clinical oncology news - December 2011, digital edition hematology edition

Independent News on Advances in Cancer Care

Hematology/Oncology Edition clinicaloncology.com • December 2011 • Vol. 6, No. 12

SOLID TUMORS

4

Using nononcologic drugs to reduce cancer recurrence risk.

Maurie Markman, MD

6 7

Aflibercept improves survival in metastatic colon cancer.

New data fuels excitement for

14

new breast cancer drug T-DM1.

Commentaries on the latest news from the journals.

FDA NEWS

7

Cetuximab gets new indication.

New mammography technology approved.

PRN

11

Improving end-of-life discussions with cancer patients.

12

Clinical Conundrums: a quiz for the practicing oncologist.

HematOlogic DISEASE

26

Study investigates secondary malignancies in multiple myeloma and MGUS.

28

Evidence mounts for bisphosphonate use in multiple myeloma.

29

First JAK inhibitor approved for myelofibrosis.

AVAPERL Trial Tests NSCLC Maintenance Regimens

Leukemia Survival Lower in Minority Patients Than in Whites

Stockholm—Progression-free survival (PFS) in patients with metastatic non-small cell lung cancer (NSCLC) improved by almost 50% when pemetrexed was added to maintenance therapy with bevacizumab, according to an interim analysis of the AVAPERL trial.

At the recent European Multidisciplinary Cancer Congress, researchers reported that median PFS increased from 6.6 months in patients receiving bevacizumab (Avastin, Genentech) alone to 10.2 months when pemetrexed (Alimta, Eli Lilly) was added (abstract LBA34). When evaluated from the end of induction therapy, PFS was doubled with the combination compared with

Wa s h i n g t o n — A l t h o u g h blacks and Hispanics have lower rates of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) than whites, they are as much as 46% more likely to die from these malignancies, according to a study by Stanford University researchers. The investigators presented their findings at the American Association for Cancer Research’s Fourth Conference on the Science of Cancer Health Disparities (abstract A82).

According to B. Douglas Smith, MD, associate professor of oncology, Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer

see AVAPERL, page 11 

Vogl, New York…

Maximizing Fertility In Breast Cancer Patients: Part 2 • Fertility is important to young women with breast cancer and their families.

• When time and money are available, embryo (and probably oocyte) freezing offers 25% to 34% chance of pregnancy later (with occasional 60% success rates reported).

• Of all the adjuvant drugs to which breast cancer patients are exposed, cyclophosphamide is clearly the major cause of later amenorrhea and sterility.

• Cyclophosphamide can be deleted from the chemotherapy regimen with little or no loss of anticancer see FERTILITY, page 8 

see MINORITIES, page 25 

POLICY & MANAGEMENT

What Is in Store for 2012?

It’s Not Just Medicare Changes

O

ncology is the service line on the top of the list for many insurers who are exploring every avenue to lower their costs.

Employers are intensifying pressure on their insurance partners and their employees to reduce costs. New drugs are more expensive and drug shortages are making many less expensive drugs impossible to find. Consumers

have less money and are required to pay more. States increasingly are cutting or capping Medicaid expenditures. It looks like 2012 is going to be another year in hell.

The insurance market is moving forward with change. In addition to passing larger copays on to employers and consumers, new benefit designs are emerging. One see IN STORE, page 30 

McMahonMedicalBooks.com Hematology and Transfusion Medicine Board Review Made Simple Tony N Talebi, MD, Joseph D Rosenblatt, MD

See page 27.

FDA News Ruxolitinib (Jakafi, Incyte) approved for myelofibrosis.

See page 29.

Now Approved

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CLINICAL ONCOLOGY NEWS

Clinical Oncology News • December 2011

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center, Penn State University Hershey, PA

Breast Cancer

Prostate Cancer

Susan K. Seo, MD

AEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD

Joseph P. DeMarco, PhD

Memorial Sloan-Kettering Cancer Center New York, NY

Cleveland State University Cleveland, OH

Hematologic Malignancies

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

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Maura N. Dickler, MD

Harry Erba, MD, PhD

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

University of Michigan Ann Arbor, MI

Shaji Kumar, MD Mayo Clinic Rochester, MN

University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Richard Stone, MD

University of Texas, MD Anderson Cancer Center Houston, TX

Leonard Saltz, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer and Sarcoma Ephraim Casper, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic Cancer

Betty Ferrell, RN, PhD

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Policy and Management

Cindy O’Bryant, PharmD University of Colorado Cancer Center Denver, CO

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

Mary Lou Bowers, MBA The Pritchard Group Rockville, MD

Rhonda M. Gold, RN, MSN The Pritchard Group Rockville, MD

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO

Editorial Philosophy Michael J. Fisch, MD, MPH University of Texas, MD Anderson Cancer Center Houston, TX

Steven Vogl, MD Medical Oncologist New York, NY

Genitourinary Cancer Ronald M. Bukowski, MD

Oncology Nursing

Pharmacy

Edward Chu, MD

Cathy Eng, MD

Bioethics

Michael A. Carducci, MD

Jennifer R. Brown, MD, PhD

Gastrointestinal Cancer

Infection Control

Symptom Control and Palliative Care William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

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

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

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

Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Lung, and Head and Neck Cancers Edward S. Kim, MD University of Texas, MD Anderson Cancer Center Houston, TX

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

Steven D. Passik, PhD Vanderbilt University Medical Center Nashville, TN

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

Russell K. Portenoy, MD Beth Israel Medical Center New York, NY

Charles F. von Gunten, MD University of California, San Diego, CA

McMahon Publishing is a 39-year-old, family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications.

Clinical Oncology News (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Copyright 2011 McMahon Publishing, New York, NY. All rights reserved.

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

3

4

MULTIPLE CANCERS

Clinical Oncology News • December 2011

Treatment Strategies

Using Non-Oncologic Drugs To Reduce Cancer Recurrence Risk

EDITORIAL BOARD COMMENTARY Maurie Markman, MD Senior Vice President of Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

Cancer prevention and screening strategies are widely appreciated to be critically important public health efforts. Despite the relevance of these approaches in the overall management of malignant disease, however, the complexities associated with proving the effectiveness of any proposed screening or prevention program are well documented.

Consider, for example, the substantial efforts undertaken during the past several decades to demonstrate the utility of an ovarian cancer screening strategy involving routine performance of vaginal ultrasounds and/or measuring CA-125 serum antigen levels. In a recent large national study, investigators discovered that this strategy not only failed to improve disease-specific mortality, but also was associated with causing excessive harm (eg, morbidity associated with unnecessary surgeries).1 The issue of “harm” is particularly relevant in a prevention or screening setting when the individual involved is currently not known to have cancer and may never develop the disease during his or her lifetime. But what about a setting where investigators are examining approaches to prevent cancer recurrence after the completion of primary (eg, surgery, radiation therapy, adjuvant chemotherapy) or even second-line therapy (eg, complete remission to systemic therapy following initial disease recurrence)?

I believe that it is rational to argue that the risk–benefit ratio may be different, with greater risk possibly being justified in an effort to prevent disease recurrence. One can also argue that the absolute “level of evidence” required to consider employing a particular intervention outside the investigative setting (clinical trial) may be less, if the existence of the cancer in the particular individual is not just “possible” but rather “definite.”

So, what if a reported, nonrandomized, population-based retrospective evaluation revealed a highly statistically significant association between the administration of a well-tolerated pharmaceutical agent routinely used for a non-oncologic indication and a

reduced risk for recurrence of a highly fatal malignant condition? And what if a biological explanation could be provided to support the reported observation? The obvious next question is as follows: What level of evidence should be required before it would be considered both scientifically rational and ethical for an oncologist to discuss the particular study results with an individual patient, and, with appropriate informed consent, consider prescribing the medication? The informed consent would, of course, describe the limited evidence of hypothesized clinical benefit and genuine potential risks.

A recent provocative report published in the Archives of Internal Medicine can serve as a case study. 2 This retrospective chart review examined the risk for recurrence in 121 patients with a thick malignant melanoma who either were (n=30) or were not (n=91) taking a betablocker (beta-adrenoceptor antagonist) for at least one year after their skin cancer diagnosis.2 In this admittedly small sample size, there were no “statistically significant” differences between the two patient groups with respect to age, sex, Breslow thickness, tumor location, or presence of ulceration.

The study noted that with a median follow-up of 30 months, the risk for recurrence was substantially greater (34.1% vs. 3.3%; P=0.002) in those individuals who were not taking a b-blocker.2 Furthermore, although there were no deaths among the patients receiving a beta-blocker, 24 deaths were observed in the other subgroup. Additionally, a model developed based on these data suggested a 36% reduction in risk for each year this class of pharmaceuticals was used in this clinical setting.

Finally, it is relevant to note that a reasonable biological rationale can be provided for the observed favorable impact of beta-adrenoceptor antagonists in this clinical setting, including direct inhibition of suggested mediators of stress that in preclinical models have been revealed to have pro-metastatic effects.2-4 The authors of this report very appropriately acknowledge its limitations, including the limited sample size, retrospective nature, and an inability to document whether patients actually took the medications as prescribed. And, as would be anticipated in any such scientific report in a major peer-reviewed journal, the investigators merely concluded that their study results “support conducting larger pharmaco-epidemiologic studies and randomized clinical trials to further investigate whether beta-blockers protect against the progression of malignant melanoma.”1 Let us return to the question advanced earlier in this commentary. In the absence of a contraindication to use this well-tolerated class of pharmaceutical agents in a specific melanoma patient, and in the presence of a disease (malignant melanoma) where recurrence is highly likely to result in death, what is wrong with at least discussing with an individual extended treatment with this drug? A doctor might decide that a single study of this nature should not (by itself ) be sufficient for such an action, but what if a second retrospective analysis reached similar conclusions or quite striking favorable results were observed in a different malignancy?3,4 Would use of the agent

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

be a consideration at this point?

Of course, if the cancer did not recur during long-term follow-up, one would never know if the delivery of a betablocker in this individual had anything to do with this most positive outcome.

However, under these circumstances it is most unlikely that the patient, or anyone directly involved in his or her life and care (family, medical team) will be concerned about the absence of such definitive data.

References 1. Buys SS, Partridge E, Black A, et al. Effect of screening on ovarian cancer mortality: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011;305:22952303, PMID: 21642681.

2. De Giorgi V, Grazzini M, Gandini S, et al.

Treatment with beta-blockers and reduced disease progression in patients with thick melanoma. Arch Intern Med. 2011; 171: 779-781, PMID: 21518948.

3. Melhem-Bertrandt A, Chavez-MacGregor M, Lei X, et al. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer.

J Clin Oncol. 2011; 29:2645-2652, PMID: 21632501.

4. Barron TI, Connolly RM, Sharp L, et al.

Beta blockers and breast cancer mortality: a population-based study. J Clin Oncol.

29:2635-2644, PMID: 21632503.

What are your thoughts?

Clinical Oncology News welcomes letters to the editor.

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

Please send comments to khorty@mcmahonmed.com.

CLINICAL ONCOLOGY NEWS

Clinical Oncology News • December 2011

Letter from the Editor TM

Farewell Dear Readers: Editorial Staff Kevin Horty, Group Editor khorty@mcmahonmed.com Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com James Prudden, Group Editorial Director David Bronstein, Editorial Director Robin B. Weisberg, Manager, Editorial Services Elizabeth Zhong, Associate Copy Chief

This is my last issue as editor of Clinical Oncology News. I am moving back to the Boston area to be closer to my family, so I’m passing the torch to the new chief editor, Kevin Horty.

Kevin has been the editor of General Surgery News, another McMahon publication, for the past 12 years. GSN is the No. 1 book in its market, and I am sure that Kevin will steer Clinical Oncology News in the direction that you would like it to go.

Another managing editor will also be joining the staff. James Prudden has been responsible for the journal commentaries that have run in the last few issues and he will continue this

effort (see pages 14-16, for example).

I’ve loved being editor of this publication, and I have appreciated the input and guidance that many of you have given me over the past five years. I hope to continue to provide you with helpful information, as I will be freelancing for this publication after my departure. If you have suggestions for Clinical Oncology News, please email them to khorty@mcmahonmed.com.

Regards, Kate O’Rourke Editor Clinical Oncology News

Sales Staff Julianna Dawson, Publication Director jdawson@mcmahonmed.com Marlena McMahon, Associate Publication Director marlena@mcmahonmed.com Jessica Pichardo, Junior Account Manager jpichardo@mcmahonmed.com Nancy Parker, Executive Manager/Classified Advertising, nparker@mcmahonmed.com

Art and Production Staff Michele McMahon Velle, Creative Director, MAX Graphics Frank Tagarello, Senior Art Director/ Managing Director, MAX Graphics Dan Radebaugh, Director of Production and Technical Operations Brandy Wilson, Circulation Coordinator Mark Neufeld, Associate Director, Project Management

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What role may MUC1 play in NSCLC

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1. Ahmad R, Raina D, Joshi MD, et al. MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor. Cancer Res. 2009;69(17):7013-7021.

2. Behrens ME, Grandgenett PM, Bailey JM, et al. The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF. Oncogene. 2010;29(42): 5667-5677. 3. Raina D, Kosugi M, Ahmad R, et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther. 2011;10(5):806-816.

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SOLID TUMORS

Clinical Oncology News • December 2011

Colorectal

Aflibercept Improves Survival in Metastatic Colon Cancer Stockholm—Oncologists treating patients with metastatic colorectal cancer (mCRC) may soon have a new weapon in their arsenal, according to results from VELOUR, a multicenter randomized trial.

When combined with chemotherapy, the investigational angiogenesis inhibitor aflibercept (Zaltrap, Sanofi/Regeneron) improved survival in patients with previously treated mCRC. “Adding aflibercept to FOLFIRI chemotherapy in metastatic colorectal cancer patients previously treated with an oxaliplatin-based chemotherapy resulted in overall survival [OS] and progression-free survival [PFS] benefits that are both statistically significant and clinically meaningful,” reported investigator Josep Tabernero, MD, at the European Multidisciplinary Cancer Conference (EMCC; abstract LBA6).

The primary results of this trial were presented at the World Congress of Gastrointestinal Cancer and subgroup analyses were reported at the EMCC. Dr. Tabernero, head of the Medical Oncology Department at Vall d’Hebron University Hospital in Barcelona, Spain, noted that previous exposure to bevacizumab did not significantly affect the safety or efficacy of aflibercept. “Preplanned subgroup analyses supported the consistency and robustness of the efficacy results for aflibercept in all the different subgroups of patients,” including those previously treated with bevacizumab, he said.

For the trial, investigators from more than 30 countries randomized 1,226 patients with mCRC who had progressed after first-line treatment containing oxaliplatin to FOLFIRI plus aflibercept (4 mg/kg IV, day 1, every two weeks) or to FOLFIRI and a placebo. Patients in both groups continued treatment until progression. The primary end point was OS, and key secondary end points included PFS and FOLFIRI plus placebo FOLFIRI plus aflibercept

15

13.5 12.1

Months

6

10

5

0

Figure. Median overall survival.

overall response rate.

After a median follow-up of 22.3 months, there was a statistically significant survival advantage for patients treated with aflibercept and FOLFIRI (hazard ratio [HR], 0.82; P=0.0032).

The primary analysis showed a median OS of 13.5 months in the aflibercept arm and 12.1 months in the placebo arm. PFS data also favored aflibercept (6.9 vs. 4.7 months; HR, 0.76; 95% confidence interval [CI], 0.58-0.99; P=0.00007), as did response rate (19.8% vs. 11.1%; P=0.0001).

The primary objective of the subgroup analysis was to examine the consistency of the aflibercept survival benefit across a variety of patient subgroups, considering Eastern Cooperative Oncology Group (ECOG) performance status (PS), prior bevacizumab treatment, demographics and baseline characteristics.

Analysis of stratification factors showed a similar effect of aflibercept on OS in patients with PS 0, 1 or 2. The investigators observed no significant differences between patients treated with prior bevacizumab and those with no previous exposure to bevacizumab.

The HR among the 30% of the study population that had already been treated with bevacizumab was 0.86, and the HR among the 70% of patients without prior bevacizumab exposure was 0.79 (P=0.723).

Analysis of survival by demographic characteristics revealed a similar benefit for patients younger than age 65 years or age 65 and older, for men and for women, and for patients from all geographic regions represented in the trial. Tests for interaction again confirmed the consistency of the results.

Examination of OS by baseline characteristics showed a similar survival benefit with aflibercept regardless of the location of the primary tumor, as well as whether or not patients had hypertension, liver metastases, or one or more metastatic sites. The analysis showed a slight trend toward improved outcomes with aflibercept in patients with liver metastasis only (HR, 0.65 vs.

0.87; P=0.090).

A similar pattern of consistency emerged from the subgroup analysis of PFS. The only exception was patients whose organ involvement was limited to the liver, because these patients derived significantly greater benefit from treatment with aflibercept (HR, 0.55 vs. 0.84; P=0.008).

VEGF

Aflibercept

Aflibercept (VEGF Trap) is a fusion protein that incorporates portions of human VEGFR1 and VEGFR2, fused to the constant region of human IgG1.

Consistent with the results for OS, PFS did not differ significantly by previous bevacizumab exposure. Patients who had not been previously treated with bevacizumab had a median PFS of 6.9 months with aflibercept versus 5.4 months with placebo. In the subgroup of bevacizumab-treated patients, median PFS was 6.7 months with aflibercept and 3.9 months with placebo. The test for interaction showed no significant differences (P=0.6954).

Invited discussant David Kerr, MD, medical oncologist at the University of Oxford in England, said the “beautifully well-designed and well-powered” trial had “changed the landscape” of second-line therapy for mCRC. However,

he cautioned that this subgroup analysis, like all such analyses, should be considered hypothesis-generating rather than practice-changing. He suggested further research, including secondline studies comparing FOLFIRI plus aflibercept with FOLFIRI plus an antiepidermal growth factor inhibitor, a possible open-access program to generate additional data, as well as evaluation of possible biomarkers to improve patient selection.

—Charles Bankhead Dr. Tabernero reported no relevant disclosures. Dr. Kerr disclosed relationships with AstraZeneca, Genomic Health, GlaxoSmithKline, Merck, and Roche.

Having trouble keeping up with all of the oncology and medical journals that cross your desk?

On a monthly basis, Clinical Oncology News highlights key studies from the journals to help you stay up to date.

We hope you find this a useful tool.

SOLID TUMORS

Clinical Oncology News • December 2011

Breast

Excitement Builds for T-DM1 Stockholm—New results from the first randomized trial evaluating T-DM1 (Genentech) has added fuel to the growing excitement surrounding the drug, which has been billed as a super Herceptin.

Results from the Phase II trial reveal that the antibody-drug conjugate improved median progression-free survival (PFS) by five months in patients with HER2-positive metastatic breast cancer (MBC) when compared with patients given trastuzumab (Herceptin, Genentech) and docetaxel. The study was reported at the recent European Multidisciplinary Cancer Congress (EMCC; abstract 5001).

DMI

Thioether Linker

Trastuzumab

Genentech is so confident in its novel approach that it has 12 antibodydrug conjugates in current trials. Others share the company’s excitement. “I believe that T-DM1 is the magic drug for oncology. It is the drug that we have been waiting for, for many years. It is a clever drug. It brings the cytotoxic agent inside the cancer cell,” said Martine Piccart-Gebhart, MD, PhD, of the Jules Bordet Institute in Brussels, Belgium. She served as the discussant for the study at EMCC. T-DM1 combines the biological HER2-targeted properties of trastuzumab with an anti-microtubule derivative of maytansine called DM1. This highly potent chemotherapy was developed in the 1980s, but was so toxic that it could not be used in patients. T-DM1 selectively delivers DM1 to HER2-positive tumor cells; DM1 is released within

Table. Comparison of Adverse Events Trastuzumab Plus Docetaxel, %

T-DM1, %

Any grade ≥3 AE

89.4

46.4

AEs leading to discontinuation of any study treatment

28.8

7.2

Neutropenia, any grade

63.6

17.4

Neutropenia, grade ≥3

60.6

5.8

Thrombocytopenia, any grade

6.1

30.4

Leukopenia, grade ≥3

25.8

0

Alopecia, any grade

66.7

4.3

Diarrhea, any grade

45.5

15.9

Peripheral edema

43.9

10.1

Increased AST

6.1

39.1

the tumor cell and thus spares healthy tissue. “The magic of this molecule is the linker, which is stable; it is not releasing the chemotherapy until the T-DM1 is internalized within the cell,” said Sara Hurvitz, MD, director of the Breast Oncology Program, Division of Hematology/Oncology, University of California, Los Angeles. She presented the results at EMCC. The Phase II study included 137 patients with HER2-positive MBC who had not received previous chemotherapy for their disease. Patients were randomized in a 1-to-1 fashion to receive T-DM1 3.6 mg/kg IV every three weeks until disease progression or trastuzumab 6 mg/kg IV (8 mg/kg in cycle 1) plus docetaxel 75 or 100 mg/m 2 IV on day 1 every three weeks. Patients were treated until disease progression, and patients in the traditional therapy arm were allowed to cross over to the T-DM1 arm at disease progression.

Characteristics, such as performance status, were well balanced between arms.

Nearly one-third of patients had de novo MBC; 17.9% of the patients in the T-DM1 arm had received previous trastuzumab therapy compared with 27.1% in the traditional therapy arm. Tumor assessments were conducted every nine weeks, and responses were categorized using the Response Evaluation Criteria in Solid Tumors guidelines.

The data presented at EMCC was collected prior to any patients in the traditional arm crossing over to the experimental therapy. The median PFS was 9.2 months in the trastuzumab plus docetaxel arm and 14.2 months in the T-DM1 arm (hazard ratio, 0.594; P=0.0353). The objective response rate (64.2% [T-DM1] vs. 58%) and clinical benefit rate (74.6%

[T-DM1] vs. 81.2%) were similar between the treatment arms. Thus, investigators said that PFS benefits were most likely caused by the fact that T-DM1 was extremely well tolerated and patients could stay on therapy longer (Table).

The median duration of treatment was 10 months with T-DM1, 8.1 months with trastuzumab and 5.5 months with docetaxel. “In the control arm, at the time of data cutoff, 21% of patients were continuing treatment compared to 43% of patients in the T-DM1 arm,” said Dr. Hurvitz. The median duration of objective response was 9.5 months in the trastuzumab plus docetaxel arm and had not been reached in the T-DM1 arm.

Quality-of-life data will be presented in a poster at the San Antonio Breast Cancer Symposium.

Dr. Piccart-Gebhart pointed out that if the trial were conducted today, presumably more patients would be exposed to adjuvant trastuzumab. She said that “it is very clear that the safety profile of T-DM1 is far better than docetaxel and trastuzumab,” but the discontinuation rate for the traditional therapy arm was higher than what has been previously reported in the literature. The control arm in the trial also

seemed “to do a little less well than the previous studies reported so far.

“I think this is a study showing very important and exciting results, but we need validation in a large Phase III trial,” said Dr. Piccart-Gebhart. “It will be very interesting to start working on biomarkers predicting the activity of T-DM1.”

Three Phase III trials of T-DM1 are currently underway: EMILIA (Trastuzumab-MCC-DM1 vs Capecitabine + Lapatinib), MARIANNE (3 arm study: Trastuzumab-DM1 Plus Pertuzumab Versus T-DM1 alone versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer) and NCT01419197 (compares T-DM1 with therapy of a physician’s choice). EMILIA is expected to report data during 2012.

“This drug will hopefully be available for our patients in the not too distant future,” Dr. Piccart-Gebhart said.

Treatment of REcurrent or MEtastatic Head and Neck Cancer). This Phase III open-label, randomized, multicenter, controlled trial was conducted outside the United States by Merck KGaA, Darmstadt, Germany, and used the European

Union (EU)-approved version of cetuximab, instead of the U.S.-approved formulation. The FDA-approved version provides approximately 22% higher exposure than the EU version. In the trial, cetuximab plus chemotherapy significantly extended patients’ median overall survival by 36%, compared with patients who received chemotherapy alone (10.1 vs. 7.4 months, respectively; hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.64-0.98; P=0.034]. Cetuximab plus chemotherapy also significantly increased median progressionfree survival by 67% (5.5 vs. 3.3 months, respectively; HR, 0.57; 95% CI, 0.46-0.72;

P<0.0001), compared with chemotherapy alone. The trial also identified a significant improvement in objective response rate (36% vs. 20%; odds ratio, 2.33; 95% CI, 1.50-3.60; P=0.0001).

Cetuximab comes with a boxed warning regarding infusion reactions and cardiopulmonary arrest. Serious infusion reactions occurred with use of the drug in approximately 3% of patients in clinical trials, with fatal outcomes reported in less than 1 in 1,000. Health care providers should immediately interrupt and permanently discontinue cetuximab infusion for serious

AE, adverse event; AST, aspartate aminotransferase

—Kate O’Rourke Dr. Hurvitz disclosed receiving a travel grant from Roche/Genentech for scientific presentations and receiving research grants from Genentech and Sanofi. Dr. Piccart disclosed serving as an advisor or consultant for Boehringer Ingelheim, GlaxoSmithKline, Roche and Pfizer.

FDA NEWS

Cetuximab Gets New Indication In Head and Neck Cancer

T

he FDA has approved cetuximab (Erbitux, Bristol-Myers Squibb) in combination with platinum-based chemotherapy with 5-fluorouracil, for the first-line treatment of recurrent locoregional or metastatic squamous cell carcinoma of the head and neck (SCCHN).

This is the first treatment regimen approved in 30 years with extended overall survival in patients with recurrent locoregional or metastatic SCCHN, according to the drugmaker.

Approval was based on data from the EXTREME trial (ErbituX in First-line

see CETUXIMAB, page 17 

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SOLID TUMORS

Clinical Oncology News • December 2011

Breast

FERTILITY continued from page 1 

activity, and with major reduction in amenorrhea.

• We, as an oncology community, need to learn how to optimally schedule other drugs without giving cyclophosphamide.

• We need to learn how large a proportion of young women desiring pregnancy will succeed in bringing a pregnancy to term after receiving adjuvant chemotherapy without cyclophosphamide.

This is the second of 2 editorials on preservation of fertility in young women with breast cancer. In the first part, I concurred with the experts that gonadal protection with gonadotropin agonist/ antagonists is interesting but that its benefits have been inconsistent. I addressed the major problem of loss of fertility during 5 years of adjuvant tamoxifen due to normal ovarian aging, and argued for delayed or interrupted tamoxifen to allow pregnancy. (The latter is the subject of a planned international study.) In this editorial, I would like to address directly the issue of sterility caused by adjuvant chemotherapy.

Maintenance of fertility is very important to young women and their families.1 As I argued in the first editorial, a major part of the problem is the decline in fertility with increasing age, so that the monthly likelihood of pregnancy from unprotected intercourse at age 38 years is one-fourth of that in women younger than 30,2 and it falls precipitously at about age 40 (Figure). If chemotherapy accelerates this process just a little, even if monthly

menses continue, most of our young patients will be unable to conceive.

Recent results from oocyte cryopreservation (for women without suitable partners) have improved such that they are sometimes comparable to those of embryo cryopreservation (the standard for women with a fertile partner whom they would like to father their next child). Rates as high as 60% for successful pregnancy and term delivery3 have been reported for each procedure. Unfortunately, results from large collected series have been less encouraging: In 2006, rates of live birth from frozen embryo transfers fell from 34% in women under 35 years to 25% in those aged 38 to 40 and 21% in those aged 41 to 42.4 Hopefully, the promising results from small series with both oocyte and embryo cryopreservation will become more common as experience increases.

However, techniques of oocyte and embryo harvest require considerable time and treatment to induce ovulation and to harvest the ova. Time, effort, and attention are often precious in the setting of newly diagnosed breast cancer.

It is difficult to stop all treatment while ovulation is induced and eggs are harvested. Worse, because oocyte harvest is expensive, insurance companies—if they pay at all—will likely delay the procedure while they review it. If they do not pay, a procedure that costs $30,000 cash for a single harvest cycle will be out of reach for most young women with breast cancer, no matter how much they want to bear children later.

A simpler, cheaper, generally available path to avoid chemotherapy-induced infertility begs exploration: Avoid drugs with gonadal toxicity! I once suggested

Follicle Number

this to Kutluk Oktay, MD, FACOG, a reproductive gynecologist well known for his work with cancer patients, and he replied, “If you [oncologists] stop giving cyclophosphamide, I am out of business,” implying that few cancer patients would become infertile if they did not receive cyclophosphamide.

Evidence that alkylating agents cause sterility in men and women is very strong,5 and it seems that lower doses of cyclophosphamide given for shorter periods cause a lower rate of immediate amenorrhea and sterility. Although I do not know of any data suggesting that lower doses and shorter courses of cyclophosphamide will delay the onset of premature menopause in women whose menses recover after chemotherapy, this may well be the case. Both lower nadir white blood cell counts during FEC (5-fluorouracil [5-FU], epirubicin, and cyclophosphamide) chemotherapy6 and host polymorphisms that lead to altered cyclophosphamide metabolism7 increase the rate of amenorrhea after cyclophosphamide, presumably reflecting more host exposure to metabolites toxic to the ovaries.

Cyclophosphamide is an important component of effective adjuvant chemotherapy—adding this drug to methotrexate and 5-FU in women younger than 50 years increased 5-year disease-free survival from 72% to 84% in NSABP B-19.8 How much of this benefit is an endocrine effect from the gonadal toxicity reducing estrogen secretion in women with estrogen receptor (ER)-positive cancers is still unclear. However, we seem to be able to substitute other drugs with little loss of benefit in modern studies: Doxorubicin and docetaxel (AT) were equivalent adjuvant therapy to doxorubicin and

Optimal fertility Decreased fertility

1,000,000

End of fertility

Birth

1,000,000

Irregular cycles

10,000

1,000 0

18

31

37

Age, y

41

45

51

Menopause

Figure. The declining oocyte/follicle pool according to Faddy et al. and the corresponding reproductive events.

Reprinted from reference 2, with permission from the European Society of Human Reproduction and Embryology.

Faddy MJ, Gosden RG, Gougeon A, et al. Accelerated disappearance of ovarian follicles in mid-life : implications for forecasting menopause.

Human Reprod 1992;7(10):1342-1346, PMID: 1291557.

EDITORIAL BOARD COMMENTARY Steven Vogl, MD Medical Oncologist, New York City

cyclophosphamide (AC),9 and doxorubicin with paclitaxel followed by weekly paclitaxel was equivalent to AC followed by paclitaxel.10 The patients in these 2 large studies had low rates of relapse, so there was plenty of opportunity to detect a decrement in regimen efficacy by substituting a taxane for cyclophosphamide. However, all women with hormone receptor (HR)-positive tumors in these trials were told to take tamoxifen for a full 5 years. The efficacy of tamoxifen could have blunted any decrement in distant relapse–free survival from deletion of cyclophosphamide.

NSABP B-30 is the most important study looking at the deletion of cyclophosphamide from modern adjuvant chemotherapy because of its large size, and thanks to the efforts of Ganz, Swain and their co-workers, it was the first to specifically gather information on menstrual function. This trial gave 5,351 node-positive women either 4 cycles of doxorubicin, cyclophosphamide, and docetaxel (ACT), 4 cycles of AT, or 4 doses of AC followed by 4 doses of docetaxel (T). Overall 8-year survival was 79% for AT and ACT, and 83% for AC followed by docetaxel.11 Distant metastases, whose prevention is the goal of adjuvant chemotherapy, occurred by 8 years in 16% of women on AT, 15% of those on ACT, and 12% of those on AC followed by docetaxel.

The almost identical results with AT and ACT suggest that cyclophosphamide could be deleted with little loss of efficacy. The BCIRG-005 trial just published12 found no difference in outcome between 3,300 women assigned to either 6 cycles of ACT or 4 cycles of AC followed by docetaxel, suggesting that both 4-cycle arms in the NSABP B-30 study were inferior, at least in part, because too few cycles of chemotherapy were given. Presumably, giving 6 cycles of AT would come close to the efficacy of 6 cycles of ACT, which the BCIRG trial showed to be equivalent to AC x 4 followed by T x 4.

In a separate paper from the same study, Ganz reported that the AT regimen produced only a 20% incidence of amenorrhea one year after chemotherapy finished among premenopausal participants. About half of the amenorrhea seemed to be reversible in women diagnosed under age 40 years.13 What we are missing is information on how many of these 80% or 90% of menstruating

9

SOLID TUMORS

Clinical Oncology News • December 2011

Breast

women diagnosed under age 40 wanted to become pregnant, how many succeeded, and when their eventual menopause ensued. It seems we will never have these data from this study.14 I do not mean to imply that chemotherapy drugs other than cyclophosphamide are free of ovarian toxicity, just that they seem to have much less ovarian toxicity, and that we need to explore both how effective they are at preventing breast cancer relapse and how gentle they are to remaining ovarian function.

If we choose to delete alkylating agents from adjuvant chemotherapy in an effort to preserve ovulation and fertility, what drugs can we safely give that are established as effective adjuvant chemotherapy drugs for breast cancer?

The literature on this issue is very difficult to interpret. First, it concentrates on rates of amenorrhea, when fertility is the end point of most interest, at least to me and to the young breast cancer patient who wants to conceive. Second, it largely consists of retrospective studies lumping together different chemotherapy programs not by the dose, route, duration, and frequency of cyclophosphamide (the drug most toxic to the ovary), but by whether anthracycline or taxane was given in addition.

In some reports, taxanes seemed protective, perhaps because (at least in France and Spain) when docetaxel was given after FEC, fewer doses of FEC were given, and thus fewer doses of cyclophosphamide. This literature was reviewed in 1996, 15 2006,16 and 2011.17 I think we can only usefully learn about fertility effects of other drugs when no alkylator was given.

Methotrexate and 5-FU have long been thought to be compatible with full return of ovarian function. Although data for methotrexate seem secure from the adjuvant sarcoma literature,18 those for 5-FU are sparse. The only North American data I could find indicated that among 57 women with resected breast cancer treated with methotrexate and 5-FU by Melody Cobleigh, MD, only 14% had amenorrhea 12 months after treatment finished.19 The NSABP treated large numbers of women in study B13 with the same regimen of methotrexate and 5-FU used by Cobleigh, but reported no data that I could find on menses after chemotherapy.20 An early study from Japan describing the very high rate of amenorrhea after adjuvant cyclophosphamide included a description of no amenorrhea among 9 women given 5-FU monotherapy.21 A report from Peking (Beijing) indicated that there was normal fertility after 5-FU given for gestational trophoblastic disease,22 but the number treated and the doses given were not stated in the paper.

Young women given doxorubicin and vinblastine for Hodgkin’s lymphoma23

and vinblastine and cisplatin for ovarian germ cell tumors24 have high rates of ovulation and pregnancy after chemotherapy. One review concluded that cumulative cisplatin doses less than 400 mg/m2 are not toxic to the ovaries, but those greater than 600 mg/m2 are indeed quite toxic.25 Docetaxel (given with doxorubicin) is probably not very toxic to ovarian function, according to NSABP B30, as noted earlier. Excellent opportunities were missed to determine gonadal toxicity in patients not given cyclophosphamide in recent randomized

trials evaluating docetaxel,9 paclitaxel,10 as well as docetaxel, carboplatin, and trastuzumab (Herceptin, Genentech).26 Among other possible drugs to employ, cisplatin in moderate doses and vinblastine probably spare gonads, but they have not been shown to be effective adjuvant drugs for breast cancer.

Vinorelbine plus epirubicin had little gonadal toxicity in a small Chinese report,27 but vinorelbine was inferior to docetaxel in the Finher study.28 Gemcitabine lacks data both for effect on ovarian function and for adjuvant benefit in breast cancer. I cannot find

published data on gonadal toxicity of paclitaxel given without an alkylator.

The only drugs that meet criteria for efficacy as breast adjuvants and complete or near-complete sparing of menstrual function are doxorubicin, docetaxel, methotrexate, and 5-FU.

Proposal for Gonadal-Sparing Adjuvant Chemotherapy It is fairly clear that we can spare menstrual function. What is not clear is that we can achieve sufficient rates of pregnancy and full-term delivery to see FERTILITY, page 10 

Op en En For rol lme n

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Clinical Trial developed as a collaborative project by:

Advertisement is supported by:

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SOLID TUMORS

Clinical Oncology News • December 2011

Breast

FERTILITY continued from page 9 

justify altering chemotherapy and perhaps compromising patient survival to some extent by doing so. This needs to be studied prospectively among women who want to get pregnant after their chemotherapy is finished.

Therefore, I suggest recruiting women at diagnosis less than 39 years old, who very much want to become pregnant in

explain the risks that the chosen chemotherapy might prove somewhat inferior to current standard regimens, and that tamoxifen delay or interruption might allow or hasten appearance of metastases.

If I were writing the study, in an effort to minimize recurrence risk to the patient, I would insist on a commitment from the HR-positive women to start or resume tamoxifen after an 18-month attempt at pregnancy in the absence of success, and in the puer-

I suggest recruiting women at diagnosis less than 39 years old, who very much want to become pregnant in the near future, to studies using gonadal-sparing chemotherapy. the near future, to studies using gonadal- perium if pregnancy is successful (forsparing chemotherapy, especially if bidding breast feeding because of toxthe women cannot undergo oocyte or ic tamoxifen metabolites in the milk). I embryo harvest and cryopreservation recognize that such commitments canfor medical, cost, availability, timing, or not be enforced, but forcing the patient insurance reasons. Those younger than to commit in writing before entry will 36 years with HR-positive tumors might at least ensure that the issues will be be suitable for chemotherapy followed considered at a time when the patient by shortened tamoxifen, 29 whereas is somewhat calm and hopeful about those aged 36 to 39 would probably lose conception. all fertility during 2 years of tamoxifen, The end point of the study should and if they really want to conceive in be viable infants with mothers free of vivo, should consider deferring tamox- breast cancer. Assuming that about 25% ifen until after pregnancy or until the of women drop out because of social attempt at pregnancy is abandoned. reasons, loss of partner, breast cancer Lower-risk patients could be treat- relapse, comorbid illness, or the like, ed with doxorubicin, 5-FU, and meth- I would count 150 viable babies with otrexate (a combination used in the mothers free of breast cancer among 1990s before consolidation with alkyl- the 450 women trying to become pregator-based high-dose chemotherapy nant to be a positive result worthy of and stem cell rescue)30 and higher risk further study and broader application. patients with these 3 drugs followed The confidence limits for the pregnanby docetaxel for 4 doses over 12 weeks. cy rate in each of the three groups of 150 Alternatively, all patients could be women will be quite narrow. given AT for 6 cycles, perhaps followed More study would be needed in ranby several months of methotrexate domized trials to define the extent of and 5-FU. increased relapse risk compared with I propose a study in which 200 standard chemotherapy and immedipatients younger than 39 years with ate tamoxifen for 5 years followed by 5 HR-negative tumors are treated with years of an aromatase inhibitor, because gonadal-sparing chemotherapy only, almost all these women will become 200 patients younger than 36 years postmenopausal by the time they have with HR-positive tumors are treated completed 5 years of tamoxifen. The with gonadal-sparing chemotherapy risks of these efforts to the prospective followed by tamoxifen which is inter- mothers are unlikely to be major, and rupted after 2 years, and 200 patients are ethically justified in my judgment aged 36 to 39 with HR-positive tumors by the potential fulfillment of the lives are treated with gonadal-sparing che- of the mothers and the creation of the motherapy and have tamoxifen delayed lives of the offspring. for 18 months while they attempt to I sincerely hope that whoever get pregnant. The consent form must designs, conducts, and analyzes such a study (whether or not it meets the criteria of success I just outlined) gets it What are your thoughts? published in The New England Journal Clinical Oncology News of Medicine, gets an endowed chair, and welcomes letters to the editor. gets high-priority scores on his or her Do you have thoughts on grant applications, in addition to the Dr. Vogl’s commentary? deserved thanks of the mothers who Please send comments to were fulfilled by raising a family and the khorty@mcmahonmed.com. much-desired children who come into being as a result of these efforts.

References

14. Ganz P. Personal communication.

1. Partridge AH, Gelber S, Peppercorn J, et al. Web-based survey of fertility issues in young women with breast cancer. J Clin Oncol. 2004;22(20):4174-4183, PMID: 15483028.

15. Bines J, Oleske DM, Cobleigh MA, et al.

Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol. 1996;14(5):17181729, PMID: 8622093.

2. teVelde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update. 2002;8(2):141-154, PMID: 12099629.

16. Walshe JM, Denduluri N, Swain SM. Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol. 2006;24(36):5769-5779, PMID: 17130515.

3. Hodes-Wertz B, et al. Retrospective analysis of outcomes following transfer of previously cryopreserved oocytes, pronuclear zygotes and supernumerary blastocytes.

Reprod BioMed Online. 2011;23(1):118-123, PMID: 21550305.

4. Lee C, Gray J, Han HS, Plosker S. Fertility and reproductive considerations in premenopausal patients with breast cancer.

Cancer Control. 2010;17(3):162-172, PMID: 20664513.

5. Warne GL, Fairley KF, Hobbs JB, Martin FI. Cyclophosphamide-induced ovarian failure. N Engl J Med. 1973;289(22):11591162, PMID: 4754963.

6. Rosendahl M, Ahlgren J, Bergh J, et al.

The risk of amenorrhoea after adjuvant chemotherapy for early stage breast cancer is related to inter-individual variations in chemotherapy-induced leukocyte nadir in young patients: data from the randomised SBG 2000-1 study. Eur J Cancer.

2009;45(18):31983204, PMID: 19818599.

7. Takada K, Arefayene M, Desta Z, et al. Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis. Arthritis Rheum. 2004;50(7):2202-2210, PMID: 15248218.

8. Fisher B, Dignam J, Mamounas EP, et al. Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol.

1996;14(7):1982-1992, PMID: 8683228.

9. Goldstein LJ, O’Neill A, Sparano JA, et al.

Concurrent doxorubicin plus docetaxel is not more effective than concurrent doxorubicin plus cyclophosphamide in operable breast cancer with 0 to 3 positive axillary nodes: North American Breast Cancer Intergroup Trial E 2197. J Clin Oncol.

2008;26(25):4092-4099, PMID: 18678836.

10. Loesch D, Greco FA, Senzer NN, et al. Phase III multicenter trial of doxorubicin plus cyclophosphamide followed by paclitaxel compared with doxorubicin plus paclitaxel followed by weekly paclitaxel as adjuvant therapy for women with high-risk breast cancer. J Clin Oncol. 2010;28(18):2958-2965, PMID: 20479419.

11. Swain S, Jeong J-H, Geyer CE, et al. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 2010;362(22):2053-2065, PMID: 20519679.

12. Eiermann W, Pienkowski T, Crown J, et al.

Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol.

2011;29(29):38773884, PMID: 21911726.

13. Ganz PA, Land SR, Geyer CE Jr, et al.

Menstrual history and quality-of-life outcomes in women with node-positive breast cancer treated with adjuvant therapy on the NSABP B-30 trial. J Clin Oncol.

2011;29(9):1110-1116, PMID: 21300930.

17. Fleischer R, et al. The effects of chemotherapy and radiotherapy on fertility in premenopausal women. Obstet Gynecol Surv.

2011;66(4):248-254, PMID: 21756407.

18. Shamberger RC, Rosenberg SA, Seipp CA, Sherins RJ. Effects of high-dose methotrexate and vincristine on ovarian and testicular functions in patients undergoing postoperative adjuvant treatment of osteosarcoma.

Cancer Treat Rep. 1981;65(9-10):739-746, PMID: 6791818.

19. Cobleigh MA, Bines, J. Lincoln, RT, et al.

Amenorrhea following adjuvant chemotherapy for breast cancer. Proc Am Soc Clin Onc. 1994;13:63. Abstract 55.

20. Fisher B, Redmond C, Dimitrov NV, et al. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with nodenegative breast cancer who have estrogenreceptor-negative tumors. N Engl J Med. 1989;320(8):473-478, PMID: 2644531.

21. Koyama H, Wada T, Nishizawa Y, Iwanaga T, Aoki Y. Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer.

Cancer. 1977;39(4):1403-1409, PMID: 85190.

22. Song HZ, Yang XY, Xiang Y. Forty-five years’ experience of the treatment of choriocarcinoma and invasive mole. Int J Gynaecol Obstet. 1998;60(suppl 1):S77-S83, PMID: 9833619.

23. Bonadonna G, Bonfante V, Viviani S, Di Russo A, Villani F, Valagussa P. ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin’s disease: long-term results. J Clin Oncol.

2004;22(14):2835-2841, PMID: 15199092.

24. Parkinson CA, Hatcher HM, Earl HM, Ajithkuma TV. Gynecol Oncol.

2011;121(3):625-636, PMID: 21353692.

25. Wallace WH, Shalet SM, Crowne EC, Morris-Jones PH, Gattamaneni HR, Price DA. Gonadal dysfunction due to cis-platinum.

Med Pediatr Oncol. 1989;17(5):409-413, PMID: 2507885.

26. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2positive breast cancer. N Engl J Med. 2011;365(14):1273-1283, PMID: 21991949.

27. Zhou WB, Yin H, Liu XA, et al. Incidence of chemotherapy-induced amenorrhea associated with epirubicin, docetaxel and navelbine in younger breast cancer patients. BMC Cancer. 2010;10:281, PMID: 20540745.

28. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006;354(8):809-820, PMID: 16495393.

29. Pagani O, Partridge A, Korde L, et al.

Pregnancy after breast cancer: if you wish, ma’am. Breast Cancer Res Treat.

2011;129(2):309-317, PMID: 21698406.

30. Rizzieri DA, Vredenburgh JJ, Jones R, et al. Prognostic and predictive factors for patients with metastatic breast cancer undergoing aggressive induction therapy followed by high-dose chemotherapy with autologous stem-cell support. J Clin Oncol.

1999;17(10):3064-3074, PMID: 10506601.

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Lung

continued from page 1 

bevacizumab monotherapy.

“This is a benefit of unprecedented magnitude,” said Fabrice Barlesi, MD, a thoracic oncologist at the University of the Mediterranean in Marseille, France, who presented the data. “Overall survival [OS] data favor maintenance therapy with bevacizumab and pemetrexed, but the data are currently immature. The results strongly favor the use of bevacizumab plus pemetrexed as continuation maintenance therapy in patients with [biologically] nonselected metastatic non-small cell lung cancer.”

The rationale for the AVAPERL trial came from previous studies that showed pemetrexed maintenance after bevacizumab-based or cisplatin-based induction therapy significantly improved PFS, explained Dr. Barlesi. Moreover, bevacizumab maintenance therapy had been shown to reduce the risk for progression after induction therapy compared with placebo. It was unclear, however, whether combining bevacizumab and pemetrexed in the maintenance phase would increase the benefit.

Investigators at 81 sites in 11 countries enrolled 376 patients with previously untreated metastatic NSCLC. All patients received induction therapy with cisplatin, bevacizumab and pemetrexed, and those who had an objective response or stable disease were randomized to maintenance therapy with

bevacizumab alone or in combination with pemetrexed.

Dr. Barlesi reported that 253 patients met the post-induction criteria for participation in the randomized phase of the trial. The primary end point was PFS, and main secondary end points were OS, overall response rate, duration of response and duration of disease control.

After a median follow-up of 11 months in patients who received randomized maintenance therapy, the two-drug regimen was associated with a 50% reduction in the risk for progression compared with bevacizumab alone (hazard ratio [HR], 0.50; P<0.001). Data were immature for a definitive analysis of OS; however, a preliminary analysis showed a median time of 15.7 months with bevacizumab maintenance, with the median survival not yet reached in patients randomized to bevacizumab plus pemetrexed.

Analysis of the secondary end points showed that best overall response rate was similar between the groups (50% with bevacizumab and 55.5% with the combination).

Median duration of response was better for the combination therapy (9.2 versus 5.7 months; HR, 0.53; P=0.006).

Patients randomized to the bevacizumab plus pemetrexed maintenance therapy also had a significantly longer median duration of disease control than the bevacizumab group (7.8 vs. 4.9 months; HR, 0.52; P<0.001).

Subgroup analysis revealed consistency in the benefit of maintenance therapy

with two drugs versus one. The data favored the bevacizumab plus pemetrexed arm regardless of patient age, performance status, smoking status, histology and whether induction therapy led to stable disease or an objective response.

The magnitude of the reduction in the risk for progression ranged from 36% to 60% across the subgroups.

Overall, both maintenance regimens were well tolerated, said Dr. Barlesi.

Grade 3-5 hematologic toxicity occurred in 10.4% of patients treated with the combination maintenance regimen compared with none of the patients in the bevacizumab monotherapy arm. Serious adverse events occurred in 1.6% of patients in the combination group.

Grade 3-5 nonhematologic toxicity occurred in 31.2% of patients in the bevacizumab plus pemetrexed arm and 21.7% of patients in the bevacizumab monotherapy arm. Serious adverse events occurred in 16.8% of the combination arm and 13.3% of patients who received only bevacizumab.

The results are impressive, but should be considered with recognition that the trial involved a selected patient population enriched with patients who had not progressed on first-line therapy, according to the discussant for the presentation Rafal Dziadziuszko, MD, PhD, an oncologist at the University of Gdansk, in Poland. Moreover, the trial did not address a key clinical issue.

“Since there are more evidence-based data for maintenance pemetrexed in non-small cell lung cancer than for

15

Maintenance with bevacizumab Maintenance with bevacizumab and pemetrexed

Months

AVAPERL

10.2

10 6.6

5

0

Figure. Progressionfree survival in NSCLC. NSCLC, non-small cell lung cancer

maintenance bevacizumab, I would be more interested in an answer [to] the question of how much bevacizumab adds to pemetrexed,” said Dr. Dziadziuszko. “A pemetrexed-only maintenance arm was needed in the trial.”

Examination of biomarkers to identify patients who might benefit from the maintenance regimen also would have been informative, Dr. Dziadziuszko added.

—Charles Bankhead AVAPERL was supported by F. HoffmannLa Roche. Dr. Barlesi disclosed a relationship with F. Hoffmann-La Roche.

Dr. Dziadziuszko disclosed relationships with Roche, Pfizer, Boehringer Ingelheim, GlaxoSmithKline and AstraZeneca.

PRN Doctor–Patient Communication

Improving End-of-Life Discussions With Your Patients State Laws Aim To Ensure Discussions Occur Months after the New York state legislature enacted a law requiring physicians to offer to discuss palliative and end-of-life care options with their terminally ill patients, palliative care experts say it will require additional time and education before doing so becomes second nature.

The New York Palliative Care Information Act, which took effect last February, states that attending physicians and nurse practitioners must offer to provide terminally ill patients with information and counseling on palliative care and end-of-life options as appropriate.

Providers unwilling or unable to provide such information should transfer their patients’ care to another provider for this information.

Improving Patient Care Although some physicians and the Medical Society of the State of New

York openly objected to the law, saying it intrudes on the physician–patient relationship, David Leven, executive director of Compassion & Choices of New York, an organization that advocates for end-of-life choices and comfort, collaborated with local politicians to write the legislation, saying that “it was desperately needed.”

“We have a serious public health crisis at the end of life when people are overtreated and are more likely to die in hospitals,” he said. “Dying patients often are not informed sufficiently or at all about palliative care or end-of-life

care. … Patients suffer unnecessarily.”

When end-of-life care is discussed, he added, “patients accept their illness better, their pain is relieved and they complete DNR [do not resuscitate] orders by a 2-to-1 margin.” Informed patients also are less likely to be admitted to ICUs, he said, and overall health care costs are reduced.

But New York is not the only state making changes regarding end-of-life care. California passed a similar law in 2009, although it obligates physicians to discuss palliative or end-of-life care information only if patients ask about

it. Eleven states—including Pennsylvania Colorado and Oregon—have Physician Orders for Life-Sustaining Treatment (POLST) paradigm programs, in which physicians can opt to fill out medical orders stating their patients’ preferences for life-sustaining treatment and end-of-life care. An additional 20 states are in the process of developing such programs, according to the POLST Web site.

Reaction to the New York legislation has been mixed. “Physicians are troubled by the law,” Mr. Leven said, “but if see END-OF-LIFE, page 13 

11

12

PRN

Clinical Oncology News • December 2011

Community Oncology

Clinical Conundrums

Prepared by

Syed A. Abutalib, MD Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

A Quiz for the Community Oncologist QUESTIONS

1.

Adjuvant chemotherapy is a reasonable therapeutic option in which of the following patients with endometrial cancer? a. A 55-year-old woman with grade 2, stage 1A disease b. A 58-year-old woman with stage 2 disease with papillary serous histology c. A 60-year-old woman with grade 1, stage 2B disease d. Both a and b

2.

All of the following are established risk factors for the development of endometrial cancer except: a. Atypical hyperplasia b. Progestin c. Obesity d. Unopposed estrogen exposure

3.

The presence of which of the following molecular genotypes is associated with the shortest leukemiafree survival in young adults with normal cytogenetic de novo non-M3 acute myeloid leukemia (AML)? a. Mutated NMP1 with wild-type FLT3 genotype b. Mutated FLT3/ITD genotype c. Wild-type NPM1 and FLT3 genotype d. Both a and b

4.

A 58-year-old man presents with fatigue and shortness of breath. He has pancytopenia. The folate, vitamin B12 levels, and thyroid profile are within normal range. He has excellent performance status, his past medical history

ANSWERS

1.

Answer: b. In endometrial cancer, the issue of postsurgical adjuvant treatment strategies continues to evolve. The patients presented in choices a and c can be closely observed following total extrafascial hysterectomy with bilateral salpingo-oophorectomy and accurate surgical staging, even without radiation therapy. The rate of disease recurrence in this group of patients is less than 10% following the aforementioned diagnostic and therapeutic procedures. The patient in choice b is at a very high risk for recurrence due to presence of high-risk unfavorable histology. The recurrences in this group of patients are often unsalvageable with conventional therapies and, therefore, adjuvant chemotherapy is a reasonable option.

is unremarkable, and he does not drink alcohol. Bone marrow aspiration and biopsy show 5% blasts with some dysplastic features in all 3 cell lines. Cytogenetic analysis demonstrates t(16;16) (p13:q22). According to the World Health Organization (WHO) classification, which of the following is the diagnosis? a. AML b. Myelodysplastic syndrome c. Multiple myeloma d. Acute lymphoblastic leukemia

5.

In the United States, which of the following postremission treatment strategies will most likely be recommended to a 45-year-old woman with de novo non-M3 AML with an inv(16) mutation without c-KIT mutation? a. Hypomethylating agent b. Allogeneic stem cell transplantation c. Repetitive cycles of high-dose cytarabine (HiDAC) d. Autologous transplantation

6.

A 60-year-old man presents with fatigue, generalized weakness, and raised skin lesions. Physical examination revealed splenomegaly. Complete blood counts demonstrated a white blood cell count of 18,000/mcL, with neutrophils and monocytes of 44% and 41%, respectively. His hemoglobin is normal and his platelet count is 84,000/mcL. Bone marrow biopsy demonstrates marked hypercellularity (>90%), grade II fibrosis, and less than 2% myeloblasts, monoblasts, and promonocytes. The cytogenetics

Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial.

PORTEC Study Group. 2000;355(9213):1404-1411, PMID:10791524.

Fader AN, Nagel C, Axtell AE, et al. Stage II uterine papillary serous carcinoma: carboplatin/ paclitaxel chemotherapy improves recurrence and survival outcomes. Gynecol Oncol. 2009;112(3):558562, PMID: 19118888.

2.

Answer: b. Progestins can sometimes be used to treat low-grade, hormone receptor–positive adenocarcinoma of the uterus.

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

Thigpen JT, Brady MF, Alvarez RD, et al. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology

are normal, 46XY. The BCR-ABL fusion gene is not detected by fluorescence in situ hybridization and polymerase chain reaction, but the JAK2 V617F mutation is present. According to WHO classification, which of the following is the diagnosis of this patient? a. Chronic myelomonocytic leukemia (CMML) b. Primary myelofibrosis c. Chronic lymphocytic leukemia d. None of the above

7.

Doxorubicin has broad range of activity in solid and hematologic malignancies. Which of the following statements about this agent is not correct? a. Doxorubicin appears to inhibit an enzyme that requires energy from adenosine triphosphate (ATP) hydrolysis. b. The incidence of congestive heart failure with doxorubicin is from 5% to 8% and 6% to 20% at cumulative doses of 450 and 500 mg/m2, respectively. c. Doxorubicin is a potent vesicant. d. Doxorubicin inhibits topoisomerase I enzyme.

a. They do not encode transcription factors. b. Aberrant microRNA expression is thought to play a role in cancer. c. They can interfere with messenger RNA (mRNA) translation. d. They can collaborate with cellular nucleases to catalyze mRNA destruction.

9.

A 45-year-old woman presents with severe, uncontrollable non-bloody diarrhea. She is dehydrated and has multiple electrolyte abnormalities. She completed cycle 2 of adjuvant chemotherapy for lung cancer 11 days previously and had a similar episode with the first cycle.

Evaluation for an infection has been unremarkable on multiple occasions.

She has failed maximum daily doses of loperamide. Beside IV fluids and electrolyte replenishment, what would you recommended for alleviation of diarrhea? a. Sucralfate b. Glutamine c. Octreotide d. Continued loperamide

10.

All of the following statements about microRNAs are correct except:

In localized prostate cancers, the TMPRSS2:ERG fusion gene causes overexpression of ERG and may have bearing on prognosis? a. True b. False

Group. Clin Oncol. 1999;17(6):1736-1744, PMID: 10561210.

leukemia with a normal karyotype. N Engl J Med. 2005;352(3):254-266, PMID: 15659725.

3.

4.

8.

Answer: b. Evaluation of genetic prognostic markers is extremely important in the evaluation of newly diagnosed AML patients and plays a central role in guiding management strategies. The largest cytogenetic subgroup of AML is normal cytogenetic disease, which is marked by heterogeneous survival. The presence of the mutated FLT3/ITD genotype is associated with significantly greater risk for relapse than is the presence of mutated NMP1 without FLT3 or wild-types of both NPM1 and FLT3.

Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909-1918, PMID: 18450602.

Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous

Answer: a. According to the WHO classification, patients with t(16;16) (p13:q22), t(8;21)(q22;q22), inv(16) (p13q22), and t(17;17)(q22;q12) are classified as having AML, regardless of the blast count.

Swerdlow SH, Campo E, Harris NL, et al, eds. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues.

Lyon, France: IARC Press; 2008.

5.

Answer: c. Patients who do not receive postremission therapy will relapse usually within months after achievement of first complete remission.

Young adults with good-risk cytogenetic group AML are usually recommended to receive 3 to 4 cycles of HiDAC therapy.

Of note, the optimal dose, frequency, and see CONUNDRUMS, page 18 

PRN

Clinical Oncology News • December 2011

Doctor–Patient Communication

END-OF-LIFE

‘At first, I thought [the law] was a terrible idea.

To legally require a doctor to have a conversation with a patient seems noxious. But the truth is many patients die badly.’

continued from page 11 

you look at it critically, it’s just because it’s a mandate, and really a soft mandate, asking physicians to offer to provide information. Patients can decline.”

Nothing in the law states what language physicians need to use or what options should be discussed, he said.

“Everything is discretionary.” For now, no organization is holding physicians accountable for compliance.

Educating Physicians

—Dana Lustbader, MD “Many physicians don’t even know what palliative care is,” Dr. Lustbader said. “Palliative care is medical treatment of pain and symptoms for patients of any age with serious illness at any

Diane E. Meier, MD, director of the Hertzberg Palliative Care Institute at Mount Sinai School of Medicine, in New York City, said one of the biggest challenges is that “physicians are simply not educated about these options.

“Before you can mandate talking to patients about their options, you have to make sure that physicians and nurse practitioners have the knowledge and skill to do that,” Dr. Meier said. “It could be a long time for medical and nursing education and graduate medical education to catch up.”

Dana Lustbader, MD, section head of palliative medicine at North ShoreLong Island Jewish Medical Center, in Manhasset, N.Y., said she has been spending time educating physicians and giving lectures on palliative care and the new law to health care workers, as well as explaining how palliative care differs from hospice care.

MUC1 (mucin 1) is a transmembrane glycoprotein that is normally found on the apical surface of most simple secretory epithelial cells and is associated with a number of diverse cellular functions.1 The functions of the extracellular domain of MUC1 are largely dictated by the extent of its glycosylation.1,2 The cytoplasmic tail of MUC1 can serve as a scaffold for interactions with intracellular proteins that affect cell survival and proliferation and can have direct effects on transcription within the nucleus.1,2

W

ant to learn more about palliative care, how to talk to your patients or find out more about programs in your area? The following Web sites offer resources.

• Center to Advance Palliative Care (resources for building a highquality palliative care team) www.capc.org

Select functions of MUC1 in normal cells • Lubricates epithelial surfaces3 • Acts as a physical barrier against microbes3 • Protects against proteolytic degradation3 • Involved in adaptive immunity against pathogens4 • Mediates normal T-lymphocyte responses and regulates T-lymphocyte proliferation5 • Involved in signal transduction, which regulates cell survival and proliferation2 • Can directly affect transcription within the nucleus1

• Compassion and Support (resources for patients and doctors) www.compassionandsupport.org • Get Palliative Care (resources for patients and family members) www.getpalliativecare.org

110718-140032

• Medical Orders for Life-Sustaining Treatment (MOLST) form, for New York practitioners www.compassionandsupport. org/pdfs/professionals/molst/ DOH-5003_06.10_.FINAL__.pdf

• Physician Orders for LifeSustaining Treatment (POLST) www.polst.org

see END-OF-LIFE, page 18 

What role may MUC1 play in NSCLC

Resources

• The National Hospice and Palliative Care Organization www.nhpco.org

point of the disease trajectory, even at diagnosis,” she said, “while hospice care is palliative care for the final six months of life.”

Dr. Lustbader said she has been

helping physicians identify terminally ill patients who are likely to die within six months, “so a timely referral to hospice can be made and patients and their families get the resources they need.” In Nassau County, where her hospital is based, patients receive an average of 12 days of hospice care before they die, “so they’re not getting the full benefit of resources available to them for home-centered end-of-life care.” Oncology patients see an average of 13 physicians in their final six months of life, she said, so their care can be fragmented.

Overexpression, altered distribution, and aberrant glycosylation of MUC1 have been observed in a variety of cancers, including non-small cell lung cancer (NSCLC).1,2,6 Aberrant overexpression of MUC1 by tumor cells is associated with several mechanisms of tumor cell survival.6-8 Overexpression of MUC1 may play a role in

abnormal cell signaling through interactions with regulatory proteins, such as with EGFR.2,7 In addition, the cytoplasmic tail of MUC1 can be targeted to the nucleus, where it interacts with transcription factors for genes related to invasion, angiogenesis, and metastasis.7,8 Furthermore, cells overexpressing tumor-associated MUC1 may escape the host immune response by suppression of the T-cell proliferation response and by failure to process and present MUC1 on class II major histocompatibility complexes.9,10 At EMD Serono, we’re investigating the significance of MUC1 and its impact on your patients with NSCLC. Visit www.emdserono.com to learn more about EMD Serono Oncology.

1. Hattrup CL, Gendler SJ. Structure and function of the cell surface (tethered) mucins. Annu Rev Physiol. 2008;70:431-457. 2. Bafna S, Kaur S, Batra SK. Membrane-bound mucins: the mechanistic basis for alterations in the growth and survival of cancer cells. Oncogene. 2010;29(20):2893-2904.

3. Carson DD. The cytoplasmic tail of MUC1: a very busy place. Sci Signaling. 2008;1(27):pe35.

4. McAuley JL, Linden SK, Png CW, et al. MUC1 cell surface mucin is a critical element of the mucosal barrier to infection. J Clin Invest. 2007;117(8):2313–2324. 5. Agrawal B, Longenecker BM. MUC1 mucin-mediated regulation of human T cells. Int Immunol. 2005;17(4):391-399.

6. Raina D, Kosugi M, Ahmad R, et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther. 2011;10(5):806-816. 7. Ahmad R, Raina D, Joshi MD, et al.

MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor.

Cancer Res. 2009;69(17):7013-7021. 8. Behrens ME, Grandgenett PM, Bailey JM, et al. The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF. Oncogene. 2010;29(42):5667-5677. 9. Agrawal B, Krantz MJ, Reddish MA, Longenecker BM. Cancer-associated MUC1 mucin inhibits human T-cell proliferation, which is reversible by IL-2.

Nat Med. 1998;4(1):43-49. 10. Hiltbold EM, Vlad AM, Ciborowski P, Watkins SC, Finn OJ. The mechanism of unresponsiveness to circulating tumor antigen MUC1 is a block in intracellular sorting and processing by dendritic cells. J Immunol. 2000;165:3730-3741.

EMD Serono Oncology | Combination is key™

EMD Serono, Inc. is an affiliate of Merck KGaA, Darmstadt, Germany

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Clinical Oncology News • December 2011

Breast

Commentaries on the Latest Studies C ontinuing in this issue is our monthly feature in which the oncologists and hematologist/oncologists at NewYorkPresbyterian Hospital provide insights about recent, published clinical studies of solid tumors, as well as hematologic malignancies. One area of expertise is cancer prevention.

The Herbert Irving Comprehensive Cancer Center and Weill Cornell Cancer Center both offer prevention and screening services as part of NewYork-Presbyterian Hospital’s Cancer Prevention Program. Headed

by Alfred I. Neugut, MD, PhD, at NewYork-Presbyterian/Columbia, and Andrew J. Dannenberg, MD, at NewYork-Presbyterian/Weill Cornell, the Cancer Prevention Program focuses on the fact that early detection of cancer and precancer saves lives and that screening should be incorporated into the practice of routine health care.

Both cancer centers offer a range of prevention and screening services designed to identify cancers early enough to positively affect outcomes. For instance, the Pap smear test, developed at NewYorkPresbyterian/Weill Cornell, has saved countless lives through the many years of its incorporation into routine care. Similar success can be seen with colorectal cancer, whose course of disease can be significantly altered when caught early enough through screening techniques.

The cancer centers at NewYork-Presbyterian Hospital have screening and awareness programs for breast, cervical, colorectal, lung, oral, ovarian, prostate, and skin cancers, among others, and maintain smoking cessation programs.

—James Prudden Group Editorial Director

Retrospective Analysis of ATAC Yields New Breast Cancer Data From Journal of Clinical Oncology

A

mong postmenopausal women with early-stage breast cancer, increased age raises the risk for recurrence, and increased age and comorbidities raise the risk for death even without recurrence, according to a retrospective analysis of the ATAC (Arimidex, Tamoxifen Alone or in Combination) study.

The analysis, published in the Journal of Clinical Oncology (2011;29:42664272) and authored by an international team of researchers from the United States, United Kingdom and Australia, was designed to examine the effects

of comorbidities and age on treatment received, breast cancer–related mortality and competing causes of mortality among patients enrolled in the original ATAC trial. It was based on 10-year follow-up data from the 2 monotherapy arms of the trial: the anastrozole (Arimidex, AstraZeneca) arm (n=3,092) and the tamoxifen arm (n=3,094). The authors compared baseline comorbidities and tumor and treatment characteristics between women aged younger than 70 years and those aged 70 years and older, and they assessed cumulative incidence of breast cancer–related and non–breast cancer–related mortality

EXPERT INSIGHT Preya Ananthakrishnan, MD Assistant Professor of Clinical Surgery Columbia University College of Physicians and Surgeons Breast Cancer Surgeon NewYork-Presbyterian/Columbia

This retrospective analysis of the ATAC trial examines the effects of comorbidities and age on mortality from breast cancer versus that due to other causes.

This analysis enhances the understanding of whether benefits of adjuvant

based on patient age and comorbidities.

The authors found that older women in the ATAC trial were more likely than their younger counterparts to have comorbidities, regardless of treatment approach used; more likely to undergo mastectomy; and less likely to receive radiotherapy or chemotherapy. Tumor characteristics and treatment choices, along with age, influenced risk for disease recurrence.

The 10-year estimated rate of disease recurrence was 26.6% in women 70 years of age and older versus 22.7% in the younger cohort of patients (hazard ratio [HR], 1.21; 95% confidence interval [CI],

1.08-1.37). In older patients who did not experience disease recurrence, the extent to which they suffered from comorbidities associated with early-stage breast cancer and its treatments influenced the risk for death from causes other than the underlying disease. Overall, 51.5% patients aged 70 years and older with a score of 2 or greater on the Charlson Comorbidity Index died without disease recurrence, compared with 26.4% of the patients aged younger than 70 years.

Women aged 70 years and older had a 10-year risk for death without recurrence of 27.1% versus 7.3% in the younger group (HR, 4.13; 95% CI, 3.53-4.83).

therapy outweigh risks in older patients with multiple comorbidities. The median age of patients in this study was 64, and there was a median of 10 years of follow-up. Women 70 and over had an increased risk of death without breast cancer recurrence compared with women younger than age 70. Higher comorbidity scores were associated with increased risk of death from other causes without breast cancer recurrence in women of all ages.

This study adds to the growing body of information illustrating that there is no longer a “one-size-fits-all” approach to cancer treatment. Although there is a great deal of information about the importance of tumor biology in decision making, patient factors such as age and comorbidities are often given less importance. If we can identify older patients who are more likely to die from other causes before breast cancer recurrence, we can potentially avoid subjecting these patients to the toxicities of adjuvant treatment. This study demonstrates that there are well-validated indices for assessing comorbidities, and that they should be routinely incorporated into clinical decision making.

Let Us Visit Your Practice Please consider inviting the staff of Clinical Oncology News to visit your practice. We want to meet you and your colleagues, listen to your concerns, and observe the physical site of your practice.

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

If you are interested, please contact Kevin Horty, group editor, at (212) 957-5300 ext. 262 or via e-mail at khorty@mcmahonmed.com.

SOLID TUMORS

Clinical Oncology News • December 2011

Sarcoma

Role of Isolated Limb Perfusion Still Unclear After Sarcoma Study From Journal of Clinical Oncology

I

solated limb perfusion with tumor necrosis factor-alpha (TNF-α, Boehringer Ingelheim) and melphalan is a viable alternative to amputation in patients with locally advanced soft tissue sarcomas of the extremity, according to a team of European investigators.

In a study published in the Journal of Clinical Oncology (2011;29:4036-4044), researchers from Erasmus MC, in Rotterdam, The Netherlands, and the Institut de Cancérologie Gustave Roussy, in Paris, analyzed 231 isolated limb perfusions in 208 consecutive patients who were candidates for functional

EXPERT INSIGHT Igor Matushansky, MD, PhD Assistant Professor of Medicine and Cell Biology/Pathology Columbia University College of Physicians and Surgeons Division of Medical Oncology, Department of Medicine Herbert Irving Comprehensive Cancer Center NewYork-Presbyterian/ Columbia

Deroose et al presented followup data on 208 patients with locally advanced extremity soft tissue sarcomas treated with TNF-α and melphalan–based isolated limb perfusion, followed by limb-sparing surgery for remaining disease when present and feasible. The median clinical followup, as limited by patient outcomes, was 29 months, although the minimum follow-up was intended to be 5 years. The

or anatomic amputation for locally advanced extremity soft tissue sarcomas between 1991 and 2005. Most of these patients (85%) had intermediate- or high-grade tumors. The researchers, led

by Jan P. Deroose, MD, noted that previously published research has shown that amputation offers no survival benefit in patients with soft tissue sarcomas (Ann Surg 1992;215:269-275).

The researchers performed melphalan-based isolated limb perfusion on the study patients under general anesthesia and mild hyperthermic conditions. When the temperature of the limb reached 38°C, patients were administered bolus injections of 1 to 3 mg (arm)

or 1 to 4 mg (leg) (median, 4 mg) of TNF-α, which has been shown to produce selective destruction of tumor vasculature (Lancet Oncol 2003;4:429-437).

Then, 30 minutes after the limb temperature reached 38°C to 39.5°C, melphalan was administered at a dose of 10 or 13 mg/L of limb volume, for leg and arm sarcomas, respectively (median dose, 70 mg). Limbs were flushed with saline solution and 6% dextran after 90 minutes of perfusion.

The authors reported an overall response rate of 71% and a local recurrence rate of 30% following the procedure. Multifocal sarcomas showed a slightly better overall response rate

(83%; P=0.008) but a higher local recurrence rate (54%; P=0.001) than other sarcomas. Five-year overall survival (OS) was 42% and the overall limb salvage rate was 81%. Patients with larger tumors and leiomyosarcomas had a poorer survival rate.

The investigators emphasized that they do not claim that isolated limb perfusion with TNF-α and melphalan offers a survival benefit in patients with soft tissue sarcomas of the extremity, but they conclude that their study, thought to be the largest long-term study of this treatment modality, supports the use of the strategy as an option for limb salvage and local control in these patients.

safety data presented reaffirm that in the hands of physicians who have expertise with isolated limb perfusion, the latter technique is safe with relatively minimal toxicity. Furthermore, they report an overall response rate of 71% (complete response, 18%; partial response, 53%); even for local therapy, a 71% response rate is noteworthy, although firmly within the range of previous reports of isolated limb perfusion.

The real question—for all solid tumors, not just sarcomas—is this: Does improved local control translate into improved OS? And if not OS— an ideal but often unattainable end point—then what about distant recurrence or metastases (the latter being an obvious surrogate for OS)? Focusing on sarcomas, we know several things: 1) because, as the authors write, there is no survival benefit of amputation for extremity soft tissue sarcomas, limb-sparing surgery has become the gold standard; and 2) more aggressive local control (ie, re-resection of R1 lesions; adjuvant radiation therapy) can decrease local recurrences by more than 50% but does not impact OS.

Thus, despite the 71% response rate, it is not surprising that the reported OS rate (34% at 5 years for high-grade tumors) is well in line with historical data for patients treated solely with surgery and observed until onset of metastatic disease. Thus, is there any benefit to this technique?

The authors state, “In terms of OS, limb-preserving surgery after [isolated limb perfusion with TNF-α and melphalan] is equivalent to amputation. However, local recurrence is more common after limb-preserving surgery.” This may or may not be true as a formal randomized trial has yet to be done, and comparing historical controls can often be misleading. But even if it is true—and to the authors’ credit, they discuss this in some detail—is isolated limb perfusion with TNF-α and melphalan better than neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy? If survival is determined by metastatic disease, and not local recurrence (and in fact the authors demonstrate that for their patients, the two are independent), wouldn’t systemic chemotherapy be

theoretically advantageous and thus superior to an isolated chemotherapy approach? The authors cite an MD Anderson neoadjuvant study in which, despite a 43% response rate, not a single planned amputation could be avoided. Perhaps even more daunting is the fact that even aggressive adjuvant chemotherapy does not seem to affect outcomes in soft tissue sarcomas and should remain firmly in the investigational realm.

In short, isolated limb perfusion may have a role in settings where downstaging is critical to allow for an R0 limb-sparing surgery. However, given that it is unclear whether this technique can routinely achieve this or if an R1 resection with adjuvant radiation therapy may be as effective in maintaining local control, and because re-resection is potentially feasible in either case, isolated limb perfusion’s practical role is unclear. Well-controlled randomized trials are needed to decide whether it has a defined role or is relegated to, in the authors’ own words, “a safe and valuable strategy” without a clear indication.

Prostate

PSA Screening May Be Overused From Journal of Clinical Oncology

A

journal brief in a previous issue of Clinical Oncology News reported on a study that estimated the proportion of men in the United States aged 70 years or older who have had PSA-based prostate cancer screening and determine whether estimated life expectancy was associated with PSA screening patterns. The study was published in the Journal of Clinical Oncology (2011;29:1736-1743, PMID: 21444863). Investigators extracted data from the cancer screening survey supplement of the National Health Interview Survey and used data from 2000 and 2005. The study concluded that 750,000 men with a life expectancy of 5 years received PSA screening last year, from which they were unlikely to benefit. Further commentary is provided.

EXPERT INSIGHT Daniel P. Petrylak, MD Associate Professor of Medicine Columbia University College of Physicians and Surgeons Director of Genitourinary Oncology Division of Medical Oncology NewYork-Presbyterian/ Columbia

Screening for prostate cancer remains a controversial subject. To add to the controversy, there are no clear guidelines as to when a patient should stop being screened for prostate cancer.

The authors evaluated the factors that predict if patient screening is discontinued above the age of 70. Screening rates were found to vary based upon performance status and declined to 24.6% in patients 85 years of age or older. It is clear from this data that before undergoing prostate cancer screening, a critical evaluation of comorbidities of the patient needs to be balanced against the potential benefits and complications of prostate cancer treatment.

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Clinical Oncology News • December 2011

Breast

Exemestane Reduces Breast Cancer Risk in Postmenopausal Women From New England Journal of Medicine

T

he aromatase inhibitor exemestane reduced the risk for invasive breast cancer by 65% in postmenopausal women at moderately increased risk, in a randomized, placebo-controlled, double-blind trial. Importantly, exemestane was not associated with an increased risk for serious adverse side effects.

The MAP.3 trial (N Engl J Med 2011;364:2381-2391, PMID: 21639806) randomized 4,560 postmenopausal women, aged 35 years and older, who had at least one of the following risk factors: age 60 years or older (49% of the enrolled population); Gail 5-year risk score greater than 1.66% (40% met this threshold); or a history of atypical ductal, lobular hyperplasia, lobular carcinoma in situ, or ductal carcinoma in situ (DCIS) treated with mastectomy (11%).

The researchers characterized these

women as having average to high risk for breast cancer.

At a median follow-up of 35 months, 11 invasive breast cancers were detected in subjects given exemestane and in 32 of those given placebo. Exemestane reduced the annual incidence of invasive breast cancer by 65% compared with placebo (0.19% vs. 0.55%; P=0.002). The researchers noted that, in comparison, 5 years of tamoxifen reduced breast cancer incidence by about 50% in high-risk women, while the same strategy with raloxifene decreased risk by 38%.

The number of patients needed to treat to prevent one breast cancer with exemestane therapy was 94 in 3 years.

That number was projected to drop to 26 in 5 years. Identification of subgroups of women who would most benefit from exemestane or who would be the most susceptible to toxic effects might reduce the number of women needed to be

EXPERT INSIGHT Tessa Cigler, MD, MPH Assistant Professor of Medicine Weill Cornell Medical College Division of Medical Oncology Weill Cornell Breast Center NewYork-Presbyterian/Weill Cornell

treated, the researchers noted.

Exemestane also reduced the risk for precursor lesions, such as DCIS, suggesting possible further reductions in invasive cancers during long-term follow-up, the researchers wrote. Exemestane cut the combined annual incidence of invasive breast cancers and noninvasive DCIS to 0.35% compared with 0.77% with placebo (hazard ratio, 0.47; P=0.004).

Exemestane’s favorable profile of lower side effects may make it a more acceptable option for chemoprevention than tamoxifen or raloxifene. In the study, the aromatase inhibitor did not carry a higher risk for skeletal fractures, cardiovascular events, other cancers or treatment-related deaths, and had a “minimal” comparative effect on quality of life, the researchers reported.

They noted that ongoing placebocontrolled trials in healthy women and patients with early breast cancer are

Breast cancer is the most common malignancy affecting women in the United States. Tamoxifen and raloxifene are approved and effective chemoprevention agents, but fears of side effects have limited their widespread use. This well-designed and well-executed randomized, placebo-controlled, double-blind trial shows that the aromatase inhibitor exemestane reduces the risk of invasive breast cancer by 65% in postmenopausal women at

evaluating the effectiveness of prolonged aromatase inhibitor therapy in postmenopausal women.

moderately increased risk of breast cancer.

Importantly, exemestane was not associated with an increased risk of serious adverse side effects. Exemestane appears to be a well-tolerated and highly effective alternative option for breast cancer chemoprevention in postmenopausal women. With, now, three options for chemoprevention, the hope is that future breast cancer incidence can be reduced.

Ovarian

Earlier Dx of Ovarian Cancer Not Associated With Improved Survival From Journal of the American Medical Association

A

journal brief in a previous issue of Clinical Oncology News discussed results of the PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening trial published in the Journal of the American Medical Association (2011;305[22]:2295-2303). The study revealed that screening for ovarian cancer using cancer antigen 125 (CA-125) and transvaginal ultrasound does not reduce mortality compared with standard medical care. According to the study authors, there was “a lack of an observed stage shift” (defined as a decrease in the absolute number of late-stage cases) among the patients offered the diagnostic intervention compared with those who opted only for standard medical care.

Research has indicated that this stage shift is necessary for, as the PLCO authors note, “a mortality benefit to be realized.” Further commentary is provided.

EXPERT INSIGHT Alfred I. Neugut, MD, PhD Professor of Medicine and Epidemiology Columbia University College of Physicians and Surgeons Co-Director, Cancer Prevention Program Herbert Irving Comprehensive Cancer Center NewYork-Presbyterian/Columbia

The PLCO study was created to evaluate screening for 4 different sites, and has so far reported out the preliminary results for PSA screening for prostate cancer. Still pending are the results of the sigmoidoscopy study for colorectal cancer and chest x-ray screening for lung cancer.

In the meantime, many have overlooked this particular part of the trial—the evaluation of CA-125 and transvaginal ultrasound as screening tools for ovarian cancer. Here the investigators demonstrate that these tools have no benefit in screening for ovarian cancer. Luckily, they never became widespread as screening tools, as happened with PSA, so the current results will not have as wrenching an impact as the negative results of the PSA screening trial. Together with a plenary paper 2 years ago showing that the use of CA-125 for surveillance in ovarian cancer survivors also had no impact on outcomes, it is clear that the role of this serum tumor marker is certainly shrinking.

SOLID TUMORS

Clinical Oncology News • December 2011

Esophageal

Photodynamic Therapy Shows Merit in Esophageal Cancer From International Journal of Cancer

A

Phase II, single-arm, open-label study has concluded that photodynamic therapy is a potentially curative and tolerable salvage treatment after chemoradiotherapy for patients with esophageal squamous cell carcinoma (ESCC) with local failure without any metastasis. The study was conducted at a single center by researchers in Japan at the Kyoto University Graduate School of Medicine, in Kyoto, and the National Cancer Center Hospital in Kashiwanoha, Kashiwa City.

Salvage surgery can be a curative treatment option for patients with ESCC with local failure at the primary site, especially for those with T2 or earlier T-stage tumors or for those without lymph node metastasis. Salvage surgery, however, is associated with high

EXPERT INSIGHT Michel Kahaleh, MD Assistant Professor of Medicine Weill Cornell Medical College Chief of Advanced Endoscopy NewYork-Presbyterian/ Weill Cornell

A recently conducted study in Japan reports that salvage photodynamic treatment is an effective and tolerable salvage treatment option for

rates of complications and treatmentrelated mortality.

In a previous study, researchers reported that endoscopic mucosal resection (EMR) or photodynamic therapy had merit as a salvage treatment for local failure after chemoradiotherapy (Endoscopy 2008;40:717-721, PMID: 18773340; Gastrointest Endosc 2005;62:31-36, PMID: 15990816). In a study published in the International Journal of Cancer (Epub ahead of print; doi: 10.1002/ijc.27320), researchers evaluated the efficacy and safety of salvage photodynamic therapy after chemoradiotherapy in ESCC, because photodynamic therapy is a more deeply penetrating treatment than EMR for esophageal cancer.

The researchers enrolled 25 patients with ESCC with histologically proven local failure limited to the submucosal

layer; all patients did not have any metastasis after definitive chemoradiotherapy (≥50 Gy). Other eligibility criteria included patient refusal to undergo salvage surgery; histologically proven squamous cell carcinoma by biopsy specimen of the local failed lesions; local failed lesions limited to the submucosal layer, EMR not indicated for reasons of concomitant deep ulceration; severe fibrosis caused by radiation or a lesion invading the deep submucosal layer; Eastern Cooperative Oncology Group performance status ≤2; and adequate bone marrow function, renal function, and liver function.

Photodynamic therapy began with intravenous administration of 2 mg/kg of porfimer sodium followed 48 to 72 hours later by excimer dye laser irradiation with a fluence of 75 J/cm2. The primary end point was a complete response.

Nineteen (76%) of patients achieved a complete response (95% confidence interval [CI], 55%-91%). At the time of study publication, 9 patients remained alive without disease and 1 patient was alive with liver metastasis and was being treated with systemic chemotherapy.

One treatment-related death was caused by gastrointestinal hemorrhage at the irradiated site, but no other adverse events greater than grade 3 were related to photodynamic treatment. The researchers reported that although a treatment-related death did occur, the incidence of 4% was lower than that seen in patients who undergo salvage surgery. The authors concluded that “salvage photodynamic therapy is a less morbid treatment option than salvage surgery for carefully selected patients with local failure at the primary site after chemoradiotherapy.”

local failure after chemoradiotherapy for esophageal squamous cell carcinoma (ESCC) in patients whose failure lesion is limited to the submucosal layer without any metastasis. Local failure at the primary site is a major problem after chemoradiotherapy in patients with ESCC. With salvage surgery being the only treatment option, there is need to introduce a safer alternative. This study aimed to evaluate the efficacy and safety of salvage photodynamic therapy after chemoradiotherapy.

Twenty-five patients between April 2005 and January 2009 with histologically proven local failure limited to the submucosal layer, and without

any metastasis after definitive chemoradiotherapy (>50 Gy) for ESCC were enrolled in this single-arm, openlabel, single-center study.

Photodynamic treatment began with administration of 2 mg/kg of porfimer sodium IV followed 48 to 72 hours later by excimer dye laser irradiation with a fluence of 75 J/cm2.

The primary end point was a complete response (CR) to treatment with photodynamic therapy, and the secondary end points were toxicity related to photodynamic therapy, progression-free survival, and overall survival. The range of esophageal surface areas that were treated was 3 to 9 cm2. Complete response was

attained in 19 of 25 patients treated (CR rate, 76%; 95% CI, 55%-91%). One treatment-related death was caused by gastrointestinal hemorrhage at the irradiated site, which occurred 33 days after therapy. No adverse events greater than grade 3 were related to photodynamic therapy in the other patients. After a median followup of 48 months after photodynamic therapy, the progression-free survival and overall survival at 3 years were 40% (95% CI, 21%-59%) and 38% (95% CI, 17%-60%), respectively. Common adverse events after treatment were chest pain (61%), pharyngeal pain (17%), dysphagia (39%), fever (48%), and photosensitivity (32%).

FDA NEWS

CETUXIMAB continued from page 7 

infusion reactions in patients. Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with SCCHN treated in a clinical trial with cetuximab and radiation therapy and in 3% of patients with this malignancy treated with EU-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU) in the EXTREME trial. Health care providers should closely monitor serum electrolytes, including magnesium, potassium and calcium, during and after cetuximab administration.

Selected adverse events of any grade occurring in at least 10% of patients receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone were acneiform

rash (70% vs. 2%, respectively), nausea (54% vs. 47%), infection (44% vs.

27%), rash (28% vs. 2%), diarrhea (26% vs. 16%), anorexia (25% vs. 14%), pyrexia (22% vs. 13%), acne (22% vs. none), dermatitis acneiform (15% vs. none), dry skin (14% vs. <1%), alopecia (12% vs. 7%), hypokalemia (12% vs. 7%), hypocalcemia (12% vs. 5%), hypomagnesemia (11% vs. 5%), infusion reaction (10% vs. <1%) and conjunctivitis (10% vs. none). Because U.S.-licensed cetuximab provides approximately 22% higher exposure than the EU-approved version, the data here may underestimate the incidence and severity of adverse reactions anticipated with cetuximab for this indication.

New Mammography Technology Approved

T

he FDA has approved SenoBright 1 Contrast Enhanced Spectral

Mammography (CESM), which is a technology designed to produce contrast-enhanced images of the breast using an approved x-ray contrast agent and a dual energy acquisition technique.

The technology, from GE Healthcare, has been in use in several European countries since 2010.

SenoBright uses x-rays at multiple energies to create two separate but almost simultaneous exposures. “CESM presents two images per mammographic view, one that looks like standard mammography and a second image that shows the contrast-enhanced areas that

can help localize a lesion,” said Clarisse Dromain, MD, Gustave Roussy Cancer Institute, in Villejuif, France, in a press statement. “As the images are familiar, it can therefore be easily reviewed by surgeons and oncologists. Moreover, in terms of workflow, a CESM exam takes from five to 10 minutes.”

CESM technology is intended to work as an upgrade to GE Healthcare’s Senographe DS and Senographe Essential digital mammography equipment.

The aim is to allow a procedure to be conducted by the same staff, using the same mammography equipment, potentially on the same day as a traditional screening examination. According to the company, the new technology will help health care providers to reduce the critical waiting time from detection to diagnosis for patients. GE Healthcare estimates that 2,500 digital mammography systems upgradeable to SenoBright are currently in clinical use.

17

18

PRN

Clinical Oncology News • December 2011

Doctor–Patient Communication

END-OF-LIFE continued from page 13 

Her department already is seeing about 10% more patient referrals as a result of outreach efforts.

“At first, I thought [the law] was a terrible idea,” Dr. Lustbader said. “To legally require a doctor to have a conversation with a patient seems noxious. But the truth is many patients die badly.

One third of cancer patients die in the ICU or hospital, and that’s dreadful for most patients and families. Terminally ill patients and their families deserve palliative care information, so they can decide the kind of care they want based on their own values and beliefs.”

Documenting Discussions Paul A. Glare, MD, chief of the Pain and Palliative Care Service at Memorial SloanKettering Cancer Center (MSKCC), in New York City, said the law “does rankle some physicians,” who feel it’s overreaching, or that they’re being forced by the state capital to do additional work, but others realize that these discussions are important. “Back in the day,” he said, “physicians had the same kind of reaction when they were required to disclose a patient’s diagnosis, then again when they had to discuss DNR with patients and families.”

“I’m definitely in support of the spirit of the law, and making sure patients are empowered to make choices,” Dr. Glare said.

Dr. Glare said his hospital has been discussing the law since it was signed in August 2010. One challenge has been working out who initiates the discussion with patients who see more than one provider. Another has been adapting the electronic patient records to create easier means to document the discussions.

There also have been difficulties convincing some colleagues that the conversation is important, or that it is a requirement at all. He also has been visiting departments at MSKCC to discuss the law, and the hospital is considering adding messages about the new requirements to plasma screen televisions set up around the hospital.

Although he has seen a societal and cultural shift toward greater understanding of palliative care over the past

three years, he said it will take time to resolve. “There are many ways to change behavior,” Dr. Glare said. “Legislating is one way, but there are many signs saying ‘Don’t park’ or ‘Curb your dog’ that people ignore.”

At Mount Sinai, Dr. Meier and colleagues have developed one-page handouts for physicians discussing the new law, and these are available on hospital intranet sites.

She said that a physician’s age also plays a role. Younger physicians are more likely to have trained in hospitals that had palliative care programs, “so for them, there’s nothing strange.” But for physicians aged 50 years and older, “it’s much more of a struggle to shift the way we’ve been practicing for decades.”

Change can’t happen overnight, she said, and policymakers will have to be patient.

North Shore-Long Island Jewish, in partnership with Hofstra University, is opening a new medical school this fall.

Reaching out to the next generation of physicians, Dr. Lustbader said, instructors will be teaching medical students how to have an effective advanced care– planning discussion during the seventh week of school. Students will roleplay with standardized patients and get feedback on their communication skills.

—Karen Blum

Community Oncology

CONUNDRUMS continued from page 12 

number of cycles of cytarabine remain to be determined. AML patients with inv(16) and mutations of c-KIT appear to have a worse prognosis and may benefit from more intensive postremission therapy, that is, allogeneic transplantation, but this has not yet been shown in prospective trials.

Weick JK, Kopecky KJ, Appelbaum, FR, et al.

A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood. 1996;88(8):2841-2851, PMID: 8874180.

Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med. 1994;331(14):896-903, PMID: 8078551.

Cascinu S, Fedeli A, Fedeli SL, Catalano G. Control of chemotherapy-induced diarrhea with octreotide. A randomized trial with placebo in patients receiving cisplatin. Oncology.

1994;51(1):70-73, PMID: 8265106.

Gebbia V, Carreca I, Testa A, et al. Subcutaneous octreotide versus oral loperamide in the treatment of diarrhea following chemotherapy. Anticancer Drugs. 1993;4(4):443-445, PMID: 8400346.

Swerdlow SH, Campo E, Harris NL, et al, eds. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues.

Lyon, France: IARC Press; 2008.

Steensma DP, Dewald GW, Lasho TL, et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes.

Blood. 2005;106(4):1207-1209, PMID:15860661.

7.

Answer: d. Anthracyclines, including doxorubicin, appear to inhibit topoisomerase II enzyme. This enzyme exhibits its function in a multistep manner and requires energy from ATP hydrolysis.

Marcucci G, Mrozek K, Ruppert AS, et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. J Clin Oncol.

2005;23(24):5707-5715, PMID: 16110030.

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

6.

8.

Answer: a. The patient has type 1 (low blast count) proliferativephase CMML. The diagnosis of CMML

continued loperamide is unlikely to be successful.

requires absolute monocytosis (>1,000/ mcL) in addition to other criteria outlined by the WHO classification. It is not uncommon to see bone marrow fibrosis in CMML. The JAK2 V617F mutation is present in less than 10% of patients with CMML.

Answer: a. MicroRNAs are small, 18to 24­-nucleotide noncoding RNAs that regulate stability and/or translation

10.

into protein of partially complementary target mRNA molecules. They do encode transcription factors.

Negrini M, Nicoloso MS, Calin GA. MicroRNAs and cancer—new paradigms in molecular oncology. Curr Opin Cell Biol. 2009;21(3):470-479. PMID: 19411171.

Schetter AJ, Harris CC. MicroRNAs as molecular classifiers for cancer. Cell Cycle.

2011;10(17):2827-2828, PMID: 21869596.

9.

Answer: c. In this patient, a short course of subcutaneous octreotide can be highly effective. The side effects are minimal. The agents mentioned in choices a and b should be avoided, and

Answer: a. ETS gene fusions are present in approximately 50% of patients with localized prostate cancers with resultant aggressive phenotype.

They probably define a distinct class of prostate cancer and might have a bearing on prognosis and future therapeutic targeting.

Kumar-Sinha C, Tomlins SA, Chinnaiyan AM. Recurrent gene fusions in prostate cancer. Nat Rev Cancer. 2008;8(7):497-511, PMID: 18563191.

Demichelis F, Fall K, Perner S, et al.

TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene. 2007;26(31):4596-4599, PMID: 17237811.

Shahid Raza, MD, assisted in preparing this manuscript.

SOLIDâ&#x20AC;&#x2C6;TUMORS

Clinical Oncology News â&#x20AC;˘ December 2011

Bladder

Study Supports CMV for Invasive Bladder Cancer From Journal of Clinical Oncology

A

journal brief in a previous issue of Clinical Oncology News reported on a study that showed that cisplatin, vincristine, and vinblastine (CMV) chemotherapy together with local therapy improves survival outcomes as first-line adjunctive treatment in invasive bladder cancer. The results came from the long-term results of a large international Phase III trial. Reflecting follow-up for patients alive at 8 years, these updated results from the BA06 30894 trial (J Clin Oncol 2011;29:2171-2177, PMID:

21502557) confirm the 4-year results published in 1999 (Lancet 1999;354:533540, PMID: 10470696).

In the study, 976 patients were recruited from 106 hospital centers in 20 countries between November 1989 and July 1995 and were randomized to receive either CMV chemotherapy (n=491) or no CMV chemotherapy (n=485). Those in the CMV group received methotrexate 30 mg/m 2 IV bolus and vinblastine 4 mg/m2 IV bolus

on day 1; cisplatin 100 mg/m2 IV infusion on day 2 (before hydration); folinic acid 15 mg (oral or IV) every 6 hours

for 4 doses on day 2 after hydration (24 hours after methotrexate on day 1); methotrexate 30 mg/m 2 IV bolus and vinblastine 4 mg/m2 IV bolus on day 8; and folinic acid 15 mg (oral) every 6 hours on day 9. The schedule was repeated every 21 days for a total of 3 cycles. AEs associated with CMV were uncommon, according to the authors.

The latest results show a statistically significant 16% reduction in the risk for death, which corresponds to an increase in 10-year survival from 30% to 36%, among patients treated with CMV. Further commentary is provided.

EXPERT INSIGHT Daniel P. Petrylak, MD Associate Professor of Medicine Columbia University College of Physicians and Surgeons Director of Genitourinary Oncology Division of Medical Oncology NewYork-Presbyterian/ Columbia

This study is an update of the Medical Research Council study of CMV as neoadjuvant chemotherapy for muscle-invasive transitional cell carcinoma of the bladder. The authors report that neoadjuvant chemotherapy results in a 16% reduction in the risk for death, which translates into a 6% increase in overall survival at both 3 and 10 years post-treatment. Acceptable toxicity was noted with both chemotherapy and cystectomy, with a treatmentrelated mortality rate of 1% and 3.6%, respectively. Although there were significant differences in trial design between this study and SWOG 8710 (N Engl J Med 2003;349:859-866) in terms of chemotherapeutic regimen (CMV vs MVAC [methotrexate, vinblastine, doxorubicin and cisplatin] and type of local therapy (surgery or radiation vs surgery), the survival benefits seen in both trials support the use of neoadjuvant therapy for this patient population.

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19

TASIGNA for adult patients with newly diagnosed Ph+ CML in chronic phase TASIGNA DOUBLED THE MAJOR MOLECULAR RESPONSE (MMR) RATE OF IMATINIB AT 12 MONTHS1

2 TASIGNA PATIENTS (<1%) PROGRESSED TO ACCELERATED PHASE OR BLAST CRISIS* (AP/BC) VS 17 IMATINIB PATIENTS (6%)1

MMR rates at 12 months1

Progression to AP/BC1 30

100

P<0.0001

60

25 20

44%

[95% CI, 38.4%-50.3%]

22%

40

[95% CI, 17.6%-27.6%]

Patients

Patients (%)

80

15 10

20

5

0

0

TASIGNA 300 mg bid (n=282)

n=17 (6%)

Imatinib 400 mg qd (n=283)

n=2 (0.7%) TASIGNA 300 mg bid (n=282)

Imatinib 400 mg qd (n=283)

ENESTnd study design: A randomized, controlled, open-label, multicenter Phase III trial of 846 patients with newly diagnosed Ph+ CML in chronic phase. Patients were randomized to receive either TASIGNA 400 mg bid (n=281), TASIGNA 300 mg bid (n=282), or imatinib 400 mg qd (n=283). The daily dose of imatinib could be escalated to 800 mg (400 mg bid), but no dose escalation was permitted with TASIGNA. A centralized laboratory was used for PCR testing.

The primary end point was MMR at 12 months. MMR was defined as ≤0.1% BCR-ABL/ABL by international scale measured by RQ-PCR, which corresponds to a ≥3-log reduction of BCR-ABL transcripts from standardized baseline.1,2

The distinct safety profile of TASIGNA supports its use in adult patients with newly diagnosed Ph+ CML in chronic phase1 ■ ■

Discontinuation for adverse events regardless of causality was observed in 7% of patients In ENESTnd, most side effects associated with TASIGNA did not lead to discontinuation in the first year

*Definition includes patients with clonal evolution and CML-related death. Time was censored at last assessment on treatment for patients without events.2,3

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

©2011 Novartis

Printed in USA

12/10

AM7-100030

Greater efficacy vs imatinib on every end point at 12 months TASIGNA (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of TASIGNA is based on major molecular response and cytogenetic response rates. The study is ongoing and further data will be required to determine long-term outcome.

Boxed WARNING and Additional Important Safety Information TASIGNA prolongs the QT interval. ECGs should be obtained to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, as well as following any dose adjustments. Sudden deaths have been reported in patients receiving TASIGNA. TASIGNA should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA administration and should be periodically monitored. The concomitant use of strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong the QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided. The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, and phenobarbital). Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment as nilotinib exposure is increased in patients with impaired hepatic function.

■ ■ ■ ■

■ ■

■

■

■

Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia Caution is recommended in patients with a history of pancreatitis

The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia (see Boxed WARNING)

The exposure of nilotinib is reduced in patients with total gastrectomy Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption

Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do

In chronic phase patients, the most commonly reported nonhematologic adverse drug reactions (>10%) were rash, pruritus, nausea, fatigue, myalgia, headache, constipation, diarrhea, and vomiting

In accelerated phase patients, the most commonly reported nonhematologic adverse drug reactions (>10%) were rash, pruritus, and fatigue

References: 1. TASIGNA® (nilotinib) capsules prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; January 2011. 2. Saglio G, Kim D-W, Issaragrisil S, et al; for ENESTnd investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251-2259. 3. Data on file. Novartis Pharmaceuticals Corporation. East Hanover, NJ.

Please see brief summary of Prescribing Information on the following pages.

Tasigna® (nilotinib) Capsules Initial U.S. Approval: 2007 BRIEF SUMMARY: Please see package insert for full prescribing information.

WARNING: QT PROLONGATION AND SUDDEN DEATHS Tasigna prolongs the QT interval (5.2). Sudden deaths have been reported in patients receiving nilotinib (5.3). Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome (4). Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored (5.2). Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided (5.7). Patients should avoid food 2 hours before and 1 hour after taking dose (5.8). A dose reduction is recommended in patients with hepatic impairment (5.9). ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments. (5.2, 5.3, 5.6, 5.12) 1 INDICATIONS AND USAGE 1.1 Newly Diagnosed Ph+ CML-CP Tasigna (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of Tasigna is based on major molecular response and cytogenetic response rates [see Clinical Studies (14.1) in the full prescribing information]. The study is ongoing and further data will be required to determine long-term outcome.

1.2 Resistant or Intolerant Ph+ CML-CP and CML-AP Tasigna is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates [see Clinical Studies (14.2) in the full prescribing information].

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing Tasigna should be taken twice daily at approximately 12 hour intervals and must not be taken with food. The capsules should be swallowed whole with water. No food should be consumed for at least 2 hours before the dose is taken and no food should be consumed for at least one hour after the dose is taken [see Boxed Warning, Warnings and Precautions (5.8), Clinical Pharmacology (12.3) in the full prescribing information].

For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in one teaspoon of applesauce (puréed apple). The mixture should be taken immediately (within 15 minutes) and should not be stored for future use [see Clinical Pharmacology (12.3) in the full prescribing information].

Tasigna may be given in combination with hematopoietic growth factors such as erythropoietin or G-CSF if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated.

Newly Diagnosed Ph+ CML-CP The recommended dose of Tasigna is 300 mg orally twice daily [see Clinical Pharmacology (12.3) in the full prescribing information].

Resistant or Intolerant Ph+ CML-CP and CML-AP The recommended dose of Tasigna (nilotinib) is 400 mg orally twice daily [see Clinical Pharmacology (12.3) in the full prescribing information].

2.2 Dose Adjustments or Modifications QT interval prolongation: Table 1: Dose Adjustments for QT Prolongation ECGs with a QTc >480 msec

1. Withhold Tasigna, and perform an analysis of serum potassium and magnesium, and if below lower limit of normal, correct with supplements to within normal limits. Concomitant medication usage must be reviewed.

2. Resume within 2 weeks at prior dose if QTcF returns to <450 msec and to within 20 msec of baseline.

3. If QTcF is between 450 msec and 480 msec after 2 weeks, reduce the dose to 400 mg once daily.

4. If, following dose-reduction to 400 mg once daily, QTcF returns to >480 msec, Tasigna should be discontinued.

5. An ECG should be repeated approximately 7 days after any dose adjustment.

Myelosuppression Tasigna may need to be withheld and/or dose reduced for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 2).

Table 2: Dose Adjustments for Neutropenia and Thrombocytopenia Newly diagnosed Ph+ CML in chronic phase at 300 mg twice daily Resistant or intolerant Ph+ CML in chronic phase or accelerated phase at 400 mg twice daily

ANC* <1.0 x 109/L and/or platelet counts <50 x 109/L

1. Stop Tasigna, and monitor blood counts 2. Resume within 2 weeks at prior dose if ANC >1.0 x 109/L and platelets >50 x 109/L 3. If blood counts remain low for >2 weeks, reduce the dose to 400 mg once daily

*ANC = absolute neutrophil count See Table 3 for dose adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases [see Adverse Reactions (6.1)].

Table 3: Dose Adjustments for Selected Non-hematologic Laboratory Abnormalities Elevated serum lipase or amylase ≥Grade 3

1. Withhold Tasigna, and monitor serum lipase or amylase 2. Resume treatment at 400 mg once daily if serum lipase or amylase return to ≤Grade 1

Elevated bilirubin ≥Grade 3

1. Withhold Tasigna, and monitor bilirubin 2. Resume treatment at 400 mg once daily if bilirubin return to ≤Grade 1

Elevated hepatic transaminases ≥Grade 3

1. Withhold Tasigna, and monitor hepatic transaminases 2. Resume treatment at 400 mg once daily if hepatic transaminases return to ≤Grade 1

Other Non-hematologic Toxicities If other clinically significant moderate or severe non-hematologic toxicity develops, withhold dosing, and resume at 400 mg once daily when the toxicity has resolved. If clinically appropriate, escalation of the dose back to 300 mg (newly diagnosed Ph+ CML-CP) or 400 mg (resistant or intolerant Ph+ CML-CP and CML-AP) twice daily should be considered. For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Test serum lipase levels monthly or as clinically indicated. For Grade 3 to 4 bilirubin or hepatic transaminase elevations, dosing should be withheld, and may be resumed at 400 mg once daily.

Test bilirubin and hepatic transaminases levels monthly or as clinically indicated [see Warnings and Precautions (5.4, 5.5), Use in Specific Populations (8.7) in the full prescribing information].

Hepatic Impairment If possible, consider alternative therapies. If Tasigna must be administered to patients with hepatic impairment, consider the following dose reduction: Table 4: Dose Adjustments for Hepatic Impairment (At Baseline) Newly diagnosed Ph+ CML in chronic phase at 300 mg twice daily

Mild, Moderate or Severe*

An initial dosing regimen of 200 mg twice daily followed by dose escalation to 300 mg twice daily based on tolerability

Resistant or intolerant Ph+ CML in chronic phase or accelerated phase at 400 mg twice daily

Mild or Moderate*

An initial dosing regimen of 300 mg twice daily followed by dose escalation to 400 mg twice daily based on tolerability

Severe*

A starting dose of 200 mg twice daily followed by a sequential dose escalation to 300 mg twice daily and then to 400 mg twice daily based on tolerability

*Mild = mild hepatic impairment (Child-Pugh Class A); Moderate = moderate hepatic impairment (Child-Pugh Class B); Severe = severe hepatic impairment (Child-Pugh Class C) [see Boxed Warning, Warnings and Precautions (5.9), Use in Specific Populations (8.7) in the full prescribing information].

Concomitant Strong CYP3A4 Inhibitors Avoid the concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit products may also increase serum concentrations of nilotinib and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, consider a dose reduction to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML-CP. 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 should be allowed before the Tasigna dose is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors [see Boxed Warning, Warnings and Precautions (5.2, 5.7), Drug Interactions (7.2) in the full prescribing information].

Concomitant Strong CYP3A4 Inducers Avoid the concomitant use of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). Patients should also refrain from taking St. John’s Wort. Based on the nonlinear pharmacokinetic profile of nilotinib, increasing the dose of Tasigna when co-administered with such agents is unlikely to compensate for the loss of exposure [see Drug Interactions (7.2) in the full prescribing information].

3 DOSAGE FORMS AND STRENGTHS 150 mg red opaque hard gelatin capsules with black axial imprint “NVR/BCR”.

200 mg light yellow opaque hard gelatin capsules with a red axial imprint “NVR/TKI”.

4 CONTRAINDICATIONS Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning].

5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Perform complete blood counts every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated.

Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction [see Dosage and Administration (2.2)].

5.2 QT Prolongation Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner [see Adverse Reactions (6.1), Clinical Pharmacology (12.4) in the full prescribing information]. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated and following dose adjustments [see Warnings and Precautions (5.12)].

Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome.

Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)].

Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided [see Warnings and Precautions (5.7, 5.8)]. The presence of hypokalemia and hypomagnesemia may further enhance this effect [see Warnings and Precautions (5.6, 5.12)].

5.3 Sudden Deaths Sudden deaths have been reported in patients with CML treated with nilotinib in clinical studies (n= 5,661; 0.3%). The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.

5.4 Elevated Serum Lipase The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous history of pancreatitis. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated.

5.5 Hepatotoxicity The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated [see Warnings and Precautions (5.12)].

5.6 Electrolyte Abnormalities The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia.

Electrolyte abnormalities must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)].

5.7 Drug Interactions The administration of Tasigna with agents that are strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning, Dosage and Administration (2.2), Drug Interactions (7.2) in the full prescribing information].

5.8 Food Effects The bioavailability of nilotinib is increased with food. Tasigna must not be taken with food. No food should be taken at least 2 hours before and at least one hour after the dose is taken. Grapefruit products and other foods that are known to inhibit CYP3A4 should be avoided [see Boxed Warning, Drug Interactions (7.2) and Clinical Pharmacology (12.3) in the full prescribing information].

In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (>10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions (>1%) were thrombocytopenia, neutropenia and anemia.

In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (>10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (>1%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia.

Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steadystate was 10 msec. Increase in QTcF >60 msec from baseline was observed in 4.1% of the patients and QTcF of >500 msec was observed in 4 patients (<1%) [see Boxed Warning, Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.4) in the full prescribing information].

Discontinuation due to drug-related adverse reactions was observed in 16% of CML-CP and 10% of CML-AP patients.

Most Frequently Reported Adverse Reactions Tables 5 and 6 show the percentage of patients experiencing treatment-emergent adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of patients who received at least one dose of Tasigna are listed.

Table 5: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg twice daily or Gleevec 400 mg once daily groups)a

5.9 Hepatic Impairment Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment (at baseline) and QT interval should be monitored closely [see Boxed Warning, Dosage and Administration (2.2) and Use in Specific Populations (8.7) in the full prescribing information].

5.10 Total Gastrectomy The exposure of nilotinib is reduced in patients with total gastrectomy. More frequent follow-up of these patients should be considered. Dose increase or alternative therapy may be considered in patients with total gastrectomy [see Clinical Pharmacology 12.3) in the full prescribing information].

5.11 Lactose Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products or of glucose-galactose malabsorption.

5.12 Monitoring Laboratory Tests Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter. Chemistry panels, including the lipid profile, should be checked periodically. ECGs should be obtained at baseline, seven days after initiation and periodically thereafter, as well as following dose adjustments [see Warnings and Precautions (5.2)]. Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician’s discretion.

5.13 Use in Pregnancy There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in animals at maternal exposures that were lower than the expected human exposure at the recommended doses of nilotinib.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna [see Use in Specific Populations (8.1) in the full prescribing information].

6 ADVERSE REACTIONS The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of the package insert [see Boxed Warning, Warnings and Precautions (5)].

Patients with Newly Diagnosed Ph+ CML-CP

Sudden deaths [see Boxed Warning, Warnings and Precautions (5.3)] Elevated serum lipase [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Electrolyte abnormalities [see Boxed Warning, Warnings and Precautions (5.6)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Newly diagnosed Ph+ CML-CP The data below reflect exposure to Tasigna from a randomized trial in newly diagnosed patients with Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment in the nilotinib 300 mg twice daily group was 18.6 months. The median actual dose intensity was 593 mg/day in the nilotinib 300 mg twice daily group.

The most common (>10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue and myalgia. Upper abdominal pain, alopecia, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema and asthenia were observed less commonly (≤10% and >5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction. Pleural and pericardial effusions occurred in 1% of patients. Gastrointestinal hemorrhage was reported in 0.4% of patients.

Increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of >500 msec.

The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (17%), neutropenia (15%) and anemia (7%) See Table 7 for Grade 3/4 laboratory abnormalities.

TASIGNA 300 mg twice daily

GLEEVEC 400 mg once daily

N=279

N=280

N=279

N=280

CTC Gradesb 3 / 4 (%)

All Grades

Skin and subcutaneous tissue disorders

Rash Pruritus Alopecia

36 19 10

16 7 5

<1 <1 0

1 0 0

Gastrointestinal disorders

Nausea Constipation Diarrhea Vomiting Abdominal pain upper Abdominal pain

19 15 14 9

38 4 37 22

1 0 <1 0

1 0 2 <1

15 12

10 9

<1 1

<1 <1

Nervous system disorders

Headache

28

16

3

<1

General disorders and administration site conditions

Fatigue Pyrexia Asthenia Edema, peripheral

19 10 11 8

14 12 9 17

<1 0 <1 0

1 0 0 0

Musculoskeletal and connective tissue disorders

Myalgia Arthralgia Muscle spasms Pain in extremity Back pain

14 15 10 9 12

16 13 29 13 10

<1 <1 0 0 <1

0 0 <1 <1 1

Respiratory, thoracic Cough and mediastinal disorders

12

9

0

0

Infections and infestations

Nasopharyngitis Upper respiratory tract infection

19

15

0

0

Eye disorders

Eyelid edema

13

9

0

0

1

14

0

<1

aExcluding bNCI

laboratory abnormalities Common Terminology Criteria for Adverse Events, Version 3.0 Table 6: Most Frequently Reported Non-hematologic Adverse Reactions in Patients with Resistant or Intolerant Ph+ CML Receiving Tasigna 400 mg Twice Daily (Regardless of Relationship to Study Drug) (≥10% in any Group)a CML-CP

CML-AP

N=321 Body System and Preferred Term

N=137

All Grades (%)

CTC Gradesb 3 / 4 (%)

All Grades (%)

CTC Gradesb 3 / 4 (%)

Skin and subcutaneous tissue disorders

Rash Pruritus Night sweat Alopecia

36 32 12 11

2 <1 <1 0

29 20 27 12

0 0 0 0

Gastrointestinal disorders

Nausea Constipation Diarrhea Vomiting Abdominal pain Abdominal pain upper Dyspepsia

37 26 28 29 15

1 <1 3 <1 2

22 19 24 13 16

<1 0 2 0 3

14 10

<1 <1

12 4

<1 0

Headache

35

2

20

1

Discontinuation due to adverse events regardless of causality was observed in 7% of patients.

Resistant or intolerant Ph+ CML-CP and CML-AP In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the recommended dose of 400 mg twice daily.

The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1-1096) and 264 (range 2-1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151–1110) and 780 mg/day (range 150-1149), respectively and corresponded to the planned 400 mg twice daily dosing.

The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range 1-345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1–234).

GLEEVEC 400 mg once daily

Body System and Preferred Term

Myelosuppression [see Warnings and Precautions (5.1)] QT prolongation [see Boxed Warning, Warnings and Precautions (5.2)]

TASIGNA 300 mg twice daily

Nervous system disorders

(continued)

Table 6: Most Frequently Reported Non-hematologic Adverse Reactions in Patients with Resistant or Intolerant Ph+ CML Receiving Tasigna 400 mg Twice Daily (Regardless of Relationship to Study Drug) (≥10% in any Group)a CML-CP

CML-AP

N=321 Body System and Preferred Term

Metabolism and Nutrition Disorders: Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia. Uncommon: dehydration, decreased appetite, increased appetite. Unknown frequency: hyperuricemia, gout, hypoglycemia, dyslipidemia.

N=137

All Grades (%)

CTC Gradesb 3 / 4 (%)

All Grades (%)

CTC Gradesb 3 / 4 (%)

General disorders and administration site

Fatigue Pyrexia Asthenia Edema, peripheral Myalgia

32 22 16 15 19

3 <1 0 <1 2

23 28 14 12 16

<1 2 1 0 <1

Musculoskeletal and connective tissue disorders

Arthralgia Muscle spasms Bone pain Pain in extremity Back pain Musculoskeletal pain

26 13 14 20 17

2 <1 <1 2 2

16 15 15 18 15

0 0 2 1 <1

11

<1

12

1

Respiratory, thoracic Cough and mediastinal Dyspnea disorders Oropharyngeal pain

27 15 11

<1 2 0

18 9 7

0 2 0

Infections and infestations

Nasopharyngitis Upper respiratory tract infection

24

<1

15

0

12

0

10

0

Metabolism and nutritional disorders

Anorexia

12

<1

15

<1

Psychiatric disorders Insomnia

12

1

7

0

Vascular disorders

10

2

11

<1

Hypertension

aExcluding

laboratory abnormalities bNCI Common Terminology Criteria for Adverse Events, Version 3.0 Laboratory Abnormalities Table 7 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna.

Table 7: Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities Patient Population Resistant or Intolerant Ph+ Newly Diagnosed Ph+ CML-CP

CML-CP

CML-AP

TASIGNA 300 mg twice daily N=279 (%)

GLEEVEC 400 mg once daily N=280 (%)

TASIGNA 400 mg twice daily N=321 (%)

TASIGNA 400 mg twice daily N=137 (%)

Hematologic Parameters Thrombocytopenia Neutropenia Anemia Biochemistry Parameters Elevated lipase Hyperglycemia Hypophosphatemia Elevated bilirubin (total) Elevated SGPT (ALT) Hyperkalemia Hyponatremia Hypokalemia Elevated SGOT (AST) Decreased albumin

10 12 4

9 20 5

301 312 11

423 424 27

7 6 5 4 4 2 <1 <1 1 0

3 0 8 <1 3 1 <1 1 1 0

18 12 17 7 4 6 7 2 3 4

18 6 15 9 4 4 7 9 2 3

Biochemistry Parameters Hypocalcemia Elevated alkaline phosphatase Elevated creatinine

<1 0 0

0 <1 <1

2 <1 <1

5 1 <1

*NCI Common Terminology Criteria for Adverse Events, version 3.0 Thrombocytopenia: 12% were grade 3, 18% were grade 4 2CML-CP: Neutropenia: 16% were grade 3, 15% were grade 4 3CML-AP: Thrombocytopenia: 11% were grade 3, 32% were grade 4 4CML-AP: Neutropenia: 16% were grade 3, 26% were grade 4 1 CML-CP:

6.2 Additional Data from Clinical Trials The following adverse drug reactions were reported in patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (1%-10%), uncommon (0.1%-1%), and unknown frequency (single events). For adverse drug reactions listed under “Investigations”, very common events (≥10%), which were not included in Tables 5 and 6, are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category.

Infections and Infestations: Common: folliculitis. Uncommon: upper respiratory tract infection (including sinusitis, nasopharyngitis, pharyngitis), bronchitis, herpes virus infection, candidiasis pneumonia, urinary tract infection, gastroenteritis. Unknown frequency: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis.

Neoplasms Benign, Malignant and Unspecified: Common: Skin papilloma. Unknown frequency: papilloma.

Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocytosis, leukocytosis.

Immune System Disorders: Unknown frequency: hypersensitivity.

Endocrine Disorders: Uncommon: hyperthyroidism hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis.

Psychiatric Disorders: Common: depression, insomnia. Uncommon: anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria.

Nervous System Disorders: Common: dizziness, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia.

Unknown frequency: brain edema, optic neuritis, peripheral neuropathy, lethargy, dysesthesia.

Eye Disorders: Common: eye hemorrhage, periorbital edema, eye pruritus, conjunctivitis, dry eye. Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, eye irritation. Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctival hemorrhage, conjunctivitis allergic, conjunctival hyperemia, ocular hyperemia, ocular surface disease, scleral hyperemia.

Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus.

Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, pericardial effusion, coronary artery disease, cyanosis, cardiac murmur. Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, ejection fraction decrease.

Vascular Disorders: Common: hypertension, flushing. Uncommon: hypertensive crisis, hematoma. Unknown frequency: shock hemorrhagic, hypotension, thrombosis.

Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, epistaxis, cough, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing.

Gastrointestinal Disorders: Common: pancreatitis, abdominal discomfort, abdominal distension, dyspepsia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dysgeusia, dry mouth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, gastritis, hemorrhoids, hiatus hernia, rectal hemorrhage, sensitivity of teeth, gingivitis.

Hepatobiliary Disorders: Common: hepatic function abnormal. Uncommon: hepatitis, jaundice. Unknown frequency: cholestasis, hepatotoxicity, hepatomegaly.

Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis, dry skin. Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis, swelling of face. Unknown frequency: erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy.

Musculoskeletal and Connective Tissue Disorders: Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, flank pain. Uncommon: musculoskeletal stiffness, muscular weakness, joint swelling. Unknown frequency: arthritis.

Renal and Urinary Disorders: Common: pollakiuria. Uncommon: dysuria, micturition urgency, nocturia.

Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia.

Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction.

Unknown frequency: breast induration, menorrhagia, nipple swelling.

General Disorders and Administration Site Conditions: Common: pyrexia, chest pain, pain (including neck pain and back pain), chest discomfort, malaise. Uncommon: face edema, gravitational edema, influenza-like illness, chills. Unknown frequency: feeling hot, localized edema.

Investigations: Common: blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, weight decreased, weight increased. Uncommon: hemoglobin decreased, blood lactate dehydrogenase increased, blood urea increased. Unknown frequency: blood insulin increased, very low density lipoprotein increased, blood parathyroid hormone increased, blood pressure increased.

6.3 Postmarketing Experience The following additional adverse reactions have been reported during post approval use of Tasigna. 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.

Cases of tumor lysis syndrome have been reported in Tasigna treated patients with resistant or intolerant CML. Malignant disease progression, high WBC counts and/or dehydration were present in the majority of these cases.

10 OVERDOSAGE Overdose with nilotinib has been reported, where an unspecified number of Tasigna capsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

16 HOW SUPPLIED/STORAGE AND HANDLING Tasigna (nilotinib) 150 mg capsules are red opaque hard gelatin capsules, size 1 with black axial imprint “NVR/BCR”. Tasigna (nilotinib) 200 mg capsules are light yellow opaque hard gelatin capsules, size 0 with the red axial imprint “NVR/TKI.” Tasigna capsules are supplied in blister packs.

150 mg Carton of 4 blister packs of (4x28) ........................................................................................NDC 0078-0592-87 Blisters of 28 capsules............................................................................................................NDC 0078-0592-51 200 mg Carton of 4 blister packs of (4x28) ........................................................................................NDC 0078-0526-87 Blisters of 28 capsules............................................................................................................NDC 0078-0526-51 Each blister pack contains one folded blister card of 28 capsules each, for dosing two in the morning and two in the evening at 12 hour intervals over a 7 day period.

Tasigna (nilotinib) capsules should be stored at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

T2010-104 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland © Novartis

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936

HEMATOLOGIC DISEASE

Clinical Oncology News • December 2011

Leukemia

MINORITIES

‘The next step in this line of research would be to evaluate other factors that may help us to understand these disparities and then to develop intervention based on them.’

continued from page 1 

Center at Johns Hopkins, in Baltimore, who was not involved with the research, the results raise many questions.

“It’s not clear from this study why these disparities exist,” Dr. Smith said.

“Whether they are a result of differences in access to care, quality of care or treatment response, demographic characteristics or biological differences, these are all possible reasons that need to be examined in future research.”

The study’s lead investigator, Manali Patel, MD, MPH, hematology-oncology postdoctoral fellow, Stanford Cancer Institute, in Stanford, Calif., told Clinical Oncology News that she and her colleagues set out to examine possible racial differences in ALL and AML incidence and outcomes after they noticed a lack of research on disparities in adult hematologic malignancies, despite the vast literature on this association in patients with solid tumors (see for example, Cancer Res 2011;71:640-644, PMID: 21135114).

To this end, they examined data from patients with ALL and AML registered in the Surveillance, Epidemiology and End Results (SEER) database between 1998 and 2008. The researchers conducted multivariable analyses to predict correlations between race and mortality, controlling for age, gender and selected

—Manali Patel, MD, MPH

chromosome translocations known to affect disease outcome.

The investigators found 2,299 cases of acute leukemia among blacks and 4,428 among Hispanics, in contrast to 22,035 among whites. Five-year mortality rates of both ALL and AML were 17% higher among blacks and 12% greater among Hispanic patients than among white patients (P<0.0001 for both). When they stratified the data according to type of leukemia, they discovered that black patients with ALL were 45% more likely to die than their white counterparts, and Hispanic patients were 46% more likely to die than white patients (P<0.0001).

Although the disparities between

mortality rates were not as large among patients with AML, they were still significant, the researchers found (hazard ratios, 1.12 and 1.06 for blacks and Hispanics, respectively, compared with whites; P<0.01 for both). Further adjustment for chromosome translocations did not significantly change these rates, the researchers reported.

Dr. Patel noted that the nature of the SEER database precluded the ability to account for patients’ socioeconomic status. “The next step in this line of research would be to evaluate other factors that may help us to understand these disparities and then to develop intervention based on them,” Dr. Patel said.

She said socioeconomic status is an important characteristic to investigate, because blacks and Hispanics in the United States are more likely to fall into a lower bracket and are known to have

more limited access to high-quality care than whites, she said.

Socioeconomic status also may affect adherence to, and completion of, the intensive and lengthy treatment regimens, particularly for patients with ALL, Dr. Smith noted.

“When you’re talking about a threeyear treatment period, it takes a strong support system as well as good social infrastructure to help patients get through therapy,” Dr. Smith said. “Individuals with lower socioeconomic status often have fewer social supports and fewer resources to help them get through such a treatment course.”

Whether the reasons for the disparities found in this study are a result of socioeconomic, treatment-related or biological causes—or “a complex interplay” of these factors, as Dr. Patel believes—it is premature to recommend any changes in the clinical treatment of black and Hispanic patients, the researchers emphasized.

—David Wild Lung

CT Screening and Lung Cancer Studied From New England Journal of Medicine

A

journal brief and editorial board commentary in a previous issue of Clinical Oncology News discussed a study that is the first to link screening with low-dose helical CT with reduced

EXPERT INSIGHT Balazs Halmos, MD Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons Section Head, Thoracic Oncology NewYork-Presbyterian/ Columbia

Despite a significant reduction in smoking rates, lung cancer remains a public health problem and a devastating illness when diagnosed in later stages. The at-risk population is very large, estimated to be 94 million in the United States alone. Therefore, the results of the landmark NLST

mortality in this complex disease (N Engl J Med 2011;365:395-409).

The study, led by members of the National Cancer Institute’s National Lung Screening Trial (NCI-NLST), enrolled 53,454 participants between the ages of 55 and 74 years. The patients were

deemed at high risk for lung cancer based on a history of cigarette smoking and/or a previous diagnosis of lung cancer. They were randomly assigned to undergo three annual screenings with either low-dose CT or single-view posteroanterior chest radiography. The researchers tracked the

participants through the end of 2009, collecting data on diagnosed cases of lung cancer as well as deaths from the disease.

The authors concluded that screenings with low-dose helical CT reduce mortality from lung cancer by 20% (P=0.004); however, the study results also highlighted concerns about the viability of lowdose helical CT as a screening tool. Further commentary is provided.

study of CT screening have been anxiously awaited since the first publications of the controversial but pioneering ELCAP [Early Lung Cancer Action Project] studies.

This study shows beyond any doubt that low-dose helical CT screening not just significantly improves the detection of early-stage, curable non-small cell lung cancer (mostly adenocarcinomas) in high-risk subjects (ages 55-74 with a 30 pack-year history of smoking), but also reduces the number of advanced lung cancer diagnoses, translating into a 20% reduction in lung cancer–related deaths and a 6.7% reduction in overall deaths.

These data strongly argue against one of the main concerns raised about CT screening (ie, an overdiagnosis bias).

Of course, this benefit was achieved

with a very significant number of positive CT screening results (40% of all CT-screened subjects had at least one abnormal finding), a very large number of additional radiography and a relatively manageable number of invasive procedures with limited complications overall as a result of screening.

Despite the noted benefit, a number of questions remain: 1. Is it cost-effective? (The number needed to screen with low-dose CT to prevent one death from lung cancer was 320!)

2. What is the definition of population to be screened? Could it be expanded to subjects with different risk profiles?

3. What is the duration of screening? The study did 3 annual screens but should such screens be then

continued, and if so, for how long?

4. Will the benefit be maintained when CT screening and follow-up procedures are performed in the community setting as opposed to leading academic centers?

5. What will be the consequences of added radiation exposure with regard to long-term risks, such as secondary cancers?

As there is no other similarly powerful study being done or planned, recommendations will need to be formulated based on this data set, and coverage decisions from insurers, principally Medicare, as well as guidelines put forth by expert panels will need to be watched. Regardless of all these issues yet to be sorted out, it seems quite clear-cut that CT screening for lung cancer is here to stay.

25

26

HEMATOLOGIC DISEASE

Clinical Oncology News • December 2011

Myeloma

Study Investigates Secondary Malignancies in Myeloma and MGUS From Blood

R

esearchers from the National Cancer Institute (NCI) and 2 hospitals in Sweden have identified potential non–treatment-related factors in the development of secondary malignancies, or plasma cell dyscrasias, following multiple myeloma (MM).

In a study published in Blood (Mailankody S et al. 2011;119:4086-4092, PMID: 21795746), researchers led by Sham Mailankody, MD, of the NCI and Washington Hospital Center in Washington, DC, identified—using a Swedish population database—8,740 patients diagnosed between 1986 and 2005 with

MM and 5,652 patients diagnosed with monoclonal gammopathy of undetermined significance (MGUS). Within this study population, they calculated standardized incidence rates for all secondary hematologic and nonhematologic malignancies for MM patients diagnosed before and after 1995, the year high-dose melphalan and autologous stem cell transplantation were introduced, and before and after 2000, the year immunomodulatory drugs were introduced.

Overall, the researchers found that MM patients had a more than 11-fold increased risk for developing acute myeloid leukemia (AML) and/or myelodysplastic syndromes (MDS), and that

this risk was similar both before and after 1995 and before and after 2000.

In short, within the study population, patient risk for secondary AML and/ or MDS following MM was the same both before and after the introduction of high-dose melphalan and the use of autologous stem cell transplantation.

MGUS patients had a more than 8-fold increased risk for developing AML and/or MDS, but this risk was confined only to patients with immunoglobulin G (IgG)/immunoglobulin A (IgA) MGUS; none of the IgM MGUS patients in the study population developed AML or MDS. Furthermore, based on what the authors characterized as

“small numbers,” there was a more pronounced risk for AML and/or MDS among MGUS patients in the study population with monoclonal protein concentrations greater than 1.5 g/dL. The authors acknowledged that the study had several limitations, including a lack of clinical and treatment information for the MM patients in the study population and the fact that the MGUS patients came from a clinical cohort and were screened for neither disease type nor process. Further study, they concluded, is needed. Nonetheless, these findings are potentially the first to identify increased risk for AML and/or MDS among patients with IgG/IgA MGUS.

pre-malignant condition: MGUS (n=5,652). The main outcome measure was the standardized incidence rates (SIRs), or observed cancers in the cohort divided by the expected number for the general population) for hematologic and nonhematologic malignancies. To evaluate the impact of potentially leukemogenic treatment, the authors evaluated the time periods before the introduction of high-dose melphalan followed by autologous stem cell transplant (1995) and the time period after the introduction of the immunomodulatory drugs thalidomide and lenalidomide

(Revlimid, Celgene; 2000).

The results of the study were compelling. Compared with the general Swedish population, patients with MM had a 1.26-fold higher risk for developing any second malignancy. The risk for developing a second hematologic malignancy was 2.04-fold higher, and a majority of this excess risk was contributed by AML/MDS (SIR=11.51). The researchers did not detect any differences in the risk of developing second malignancies when the periods of time before and after the introduction of stem cell transplant were compared. Unfortunately,

since most patients were treated with melphalan-based induction chemotherapy in the pretransplant era as well as with high-dose melphalan as a conditioning regimen prior to transplant, it is impossible to conclude to what extent melphalan contributed to the excess risk of AML/MDS. Similarly, the risk of developing a second malignancy was the same when the period of time before the introduction of the immunomodulatory drugs was compared with the period of time after their introduction.

Admittedly, the follow-up time period was short, and data concerning which patients were on these novel therapies were lacking from the analysis. One novel observation pertaining to the non-treated cohort was an excess risk for AML/MDS following the diagnosis of MGUS (SIR=8.01).

Because these patients were never exposed to antimyeloma therapy, this finding supports an underlying non– treatment-related cause of AML/ MDS. Although the numbers were small, the risk was higher in patients with a greater degree of paraprotein production.

transplantation and now immunomodulatory drugs, the overall survival of patients diagnosed with MM has steadily increased. Numerous studies have found an increased risk of secondary malignancies, most notably AML and MDS, in patients with MM treated with these therapies.

In their article in Blood, Mailankody et al ask an important question: Is the increased risk of AML/MDS in patients treated for MM solely a consequence of treatment, or is there an underlying tendency toward development of secondary malignancies in this patient population? Mailankody et al used a high-quality population-based study to determine the

risk of development of a secondary malignancy for all patients in Sweden diagnosed with either MM or MGUS between 1986 and 2005. The MGUS population was used as a control group to estimate the risk of secondary malignancy for patients with an underlying plasma cell dyscrasia in the absence of therapeutic intervention.

Results for MM (n=8,740) and MGUS (n=5,652) patients were compared with the Swedish population at large during this time frame. As anticipated, patients with MM had an increased risk of developing AML/ MDS (11.51-fold), and this risk did not vary relative to the treatment

standard during the evaluated time frame. Patients with MGUS also were found to have an increased risk of AML/MDS (8.01-fold). MGUS patients with higher IgG/IgA monoclonal-protein levels (>1.5 g/dL) were at highest risk, and no patients with IgM monoclonal proteins were found to develop AML/MDS. In addition, MM and MGUS patients were found to have an increased risk of non-melanoma skin cancers (SIR=2.22 and 3.30, respectively). These data suggest the important finding that not only the treatment of plasma cell dyscrasias, but in fact the disease itself is an important predisposing factor for development of AML/MDS.

EXPERT INSIGHT Jordan Schecter, MD Assistant Professor of Clinical Medicine Columbia University College of Physicians and Surgeons Hematologist/Oncologist NewYork-Presbyterian/ Columbia

For more than 40 years, hematologists have noted a troubling excess of AML and MDS following the diagnosis of MM. It remains unclear whether this is an inherent feature of the underlying disease, a result of treatment, or both. Mailankody and colleagues shed some light on this subject in their large, retrospective cohort study published recently in Blood.

Using the exceptionally complete cancer registry in Sweden, the researchers analyzed all patients with MM diagnosed between 1986 and 2005 (n=8,740). As a non-treated cohort, the researchers evaluated patients diagnosed with an asymptomatic, EXPERT INSIGHT Karen Carlson, MD, PhD Assistant Professor of Medicine Weill Cornell Medical College Assistant Attending Physician, Hematologist/ Oncologist NewYork-Presbyterian/ Weill Cornell

With the advent of melphalan, melphalan prednisone, high-dosed melphalan autologous stem cell

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Atlas of Diagnostic Oncology: Expert Consult: Online and Print

Arthur T. Skarin Elsevier/Mosby, December 23, 2009 This atlas, a collection of more than 2,500 images and drawings, combined with succinct, clinically focused text equips you with essential information on pathology, diagnostic studies, staging and clinical manifestations. Discussions on modern diagnostic PET imaging of cancer and expanded coverage on the side effects of chemotherapy are included.

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Cancer Risk Evaluation: Methods and Trends

Gunter Obe; Gary E. Marchant; Burkhard Jandrig; Holger Schutz; Peter M. Wiedemann John Wiley, June 21, 2011

ORDER OnlinE For pricing, a more complete review and easy ordering with a credit card, go to McMahonMedicalBooks.com.

We can supply any medical book in print, so if you don’t find the book you want, email your request with billing information to RMcMahon@McMahonMed.com.

If you are an author and would like your medical book featured in this book section, contact Ray McMahon, Publisher, at RMcMahon@McMahonMed.com.

The main focus is on the carcinogenic effects of ionizing and non-ionizing radiation, demonstrating the difficulties in accurately assessing those factors that may or may not pose a significant cancer risk. The book highlights various aspects of risk management.

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Clinical Radiation Oncology: Expert Consult Online and Print: Third Edition

Leonard L. Gunderson Elsevier/Saunders, October 31, 2011 From a multidisciplinary perspective, this book examines the therapeutic management of specific disease sites based on both single-modality and combined-modality approaches—providing you with the well-rounded, cutting-edge guidance you need to offer the most effective treatments.

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Drug Delivery in Oncology: From Basic Research to Cancer Therapy

Felix Kratz; Peter Senter John Wiley, December 20, 2011 This handbook and ready reference enables the efficient transfer of knowledge between different disciplines, from basic research to the clinician and vice versa. It is equally well suited for professionals, researchers and students in medical oncology and cancer biology.

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Handbook of Cancer Chemotherapy, Eighth Edition

Roland T. Skeel; Samir Khleif Lippincott Williams & Wilkins, May 18, 2011 This handbook provides complete coverage of the principles of rational chemotherapy, the chemotherapeutic and biotherapeutic agents available, the treatment of specific cancers and selected aspects of supportive care.

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MD Anderson Manual of Medical Oncology, Second Edition

Hagop M. Kantarjian; Robert A. Wolff; Charles A. Koller McGraw-Hill, April 22, 2011 A hands-on desk reference for the practicing oncologist, this book details the personalized multidisciplinary approach to cancer management pioneered by The University of Texas MD Anderson Cancer Center. It is intended to bring a pragmatic approach to cancer management that can serve as a guide for oncologists around the world.

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Understanding Skin Cancer Anatomical Chart

Anatomical Chart Company Lippincott Williams & Wilkins, February 8, 2011 This chart defines skin cancer and provides detailed illustrations of how it develops from sun exposure. It shows and discusses various types of ultraviolet radiation and how each kind penetrates the skin layers. It illustrates and shows photos of various types of precancer and cancer.

It lists the ABCD’s of malignant melanoma, shows how skin naturally works to prevent skin cancer and illustrates differences between sunscreen and sunblock.

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Year Book of Oncology 2011

Robert J. Arceci, MD, PhD Elsevier/Mosby, November 1, 2011 The Year Book of Oncology brings you abstracts of the articles that reported the year’s breakthrough developments in oncology, carefully selected from more than 500 journals worldwide. Expert commentaries evaluate the clinical importance of each article and discuss its application to your practice. There’s no faster or easier way to stay informed!

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28

HEMATOLOGIC DISEASE

Clinical Oncology News • December 2011

Multiple Myeloma

Evidence Mounts for Bisphosphonate Use in Multiple Myeloma Stockholm—Evidence continues to accumulate for the use of bisphosphonates in patients with multiple myeloma.

often in this setting are pamidronate and zoledronic acid.

However, Dr. Kumar cautioned that the duration of treatment “is still a question that needs to be answered.”

The initial results of the MRC Myeloma IX trial were presented at the In the initial report of the MRC Myelo- 2010 meeting of the American Socima IX trial, patients with myeloma ety of Clinical Oncology (ASCO) and who received zoledronic acid (Zometa, published that same year (Lancet Novartis) had improved overall surviv- 2010;376:1989-1999, PMID: 21131037). al (OS) compared with patients who In the trial, 1,960 myeloma patients received clodronic acid. In new sub- receiving either an intensive or nongroup analyses, zoledronic acid dem- intensive thalidomide-based chemoonstrated an OS benefit over clodronic therapy regimen were randomized to acid when both therapies were contin- receive 4 mg of zoledronic acid as an ued after disease progression. infusion every three to four weeks or “The relative benefit of zoledron- 1,600 mg of oral clodronic acid daily. ic acid was most profound for patients The study was not masked. treated for more than two years,” said Patients randomized to zoledronic Gareth Morgan, MD, Royal Marsden acid had a median survival extension Hospital, in Surrey, United Kingdom. of 5.5 months (P=0.04) compared with Presenting these subgroup analyses at those randomized to clodronic acid, the 2011 European Multidisciplinary according to the published data. ZoleCancer Congress (EMCC), Dr. Morgan dronic acid was also associated with reported that the relative advantages a two-month extension of progresof zoledronic acid over clodronic acid sion-free survival (PFS), although this extended to other outcomes, particu- fell just short of statistical significance larly skeletal-related events (SRE), over (P=0.07). However, the new data bolthe long term. Additionally, the benefits ster the evidence for a relative advanof the drug did not depend on the base- tage. For example, the two-month PFS line bone disease status. advantage is now significant (P<0.02), Shaji Kumar, MD, associate professor and subgroup analysis has demonstrat-

‘The relative benefit of zoledronic acid was most profound for patients treated for more than two years.’

—Gareth Morgan, MD

42.8%; P=0.0031) and those without bone lesions (9.6% v s . 1 7. 4 % ; P = 0.0 0 6 9 ) .

Th e reduction in new bone lesions among those with lesions at baseline (5.7% vs. 11.4%; P=0.00002) and those without (2.3% vs. 5.8%; P=0.035) also were significant.

When protection from SREs was calculated starting at two years of treatment, the relative advantage of zoledronic acid remained significant (P=0.0102) for the subsequent 42 months of follow-up. When protection was calculated starting at three years of

‘The two important messages here are bisphosphonates improve overall survival, and the benefit of improved outcomes both in terms of skeletal events and survival extends to the patient without any skeletal lesions at diagnosis. In other words, everyone benefits.’

—Shaji Kumar, MD

of medicine, Department of Hematology, Mayo Clinic, in Rochester, Minn., who was not involved with the study, called the findings “important.” They are not only a clear demonstration of benefit from bisphosphonates in multiple myeloma, he said, but provide the first evidence that bisphosphonates can improve overall survival. “The two important messages here are bisphosphonates improve overall survival, and the benefit of improved outcomes both in terms of skeletal events and survival extends to the patient without any skeletal lesions at diagnosis,” Dr. Kumar commented. “In other words, everyone benefits.”

According to Dr. Kumar, the results of the study “do not help us as much in the United States in terms of selection of bisphosphonates,” because clodronic acid is not approved by the FDA. He said the bisphosphonates used most

ed that the relative advantage of zoledronic acid, although not always statistically significant, was consistent across gender and International Staging System (ISS) class.

Additionally, the relative OS advantage of zoledronic acid persisted (P=0.02) when isolating those patients who received therapy for at least two years. Among patients treated for at least two years and who had disease progression, the OS was also significant (P=0.03) with a median advantage of seven months (34 vs. 27 months).

The protection against SREs, defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to control bone lesions, was significantly increased regardless of baseline bone disease status. This included patients with bone lesions at baseline (34.9% vs.

treatment, the numerical advantage of zoledronic acid persisted over the subsequent follow-up, although statistical significance was lost (P=0.1012). Analyzed by 12-month intervals from initial randomization, the relative advantage of zoledronic acid remained significant at 36 months and trended toward significance (P=0.0510) at 48 months.

The relative advantage at 60 months was about the same as at 48 months, but there were too few events to show statistical significance.

Importantly, treatment effectiveness was not countered by adverse events.

In the most recent analysis, the two therapies were compared in the intensive and non-intensive pathways relative to the therapies that the patients received. The only significant difference in the rate of serious adverse events (SAE) was for patients

in the non-intensive pathway who were treated with cyclophosphamide, thalidomide and dexamethasone (C-TD). In these patients, 58% of the zoledronic acid patients compared with 45% of the clodronic acid patients experienced SAE (P<0.05). No significant differences in treatmentemergent SAE between groups were identified, but zoledronic acid was associated with significantly higher rates of osteonecrosis of the jaw in both the intensive (5% vs. 0%; P<0.05) and non-intensive (5% vs. 1%; P<0.05) groups and with significantly higher thromboembolic events in the non-intensive C-TD group (20% vs.

12%; P<0.05).

Overall, the most recent analyses reinforce the initial results and suggest that the relative benefits extend over prolonged treatment, according to Dr. Morgan. Indeed, he characterized the relative benefit of zoledronic acid over clodronic acid in patients treated for more than two years as “profound.”

—Ted Bosworth

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Clinical Oncology News encourages letters to the editor.

Please send comments to khorty@mcmahonmed.com.

HEMATOLOGIC DISEASE

Clinical Oncology News • December 2011

29

Myelofibrosis/Leukemia

JAK Inhibitor Approved for Myelofibrosis Under its priority review program, the FDA has approved ruxolitinib (Jakafi, Incyte), the first drug approved to specifically treat patients with myelofibrosis (MF), a bone marrow disease.

The oral drug is approved for intermediate- or high-risk myelofibrosis, including primary MF, post–polycythemia vera MF and post–essential thrombocythemia MF. Patients with intermediate- and high-risk MF represent 80% to 90% of MF patients. Ruxolitinib is the first in a new class of drugs, known as a Janus K inhibitor, to be approved for any indication. The drug inhibits oral JAK1 and JAK2.

The approval was based on results from two randomized Phase III trials, COMFORT-I and COMFORT-II, which tested the drug in patients with post– polycythemia vera MF and post–essential thrombocythemia MF. Patients in both trials were resistant or refractory to available therapy or ineligible for allogeneic bone marrow transplantation. All

patients had enlarged spleens and were in need of treatment as a result of disease-related symptoms.

The COMFORT trials demonstrated that patients treated with ruxolitinib experienced significant reductions in splenomegaly. COMFORTI also demonstrated improvements in symptoms as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) v.2.0 electronic diary and the MFSAF Total Symptom Score (TSS), comprised of six symptoms (abdominal discomfort, pain under the left ribs, a feeling of early fullness, night sweats, bone

and muscle pain, and itching). Most patients on placebo experienced worsening of these same symptoms.

COMFORT-I compared ruxolitinib to placebo in 309 patients. The trial met its primary end point, showing that 41.9% of patients treated with the new drug had a 35% or greater reduction in spleen volume at 24 weeks, compared with 0.7% of patients on placebo (P<0.0001). A 35% reduction in spleen volume correlates to an approximately 50% reduction in spleen size on palpation. At week 24, the percentage of patients with a greater than or equal

to 50% improvement in the TSS was 45.9% for ruxolitinib and 5.3% for placebo (P<0.0001), with a median time to response of less than four weeks.

The COMFORT-II trial compared ruxolitinib to best available therapy in 219 patients. This trial also met its primary end point, showing that 28.5% of patients treated with ruxolitinib had a 35% or greater reduction in spleen volume at 48 weeks, compared with none of the patients in the best available therapy arm (P<0.0001).

The most common adverse reactions in both studies were thrombocytopenia and anemia. These events were manageable and rarely led to discontinuation of treatment. The most common non-hematologic adverse reactions were bruising, dizziness and headache. The most serious side effects occurring in patients treated with ruxolitinib included low blood platelet levels (thrombocytopenia), anemia, fatigue, diarrhea, shortness of breath (dyspnea), headache, dizziness and nausea.

Dasatinib Could Increase Risk for Pulmonary Hypertension The FDA has warned that dasatinib (Sprycel, Bristol-Myers Squibb) may increase the risk for pulmonary arterial hypertension (PAH).

A recent communication from the agency was prompted by 12 postmarketing surveillance reports of PAH in patients receiving the drug. According to the letter, although most of these individuals also had comorbid illnesses and were receiving concomitant medications, dasatinib “was the most likely cause” of PAH. “This information is definitely worth keeping in mind, particularly in patients who do develop PAH, but I don’t see it making a significant difference in prescribing behavior,” said Richard Stone, MD, professor, Department of Medicine, Harvard Medical School and director, Adult Leukemia Program, Dana-Farber Cancer Institute, Boston.

The FDA communication noted the 12 patients had been treated for varying lengths of time before developing PAH, with one individual experiencing the complication after more than one year of receiving the drug. The FDA

said clinicians were able to induce a degree of hemodynamic and clinical improvement in some of the 12 cases by discontinuing treatment.

The communication did not specify the ages of the patients who developed PAH or whether they were being treated for Philadelphia chromosome– positive chronic myeloid leukemia or acute lymphoblastic leukemia. It did emphasize that many of the patients had comorbid illnesses and were being administered other medications when they developed PAH. “There may be a combination of factors contributing to the development of PAH in patients taking Sprycel,” the FDA letter stated.

In light of the reports, the FDA is urging clinicians to screen patients for underlying cardiopulmonary disease prior to initiating dasatinib treatment and to remain vigilant throughout treatment for the symptoms of PAH, which include dyspnea, fatigue, hypoxia and edema.

Because diagnosis of PAH requires

invasive right heart catheterization, clinicians should first rule out other possible known adverse events of dasatinib, including pleural effusion, pulmonary edema, anemia and lung infiltration, the FDA said. If PAH is still suspected, a right heart catheterization should be conducted with normal pulmonary capillary wedge pressure (<15 mm Hg) with elevated pulmonary artery pressure (mean pressure >25 mm Hg) indicating the presence of PAH. The 12 cases reported to the manufacturer were confirmed in this way, the FDA said.

The agency suggested clini- cians can determine whether PAH is dasatinib-related by interrupting treatment and observing any improvements.

“If PAH is confirmed, Sprycel should be permanently discontinued,” the FDA advised.

—David Wild Dr. Stone has received clinical research support from Novartis and is an ad hoc consultant for Ariad Pharmaceuticals.

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30

POLICY & MANAGEMENT

Clinical Oncology News • December 2011

Insurance

IN STORE continued from page 1 

new product popular with employers adds percentage copayments to physician visits. Insurers have evidence that higher consumer payments alter health care choices made by patients. They are working to make consumers more aware of the costs involved in controlling the disease states that impact insurers the most. Oncology is one of those disease states.

Most providers have seen increased requirements for pre-authorization.

Insurers want to use the knowledge they’ve gained by studying and profiling treatments and providers. They believe that sharing this knowledge with consumers from the insurers’ point of view is part of creating the new benefit design. For example, plans are increasing consumer payments for selected services that cost more than others in many new contracts, and they are in the process of bundling costs for service through a continuum. Costs of hospitalizations resulting from toxicities of treatment may be bundled with payment for the treatment and providers would be responsible for those costs. This rewards physicians and programs that manage patients without hospitalizations and penalizes those who do not. It also punishes physicians and programs in high-cost areas more than those who work in low-cost areas.

Another change in benefit design that insurers are examining is developing their own specialty pharmacies for oncology products to lower their drug costs. The insurer benefits by moving into the distribution arena for high-cost pharmaceuticals, and thus manages one

Correction

Insurers are examining developing their own specialty pharmacies for oncology products to lower their drug costs.

The insurer benefits by moving into the distribution arena for high-cost pharmaceuticals, and thus manages one of their largest unknowns more closely.

of their largest unknowns more closely. Insurers also are employing physicians and evaluating the benefit of having a very tightly controlled provider workforce. While the number of physicians employed by insurance companies is currently small and mainly involves primary care, the lessons learned today will be passed through benefit design that will impact oncology tomorrow.

For oncology, the focus seems to be determining the right mix between limiting market providers and services and maintaining quality services and treatments. Insurers already have begun to reduce the numbers of contracting entities by reducing reimbursements.

Clinical Oncology News regrets the following error.

Thanks for bringing it to our attention.

To the Editor:

T

he article by Gina Shaw in the November issue of Clinical Oncology News, “Drug Shortage Sparks Mayhem in Many Oncology Pharmacies,” reports patients are unable to access our product Doxil (doxorubicin HCl liposome injection), a critical therapy for patients with certain types of cancer. We deeply regret the circumstances that have caused this shortage. We are writing to address some points in Ms. Shaw’s article.

Although there are a variety of factors causing drug shortages nationwide in many different disease areas, the Doxil shortage is due to the inability of our supplier to consistently produce the medication. Equipment failures have been a significant cause of these manufacturing delays. Such equipment failures require investigation and repair, sometimes resulting in the shutdown of entire production lines, which is the case for Doxil.

Importantly, we wanted to clarify that we’ve contracted with Ben Venue Laboratories, Inc.—not Bedford—to manufacture Doxil. Thus, the current challenges faced

by Bedford have no relation to or impact on Doxil supply.

While we work with our contract manufacturer to resolve these production issues, Doxil will be intermittently available during the next several months. We recognize

This will continue as insurers find fewer contracting entities to be easier to monitor and coordinate. Many payers are concerned about costly out-of-state providers, inappropriate utilization by some providers and lack of quality. All insurers would like to eliminate waste and fraud. Clearly, there is a move toward shifting more risk to providers through bundled payments.

State Medicaid programs are cutting back drastically. It seems each week, we see more reductions in state services and news that others are in deficit conditions that will require more cuts.

According to a new report by the Kaiser Commission on Medicaid and the

Uninsured, officials in states throughout the nation are cutting medical providers’ payments, turning more to managed care strategies and pushing some costs on to patients in order to compensate for the biggest one-year increase in spending in the program’s history (The Commonwealth Fund, October 31, 2011).

Additionally, workers are being asked to take on more of their health care costs, hitting high-cost chronic care particularly hard. Figures released in September from the Employer Health Benefits Survey 2011, Kaiser Family Foundation, and Health Research & Educational Trust show that 12% of workers have deductibles of $2,000 or more today and coinsurance of 20% without upper limits.

As the Congressional “super committee” meets to find $1.2 trillion to trim from the federal budget, many observers are wondering how deficit-reduction efforts will impact Medicare. It is certainly a reality that there will be changes made to Medicare between now and Jan. 1, 2012, that are beyond those proposed in the planned 2012 reimbursements. It is imperative that providers maintain awareness of the changes.

It seems unlikely that providers will have much input into the Medicare and Medicaid changes that are driven by lack of funding and the desire for reduced government spending on health care services by many of our politicians. However, there is opportunity to open doors in the insurance and employer markets, if we are willing to create new paradigms away from feefor-service medicine.

—Mary Lou Bowers Mary Lou Bowers is President & CEO of The Pritchard Group, LLC, Rockville, Md. www.thepritchardgroup.net

this is a challenging situation and are committed to continuing to work with our supplier to ensure that as we receive new and limited supply of Doxil, it is quickly made available through the Doxil Creating Awareness & Reinforcing Education Support (C.A.R.E.S.) Physician Access Program to patients next on the wait list.

Since its launch on Aug. 5, Doxil has been received by approximately 2,000 patients through the Doxil C.A.R.E.S. Physician Access Program. The story notes that patients were already on ‘the wait list’ as of Aug. 9. That is not accurate.

On that date, we were still validating enrollment forms and lining up physician requests to the modest and limited supplies announced available on Aug. 5, in conjunction with the program. Importantly, we have provided and will continue to provide regular updates to the FDA on the progress of the allocation program and the Doxil supply situation. Program information and regular updates we’ve shared with the health care community are available at www.DOXIL.com.

We encourage you to update your readers by issuing a correction clarifying that Bedford is not our contracted Doxil manufacturer.

Thank you.

Sincerely, Monica Neufang Business Unit Communication Leader, Immunology & Oncology Global Pharmaceuticals Communication & Public Affairs

BRIEF SUMMARY OF PRESCRIBING INFORMATION WARNING: QT PROLONGATION FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided [see Warnings and Precautions].

INDICATIONS AND USAGE FARESTON® is an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed.

DOSAGE FORMS AND STRENGTHS Tablet is 60 mg, round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side.

CONTRAINDICATIONS Hypersensitivity to the Drug FARESTON is contraindicated in patients with known hypersensitivity to the drug.

QT Prolongation, Hypokalemia, Hypomagnesemia Toremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia.

WARNINGS AND PRECAUTIONS Prolongation of the QT Interval Toremifene has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death.

Toremifene should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated [see Drug Interactions and Clinical Pharmacology].

Hypercalcemia and Tumor Flare As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and, if hypercalcemia is severe, FARESTON treatment should be discontinued.

Tumorigenicity Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available.

Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene [see Nonclinical Toxicology].

General Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment [see Warnings and Precautions]. Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia.

Laboratory Tests Periodic complete blood counts, calcium levels, and liver function tests should be obtained.

Use in Pregnancy Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

Women of Childbearing Potential FARESTON is indicated only in postmenopausal women. However, premenopausal women prescribed FARESTON should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur.

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trials Experience Adverse drug reactions are principally due to the antiestrogenic actions of FARESTON and typically occur at the beginning of treatment.

The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related.

North American Study FAR60 n = 221

TAM20 n = 215

Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4% Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction).

Serious adverse reactions occurring in at least 1% of patients receiving FARESTON in the three major trials are listed in the table below.

Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively [see Clinical Studies].

Adverse Reactions Cardiac Cardiac Failure Myocardial Infarction Arrhythmia Angina Pectoris Ocular* Cataracts Dry Eyes Abnormal Visual Fields Corneal Keratopathy Glaucoma Abnormal Vision/Diplopia Thromboembolic Pulmonary Embolism Thrombophlebitis Thrombosis CVA/TIA Elevated Liver Tests** AST Alkaline Phosphatase Bilirubin Hypercalcemia

North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) 1 (<1) 3 (1.5) -

1 1

(10) (9) (4) (2) (1.5)

16 (7.5) 16 (7.5) 10 (5) 2 (1) 2 (1) -

1 -

(2)

2 (1) 2 (1) 1 (<1) -

1 1 1 -

(<1) (<1) (<1)

4 24 4 6

30 16 2 1

(19) (10) (1) (<1)

2 2 -

(1) (1)

22 20 8 4 3 4 1

(<1)

11 (5) 41 (19) 3 (1.5) 6 (3)

(2) (11) (2) (3)

(<1) (<1)

(<1)

1 (<1) 2 (1) -

2 (1) 3 (1.5) 1 (<1)

3 (1.5) 1 (<1) 1 (<1) 2 (1)

-

3 (1.5)

5 (3) 1 (<1) 1 (<1) -

(<1)

4 (2) 3 (1.5) 4 (2)

1 (<1) 3 (1.5) 4 (2) 4 (2)

22 (15) 13 (9) 1 (<1) -

32 (15) 18 (8) 2 (1) -

35 (17) 31 (15) 3 (1.5) -

1 1

(<1)

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

Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors.

The incidence of AST elevations was greater in the 200 and 240 mg FARESTON dose arms than in the tamoxifen arms. Higher doses of FARESTON were also associated with an increase in nausea.

Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor.

Post-marketing Experience The following adverse reactions were identified during post approval use of FARESTON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions reported during post approval use of FARESTON have been consistent with clinical trial experience. The most frequently reported adverse reactions related to FARESTON use since market introduction include hot flash, sweating, nausea, and vaginal discharge.

DRUG INTERACTIONS Drugs that Decrease Renal Calcium Excretion Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. Agents that Prolong QT The administration of FARESTON with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated [see Boxed Warning and Warnings and Precautions].

Effect of Strong CYP3A4 Inducers on Toremifene Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s Wort, lower the steady-state concentration of toremifene in serum.

Effect of Strong CYP3A4 Inhibitors on Toremifene In a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene Cmax and AUC by 1.4- and 2.9-fold, respectively.

N-demethyltoremifene Cmax and AUC were reduced by 56% and 20%, respectively.

The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning and Warnings and Precautions].

Effect of Toremifene on CYP3A4 Substrates In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and -hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and -hydroxymidazolam Cmax and AUC were reduced by less than 20%.

Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely.

Effect of Toremifene on CYP2C9 Substrates In a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide Cmax and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide Cmax and AUC. Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with FARESTON should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure).

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

In animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies.

Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo-fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly.

Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits.

In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis).

Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol in utero.

Nursing Mothers It is not known if toremifene is excreted in human milk. Toremifene is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FARESTON, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use There is no indication for use of FARESTON in pediatric patients.

Geriatric Use The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.

Renal Impairment The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function.

Hepatic Impairment The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.

Race The pharmacokinetics of toremifene in patients of different races has not been studied.

Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted.

OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement.

Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient.

Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

CLINICALPHARMACOLOGY Mechanism of Action Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mammary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, i.e., its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor.

Pharmacodynamics Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH).

Effects on Cardiac Electrophysiology The effect of 20 mg, 80 mg, and 300 mg of toremifene on QT interval was evaluated in a double-blind, randomized study in healthy male subjects aged 18 to 45 years. The QT interval was measured at steady state of toremifene (Day 5 of dosing), including the time of peak plasma concentration (Tmax), at 13 time points (4 ECGs/time point) over 24 hours post dose in a time matched analysis. The 300 mg dose of toremifene (approximately five times the highest recommended dose 60 mg) was chosen because this dose produces exposure to toremifene that will cover the expected exposures that may result from potential drug interactions and hepatic impairment [see Drug Interactions].

Dose and concentration-related increases in the QTc interval and T wave changes were observed (see Table 1). These effects are believed to be caused by toremifene and N-demethyltoremifene. Toremifene had no effects on heart rate, PR and QRS interval duration [see Boxed Warning and Warnings and Precautions].

Table 1: QTc Prolongation in Healthy Male Volunteers Treatment Arm Toremifene 20 mg (N = 47) Toremifene 80 mg (N = 47) Toremifene 300 mg (N = 48)

Mean (90% CI) ΔΔQTc, ms 7 (0.9, 13.6) 26 (21.1, 31.2) 65 (60.1, 69.2)

ΔQTc > 60 ms (n, %) 0 2 (4.3%) 43 (89.6%)

QTc > 500 ms (n, %) 0 0 5 (10.4%)

Pharmacokinetics Absorption – Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady state concentrations were reached in about 4-6 weeks.

Distribution – Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly albumin.

Metabolism – Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state.

Following multiple dosing with toremifene in 20 healthy volunteers, plasma toremifene exposure was lower on Day 17 compared to Day 5 by approximately 14%. N-demethyltoremifene exposure was higher on Day 17 compared to Day 5 by approximately 80%. Based on these data and an in vitro induction study in human hepatocytes, auto- induction of CYP3A4 by toremifene is likely. The effect of auto-induction on efficacy was likely captured following prolonged dosing in the clinical studies.

Elimination – The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days.

Elimination half-lives of major metabolites, N-demethyltoremifene and (Deaminohydroxy) toremifene, were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5 L/h. Toremifene is eliminated as metabolites primarily in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation.

Renal insufficiency – The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and patients with impaired kidney function.

Hepatic insufficiency – The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients.

Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.

Geriatric patients – The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.

Food – The rate and extent of absorption of FARESTON are not influenced by food; thus FARESTON may be taken with or without food.

Race – The pharmacokinetics of toremifene in patients of different races has not been studied.

Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (approximately 1/50 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (approximately 1/15 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human estrogen agonists/antagonists that have primarily estrogenic activity in mice. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (approximately 1/3 and 1.4 times, respectively, the daily maximum recommended human dose of 60 mg, on a mg/m2 basis).

Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests).

Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes).

Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (approximately 4 times and 1/50 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (approximately 1.5 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/3 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 52 weeks.

PATIENT COUNSELING INFORMATION Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs.

FARESTON may harm the fetus and increase the risk for pregnancy loss [see Warnings and Precautions and Use in Specific Populations].

Premenopausal women using FARESTON should use nonhormonal contraception during treatment and should be apprised of the potential hazard to the fetus should pregnancy occur [see Warnings and Precautions].

Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur.

Patients who must take medications known to prolong the QT interval, or potent CYP3A4 inhibitors, should be informed of the effect of toremifene on QT interval. Toremifene has been shown to prolong the QTc interval in a dose-related manner [see Boxed Warning, Warnings and Precautions, and Clinical Pharmacology].

Specific interactions with foods that inhibit CYP3A4, including grapefruit juice, have not been studied but may increase toremifene concentrations. Patients should avoid grapefruit products and other foods that are known to inhibit CYP3A4 during FARESTON treatment.

Certain other medicines, including over-the-counter medications or herbal supplements (such as St. John’s Wort) and toremifene, can reduce concentrations of coadministered drugs [see Drug Interactions].

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

2E Rev. 03/2011

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Important safety information: FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia.

Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. FARESTON is contraindicated in patients with known hypersensitivity to the drug. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor flare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively.

References: FARESTON® Prescribing Information, 2011. Data on file, GTx, Inc.

Please see brief summary of prescribing information including boxed warning on the following page.

For more information about Fareston call 1-877-362-7595 or visit www.fareston.com