Clinical Oncology News - Jan/Feb 2009 - Vol. 4, No. 1 by McMahon Group

McMahon Publishing

Advances in Cancer Care clinicaloncology.com • JANUARY/FEBRUARY 2009 • Vol. 4, No. 1

F DA approves oral fludarabine, Gleevec for GIST, and degarelix for prostate cancer. Mozobil helps SCT. SOLID TUMORS

4 6 8

E ndoTAG-1 shows promise for pancreatic cancer.

C h17 polysomy predicts response to anthracyclines.

A Is trump tamoxifen for preventing breast cancer recurrence.

HematOlogic DISEASE

R ichard Stone, MD, and Jennifer Brown, MD, PhD, highlight ASH meeting news.

New Standard for Previously Untreated Advanced CLL

Large Study Confirms Risk for Death From ESA Use

meta-analysis of cancer patients in randomized controlled trials adds to the growing evidence that erythropoiesis-stimulating agents (ESAs) can harm patients. The study revealed that the use of ESAs was associated with a relative increase in on-study mortality of 17% and a relative decrease in overall survival of 6%. “What are the implications for clinical practice? The increased risk of death must be balanced against the benefits of ESAs, taking into account each patient’s clinical circumstances and preferences,” said Julia Bohlius, MD, MScPH, from the University of Bern, in Switzerland. She presented the study (LBA6) at the annual meeting of the American Society of Hematology (ASH). Previous studies have shown that see ESAs, page 34

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CLINICAL TRIALS

A list of Phase II and III trials initiated within the past 30 days.

EDUCATIONAL REVIEWS

E arly Stage Breast Disease: Endocrine Therapy and Biphosphonates After page 6.

Myelodysplasia: Recent Advances After page 14. CONTINUING MEDICAL EDUCATION

I ndividualizing Cancer Care in the Era of Evidence-based Treatment Part 4: Breast Cancer

WWW.CMEZONE.COM

Pharmacist’s Touch Helps Private Onc Offices Thrive

POLICY & MANAGEMENT

Louisville, Ky.—By adding just one clinical pharmacist to its staff, a medium-sized private oncology practice was able to secure millions of dollars in research grants and use the funds to help patients gain access to potentially lifesaving investigational drug therapies. The grants and related cost-saving measures more than paid for the pharmacist’s salary, according to Siu-Fun Wong, PharmD, associate professor of pharmacy practice and administration, Western University of Health Sciences, Pomona, Calif. But more importantly, the staffing strategy enabled see TOUCH, page 27

San Francisco—Clinicians have a new first-line treatment for physically fit patients with advanced chronic lymphocytic leukemia (CLL), according to a multinational Phase III trial presented at the annual meeting of the American Society of Hematology (abstract 325). The addition of rituximab (Rituxan, Genentech/Idec) to the previous standard of fludarabine and cyclophosphamide (FC) nearly doubled complete response Rituximab is an immunotherapy. rates and lengthened progression-free survival by 10 months. The proportion of patients who achieve a comstudy was characterized as the largest plete response and for the median length ever conducted in the CLL subgroup. of the progression-free survival,” said “The trial demonstrates that the addi- Michael Hallek, MD, University of Cologne tion of rituximab is superior for the see NEW STANDARD, page 15 

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Billing/Payment Changes, Audits Will Impact Oncology Practices

everal changes to Medicare regulations will affect the day-to-day activity of oncology practices in 2009. In addition, the Office of Inspector General’s work plan includes measures that could increase scrutiny of your practice. Are you ready?

Physician Fee Schedule The CMS-1403-FC 2009 Final Rule includes changes to Medicare’s payment policies under the Physician Fee Schedule and other revisions to Part B for CY 2009. The rule also includes information on the e-prescribing exemption for

McMahonMedicalBooks.com

PRSRT STD U.S. POSTAGE

PAID EASTON, PA PERMIT #117

Abeloff’s Clinical Oncology: Expert Consult: Online and Print Martin D. Abeloff, James O. Armitage, John E. Niederhuber, Michael B. Kastan, W. Gillies McKenna See page 35.

computer-generated facsimile transmissions and payment for certain durable medical equipment, prosthetics, orthotics and supplies. The following list describes significant changes found in the final rule that will impact physicians. • Includes a 1.1% increase in total Medicare reimbursement, but not across the board. The process used is complicated with increases of 12% in many relative value units and a reduction of the conversion factor, from $38.09 to $36.07, by approximately 6%. Centers for Medicare see PRITCHARD GROUP/REGULATORY, page 32

NEW INDICATION Gleevec gets indication for GIST. See page 15.

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Courtesy of Roche/Genentech

FDA NEWS

Clinical Oncology News • JANUARY/FEBRUARY 2009

Degarelix Approved for Prostate Cancer

Hypothalamus GnRH

he FDA has approved degarelix (Ferring Pharmaceuticals), an injectable gonadotropin-releasing hormone (GnRH) receptor antagonist, for the treatment of advanced prostate cancer. Potential trade names are still under review with the FDA. Phase III trials showed that degarelix is at least as effective as leuprolide (Lupron Depot, Abbott Laboratories) in sustaining castrate levels or lower of testosterone, and resulted in a statistically significant faster reduction of testosterone. By day 3 of treatment, 96% of patients receiving degarelix achieved castrate levels of testosterone, compared with

Anterior Pituitary Gland

FSH, LH Testis Prostate Gland

Hormonal regulation of the prostate gland Academy GmbH & Co. KG Provided by www.prostatecancerliving.com

see FDA NEWS, page 15 

Copyright © 2009 by McMahon Publishing, New York, NY 10036. All rights reserved. Clinical Oncology News (ISSN 1933-0677) is published monthly for $70.00 per year by McMahon Publishing. Postage paid at New York, NY, and at additional mailing offices.

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Advisory Board Bioethics Joseph P. DeMarco, PhD, Professor Emeritus of Philosophy, Department of Philosophy, Cleveland State University, Cleveland, OH Paul J. Ford, PhD, Associate Staff in Bioethics and Neurology, The Cleveland Clinic Foundation; Assistant Professor, Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Community Oncology John W. Finnie, MD, Staff Hematologist and Medical Oncologist, David C. Pratt Cancer Center, St. John’s Mercy Medical Center, St. Louis, MO

Hematologic Malignancies Jennifer R. Brown, MD, PhD, Attending Physician, CLL & Lymphoma Program, Dana-Farber Cancer Institute; Assistant Professor of Medicine, Harvard Medical School, Boston, MA Agnes Y.Y. Lee, MSc, MD, Associate Professor, Department of Medicine, McMaster University; Consultant, Thromboembolism Service, Hamilton Health Sciences Henderson General Hospital, Hamilton, Ontario Richard Stone, MD, Clinical Director of the Adult Acute Leukemia Program, Dana-Farber Cancer Institute; Associate Professor of Medicine, Harvard Medical School, Boston, MA

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

Pharmacy Polly E. Kintzel, PharmD, Clinical Pharmacy Specialist—Oncology, Spectrum Health Hospitals, Grand Rapids, MI Melvin E. Liter, MS, PharmD, Liter Enterprises, Liter Consulting Services, Lexington, KY

Policy and Management Mary Lou Bowers, MBA, President and CEO, Barbara Constable, RN, MBA, Director,

Testosterone

0% receiving leuprolide. By day 14, 99% of patients receiving degarelix achieved castrate levels of testosterone, compared with 18% receiving leuprolide. In the clinical trial, prostate-specific antigen (PSA) levels were also monitored as a secondary end point. PSA levels were reduced by 64% two weeks after administration of degarelix; 85% after one month; 95% after three months; and remained suppressed throughout the one-year period of treatment. These results should be interpreted with caution because of the heterogeneity of the patient population studied. There is no evidence showing that the rapidity of PSA decline is related to a clinical benefit.

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

Solid Tumors Bone Metastases Allan Lipton, MD, Professor of Medicine and Oncology, Milton S. Hershey Medical Center, Penn State University, Hershey, PA

Breast Cancer Andrew Seidman, MD, Attending Physician, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center; Associate Professor, Weill Cornell Medical College, New York, NY

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Gynecologic Cancer

Editorial Staff

Maurie Markman, MD, Vice President for Clinical Research, University of Texas M.D. Anderson Cancer Center, Houston, TX

Kate O’Rourke, Editor korourke@mcmahonmed.com

Lung, and Head and Neck Cancers Edward S. Kim, MD, Assistant Professor, Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX

Lung Cancer, Emesis Richard J. Gralla, MD, President, New York Lung Cancer Alliance, New York, NY

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com James Prudden, Group Editorial Director David Bronstein, Editorial Director, Hospital Group Robin B. Weisberg, Manager, Copyediting Services Elizabeth Zhong, Associate Copy Chief Vanessa Atanasio, Contributing Editor Barbara Gormise, Senior Copy Editor

Gastrointestinal Cancer

Infection Control

Edward Chu, MD, Chief, Section of Medical Oncology; Professor of Medicine and Pharmacology; Deputy Director of Clinical Research, Yale Cancer Center, Yale University, New Haven, CT

Susan K. Seo, MD, Director, Antibiotic Management Program, Assistant Member, Memorial Sloan-Kettering Cancer Center, New York, NY

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Cathy Eng, MD, Associate Professor, Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX Leonard Saltz, MD, Attending Physician, Memorial Sloan–Kettering Cancer Center; Professor of Medicine, Weill Cornell Medical College, New York, NY

Gastrointestinal Cancer and Sarcoma Ephraim Casper, MD, Associate Chairman, Regional Network, Department of Medicine, Memorial Sloan-Kettering Cancer Center; Professor of Medicine, Weill Cornell Medical College, New York, NY

General Oncology Michael J. Fisch, MD, MPH, Medical Director, Clinical Community Oncology Program Research Base, Associate Professor of General Oncology and Palliative Care, University of Texas M.D. Anderson Cancer Center, Houston, TX

Genitourinary Cancer Ronald M. Bukowski, MD, Director of Experimental Therapeutics Program, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH

Russell K. Portenoy, MD, Chairman, Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, NY Charles F. von Gunten, MD, PhD, Director of the Center for Palliative Studies, San Diego Hospice and Palliative Care; Medical Director of the Doris A. Howell Service and Associate Clinical Professor of Medicine at the University of California, San Diego, CA

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SOLID TUMORS

Clinical Oncology News • JANUARY/FEBRUARY 2009

Pancreatic

EndoTAG-1 Proves Promising in Pancreatic Cancer Stockholm, Sweden–EndoTag-1, an experimental drug, showed encouraging results in combination with standard gemcitabine (Gemzar, Lilly) therapy in a Phase II trial of patients with pancreatic adenocarcinoma who were not candidates for surgery. Although this was a dose-finding study, EndoTag-1 in combination with gemcitabine substantially extended overall survival compared with gemcitabine alone. “These results are the best I have seen for a palliative treatment in pancreatic cancer. A Phase III study is planned,” said Matthias Löhr, MD, professor of gastroenterology at the Karolinska Institute in Stockholm. Dr. Löhr presented the results of the study at the recent annual congress of the European Society for Medical Oncology (LBA7). EndoTAG-1, developed by MediGene, consists of

cationic (positively charged) liposomes that encapsulate paclitaxel. The liposomes bind preferentially to proliferating endothelial cells, release paclitaxel, and interfere with the tumor’s blood supply. “EndoTAG-1 directly targets the vessels. Paclitaxel on its own is not an efficient drug in pancreatic cancer,” Dr. Löhr said.

Survival Data The Phase II study included 200 patients. Median survival in those who received gemcitabine alone was 7.2 months, whereas it was up to 13.6 months in some

% of Patients Surviving

50 40

30 22

17.5

10 0

Gemcitabine onlya

Endo 11 mg/m2 plus gema

Endo 22 mg/m2 plus gema

Endo 44 mg/m2 plus gema

Gemcitabine was given weekly at 1,000 mg/m2 treatment and EndoTag-1 was given biweekly. Treatment was given for seven weeks.

Figure 1. Survival at 12 months.

Gemcitabine onlya

Gema plus biweekly EndoTAG-1 11 mg/m2 until disease progression

Gema plus biweekly EndoTAG-1 22 mg/m2 until disease progression

Gema plus biweekly EndoTAG-1 44 mg/m2 until disease progression

13.6

10.8 9.1

9 6.8

6 3 0 a

patients who received repeated doses of EndoTAG-1 plus gemcitabine, said Dr. Löhr. The study compared three different doses of biweekly EndoTAG-1 (11, 22 and 44 mg/m2) in combination with weekly gemcitabine at a dose of 1,000 mg/m 2. Treatment was given for seven weeks; the trial was then amended to allow patients who showed clinical benefit to continue receiving EndoTAG-1 until their disease progressed. Of the 200 patients, 102 received repeated treatment of up to seven additional cycles. At six and 12 months, survival was superior for all EndoTAG-1 doses plus gemcitabine compared with gemcitabine alone. In the patients given the two higher doses of EndoTAG-1, the six-month survival rates were 72% and 81%, compared with 63% in those given gemcitabine alone. The 12-month survival rates in patients given the two higher doses of EndoTAG-1 were 36% and 33%, respectively, compared with 17.5% in those given gemcitabine alone (Figure 1). The median overall survival of 7.2 months in patients given gemcitabine alone is similar to what has been reported in previous pancreatic cancer trials, Dr. Löhr said. Median survivals were 8.4 months in patients given the lowest dose of EndoTAG-1, 8.7 months in those given the 22-mg/m2 dose and 9.4 months in those given 44 mg/m2. The one-year survival rate was 12% in the gemcitabine-alone arm and 30% in patients with the best EndoTAG-1 result, he said. In patients who received EndoTAG-1 after the initial seven weeks (after the trial had been amended), the median overall survivals were 9.1 months for those who received the lowest dose, 13.6 months for those who received the intermediate dose and 10.8 months for those who received the highest dose, compared with 6.8 months for those who received gemcitabine alone (Figure 2). EndoTAG-1 was well tolerated, with infusionrelated reactions the most common adverse event.

Caution on Phase II Data

Overall Survival in Months

Gemcitabine was given weekly at 1,000 mg/m2 for seven weeks.

Figure 2. Comparison of overall survivals.

According to Margaret Tempero, MD, clinicians should be cautious about being overly enthusiastic about Phase II trials. She noted that Phase II trials of oxaliplatin (Eloxatin, Sanofi-Aventis) and bevacizumab (Avastin, Genentech) for pancreatic cancer showed comparable one-year survival data, but the drugs did not fulfill their promise in Phase III trials. Dr. Tempero is Doris and Donald Fisher Distinguished Professor in Clinical Cancer Research and chair of the Department of Clinical Cancer Research at the University of California at San Francisco School of Medicine. “We don’t know why these drugs failed to demonstrate survival benefit in Phase III trials. Perhaps we overestimated the group benefit, or perhaps a specific drug is active only in a subset of patients who should be studied in Phase III trials,” she suggested. She pointed to cetuximab (Erbitux, ImClone) as an example—recent data have revealed that patients with K-ras mutations are not likely to respond to cetuximab. She suggested that researchers “take a step back” before mounting a Phase III trial of EndoTAG-1 and attempt to identify subsets of patients most likely to derive benefit from this new agent. The study presented by Dr. Löhr enrolled a mix of patients with different outcomes (i.e., metastatic disease and locally advanced disease), she said, and perhaps some of these patients are less likely to respond. —Bonnie Gillis

Today’s Clinical Trials... Tomorrow’s Breakthroughs

The NIH Clinical Center in Bethesda, Md.

or your patients in need of more options, the National Cancer Institute (NCI) conducts more than 150 clinical trials. In our state-of-theart Clinical Center on the campus of the National Institutes of Health (NIH), the latest innovations in medicine are put into practice every day.

NCI is currently conducting trials for many types of cancer including, but not limited to: • Kidney Cancer (Renal Cell) • Melanoma • Brain Tumor • Prostate Cancer

To learn whether your patients may be eligible, visit

bethesdatrials.cancer.gov or call

1-888-NCI-1937(1-888-624-1937)

SOLID TUMORS

Clinical Oncology News • JANUARY/FEBRUARY 2009

Breast SPOTLIGHT ON TARGETED THERAPIES AND DIAGNOSTICS

Predicting Patient Response to Anthracyclines San Antonio—In patients with early breast cancer, chromosome 17 polysomy (extra copies of Ch17) predicts improved response to adjuvant anthracycline chemotherapy. This was the conclusion of a biomarker substudy of NEAT (National Epirubicin Adjuvant Trial) presented at the San Antonio Breast Cancer Symposium (SABCS, abstract 45). The same study showed that amplification of HER2, topoisomerase II-A (TOP2A) status or HER 1-3 expression did not predict response to anthracyclines. In a separate meta-analysis of four Phase III trials, investigators found that HER2 and TOP2A were at best only modestly predictive for response to anthracyclines as adjuvant therapy in early breast cancer (SABCS abstract 705).

‘The data do not support use of HER2 or TOP2A as biomarkers to help decide which chemotherapy to use.’ —Angelo DiLeo, MD According to John Bartlett, PhD, all breast cancer patients should be routinely examined for HER2 status using fluorescence in situ hybridization (FISH) testing, and this test also assesses Ch17 status. Dr. Bartlett, professor of molecular pathology at the University of Edinburgh in Scotland, who presented the biomarker study, said that FISH is considered the most reliable test for HER2. Ch17 is of interest because it contains genes for HER2 and TOP2A as well as other genes implicated in breast cancer. “Ch17 is the second most gene-dense chromosome and it contains the HER2 and TOP2A genes as well as other breast cancer genes, such as BRCA-1 and p53. Any FISH test that has a chromosomal control includes Ch17,” Dr. Bartlett said. “The challenge is to ensure quality control of testing for this new marker. We are hoping to confirm our findings [about Ch17] soon in a formal meta-analysis that will include additional data on other biomarkers.”

Identifying Who Will Benefit Although anthracyclines are a major building block of therapeutic regimens for adjuvant therapy of breast cancer, they have side effects, including cardiotoxicity. If doctors can identify patients who will not respond to this drug, they can spare them the side effects and initiate other treatments. “These are exciting results that we hope will benefit breast cancer patients in the future. We are close to using this new marker in the clinic to select appropriate therapies in early breast cancer,” said Christopher Poole, MB, BChir, principal investigator of NEAT, and professor of medical oncology at the University of Warwick, Coventry, England. NEAT included 2,021 women with early breast cancer who required chemotherapy after surgery and found that adding epirubicin to standard chemotherapy improved survival rates. Epirubicin is now considered part of standard chemotherapy for breast cancer.

In the substudy presented at SABCS, tumor samples from 1,646 NEAT participants were tested for biomarkers that might drive anthracycline response, including HER2 1, 2, and 3 and TOP2A. Although HER2 amplification and TOP2A were shown to be prognostic for poor relapse-free survival and overall survival, no treatment interaction with anthracyclines was found. Tumors with Ch17 polysomy, however, had a significant treatment interaction for relapse-free survival and overall survival. Patients with Ch17 polysomy derived a significant benefit from anthracycline, with a relative improvement of 41% in recurrence-free survival (P=0.04), whereas patients who had tumors that were Ch17-normal derived no significant benefit from the therapy. Prior to conducting the NEAT biomarker substudy, Dr. Bartlett and colleagues assessed more than 1,000 tumor samples from two other studies of adjuvant anthracycline therapy (MA5 and BR9-601) as a pilot trial that demonstrated an interaction between Ch17 polysomy and anthracycline (SABCS abstract 6059). In those trials, women with Ch17 polysomy who were treated with anthracycline therapy had a 37% relative improvement in recurrence-free survival (P=0.012). Of the total number of patient samples (more than 2,500 from all three trials), Dr. Bartlett said that 20% to 30% of tumors exhibited Ch17 polysomy. This suggests that 70% to 80% of women treated with an anthracycline in these trials derived little or no benefit from it. “The benefit of anthracycline therapy was confined to patients with Ch17 polysomy, regardless of whether they were HER2-1, 2 or TOP2A-positive,” Dr. Bartlett commented. “In the NEAT trial, HER2 1-3 and topoisomerase II-alpha did not predict anthracycline benefit.” Previous studies have suggested that HER2 amplification and TOP2A are predictive for response to anthracyclines. Dr. Bartlett suggested that these studies may have been underpowered. He also hypothesized that Ch17 polysomy is a unifying predictive marker for chromosomal instability.

Meta-analysis Shows Modest Effect In another presentation at SABCS, an interim analysis of a meta-analysis of individual data from four Phase III trials comparing anthracycline with CMF chemotherapy (cyclophosphamide, methotrexate, fluorouracil) in patients with early breast cancer found that HER2 and TOP2A had a clinically modest effect (abstract 705). “Interim results of our meta-analysis are not very encouraging for the use of HER2 and TOP2A as biomarkers to decide whether to use anthracyclines. Our data do not strongly support anthracyclines in HER2positive patients, but there appears to be a benefit for anthracyclines in HER2-negative patients. One take-away message from this trial is, ‘Don’t consider anthracyclines obsolete drugs for HER2-negative breast cancer,’” said Angelo DiLeo, MD, head of the Sandro Pitigliani Medical Oncology Unit, Hospital of Prato, in Prato, Italy.

This suggests that 70% to 80% of women treated with an anthracycline in these trials derived little or no benefit from it. The international meta-analysis was based on tumor samples from 1,944 patients treated with anthracyclines or CMF. Tumor testing was done by FISH, and random samples were sent to a central laboratory for validation. Preliminary studies suggested that HER2-positive patients did not derive much benefit from CMF and did somewhat better on anthracycline, whereas HER2-negative patients had a better response to an anthracycline than to CMF. In the case of tumors with TOP2A deletions, anthracyclines were associated with marginally better response than CMF. “The data do not support use of HER2 or TOP2A as biomarkers to help decide which chemotherapy to use,” Dr. DiLeo said. Not all researchers agree, however. According to Steven Jones, MD, medical director at U.S. Oncology Research in Houston, the final word is not in on which biomarkers can best predict response to anthracyclines. “New data at SABCS suggest we need to continue to look for markers that will allow us to use or not use anthracyclines. TOP2A gene expression is the best candidate in my mind, but there is some controversy here,” said Dr. Jones. “Fortunately, U.S. Oncology is conducting the TC Versus TAC trial, with a goal of prospectively identifying markers that might predict for anthracycline sensitivity,” Dr. Jones said. In response to Dr. Jones’s comment, Dr. Bartlett said, “Caution is not a bad thing.” —Alice Goodman

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Breast Cancer Management: Updates in Adjuvant Endocrine Therapy and Bisphosphonates for Early-Stage Disease Christina I. Herold, MD Division of Medical Oncology, Department of Medicine Duke University School of Medicine Durham, North Carolina

Carey K. Anders, MD Division of Medical Oncology, Department of Medicine University of North Carolina at Chapel Hill School of Medicine Chapel Hill, North Carolina

Kimberly L. Blackwell, MD Division of Medical Oncology, Department of Medicine Duke University School of Medicine Durham, North Carolina

reast cancer is increasingly coming to be understood as a chronic disease in which the risk for recurrence persists decades beyond the

initial diagnosis; the majority of recurrences, as well as two-thirds of

breast cancer–related deaths, occur after 5 years of initial endocrine therapy.1

These sobering statistics highlight the need for effective long-term adjuvant treatment strategies to protect women from late recurrences. In the past few years, several important trials have provided initial and updated results. The data continue to offer guidance to clinicians seeking to optimize and customize adjuvant endocrine therapy in various clinical scenarios, including the care of postmenopausal and premenopausal women. Preservation of bone health in the context of endocrine therapy also continues to be an important clinical issue. Maturing data indicate that bisphosphonates are effective in this context, and emerging data suggest that they also may

have a powerful role as an adjuvant strategy to prevent the recurrence of breast cancer.

Updates in Adjuvant Endocrine Therapy For Postmenopausal Women Adjuvant Tamoxifen Duration of Therapy: ATLAS and aTTom. Even with the known and significant risks for late recurrence of breast cancer and mortality, the traditional adjuvant use of tamoxifen has been limited to 5 years. This recommendation is based in part on the results from NSABP

I n d e p e n d e n t ly d e v e l o p e d b y M c M a h o n P u b l i s h i n g CL I N I CAL ONCOLOGY NE W S • J ANUA R Y/ F EB R UA R Y 2 0 0 9

Tamoxifen 20 mg/d × 5 y

R a n d o m i z a t i o n

Letrozole 2.5 mg/d × 5 y

Tamoxifen 20 mg/d × 2 y followed by letrozole 2.5 mg/d × 3 y

Letrozole 2.5 mg/d × 2 y followed by tamoxifen 20 mg/d × 3 y

N=8,028

Letrozole

5-y DFS, %

Tamoxifen

P Value

Adjuvant Aromatase Inhibitors

81.4

0.003

Letrozole vs Tamoxifen: BIG 1-98. The BIG (Breast International Group) 1-98 study was designed to evaluate both the benefit of upfront letrozole versus tamoxifen and the benefit of switching agents after 2 years of therapy.5 The study enrolled more than 8,000 postmenopausal women from 27 countries with hormone receptor–positive breast cancer to 1 of 4 treatment arms: tamoxifen, letrozole, tamoxifen followed by letrozole, or letrozole followed by tamoxifen (Figure 1). When the results were initially reported in 2005, at a median follow-up of 25.8 months, a statistically significant improvement in DFS, the primary end point, was observed at 5 years in the letrozole arms compared with the tamoxifen arms (84.0% vs 81.4%; P=0.003). There was no statistically significant difference between OS values in the groups. Regarding toxicity profiles, in the tamoxifen group, thromboembolic events occurred more frequently (3.5% vs 1.5%; P<0.001), and the incidence of hypercholesterolemia was reduced. In the letrozole group, grade 3 to 5 cardiac adverse events (2.1% vs 1.1%; P<0.001) and fractures (5.7% vs 4.0%; P<0.001) occurred more frequently. There was no statistically significant difference between rates of invasive endometrial cancer in the groups. The 2005 results from BIG 1-98 raised concerns regarding the observed differences in cardiovascular adverse events and prompted further safety analysis, which was subsequently reported with a median followup of 30.1 months.6 In this analysis, the overall incidence rates of cardiac adverse events were similar in the letrozole and tamoxifen groups (4.8% and 4.7%, respectively). However, more grade 3 to 5 cardiac adverse events continued to be observed in the letrozole group (2.4% vs 1.4%; P=0.001), whereas more overall and grade 3 to 5 thromboembolic adverse events were observed in the tamoxifen group (3.9% vs 1.7%; P<0.001 and 2.3% vs 0.9%; P<0.001, respectively). In summary, these data confirmed an overall low incidence of cardiovascular adverse events in both treatment groups, with distinct safety profiles emerging for each agent. In 2008, updated BIG 1-98 results regarding both the monotherapy and sequential comparisons were

84.0

Figure 1. BIG 1-98: schema and results. BIG, Breast International Group; DFS, disease-free survival Based on reference 5.

(National Surgical Adjuvant Breast and Bowel Project) B-14. In this trial, approximately 1,150 women who had received 5 years of tamoxifen and were free of recurrence were randomized either to continued treatment with tamoxifen (for a planned total course of 10 years) or to placebo.2 The trial was stopped early, at 4 years following the reassignment, when significant advantages in both disease-free survival (DFS) and distant disease-free survival (DDFS) were observed in the cohort of patients who stopped tamoxifen at 5 years (92% vs 86%; P=0.003 and 96% vs 90%; P=0.01, respectively). In addition, although not statistically significant, overall survival (OS) was better in the group treated with tamoxifen for just 5 years (96% vs 94%; P=0.08). Despite these findings from NSABP B-14, 2 large international trials were undertaken to further examine the use of 10 years of tamoxifen; preliminary results from both studies were recently presented. The ATLAS study (Adjuvant Tamoxifen—Longer Against Shorter) randomized 11,500 women from 38 countries with estrogen receptor (ER)–positive (59%) or ER-untested (41%) disease who had completed 5 years of tamoxifen either to receive another 5 years of tamoxifen or to stop tamoxifen.3 The ATLAS investigators reported a 13% reduced risk for disease recurrence among the group of patients who continued tamoxifen, with no observed difference in mortality. The aTTom study (Adjuvant Tamoxifen Treatment— Offer More?) randomized nearly 7,000 women with ER-positive (39%) or ER-untested (61%) breast cancer who had completed at least 4 years of adjuvant

tamoxifen either to another 5 years of tamoxifen or to placebo.4 Consistent with the early results from ATLAS, preliminary results from aTTom, with a median follow-up of 4.2 years, showed a 6% reduction in risk for disease recurrence among patients in the extended-tamoxifen arm; of note, this difference was not statistically significant (P=0.4). Longer follow-up of both ATLAS and aTTom is required for a fuller understanding of the effect of 10 years of adjuvant tamoxifen therapy on breast cancer recurrence and mortality. The eventual interpretation of both studies likely will be affected by the large proportions of ERuntested patients and the unknown rates of treatment adherence among patients who were prescribed longterm tamoxifen therapy in these studies.

I n d e p e n d e n t ly d e v e l o p e d b y M c M a h o n P u b l i s h i n g

reported.7 In 2005, following the report of improved DFS associated with letrozole, the tamoxifen monotherapy arm had been unblinded, and 619 patients (25.2%) elected to cross over to letrozole. The updated BIG 1-98 monotherapy results were therefore analyzed with 2 statistical methods: intent-to-treat (ITT) and censoring at crossover. Both methods introduced bias into the results, with ITT favoring tamoxifen and censoring favoring letrozole. The ITT analysis of the monotherapy arms showed significantly improved DFS (hazard ratio [HR], 0.88; P=0.03) and trends toward improvement in both OS (HR, 0.87; P=0.08) and time to distant recurrence (TDR; HR, 0.85; P=0.05) associated with letrozole. The sequential therapy arms were compared with letrozole monotherapy, with a median follow-up of 71 months. For both pairwise comparisons, no statistically significant differences were found in DFS, OS, or TDR. The investigators did, however, note a trend toward improved OS (HR, 1.13; 95% confidence interval [CI], 0.83-1.53) and TDR (HR, 1.22; 95% CI, 0.88-1.69) for letrozole monotherapy compared with the sequencing strategy of 2 years of tamoxifen followed by 3 years of letrozole. Based on these results from the monotherapy and sequential comparisons, the investigators recommended a strategy of initiating adjuvant endocrine therapy with letrozole, with a subsequent switch to tamoxifen later in the course of therapy if required. Upfront Anastrozole vs Tamoxifen: ATAC. The ATAC study (Arimidex and Tamoxifen Alone or in Combination) directly compared 5 years of tamoxifen and anastrozole (Arimidex, AstraZeneca).8 More than 9,000 postmenopausal women with operable breast cancer who underwent definitive surgery, radiation, and chemotherapy were randomized to treatment arms containing tamoxifen, anastrozole, or a combination of both (Figure 2). The 5-year update from ATAC, with a median followup of 68 months, showed a significant DFS advantage for anastrozole over tamoxifen in all patients (HR, 0.87; P=0.01) and a significant reduction in invasive contralateral breast cancers (HR, 0.58; P=0.01).9-11 Side-effect profiles showed statistically significant higher rates of fractures in the anastrozole arm and higher rates of hot flashes, vaginal bleeding, endometrial cancer, thromboembolic events, and ischemic cardiovascular events in the tamoxifen arm. In 2008, long-term efficacy and toxicity results from ATAC were published, with a median follow-up of 100 months.12 For DFS, the primary study end point, ITT analysis showed significant benefit associated with anastrozole (HR, 0.90; P=0.025). Improved DFS with anastrozole was also seen in a predefined subpopulation of patients with hormone receptor–positive disease (HR, 0.85; P=0.003). Outcomes were improved across other study end points, including time to recurrence, TDR, and incidence of contralateral breast cancer, in both the ITT and the hormone receptor–positive subgroup analyses. Despite these benefits associated with anastrozole use, there continues to be no associated

Tamoxifen 20 mg/d × 5 y

R a n d o m i z a t i o n

Anastrozole 1 mg/d × 5 y

Tamoxifen 20 mg/d + anastrozole 1 mg/d × 5 y

N=9,366

Anastrozole Tamoxifen HR P Value

5y FFR, % 76.9

74.3

0.74 0.0002

Figure 2. ATAC: schema and results. ATAC, Arimidex and Tamoxifen Alone or in Combination; HR, hazard ratio; FFR, freedom from recurrence Based on reference 8.

advantage in OS (HR, 0.97; P=0.7). Regarding long-term toxicity, annual fracture rates were higher during treatment with anastrozole (2.93% vs 1.90%); however, this difference did not persist during follow-up after treatment was completed. No differences between rates of cardiovascular morbidity and mortality were observed in the 2 treatment groups. Upfront Exemestane vs Tamoxifen: TEAM. The TEAM (Tamoxifen Exemestane Adjuvant Multicenter) trial was originally designed to compare 5 years of exemestane (Aromasin, Pfizer) alone with tamoxifen alone in postmenopausal women who had hormone receptor–positive breast cancer.13 Following the initial results of IES (Intergroup Exemestane Study) in 2004, the TEAM study design was amended to evaluate a tamoxifen– exemestane switch (tamoxifen for 2-3 years followed by exemestane for a total duration for both of 5 years) versus exemestane alone for 5 years (Figure 3). In the first planned ITT analysis, data from 9,775 randomized patients, with a median follow-up of 2.75 years, showed significant benefit associated with exemestane alone with respect to relapse-free survival (RFS; HR, 0.85; P=0.02) and time to distant metastases (HR, 0.81; P<0.02).14 Regarding 2.75-year DFS, the other primary study end point (along with 5-year DFS), overall, a trend toward benefit in the exemestane-alone arm was noted that did not reach statistical significance (HR, 0.89; P=0.12). In a subset analysis among patients who remained on the study drug, 2.75-year DFS was significantly better in the exemestane-alone arm (HR, 0.83; P=0.02). Possible explanations for these findings put

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N=9,775

N=2,992

Postmenopausal women ER- and/or PR-positive breast cancer Early-stage breast cancer (node-positive and node-negative) Surgery ± XRT and ± adjuvant chemotherapy

Randomization 1:1

Tamoxifen 20 mg qd x 2-3 y then exemestane 25 mg qd (5-y total duration)

Exemestane 25 mg qd x 5 y

Main outcomes at 2.75-y median follow-up: • Improved RFS in exemestane-only arm (HR, 0.85; P=0.02)

Tamoxifen 20 mg/d × 2 y

Randomization

Tamoxifen 20 mg/d × 3 y

Anastrozole 1 mg/d × 3 y

Sequencing anastrozole improved RFS (HR, 0.79; P=0.038) and OS (HR, 0.77; P=0.025).

Figure 4. ABCSG8: sequencing analysis: schema and results. HR, hazard ratio; OS, overall survival; RFS, relapse-free survival Based on reference 16.

• Improved time to distant metastases in exemestane-only arm (HR, 0.81; P<0.02) • Trend toward improved DFS in exemestane-only arm (HR, 0.89; P=0.12)

Figure 3. TEAM. DFS, disease-free survival; ER, estrogen receptor; PR, progesterone receptor; RFS, relapse-free survival; XRT, radiation therapy Based on references 13 and 14.

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forth by the investigators were that the rate of breast cancer events was low (total of 570), that there were high rates of early tamoxifen discontinuation in the switch arm, and that difficulties were encountered in the timing of the switch. The 5-year results from TEAM are expected in 2009. Tamoxifen Followed by Anastrozole: ABCSG 8/ ARNO 95. The ABCSG 8/ARNO 95 (Austrian Breast and Colorectal Cancer Study Group Trial 8/German Adjuvant Breast Cancer Group Arimidex/Nolvadex 95) trials were designed to evaluate the benefit of a switch to anastrozole after 2 years of tamoxifen in postmenopausal women with hormone receptor–positive breast cancer.15 The results of these trials, which together randomized 3,224 women, were analyzed jointly. At a median follow-up of 28 months, a statistically significant improvement was noted in event-free survival, the primary study end point (HR, 0.60; P=0.0009). No statistically significant difference in OS was demonstrated. Although both drugs were well tolerated, differences were noted between their toxicity profiles; anastrozole was associated with significantly more fractures and fewer thromboses than tamoxifen. Updated results from ABCSG 8, with a median follow-up of 72 months, were recently presented at the San Antonio Breast Cancer Symposium (Figure 4).16 Of note, ABCSG 8 enrolled a homogeneous population of low- to intermediate-risk postmenopausal patients (hormone receptor–positive, grade 1-2 ductal and lobular tumor types, no adjuvant chemotherapy permitted). This analysis focused on 2,922 patients who were eligible for a true sequencing analysis (as opposed to a

switching analysis, in which events before the planned switch are censored). Sequencing anastrozole was associated with improved RFS (HR, 0.79; P=0.038) and significantly improved OS (HR, 0.77; P=0.025). Tamoxifen Followed by Exemestane: IES. Results from IES were updated in 2006 (Figure 5).17,18 In this trial, 4,742 postmenopausal women who had received adjuvant tamoxifen for 2 to 3 years were randomly assigned either to continue tamoxifen or to switch to exemestane. At 55.7 months of follow-up, exemestane was associated with a 24% reduction in disease recurrence (HR, 0.76; P=0.0001) and a 3.3% absolute benefit in DFS compared with tamoxifen. No statistically significant improvement in OS was observed (HR, 0.85; P=0.08). As in other aromatase inhibitor (AI) trials, the reported incidence of fractures was higher with exemestane than with tamoxifen (7.0% vs 4.9%; P=0.003).

Extended Adjuvant Endocrine Therapy Tamoxifen Followed by Letrozole: NCIC CTG MA.17 Trial. Results from the NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) MA.17 trial of more than 5,000 postmenopausal women randomized to receive letrozole or placebo after completion of 5 years of tamoxifen, initially published in 2003 at a median follow-up of 2.4 years, showed a statistically significant improvement in estimated 4-year DFS associated with the extended adjuvant use of letrozole (93% vs 87%; HR, 0.57; P=0.00008; Figure 6).19 These results quickly prompted many care recommendations, including those of the National Comprehensive Cancer Network, to add letrozole as a treatment option after 5 years of tamoxifen. The MA.17 trial was stopped early at the first planned interim analysis on the recommendation of the data and safety monitoring committee because of the observed superiority of letrozole to placebo. At that time, study participants were given the option of crossing over to letrozole treatment. Updated results from MA.17, at a median follow-up of 30 months, continued to show benefit associated with the extended use of letrozole in regard to both DFS and DDFS.20 Although no significant difference between OS values was noted in the 2 treatment groups (HR, 0.82; P=0.3), a survival benefit associated with letrozole use was observed in a planned subgroup analysis among lymph node-positive patients (HR, 0.61, P=0.04) but not in the node-negative group. Many informative analyses have emerged from this important trial, including an investigation of age-dependent differences in survival outcomes, toxicity, and quality of life.21 Of the 5,169 postmenopausal patients from MA.17 included in this analysis, 1,323 (26%) were 70 years of age or older. No statistically significant interactions were found between age and treatment with regard to survival outcomes (including DFS, DDFS, and OS), indicating that the effects of extended adjuvant letrozole are similar across the age groups. In terms of toxicity, the older women experienced more adverse events than did the younger women; however, among the older women, no significant differences were found

N=4,742

Tamoxifen 20 mg/d × 2-3 y

Randomization

Tamoxifen 20 mg/d × 2-3 y

Exemestane 25 mg/d × 2-3 y

Tamoxifen Exemestane P Value

3-y DFS, % 90.0

94.0

<0.001

3-y OS, %

96.0

96.4

Figure 5. IES: schema and results. DFS, disease-free survival; IES, Intergroup Exemestane Study; NS, not statistically significant; OS, overall survival Based on references 17 and 18.

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N=5,187

Tamoxifen 20 mg/d × 5 y

Randomization

Letrozole 2.5 mg/d

Placebo

Median follow-up 2.4 y

4-y DFS, %

Letrozole Placebo 93

P Value 0.00008

Figure 6. NCIC CTG MA.17: schema and results. DFS, disease-free survival; NCIC CTG, National Cancer Institute of Canada Clinical Trials Group Based on references 19 and 20.

between toxicities in those treated with letrozole and toxicities in those treated with placebo. Although the older women in the 2 treatment groups exhibited early differences in QOL, by 36 months of follow-up the profiles were similar. Finally, study discontinuation rates did not differ between the letrozole and placebo arms, with 24% of the older women discontinuing treatment overall. In summary, these data indicate that the benefits associated with extended letrozole use persist across the age spectrum and that letrozole is equally tolerated in older and younger women. The compelling efficacy data regarding adjuvant aromatase inhibition from MA.17 and other trials have raised several intriguing clinical questions, such as what the optimal management is of postmenopausal women whose initial adjuvant endocrine therapy was restricted to tamoxifen. Recalling that upon early trial termination, women in the placebo arm were offered the choice to switch to letrozole, the MA.17 investigators recently reported on clinical outcomes in the “late extended adjuvant” setting.22 Of the 2,594 women initially randomized to placebo following 5 years of tamoxifen, 1,579 chose to take letrozole (PLAC-LET) at unblinding, whereas 804 remained on placebo (PLAC-PLAC). In the PLAC-LET group, the median time elapsed from the end of tamoxifen to the initiation of letrozole was 2.8 years (range, 1.1-7.1 years). There were statistically

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significant differences between the 2 treatment groups, including that the women who opted to initiate letrozole were younger, had a better performance status, and were more likely to have had a positive hormonereceptor status. In addition, these women were more likely to have undergone an axillary lymph node dissection, to have had involved lymph nodes, and to have received adjuvant chemotherapy. At a median follow-up of 5.3 years from initial randomization and 2.8 years from unblinding, the PLAC-LET group demonstrated superior DFS (HR, 0.37; P<0.0001) and DDFS (HR, 0.39; P=0.004). These data add to the view that patients with hormone receptor–driven breast cancers remain at high risk for relapse beyond 5 years past diagnosis and that effective endocrine manipulation beyond this initial treatment window may provide long-term durable benefits, even if initiated in a delayed fashion. Tamoxifen Followed by Exemestane: NSABP B-33. NSABP B-33 randomized 1,598 postmenopausal women who were disease-free at the completion of 5 years of adjuvant tamoxifen therapy to receive 5 years of exemestane or placebo (Figure 7).23 The primary aim was to determine if the addition of exemestane resulted in an improvement in DFS. In October 2003, with the results of MA.17, NSABP B-33 was closed early (original accrual goal was 3,000 patients), treatment was unblinded, and exemestane was offered to patients who had originally been randomized to placebo. At unblinding, 44% of the placebo group chose to take exemestane, and 72% of the original exemestane group elected to continue treatment. At 30 months of follow-up, analysis by ITT showed an improvement in 4-year DFS favoring exemestane that was not statistically significant (91% vs 89%; HR, 0.68; P=0.07) and a statistically significant improvement in 4-year RFS (96% vs 94%; HR, 0.44; P=0.004). There were few deaths in either treatment group (exemestane, 16; placebo, 13) and no observed difference in OS.

Ongoing Adjuvant Trials Involving Aromatase Inhibitors Although the updated results from the pivotal trials reviewed here continue to expand our knowledge regarding the use of AIs in the adjuvant setting, multiple outstanding questions regarding the choice of agent and duration of therapy remain to be answered to optimize this treatment strategy. The results of several important ongoing clinical trials should help clarify these critical clinical issues. Regarding the choice of agent, FACE (Femara Versus Anastrozole Clinical Evaluation) and NCIC CTG MA.27 are both head-to-head direct comparisons of upfront AIs. FACE is a Phase IIIb randomized multicenter study that has enrolled 4,000 postmenopausal women with hormone receptor–positive and node-positive disease to 5 years of letrozole or anastrozole.24 Similarly, the choice of exemestane or anastrozole for 5 years is being evaluated in the Phase III randomized multicenter MA.27 trial, with a target accrual of 6,830 hormone receptor– positive postmenopausal patients.25

Meanwhile, the optimal duration of adjuvant aromatase inhibition is being studied in 3 ongoing Phase III trials. Specifically, each of these trials is investigating various approaches to extending adjuvant therapy up to 10 years or even, as is possible for patients enrolled in MA.17R, up to 15 years beyond the original diagnosis of breast cancer. The MA.17R trial will re-randomize women who have completed an initial 5 years of any AI, as part of the original MA.17 study or in routine clinical practice, to 5 more years of letrozole or placebo.26 MA.17R will stratify patients according to whether the AI for the initial 5 years was given as upfront therapy or after tamoxifen. NSABP B-42 is enrolling women who have completed 5 years of endocrine therapy (either 5 years total of an AI or up to 3 years of tamoxifen followed by an AI) to receive 5 years of letrozole or placebo, with DFS as the primary outcome measure.27 Finally, ABCSG 16/SALSA (Secondary Adjuvant Longterm Study with Anastrozole) has randomized more than 1,700 women who have received 5 years of any adjuvant endocrine therapy to 2 or 5 years of additional adjuvant anastrozole, with planned analyses to include DFS and OS.28

Updates in Adjuvant Endocrine Therapy for Premenopausal Women ABCSG 12. ABCSG 12 enrolled 1,803 premenopausal women with hormone receptorâ&#x20AC;&#x201C;positive early breast cancer (<10 involved lymph nodes; Figure 8).29 Of note, the use of adjuvant chemotherapy was an exclusion criterion, although neoadjuvant chemotherapy was permitted. The study was designed to ask whether, in the context of ovarian suppression, anastrozole would be superior to tamoxifen and also to determine if the addition of zoledronic acid (Reclast, Zometa, Novartis) would improve outcomes beyond that observed with endocrine therapy alone. All patients were treated with monthly goserelin (Zoladex, AstraZeneca) and then randomized to 1 of 4 arms: tamoxifen, anastrozole, tamoxifen plus zoledronic acid, or anastrozole plus zoledronic acid. At a median follow-up of 47.8 months, survival outcomes in ABCSG 12 were excellent, with a 4-year DFS of 92.4% and corresponding OS of 97.7%. Zoledronic acid was well tolerated, with no reported cases of osteonecrosis of the jaw or renal impairment associated with treatment. From the 4 preceding treatment arms, 2 pairwise comparisons were conducted: tamoxifen versus anastrozole and zoledronic acid versus no zoledronic acid. No significant difference was observed between the DFS of patients treated with tamoxifen and the DFS of those treated with anastrozole (HR, 1.10; P=0.59). Although no benefit was observed for anastrozole compared with tamoxifen in the context of ovarian suppression, the results from other large randomized trials that also address this question, including SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial), are pending. A significant benefit in DFS, including nonâ&#x20AC;&#x201C;bone-related events, was associated with the use of zoledronic acid (HR,

N=1,598

Tamoxifen 20 mg/d x 5 y

Randomization

Exemestane 25 mg/d

Placebo

Median follow-up 30 mo, ITT analysis

Exemestane Placebo P Value

4-y DFS, %

0.07

4-y RFS, %

0.004

Figure 7. NSABP B-33: schema and results. DFS, disease-free survival; ITT, intent-to-treat; RFS, relapse-free survival Based on reference 23.

0.64; P=0.01), as was a trend toward improvement in OS (HR, 0.60; P=0.10). These results indicate that the adjuvant use of zoledronic acid can significantly decrease disease recurrence among premenopausal women receiving the combination of ovarian suppression and adjuvant endocrine therapy. Although it is an exciting possibility that the adjuvant use of bisphosphonates may eventually prove to affect breast cancerâ&#x20AC;&#x201C;related outcomes more generally, at present, the extrapolation of these results to the use of zoledronic acid beyond the clinical scenario examined in ABCSG 12 is not recommended.

Bisphosphonates and Denosumab CALGB 79809. Cancer and Leukemia Group B (CALGB) 79809 was undertaken to investigate the effect of zoledronic acid on bone mineral density (BMD) among premenopausal women with ovarian failure in the context of adjuvant chemotherapy.30 Specifically, the study was designed to compare early zoledronic acid (4 mg I.V. every 3 months started within 3 months of adjuvant chemotherapy) with late zoledronic acid (as above, but started 12 months after randomization). All patients were instructed to take daily supplemental calcium and vitamin D. The primary study end point was percentage change in BMD at 12 months. First results from CALGB 79809 were presented in 2008, at 12 months from randomization, and included a comparison of early

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N=1,803

Premenopausal women ER- and/or PR-positive breast cancer Stage I/II breast cancer (<10 positive nodes) No adjuvant chemotherapy (neoadjuvant allowed) Surgery ± XRT then goserelin 3.6 mg q28d

Randomization 1:1:1:1

Tamoxifen 20 mg qd

Tamoxifen Anastrozole 20 mg qd + 1 mg qd zoledronic acid 4 mg q6mo

Anastrozole 1 mg qd + zoledronic acid 4 mg q6mo

Main outcomes at 47.8 mo median follow-up: • No difference in DFS between tamoxifen and anastrozole (HR, 1.1; P=0.59) • Improved DFS, including non-bone events in zoledronic acid arms (HR, 0.64; P=0.01) • Trend toward improved OS in zoledronic acid arms (HR, 0.60; P=0.10)

Figure 8. ABCSG 12. DFS, disease-free survival; ER, estrogen receptor; HR, hazard ratio; OS, overall survival; PR, progesterone receptor; XRT, radiation therapy Based on reference 29.

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zoledronic acid with “control” (defined as such in this context because these patients, comprising the late treatment arm, had not started zoledronic acid). Of 439 premenopausal women enrolled in this trial, ovarian failure (defined as ≥3 months of amenorrhea with a folliclestimulating hormone level ≥30 mIU/mL) developed in 166 (38%) at 12 months from randomization, and they were included in this analysis. From baseline to 12 months, the mean change in spinal BMD in the treatment group was an increase of 2.2%, whereas the control group experienced a median loss of 6.6% (P<0.0001), for a total difference between the 2 groups of 8.8%. At the first planned interim analysis, these results crossed the prespecified boundary for superiority and were released by the data safety monitoring board. Zoledronic acid was well tolerated and added minimal toxicity to adjuvant chemotherapy. Conclusions regarding the optimal administration of zoledronic acid in this context would be premature because comparisons between the early and late schedules are pending. However, even these early data from CALGB 79809 provide strong evidence that zoledronic acid can preserve bone density when given to premenopausal women in whom ovarian failure develops during the course of adjuvant chemotherapy. ZO-FAST. The ZO-FAST (Zoledronic Acid in the Prevention of Cancer Treatment-Induced Bone Loss in Postmenopausal Women Receiving Letrozole as Adjuvant Therapy for Early Breast Cancer) trial enrolled 1,065 postmenopausal women who had hormone receptor–positive early-stage breast cancer, no evidence of osteoporosis at baseline (lumbar spine and total hip T-scores of –2 or higher), and were receiving adjuvant letrozole. The patients were assigned to receive immediate or delayed zoledronic acid, with the primary objective of assessing change in BMD at 12 months.31 Patients in the immediate-use group received 4 mg of zoledronic acid I.V. every 6 months for 5 years from study start, whereas those in the delayeduse group began zoledronic acid only if their BMD fell into a severely osteopenic or osteoporotic range (T-score below –2) or they had a nontraumatic fracture. Initial efficacy results from ZO-FAST showed an increase in BMD from baseline to 12 months in the immediate group and a fall in BMD during the same time period in the delayed group. At 12 months, the 2 groups exhibited significant differences in both lumbar spine BMD (5.7%; P<0.0001) and total hip BMD (3.6%; P<0.0001). Results from ZO-FAST were updated in 2008 with 36 months of follow-up.32 At this extended follow-up, both the difference between mean lumbar spine BMD (9.3%; P<0.0001) and the difference between mean total hip BMD (5.4%; P<0.0001) between the 2 groups continued to be significant. The overall incidence rates of fractures were not different: 5% in the immediate group and 6% in the delayed group (P=0.502). Perhaps of most interest was the finding that DFS was significantly improved with the upfront use of zoledronic acid (HR, 0.588; P=0.0314). Regarding toxicity, no cases of treatment-related renal toxicity were reported, and 1 case of osteonecrosis of the jaw was observed in the

Table. Ongoing Trials: Adjuvant Use of Bisphosphonates Trial

Question

Status

Accrual (Goal)

NSABP 34

Does clodronate improve DFS?

Accrual complete

3,400

AZURE

Does ZOL improve DFS?

Accrual complete

3,360

SUCCESS

3 vs 5 y of ZOL during endocrine treatment

Accrual complete

3,754

S0307

Comparison of 3 bisphosphonates (ZOL, clodronate, ibandronate)

Active

1,102 (4,500)

NATAN

Does ZOL improve DFS?

Active

392 (654)

AZURE, Adjuvant Zoledronic Acid To Reduce Recurrence; DFS, disease-free survival; NATAN, Postoperative Use of Zoledronic Acid in Breast Cancer Patients After Neoadjuvant Chemotherapy; NSABP 34, National Surgical Adjuvant Breast and Bowel Project Trial 34; S0307, Bisphosphonates as Treatment in Breast Cancer; SUCCESS, Extended Bisphosphonate and Surveillance; ZOL, zoledronic acid

immediate-use group (0.2%). In summary, these data continue to show bone health benefits associated with the immediate use of zoledronic acid in the context of letrozole therapy, as manifested by significantly higher BMD values, although with no apparent affect on fracture rates. Furthermore, the observed improvement in DFS in the immediate-use group adds to the growing body of evidence that adjuvant use of zoledronic acid may improve disease-related outcomes. In addition to the results from trials reviewed here, the results from several ongoing studies of the adjuvant use of bisphosphonates in breast cancer are awaited (Table). Neoadjuvant AZURE. Data presented in 2008 from the AZURE (Adjuvant Zoledronic Acid To Reduce Recurrence) trial also suggest improved outcomes associated with the use of zoledronic acid in the neoadjuvant setting.33 AZURE enrolled 3,360 women with stage II or III breast cancer who were receiving neoadjuvant or adjuvant chemotherapy and randomized the patients to the addition of zoledronic acid (4 mg given I.V. every 3-4 weeks for 6 months during chemotherapy) or to placebo. The investigators conducted a retrospective exploratory analysis of a subgroup of 205 patients who were treated in the neoadjuvant setting to determine whether the addition of zoledronic acid improved outcomes including residual invasive tumor size (RITS), pathologic complete response (pCR) in the breast and axilla, number of involved lymph nodes, and proportion of patients requiring mastectomy. In the group of patients who received zoledronic acid, the adjusted mean RITS was significantly smaller (28.2 vs 42.4 mm; difference between mean sizes, 14.1 mm; P=0.002), the pCR rate was higher (10.9% vs 5.8%; P=0.033), and the proportion of patients requiring mastectomy was lower (65.3% vs 77.9%). No significant difference was found between the numbers of involved lymph nodes. These exciting results suggest that zoledronic acid may have direct antitumor effects in the neoadjuvant setting, but prospective studies are required to substantiate them.

Denosumab. Osteoclastic bone resorption is known to be mediated by the receptor activator of nuclear factorκB ligand (RANKL). Therefore, inhibition of RANKL represents a novel strategy to suppress bone loss. Recently, the first Phase III double-blind, placebo-controlled study of denosumab (Amgen), a fully human monoclonal antibody with specific activity against RANKL, was reported to increase BMD in the context of adjuvant use of AIs.34 In this trial, 252 patients with low baseline BMD (T-score in the osteopenic range of –1.0 to –2.5 in the lumbar spine or hip) were stratified by length of AI therapy (≤6 vs >6 months) and randomized to receive 60 mg of denosumab subcutaneously every 6 months or placebo. All patients were treated with calcium and vitamin D supplementation. The primary study end point was change from baseline in lumbar spine BMD at 12 months. Significant increases in lumbar spine BMD were observed for denosumab versus placebo at both 12 and 24 months (5.5% and 7.6%, respectively; P<0.0001 for both). The overall incidence rates of adverse events were similar in the 2 treatment groups. Although this study was not powered to detect a difference between fracture rates in the treatment groups, the data provide early support that inhibition of RANKL may be a useful strategy to preserve bone density in the context of adjuvant therapy for breast cancer.

Conclusion Taken together, the results from these adjuvant endocrine trials will have a profound effect on the treatment and lives of women with early-stage breast cancer. Of particular note, recent data from both NCIC CTG MA.17 and NSABP B-33 strongly suggest a role for extending endocrine therapy beyond 5 years. These results are consistent with the natural history of hormone receptor–positive breast cancer and the known enduring risk for relapse years and decades after initial diagnosis. Ongoing clinical trials seek to clarify issues such as the sequencing, relative potency, and duration of treatments with endocrine agents to optimize

I n d e p e n d e n t ly d e v e l o p e d b y M c M a h o n P u b l i s h i n g

adjuvant treatment for early-stage disease. These efficacy data are clearly much anticipated; however, the potential for deleterious long-term side effects, in addition to the associated financial costs to both individual patients and society, mandate a continuous effort to accurately define the subgroups of patients who will benefit most from these extended endocrine strategies. First efficacy results from ABCSG 12 showing improved DFS associated with the adjuvant use of zoledronic acid represent another major advance in the care of patients with breast cancer, although it must be emphasized that widespread application of these results would be premature without further confirmation from other large randomized trials. Longterm results from these pivotal trials and new results from ongoing studies are eagerly anticipated as we strive to further our understanding of the complex biology of breast cancer and improve adjuvant treatment strategies. References 1. Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717, PMID: 15894097. 2. Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001;93(9): 684-690, PMID: 11333290. 3. Peto R, Davies C, on behalf of the ATLAS Collaboration. ATLAS (Adjuvant Tamoxifen, Longer Against Shorter): international randomized trial of 10 versus 5 years of adjuvant tamoxifen among 11 500 women-preliminary results. Breast Cancer Res Treat. 2007;106(suppl): LBA48. 4. Gray RG, Rea DW, Handley K, et al. aTTom (adjuvant Tamoxifen— To offer more?): randomized trial of 10 versus 5 years of adjuvant tamoxifen among 6,934 women with estrogen receptor-positive (ER+) or ER untested breast cancer—preliminary results. J Clin Oncol. 2008;26(suppl):abst 513. 5. Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women

I n d e p e n d e n t ly d e v e l o p e d b y M c M a h o n P u b l i s h i n g

with early breast cancer. N Engl J Med. 2005:353(26):2747-2757, PMID: 16382061. 6. Mouridsen H, Keshaviah A, Coates AS, et al. Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: safety analysis of BIG 1-98 trial. J Clin Oncol. 2007;25(36):5715-5722, PMID: 17998546. 7. Mouridsen HT, Giobbie-Hurder A, Mauriac L, et al. BIG 1-98: a randomized double-blind phase III study evaluating letrozole and tamoxifen given in sequence as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. Presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 13. 8. Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet. 2005;365(9453):60-62, PMID: 15639680. 9. Baum M, Buzdar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial [published correction appears in Lancet. 2002;360(9344):1520]. Lancet. 2002;359(9324):2131-2139, PMID: 12090977. 10. Baum M, Buzdar AU, Cuzick J, et al; ATAC Trialists’ Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer. 2003;98(9):1802-1810, PMID: 14584060. 11. Buzdar A, Cuzick J. Anastrozole as an adjuvant treatment for post-menopausal patients with breast cancer: emerging data. Clin Cancer Res. 2006;12(suppl 3):1037-1048. 12. Arimidex, Tamoxifen Alone or in Combination (ATAC) Trialists’ Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 2008;9(1):45-53, PMID: 18083636. 13. Jones SE. Exemestane as adjuvant treatment of early breast cancer: Intergroup Exemestane Study/Tamoxifen Exemestane Adjuvant Multicenter trials. Clin Breast Cancer. 2006;6(suppl 2):s41-s44, PMID: 16595025. 14. Jones SE, Seynaeve C, Hasenburg A, et al. Results of the first planned analysis of the TEAM (tamoxifen exemestane adjuvant multinational) prospective randomized phase III trial in hormone sensitive postmenopausal early breast cancer. Presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 15.

15. Jakesz R, Jonat W, Gnant M, et al. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005;366(9484):455-462, PMID: 16084253. 16. Jakesz R, Gnant M, Griel R, et al. Tamoxifen and anastrozole as a sequencing strategy in postmenopausal women with hormoneresponsive early breast cancer: updated data from the Austrian breast and colorectal cancer study group trial 8. Presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 14. 17. Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer [published correction appears in N Engl J Med. 2004;351(23):2461]. N Engl J Med. 2004;350(11):1081-1092, PMID: 15014181.

25. Pritchard K, Whelan T. Clinical trial update: National Cancer Institute of Canada. Breast Cancer Res. 2005;7(2):48-51, PMID: 15743510. 26. Goss PE. Update on the MA.17 extended adjuvant trial. Best Pract Res Clin Endocrinol Metab. 2006;20(suppl 1):s5-s13. 27. Mamounas EP, Lembersky B, Jeong JH, et al. NSABP B-42: a clinical trial to determine the efficacy of five years of letrozole compared with placebo in patients completing five years of hormonal therapy consisting of an aromatase inhibitor (AI) or tamoxifen followed by an AI in prolonging disease-free survival in postmenopausal women with hormone receptor-positive breast cancer. Clin Breast Cancer. 2006;7(5):416-421, PMID: 17239269. 28. Secondary adjuvant long term study with Arimidex (SALSA). http://clinicaltrials.gov/ct2/show/ NCT00295620?term=SALSA&rank=1. Accessed January 23, 2009.

18. Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial [published correction appears in Lancet. 2007;369(9565):906]. Lancet. 2007;369(9561):559-570, PMID: 17307102.

29. Gnant M, Mlineritsch B, Schippinger W, et al. Adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with hormone-responsive stage I and II breast cancer: first efficacy results from ABCSG-12. J Clin Oncol. 2008;26(suppl):LBA4.

19. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349(19):17931802, PMID: 14551341.

30. Shapiro CL, Halabi S, Gibson G, et al. Effect of zoledronic acid (ZA) on bone mineral density (BMD) in premenopausal women who develop ovarian failure (OF) due to adjuvant chemotherapy (AdC): first results from CALGB trial 79809. J Clin Oncol. 2008;26(suppl):abst 512.

20. Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005;97(17):1262-1271, PMID: 16145047. 21. Muss HB, Tu D, Ingle JN, et al. Efficacy, toxicity, and quality of life in older women with early-stage breast cancer treated with letrozole or placebo after 5 years of tamoxifen: NCIC CTG intergroup trial MA.17. J Clin Oncol. 2008;26(12):1956-1964, PMID: 18332474. 22. Goss PE, Ingle JN, Pater JL, et al. Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen [published correction appears in J Clin Oncol. 2008;26(21):3659]. J Clin Oncol. 2008;26(12):1948-1955.

31. Bundred NJ, Campbell ID, Davidson N, et al. Effective inhibition of aromatase-inhibitor associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST study results. Cancer. 2008;112(5):1001-1010, PMID: 18205185. 32. Eidtmann H, Bundred NJ, DeBoer R, et al. The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36 months follow-up of ZO-FAST. Presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 44.

23. Mamounas E, Jeong JH, Wickerham L, et al. Benefit from exemestane as extended adjuvant therapy after 5 years of tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 trial. J Clin Oncol. 2008;26(12):1965-1971, PMID: 18332472.

33. Winter MC, Thorpe HC, Burkinshaw R, et al. The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response—exploratory evidence for direct anti-tumor activity in breast cancer. Presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 5101.

24. De Boer R, Burris H, Monnier A, et al. The head to head trial: letrozole vs anastrozole as adjuvant treatment of postmenopausal patients with node positive breast cancer. J Clin Oncol. 2006; 24(18 suppl):abst 10672.

34. Ellis GK, Bone HG, Chlebowski R, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol. 2008;26(30):48754882, PMID: 18725648.

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•

Patient Guide to

Treating Early-Stage Breast Cancer

reast cancer is the most common, and second deadliest, cancer in women in the United States. Although the overall incidence of breast cancer has been on the rise, improved screening and better therapy have contributed to a decline in deaths from the disease.

Surgery Early-stage breast cancers can be treated by mastectomy (removal of the breast) or breast conservation therapy, which is a lumpectomy (removal of the breast lump and surrounding tissue) followed by local breast radiation therapy. Lumpectomy and mastectomy are both routinely combined with axillary (underarm) lymph node removal and examination to see if cancer cells are present. Studies have shown that breast conservation therapy is as effective as mastectomy, with no difference in overall survival.

Adjuvant Therapy A woman who has no detectable cancer after surgery may be given adjuvant therapy, which refers to treatment targeted at cancer cells that may have spread beyond the breast. Some breast cancer patients receive neoadjuvant therapy, which is chemotherapy given before surgery to shrink a tumor. Adjuvant therapy refers to treatment targeted at microscopic breast cancer cells that may have spread beyond the breast despite adequate surgery and radiation therapy. It is usually recommended for women whose breast cancer has spread to the lymph nodes because they are more likely to have a relapse of their cancer. This treatment has also been shown to benefit women who are thought to be at high risk for a recurrence even though the cancer has not spread to their lymph nodes. In most cases, chemotherapy is most effective, either as an adjuvant or neoadjuvant therapy, when combinations of more than 1 chemotherapy drug are used together.

Endocrine Therapy Endocrine therapy is used to manage a breast tumor that uses the hormones estrogen or proges-

terone to fuel its growth. Blocking the hormones usually limits the growth of the tumor. One of the oldest forms of endocrine therapy is tamoxifen, which blocks the effects of estrogen within breast tumor cells. Another newer type of endocrine therapy includes treatment with aromatase inhibitors. These drugs significantly reduce the amount of estrogen produced in postmenopausal women; they are not indicated for use in premenopausal women. This class of drugs includes letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin). Research supports the use of either an aromatase inhibitor instead of tamoxifen, or switching to it after several years of tamoxifen, rather than keeping postmenopausal women on tamoxifen alone.

HER2-Positive Breast Cancer HER2-positive breast cancer is a form of breast cancer caused by the amplification of a gene called HER2 in tumor cells. This amplification can cause cells to divide, multiply, and grow more rapidly than normal. One treatment for women with HER2positive breast cancer is trastuzumab (Herceptin). Trastuzumab can be given either alone or in combination with chemotherapy drugs. Recent studies show that adding trastuzumab to chemotherapy can boost survival rates compared with chemotherapy alone in women with HER2-positive breast cancer.

For More Information: American Cancer Society (800) ACS-2345

www.cancer.org

National Cancer Institute (800) 4-CANCER

www.cancer.gov

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�e�� Ind p e n d e n t ly d e v e l o p e d b y M c M a h o n P u b l i s h i n g ��

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HER2 FISH pharmDxTM Kit – FDA-approved HER2 FISH pharmDx Kit is a direct fluorescence in situ hybridization (FISH) assay designed to quantitatively determine HER2 gene amplification in formalin-fixed, paraffin-embedded breast cancer tissue specimens. Results from the HER2 FISH pharmDx Kit are intended for use as an adjunct to the information currently used for estimating prognosis in stage II, node-positive breast cancer patients. ER/PR pharmDxTM Kit – FDA-cleared ER/PR pharmDx Kit is a semi-quantitative immunohistochemical kit system to identify estrogen receptor (ER) protein and progesterone receptor (PR) protein expression in normal and neoplastic tissues. ER/PR pharmDx Kit is indicated as an aid in identifying patients eligible for treatment with anti-hormonal or aromatase inhibitor therapies as well as an aid in the prognosis and management of breast cancer. TOP2A FISH pharmDxTM Kit – FDA-approved TOP2A FISH pharmDx Kit is designed to detect amplifications and deletions (copy number changes) of the TOP2A gene using fluorescence in situ hybridization (FISH) technique on formalin-fixed, paraffin-embedded human breast cancer tissue specimens. Deletions and amplifications of the TOP2A gene serves as a marker for poor prognosis in high-risk breast cancer patients. Results from the TOP2A FISH pharmDx Kit are intended for use as an adjunct to existing clinical and pathological information. EGFR pharmDxTM Kit – FDA-approved EGFR pharmDx Kit is a qualitative immunohistochemical kit system that includes all reagents necessary to identify expression of epidermal growth factor receptor (EGFR) protein on the surface of normal and neoplastic cells. EGFR is indicated as an aid in identifying colorectal cancer patients eligible for treatment with Erbitux® (cetuximab) or VectibixTM (panitumumab). Please visit us at USCAP booth 602 for a demonstration of our patient tracking system. www.dako.com

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Clinical Oncology News • JANUARY/FEBRUARY 2009

Breast

Aromatase Inhibitors Trump Tamoxifen Large Meta-analysis Reveals AIs Superior to Tamoxifen in Preventing Breast Cancer Recurrence

San Antonio—A large metaanalysis of several international clinical trials demonstrates that aromatase inhibitors (AIs) are more effective than tamoxifen in preventing the recurrence of breast cancer. Although the absolute difference in recurrence rates between these two hormonal therapies was small, AIs can potentially spare a large number of breast cancer survivors from a recurrence, explained James Ingle, MD, professor at Mayo Clinic in Rochester, Minn. Dr. Ingle presented the meta-analysis results at the San Antonio Breast Cancer Symposium on behalf of the Aromatase Inhibitors Overview Group (AIOG; abstract 12). “If 80,000 to 90,000 women in the U.S. are using endocrine therapy this year, a 3% difference in recurrence rates means that several thousand women can be spared from a breast cancer recurrence,” Dr. Ingle stated. Although individual studies of tamoxifen and AIs have shown a benefit for anastrozole (Arimidex, AstraZeneca), letrozole (Femara, Novartis) and exemestane (Aromasin, Pfizer), pooling data from studies of these agents provides a different and important look at the data, according to co-author Mitch Dowsett, PhD, of the Royal Marsden Hospital in London, who leads the AIOG collaboration. “Even though the individual trials have been large, women taking tamoxifen have such good outcomes that it takes a very large meta-analysis to have enough events to power the analyses of mortality and those based on subgroups. This meta-analysis allowed us to have confidence that the improvement in preventing the return of breast cancer applies to all subgroups of patients [i.e., age, nodal status and tumor grade], but that those at risk have the most to gain. The global community has to come together to do this kind of meta-analysis,” Dr. Dowsett said. For the meta-analysis, the major studies comparing tamoxifen and an AI were divided into two cohorts. Cohort 1 comprised clinical trials directly comparing five years of treatment with tamoxifen versus an AI. Cohort 2 looked at studies where patients received two to three years of tamoxifen and then were randomized to continue on tamoxifen or to receive an AI for the remainder of the trial; endocrine therapy totaled five years in both groups. Cohort 1 trials included ATAC and BIG 1-98 (N=9,856 patients); cohort 2 trials were ABCSG 8, ARNO 95, IES/BIG 2-97 and ITA (N=9,015 patients). Patients with estrogen receptor–negative (ER–) and ER-unknown status were excluded from the analysis.

Recurrence Rates In cohort 1, women who took AIs for five years had a 2.9% lower rate of recurrence compared with women who took tamoxifen for five years: 9.6% versus 12.6%, respectively at the five-year time point. A nonsignificant decrease in mortality of 1.6% was also observed for AIs versus tamoxifen. At a follow-up of eight years after diagnosis, the difference in recurrence rates between

Aromatase inhibitors Tamoxifen

19.2

Recurrence Rate, %

15.3

10 5 0

Figure. Comparison of follow-up after eight years. the two groups increased to 3.9%: 15.3% versus 19.2%, respectively (logrank 2; P<0.00001). At eight years of follow-up, no difference in breast cancer–related mortality or death from any cause was observed between treatment groups. Differences in overall survival will need 10- to 15-year follow-up, Dr. Ingle said. He pointed out that in tamoxifen studies done to date, tamoxifen’s survival advantage at five years was only onethird of the advantage shown at 15 years. In cohort 2, with an average follow-up of 3.9 years, women who switched to AIs following two to three years of tamoxifen had a 3.1% reduced risk for breast cancer recurrence at three years after the switch (5% vs. 8.1%, respectively) and an absolute gain of 3.5% six years after the switch (12.6% vs. 16.1%, respectively, logrank 2; P<0.00001) compared with those who continued on tamoxifen for their five years of therapy. Analysis of data from cohort 2 also showed a 1.6% reduced risk for breast cancer–related mortality, which was statistically significant. For both cohorts, greater reductions favoring AIs were observed for isolated local recurrence and contralateral recurrence compared with distant disease, but the difference between treatment groups did not reach statistical significance. Reductions in recurrence in cohort 1 were similar in the first two and last three years of treatment, but further reductions beyond five years were not significant. In cohort 2, significantly greater reductions in recurrence were observed during the first three years on treatment than after. Regarding safety, investigators noted that non–breast cancer deaths and overall mortality did not increase in patients taking AIs. Longer follow-up should shed more light on the relative efficacy of tamoxifen and AIs. The AIOG investigators plan to continue to mine the meta-analysis data for other findings of import. “For the individual patient, we need to balance efficacy gain with tolerability,” Dr. Ingle said.

Modest Benefit According to Eric Winer, MD, director of the Breast Oncology Center at Dana-Farber Cancer Institute in

Boston, the meta-analysis raises several issues, including the need to discuss risk versus benefit of tamoxifen and AIs with each patient prior to initiating therapy because these agents have different side-effect profiles. “When we put women on hormonal therapy, we need to make sure they are given a drug they are willing to take,” said Dr. Winer. “The compliance issue is huge. Many women do not take these drugs even though we prescribe them.” In addition to a discussion prior to initiating hormonal therapy, “another important discussion about side effects should be after a woman has been on therapy for a few months, so that we can address compliance,” he continued. “One of the clear messages from all the trials comparing tamoxifen alone versus the substitution or addition of an aromatase inhibitor is that the improvement in mortality with the use of aromatase inhibitors remains very modest. If we want to decrease deaths from hormone receptor–positive breast cancer, we will need to look beyond hormonal therapy to see why some tumors respond and others don’t. Our energy should be focused on new treatments,” Dr. Winer said.

‘If 80,000 to 90,000 women in the U.S. are using endocrine therapy this year, a 3% difference in recurrence rates means that several thousand women can be spared from a breast cancer recurrence.’ —James Ingle, MD

Quality-of-Life Implications Lesley Fallowfield, DPhil, director of the CRUK Sussex Psychosocial Oncology Group at Brighton & Sussex Medical School in Falmer, U.K., had a somewhat different outlook on the study. “It is perhaps disappointing that the absolute benefit in terms of reduction in recurrence is somewhat modest [in the metaanalysis], and, as pointed out, there is still no evidence of a survival benefit,” she said. “Modest benefit means that many thousands of women may well be receiving a treatment from which they will derive no benefit at all, but will almost certainly experience a large number of side effects. Vasomotor complaints in particular may not be life-threatening, but are quality-of-life–threatening,” Dr. Fallowfield pointed out. She added that women who take extended hormonal therapy “will have a considerable detriment to their quality of life, hence Dr. Ingle is correct in commenting that physicians need to have clear discussions with individual patients about the potential gains and pains of treatment.” Dr. Winer said that the public health benefit is important for patient populations, but for an individual woman, “the real trade-off is between an absolute 2% reduction in risk of recurrence versus side effects she is experiencing.” —Alice Goodman

Finally in the treatment of higher-risk MDS*â&#x20AC;Ś

* MDS, myelodysplastic syndromes; higher-risk MDS, Intermediate-2- and High-risk MDS per International Prognostic Scoring System (IPSS).

Please see Important Safety Information and Brief Summary of full Prescribing Information on following pages.

...

A Breakthrough in

azacitidine for injection Proven Results. Extended Survival.

S U R V I V A L VIDAZA is the first and only agent proven to extend overall survival vs conventional care regimens (CCR) in patients with higher-risk MDS VIDAZA nearly doubled the 2-year overall survival rate1 1.0 0.9

Log–Rank P =.0001 HR=0.58 (95% CI, 0.43–0.77)

Proportion Surviving

0.8 0.7 0.6

24.5 months

0.5

15.0 months

0.4

VIDAZA

0.3

CCR

0.2 0.1 0.0

Time (Months) From Randomization

Study 4, the Survival Study (AZA-001), was a phase 3, prospective, international, multicenter, randomized, controlled, parallel-group, non-crossover study of 358 adult (≥18 years) patients with higher-risk MDS (IPSS Intermediate-2 or High), and FAB*-defined refractory anemia with excess blasts (RAEB), or RAEB in transformation (RAEB-T†), or dysplastic-type chronic myelomonocytic leukemia (CMMoL), using modified FAB criteria. Patients were randomized to receive either VIDAZA (75 mg/m2 SC daily for 7 days each 28-day cycle) + best supportive care (BSC; transfusions, antibiotics, G-CSF for neutropenic infection), or 1 of 3 conventional care regimens (CCR). CCR treatments included BSC alone; low-dose cytarabine (L-DAC; 20 mg/m2 SC daily for 14 days every 28 to 42 days); or 7+3 chemotherapy (induction with cytarabine 100-200 mg/m2/d by continuous IV infusion over 7 days plus an anthracycline days 1-3 [plus a maximum of 2 consolidation cycles]). CCR were pre-selected by study investigators. The primary end point of the study was overall survival.1 * French-American-British classification for MDS. † Bone

marrow blast count ≥20% is classified by the WHO as AML. The investigators in the Survival Study (AZA-001) classified RAEB-T as blasts 21%-29%.1

VIDAZA® is indicated for treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). Please see Important Safety Information and Brief Summary of full Prescribing Information on following pages.

For proven survival in higher-risk MDS

There’s only VIDAZA

VIDAZA significantly extended median overall survival vs CCR P

VIDAZA nearly doubled the 2-year overall survival rate vs CCR Patients continued treatment until disease progression, relapse after response, or unacceptable toxicity

Important Safety Information

Reference: 1.

azacitidine for injection

Proven Results. Extended Survival.

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•

Myelodysplasia: Recent Advances Haifaa Abdulhaq, MD

James M. Rossetti, DO

Richard K. Shadduck, MD

Assistant Director, Blood and Marrow Transplantation Program Western Pennsylvania Cancer Institute Pittsburgh, Pennsylvania

Associate Director, Blood and Marrow Transplantation Program Western Pennsylvania Cancer Institute Pittsburgh, Pennsylvania

Professor of Medicine Temple University School of Medicine Director, Western Pennsylvania Cancer Institute Pittsburgh, Pennsylvania

he myelodysplastic syndromes

(MDS) are a heterogeneous group of clonal hematopoietic disorders

characterized by varying degrees of cytopenia and abnormal morphology and impaired maturation of cellular bone marrow.1 Some MDS subtypes evolve rapidly to acute myeloid leukemia (AML). Others develop into progressive cytopenias.

MDS can be either idiopathic or secondary, occurring at a delayed interval after exposure to alkylating agents, radiation, or both,2,3 or with chronic exposure to solvents such as benzene. MDS have become the most common malignant bone marrow disorders, affecting approximately 55,000 patients in the United States.4

Clinical Presentation and Diagnosis In many patients there are no symptoms initially, and MDS are discovered incidentally by a review of routine blood cell counts. Others present with symptoms of anemia, which may be normocytic or macrocytic.5 Neutropenia or thrombocytopenia may be found initially or may appear with progression of the disease. Peripheral blood smears reveal morphologic abnormalities such as hypogranulated neutrophils with hyposegmented nuclei (pseudo–Pelger-Huët anomaly) and giant platelets.6 The bone marrow is typically cellular or hypercellular with various morphologic abnormalities. Alternatively, 10% to 20% of patients have a hypocellular marrow that either is present at the outset or evolves as the disease progresses. The approach to diagnosis should begin with the exclusion of more common types of normocytic or mac-

rocytic anemia. Then, the possibility of MDS should be considered. A similar approach should be used in patients with other unexplained cytopenias. Anemia and other cy topenias must be evaluated by bone marrow aspiration to detect morphologic abnormalities. Bone marrow biopsy is necessary to assess marrow cellularity and topography and to identify nonrandom chromosomal abnormalities to aid in diagnosis and establish prognosis.

Classification Various classification systems have been developed, the most widely used being the French–American– British (FAB; Table 1)7 and the World Health Organization (WHO) classification systems (Table 2).8 The International Prognostic Scoring System (IPSS)9 is useful for predicting survival and the risk for leukemic transformation, facilitating clinical decision making in individual cases (Table 3). A recent WHO classification–based prognostic scoring system (WPSS) was suggested based on a study that identified WHO subgroup, karyotype, and transfusion requirements as the most important prognostic factors for predicting survival and leukemic transformation. It classifies patients into 5 risk groups with survival ranging between 12 and 103 months (Table 4).10

I n d e p e n d e n t ly d e v e l o p e d b y M c M a h o n P u b l i s h i n g CL I N I CAL ONCOLOGY NE W S • J ANUA R Y/ F EB R UA R Y 2 0 0 9

Biology

Table 1. FAB Classification Of Acute Leukemias Type

Transfor– Frequency, Blasts, mation to % % AML, %

10-40

10-20

RARS

10-20

RAEB

25-30

5-20

40-50

CMML

10-20

≤20

RAEB-t

10-30

21-30

50-60

Other

>15% RS

>109 monocytes

AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; FAB, French–American–British; RA, refractory anemia; RAEB, refractory anemia with excess blasts; RAEB-t, refractory anemia with excess blasts in transformation; RARS, refractory anemia with ringed sideroblasts; RS, ringed sideroblasts Based on reference 7.

MDS comprise a group of clonal disorders of hematopoietic stem cells that result in excessive apoptosis, reflected by the degree of dysplasia and loss of differentiation of hematopoietic progenitor cells.11 Cytogenetic abnormalities occur in up to 60% of patients with primary MDS and in 80% to 100% of patients with secondary MDS.12 Complete or partial deletions of the long arm of chromosomes 5, 7, and 20 are common: del(5q), 5q–, del(7q), 7q–, del(20q), 20q–. Patients with 5q– tend to have a better prognosis. Patients with an isolated 5q– defect are typically transfusion-dependent for red blood cells only and have a low risk for leukemic transformation. A retrospective study from M.D. Anderson presented at the 2008 annual meeting of the American Society of Hematology revealed a heterogeneous prognosis associated with chromosome 5 abnormalities.13 5q– was associated with better survival than monosomy 5. The latter was more frequently associated with higher-risk MDS. A minority of patients with CMML may have balanced reciprocal translocations involving the platelet-derived growth factor receptor-β gene (PDGFRB). This subset of patients may benefit from imatinib (Gleevec, Novartis).14

Table 2. WHO Classification and Criteria for Myelodysplastic Syndromes Type

Blood Findings

Bone Marrow Findings

Anemia; no or rare blasts

Erythroid dysplasia only; 5% blasts; <15% RS

RARS

Anemia; no blasts

Erythroid dysplasia only; ≥15% RS; <5% blasts

RCMD

Cytopenias (bicytopenia or pancy topenia); no or rare blasts; no Auer rods; <1 × 109 monocytes per liter

Dysplasia in ≥10% of cells in ≥2 myeloid cell lines; <5% blasts in marrow; no Auer rods; <15% RS

RCMD-RS

Cytopenias (bicytopenia or pancy topenia); no or rare blasts; no Auer rods; <1 × 109 monocytes per liter

Dysplasia in ≥10% of cells in ≥2 myeloid cell lines; ≥15% RS; <5% blasts; no Auer rods

RAEB-1

Cytopenias; <5% blasts; no Auer rods; Unilineage or multilineage dysplasia; <1 × 109 monocytes per liter 5%-9% blasts; no Auer rods

RAEB-2

Cytopenias; 5% to 19% blasts; ± Auer rods; <1 × 109 monocytes per liter

Unilineage or multilineage dysplasia; 10%-19% blasts; ± Auer rods

MDS, unclassified

Cytopenias; no or rare blasts; no Auer rods

Unilineage dysplasia in granulocytes or megakaryocytes; <5% blasts; no Auer rods

MDS associated with isolated del(5q)

Anemia; <5% blasts; platelets normal or increased

Normal to increased megakaryocytes with hypolobated nuclei; <5% blasts; no Auer rods; isolated del(5q)

MDS, myelodysplastic syndrome; RA, refractory anemia; RAEB-1, refractory anemia with excess blasts-1; RAEB-2, refractory anemia with excess blasts-2; RARS, refractory anemia with ringed sideroblasts-1; RCMD, refractory cytopenia with multilineage dysplasia; RCMD-RS, refractory cytopenia with multilineage dysplasia and ringed sideroblasts; WHO, World Health Organization This research was originally published in reference 8; © American Society of Hematology.

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Treatment

doubles the response rate, mitigating anemia and reducing transfusion requirements in almost 40% of patients.17 The response rate to growth factor therapy approaches 75% in patients who have a low level of endogenous Epo (<100 units/L) and a low transfusion requirement (<2 units of red blood cells per month). On the other hand, the response rate is 7% in patients with a high level of endogenous Epo (>500 units/L) and a high transfusion requirement (≥2 units of red blood cells per month; Figure 1).18 Darbepoetin (Aranesp, Amgen) is a modified form of Epo with a prolonged serum half-life and increased in vivo biologic activity, allowing less frequent dosing. The utility of darbepoetin in the treatment of MDS needs to be established; however, preliminary results suggest substantial responses to this agent as well.19,20 Although these agents may improve quality of life without adverse effects on long-term outcome, they do not alter the natural history of the disease.

Supportive care measures, including the transfusion of blood products and the administration of antibiotics and hematopoietic growth factors, remain the mainstay of management for patients with MDS.

Response Criteria An international working group (IWG) of experienced clinicians has developed a uniform set of guidelines to evaluate and compare the responses to various new treatment modalities in MDS.15 According to these guidelines, the designated response values must last at least 2 months without the patient taking growth factors. Complete remission (CR) is defined by a repeat bone marrow analysis showing less than 5% myeloblasts with normal maturation of all cell lines and no evidence of dysplasia. In addition, peripheral blood cell counts must show hemoglobin levels of greater than 11 g/dL, neutrophils 1,500/mm3 or higher, platelets 100,000/mm3 or more, and no peripheral blasts. Partial remission (PR) is similar to CR, although marrow blasts may still be elevated as long as the count has decreased by at least 50% from pretreatment values. Reduction to a lower FAB classification also qualifies as a PR. For patients whose blood counts improve but who do not meet criteria for CR or PR, a scale of major and minor hematologic improvement for each cell line has been established, although the significance of minor responses in relation to quality of life is not clear. Cytogenetic response is defined as either major response, indicating disappearance of cytogenetic abnormality, or minor response, referring to at least a 50% reduction of abnormal metaphases.

Immune Modulation As many as 20% of patients are candidates for immuno suppressive therapy with antithymocyte globulin at a dose of 40 mg/kg I.V. per day for 4 days,21 cyclosporine,22 and steroids. This regimen, which is similar to that used for aplastic anemia, is most useful in younger patients with hypocellular MDS and in those with HLA-DR15.23 Response rates are as high as 70% in these selected populations, although relapses can occur after treatment.

Epigenetic Modifiers The major pathogenetic component of MDS is the failure of normal hematopoietic differentiation. Enhancing the transcription of genes associated with differentiation can promote maturation and differentiation. In normal cells, CpG islands, where the transcription of DNA into RNA begins, are protected from methylation. By contrast, cancer cells often exhibit abnormal methylation patterns. Certain genes, including tumor suppressor genes such as P15, become silenced when CpG islands are methylated, resulting in altered

Hematopoietic Growth Factors Erythropoietin (Epo; epoetin alfa, Epogen, Amgen/ Prokrit, Ortho) reduces transfusion requirements in roughly 20% of patients who receive the equivalent of 40,000 to 80,000 units weekly. The response rate is highest in patients with low-risk disease.16 The addition of granulocyte colony-stimulating factor (G-CSF) to Epo nearly

Table 3. International Prognostic Scoring System Prognostic Variable

Score Valuea 0

0.5

1.0

1.5

2.0

Bone marrow blasts, %

5-10

11-20

21-30

Karyotypeb

Good

Intermediate

Poor

Cytopeniasc

0/1

2/3

Scores for risk groups are as follows: low, 0; int-1, 0.5-1.0; int-2, 1.5-2.0; high, ≥2.5. Good: normal, –Y, del(5q), del(20q); poor: complex (≥3 abnormalities) or chromosome 7 abnormalities; intermediate: other abnormalities. c Hemoglobin <10 g/dL; absolute neutrophil count <1,800/mcL; platelet count <100,000/mcL. a

This research was originally published in reference 9; © American Society of Hematology.

I n d e p e n d e n t ly d e v e l o p e d b y M c M a h o n P u b l i s h i n g

RA, RAEB, RARS

Score > +1

Good response (74%, n=34)

Score = –1 to +1

Intermediate response (23%, n=31)

Score < –1

Poor response (7%, n=29)

Treatment response criteria CR PR

Treatment response score S-EPO U/I

Stable hemoglobin >11.5 g/dL Increase in Hb with >1.5 g/dL or total stop in RBC transfusion

Transfusion U RBC/m

<100 100-500 >500 < 2 units/m = or > 2 units/m

+2 +1 –3 +3 –2

Figure 1. A predictive model for the response to EPO and G-CSF in MDS patients. CR, complete response; EPO, erythropoietin; G-CSF, granulocyte-colony stimulating factor; MDS, myelodysplastic syndromes; PR, partial response; S-EPO, serum erythropoietin; RA, refractory anemia; RAEB, refractory anemia with excess blasts; RARS, refractory anemia with ringed sideroblasts Based on reference 18.

transcriptional competency. Epigenetic changes are reversible, and demethylating agents have been shown to alter the methylation patterns in the promoter regions of genes. The most active agents available for the treatment of high-risk MDS are the demethylating agents.24,25 The demethylating agent azacitidine (Vidaza, Celgene) was the first drug approved by the FDA for treatment of MDS.26-28 Silverman et al reported a response rate of 60% (CR, 7%; PR, 16%; hematologic improvement, 37%) in a Phase III clinical trial of azacitidine, at a dose of 75 mg/m2 per day given subcutaneously for 7 days every 4 weeks, versus supportive care.29 Cancer and Leukemia Group B (CALGB) response criteria were used in this trial because accrual predated IWG criteria. Silverman et al reanalyzed the response rates by using IWG criteria and

reported a response rate of 48% (CR, 10%; PR, 1%; hematologic improvement, 36%).30 The azacitidine arm of this trial demonstrated a marked improvement in quality of life, a significant delay in leukemic transformation, and a trend toward a survival advantage. Given a crossover design of the trial, a landmark analysis was performed at 6 months that demonstrated a survival advantage in patients who received azacitidine. Treatment-related mortality in this trial was less than 1%. The most common side effects reported in clinical studies have been nausea, vomiting, and myelosuppression. Nausea and vomiting can typically be overcome with prophylactic serotonin type 3 (5-HT3) antagonists. Early myelosuppression is common and tends to lessen as a response is seen. The typical nadir period is roughly 2 weeks after the start of therapy. Although the CALGB

Table 4. WHO Classification–Based Prognostic Scoring System (WPSS) Variable

WHO category

RA, RARS, 5q-

RCMD, RCMD-RS

RAEB-1

RAEB-2

Karyotype

Good

Intermediate

Poor

–

Transfusion requirement

Regular

–

Risk groups: Very low (0), low (1), intermediate (2), high (3-4), very high (5-6). RA, refractory anemia; RAEB, refractory anemia with excess blasts; RARS, refractory anemia with ringed sideroblasts; RCMD, refractory cytopenia with multilineage dysplasia; RCMD-RS, refractory cytopenia with multilineage dysplasia and ringed sideroblasts; WHO, World Health Organization

I n d e p e n d e n t ly d e v e l o p e d b y M c M a h o n P u b l i s h i n g

protocol prohibited the use of hematopoietic growth factors, some centers have found that such therapy may limit the degree and duration of neutropenia. In addition, recognizing the limitations of a 7-day dosing schedule, many centers are delaying the last 2 doses of each cycle until the following week. Alternative dosing schedules are under investigation, with some centers beginning to report experiences with a 5-day schedule. Results of the recently completed initial treatment phase (6 cycles of randomized treatment) of an ongoing Phase II study evaluating 3 alternative azacitidine dosing schedules were reported at the American Society of Hematology meeting in 2007.31 Patients were randomly assigned to 1 of 3 regimens: azacitidine 5-2-2 (75 mg/m2 per day for 5 days, followed by 2 days of no treatment, followed by 75 mg/m2 per day for 2 days); azacitidine 5-2-5 (50 mg/m2 per day for 5 days, followed by 2 days of no treatment, followed by 50 mg/m2 per day for 5 days); or azacitidine 5 (75 mg/m2 per day for 5 days). Hematologic improvement (HI) was seen in 44%, 52%, and 57%, respectively. The proportions of patients with red blood cell (RBC) transfusion dependence who achieved RBC transfusion independence were 55%, 60%, and 67%, respectively. All results were statistically similar. An overall survival (OS) benefit was recently demonstrated in a Phase III international multicenter trial that randomized 358 patients with Int-2 or high IPSS scores to azacitidine versus a conventional care regimen (CCR). 32 CCR was preselected by investigators as 1 of 3 options: best supportive care, low-dose cytarabine, or standard chemotherapy. Erythropoietin was not allowed on this trial. Median follow up was 21.1 months. Azacitidine demonstrated statistically superior OS (24.4 months vs 15 months). Hazard ratio was 0.58 for a 74% OS improvement. Azacitidine maintained a significant survival benefit when CR patients were excluded from the analysis (hazard ratio, 0.65). 33 Investigators at the Western Pennsylvania Cancer Institute (WPCI) have had considerable experience with azacitidine in MDS. Of 48 patients evaluated for efficacy in the WPCI azacitidine program, 46 were transfusiondependent before treatment. Eighteen of these patients (39%) became transfusion-independent. The majority of this group required 3 or more cycles to respond. The median duration of response was 7 months (range, 2-68+ months), with 3 responses continuing beyond 2 years. The FAB classification and the IPSS did not predict response to azacitidine. However, a decrease in the white blood cell count during the initial cycle of azacitidine correlated with a higher response rate.34 Further studies at the WPCI revealed improvement in hematologic response to azacitidine if given in combination with G-CSF (84% vs 51%).35 A second demethylating agent, decitabine (Dacogen, MGI Pharma), also has been approved by the FDA for the treatment of MDS. It is given at a dose of 45 mg/m2 daily (15 mg/m2 I.V. over 4 hours every 8 hours) for 3 days every 6 weeks. Kantarjian et al studied decitabine in a Phase III trial and found a 30% response rate (CR,

9%; PR, 8%; hematologic improvement, 13%) according to the IWG 2000 response criteria. This study also showed a decrease in transfusion dependence. All responders became transfusion-independent. A trend toward a delay in leukemic transformation/death as well as improvement in quality of life were seen. A cytogenetic CR was observed in 35% of patients.36 A recent study comparing different dosing schedules of the drug showed a CR in 39% of patients given an alternative regimen of 20 mg/m2 daily as an I.V. infusion over 1 hour for 5 days every 4 weeks.37 Cytogenic response was seen in 57% of patients, including 33% with complete cytogenic responses. In a retrospective study reviewing M.D. Anderson Cancer Center data on MDS patients with intermediate/high IPSS scores treated with decitabine, 70% achieved a response using modified IWG criteria (35% CR, 2% PR, 23% marrow CR, 10% HI).38 Median survival was 22 months and 2-year survival was 47%. Independent adverse prognostic factors for survival were chromosome 5 and/or 7 abnormalities, older age, and prior MDS therapy. Because silencing of gene transcription involves chromatin remodeling, agents targeting this process are being investigated. Deacetylation of histones has been associated with transcriptionally inactive chromatin. Various histone deacetylase inhibitors, including suberoylanilide hydroxamic acid, depsipeptide (FK228), MS-275, and valproic acid, are under investigation in clinical trials.39,40 Recently, the combination of azacitidine and vorinostat (Zolinza, Merck) was studied in a Phase I/II trial.41 It was well tolerated, with response in 9 of 11 evaluable patients (82%). Median time to respond was 2 cycles. The combination of decitabine and vorinostat has been tested in a Phase I study of patients with MDS or acute myelogenous leukemia, with promising activity and no major toxicity.42

Angiogenesis Inhibitors Interactions between the microenvironment of the bone marrow stroma and the MDS clone are essential for clonal expansion and modulation of the level of apoptosis in bone marrow progenitor cells. Angiogenesis has emerged as a key biologic process in MDS. Vascular endothelial growth factor-alpha (VEGF-α) is a particularly important angiogenic factor that is known to be overexpressed in MDS clones.43 Tumor necrosis factor-alpha (TNF-α) has also been implicated as a potential mediator of marrow failure. Thalidomide (Thalomid, Celgene) is an antiangiogenic agent with anticytokine (anti–TNF-α) properties. In a Phase II trial of thalidomide at doses between 100 and 400 mg daily in MDS patients at the Rush Presbyterian Cancer Institute, 15 (18%) of 83 evaluable patients achieved either red blood cell transfusion-independence or more than a 50% decrease in transfusion burden.44 A second analysis, including only patients who received at least 12 weeks of therapy, demonstrated a 10% improvement in the response rate. Improvement in nonerythroid lineages was uncommon. Dose escalation beyond 200 mg daily was limited by cumulative neurologic toxicity.

I n d e p e n d e n t ly d e v e l o p e d b y M c M a h o n P u b l i s h i n g

Stem Cell Transplantation Candidate Yes

High/ Intermediate-2

Low/ Intermediate-1

High/ Intermediate-2

Epo/G-CSF Thalidomide Lenalidomide (5q–) Immune Therapy MTIs ATO

MTIs ATO

No Response

Clinical Trial

Figure 2. Treatment algorithm for MDS. ATO, arsenic trioxide; Epo/G-CSF, etoposide, granulocyte colony–stimulating factor; MDS, myelodysplastic syndromes; MTIs, methyltransferase inhibitors (demethylating agents)

Lenalidomide (Revlimid, Celgene) is an analog of thalidomide that is more potent and appears to lack neurotoxic and teratogenic effects. It is used at doses of 10 mg per day or 10 mg per day for 21 days of every 28-day cycle with dose adjustment for patients who develop thrombocytopenia. Studies revealed higher responses in the red blood cell line, especially in patients who had low or intermediate-1 IPSS scores with a 5q– abnormality (alone or in combination with other cytogenetic abnormalities). List et al reported red blood cell transfusion independence in 67% of 5q– patients treated with lenalidomide. The median duration of transfusion independence was still not reached at 104 weeks of follow-up.45 The complete cytogenetic response rate in patients with isolated 5q– was 35%. On the basis of these results, the FDA approved this drug for the treatment of low-risk, transfusion-dependent MDS in patients with 5q–.45,46 Lenalidomide was also studied predominately in patients with low to intermediate-1 IPSS scores and without the 5q– abnormality. Red blood cell transfusion independence was reported in 26% of patients, with a median response duration of 41 weeks.47 The most common adverse events with this agent are neutropenia and thrombocytopenia, which usually occur early in the course of treatment and may require dose modification in the first 8 weeks of therapy.

Treatment with anti–TNF-α antibodies has achieved only moderate hematologic improvement in a minor subset of patients.48 Small molecule inhibitors of VEGF-receptor tyrosine kinases are being studied. One of the first inhibitors, SU5416, demonstrated some biologic activity when evaluated in high-risk MDS and AML.49

Farnesyl Transferase Inhibitors

MTIs MTI Allogenic Stem Cell Transplantation

Other Therapeutic Approaches Targeting the Marrow Microenvironment

I n d e p e n d e n t ly d e v e l o p e d b y M c M a h o n P u b l i s h i n g

The ras gene family affects critical regulatory pathways in signal transduction and proliferation. The activation of these pathways is dependent on farnesylation. Tipifarnib (Zarnestra, Johnson & Johnson), a farnesyl transferase inhibitor, has shown promising activity in patients with highrisk MDS. The starting dose in clinical trials was 300 mg given orally twice daily. Fatigue and confusion were doselimiting toxicities, and they occurred when 900 mg was given twice daily. Other studies used tipifarnib at a dose of 600 mg given orally twice daily in cycles of 4 weeks followed by 2 weeks of rest.50

Arsenicals Arsenic trioxide (Trisenox, Cephalon) has multiple mechanisms of action, including induction of apoptosis and tumor cell differentiation, abrogation of cellular proliferation, and inhibition of angiogenesis. It has shown moderate activity in both high- and low-risk MDS. Response rates of up to 35% have been reported, mainly involving the erythroid series. Occasional platelet and white blood cell responses have also been seen. Many patients maintained stable disease, although the effect of this is not yet known. Different dosing schedules were used in clinical trials, one of which was 0.30 mg/kg daily for 5 days followed by maintenance with 0.25 mg/kg daily twice per week for up to 15 weeks.51

Stem Cell Transplantation Although allogeneic hematopoietic stem cell trans plantation (SCT) is the only known curative option for MDS, because of age restrictions, concomitant medical conditions, and donor availability, fewer than 5% of MDS patients are transplant candidates. For those who do undergo SCT, results from several large centers indicate disease-free survival (DFS) rates of approximately 30% to 50%, depending on MDS type.52 Failure is due primarily to transplant-related mortality in patients with low-risk MDS and disease recurrence in patients with high-risk MDS. Long-term follow-up data demonstrate an overall DFS rate of 40%, similar to rates in patients who received intensive chemotherapy.53 A large retrospective review of MDS patients who underwent transplantation suggests that it is best to use SCT in low-risk patients at disease progression and in high-risk patients at diagnosis.54 Several groups have reported their experience with nonmyeloablative and reduced-intensity SCT, with an OS rate of up to 30% at 2 years and DFS rates of 55% at

1 year.55,56 Although the role of such therapy in treating this disease remains investigational, early data suggest high relapse rates in high-risk patients. A recent study suggests that administration of azacitadine before conventional SCT may lower posttransplantation relapse rates in high-risk MDS patients.57 Alternatively, a safety study of posttransplant low-dose azacitadine revealed good tolerability and detectable hypomethylation at a dosage as low as 8 mg/m2 for 5 days. At 5 months’ follow-up, none of the high-risk patients had relapsed.58 Further studies are required to evaluate whether this effect will translate into longterm improvements in DFS and OS.

Treatment Summary Treatment selection for MDS depends initially on whether the patient is a candidate for SCT (Figure 2). Such candidates may benefit from azacitidine or decitabine to reduce the abnormal cell burden before transplantation. Patients with low-grade disease are best managed with a trial of growth factors. Usually, 3 months of treatment are required to see a response. Subsequent therapy may include thalidomide or lenalidomide, although the latter is approved only for patients with the 5q– abnormality. Close attention to blood cell counts is necessary during the first 6 to 8 weeks of therapy with lenalidomide because severe but transient cytopenias may ensue. Patients who fail such therapy generally proceed to azacitidine or decitabine and may require as many as 6 cycles before a response is seen. Close blood cell count monitoring is recommended initially, and growth factor support may be very useful in the early months of treatment until the neutrophil count improves. As a practical matter, azacitidine is typically given by deep subcutaneous injection, with a needle change after mixing with diluent. This tends to reduce the local reactions that may occur. Arsenic trioxide may be useful in patients who have failed the preceding measures. It is essential to monitor electrocardiogram changes to avoid cardiac arrhythmias. Patients with a hypocellular marrow or with HLA-DR15 are most likely to benefit from immunosuppressive therapy. Patients with high-risk disease generally proceed directly to azacitidine or decitabine, with arsenic as a rescue therapy.

Conclusion Recent years have witnessed an evolution in our understanding of the pathophysiologic pathways involved in MDS. Many novel and targeted agents have been introduced into clinical trials in MDS, some with encouraging results. While supportive care continues to improve, we are also seeing the introduction of agents that are affecting the natural history of this group of diseases. As more agents are developed, the role of hematopoietic SCT will certainly continue to evolve. Improved classification systems and identification of risk groups will become more clinically relevant as clinicians gain a better understanding of the biology of this heterogeneous group of disorders.

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44. Raza A, Meyer P, Dutt D, et al. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood. 2001;98(4):958-965, PMID: 11493439.

26. FDA approves new drug for bone marrow disease. FDA News. May 19, 2004:4-56. 27. Rossetti JM. A step forward in the treatment of myelodysplastic syndrome. Community Oncol. 2005;Jan/Feb:16; www.community oncology.net. Accessed January 29, 2009. 28. Stenger M, Rossetti JM. Azacitidine in myelodysplastic syndrome. Community Oncol. 2005;Jan/Feb:14-15; www.community oncology. net. Accessed January 29, 2009. 29. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J Clin Oncol. 2002;20(10):2429-2440, PMID: 12011120. 30. Silverman LR, McKenzie DR, Peterson BL, et al. Response rates using International Working Group criteria in patients with myelodysplastic syndromes treated with azacitadine. Blood. 2005;106:abst 2526. 31. Lyons R, Cosgriff T, Modi S, et al. Results of the initial treatment phase of a study of three alternative dosing schedules of azacitidine (Vidaza) in patients with myelodysplastic syndromes (MDS). Blood. 2007;110:abst 819. 32. Fenaux P, Mufti G, Finelli S, et al. Azacitidine (AZA) treatment prolongs overall survival (OS) in higher-risk MDS patients compared with conventional care regimens (CCR): results of the AZA-001 Phase III study. Blood. 2007;110:abst 817. 33. List A, Fenaux P, Mufti G, et al. Effect of azacitidine (AZA) on overall survival in higher-risk myelodysplastic syndromes (MDS) without complete remission. J Clin Onc. 2008;26(suppl):abst 7006. 34. Gryn J, Ziegler Z, Shadduck R, et al. Treatment of myelodysplastic syndromes with 5-azacytidine. Leuk Res. 2002;26(10):893-897, PMID: 12163049. 35. Rossetti JM, Falke E, Shadduck R, et al. G-CSF increases hematological response among patients with myelodysplasia treated with azacitidine. Blood. 2006;108:abst 4868. 36. Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106(8):1794-1803, PMID: 16532500. 37. Kantarjian H, Oki Y, Garcia-Manero G et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007;109(1):52-57, PMID: 16882708. 38. Kantarjian HM, O’Brien S, Shan J, et al. Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome. Cancer. 2007; 109(2):265-273, PMID: 17133405. 39. Kuendgen A, Strupp C, Aivado M, et al. Treatment of myelodysplastic syndromes with valproic acid alone or in combination with alltrans retinoic acid. Blood. 2004;104(5):1266-1269, PMID: 15155466.

45. List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005;352(6): 549-557, PMID: 15703420. 46. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355(14):1456-1465, PMID: 17021321. 47. Raza A, Reeves J, Feldman E. Long-term clinical benefit of lenalidomide (Revlimid) treatment in patients with myelodysplastic syndrome without del 5q cytogenetic abnormalities. Blood. 2006;108:abst 250. 48. Maciejewski JP, Risitano AM, Sloand EM, et al. A pilot study of the recombinant soluble human tumour necrosis factor receptor (p75)-Fc fusion protein in patients with myelodysplastic syndrome. Br J Haematol. 2002;117(1):119-126, PMID: 11918541. 49. Giles FJ, Stopeck AT, Silverman LR, et al. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood. 2003;102(3):795-801, PMID: 12649163. 50. Kurzrock R, Albitar M, Cortes JE, et al. Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome. J Clin Oncol. 2004;22(7):1287-1292, PMID: 15051776. 51. Vey N, Bosly A, Guerci A, et al. Trisenox (arsenic trioxide) in patients with myelodysplastic syndromes: a Phase II multicenter study. J Clin Oncol. 2006;24(16):2466-2471, PMID: 16651646. 52. Runde V, de Witte T, Arnold R, et al. Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: early transplantation is associated with improved outcome. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 1998;21(3):255-261, PMID: 9489648. 53. Appelbaum FR, Anderson A. Allogeneic bone marrow transplantation for myelodysplastic syndrome: outcomes analysis according to IPSS score. Leukemia. 1998;12(suppl 1):S25-S29. 54. Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood. 2004;104(2):579-585, PMID: 15039286. 55. Ho AYL, Kenyon M, El-Hemaidi I, et al. Reduced-intensity allogeneic haematopoietic stem cell transplantation (HSCT) in 75 patients with myelodysplastic syndromes following conditioning with fludarabine, busulphan and alemtuzumab. Blood. 2003;102:78a. 56. Alyea EP, Kim HT, Cutler C, et al. AML and MDS treated with nonmyeloablative stem cell transplantation: overall and progression free survival comparable to myeloablative transplantation. Blood. 2003;102:79a.

40. Marcucci G, Bruner RJ, Binkley PF, et al. Phase I trial of the histone deacetylase inhibitor depsipeptide (FR901228) in acute myeloid leukemia. Blood. 2002;100:86a.

57. Field T, Perkins J, Alsina M. Pre-transplant 5-azacitidine may improve outcome of allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome. Blood. 2006;108:abst 3664.

41. Silverman LR, Verma A, Odchimar-Reissig R, et al. A phase I/ II study of vorinostat, an oral histone deacetylase inhibitor, in combination with azacitidine in patients with the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Initial results

58. Soriano A, Champlin R, McCormick G. Maintenance therapy with 5-azacitidine after allogeneic stem cell transplantation for acute myelogenous leukemia and high-risk myelodysplastic syndrome: A dose and schedule finding study. Blood. 2006;10:abst 3668.

I n d e p e n d e n t ly d e v e l o p e d b y M c M a h o n P u b l i s h i n g

See the patient guide for this review at clinicaloncology.com

FDA NEWS

Clinical Oncology News • JANUARY/FEBRUARY 2009

continued from page 3 

Mozobil Gets Green Light

he FDA has granted marketing approval for plerixafor injection (Mozobil, Genzyme), a drug intended to be used in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the bloodstream for collection and subsequent autologous transplantation in patients with non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). In addition, the product has been granted orphan drug designation. Plerixafor is designed to mobilize hematopoietic stem cells from the bone marrow into the bloodstream where they can be collected, making it more likely for patients with certain types of cancers to proceed to transplantation. In the pivotal trials of plerixafor, 59% of patients with NHL who received plerixafor and G-CSF

collected the target number of at least 5 million stem cells/kg of body weight in four or fewer apheresis sessions compared with 20% of placebo patients. The median number of days to reach the target cell count was three days for the plerixafor group and not evaluable in the placebo group. Of patients with MM, 72% who received plerixafor and G-CSF collected the target number of at least 6 million stem cells/kg of body weight in two or fewer apheresis sessions compared with 34% of placebo patients. The median number of days to reach the target cell count was one day for the plerixafor group and four days for the placebo group. The target numbers of stem cells in the pivotal studies were chosen based on literature that suggests that reaching these targets can help to facilitate engraftment. Updated 12-month followup findings showed that graft durability rates for patients in the plerixafor plus

G-CSF and in the placebo plus G-CSF arms were comparable.

did not. The most frequently reported adverse reactions were diarrhea, fatigue, nausea, swelling of the feet, decreased red blood cell counts, rash, vomiting and abdominal pain.

Gleevec Gets New Indication

he FDA has approved imatinib mesylate (Gleevec, Novartis) for a new indication—in patients after surgical removal of a gastrointestinal stromal tumor (GIST). The efficacy of imatinib was established in a clinical trial in which patients received either imatinib or a placebo for one year after surgical removal of the tumor. The optimal treatment duration is not known. There were significantly fewer recurrences of GIST in patients who received imatinib than in patients who

Oral Second-line Treatment for CLL Approved

he FDA has approved a tablet formulation of fludarabine phosphate (oral fludarabine, Antisoma) as a second-line treatment for chronic lymphocytic leukemia (CLL). Antisoma, a British company with a location in Boston, plans to make the drug available to patients in the United States through a commercialization deal. Talks are ongoing with a number of companies that have established oncology marketing operations in the United States. Antisoma expects to conclude a deal early in 2009.

WEB EXCLUSIVES To read the following stories, visit www.clinicaloncology.com and click on “Web Exclusives” underneath “Departments” on the left hand navigation bar.

Protecting Hearing Loss in Children: Two-Dose Amifostine Approach Works

FDA Strengthens Policies on Transparency, Public Disclosure for Advisory Committees

When it comes to preventing cisplatin-induced hearing loss in children, timing is everything. When a bolus dose of the cytoprotectant amifostine was given to children with medulloblastoma immediately before and during cisplatin therapy, the regimen significantly reduced the risk for severe hearing loss.

The FDA has initiated several improvements to its policies and procedures for its advisory committees in an attempt to make their decisions more public, open and transparent.

Elevated Glucose Levels Predate Pancreatic Cancer Diagnosis New data show that fasting blood glucose goes up nearly two years prior to a pancreatic cancer diagnosis, a finding that suggests an opportunity to eventually screen patients for pancreatic cancer based on high blood sugars.

HEMATOLOGIC DISEASE Chronic Lymphocytic Leukemia

NEW STANDARD

continued from page 1 

42.8

PFS in Months

in Germany. Dr. Hallek said that as “CLL is a disease of the elderly, safety is important,” and that the addition of rituximab to FC (FCR) was reasonably well tolerated even in patients older than age 70. The most significant difference in tolerability was an increased rate of neutropenia in patients receiving FCR, but the addition of rituximab did not increase the risk for infections. In the study conducted by the German CLL Study Group, 817 patients with previously untreated but advanced CLL were randomized to six courses of FC or FCR. The doses of fludarabine (25 mg/m2) and cyclophosphamide (250 mg/m2), administered on days 1 and 3 of each 28-day cycle, were the same in both study arms. In the FCR arm, rituximab was administered in a dose of 375 mg/m2 on day 0 of the first cycle and then in a dose of 500 mg/m2 on day 1 of the five subsequent cycles. The complete response (CR) rates were 44.5% in patients who received FCR compared with 22.9% in patients on FC (P<0.01). Although the partial response

FCR

32.3 30 20 10 0

Figure. Comparison of progression-free survival.

‘The trial demonstrates that the addition of rituximab is superior for the proportion of patients who achieve a complete response and for the median length of the progression–free survival.’ —Michael Hallek, MD

FC, fludarabine and cyclophosphamide; FCR, fludarabine, cyclophosphamide and rituximab

rates were higher in the FC group (50.4% vs. 39.6%; P<0.01), the rates of progressive disease (3.3% vs. 8.1%; P<0.01) remained significantly lower on FCR, indicating that the addition of rituximab shifted partial responders to complete responders. More importantly, the 10-month increase in progression-free survival after a median observation time of 25.5 months favoring the FCR regimen (42.8 vs. 32.3 months; P<0.000007) was highly statistically significant. Dose reductions were more common in the FCR arm, but a greater proportion of FCR than FC patients completed all six

cycles of therapy. When patients were stratified by age, adverse events were more common in those 70 or older than in patients younger than 70. Both regimens were equally tolerated in older patients. The difference in the two arms in terms of objective response rate was not significant (92.8% vs. 85.2%), but objective response rate appears to be far less important than CR for predicting long-term benefits. “Several studies including our own suggest that patients who achieve a CR clearly have a longer interval until disease progresses,” Dr. Hallek said. Although no dissent was voiced about the role of FCR as a new standard for

untreated, physically fit patients with advanced CLL, there was some modest controversy stimulated by a discussion of dose. According to Kanti R. Rai, MD, chief, Division of Hematology/Oncology, Long Island Jewish Medical Center, New Hyde Park, N.Y., the standard dose of rituximab has been 375 mg/m2 per cycle and should remain so until a study has proven a relative advantage for the 500 mg/m2 employed in the final five cycles. Dr. Hallek disagreed. He argued that the 500 mg/m2 dose of rituximab had already been established in Phase II CLL studies led by Michael J. Keating, MD, professor of medicine, M.D. Anderson Cancer Center, Houston. On the premise that larger drug exposure may be expected to provide greater anti-tumor activity, he did not see the rationale for moving to a lower and untested dose when results of this study indicated the higher dose was well tolerated. He maintained this position even though Dr. Keating joined the discussion and admitted that the decision to increase the dose from 375 to 500 mg/m2 in cycles 2 to 6 in the Phase II studies “was not based on any data.” —Ted Bosworth

Identification of patients with lower-risk MDS * and a poor prognosis

Clinical challenge: MDS treatment selection Approximately two-thirds of patients with myelodysplastic syndromes (MDS) have lowerrisk disease, defined as Low- and Intermediate-1–risk per IPSS.* However, existing prognostic tools for MDS do not differentiate those patients with lower-risk disease who have a poor prognosis.1

The International Prognostic Scoring System (IPSS) The IPSS helps to estimate the overall survival of patients with MDS. One limitation of the IPSS is that it does not identify patients with lower-risk MDS and poor prognosis who may be candidates for early therapeutic intervention. Certain patients classified with lower-risk MDS by the IPSS system may benefit from the “wait and watch” approach currently used by many physicians; but some patients with lower-risk MDS have a worse prognosis and may benefit from active therapy.1

A proposed prognostic scoring system for patients with lower-risk MDS This scoring system stratified patients with lower-risk MDS into 3 risk categories and evaluated the characteristics associated with survival.1 Following a multivariate analysis, the parameters below were found to be associated with decreased survival1: • Platelets (<50 x 109/L; 50–200 x 109/L) • Age (≥60 years) • Unfavorable cytogenetics† • Hemoglobin (<10 g/dL-1) • Percent of marrow blasts (≥4%–10%) The authors recommend the validation of this model by confirming the results in another patient population. Until these results are validated, the main use of this model will be to assign patients with poor prognoses to investigational clinical trials.1

Benefit of proposed scoring system This scoring system may help to identify those patients with lower-risk MDS who may benefit from early active therapy. Using this system, the authors determined that of the 673 patients in Risk Categories 2 and 3, 80% had a poor prognosis if untreated. They believed that the need to treat this population was further supported by the number of patients who died (90%) before their disease transformed to acute myelogenous leukemia.1 Results from 856 patients showed 31% of patients with a median survival of 14.2 months (1.2 years) (Risk Category 3), 48% with a median survival of 26.6 months (2.2 years) (Risk Category 2), and 21% with a median survival of 80.3 months (6.7 years) (Risk Category 1).1‡

Estimated Survival of Lower-risk MDS Patients by Risk Category1

Assigned Score

‡

0-2 3-4 ≥5

Cumulative Proportion Alive

1.0

Survival Total (%) Dead (No.) Median (mo) 4-yr (%) 182 (21) 408 (48) 265 (31)

43 212 173

80 27 14

65 33 7

0.8 0.6 0.4 0.2 0 0

Months from Referral Reprinted with permission from Garcia-Manero et al (2008).1

A study indicated that it is possible to identify those lower-risk MDS patients with a poor prognosis (those in Risk Categories 2 and 3) who may benefit from active therapy. The proposed prognostic tool based on the IPSS classification of this specific patient type may have a significant impact on1: • MDS treatment approaches • Benefits of different therapies for lower-risk MDS • Clinical trial development • Targeted interventions

This proposed model may have significant implications for clinical trial design and ultimately for the treatment decision process for patients with lower-risk MDS.1

*MDS, myelodysplastic syndromes; lower-risk MDS, Low- and Intermediate-1–risk per International Prognostic Scoring System. †In this scoring system, only diploid and 5q were considered favorable cytogenetics; all others were considered unfavorable.1 ‡Category scoring based on: Category 1 = score 0-2, Category 2 = score 3-4, Category 3 = ≥5. Assigned score: age (≥60 years) = 2; platelets (<50 x 109/L) = 2, platelets (50–200 x 109/L) = 1; hemoglobin (<10 g/dL-1) = 1; bone marrow blasts (≥4%–10%) = 1; unfavorable cytogenetics = 1.1 Reference: 1. Garcia-Manero G, Shan J, Faderl S, et al. A prognostic score for patients with lower risk myelodysplastic syndrome. Leukemia. 2008;22(3):538-543.

01/09

CELG08070T

HEMATOLOGIC DISEASE

Clinical Oncology News • JANUARY/FEBRUARY 2009

Multiple Cancers

Experts Highlight ASH Meeting News Advisory board members of Clinical Oncology News offer their views on practice-changing abstracts and noteworthy news presented at the recent annual meeting of the American Society of Hematology. Richard Stone, MD, highlights news on acute leukemias, chronic myelogenous leukemia (CML), and myelofibrosis. Dr. Stone is clinical director of the Adult Leukemia Program, Dana-Farber Cancer Institute, and is an associate professor of medicine, Harvard Medical School, both in Boston.

Clofarabine’s Role in Older Adults With AML

lder adults with acute myeloid leukemia (AML) fare poorly due to a combination of impaired tolerance of chemotherapy and intrinsically resistant disease biology. The complete remission rate for those “fit” enough to receive chemotherapy is no more than 50%, with only 20% of patients achieving remission and experiencing longterm disease-free survival. This dismal outcome has been replicated in multiple trials over the years in which induction chemotherapy has consisted of an anthracycline for several days plus seven days of cytarabine or a variant. Clinicians have wondered whether it might be possible to achieve at least as good a result with a lower level of treatment-related mortality. A nucleoside analog, clofarabine (Clolar, Genzyme), is approved in the United States for treatment of relapsed childhood acute lymphoblastic leukemia (ALL). Previous trials have shown that this drug alone or in combination with cytarabine has activity in patients with AML. At the ASH meeting (abstract 558), investigators presented an update of results from a Phase II trial in which clofarabine was given at a dose of 30 mg/m2 per day for five days to patients with AML not likely to benefit from standard induction chemotherapy. To fall into this specific category, patients had to be older than 70 years, have a performance status of 2, have a history of antecedent hematologic abnormality or have nonfavorable cytogenetics at diagnosis. These “risk factors” were based on data from a large M.D. Anderson series of older patients with AML treated with standard induction chemotherapy. The results suggested that the drug was effective in older adults with AML. The overall complete remission rate was 46%, including 8% who achieved remission but did not achieve count

Overall complete remission rate, %

40 30 20 10 0

Figure 1. AML patients on clofarabine. recovery (Figure 1). This remission rate was comparable to what would have been achieved with standard 3+7 chemotherapy in an unselected group of older adults. The number of risk factors did not grossly affect the remission rate. The 30-day all-cause mortality was 10%, approximately half of the rate expected with standard chemotherapy. Whether or not this level of response will mandate approval for this clofarabine regimen in this type of patient remains to be seen. The FDA will take remission duration and quality-of-life factors into account when considering approval. Moreover, the Eastern Cooperative Oncology Group is embarking on a trial that will compare treatment with 3+7 chemotherapy with treatment with clofarabine in adults older than 60 years with previously untreated AML.

Can CML Patients Take An Imatinib Holiday?

aregivers and patients are delighted that the use of imatinib (Gleevec, Novartis) in chronic myeloid leukemia leads to a rapid reduction in disease burden, with as many as 82% of previously untreated chronic phase patients achieving a complete cytogenetic response (based on the seven-year IRIS [International Randomized Study of Interferon vs. STI571] trial follow-up

data; ASH abstract 186). Nonetheless, because patients are required to take the drug for the remainder of their life and the long-term consequences of this is unknown, many patients have questioned whether it is possible to take a drug holiday. In the past, clinicians have been understandably reluctant to allow patients to do so, given the fact that many patients who have stopped the drug (e.g., to become pregnant) have relapsed and no prospective trials have dealt with the issue. François-Xavier Mahon, MD, from Hématopoïèse leucémique, Université Victor Segalen CHU de Bordeaux, in France, reported preliminary results from the “stop imatinib” study conducted in France beginning in July 2007. To enter the study, patients had to have taken imatinib for at least three years and have a sustained complete molecular remission. Fifty patients in this state of profound response discontinued imatinib. Of the 19 patients who relapsed during the relatively short (around six-month) follow-up period, eight had received prior interferon. A higher percentage of the prior interferon users remained disease-free. Although very preliminary, it seems that prior interferon treatment reduced the risk for relapse after imatinib was stopped. Given the short follow-up and the small number of patients, it is very difficult to reach any conclusions. Although the prior use of interferon could have provided an “immunologic milieu” making it less likely for disease relapse after imatinib therapy was halted, it is possible that other factors might have been more important. It might be more interesting to use interferon after stopping imatinib to deal with the residual undetectable leukemic burden that might be susceptible to immunologic manipulation. Investigators could conduct a study that stopped imatinib in all patients and then randomized the patients to interferon or observation. In summary, although some patients with very low CML disease burden levels were able to stop imatinib for a few months, discontinuing imatinib cannot be considered standard of care in any subset of patients at this time. More research on the potential benefit of interferon is needed. In this regard, the ASH meeting yielded further data from France (abstract 183) suggesting that early treatment with imatinib plus

pegylated interferon might be beneficial and from Germany (abstract 184) in which the benefit of early interferon was less clear.

What Is Decitabine’s Role in Older Patients With AML?

he DNA hypomethylating agents are probably the most commonly used class of drugs to treat patients with myelodysplastic syndromes (MDS). Both 5-azacitidine (75 mg/m2 for seven days every 28 days) and decitabine (Dacogen, Eisai) (approved dose is 15 mg/m2 every eight hours for nine doses every six weeks) are associated with complete remission and hematologic improvement in patients with MDS. Recently, Kantarjian et al conducted a Phase IIB Bayesian randomized trial and determined that a dose of 20 mg/m2 per day of decitabine for five days yielded a 39% remission rate in patients with MDS (Blood 2007; 109:52-57, PMID: 16882708). Amanda Cashen, MD, assistant professor in the Department of Medicine, Oncology Division, Washington University, St. Louis, presented an abstract (560) describing the treatment of 55 patients aged 60 years and older with newly diagnosed, untreated AML who were not candidates for standard induction chemotherapy with decitabine (20 mg/m2 over one hour for five consecutive days every four weeks). The complete remission rate was 26%; 13 (24%) had a complete morphologic remission and one (2%) had a complete remission with incomplete blood count recovery (Figure 2). Although the numbers were small, the complete remission rate did not seem to be affected by whether or not the patient had prior MDS or poor cytogenetics. The median survival was 9.6 months, not different from what one would expect in a comparable group of older adults with AML treated with induction chemotherapy. The 30-day mortality rate was only 4%, which certainly compares favorably to the approximately 20% mortality rate seen in patients treated with standard induction chemotherapy. The treatment field of AML in older adults is apparently moving toward the use of single agents with less toxicity than the 3+7 regimen, but it remains

HEMATOLOGIC DISEASE

Clinical Oncology News • JANUARY/FEBRUARY 2009

Multiple Cancers

JAK2 Inhibitors Show Promise for Myelofibrosis

he critical discovery that an activating mutation of the JAK2 tyrosine kinase (JAK2V617F) is found in virtually all patients with polycythemia vera and many patients with other myeloproliferative disorders, including essential thrombocytosis and myelofibrosis, prompted an aggressive search for a JAK2 inhibitor. Investigators hoped that such JAK2 inhibitors might have the same type of disease-remitting activity seen with the tyrosine kinase inhibitors in chronic myeloid leukemia (caused by the activated bcr-abl tyrosine kinase). At the 2008 ASH meeting, investigators provided updates about several potential JAK2 inhibitors used for patients with myelofibrosis. Investigators presented results of a Phase I dose escalation study of TG10138, an orally bioavailable selective JAK2 inhibitor in patients with myelofibrosis (abstract 97). Doses of up to 520 mg per day were tolerable. Notably, there were no dose-limiting toxicities or significant nonhematologic side effects up to that dose level. Patients frequently experienced a decrease in spleen size and in some

Jennifer R. Brown, MD, PhD, highlights news regarding chronic lymphocytic leukemia (CLL), Hodgkin’s disease, non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). Dr. Brown is an attending physician with the CLL & Lymphoma Program, Dana-Farber Cancer Institute, and an assistant professor of medicine at Harvard Medical School, both in Boston.

New Standard Identified for CLL

he German Chronic Lymphocytic Leukemia Study Group (GCLLSG) reported the initial results of their CLL8 study, which randomized previously untreated patients with CLL and a good performance status to receive six cycles of either fludarabine (Fludara, Berlex) and cyclophosphamide (FC) or fludarabine, cyclophosphamide and rituximab (Rituxan, Biogen Idec/Genentech; FCR) (abstract 325). The overall response rate (ORR),

complete response rate and progression-free survival (PFS) were all significantly improved with FCR, with manageable toxicity. The 10-month increase in PFS after a median observation time of 25.5 months favoring the FCR regimen (42.8 vs. 32.3 months; P<0.00007) was highly statistically significant (Figure 3). Benefits primarily accrued to early-stage patients, for unclear reasons that are currently being investigated. Analysis of prognostic markers in the CLL8 study found that patients with deletion of chromosome 17p continued to have poor PFS and

Without any truly effective therapy for patients with advanced myeloproliferative disorders, such as those with myelofibrosis, there is great interest in the clinical development of JAK2 inhibitors. Thus far, spleen reductions and improvement in constitutional symptoms have been seen with all of these agents, although differences in pharmacology and toxicity may ultimately determine which of these agents becomes available for widespread use.

Can Older Adults With AML Benefit From Androgens?

provocative trial presented by the GOELAMS French Leukemia Cooperative Group (abstract 556) suggested that there may be value in adding androgens to postremission therapy in older adults with de novo AML. In this trial, patients older than 60 years with AML received standard induction chemotherapy (plus lomustine [CeeNu, Bristol-Myers Squibb Oncology]); those who achieved remission received six fairly intensive consolidation courses interspersed with low-dose antimetabolite therapy. Patients were randomized to receive or not receive norethandro-lone at 10 to 20 mg per day according to body weight, beginning 20 to 30 days after induction chemotherapy and continuing throughout the two-year maintenance therapy. Although the complete remission, leukemia-free and overall survival rates were not affected by the use of the androgen drug, if one looks

Figure 2. AML patients on decitabine. only at the time period starting one year from diagnosis, there is a statistically significant leukemia-free and overall survival benefit associated with the use of the androgen. Interestingly, the beneficial effects of the drug were much more pronounced in males and in patients with a low white cell count at diagnosis. This study is certainly not conclusive. An unusual type of analysis was required to show that the androgen was beneficial. The benefit was seen only in patients who were in remission for one year, possibly suggesting some degree of suppression of relapse in patients with minimal levels of disease. The intriguing finding that the benefit was mainly in those with low white cell counts and in men suggests that perhaps this drug was replacing testosterone. Unfortunately, no androgen levels were measured to investigate this hypothesis. Although this prospective randomized trial certainly does not support the routine use of androgens, it at least suggests that more research in this area is warranted.

PCR and FCR Tested in Community Setting

Complete Remission Rate, %

cases an improvement in constitutional symptoms. This drug certainly has the potential to benefit patients with myelofibrosis and is being studied further. Other JAK2 inhibitors for which early results were reported at this meeting included XL019 (abstract 98), CEP701 (abstract 99) and INCB018424 (abstract 1760). Although all three drugs have been associated with spleen-size reduction in patients with myelofibrosis, there are a few distinguishing features. XL019 was associated with reversible, low-grade peripheral neuropathy in seven of nine patients treated at daily doses greater than 100 mg. Although spleen reduction was seen at lower doses, whether or not this drug will be developed further is unclear. CEP-701 is being tested extensively in patients with FLT3 mutant acute myeloid leukemia, but because of its ability to inhibit JAK2, it is also being tested in polycythemia vera and essential thrombocytosis. INCB018424 decreases spleen size and clinical symptoms in patients with myelofibrosis. An abstract at this year’s ASH meeting detailed 34 myelofibrosis patients treated for at least two months with 25 mg twice daily. There was a correlation between resolution of splenomegaly and decrease in anorexia and early satiety. This improvement was associated with an increase in leptin levels. The authors hypothesized that improved nutritional status of patients treated with INCB01824 may reflect the ability of the JAK2 inhibition to decrease splenomegaly and decrease the synthesis of proinflammatory cytokines.

FCR

42.8

40 32.3

Months

unclear whether the disease-free and overall survival rates will be sufficient to justify such an approach. This relatively small Phase II trial seemed to support further testing of decitabine against either 3+7 chemotherapy in a fit group of patients or against supportive care or low-dose ara-C in less fit patients.

30 20 10 0

Figure 3. Comparison of progression-free survival. FC, fludarabine and cyclophosphamide; FCR, fludarabine, cyclophosphamide and rituximab

overall survival (OS) following therapy with FCR (abstract 781). Patients with deletion of chromosome 11q, however, had a worse PFS with FC, but after FCR had a PFS comparable to other more neutral cytogenetic abnormalities, suggesting that this group may derive particular benefit from treatment with FCR. (See story on page 1.)

he U.S. Oncology Group conducted a randomized trial in patients with CLL comparing FCR with pentostatin (Nipent, SuperGen), cyclophosphamide and rituximab (PCR) in a community-based setting (abstract 327). The trial found that both regimens had significant and comparable toxicity, with only 50% of patients completing the planned therapy (28% of FCR and 27% of PCR patients discontinued because of adverse effects). As of May 2008, 10 patients receiving the FCR regimen and 17 patients receiving PCR have died; two deaths (pneumonia and sepsis) with FCR were related to infection. The ORR was 59.8% in patients receiving FCR and 46.9% in patients receiving PCR. The CR rate was 17% in patients receiving FCR and 7% in patients receiving PCR, but this was not significantly different (P=0.07). Response rates were significantly lower than those reported from academic medical centers. Although both chemotherapy schedules continued on page 20 

HEMATOLOGIC DISEASE

Clinical Oncology News • JANUARY/FEBRUARY 2009

Multiple Cancers

New Drug Sparks Hope For Refractory CLL

LL patients with fludarabine-refractory disease who have failed alemtuzumab (double refractory [DR]) or who have bulky adenopathy (bulky fludarabine-refractory [BFR]) have few therapeutic options available to them. An international trial of ofatumumab (HuMax-CD20, Genmab/GlaxoSmithKline), a human monoclonal antibody that targets a unique CD20 epitope, found that ofatumumab resulted in a 51% ORR (abstract 328) in DR disease patients and a 44% ORR in BFR disease patients (Figure 4). Ofatumumab may prove to be an effective therapy in refractory CLL patients.

one complete response. Neutropenia and hypertension were the principal toxicities. In the coming years, development of this drug will continue, and an exciting array of other targeted therapies will follow.

Pralatrexate Promising For T-cell Lymphomas Overall response rate Complete response rate

Rate of Response

continued from page 19 

differed from the established regimens, this study nonetheless provides a realistic estimate of the safety and efficacy of these regimens in a community setting.

Figure 5. Outcomes of pralatrexate in relapsed and refractory peripheral T-cell lymphomas.

Double refractory CLL patients Bulky fludarabine refractory patients

Overall Response, %

51 50

40 30 20 10 0

Figure 4. Patients with CLL taking ofatumumab.

Role of Lenalidomide in CLL Unclear

he use of lenalidomide (Revlimid, Celgene) in CLL has attracted attention because of reported response rates of 40% to 50% in relapsed patients. Two studies (abstracts 44 and 45) looked at single-agent lenalidomide for the initial therapy of CLL and found that the drug can cause severe tumor flare and/ or tumor lysis syndrome, so that therapy must be started at a very low dose (2.5 mg) with tumor lysis precautions and escalated very slowly. Hematologic toxicity was significant. Response rates were disappointingly low for an upfront therapy. The appropriate role, if any, for lenalidomide in CLL is currently unclear.

Oral Drug Targets SYK

n a plenary session, investigators reported promising activity in lymphoma of an oral targeted inhibitor of SYK, a tyrosine kinase involved in B-cell receptor signaling (abstract 3). In the Phase I component of the study, the dose-limiting toxicity was neutropenia. In the Phase II component, response rates of 55% were observed in CLL/SLL, and 22% in diffuse large B-cell lymphoma (DLBCL), including

he PROPEL study investigated pralatrexate (Allos Therapeutics), a novel targeted antifolate, for the treatment of relapsed and refractory peripheral T-cell lymphomas (abstract 261). Pralatrexate resulted in an ORR of 27%, with 10% complete responses, in a very challenging patient population (Figure 5). Thrombocytopenia and mucositis were the most frequent adverse events. This drug may add to the armamentarium for this type of lymphoma in the future.

FL Study Disappoints

diotype-specific vaccines have generated much excitement in B-cell lymphomas, and three randomized trials have been performed in the past several years. A Phase III study (abstract 236) in treatment-naïve or rituximab-sensitive follicular lymphoma patients included initial rituximab therapy followed by randomization to patient-specific vaccine or placebo, with granulocyte macrophage-colony stimulating factor (GMCSF; abstract 236). A significant PFS advantage was seen in the placebo arm, which on further analysis was due to an increased proportion of patients with high Follicular Lymphoma International Prognostic Index (FLIPI) score in the patient-specific vaccine group. When FLIPI was taken into account, no difference in time to progression was observed between the groups. Given the promising Phase II results, these new results are disappointing, and the reason for them is unclear.

Role of FDG-PET in DLBCL Still Undefined

he role of fluorodeoxyglucose–positron emission tomography (FDG-PET) in the interim evaluation of therapy for DLBCL is unclear. In one study (abstract

371), investigators prospectively evaluated the role of PET scanning after two cycles of rituximab + cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) in DLBCL patients, and found that the interim scans were not predictive of PFS, although the posttreatment PET scans were highly predictive. In another study (abstract 372), investigators conducted a central and external review of interim PET scans obtained on ECOG 3404, in which a positive interim PET results in change of therapy from R-CHOP to R + ifosfamide, carboplatin and etoposide. This study found that interobserver agreement was only moderate (about two-thirds of cases), and areas of disagreement typically related to bone or splenic disease or the nature of residual uptake. Further research is needed to define the role of interim PET.

Additional RT No Help For Some DLBCL

study compared the outcomes of elderly DLBCL patients with initially bulky disease who received six cycles of R-CHOP-14, either followed by planned radiation therapy (RICOVER60 trial), or without planned radiation therapy (subsequent Phase II study; abstract 584). In patients with initially bulky disease, the event-free survival rate was lower without radiation therapy, due to the subgroup of patients who had partial response (PR) after six cycles of R-CHOP-14. Patients with complete response (CR) had similar outcomes with or without radiation therapy, suggesting that additional radiotherapy was not helpful for those with CR following R-CHOP-14, but may be helpful for those with PR.

Stanford V and ABVD Regimens Face Off

bstract 370 reports on a U.K. Lymphoma Group study that randomized newly diagnosed Hodgkin’s lymphoma patients to receive Stanford V or doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) and found no difference in outcome. Half of the patients had early-stage disease and radiation therapy was used extensively, in 62% of patients overall, which is likely important, particularly in Stanford V.

Predictive Power of PET Scan Determined

wo studies (abstracts 775 and 776) evaluated the predictive power of a negative PET scan following salvage therapy before autologous stem cell transplantation. In the first study, patients who had improvement by computed tomography (CT) with ongoing PET positivity following their first salvage regimen went on to receive a second salvage regimen; those who

became PET-negative with the second salvage regimen had outcomes similar to the group who became PET-negative with one salvage regimen. The second study looked retrospectively at patients receiving salvage therapy before autologous stem cell transplantation, and found that a residual abnormality on CT predicted a worse OS than patients with no residual abnormality, but that those patients whose functional imaging (PET or gallium) remained positive had a markedly worse outcome than either of the other groups.

VISTA Trial Updated

he VISTA trial compared bortezomib (Velcade, Millenium Pharmaceuticals)-melphalan-prednisone (VMP) with melphalan-prednisone (MP) in untreated MM patients who were not candidates for autologous stem cell transplantation (abstract 650). VMP was well tolerated and improved time to next therapy and OS at three years (72% vs. 59%). Patients could be re-treated with bortezomib-based therapy with good response or treated with thalidomide or lenalidomide combinations at disease progression.

VMP Regimens Studied

he study described in abstract 651 compared VMP with bortezomibthalidomide-prednisone in patients with MM and found similar efficacy but higher toxicity in the thalidomide arm, especially cardiac events, suggesting that lenalidomide may be a preferred partner in bortezomib combinations. In another study in MM patients (abstract 652), thalidomide was added to VMP and improved response rates, but required a decrease in bortezomib to weekly dosing to decrease the incidence of grade 3-4 neuropathy.

Phase I Studies Test Regimens for MM

Phase I study of the combination of lenalidomide, bortezomib and dexamethasone in previously untreated patients with MM established the optimal doses to be 25 mg on days 1-14, 1.3 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle and 20 mg on the day of bortezomib and one day after, respectively (abstract 92). Including the Phase II portion of the study, the response rate at those doses was 100%, despite adverse cytogenetics or ISS stage III disease. Another Phase I study in newly diagnosed MM added cyclophosphamide at escalating doses to lenalidomide (15 mg on days 1-14), bortezomib (as in abstract 92) and dexamethasone (40 mg on days 1, 8, and 15 of a 21-day cycle), and found that cyclophosphamide was tolerated at the highest dose of 500 mg/m2 orally on days 1 and 8. The ORR was 100%. These regimens deserve further study in clinical trials.

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ClINICAl ONCOlOGy NEWS • JANUARy/FEBRUARy 2009

Individualizing Cancer Care in the Era of Evidence-based Treatment

Part 4: Breast Cancer Release Date: December 1, 2008 Expiration Date: January 31, 2010

NEEDS STATEMENT Breast cancer accounts for approximately 40,000 deaths annually in US women. Prognostic factors predictive of survival include age, race, performance, stage at diagnosis, hormone receptor status, tumor grade, and histology, and human epidermal growth factor receptor type 2 (HER2/neu) status. These factors also may be used to guide treatment decisions. Combination therapy often represents the best treatment modality based on studies showing that this approach is beneficial in reducing micrometastasis and tumor bulk and potentially extends survival. A number of combination and single-agent regimens are recommended for possible adjuvant use and may be considered for preoperative (neoadjuvant) use as well. This is the fourth of a 4-part series that reviews the current standard of care for several tumor types. Through individual patient case studies and expert physician and nurse commentary, the focus is not only on treatment efficacy but also on important supportive care topics. Oncology nurses are in a unique position to provide supportive care and minimize the risks associated with therapy. Nurses and oncologists alike must maintain up-todate knowledge of specific agents and clinical profiles, counsel patients about expected side effects and those that should be reported, and provide necessary treatment.

AUTHORS William J. Gradishar, MD, FACP Professor of Medicine Director, Breast Medical Oncology Program Director, Hematology/Oncology Fellowship Robert H. Lurie Comprehensive Cancer Center Northwestern University Feinberg School of Medicine Chicago, Illinois Dr. Gradishar has no relevant commercial interests to disclose.

FACULTY

Memorial Sloan-Kettering Cancer Center New York, New York Dr. Kline has no relevant commercial interests to disclose.

ACCREDITATION STATEMENTS Physician: This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of AKH Inc. and Applied Clinical Education. AKH Inc. is accredited by the ACCME to provide continuing medical education for physicians. AKH Inc. designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Nurse: AKH Inc. is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC-COA). AKH Inc designates this educational activity for 1.0 contact hour (0.1 CEU). Accreditation applies solely to educational activities and does not imply approval or endorsement of any commercial product by the ANCC-COA.

LEARNING OBJECTIVES At the completion of this educational activity, participants should be able to: 1. Identify treatment options for patients with HER2-positive advanced breast cancer. 2. Discuss specific characteristics of both tumors and patients that may guide treatment selection for breast cancer. 3. Discuss the toxicities and supportive care issues related to therapy for breast cancer.

TARGET AUDIENCE This activity is intended for physicians, nurses, and other health care professionals who treat patients with breast cancer or are interested in the topic.

Chair Robert Dreicer, MD, FACP Chair, Department of Solid Tumor Oncology Taussig Cancer Institute Cleveland Clinic Professor of Medicine Cleveland Clinic Lerner College of Medicine Cleveland, Ohio Dr. Dreicer discloses that he has served on the speakers’ bureau of Sanofi-Aventis and the advisory committees of AstraZeneca and Lilly.

CONFLICT-OF-INTEREST STATEMENT

Nurse Commentary Nancy Kline, RN, PhD, CPNP, FAAN Director of Nursing Evidence-Based Practice and Research

This educational activity contains discussion of published and/ or investigational uses of chemotherapeutic and biologic agents for the treatment of breast cancer. Some uses of these agents have not been approved by the FDA. Please refer to the official

Introduction Robert Dreicer, MD, FACP Even in an era when breast cancer treatment consisted of systemic therapy options such as cyclophosphamide, methotrexate, doxorubicin, 5-fluorouracil (5-FU), and tamoxifen, medical oncologists were still faced with the challenge of making optimal treatment and management recommendations when faced with the seemingly infinite manifestations of breast cancer. Despite the ever increasing understanding of the biology of breast cancer and the development of a new generation of therapeutic agents, the complexity of management decisions is still ever increasing. Dr. William Gradishar, director of the breast oncology program at Northwestern University, offers 2 representative cases of metastatic disease that illustrate several aspects of the challenges clinicians face in the management of this fascinating and difficult neoplasm.

Case 1: HER2-positive, ER/PgR-negative Breast Cancer William J. Gradishar, MD, FACP A 44-year-old woman, previously diagnosed with early-stage breast cancer, presents for a second opinion

It is the policy of AKH Inc. to ensure the independence, balance, objectivity, scientific rigor, and integrity in all of its continuing education activities. The faculty must disclose to the participants any significant relationships with commercial interests whose products or devices may be mentioned in the activity or with the commercial supporter of this continuing education activity. Identified conflict of interest is resolved by AKH prior to accreditation of the activity.

prescribing information for each product for discussion of approved indications, contraindications, and warnings.

ESTIMATED TIME OF COMPLETION This activity should take approximately 1 hour to complete.

METHOD OF PARTICIPATION There are no fees for participating in and receiving credit for this activity. The participant should, in order, read the objectives and monograph and answer the multiple-choice post-test. Participation is available online at CMEZone.com (availability may be delayed from original print date). Enter the project number “IP0861” in the keyword field to directly access this activity and receive instantaneous participation. Or, complete the answer sheet with registration and evaluation on page 26 and mail to: AKH Inc., PO Box 2187, Orange Park, FL, 32067-2187; or fax to (904) 215-0534. Statements of participation will be mailed/e-mailed approximately 4 weeks after receipt of the mailed or faxed submissions. A score of at least 70% is required to successfully complete this program. One retake is allowed. The corrected answer sheet will be provided for comparison with the course information. Credit is available through January 31, 2010.

DISCLAIMER This course is designed solely to provide the health care professional with information to assist in his/her practice and professional development and is not to be considered a diagnostic tool to replace professional advice or treatment. The course serves as a general guide to the health care professional and therefore cannot be considered as giving legal, nursing, medical, or other professional advice in specific cases. AKH Inc., the authors, and the publisher specifically disclaim responsibility for any adverse consequences resulting directly or indirectly from information in the course, from undetected error, or from the reader’s misunderstanding of the content.

JOINT SPONSORSHIP STATEMENT Jointly sponsored by AKH Inc. and Applied Clinical Education.

SUPPORT STATEMENT This activity is made possible by an educational grant from Sanofi-Aventis.

DISCLOSURE OF UNLABELED USE

regarding the management of recently documented, recurrent breast cancer. She had initially been diagnosed with a 2.2-cm, stage II, infiltrating ductal carcinoma of the left breast 21 months earlier. The tumor had metastasized to 2 of 12 axillary lymph nodes. Pathology indicated an estrogen (ER)- and progesterone (PgR)-negative phenotype that was HER2-positive (via fluorescent in situ hybridization [FISH]). The patient underwent lumpectomy followed by adjuvant chemotherapy with docetaxel (Taxotere, Sanofi-Aventis), carboplatin, and trastuzumab (TCH). Trastuzumab (Herceptin, Genentech) therapy was continued for 12 months and supplemented with adjuvant radiation therapy. Two months ago, approximately 7 months after completion of a 12-month course of adjuvant trastuzumab therapy, the patient began to experience very mild shortness of breath accompanied by intermittent rib and back pain. The pain had been growing continually more persistent. The patient demonstrated no additional masses or lymphadenopathy. Her lungs were clear and her neurologic examination was normal. Further evaluation, including restaging scans, revealed several small bilateral lung nodules ranging from 1 to 1.5 cm in diameter, as well as a small left pleural effusion. A biopsy of one lung nodule was consistent with the original diagnosis of HER2-positive,

ER/PgR-negative breast cancer. A bone scan revealed metastases in several ribs as well as the thoracic spine. The patient was started on bisphosphonate therapy and has received several different opinions about options for systemic therapy.

Commentary This patient poses a significant dilemma regarding optimal management of a fairly rapid recurrence of breast

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ClINICAl ONCOlOGy NEWS • JANUARy/FEBRUARy 2009

Table 1. Trastuzumab Beyond Progression Trial: Previous Treatment and Efficacy

100

Cumulative PFS, %

80 60

Capecitabine

Capecitabine + Trastuzumab

P Value

Median TTP

5.6 mo

8.2 mo

0.69

0.034

Median OS

20.4 mo

25.5 mo

0.76

0.26

ORR

27%

48%

–

0.011

CBR

54%

75%

–

0.0068

0 0

Time, wk

Note: Administered pretreatments (N=156): First-line taxane + trastuzumab (n=111); trastuzumab monotherapy or trastuzumab + first-line chemotherapy (n=42); taxane + trastuzumab as adjuvant therapy (n=3). CBR, clinical benefit rate (CR+PR); HR, hazard ratio; ORR, overall response rate (CR+PR+SD >24 wk); OS, overall survival; TTP, time to progression

Figure 1. Lapatinib therapy resulted in doubling of progressionfree survival in ITT patients.

Adapted from Von Minckwitz G, et al. J Clin Oncol. 2008;26. Abstract 1025.

ITT, intent-to-treat; PFS, progression-free survival Adapted from Geyer CE, et al. New Engl J Med. 2006;355(26):2733-2743.

Eligibility criteriaa: • Progressive MBC or LABC • HER2 overexpression • Previous treatment with trastuzumab • Trastuzumab-free interval <6 wk • LVEF ≥50%

R A N D O M I Z E

Trastuzumab 6 mg/kg q3wk

Capecitabine 2,500 mg/m2/d PO d 1-14 q21d

Primary end point: time-to-progression Secondary end points: overall survival, overall response rate, and safety

Figure 2. Trastuzumab beyond progression trial. a

Study closed at 156 patients because of slow accrual following FDA registration of lapatinib for this indication.

LABC, locally advanced breast cancer; LVEF, left ventricular ejection fraction; MBC, metastatic breast cancer Adapted from Von Minckwitz G, et al. J Clin Oncol. 2008; 26. Abstract 1025.

cancer that is now manifesting as metastatic disease in the bone and lung. The speed of recurrence poststandard adjuvant chemotherapy program (TCH) for a HER2-positive breast cancer is characteristic of aggressive disease and may be a harbinger of resistance to other systemic therapy programs. From a clinical standpoint, the patient is experiencing disease site–related symptoms (eg, bone pain, shortness of breath) but is not in visceral crisis. Nevertheless, treatment should be initiated quickly. The tissue biopsy of one metastatic lesion—a pulmonary nodule— confirms that the tumor characteristics are unchanged (ER/PR– and HER2+). The issues that must be considered for a treatment plan at this time include: • Should single-agent chemotherapy or combination chemotherapy be used in this setting? • Should anti-HER2 therapy be reinstituted? • If so, should the patient be treated with trastuzumab or lapatinib (Tykerb, GlaxoSmithKline)? The question of combination versus single-agent chemotherapy in the setting of metastatic breast cancer (MBC) is a frequently debated issue. Many single agents have activity in this setting, and the potential for significant synergism between chemotherapy agents has led to many combination chemotherapy trials. In the pretaxane era, early support for combination chemotherapy was provided by the meta-analytic approach. Fossati et al reviewed 15 randomized clinical trials (2,442 patients) that compared polychemotherapy

Patient population • HER2-positive MBC • Newly diagnosed or post-failure of adjuvant therapy • No CNS metastases as confirmed by MRI/CT

Stratification factors • Prior (neo)adjuvant HER2 targeted therapy • Prior (neo)adjuvant taxane chemotherapy • Taxane on study • Liver metastases

R A N D O M I Z E

regimens (PCHT) with single agents.1 Survival data were available for 12 of the trials (15 comparisons, 1,986 patients). The combined hazard ratio (HR) favored PCHT regimens (HR, 0.82; 95% confidence interval [CI], 0.750.90). This 18% lower risk for death translated into an absolute benefit from PCHT of 9% at 1 year, 5% at 2 years, and 3% at 3 years. Similar results were obtained by the Cochrane Breast Cancer Group, which extracted data from 37 published trials that looked at the effectiveness of combination versus single-agent chemotherapy.2 These data—based on 4,220 deaths in 5,707 women—demonstrated an HR of 0.88 (95% CI, 0.83-0.94; P<0.0001). Two large, individual, randomized Phase III trials comparing newer combinations with single-agent chemotherapy demonstrated a survival benefit for the combination approach. O’Shaughnessy et al randomized 511 anthracycline-pretreated patients with MBC to 21-day cycles of docetaxel 100 mg/m2 on day 1 versus docetaxel 75 mg/m2 on day 1 combined with capecitabine (Xeloda, Roche) 1,250 mg/m2 twice daily on days 1 through 14.3 The capecitabine-docetaxel combination was significantly more effective than single-agent docetaxel in objective response rate (OR, 42% vs 30%; P=0.006), time to disease progression (TTP, 6.1 mo vs 4.2 mo; HR, 0.652; 95% CI, 0.545-0.780), and overall survival (OS, 14.5 mo vs 11.5 mo; HR, 0.775; 95% CI, 0.634-0.947). A similar trial using paclitaxel randomized 529 anthracycline-pretreated patients with MBC to 21-day cycles of paclitaxel 175 mg/m2 on day 1

Lapatanib + taxanea x 24 wk

Lapatanib until disease progression

Trastuzumab + taxanea x 24 wk

Trastuzumab until disease progression

Radiologic assessment including MRI and CT

Primary objective: progression-free survival Secondary objectives: OS, time-to-progression, time to incidence of CNS metastases at first PD, ORR, CBR, safety, biomarkers, QoL, health economics, pharmacogenetics

Figure 3. MA.31 study design. a

Pacitaxel 80 mg/m2 qwk x 4 wk schedule or docetaxel 75 mg/m2 q3wk at investigator’s discretion/

CBR, clinical benefit rate; CNS, central nervous system; CT, computed tomography; MBC, metastatic breast cancer; MRI, magnetic resonance imaging; ORR, overall response rate; OS, overall survival; PD, progressive disease; QoL, quality of life

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ClINICAl ONCOlOGy NEWS • JANUARy/FEBRUARy 2009

Why wait? Access this program and post-test @ CMEZone.com versus paclitaxel 175 mg/m2 on day 1 and gemcitabine (Gemzar, Eli Lilly) 1,250 mg/m2 on days 1 and 8.4,5 The gemcitabine-paclitaxel combination yielded significantly better results than single-agent paclitaxel in relative risk (41.4% vs 26.2%; P=0.0002), TTP (6.14 mo vs 3.98 mo; P=0.0002), and OS (18.6 mo vs 15.8 mo; P=0.187). Both trials have been criticized for lack of a planned, controlled crossover for progression on single-agent therapy. Miles et al examined the poststudy course of the patients enrolled in the capecitabine-docetaxel trial.6 Although the data for patients who received capecitabine following progression on single-agent docetaxel suggested that sequential and combination therapy may be equivalent, 35% of patients did not receive additional cytotoxic chemotherapy following progression on docetaxel monotherapy. This issue was also suggested in the results of ECOG (Eastern Oncology Cooperative Group) 1193, which compared sequential doxorubicin followed by paclitaxel with a combination of both.7 This trial often is used as an argument against combination therapy because no survival benefit was observed for the combination arm; however, of the randomized patients (doxorubicin, 245; paclitaxel, 242), only 50% crossed over to the other single agent (129 and 128, respectively). Although one could postulate numerous reasons why an individual patient might not cross over, it is reasonable to question whether the patients who did so may have been “better” patients in terms of disease burden, performance status, and other prognostic factors. If so, it would be very difficult, if not impossible, to demonstrate a significant survival difference between sequential and combination therapy. In the end, the decision about the “best” treatment approach for metastatic disease needs to be made on an individual basis. For this patient, one must take into account the recently used chemotherapy agents and whether anti-HER2 therapy will be used. The latter point has to be considered because of potential toxicities encountered when combining certain chemotherapy drugs with anti-HER2 therapy (ie, anthracyclines and trastuzumab). Regarding the question of how to exploit the HER2-positive feature of the tumor in this case, the issue is whether to restart trastuzumab or use the other anti-HER2 therapy option, lapatinib. Patients developing disease progression while receiving chemotherapy and trastuzumab frequently

continued on trastuzumab in combination with a different chemotherapy drug. Efforts to formally address this clinical dilemma through the conduct of clinical trials failed because of poor accrual. Clinicians “knew the answer” without the data. The approval of lapatinib provided an alternative to continuation of trastuzumab. The rapid development of recurrence in this case raises the issue of resistance to trastuzumab, either de novo or acquired. Although there is no way of knowing with certainty the underlying explanation for disease recurrence in this patient, there is evidence that tumors that possess a truncated HER2 receptor (p95) and lack the external domain will not bind with trastuzumab. The truncated receptor demonstrates increased kinase activity and is associated with increased transforming potential. Approximately 25% of patients with breast cancer express p95, and in 9% of these cases p95 is expressed at high levels that are indicative of worse outcome.8 Lapatinib is a new, orally administered, small-molecule tyrosine kinase inhibitor of HER1 and HER2 that has antitumor activity when used as a single agent in patients with HER2-positive MBC, including inflammatory breast cancer. Researchers recently reported an industry-sponsored, international, randomized, open-label trial in which 324 patients with HER2-positive MBC that had progressed during treatment with an anthracycline, a taxane, and trastuzumab received either the FDA-approved dose of capecitabine (2,500 mg/m2 for 14 of 21 days) or a combination regimen of capecitabine (2,000 mg/m2 for 14 of 21 days) plus lapatinib (1,250 mg/d continuously).9 A prespecified interim analysis showed that patients who received the combination had a longer median TTP than those who received capecitabine alone (8.4 vs 4.4 mo; HR, 0.49; 95% CI, 0.34-0.71) (Figure 1).9 The response rate with the combination was somewhat higher than the rate with capecitabine alone (22% vs 14%; P=0.09). Adverse events (including cardiac events) were similar between the groups, with only modest increases in grade I/II diarrhea, dyspepsia, and rash among those who received lapatinib. In a population of patients who developed progressive disease following treatment with trastuzumab, the clinical benefit observed when lapatinib was added to capecitabine supports the hypothesis that the mechanism of action of lapatinib is distinct from that of trastuzumab. In clinical practice, when patients’ disease progresses while

they are receiving treatment with chemotherapy plus trastuzumab, they often continue receiving trastuzumab but initiate a new chemotherapy regimen. Because clinical trials that were designed to assess this practice failed to accrue enough patients, the validity of this course of action probably never will be determined. Lapatinib clearly enhances the effects of chemotherapy following disease progression with trastuzumab and does not significantly increase toxicity. A recently reported German trial provides evidence for the continuation or reinstitution of trastuzumab even if disease progression occurred during or after trastuzumab-based therapy. The Trastuzumab Treatment Beyond Progression study evaluated this issue, assessing 156 women with HER2-positive metastatic disease treated with trastuzumab with or without chemotherapy in the adjuvant setting or as first-line therapy for metastatic disease (Figure 2).10 At disease progression, patients received capecitabine with or without trastuzumab in a randomized fashion, with TTP as the primary end point. The patients who continued on trastuzumab with concurrent capecitabine demonstrated response rates of 48% at interim analysis versus 27% in those receiving single-agent capecitabine; progression-free survival was 8.2 months and 5.6 months, respectively (Table 1).10 In the case described here, there is a rationale for either restarting trastuzumab with an alternative chemotherapy or initiating lapatinib with capecitabine. The most favorable available anti-HER2 approach is not known at this time. The MA-31 study design in Figure 3 will address this issue, but no data are available at this time.

Case 2 A 51-year-old, perimenopausal woman with HER2-positive (ER/PgR+) MBC presents with progression of metastatic disease while receiving therapy consisting of weekly paclitaxel and trastuzumab. She presents with progression in size and number of previously identified liver metastases. The patient was initially diagnosed with a 1.5-cm, stage I, infiltrating ductal carcinoma (IDC) of the left breast 7 years earlier. A lumpectomy was performed, revealing that the tumor had metastasized to none of the 10 axillary lymph nodes. Pathology indicated an ER- confirm positive and PgR-positive phenotype that was HER2-3+ via immuno-

70 P < 0.0001

P < 0.001

Mean LVEF

50 40

Following standard therapy for heart failure (n=32) or observation (n=6)

Following trastuzumab rechallenge (n=25; all on standard therapy)a

30 20 10 0

Prior to trastuzumab therapy (n=38)

At time of cardiac dysfunction (n=38)

Figure 4. Recovery from trastuzumab-related cardiotoxicity. Note: LVEF improved in most patients who stopped trastuzumab to receive therapy for heart failure, permitting trastuzumab retreatment. a

22 of 25 patients treated had no subsequent LVEF dysfunction.

LVEF, left ventricular ejection fraction Adapted from Ewer MS, et al. J Clin Oncol. 2005;23(31):7820-7826.

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ClINICAl ONCOlOGy NEWS • JANUARy/FEBRUARy 2009

Table 2. Outcomes of Combined Lapatinib and Trastuzumab Therapy Lapatanib (n=148)

Lapatanib + trastuzumab (n=148)

HR (95% CI)

P Value

Median PFS

8.1 wk

12 wk

0.73 (0.57-0.93)

0.008

6-mo OS

70%

80%

12-mo OS

36%

45%

Median OS

39.0 wk

51.6 wk

0.75 (0.53-1.07)

0.106

Response rate

6.9%

10.3%

1.5 (0.6-3.9)

0.46

Clinical benefit rate

12.4%

24.7%

2.2 (1.2-4.5)

0.01

CI, confidence interval; HR, hazard ratio; NA, not applicable; OS, overall survival; PFS, progression-free survival Adapted from O’Shaugnessy J, et al. J Clin Oncol. 2008;26(15S). Abstract 1015.

histochemistry (IHC). The patient received 4 cycles of AC chemotherapy (doxorubicin [Adriamycin, Bedford] and cyclophosphamide [Cytoxan, Bristol-Myers Squibb]) followed by adjuvant radiation therapy; adjuvant tamoxifen therapy was then continued for 5 years. She remained asymptomatic with no symptom of disease until 9 months ago, when she presented with a palpable left supraclavicular mass measuring approximately 2 cm in diameter. Restaging scans performed at that time revealed 2 small liver lesions (approximately 1 cm each), multiple lytic bone lesions, and left supraclavicular lymphadenopathy. A biopsy of the left supraclavicular node was positive and consistent with IDC, with tumor markers the same as at diagnosis (ER/PgR+; HER2+ via FISH at recurrence). Multiple gated acquisition (MUGA) scan showed an ejection fraction of 49%. Treatment with weekly paclitaxel and trastuzumab was initiated and well tolerated by the patient. Scans at 3 and

6 months post-therapy indicated steady improvement with reduction in liver metastases (undetectable) and no further progression of bone metastases. The patient then presented with increasing fullness in the left supraclavicular nodal basin. Computed tomography imaging demonstrates several new liver lesions measuring less than 1 cm, increased bone metastases, and additional lymphadenopathy in the previously biopsied nodal region (subepidermal calcified nodule). A repeat MUGA scan now shows an ejection fraction of 42%.

How Should This Patient be Managed? In this case, there is unambiguous progression of disease while receiving trastuzumab therapy—as opposed to case 1, where the patient received trastuzumab in the adjuvant setting and had discontinued therapy for some time. In this case, there was a clear indication that the patient was responding to paclitaxel and trastuzumab prior to overt disease progression while receiving therapy. To

further complicate this case, the cardiac function of the patient appears to have deteriorated from baseline with trastuzumab therapy, although she had no clinical evidence of congestive heart failure (CHF). Before the optimal choice of systemic therapy is decided, the clinical course of cardiac effects for patients who receive trastuzumab therapy should be discussed. Research by Ewer et al shed some light on this issue; their retrospective study of 38 patients with HER2-positive breast cancer focused on patients who had previously received doxorubicin-based chemotherapy and were now believed to be suffering from trastuzumab-related cardiotoxicity.11 The 4-year experience with patients who developed trastuzumab-related cardiotoxicity was evaluated by following left ventricular ejection fraction (LVEF) in a serial fashion. Mean LVEF values were determined at 4 stages: 1) after doxorubicin-based chemotherapy was completed, but prior to initiation of trastuzumab treatment (in all patients; N=38); 2) after stopping trastuzumab treatment, which was discontinued in all patients upon identification of potential heart failure based on LVEF dysfunction or CHF (n=32); 3) following standard therapy for heart failure (n=32) or observation-only (n=6); and 4) while maintained on therapy for heart failure, 25 patients who had responded well to earlier treatment with trastuzumab were re-treated with trastuzumab. After the completion of chemotherapy, but prior to initiation of therapy, the mean LVEF for the 38 patients was 0.61±0.13. Once either LVEF dysfunction or CHF was identified, mean LVEF significantly decreased to 0.43±0.16 (P<0.0001 relative to the mean pre-trastuzumab value) upon discontinuation of trastuzumab therapy. Following standard therapy for heart failure (in 32 of 38 patients; observation only in 6), mean LVEF increased to 0.55±0.11, a significant improvement over the previous nadir (P<0.001). While maintained on heart failure therapy, 25 patients who responded well to earlier treatment with trastuzumab were re-treated with trastuzumab; mean LVEF stabilized at 0.55 ±0.10. Only 3 of these 25 patients experienced subsequent LVEF dysfunction; as a result, the conclusion can be drawn that most patients who develop

EX PER T COM M ENTAR Y Robert Dreicer, MD, FACP In contrast to the situation for some other common epithelial cancers, breast oncologists (ie, surgical, medical, and radiation oncologists) have for decades led the way in the development and completion of Phase II and III trials that have provided evidencebased guidelines for the management of patients with localized and MBC. Dr. Gradishar has highlighted the available data, controversies, and questions that still remain with regard to the management of patients with HER2-positive metastatic disease. Although he notes that at times the “I already know the answer” syndrome does indeed have an impact on a physician’s management of these patients, there are also many important and essential questions (ie, the role of continued trastuzumab in patients with documented disease progression while receiving combination chemotherapytrastuzumab therapy) have been addressed in Phase III studies. In the current economic climate, these questions must be addressed prospectively in order to provide optimal management choices for physicians and patients. Oncologists must also remember to be self critical in their therapeutic choices so as to allow for the introduction of more advanced and effective agents down the road.

Nancy Kline, RN, PhD, CPNP, FAAN These 2 case studies describe women who were diagnosed with breast cancer and experienced either progression of disease while on initial treatment or recurrent breast cancer with multiple sites of metastasis. Both cases present unique considerations with regard to nursing assessment and intervention. Recurrent breast cancer is treated in several different ways, depending on the site of disease and prior therapy. Neither of these patients is a surgical candidate, as none of the sites are amenable to resection. Skeletal metastases occur in up to 70% of patients with MBC, resulting in substantial morbidity as well as bone pain, pathologic fracture, spinal cord compression, and hypercalcemia. Radiation therapy may have a palliative role in patients who develop metastatic cancer of the bone, skin, or selected lymph nodes. Radiation may relieve symptoms from cancer and prevent fractures of bone

when used early. Over the last 20 years, bisphosphonates have been investigated for the treatment of bone metastases and have been shown to reduce the associated skeletal complications. Intravenous administration of bisphosphonates is generally safe and well tolerated for long-term use. Trastuzumab is a monoclonal antibody that binds to HER2 and can kill HER2-positive cancer cells. It is used with other chemotherapy agents to treat HER2-positive breast cancer after surgery or to treat breast cancer that is HER2-positive and has spread after treatment with other drugs. Side effects of trastuzumab most commonly include fever, chills, fatigue, nausea, diarrhea, and cough and, less commonly, ventricular dysfunction, CHF, neutropenia, and anemia. The 51-year-old woman in case 2 demonstrated decreased cardiac function following administration of trastuzumab, although she does not yet exhibit clinical signs and symptoms of CHF. If she is continued on trastuzumab therapy, she will require close cardiac assessment and imaging to monitor heart function. Both of these women are relatively young, and multiple role responsibilities may be a factor in treatment choices and ongoing follow-up. In addition, it is likely that both will have job responsibilities outside the home and employment, and child-care issues may need to be considered at the time of hospital discharge or when scheduling follow-up visits. In addition, it is important to discuss with these women how and what to tell their children. Information for children should be delivered at a developmentally appropriate level, providing small amounts of information at a time. Children’s questions should be answered honestly and as directly as possible in an attempt to reassure them and allay their fears. The prognosis for MBC is usually better when metastases are located in the chest wall, lymph nodes, or bones as opposed to organs such as the liver or lungs. A cure is an unlikely outcome for women with MBC; as a result, other goals are of greater importance. These include relief of symptoms, improved quality of life, and a longer progression-free or relapse-free survival. Although chemotherapy and biologic therapies have associated side effects, quality of life, and symptom management can be improved with these treatments.

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ClINICAl ONCOlOGy NEWS • JANUARy/FEBRUARy 2009

Why wait? Access this program and post-test @ CMEZone.com cardiotoxicity while on trastuzumab treatment improve when therapy is discontinued, following standard therapy for heart failure. Once these patients recover from trastuzumab-associated cardiotoxicity, re-treatment with trastuzumab can be successful as long as therapy for heart failure is continued. In this case, recovery from trastuzumab-associated cardiotoxicity permitted successful retreatment with trastuzumab while continuing therapy for heart failure (Figure 4).11 Although the patient did not have overt CHF, trastuzumab therapy could be continued with a different chemotherapy, as most patients are able to continue with medical management of cardiac issues. Patients such as this woman should, however, be evaluated by a cardiologist prior to change of therapy. Would lapatinib be a better anti-HER2 therapy for this patient because of issues related to cardiac concerns? There is not yet enough direct comparative data available to address this issue. A prospective review of multiple clinical trials involving lapatinib that was recently published places focus on these cardiac side effects. The study monitored 3,127 patients prospectively, in 18 Phase I-III studies (10 lapatinib immunotherapy studies and 8 combination regimens with either chemotherapy or endocrine therapy). Breast cancer was reported in 1,674 patients. Lapatinib-associated cardiotoxicity was defined differently than in trastuzumab studies, and cardiac function was monitored more frequently. Cardiac toxicity was defined as an asymptomatic LVEF decline of 20% or more compared with baseline measurement, and below the institution’s lower limit of normal. LVEF measurements by either MUGA or echocardiogram scan were performed every 8 weeks while patients were undergoing treatment, as well as at the conclusion of the study or at termination of treatment. In this prospective study,12 41 of 3,127 patients (1.3%) who received lapatinib had declines in LVEF; of those, 66% occurred within the first 9 weeks after initiation of therapy. Lapatinib-associated cardiotoxicity was rarely symptomatic (0.1%), and generally reversible or nonprogressing.

In 22 patients with breast cancer who had reduced LVEF, the average decrease was 29%, ranging from 22% to 42.3% (average duration, 40 days). Of these 22, 13 (59%) patients recovered; 9 (41%) achieved recovery while still receiving lapatinib treatment. This experience suggests that lapatinib monotherapy or combination therapy was associated with only 1.3% LVEF dysfunction, and most LVEF cases were asymptomatic. Only 4 (0.1%) symptomatic cases were observed, and all resolved after discontinuation or interruption of lapatinib treatment. Regarding the best systemic therapy for this patient who is progressing while receiving trastuzumab-based therapy, one could choose to change chemotherapy and continue trastuzumab. This approach is supported by the German experience reported by von Minckwitz at the 2008 San Antonio Breast Cancer Symposium.10 As outlined in case 1, patients who developed disease progression on a chemotherapy/trastuzumab combination were randomized to capecitabine alone or the combination of capecitabine and trastuzumab. Patients continuing on trastuzumab were more likely to have an anti-tumor response and longer time to disease progression, compared with capecitabine alone. Alternatively, this patient could receive lapatinib plus capecitabine, which proved superior to capecitabine alone in a study reported by Geyer et al. Either approach would be acceptable although there are currently no data that definitively state which treatment is superior.9 Data recently presented by O’Shaughnessy raise the possibility of a nonchemotherapy option in which patients with progressive disease while receiving trastuzumab were randomized to lapatinib alone or the combination of lapatinib with the continuation of trastuzumab.13 Patients receiving dual anti-HER2 therapy resulted in a higher objective response rate and longer time to disease progression as compared with lapatinib alone. These data are very interesting because they suggest a synergy between the 2 agents. Although not viewed as a standard practice, the strategy of combining targeted therapy is very attractive (Table 2).13

CME/CE Post-test

4. Anti-HER2-positive agents include: a. capecitabine b. trastuzumab c. lapatanib d. B and C

Select the single-letter response that best answers the question or completes the sentence. 1. The following combination therapies demonstrated efficacy in clinical trials: a. capecitabine-docetaxel b. trastuzumab-lapatanib c. gemcitabine-paclitaxel d. All of the above 2. p95 is expressed in roughly what percentage of patients with breast cancer? a. 75% b. 15% c. 25% d. 10% 3. High expression levels of p95 are indicative of: a. acquired trastuzumab resistance b. poorer survival prognosis c. better survival prognosis d. de novo trastuzumab resistance

5. The FDA-approved dose for capecitabine is: a. 2,500 mg/m2 for 21 days b. 2,500 mg/m2 for 14 of 21 days c. 2,000 mg/m2 for 21 days d. 2,000 mg/m2 for 14 of 21 days 6. Common side effects of capecitabine and lapatinib include: a. diarrhea b. dyspepsia c. rash d. All of the above 7. Patients receiving anti-HER2-positive therapy for advanced breast cancer should be monitored for rare occurrences of: a. diarrhea b. cardiotoxicity c. rash d. All of the above

References 1.

Fossati R, Confalonieri C, Torri V et al. Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women. J Clin Oncol. 1998;16(10):3439-3460.

Carrick S, Parker S, Wilcken N, Ghersi D, Marzo M, Simes J. Single agent versus combination chemotherapy for metastatic breast cancer. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD003372.

O’Shaughnessy J, Miles D, Vukelja S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002;20(12):2812-2823.

O’Shaughnessy J, Nag S, Calderillo-Ruiz G, et al. Gemcitabine plus paclitaxel (GT) versus paclitaxel (T) as first-line treatment for anthracycline pre-treated metastatic breast cancer (MBC): interim results of a global phase III study. Proc Am Soc Clin Oncol. 2003;22:7. Abstract 25.

Albain KS, Nag SM, Calderillo-Ruiz G, et al. Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008;26(24):3950-3957.

Miles D, Vukelja S, Moiseyenko V, et al. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer. 2004;5(4):273-278.

Sledge GW, Neuberg D, Bernardo P, et al. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: An Intergroup Trial (E1193). J Clin Oncol. 2003;21(4):588–592.

Saéz R, Molina MA, Ramsey EE, et al. p95HER-2 predicts worse outcome in patients with HER-2-positicve breast cancer. Clin Cancer Res. 2006;12(2):424-431.

Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733-2743.

10. von Minckwitz G, Zielinski C, Maarteense E, et al. Apecitabine vs. capecitabine + trastuzumab in patients with HER2-positive metastatic breast cancer progressing during trastuzumab treatment: The TBP phase III study (GBG 26/BIG 3-05). J Clin Oncol. 2008;26. Abstr 1025. 11. Ewer MS, Vooletich MT, Durand J-B, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol. 2005;23(31):7820-7826. 12. Perez EA, Koehler M, Byrne J, Preston AJ, Rappold E, Ewer MS. Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clinic Proceedings. 2008;83(6):679-686. 13. O’Shaughnessy J, Blackwell KL, Burstein H, et al. A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy. J Clin Oncol. 2008;26. Abstract 1015.

8. Skeletal metastases occur in up to ______ of patients with metastatic breast cancer? a. 25% b. 50% c. 70% d. 75% 9. Patients developing trastuzumab-associated cardiotoxicity must a. not resume anti-HER2 therapy b. be started on a different anti-HER2 agent c. continue therapy for heart failure post-recovery d. B and C 10. Newer therapies for progressive HER2-positive metastatic disease include: a. dual anti-HER2 therapy b. polychemotherapy (PCHT) c. PCHT in combination with lapatanib d. none of the above

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ClINICAl ONCOlOGy NEWS • JANUARy/FEBRUARy 2009

✃ Answer Sheet & Evaluation Form

Release Date: December 1, 2008

Individualizing Cancer Care in the Era of Evidence-based Treatment—Part 4: Breast Cancer

Expiration Date: January 31, 2010

Directions: Select an answer for each question in the exam and circle the appropriate letter. A minimum score of 70% is required to earn credit. You are allowed 2 attempts to complete this exam successfully. Please submit your answers only once through a method listed below. Allow 4 weeks for processing. Multiple statements will not be issued.

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Participant Information (Please print) First Name: ________________________________________________________________ Last Name: _______________________________________________________________________ Address: ______________________________________________________________________ City/State: ______________________________ ZIP: _________________________________ Daytime Phone:___________________________ Fax:__________________________ E-mail: _______________________________________________________________________________ Profession: ❑ Physician: I am claiming ____ (in increments of 0.25) AMA PRA Category 1 Credit(s)™. ❑ Nurse ❑ Other–Specify: _____________________________________________________________________________________________________________________________________ License #: ___________________________________________________________ State of Licensure: _______________________________________________________________________

Post-test Answers 1. 2. 3. 4. 5.

a a a a a

b b b b b

c c c c c

d d d d d

6. 7. 8. 9. 10.

a a a a a

b b b b b

c c c c c

d d d d d

Evaluation Please answer the following questions by circling the appropriate rating. 4=Strongly agree; 3=Agree; 2=Disagree; 1=Strongly disagree After participating in this activity, I am better prepared to: 1. Identify treatment options for patients with HER2-positive advanced breast cancer. 2. Discuss specific characteristics of both tumors and patients that may guide treatment selection for breast cancer. 3. Discuss the toxicities and supportive care issues related to therapy for breast cancer. The information was relevant to my professional needs and practice. The educational level of this activity was appropriate. The faculty was knowledgeable and effective in presentation of content. The teaching method(s) and learning materials were effective. Overall, I was satisfied with this educational activity.

4 4 4

3 3 3

2 2 2

1 1 1

4 4 4

3 3 3

2 2 2

1 1 1

The content was objective, current, scientifically based, and free of commercial bias. ❑ Yes ❑ No Please explain: ________________________________________________ Based on information presented in this activity, I will: ❑ do nothing as the content was not convincing. ❑ seek additional information on this topic. ❑ change my practice. ❑ do nothing as current practice reflects program’s recommendations. The most important concept learned during this activity that may effect a change in patient care is: ________________________________________________________________________ What issue(s) related to the therapeutic area discussed in this activity, or other topics, would you like addressed in future continuing education? ___________________________________ ___________________________________________________________________________ Comments: _________________________________________________________________ ___________________________________________________________________________

IP0861

POLICY & MANAGEMENT

Clinical Oncology News • JANUARY/FEBRUARY 2009

Pharmacy

TOUCH

‘This experience demonstrates that pharmacists can bring protocols to the private practice that are often reserved for academic centers.’

continued from page 1 

patients to be treated without leaving the practice. “Our approach permitted many patients in advanced stages of cancer to remain at the center where they were treated initially, avoiding the traumatizing experience of switching caregivers at a time when they are already feeling vulnerable,” Dr. Wong reported at the recent annual meeting of the American College of Clinical Pharmacy. “For many patients, this is an important quality-of-life issue.” Over a four-year period, 25 clinical protocols with five investigator-initiated trials were initiated by the pharmacist, allowing patients access to therapies that normally would have required referral to larger clinical centers, Dr. Wong noted. The grants totaled $1.5 million—funds that not only helped the practice maintain continuity of care, but also enabled the oncology office to develop “into a progressive practice environment for teaching and training activities,” Dr. Wong said. Some private practices have already begun hiring pharmacists at least on a part-time basis to improve the efficiency and accuracy of delivering challenging combination chemotherapy regimens. However, the initiative reported by Dr. Wong, which was actually an analysis of her experience in a private practice, extended far beyond this role. In addition to overseeing delivery of chemotherapy and providing therapeutic consultations, Dr. Wong developed a clinical research program. Her responsibilities included selecting, developing and activating treatment protocols, negotiating contracts associated with these protocols and documenting compliance. She also managed all the protocol patients in collaboration with the physicians. The $1.5 million in research grants not only was more than sufficient to cover the pharmacist’s salary; the grants also permitted physicians in the practice to offer patients new and innovative drug therapy protocols. Without such a funded program, Dr. Wong noted, the participating physicians would not have had the time to invest in protocol development. “Additional accomplishments included initiation of a cofounded pharmacy research fellowship, standardization of chemotherapy orders to reduce medication errors and administration costs, administrative analyses leading to personnel justification of pharmacy technician and data managers, and medical economic analyses to optimize drug therapy for major cancer types,” Dr. Wong reported.

—Ernest R. Anderson Jr., MS, RPh

‘Our approach permitted many patients in advanced stages of cancer [to avoid] … the traumatizing experience of switching caregivers at a time when they are already feeling vulnerable.’ —Siu-Fun Wong, PharmD

Even More Savings Possible For the purposes of cost analysis, Dr. Wong, who holds a full-time academic position, calculated her costs to the practice as 60% of the national average of a pharmacist’s salary. This reflected the proportion of time she was able to devote to this project. However, she suggested that a full-time position would have generated at least a commensurate increase in income because her ability to bring protocols to the practice and conduct proactive patient screening was limited by time rather than by the availability of research grants. “A full-time person may actually have generated more income for the practice,” said Dr. Wong, adding that the practice had six physicians when she began and grew to eight medical oncologists, a physician assistant and two nurse practitioners over the course of her time there. The net gains for the oncology practice from hiring a pharmacist increased over time, but even by the second year the increased income exceeded the costs of the pharmacist by $8,000. By the end of the four-year study, the annual cost advantage reached $145,000 as the grant proposals were funded and the advantages of a staff pharmacist were fully realized. “There are some private practices that have hired a full-time pharmacist with primary responsibility at the infusion area, but this experience reported demonstrates that there are numerous additional advantages,” Dr. Wong said. “Not only do the contributions of the pharmacist more than compensate for salary costs, but he or she offers an

important opportunity to expand treatment options for the patient.” These data are highly encouraging for the prospects of pharmacists in the

private practice setting, according to Ernest R. Anderson Jr., MS, RPh, director of pharmacy, Lahey Clinic, Burlington, Mass. Mr. Anderson suggested that this is an appropriate expansion of their skills. Usually when pharmacists are hired in a private oncology practice, the focus “is on the mixing of the chemotherapy, cost-effective purchasing, accurate billing and standardization of chemotherapy regimens,” said Mr. Anderson, who is the president of the Association of Community Cancer Centers. “This experience demonstrates that pharmacists can bring protocols to the private practice that are often reserved for academic centers.” —Ted Bosworth

Director of the Prostate Cancer Research Center (PCRC) Division of Hematology/Oncology Department of Medicine Cedars-Sinai is pleased to announce an outstanding Medical Oncology leadership opportunity in our Prostate Cancer Program. The successful candidate for the position will be an innovative leader with a background that spans a robust medical oncology clinical practice and an active laboratory. An outstanding group of peer program leaders add to the potential for a world class program. Focus of the position includes: 

Leading the development, coordination, and administration of the PCRC

 Maintaining an active research program in prostate cancer, creating new opportunities for basic and clinical prostate cancer research, publications in peer reviewed journals/publications; cancer research grant submittals to various federal and state granting agencies and pharmaceutical companies, and actively participating in philanthropic endeavors to enhance the Center.  Overseeing and maintaining quality control at the Center in order to provide the highest standard of care to both the inpatient and outpatient populations, and to attract physicians of exceptional ability to the Medical Center. 

Establishing training and procedural criteria and standards for performing prostate cancer clinical research.

 Responsible for the development and strengthening of an active teaching program in urologic malignancies within the Division, with activities that would include educational programs such as teaching rounds, formal rounds and lectures to medical students, house staff, fellows and other attending staff.  Works closely with the Directors of the Hematology/Oncology Fellowship Program and the Medicine Residency Program to optimize the knowledge and experience of students, house staff, and fellows in urologic malignancies, and is involved in the recruitment of research and clinical fellows Ideal candidates will demonstrate the following qualifications:        

Medical Degree from an accredited medical school Board Certification (or eligibility) in General Internal Medicine and in the subspecialty of Hematology/Oncology. Eligible for an unrestricted California license as Physician Successful application for CSMC Medical Staff Membership Demonstrated evidence of focus in prostate cancer A published author of high value peer reviewed articles Demonstrated ability to serve as principal investigator for peer reviewed funding A track record of excellence in teaching, patient care and administration

Cedars-Sinai, a tertiary acute care academic medical center is proud to be on the list of “America’s Best Hospitals” as ranked by US News and World Report. If you are interested in this opportunity to join a flourishing clinical, teaching and research environment, please send your curriculum vitae to: Search Committee Chairman, Dr. Steven Piantadosi c/o Patricia Carson 8700 Beverly Boulevard, 5th Floor, South Tower, 5724 ~ Los Angeles, California 90048 Email: carsonp@cshs.org CEDARS-SINAI ENCOURAGES AND WELCOMES DIVERSITY IN THE WORKPLACE. AA/EOE

PRN

Clinical Oncology News • JANUARY/FEBRUARY 2009

Eye on the Community Oncologist

Q&A With ACCC President Provides Insight Ernest R. Anderson Jr., Discusses Challenges Facing Community Cancer Centers

n 2008, Ernest R. Anderson Jr., MS, RPh, became the first pharmacist to be named president of the Association of Community Cancer Centers (ACCC). Most ACCC members were probably not surprised by the choice, because for years, Mr. Anderson, director of pharmacy at the Lahey Clinic in Burlington, Mass., has been a steady presence at ACCC meetings, offering his expertise in oncology drug reimbursement and other key practice management issues. After several months in office, Mr. Anderson spoke with Clinical Oncology News about his initial experience as ACCC president, his goals for the future and his continuing efforts to forge a strong multidisciplinary team approach to cancer care.

: What other signs are there, aside from your ACCC presidency, suggesting that pharmacists are making their mark in community oncology practice? A: Just take a look at last year’s ACCC annual meeting, held in April. There were several presentations by pharmacists, one of which, by Jim Koeller [MS, RPh], focused on the clinical and economic benefits that result when a pharmacist is brought into a community oncology practice. As Mr. Koeller noted, you have lots of large, multisite, multiphysician oncology practices that are dispensing millions of dollars worth of expensive pharmaceuticals annually. You need an expert to handle that, to ensure that both patients and providers can afford the potentially lifesaving medications. [Mr. Koeller is a professor of medicine in the University of Texas College of Pharmacy, Austin.] Remember, in hospitals, it is required by law that you have pharmacists on staff who are directly involved in the preparation and administration of oncolytics. That’s not the case in office-based oncology practice. Yet what I’ve seen around the country is that private oncology practices are finally recognizing the value of having a pharmacist on staff; they’re finding out that pharmacists are an incredibly valuable clinical resource. Plus, they bring much more than clinical skills to the table—their financial acumen can really be the difference between a profit and a loss at some practices.

: What are the main financial pressures that pharmacists can help relieve? A: Each year, it seems that CMS [Centers for Medicare & Medicaid Services] changes the rules on reimbursement. If you miss just a few coding changes—a likely scenario in an oncology practice that does

a huge benefit for an oncology practice to have that expertise in-house.

: What are some of the biggest challenges facing oncology practices today? A: Access to care comes to mind, because it is so closely related to the issue of fair reimbursement for providing oncology drugs. When reimbursement rates are continually ratcheted down, many smaller office-based practices and also hospital-based cancer centers are threatened. When that happens—especially in rural areas—patients could have to travel hundreds of miles to get cancer care. That’s simply unacceptable.

Mr. Anderson demonstrates the features of a spreadsheet he developed to calculate the impact a particular drug will have on profitability, based on reimbursement rate, acquisition cost and other key variables.

not have a pharmacist or other reimbursement expert on staff—it could result in a huge hit to a practice’s bottom line. Also, pharmacists are experts in the efficient use of injectable oncology drugs and can often help practices avoid waste from unused dosages. They’re also great at analyzing a practice’s patterns of drug usage and linking that usage to inventory levels, so that not too much money is tied up stocking seldomdispensed medications. In fact, we’ve documented that oncology practices can save hundreds of thousands of dollars annually by having pharmacists with this expertise on staff. This is just the way pharmacists think—it’s a different outlook than what you might have if you only had nurses on staff mixing drugs, as is the case in many office-based practices.

: You’ve developed a spreadsheet tool to help practices get a better handle on drug reimbursement and how payments affect profitability. Can you explain that? A: Sure. I first presented the spreadsheet a few years ago, during a one-day session of the Oncology Pharmacy Education Network (OPEN) that took place the day before the kickoff of the ACCC annual meeting. By plugging in details on a drug’s cost, markup and insurance reimbursement into the spreadsheet, an oncology practice or a pharmacy department can quickly determine whether it will make or lose money on any cancer drug it needs to purchase. In the process, you get a good

sense of how a drug will impact profitability. But for me, the spreadsheet has also been a great advocacy tool. Several times in recent years, when proposed cuts to oncology drug reimbursement were announced, I was able to use the spreadsheet to show CMS officials the negative impact the cuts would have on oncology practices. In some years, the cuts actually threatened the survival of smaller oncology offices. Seeing that in a simple-to-understand spreadsheet is very powerful. [The spreadsheet can be downloaded at www. pharmacypracticenews.com/download/ OPENspreadsheet.pdf ] Of course, I don’t want to give the impression that pharmacists’ main skills are financial; administering complex oncology drug infusions to patients can be tricky. Pharmacists who have spent years managing these infusions in hospitals, avoiding drug interactions and compatibility problems—that’s a huge asset for a private, community-based oncology office to have. And then there’s the issue of compliance with sterile compounding regulations under NIOSH [National Institute for Occupational Safety and Health]. These regulations provide a template for how to set up an oncology drug mixing area in a practice in a way that protects the safety of patients and staff. Pharmacists are the experts in this area because we have so many years of experience complying not only with NIOSH but also with USP <797>, Joint Commission regulations, etc. Again, it is

: What are some of the clinical challenges in oncology practice? A: One significant challenge is the lack of clear guidance from CMS on use of the newly recognized drug compendia. We are in a state of transition in Medicare reimbursement: Recently CMS announced additional updates to the information it uses in determining which drugs may be covered under Medicare Part B when used to treat patients undergoing cancer treatment through chemotherapy. CMS is adding the National Comprehensive Cancer Network’s Drugs & Biologics Compendium, Thomson Micromedex’s DrugDex and Elsevier Gold Standard’s Clinical Pharmacology compendium to the list of Medicare anti-cancer treatment compendia. [The American Hospital Formulary Service Drug Information (AHFS-DI), published by the American Society of Health-System Pharmacists, is also a recognized compendium.] ACCC approves of this decision. However, there’s one significant challenge: CMS has not yet released guidance on the new compendia. Medicare local contractors, which process and pay Medicare claims and approve coverage for drugs under Medicare Part B, use compendia as one of several tools to determine whether an anti-cancer drug may be covered under Medicare Part B. And they are adrift without clear guidance. We’re hearing lots of discussion from physician practices and pharmacists that CMS’s lack of guidance is resulting in reimbursement denials and confusion.

: In hospitals, you have done a lot to promote best practices in medication safety—for example, your work in establishing VHA New England’s Medication Error Prevention Initiative (MEPI) has helped member hospitals slash their medication error rate. Are similar efforts needed in private oncology practice? see CHALLENGES, page 30 

Important Safety Information Including Boxed WARNINGS: Safety data are available from 15 clinical trials in which 1467 patients received Vectibix®; of these, 1293 received Vectibix® monotherapy and 174 received Vectibix® in combination with chemotherapy. WARNING:DERMATOLOGICTOXICITYandINFUSIONREACTIONS

The first fully human* anti-EGFR monoclonal antibody

DermatologicToxicity:Dermatologictoxicitiesoccurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy. Withhold Vectibix® for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤grade 2 within1month,permanentlydiscontinueVectibix®.The clinical manifestations included, but were not limited to,dermatitisacneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequenttothedevelopmentofseveredermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage were reported. Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Severe infusion reactions included anaphylactic reactions, bronchospasm,andhypotension.Althoughnotreported with Vectibix®, fatal infusion reactions have occurred withothermonoclonalantibodyproducts.Stopinfusion if a severe infusion reaction occurs. Depending on the severityand/orpersistenceofthereaction,permanently discontinue Vectibix®.

* Correlation with safety andefficacyisunknown

Vectibix®isindicatedasasingleagentforthetreatmentofEGFR-expressing,metastaticcolorectalcarcinoma (mCRC)withdiseaseprogressiononorfollowingfluoropyrimidine-,oxaliplatin-,andirinotecan-containing chemotherapy regimens. The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-freesurvival(PFS).Currently,nodatademonstrateanimprovementindisease-relatedsymptomsor increased survival with Vectibix®.

Basedonindependentreviewofdiseaseprogression, a statistically significant prolongation in PFS was observed with Vectibix®1 100%

Q2Wdosing,typicallyadministered over 60 minutes (doses >1000 mg administered over 90 minutes), with no loading dose required† 3 available vial sizes: 400 mg (20 mL), 200 mg (10 mL), 100 mg (5 mL)

Vectibix® + BSC‡ (n=231) (Mean PFS: 96 days)

80%

BSC‡ Alone (n=232) (Mean PFS: 60 days)

70% 60%

P < 0.0001

50%

†

40% 30% 20%

Dose modifications may be needed if toxicity occurs; appropriate medical resources for the treatment of severe infusion reactions should be available. Reference: 1. Vectibix® (panitumumab) prescribing information. Amgen.

10% 0%

Convenient dosing1

Kaplan-Meier Estimate of PFS Time

90%

Proportion Event Free

Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized (1:1) clinical trial of patients with previously untreated metastatic colorectal cancer, the addition of Vectibix® to thecombinationofbevacizumabandchemotherapyresulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. In a single-arm study of 19 patients receiving Vectibix® in combinationwithIFL,theincidenceofNCI-CTCgrade3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. Pulmonary fibrosis occurred in less than 1% (2/1467) of patientsenrolledinclinicalstudiesofVectibix®.Following the initial fatality, patients with a history of interstitial pneumonitis,pulmonaryfibrosis,evidenceofinterstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in such patientsisuncertain. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates. In the randomized, controlled clinical trial, median magnesiumlevelsdecreasedby0.1mmol/LintheVectibix® arm.Additionally,hypomagnesemia(NCI-CTCgrade3or4) requiringelectrolyterepletionoccurredin2%ofpatients 6 weeks or longer after the initiation of Vectibix®. In some patients,bothhypomagnesemiaandhypocalcemiaoccurred. Patients’electrolytesshouldbeperiodicallymonitoredduring andfor8weeksafterthecompletionofVectibix® therapy, and appropriate treatment instituted, as needed. Exposuretosunlightcanexacerbatedermatologictoxicity.It isrecommendedthatpatientswearsunscreenandhatsand limit sun exposure while receiving Vectibix®. Dermatologic, mucosal, and ocular toxicities were also reported. Adequatecontraceptioninbothmalesandfemalesmustbe used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. ThemostcommonadverseeventsofVectibix®areskinrash withvariablepresentations,hypomagnesemia,paronychia, fatigue,abdominalpain,nausea,anddiarrhea,including diarrhea resulting in dehydration. The most serious adverseeventsofVectibix®arepulmonaryfibrosis,severe dermatologictoxicitycomplicatedbyinfectioussequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Weeks

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best supportive care

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Eye on the Community Oncologist

CHALLENGES continued from page 28 

A: The current emphasis on medication safety can arguably be traced, at least in part, to high-profile errors in chemotherapy. Think back, for example, to the Dana-Farber incident in 1994, when a Boston Globe columnist died as a direct result of receiving a fourfold overdose of chemotherapy for her breast cancer. If you read press reports on that, you’ll see that the overdose was missed for weeks by as many as 25 medical staffers who were involved in the patient’s

S:9.75 in

If you miss just a few coding changes—a likely scenario in an oncology practice that does not have a pharmacist or other reimbursement expert on staff—it could result in a huge hit to a practice’s bottom line. care. We’ve learned a lot since then; triple checks of all chemotherapy orders by a multidisciplinary team of nurses, physicians and pharmacists are now the norm, at least in hospitals. Are we doing enough? Well, I’m not sure you can ever do enough. There is always the potential for another “Dana-Farber” out there. Clinicians have to be very vigilant

Vectibix® (panitumumab) Injection for Intravenous Use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy. [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions]. Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. [see Warnings and Precautions and Adverse Reactions]. Although not reported with Vectibix®, fatal infusion reactions have occurred with other monoclonal antibody products. [see Dosage and Administration]. INDICATIONS AND USAGE Vectibix® is indicated as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progression-free survival [see Clinical Studies (14) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®. DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Preparation and Administration]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions. Dose Modifications for Infusion Reactions [see Adverse Reactions] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. • Immediately and permanently discontinue Vectibix® infusion in patients experiencing severe (grade 3 or 4) infusion reactions. Dose Modifications for Dermatologic Toxicity [see Adverse Reactions] • Withhold Vectibix® for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix®. • If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of Vectibix®, treatment may be resumed at 50% of the original dose. – If toxicities recur, permanently discontinue Vectibix®. – If toxicities do not recur, subsequent doses of Vectibix® may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached. Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus. Preparation Prepare the solution for infusion, using aseptic technique, as follows: • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Although Vectibix® should be colorless, the solution may contain a small amount of visible translucent-to-white, amorphous, proteinaceous, panitumumab particulates (which will be removed by filtration; see below). Do not shake. Do not administer Vectibix® if discoloration is observed. • Withdraw the necessary amount of Vectibix® for a dose of 6 mg/kg. • Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium chloride injection, USP. Do not exceed a final concentration of 10 mg/mL. • Mix diluted solution by gentle inversion. Do not shake. Administration • Administer using a low-protein-binding 0.2 µm or 0.22 µm in-line filter. • Vectibix® must be administered via infusion pump. – Flush line before and after Vectibix® administration with 0.9% sodium chloride injection, USP, to avoid mixing with other drug products or intravenous solutions. Do not mix Vectibix® with, or administer as an infusion with, other medicinal products. Do not add other medications to solutions containing panitumumab. – Infuse over 60 minutes through a peripheral intravenous line or indwelling intravenous catheter. Doses higher than 1000 mg should be infused over 90 minutes. Use the diluted infusion solution of Vectibix® within 6 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36° to 46°F). DO NOT FREEZE. Discard any unused portion remaining in the vial.

about their processes and their safety checks, and make sure that they are firmly in place. Having a pharmacist on staff can certainly help in that effort. We already touched on this in terms of admixture preparation, but here’s another area to consider: making sure that you obtain a full and thorough history

for all patients, so that you can understand what medications they’re taking apart from their chemotherapy and make sure that there is no potential for adverse drug interactions. It’s incumbent upon everybody in health care to do this, but pharmacists are especially good at it, in part because it’s one of our responsibilities when it comes to meeting the Joint Commission’s medication reconciliation requirements. Based on what we find, we can recommend adjustments in drug doses or changes in drug regimens.

Table 1. Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients with a Between-Group Difference of ≥ 5% (Study 1) Patients Treated With Vectibix Plus BSC (n = 229) Best Supportive Care (BSC) Alone (n = 234) Grade* All Grades Grade 3–4 All Grades Grade 3–4 % % % % Body as a Whole Fatigue 26 4 15 3 General Deterioration 11 8 4 3 Digestive Abdominal Pain 25 7 17 5 Nausea 23 1 16 <1 Diarrhea 21 2 11 0 Constipation 21 3 9 1 Vomiting 19 2 12 1 Stomatitis 7 0 1 0 Mucosal Inflammation 6 <1 1 0 Metabolic/Nutritional Hypomagnesemia (Lab) 38 4 2 0 Peripheral Edema 12 1 6 <1 Respiratory Cough 14 <1 7 0 Skin/Appendages All Skin/Integument Toxicity 90 16 9 0 Skin 90 14 6 0 Erythema 65 5 1 0 Acneiform Dermatitis 57 7 1 0 Pruritus 57 2 2 0 Nail 29 2 0 0 Paronychia 25 2 0 0 Skin Exfoliation 25 2 0 0 Rash 22 1 1 0 Skin Fissures 20 1 <1 0 Eye 15 <1 2 0 Acne 13 1 0 0 Dry Skin 10 0 0 0 Other Nail Disorder 9 0 0 0 Hair 9 0 1 0 Growth of Eyelashes 6 0 0 0 *Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0. ®

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: You attended the ACCC’s Annual Economics Conference—any presentations you’d like to highlight? A: The meeting was a huge success; this is a multidisciplinary organization that encourages networking and learning among a group of incredibly talented and dedicated practitioners. The highlight for many pharmacists, of course, was the OPEN presentations. One presentation, by Susan Goodin [PharmD], focused on the practice challenges posed by all of the new oral chemotherapy medications being approved. Patients are taking these potent drugs at home, so compliance is a huge issue. Fortunately, there are some tools for promoting adherence, several of which Dr. Goodin covered (cell phone alerts, etc.). But we still haven’t figured out the best way to stay in contact with these patients to ensure optimal outcomes. [Dr. Goodin is an associate professor of medicine at the Cancer Institute of New Jersey, in New Brunswick.] And then there’s the issue of cost. These medications are extremely expensive, so many Medicare patients reach their coverage gap (the “doughnut hole”) very quickly and have to pay for these oral chemotherapy agents out-ofpocket. We have to help them with that. And we also have to figure out optimal reimbursement for these agents, which still seems to be a bit of a moving target. The good news is that with meetings such as the economics conference, we have a powerful networking system in place to figure out these challenges. S:13.75 in

Dermatologic, Mucosal, and Ocular Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to: conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced a NCI-CTC grade 3 event of mucosal inflammation.The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions]. Median time to the development of dermatologic, nail, or ocular toxicity was 14 days; the time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibix®-treated patients [see Dosage and Administration]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported. Infusion Reactions Infusional toxicity was defined as any event described at any time during the clinical study as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix® monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration]. Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity.The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay (detecting both high- and low-affinity antibodies). The incidence of binding antibodies to panitumumab (excluding CONTRAINDICATIONS None. Mr. Anderson, incoming (left), anby award appreciation predose and transientACCC positive patients), president as detected by the acid dissociation ELISA, waspresents 3/613 (< 1%) and as detected the Biacore® assay of was 28/613 (4.6%). WARNINGS AND PRECAUTIONS For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Excluding predose Dermatologic Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with Richard past-president B. Reiling, MD, FACS. and transient positive patients, 10 of the 613 patients (1.6%) with postdose samples and 3/356 (0.8%) of the patients with follow-up samples tested positive for mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, neutralizing antibodies. paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, No evidence of altered pharmacokinetic profile or toxicity profile was found between patients who developed antibodies to panitumumab as detected by screening and abscesses requiring incisions and drainage were reported. Withhold Vectibix® for severe or life-threatening dermatologic toxicity [see Boxed Warning, immunoassays and those who did not. Adverse Reactions, and Dosage and Administration]. Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCI-CTC grade 3–4). The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including ® neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, Across all clinical studies, severe infusion reactions occurred with the administration of Vectibix in approximately 1% of patients. Severe infusion reactions concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to included anaphylactic reactions, bronchospasm, and hypotension [see Boxed Warning and Adverse Reactions]. Although fatal infusion reactions have not been other products may be misleading. reported with Vectibix®, fatalities have occurred with other monoclonal antibody products. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix® [see Dosage and Administration]. DRUG INTERACTIONS ® Increased Toxicity With Combination Chemotherapy Vectibix is not indicated for use in combination with chemotherapy. In an interim analysis of Study 2, No formal drug-drug interaction studies have been conducted with Vectibix®. the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCI-CTC grade 3–4 adverse drug reactions occurring at a higher USE IN SPECIFIC POPULATIONS rate in Vectibix®-treated patients included rash/dermatitis/acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in Pregnancy patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs <1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3–5 pulmonary embolism Pregnancy Category C. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the occurred at a higher rate in Vectibix®-treated patients (7% vs 4%) and included fatal events in three (<1%) Vectibix®-treated patients. recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of [See Reproductive and Developmental Toxicology]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing bevacizumab and chemotherapy. embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3–4 diarrhea was 58%; in addition, grade 5 to cause fetal harm when administered to pregnant women. diarrhea occurred in one patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should ® Pulmonary Fibrosis Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix . Following the initial fatality, call 1-800-772-6436 (1-800-77-AMGEN) to enroll. patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical Nursing Mothers It is not known whether panitumumab is excreted into human milk; however human IgG is excreted into human milk. Published data suggest that studies. Therefore, the estimated risk in a general population that may include such patients is uncertain. breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the One case occurred in a patient with underlying idiopathic pulmonary fibrosis who received Vectibix® in combination with chemotherapy and resulted in death potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking from worsening pulmonary fibrosis after four doses of Vectibix®. The second case was characterized by cough and wheezing 8 days following the initial dose, into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier exertional dyspnea on the day of the seventh dose, and persistent symptoms and CT evidence of pulmonary fibrosis following the 11th dose of Vectibix® as than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3) in Full Prescribing Information]. monotherapy. An additional patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia after 23 doses of Vectibix® in combination with chemotherapy. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates. Pediatric Use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied Electrolyte Depletion/Monitoring In Study 1, median magnesium levels decreased by 0.1 mmol/L in the panitumumab arm; hypomagnesemia (NCI-CTC grade in pediatric patients. 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®. Geriatric Use Of 229 patients with mCRC who received Vectibix® in Study 1, 96 (42%) were ≥age 65. Although the clinical study did not include a sufficient number In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix® completion of Vectibix® therapy. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed. between these patients and younger patients. Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while OVERDOSAGE receiving Vectibix®. Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. EGF Receptor Testing Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix® therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage, and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal NONCLINICAL TOXICOLOGY cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit. Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of panitumumab have been conducted. It is not known if Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay panitumumab can impair fertility in humans. Prolonged menstrual cycles and/or amenorrhea occurred in normally cycling, female cynomolgus monkeys treated weekly performance, including use of suboptimally fixed tissue, failure to utilize specific reagents, deviation from specific assay instructions, and failure to include with 1.25 to 5 times the recommended human dose of panitumumab (based on body weight). Menstrual cycle irregularities in panitumumab-treated female monkeys ® appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx test kit, or other test kits were accompanied by both a decrease and delay in peak progesterone and 17 -estradiol levels. Normal menstrual cycling resumed in most animals after approved by FDA, for identification of patients eligible for treatment with Vectibix® and for full instructions on assay performance. discontinuation of panitumumab treatment.A no-effect level for menstrual cycle irregularities and serum hormone levels was not identified.The effects of panitumumab on male fertility have not been studied. However, no adverse effects were observed microscopically in reproductive organs from male cynomolgus monkeys treated for ADVERSE REACTIONS 26 weeks with panitumumab at doses of up to approximately 5-fold the recommended human dose (based on body weight). The following adverse reactions are discussed in greater detail in other sections of the label: Animal Toxicology and/or Pharmacology Weekly administration of panitumumab to cynomolgus monkeys for 4 to 26 weeks resulted in dermatologic findings, • Dermatologic Toxicity [see Boxed Warning and Warnings and Precautions] including dermatitis, pustule formation and exfoliative rash, and deaths secondary to bacterial infection and sepsis at doses of 1.25 to 5-fold higher (based on body • Infusion Reactions [see Boxed Warning and Warnings and Precautions] weight) than the recommended human dose. • Increased Toxicity With Combination Chemotherapy [see Warnings and Precautions] Reproductive and Developmental Toxicology Pregnant cynomolgus monkeys were treated weekly with panitumumab during the period of organogenesis (gestation • Pulmonary Fibrosis [see Warnings and Precautions] day [GD] 20–50). While no panitumumab was detected in serum of neonates from panitumumab-treated dams, anti-panitumumab antibody titers were present in 14 • Electrolyte Depletion/Monitoring [see Warnings and Precautions] of 27 offspring delivered at GD 100. There were no fetal malformations or other evidence of teratogenesis noted in the offspring. However, significant increases in • Photosensitivity [see Warnings and Precautions] embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight). The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. PATIENT COUNSELING INFORMATION ® The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and Advise patients to contact a healthcare professional for any of the following: septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix® • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis. • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning and Warnings and Precautions], • Persistent or recurrent coughing, wheezing, or dyspnea [see Warnings and Precautions], Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates in the clinical studies of a drug cannot • Pregnancy or nursing [see Use in Specific Populations]. be directly compared to rates in clinical studies of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Advise patients of the need for: ® ® Safety data are available from 15 clinical trials in which 1467 patients received Vectibix ; of these, 1293 received Vectibix monotherapy and 174 received • Periodic monitoring of electrolytes [see Warnings and Precautions], ® Vectibix in combination with chemotherapy [see Warnings and Precautions]. • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix® therapy. [see Warnings and Precautions], • Adequate contraception in both males and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered as a single agent at the recommended Populations]. dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial. The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% This brief summary is based on the Vectibix® prescribing information v4, 6/2008. were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other. Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent No. 6,235,883, as well as other patents or patents pending. © 2006–2008 Amgen Inc.All rights reserved.

Mr. Anderson, incoming ACCC president (left), presents an award of appreciation to past-president Richard B. Reiling, MD, FACS.

—David Bronstein

IN BRIEF

Clinical Oncology News • JANUARY/FEBRUARY 2009

Noncompliance With Tamoxifen Therapy Scrutinized New York—Patients are more likely to ignore recommendations to take tamoxifen than to undergo chemotherapy or radiation, according to an analysis of noncompliance among breast cancer patients. In a series of patients who had undergone lumpectomy and were evaluated at a single institution from 1988 to 2002, the rate of noncompliance with physician-recommended radiation was 4% (30 of 855) and the rate of noncompliance with physician-recommended chemotherapy was 7% (31 of 421). In contrast, more than a third of patients, or 37% (287 of 781), failed to take tamoxifen, and this had a markedly negative impact on their outcomes. The study was presented at the annual meeting of the American Society of Breast Surgeons (ASBS). “Those who did not take this therapy had a significantly increased risk of both local and distant disease recurrence,” said Aye Moe Thu Ma, MD, assistant attending breast surgeon at St. Luke’s-Roosevelt Hospital, New York City. Speaking at the ASBS meeting, Dr. Ma noted that younger women were the most likely to ignore a recommendation to remain on tamoxifen and speculated that fear of menopausal symptoms might be an important factor contributing to their noncompliance. Outcomes were evaluated by chart review. In the 4% of patients who did not comply with radiation therapy, local recurrence rates were higher than in those who did comply (13% vs. 6%), but the difference did not reach statistical significance, “probably

due to low numbers,” Dr. Ma said. She noted that noncompliant patients tended to be slightly older and to have smaller tumors. Although the rate of failure to comply with chemotherapy was higher, at 7%, the unadjusted diseasefree survival (DFS) rate at five years was actually significantly better in the noncompliant group than in the compliant group (88% vs. 71%; P=0.04). However, noncompliant patients were slightly less likely to have positive nodes and more likely to have well-differentiated tumors. When these factors were controlled for, DFS rates were 80% for compliant and 78% for noncompliant patients, a difference that was not statistically significant. Again, the failure to reach statistical significance may have been a consequence of the small proportion of noncompliant patients. Of the 781 patients for whom tamoxifen was recommended, 287 (37%) refused completely or remained on the therapy for less than a year. Noncompliant patients tended to be younger (54 vs. 59 years old) and more likely to have undergone mastectomy (38% vs. 25%; P<0.001). DFS rates in patients with local recurrences at the end of five years of follow-up were 87% for those who were noncompliant and 96% for those who were compliant (P<0.001). Of patients who complied with tamoxifen therapy, 87% were free of distant recurrences at five years, versus 76% for noncompliant patients (P<0.001). Interestingly, white patients were more

Racial Divide Found in Radiation Therapy for Breast Cancer

lack women are less likely than white women to receive radiation therapy after lumpectomy for early-stage breast cancer, according to a study presented at the Breast Cancer Symposium, sponsored in part by the American Society of Clinical Oncology (abstract 91). “The results of this study indicate that we need to identify and correct the obstacles that are causing these disparities, and work to increase awareness about the benefits of radiation therapy following lumpectomy among breast cancer patients,” said Grace Smith, MD, PhD, MPH, in a statement. She is a postdoctoral fellow in the Department of Radiation Oncology at the University of Texas M.D. Anderson Cancer Center in Houston, and the study’s lead author. “We don’t know if fewer black women are receiving radiation therapy because it is not offered to them, because they decline the treatment or perhaps because they are unable to complete a whole course of treatment.” The study was based on an analysis of more than 37,000 Medicare records. Investigators used the database to review the treatment of all female beneficiaries aged 66 years and older who were treated in 2003 for early-stage, newly diagnosed breast cancer. They found that of 37,305 women treated with lumpectomy, 34,024 were white and 2,305 were black. Overall, 74% of white women received radiation therapy after lumpectomy, but only 65% of black women did so (P<0.001). Geographically, the largest racial disparities were seen in the East South Central region (Alabama, Kentucky, Mississippi and Tennessee), where 72% of whites received radiation therapy versus 57% of blacks; the Pacific West, 72% versus 55%, respectively; and New England, 70% versus 58%, respectively. The investigators say the reasons for these geographic differences in radiation therapy are unclear. —Kate O’Rourke

likely to be noncompliant with tamoxifen than African-Americans. The study period in this analysis was before the widespread introduction of aromatase inhibitors, so compliance with this adjunctive treatment was not studied. However, if resistance to tamoxifen is driven by menopausal symptoms, as Dr. Ma speculates, the problem may not be unique to tamoxifen. In the discussion following Dr. Ma’s presentation, Jane Mendez, MD, assistant professor of surgery at Boston University School of Medicine, questioned whether any attempt had been made to evaluate changes in compliance over time. She suggested that patients’ greater awareness of breast cancer risks may have led to a gradual reduction in noncompliance. Questions were also raised about alternative drug treatments among patients noncompliant with tamoxifen. Dr. Ma agreed that this would be an interesting point to pursue because of the availability of “natural” agents purported to provide effects similar to those of tamoxifen. The moderator of the session, Sheldon Feldman, MD, associate professor of clinical surgery at Albert Einstein College of Medicine in New York City, agreed. “In the New York area, we now have a lot of women using Eastern approaches that are so-called hormonal blockers,” said Dr. Feldman, speaking from his own experience. He noted that some women might be willing to substitute an alternative therapy with activity purportedly parallel to that of tamoxifen, even when they were unlikely to seek alternatives to radiation or chemotherapy. —Ted Bosworth

Vitamins E and C Don’t Protect Against Cancer

itamin E and C supplements do not protect against cancer, according to a study of approximately 15,000 individuals presented at the American Association for Cancer Research’s Seventh Annual International Conference on Frontiers in Cancer Prevention Research. “After nearly 10 years of supplementation with either vitamin E or vitamin C, we found no evidence supporting the use of either supplement in the prevention of cancer,” said Howard D. Sesso, ScD, MPH, an assistant professor of medicine at Boston’s Brigham and Women’s Hospital, in a press statement. “While vitamin E and C supplement use did not produce any protective benefits, they also did not cause any harm.” The Physicians’ Health Study II included 14,641 physicians who were at least 50 years old at enrollment. Individuals were given 400 IU of vitamin E every other day or its placebo, or 500 mg of vitamin C daily or its placebo. Patients were followed for up to 10 years for the development of cancer and filled out annual questionnaires. Investigators found that vitamin E did not have a significant effect on the development of prostate cancer or cancer overall, and vitamin C had no effect on overall cancer development. Previous studies have suggested that eating a diet rich in vitamins E and C could lower the risk for cancer, sparking the idea that supplements could offer some protective

benefits. “Individual vitamin supplements such as vitamin E and C do not appear to provide the same potential advantages as vitamins included as part of a healthy, balanced diet,” said principal investigator J. Michael Gaziano, MD, MPH, an associate professor of medicine at Brigham and Women’s Hospital and VA, Boston. An initial, independent review of study data from the Selenium and Vitamin E Cancer Prevention Trial (SELECT) supports some of the conclusions of the Physicians’ Health Study II. The SELECT trial was recently halted after it showed that selenium and vitamin E supplements, taken either alone or together, did not prevent prostate cancer, and data also revealed two concerning trends. The study showed a small but not statistically significant increase in the number of prostate cancer cases among men taking only vitamin E and a small, but not statistically significant increase in the number of cases of adult-onset diabetes in men taking only selenium. The SELECT trial enrolled roughly 35,000 men aged 50 and older and randomly assigned them to one of four groups. One group took both selenium and vitamin E; one took selenium and a vitamin E placebo; one took vitamin E and a selenium placebo; and the final group received placebos of both supplements. —Kate O’Rourke

POLICY & MANAGEMENT

Clinical Oncology News • JANUARY/FEBRUARY 2009

Policy and Management

REGULATORY continued from page 1 

& Medicaid Services (CMS) analysis expects hematology/oncology to see a decrease of 1%. That may not be the case for you as evaluation and management procedures will see increased payment and drug administration will see reductions. You may want to evaluate payment by using data for 2008 and comparing expected payment for 2009 to this year’s income. • Eliminates the additional payment for intravenous immunoglobulin, or IVIG (Code G0332). • Moves decision on certification for imaging to the accreditation organizations. • Reinstates the use of fax transmissions for prescriptions. (See information under e-prescribing.) • Shortens billing opportunity from 27 months prior to getting a provider number from Medicare to 30 days. • Subjects practices to revocation of privileges and to overpayment fines if they fail to meet notification requirements for Medicare participation (ownership, location, adverse events).

Table. Summary of Coding Changes Type of Change

Code

Description

New codes

J0641

Injection levo-leucovorin calcium 0.5 mg

J1453

Injection fosaprepitant 1 mg

J1459

Injection immune globulin intravenous, nonlyophilized

J8705

Oral topotecan 0.25 mg

J9033

Injection bendamustine HCl 1 mg

J9207

Injection ixabepilone 1 mg

Changed descriptors

Deleted codes

Reinstated code

J9330

Injection temsirolimus 1 mg

J1572

Injection immune globulin, intravenous

J2788

Injection Rho D immune globulin human minidose 50 mcg (250 IU)

J2790

Injection Rho D immune globulin, human full dose 300 mcg (1,500 IU)

Q4096

Injection von Willebrand factor complex human ristocetin cofactor

Q4097

Injection immune globulin intravenous, nonlyophilized

Q4098

Injection iron dextran 50 mg

J1750

Injection iron dextran 50 mg

• Delays changes to physician selfreferral laws in order to gather more information from providers through a comment period; Medicare will review comments before issuing changes. • Modifies the anti-markup rules for technical and professional charges beginning Jan. 1, 2009. Prohibits markup unless the test is processed and interpreted by an employee or contractor who spends at least 75% of their time in the practice. You may only bill the net charge to you or allowable amount. • Requires nurse practitioners who have practiced since 2003, to have a master’s or doctorate degree in nursing to bill, starting January 2009. • Commits to move forward with value-based incentives, such as the 2% incentive seen in hospitals for care quality reporting, to other settings such as nursing homes and other health care settings.

Incentive Payment Programs In order to encourage the adoption and use of e-prescribing, Congress (under the Medicare Improvements for Patients and Providers Act of 2008) authorized the creation of a new and separate program to report on e-prescribing quality measures. Beginning Jan. 1, 2009, physicians can earn an incentive of 2% of their total allowed Medicare charges during 2009, if they adopt and use qualified electronic prescribing systems to transmit prescriptions to pharmacies. You must report the e-prescribing quality measure through your Medicare Part B claims on at least 50% of applicable cases during the reporting year. The e-prescribing document is available at www.cms.hhs.gov/partnership/download/11399.pdf. Physicians can also earn an additional 2% incentive payment in 2009 under the Physician Quality Reporting Initiative (PQRI). The 153 quality measures selected for the 2009 PQRI were published by the CMS in the Medicare Physician Fee Schedule 2009 Final Rule. Several new measures were added for oncology, and others found in the 2008 PQRI program were eliminated.

Oncology-Specific Coding Changes Oncology practices need to be aware of several changes to billing codes. The table includes information regarding the new, deleted and reinstated codes as well as changed descriptors. The entire code list and details for other changes appear in the CMS Final Rule, which can be found at: www.cms. hhs.gov/PhysicianFeeSched/PFSFRN/itemdetail. asp?filterType=none&filterByDID=-99&sortByDID= 4&sortOrder=ascending&itemID=CMS1216674&intN umPerPage=10.

conduct diagnostic testing, non–hospital-based practices with increased diagnostics. And finally, the OIG will review the appropriateness of providers’ use of the modifier GY on claims for services that are not covered by Medicare. In 2009, the CMS will join the OIG in placing increased scrutiny on oncology practices. The CMS has taken the next steps in the agency’s comprehensive efforts to identify improper Medicare payments and fight fraud, waste and abuse in the Medicare program by awarding contracts to four permanent Recovery Audit Contractors (RACs) designed to guard the Medicare trust fund. While the CMS has postponed all activity involving the recovery audit contractors, clinicians should keep the RAC contracts on their radar. The CMS was required to delay implementation because of complaints to the Government Accountability Office by two unsuccessful bidders for the RAC program. The issue may be resolved in February. To learn more about the RAC program, visit www.cms. hhs.gov/RAC.

Happy New Year? In 2009, a new federal government that espouses the word ”change” as its mantra will be installed. Clinicians can expect even more changes in the years ahead. President-elect Barack Obama’s Plan for a Healthy America focuses on lowering health care costs and ensuring affordable, high-quality health care for all. Oncologists can expect more reductions in payment to providers and more scrutiny of costs. In the new year, resolve to stay on top of the changes that are on the horizon. Plan ahead now and implement practices proactively, to ensure that you won’t have to back-pedal and catch up in the future. Change is in the air! —Mary Lou Bowers, MBA, President & CEO and Rhonda M. Gold, RN, MSN, Director of The Pritchard Group, LLC, in Rockville, Md. www.thepritchardgroup.net

Web Resources

Ensuring You Are On the Up and Up In 2009, the Office of Inspector General (OIG) Work Plan will place greater scrutiny on four aspects of oncology practice. First, the OIG will examine whether physician practices or hospital-based facilities are being overpaid, because they are improperly identifying their practice situations. Second, the OIG will review “incident to” services for which physicians bill Medicare but that are typically performed by nonphysician staff. Practices should examine the qualifications of nonphysician staff that perform these services and assess whether their qualifications are consistent with professionally recognized standards of care. Third, the OIG will review communities that have an increase in freestanding physician clinics that

CMS Final Rule 1403-FC www.cms.hhs.gov/PhysicianFeeSched/PFSFRN/ itemdetail.asp?filterType=none&filterByDID=99&sortByDID=4&sortOrder=ascending&itemID= CMS1216674&intNumPerPage=10

The OIG Work Plan www.oig.hhs.gov/publications/docs/workplan/2009/WorkPlanFY2009.pdf

Summary of PQRI Measures www.cms.hhs.gov/PQRI/ Downloads/2009PQRIMeasuresList.pdf

CLINICAL TRIALS

Clinical Oncology News • JANUARY/FEBRUARY 2009

New Phase II and III Clinical Trials

Hematologic

Solid tumors

Trials added to the National Cancer Institute’s list of clinical trials in the 30 days prior to Jan. 7, 2009. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials, click on the advanced link and enter the protocol ID.

Protocol Type

Age

Protocol ID

Trial Sites

Intraoperative Celiac Plexus Neurolysis for Patients With Operable Pancreatic and Periampullary Cancer, Phase III

18 and over

CCRRC 2007-32

Study to Test the Benefit of a New Kind of Anti-Cancer Treatment in Patients With Melanoma After Surgical Removal of Their Tumor, Phase III

18 and over

111482

FL, TX

Randomized Study of a Lymphodepleting Conditioning Regimen Comprising Cyclophosphamide, Fludarabine Phosphate, and Total-Body Irradiation Followed by Anti-MART-1 and Anti-gp100 T-Cell Receptor Gene-Engineered Autologous Peripheral Blood Lymphocytes, High-Dose Aldesleukin and gp100:154-162 or MART-1:26-35(27L) Peptide Vaccination in Patients With Metastatic Melanoma, Phase II

18 and over

NCI-09-C-0051

A Study to Determine the Maximum Tolerated Dose of Elesclomol Sodium Given With a Fixed Dose of Docetaxel and Prednisone in Patients With Metastatic Prostate Cancer, Phase I/II

18 and over

4783-12

Biomarker Study of Neoadjuvant Vitamin E in Patients With Locally Treatable Prostate Cancer Prior to Prostatectomy or Brachytherapy, Phase III

18 and over

INST 0808

Randomized Study of Bicalutamide With Versus Without Everolimus in Patients With Hormone-Independent Recurrent or Metastatic Adenocarcinoma of the Prostate, Phase II

18 and over

UCDCC-215

Efficacy and Safety of Masitinib (AB1010) in Comparison to Imatinib in Patients With Gastrointestinal Stromal Tumour, Phase III

18 and over

AB04030

FL, MI, NY

Trial of Postoperative Radiation, Cisplatin, and Panitumumab in Locally Advanced Head and Neck Cancer, Phase II

Over 18

UPCI 06-120

Study of Nonmyeloablative Lymphodepleting Conditioning Comprising Cyclophosphamide and Fludarabine Phosphate Followed by Anti-HER-2 Gene-Engineered Autologous Peripheral Blood Lymphocytes and High-Dose Aldesleukin in Patients With Metastatic Cancer That Expresses HER-2, Phase I/II

18 and over

NCI-09-C-0041

Pilot Study of Exemestane in Postmenopausal Women With Stage IV Breast Cancer, Phase II

18 and over

CHNMC-08063

Study to Evaluate the Safety and Efficacy of NKTR-102 (PEG-Irinotecan) in Patients With Metastatic or Locally Advanced Breast Cancer, Phase II

18 to 120

08-PIR-05

IL, KY

Study of Nonmyeloablative Lymphodepleting Conditioning Comprising Cyclophosphamide and Fludarabine Phosphate Followed by Anti-CEA TCR-Gene Engineered Autologous Lymphocytes and High-Dose Aldesleukin in Patients With Metastatic Cancer That Expresses CEA, Phase I/II

18 and over

NCI-09-C-0047

Study of Neoadjuvant Stereotactic Radiosurgery in Patients With Brain Metastases, Phase II

18 and over

DUMCPRO00006870

Pilot Study of Adjuvant Stereotactic Radiosurgery in Patients With Brain Metastases, Phase II

18 and over

DUMCPRO00004373

Evaluation of the Efficacy and Safety of [18F]-ML-10, as a PET Imaging Radiotracer, in Early Detection of Response of Brain Metastases of Solid Tumors to Radiation Therapy, Phase II

18 and over

NST-CA004CTIL

Neuroblastoma Protocol 2008: Therapy for Children With Advanced Stage High-Risk Neuroblastoma, Phase II

Under 18

NB2008

Randomized Study of Intralesional Lymphokine-Activated Killer Cells Versus Polifeprosan 20 With Carmustine Implant (Gliadel Wafer) as Consolidation Therapy After Primary Therapy in Patients With Newly Diagnosed Resectable Glioblastoma Multiforme, Phase II

18 and over

HOAG-HCC-08-01

Everolimus (RAD001) in Metastatic Transitional Cell Carcinoma of the Urothelium, Phase II

18 and over

08-123

NJ, NY

Dose-Dense MVAC With Pegfilgrastim Support in Subjects With Muscle-Invasive Urothelial Carcinoma, Phase II

18 and over

08-208

Study to Evaluate the Safety and Efficacy of NKTR-102 (PEG-Irinotecan) in Patients With Metastatic or Locally Advanced Ovarian Cancer, Phase II

18 and over

08-PIR-04

Rollover Protocol for Prior SU011248 Protocols (gastrointestinal stromal tumors and kidney cancer), Phase II

18 and over

A6181030

CA, CO, MI, NY, PA, TN, TX, WI

Study of Sorafenib Tosylate Dose Re-Escalation in Patients With Advanced Malignant Solid Tumors, Phase II

18 and over

UCDCC-213

Paclitaxel, Bevacizumab and Pemetrexed in Patients With Untreated, Advanced Non-Small Cell Lung Cancer Using Web-Based Data Collection, Patient Self-Reporting of Adverse Effects and Automated Response Assessment, Phase II

18 and over

08-109

NJ, NY

Vorinostat and Bortezomib as Third-Line Treatment in Advanced Non-Small Cell Lung Cancer, Phase II

18 and over

H-2008-0229

Vaccination of Patients With Ovarian Cancer With Dendritic Cell/Tumor Fusions With Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF) and Imiquimod, Phase II

18 and over

07-380

A Dose Range Finding Study of Lenalidomide in Non-5q Chromosome Deletion in Low and Intermediate Risk Myelodysplastic Syndrome (MDS) Patients, Phase I/II

18 and over

RV-MDS-PI-244

Double Cord Blood Transplantation, Phase I/II

30 and under

CHNY-06-533

Autologous and Allogeneic Transplant for Relapsed Lymphoma, Phase I/II

30 and under

CHNY-01-501

Study of T-Cell–Reduced Unrelated Donor Peripheral Blood Stem Cell Transplantation After Reduced-Intensity Conditioning Comprising Pentostatin and Low-Dose Total-Body Irradiation in Patients With Hematological Malignancies, Phase I/II

19 to 75

UNMC-16407

Study of Nilotinib in Patients With Newly Diagnosed Philadelphia Chromosome-Positive Chronic Phase Chronic Myelogenous Leukemia, Phase II

18 and over

CORG-08-02

Hematologic

CLINICAL TRIALS

Supportive

Clinical Oncology News • JANUARY/FEBRUARY 2009

Protocol Type

Age

Protocol ID

Trial Sites

Study of Induction and Consolidation Therapy Comprising Clofarabine and Daunorubicin Hydrochloride in Older Patients With Newly Diagnosed Acute Myeloid Leukemia, Phase II

60 and over

RPCI-I-132208

Fludarabine, Cytarabine, G-CSF and Gemtuzumab Ozogamicin in CBF Leukemias, Phase II

18 and over

2007-0147

Thymoglobulin and Cyclosporine in Patients With Aplastic Anemia or Myelodysplastic Syndrome, Phase II

15 and over

2005-0115

Lenalidomide (Revlimid) Plus Low-Dose Dexamethasone (Ld × 4 Cycles) Then Stem Cell Collection Followed by Randomization to Continued Ld or Stem Cell Transplantation (SCT) Plus Maintenance Ld for SCT Patients Not Achieving at Least Very Good Partial Response (VGPR) or Having High-Risk Disease, Phase II

18 to 75

08-121

NJ, NY

Safety Study of Bone Marrow Transplant Using Mismatched Tissue Followed by Chemotherapy, Phase II

6 months to 65

J0820

Prevention of Breast Cancer: As Simple as hCG—A Randomized Clinical Trial in High-Risk Women, Phase III

30 to 75

GD-10-08

Dose Escalation Study Using Extracranial Stereotactic Radiosurgery to Control Pain, Phase I/II

18 and over

07-1149

Busulfan and Fludarabine Followed by Post-Transplant Cyclophosphamide After Allogeneic Stem Cell Transplantation, Phase II

6 months to 70

2008-0261

Study of the Intrathecal Administration of Resiniferatoxin for Treating Severe Refractory Pain Associated With Advanced Cancer, Phase I/II

18 and over

090039

SUPPORTIVE CARE

ESAs continued from page 1 

although ESAs can reduce the number of cancer patients who require transfusions, they can also have adverse effects such as increasing the risk for thromboembolic events, impairing tumor control and even decreasing survival. An international team of investigators set out to further examine the issue and determine whether all or subsets of patients experience these adverse effects. The investigators conducted a meta-analysis of 53 studies involving data from 13,933

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Table. Survival Outcomes In 13,933 Patients Receiving ESAs

End Point

Hazard Ratio (CI)

On-study mortality

1.17 (1.06-1.30)

0.002

Overall survival

1.06 (1.00-1.12)

0.05

‘The increased risk of death must be balanced against the benefits of ESAs, taking into account each patient’s clinical circumstances and preferences.’ —Julia Bohlius, MD, MScPH

P Value

‘We need to know what is going on at the cellular level.’ —Julia Bohlius, MD, MScPH

cancer patients enrolled in randomized controlled trials comparing epoetin alfa (Epogen, Amgen; Procrit, Ortho Biotech), epoetin beta (NeoRecormon, Roche) or darbepoetin alfa (Aranesp, Amgen) plus red blood cell transfusions as needed versus transfusion alone, for prophylaxis or treatment of anemia while or after receiving anti-cancer therapy. (Epoetin beta is sold only in Europe.) The analysis was based on the intention-to-treat principle, and 38 trials (10,441 patients) used mainly chemotherapy. The primary end points were overall survival and on-study mortality, defined as death from any cause between the date of randomization until the end of the treatment period plus a follow-up of four weeks, the longest follow-up available. Overall survival was defined as death from any cause between date of randomization and longest follow-up available. Investigators found that ESAs increased

on-study mortality by 17% (hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.06-1.30; P=0.002) and decreased overall survival by 6% (HR, 1.06; 95% CI, 1.00-1.12; P=0.0046). In the chemotherapy population, ESAs increased onstudy mortality by 10% (HR, 1.10; 95% CI, 0.98-1.24; P=0.12) and decreased overall survival by 4% (HR, 1.04; 95% CI, 0.97-1.11; P=0.26). Evidence did not prove that these outcomes were affected by characteristics such as age, sex, hemoglobin (Hb) and hematocrit at baseline, Hb ceiling, type and stage of tumor, anti-cancer treatment type, ESA treatment schedules or study design and quality. Individual trialists and companies that produce ESAs provided investigators with individual patient data, but Dr. Bohlius emphasized that the companies had no involvement in the study funding, design or data analysis and interpretation. The study was entirely funded by industry-independent sources: German Ministry of Education and Research and OncoSuisse. According to Dr. Bohlius, it is clear that ESAs increase the risk for death in some, not all, people but it is unclear exactly why this happens. ESAs’ ability to increase thromboembolic events or impair tumor control are two possible explanations. According to Dr. Bohlius, studies should focus on elucidating the mechanisms

involved. “We need to know what is going on at the cellular level,” she said. Although some evidence has linked poor outcomes with ESAs to high levels of erythropoietin receptor messenger RNA in tumors, Andreas Engert, MD, senior author of the study, said he didn’t really buy it. “There are no convincing data to suggest this is clinically relevant,” said Dr. Engert, MD, professor of internal medicine, University of Cologne, in Germany. Investigators not involved in the study applauded the Herculean task of analyzing the enormous amount of data. “The American Society of Hematology was really looking forward to the presentation of this abstract. This is a huge amount of work,” said Samuel Silver, MD, PhD, chair of the ASH subcommittee on reimbursement and professor of internal medicine at the University of Michigan Medical School, Ann Arbor. “ASH in collaboration with the American Society of Clinical Oncology updated ESA guidelines last year and … the guidelines parallel and anticipate the findings that Dr. Bohlius gave.” He said that the guidelines would be revisited in early 2009, but would not comment on whether he thought the guidelines would be changed. “I’m not going to anticipate the guideline committee,” said Dr. Silver. —Kate O’Rourke

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This book is intended to outline our style of executing these anesthetics—that is, our NEUrosurgical anesthetic RECIPES. The goal of this manual is to aid the new anesthesia oncology clinician, fellow, or resident in quickly reviewing MD Anderson’s approach to the neurosurgical cases.

PET-CT in Radiotherapy Treatment Planning Arnold C. Paulino; Bin S. Teh

Here is an exciting new guide to the use of PET-CT imaging in radiotherapy. You'll get practical, useful information for utilizing this novel imaging technique—from different methods for contouring biological target volumes in various anatomic regions to how different experts use this imaging in targeted treatment. This thorough text helps you make concise, accurate treatment choices based on current evidence and expert authority. The result is an essential tool for everyone on the radiotherapy treatment team in the era of image-guided radiotherapy. CO0109

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