referred to nonmyeloablative allogeneic stem cell transplantation (abstract 720).

Therapeutic options for patients with HL who have relapsed after autologous stem cell transplantation (ASCT) can be limited. Early results of a Phase II study of bendamustine 120 mg/m2 on days 1 and 2 every 28 days with pegfilgrastim (Neu-lasta, Amgen) support suggest significant efficacy, albeit with myelotoxicity. The overall response rate (ORR) was 75% with six CRs (38%) and six partial responses (38%), in the first 18 patients of a planned 37 patients. Although the data are prelim-inary, this study suggests another active treatment for relapsed HL.

Non-Hodgkin’s Lymphoma

Bendamustine-R for Indolent Lymphomas

The German Indolent Lymphoma Study Group reported the final results of their randomized Phase III trial com-paring initial therapy with bendamus-tine (Treanda, Cephalon; 90 mg/m2) plus rituximab (Rituxan, Biogen/Idec) to initial therapy with CHOP-R (cyclo-phosphamide, hydroxydaunorubicin, vincristine, prednisone, plus rituximab) for follicular, indolent and mantle cell lymphomas (abstract 405).

In the trial, 549 patients were enrolled,

with 513 evaluable, and the arms were equally balanced for all patient charac-teristics, including histology and stage (with approximately 75% stage 4). The ORR for patients treated with bendamus-tine and rituximab (BR) was similar to that of the CHOP-R group (about 94%). The CR rate was significantly higher at 40.1% for BR compared with 30.8% for CHOP-R (P=0.0323). The median PFS, EFS and time to next treatment (TTNT) were significantly longer after BR com-pared with CHOP-R: PFS at 54.8 months for BR compared with 34.8 months for CHOP-R (P=0.0002); EFS at 54 months for BR compared with 31 months for

CHOP-R (P=0.0002); and TTNT medi-an not yet reached in the BR group com-pared with 40.7 months in the CHOP-R group (P=0.0002). The OS did not differ between the groups.

In addition to the improved CR rate and PFS, the BR regimen was also bet-ter tolerated, with less hematologic tox-icity, less hair loss, less neuropathy and fewer infections. These data suggest that BR is a reasonable up-front thera-py for indolent lymphomas.

Initial Therapy of MCL

Initial therapy of mantle cell lymphoma

HEMATOLOGIC DISEASE

Multiple Cancers

see HIGHLIGHTS, page 12 �

Dosage & Administration

Proven After 1st-line MBC

2010 NCCN CLINICAL PRACTICE GUIDELINES TYKERB + capecitabine is listed as a preferred regimen for second-line treatment of HER2+ MBCpatients who have received prior therapy including an anthracycline, a taxane, and trastuzumab2

28% TO 43% REDUCTION IN RISK OF PROGRESSION TYKERB plus capecitabine reduced risk of progression 28% to 43% vs capecitabine alone†1

IN HER2+ METASTATIC BREAST CANCER (MBC)

WHEN FIRST-LINE THERAPY FAILS*

† TYKERB was studied in a phase 3 trial of 399 women with HER2+ MBC; ≈95% of patients had prior treatment with an anthracycline, a taxane, and trastuzumab. Patients were randomized to either: TYKERB 1250 mg orally daily throughout the trial + capecitabine 2000 mg/m2/day orally in 2 divided doses, days 1-14 every 21 days (n=198); or capecitabine 2500 mg/m2/day orally in 2 divided doses, days 1-14 every 21 days (n=201). Primary end point was time to progression (time from randomization until objective tumor progression or death due to breast cancer).1

TREAT HER DIFFERENTLY WITH TYKERB

*TYKERB is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.1

Please see Brief Summary of Prescribing Information on adjacent pages.

MCONCS644.indd 1 11/11/09 5:00:44 PM


(MCL) remains controversial. The authors of the study described in abstract 403 used the National Comprehen-sive Cancer Network database to com-pare the outcomes of newly diagnosed patients treated with R-CHOP (ritux-imab plus cyclophosphamide, hydroxy-daunorubicin, vincristine, prednisone), R-CHOP with autologous SCT for con-solidation, or R-hyperCVAD (ritux-imab with hyperfractionated cyclophos-phamide, doxorubicin, vincristine and

dexamethasone). At the presentation at ASH, 156 patients were evaluable, with a median follow-up of 30 months.

R-CHOP alone showed inferior PFS and a trend toward inferior OS. Howev-er, R-CHOP followed by autologous SCT was equivalent to R-hyperCVAD for both PFS and OS, and had less toxicity and few-er days in the hospital. Unfortunately, the study revealed that with either treatment, the median PFS is only three years in this younger patient population, suggesting a need for novel therapeutic options.

R-CHOP-21 Remains Standard For Elderly DLBCL

Results from a study reported at ASH suggest that R-CHOP-21 should remain the standard therapy for elderly patients

with diffuse large B-cell lymphoma (DLBCL).

Following the studies of the German lymphoma group that suggested that CHOP given every two weeks may be better than CHOP given every three weeks in DLBCL, the GELA (Groupe d’Étude des Lymphomes de l’Adulte) initiated LNH03-6B, a multicenter Phase III randomized trial compar-ing R-CHOP given every 14 days with R-CHOP given every 21 days, in elderly patients with DLBCL. At the ASH meet-ing, they reported a planned interim analysis of 202 patients, with a median follow-up of 24 months (abstract 406).

HEMATOLOGIC DISEASE

Multiple Cancers

HIGHLIGHTScontinued from page 11 �

100

80

60

40

20

0

% o

f P

ati

en

ts

R-CHOP-14

R-CHOP-21

6775

6775

Figure. Comparison of response rate.

TYKERB® (lapatinib) tabletsThe following is a brief summary only; see full prescribing information forcomplete product information.

WARNING: HEPATOTOXICITYHepatotoxicity has been observed in clinical trials and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. [See Warnings and Precautions (5.2).]

1 INDICATIONS AND USAGE TYKERB is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.

2 DOSAGE AND ADMINISTRATION2.1 Recommended Dosing The recommended dose of TYKERB is 1,250 mg (5 tablets) given orally once daily on Days 1-21 continuously in combination with capecitabine 2,000 mg/m2/day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21 day cycle. TYKERB should be taken at least one hour before or one hour after a meal. The dose of TYKERB should be once daily; dividing the daily dose is not recommended [see Clinical Pharmacology (12.3) of full prescribing information]. Capecitabine should be taken with food or within 30 minutes after food. If a day’s dose is missed, the patient should not double the dose the next day. Treatment should be continued until disease progression or unacceptable toxicity occurs.

2.2 Dose Modification Guidelines Cardiac Events: TYKERB should be discontinued in patients with a decreased left ventricular ejection fraction (LVEF) that is Grade 2 or greater by NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) and in patients with an LVEF that drops below the institution’s lower limit of normal [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. TYKERB may be restarted at a reduced dose (1,000 mg/day) after a minimum of 2 weeks if the LVEF recovers to normal and the patient is asymptomatic. Hepatic Impairment: Patients with severe hepatic impairment (Child-Pugh Class C) should have their dose of TYKERB reduced. A dose reduction to 750 mg/day in patients with severe hepatic impairment is predicted to adjust the area under the curve (AUC) to the normal range and should be considered. However, there are no clinical data with this dose adjustment in patients with severe hepatic impairment. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit may also increase plasma concentrations of lapatinib and should be avoided. If patients must be coadministered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a dose reduction to 500 mg/day of lapatinib is predicted to adjust the lapatinib AUC to the range observed without inhibitors and should be considered. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose. [See Drug Interactions (7.2).] Concomitant Strong CYP3A4 Inducers: The concomitant use of strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John’s Wort). If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dose of lapatinib should be titrated gradually from 1,250 mg/day up to 4,500 mg/day based on tolerability. This dose of lapatinib is predicted to adjust the lapatinib AUC to the range observed without inducers and should be considered. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the lapatinib dose should be reduced to the indicated dose. [See Drug Interactions (7.2).] Other Toxicities: Discontinuation or interruption of dosing with TYKERB may be considered when patients develop ≥Grade 2 NCI CTC toxicity and can be restarted at 1,250 mg/day when the toxicity improves to Grade 1 or less. If the toxicity recurs, then TYKERB should be restarted at a lower dose (1,000 mg/day). See manufacturer’s prescribing information for capecitabine dosage adjustment guidelines in the event of toxicity.

4 CONTRAINDICATIONS None. See manufacturer’s prescribing information for capecitabine contraindications.

5 WARNINGS AND PRECAUTIONS5.1 Decreased Left Ventricular Ejection Fraction TYKERB has been reported to decrease LVEF [see Adverse Reactions (6.1)]. In the randomized clinical trial, the majority (>60%) of LVEF decreases occurred within the first 9 weeks of treatment; however, data on long-term exposure are limited. Caution should be taken if TYKERB is to be administered to patients with conditions that could impair left ventricular function. LVEF

should be evaluated in all patients prior to initiation of treatment with TYKERB to ensure that the patient has a baseline LVEF that is within the institution’s normal limits. LVEF should continue to be evaluated during treatment with TYKERB to ensure that LVEF does not decline below the institution’s normal limits [see Dosage and Administration (2.2)].

5.2 Hepatotoxicity Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >1.5 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with TYKERB should be discontinued and patients should not be retreated with TYKERB [see Adverse Reactions (6.1)].

5.3 Patients with Severe Hepatic Impairment If TYKERB is to be administered to patients with severe pre-existing hepatic impairment, dose reduction should be considered [see Dosage and Administration (2.2) and Use in Specific Populations (8.7)]. In patients who develop severe hepatotoxicity while on therapy, TYKERB should be discontinued and patients should not be retreated with TYKERB [see Warnings and Precautions (5.2)].

5.4 Diarrhea Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB [see Adverse Reactions (6.1)]. Proactive management of diarrhea with anti-diarrheal agents is important. Severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids, and interruption or discontinuation of therapy with TYKERB.

5.5 Interstitial Lung Disease/Pneumonitis Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies [see Adverse Reactions (6.1)]. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis. TYKERB should be discontinued in patients who experience pulmonary symptoms indicative of interstitial lung disease/pneumonitis which are ≥Grade 3 (NCI CTCAE).

5.6 QT Prolongation QT prolongation measured by automated machine-read evaluation of ECG was observed in an uncontrolled, open-label dose escalation study of lapatinib in advanced cancer patients [see Clinical Pharmacology (12.4) of full prescribing information]. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc. These conditions include patients with hypokalemia or hypomagnesemia, with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Hypokalemia or hypomagnesemia should be corrected prior to lapatinib administration. The prescriber should consider baseline and on-treatment electrocardiograms with QT measurement.

5.7 Pregnancy Pregnancy Category D TYKERB can cause fetal harm when administered to a pregnant woman. In a study where pregnant rats were dosed with lapatinib during organogenesis and through lactation, at a dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC), 91% of the pups had died by the fourth day after birth, while 34% of the 60 mg/kg/day pups were dead. The highest no-effect dose for this study was 20 mg/kg/day (approximately equal to the human clinical exposure based on AUC). Lapatinib was studied for effects on embryo-fetal development in pregnant rats and rabbits given oral doses of 30, 60, and 120 mg/kg/day. There were no teratogenic effects; however, minor anomalies (left-sided umbilical artery, cervical rib, and precocious ossification) occurred in rats at the maternally toxic dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC). In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (approximately 0.07 and 0.2 times the human clinical exposure, respectively, based on AUC) and abortions at 120 mg/kg/day. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations. There are no adequate and well-controlled studies with TYKERB in pregnant women. Women should be advised not to become pregnant when taking TYKERB. 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.

6 ADVERSE REACTIONS6.1 Clinical Trials Experience The safety of TYKERB has been evaluated in more than 3,500 patients in clinical trials. The efficacy and safety of TYKERB in combination with capecitabine in breast cancer was evaluated in 198 patients in a randomized, Phase 3 trial. [See Clinical Studies (14) of full prescribing information.] Adverse reactions which occurred in at least 10% of patients in either treatment arm and were higher in the combination arm are shown in Table 1. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be

MCONCS645.indd 1 11/11/09 5:01:26 PM


The response rate (CR+CRu) was 67% in the R-CHOP-14 arm and 75% in the R-CHOP-21 arm (P=NS). The two-year EFS was 48% with R-CHOP-14 compared with 61% with R-CHOP-21 (P=NS). A similar trend was observed for two-year PFS (49% vs. 63%), two-year disease-free survival (57% vs. 70%) and two-year OS (67% vs. 70%; P=NS for all). Hematologic toxicity was higher in the R-CHOP-14 group, but no difference was observed in oth-er toxicities. These results suggest that R-CHOP-21 will remain the stan-dard therapy for elderly patients with DLBCL.

Pooled Analysis of MCL TrialsResults from a study suggest that both

rituximab in induction and autologous SCT in first remission confer prolonged response duration and survival in MCL, although this response is still relatively short (abstract 880).

The German Low-Grade Lympho-ma Study Group and European MCL Network carried out a pooled analy-sis of three previous randomized trials (involving CHOP or R-CHOP induction followed by randomization to autologous SCT or interferon-α for consolidation), in order to determine the relative con-tributions of rituximab and autologous

SCT to the up-front therapy of MCL. With a median follow-up of 63 months and 180 evaluable patients, median response duration was 16 months after CHOP without ASCT, 26 months after R-CHOP without ASCT, 39 months after CHOP with ASCT, and 41 months after R-CHOP with ASCT.

In multivariate Cox regression analysis including R and ASCT, the hazard ratios of R (0.60; P=0.0056) and ASCT (0.50; P=0.0001) were both significant. Median OS was 54 months after CHOP without ASCT, 66 months after R-CHOP with-out ASCT, 90 months after CHOP with ASCT, and not reached after R-CHOP

with ASCT. The hazard ratios for OS were 0.70 (95% CI, 0.44-1.12; P=0.14) for R and 0.63 (95% CI, 0.41-0.97; P=0.0379) for ASCT.

Multiple Myeloma

VMP Induction Followed by VT Maintenance Best

The previously reported VISTA tri-al showed that adding bortezomib (Vel-cade, Millennium Pharmaceuticals) to melphalan and prednisone (MP) was better than MP alone in patients with MM. The question of whether an

HEMATOLOGIC DISEASE

Multiple Cancers

see BROWN HIGHLIGHTS, page 14 �

directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic (palmar-plantar erythrodysesthesia and rash), and fatigue. Diarrhea was the most common adverse reaction resulting in discontinuation of study medication. The most common Grade 3 and 4 adverse reactions (NCI CTC v3) were diarrhea and palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 2.

Table 1. Adverse Reactions Occurring in ≥10% of Patients

TYKERB 1,250 mg/day + Capecitabine

2,000 mg/m2/day (N = 198)

Capecitabine 2,500 mg/m2/day

(N = 191)

ReactionsAll

Gradesa

%

Grade 3 %

Grade 4 %

All Gradesa

%

Grade 3 %

Grade 4 %

Gastrointestinal disorders

Diarrhea 65 13 1 40 10 0

Nausea 44 2 0 43 2 0

Vomiting 26 2 0 21 2 0

Stomatitis 14 0 0 11 <1 0

Dyspepsia 11 <1 0 3 0 0

Skin and subcutaneous tissue disorders

Palmar-plantar erythrodysesthesia

53 12 0 51 14 0

Rashb 28 2 0 14 1 0

Dry skin 10 0 0 6 0 0

General disorders and administrative site conditions

Mucosal inflammation 15 0 0 12 2 0

Musculoskeletal and connective tissue disorders

Pain in extremity 12 1 0 7 <1 0

Back pain 11 1 0 6 <1 0 Respiratory, thoracic, and mediastinal disorders

Dyspnea 12 3 0 8 2 0

Psychiatric disorders

Insomnia 10 <1 0 6 0 0a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

b Grade 3 dermatitis acneiform was reported in <1% of patients in TYKERB plus capecitabine group.

Table 2. Selected Laboratory Abnormalities

TYKERB 1,250 mg/day + Capecitabine

2,000 mg/m2/day

Capecitabine 2,500 mg/m2/day

ParametersAll

Gradesa

%

Grade 3 %

Grade 4 %

All Gradesa

%

Grade 3 %

Grade 4 %

Hematologic

Hemoglobin 56 <1 0 53 1 0

Platelets 18 <1 0 17 <1 <1

Neutrophils 22 3 <1 31 2 1

Hepatic

Total Bilirubin 45 4 0 30 3 0

AST 49 2 <1 43 2 0

ALT 37 2 0 33 1 0a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Decreases in Left Ventricular Ejection Fraction: Due to potential cardiac toxicity with HER2 (ErbB2) inhibitors, LVEF was monitored in clinical trials at approximately 8-week intervals. LVEF decreases were defined as

signs or symptoms of deterioration in left ventricular cardiac function that are ≥Grade 3 (NCI CTCAE), or a ≥20% decrease in left ventricular cardiac ejection fraction relative to baseline which is below the institution's lower limit of normal. Among 198 patients who received lapatinib/capecitabine combination treatment, 3 experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTC 3.0). [See Warnings and Precautions (5.1).] Hepatotoxicity: Lapatinib has been associated with hepatotoxicity [see Boxed Warning and Warnings and Precautions (5.2)]. Interstitial Lung Disease/Pneumonitis: Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies [see Warnings and Precautions (5.5)].

7 DRUG INTERACTIONS7.1 Effects of Lapatinib on Drug Metabolizing Enzymes and Drug Transport Systems Lapatinib inhibits CYP3A4 and CYP2C8 in vitro at clinically relevant concentrations. Caution should be exercised and dose reduction of the concomitant substrate drug should be considered when dosing lapatinib concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4 or CYP2C8. Lapatinib did not significantly inhibit the following enzymes in human liver microsomes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6 or UGT enzymes in vitro, however, the clinical significance is unknown. Lapatinib inhibits human P-glycoprotein. If TYKERB is administered with drugs that are substrates of Pgp, increased concentrations of the substrate drug are likely, and caution should be exercised.

7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Lapatinib undergoes extensive metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 alter lapatinib concentrations significantly (see Ketoconazole and Carbamazepine sections, below). Dose adjustment of lapatinib should be considered for patients who must receive concomitant strong inhibitors or concomitant strong inducers of CYP3A4 enzymes [see Dosage and Administration (2.2)]. Ketoconazole: In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 200 mg twice daily for 7 days, systemic exposure (AUC) to lapatinib was increased to approximately 3.6-fold of control and half-life increased to 1.7-fold of control. Carbamazepine: In healthy subjects receiving the CYP3A4 inducer, carbamazepine, at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, systemic exposure (AUC) to lapatinib was decreased approximately 72%.

7.3 Drugs that Inhibit Drug Transport Systems Lapatinib is a substrate of the efflux transporter P-glycoprotein (Pgp, ABCB1). If TYKERB is administered with drugs that inhibit Pgp, increased concentrations of lapatinib are likely, and caution should be exercised.

7.4 Other Chemotherapy Agents In a separate study, concomitant administration of lapatinib with capecitabine did not meaningfully alter the pharmacokinetics of either agent (or the metabolites of capecitabine).

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.7)].

8.3 Nursing Mothers It is not known whether lapatinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from TYKERB, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of TYKERB in pediatric patients have not been established.

8.5 Geriatric Use Of the total number of metastatic breast cancer patients in clinical studies of TYKERB in combination with capecitabine (N = 198), 17% were 65 years of age and older, and 1% were 75 years of age and older. No overall differences in safety or effectiveness of the combination of TYKERB and capecitabine were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment Lapatinib pharmacokinetics have not been specifically studied in patients with renal impairment or in patients undergoing hemodialysis. There is no experience with TYKERB in patients with severe renal impairment. However, renal impairment is unlikely to affect the pharmacokinetics of lapatinib given that less than 2% (lapatinib and metabolites) of an administered dose is eliminated by the kidneys.

8.7 Hepatic Impairment The pharmacokinetics of lapatinib were examined in subjects with pre-existing moderate (n = 8) or severe (n = 4) hepatic impairment (Child-Pugh Class B/C, respectively) and in 8 healthy control subjects. Systemic exposure

MCONCS645.indd 1 11/11/09 5:01:26 PM


alkylating agent or immunomodulato-ry agent is the better partner with bort-ezomib, however, was not answered by the trial. The Spanish Myeloma Group therefore undertook a study to answer this question (abstract 3).

The trial randomized 260 patients to receive six cycles of VMP (bortezomib, melphalan [Alkeran, Celgene], predni-sone) or VTP (bortezomib, thalidomide, prednisone) as induction therapy fol-lowed by maintenance with VT or VP for up to three years. Bortezomib was giv-en on the usual schedule for the first six weeks, and then weekly thereafter dur-ing induction. The patient characteristics were well balanced between arms. The ORR was 80% in both arms with CR rates of 20% to 27%; maintenance improved the CR rate for both groups to 42%. A trend toward better PFS with VMP induction was observed. The main difference was observed during maintenance, where VT improved PFS and OS regardless of the induction therapy. The group with the best PFS, therefore, had VMP induction followed by VT maintenance.

Optimal Timing of ASCT

The optimal timing of ASCT in the era of new therapies is not clear. Mayo Clinic therefore conducted a retrospec-tive review of 292 patients with MM between 2000 and 2008 who were

treated initially with thalidomide–dex-amethasone or lenalidomide–dexameth-asone as their up-front therapy (abstract 956). The median estimated follow-up for the entire group was 54 months from diagnosis, 52 and 61 months respectively for the early and delayed SCT groups.

The investigators found that continu-ing initial therapy with delay of SCT until relapse proved similar to early consolida-tion transplantation, in terms of OS.

VDCR Appears Promising

While lenalidomide–bortezomib–dex-amethasone (RVD) regimens have been found to be safe and effective in myelo-ma, the role of cyclophosphamide in this regimen has not been established. The Phase I multicenter EVOLUTION study revealed that the VDCR regimen (bort-ezomib, dexamethasone, cyclophos-phamide, lenalidomide [Revlimid, Cel-gene]) is a highly active and generally well-tolerated induction therapy in pre-viously untreated MM patients.

This year, the results of the noncom-parative Phase II trial including VDR, VDC and VDCR, were reported (abstract 127). Thus far, the VDCR arm may have a slightly higher rate of high-quali-ty responses (CR or vgPR), albeit with greater toxicity. Longer follow-up will be required to see what cyclophosphamide will add to the regimen.

Chronic Lymphocytic Leukemia

German CLL Study UpdatesThe German CLL Study Group

(GCLLSG) updated the results of the CLL8 study, a randomized controlled trial comparing FCR (fludarabine, cyclo-phosphamide, rituximab) to FC (fludar-abine, cyclophosphamide) in fit patients with CLL requiring initial therapy

(abstract 535). The median PFS for FC is now 33 months, compared with 52 months for FCR. An OS benefit is now observed for FCR, with 82.5% of FC patients alive compared with 87.2% of FCR patients (P=0.012), with a median follow-up of 37.7 months. FCR appeared to overcome the adverse impact of 11q deletion, but did not overcome the adverse impact of 17p deletion, which was still associated with a significant-ly shorter PFS. In multivariate analysis, the only predictors of improved OS were receiving FCR, low β2-microglobulin and absence of 17p deletion.

The GCLLSG also reported the results of their Phase II study of bendamustine (90 mg/m2)–rituximab (BR) as up-front therapy for CLL (abstract 205). The study enrolled 117 patients; 48% were Binet C patients. Although hematologic toxicity was low (20%-25% grade 3/4 neutrope-nia or thrombocytopenia), the treatment-related mortality was 3.4%, with two fatal septic events, one case of fatal pneumo-nia and one death due to liver failure associated with suicide. The ORR was 91%, with CR rate of 33%. Minimal resid-ual disease was not detectable in 58% of patients in peripheral blood and 28% in bone marrow. With a median follow-up of 15 months, 85% of patients remain in remission. The GCLLSG has an ongo-ing randomized trial comparing BR to FCR in up-front CLL. Although these data for up-front BR are typical of many chemoimmunotherapy regimens, overall they are not as impressive as the up-front data for FCR.

Updates of CALGB Trials

Kanti Rai, MD, updated the results of CALGB 9011, a randomized trial com-paring initial therapy with chlorambu-cil, fludarabine, or chlorambucil plus fludarabine (abstract 536). He report-ed that the OS curves start to separate at six years, and that by eight years, 31% of fludarabine patients are alive compared with 19% of chlorambucil patients (P=0.04). The chlorambucil plus fludarabine arm was closed early due to excessive toxicity. The finding of improved overall survival in the flu-darabine arm is intriguing, suggesting that initial therapy selection may have a delayed impact on survival. Howev-er, the result is a little hard to interpret given that no information about subse-quent therapies was available for either patient group.

Investigators also presented long-term follow-up of CALGB 9712, which com-pared sequential and concurrent sched-ules of FR (fludarabine, rituximab; abstract 539). At a median follow-up of 117 months, the overall PFS is 42 months. PFS remains shorter in patients with unmutated IgVH (33 months) and dele-tions 11q and 17p (25 months), suggesting that this regimen is best for low-risk CLL patients.

—Jennifer R. Brown, MD, PhD

HEMATOLOGIC DISEASE

Multiple Cancers

HIGHLIGHTScontinued from page 13 �

The group with the best PFS, therefore, had VMP induction followed by VT maintenance.

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% o

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live

a

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FCRamedian follow-up of 37.7 months

82.587.2

82.587.2

Figure. Comparison of overall survival.

(AUC) to lapatinib after a single oral 100-mg dose increased approximately 14% and 63% in subjects with moderate and severe pre-existing hepatic impairment, respectively. Administration of TYKERB in patients with severe hepatic impairment should be undertaken with caution due to increased exposure to the drug. A dose reduction should be considered for patients with severe pre-existing hepatic impairment [see Dosage and Administration (2.2)]. In patients who develop severe hepatotoxicity while on therapy, TYKERB should be discontinued and patients should not be retreated with TYKERB [see Warnings and Precautions (5.2)].

10 OVERDOSAGE There is no known antidote for overdoses of TYKERB. The maximum oral doses of lapatinib that have been administered in clinical trials are 1,800 mg once daily. More frequent ingestion of TYKERB could result in serum concentrations exceeding those observed in clinical trials and could result in increased toxicity. Therefore, missed doses should not be replaced and dosing should resume with the next scheduled daily dose. There has been a report of one patient who took 3,000 mg of TYKERB for 10 days. This patient had Grade 3 diarrhea and vomiting on Day 10. The event resolved following IV hydration and interruption of treatment with TYKERB and letrozole. Because lapatinib is not significantly renally excreted and is highly bound to plasma proteins, hemodialysis would not be expected to be an effective method to enhance the elimination of lapatinib.

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies with lapatinib are ongoing. Lapatinib was not clastogenic or mutagenic in the Chinese hamster ovary chromosome aberration assay, microbial mutagenesis (Ames) assay, human lymphocyte chromosome aberration assay or the in vivo rat bone marrow chromosome aberration assay at single doses up to 2,000 mg/kg. However, an impurity in the drug product (up to 4 ppm or 8 mcg/day) was genotoxic when tested alone in both in vitro and in vivo assays. There were no effects on male or female rat mating or fertility at doses up to 120 mg/kg/day in females and 180 mg/kg/day in males (approximately 6.4 times and 2.6 times the expected human clinical exposure based on AUC, respectively). The effect of lapatinib on human fertility is unknown. However, when female rats were given oral doses of lapatinib during breeding and through the first 6 days of gestation, a significant decrease in the number of live fetuses was seen at 120 mg/kg/day and in the fetal body weights at ≥60 mg/kg/day (approximately 6.4 times and 3.3 times the expected human

clinical exposure based on AUC, respectively).

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (17.6) of full prescribing information.

17.1 Decreased Left Ventricular Ejection Fraction Patients should be informed that TYKERB has been reported to decrease left ventricular ejection fraction which may result in shortness of breath, palpitations, and/or fatigue. Patients should inform their physician if they develop these symptoms while taking TYKERB.

17.2 Diarrhea Patients should be informed that TYKERB often causes diarrhea which may be severe in some cases. Patients should be told how to manage and/or prevent diarrhea and to inform their physician if severe diarrhea occurs during treatment with TYKERB.

17.3 Drug Interactions TYKERB may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products.

17.4 Food Patients should be informed of the importance of taking TYKERB at least one hour before or one hour after a meal, in contrast to capecitabine which should be taken with food or within 30 minutes after food.

17.5 Divided Dosing The dose of TYKERB should not be divided. Patients should be advised of the importance of taking TYKERB once daily, in contrast to capecitabine which is taken twice daily.

TYKERB is a registered trademark of GlaxoSmithKline.

©2009, GlaxoSmithKline. All rights reserved.Revised: August 2009TKB:5BRS©2009 The GlaxoSmithKline Group of Companies. All rights reserved. Printed in USA. TKB834R0 October 2009


decreasing trend for darbepoetin use after restrictions were in place (28% vs. 21%; not significantly different), transfusions showed an upward trend. After imple-mentation of the NCD, more patients received transfusions than before imple-mentation (29% vs. 21%; P=NS). Transfu-sions also increased after each of the other three darbepoetin-related events.

Dr. Adamson said that because Saint Barnabas was slow to adopt the NCD restrictions, only two to three months of data were generated after implemen-tation. Thus, he speculated that if they looked further out, the transfusion rate would continue to increase.

Philip E. Johnson, MS, RPh, said thatalthough transfusions have not increased at his center, it is not clear whether this is “because there’s not blood available or that there’s no clinical need.” The changes in ESA prescribing appear to be “affecting different places different-ly,” said Mr. Johnson, director of phar-macy at H. Lee Moffitt Cancer Center, in Tampa, Fla. “A lot has to do with the phy-sician’s philosophy” and how conserva-tively they treat anemia.

Jerry Siegel, PharmD, senior direc-tor of pharmaceutical sciences at The Ohio State University Medical Center in Columbus, said that while “ESA use is way down, it’s harder to assess trans-fusion rates because transfusion tipping points vary by center.” Some centers, for example, wait until the hemoglobin is less than 7 g/dL or even lower, while some have higher thresholds; and some con-sider whether the patient is symptomat-ic, while others may not, he noted.

Dr. Siegel added that because the cost of blood is so high, if transfusions have gone up, the overall costs of therapy for che-motherapy-induced anemia may be high-er now than before the restrictions were put in place. “The message here,” he said, “is if you haven’t already looked at your transfusion rates and cost of treating ane-mia post-NCD, maybe you should. Are you just transferring costs?”

While Saint Barnabas has an approach to reduce ESA waste and costs, Dr. Sie-gel also suggested that centers can try to reduce transfusion rates and costs in ways unrelated to ESA use. A simple example, he said, is to just “draw less blood.”

When Ohio State University Medical Center implemented a blood conserva-tion program in 2005, “it really had a big impact on decreasing the need for trans-fusions,” Dr. Siegel said. The actions they took were “switching from adult to pedi-atric tubes for blood samples to reduce the volume of blood taken when blood is drawn” and putting “more clinical input into the decision of when they are going to do a transfusion.” They included

hemoglobin levels and clinical symp-toms into the mix, eliminating a lot of transfusions that were done automati-cally but were not necessarily clinically appropriate.

At this point, Mr. Johnson said, “I don’t

think there’s conclusive data. There’s still a blood supply problem in this country. We are still at war.” With the reductions in ESA use, “the call is out to look at whether transfusions are being used appropriately and how does it affect patient outcomes.

That’s what we need more data on.”Dr. DiBona agreed that more informa-

tion is needed. He said that the findings of the studies raise more questions than they answer, including the question of “whether any consideration was giv-en to these issues when the NCD was made.”

—Sarah Tilyou

Sejal Badre, MS, and Larry Green, PharmD,

from Amgen Inc., were co-investigators

involved with the Saint Barnabas study,

and Dr. Green was also a co-investigator on

the Sinai Hospital of Baltimore study, along

with Leo Lichtig, PhD, of AON Consulting.

SUPPORTIVE CARE

Anemia

RESTRICTIONScontinued from page 5 �

Dr. Siegel added that because the cost is so high, if transfusions have gone up, the overall costs of therapy for chemotherapy-induced anemia may be higher now than before the restrictions were put in place.


entities,” said Dr. Mathias J. Rummel, MD, PhD, head of the Department of Hematology, University Hospital, Giessen, Germany. Presenting these results on behalf of Studiengruppe Indolente Lymphoma at the annual meeting of the American Society of Hematology (ASH; abstract 405), Dr. Rummel said the study did not just suggest comparable efficacy, but “clear, statistically sig-nificant superiority for a better-tolerated regimen.”

The study found that the overall response rates were similar in the two arms, but in patients who received bendamustine plus rituximab, there were a greater number of complete responses (CRs) and progression-free survival (PFS) was extended.

Although the data are impressive, both Dr. Rummel and the co-chairman of the Scientific Program Com-mittee for this year’s ASH meeting, Richard A. Van Etten, MD, PhD, were careful to describe the data not as practice changing but as “potentially” practice changing. This caution despite a Phase III study that clearly showed both an efficacy and a safety advantage was explained by Dr. Van Etten, chief of the Division of Hematology and Oncology at Tufts Medical Center, Boston. He clarified that both experts and regulating agencies are reluctant to declare any therapy as first-line on the basis of PFS alone.

“In oncology, what we ideally want to see is an [over-all] survival advantage for a therapy that is identified as a new standard,” Dr. Van Etten commented. Although he agreed that the results were compelling, he indicat-ed that there are a number of additional steps in the process, including longer follow-up and publication of the data, which would be necessary for changing the characterization of bendamustine-R from a potential to an established first-line therapy.

In the study, conducted at 82 centers in Germa-ny, patients with a relapsed or refractory indolent

lymphoma (follicular, marginal zone, Waldenströms or small lymphocytic) or mantle cell lymphoma were ran-domized to the conventional CHOP-R regimen given on a 21-day schedule or to a regimen on a 28-day schedule that combined 90 mg/m2 bendamustine on days 1 and 2 with 375 mg/m2 rituximab on day 1. The median age of the study population was 65 years. Relevant character-istics, including age, stage, bone marrow infiltration and extranodal involvement, were comparable between the groups. The primary outcome was PFS, but safety and tolerability also were monitored closely.

Overall response rates over a median observation time of 32 months and a median of six treatment cycles in both groups were almost identical—92.7% for ben-damustine-R and 91.3% for CHOP-R. However, the quality of the response was better with bendamustine-R, including a greater number of CR (39.6% vs. 30%; P=0.03). More importantly, the PFS was two years lon-ger in patients on bendamustine-R relative to CHOP-R (54.9 vs. 30 months; P=0.0002). The efficacy advantage was reinforced by other data showing that the benda-mustine-R arm was superior including longer time to next treatment (not yet reached on bendamustine-R vs. 46 months on CHOP-R; P=0.0002) and event-free sur-vival (54 vs. 31 months; P=0.0002). In the follow-up so far, there has been a similar number of deaths in each arm, so overall survival has not differed.

When efficacy was assessed separately in those with follicular lymphoma, which represented 54% of the study population, the relative advantage of ben-damustine-R over CHOP-R was consistent with that observed for the whole population. For example, the median time to PFS has not yet been reached in those randomized to bendamustine-R versus 46 months in those who received CHOP-R.

These efficacy advantages were achieved with a treat-ment that was much better tolerated from the perspec-tive of laboratory analyses and side effects. Most grade 3 and 4 hematologic side effects, including neutropenia (10.7% vs. 46.5%; P<0.0001) and leukocytopenia (12.1%

vs. 38.2%; P<0.0001) were far less common on benda-mustine-R. Those on bendamustine-R were also less likely to receive granulocyte colony-stimulating factor than those on CHOP-R. The lower rate of cytopenias is likely to explain the lower rate of infectious complica-tions in the bendamustine-R arm (P=0.04).

Whereas almost all patients on the CHOP-R regi-men had hair loss, there was no hair loss in patients on bendamustine-R more severe than grade 1. Peripheral neuropathy (P<0.0001) and stomatitis (P<0.0001) also were significantly less common with bendamustine-R. The only side effects more common with bendamus-tine-R were erythematous skin reactions (P=0.01).

Although CHOP-R remains the standard of care for aggressive lymphomas in which there is potential for cancer remission, a better-tolerated therapy for indo-lent lymphomas, which are considered incurable, has major clinical advantages. The authors emphasized that it is particularly important for noncurative treatments to extend survival with an acceptable quality of life.

—Ted Bosworth

Rituximab (Rituxan, Genentech/Biogen Idec) is generally well tolerated by

patients with non-Hodgkin’s lymphoma (NHL), but the probability of infusion-related toxicities still exists. Due to the risk of these toxicities, the manufacturer of rituximab recommends a slow standard administration schedule, requiring an average of five to six hours during the ini-tial infusion and three to four hours during subsequent infusions. Rituximab’s long infusion times and expanding indications have increased nursing resource and time demands in community-based outpatient infusion clinics that could potentially lead to administration errors and increased patient stress. To help alleviate some of these concerns, we implemented a rapid rituximab infusion protocol in effort to decrease infusion times along with nursing and patient stress.

From September 2008 to June 2009, we initiated a 90-minute rapid rituximab infusion protocol at three community-based outpatient infusion clinics located in Gainesville, Ga. Study participants were diagnosed with CD20-positive NHL and

were allowed to enter the trial at any point in their treatment cycle. Patients received the standard rituximab dose of 375 mg/m2 over 90 minutes (20% of the dose during the first 30 minutes and 80% over the subsequent 60 min-utes) in a total volume of 250-mL normal saline. Premedications were not standard-ized and could vary per facility protocol. We used a strict safety monitoring algo-rithm, measuring blood pressure, heart rate and respiratory rate before the infu-sion and at 15, 30, 60 and 90 minutes to monitor respiratory or cardiac symptoms. We also monitored temperature prior to the infusion and questioned patients about adverse reactions throughout the infusion and at each visit. Sixteen patients were enrolled and treated with a total of 51 rapid rituximab infusions. The median number of infusions each patient received was three (range, one to seven). Most of the patients were younger than 60 and male. Three patients experienced minor adverse reactions which were expect-ed with rituximab administration. The total infusion time saved compared with

standard infusion rates was 2,925 min-utes (49 hours; 57 minutes per infusion). Patient and nursing satisfaction, assessed through surveys, was extremely high in all but one statement.

We report excellent safety and tol-erability using a 90-minute rapid ritux-imab infusion in our community outpa-tient infusion clinics. The results of this study support other reports of success with decreased rituximab infusion time. Patients and nurses preferred the rap-id infusion to the standard infusion rate because of the time saved with this regi-men. Nursing staff, however, did feel that the intense monitoring schedule in this tri-al required equal attention to that of the standard infusion. If medical oncologists at these practice sites adopted this regi-men as standard practice, an easier mon-itoring schedule should be employed to

free up nursing time and resources.We believe that most patients will tol-

erate the rapid rituximab infusion as long as no severe adverse reactions are seen on initial infusions. Other investigators have adopted this as the standard of care and have had excellent results. Sehn et al reported the use of a 90-minute rapid rituximab infusion in more than 1,200 patients with only one grade III reaction (Blood 2007;109:4171-4173, PMID: 17244675). Furthermore, one study has assessed a 60-minute rapid rituximab infusion without severe adverse reactions (Ann Oncol 2006;17:1027-1028, PMID: 16322113).

—Chad J. Coulter, PharmDAssistant Professor of Clinical and

Administrative Sciences

Sullivan University College of Pharmacy

Louisville, Ky.

Rapid Infusion of Rituximab Works in Community Setting

HEMATOLOGIC DISEASE

Lymphoma

BENDAMUSTINE-Rcontinued from page 1 �

Eye on the Community Oncologist

PRN

Do you have something that you would like to share with community oncologists? Send submissions (300-600 words) that you would like considered for publication to [email protected].

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CHOP-R

30

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30

Figure. Comparison of progression-free survival.CHOP-R, cyclophosphamide, hydroxydaunorubicin, vincristine and prednisone plus rituximab; PFS, progression-free survival


Cathy Eng, MD, can provide you with what you need to know. Dr. Eng, an associate professor in the

Department of Gastrointestinal Medical Oncology at the University of Texas M.D. Anderson Cancer Center, in Houston, recently gave the highlights to Clinical Oncology News.

ClinOnc: What were the most significant studies in colon cancer to come out of the ECCO-ESMO meeting?Dr. Eng: I think the ESMO meeting had some very informative studies. We have now confirmed the role for adjuvant capecitabine (Xeloda, Roche) in combination with oxaliplatin (Eloxatin, Sanofi-Aventis). XELOX-A was a Phase III trial that randomized patients to XELOX (capecita-bine 1,000 mg/m2 bid, days 1-14; oxaliplatin 130 mg/m2, day 1, every 21 days) or a regimen of Roswell Park or Mayo Clinic bolus 5-fluorouracil (5-FU)/leucovorin (control arm). The investigators determined that XELOX was superior in terms of prolonging disease-free survival (DFS) when com-pared with the bolus 5-FU regimens (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.69–0.93; P=0.0045); the difference in three-year DFS was 4.5%. From these results, it appears reasonable for clinicians to consider the XELOX combination in the adjuvant setting, but doctors must believe that the patient will be adherent and will properly communicate informa-tion about any potential toxicities.

In patients with metastatic colorectal cancer, Eric Van Cutsem, MD, reported that there was over-all survival (OS) benefit to using cetuximab (Erbitux, Bristol-Myers Squibb) in the front-line setting. The addition of cetuximab improved OS by 3.5 months in KRAS wild-type patients [HR, 0.796; 95% CI, 0.0670-0.946; P=0.0094]. The response rate was 57.3% for the addition of cetuximab compared with 39.7% (P<0.0001). You can infer from this trial that cetuximab plus FOL-FIRI (5-FU, folinic acid and irinotecan) has a role in the front-line setting in comparison with standard

cytotoxic chemotherapy alone, specifically in patients with KRAS wild-type tumors. Currently, cetuximab is FDA-approved in previously treated patients. The results of this study open up another therapeutic possi-bility in the front-line setting. Rather than giving beva-cizumab (Avastin, Genentech) to all front-line patients, this trial shows there might be another treatment option for patients with wild-type KRAS tumors.

It’s important to keep in mind that this study is not a direct head-to-head comparison of cetuximab and

bevacizumab. Once completed, the trial that may potential-

ly answer this question is CALGB 80405 [Cancer and

Leukemia Group B], but the results may be difficult to interpret.

ClinOnc: Why will the results be difficult to interpret?Dr. Eng: The CALGB 80405 trial was created and opened for patient accrual before the importance of KRAS status was known. The trial also included an arm of combined biologic therapy. In the original study design, patients received either FOLFOX (5-FU, leucovorin and oxali-platin) or FOLFIRI and then were randomized either to bevacizumab or cetuximab or the combination of beva-cizumab and cetuximab. After data regarding the signif-icance of KRAS were reported at the American Society of Clinical Oncology (ASCO) 2008 meeting, the study was amended to only include KRAS wild-type patients. Shortly after, data came from the PACCE trial (evalu-ating panitumumab) and the CAIRO 2 trial (examining capecitabine, irinotecan [Camptosar, Pfizer] and oxali-platin) that demonstrated that combined biologic ther-apy was not beneficial to patients resulting in a recent amendment to remove the third arm of combined bio-logic therapy. The revised study design will be a direct head-to-head comparison of cetuximab and bevacizum-ab, but these recent amendments are likely to confound the final results.

ClinOnc: What other studies presented at ESMO were noteworthy?Dr. Eng: There were two large Phase III studies reported that discussed data on panitumumab (Vectibix, Amgen) in combination with chemotherapy. The PRIME trial

(LBA10) showed that panitumumab improved progres-sion-free survival (PFS) by roughly 1.6 months and was well tolerated when added to FOLFOX4 as first-line chemotherapy in patients with metastatic colorec-tal cancer who have wild-type KRAS (abstract LBA10). The study also found that patients with mutated KRAS had worse PFS if they received panitumumab than if they received chemotherapy alone (7.3 vs. 8.8 months; P=0.02). The second study (LBA14) showed that adding panitumumab to FOLFIRI prolongs PFS by two months compared with FOLFIRI alone when used as second-line therapy for metastatic colorectal cancer in patients with wild-type KRAS. I presume these two studies are likely to be updated at the 2010 ASCO Gastrointestinal Cancers Symposium.

ClinOnc: Were there important studies focusing on markers?Dr. Eng: There was a small study by Farina (abstract 6114) that looked at the role of BRAF as a prognos-tic marker in patients with stage III colon carcinoma. Some investigators have focused specifically on BRAF as a predictive marker, other than KRAS, to predict response to EGFR (epidermal growth factor receptor) inhibition. In the Farina study of 213 surgically resect-ed stage III patients, investigators looked at BRAF as a prognostic marker. They reported a higher than expected number of individuals with a presence of a BRAF mutation—19.5% of patients (the BRAF muta-tion is commonly reported to be in less than 10% of patients). The investigators concluded that the pres-ence of the BRAF V600E mutation was an indepen-dent prognostic factor for worse OS (P=0.006).

Another study discussed was the CAIRO2 study that was originally reported at ASCO 2008. The inves-tigators retrospectively evaluated the prognostic role of BRAF in those patients. CAIRO2 was a random-ized Phase III trial in which patients either received capecitabine plus oxaliplatin (CAPOX) for six cycles, followed by capecitabine and bevacizumab (control arm) or they received CAPOX for six cycles plus beva-cizumab and cetuximab followed by capecitabine and bevacizumab and cetuximab. Dr. [J.] Tol reported in abstract 6002 that the BRAF mutation was present in 8.7% of all patients and he noted that the presence of the BRAF mutation was a prognostic indicator, regard-less of treatment arm or KRAS status. Patients with BRAF mutations had decreased median PFS compared with patients with wild-type tumor irrespective of the treatment arm—5.9 versus 12.2 months (P=0.003, control arm) compared with 6.6 versus 10.4 months (P=0.010) in the investigational arm. The same held true for OS—15 versus 24.6 months in the control arm (P=0.002), and 15.2 versus 21.5 months in the investi-gational arm (P=0.001).

These two reported studies are of interest because people have been looking at BRAF as a predictive

Colon Cancer Highlights From International MeetingWhich colon cancer news was all the rage at the recent joint meeting of the European CanCer Organisation and the European Society for Medical Oncology (ECCO-ESMO)?

SOLID TUMORS

Colon

Cathy Eng, MD

Associate ProfessorDepartment of Gastrointestinal Medical OncologyUniversity of TexasM.D. Anderson Cancer CenterHouston, Texas

ADVISORY BOARD EDITORIAL

see COLON HIGHLIGHTS, page 25 �

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FOLFIRI plus cetuximab

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Figure. Comparison of regimens in metastatic colorectal cancer.

BRAF is a prognostic indicator for overall survival.

MCCON332.indd 1 11/11/09 5:04:48 PM

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maintain through progression in this setting,” said Edith Perez, MD, director of the Breast Cancer Pro-gram at Mayo Clinic in Jacksonville, Fla., who was not involved with the study.

Practice-Changing News

Early results from this trial, which were reported at the 2008 annual meeting of the American Soci-ety of Clinical Oncology, showed the combination improved progression-free survival by rough-ly one month. The updated and planned event-driven survival analysis report-ed at SABCS, with 75% of the wom-en having died, revealed that patients who received the combination therapy had a 26% reduction in the risk for dying compared with patients who received lapatinib alone, according to Kimberly Blackwell, MD, who led the study.

“The survival benefit was seen in spite of the fact that over half of the patients crossed over to go on to receive dual HER2 blockade,” said Dr. Black-well, an associate professor of medicine and direc-tor of the Clinical Trials Program in Breast Cancer at Duke University Medical Center, Durham, N.C. “As a practicing clinician, I think it is really amazing that there was not a significant safety signal considering the heavily pretreated nature of these patients.”

According to Andrew Seidman, MD, an attending physician at the Breast Cancer Medicine Service at Memorial Sloan-Kettering Can-cer Center, New York City, there are three common approaches to treating patients with trastu-zumab-refractory MBC: discon-tinue trastuzumab and switch to capecitabine (Xeloda, Roche) plus lapatinib; continue trastu-zumab and add capecitabine, or continue trastuzumab and add lapatinib. The new data, he said, support the use of the trastuzum-ab-lapatinib option because it is the only approach that has been demonstrated to improve overall survival.

The study that spurred FDA approval of lapatinib in combi-nation with capecitabine in this patient population was based on data that showed improved response rate and time to progres-sion (N Engl J Med 2006;355:2733-2744, PMID: 17192538). Results from the study testing the com-bination of capecitabine with or without trastuzumab, pub-lished in 2009 (J Clin Oncol2009;27:1999-2006, PMID: 19289619), also only showed an improvement in response rate and time to progression.

“The [overall] survival data from the new study will set this approach apart from the other

studies. This is noteworthy and likely will impact clinical practice,” Dr. Seidman said. “It will

also drive interest in beginning lapatinib plus trastuzumab alone or in com-bination with cytotoxic agents even

earlier in the treatment of metastat-ic breast cancer. Indeed, the combina-tion is already being studied in the post-

operative adjuvant setting in the ALTTO [Adjuvant Lapatinib and/or Trastuzum-

ab Treatment Optimization] trial.”

Study Details

The study reported at SABCS randomized 296 women with HER2-positive MBC who had pro-gressed on trastuzumab-containing regimens to receive either lapatinib 1,500 mg once daily or lapa-tinib 1,000 mg once daily in combination with tras-tuzumab 2 mg/kg (after a 4-mg/kg loading dose).

If patients had objective dis-ease progression at or after four weeks of lapatinib alone, they were allowed to cross over to the combination arm—52% ended up crossing over. “Half of these patients [crossed over] before or at week 8, and 46% [did so] after week 8,” Dr. Blackwell said.

The two arms of the study were well matched. One-third of the patients had received six or more regimens and the median number of prior trastuzumab-contain-ing regimens was three. Half of the patients were estrogen recep-tor-negative. “Unlike many of the studies that were done with HER2-targeted agents in the early days, we allowed for known brain metastases and these were equally matched between the two arms,” Dr. Blackwell said.

Median overall survival (Fig-ure) following treatment with lapatinib plus trastuzumab was 60.7 weeks compared with 41.4 weeks in patients who received lapatinib alone (hazard ratio [HR], 0.74; 95% confidence inter-val [CI], 0.57-0.97; P=0.026). The survival benefit was maintained after adjusting for baseline prog-nostic factors (HR, 0.71; 95% CI, 0.54-0.93; P=0.012).

Both regimens were well toler-ated. One cardiac-related death occurred in the combination arm and was attributable to a fatal pul-monary embolism. “There was

only one significant grade 3/4 adverse event seen in greater than or equal to 5% of the patients enrolled in this heavily pretreated population and that was diar-rhea, almost certainly attributable to lapatinib, at 8% in the combination arm and 7% in the lapatinib arm,” Dr. Blackwell said.

Perspective

Lapatinib is the only small molecule inhibitor cur-rently approved for the treatment of HER2-positive breast cancer; it is a dual-targeting agent aimed at HER1 and HER2. Trastuzumab is a monoclonal anti-body that targets HER2.

“Because of the different mechanisms of attack on the HER2 receptor, it was very appealing to com-bine the two agents within the clinical arena without using a chemotherapy backbone,” Dr. Blackwell said. “In addition, this study was really based on preclini-cal data that there was synergy between trastuzumab and lapatinib which included enhancement of apop-tosis through the downregulation of survivin.” She added that lapatinib has a potential benefit of work-ing against tumors that have become resistant to tras-tuzumab through a potential resistance mechanism of cleavage of the extracelluar domain, the known binding site for trastuzumab.

Dr. Seidman said the study was important in show-ing that there was benefit to continuing trastuzumab in patients who appeared to be resistant to the drug. “These are patients who had Herceptin in combina-tion with a number of different agents and had pro-gressed, and now fairly far along in the course of their disease, lapatinib is being added and they had a 60-week survival at that juncture,” he said. “It’s pret-ty compelling.”

Dr. Perez pointed out that the results of the trial support the ALTTO study, which is testing four treat-ment options: trastuzumab alone for 52 weeks; lapa-tinib alone for 52 weeks; trastuzumab for 12 weeks, followed by a six-week break, then lapatinib for 34 weeks; or lapatinib in combination with trastuzumab for 52 weeks. The study also supports the neo-ALTTO trial, which will study the same regimens but before breast surgery. This latter trial is expected to report results in the next 18 months.

Dr. Blackwell disclosed that she has received hon-oraria from Genentech and GlaxoSmithKline and served as a consultant to Genentech.

—Kate O’Rourke

ONE-TWO PUNCHcontinued from page 1 �

SOLID TUMORS

Breast

‘The survival data from the new study will set this approach apart from the other studies. This is noteworthy and likely will impact clinical practice.’

—Andrew Seidman, MD

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Figure. Comparison of overall survival.

Patients had HER2-positive metastatic breast cancer and had progressed on trastuzumab-containing regimens.

The HER2 receptor shown in its transmembrane position, withtrastuzumab bound to the extracellular domain, and lapatinib to the intracelullar tyrosine kinase domain, inhibiting downstream signalling through the PI3K/Akt and the Ras/Raf/Mek/MAPK pathways.

Lapatinib

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PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

1INDEPENDENTLY DEVELOPED BY MCMAHON PUBLISHING CLINICAL ONCOLOGY NEWS • JANUARY 2010

Gastrointestinal Stromal Tumors What Oncologists Need to Know About theTreatment of Localized and Advanced Disease

CHANDRAJIT P. RAUT, MD, MSC

Department of SurgeryBrigham and Women’s Hospital

and Dana-Farber Cancer InstituteAssistant Professor of Surgery

Harvard Medical SchoolBoston, Massachusetts

Gastrointestinal stromal tumors

(GISTs) are rare, represent-

ing only 0.1% to 3% of all

gastrointestinal (GI) malignancies,1-4

but they account for 80% of GI

mesenchymal neoplasms.5 Mazur

and Clark coined the descriptive term

in 1983 to define intra-abdominal

noncarcinomatous neoplasms that

lacked the ultrastructural features of smooth muscle cells and

immunohistochemical characteristics of nerve cells.6

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A. C

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D

Until the late 1990s, there were no objective crite-ria to classify GISTs. They were frequently misclassified as leiomyomas, leiomyoblastomas, leiomyosarcomas, Schwannomas, or GI autonomic nerve tumors.7 Conse-quently, the interpretation of clinical results for GISTs published before 2000 is challenging.

Receptor Tyrosine Kinase MutationsSince 1998, a series of major breakthroughs have

drastically changed the management of primary and metastatic GIST in particular, and have served as a model for the targeted management of solid tumors in general. The first key development was the 1998 dis-covery of gain-of-function mutations in the c-kit proto-oncogene in GISTs.8 KIT encodes the transmembrane KIT receptor tyrosine kinase (TK), which is activated by binding its cytokine ligand, stem cell factor.9 Mutated KIT remains constitutively active even in the absence of ligand binding and results in both unregulated cell growth and malignant transformation.8

More than 85% of GISTs have activating KIT muta-tions.10 Some GISTs that stain strongly for KIT by immu-nohistochemistry (KIT-positive) lack KIT mutations,10 whereas KIT-negative GISTs harbor KIT mutations.11 Another 3% to 5% of KIT-negative neoplasms have acti-vating mutations in the platelet-derived growth factor receptor-α (PDGFRA) gene encoding a related recep-tor TK.12-14

EpidemiologyAGE

GIST has been documented in individuals of all ages, but is generally a malignancy of adults, with a median age at diagnosis of 60 years (range, 40-80).2,15 No con-sistent gender predilection has been noted. Occasion-ally, GISTs may be observed in children, often as a familial syndrome or as part of Carney’s triad (a rare constella-tion of gastric GIST, extra-adrenal paraganglioma, and

pulmonary chondroma).16,17 Children more commonly present with multifocal gastric GISTs, harbor wild-type KIT/PDGFRA genes, and have a higher incidence of lymph node metastases.18

HEREDITARY GISTMost GISTs are sporadic. However, a growing num-

ber of kindreds with germline KIT mutations and at least one family member carrying a PDFGRA mutation have been characterized with a predilection for devel-oping multiple GISTs.19-27 Individuals with GISTs sec-ondary to germline KIT mutations are usually younger than those with sporadic GISTs, but metastases are uncommon.26

GISTs are found in approximately 7% of individuals with von Recklinghausen’s neurofibromatosis (NF1), most commonly in the small intestine.28-30 KIT and PDG-FRA point mutations have been reported in 8% and 6% of GISTs, respectively, from patients with NF1.31 Con-versely, NF1 gene mutations have not been identified in GISTs in non-NF1 individuals.32

INCIDENCE

The true incidence of GIST remains uncertain. Epi-demiologic data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program are difficult to interpret because many GISTs were previously misclassified as other GI mesenchymal neoplasms.33 The near doubling in the observed inci-dence of all GI mesenchymal tumors (more than 80% were GIST), from 0.17 per 100,000 in 1992 to 0.31 per 100,000 in 2002, in a contemporary SEER analysis is potentially the result of an increase in recognition, an increase in screening, and quite possibly a true increase in incidence of the tumor.33 The most recent National Comprehensive Cancer Network (NCCN) guidelines estimate an annual incidence of approximately 5,000 new cases in the United States.34 Population-based studies from Iceland and Sweden identified annual inci-dence rates of 11 and 14.5 cases per 1 million population, respectively.15,35

Clinical PresentationGISTs demonstrate a broad spectrum of clinical

behavior. In a population-based study, 69% of tumors were symptomatic, 21% were discovered incidentally at surgery, and 10% were discovered at autopsy.15 Small GISTs (<2 cm) may remain asymptomatic, only detected incidentally on radiographic studies, endoscopy, or lap-arotomy. Approximately 50% to 70% of primary GISTs are identified in the stomach, 25% to 35% in small intes-tine, 5% to 10% in colon and rectum, 7% in mesentery or omentum, and less than 5% in the esophagus.7,36

Between 15% and 47% of GISTs are metastatic at diagnosis.2,37 Common sites of metastasis include liver, peritoneum, and omentum; lymph node metastases are rare. Unlike other sarcomas, lung and brain metasta-ses are uncommon and appear only late in the disease course, if ever.

Figure 1. Computed tomography image of primary jejunal gastrointestinal stromal tumor.

INDEPENDENT LY DEVELOP ED BY M C M AH ON P UBL ISHIN G2

DiagnosisRADIOGRAPHIC STUDIES

Contrast-enhanced computed tomography (CT) of the abdomen and pelvis is the most common imag-ing modality for both initial evaluation and surveillance for recurrence.38 Primary GISTs appear as well-circum-scribed, often highly vascular masses associated with hollow viscera (Figure 1). Magnetic resonance imaging (MRI) may be of value in characterizing disease in the liver or around the rectum. [18F]fluorodeoxyglucose pos-itron emission tomography (FDG-PET) is a functional imaging technique that is sensitive in identifying met-abolic activity within these tumors. It complements CT for detecting GISTs, characterizing ambiguous masses, monitoring response to therapy, and identifying emer-gence of drug-resistant clones, but is not specific enough for the diagnosis of the disease.39-41 Routine use of PET for surveillance after complete resection is not recommended.39

ENDOSCOPY, FINE-NEEDLE ASPIRATION, AND BIOPSY

Endoscopic ultrasound (EUS) is not generally nec-essary to evaluate the extent of the disease. Because endoscopic biopsies and EUS-guided fine-needle aspi-ration (FNA) are not consistently diagnostic,42 diag-nosis may require additional cytologic morphology, immunohistochemistry, and reverse transcriptase–polymerase chain reaction analysis for KIT mutations from an EUS-FNA specimen.43

A preoperative biopsy is not routinely necessary for a primary, resectable neoplasm that doctors sus-pect is GIST. In fact, preoperative biopsy may rupture

a suspected GIST and increase the risk for dissemi-nation. However, if the differential diagnosis includes entities such as lymphoma, which would be treated differently, if neoadjuvant therapy is under consider-ation, or if there is metastatic disease, then biopsy is appropriate.

Prognostic FactorsMost experts now consider all GISTs to have malig-

nant potential. Although tumors less than 1 cm likely have a low risk for recurrence, no tumors can be defin-itively called benign. Tumor size, mitotic index, and tumor site of origin are the 3 most widely accepted indices predictive of outcomes (Table 1).44,45 The mitotic index may be the most important single variable.46 Indi-viduals with small-bowel GISTs carry a higher risk for progression than those with gastric tumors of compa-rable size and mitotic count.

Additional independent adverse prognostic fac-tors observed in some but not all studies include high cellular proliferation index,47 aneuploidy,47,48 and telo-merase expression.49,50 Univariate analysis suggests that KIT exon 9 mutations and KIT exon 11 deletions involving amino acid W557 and/or K558 have a higher risk for recurrence, whereas point mutations and inser-tions of KIT exon 11 may have a favorable prognosis.46,51 A macroscopically complete resection with or with-out microscopically negative margins (R0 or R1 resec-tion, respectively) is better than a macroscopically incomplete resection (R2 resection); there are no data to confirm that a microscopically positive margin (R1 resection) impacts survival.2

Table 1. Risk Assessment for Primary Gastrointestinal Stromal Tumors45

Mitotic Rate Tumor Size

% of Patients With Progressive Disease/Risk Classification, Based on Site of Origin

Stomach Duodenum Jejunum/Ileum Rectum

≤/50 hpf ≤2 cm 0 0 0 0

>2 to ≤5 cm 1.9/very low 8.3/low 4.3/low 8.5/low

>5 to ≤10 cm 3.6/low insuff. data 24/moderate insuff. data

>10 cm 12/moderate 34/high 52/high 57/high

>5/50 hpf ≤2 cm insuff. data insuff. data insuff. data 54/high

>2 to ≤5 cm 16/moderate 50/high 73/high 52/high

>5 to ≤10 cm 55/high insuff. data 85/high insuff. data

>10 cm 86/high 86/high 90/high 71/high

hpf, high-power field; insuff., insufficient

Risk for recurrence based on data from the pre-imatinib era.

Reprinted from Raut CP, Hornick JL, Bertagnolli MM. Advanced gastrointestinal stromal tumor: potential benefits of aggressive surgery combined with targeted tyrosine kinase inhibitor therapy. Am J Hematol/Oncol. 2006;5(12):707-712, with permission from Haymarket Media Inc.

IN D E PE N D E N TLY D E VE LOPE D BY MCMA HON PUBL ISHING 3

Surgical TherapyThe standard of care and only potentially curative

therapy for patients with primary, resectable, local-ized GIST is surgery. The goal of the surgery should be a macroscopically complete resection with an intact pseudo-capsule and a negative microscopic mar-gin (R0 resection). In general, primary GISTs do not invade surrounding organs despite CT appearance. Wedge or segmental resection of the involved stom-ach or bowel is typically all that is required. Rarely, a more extensive resection (total gastrectomy for a large proximal gastric GIST, pancreaticoduodenec-tomy for a periampullary GIST, or abdominoperineal resection for a low rectal GIST) may be necessary. In a series of 140 patients with gastric GISTs, wedge resec-tions were performed in 68%, partial gastrectomies in 28%, and total gastrectomies in only 4%.52 Lymph-adenectomy is not required because lymph nodes are rarely involved.

All GISTs at least 2 cm in size should be resected when safely possible, as none of these are considered benign.45 Management of GISTs smaller than 2 cm is more debatable, as their natural history is unknown. Any symptomatic small GISTs (eg, hemorrhage from erosion through the mucosa) or GISTs that increase in size on serial follow-up should be resected.

Historically, small lesions (<1 cm) have been fol-lowed rather than resected. However, with the under-standing that all GISTs have malignant potential, the rationale for observation is called into question. Such subcentimeter gastric GISTs are relatively common, found in 22.5% of autopsies in German individuals over the age of 50 and in 35% of Japanese patients under-going gastrectomy for gastric cancer.53,54 Yet few of these neoplasms ever become clinically relevant, and thus management remains undefined. Further data are required to determine the natural history of these

subcentimeter GISTs. Endoscopic resection of small gastric GISTs has been reported, but because of the inherent risks for positive margins (GISTs frequently involve the muscularis propria), its role remains controversial.55

GISTs 1 to 2 cm in size pose an even greater dilemma. Again, the natural history of such tumors is not known. The very low risk for recurrence in patients with GISTs less than 2 cm and a low mitotic index supports a more conservative, nonoperative approach. However, an accurate mitotic index cannot be determined on biopsy or FNA, and thus observation cannot be recom-mended based on size alone. Resection is preferred, particularly when laparoscopy is possible. The risks and benefits associated with surgery versus observa-tion should be reviewed with the individual patient.

Given the higher risk for aggressive behavior in tumors originating in the small bowel and colon, any GIST in these locations should be resected irrespec-tive of size.

Laparoscopic or laparoscopy-assisted resection of primary GISTs may be performed under appro-priate circumstances using standard oncologic prin-ciples ( Figure 2). Two studies confirmed the safety and feasibility of using a laparoscopic approach early on. Among 35 gastric GISTs resected laparoscopi-cally, no local or distant recurrences were noted for tumors smaller than 4 cm with a median follow-up of 53 months.56 In another study of 50 gastric GISTs (1.0-8.5 cm) resected laparoscopically or using lap-aroscopy assistance, 92% of patients were disease-free with a mean follow-up of 3 years.57

The management of surgical margins is not as well defined for GISTs as it is for epithelial tumors such as adenocarcinoma. There are no data supporting the need for the same wide margins of resection typically recommended for adenocarcinomas.58 There also are


Figure 2. Endoscopic image of GIST along greater curvature of stomach (A) (arrow). Laparoscopic view of same tumor, with traction sutures placed proximally and distally (B). Stomach partially divided using stapling device (C).

A

B C

no data indicating that patients who have an R1 resec-tion require re-excision.34

OUTCOMES

Even after a macroscopically complete resection,

disease may recur in as many as 50% of patients, with a median time to recurrence of 24 months.2,59 An R0 or R1 resection is associated with 5-year overall survival (OS) rates of 34% to 63%, whereas R2 resection is asso-ciated with 5-year OS as low as 8%.1,2,60-64


Figure 3. (A) Recurrence-free survival and (B) overall survival Kaplan-Meier curves from the ACOSOG Z9001 Phase III trial of 1 year of adjuvant imatinib versus placebo after complete macroscopic resection of primary gastrointestinal stromal tumor.76

Reprinted from Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointesti-nal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373(9669):1097-1104, with permission from Elsevier.

Re

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Alive, %

HR, 0.35 (95% CI, 0.22-0.53); P<0.0001

0 6 12 18 24 30 36 42 48

Total Events

Imatinib 359 30

Placebo 354 70

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Number at risk

Placebo 354 188 89 34 8

Imatinib 359 207 105 33 6

A

Alive, %

HR, 0.66 (95% CI, 0.22-2.03); P=0.47

0 6 12 18 24 30 36 42 48

Total Events

Imatinib 359 5

Placebo 354 8

100

90

80

70

60

50

40

30

20

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Number at risk

Placebo 354 241 151 58 15

Imatinib 359 226 137 51 15

B

Adjuvant Therapy for Primary Disease

Another critical advancement in the management of GIST was identification of 2 effective, relatively well-tolerated, orally available, targeted tyrosine kinase inhibitors (TKIs), imatinib mesylate (Gleevec, Novar-tis) and sunitinib malate (Sutent, Pfizer, Inc.). These agents initially were developed for the management of patients with metastatic disease in whom standard sys-temic chemotherapy and radiation therapy were largely ineffective.1,2,65 The first effective agent identified was

imatinib, which selectively inhibits several TKIs, includ-ing KIT, PDGFRA, and ABL, among others.66-69 Its clini-cal potential was first demonstrated in a landmark case report of a Finnish patient with metastatic GIST who was treated with a daily dose of imatinib 400 mg and demonstrated a rapid and sustained partial response.70 Several clinical trials have subsequently confirmed that up to 80% of patients with metastatic GIST achieve a complete or partial response or demonstrated disease stability on imatinib.71,72

Because recurrence rates are so high and survival rates so low after an R0/R1 resection, investigators have explored the role of adjuvant therapy with imatinib after resection of primary disease. These trials tested dura-tions of adjuvant imatinib of 12 months (American Col-lege of Surgeons Oncology Group73 Z9000, ASOSOG Z9001, China Cooperative Group), 24 months (European Organization for the Research and Treatment of Cancer [EORTC] 62024), or 12 versus 36 months (Scandinavian Sarcoma Group [SSG] XVIII).74-76 For the sake of brevity, only data from the recently published ACOSOG Z9001 trial are discussed in detail. In this Phase III trial, patients with completely resected primary GISTs at least 3 cm in size were randomized to receive either postopera-tive placebo or imatinib for 1 year. This trial was halted early when a planned interim analysis of 644 evaluable patients confirmed that the 1-year recurrence-free sur-vival (RFS) was significantly better in the imatinib arm (97% vs 83%; P=0.0000014). However, the slope of the Kaplan-Meier curves representing the 2 treatment arms were similar (Figure 3A). This suggested that adjuvant imatinib delayed recurrence, but did not result in a cure. Furthermore, there was no difference in OS between the 2 treatment arms (Figure 3B). Thus, the long-term impact of adjuvant imatinib currently is unknown. This issue will be explored further in EORTC 62024, which, like ACOSOG Z9001, compared placebo with 400 mg imatinib daily, but in contrast will examine OS as its pri-mary end point. This study completed accrual in late 2008, but results are not yet available nor are they expected for quite some time. The SSG XVIII trial, which also completed accrual in late 2008, will in part address whether 3 years of imatinib results in improved RFS and OS compared with 1 year. However, the eligibility crite-ria for this trial also allowed enrollment of patients with tumor rupture or metastatic disease, so the data may not be directly applicable to the adjuvant setting. Thus, although adjuvant imatinib does seem to improve RFS, its long-term benefit in terms of OS and the optimal duration of treatment remain unknown. Perhaps most important is the question of whether administration of imatinib as an adjuvant agent following resection of pri-mary disease is better than waiting until objective dis-ease recurrence.

Optimal imatinib dosage in the metastatic set-ting appears to be related to the mutational status of the primary tumor. Although the adjuvant trials to date employed an imatinib dose of 400 mg daily, it is known that patients with advanced GIST whose


Figure 4. Computed tomography image of large locally advanced gastric gastrointestinal stromal tumor (A) before and (B) after 9 months of neoadjuvant imatinib therapy. Note not only the change in size of the mass, but also the change in density.

A

B

tumors contain KIT exon 9 mutations have improved survival if treated with 800 mg daily.77 It is not known whether imatinib dosing in the adjuvant setting should be adjusted based on GIST mutational status, an issue further complicated by the fact that mutational status is not routinely determined.

Neoadjuvant Therapy for Primary DiseaseThe Radiation Therapy Oncology Group (RTOG) 0312

trial is the only reported multicenter study thus far to evaluate the use of imatinib as a neoadjuvant agent. In this Phase II trial, patients with resectable primary or recurrent GIST were treated with imatinib 600 mg per day for 8 to 12 weeks before surgery. Patients who did not progress were eligible for surgery followed by 2 years of adjuvant imatinib.78 Of patients with primary GIST, 90% demonstrated an objective response before surgery, and 92% underwent R0/R1 resections. The 2-year RFS was 83%, which compares favorably withthe 2-year RFS of 73% reported from the Phase II ACO-SOG Z9000 trial, which treated patients with 1 year of adjuvant imatinib (and no neoadjuvant imatinib) after resection of solitary GISTs at least 10 cm in size, rup-tured/hemorrhaging GISTs, or multifocal GISTs (<5). Although it is impossible to compare the results of RTOG 0132 and ACOSOG Z9000, the data raise 2 questions: Does neoadjuvant imatinib improve progression-free survival (PFS)? Is 2 years or more of adjuvant imatinib better than just 1 year?

RTOG 0132 confirmed the safety of neoadjuvant ima-tinib, but only treated patients with a relatively short

course of preoperative therapy. Data from trials of advanced GIST have demonstrated that maximal radio-graphic response to imatinib generally required 6 to 9 months of treatment.1,2,64 Consequently, the opti-mal preoperative imatinib regimen may be upward of 6 months or more as long as continued radiographic response is observed (Figure 4).

Advanced DiseaseThe majority of patients experience tumor recurrence

despite successful resection of their primary tumor. At the time of recurrence, 66% have liver disease and 50% have peritoneal disease.79,80 Imatinib (400 mg/d) is the first-line therapy for advanced (unresectable primary or metastatic) GIST. In patients who develop progres-sive disease on 400 mg, dose escalation is effective.81-84 If disease progresses on higher doses of imatinib, or if such doses are not tolerated, then second-line sunitinib is started. When sunitinib resistance develops, proto-col-based therapies should be considered.

Surgery for metastatic disease or disease rendered resectable following neoadjuvant chemotherapy is a relatively common practice for some solid tumors, such as those from ovarian, testicular, and colonic primary sites. With the advent of imatinib and sunitinib therapy, the philosophy on the role of surgery in the manage-ment of advanced GIST is changing. Three observa-tions support the consideration of a similar strategy of aggressive cytoreductive surgery in patients with metastatic GIST on TKI therapy. First, the majority of patients experience durable periods of partial response

Table 2. Resection and Survival Rates for Cytoreductive Surgery For Advanced GIST After TKI Therapy

AuthorNo. of Patients

RTK-I Therapy

PR/SD on RTK-I, % PD on RTK-I, %

R0/R1, % 1-Yr PFS, % 1-Yr OS, %

Raut85 69 IM/SU 33 Limited, 47Generalized, 20

83 PR/SD, 80 Limited PD, 33 Generalized PD, 0

PR/SD, 80 Limited PD, 33 Generalized PD, 0

Rutkowski89 24 IM 75 25 91

Bonvalot87 22 IM 95 5 68

Andtbacka86 46 IM 45 55 48

DeMatteo78 40 IM/SU 50 Limited, 33Generalized, 17

80 PR/SD, 70 Limited PD, 48 Generalized PD, 14

PR/SD, 100Limited PD, 90 Generalized PD, 36

Gronchi88 38 IM 71 Limited, 21Generalized, 8

82 PR/SD, 96PD, 0

PR/SD, 100PD, 60

IM, imatinib mesylate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; R0, macroscopi-cally complete resection with negative microscopic margins; R1, macroscopically complete resection with positive microscopic margins; RTK-I, receptor tyrosine kinase inhibitor; SD, stable disease; SU, sunitinib malate

Reprinted from Raut CP, Bertagnolli MM. Controversies in the surgical management of GIST in the era of imatinib. Oncology. 2009;23(1):69, 74-76, with permission from CMPMedica LLC.


or stable disease on imatinib, lasting months to years. Second, pathologic complete responses are rare, noted in less than 5% of patients.83,84 Third, response to ima-tinib is not maintained indefinitely; the median time to progression due to the development of secondary resistance to imatinib is 18 to 24 months.71,72 When drug resistance develops, disease progression may be either limited (progression at one site of tumor, with other tumor deposits showing ongoing response to TKI) or generalized (progression at more than one site).78,85 If imatinib treatment does not cure the patient, but instead suppresses metastatic cells present at the time of resection for a finite period of time, then additional surgery may prolong the time until second-line suni-tinib therapy is necessary.

Several single-institution retrospective studies have documented the first PFS and OS rates following exten-sive cytoreductive surgery in patients with advanced GIST treated with TKI therapy (Table 2).78,85-89 The goal of such operations is to perform an R0 or R1 resection when safely possible. However, the disease frequently may be too extensive to be removed completely,

in which case progressing lesions are preferentially removed. Following surgery, these patients remain on imatinib indefinitely, as failure to resume imatinib results in rapid disease recurrence.

In the experience at Brigham and Women’s Hospi-tal/Dana-Farber Cancer Institute (BWH/DFCI), liver resections were required in approximately 40% of patients, and more than 60% included peritonectomy and/or omentectomy.85 More than 60% underwent mul-tivisceral resections.85 Radiofrequency ablation may be considered for liver disease. Complication rates ranged from 40% to 60%, although the majority were minor.78 Perioperative deaths were rare, usually occurring in the setting of emergency procedures.87,89

In the BWH/DFCI series, the best results were generally seen in patients whose disease was still responsive to TKI therapy at the time of surgery. The ability to remove all macroscopic disease was great-est in patients demonstrating ongoing response to TKI therapy. After surgery, there was no evidence of any residual disease in 78%, 25%, and 7% of patients with responsive disease, limited progression, and general-ized progression, respectively (P<0.0001).85 On the other hand, bulky residual disease remained after sur-gery in 4%, 16%, and 43% of patients with responsive disease, limited progression, and generalized progres-sion, respectively.

Another critical finding in 3 of the series was that the highest rates of PFS and OS were observed when cytore-ductive surgery occurred while the patients were still responding to TKI therapy. PFS rates for patients with ongoing response to TKI therapy (ie, partial response or stable disease at the time of surgery) were 70% to 96% at 1 year after surgery and 72% at 4 years from initiation of imatinib therapy (Figure 5).78,85,88 In con-trast, the 1-year PFS for patients with generalized pro-gression ranged from 0% to 14%. OS rates approached 100% at 1 year after surgery in patients responding to TKI therapy and only 0% to 60% at 1 year in the set-ting of generalized progression. Although patients with limited progression had lower rates of PFS than those with responsive disease, the rates of OS were not con-sistently different; the benefits of surgery in this popu-lation remain uncertain.

Based on these data from limited single-institution series, the patients who seemed to derive the most benefit from cytoreductive surgery were those still responding to TKI therapy at the time of surgery (partial response or stable disease). These patients should be considered for surgery on an individual basis. Patients with generalized progression do not appear to derive any benefit from surgery and are best treated with non-surgical therapies, except for palliative or emergency purposes. Most importantly, although cytoreductive surgery is feasible, there is still no evidence that out-comes are superior or even equal to those for patients who continue on TKI therapy without surgery. This only can be answered in a randomized clinical trial; such tri-als are under development in the United States and


Figure 5. Progression-free survival after cytoreductive surgery in patients with metastatic gastroin-testinal stromal tumor corresponds to response to tyrosine kinase inhib-itor therapy at the time of surgery.85

Reprinted from Raut CP, Posner M, Desai J, et al. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibi-tors. J Clin Oncol. 2006;24(15):2325-2331, with permission from the American Society of Clinical Oncology (ASCO). Copyright 2008 ASCO. All rights reserved.

Time, mo

Pro

bab

ilit

y

P<0.001

P=0.002

Generalized disease progression

Limited disease progression

Stable disease

0 5 10 15 20 25 30 35 40

1.0

0.8

0.6

0.4

0.2

already have opened in Europe and China.

SurveillanceThe postoperative follow-up for patients who have

successfully undergone surgical resection of a primary GIST recommended by the NCCN consensus panel includes history and physical examination every 3 to 6 months during the first 5 years and abdomen/pelvis CT scans with IV contrast every 3 to 6 months during the first 3 to 5 years, then annually thereafter.34

ConclusionPrior to the development of imatinib, the principal

treatment modality for GIST was surgery. Recurrence was common, and survival in the setting of recur-rent or metastatic disease was poor. With the advent of therapy with TKIs—first imatinib, and then suni-tinib—patient outcomes have improved considerably. Ongoing studies will establish the role of TKIs as adju-vant and neoadjuvant agents. The type and dose of TKI administered soon may be guided by mutational analysis. Future studies will focus on the integration of surgery with targeted therapy and the development of new agents for drug-resistant GIST.

Because of its relatively low toxicity and significant efficacy in treatment of GIST, TKI therapy has altered dramatically the natural history of this disease. Early studies have demonstrated the feasibility and safety of neoadjuvant imatinib for primary GIST and dramatic improvement in RFS with adjuvant imatinib after com-plete macroscopic resection of primary GIST. They have not adequately addressed the optimal length and dose of adjuvant and neoadjuvant imatinib therapy, defined the subset of candidates most likely to ben-efit from such therapy, or determined the long-term impact on OS. Studies also suggest that cytoreductive surgery should be considered in a certain subset of patients with advanced disease, but Phase III trial data are necessary to determine if surgery adds any benefit in terms of PFS/RFS and OS over continuing imatinib therapy alone.

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Figure 2 will appear in a chapter by Dr. Raut in the Atlas of Minimally Invasive Surgical Techniques,

edited by Ashley SW and Vernon AH, to be published by Elsevier in 2010.

AUTHOR DISCLOSURES—Dr. Raut discloses that he serves on the advisory board of Novartis.

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marker for EGFR inhibition based on a small analysis (N=113) by Di Nicolantonio (J Clin Oncol 2008;26:5705-5712, PMID: 19001320). This retrospective analysis indicated that in the presence of the BRAF mutation, the benefit of EGFR inhibition may be possibly negat-ed despite having a KRAS wild-type tumor. These new data strongly indicate that BRAF may be more of a prog-nostic indicator than predictive.

ClinOnc: What does this potentially mean for clinicians down the road?Dr. Eng: The presence of the BRAF mutation may serve as a poor prognostic indicator for patients and physicians and will aid in decision making, analo-gous to our concerns regarding histology, number of involved lymph nodes and/or dissected, and gastroin-testinal perforation.

ClinOnc: Are there any other studies you would like to highlight?Dr. Eng: Toxicity data were reported from the AVANT trial (abstract 6010) that is evaluating the role of bevacizumab (Bev; Avastin, Genentech) in combination with FOLFOX as adjuvant therapy in

stage II and III colon cancer patients. Clinicians are anxiously awaiting the final results of AVANT. At ASCO 2009, investigators reported that 12 months of bevacizumab did not improve the DFS of patients versus that of six months of adjuvant FOL-FOX alone (NSABP C-08). In AVANT, of those individ-uals who received FOLFOX/Bev in the adjuvant setting, 8.3% of patients versus 5.5% developed a venous throm-botic event. The arterial thrombotic event rate was sim-ilar—1.6% for the investigational arm versus 1%.

The final results of the COIN trial also were report-ed (abstract 5733). COIN was a three-arm, Phase III trial of oxaliplatin therapy (continuous vs. intermit-tent oxaliplatin) with a third arm that included cetux-imab. In the final results of this trial, a difference in OS or PFS was not identified, even in the KRAS wild-type patient. The results are a bit perplexing—they conflict with data from the Phase III CRYSTAL and the Phase II OPUS trials. It is important to note that a majori-ty of patients received capecitabine (1,000 mg/m2 bid, days 1-14) in combination with oxaliplatin (Eloxatin, Sanofi-Aventis) resulting in approximately 50% of the patients requiring a dose reduction because of grade 3/4 toxicities. The question then is—did these patients not fare well due to the toxicity of the capecitabine combination or possibly because of the decreased effi-cacy of cetuximab in combination with oxaliplatin-based therapy? It will be very interesting to see how

the authors will account for these differences after they analyze their data further.

ClinOnc: Which trials are clinicians eagerly anticipating results from in 2010?

Dr. Eng: We await the final results from the AVANT tri-al. Its results may impact the ongoing ECOG 5202 stage II adjuvant trial. The other trial of interest includes NSABP R-04, which is examining the role of oxaliplatin versus fluoropyrimidine-based therapy for radiosensi-tization in patients with rectal carcinoma. The STAR trial and the ACCORD 12 were conducted with our European colleagues and showed that the addition of oxaliplatin for radiosensitization for rectal cancer resulted in increased toxicities with no additional ben-efit for pathologic complete response rate. NSABP R-04 is near accrual completion, so I presume toxicity results will be available in 2011. However, there are many inter-esting biologic agents in Phase I/II development, so I am eager to see the role of these various agents in advanced colorectal cancer (c-met, IGF-R, src-kinase, PARP, etc.) especially given the increased recognition of the significance of predictive and prognostic markers. It is imperative that all investigators continue to encour-age patients to provide blood and tissue for correlatives. As you can see, our understanding of colorectal carcino-genesis is evolving daily.

Presented at the recent San Antonio Breast Cancer Symposium (SABCS), the two studies are part of a series of four worldwide Phase IIb clinical tri-als testing the use of sorafenib (Nexa-var, Bayer Healthcare Pharmaceuticals) in advanced HER2-negative breast can-cer in a program called TIES (Trials to Investigate the Effects of Sorafenib in Breast Cancer). Sorafenib is an oral multikinase inhibitor approved for advanced renal cell carcinoma and hepatocellular carcinoma; it is investi-gational in breast cancer.

Sorafenib Plus Paclitaxel Combo

The first study (abstract 44) was a double-blind, randomized placebo-controlled Phase IIb trial that includ-ed 237 patients from the United States, India and Brazil with HER2-negative, advanced or MBC. The study random-ized 119 patients to paclitaxel (90 mg/m2 weekly) plus sorafenib 400 mg twice daily and 118 patients to the same dose and schedule of paclitaxel plus placebo.

“The study showed activity for sorafenib. Sorafenib may provide added benefit when combined with paclitaxel compared with single-agent paclitaxel

in the first-line treatment of advanced breast cancer,” said lead investigator, William S. Gradishar, MD, a profes-sor of medicine at Northwestern Uni-versity Feinberg School of Medicine, in Chicago.

Median PFS was 6.9 months in patients in the sorafenib-containing arm com-pared with 5.6 months in patients receiv-ing paclitaxel alone, representing a 21% reduced relative risk for death or pro-gression, although this was not statisti-cally significant (P=0.0857).

According to Dr. Gradishar, the fail-ure for PFS to reach statistical signifi-cance may have been the result of excess deaths in the sorafenib arm (17 of 20) that were not drug-related. These deaths occurred mainly among 17 patients enrolled in India who died of causes not usually seen in the United States, includ-ing malaria and tuberculosis.

“These deaths [in India] appeared to skew the PFS,” Dr. Gradishar said. “Time to progression, which does not include deaths, showed a greater advantage for sorafenib plus paclitaxel spread that looks more impressive.”

The addition of sorafenib increased time to progression by 33%. Median duration of response was 5.6 months in

patients receiving sorafenib compared with 3.7 months in the paclitaxel-alone arm (P=0.0079), and objective response rates were 67% versus 54%, respec-tively (P=0.0234). Median duration of response was 5.6 months compared with 3.7 months, respectively (P=0.0079).

No unexpected toxicities were report-ed with the combination of sorafenib and paclitaxel. Hand–foot syndrome was the major toxicity seen in patients receiving sorafenib. Grade 3 hand–foot syndrome occurred in 30% of the sorafenib arm compared with 3% of the paclitaxel-alone arm.

“We are not suggesting that the inci-dence of hand–foot syndrome is accept-able. As we go forward [with sorafenib], we will have to modify the dose,” Dr. Gradishar said.

According to some researchers not involved in the study, further trials should consider whether the appropri-ate dose of sorafenib is being used. “It is not clear that the dose of sorafenib in this Phase IIb trial is the best dose. Target-ed therapy may not require the maximal dose,” said C. Kent Osborne, MD, direc-tor of the Breast Center at Baylor College of Medicine in Houston. “We are learn-ing as we go along, and it is possible that we can get away with a lower dose.”

Sorafenib Plus Capecitabine

In a separate Phase IIb study present-ed at SABCS (abstract 45), investigators tested the combination of sorafenib plus

capecitabine (Xeloda, Roche). Accord-ing to the lead author Jose Baselga, MD, a professor at Vall d’Hebron University Hospital, Barcelona, Spain, the combina-tion of sorafenib plus capecitabine was tolerable, with no unexpected major tox-icities, and the toxicities that did occur were clinically manageable. A significant benefit was found for PFS with the addi-tion of sorafenib, and subgroup analy-ses confirmed the robust benefit in both first- and second-line therapy for MBC.

The SOLTI-0701 trial had a similar design to the trial led by Dr. Gradishar; 220 patients with HER2-negative MBC from Spain, France and Brazil were randomized in a 1:1 fashion to receive capecitabine 1,000 mg/m2 for 14 of every 21 days and sorafenib 400 mg twice dai-ly continuously or the same dose and schedule of capecitabine plus placebo. The dose of capecitabine in this trial is lower than the approved dose of 1,250 mg/m2, Dr. Baselga said. Treatment was continued until progression or unaccept-able toxicity.

Patients were over the age of 18 with confirmed HER2-positive, local-ly advanced unresectable or MBC. Sev-enty percent were hormone receptor-positive; 80% had one prior adjuvant or neoadjuvant chemotherapy. Prior beva-cizumab was an exclusion criterion.

The investigators found that the reg-imen was well tolerated. Most adverse events were grade 1 or 2, with the

Sorafenib Potential Partner for Chemo in Metastatic Breast CaSan Antonio—Adding sorafenib to chemotherapy extends progression-free survival (PFS) in patients with locally advanced or metastatic breast cancer (MBC), according to two companion Phase IIb studies.

Colon

SOLID TUMORS

Breast

COLON HIGHLIGHTScontinued from page 17 �

see SORAFENIB, page 26 �


This news comes from presentations at the 13th World Conference on Lung Cancer (B2.6 and D7.1). Although high TS expression is correlated with squamous cell histology, it appears to be a much more specific predictor of response to folate antimetabolites such as pemetrexed (Alimta, Eli Lilly). The level of TS expression is likely the primary reason that squamous cell NSCLC responds poorly to chemother-apies such as pemetrexed. However, not all squamous cell NSCLCs have high TS levels and not all non-squamous cell NSCLCs have low TS levels.

In one of the studies presented at the 13th World Conference on Lung Cancer exploring the potential clinical value of measuring TS, median TS RNA expression was almost twice as great in squamous cell carcinomas as in adenocar-cinomas (4.10 vs. 2.5 × 10(–3); P<0.001), but there was tremendous overlap of expression ranges in individ-ual patient tumors, according to David R. Gandara, MD. Dr. Gandara, director of the Thoracic Oncology Program at the University of California, Davis Cancer Center, Sacramento, said that evaluation of TS levels might allow clinicians to individualize treatment irre-spective of histology.

The ability of TS gene expression to predict response to pemetrexed on an experimental basis has been recognized for several years (J Clin Oncol 2006;24: abstract 13058). These studies have associated low numbers of TS gene copies with sensitivity to pem-etrexed and high numbers with resistance. Clinical-ly, differences in response to pemetrexed have been correlated with histology. Most recently, a mainte-nance study with pemetrexed after first-line che-motherapy found almost all benefit confined to non-squamous NSCLC (J Clin Oncol 2009;27: abstract CRA8000). However, histology may be a surrogate for

TS expression and a much less sensitive discriminator for treatment choice.

“Our findings suggest that such molecular bio-markers as TS as well as others in development will supplant histology in decision making for personal-izing pemetrexed therapy in patients with NSCLC,” Dr. Gandara said.

TS, an important enzyme in the pathway of DNA and RNA synthesis, is easily and reproducibly quantified with standard immunohistochemistry techniques, but it still requires tissue samples. The new studies indi-cate that an important shift is under way in the routine

management of patients with advanced NSCLC, inde-pendent of TS measurements specifically. The need to collect tissue samples to better characterize NSCLC and identify the best therapies was an often-repeated refrain during the course of the World Congress.

“While we are trying to better assess histology, bio-markers and gene profiles, what we are realizing is that the most important first step is getting adequate tissue,” said Sarita Dubey, MD, assistant clinical pro-fessor of medicine in the Division of Medical Oncol-ogy, University of California, San Francisco. Caution-ing that the time is rapidly approaching when “it is no

longer going to be acceptable to have just a FNA [fine needle aspiration] for advanced NSCLC,”

Dr. Dubey predicted that biopsy “is going to be a standard of care.”

The list of therapies that might be guided by biomarker status is lengthening quickly. At

the World Congress, data were presented associ-ating positive EGFR mutation status with greater

response to tyrosine kinase inhibitors (TKIs), low ERCC1 expression with greater response to platinum chemotherapy and low RRM1 expression with greater response to gem-

citabine (Gemzar, Eli Lilly). George R. Simon, MD, director of the Thoracic Oncology Program at Fox Chase Cancer Center, Philadelphia, a member

institution of the National Comprehensive Cancer Network, suggested that individualized chemothera-py may change the disease course.

“We postulate that the tumors low in ERCC1/RRM1 will upregulate their ERCC1/RRM1 after they are exposed to platinum/gemcitabine, thereby altering the intrinsic disease biology to a more indolent form, the benefit of which will persist well after the chemo-therapy has been discontinued,” said Dr. Simon, who provided clinical data from prospective studies that led to the generation of this postulate. Although the survival benefit of individualized therapy relative to conventional chemotherapy (not guided by biomark-ers) is still being confirmed in ongoing prospective randomized trials, the studies presented at the World Congress capture an important direction in NSCLC research and care.

—Ted Bosworth

In NSCLC ...

TS Biomarker Ready for Routine Clinical ApplicationSan Francisco—After EGFR mutation status, thymidylate synthase (TS) may be one of the most promising biomarkers for individualizing therapy in patients with advanced non-small cell lung cancer (NSCLC).

exception of grade 3/4 hand–foot syn-drome, which occurred in 45% of the experimental arm compared with 13% of patients receiving only capecitabi-ne. Management of hand–foot syn-drome was prespecified in the proto-col. For grade 2, 3 and higher, sorafenib was withheld until the condition resolved; a reduced dose was initiated for grade 3 and higher. In the patients who received sorafenib, 65% discon-tinued treatment due to adverse events compared with 29% of patients in the

capecitabine plus placebo arm. Treat-ment discontinuations due to progres-sive disease also were higher in the patients who received sorafenib, 15% compared with 7%.

Sorafenib significantly increased median PFS: 6.4 compared with 4.1 months (P=0.006), representing an abso-lute improvement of 2.3 months and a 42% relative risk reduction in progres-sive disease or death. Response rates were 38% and 30.7%, respectively. In a prespecified subgroup analysis, median PFS in the first-line setting was 7.6 ver-sus 4.1 months, representing a 50% rel-ative risk reduction with the addition of sorafenib. In the second-line setting,

median PFS was 5.7 versus 4.1 months, for a 35% relative risk reduction.

More Study Needed

“These are impressive results but the toxicity is worrying,” said Stephen R.D. Johnston, MA, PhD, of Royal Marsden NHS Foundation and Trust and Insti-tute of Cancer in London, who was not involved with the study. At the SABCS, he asked Dr. Baselga what percent-age of the prescribed dose of sorafenib patients were able to receive. Dr. Basel-ga said the majority had dose reductions of capecitabine and sorafenib for grade 3 toxicity and only 10% of the sample kept to the initial dose.

According to other clinicians not involved with the studies, the trials show sorafenib has promise in MBC, but larger studies are needed to confirm the preliminary suggestion of benefit and optimal dosing needs to be stud-ied. “Although promise is demonstrat-ed for sorafenib-based chemotherapy combinations based on these studies, additional study is needed to maximize efficacy and reduce toxicity,” said Mau-ra Dickler, MD, attending physician in the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Cen-ter, New York City.

—Alice Goodman

SOLID TUMORS

Lung

Breast

SORAFENIB continued from page 25 �

Ribbon diagram of human thymidylate synthase in complex with deoxyuridine monophosphate (orange) and the antimetabolite chemotherapy drug raltitrexed (lime green).


Too often, one struggles to prepare and deliv-

er a presentation while the audience struggles to main-tain interest. Most present-ers, even those who fail, begin with good intentions. But effec-tive public speaking is a learned skill that can be honed by applying specif-ic techniques. The fastest way to improve your presentation skills is to learn the five basic principles of communication:

Understand your audience; 1. Define your purpose; 2. Have a clear message; 3. Organize your content for optimal 4. impact; and Maintain a natural, relaxed state.5. The ability to connect with the audi-

ence improves if your presentation is aligned with their needs. Begin by ask-ing yourself some simple questions: Who is my audience? What are their medical backgrounds? What do they hope to gain from my presentation? How much knowl-edge do they have about this subject? Will they be receptive or hostile to the subject matter? Answering these questions will clarify the needs of the audience, and help you tailor your presentation to heighten its relevance.

Once you have completed the audience analysis, you need to determine the pur-pose of the presentation. Are you seeking support for your research? Are you trying to establish your credentials, further the quest for a cure, or promote a promising new drug? Presenting copious amounts of information with an ambiguous purpose may frustrate and confuse the audience. By defining the objectives, you will make it less difficult to create the presentation and easier for your audience to under-stand its content.

Next, state your message in a clear and concise manner. Your presentation is an opportunity to deliver a message that can motivate and inspire the audience. Remember that you are the expert on the subject and your audience may not have the same depth of understanding. Keep-ing the message brief, specific and repeat-able will guide audience members in their interpretation of what you are saying. Ask yourself, “If they only remember one key concept about my talk, what is it I want them to remember?” Then state that con-cept clearly throughout the presentation. Every major point of your talk should end with, “…and that’s why it is so important that we fund this research”; or “…drug X accomplishes this goal”; or “…and this will help us provide cost-effective care.”

After clarifying your message, it is

essential to develop a strat-egy for effectively deliver-ing the content. Your for-mat will affect the overall impression with which you

leave the audience. There are five formats from which

to choose when presenting

medical or clinical information; make sure you choose the one that best con-veys your message. They are:

Timing—arrange information in 1. sequential order; Climax—deliver the main points in 2. order of escalating importance;Problem/Solution—present a prob-3. lem followed by a solution and its benefits;Classification—focus the presentation 4. on important items that are not deliv-ered in any particular order; and

Simple/Complex—arrange informa-5. tion from the simplest concepts to the most complex. When delivering your content, remem-

ber that body language communicates a variety of information to the audience. It is important to recognize that the audi-ence is not only listening to your presen-tation, but also is interpreting any non-verbal messages you may be sending. It is critical that you project confidence, while at the same time appearing relaxed during

Five Steps To Delivering an Effective Presentation Being asked to present at a medical conference or to a group of your peers can be challenging and, for some, even frightening.

PRN

Communication

see PRESENTATION, page 29 �

In the treatment of patients with documented iron defi ciency in whom oral administration is unsatisfactory or impossible

Making the Case for INFeD®

Broad usage1

Allows FDA-approved treatment of a wide range of patients with documented irondefi ciency anemia

Proven safety profi le of iron dextran In a retrospective analysis of 841,252 doses, dyspnea, hypotension, and neurological

symptoms were the most common major adverse drug events (ADEs)2

— The most common minor ADEs were nausea, vomiting, fl ushing, and pruritus2

Serious adverse events are rare— In a nonuremic population, 3 serious adverse events occurred in 481 patients (0.6%)

receiving 2099 iron dextran injections (0.1%), with no fatalities reported3

— In a retrospective analysis of 61,950 hemodialysis patients, the incidence of reactions requiring resuscitative medications was 0.0016% (7 episodes in 440,406 exposures)4

Iron dextran products are not clinically interchangeable1

— Differ in chemical characteristics and may differ in clinical effects

Important Safety Information1

Anaphylactic-type reactions, including fatalities, have followed the parenteral administration of iron dextran injection. A test dose should be administered prior to the fi rst therapeutic dose, followed by the full therapeutic dose if no signs or symptoms of anaphylactic-type reactions are seen. Resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions must be readily available during all INFeD® administrations. Patients should be observed for signs or symptoms of anaphylactic-type reactions during all INFeD® administrations. Fatal reactions have followed the test dose and have also occurred in situations where the test dose was tolerated. Use INFeD® only in patients in whom clinical and laboratory investigations have established an iron defi cient state not amenable to oral iron therapy. Patients with a history of drug allergy or multiple drug allergies may be at increased risk of anaphylactic-type reactions. INFeD® should be used with caution in individuals with histories of signifi cant allergies and/or asthma, and is contraindicated in patients with hypersensitivity to the product and patients with all anemias not associated with iron defi ciency. INFeD® should be used with extreme care in patients with serious impairment of liver function, and should not be used during the acute phase of infectious kidney disease. Unwarranted therapy with parenteral iron will cause excess storage of iron with the consequent possibility of exogenous hemosiderosis, which is particularly apt to occur in patients with hemoglobinopathies and other refractory anemias.

Please see next page for references and brief summary of full Prescribing Information.

www.infed.com

© 2009, Watson Pharma, Inc., Morristown, NJ 07960. All rights reserved. 06107 11/09


Arzerra Gets Accelerated Approval for CLL

The FDA has granted accelerated approval to ofatumumab (Arzerra,

GlaxoSmithKline) for the treatment of patients with chronic lymphocytic leu-kemia (CLL) that is refractory to flu-darabine (Fludara, Berlex Laboratories) and alemtuzumab (Campath, Berlex).

The approval is based on results from a study of 59 patients with CLL who were refractory to both fludarabine and alemtuzumab. In this population, 42% responded to treatment with ofatu-mumab; median duration of response in patients who responded was 6.5 months.

The drug’s safety was evaluated in 181

patients in two studies of patients with

cancer. Common side effects includ-

ed a decrease in normal white blood

cells, pneumonia, fever, cough, diarrhea,

reduced red blood cell counts, fatigue,

shortness of breath, rash, nausea, bron-

chitis and upper respiratory tract infec-

tions. The most serious side effects of

ofatumumab are increased risks for

infections, including progressive mul-

tifocal leukoencephalopathy. Patients

at high risk for hepatitis B should be

screened before being treated with ofa-

tumumab. Patients with evidence of

inactive hepatitis should be monitored

for reactivation of the infection during

and after completing treatment.

Further studies are needed for the accelerated approval to be turned into full approval.

Istodax for Patients With Cutaneous T-cell Lymphoma

The FDA has approved romidepsin (Istodax, Gloucester Pharmaceu-

ticals) for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. Approval was based on overall response rate (ORR), defined as the proportion of patients with con-firmed complete response (CR) or par-tial response (PR). The drug, a histone

deacetylase inhibitor, is expected to be commercially available in January 2010.

The FDA granted approval based on results from two prospective, mul-ticenter, single-arm clinical studies in patients with CTCL. In one study, spon-sored by Gloucester Pharmaceuti-cals, 96 patients with confirmed CTCL after failure of at least one prior sys-temic therapy were enrolled. The sec-ond study, sponsored by the Nation-al Cancer Institute, included 71 patients with a primary diagnosis of CTCL who received at least two prior skin-direct-ed therapies or one or more system-ic therapies. Patients were treated with romidepsin at a starting dose of 14 mg/m2 infused over four hours on days 1, 8 and 15 every 28 days.

In both studies, patients could be treated until disease progression at the discretion of the investigator and local regulators. Objective disease response was evaluated according to a compos-ite end point that included assessments of skin involvement, lymph node and visceral involvement, and abnormal cir-culating T-cells (Sézary cells).

The ORRs in these two trials were similar (34% in the first study and 35% in the second study, respectively) and CR rates were the same (6%). Medi-an response duration was 15 months (range, one to more than 20 months) in the first study and 11 months (range, one to more than 66 months) in the second study. Median time to first response was two months (range, one to six months) in both studies. Median time to CR was six months in the first study and four months in the second study (range, two to nine months). The most common adverse reactions were nausea, fatigue, anemia, infections, elec-trocardiographic T-wave changes, neu-tropenia, lymphopenia, thrombocytope-nia, vomiting and anorexia.

In the first study, the median num-ber of prior skin-directed therapies and of prior systemic therapies was two for both. In the second study, the medi-an number of prior skin-directed thera-pies was one and of prior systemic ther-apies was two. In the first study, 71% of the patients had stage IIB or greater disease and 87% of the patients in the second study had stage IIB or greater disease.

Elitek Effective in Managing Plasma Uric Acid

The FDA has approved rasburicase (Elitek, Sanofi-Aventis) at a daily

dose of 0.20 mg/kg intravenously for up to five days for the initial manage-ment of plasma uric acid (PUA) levels in

FDA NEWS

BRIEF SUMMARY: For full Prescribing Information, see package insert.

INDICATIONS AND USAGE: Intravenous or intramuscular injections of INFeD are indicated for treatment of patients with documented iron deficiency in whom oral administration is unsatisfactory or impossible.

CONTRAINDICATIONS: Hypersensitivity to the product. All anemias not associated with iron deficiency.

WARNINGS:

Risk for Anaphylactic-type Reactions: Anaphylactic-type reactions, including fatalities have followed the parenteral administration of iron dextran. Always have resuscitation equipment and personnel trained in the detection and treat-ment of anaphylactic-type reactions readily available during INFeD administration. Prior to the first therapeutic dose, administer a test INFeD dose of 0.5 mL. (See DOSAGE AND ADMINISTRATION.) Although reactions are usually evident within a few minutes, observe patients for at least one hour before administering the therapeutic dose. During all INFeD administrations, observe patients for signs or symptoms of anaphylactic-type reactions. Fatal reactions have followed the test dose of iron dextran and have also occurred in situations where the test dose was tolerated. Use INFeD only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy.

The factors that affect the risk for anaphylactic-type reactions to iron dextran products are not fully known but limited clinical data suggest the risk may be increased among patients with a history of drug allergy or multiple drug allergies. Additionally, concomitant use of angiotensin-converting enzyme inhibitor drugs may increase the risk for reactions to an iron dextran product. The extent of risk for anaphylactic-type reactions following exposure to any specific iron dextran product is unknown and may vary among the products.

Iron dextran products differ in chemical characteristics and may differ in clinical effects. Iron dextran products are not clinically interchangeable.

Delayed Reactions: Large intravenous doses, such as used with total dose infusions (TDI), have been associated with an increased incidence of adverse effects. The adverse effects frequently are delayed (1-2 days) reactions typified by one or more of the following symptoms: arthralgia, backache, chills, dizziness, moderate to high fever, headache, malaise, myalgia, nausea, and vomiting. The onset is usually 24-48 hours after administration and symptoms generally subside within 3-4 days. The etiology of these reactions is not known. The potential for a delayed reaction must be considered when estimating the risk/benefit of treatment.

The maximum daily dose should not exceed 2 mL undiluted iron dextran.

Risk in Patients with Underlying Conditions: INFeD should be used with extreme care in patients with serious impairment of liver function. It should not be used during the acute phase of infectious kidney disease.

Adverse reactions experienced following administration of INFeD may exacerbate cardiovascular complications in patients with pre-existing cardiovascular disease.

Carcinogenesis: A risk of carcinogenesis may attend the intramuscular injection of iron-carbohydrate complexes. Such complexes have been found under experimental conditions to produce sarcoma when large doses or small doses injected repeatedly at the same site were given to rats, mice, and rabbits, and possibly in hamsters.

The long latent period between the injection of a potential carcinogen and the appearance of a tumor makes it impossible to measure accurately the risk in man. There have, however, been several reports in the literature describing tumors at the injection site in humans who had previously received intramuscular injections of iron- carbohydrate complexes.

PRECAUTIONS: General: Unwarranted therapy with parenteral iron will cause excess storage of iron with the conse-quent possibility of exogenous hemosiderosis. Such iron overload is particularly apt to occur in patients with hemoglobin-opathies and other refractory anemias that might be erroneously diagnosed as iron deficiency anemias.

INFeD should be used with caution in individuals with histories of significant allergies and/or asthma.

Anaphylaxis and other hypersensitivity reactions have been reported after uneventful test doses as well as therapeutic doses of iron dextran injection. Therefore, administer a test dose prior to the first therapeutic dose of INFeD. (See BOXED WARNING and DOSAGE AND ADMINISTRATION: Administration.)

Epinephrine should be immediately available in the event of acute hypersensitivity reactions. (Usual adult dose: 0.5 mL of a 1:1000 solution, by subcutaneous or intramuscular injection.) Note: Patients using beta-blocking agents may not respond adequately to epinephrine. Isoproterenol or similar beta-agonist agents may be required in these patients.

Patients with rheumatoid arthritis may have an acute exacerbation of joint pain and swelling following the admin-istration of INFeD.

Reports in the literature from countries outside the United States (in particular, New Zealand) have suggested that the use of intramuscular iron dextran in neonates has been associated with an increased incidence of gram- negative sepsis, primarily due to E. Coli.

Information For Patients: Patients should be advised of the potential adverse reactions associated with the use of INFeD.

Drug/Laboratory Test Interactions: Large doses of iron dextran (5 mL or more) have been reported to give a brown color to serum from a blood sample drawn 4 hours after administration.

The drug may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium.

Serum iron determinations (especially by colorimetric assays) may not be meaningful for 3 weeks following the admin-istration of iron dextran.

Serum ferritin peaks approximately 7 to 9 days after an intravenous dose of INFeD and slowly returns to baseline after about 3 weeks.

Examination of the bone marrow for iron stores may not be meaningful for prolonged periods following iron dextran therapy because residual iron dextran may remain in the reticuloendothelial cells.

Bone scans involving 99m Tc-diphosphonate have been reported to show a dense, crescentic area of activity in the but-tocks, following the contour of the iliac crest, 1 to 6 days after intramuscular injections of iron dextran.

Bone scans with 99m Tc-labeled bone seeking agents, in the presence of high serum ferritin levels or following iron dextran infusions, have been reported to show reduction of bony uptake, marked renal activity, and excessive blood pool and soft tissue accumulation.

Carcinogenesis, Mutagenesis, Impairment Of Fertility: See WARNINGS.

Pregnancy: Pregnancy Category C: Iron dextran has been shown to be teratogenic and embryocidal in mice, rats, rabbits, dogs, and monkeys when given in doses of about 3 times the maximum human dose.

No consistent adverse fetal effects were observed in mice, rats, rabbits, dogs and monkeys at doses of 50 mg iron/kg or less. Fetal and maternal toxicity has been reported in monkeys at a total intravenous dose of 90 mg iron/kg over a 14 day period. Similar effects were observed in mice and rats on administration of a single dose of 125 mg iron/kg. Fetal abnormalities in rats and dogs were observed at doses of 250 mg iron/kg and higher. The animals used in these tests were not iron deficient. There are no adequate and well-controlled studies in pregnant women. INFeD should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Placental Transfer: Various animal studies and studies in pregnant humans have demonstrated inconclusive results with respect to the placental transfer of iron dextran as iron dextran. It appears that some iron does reach the fetus, but the form in which it crosses the placenta is not clear.

Nursing Mothers: Caution should be exercised when INFeD is administered to a nursing woman. Traces of unmetabolized iron dextran are excreted in human milk.

Pediatric Use: Not recommended for use in infants under 4 months of age. (See DOSAGE AND ADMINISTRATION.)

ADVERSE REACTIONS: Severe/Fatal: Anaphylactic reactions have been reported with the use of iron dextran injection; on occasions these reactions have been fatal. Such reactions, which occur most often within the first several minutes of administration, have been generally characterized by sudden onset of respiratory difficulty and/or cardiovascular collapse. Because fatal anaphylactic reactions have been reported after administration of iron dextran injection, the drug should be given only when resuscitation techniques and treatment of anaphylactic and anaphylactoid shock are readily available. (See BOXED WARNING and PRECAUTIONS: General, pertaining to immediate availability of epinephrine.)

Cardiovascular: Chest pain, chest tightness, shock, cardiac arrest, hypotension, hypertension, tachycardia, bradycardia, flushing, arrhythmias. (Flushing and hypotension may occur from too rapid injections by the intravenous route.)

Dermatologic: Urticaria, pruritus, purpura, rash, cyanosis.

Gastrointestinal: Abdominal pain, nausea, vomiting, diarrhea.

Hematologic/lymphatic: Leucocytosis, lymphadenopathy.

Musculoskeletal/soft tissue: Arthralgia, arthritis (may represent reactivation in patients with quiescent rheumatoid arthritis – See PRECAUTIONS: General), myalgia; backache; sterile abscess, atrophy/fibrosis (intramuscular injection site); brown skin and/or underlying tissue discoloration (staining), soreness or pain at or near intramuscular injection sites; cellulitis; swelling; inflammation; local phlebitis at or near intravenous injection site.

Neurologic: Convulsions, seizures, syncope, headache, weakness, unresponsiveness, paresthesia, febrile episodes, chills, dizziness, disorientation, numbness, unconsciousness.

Respiratory: Respiratory arrest, dyspnea, broncho spasm, wheez ing.

Urologic: Hematuria.

Delayed reactions: Arthralgia, backache, chills, dizziness, fever, headache, malaise, myalgia, nausea, vomiting. (See WARNINGS.)

Miscellaneous: Febrile episodes, sweating, shivering, chills, mal aise, altered taste.

OVERDOSAGE: Overdosage with iron dextran is unlikely to be associated with any acute manifestations. Dosages of iron dextran in excess of the requirements for restoration of hemoglobin and replenishment of iron stores may lead to hemosiderosis. Periodic monitoring of serum ferritin levels may be helpful in recognizing a deleterious progressive accumulation of iron resulting from impaired uptake of iron from the reticuloendothelial system in concurrent medical conditions such as chronic renal failure, Hodgkins disease, and rheumatoid arthritis. The LD50 of iron dextran is not less than 500 mg/kg in the mouse.

Rx Only

Revised: September 2009

Address medical inquiries to:WATSONMedical CommunicationsP.O. Box 1953Morristown, NJ 07962-1953800-272-5525

Distributed by:Watson Pharma, Inc.Morristown, NJ 07962

Manufactured by:Patheon Italia S.p.A.Ferentino, Italy 03013

251279S0909

WARNING: RISK FOR ANAPHYLACTIC-TYPE REACTIONS

Anaphylactic-type reactions, including fatalities, have followed the parenteral administration of iron dextran injection.

Have resuscitation equipment and personnel trained in the detection and treatment of anaphylactic- ßtype reactions readily available during INFeD administration.

Administer a test INFeD dose prior to the first therapeutic dose. If no signs or symptoms of anaphy- ßlactic-type reactions follow the test dose, administer the full therapeutic INFeD dose.

During all INFeD administrations, observe for signs or symptoms of anaphylactic-type reactions. ßFatal reactions have followed the test dose of iron dextran injection. Fatal reactions have also occurred in situations where the test dose was tolerated.

Use INFeD only in patients in whom clinical and laboratory investigations have established an iron ßdeficient state not amenable to oral iron therapy.

Patients with a history of drug allergy or multiple drug allergies may be at increased risk of anaphy- ßlactic-type reactions to INFeD.

References: 1. INFeD® full Prescribing Information. Watson Pharma, Inc. September 2009. 2. Fletes R, Lazarus JM, Gage J, Chertow GM. Suspected iron dextran-related adverse drug events in hemodialysis patients. Am J Kidney Dis. 2001;37:743-749. 3. Hamstra RD, Block MH, Schocket AL. Intravenous iron dextran in clinical medicine. JAMA. 1980;243:1726-1731. 4. Walters BAJ, Van Wyck DB. Benchmarking iron dextran sensitivity: reactions requiring resuscitative medication in incident and prevalent patients. Nephrol Dial Transplant. 2005;20:1438-1442.


your presentation. Speakers who express nervousness through actions transmit discomfort to their audiences. To counter this effect, apply key presentation skills, such as maintaining good eye contact, using purposeful gestures, and speaking in an expressive manner. These skills will enhance your credibility and keep the audience engaged.

The most important of these skills is eye contact. Rather than scanning the audience, focus on one person at a time

while relaying a full thought. Remain-ing focused on one person for a com-plete sentence creates the impression that you are simply having a conver-sation with the audience rather than delivering a formal presentation. Addi-tionally, this skill helps reduce your nervousness and increases your ability to remain calm.

As you prepare your next presenta-tion for a medical conference or peer group discussion, remember that pre-senting is a learned skill and not an innate talent. Delivering a powerful and effective presentation requires learning and practicing and, finally, using these

techniques successfully.

— Dalli Simmons

Dalli Simmons, certified

school psychologist, is a

consultant at Exec|Comm

LLC, a New York City-

based communications

consulting firm, where

she coaches medical pro-

fessionals, scientists and

senior-level executives in

a wide variety of commu-

nication skills. She can be

reached at dsimmons@

exec-comm.com.

adults with leukemia, lymphoma and solid tumors receiving anticancer therapy expected to result in tumor lysis syndrome (TLS) and subsequent elevation of plasma uric acid.

Approval was based on data from a Phase III trial that demonstrated the drug significantly reduced PUA levels compared with the current stan-dard of care (oral allopurinol) in adults with hematologic cancers at risk for TLS, a potentially life-threatening complication.

The multicenter, open-label, random-ized Phase III trial compared the safe-ty and effectiveness of three treat-ments for achieving uric acid response: intravenous rasburicase alone daily for five days, intravenous rasburicase dai-ly for day 1 to day 3 followed by oral allopurinol daily for day 3 to day 5, and oral allopurinol alone daily for five days. The PUA response rate was defined as the proportion of patients with PUA lev-els of 7.5 mg/dL or lower from day 3 to day 7 after initiation of treatment.

Results showed that among patients treated with rasburicase alone or followed by oral allopurinol, uric acid levels were 2.0 mg/dL or lower in 96% of patients (at four hours of dosing on day 1). There were no failures to control PUA in patients in either rasburicase treatment group. In patients treated with rasburicase alone (n=92), the PUA response rate was 87%, which was high-er than that seen in patients treated with oral allopurinol alone (n=91) at 66% (P=0.0009), a statistically significant difference, or in those treated with combined rasburicase and oral allopurinol(n=92) at 78%. The difference in PUA response rate between rasbu-ricase treatment versus rasburicase and oral allopurinol treatment was not sta-tistically significant.

PRN

Communication

PRESENTATIONcontinued from page 27 �

FDA UPDATE

Part 1 of a 3-Part SeriesBe sure to watch for more articles on effective communication skills in future issues:

PART 2: “Open Body Language: Optimizing Your Nonverbal Communication”

PART 3: “The Other Side of a Two-Way Street: Active Lis-tening is Essential for Conversation”


in Richfield, Ohio.The CMS, Ms. Pierce explained, col-

lects charge data from hospitals and then aggregates them to use in a formu-la for establishing national levels of pay-ment. “If the payment rates are set arti-ficially low—which they may be if too many hospitals fail to maintain their charge master—everyone suffers,” Ms. Pierce said. “So there are compelling reasons why hospitals should scruti-nize and update their hospital phar-macy charge masters at frequent inter-vals—especially when you consider the growth of high-cost drug products such as biologics.”

The study was based on a self-report-ing questionnaire that was sent to the directors of pharmacy and chief financial officers at 4,000 U.S. hospitals. A total of 48 states were included in the survey (rural 72%, urban 28%; beds: <100 52%, 100-300 30%, >300 18%). Participation was voluntary and no payments were offered for completing the survey.

Wide Variation Seen

The frequency of reviewing and changing line-item drug products var-ied considerably, said Ms. Pierce. Some of the respondents reported updating the products continually, in “real time,” when manufacturers and distributors announce drug price changes. In con-trast, “some of the respondents said they only looked at pricing information in their hospital charge master data once a year,” she said. “And in more than 15% of cases, the respondents said the meth-odology used to develop the charge mas-ter had not been reviewed or changed in more than five years.”

Ms. Pierce acknowledged several lim-itations to the study, which was dis-cussed at a meeting of the American Society of Health-System Pharmacists. The findings, for example, were based on only 356 returned surveys. “So from a power calculation standpoint, the sam-ple size is too low for these results to be generalizable,” she said. Additional-ly, the survey is a self-reporting instru-ment, “so there’s always the potential for bias—that people’s perceptions come through, rather than objective data.” Ms. Pierce stressed, however, that the results “do provide a snapshot of what’s happening in hospitals of varying siz-es across the United States, and what it suggests is that many facilities may not be paying enough attention to keeping their charge masters up to date.”

Understanding the Problem

Asked to explain the lax updating, Ms. Pierce replied, “I don’t think it’s a lack of awareness.” Instead, she cited sever-al factors, particularly the challenge of

managing today’s business while bal-ancing the long-term implications of untimely pricing updates. “Hospitals are scampering to deal with what’s immediately in front of them, espe-cially in this ongoing economic downturn,” she said. As a result, “it just may be too much” to expect hospitals to constantly be think-ing about what they do today impacting their reimbursement in the future. Under CMS rate-setting methodology, Ms. Pierce noted, cost reports from today will be used to determine reimbursement rates two years later.

“In hospital-think,” she said, “that two-year time frame is infinity—it’s too far away from what they have to deal with today to survive, whether it be crushing loads of charity care, lost endowments, regulatory and accreditation reviews, a tough new technology rollout and so on.”

Ms. Pierce listed several steps hospi-tals can take to ensure that their pharma-cy charge master is updated consistently. The first step is to have all stakeholders understand why that process is such an important undertaking for maintaining fiscal health.

“Hospital finance, pharmacy and clin-ical departments must work synergisti-cally so that updates are not missed,” she said. “If your charges are understat-ed on the charge master, that flows to your cost report into a category called drugs charged to patients, which pro-vides an aggregate snapshot of hospital drug charges. So when Medicare goes to set [national] reimbursement rates and it looks at your data, it is starting with a flawed baseline. Coupled with oth-er hospitals that don’t update regular-ly, over time, that is going to give Medi-care the impression that the products and services you rendered cost you less

than they actually did.”Hospitals already are under intense

financial pressure, she added, “but you don’t need to add to that with flawed charging practices.”

Fixing the Problem

Hospitals that want to improve their charge master updating should follow the lead of facilities that excel at the process, Ms. Pierce noted; one common strategy “is the wisdom to get someone at a very senior level to take ownership of this [process].”

Increasingly, Ms. Pierce said, positions such as vice president or senior vice pres-ident of the revenue cycle are being cre-ated to tackle the hospital charge master as an essential aspect of reimbursement accuracy. Such an approach is important, she added, because the charge master “is just one cog in the wheel of the entire revenue cycle. So appointing someone in

a leadership position in finance is crucial to pulling this off.”

The next step is to team up the finance person with a colleague in

pharmacy who can take ownership of the pharmacy-specific aspects of the charge master. This com-monly, she said, is the pharma-cy director, who typically has both the clinical and business acumen to understand the spec-trum of drug costs, handling and

what needs to be done to ensure adequate payment rates.“When new drug payment rates

and coding are released,” Ms. Pierce explained, “the phar-macy director is usually in an ideal position to bring that new information to the attention of the vice

president of revenue cycle or a similar position with-

in finance, and then have the team determine how the information will impact charging strategy going forward.”

A Not Uncommon Failing

Rob Adamson, PharmD, corporate vice president of clinical services, Saint Barn-abas Health Care System, West Orange, N.J., said he was not surprised that 15% of respondents to Ms. Pierce’s survey failed to upgrade their hospital charge masters. “Most pharmacy departments do a great job negotiating contracts with manufacturers and insurers and in gen-eral holding drug costs down as much as possible,” Dr. Adamson said. “But the charge master is where the rubber meets the road. I can get a great contract price for a drug, but if I’m not tracking price updates and entering them into the charge master on a regular basis, those savings can go out the window.”

Saint Barnabas is certainly not immune to the oversight. After more than a year of not tracking its hospital charge mas-ter on a regular basis, Dr. Adamson said, the institution found several problems, including wrong reimbursement codes for drugs, out-of-date drug prices and a lack of dose “multipliers” that result in underbilling. “The lesson we learned,” he said, “is that it’s not just about the charge master—there are other pieces to the reimbursement puzzle that have to be in place.”

Accurate charging is all the more important because of the growth of high-ticket pharmaceuticals. “Very few drugs come to market at anywhere near the pricing structure of five to eight years ago,” Dr. Adamson said. “Biolog-ics are a case in point; these treatments can cost hundreds of thousands of dol-lars per patient per year, and they’re the fastest growing line of the business. You can’t afford to not get this right.”

—David Bronstein

POLICY & MANAGEMENT

Reimbursement

DRUG PRICINGcontinued from page 1 �

‘The charge master is where the rubber meets the road. I can get a great contract price for a drug, but if I’m not tracking price updates and entering them into the charge master on a regular basis, those savings can go out the window.’

—Rob Adamson, PharmD


Pediatric Oncologist Leads COGPeter C. Adamson, MD, a pediat-

ric oncologist and leading scientist at the Children’s Hospital of Philadelphia Research Institute, has been selected to lead the Children’s Oncology Group (COG). Dr. Adam-son is the director of clinical and transla-tional research and chief of the Division of Clinical Pharma-cology and Thera-peutics at Children’s Hospital. He is also a professor of pedi-atrics and pharmacology at the Universi-ty of Pennsylvania School of Medicine, in Philadelphia. He will remain on the staff of Children’s Hospital and on the UPenn faculty while serving as COG chair. Dr. Adamson came to the Children’s Hospital of Philadelphia in 1999 from the National Cancer Institute.

Dr. Adamson’s previous roles at COG included leading a 21-site Phase I con-sortium that conducted initial evalua-tions of drugs being developed to treat cancer in children. During the eight years that Dr. Adamson led this effort, the collaborating sites conducted more than 25 studies designed to test the safe-ty of novel anticancer drugs.

Doctor Wins Lawsuit

A radiation oncologist who former-ly worked for the University of Pitts-burgh Cancer Institute (UPCI) has won a potential $3 million verdict in federal court based on a jury conclusion that the institute retaliated against her for raising discrimination concerns.

The lawsuit by Kristina Gerszten, MD, alleged that she had been dis-criminated against because of her gender and retaliated against for making a com-plaint to hospital offi-cials. The jury did not

find evidence of sex discrimination, but concluded that she

was retaliated against when the UPCI did not

hire her as medical director at both Uni-versity of Pittsburgh Medical Center (UPMC) St. Margaret and at its facility in Natrona Heights, Pa.

According to an article in the Pitts-burgh Post-Gazette, after leaving her position as medical director of radia-tion oncology at Magee-Womens Hos-pital in February 2004, Dr. Gersz-ten signed a two-year contract under which she traveled to various UPMC cancer centers and provided coverage.

Dr. Gerszten negotiated her schedule so that she would work only 180 to 200 days each year but would still be consid-ered a full-time employee. According to the Post-Gazette, Dr. Gerszten was giv-en a new, one-year contract at the UPCI in 2006, but in January 2007, the insti-tute chose not to renew. As part of that contract, Dr. Gerszten said, she had an 18-month non-compete clause and was left without work until January 2009.

The jury recommended that Dr. Gersz-ten be awarded $1.5 million in back pay

and $827,292 in front pay from the UPCI, $200,000 in compensatory damages and $300,000 in punitive damages. A judge will determine the actual amount.

Durden on the Move

Donald L. Durden, MD, PhD, has been named professor and vice chair for research in the Department of Pediatrics and research director, Division of Hema-tology/Oncology at the Rebecca and John Moores Cancer Center of the University of California, San Diego (UCSD).

Dr. Durden was formerly the Aflac Endowed Chair and professor of pediat-rics at Emory Univer-sity School of Med-icine and scientific director of basic and translational research at Emory’s Aflac Cen-ter for Cancer and B l o o d D i s o rd e r s , in Atlanta.

Around the Water CoolerThis section brings you news about people and places in the field of

oncology. If you have news to share (a new job, an award, a cancer center closure or expansion, etc.), please send information to [email protected].

IN BRIEF

Peter C. Adamson, MD

Donald L. Durden, MD, PhD

INDICATION: Vectibix® is indicated as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®.

Important Safety Information including Boxed WARNINGS:Safety data are available from 15 clinical trials in which 1467 patients received Vectibix®; of these, 1293 received Vectibix® monotherapy and 174 received Vectibix®

in combination with chemotherapy.

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONSDermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy. Withhold Vectibix® for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within1 month, permanently discontinue Vectibix®. The clinical manifestations included,but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage were reported.

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Severe infusion reactions included anaphylactic reactions, bronchospasm, and hypotension. Although not reported with Vectibix®, fatal infusion reactions have occurred with other monoclonal antibody products. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction,permanently discontinue Vectibix®.

Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized (1:1) clinical trial of patients with previously untreated metastatic colorectal cancer, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increasedincidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions.

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Following the initial fatality, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in such patients is uncertain. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.

In the randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm. Additionally, hypomagnesemia (NCI-CTC grade 3 or 4) requiring electrolyte repletion occurred in 2% of patients 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy, and appropriate treatment instituted, as needed.

Exposure to sunlight can exacerbate dermatologic toxicity. It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

Dermatologic, mucosal, and ocular toxicities were also reported.

Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy.

The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix® are pulmonary fibrosis, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

Please see brief summary of Prescribing Information on next page.

References: 1. Vectibix® (panitumumab) prescribing information, Amgen. 2. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumabplus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;13:1658-1664.

©2009 Amgen. All rights reserved. 4-09 45904

*Correlation with safety and efficacy is unknown

The first fully human*

anti-EGFR monoclonalantibody

Based on independent review of disease progression, a statistically

significant prolongation in PFS was observed in patients receiving

Vectibix® plus BSC vs those patients receiving BSC alone1,2

Weeks

Prop

orti

on E

vent

Fre

e

0%

10%

20%

30%

60%

70%

100%

90%

80%

50%

40%

0 4 10 12 14 16 40 42 44 46 4832 34 36 388 186 20 302 50 5222 24 26 28

Kaplan-Meier Plot of PFS Time as Determined by the Independent Review Committee1,2

Treatment Group

Vectibix® + BSC (n=231)

BSC Alone (n=232)

P < 0.0001

Subjects at risk:

Vectibix® + BSCBSC Alone

231 217 209 197 118 85 76 65 49 41 40 40 31 22 19 19 13 8 8 8 5 2 2 1 1 1

232 209 175 149 75 41 31 20 17 11 7 7 7 4 4 3 3 3 2 1 1 1 1 1 1 0

Statistically significant prolongation in PFS time vs BSC alone1,2

The recommended dose of Vectibix® is 6 mg/kgadministered over 60 minutes (for doses over1000 mg infuse over 90 minutes) as an intravenous infusion every 14 days1

The use of premedication was not standardized in clinical trials (the utility of premedication in preventing infusional toxicity is unknown)1

~1% incidence of severe infusion reactions reported1

- See Important Safety Information includingBoxed WARNINGS for infusion reactions

Infusionreactions

Q2Wdosing

ProlongedPFS

clinical oncology news - january 2010 - digital edition

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