clinical oncology news - October 2011, digital edition hematology edition

Independent News on Advances in Cancer Care

Hematology/Oncology Edition clinicaloncology.com • October 2011 • Vol. 6, No. 10

LETTER TO THE EDITOR

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Victor Vogel, MD, faces off against Steven Vogl, MD, over breast cancer prevention.

PRN

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M aurie Markman, MD, discusses the meaning of clinical benefit rate.

Clinical Conundrums: A Quiz for the Community Oncologist.

SOLID TUMORS

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Using Oncotype DX recurrence score to select adjuvant chemotherapy. Is it beyond the state of the art?

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News from recently published

Is That Lung Cancer Drug Right For Your Patient?

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f you treat lung cancer, you probably select a drug regimen for your patients based largely on the outcomes of large, randomized clinical trials. But those trials may not be valid for a significant percentage of your patient base—women, minorities and the elderly.

In a study released at the recent 14th World Conference on Lung Cancer, researchers from the FDA reported that enrollment in major clinical trials of agents approved to treat non-small cell lung cancer (NSCLC) significantly underrepresents these three groups.

Between January 2000 and December

journal studies regarding solid tumors.

see Your Patient, page 10 

EDITORIAL BOARD COMMENTARY HematOlogic DISEASE

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Higher lenalidomide dose yields better response in MDS, but questions linger.

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Secondary malignancies in multiple myeloma explored.

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News from recently published journal studies on hematologic malignancies.

EDUCATIONAL REVIEW

Management of Oral Mucositis in Cancer Patients Between pages 16 and 17

Vogl, NY, Calls for Annual Lung CT Scans Now To Save Lives!

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n Aug. 4, 2011, the National Cancer Institute’s Division of Cancer Prevention finally published the first results of the National Lung ScreenVogl, ing Trial in The New Eng- Steven MD land Journal of Medicine.1 The trial design and the paper as written have many problems, but the biggest problem by far is the timidity of the conclusions and the failure to recommend immediate application.

A positive effect of computed tomography (CT) screening on lung cancer see SCREENING, page 12

In Elderly MCL Patients …

Maintenance With Rituximab Doubles Remission Duration

London—Rituximab maintenance therapy significantly prolongs duration of remission in elderly patients with mantle cell lymphoma (MCL) and should be considered the new standard of care, according to a study by German researchers. In patients who responded to induction therapy, duration of remission doubled for those who received maintenance with rituximab (Rituxan, Genentech) compared with patients who received maintenance with interferon (IFN)-alfa, according to results from a see RITUXIMAB, page 25 

POLICY & MANAGEMENT

Succeeding in Today’s Oncology Arena

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hat makes a successful community cancer center? With the idea that practices can learn tips on how to succeed from others in the same boat, Clinical Oncology News turned to Florida Cancer Specialists (FCS) for some practice pearls. From a small oncology practice founded in 1984, FCS has grown into a dominant statewide force in cancer care. According to FCS, the organization now employs more than 1,000 people, including 100 physicians and 60 nurse practitioners,

McMahonMedicalBooks.com MD Anderson Manual of Medical Oncology, Second Edition Hagop M. Kantarjian; Robert A. Wolff; Charles A. Koller

For more information, see page 32.

and has 270,000 active patients.

Throughout its dramatic growth, FCS has kept a close eye on maintaining quality, according to founder William N. Harwin, MD, lead physician and president of FCS. “It’s a challenge to manage so many physicians,” he said. “We’re always working to refine our quality assurance initiatives.” According to Dr. Harwin, one of the keys has been the extreme care that FCS takes when bringing other practices into see SUCCEEDING, page 8 

FDA News Crizotinib (Xalkori, Pfizer) approved for NSCLC. See page 5.

Now Approved

ADCETRIS and the ADCETRIS logo are trademarks and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. Š 2011 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA US/BVP/2011/0046

ADCETRIS.com

CLINICAL ONCOLOGY NEWS

Clinical Oncology News • October 2011

EDITORIAL BOARD

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

Breast Cancer

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

Hematologic Malignancies

Andrew Seidman, MD

Jennifer R. Brown, MD, PhD

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

Gastrointestinal Cancer Edward Chu, MD University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Cathy Eng, 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

Harry Erba, MD, PhD University of Michigan Ann Arbor, MI

Shaji Kumar, MD Mayo Clinic Rochester, MN

Richard Stone, MD

Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic Cancer

Bioethics

Susan K. Seo, MD

Joseph P. DeMarco, PhD

Memorial Sloan-Kettering Cancer Center New York, NY

Cleveland State University Cleveland, OH

Oncology Nursing

Paul J. Ford, PhD

Betty Ferrell, RN, 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

Pharmacy

Mary Lou Bowers, MBA Cindy O’Bryant, PharmD University of Colorado Cancer Center Denver, CO

The Pritchard Group Rockville, MD

Rhonda M. Gold, RN, MSN Sara S. Kim, PharmD The Mount Sinai Medical Center New York, NY

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

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

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

Edward S. Kim, MD

Joseph V. Pergolizzi Jr., MD

University of Texas, MD Anderson Cancer Center Houston, TX

Johns Hopkins University School of Medicine Baltimore, MD

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

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

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.

Charles F. von Gunten, MD

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.

University of California, San Diego, CA

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

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CLINICAL ONCOLOGY NEWS

Clinical Oncology News • October 2011

Letter to the Editor

Breast Cancer Prevention: Vogel Vs. Vogl Response to “Is It Good to Prevent Breast Cancer With Exemestane?”

To the Editor:

I

am writing to provide necessary clarification in response to the editorial board commentary written by Steven Vogl, MD, in the July 2011 issue of Clinical Oncology News. Dr. Vogl misrepresents, unfortunately, a number of the facts related to both tamoxifen and exemestane for the prevention of breast cancer.

First, no one has ever advocated “putting every woman in the developed world on five years of medicines that will make many of them miserable ….” Apparently, Dr. Vogl has not read the quality-of-life studies1-3 that accompanied the publication of the Breast Cancer Prevention trial in 1998,4 the STAR trial in 20065 (updated in 20106) and the IBIS-I study in 2002.7 It is simply not correct, as Dr. Vogl alleges, that these treatments “may give many premature osteoporosis, and may have long-term deleterious consequences we cannot even imagine.” It is quite evident that tamoxifen and raloxifene, rather than causing osteoporosis, actually reduced the incidence of fractures. There is also no evidence from the MAP.3 study that there is a problem with osteoporosis. In fact, the adjuvant treatment trials with aromatase inhibitors show that monitoring bone density and treating with timely bisphosphonate therapy not only prevents osteoporosis but also does not lead to an increased risk for fracture.

While Dr. Vogl is of the opinion that “we should not recommend breast cancer prevention with exemestane,” he fails to recognize that the American Society of Clinical Oncology (ASCO)8 and an international panel of experts9 have recommended breast cancer risk reduction with either tamoxifen for premenopausal or postmenopausal women or raloxifene for postmenopausal women. ASCO has not yet made a recommendation about exemestane.

He also says that “it is no surprise that the NSABP P1 trial demonstrated that tamoxifen prevents breast cancer, nor is it a surprise that the MAP.3 trial shows that exemestane prevents breast cancer.” He forgets that in the early 1990s, when the Breast Cancer Prevention Trial (P1) was being designed, there were many critics who said that tamoxifen could not possibly reduce the risk for breast cancer. Only when a properly conducted, prospective, randomized clinical trial showed convincingly a 49% reduction in the incidence

of invasive breast cancer among high-risk pre- and postmenopausal women were some of the critics silenced. The demonstration of a reduction in the risk for contralateral breast cancers among women with first breast cancer taking tamoxifen was not sufficient for the FDA to grant a risk-reduction labeling for tamoxifen. It would have been helpful to all of us, and would have saved millions of dollars, if the FDA had shared Dr. Vogl’s opinion that “the prevention trials were almost guaranteed to be positive for reduction in breast cancer incidence.”

They were not, as he argues, a waste of money and effort. Rather, they were a careful, thoughtful, prospective demonstration of the effectiveness of tamoxifen or raloxifene for the reduction of breast cancer risk and a demonstration of their safety in high-risk women. He also neglects to mention that careful risk–benefit analyses have been conducted and published to show that, for appropriate groups of high-risk women, tamoxifen or raloxifene affords great net benefit.10,11 Dr. Vogl argues, “The real question, which remains to be answered, is do these agents benefit the population of women exposed to them and how much do they benefit?” This question has been asked and answered elegantly in two publications that use the information derived from the published risk-reduction trials.

Dr. Vogl uses the argument that breast cancer “has spawned a huge industry aimed at early detection that produces many negative biopsies, painful procedures, and repeated testing that causes lots of anxiety and loss of time.” He fails to recognize, however, that risk reduction with a selective estrogen receptor modulator (SERM) or an aromatase inhibitor averts incalculable morbidity and suffering among the women who derive the benefit of these pharmacologic interventions. Does he also argue that it is not worth treating hypertension or hypercholesterolemia for reduction in the risk for stroke and heart attack?

+

Victor G. Vogel, MD Director, Geisinger Cancer Institute Geisinger Health System

A mortality reduction trial for an agent that reduces the incidence of a disease would require hundreds of thousands of women in the trial.

While Dr. Vogl wonders whether it is good to prevent breast cancer with a specific agent like exemestane, tamoxifen or raloxifene, ASCO believes that it is appropriate based on the published peer-reviewed evidence. While he says that “none of the breast cancer prevention studies have come close to demonstrating improvement in quality of life,” he fails to mention that they have not shown a significant detriment or decrease in quality of life either. He also makes the tired argument that neither cause-specific mortality nor all-cause mortality has been diminished, but these end points were never the stated intention of any of the risk-reduction trials.

A mortality reduction trial for an agent that reduces the incidence of a disease would require hundreds of thousands of women in the trial. The fact that both the SERMs and exemestane reduce the incidence of cancer is sufficient to demonstrate a commendable and commensurate reduction in morbidity.

Why does Dr. Vogl discount a reduction in morbidity and incidence as unimportant? Why does a prevention study need to show a reduction in mortality to be a significant public health achievement? Why do women have to live longer for us to say that an agent that reduces breast cancer incidence by 50%—or 65% in the case of exemestane—is unimportant? Living well without breast cancer for many women will be as important as living longer.

Dr. Vogl argues unconvincingly that “the populations at risk are crudely defined.” Actually, the studies very carefully defined at-risk subjects and included only women with increased five-year Gail model

risk scores or who had lobular carcinoma in situ. He also alleges erroneously that “there is a great deal of acute toxicity during therapy,” but offers no data to support this claim. In fact, the published data demonstrate that there is very little acute toxicity. The dropout rate in both the NSABP P1 and STAR trials met the design assumptions. If there had been “a great deal of acute toxicity,” as he alleges, the dropout rate would have been significantly higher.

Dr. Vogl criticizes the eligibility criteria used for the NSABP P1 trial, and decries that fact that the Gail model does not include cases of known hereditary breast cancer. He overlooks the fact that it would be virtually impossible to randomize known mutation carriers to a placebo-containing clinical trial, and he also overlooks the fact that fewer than one in 600 women carry such deleterious mutations. In contrast, as many as 15% of women are at increased risk using the Gail model that was employed in the NSABP PI and STAR trials, and published estimates show that 15% of the population would meet criteria for being at “high risk” using the Gail model.

Dr. Vogl also claims that the agents prevent the “less aggressive cancers only,” but overlooks the information that says they prevent more than 70% of hormone-responsive tumors. Women can die from these malignancies, and preventing them, by implication, prevents death.

He also claims that “hot flashes and especially joint pain can be very troublesome,” but very few women dropped out of the trials because of these reasons.

He also claims that compliance would be worse in women taking exemestane, but the MAP.3 study showed no indication of a high rate of discontinuation due to treatment toxicity. Although it is remotely possible that the quality-of-life instruments used by the authors in the MAP.3 study were “too crude to measure the misery and discomfort” associated with the trial, patients would have indicated toxicity by leaving the trial in large numbers, which they did not do.

Dr. Vogl discounts the fact that only 26 women would need to be treated with exemestane to prevent one breast cancer, and he ignores the comparability of this number to the number needed to treat with statins to prevent one stroke or heart attack or the number of patients who need to take antihypertensive medication to prevent similar cardiovascular events. see VOGEL, page 6 

FDA NEWS

Clinical Oncology News • October 2011

Crizotinib Approved For Late-stage NSCLC

U

nder its accelerated approval program, the FDA has approved crizotinib (Xalkori, Pfizer) for patients with locally advanced or metastatic, nonsmall cell lung cancers (NSCLC) that express the abnormal anaplastic lymphoma kinase (ALK) gene.

The drug is being approved with a companion diagnostic test, the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular), which will identify patients who have the abnormal gene.

Approximately 1% to 7% of patients with NSCLC have the ALK gene abnormality, which causes cancer development and growth. Patients with this form of lung cancer are typically nonsmokers. Crizotinib works by blocking kinases, including the protein produced by the abnormal ALK gene. Crizotinib, which is available in pill form, is taken twice a day as a single-agent treatment.

Crizotinib’s safety and effectiveness were established in two multicenter, single-arm studies enrolling 255 patients with late-stage ALK-positive NSCLC. A sample of a patient’s lung cancer tissue

was collected and tested for the ALK gene abnormality prior to study enrollment. The studies were designed to measure objective response rate (ORR).

Most patients in the studies had received prior chemotherapy.

In one study, the ORR was 50% with a median response duration of 42 weeks.

In another, the ORR was 61% with a median response duration of 48 weeks.

The most common side effects reported in patients receiving crizotinib included vision disorders, nausea, diarrhea, vomiting, edema and constipation. Vision disorders included visual

impairment, flashes of light, blurred vision, floaters, double vision, sensitivity to light and visual field defects. Crizotinib use also has been associated with pneumonitis, which can be life-threatening. Patients with treatment-related pneumonitis should permanently stop treatment with crizotinib. The drug should not be used in pregnant women.

TM

Editorial Staff Kate O’Rourke, Managing Editor korourke@mcmahonmed.com Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com James Prudden, Group Editorial Director David Bronstein, Editorial Director, Hospital Group Robin B. Weisberg, Manager, Editorial Services Elizabeth Zhong, Associate Copy Chief

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CLINICAL ONCOLOGY NEWS

Clinical Oncology News • October 2011

Letter to the Editor

for prevention now assumes no progress in the treatment of breast cancer in the future.” On the contrary, most preventionists are hopeful that treatment advances will occur. However, in the 40 years of the War on Cancer, we have not yet seen definitive cures for all breast cancers. Prevention is a very prudent option for those women at increased risk for the disease.

Admittedly, women at lower or average risk are not good candidates for prevention, and we should reserve treatment for those women when they do develop their disease. For women at increased risk, however, a targeted prevention strategy is both prudent and recommended.

Dr. Vogl notes that the eligibility for the MAP.3 and P1 trials was open to women at least 60 years old or to younger women with other identified risk factors putting their five-year breast cancer risk at 1.66% or greater. He then goes on to make the erroneous statement that this is “equivalent to that of the population of 60-yearold women.” A risk of 1.66% in five years is the average risk for a 60-year-old North American white woman. This means that half of the 60-year-old population of women would not be eligible for breast cancer risk reduction, and he also ignores the fact that there are racial and ethnic differences in baseline breast cancer incidence rates that would make large proportions of non-white women ineligible using the published criteria for the riskreduction trials.

Just as no one proposes to put all individuals on statin therapy or antihypertensive therapy, no one in the prevention community is advocating treating all

women with either SERMs or an aromatase inhibitor for the reduction of breast cancer risk. The field of breast cancer risk reduction is far more sophisticated, and we need to educate all clinicians about the remarkable achievements of the published breast cancer risk-reduction trials and encourage more women at risk to weigh the risks and benefits of these very useful agents. Rather than making blanket statements about imagined limitations of our ability to reduce breast cancer, we should make concerted efforts to ensure wider utilization of these beneficial drugs among the appropriate highrisk populations.

Reply From Steven Vogl, MD, to Victor Vogel, MD

toxicity. The reference indicating how many women in various racial and ethnic groups would benefit uses as a definition of “benefit” eligibility for tamoxifen according to the package insert, again assuming that breast cancer prevention per se is favorable, and subtracts quantitative estimates of the toxicity in various population groups. Freedman estimates 15.5% of women in the United States between ages 15 and 79 years

VOGEL continued from page 4 

Does he advocate that we abandon prevention of all diseases altogether?

His assertions that the long-term toxicity of aromatase inhibitors will produce an epidemic of premature osteoporosis are not supported by the use of these agents in several studies of aromatase inhibitors for the adjuvant treatment of breast cancer.

His argument to avoid prevention because “the prognosis of ER-positive cancers keeps getting better” is a cruel and senseless statement that ignores the morbidity related to lumpectomy and radiation or to mastectomy among the 100,000 postmenopausal and 50,000 premenopausal women who develop estrogen receptor–positive breast cancer annually in the United States. Similarly, his argument that a 75% reduction in events using letrozole after five years of tamoxifen is superior to prevention begs the question about why a 65% reduction in incidence of breast cancer using exemestane would be inferior to treating women with an aromatase inhibitor in the adjuvant treatment setting. Although it is likely he would argue that far fewer women need to be treated with adjuvant therapy, why should women at increased risk (particularly those with lobular carcinoma in situ, atypical ductal hyperplasia or family histories of breast cancer in first-degree relatives) be denied the opportunity for risk reduction?

He argues that “any benefit we project

M

y thanks to Dr. Victor Vogel for his attention to my editorial and for his thoughtful critique. I learned many things from his “clarification.” First, I learned the word “preventionist.” Second, I learned the price of raising the ire of preventionists; Dr. Vogel makes his points strongly indeed.

The central point of my article is that, as is done in the major studies published to date, breast cancer prevention is being strongly advocated for very large populations without persuasive evidence that it makes lives longer or better. Put another way, before we put a billboard next to the highway announcing to healthy women, “Come to Dr. Vogel (or Dr. Vogl) to get your pill to prevent breast cancer,” we need such evidence. Administering medication to those without illness converts them into patients—and this should not be done lightly.

I was upset in the 1990s that the end point of the NSABP P1 trial was breast cancer incidence, not mortality, and I am still upset by this. The risk–benefit analyses cited by Dr. Vogel1,2 use

Steven Vogl, MD Medical Oncologist, New York City

Sincerely, Victor G. Vogel, MD Director, Geisinger Cancer Institute Geisinger Health System Danville, Pa.

References 1. Day R, Ganz PA, Costantino JP, et al.

Health-related quality of life and tamoxifen in breast cancer prevention: a report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin Oncol.

1999;17:2659-2669, PMID: 10561339.

2. Land SR, Wickerham DL, Costantino JP, et al. Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention: the NSABP study of tamoxifen and raloxifene (STAR) P-2 trial. JAMA. 2006;295:27422751, PMID: 16754728.

3. Cuzick J, Forbes JF, Sestak I, et al. For the International Breast Cancer Intervention Study (IBIS) I Investigators. Long-term results of tamoxifen prophylaxis for breast cancer—96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst.

2007;99: 272-282, PMID: 17312304.

The breast cancer prevention studies should have used mortality as a major end point, and should have avoided crossover (to the active treatment as soon as some reduction in cancer incidence was demonstrated) so this end point could be validly analyzed.

reduction in breast cancer incidence as the positive end point, and compare this reduction with the known deleterious effects of tamoxifen and raloxifene. My problems with the analyses remain that the primary end point is wrong—it takes into account only the known toxicities— and that the follow-up is too short for

were eligible for tamoxifen chemoprevention in 2002. One can assume that most of the rest would be eligible as they age to 60 years and beyond (because risk increases with increasing age, those who have a lower risk at age 60 will have a much higher risk over the following five years when they reach 65), by

4. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388, PMID: 1628818.

5. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2727-2741, PMID: 16754727.

6. Vogel VG, Costantino JP, Wickerham DL, et al. Update of the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial: preventing breast cancer. Cancer Prev Res. 2010;3:696-706, PMID: 2040400.

7. Cuzick J, Forbes J, Edwards R, et al. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet.

2002;360:817-824, PMID: 12243915.

8. Visvanathan K, Chlebowski RT, Hurley P, et al. American Society of Clinical Oncology practice guideline update on the use of pharmacologic intervention including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction.

J Clin Oncol. 2009;27:3235-3258, PMID: 19470930.

9. Cuzick J, DeCensi A, Arun B, et al.

Preventive therapy for breast cancer: an international consensus statement. Lancet Oncol. 2011;12:496-503, PMID: 19410194.

10. Freedman AN, Graubard BI, Rao SR, et al.

Estimates of the number of U.S. women who could benefit from tamoxifen for breast cancer chemoprevention. J Natl Cancer Inst. 2003;95:526-532, PMID: 12671020.

11. Freedman AN, Costantino JP, Gail MH, et al. A benefit/risk assessment tool for breast cancer chemoprevention treatment. J Clin Oncol. 2011;29:2327-2333, PMID: 21537036.

Victor G. Vogel, MD, has no relevant disclosures.

Freedman’s criteria.

Dr. Vogel asserts he does not want to treat almost the entire female population to prevent breast cancer. However, in Goss’s MAP.3 trial, 49% of women were entered because they were over 60 years old and had no other risk factors.3 Dr. Vogel only wants to treat only higher-risk women over 60, and as far as I can tell, this strategy has not been tested in randomized trials. Clearly, the higher the risk for breast cancer, the more attractive prevention becomes. All of us find it unfortunate that we have no prospective trials of cancer prevention in BRCA1 and BRCA2 gene mutation carriers, for whom most of us think we really need them.

Dr. Vogel cites the American Society of Clinical Oncology (ASCO) guidelines for breast cancer prevention, which he helped write. My reading of these is that the ASCO committee accepts that tamoxifen and raloxifene “may” be used, but did not assert that they “should” be used, for cancer prevention. I accept the guideline’s conclusion, and would use one drug or the other in a patient who demands breast cancer prevention, or who chooses

PRN

Clinical Oncology News • October 2011

Clinical Benefits

Clinical Benefit Rate: What Does This Really Mean?

Oncologists are quite familiar with the term objective response rate (complete response, partial response) in clinical trials—it provides an indication of the relative degree of an antineoplastic regimen’s biologic activity.

In many circumstances, evidence of measurable decreases in the size of malignant tumor masses is translated into documented improvement in clinically relevant study end points.

These can include a decrease in pain, an increase in appetite and activities of daily living and prolongation of time to disease progression and overall survival.

Clinical benefit rate is a relatively recent addition to the parameters used to evaluate efficacy in clinical trials. This somewhat vague term has been defined in a variety of ways, but generally includes individuals who have achieved an objective response (as noted above) plus patients who do not appear to have cancers that have progressed for a prospectively trial-specified period of time (eg, 8 weeks, 3 months, etc) from the time the study was initiated.

In initiating this brief critique of the general concept of the so-called “clinical benefit rate,” a past experience of mine is particularly germane. In an attempt to highlight the impact of a novel anticancer strategy that he had developed, a well-recognized researcher noted in public presentations that “one patient was able to climb the Rocky Mountains after undergoing this treatment.”

Does this sound impressive? Yes. Unfortunately, what the investigator failed to mention was that the patient

was also able to “climb the Rocky Mountains” immediately before beginning the treatment. The point, of course, is that there was no evidence that the particular outcome (physical ability to climb a mountain) had anything to do with a favorable effect of the specific treatment.

In the context of the current discussion, the question to be raised is whether an 8 week or 3 month time to subsequent disease progression has anything to do with the regimen the patient received, versus the fact that what is being observed is merely the natural history of the disease process associated with the individual patient’s cancer.

Although reproducibly and objectively measured decreases in the size of malignant mass lesions does not necessarily indicate there has been any improvement in survival, cancer-specific symptoms or overall quality of life, such data surely indicate a definite impact of the treatment regimen on the inherent biology of the disease process. However, in my opinion, it is important to appreciate that the mere observation that an individual patient’s cancer has not progressed for a set period of time fails even this quite modestly relevant test of the demonstration of “clinical utility” or “clinical benefit.”

This rather negative conclusion can be appropriately challenged if a person can demonstrate that for a specific individual

it in the face of elevated risk from atypical hyperplasia or lobular or ductal carcinoma in situ, knowing what we know and do not know about the toxicities and consequences of therapy.

All of us who treat patients firsthand know the difficulties of maintaining compliance with tamoxifen and aromatase inhibitors as part of adjuvant therapy.4 Dr. Vogel denies this toxicity based on compliance rates in the adjuvant trials and quality-of-life analyses. As cancer treatment drugs go, selective estrogen receptor modulators and aromatase inhibitors are “pieces of cake” compared with cyclophosphamide, anthracyclines and taxanes. Nevertheless, I believe we need strong evidence of overall benefit to subject 25 women to therapy, which will be very annoying to some of them, in order to prevent a treatable cancer in the 26th woman.

Dr. Vogel wonders if I would advocate cessation of use of antihypertensive medications and statins. I favor both of these, but note that the basis of therapy for hypertension is a randomized Veterans Administration study showing reductions in morbidity and organ damage as well as in overall mortality.5 The trial was, nevertheless, underpowered by current standards. Evidence for primary prevention of coronary disease by statins is on much shakier ground, and I tell every patient I treat how shaky the ground is. A recent metaanalysis of about 43,000 subjects in seven studies shows reductions in relative risk for coronary and cerebrovascular events, as well as in coronary re-vascularization procedures, but no significant reduction in coronary or overall mortality.6 The trends in the latter results (which were

the time to cancer progression following treatment with a particular antineoplastic regimen actually exceeds the time to disease progression documented with that patient’s preceding therapeutic program.

In this circumstance, it is implausible to suggest that the observation is solely due to the natural history of the cancer and, realistically, the outcome must result, at least in part, from a favorable impact of the therapy on the biology of the malignant process.

Thus, “clinical benefit” here is not defined by the duration of time to progression in a group of patients, but rather by the time to disease progression by individual patients compared with their own prior experience.

Several published reports have provided solid support for the relevance of a shortening of the subsequent time to disease progression as an expected outcome defining the natural history of cancer in individual patients.1,2 Furthermore, use of this important observation in innovative clinical trial designs has permitted investigators to obtain highly provocative data suggesting the clinical utility of novel therapeutic approaches to the management of malignant disease.3,4 In summary, although a “clinical benefit rate of “70% to 80%+” in a nonrandomized Phase II clinical trial may superficially appear quite impressive, additional important details are absolutely required before the claim of “actual clinical benefit” should be accepted as a valid conclusion. In defining benefit within a trial, it is possible that there is a far more relevant question that should be asked: “How does the time to progression observed in looked for) give hope that they are, in truth, present.

None of us likes to watch women suffer with and die of breast cancer. Emphasizing the misery of women so afflicted: “risk reduction … averts incalculable morbidity and suffering among the women who derive the benefits of the pharmacologic interventions,” misses the point.

As physicians and scientists confronting healthy women at risk for breast cancer, we are obligated to calculate the suffering and deaths averted as well as the (so far minor) toxicity that the treatments cause. The breast cancer prevention studies should have used mortality as a major end point, and should have avoided crossover (to the active treatment as soon as some reduction in cancer incidence was demonstrated) so this end point could be validly analyzed.

References 1. Freedman AN, Graubard BI, Rao SR, et al.

Estimates of the number of US women who could benefit from tamoxifen for breast

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

specific patients treated on the trial compare with the observed natural history of the disease process in those particular individuals?” The answer to this question may be of genuine clinical significance.

References 1. Markman M, Markman J, Webster, et al. Duration of response to secondline platinum-based chemotherapy for ovarian cancer: Implications for patient management and clinical trial design. J Clin Oncol. 2004;22:3120-3125, PMID: 15284263.

2. Harrison ML, Gore ME, Spriggs, et al.

Duration of second or greater complete clinical remission in ovarian cancer: Exploring potential end points for clinical trials. Gynecol Oncol. 2007;106:469-475, PMID: 17614127.

3. White AJ, Coleman RL, Armstrong DK, et al. Efficacy and safety of farletuxumab, a humanized monoclonal antibody to folate receptor alpha, in platinum-sensitive relapsed ovarian cancer subjects: Final data from a multicenter phase II study. J Clin Oncol. 2010; 28(18S):390s (Abstract 5001).

4. Von Hoff, DD, Stephenson JJ Jr, Rosen P, et al. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010;28:4877-4883, PMID: 20921468.

cancer chemoprevention. J Natl Cancer Inst. 2003;95(7):526-532, PMID: 12671020.

2. Freedman AN, Yu B, Gail MH, et al.

Benefit/risk assessment for breast cancer chemoprevention with raloxifene or tamoxifen for women age 50 years or older.

J Clin Oncol. 2011;29(17):2327-2333, PMID: 21537036.

3. Goss PE, Ingle JN, Alés-Martínez JE, et al.

Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364(25):2381-2391, PMID: 21639806.

4. Hershman DL, Kushi LH, Shao T, et al Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients.

J Clin Oncol. 2010;28(27):4120-4128, PMID: 20585090.

5. Freis ED, et al. Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA. 1970;213(7):1143-1152, PMID: 4914579.

6. Thavendiranathan P, Bagai A, Brookhart MA, et al. Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials. Arch Intern Med. 2006;166(21): 2307-2313, PMID: 17130382.

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POLICY & MANAGEMENT

Clinical Oncology News • October 2011

Practice Management

SUCCEEDING continued from page 1 

its system. It considers the reputation of each practice and verifies that physician training is what it claims to be. FCS also reviews the practice history of each clinician and evaluates any history of malpractice cases. During compliance and quality audits of a practice, FCS carefully reviews patient charts to ensure that the level of care provided meets FCS standards.

“The last thing we want to do is put our reputation at risk, which we’ve worked so hard to build, by acquiring a practice that’s not going to meet the standards we have in place,” said Brad Prechtl, CEO. Dr. Harwin added that FCS has also begun to establish clinical pathways and guidelines that will be integrated into its system-wide electronic medical record.

One goal of that initiative is the ability to evaluate treatment efficacy. “It’s a way we can measure our quality but also provide consistency and confirm that quality to payers,” he said. “That information is important when we negotiate reimbursement contracts.”

FCS’s size allows it to negotiate lower drug prices and has created efficiencies because overhead costs are spread across

a large group of physicians. “There’s no doubt that our financial success is one of the attractions to the physicians who look to join FCS,” said Mr. Prechtl. “I strongly believe that being financially strong translates to good patient care, because it allows us to do things that many other practices wouldn’t be able to do, such as making sure we have the most up-to-date equipment and to expand our number of sites so that we can keep patient care close to home.”

FCS has also made clinical trials one of its priorities. “We think clinical trials are extremely important for offering cutting-edge opportunities for patients, and they move the field forward,” said Dr. Harwin, who is the leading accruer of patients for clinical trials within FCS. In 2011, the Conquer Cancer Foundation of the American Society of Clinical Oncology named FCS a recipient of the 2011 Clinical Trials Participation Award, which “recognizes practices that have established high-quality clinical cancer research programs.”

The large majority of FCS studies are Phase I trials conducted in partnership with the Sarah Cannon Research Institute, in Nashville, Tenn., which handles many of the regulatory and research support functions. FCS runs two offices dedicated to conducting Phase I trials,

‘I strongly believe that being financially strong translates to good patient care.’

—Brad Prechtl

W

ith the idea that community cancer centers can learn how to succeed from other practices, Clinical Oncology News has started spotlighting these centers.

Our first spotlight, which ran in the June issue, was ProHealth Care Regional Cancer Center, in Waukesha, Wis. It is available online at www.clinicaloncology.com.

Just search the site using the term ProHealth. If you have a smartphone, you can scan the bar code on the right.

‘We think clinical trials are extremely important for offering cutting-edge opportunities for patients, and they move the field forward.’

—William N. Harwin, MD

and some Phase II and III trials are conducted by individual practices within the organization.

Subjects in Phase I trials are typically patients for whom other standard therapies have failed or no known alternative therapy is available, said Dr. Harwin. According to FCS, 85% of all cancer patients in the United States would consider participation in a clinical trial, but only 9% are offered this opportunity.

At first, Dr. Harwin thought that enrolling adequate numbers of cancer patients in Phase I trials would be difficult. Historically that was true because most patients could not expect to benefit directly from either the standard or the experimental treatments they would receive. “That’s what I used to think,” he said. “But we’ve actually found that some patients do benefit. I

think one reason is that, in some cases, the patients start trials in better condition than they used to.” He recommends that practices that want to expand their involvement in clinical trials do so in partnership with organizations that have a track record and the resources necessary for the undertaking.

“It’s really difficult to do on a smaller scale,” he said.

The ability to offer clinical trials provides an important competitive edge for FCS, particularly in markets where it competes with academic medical centers like Moffitt Cancer Center in Tampa, Fla. “It’s a huge benefit for patients,” said Mr. Prechtl, “because those who want to participate in trials don’t have to travel outside of FCS or the market where they live.”

—Steve Frandzel

SOLID TUMORS

Clinical Oncology News • October 2011

Breast

Using Oncotype DX Recurrence Score To Select Adjuvant Chemo: Beyond the State of the Art? The 21-gene Oncotype DX recurrence score (RS) has emerged as a powerful tool that is validated to be of prognostic and predictive significance for patients with hormone receptor–positive breast cancer in both lymph node–negative and node–positive disease.1-4 Beyond influencing the decision of whether to recommend chemotherapy, should RS also impact the choice of adjuvant chemotherapy regimen? In a setting of higher-risk RS, should oncologists recommend more intensive adjuvant chemotherapy such as an anthracycline-based regimen or dose-dense scheduling? These are questions that have been discussed in breast oncology clinics around the country. As background to this controversy, key completed and ongoing studies are reviewed, followed by commentary regarding the evidence-based use of RS. Data from the National Surgical Adjuvant Breast and Bowel Project B20, a study that randomized women to receive adjuvant tamoxifen alone or tamoxifen and cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy, validated RS as a test that predicts benefit from the addition of chemotherapy to tamoxifen alone for women with node-negative breast cancer. In a retrospective, correlative tissue analysis of this study, involving 651 patients who had accessible reverse transcriptase polymerase chain reaction (RT-PCR) data (28% of overall study), women with a low RS (<18) showed little improvement in diseasefree survival (DFS) with the addition of chemotherapy.2 Conversely, for women with an intermediate (18-31) or high RS (>31), the addition of chemotherapy resulted in a significant improvement in DFS (relative risk, 0.26; 95% confidence interval, 0.13-0.53).

The predictive value of RS for patients with node-positive breast cancer also has been established by a retrospective analysis of Southwest Oncology Group 8814, a trial that randomized women to receive adjuvant tamoxifen alone or tamoxifen and cyclophosphamide, doxorubicin, and fluorouracil (CAF) chemotherapy.3 In 367 patients with accessible RT-PCR data (40% of the overall study), and after adjustment for lymph node status, there was no additional benefit of CAF chemotherapy beyond tamoxifen alone for women with a low-risk RS. Given the superior DFS associated with aromatase inhibitors (AIs) compared with tamoxifen for postmenopausal women, data from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial has provided

reassuring evidence that RS is also applicable for prognosis in the context of AI use for node-negative or nodepositive disease.4 Although consistent and compelling, all of the data reviewed above is derived from retrospective analyses of the parent trials. Ongoing Phase III randomized clinical trials are seeking to validate these findings in both node-negative and node-positive disease.5,6 In node-negative disease, the TAILORx (Trial Assessing Individualized Options for Treatment) study has randomized more than 10,000 women with an RS between 11 and 25 to endocrine therapy consisting of 5 to 10 years of tamoxifen and/or an AI at the discretion of physician and patient with or without chemotherapy.5 In nodepositive disease, the RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) trial will randomize 4,000 women with N1 disease and an RS of 25 or less to endocrine therapy as above with or without chemotherapy.6 Of note, in both studies, the choice of adjuvant chemotherapy regimen must be protocol-approved but is not specified to one regimen.

What impact has RS had on patient and physician decision-making regarding adjuvant therapy for breast cancer?

In one study, oncologists were asked to report their treatment recommendations and patients were asked to report their treatment preferences before and after learning the RS.7 Approximately 32% of doctors and 27% of patients changed their treatment decision once the RS was known, with the largest change being the oncologist’s initial recommendation for chemotherapy with endocrine therapy changing to endocrine therapy alone. The study also showed that RS improved physician confidence in treatment recommendation and decreased patient anxiety.

Adjuvant! is a popular online tool that often is used in the clinic to assist in adjuvant therapy decision making.

Using patient- and tumor-specific variables, such as age, estrogen-receptor status, tumor grade and size, and node status, this computer program uses data from the Surveillance, Epidemiology and End Results and Early Breast Cancer Trialists’ Collaborative Group to project prognosis as well as predicted benefit from endocrine therapy and/

or chemotherapy.9 Regarding correlation between Adjuvant! and RS, multiple studies have shown that the prognostic information generated by the 2 methods is independent.4,8 Despite all the information that RS provides to assist patients and oncologists in deciding whether or not a patient will benefit from adjuvant chemotherapy, this influential tool does not provide information regarding which chemotherapy regimen should be recommended. The retrospective studies that validated the predictive value of RS were derived from older adjuvant chemotherapy studies using regimens, such as CMF and CAF, which are now infrequently used in current clinical practice. Furthermore, the ongoing prospective studies, TAILORx and RxPONDER, do not specify chemotherapy regimen and therefore are seeking to further the core use of RS, which is whether or not to include chemotherapy in a patient’s adjuvant treatment.

If using RS to choose chemotherapy regimen is an application beyond the test’s evidence-based use, how should clinician’s decide which adjuvant chemotherapy regimen to recommend for a particular patient? As mentioned above, Adjuvant! provides gradations of predicted benefit based on generation of chemotherapy, such as the decision between cyclophosphamide-doxorubicin (AC) and, by extrapolation from USO9735, docetaxel-cyclophosphamide (TC), compared with 3-drug regimens like AC plus a taxane given in standard or dose-dense schedules.10 Finally, familiarity with the patient populations enrolled in individual trials, and the outcomes in preplanned analyses of clinically relevant groups, can be translated from the study’s results directly to the clinic.

Dr. Herold has no relevant disclosures.

References: 1. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen treated, node-negative breast cancer.

N Engl J Med. 2004;351(27):2817-2826, PMID: 15591335.

2. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006; 24(23):3726-3734, PMID: 16720680.

GUEST COMMENTARY Christina I. Herold, MD Division of Hematology/ Oncology, Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School Boston, Massachusetts

‘In the setting of higherrisk RS, should oncologists recommend more intensive adjuvant chemotherapy?’

3. Albain KS, Barlow WE, Shak S, et al.

Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, estrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 2010;11: 55-65, PMID: 20005174.

4. Dowsett M, Cuzick J, Wale C, et al.

Prediction of risk of distant recurrence using the 21-gene recurrence score in nodenegative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study. J Clin Oncol. 2010;28:1829-1834, PMID: 20212256.

5. NCT00310180. Hormone therapy with or without combination chemotherapy in treating women who have undergone surgery for node-negative breast cancer (the TAILORx trial). www.clinicaltrials.gov.

Accessed September 6, 2011.

6. NCT01272037.Tamoxifen citrate, letrozole, anastrozole, or exemestane with or without chemotherapy in treating patients with invasive RxPONDER breast cancer. www.clinicaltrials.gov. Accessed September 6, 2011.

7. Lo SS, Mumby PB, Norton J, et al.

Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection. J Clin Oncol. 2010;28:1671-1676, PMID: 20065191.

8. Tang G, Shak S, Paik S, et al. Comparison of the prognostic and predictive utilities of the 21-gene Recurrence Score assay and Adjuvant! for women with node-negative, ER-positive breast cancer: results from NSABP B-14 and NSABP B-20. Breast Cancer Res Treat. 2011;127:133–142, PMID: 21221171.

9. Ravdin PM, Siminoff LA, Davis GJ, et al.

Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol.

2001;19:980–991, PMID: 11181660.

10. Jones S, Holmes FA, O’Shaughnessy J, et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-Year follow-up of US Oncology Research Trial 9735. J Clin Oncol.

2009; 27:1177-1183.

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Clinical Oncology News • October 2011

Lung

YOUR PATIENT continued from page 1 

2010, the investigators reviewed 10 national and international trials for agents approved to treat NSCLC. They found the following: • Individuals over the age of 65 made up just 36% of the drug trial population, but represent 73% of U.S. lung cancer patients.

• Of trial enrollees, 68% were men and 32% were women. But according to the National Cancer Institute’s (NCI) Surveillance, Epidemiology and End Results (SEER) data, women represent 42% of all NSCLC patients.

• Just 2% of trial participants were black, despite African Americans developing lung cancer at higher rates (72.7 per 100,000) than whites (68 per 100,000).

Troubling though they are, these findings should not come as a surprise to anyone—and the issue isn’t confined to lung cancer research, said Joy Lewis, DO, PhD, assistant professor of family and community medicine and director of the Practice-Based Research Network at A.T. Still University School of Osteopathic Medicine in Mesa, Ariz., who has studied the issue of enrollment of the elderly in clinical trials.

In 2003, while a researcher at RAND Health, she led a retrospective analysis of patient and trial characteristics for 59,300 patients enrolled into 495 NCIsponsored, cooperative group trials, active from 1997 through 2000. Published in the Journal of Clinical Oncology, her findings closely tracked the FDA researchers’ recent results: Overall, only 32% of participants in Phase II and III clinical trials were elderly, although elderly people account for 61% of U.S. cancer cases (J Clin Oncol 2003;21:13831389, PMID: 12663731).

And a cross-sectional, populationbased analysis of all participants in therapeutic nonsurgical NCI Clinical Trial Cooperative Group breast, colorectal, lung, and prostate cancer clinical trials from 2000 through 2002, published in the Journal of the American Medical Association, found that not only were women, the elderly and minorities underrepresented in these trials, the situation seemed to actually be getting worse rather than better (JAMA 2004;291:2720-2726, PMID: 15187053). “Although the total number of trial participants increased during our study period, the representation of racial and ethnic minorities decreased,” they noted.

These disparities in representation can mean real problems in terms of incorporating the results of trials into clinical practice. Some drugs may have a different side-effect profile in women than in men, for example, a fact that

‘Are we writing protocols so that people have to come into the medical center three times a week for blood draws that take an hour each time, so they have to take time off work and pay $15 to park?’

—Lynne Nguyen, MPH

would be harder to tease out when men represent the lion’s share of enrollees. And elderly patients may be more vulnerable to a drug’s toxicities than younger patients.

Before investigators can improve this picture, they must first understand what the actual barriers are that impede these patient groups from enrolling in trials, said Lynne Nguyen, MPH, director of the Minority & Women Clinical Trials Recruitment Resource in the Department of Health Disparities Research at the University of Texas MD Anderson Cancer Center, in Houston.

“A common mistake made in academia is thinking too simply about the barriers facing our populations of interest,” she explained. “For example, for African Americans, we cite incidents such as the Tuskegee syphilis studies and say that there is a mistrust and fear of researchers among this community as a result. Of course, that’s true. But— are we looking at our own barriers, the

ones we construct? Are we writing protocols so that people have to come into the medical center three times a week for blood draws that take an hour each time, so they have to take time off work and pay $15 to park?”

Ms. Nguyen also cited health literacy as a key barrier for all populations, but particularly for the elderly. “We know from national health literacy surveys that people aged 65 and older have the lowest levels of health literacy.

Are we writing consent forms in a way that’s understandable?” she asked. “And what about the legal piece of the consent form, written by lawyers? That’s the piece that causes mistrust. People read it and when they get the gist, they see that the institution is protecting its own interests, not theirs. That’s a significant issue.”

Many trial protocols end up automatically excluding seniors in a way that may not be necessary, said Dr. Lewis.

“Some exclusion criteria are used again

‘A fundamental step in applying the principles of evidencebased medicine is that when you look at a published study, you have to ask if the results apply to your patient. If the people in that study have fundamental differences from your patient, then the answer is no.’

—Joy Lewis, DO, PhD

and again, the criteria need to be evaluated in the context of each trial,” she noted. “For example, 41% of Phase II and 47% of Phase III trials have any history of congestive heart failure as an exclusion criterion. Is that always necessary? Are you using a cardiotoxic drug? Can you be more precise and say that you need an ejection fraction or cardiac output above a certain level?”

Although exclusion criteria are there for a reason, Dr. Lewis said, due diligence should be taken in developing each screening instrument. “Make sure the investigators justify the use of each specific exclusion criteria for each specific study.”

If that were to happen, and if this critical review resulted in fewer restrictions, participation by the elderly in trials should increase markedly, Dr. Lewis said. “If you relax organ system and functional status exclusions, our model predicts 60% participation for the elderly, which is much more representative of the population of cancer patients generally.”

Of course, researchers want to recruit the healthiest participants to their trials because they have the best chance of being successful with the drug. “But in reality, who is more likely to have cancer? Older people,” said Ms. Nguyen.

“And they are the ones with all these other conditions. If you test drugs in people without these conditions, how generalizable are your results going to be?”

Rather than focusing on changing how patients feel about clinical trials, Ms. Nguyen stressed, the emphasis must be on changing how trials are conducted in order to make recruitment more open to these groups. “We can’t change the patient’s economic situation. We can educate, but we can’t change core beliefs. But we can reduce inequities in our own internal system, and that’s what we’ve got to work on.”

In the meantime, practicing community oncologists are well advised to read the literature closely, with an eye toward the “methods” section of each trial. “A fundamental step in applying the principles of evidence-based medicine is that when you look at a published study, you have to ask if the results apply to your patient. If the people in that study have fundamental differences from your patient, then the answer is no,” Dr. Lewis said. “That may make it difficult to generalize results related to efficacy and toxicity for your female patients, your minority patients, and in particular your elderly patients.”

That doesn’t mean that they can’t receive the same drugs, of course. But it does mean that oncologists should be aware that the outcomes they expect based on the trial population may not, in fact, be the outcomes they get in the real world.

—Gina Shaw

SOLID TUMORS

Clinical Oncology News • October 2011

Lung

Study Shines Light on Palliative Care Consultations From Journal of Palliative Medicine

A

recent study published in the Journal of Palliative Medicine has found that the extent and content of early palliative care consultation in patients with non-small cell lung cancer (NSCLC) largely depends on the patient’s state of mind and quality of life (QoL) at the time of diagnosis (2011;14:459-464, PMID: 21417739).

The study compared early palliative care to standard care in 141 patients with newly diagnosed metastatic NSCLC from Massachusetts General Hospital’s outpatient thoracic oncology clinic.

Researchers analyzed electronic medical record documentation of the components of the initial palliative care consultation. The consultation approach was based on guidelines from the National Consensus Project for Quality Palliative Care and included discussion of symptom management, disease education, treatment decision making, patient and family caregiver coping skills and care planning and referrals.

Patient QoL at the time of diagnosis was measured using the Functional Assessment of Cancer Therapy-Lung Trial Outcome Index (FACT-L TOI). Patient mood was measured using the Patient Health Questionnaire-9 (PHQ-9). The researchers conducted a retrospective chart

review to determine if discussion of additional topics such as religion/spirituality and advance directives were documented.

Patients were randomized to standard care (n=74) or early palliative care (n=67).

The study did not include any statistical analysis of the standard care group.

In the early palliative care group, the median total time spent with patients during the initial visit was 55 minutes. Physicians performed more than half (55.2%) of these consultations;

advanced-practice nurses performed the others. Roughly 20 minutes (median) of the consultation time was spent discussing symptom management, whereas another 15 minutes (median) was devoted to “patient and family coping.” Patient education on NSCLC and its symptoms and course accounted for 10 minutes (median) of discussion time.

Odds ratios were calculated to study the relationship between scores on the QoL and patient health measures and

consultation time. Perhaps not surprisingly, the researchers found that lower scores on these measures—particularly on the FACT-L TOI and PHQ-9 (particularly depression scores)—correlated with longer consultation times. Patient age, gender, marital status, smoking history or presence of brain metastases did not influence consultation time. Nearly half (49.3%) of the clinicians documented a discussion about religious or spiritual practice during the initial consultation, but far fewer documented a discussion about a healthcare agent (20.9%) or code status (19.4%).

What role may MUC1 play in NSCLC

EXPERT INSIGHT 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

Betty Ferrell, RN, PhD Research Scientist City of Hope National Medical Center Duarte, CA

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

110718-140032

“In recent years, the concept of palliative care has gradually gained recognition in health care as a viable method for sustaining quality of life for individuals diagnosed with life-threatening illnesses such as cancer. In this article

by Jacobsen and colleagues, the investigators described the components of a palliative care consultation system that improved quality of life and survival in metastatic NSCLC. The findings have clinical implications in that it again underscores the importance of symptom management, coping and illness understanding in palliative care settings. Uncontrolled symptoms also must be addressed aggressively because it negatively impacts quality of life.

Findings presented in this study should serve as models of palliative care consultation components that must be addressed for individuals with metastatic NSCLC in order to impact positively on overall quality of life.”

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 • October 2011

Lung EDITORIAL BOARD COMMENTARY

SCREENING

Steven Vogl, MD

continued from page 1 

Medical Oncologist, New York City

mortality and death from any cause had been announced in November 2010.

Many of us expected to hear the results at national meetings—none were presented that I heard. I went to the American Society of Clinical Oncology 2011 meeting in vain expecting to hear the results.

I am amazed that lung cancer advocacy groups and the public health community have not been more vocal and active in demanding the obvious actions mandated by this strongly positive result for allcause mortality, the strongest end point imaginable.

Large Benefit The paper demonstrates that 3 annual low-dose CT scans reduces mortality in smokers aged 55 to 74 years.1 A committee (blinded to screening assignment) assigned cause of death and found a 20% reduction in lung cancer death rate with CT screening compared with 3 annual posteroanterior chest x-rays. Much more convincing, to my mind, is that allcause mortality was reduced by 7% with the CT scans: 1,877 deaths among 26,722 smokers followed a median of about 6 years from entry compared with 2,000 deaths among 26,732 smokers who did not get CT scans. Cause-specific mortality, as is standard in prevention and screening studies, was the primary end point of this trial.2 I find this end point less than convincing because of the great difficulty in consistently assigning the cause of death. If someone with hip pain from metastatic lung cancer is limping across a busy street and is hit by a car, is the cause of death an automobile accident or the metastatic lung cancer that made the individual limp? In New York City, where I practice, a funeral director often argues in favor of a diagnosis that will minimize questions from the Board of Health: “Put down cancer, Doc, and let the family bury Pop.” All-cause mortality is a much more certain end point. Because there are many other causes of death besides lung cancer in smoking populations, this end point requires much larger studies and may miss a positive effect because of dilution. So far as I know, this is the first cancer screening method for any cancer to document a decrease in all-cause mortality in a randomized prospective clinical trial. The evidence in favor of annual low-dose CT scans in heavy smokers is thus much stronger than that for mammography, colonoscopy, fecal occult blood testing, cervical Pap smears, or HPV testing in appropriate populations.

The evidence is far stronger than for prostate-specific antigen screening for prostate cancer, which to date has shown at best a tiny improvement in causespecific mortality at 12 years with no

Dr. Vogl wants clinicians to heed evidence showing that CT screening can help smokers avoid the grave.

Table 1. Problems With the NEJM Study Design Wrong control group. Posteroanterior chest film is not an established screening standard in the community. Even though it has never been shown to be effective, if it is somewhat effective it could dilute the benefit of CT screening compared with what is happening in the United States and Europe, which is no screening at all on an organized basis.

Use of only 3 screens. Many of the cancers in the screened group were diagnosed after screening stopped. The incidence of new cancers in smokers rises every year with increasing age and increased smoking, so the use of only 3 screens grossly underestimates the benefit of annual screening carried on for 10 to 20 years.

No protocol for evaluation of a positive scan. Just how to evaluate a positive scan was left to the participating institution, limiting our ability to know how to reproduce the observed benefit. If no significant benefit was found, it could have been because nodules were evaluated and treated inappropriately. At the moment, we have to guess what protocol to follow to achieve the very impressive survival benefit reported in this study.

Somewhat arbitrary and unsophisticated choice of subjects. The 10-year risk for developing lung cancer in trial participants has been estimated to vary from 0.8% for a 51-year-old woman who smoked 1 pack per day for 28 years and quit 9 years earlier up to 15% for a 68-year-old man who continues to smoke 2 packs per day.11 CT, computed tomography; NEJM, The New England Journal of Medicine

detectable effect on all-cause mortality.

This clearly positive study illustrates the folly of trying to assign cause of

death—only 60% of the excess deaths (123 deaths) in those not having CT scans were attributed to lung cancer (2,000

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deaths in the controls vs 1,877 in the CT-screened population). Rather than assume the existence of some mysterious fatal disease that was ameliorated by CT screening, I suggest that the assigned cause of death was probably incorrect, which is to be expected without autopsies on each patient. I hope that one of the many promised follow-up papers from this study will include a thorough review of all the medical records of each death with an analysis of contributing factors, so that we can discover the ways in which CT-screened subjects actually benefited.

How big are the potential benefits? If there were 123 fewer deaths among about 25,000 patients with 3 screens, then there will likely will be at least 410 fewer deaths after 10 annual screens—1.6% of screened patients will be spared an early death by 10 years of CT screening. Contrast this with the estimate of the US Public Health Task Force of a 0.5% reduction in mortality from a lifetime of mammography screening. This 1.6% mortality benefit is likely a gross underestimate for many reasons, the biggest of which is that serial scanning allows the detection of new small masses, whereas the first scan will more often find larger and already metastatic cancers that will kill the patient regardless of discovery. Also, note that one-third of the cancers in the screened population in the NEJM article were diagnosed after screening stopped, and were then about 30% more often (50% vs 20%) beyond stage IA (<3 cm with no pleural involvement, negative nodes, and no distant metastases) than were screendetected cancers in the second and third years of screening (when new, very small nodules can be declared worthy of evaluation because they were not present a year earlier).1 My assumption of a linear benefit as screening proceeds is probably wrong and seriously underestimates the benefit. I would be very pleased to hear from epidemiologists and statisticians on more sophisticated ways to estimate the benefit of annual screening extended to 10 years or more.

Small, screen-detected lung cancers have an excellent prognosis. In one series, screen-detected lung cancers were associated with a 5-year death rate from lung cancer of only 20%—alas, the authors do not give all-cause mortality.3 Most of the benefit from screening is likely to be from the detection of lung

SOLID TUMORS

Clinical Oncology News • October 2011

Lung

cancers in an early, largely curable stage, for which the 5-year lung cancer mortality rate is reported as 8%.3

Methodology Flaws Serious problems with the NEJM article as written limit our ability to interpret the results. The population is poorly defined. What were the patients’ comorbid conditions? How were they recruited? We need more details on how much they smoked, when they stopped, and whether they were they exposed to asbestos. My radiology colleagues hope the follow-up papers will provide detailed information on the imaging characteristics of the lesions that turned out to be cancers, so that their recommendations for evaluation can be maximally effective. Hopefully these issues will be elucidated in subsequent papers.

Claudia Henschke, MD, has been describing the flaws of this study for many years.4 She feared that the flaws would yield a false-negative result and lead to the abandonment of a screening tool that she was convinced saved lives.

I have my own list of study flaws (Table 1). These would have been terrible if the study were negative, but because the study is strongly positive, the flaws are unimportant. Still, some of them could have resulted in a serious underestimate of the benefit of screening. For instance, inclusion of lower-risk participants makes the likelihood of a false-negative result greater.

Several experts think we should begin screening patients who match the population eligible for the NEJM trial. These criteria include some lower risk smokers and exclude some higher risk smokers. In contrast, I think we should use the most sophisticated means we have at our disposal to identify a person’s risk for developing lung cancer, quantify the risk level we think justifies screening, and then screen those patients.

We now have to address the issues of how to implement low-dose CT screening. The following suggestions represent my ideas based on what I know. I hope they are rational, and I am certainly open to modifying them as more data accumulate on each issue and on issues I fail to consider.

years (eg, 3 to 4) and start screening at age 52 or 53 to catch the cancers when in the early stage, when they are small and nonmetastatic. These cancers would not cause symptoms until 3 or 4 years later. Alternatively, we could use a similar model based on lung cancer death rate6 and subtract 8 or 9 years and then start screening (assuming it takes up to 8 to 9 years for a tiny cancer to grow, metastasize, and kill). The Web-based calculator will help smokers and their physicians, as well as radiologists, decide when to recommend screening. If the grim statistics of increasing risk using the calculator induce some smokers to stop, so much the better.

Because those who have screeningdetected small cancers will almost all be cured, screening younger patients rather than older ones is more attractive because they will likely get more years of good life from the cure and they will be less likely to have serious toxic effects from the treatment (surgery) as their hearts and lungs have been less ravaged by the effects of tobacco than those of older smokers.

How Often?

Although the NEJM report studied annual screening, it is worth asking if semi-annual screening might reduce the number of interval cancers (about 4% in the current trial). Perhaps the highest annual risk for cancer is in patients with previously resected lung cancers—1% to 2% per year in older7 and more recent reports,8 and perhaps double that in patients with cured small cell lung cancer (probably because so much lung was

Table 2. Fleischner Society Recommendations For Follow-up and Management of Nodules <8 mm Detected Incidentally at Nonscreening CT Nodule Size (mm)a

Low-Risk Patientb

High-Risk Patientc

≤4

No follow-up neededd

Follow-up CT at 12 mo; if unchanged, no further follow-upe

>4-6

Follow-up CT at 12 mo; if unchanged, no further follow-upe

Initial follow-up CT at 6 to 12 mo then at 18 to 24 mo if no changee

>6-8

Initial follow-up CT at 6 to 12 mo then at 18 to 24 mo if no change

Initial follow-up CT at 3 to 6 mo then at 9 to 12 and 24 mo if no change

>8

Follow-up CT at around 3,9, and 24 mo, dynamic contrast-enhanced CT, PET, and/or biopsy

Same as for low-risk patient

Whom Should Be Screened And When?

To determine whom to screen, I suggest we pick an annual incidence rate based on a sophisticated model such as the one suggested by Bach et al, that uses age, duration of smoking, time since quitting, number of cigarettes smoked per day, and gender and asbestos exposure (model available at www. mskcc.org/mskcc/html/12463.cfm).5 If this model suggests a particular patient will reach the threshold annual risk for symptomatic lung cancer (eg, 0.1% per year) at age 56, I would subtract several

exposed to therapeutic radiation in these patients). It makes sense to screen these people twice a year, and this should be studied. Similarly, it is worthwhile to study semi-annual screening in patients at very high risk, such as the 68-yearold man who continues to smoke 2 packs of cigarettes per day with a 1.6% annual rate of new cancers mentioned

by Bach et al, as an example. Radiation exposure is a risk, and it can cause cancer over the long term, but in the highest-risk patients, smoking-induced cancers are likely the much larger risk. As CT screening for lung cancer becomes widespread, we should seek improvement in machinery and technology leading to lower radiation exposure, as has been the case for mammography in the past 4 decades.

There is a concern that interval cancers that develop between annual scans may be inherently more aggressive, more likely metastatic and thus incurable, even when quite small. Because of this, some researchers say that decreasing the length of time between screenings might not be helpful. However, the evidence for this effect comes from nonrandomized trials with questionable end points, and therefore I do not think this should dissuade us from looking at the possible benefits of semi-annual low-dose CT screening in very high-risk patients (eg, those with a 14-year risk >10% for new symptomatic lung cancer).

When to stop CT lung screening, similar to when to stop mammography or colonoscopy, is not clear. The nearuniversal case-fatality rate (>90% of patients with lung cancer now die of the

CT, computed tomography; PET, positron emission tomography Courtesy of Radiological Society of North America Note: Newly detected indeterminate nodule in persons aged ≥35 years. a

Average length and width

b

Minimal or absent history of smoking and of other known risk factors.

c

History of smoking or of other known risk factors.

d

The risk for malignancy in this category (<1%) is substantially less than that in a baseline CT scan of an asymptomatic smoker.

e Nonsolid (ground-glass) or partly solid nodules may require longer follow-up to exclude indolent adenocarcinoma.

disease) for symptom-detected lung cancer argues for continued screening late in life for those at highest risk. Although frailty and comorbid conditions caused by smoking could make operative mortality exceed 20%, the availability of stereotactic radiotherapy with local control rates in excess of 90% without thoracotomy suggests that years of life could be saved even under these circumstances.

A 4-cm cancer with hilar node metastasis would be incurable in a smoker with a forced vital capacity in 1 second of 700 mL, but could easily have been cured 3 years earlier with stereotactic radiation when it was 1 cm in size and had not spread to any nodes. Obviously, situations exist where screening is foolish. I suppose having a chance of living more than 3 years of less than 20% would constitute such a situation for me.

Because screening saves lives, and starts to do so in about 2 years in the current NEJM article, I would not want to deny the benefits of screening to even the frail and elderly high-risk patients.

Ensuring Quality So, how can we ensure the quality of the screening process? This is not trivial at all. The dose of radiation used to acquire the image, the quality of the machines, the quality of readers, the communication of level of risk to the readers, the quality of the reports, the communication of the results to the subjects and their physicians, and the adherence to protocols for the follow-up of discovered nodules of varying sizes are all significant issues to be addressed. A group of distinguished radiologists wrote a set of guidelines for the Fleischner Society (Table 2) whose major contribution was that nodules less than 5 mm in size could be followed in 1 year, not 3 months as had been previously suggested, because their likelihood of being cancer is less than 1%.9 Even if a very small nodule turned out to be cancer, the likelihood of it metastasizing before 1 year is very low. Unfortunately, awareness of these guidelines is far from universal among radiologists, and compliance with them considerably lower.10 Because of the risks associated with excess radiation, the inconvenience of repeated imaging, the cost of useless imaging, and the risk for inappropriate treatment recommendations, major efforts at radiologist education are needed. We should guard against self-serving reimaging or referral for positron emission tomography scans for very lowrisk lesions in the for-profit sector. We need to reassure conscientious but worried radiologists that they will not be sued if they follow the guidelines, even if the patient develops lung cancer later.

Radiologic societies and the federal government need to develop programs similar to those in place for mammography see SCREENING, page 24 

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Clinical Oncology News • October 2011

Lung

Introducing Commentaries on the Latest Studies Clinical Oncology News is very pleased to introduce a new feature this month, in which oncologists and hematologist/ oncologists at NewYork-Presbyterian Hospital’s Herbert Irving Comprehensive Cancer Center, an NCI-designated center located at Columbia University Medical Center, and Weill Cornell Cancer Center, located at Weill Cornell Medical Center, choose recent clinical studies that they consider to be important and provide brief commentaries. We believe these

summaries with insights from experts, many of whom are heavily involved in oncology research, will assist our readers in keeping abreast of the latest medical information.

—James Prudden, Group Editorial Director (Note that this issue includes some commentaries from other medical centers.)

NewYork-Presbyterian/ Weill Cornell Medical Center

NewYork-Presbyterian/ Columbia University Medical Center

Mixed Results for Erlotinib-Tivantinib Combo in NSCLC From Journal of Clinical Oncology

T

he combination of erlotinib plus tivantinib in the treatment of non-small cell lung cancer (NSCLC) is safe, at least compared with therapy consisting of erlotinib plus placebo, according to a new study (J Clin Oncol 2011;29:3307-3315, PMID: 21768463).

Overall efficacy of this regimen, however, remains in question.

The study evaluated 167 previously treated patients with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-naive NSCLC. Patients EXPERT INSIGHT Balazs Halmos, MD Associate Professor of Clinical Medicine Columbia University College of Physicians & Surgeons Section Head Thoracic Oncology NewYork-Presbyterian Hospital/Columbia

“This very interesting randomized Phase II study demonstrates a trend toward improvement with the addition of the small-molecule MET inhibitor,

were randomly assigned to receive either erlotinib (Tarceva, Genentech/ Astellas Oncology) plus tivantinib (ARQ 197, ArQule/Daichii Sankyo) or erlotinib plus placebo.

Tivantinib, a novel MET inhibitor, is still awaiting FDA approval. c-MET receptor activation is associated with poor prognosis and EGFR TKI resistance in NSCLC. Patients in the study received oral erlotinib (150 mg daily) plus oral tivantinib (360 mg twice daily) or erlotinib (150 mg daily) plus placebo. Treatment was administered continuously in 28-day

cycles. Progression-free survival (PFS) was the primary end point and, at the time of analysis, median follow-up was 11 months.

At the time of analysis, median PFS was 3.8 months for the erlotinib plus tivantinib group and 2.3 months for the erlotinib plus placebo group (P=0.24).

Median overall survival (median follow-up was 14 months) was 8.5 and 6.9 months, respectively (P=0.47). The erlotinib plus tivantinib combination appeared to be particularly effective in patients with KRAS mutations.

The 15 patients in the study with KRAS

mutations treated with the combination achieved a PFS hazard ratio of 0.18 (P=0.006).

In the intent-to-treat population, patients treated with erlotinib plus tivantinib had a median time-to-new metastatic lesions of 7.3 versus 3.6 months for patients treated with erlotinib plus placebo (P<0.01). Overall, adverse events and toxicities were similar between the two groups.

The authors believe the combination of erlotinib and tivantinib warrants further study in NSCLC, particularly in patients who are EGFR TKI-naive.

tivantinib, when added to erlotinib therapy in the second- or subsequentline treatment of EGFR TKI-naive advanced NSCLC. Results from several preclinical studies suggested a potential benefit for such a combination, as concurrent MET inhibition might possibly overcome acquired resistance mechanisms and also synergize in tumors with baseline activation of concurrent MET signaling pathways. Although the study failed to reach its primary end point (PFS prolongation, hazard ratio [HR], 0.81; P=0.24), several trends (including a 1.5-month prolongation of PFS) were clearly noticeable, suggestive

of a potential benefit, in particular in patients with nonsquamous histology.

An adjusted PFS analysis based on the proportional hazards model was positive (HR, 0.68; P=0.04).

In exploratory analyses, KRAS mutation-positive tumors seemed to derive a quite strikingly improved outcome (HR, 0.18, but in a very small number of patients). With the lack of a tivantinibalone treatment group, it is unclear whether the benefit is specifically related to combination therapy and will require further studies. MET status as determined by MET gene copy number analyses demonstrated trends toward correlating with tivantinib-treatment

benefit, but these observations are not as dichotomous as seen with the METmonoclonal antibody studies. Lastly, as MET signaling plays a major role in invasion and metastases, an exploratory analysis was conducted and showed a trend toward prolongation of median time-to-metastatic lesions.

A pivotal, worldwide Phase III study is now ongoing in patients with advanced, nonsquamous NSCLC with appropriate built-in biomarker studies. The results of this study are eagerly awaited to advance our understanding of the exploration of MET inhibition as a promising additional strategy in the treatment of advanced NSCLC.”

Biomarkers Help Personalize Lung Cancer Therapy From Cancer Discovery

T

he era of personalized care in oncology took a significant step forward, according to results of the first biopsy-mandated, biomarkerbased, adaptively randomized clinical trial in lung cancer (Cancer Discovery 2011;1:44-53).

The BATTLE (Biomarker-integrated Approaches of Targeted Therapy

for Lung Cancer Elimination) trial, included 255 pretreated patients with

non-small cell lung cancer (NSCLC).

Patients had not responded to a median of two prior therapies for metastatic disease.

Eleven molecular biomarkers associated with four molecular pathways involved in NSCLC were analyzed on initial biopsy: mutations in epidermal growth factor receptor (EGFR), KRAS, and BRAF; EGFR and cyclin D1 copy number by fluorescence in situ

hybridization; vascular endothelial growth factor (VEGF), VEGFR, 3 RXR receptors and cyclin D1 by immunohistochemistry. The first 97 patients were equally randomized to four different targeted therapies: erlotinib (Tarceva, OSI/ Genentech), vandetanib (Zactima, AstraZeneca), erlotinib plus bexarotene (Targretin, Eisai) or sorafenib (Nexavar, Bayer). The next 158 patients underwent adaptive randomization in which more patients were assigned to more effective see BIOMARKERS, page 26 

SOLID TUMORS

Clinical Oncology News • October 2011

Colorectal

Oxaliplatin Regimen Is Toxic in Rectal Cancer Patients From Journal of Clinical Oncology

T

he combination of oxaliplatin and 5-fluorouracil (5-FU)–based chemoradiotherapy in patients with locally advanced rectal cancers may produce significant drug toxicities, and its effectiveness may not justify the risk, according to a new study (J Clin Oncol 2011;29:2773-2780, PMID: 21606427).

The STAR-01 trial results revealed EXPERT INSIGHT Joseph T. Ruggiero, MD Associate Professor of Clinical Medicine Weill Cornell Medical College Gastrointestinal Oncology Service Division of Hematology and Oncology NewYork-Presbyterian/ Weill Cornell

“5-FU–based preoperative chemoradiotherapy remains a standard approach for locally advanced (T34 and/or cN1-2) adenocarcinoma of the rectum. Oxaliplatin in combination with 5-FU (either as an infusion, a bolus, or orally as capecitabine) has

that grade 3/4 adverse events (AEs) during preoperative treatment were more frequent with oxaliplatin (Eloxitan, Sanofi-aventis) plus 5-FU and radiation than with radiation and 5-FU alone. In the study, 24% of the patients treated with the oxaliplatin-based combination reported AEs such as diarrhea (15.3%), radiation dermatitis (4.5%) and asthenia (3.1%), compared with only 8% total AEs in patients treated with radiation

and 5-FU alone (P<0.001). The rate of AEs ultimately affected treatment compliance with the oxaliplatin-based regimen.

The study enrolled 747 patients, randomly assigning them to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused 5-FU (225 mg/ m2 per day) either alone (n=379) or in combination with oxaliplatin (60 mg/ m2 weekly for six weeks; n=368).

been shown to improve OS or diseasefree survival in stage III intraperitoneal adenocarcinoma of the colon.

Additionally, preclinical studies have shown oxaliplatin to be a potent radiosensitizing agent.

Therefore, it would be reasonable to expect a clinical benefit from the addition of oxaliplatin to 5-FU in the neoadjuvant therapy of rectal cancer. The STAR-01 trial referenced here is a randomized clinical trial of more than 700 patients comparing infusional 5-FU with the combination of 5-FU and weekly oxaliplatin at the dose of 60 mg/ m2 weekly for six weeks in combination with pelvic radiation to a dose of 50.4 Gy. The primary end point of the study is OS, which is not reported here.

This paper is the planned analysis of the pathologic response to treatment.

The results are both somewhat surprising and disappointing. Simply put, there was no difference in any of the measures of response chosen for analysis. Both arms of the study had similar rates of abdominal-perineal resection, pCR, pathologic node involvement and positive radial margin or tumor infiltration beyond the muscularis propria. Grade 3/4 AEs were seen more commonly in the combination arm.

The lack of an improvement in pCR does not preclude the study goal of improved survival. However, that analysis is pending. Until data showing improved survival are reported this study supports the continued use of single-agent fluorouracil as the standard agent for chemoradiation in locally advanced rectal cancer.”

Results for the study’s primary end point—overall survival (OS)—will be published at a later date. However, the data from this report do not indicate that thus far there is any substantive difference in efficacy with the addition of oxaliplatin to the chemoradiotherapeutic regimen. For example, pathologic complete response (pCR) was identical (16%) in both treatment arms (P=0.904). Additionally, 29% of the patients in the oxaliplatin group had pathologically positive lymph nodes, compared with 26% in the group that did not receive oxaliplatin, and 44% of the patients in the oxaliplatin group had tumor infiltration beyond the muscularis propria, compared with 46% in the other group (P=0.701). Intraabdominal metastases were identified at surgery in 0.5% of the patients in the oxaliplatin arm, compared with 2.9% in the other treatment group (P=0.014).

In addition to OS, follow-up data to this study will include an evaluation of molecular profiles in an attempt to identify potential predictors of tumor response and/or long-term treatment outcomes as well as “knowledge of the biologic mechanisms underlying sensitivity or resistance to chemoradiotherapy” in locally advanced rectal cancer.

New Tool Predicts Response to Chemotherapy in Metastatic CRC From Cancer Research

I

nvestigators have developed and validated a predictive tumor-infiltrating lymphocytes (TIL) density scoring system that they believe can be used to predict response to chemotherapy in patients with metastatic colorectal cancer (CRC). The tool is described in a recent issue of Cancer Research (2011;71:5670-5677, PMID: 21846824).

Analysis of TIL by in situ immunoEXPERT INSIGHT Manish A. Shah, MD Assistant Professor of Medicine Weill Cornell Medical College Director, Gastrointestinal Oncology NewYork-Presbyterian/ Weill Cornell

“Metastatic colon cancer remains a significant cause of cancer-related mortality in the United States and around the world. Unique to most solid

histochemical staining supports the concept that adaptive immune responses influence the overall course of primary CRC. High densities of TILs in the primary tumor support a better prognosis, irrespective of findings from other prognostic markers.

To investigate the role of TIL in the prognosis of metastatic CRC, researchers analyzed how TIL density at the invasive margin of CRC liver metastases responded following chemotherapy

and its relationship to progression-free survival (PFS).

High-resolution automated micro­ scopy on 101 large section samples generated cell densities for CD3, CD8, granzyme B or FOXP3-positive immune cells.

The investigators found that TIL densities at the invasive margin of liver metastases predicted response to chemotherapy with a sensitivity of 79% and a specificity of 100%. Furthermore,

high-density values were statistically associated with longer PFS. The results serve to extend the effect of the local immune response on the clinical course of the disease from the primary tumor to its metastatic lesions.

The researchers say the tool might help clinicians select those patients most likely to benefit from systemic treatment and prevent patients who are unlikely to benefit from suffering treatment-related side effects.

tumors, patients with metastatic colon cancer who are able to undergo resection of metastatic disease have a survival advantage compared with not having resection, and in some cases a cure. This has been most clearly established in metastatic colon cancer to the liver in which approximately 20% of patients can be cured with resection (J Clin Oncol 2009;27:3677-3683, PMID: 19470929). There remains controversy regarding the role of perioperative chemotherapy in this patient population, and improving our selection of patients who would benefit from resection and chemotherapy is an active area of research.

Cancer immunobiology is a burgeoning area of cancer research. The article by Halama and colleagues provides important new data on the prognostic implications of TIL in patients with metastatic CRC receiving chemotherapy. Specifically, in more than 100 patients with resected colorectal cancer liver metastases that encompassed both a training and validation set, a high density of TIL at the invasive margin of liver metastases correctly predicted radiographic response to chemotherapy. Importantly, the specificity for nonresponse was 100%, suggesting that this new immunohistochemistry analysis may provide

important new prognostic information for the value of chemotherapy in this patient population.

As this was a retrospective analysis, it is not clear to me that the TIL density is dependent on treatment or a function of the biology of tumors that respond and do not respond to therapy.

Outstanding questions also include the timing of the TIL response at the invasive edge of the liver metastases, and how different treatments may modify this response. However, TIL density at the invasive edge may become a promising new biomarker to help us decide on the adjuvant therapy in these potentially curative patients.”

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Clinical Oncology News • October 2011

Sarcoma

Gemcitabine-based Combo Tested for Soft Tissue Sarcoma From Journal of Clinical Oncology

R

esults from a Phase II study have concluded that a regimen of gemcitabine (Gemzar, Lilly) plus dacarbazine is safer and more effective than dacarbazine alone in patients with previously treated advanced soft tissue sarcoma (J Clin Oncol 2011;29:2528-2533, PMID: 21606430).

The study, conducted at several hospital centers in Spain, compared combination therapy with gemcitabine and

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

dacarbazine with dacarbazine monotherapy in 113 patients. Study participants were randomly assigned to receive either fixed-dose rate gemcitabine (10 mg/m2 per minute) at 1,800 mg/m2 followed by dacarbazine at 500 mg/m2 every two weeks or dacarbazine alone at 1,200 mg/ m2 every three weeks.

Progression-free survival (PFS) at three months, the study’s primary end point, was 56% in the gemcitabine plus dacarbazine group compared with 37% for dacarbazine alone (P=0.001). Median PFS was

4.2 months for the combination therapy compared with two months in the monotherapy group (P=0.005). Median overall survival was 16.8 months in the combination therapy group and 8.2 months in the monotherapy group (P=0.014).

Additionally, gemcitabine plus dacarbazine combination therapy was associated with a 44% reduction in the relative risk for death. The combination therapy showed a significantly higher objective response rate than dacarbazine monotherapy (49% vs. 25%; P=0.009).

Treatment adherence in the study group was high (>90%). Severe toxicities were uncommon in both patient groups, but 21% of the patients in the monotherapy group and 11% of the patients in the combination regimen group required hospitalization because of treatment-related adverse events.

The authors note that the results are promising but further study is needed before the combination therapy can be included in clinical guidelines for this patient population.

“The authors here report an objective response rate of 49% versus 25% comparing gemcitabine with DTIC (dacarbazine) to DTIC alone in a previously treated group of patients with soft-tissue sarcomas. This is an extremely impressive response rate.

However, two cautionary points need to be made: 1. First-line response rate in soft tissue sarcomas is 25% to 30% using doxorubicin-based therapy, which has historically been the most effective drug for these cancers, thus the almost doubling of the first-line response rate in the second-line setting by what was previously considered inferior regimens is surprising.

2. In the past several years, gem-

citabine has received significant attention as an active drug in sarcomas following initial results of a 53% response rate of a gemcitabine-docetaxel combination in a nonrandomized, Phase II trial in soft tissue sarcoma; results from a subsequent Phase II randomized trial, however, showed an 18% response rate for the combination and an 8% response rate for gemcitabine alone.

DTIC as a single agent has been previously studied with a known response rate of about 18%, and thus in general agreement with the 25% response rate reported here. DTIC also has been combined with other drugs active in sarcomas (e.g, CYVADIC: cyclophosphamide, vincristine, doxorubicin,

and DTIC) without improvement in overall response rates from single-agent doxorubicin given at higher concentrations. Thus, to accept the 49% response rate, one would have to invoke significant synergism between gemcitabine and DTIC, of which there are no reports in the general scientific literature.

In short, this is an extremely promising combination, and the randomized trial design certainly supports the author’s conclusions. However, taken in the larger context of previous work in soft tissue sarcomas, we should follow one of the rules of clinical oncology trials: All promising trial results need to be validated in a second independent trial.”

Prostate

Radical Prostatectomy vs. Watchful Waiting From Lancet Oncology

N

egative side effects are common among men diagnosed with prostate cancer, whether they are treated with radical prostatectomy or managed with watchful waiting, according to the latest findings from the SPCG-4 (Swedish Prostate Cancer Group-4) trial.

The trial randomized 695 Swedish and Finnish men to either radical prostatectomy or watchful waiting for the management of localized prostate cancer. Previously published results of SPCG-4 have reported a survival benefit associated with surgery among this group.

In the new article, the authors focus on the long-term side effects associated with both approaches, which they say are understudied (Lancet Oncol 2011 [Epub ahead of print], PMID: 21821474).

They included all living patients from the trial (400 of 695) in their analysis and asked them to respond to a studyspecific questionnaire about symptoms.

An additional 281 men (not diagnosed with prostate cancer) were included in a population-based control group

matched for region and age.

Although many men may elect watchful waiting as a management strategy for localized prostate cancer out of concern about loss of sexual function or urinary incontinence, the study found that these side effects still occur whether or not a patient undergoes surgery (although erectile dysfunction was more often reported to be distressing by the prostatectomy group than the watchful-waiting group.)

The prevalence of erectile dysfunction and urinary leakage were 84% and 41%, respectively, among the 173 men

in the radical prostatectomy group, 80% and 11% among the 153 men in the watchful-waiting group, and 46% and 3% among those in the control group.

The authors note that advancement of the cancer itself probably plays a role in these symptoms for those assigned watchful waiting.

Among those assessed at two followup points that were nine years apart, 38 of the 85 men in the surgery group (45%) and 48 of 80 men in the watchful-waiting group (60%) reported an increase in number of physical symptoms; 50 of 82 (61%) and 47 of 74 men

(64%), respectively, reported a reduction in quality of life. Anxiety was higher in the SPCG-4 groups (43% for both arms) than in the control group (33%) (relative risk, 1.42; 95% confidence interval, 1.07-1.88).

What does this mean for clinical decision making? The authors concluded that the “data emphasize that choice of treatment has to be guided by complete information and understanding of patient preferences since watchful waiting and radical prostatectomy involve complex scenarios that are not directly comparable.”

EXPERT INSIGHT

“A series of large randomized studies that have investigated the benefits of screening and treatment for early prostate cancer have been reported and updated recently, including the current Scandinavian SPCG-4 trial.

The results and conclusions remain controversial, and patients continue to face difficult decisions. The current report presents a timely update of the randomized prospective SPCG4 data including quality-of-life data.

These suggest both the prostatectomy and observational groups experienced deterioration of their quality of life compared with a matched group without prostate cancer. It appears the diagnosis of cancer can affect quality of life, perhaps by increasing anxiety. In conclusion, the current report provides additional information to assist the management of patients with localized prostate cancer.”

Ronald M. Bukowski, MD Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Management of

Oral Mucositis in Cancer Patients POLLY E. KINTZEL, PHARMD, BCPS, BCOP Clinical Specialist for Adult Oncology Spectrum Health Hospitals Grand Rapids, Michigan

M

ucositis, a painful adverse effect of systemic anticancer treatments and radiation therapy, can limit the efficacy of anticancer

therapy due to toxicity-related treatment interruptions, thereby

increasing morbidity, mortality, and the financial burden of therapy.1-3

Mucositis, which can affect the entirety of the gastrointestinal tract,4,5 is a complex biologic process that is part of a cluster of toxicity (Figure 1). Patients developing mucositis are more likely to develop diarrhea, fatigue, cutaneous lesions, and other regimen-related adverse effects.1,2 Much of the care provided to treat mucositis is aimed at symptom reduction and prevention of secondary complications, such as opportunistic infections.1,6 Mucositis can be associated with treatment with mammalian target of rapamycin inhibitors, tyrosine kinase inhibitors, biologic agents, microbial infection, malignancy, graft-versus-host disease, and other pathophysiologic conditions.2,6,7 The focus of this review is mucositis affecting the oral cavity, oropharynx, and hypopharynx that results from administration of systemic cytotoxic anticancer treatments and external beam radiation therapy (EBRT).

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The overall incidence of mucositis attributed to anticancer therapy ranges from 10% to 100%, depending on the treatment regimen used.1,2 Furthermore, the type, dose, and administration schedule of cytotoxic chemotherapy impact the severity and duration of mucositis. Regimen-related mucositis is practically a universal adverse effect with chemoradiotherapy for head and neck cancers and after intensive systemic treatment of hematologic malignancies.1,2 Antimetabolites, such as methotrexate and fluorouracil, are associated with a greater risk for oral mucositis than cytotoxic agents in general.8 The rate of severe oral mucositis for patients treated with standard chemotherapy regimens (without concurrent radiation therapy) averages 7% for nonHodgkinâ&#x20AC;&#x2122;s lymphomas, 4% for breast cancer, 1% for lung cancer, and 2% for colorectal cancer.9 For EBRT-related mucositis, the dose and exposure field determines

C L I N I C A L O N CO LO GY N E WS â&#x20AC;˘ O C TO B E R 2 0 1 1

1

Pain

Diarrhea

Dysphagia

Malabsorption

Ulceration Microbial colonization Bleeding

Reduced oral intake

Fluid imbalance

Malnutrition

Electrolyte disorders

Local infection Systemic infection

Mortality

Figure 1. Symptomatology associated with oral mucositis.

Based on reference 9.

severity. The risk for oral mucositis is 100% when radiation therapy is given to treat tongue cancer; it drops to 50% for patients undergoing radiation therapy for hypopharyngeal cancer. Additionally, certain cytotoxic treatments have a radiosensitizing effect and enhance the severity of toxicity when they are given concurrently with radiation therapy.1

Factors Contributing to Mucositis Saliva production, dental health, and mucosal health influence the risk for and severity of mucositis.1,2 Psoriasis increases the risk for mucositis, presumably due to preexisting epithelial dysfunction. Patients with Addison’s disease are prone to regimen-related mucositis, presumably due to a preexisting inflammatory condition.1 Additional health conditions that can increase the risk for mucositis include diabetes mellitus and renal impairment. Impaired hepatic or renal function can delay the systemic elimination of anticancer treatments

and increase the risk for regimen-related mucositis.1,2 Genetic characteristics that prolong systemic or intracellular exposure to chemotherapy modulate the severity of mucositis.10 Genetic variants of difluoropyrimidine dehydrogenase influence the likelihood of developing mucositis with fluorouracil administration.1 Another example of this is increased sensitivity to the oromucosal toxicity of methotrexate in patients with Down syndrome because trisomy 21 increases the expression of the folate carrier that transports this molecule into the cell.11 Additionally, a series in pediatric patients identified a relative risk of almost 3 for development of chemotherapy-induced oropharyngeal mucositis in patients with ABO blood type O compared with those with type A or B.8 Additional patient-specific factors that may influence the risk for developing regimen-related mucositis include age, body size, and gender.1,2 Worse mucositis has been demonstrated in female patients receiving

Table 1. Phases of Oral Mucositis Phase

Activity

Initiation

Generation of oxygen free radicals that damage DNA and cause lipid peroxidation

Upregulation

Activation of transcription factors NF-κB, COX-2, iNOS, SOD, IL-6, TNF

Message generation

Message amplification and generation

Ulceration

Bacterial colonization, inflammation, pain

Healing

Spontaneous recovery of mucosal tissue

COX-2, cyclooxygenase-2; IL, interleukin; iNOS, inducible nitric oxide synthase; NF-κB, nuclear factor kappa B; SOD, superoxide dismutase; TNF, tumor necrosis factor Based on reference 1.

2

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Table 2. Severity Grading of Mucositis Grade 0

Grade 1

Grade 2

Grade 3

Grade 4

No signs or symptoms

Painless ulcers, erythema, or mild soreness in the absence of lesions

Painful erythema, edema, or ulcers, but can eat/ swallow

Painful erythema, edema, or ulcers requiring IV hydration

Severe ulceration or requires IV or enteral nutritional support or prophylactic intubation

Based on reference 14.

treatment with fluorouracil and methotrexate.1 Bacterial colonization increases with mucosal damage and decreases with the healing of mucosa. Oral microflora can influence the clinical course of mucositis. In the absence of preexisting microbial disease, oral microflora does not have an identifiable role in the initiation of mucositis,1,2 but the role of microflora in regimen-related morbidity is an active area of research.12,13

Symptoms of Mucositis Hallmarks of mucositis include inflammation of the oral and alimentary tract mucosa, with subsequent tissue atrophy, swelling, erythema, and ulceration.2 The kinetics of mucosal damage differ following systemic treatment and EBRT. The onset of clinically evident mucositis following cytotoxic chemotherapy administration is 3 to 5 days, with resolution occurring within 2 weeks.

With radiation therapy, the subclinical events that yield tissue damage occur in a daily incremental fashion that can progress in an insidious manner as clinical evidence of toxicity evolves.1 The onset of clinical signs and symptoms of mucositis generally occurs after delivery of 15 Gy, with membrane ulceration occurring after delivery of 30 Gy. Clinical signs and symptoms of mucositis often last for 3 to 4 weeks following completion of radiotherapy.1,2

Pathophysiology of Mucositis Oral mucositis is a consequence of treatment-related pathophysiology affecting the oromucosal epithelium, underlying connective tissue, and blood vessels.1 Much of the clinical toxicity results from the bodyâ&#x20AC;&#x2122;s response to regimen-related tissue injury. A current model describes the process of oral mucositis in 5 overlapping phases: initiation, upregulation, message generation, ulceration, and healing (Table 1). Initiation occurs secondary to direct chemical or physical damage that results in clonogeneic death of epithelial cells. Cellular injury generates oxygen free radicals that damage epithelium, blood vessels, and connective tissue. Upregulation occurs subsequent to DNA damage and lipid peroxidation that induces the activation of transcription factors and promotes expression of inflammatory factors. Message generation is characterized by self-perpetuating enhancement of the intracellular signaling and second-message

generation that promotes the physiologic inflammatory response. Ulceration is the resulting physical damage that creates an environment that supports bacterial colonization, which, in turn, results in the recruitment of macrophages to the area, adding to the inflammatory process. This phase is associated with pain, opportunistic infections, and herpes simplex reactivation. The risk for disease from opportunistic infection often is enhanced by accompanying iatrogenic or disease-related neutropenia and impaired cell-mediated immunity. Healing occurs spontaneously over time, but subclinical damage may persist, increasing the risk that severe oral mucositis will occur if treatment is repeated.1 The risk for opportunistic infections increases markedly in the presence of oral mucositis. The oral cavity is a favorable environment for microbial growth. Mucosal injury enhances the ability of microbes to colonize the oral cavity. Moreover, the risk for microbial translocation through the damaged mucosal barrier often coincides with reduced immune competence as a result of treatment-related neutropenia and impaired cell-mediated immunity. Severe mucositis increases the risk for bacterial, yeast, and herpesviral infections.1,2 Pain from mucosal injury can be severe and difficult to manage, even with opioid analgesia. Pain and swelling can lead to reduced oral intake, which yields impaired fluid, electrolyte, and nutritional maintenance. Xerostomia from salivary gland dysfunction can be a troubling side effect of oral mucositis. Patients also can suffer from abnormal taste sensation, dyspepsia, and difficulty speaking. In extreme situations, oromucosal swelling can compromise the airway, necessitating intubation and mechanical ventilation. The National Cancer Institute Common Toxicity Criteria for Adverse Events grades the severity of mucositis according to symptomatology and required medical support (Table 2).14

Risk Reduction Minimizing the severity of mucosal damage and secondary sequelae is a priority in the management of oral mucositis. Most interventions are aimed at reducing discomfort and the risk for opportunistic infection, but one commercially available product, palifermin (Kepivance, Biovitrum), reduces clinical toxicity by

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3

Table 3. Efficacy of Palifermin for Reducing Severe Oral Mucositis Results Median Time to Severe Oral Mucositis, d

Patient Population

Intervention

Incidence, %

Median Duration of Severe Oral Mucositis, d

Hematologic malignancies

Palifermin (n=106)

63

3; P<0.001

Myeloablative chemoradiotherapy

Placebo (n=106)

98

9

Head and neck cancer

Palifermin (n=94)

54; P=0.027

4.5

47

Definitive chemoradiotherapy

Placebo (n=94)

69

26

35

Head and neck cancer

Palifermin (n=92)

51

5

45

Postoperative chemoradiotherapy

Placebo (n=92)

64

22

32

Soft tissue sarcoma

Palifermin (n=32)

13; P=0.002

3

Placebo (n=16)

51

6

Not reported

Not reported

Based on references 16, 19-21.

promoting epithelial growth and differentiation.15,16 Oral hygiene and good dental health are essential for minimizing morbidity from mucositis.9 It is important for facilities that care for cancer patients to have interdisciplinary practice guidelines to ensure systematic delivery of oral care. Dental evaluation prior to initiation of therapy is important for detection and correction of caries or gum disease that harbor or increase the risk for infection.2,9 Routine oral care that includes brushing, flossing, and flushing with bland mouth rinses makes the mouth a less favorable environment for microbial growth. A soft toothbrush should be used and replaced regularly. A cotton swab can be used as an alternative to a soft toothbrush.

Bland mouth rinses are useful for removing debris from the oral cavity and adding some moisture to the environment. Use of antiseptic and analgesic topical products should be based on patient tolerance, cost, and institutional practice.6 Dilute bicarbonate solution and sodium chloride 0.9% for irrigation are examples of suitable mouth rinses. One purported benefit of dilute bicarbonate mouth rinses is increased local pH, which makes the mouth unfavorable to microbial growth. Chlorhexidine 0.12% solution may be used as part of an oral care regimen to reduce microbial colonization, but it does not prevent or treat mucositis,9 and it contains alcohol, which can have a drying and irritating effect on damaged tissue. Mouth rinses containing allopurinol or sargramostim (Leukine, Genzyme), zinc sulfate, and glutamine have been tested only in small noncomparative trials, and thus their usefulness is uncertain.6 Sucralfate and antibiotic lozenges

4

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have not been shown to be beneficial for reducing radiotherapy-induced mucositis in controlled trials.9 Cryotherapy has demonstrated efficacy for reducing oral mucositis following bolus administration of fluorouracil and high-dose melphalan. The utility of cryotherapy is greatest for mucotoxic chemotherapy that is administered by IV bolus and rapidly excreted from the body. To receive cryotherapy, patients must hold ice chips in their mouth beginning before chemotherapy administration and continuing for up to several hours following drug administration. The local application of cold is thought to induce vasoconstriction within the oral cavity, reducing blood supply to the area and exposure of the oral mucosa to systemic chemotherapy.

One drawback to cryotherapy is the discomfort experienced by patients required to hold ice chips inside their mouth for several hours at a time.6 Additionally, it is imperative to avoid cryotherapy in patients receiving oxaliplatin because cold exposure can exacerbate painful drug-related neurotoxicity associated with this agent.17 Palifermin is a recombinant analogue of human keratinocyte growth factor approved to decrease the incidence and duration of severe mucositis in patients with hematologic malignancies who are undergoing treatment with myelotoxic chemotherapy requiring hematopoietic stem cell transplantation. Palifermin works in a dose-dependent receptor-mediated manner to modulate epithelial cell proliferation, differentiation, and migration, physically enhancing the epithelial barrier.15,18 Clinically, palifermin administration yields oromucosal edema and epithelial hyperplasia.16

Palifermin reduced the incidence and duration of severe mucositis compared with placebo during a controlled and randomized clinical trial (RCT) of patients with hematologic malignancies treated with myeloablative chemoradiotherapy—cyclophosphamide (total dose, 75-100 mg/kg), etoposide (60 mg/kg), and fractionated total body EBRT (total dose, 12 Gy)—and autologous hematopoietic stem cell transplantation (Table 3).19 Mucositis severe enough to hinder ingestion of anything orally occurred in 20% of patients treated with palifermin and 62% of those given placebo.

Opioid analgesia requirements were decreased among patients receiving palifermin. Patients in the palifermin group required a median of 7 days of opioid therapy for mucositis-related pain compared with a median 11 days in the placebo group.

Palifermin also was tested in patients with squamous cell cancer of the head and neck in 2 placebocontrolled, double-blind RCTs (Table 3).20,21 One trial enrolled patients with locally advanced cancer receiving definitive chemoradiotherapy for nonresectable tumors—70 Gy of EBRT delivered in 2-Gy fractions 5 days per week, and cisplatin 100 mg/m2 on treatment days 1, 22, and 43.20 The other RCT enrolled patients with stage II-IVB head and neck cancer undergoing postoperative chemoradiotherapy—60 Gy of EBRT for those with complete tumor resection or 66 Gy for those with incomplete tumor resection, delivered in 2 Gy fractions 5 days per week, and cisplatin 100 mg/m2 administered on treatment days 1 and 22, and for those with incomplete tumor resection, also on day 43.21 The incidence and duration of severe oral mucositis were reduced by palifermin administration in both studies. Patients receiving palifermin during postoperative chemoradiotherapy required less opioid analgesia than the placebo group,21 whereas those receiving palifermin during definitive chemoradiotherapy did not have reduced opioid administration compared with patients in the placebo group.20 In both trials, patient-reported mouth soreness scores and the number of interruptions in radiation therapy for symptoms of mucositis were similar between the treatment groups. Additionally, in both trials, 14% to 15% of patients missed 5 or more consecutive radiation fractions. Overall survival and disease response were similar for paliferminand placebo-treated patients after a median follow-up of 26 and 33 months for all patients receiving definitive chemoradiotherapy and postoperative chemoradiotherapy, respectively.20,21 Administration of palifermin as a single dose before repeated cycles of doxorubicin-based chemotherapy reduced the incidence and severity of mucositis in patients undergoing treatment for soft tissue sarcoma in a placebo-controlled RCT (Table 3).16 This study enrolled 48 patients randomized in a 2:1 fashion to receive palifermin or placebo. According to patient-reported

symptoms, palifermin reduced regimen-related mouth pain (P=0.002), throat soreness (P=0.010), and rectal pain (P=0.015). Additionally, the palifermin-treated group reported relatively less difficulty swallowing (P=0.013), drinking (P=0.012), and eating (P=0.024).

Seven of 16 patients in the placebo group who developed severe mucositis were switched to open-label palifermin. Subsequently, all of these patients were able to continue chemotherapy without dosage reduction and without developing severe mucositis.16 Adverse effects associated with palifermin administration tend to be transient and mild to moderate in severity.15,16,19 Patients generally report feeling thickness of the oral mucosa, tongue, and lips.16 Dermatologic adverse effects, such as rash, erythema, edema, and itching, commonly occur within 6 days of beginning palifermin therapy.15 Additional common adverse effects include altered taste, tongue discoloration, flushing, sensation of warmth, and increased saliva.15,16,19 Elevated values of serum amylase and lipase can occur with palifermin therapy. The vector for palifermin production is Escherichia coli, so use of this product is contraindicated in patients with a history of hypersensitivity to E. coli–derived proteins.15 Appropriate scheduling of palifermin administration relative to cytotoxic treatment is essential for optimal therapy. Administration of palifermin concurrently with chemotherapy can cause increased severity of mucositis because epithelial cells are stimulated to proliferate when exposed to the systemic cytotoxic therapy.15 Palifermin can be injected intravenously over 30 to 60 seconds.16 Various dosages of palifermin are presented in Table 4.

Management Pain control is a primary concern in patients with oral mucositis. Mouth rinses and topical products play a major role in pain management. Patients should be encouraged to use mouth rinses composed of sodium chloride 0.9% solution, sterile water, or dilute sodium bicarbonate (<1% solution) in a swish-and-expectorate manner as frequently as possible, or at least 4 to 6 times daily. Various topical products are used to provide local analgesia and other unproven benefits, such as antiseptic and anti-inflammatory effects. Many institutions compound extemporaneous solutions that contain mixtures of the following products: lidocaine, diphenhydramine, dexamethasone, nystatin, tetracycline, and liquid antacid. Extemporaneously compounded products also should be used in a swish-and-expectorate manner to avoid systemic absorption of the pharmaceutical constituents. Topical lidocaine is useful for providing local analgesia. Gargling with and ingestion of lidocaine are not advised because its numbing effect decreases the gag reflex and it is absorbed from the gastrointestinal tract. To reduce the risk for aspiration or

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5

Table 4. Palifermin Administration Use

Dosage

Comment(s)

Labeled dose

60 mcg/kg per dose IV daily x 3 d before myelotoxic chemotherapy; then 60 mcg/kg per dose IV daily x 3 consecutive days after myelotoxic chemotherapy

Premyelotoxic administration should be completed 24-48 h before the first dose of chemotherapy; postmyelotoxic palifermin should be administered on the same day but after hematopoietic stem cell infusion and at least 4 d after the last dose of myelotoxic chemotherapy

With chemoradiotherapy

180 mcg/kg per dose IV once before starting chemotherapy, then once weekly x 6-7 wk (throughout period of chemoradiotherapy)

Weekly palifermin is generally administered on Friday before Monday administration of chemotherapy

Single dose

180 mcg/kg per dose IV once, starting 3 d before chemotherapy

inadvertent traumatic injury, patients should be counseled against eating or performing oral hygiene after using lidocaine-containing products. Mucositis-related pain that is inadequately controlled using topical analgesia should be treated with systemic pain medication.

Systemic opioid therapy often is required for palliation of moderate to severe pain from oral mucositis.2 Gabapentin may be considered as an adjunct to standard pain medications.22 Xerostomia secondary to parotid gland dysfunction can be a problematic adverse effect of mucositis.2 Amifostine is an aminothiol cytoprotectant agent approved for reducing the incidence of moderate to severe xerostomia in patients undergoing postoperative radiation therapy for head and neck cancer, in which the radiation field involves a substantial portion of the parotid glands. The pharmacologic effect of amifostine is attributed to its metabolism by alkaline phosphatase enzymes to a sulfhydryl-bearing moiety that scavenges reactive

6

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oxygen species generated by radiation.23 Oral pilocarpine is a cholinergic medication approved for treatment of xerostomia attributed to radiotherapy in the treatment of head and neck cancers.24 Increased saliva production is greatest approximately 1 hour after ingestion of pilocarpine. Pilocarpine should be used with caution in patients who have preexisting cardiovascular disease.24 Malnutrition, fluid imbalance, and electrolyte disorders, which also can occur as a result of impaired oral intake with mucositis, also must be handled as clinically indicated.6

Conclusion Meticulous management of mucositis is essential for optimal patient outcome. Medical facilities that care for cancer patients must have interdisciplinary practice guidelines to ensure that patients at risk for oral mucositis receive thorough oral evaluations and systematic delivery of appropriate care.

References 1.

Sonis ST. Mucositis: the impact, biology and therapeutic opportunities. Oral Oncol. 2009;45(12):1015-1020.

2. Raber-Durlacher JE, Elad S, Barasch A. Oral mucositis. Oral Oncol.

2010;46(6):452-456.

3. Nonzee NJ, Dandade NA, Markossian T, et al. Evaluating the supportive care costs of severe radiochemotherapy-induced mucositis and pharyngitis: results from a Northwestern University Costs of Cancer Program pilot study with head and neck and nonsmall cell lung cancer patients who received care at a county hospital, a Veterans Administration hospital, or a comprehensive cancer care center. Cancer. 2008;113(6):1446-1452.

4. Triantafyllou K, Dervenoulas J, Tsirigotis P, Ladas SD. The nature of small intestinal mucositis: a video capsule endoscopy study.

Support Care Cancer. 2008;16(10):1173-1178.

5. Krishna SG, Zhao W, Grazziutti ML, Sanathkmar M, Barlogie B, Anaissie EJ. Incidence and risk factors for lower alimentary tract mucositis after 1529 courses of chemotherapy in a homogeneous population of oncology patients: clinical and research implications.

Cancer. 2011;117(3):648-655.

6. Bensinger W, Schubert M, Ang KK, et al. NCCN Task Force Report: prevention and management of mucositis in cancer care. J Natl Comprehen Canc Netw. 2008;6(suppl 1): S1-S21.

7.

Sonis S, Treister N, Chawla S, Demetri G, Haluska F. Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer.

2010;116(1):210-215.

8. Otmani N, Alami R, Soulaymani A, El Mokhtari A, Khattab M. Sex, age and ABO blood groups in chemotherapy-induced oropharyngeal mucositis. Minerva Stomatol. 2008;57(10):505-509.

9. Keefe DM, Schubert MM, Elting LS, et al. Updated clinical practice guidelines for prevention and treatment of mucositis, Cancer.

2007;109(5):820-831.

10. Ulrich CM, Yasui Y, Storb R, et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism.

Blood. 2001;98(1):231-234.

11. Taub JW, Ge Y. Down syndrome, drug metabolism and chromosome 21. Pediatr Blood Cancer. 2005;44(1):33-39.

12. Stringer AM, Gibson RJ, Bowen JM, Keefe DM. Chemotherapyinduced modification to gastrointestinal microflora: evidence and implications of change. Curr Drug Metab. 2009;10(1):79-83.

13. Van Vliet MJ, Harmsen HU, de Bont ES, Tissing WJ. The role of intestinal microbiota in the development and severity of chemotherapy-induced mucositis. PLoS Pathog. 2010;6(5):e1000879.

14. National Cancer Institute. Common Terminology Criteria for Adverse Events.version 4. http://ctep.cancer.gov/protocol Development/electronic_applications/ctc.htm#ctc_40.

Accessed September 12, 2011.

15. Kepivance (palifermin) [package insert]. Thousand Oaks, CA: Amgen, Inc; December 12, 2005.

16. Vadhan Raj S, Trent J, Patel S, et al. Single-dose palifermin prevents severe oral mucositis during multicycle chemotherapy in patients with cancer: a randomized trial. Ann Intern Med. 2010;153(6):358-367.

17. Eloxatin (oxaliplatin) injection [package insert]. Bridgewater, NJ: Sanofi-Aventis USA; March 13, 2009.

18. Weigelt C, Haas R, Kobbe G. Pharmacokinetic evaluation of palifermin for mucosal protection from chemotherapy and radiation. Expert Opin Drug Metab Toxicol. 2011;7(4):505-515.

19. Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers.

N Engl J Med. 2004;351(25):2590-2598.

20. Le QT, Kim HE, Schneider CJ, et al. Palifermin reduces severe mucositis in definitive chemoradiotherapy of locally advanced head and neck cancer: a randomized, placebo-controlled study.

J Clin Oncol. 2011;29(20):2808-2814.

21. Henke M, Alfonsi M, Foa P, et al. Palifermin decreases severe oral mucositis of patients undergoing postoperative radiochemotherapy for head and neck cancer: a randomized, placebo-controlled trial. J Clin Oncol. 2011;29(20):2815-2820.

22. Bar Ad V, Weinstein G, Dutta PR, Chalian A, Both S, Quon H. Gabapentin for the treatment of pain related to radiation-induced mucositis in patients with head and neck tumors treated with intensity-modulated radiation therapy. Head Neck.

2010;32(2):173-177.

23. Ethyol (amifostine) [package insert]. Nijmegen, The Netherlands: Medimmune, Inc.; May 2007.

24. Salagen (pilocarpine hydrochloride) tablets [package insert].

Woodcliff Lake, NJ: Eisai, Inc.; April 18, 2003.

Dr. Kintzel reports no relevant conflicts of interest.

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Head and Neck

Palifermin Studied in Patients With Head and Neck Cancer From Journal of Clinical Oncology

P

alifermin is safe and effective in treating the oral mucositis associated with definitive chemoradiotherapy in head and neck cancers, however, it does not perform significantly better than placebo on key measures such as progression-free survival (PFS) and overall survival (OS), according to a recent study (J Clin Oncol 2011;29:28082814, PMID: 21670453).

Palifermin (Kepivance, Biovitrum), which is derived from recombinant human keratinocyte growth factor, has been approved by the FDA to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies (specifically those undergoing treatment with myelotoxic therapy requiring hematopoietic stem cell support).

The new study was designed to test the drug in patients with locally advanced head and neck cancer. After exclusion

criteria were applied, 188 patients receiving conventionally fractionated radiotherapy (2 Gy per day for five days a week to 70 Gy) with cisplatin (100 mg/m2 on days 1, 22, and 43) were randomized to receive either palifermin (180 mcg/kg) or placebo prior to the start of chemoradiotherapy, and then weekly for seven weeks following the initiation of therapy. The primary end point was the incidence of severe, observable and functional oral mucositis.

The study was conducted at 46 hospital centers in North America and Europe.

The incidence of severe oral mucositis was significantly lower among patients treated with palifermin (54%) compared with placebo (69%; P=0.041).

Palifermin also appeared to delay the onset of oral mucositis. Median time to severe oral mucositis was 35 days for patients treated with the drug, compared with 47 days with placebo.

Palifermin also shortened the course of the condition; patients on palifermin experienced oral mucositis symptoms

for five days, compared with 26 days for those in the placebo group. These differences, however, were not statistically significant after multiplicity adjustments were made.

The study also found that opioid analgesic use, average mouth and throat soreness scores and chemoradiotherapy compliance were not significantly different

between the two groups. Adverse events (AEs) also were similar, with the most common study drug-related AEs being rash, flushing and dysgeusia. Finally, there were insignificant differences in OS and PFS (hazard ratios of 0.98 and 1.13, respectively) among patients treated with palifermin versus placebo (median follow-up, 25.8 months).

EXPERT INSIGHT

“Concurrent chemoradiotherapy is probably the most commonly used approach to treating locally advanced squamous cell cancers of the head and neck. Oral mucositis is a common, major toxicity of such treatment and effective means of reducing such side effects are needed. Palifermin, a recombinant human keratinocyte growth factor, is a possible agent for this; in this study, it appeared to lessen severe oral mucositis without interfering with treatment efficacy. Further studies and approaches are clearly needed.”

Martin W. Oster, MD Associate Professor of Clinical Medicine Columbia University College of Physicians & Surgeons Attending Physician NewYork-Presbyterian Hospital/Columbia

Melanoma

Vemurafenib Improves Survival in Metastatic Melanoma From The New England Journal of Medicine

V

emurafenib (Zelboraf, Roche), a novel B-Raf enzyme inhibitor, dramatically improves both progressionfree survival (PFS) and overall survival (OS) in patients with metastatic melanoma when compared with dacarbazine, according to a study in The New England Journal of Medicine (2011;364:25072516, PMID: 21639808).

The Phase III study randomized 675

EXPERT INSIGHT Elizabeta C. Popa, MD Assistant Professor of Medicine Weill Cornell Medical College Department of Medicine Division of Hematology/ Oncology NewYork-Presbyterian/ Weill Cornell

“This article reports on a new oral drug against a specific molecular mutation [in] BRAF, which is present in approximately half of melanomas. It represents the first truly targeted therapy in the treatment of melanoma. Mutant BRAF has constitutive kinase activity and causes

patients with unresectable, previously untreated stage IIIC or IV melanoma that tested positive for the V600EBRAF mutation to receive either vemurafenib (at a dose of 960 mg twice daily orally) or dacarbazine (at a dose of 1,000 mg/m2 of body surface area by IV infusion every three weeks).

At six months, OS was 84% in the vemurafenib group (95% confidence interval [CI], 78%-89%) compared with 64% in the dacarbazine group (95% CI, 56%73%). An interim analysis for OS and final

analysis for PFS found that vemurafenib was associated with a relative reduction of 63% in the risk for death and 74% in the risk for either death or disease progression (P≤0.001 for both). In the vemurafenib group, 48% of patients met the criteria for confirmed response, compared with 5% of the dacarbazine group.

Vemurafenib’s effectiveness appeared to extend to all subgroups of patients analyzed, including those with predictors of a poor prognosis, such as stage M1c disease or an elevated lactate

hyperactivation of the MAPK [mitogen-activated protein kinase] pathway. BRAF silencing induces regression of melanoma in xenografts.

Vemurafenib is a small-molecule ATP [adenosine triphosphate]-competitive and reversible inhibitor engineered to be specific to the V600EBRAF mutation.

The response rate (complete response plus partial response) of approximately 50% duplicates the result obtained in a previous multicenter, single-arm study and is one of the highest response rates ever obtained in this disease.

In this study, vemurafenib produced a highly statistically significant improvement in OS and PFS when compared in a randomized fashion with the standard, FDA-approved therapy for metastatic melanoma,

DTIC [dacarbazine].

The results of this study led to FDA approval of this drug in August 2011.

Final OS outcomes are not yet certain as median survival of patients receiving vemurafenib had not been reached. Regarding adverse effects, there are concerns regarding promotion of non-melanoma skin cancer growth due to a paradoxic stimulation of wild-type RAF kinases. Close patient surveillance for the development of other malignancies while on vemurafenib is required.

This new method of treating melanomas represents a breakthrough in treatment for this disease.”

dehydrogenase level.

Patients receiving vemurafenib required dose modification or interruption more frequently than patients in the dacarbazine group (38% vs. 16%), and the authors noted that the development of secondary cutaneous neoplasias in 18% of patients will require careful further investigation. They also recommend further study into the mechanism by which melanomas become resistant to vemurafenib, and trials of combination therapies.

Article Reprints Reprints of Clinical Oncology News articles are available.

Call Julianna Dawson at (212) 957-5300 x271.

Reprints can be ordered in black & white or 4-color.

17

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

SOLID TUMORS

Clinical Oncology News • October 2011

23

Breast

In Young Women …

Mastectomy Gives No Survival Gain Over Lumpectomy San Francisco—Women 40 years old and younger who are treated for breast cancer have similar recurrence and survival rates regardless of whether they opt for breast-conservation therapy (BCT) or mastectomy, according to two new studies. The results were presented at the recent 2011 Breast Cancer Symposium.

In the first study, Julliette Buckley, MD, a breast surgery fellow at Massachusetts General Hospital, in Boston, and colleagues reviewed medical records of 628 women aged 40 and younger who were diagnosed with up to stage III breast cancer between 1996 and 2008. They collected data on the women’s cancer stage, treatment, recurrence and overall survival (OS) during an average follow-up time of 72 months.

Analyzing the data according to the type of surgery the women received,

‘These patients should be counseled appropriately regarding their treatment options, and should not choose a mastectomy based on the assumption of improved survival.’

—Usama Mahmood, MD

‘Together, these studies should make us question any possible conventional wisdom that mastectomy is the only or even best option for most young women with breast cancer.’

—Andrew Seidman, MD

researchers found no statistically significant difference in risk for local cancer recurrence. Of the 421 women who underwent BCT, 30 (7.1%) developed a local recurrence during the study period, whereas of the 161 women who had a mastectomy, 12 (7.5%) developed a local recurrence.

The overall rates of local recurrence, including both groups, were 5.6% five years after diagnosis and 13% 10 years after diagnosis. Overall rates of distant recurrence were 12% five years after diagnosis and 19% 10 years after diagnosis. The average time to a recurrence was 35 months.

Of the women, 93% were alive five years after diagnosis and 87% were alive

characteristics such as tumor size or grade, and again found no statistically significant difference. The 10-year OS rate was 83.5% in the BCT group and 83.6% in the mastectomy group (P=0.99).

10 years after diagnosis. Nearly 83% were alive with no evidence of breast cancer five years after diagnosis, and at 10 years after diagnosis that number was nearly 69%.

The study suggests that younger women diagnosed with breast cancer have a good prognosis with a low risk for recurrence, and that lumpectomy is a safe option for women, Dr. Buckley said.

“We believe that awareness of the genetic risks for breast cancer, advances in screening for breast cancer and improvements in systemic and radiation therapy have contributed to longer overall survival for young women with breast cancer,” she said.

A second study also found no difference in survival rates among younger women treated with BCT versus mastectomy.

Using the National Cancer Institute’s Surveillance, Epidemiology and End Results database, Usama Mahmood, MD, radiation oncology fellow at the University of Texas MD Anderson Cancer Center in Houston, and colleagues compared OS and breast cancer–specific survival rates among 14,764 women ages 20 to 39 who were diagnosed with early-stage breast cancer between 1990 and 2007. Of these patients, 45% received BCT, including adjuvant radiation, while 55% underwent mastectomy. Of those undergoing mastectomy, 17% had radiation. The average follow-up period was 5.7 years.

After accounting for all available patient and tumor characteristics, including year of diagnosis, age, ethnicity, histology, grade, tumor size, number of positive lymph nodes and estrogen-receptor status, the two treatments were found to result in similar OS rates (hazard ratio [HR], 0.93; P=0.16) and breast cancer–specific survival (HR, 0.93; P=0.26).

Researchers also studied a smaller subset of 4,644 women, who were matched 1-to-1 according to specific

The 10-year breast cancer–specific survival rate in both groups was 85.5% (P=0.88).

“Young women with early-stage breast cancer have equivalent survival whether treated with breast-conservation therapy or mastectomy,” said Dr. Mahmood, who conducted most of the research while at the University of Maryland in Baltimore. “These patients should be counseled appropriately regarding their treatment options, and should not choose a mastectomy based on the assumption of improved survival.”

“Together, these studies should make us question any possible conventional wisdom that mastectomy is the only or even best option for most young women with breast cancer,” said Andrew Seidman, MD, an attending physician in the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, in New York City.

Emerging data show that biological subtype, luminal subtype and Oncotype DX recurrence score may offer additional information on the risk for local relapse in younger patients, but most oncologists don’t consider these, he said.

—Karen Blum

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 evidencebased, clinically relevant information that you can use to benefit your patients and practice.

If you are interested, please contact Kate O’Rourke, editor, at (212) 957-5300 ext. 265 or via e-mail at korourke@mcmahonmed.com.

24

SOLID TUMORS

Clinical Oncology News • October 2011

Lung

SCREENING continued from page 13 

quality assurance and communication.

The presence of some overdiagnosis (detection of some cancers that will never cause symptoms or metastasize) was suggested in a summary of 3 small screening trials.11 We therefore need to explore the least dangerous and least toxic treatments available because some patients we think need them based on histologic evaluation probably really do not. On the other hand, we need to be certain that the treatments are effective enough, so that those who have cancers that will grow, metastasize, and kill are cured. If the CT radiation doses are minimized, unnecessary short follow-up curtailed, and machine quality and performance monitored and, hopefully, improved, then risks for second malignancies from radiation will be minimized.

One could argue that, worse than over diagnosis, is the resection of lung nodules that are not neoplastic at all, but inflammatory. The rate of these on the initial screen in a recent meta-analysis of 6 small, randomized CT-screening trials was about 0.4% of screened subjects.12 The incidence of these could be minimized by following smaller lesions looking for their growth under observation and, especially in subjects with lower annual risk, using needle biopsy preoperatively before resection if the lesion has not grown. Clearly, the criteria for when to resect remains a work in progress. I argue that in a high-risk patient (1% per year or greater), any enlarging nodule should be removed.

Recently, Travis et al described very small lung neoplasms (adenocarcinomas with lepidic growth along the alveolar septae) that have an excellent prognosis after resection.13 Although one could argue that resecting these does the patient no good, I suggest that these only have been described in the era of incidental CT screening (see below). This has 2 implications. First, if they had not been resected, they would have evolved into real cancers that kill (that is why they were not observed in the first 100 years of the tobacco epidemic). Second, resecting them before they evolve into lethal cancers is of great benefit to the patient.

I suggest that nonprofit foundations set up high-quality low-dose multidetector CT scanners in major cities throughout the country to screen in single 30-second passes a maximal number of high-risk current or former smokers at low cost. They could use the machines 16 hours per day to reduce the cost per scan and the number of scanners needed. The low costs achieved at such centers should set the market price. Nothing should prevent academic centers and private radiology practices from performing lung cancer screening, but the

quality of the equipment and interpretation will need to be regulated and reviewed at least as carefully as is now the case for mammography.

Treating Small Cancers It is not entirely clear whether to do lobectomy or wedge or segmental resection for very small cancers. For these, smaller resections make sense, although their equivalence to lobectomy and node dissection is the subject of ongoing studies. Needle biopsy followed by stereotactic radiation is an option that obviates the need for thoracotomy and should nearly eliminate treatment-related mortality. As data accumulate, it may even become clear that a small population exists of very sick patients for whom the best option is to ablate a tiny lesion with radiation therapy rather than put the patient through the risks associated with a biopsy. This should be studied prospectively in carefully defined populations of study subjects.

How To Pay I do not think the expense of the screening studies is a major obstacle.

Some individuals in society feel that smokers brought the disease on themselves, and that as a society, we should not act to prevent their early deaths.

This is cruel, sadistic, and inhumane.

It is also a foolish position for society to take. Many productive and respected members of society do or did smoke.

Losing their productive lives would be a waste for society.

The cost of excising a tiny lung cancer is much less than that of treating a locally advanced cancer with surgery, radiation, and chemotherapy. Of course, someone cured of a tiny lung cancer will live to get ill from something else, and caring for that will cost money. If one follows this logic to its ultimate conclusion, however, then we should assassinate our population to save on long-term care costs.

The proper goal should be to act to preserve as many years of productive, relatively healthy, functional, and relatively contented life as possible. Our hope as a society must be not to save lives per se, but to save years of “good life.”

In New York City, the cost of a pack of cigarettes is $10 to $14. The experts claim we can do low-dose CT scans for the price of 2 to 3 cartons of cigarettes.7 I would be content to let the smokers themselves pay for the initial screen, and perhaps even for the annual screen as long as the screens are negative. The cost is that of about 2 cartons of cigarettes—if they quit smoking the 2 cartons to pay for the screen, so much the better! Once the screen turns up an area of concern, then the smoker has turned into a patient with a problem, and insurance should pay for this individual’s care just as it does for other members of society. In 2011, Medicare and the insurance

What are your thoughts?

Clinical Oncology News welcomes letters to the editor.

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

Please send comments to

korourke@mcmahonmed.com. industry have no problem paying for the evaluation of a lung nodule found incidentally in evaluating a cough (that cleared) or chest wall trauma.

Immediate Action Needed We have been screening for years, just in a haphazard way. In 1975, a radiologist seeing a 3-mm lung nodule in the superior images of an abdominal CT conducted for abdominal pain would describe a probable granuloma. Now the radiologist recommends follow-up to make sure it does not grow because he or she feels obligated to screen for lung cancer.

A busy thoracic surgeon in New York (Steven Keller, MD, personal communication) estimates that more than 80% of the patients on whom he operates for cure of lung cancer are referred for incidental findings that led to a lung cancer diagnosis. If his observation represents the common experience, then nearly all the people now being cured of lung cancer have had their cancers discovered in this incidental screening process. This reinforces the argument for organized screening based on statistical estimates of risk and annual incidence.

The US government and the committee writing the NEJM article seem poised to do nothing. Medical oncologists as a group have jobs of caring for dying lung cancer patients and struggling to buy them a few extra months of fairly uncomfortable life. I suggest we immediately tell our patients, their families, our hospital administrators, and our colleagues in primary care, radiology, and chest medicine that low-dose CT screening prevents needless early deaths from lung cancer. Tell them we are tired of watching advanced lung cancer patients die of their disease, and that annual screening by low-dose chest CT will substantially reduce the number who need our feeble ministrations for advanced lung cancer.

Until the country sets up a lung cancer screening program, we should write prescriptions for lung cancer screens 3 to 4 years before patients’ annual risk for symptomatic lung cancer exceeds a certain threshold (I suggest 0.1% per year as a start). Our primary care colleagues should get used to using calculators to estimate risks, and refer their patients for scans that give years of good life for those whose cancers are discovered and treated when they are tiny and localized.

I fully support efforts to prevent cigarette addiction and encourage smoking cessation, but both have had limited

success. Lung cancer is a huge public health hazard with a sky-high case fatality rate of about 90%. Efforts to help smokers quit will not immediately reduce the very high risk for people who have smoked 1 to 2 packs per day for 40 years—although risk for lung cancer decreases with time after smokers quit.

Most patients who are diagnosed with lung cancer when they have symptoms are already beyond chance of cure.

There are huge numbers of smokers at risk—they will smoke whether we screen them or not. If we screen them, many of them will have many years of productive life after the diagnosis and resection of a small lung cancer. The time to act is now.

References 1. National Lung Screening Trial Research Team, Alberle DR, Adams AM, et al.

Reduced lung-cancer mortality with lowdose computed tomographic screening. N Engl J Med. 2011;365(5):395-409, PMID: 21714641.

2. Kramer BS, Gohagan JK, Prorok PC, eds.

Cancer Screening: Theory and Practice. New York, NY: Marcel Dekker; 1999.

3. International Early Lung Cancer Action Program Investigators, Henschke CI, Yankelevitz DF, et al. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med. 2006;355(17):1763-1771, PMID: 17065637.

4. Lung cancer screening. In: DeVita, Hellman and Rosenberg’s Cancer: Principles & Practice of Oncology. Lippincott Williams & Wilkens;2008:681.

5. Bach PB, Elkin EB, Pastorino U, et al.

Benchmarking lung cancer mortality rates in current and former smokers. Chest.

2004;126(6):1742-1749, PMID: 15596668.

6. Bach PB, Kattan MW, Thornquist MD, et al.

Variations in lung cancer risk among smokers. J Natl Cancer Inst. 2003;95(6):470-478, PMID: 12644540.

7. Johnson BE, Cortazar P, Chute JP. Second lung cancers in patients successfully treated for lung cancer. Semin Oncol.

1997;24(4):492-499, PMID: 9280229.

8. Bae MK, Byun CS, Lee CY, et al. The role of surgical treatment in second primary lung cancer. Ann Thorac Surg. 2011;92(1):256262, PMID: 21600562.

9. MacMahon H, Austin JH, Gamsu G, et al.

Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology. 2005;237(2):395-400, PMID: 16244247.

10. Eisenberg RL, Bankier AA, Boiselle PM. Compliance with Fleischner Society guidelines for management of small lung nodules: a survey of 834 radiologists. Radiology.

2010;255(1):14-15, PMID: 20308458.

11. Bach PB, Jett JR, Pastorino U, et al. Computed tomography screening and lung cancer outcomes. JAMA. 2007;297(9):953-961, PMID: 17341709.

12. Gopal M, Abdullah SE, Grady JJ, et al.

Screening for lung cancer with low-dose computed tomography: a systematic review and meta-analysis of the baseline findings of randomized controlled trials. J Thorac Oncol.

2010 5(8):1233-1239, PMID: 20548246.

13. Travis WD, Brambilla E, Noguchi M. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma. J Thorac Oncol.

2011;6(2):244-285, PMID: 21252716.

HEMATOLOGIC DISEASE

Clinical Oncology News • October 2011

Mantle Cell Lymphoma

RITUXIMAB continued from page 1 

large, randomized controlled trial.

“I think the study strongly suggests significant benefit from rituximab maintenance in this patient population, although ideally we would like to see an effect on overall survival, which may yet emerge,” said Jennifer Brown, MD, PhD, an expert in the field who was not involved with the study. She is an attending physician with the Chronic Lymphocytic Leukemia & Lymphoma Program, Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard

Maintenance with IFN Maintenance with rituximab

100

Patients, %

80 60

57

40 26

20 0

Figure. Remission at four years.

recurrence of the disease could be postponed and thereby survival could be prolonged. To this end, we introduced maintenance therapy with rituximab, one injection every two months, beginning after successful initial chemotherapy.”

Eight countries participated in the European MCL Elderly trial that included 560 elderly patients with a median age of 71 years. All had extensive MCL. The patients were older than age 60 and were not eligible for high-dose therapy.

Initially, patients were randomized between eight cycles of R-CHOP every three weeks or six cycles of rituximab plus fludarabin and cyclophosphamide (R-FC) every four weeks. Subsequently, 288 patients in complete or partial remission underwent a second randomization between maintenance with rituximab 375 mg/m2 every two months or IFN alfa-2a or 2b (IFN), either weekly 3×3 million international units or pegylated IFN 1×1 mcg/kg. The second randomization was stratified for induction regimen, study group, age, international prognostic index and response.

Both maintenance regimens were continued until progression.

Data from 248 patients were evaluable. Roughly 61% of patients had a complete response or unconfirmed complete response upon induction therapy. More than half (58%) of patients received R-CHOP induction.

The results showed that maintenance therapy with rituximab reduced the risk for progression by 46%, resulting in 57%

‘For elderly patients not suitable for standard up-front autologous transplant, rituximab maintenance should become the standard of care for patients who obtained a partial or complete remission upon induction therapy with R-CHOP therapy.’

—Hanneke C. Kluin-Nelemans, MD, PhD

Medical School, both in Boston.

A combination of rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy (R-CHOP) is considered the standard regimen for elderly patients with MCL, but remissions are of short duration, said Hanneke C. Kluin-Nelemans, MD, PhD, head of the Department of Hematology at the University Medical Center Groningen, Groningen, The Netherlands.

She presented the findings of the new study at the 16th Congress of the European Hematology Association meeting (abstract 0504).

Maintenance with IFN has been suggested to be effective, but the side effects can be serious. In contrast, “rituximab seems a promising candidate for improvement,” said Dr. Kluin-Nelemans. “We wanted to find out whether

of patients being in remission four years later in comparison with 26% treated with IFN (Figure). “We did not compare rituximab with no maintenance but with interferon-alfa and found a significant prolongation of remission duration,” Dr. Kluin-Nelemans told Clinical Oncology News. “We collected data from patients who were responsive upon R-CHOP but did not undergo the second randomization for various reasons. Those patients had a far worse outcome, supporting our view that rituximab adds a long diseasefree period.”

Four years after the start of first therapy, 77% of the patients on rituximab are still alive compared with 62% of the patients on IFN. Patients who had been successfully treated initially with the R-CHOP regimen did extremely well, with 87% surviving at four years.

Micrograph of terminal ileum with mantle cell lymphoma (bottom of image, brown area).

‘I think the study strongly suggests significant benefit from rituximab maintenance in this patient population, although ideally we would like to see an effect on overall survival, which may yet emerge.’

—Jennifer Brown, MD, PhD

She noted that it is still too early to tell whether this result will lead to an improvement in overall survival, but “I believe this will translate into an overall survival advantage,” said Dr. Kluin-Nelemans. “It already did so for those patients who had been treated by R-CHOP upfront.” She noted that the researchers will continue lifelong follow-up of these patients, and pointed out that this is still not a cure because patients relapse even on rituximab maintenance.

In terms of toxicity, hematologic grade 3/4 toxicity was higher in the IFN arm— 36% leukocytopenia and 16% thrombocytopenia compared with 17% and 7%, respectively, in the rituximab arm. Nonhematologic grade 3/4 toxicity was rare, except for 7% infections in both arms.

R-FC followed by rituximab resulted in the highest infection rate, she said.

“Nonhematologic toxicity was mild with less than 10% grade 3/4 infections,” Dr. Kluin-Nelemans said.

Rituximab was better tolerated than IFN. Among patients who stopped maintenance despite the fact that they were still in remission, one-third of patients in the rituximab group did so because of side effects or other reasons compared with 80% in the IFN group. With respect to induction therapy, Dr. KluinNelemans suggested that R-CHOP is preferable to R-FC. After that, responders should receive rituximab once every two months for maximum benefit.

“For elderly patients not suitable for standard up-front autologous transplant,

rituximab maintenance should become the standard of care for patients who obtained a partial or complete remission upon induction therapy with R-CHOP therapy,” Dr. Kluin-Nelemans said. She added that “elderly patients with MCL should be candidates for clinical trials, and, if they are fit enough to undergo R-CHOP chemotherapy, should receive appropriate induction therapy (six to eight cycles), and if responsive, should continue with maintenance therapy with rituximab, one dose every two months until progression. With this regimen, a median four-year overall survival of 87% can be reached. This is an unbelievably good result for this age category.”

According to Dr. Kluin-Nelemans, it is not known whether this therapy may benefit younger patients who undergo a far more intensive induction therapy consisting of high doses of cytarabine and autologous stem cell transplantation.

—Mark Fuerst What are your thoughts?

Clinical Oncology News encourages letters to the editor.

Please send comments to

korourke@mcmahonmed.com.

25

26

HEMATOLOGIC DISEASE

Clinical Oncology News • October 2011

MDS

Study Investigates Optimal Lenalidomide Dose in MDS Higher Dose of Lenalidomide Yields Better Response in MDS, but Questions Linger A standard 10-mg initial dose of lenalidomide produces more cytogenetic remissions and a longer duration of red blood cell transfusion independence (RBC-TI) than lower lenalidomide doses in patients with lower-risk deletion-5q myelodysplastic syndromes (MDS).

This conclusion comes from pooled results of two studies, a Phase II multicenter, single-arm trial (MDS-003) and a Phase III multicenter, randomized placebo-controlled trial (MDS-004).

Alan List, MD, executive vice president and physician-in-chief at H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla., presented the results at the American Society of Clinical Oncology’s annual meeting (abstract 6522). The results appear to quash the hopes of clinicians who thought that a lower dose of lenalidomide (Revlimid, Celgene) would be just as effective as a higher dose but cause less toxicity.

The report was an update on data presented at the American Society

of Hematology meeting in December 2010. In the new analysis, investigators found that the total first-cycle lenalidomide dose received was directly correlated with cytogenetic remission (odds ratio, 1.089; P<0.0001) and that patients with cytogenetic remissions—either complete or partial—had more durable RBC-TI than nonresponders (median, 518 days; log rank test, P=0.0015).

Studies have suggested that transfusion dependence has an adverse effect on survival in lower-risk MDS patients.

“Lenalidomide is the most commonly used therapy for lower-risk MDS associated with del5q, and it is very effective in those patients,” said David Steensma, MD, a faculty member in the

‘Since toxicity was not any less with the 5-mg dose, this study cautions against starting with the lower dose.’

—Harry P. Erba, MD, PhD

Adult Leukemia Program at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School, both in Boston. “Del5q MDS has been a labeled indication for lenalidomide since December 2005, but one problem is that the optimal dose and schedule aren’t known.”

Because patients receiving lenalidomide often need their doses reduced as a result of the development of cytopenias, and many patients still respond to the lower dose, it was thought that a lower starting dose of 5 mg might be as effective as an initial dose of 10 mg, without as much toxicity. But, said Dr. Steensma, it appears that the 10-mg starting dose is significantly associated with better cytogenetic and RBC-TI responses than lower doses.

Harry P. Erba, MD, PhD, associate professor of internal medicine, Department of Internal Medicine Division of Hematology and Oncology, University of Michigan Medical School, Ann Arbor, agreed, but had another perspective. “The analysis shows a benefit of lenalidomide dose intensity in cycle one. Since the majority of patients in this analysis were treated on the nonrandomized MDS 003 study with a starting dose of 10 mg daily, dose interruptions and reductions occurred due to toxicity. You could just argue that the absence of hematologic toxicity in cycle one correlated with better outcomes,” he said. “Nonetheless, since toxicity

was not any less with the 5-mg dose, this study cautions against starting with the lower dose.”

—Gina Shaw Dr. List disclosed a consulting or advisory role with Celgene, along with research funding and honoraria from the company.

Dr. Steensma reported serving on an advisory board for Celgene approximately one year ago. Dr. Erba is on the Celgene speakers bureau for Vidaza and Revlimid in MDS.

SOLID TUMORS Lung

BIOMARKERS continued from page 14 

therapy within one biomarker group.

The primary end point of the Phase II study was the disease control rate at eight weeks. Overall, 46% of lung cancer patients experienced control of EXPERT INSIGHT Himisha Beltran, MD Assistant Professor of Medicine Weill Cornell Medical College Attending Physician Division of Hematology and Medical Oncology NewYork-Presbyterian/ Weill Cornell

disease. After a median follow-up of 10.3 months, the median overall survival (OS) duration was 8.8 months, and the one-year survival rate was 35%.

Median OS duration was 9.6 months in patients who experienced disease control, compared with 7.5 months in those who did not.

NSCLC patients with EGFR

mutations had the best disease control with erlotinib (P=0.04); the erlotinib-bexarotene combination was most effective for cyclin D1 expression (P=0.01) and EGFR amplification (P=0.006); and vandetanib produced the best disease control for tumors with VEGFR2 expression (P=0.05).

Sorafenib was most effective for tumors

without EGFR mutations (P=0.01) or polysomy (P=0.05) and tended to be best for patients with KRAS mutations (P=0.11).

The biopsy-driven approach did not present excessive risks to patients.

Pneumothorax occurred in 11.5% of patients and grade 3/4 toxicity occurred in 6.5% of patients.

“As we are moving toward an era of personalized oncology, the authors of this study should be commended for reporting the first completed biopsy-mandated, biomarker-based, adaptively randomized clinical study.

This Phase II single-institution study included previously treated patients with NSCLC. Several molecular biomarkers were analyzed on initial biopsy, and the first 97 patients were equally randomized to four different

targeted therapies (erlotinib, vandetanib, erlotinib plus bexarotene and sorafenib). The next 158 patients underwent adaptive randomization, meaning more patients were assigned to more effective therapy within one biomarker group. The primary end point was eight-week disease control rate, as a surrogate for OS. They found several biomarker– response associations that are hypothesis-generating, but that now

require randomized controlled validation studies. Although there were small numbers of patients in each group and statistical design was complex, this study is an important step toward understanding how molecular biomarkers can be used to design hypothesis-driven trials in clinical oncology. We are in need of such approaches to more efficiently translate new molecularly targeted drugs to the clinic.”

HEMATOLOGIC DISEASE

Clinical Oncology News • October 2011

Multiple Myeloma

Development of Second Cancers in Multiple Myeloma Probed I n the past year, oncologists have been put on the alert to monitor patients with multiple myeloma (MM) who are receiving lenalidomide maintenance therapy for the development of secondary malignancies. Although the alert is new, the problem of secondary malignancies in MM is not, and in the absence of biomarkers to predict which patients may develop a second cancer, many experts say the risk–benefit ratio still weighs heavily in favor of therapy with lenalidomide (Revlimid, Celgene).

A Long History According to Ola Landgren, MD, PhD, senior investigator and chief, Multiple Myeloma Section, National Cancer Institute, the development of acute myeloid leukemia (AML) after MM was first noted in the mid-1960s, with more cases reported in the 1970s. In 1970, Mayo Clinic researchers identified four AML cases among patients with MM treated with prolonged courses of melphalan for 30 to 57 months. In 1979, results from a New England Journal of Medicine study of 375 patients with MM who were treated with melphalan-based therapy found that 14 patients developed AML (1979;301:743748, PMID: 481481). This represented a 17% risk for developing AML at 50 months, said Dr. Landgren. The authors wrote, however, that “it is not possible to decide whether treatment with leukemogenic agents (γ-irradiation and alkylating agents) increases the risk of developing acute leukemia, because we do not know what the incidence is in untreated patients.”

“If we look at secondary malignancies in

relation to cumulative incidence of dying due to competing causes, the risk of secondary malignancies is about 7% based on SEER [Surveillance, Epidemiology, and End Results] data up to 2003,” said Dr. Landgren. “Clearly, the risk of dying is a much larger problem than developing a secondary malignancy, on average.

Investigators often thought that therapy caused secondary malignancies, but little is known about the mechanisms. “Is it only therapy that drives this? Are there certain types of drugs that are more prone to cause secondary malignancies?” asked Dr. Landgren.

In addition to treatment, other factors, such as cytogenetic or biological differences in the myeloma itself, could spur the development of second cancers.

Host-related factors, such as singlenucleotide polymorphisms, may predispose to myeloma and secondary malignancies. Behavioral and environmental factors may also play a role. “Maybe these factors interact and cause myeloma. We need to look further into this,” he said.

In his home country of Sweden, the risk for AML/myelodysplastic syndromes (MDS) is about 11 times higher in patients treated for MM compared with the general population. The risk for developing AML/MDS after monoclonal gammopathy of undetermined significance (MGUS) is eightfold higher. He noted that there is a dose–relationship effect in M-protein concentration. MGUS patients with higher M-protein concentrations have a risk similar to patients with MM. “This suggests there may be some inherent risk in having a plasma cell dyscrasia

in the absence of any therapy,” Dr. Landgren said. “This does not provide any information on mechanisms, but it provides a clue.”

Clinical Implications Three randomized studies presented in the last year identified more second malignancies with lenalidomide maintenance for transplant-eligible or -ineligible patients with MM compared with those who did not receive it.

The Intergroupe Francophone du Myelome 2005-12 trial found 19 secondary malignancies (hematologic and solid tumors) following myeloma, 16 (10 hematologic) in the lenalidomide arm and three in the placebo arm. The results showed improvement in progression-free survival (PFS) to 42 months in patients in the lenalidomide arm compared with 24 months in the placebo arm, but there was no overall survival (OS) benefit.

The Cancer and Leukemia Group B 100104 study identified 21 secondary malignancies (hematologic and solid tumors) following myeloma, 15 in the lenalidomide arm and six in the placebo arm (5 of 21 were AML/MDS). At a median follow-up of 28 months, the lenalidomide group showed better OS (90%) than the placebo group (83%).

In the MM015 trial, there was an imbalance of secondary malignancies with four cases of AML in those taking melphalan-predisone-lenalidomide (MPR) and MPR with lenalidomide maintenance (MPR-R) compared with two cases of AML among those who received only melphalan-prednisone

after a median 25 months of follow-up.

Median PFS of MPR-R was 31 months compared with 13 months for the melphalan-prednisone group, representing a reduced risk for progression of 60%.

In presenting the MM015 data at the 2011 ASCO meeting, Antonio Palumbo, MD, chief, Myeloma Unit Department of Oncology University of Torino, Torino, Italy, concluded that continuous lenalidomide demonstrated an unprecedented PFS improvement. “At present, the risk– benefit profile is strongly in favor of continuous lenalidomide for patients with newly diagnosed multiple myeloma.” Dr. Palumbo said. He added that “there is a slight increase in the risk for hematologic tumors when using lenalidomide with alkylating agents. But the risk for dying of myeloma is five times higher than the risk for developing a secondary malignancy.”

Dr. Landgren said “we always have to put benefits and risks in the algorithm when we think about secondary malignancies. Despite the fact that we don’t have clear data, we always have to discuss these facts with our patients.”

Acccording to Dr. Landgren, a key question is: what are the mechanisms? “There is a need for a concerted effort to characterize molecular features of patients who develop secondary malignancies following myeloma,” he said. “Imagine if we had a biomarker to predict who is at an increased risk for developing a secondary malignancy, and we knew that certain drugs would be preferable to limit the risks, that would make a huge difference for the individual patient.”

—Mark Fuerst Stem Cell Transplantation

Study Shows No Genotoxic Effects From G-CSF From Blood

A

recent study has demonstrated that granulocyte colony-stimulating factor (G-CSF) priming in healthy peripheral blood stem cell (PBSC) donors does not cause genotoxic effects (Blood 2011;118:2602-2608, PMID: 21719598).

G-CSF priming for autologous and allogeneic hematopoietic stem cell transplantations increases CD34positive cells in PBSC transplantations, leading to faster engraftment and reduced infections. However, the potential long-term genotoxic and other deleterious effects of G-CSF priming on healthy donors have been a concern. Some reports have found cases of acute myeloid leukemia (AML) years after donation, although a large review of a patient registry did not (Blood 2009;113:3604-3611, PMID: 19190248).

Other studies have found increases in

tetraploidy, de novo DNA synthesis, and relaxation of double-stranded DNA. Transient gene expression changes also have been noted; for instance, monosomy 7 has been identified in patients treated with G-CSF. Monosomy 7 is of particular relevance because it has been identified in patients with myelodysplastic syndrome (MDS) and AML who have received G-CSF. The current study prospectively explored G-CSF effects on chromosomal instability, including aneuploidy and replication kinetics, in normal donors.

Using fluorescence in situ hybridization (FISH), researchers evaluated the peripheral blood lymphocytes of 22 PBSC donors and 22 matched controls over a period of one year. Subjects were evaluated before receiving G-CSF, at the time of PBSC harvest, and at two, six and 12 months following donation.

Nine loci were evaluated for aneuploidy,

at chromosomes 8, 9, 17, 21 and 22, as well as three at chromosome 7. The investigators also evaluated replication kinetics for chromosomes 15 and 17 loci.

The study found no significant increase in aneuploidy or alteration in replication kinetics after short-term G-CSF treatment. There was no EXPERT INSIGHT Usama Gergis, MD Assistant Professor of Medicine Weill Cornell Medical College Bone Marrow Transplant Service NewYork-Presbyterian/ Weill Cornell

increase in monosomy 7, nor in trisomy 8, an abnormality associated with MDS. There was no significant chromosome 17 aneuploidy, despite an earlier study that had found such an effect in healthy controls following G - CSF priming (Exp Hematol 2004;32:122-130, PMID: 14725909).

The researchers concluded that PBSC mobilization procedure is safe.

“Hirsch and colleagues address the question of chromosomal instability in healthy stem cell donors who get mobilized by G-CSF. They used FISH to evaluate the peripheral lymphocytes in 22 donors at five time points during a 12-month interval. They found no evidence of chromosomal instability caused by G-CSF in healthy donors. It is important to recognize these efforts because mobilized stem cells have surpassed bone marrow as graft sources and we are faced with short- and longterm concerns.”

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HEMATOLOGIC DISEASE

Clinical Oncology News • October 2011

CLL

Novel Therapy Induces Complete Response in Refractory CLL From The New England Journal of Medicine

A

low-dose treatment with autologous T cells genetically modified to target the B-cell antigen CD19 through transduction with a lentivirus vector allowed a patient with refractory chronic lymphoid leukemia (CLL) to attain a complete response within three weeks, according to a recent case report (N Engl J Med 2011;365:725733, PMID: 21830940). The patient also had delayed development of tumor lysis syndrome. Genetically modified cells were present at high levels in the patient’s bone marrow for at least six months after infusion.

The news comes from a pilot clinical trial that tested this novel therapy in three patients with B-cell cancers. The patient described in the journal article had stable disease without treatment for six years and remained well controlled with chemotherapy for another seven years, but eventually progressed to

refractory, advanced p53-deficient CLL. T cells previously collected from the patient were transfected with the chimera-expressing lentivirus and a low dose was infused back into the patient.

This infusion induced no initial toxic effects. The main side effect was grade 3 tumor lysis syndrome, which presented with fever, chills, nausea and diarrhea, and was diagnosed 22 days after infusion. The patient was hospitalized and made a full recovery. Lymphopenia was the only other moderate or severe side effect. As expected, the researchers observed hypogammaglobulinemia, but this was mild and easily correctable, they reported.

One month after the infusion, the patient’s bone marrow showed no evidence of CLL, with normal karyotypes and no evidence of p53 deletion.

The patient remained in remission 10 months later.

Throughout the study, the patient’s serum and bone marrow were tested for immune responses. The researchers

observed a temporary increase in the inflammatory cytokines interferon-g, interleukin-6, CXCL9 and CXCL10, which peaked at approximately the same time as the clinical symptoms of tumor lysis syndrome.

T cells expressing the CART19 receptor were observed from day 1 postinfusion, with the peak concentration indicating a more than 1,000-fold

expansion of these cells from the infused levels. Neither normal CD19expressing B cells nor leukemia cells could be observed in the bone marrow.

In the discussion, the researchers noted that T-cell responses do not depend on a patient’s HLA molecules. This could set the stage to treat more patients with not only with CLL but other hematologic and solid malignancies as well.

EXPERT INSIGHT

with a low dose of autologous chimeric antigen receptor-modified T cells. The patient attained complete response with delayed tumor lysis syndrome. Interestingly, the very low dose of T cells that were infused resulted in a clinically evident antitumor response. Moreover, the T cells expanded in vivo to a level that is 1,000 times higher than the initial infusion. The technique used could set the stage to treat more patients not only with CLL, but also with other hematologic and solid malignancies.”

Usama Gergis, MD Assistant Professor of Medicine Weill Cornell Medical College Bone Marrow Transplant Service NewYork-Presbyterian/ Weill Cornell

“In this report, the authors treated a patient with refractory CLL

Follicular Lymphoma

Maintenance Rituximab Delays FL Progression From Lancet

T

wo years of maintenance rituximab (Rituxan, Genentech\Biogen Idec) following first-line immunochemotherapy significantly improves progression-free survival (PFS) in patients with follicular lymphoma (FL), according to results from the PRIMA (Primary Rituximab and Maintenance) trial (Lancet 2011;377:42-51, PMID: 21176949). This Phase III trial showed that the improved PFS comes at the price of increased adverse events (AEs), although these were mostly mild.

The mulitnational team of investigators randomized 504 patients with previously untreated FL to two years of rituximab maintenance therapy

EXPERT INSIGHT Adrienne A. Phillips, MD, MPH Assistant Professor of Clinical Medicine Columbia University College of Physicians & Surgeons Assistant Attending NewYork-Presbyterian/ Columbia

(375 mg/m2 every eight weeks) and 513 patients to observation following immunochemotherapy (rituximab plus one of three standard chemotherapy regimens).

Although the benefits of this initial immunochemotherapy protocol in lymphoma have been well established, as have the benefits of rituximab maintenance in patients with relapsed disease or following initial single-agent treatment, PRIMA is the first Phase III trial in FL to combine what is considered an optimal initial treatment with immediate rituximab maintenance.

At a median follow-up of 36 months, PFS was 74.9% in patients receiving rituximab maintenance and 57.6% in patients in the the observation arm (P≤0.001), representing a significant

reduction in risk for progression for those on maintenance therapy (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.44-0.68).

Patients receiving rituximab maintenance experienced a significantly higher rate of adverse events. Overall, 56% of patients undergoing maintenance therapy experienced at least one AE, compared with just 37% in the observation group (relative risk [RR], 1.51; P<0.0001).

The most frequent AEs in both groups were mild infections (seen in 39% of maintenance and 24% of observation patients; RR, 1.62; P<0.0001), most commonly bronchitis, upper respiratory tract infections, sinusitis, urinary tract infections and nasopharyngitis. AEs resulting in treatment discontinuation

were relatively few in both groups—4% for maintenance rituximab and 2% for the observation group (RR, 2.41; P=0.029).

With only 26 deaths in the rituximab maintenance group and 30 in the observation group (HR, 0.87; 95% CI, 0.511.47), the improved PFS gleaned from maintenance rituximab did not appear to translate into an OS benefit.

The authors suggest that given the overall high rate of efficacy for salvage therapies used after initial treatment failure in FL, their three-year data are still relatively immature and could change with further follow-up.

They noted, “Attainment of a complete response is associated with improved long-term survival in patients with follicular lymphoma.”

“Follicular lymphoma is the most common indolent lymphoma in the United States and is generally an incurable disease, characterized by periods of remission and relapse over a number of years. Rituximab, an anti–B-cell monoclonal antibody that targets the CD20 antigen, combined with chemotherapy has become the most commonly used regimen for initial treatment and has had a profound impact on the outcome of FL. Until now, the benefit of rituximab maintenance after rituximab plus chemotherapy was not known.

PRIMA is a Phase III randomized study of 1,217 patients with previously untreated advanced-stage FL who were randomized to induction therapy with rituximab plus chemotherapy (either CHOP, CVP or FCM) or chemotherapy alone. Patients who responded to therapy were then randomized to maintenance rituximab, given once every two months for two years, or observation.

Patients receiving rituximab maintenance had significantly better threeyear PFS than those in the observation arm (75% vs. 58%) at the expense

of higher toxic effects—primarily mild, self-limited infections. There was no difference in OS. This is the largest randomized study in FL with an impressive improvement in PFS at three years. Longer follow-up is necessary to answer a number of remaining questions, including whether OS is improved, whether safety is further impaired, and whether retreatment at time of progression offers similar improvement in outcomes. However, maintenance is now an option and the PRIMA investigators should be congratulated on this important study.”

HEMATOLOGIC DISEASE

Clinical Oncology News • October 2011

AML and MDS

Improving HCT Using HLA-haploidentical Grafts From Blood

A

recent study in the journal Blood demonstrates that hematopoietic cell transplantation (HCT) using HLA-haploidentical grafts with reduced-intensity conditioning (RIC) achieves good outcomes in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) (Blood 2011;118:2609-2617, PMID: 21715313).

Patients with MDS and AML can be cured following allogeneic HCT from an HLA-matched donor, but suitable donors, whether they are family members or from a donor registry, are only available for about 60% of patients in need. For certain ethnicities, that number is far lower.

Other sources of allogeneic HCT include HLA-haploidentical familial donors, HLA partially matched nonfamily donors and unrelated umbilical cord blood, with the former being most readily available. HLA mismatch between donor and recipient during allogeneic HCT increases graft failure and both acute and chronic graftversus-host disease (GVHD), slows immune recovery and increases the rate of transplantation-related mortality (TRM). Studies have shown, however,

that a haplotype mismatch can be overcome in the major histocompatibility complex with RIC, increasing engraftment success to greater than 90%. Furthermore, HLA-haploidentical HCT with RIC keeps rates of grades 2 to 4 acute GVHD, chronic GVHD, and TRM relatively low. The researchers noted that, because of its relative success, the role of RIC in HLA-haploidentical HCT is important to investigate further.

Investigators had previously shown in a study of 29 patients that HCT from an HLA-haploidentical familial donor was successful without ex vivo T-cell depletion with RIC, which was comprised of busulfan, fludarabine and antithymocyte globulin (Biol Blood Marrow Transplant 2009;15:61-72, PMID: 19135944).

The new study published employs the same procedure on 54 new patients with either AML (34 in remission, 34 refractory) or MDS (15).

The HLA-haploidentical donors were offspring (n=38), mothers (n=24) or siblings (n=21) who received granulocyte colony-stimulating factor and underwent leukapheresis and GVHD prophylaxis (with cyclosporine and methotrexate). After HCT, the cumulative incidence of neutrophil engraftment was 92%; grade 2 to 4 acute

GVHD, 20%; chronic GVHD, 34%; and TRM, 18%. Median follow-up was 26.6 months (range, 16.8-78.8 months), at which the event-free and overall survival rates for patients with AML in remission were 56% and 45%, respectively; for patients with refractory

AML, 9% and 9%, respectively; and for patients with MDS, 53% and 53%, respectively.

The researchers concluded that HCT from an HLA-haploidentical familial donor resulted in outcomes that were favorable when RIC was performed.

EXPERT INSIGHT

and MDS who received haploidentical grafts after conditioning with busulfan, fludarabine and antithymocyte globulin. Interestingly, the outcome of these patients compares favorably with Center for International Blood & Marrow Transplant Research patients who received HLAmatched grafts and were conditioned with similar regimens. This study provides more evidence that haploidentical grafts can be used with success in selected patients who lack matched graft sources.”

Usama Gergis, MD Assistant Professor of Medicine Weill Cornell Medical College Bone Marrow Transplant Service NewYork-Presbyterian/ Weill Cornell

“Lee et al. report a favorable longterm outcome for patients with AML

SUPPORTIVE CARE Diarrhea

Novel Diarrhea Syndrome Linked to HSCT From The New England Journal of Medicine

I

nvestigators from Boston have identified a novel syndrome that causes diarrhea among patients who have undergone cord-blood hematopoietic stem cell transplantation (HSCT). Distinct from acute graft-versus-host disease (GVHD), cord colitis syndrome causes culture-negative diarrhea that responds to antibiotic therapy.

Potential causes of diarrhea after HSCT include acute GVHD and gastrointestinal infection, and discerning the difference is important because treatment varies: GVHD requires heightened immunosuppression, whereas infection requires antimicrobial therapy. Viral causes of diarrhea after HSCT include cytomegalovirus, adenovirus, rotavirus, norovirus and Epstein-Barr virus; protozoal infections causing diarrhea include giardia and cryptosporidium.

Investigators performed a retrospective cohort study of 104 patients who had received cord-blood HSCT over a seven-year period (N Engl J Med

2011;365:815-824, PMID: 21879899). The underlying diseases in these cases were acute myeloid or lymphoblastic leukemia, chronic myeloid or lymphocytic leukemia, myelodysplastic syndrome, myeloproliferative disorder, non-Hodgkin’s lymphoma, Hodgkin’s disease and aplastic anemia.

Conditioning regimens varied: 26 patients underwent myeloablative conditioning, usually with cyclophosphamide, total-body irradiation, and fludarabine; 78 patients received reducedintensity conditioning, most commonly with a regimen of fludarabine, melphalan and antithymocyte globulin. The median follow-up period was 452 days; 101 of the patients received two units of cord-blood stem cells and three patients received one unit.

Investigators defined cord colitis syndrome as persistent diarrhea lasting more than one week that is not caused by acute GVHD, bacterial or viral infection, post-transplantation lymphoproliferative disease or any other cause following microbiologic and histopathologic examination. Of the 104 patients,

11 (10.6%) had cord colitis syndrome; the one-year cumulative probability for the syndrome was 0.16. The median time to onset after cord-blood HSCT was 131 days (range, 88-314). Most patients (91%) with cord-blood syndrome lost weight (median loss, 2.3 kg) and eight patients (73%) required hospitalization.

After ruling out all other causes of diarrhea in the patients with cord-blood colitis, the investigators initiated a 10- to 14-day course of metronidazole antibiotic therapy, alone or in combination with a fluoroquinolone. All patients responded; however, the diarrhea recurred in five of the 11 patients (45%), prompting a second course of antibiotic therapy.

Histologic examination showed that all the patients with cord colitis syndrome had chronic active colitis; in seven of the patients (64%) granulomatous inflammation was also present.

The investigators concluded that cord colitis syndrome should be considered a possible cause of unexplained diarrhea in patients who have undergone cordblood HSCT.

EXPERT INSIGHT Usama Gergis, MD Assistant Professor of Medicine Weill Cornell Medical College Bone Marrow Transplant Service NewYork-Presbyterian/ Weill Cornell

“Herrera et al. report the recognition of a new syndrome associated with cord-blood HSCT, cord colitis syndrome. The pathophysiology of this disease is different than GVHD and similar to Crohn’s disease. The syndrome occurred at a median of 131 days and responded to antibiotics, despite the lack of evidence of a pathogenic cause. It is important to recognize and study new syndromes in the evolving field of cord transplantation because they often go unrecognized or get mixed up with more common diseases such as GVHD.”

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PRN

Clinical Oncology News • OCTO ber 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.

Patients with non-germinal center B-cell diffuse large B-cell lymphoma (non-GCB-DLBCL) have worse outcomes following conventional immunochemotherapy compared with patients with GCB-DLBCL. Upfront recognition of non-GCB DLBCL has important prognostic and probably newer therapeutic implications. According to the classification described by Hans and colleagues, all of the following immunohistochemistry (IHC) profiles characterize non-GCB DLBCL except: a. Immunoperoxidase stain is negative for CD10, positive for bcl-6 and positive for MUM-1 b. Immunoperoxidase stain is negative for CD10 and bcl-6 c. Immunoperoxidase stain is negative for CD10, positive for bcl-6 and negative for MUM-1

2.

All of the following statements about the drug bortezomib (Velcade, Millenium) are correct except: a. It can only be administered intravenously in multiple myeloma. b. It has clinical activity in mantle cell lymphoma (MCL). c. A dose adjustment is not required when a patient is in renal failure. d. It can enhance activity of chemoimmunotherapy in non-GCB DLBCL.

3.

Based on a high modified Gail model (MGM) risk assessment score of 2.1%, you have recommended tamoxifen therapy to one of your postmenopausal 60-year-old patients. She has hyperlipidemia, severe osteoporosis, and history of total abdominal hysterectomy and bilateral salpingo-oophorectomy. She is motivated to start primary prevention therapy, and she asks you to comment

on a recently published New England Journal of Medicine article that discusses exemestane (Aromasin, Pfizer) for breast cancer prevention in postmenopausal women. She wants to know if she can take exemestane or something besides tamoxifen for breast cancer prevention. All of the following statements address her concerns and are true except: a. Exemestane has anti-osteoporosis effects. b. The MAP.3 study with exemestane has a shorter follow-up period compared with the P-1 study with tamoxifen. c. Tamoxifen has anti-osteoporosis effects. d. If this patient is reluctant to start tamoxifen, then raloxifene is a reasonable alternative.

4.

All of the following factors are part of the MGM risk assessment tool except: a. History of lobular carcinoma in situ (LCIS) b. Age at menarche c. Number of breast biopsies d. Age e. Number of first-degree relatives with breast cancer

5.

You are seeing a 46-year-old patient with metastatic ovarian cancer who is on chemotherapy. She reports a 2-month history of loss of balance, which has progressively worsened over the past few weeks. More recently, she has developed dysphagia and slurred speech. Vitals are normal. The physical examination localizes to the cerebellum.

The laboratory tests, including cynaocabalamin levels, are within normal range.

Rapid plasma regain and HIV tests are

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negative. A brain magnetic resonance imaging scan and lumbar puncture are unremarkable. Which of the following statements about this patient’s clinical condition is correct? a. She is malingering and will most likely request disability. b. She has developed chemotherapyinduced encephalopathy. c. She most likely has serologic evidence of anti-Yo antibodies accounting for loss of cerebellar Purkinje fibers.

6.

A 19-year-old Asian boy presents with a bilateral cervical lymphadenopathy. A biopsy of the cervical lymph node is consistent with a nasopharyngeal tumor. The scans identify a primary tumor that is confined in the nasopharynx with bilateral cervical lymph nodes; the largest lymph node is approximately 4 cm in size. All of the following statements about this patient’s nasopharyngeal cancer are correct except: a. He most likely has World Health Organization (WHO) type II (nonkeratinizing) or type III (undifferentiated) nasopharyngeal cancer. b. He most likely has the endemic type of nasopharyngeal cancer. c. Late relapses are not uncommon in this disease. d. His disease is most likely associated with chronic respiratory syncytial virus (RSV) infection.

7.

According to the American Joint Committee on Cancer (AJCC),

which of the following is the correct stage of the patient described in question 6? a. II b. III c. IVa d. IVb

8.

In the United States, what is the most commonly recommended treatment strategy for the patient described in question 6? a. Concurrent chemoradiation therapy (CRT) followed by surgery b. Concurrent CRT followed by chemotherapy c. Radiation therapy followed by surgery d. Radiation therapy alone

9.

Hairy cell leukemia (HCL) is associated with the BRAF V600F mutation. a. True b. False

10.

Which of the following statements is correct about a Phase

I trial? a. The primary objective is to determine the maximum tolerated dose (MTD) of a cytotoxic drug. b. The primary objective is to define the biologically active dose of a cytostatic drug. c. The primary objective is to determine if patients with a particular biomarker are more likely to respond to a molecularly targeted agent.

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Clinical Oncology News • OCTOber 2011

Community Oncology

ANSWERS

1.

The answer is c. According to the tissue microarray classification as described by Hans and colleagues the IHC profile in choice c is not consistent with non-GCB DLBCL but with GCB-DLBCL. Hans CP, Wiesenberger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood.

2004;103(1):275-282, PMID: 14504078.

2.

The answer is a. Subcutaneous administration of bortezomib has been studied and is an attractive option. It causes significantly less neuropathy and offers noninferior efficacy when compared with the IV formulation. Bortezomib is approved by the FDA for relapsed/refractory MCL. Frontline administration of bortezomib to conventional chemoimmunotherapy has shown reassuring activity in newly diagnosed non-GCB DLBCL and MCL. Dose adjustments of bortezomib are required with hepatic not renal impairment.

Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomized, phase 3, non-inferiority study.

Lancet Oncol. 2011;12(5):431-440, PMID: 21507715.

Fisher RI, Bernstein SH, Kahl BS, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma.

J Clin Oncol. 2006;24(30):4867, PMID: 17001068.

Ruan J, Martin P, Furman RR, et al. Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J Clin Oncol. 2011;29(6):690-697, PMID: 21189393.

3.

The answer is a. In high-risk postmenopausal women, both tamoxifen and raloxifene have been approved by the FDA for primary prevention against breast cancer. Both medications also have bone-protective effects.

Tamoxifen also can be administered for primary prevention of breast cancer in high risk premenopausal women older than age 35. Exemestane does not have anti-osteoporosis effects, and, in fact

has been associated with an increase in osteopenia and osteoporosis.

paraneoplastic cerebellar degeneration. N Engl J Med. 1990;322(26):1844, PMID: 2348838.

Fisher B, Costantino JP, Wickerham DL, et al.

Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005;97(22):1652-1662, PMID:16288118.

6.

Vogel VG, Costantino JP, Wickerham, et al.

Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer. Cancer Prev Res. 2010;3(6):696-706. Epub 2010 Apr 19, PMID: 20404000.

Goss PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364(25):2381-91, PMID: 21639806.

4.

The answer is a. Other factors that are part of the MGM risk assessment tool are age of first live birth or nulliparity and race/ethnicity. The MGM risk assessment tool does not take into account LCIS, ductal carcinoma in situ, family history of ovarian or male breast cancers, family history of second-degree relatives, or hereditary mutations. The MGM risk assessment tool can be easily accessed at www.cancer.gov/bcrisktool and www.breastcancerprevention.com.

Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81(24):1879-1886, PMID: 2593165.

5.

The answer is c. Paraneoplastic cerebellar degeneration (PCD) is a heterogeneous group of disorders characterized by subacute cerebellar ataxia and associated with specific tumor types. It is frequently associated with antineuronal antibodies. Nine specific antineuronal antibodies are associated with PCD. Two antibodies, anti-Yo and anti-Tr, predominantly are associated with cerebellar dysfunction. AntiYo antibody, also known as Purkinje cell antibody (PCA-1), is most commonly detected in breast and gynecologic cancers.

Furneaux HM, Rosenblum MK, Dalmau, et al. Selective expression of Purkinje-cell antigens in tumor tissue from patients with

The answer is d. Nasopharyngeal cancer, especially the endemic type, is commonly associated with Epstein-Barr virus not RSV. The WHO type 1 (squamous histology) is usually the nonendemic type and is more commonly observed in US population and older adults.

practical approach in nasopharyngeal cancer and neck dissection is usually not required due to high success rates obtained with choice b.

National Comprehensive Cancer Network (NCCN) guidelines. www.nccn.org. Accessed September 12, 2011.

Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol.

1998;16(4):1310-1317, PMID:9552031.

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

Chan AT, Leung SF, Ngan RK, et al. Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst. 2005;97(7):536-539, PMID: 15812080.

7.

9.

The answer is b. He has stage III disease (T1N2). Nasopharyngeal tumors tend to metastasize to neck nodes early during the course of disease due to rich lymphatic supply. A tumor that is confined to the nasopharynx and with involvement of bilateral cervical lymph nodes (6 cm or less) is consistent with T1 and N2 disease, respectively.

AJCC (American Joint Committee on Cancer) Staging Manual, 7th, Edge, SB, Byrd, DR, Compton, CC, et al (Eds), Springer, New York 2010.

8.

The answer is b. This patient with stage III disease should be treated with curative intent. The intergroup study 0099 (Intergroup [INT] 0099) and multiple other important trials demonstrated superiority of choice b over choice d. Of note, in the INT 0099 study, only 63% of the patient completed 3 full cycles of concurrent cisplatin at a dose of 100 mg/m2 with 75 Gy of radiation therapy in 35 fractions over 7 weeks and only 53% of the patients completed the planned 3 full cycles of adjuvant chemotherapy with cisplatin (80 mg/m2) and 5-FU (1,000 mg/ m2 over 4 days) administered every 4 weeks. Despite these limitations, the overall survival was significantly better with concurrent chemoradiation therapy followed by chemotherapy compared to radiation therapy alone.

Surgery of the primary lesion is not a

The answer is a. The BRAF V600F mutation has been well described in a variety of other conditions (multiple myeloma, Langerhan’s cell histiocytosis, melanoma, non-small cell lung cancer, cholangiocarcinoma, papillary thyroid cancer, colorectal cancer).

Its invariable presence in HCL, a disease that has long awaited cytogenetic/ molecular characterization, has important diagnostic and, potentially, therapeutic implications.

Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011;364(24):2305-2315, PMID: 21663470.

10.

The answer is a. Although MTD is the primary objective for cytotoxic drugs, it may not be the only relevant factor for cytostatic or targeted drugs, and other goals may be as or even more important. Ideally, in a Phase I trial, defining the relevance of a specific biomarker and an optimal biologically active dose are important considerations for cytostatic and molecularly targeted drugs, respectively, in a Phase I trial.

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.

Shahid Raza, MD, assisted in preparing this manuscript.

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

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