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MEDICAL MINUTES Do sleeping pills increase cancer risk?
CANCER CENTER PROFILE University of Texas M.D. Anderson Cancer Center
HEMATOLOGIC CANCERS 18-month response and survival rates for nilotinib in CP-CML
SEPTEMBER/OCTOBER 2008 • VOL. 1, NO. 4
The Official Newspaper of Record for the Hem/Onc Pharmacist
GASTROINTESTINAL CANCERS KRAS Status Has Major Impact on Response in Colorectal Cancer
Advancing Oncology Pharmacy to a New Level An interview with Siu-Fun Wong, PharmD, FASHP, FCSHP
ncology pharmacy is an increasingly sophisticated field, and oncology pharmacists are involved in direct patient care as well as research, teaching, and drug preparation and handling. Siu-Fun Wong, PharmD, FASHP, FCSHP, of Western University College of Pharmacy, has the distinction of having served as principal inves-
tigator in clinical trials. She discusses her research activities as well as her teaching philosophy in this interview.
Could you please describe your background? I was born and raised in Hong Kong and came to the United States when I started my college education. I received my Bachelor
of Science degree in biochemistry at the University of California, Los Angeles, and my Doctor of Pharmacy degree at the University of California, San Francisco. Afterwards, I did 1 year of clinical pharmacy residency at the University of California, Irvine.
CHICAGO—A retrospective analysis indicates that the KRAS mutation status of tumors has a significant impact on response rate and progression-free survival (PFS) in patients receiving first-line treatment for metastatic colorectal cancer (mCRC). The Oxaliplatin and Cetuximab in First-line Treatment of Metastatic Colorectal Cancer (OPUS) study, reported by Carsten Bokemeyer, MD, Universitätsklinikum Eppendorf, Hamburg, Germany, at the 2008 Annual Meeting of Continued on page 13
Complimentary CE Credit
Continued on page 7
Oral Chemotherapy Adherence Enhanced by Multiple Strategies
HOPA: CMS Regulations Impact ESA Utilization, Patient Outcomes
ANAHEIM—Oncology pharmacists can enhance patient adherence with oral chemotherapy through a combination of educational interventions, medication reconciliation, and other strategies, said Gary Yee, PharmD, University of Nebraska Medical Center, Omaha. Nearly one third of oncology drugs currently in
ANAHEIM—Compliance with new Centers of Medicare and Medicaid Services (CMS) guidelines on the use of erythropoiesis-stimulating agents (ESAs) in patients with chemotherapy-induced anemia (CIA) may result in decreased utilization of ESAs and increased use of red blood cell (RBC) transfusions and other resources.
Continued on page 10
Continued on page 8
Program #CIK 9944: Treatment of Cancer Anemia with Erythropoiesisstimulating Agents and IV Iron Supplementation
LEBANON JUNCTION, KY
Laura Boehnke Michaud, PharmD
Gene expression identifies highrisk prostate neoplasia
page 7 © 2008 Green Hill Healthcare Communications, LLC
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Advanced RCC: A Path Forward
Novartis Oncologyâ€”A commitment to clinical research
A rapidly changing environment
The potential for progress
Over the past several years there have been significant advances made in the management of renal cell carcinoma (RCC). Targeted therapies have provided new options for oncologists treating this disease. Through the development of tumor-specific programs, Novartis Oncology continues to conduct clinical research with the goal of advancing our understanding of RCC.
The fast pace of emerging data within this dynamic environment is changing the landscape of RCC. There is a clear need to harness the potential of these recent advances by establishing a clear path forward.
Novartis Oncology has built a strong history of furthering the development of cancer therapies. As we bring new research to the forefront of cancer care, our aim is to better address the outstanding issues in RCC, a disease we are dedicated to combating.
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Medical Minutes BY JOHN SCHIESZER
Prescription Sleeping Pills May Be Associated with Increased Cancer Risk John Schieszer is an award-winning national journalist and radio broadcaster of The Medical Minute. He can be reached at firstname.lastname@example.org.
developed kidney, thyroid, and testicular cancers and suffered chromosome damage, a sign of carcinogenicity. Although a direct causal link between cancer and sleeping pills has still not been proved, Kripke is now urging additional studies. He said this issue is critical today given the fact that sleeping pill use has been steadily rising in the United States and three new types have been approved for commercial use in addition to zolpidem, which is the most popular sleep-aid drug used in the United States. “Because the compilation mixes diverse studies of several drugs, and the number of cancers observed during controlled hypnotics trials remains small,” writes Kripke, “this preliminary analysis should be viewed as an investigative step, rather than sufficient proof that modern hypnotics cause cancer.” He is urging regulatory bodies and the US National Institutes of Health to keep an eye on cancer cases reported by sleeping pill users. ©iStockphoto.com/Leigh Schindler
The next time you consider popping a pill when you have trouble sleeping, it might be worth counting sheep instead. A senior psychiatrist at the Scripps Clinic Sleep Center in San Diego, California, has found evidence that taking sleeping pills on a regular basis may increase the risk of skin cancer. Daniel Kripke, MD, and his colleagues have published a study in the Journal of Sleep Research (Kripke DF, et al. J Sleep Res. 2008;17:245-250.) that is based on a compilation of studies involving sleeping pills and cancer. The researchers assessed the effects of 556 person-years of taking zaleplon, eszopiclone, ramelteon, or zolpidem compared with a control group who took placebo more than 230 person-years. They found eight nonmelanoma skin cancers and four tumors of uncertain malignancy in the groups that took sleeping pills compared with none in the placebo groups. Laboratory animals given high doses of hypnotic drugs have
Seeking to improve on nature, scientists are now using spice- these molecular targets can initiate cell death or stop cell migrabased compounds as a starting point, and they have developed tion in the cancers. synthetic pharmaceutical compounds that may be able to kill A major component of their strategy is called structure-based, cancer cells and stop the cells from spreading. Investigators are computer-aided design. This is a relatively new technology in combining organic chemistry, computer-aided design, and the drug discovery field. Before working with an actual commolecular biology techniques for developing compounds that pound, scientists can manipulate computer-designed molecules can fight breast cancer and prostate cancer. The synthetic mol- and observe simulated interactions between molecules and proecules are derived from curcumin, a naturally occurring com- teins to predict which structural changes will make the most pound found in the spice turmeric. sense to pursue. Centuries of anecdotal evidence and recent scientific research “Most of the interaction between our compound and the oversuggest that curcumin has multiple disease-fighting features, active protein comes from what are called hot spots on the proincluding antitumor properties. However, when eaten, curcumin tein’s surface,” said Chenglong Li, PhD, an assistant professor of is not absorbed well by the body. Instead, most digested curcu- medicinal chemistry and pharmacognosy and an expert in commin in food or supplement form remains in the gastrointestinal putational chemistry at Ohio State University. “For each spot, system and is eliminated before it is able to enter the blood- we can design small chemical fragments and link them together stream or tissues. to make a molecule. This is what computer-aided design and “Newer evidence describes how curcumin interacts with cer- modeling can do.” tain proteins to generate anticancer activity inside the body. We’re focusing on the pathways that are most involved Sorafenib Found to Have Benefits in the in cancer and trying to optimize for Treatment of Liver Cancer those properties,” said James Fuchs, PhD, assistant professor of medicinal Researchers at Mount Sinai School of ined overall survival and the time it took chemistry and pharmacognosy at Ohio Medicine in New York have found that for cancer to progress in patients with State University, Columbus. sorafenib may prolong the lives of previously untreated liver cancer. All the Fuchs, who is the principal investigapatients with advanced liver cancer by subjects were randomly assigned to tor for this study, said a selection of 40 about 44% compared with patients who receive either 400 mg of sorafenib twice compounds appear to have the most received placebo. Liver cancer is current- daily (229 patients) or a placebo (303 potential to date to serve as the basis for ly the third leading cause of cancer death patients). anticancer drug development. He and globally, often resulting in death within 1 Patients who received sorafenib lived a his colleagues are continuing to refine year of diagnosis. median of 10.7 months compared with compounds that are best structured to “This is the first time that we’ve had an 7.9 months for those who received a interact with a few overactive proteins effective systemic treatment for liver cancer,” placebo. Time to radiologic progression that are associated with cell activity in said lead study investigator Josep Llovet, MD, was significantly longer in the treatment breast and prostate cancers. Blocking who is director of research in Liver Cancer at group: 5.5 months versus 2.8 months. Mount Sinai School of Medicine. “Our find- Llovet said because the findings were so ings demonstrated survival advantages that positive the trial was stopped early. are both statistically significant and clinically The incidence of adverse effects was meaningful.” similar in the two groups (52% in the Taken orally, sorafenib is approved in sorafenib group and 54% in the placebo the United States for treatment of group). The most common moderate-toadvanced kidney cancer, but it is current- serious side effects were diarrhea, skin ly being evaluated in patients with other reactions on the hands and feet, fatigue, cancers. Llovet and his associates exam- and bleeding. ©iStockphoto.com/Elena Molseeva
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Spicing Up the Fight Against Cancer
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Vol. 1, No. 4
Feature Articles CONTENTS
Cancer Center Profile
Publisher Philip Pawelko email@example.com
Editorial Director Karen Rosenberg firstname.lastname@example.org
M.D. Anderson Cancer Center
13 Gastrointestinal Cancers KRAS status and skin toxicity predict response in colorectal cancer
14 Hematologic Cancers Sustained dasatinib benefits
15 Continuing Education Treatment of Cancer Anemia with ESAs and IV Iron
Managing Editor Lara J. Reiman
Directors, Client Services John W. Hennessy email@example.com
Russell Hennessy firstname.lastname@example.org
Senior Production Manager Stephanie Laudien
10 Recent FDA Approvals
Director of Human Resources Blanche Marchitto email@example.com Circulation firstname.lastname@example.org
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David Baribeault, RPh, BCOP Boston Medical Center Boston, MA
Sylvia Bartel, RPh, MPH Dana Farber Cancer Institute Boston, MA
Deborah Blamble, PharmD, BCOP University of Texas MD Anderson Cancer Center Houston, TX
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Laura Boehnke Michaud, PharmD, BCOP, FASHP The University of Texas MD Anderson Cancer Center Houston, TX
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University of Florida Gainesville, FL
University of Nebraska College of Pharmacy Omaha, NE
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Desert Regional Medical Center Palm Springs, CA
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vision extends beyond science
…making today’s therapies more accessible and tomorrow’s breakthroughs more achievable Supporting today The Genentech® Access to Care Foundation makes our marketed products available to qualified patients in need* Genentech BioOncology™ Access Solutions™, formerly known as SPOC® (Single Point of Contact) — For patients and their healthcare providers, Genentech BioOncology Access Solutions provides coverage and reimbursement support, patient assistance, and informational resources Investing in tomorrow Genentech BioOncology invests deeply in research and development and is an industry leader in investing a percentage of annual revenues back into R&D Genentech BioOncology funds grant and fellowship programs to support medical education, partner with professional societies, and encourage independent research *The Genentech Access to Care Foundation was established to help qualified patients with unmet medical needs who are uninsured or rendered uninsured by payer denial and who meet specific medical criteria to receive proper medical treatment. The Genentech Access to Care Foundation may be available to help those who are not able to obtain Genentech therapeutics for financial reasons.
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All rights reserved.
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A Letter from the Editor A SUSAN GOODIN, PHARMD, FCCP, BCOP
study published in the July 28 issue of Archives of Internal Medicine shows a dramatic 360.5% increase in the overall deaths from fatal medication errors (FMEs) in the United States from 1983 to 2004. The authors suggest that the increase is linked to “a shift in the location of medication consumption from clinical to domestic settings” and that “it may now be possible to reduce FMEs by focusing not only on clinical settings but also on domestic settings.” Although this study was not specifically about cancer drugs, it has important implications for oncology pharmacists in view of the increasing use of oral chemotherapy agents administered at home rather than in the clinic. A major concern for oncology pharmacists and other healthcare providers is how to ensure adherence to oral chemotherapy regimens, avoid medication errors, and improve treatment outcomes. Nonadherence to treatments for chronic medical conditions is so prevalent, in fact, that it has been termed “America’s other drug problem.” One observer wrote “Increasing the effectiveness of adherence interventions may have a far greater impact on the health of a population than any improvement in specific medical treatments” (Haynes RB, et al. Cochrane Database Syst Rev. 2002;CD000011). No matter how many new drugs are developed or how effective they are, if patients do not take their medicines as prescribed, they will not work, and we will fail as healthcare
Coming Soon CE article: Does Finasteride Prevent Prostate Cancer?
“Growing Pains” of Oncology Specialty Pharmacy Opportunities for Oncology Pharmacists at the FDA Setting Up a Chemotherapy Prep Area in a Community Practice Using Nanoparticles to Deliver Chemotherapy
Reports from ASCO Breast Cancer Symposium, European Society for Medical Oncology
For a free subscription go to www.theoncologypharmacist.com 4
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providers. The impact of nonadherence on treatment outcomes and strategies for improving adherence to oral chemotherapy were presented in a symposium held during the annual HOPA/ISOPP meeting and summarized in an article in this issue. Another issue that has generated much discussion in the past year has been the appropriate use of erythropoiesis-stimulating agents (ESAs) for cancer-related anemia. The continuing education article this month discusses the use of intravenous iron supplementation to increase the efficacy of ESAs in cancer patients with anemia. Use of ESAs was also addressed in several studies presented at HOPA/ISOPP and the findings are reported here. Also of note in this issue is the interview with Siu-Fun Wong, an oncology pharmacist who has served as prinicipal investigator in a number of clinical trials, one of the many new roles oncology pharmacists are now playing in cancer care. October is American Pharmacists Month, which recognizes the many contributions pharmacists make to healthcare whether they work in a retail pharmacy, hospital or clinic, industry, managed care, or other setting. The Oncology Pharmacist seeks to highlight the accomplishments of pharmacists in this increasingly complex field. Please write to us (Karen@greenhillhc.com) and tell us about your own experiences and thoughts on issues of importance to you and your colleagues. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist™, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: email@example.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in The Oncology Pharmacist™, do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Pharmacist™, should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director. ISSN #1944-9607. The Oncology Pharmacist™, is published 5 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2008 by Green Hill Healthcare Communications LLC. All rights reserved. The Oncology Pharmacist™ logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.
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News Notes NEWS NOTES
Link Between Smoking and Bladder Cancer Not Well Known
Physicians need to educate patients that smoking increases the risk of bladder cancer and direct them to smoking cessation programs, a new study suggests. Up to half of bladder cancer cases may be attributed to cigarette smoking, but a recent study indicates most people are not aware of the relationship between the two. Results showed little more than one third of adults were aware smoking increased the risk of bladder cancer; even among those with early-stage bladder cancer, just 22% were aware of smoking’s contribution to the disease. Smoking cessation decreases the risk, as well as the recurrence of bladder cancer, by as much as 30%, but researchers also found physicians are not actively counseling their patients. Even smokers with bladder cancer claimed their physicians had not advised them to quit smoking. One US study found that only half of smokers, and in the United Kingdom only 7% of smokers, had been advised to quit. (Strope SA, Montie JE. J Urol. 2008;180:31-37.)
Topical Analgesic May Ease Discomfort of Mammography
Pretreatment with lidocaine can significantly reduce the discomfort of mammography according to a new study. A double-blind, placebo-controlled study of 418 women between the ages of 32 and 89 years showed that women who premedicated with a
4% lidocaine gel experienced significantly less discomfort than those who used 1000 mg acetaminophen or 800 mg ibuprofen, which had no beneficial effect. Patient satisfaction was significantly lower in patients who reported discomfort. Patient satisfaction significantly affected the women’s plans to have another mammogram the following year. Positive interactions between the patient and the nurse or technologist increased patient satisfaction. The researchers noted that lidocaine has few side effects, is available over the counter, and can be applied at home approximately 1 hour before a mammogram is scheduled to take place. (Lambertz CK, et al. Radiology. 2008;248:765.)
Cancer Treatment’s Effects on
Beneficial for Depressed Cancer Patients
Skin Affect Quality of Life
Exercise Testing Not Adhering
The findings of the survey indicate a need to
to National and International Guidelines
educate patients with cancer about their
Exercise testing is used increasingly in both cancer care and research to evaluate either a patient’s presurgical or cardiorespiratory fitness after a cancer diagnosis. A new study indicates, however, that exercise tests are not administered according to national and international guidelines. The researchers found that key physiological outcomes that provide information rapidly on a patient’s fitness level or the validity of the test are frequently not reported. They recommend standardizing exercise tests for oncology patients to ensure safety and reliable test results. (Jones LW, et al. Lancet Oncol. 2008;9:757-765.)
One-on-one problem-solving therapy with an oncology nurse is more effective than usual care in helping patients with cancer cope with depression, Scottish researchers report. In a study of 200 outpatients with cancer and depression, 99 patients were assigned to usual care, and 101 received usual care as well as psychotherapy. Patients participated in approximately seven 45-minute sessions with an oncology nurse, after which they received monthly telephone calls for 3 months to evaluate their depression. If it was worsening, patients could have one
treatment’s possible effects on their skin and to assist them find ways to alleviate their symptoms. to two more therapy sessions. At 3 months, the patients who received psychotherapy gained 0.34 points on the self-reported Symptom Checklist-20 depression scale (range, 0-4) compared with those who received usual care, and this effect was sustained at 6 and 12 months. The psychotherapy intervention was estimated to cost approximately $10,556 per quality-adjusted life-year gained. (Strong V, et al. Lancet. 2008;372:40-48.)
Eliminating H Pylori Reduces Recurrence of Stomach Cancer
“These are the possible side effects.” 6
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Skin-related side effects negatively affect cancer patients’ quality of life, a CancerCare survey shows. Of 345 patients who were either undergoing or had recently completed treatment for breast, ovarian, lung, colorectal, prostate, bladder, or kidney cancer, 63% believed the condition of their skin had gotten worse as a result of treatment, and one in three patients believed these side effects had had a negative impact on their lives. Fewer than two in five people had been concerned about skin-related side effects on beginning their cancer treatment,
Prophylactic eradication of Helicobacter pylori after endoscopic resection of early gastric cancer reduces the risk of cancer recurrence, according to Japanese researchers. Results of a multicenter trial showed that among 544 patients having surgery for early-stage cancer of the stomach, patients whose regimen included H pylori elimination had a two thirds lower risk of recurrence than those in the control group. After 3 years, stomach cancer had recurred in nine of the 272 patients given the regimen compared with 24 of 272 patients in the control group, with an odds ratio for gastric carcinoma of 0.353 (P = .009) and a hazard ratio of 0.339 (P = .003). The elimination regimen included lansoprazole 30 mg twice daily, amoxicillin 750 mg twice daily, and clarithromycin 200 mg twice daily for 1 week. The control group received standard care only. Among patients receiving the H pylori regimen, adverse effects included diarrhea (in 19 patients [7%]) and soft stools (in 32 patients [12%]). (Fukase K, et al. Lancet. 2008;372:392-397.)
but almost 80% became concerned about the actual side effects they ultimately experienced. These side effects included, in particular, irritation, rash, and dryness (which led the list of complaints at 61%). Almost half (49%) complained of fingernail problems and 34% complained of both redness and itching. The findings of the survey indicate a need to educate patients with cancer about their treatment’s possible effects on their skin and to assist them find ways to alleviate their symptoms. (http://www. cancer care.org/about_us/press_releases/pr_ 2008_05_27.php.)
Triple-negative Breast Cancer an Unmet Need
Among patients with metastatic breast cancer, the biggest unmet need is for new treatments for those with “triple-negative” disease, whose tumors do not overexpress human epidermal growth factor receptor 2 (HER2), the estrogen receptor (ER), or the progesterone receptor (PR), a survey of key opinion leaders in oncology indicates. Respondents to the survey, conducted by The Mattson Jack Group, Inc, described the field as “wide open” for these patients, who typically have more aggressive disease and shorter survival than breast cancer patients who overexpress HER2, ER, or PR. It is estimated that about 18.5% of patients with breast cancer are “triple negative,” but no specific therapy other than traditional cytotoxic chemotherapy is currently available for these patients.(http://biz.yahoo.com/iw/ 080723/0418272.html). September/October 2008
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learn much from the oncology patients I have cared for. This is one of the unique aspects of oncology patient care.
How did you get involved in oncology pharmacy? My interest in oncology pharmacy began during my fourth year of clerkship rotation in pharmacy school. I had a great preceptor who was very active in oncology pharmacy, and my rotation with him opened my eyes to the important role of the oncology pharmacist in patient care. The pharmacy program at UC Irvine is multidisciplinary, and there I learned to view patients in a comprehensive manner. While fulfilling my clinical pharmacy residency requirements, I made a special request to follow two oncology patients for an entire year. That experience provided me with greater insight into the challenges of caring for chronically ill patients on a longterm basis and secured my interest and commitment to oncology pharmacy.
Could you describe your current teaching activities? I am a full-time associate professor at the Western University College of Pharmacy. My primary teaching responsibilities used to be oncology. With the recruitment of a second oncology faculty member, I teach less oncology and am now teaching an integrated course at the end of the second-year curriculum. I am also a clinical professor of medicine at UC Irvine, where I teach a pharmacology course for oncology fellows. This is an 8-hour course, and the goal is to provide knowledge on oncologic pharmacology and related supportive care and to teach oncology fellows how to compose chemotherapy orders.
My teaching philosophy is to empower students with critical thinking and integration skills. What do you find most rewarding about working with oncology patients? When faced with a life-threatening disease, many oncology patients look at life differently than others. In many cases, patients choose to avoid dwelling on their illness and instead focus on celebrating life. I have had the privilege to
What are your teaching philosophies? My teaching philosophy is to empower students with critical thinking and integration skills. Another one of my major teaching philosophies in clinical rotation is the importance of providing students with the experience of direct patient care. My students have the opportunity to interact with patients on a continual basis for 6 weeks. The students are required to document all patient interventions and incorporate these interactions into the patientâ€™s medical records. I think this approach gives students a sense of responsibility and helps emphasize the connection between pharmacy practice and patient outcomes.
What are your clinical research activities? I serve as an advisor for the clinical research program at St. Joseph Hospital Cancer Institute. My primary role there is to develop strategic plans for clinical research in various disease management groups. I evaluate different disease and therapeutic categories, determine the need and targets for research, develop cost projections, and identify potential investigators. Frequently, I serve as a principal investigator or participate as a subinvestigator in the clinical trials. I also collaborate on research projects with some of the scientists here at Western University. What types of treatment trials are you participating in? A majority of my research is in supportive care. Right now, my major focus is on therapeutic issues related to lung cancer. What professional organizations are you active in? I have chaired the Pharmacy Committee of the Southwest Oncology Group (SWOG) since 1994 and recently received an unprecedented appointment as Leader of SWOG Pharmaceutical Sciences, which I hope brings more recognition of pharmacy practitioners in the area of research. SWOG is one of the largest cooperative oncology groups focusing on clinical and translational research. I am also a member of the North American Pharmacist Licensure Examination Review Committee and am involved in several of the national professional organizations, including
the Hematology/Oncology Pharmacy Association (HOPA).
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How has oncology pharmacy changed over the past few years? I think oncology pharmacy has become much better organized during the past several years. With the formation and growth of HOPA, oncology pharmacists across the country have been provided an opportunity to meet their colleagues, network, and fulfill their needs for continuing education. The quality of the annual meeting program has improved every year, and this reflects the hard work of oncology pharmacists across the country. How will oncology pharmacy change in the next few years? I see a growing interest among younger practitioners in taking a second year of postdoctoral training and specializing in oncology pharmacy. I think the practice of oncology pharmacy will grow exponentially over the next few decades, due in part to the enthusiasm of these young practitioners and the work of some of the great leaders in our field. I am very encouraged about the level of motivation I have seen among new practitioners in this field. These newer oncology pharmacists have received sophisticated training from some great educators and are highly capable of providing quality care to their patients. I think the efforts of these newer graduates will elevate the practice of oncology pharmacy to a new level. â€”David S. MacDougall
ent predictor of cancer in multivariate analysis. A threshold Histo-score of 100 for PTOV1 expression in HG-PIN lesions provided 90.9% sensitivity, 51.3% specificity, 34.5% positive predictive value, and 95.2% negative predictive value for the development of prostate cancer. (Morote J, et al. Clin Cancer Res. 2008;14:2617-2622.)
>>> Pain Predicts Survival in Men with Metastatic Castration-Refractory Prostate Cancer Pain is a significant predictor of overall survival in men with metastatic castration-refractory prostate cancer (CRPC), according to an analysis of combined data from three randomized phase 3 multicenter trials. All patients had progressive CRPC, an Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate hematologic, renal,
and hepatic function. The impact of pain on daily activities and quality of life was measured using seven items from the Brief Pain Inventory scale. Overall, 38% of the men used opioid analgesics at baseline. The median survival times were 17.6 months and 10.2 months in men with low (<17) and high (â‰Ľ17) pain scores, respectively (P <.001). Pain was inversely associated with the likelihood of prostate-specific antigen decline, objective therapeutic response, and time to bone progression. (Halabi S, et al. J Clin Oncol. 2008;26:2544-2549.)
>>> Chemotherapy Provides No Added Benefits in Patients with Malignant Pleural Mesothelioma The addition of chemotherapy to active symptom control (ASC) provides no significant survival or quality-of-life benefits in patients with
malignant pleural mesothelioma (MPM). A group of 409 patients with MPM was randomized to ASC alone (treatment could include steroids, analgesic drugs, bronchodilators, and palliative radiotherapy), ASC plus chemotherapy (mitomycin, vinblastine, and cisplatin), or ASC plus vinorelbine. Follow-up was every 3 weeks to 21 weeks after randomization and every 8 weeks thereafter. Because of slow accrual, the two chemotherapy groups were combined and compared with ASC alone for the primary outcome of overall survival. Median survival was 7.6 months in the ASC alone group and 8.5 months in the ASC plus chemotherapy group. Compared with ASC alone, ASC plus chemotherapy provided a small, nonsignificant survival benefit (hazard ratio [HR], 0.89; P = .29). Statistical analysis revealed a small survival advantage
>>> Gene Expression Identifies High-risk Prostate Neoplasia PTOV1, a novel gene overexpressed in prostate cancer, is overexpressed in men with high-grade prostatic intraepithelial neoplasia (HG-PIN) and a potential marker for studying the carcinogenesis and progression of prostate cancer. PTOV1 expression was analyzed by semiquantitative immunohistochemistry (Histoscore) in HG-PIN lesions obtained from 140 patients. The patients were followed with a mean of 2.5 repeat prostate needle biopsies during a mean period of 12.4 months. PTOV1 expression was significantly higher in HG-PIN lesions from patients in whom cancer was detected during follow-up than in lesions from patients in whom it was not detected (mean Histo-score, 151.4 vs 94.6). PTOV1 expression in HGPIN lesions was the only independ-
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CMS REGULATIONS Continued from cover
The findings emerged in studies presented in poster sessions held during the 2008 Hematology Oncology Pharmacy Association/International Society of Oncology Pharmacy Practitioners joint annual conference. In July 2007, CMS released a National Coverage Decision (NCD) that defines criteria for reimbursement for ESAs when used in the treatment of patients with CIA (Table). The NCD is designed to reduce costs associated with ESA use without compromising patient safety, but impact of the NCD on resource utilization and clini-
cal outcomes in patients with CIA has not been determined. The clinical outcomes of 61 patients with CIA who were treated with ESAs before or after the implementation of the CMS NCD were described by Kenneth Utz, PharmD, and his colleagues from the University of Colorado, Denver. The study group was treated at the University of Colorado Cancer Center between January and December 2007 and included Medicare patients treated before (Group A) or after (Group B) the release of the NCD and nonMedicare patients with other primary payer sources (Group C). Patients who were treated before
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the release of the NCD received ESA therapy according to an algorithm for the management of CIA that was based on guidelines developed by the National Comprehensive Cancer Network. The proportion of patients receiving RBC transfusion was higher in Group B (56%) than in Group A (33%) or Group C (24%). The mean number of ESA doses was lower in Group B (2.67) than in Group A (3.67) or Group C (3.92). Overall, fewer Medicare patients achieved their target hemoglobin (Hb) level (Group A, 40%; Group B, 44%) compared with non-Medicare patients (65%). None of the differences in outcomes between the groups were statisti-
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Presents The First Annual 2008 Curriculum for
CONSIDERATIONS IN MULTIPLE MYELOMA A Newsletter Series for Cancer Care Professionals Center of Excellence Media, along with Editor-in-Chief Sagar Lonial, MD, of Emory University, will proudly offer the multidisciplinary cancer team at your center a series of newsletters focusing on the challenges in treating patients with multiple myeloma.
SAGAR LONIAL, MD Associate Professor of Hematology and Oncology Emory University
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About Multidisciplinary Cancer Care Multidisciplinary Cancer Care newsletters provide a forum for sharing expert interdisciplinary treatment perspectives on patient care with the ultimate goal of promoting ongoing professional education to physicians, nurses, and pharmacists in the hematology/oncology community. Target Audience This educational publication is designed for physicians, nurses, and pharmacists who wish to enhance their knowledge concerning the management of patients with multiple myeloma and renal dysfunction.
At the completion of this educational activity, you should be able to: • Describe the prevalence of renal insufficiency among patients with multiple myeloma (MM) • Recognize the special challenges in pharmacologic treatment of the many patients with MM who also have renal insufficiency, especially those requiring dialysis • Discuss the results of studies showing treatments that are active and safe in MM patients with renal impairment, including those with advanced renal failure requiring dialysis
Accreditation Physicians 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 CME Consultants and Center of Excellence Media. CME Consultants is accredited by the ACCME to provide continuing medical education for physicians. CME Consultants designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Supported by an educational grant from Millennium Pharmaceuticals, Inc.
Pharmacists CME Consultants is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity has been designated for 1 contact hour (0.100 CEU). In order to receive credit, all participants must complete an evaluation, request for credit form, and a posttest. Statements of Credit will be mailed to participants within six weeks. ACPE #309-999-08-012-H01-P Initial Release Date: 05/07/08. Planned Expiration Date: 05/07/09. Nurses CME Consultants is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. CME Consultants designates this program for 1 contact hour. Participants should claim only those contact hours actually spent in the educational activity. In order to receive credit for this program, each participant must complete the evaluation form, posttest, and certificate request form. Certificates will be mailed to program participants in approximately four to six weeks after receipt of the completed evaluation form, posttest, and certificate request form.
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Table. Highlights of the CMS NCD on the use of ESAs in patients with CIA • Allows ESA administration only when Hb <10 g/dL (previous guidelines allowed ESA usage at Hb <12 g/dL) • Allows 25% dose adjustment after week 4 for each chemotherapy cycle (previous guidelines allowed 50%100% dose adjustment) • Limits duration of ESA treatment to 8 weeks in patients who achieve an Hb increase <1 g/dL (previous guidelines allowed duration up to 12 weeks)
cally significant. A trend towards decreased use of ESAs throughout 2007 was observed. Resource utilization may be increased in patients with CIA who are classified as nonresponders to ESA therapy according to the revised CMS criteria, reported Siu-Fun Wong, PharmD, and her colleagues from Western University of Health Sciences, Pomona, California. CMS currently defines an Hb response to ESA therapy as Hb >10 g/dL and a hematopoietic response as Hb >10 g/dL and >1 g/dL from baseline. Previous CMS guidelines allowed the use of ESAs in patients with CIA and Hb <12 g/dL. To determine the impact of the new CMS NCD on resource utilization and clinical outcomes in patients with CIA, the researchers performed a retrospective chart review of 28 patients with CIA who received ESAs after implementation of the revised CMS guidelines. The mean age of the study population was 60 years, and breast cancer was the most common cancer type (43%). A total of 22 patients (79%) achieved an Hb response, but only 14 patients (50%) achieved a hematopoietic response according to CMS criteria. A total of 6 patients were Hb and hematopoietic nonresponders. The total number of RBC units transfused was 8 in the responders and 22 in the nonresponders (P = .23). The mean length of hospitalization was 4 days in the responders and 11 days in the nonresponders (P = .016). Total resource utilization (the cost of RBC transfusions plus hospitalization) was $7800 in responders and $21,420 in nonresponders. The mean resource utilization cost per patient was $354.50 in responders and $3570 in nonresponders. Implementation of the revised CMS guidelines did not compromise patient safety, but may have resulted in higher resource utilization in the nonresponder group, the researchers concluded. They noted that the possible impact of ESA dose escalation performed according to approved package inserts on resource utilization in nonresponders remains unclear. —DSM
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ORAL CHEMOTHERAPY Continued from cover
development are oral agents. The increasing availability of oral oncology drugs and percentage of oral agents considered “targeted therapies” underscore the importance of maximizing patient adherence with oral chemotherapy regimens, Yee said during a symposium held at the 2008 Hematology Oncology Pharmacy Association/ International Society of Oncology Pharmacy Practitioners joint annual conference. According to Yee, no consensual standard exists for differentiating adherence from nonadherence. Patients who take at least 80% of the prescribed number of pills daily within the correct prescribed period are considered adherent in most standard clinical studies, he explained, although rates as high as 95% have been used to establish adherence in studies of patients with HIV infection and other populations. “Nonadherence to oral chemotherapy can have far-reaching negative consequences,” Yee
• Expanded Approval for Azacitidine Azacitidine (Vidaza; Celgene) has received expanded US Food and Drug Administration (FDA) approval, reflecting new overall survival achieved in the AZA-001 survival study, an international phase 3 trial in patients with higher-risk myelodysplastic syndromes (MDS). In 2004, the demethylation agent became the first therapy approved by the FDA for treatment of MDS; it was approved for all five French American British subtypes of MDS, which include both low-risk and high-risk patients. • New Indication for Bortezomib The FDA has approved bortezomib (Velcade; Millenium, Takeda) for patients with previously untreated multiple myeloma based on the results of an international, open-label, active-control trial. The agent was previously approved as second- or third-line therapy for multiple myeloma and is also approved for patients with mantle cell lymphoma who have received at least one prior therapy.
• Oral Formulation of Palonosetron An oral formulation of palonosetron hydrochloride (Aloxi; Eisai, Helsinn) has been approved by the FDA for prevention of chemotherapy-induced nausea and vomiting. An injectable form was approved in 2003. • Blood Test for Colorectal Cancer The AMDL-ELISA DR-70(R) (FDP) has been cleared by the FDA for monitoring disease progression in patients previously diagnosed with colorectal cancer. The blood test is the first monitoring product for colorectal cancer cleared by the FDA since 1982.
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said. Adverse consequences of nonadherence include misinterpretation of a patient’s worsening condition as an absence of drug activity, increased physician visits, unnecessary diagnostic testing, longer length of hospital stay, unnecessary changes in medication dose or regimen, and deterioration of the patient– provider relationship, he noted. Medication adherence can be determined directly through continual observation or the use of blood assays or physiologic markers of drug activity. Indirect methods of determining medication adherence include the use of patient questionnaires, diaries, pill counts, refill rates, electronic monitors, and pharmacy record review. The presence of psychological problems, particularly depression, is a major predictor of medication nonadherence, Yee explained. Other factors associated with nonadherence include cognitive impairment, treatment of asymptomatic disease, adverse medication effects, patient’s lack of belief in treatment benefit, complexity and costs of treatment, and a poor provider–patient relationship (Table 1). Medication adherence can be enhanced through a combination of behavioral, educational, and affective interventions, Yee said (Table 2). Such interventions are designed to influence specific behavioral patterns, convey information, and appeal to emotions and social relations, respectively, in an effort to improve adherence. Yee described the findings of a systematic review of 37 randomized controlled trials of interventions intended to improve medication adherence (JAMA. 2002;288:2868-2879). All trials were in patients with chronic medical conditions and none of the trials enrolled patients with cancer. Of the 37 trials, 12 evaluated educational interventions, 10 evaluated behavioral interventions, and 15 evaluated combined interventions. Educational interventions typically included counseling by a physician, pharmacist, or health educator, and behavioral interventions included dosage simplification, cognitive behavior therapy, and the use of specialized packaging and directly observed therapy. Overall, 20 (54%) of the 37 studies reported a significant increase in at least one adherence measure. The most consistent increases in adher-
Table 1. Major predictors of poor adherence • Presence of psychological problems • Presence of cognitive impairment • Treatment of asymptomatic disease • Inadequate follow-up or discharge planning • Side effects of medications • Patient’s lack of belief in benefit of treatment • Patient’s lack of insight into illness • Poor provider–patient relationship • Missed appointments • Complexity of treatment • Cost of medication, copayment, or both Adapted with permission from Osterberg L, et al. N Engl J Med. 2005;353:487-497.
Table 2. Types of Interventions Behavioral Designed to change adherence by targeting, shaping, or reinforcing specific behavioral patterns Educational (informational or cognitive) Designed to convey information Affective (social/environmental) Designed to change adherence through appeals to feelings and emotions or social relationships and social supports Source: Roter DL, et al. Med Care. 1998;36:1138-1161.
ence were achieved with behavioral interventions that reduced dosing demands and those involving repeated monitoring of medication use with feedback and reinforcement.
Patient adherence programs A review of patient adherence programs implemented at leading sites across the United States was provided by Shauna Choi, PharmD, University of Texas M.D. Anderson Cancer Center, Houston. According to Choi, oral chemotherapy adherence initiatives at her institution include individualized patient counseling, dispensing of one chemotherapy cycle per pill bottle, and the use of patient education materials and industry-sponsored tools written in various languages. A system designed to educate and monitor patients starting new oral chemotherapy has been developed by the Cincinnati Veterans Administration Medical Center. In this system, patients receive education and monitoring from a team member who is assigned particular oral chemotherapy agents and are followed up weekly for adherence and adverse drug reactions (ADRs). The incidence of ADRs in patients receiving oral chemotherapy agents decreased from 33% to 26% during the first few months after implementation of the program, Choi said, and the medication adherence rate during the program has been documented at 94%. At BioScrip, a specialty pharmaceutical healthcare organization, efforts to enhance oral chemotherapy adherence include the reduction of financial barriers to treatment availability. Such efforts involve the identification of economic reality and feasibility before the start of treatment and helping patients navigate cost assistance programs and organizations. A primary adherence enhancement initiative underway at BioScrip is the Refill Adherence Management Program (RAMP). The program is designed to prevent treatment interruptions by addressing ADRs, resolving drug delivery issues, and partnering with physicians to ensure that prescriptions are sent in a timely manner. In patients with HIV infection receiving antiretroviral therapy, RAMP produced an overall adherence rate 20% greater than BioScrip’s customary pharmaceutical services program, Choi said. The implementation of RAMP also led to a 60% increase in the proportion of patients achieving 85% or better adherence levels (96% vs 60%) and a nearly 200% increase in the proportion achieving 95% or better adherence (92% vs 32%). —DSM September/October 2008
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Strip away the claims
See for yourself what others have already conﬁrmed Other drug transfer devices claim to be closed, but they lack the independent, clinical evidence to prove it. They claim to offer affordability, but their incompatibility with all drugs and vial sizes means you’ll pay more with inadequate coverage and drug waste. They claim familiar ease of use, but their wet connections guarantee exposure, even with perfect user form. Strip away the claims and see for yourself what others have already conﬁrmed. Ordinary lemon juice and litmus strips are all you need to conduct a simple pH test to determine the leakproof integrity of today’s available transfer devices. So take the test—and then demand the facts.
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CANCER CENTER PROFILE
M.D. Anderson Cancer Center T
CANCER CENTER PROFILE
he University of Texas M.D. Anderson Cancer Center is a component of the University of Texas System. Over its 66 years, more than 700,000 patients have been treated with surgery, chemotherapy, radiation therapy, immunotherapy, or combinations of these and other leading treatments. The stated mission of M.D. Anderson is to eliminate cancer through outstanding programs that integrate patient care, research, and prevention, and through education for undergraduate and graduate students, trainees, professionals, employees, and the public. M.D. Anderson employs more than 17,000 people at facilities that total more than 9 million square feet. It now has five satellite centers, four of which offer radiation therapy and one that offers radiation and a medical oncology practice. Two to three additional satellites are planned each year, and chemotherapy and linked surgical services will be offered at some of these facilities. Patient visits number nearly 85,000 annually, of whom 29,000 were newly registered in 2007. More than 11,000 patients per year participate in therapeutic clinical research exploring novel treatments, making it the largest such program in the nation. M.D. Anderson earned the distinction of being voted the number one cancer center in the United States by U.S. News & World Report’s annual “Best Hospitals” survey. The 2008 recognition was the fourth time in 6 years that M.D. Anderson has been ranked number one in this survey. In his state-of-the-institution address delivered in October 2007, John Mendelsohn, MD, president of M.D. Anderson, said, “We have articulated a vision of a cancer care cycle that includes a continuum involving prevention, early detection, treatment, and survivorship, and are planning expansion of our prevention and survivorship programs both clinically and in research.” The survivorship program will provide more appropriate, complete, and convenient services to patients who have responded well to therapy, he said. Such a program is needed as the number of cancer survivors increases due to successes in early diagnosis and treatment. Over the past year, phase 1 clinical trials at M.D. Anderson have tested more than a dozen new anticancer agents for the first time in humans. New laboratory facilities to support research activities and centers of excellence are under construction, which will provide more than 500,000 gross square feet of new space for research when completed.
The increased emphasis on cancer prevention will include expanded clinical services in personalized risk assessment, genetic testing, counseling in behavior and lifestyle modification, and sophisticated cancer screening that will incorporate evaluation of markers and new imaging modalities. The Clinical Cancer Genetics program comprises a multidisciplinary team of specially trained genetic counselors and physicians working together to provide education, hereditary risk assessment, and individualized cancer screening and prevention to people who are concerned about their personal and family history of cancer. The Division of Cancer Prevention and Population Sciences has more than 500 employees, 69 faculty members, and an annual research budget of $24 million, making it one of the largest programs of its kind in the world. Risk assessment models have been developed to predict an individual’s chance of developing lung and bladder cancer based on genetic, environmental, and lifestyle factors. The causes of primary brain tumors are also being explored in the division by studying biologically related members diagnosed with primary brain tumors; the research will also attempt to identify a panel of genes that can predict who will develop the disease. A 300,000 square foot building will be devoted primarily to pathology and laboratory medicine, and the pharmacy will handle the increase in diagnostic tests and services and the growth in demand on the institution’s pharmacy. The aim is to open this facility within 4 years. M.D. Anderson was designated a magnet nursing organization by the American Nurses Credentialing Center, a recognition held by fewer than 200 institutions worldwide. Formal training programs and academic programs for nurses are expanding at M.D. Anderson. From 2005 to 2007, 209 registered nurses have enrolled in the postbaccalaureate residency programs, and 81% of graduates accept jobs at M.D. Anderson. The Ben Love/El Paso Corporation Melanoma and Skin Center opened in 2006, and more than 4000 new patients were among the more than 15,000 patients with melanoma and other skin cancers treated there in 2007. Research at the center is focusing on the development of blood markers to predict recurrence of melanoma. A clinical trial is testing a vaccine as adjuvant therapy for patients with melanoma who are at high risk of recurrence. Investigators in the Department of Neuro-oncology are collaborating on Delta-24-RGD, a virus designed to destroy a highly-resistant and lethal form of glioblastoma multiforme. Four brain tumor cell lines have been characterized from four specimens of glioblastoma multiforme, and Delta-24-RGD was successful at killing all four types. A clinical trial of the virus in patients is expected soon. Clinical trials in patients with low-grade lymphoma have started using a second-generation vaccine made with a genetically engineered chemokine molecule that was developed at M.D. Anderson. Undergoing early clinical evaluation is a customized vaccine developed at M.D. Anderson for patients with relapsed myeloma. In 2007, investigators in the Department of Gynecologic Oncology published research showing
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Clinical Pharmacy Services Manager
Laura Boehnke Michaud, PharmD Expanding pharmacy’s walls has been part of the culture at M.D. Anderson during the 15-year tenure of Laura Boehnke Michaud, PharmD. She has been manager of clinical pharmacy services at M.D. Anderson since 2005; for the previous 12 years she was a clinical pharmacy specialist. During that time, she has witnessed the integration of pharmacy into every aspect of care, “including the administrative side, which is a big part of what I do now in terms of guideline development within the institution, developing institutional order sets for high-risk medications and chemotherapy, and our chemotherapy policy,” she said. “I like being involved in the institutional initiative and driving quality care as a whole. That’s exciting to me because I know that I not only affect the patients that I see on a day-in, day-out basis, but I can affect all patients in that manner.” Because M.D. Anderson is not a traditional teaching hospital, much of the patient care is managed by mid-level clinicians, including the clinical pharmacists. The operations of M.D. Anderson are separated into 13 care centers that have individual clinical care teams, each with its own set of clinical pharmacists, the number of which depends on the volume and acuity of patients in each particular center. “We’ve been integrated with the teams for so long that they rely on us to do even more than just day-to-day patient care,” said Michaud. Clinical pharmacists in Texas have prescriptive authority for inpatient medication orders, and the clinical pharmacists at M.D. Anderson conduct rounds with the clinical care team. Of the 250 pharmacists employed in the Division of Pharmacy, approximately 70 are clinical pharmacists. “At most institutions you’re trying to justify every single position and it’s difficult to get more clinical pharmacists because often the medical staff doesn’t see the value. They see the pharmacists dispense the drugs and review the orders; they don’t understand what they can do outside of the pharmacy walls,” she said. “There’s a reason we have 70 people in the clinical group; it’s purely from physician demand. They value our input to service, not only patient care but research and education programs. It has been a benefit to the profession of pharmacy to see us move in this direction and become independent practitioners, having our own set of skills.”
that insulin resistance was an independent risk factor for endometrial cancer. The next step to the finding will be a chemoprevention study of obese, insulin-resistant women to test the efficacy of metformin in preventing endometrial cancer. —Wayne Kuznar September/October 2008
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(7.2 months each). The advantage for the cetuximab + FOLFOX4 patients, when the researchers examined the the American Society of Clinical Oncology, 134 KRAS wild-type and 99 KRAS included 337 mCRC patients receiving mutant patients separately, however, either FOLFOX4 (oxaliplatin 85 mg/m2 5- became significant. fluorouracil/folinic acid [+5FU/FA] every 2 The response rate in the KRAS weeks) or cetuximab (400 mg/m2 initial wild-type patients was 37% for FOLintravenous infusion on day 1 then 250 FOX4 and 61% for the cetuximab + mg/m2 weekly) plus FOLFOX4. FOLFOX4 combination (P = .011). Previous retrospective analyses have For those with the KRAS mutation, shown KRAS gene mutations to be associ- there was no significant difference ated with poor prognosis and have suggest- between treatments, with FOLFOX4 ed that KRAS mutations may explain lack numerically favored (49% vs 33% for of response to endothelial growth factor FOLFOX4 and cetuximab + FOLreceptor inhibitors like cetuximab and pan- FOX4, respectively; P = .106). “The itumumab in some patients. KRAS muta- benefit for patients with the wild-type tions are found in 40% to 50% of CRC KRAS was clearly significantly different—with high significance,” Bokemeyer patients, Bokemeyer said. said. With mutant KRAS, he Adding cetuximab to FOLFOX4 noted, “It was somewhat the way around.” resulted in significant, relevant other The pattern for median PFS similar. PFS was 7.2 months improvements in response rates was for FOLFOX4 and 7.7 months for the cetuximab + FOLFOX4 and in PFS. combination (hazard ratio, 0.57; The Initial OPUS efficacy analysis P = .016) with wild-type, but actually showed a strong trend favoring the cetux- reversed for KRAS mutation patients at imab combination for response rate (35.7% 8.6 months for FOLFOX4 and 5.5 months FOLFOX4; 45.6% cetuximab plus FOL- for cetuximab plus FOLFOX4 (P = .019). Neither duration of treatment nor relaFOX4, P = .064), but identical median PFS
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tive dose intensity varied significantly between treatments. There were no differences in the most common grade 3 to 4 adverse events, and the safety profiles were consistent with those seen in earlier trials. Adding cetuximab to FOLFOX4 resulted in significant, relevant improvements in response rates and in PFS among patients with KRAS wild-type tumors, Bokemeyer concluded. In patients with KRAS mutant tumors, adding cetuximab to FOLFOX had no apparent benefit.
when mutated), such as KRAS, are important in growth signaling, differentiation, and cell division in normal cells. KRAS mutation status was tested in tumors from 148 patients. In those with wild-type KRAS status (n = 54), the relative response rate was 30.4% among controls who received the standard cetuximab dose and 41.9% among dose-escalated patients (P = .396). The response rate was 0% in KRAS mutant controls (n = 44) and dose-escalation patients (n = 45). Estimated progression-free survival (PFS) was 173 days in KRAS wild-type patients and 83 days in KRAS mutant patients (P <.0001). PFS in wild-type KRAS status patients was significantly better in the dose-escalation group (P <.0001), the control group (P = .014), and in a group of nonrandomized patients (n = 62, P = .020). In the entire EVEREST population, PFS was longer among those with skin toxicity, with a general pattern of correlation between skin toxicity severity and PFS length. The pattern persisted among wild-type KRAS patients and less clearly in KRAS mutant patients. Tejpar concluded that patients with KRAS wild-type tumors benefited from irinotecan plus cetuximab treatment. In the dose-escalation arm, there was a trend toward increased responses in patients with KRAS wild-type tumors, but dose escalation did not improve efficacy in KRAS mutant tumors. She also pointed out that “skin toxicity and KRAS status are independent predictors of outcome.” American Society of Clinical Oncology discussant Mace L. Rothenberg, MD, from the Vanderbilt-Ingram Cancer Center, Nashville, Tenn, underscored that no responses were seen in KRAS mutant patients regardless of cetuximab dose, and that the rate of stable disease was actually lower in the dose-escalation arm than in the standard arm (33% vs 45%). The trend toward increased responses in the KRAS wild-type tumors, he added, was not matched in PFS. Lastly, Rothenberg noted that while both skin toxicity and KRAS status were independent predictors of outcome, “KRAS was the much stronger of the two.”
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15 GASTROINTESTINAL CANCERS
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KRAS Status and Skin Toxicity Predict Response in Colorectal Cancer CHICAGO—In patients with metastatic colorectal cancer in the EVEREST trial, both skin toxicity and KRAS status independently predicted response. Also, patients who had KRAS wild-type tumors benefited from treatment with irinotecan plus cetuximab, and escalating the cetuximab dose created a trend toward further increased responses. Sabine Tejpar, MD, University Hospital Gasthuisberg, Leuven, Belgium, noted that EVEREST investigators have already shown that increasing the cetuximab dose in patients already receiving standard-regimen irinotecan (180 mg/m2 every 2 weeks) improves efficacy in patients with grade 0/1 skin reactions. Her presentation at the American Society of Clinical Oncology 2008 Annual Meeting addressed whether patients with mutated KRAS status benefit when standarddose cetuximab (250 mg/m2) is increased in 50 mg/m2 increments up to 500 mg/m2 in combination with standard-dose irinotecan. Ras family members (genes that cause cancer
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Hematologic Cancers Two-year Data Show Sustained Dasatinib Benefits in Imatinib-resistant, intolerant CP-CML CHICAGO—“This is a drug that can deal with resistance,” said Richard M. Stone, MD, who presented long-term results of the phase 2 START-C trial of dasatinib in patients with chronicphase chronic myelogenous leukemia (CP-CML) who are resistant to or intolerant of imatinib at the American Society of Clinical Oncology 2008 annual meeting. Stone is clinical director of the Adult Leukemia Program at DanaFarber Cancer Institute, Boston. The 387 patients enrolled in the multicenter trial were treated with dasatinib 70 mg twice daily. All patients were resistant to or intolerant to imatinib. Before imatinib failure, 82% of participants had a complete hematologic response (CHR) to imatinib; 37% had a major cytogenetic response (MCyR); and 19% had a complete cytogenetic response (CCyR). Ten percent had prior stem cell transplantation. Forty percent of patients had BCR-ABL mutations. At 2 years, CCyRs were achieved by 53% of patients, and among these, 79% had major molecular responses (defined as more than a 3-log reduction in BCR-ABL burden). Overall, 62% had MCyRs, and 91% had CHRs. Looking separately at patients with imatinib resistance, Stone said
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that rates were similar to those in the overall trial population (CHR, 87%; MCyR, 59%; CCyR, 52%). The same was noted for progression-free survival (PFS) (91% at 12 months; 80% at 24 months) and overall survival (OS) (97% at 12 months; 94% at 24 months). Among imatinib-resistant patients, whom Stone called “the worst of the worst,” PFS was 88% at 12 months and 75% at 24 months. OS was 96% at 12 months and 94% at 24 months. Dasatinib responses were found for all BCR-ABL mutations except for the T3151 mutation. The likelihood of response was similar regardless of mutation status, with CCyRs in 52%
High Response and Survival Rates at 18 Months for Nilotinib in CP-CML
CHICAGO—Updated 18-month results for nilotinib in patients with imatinib-resistant or imatinib-intolerant chronic-phase chronic myelogenous leukemia (CP-CML) showed favorable response and survival rates with excellent tolerability according to Hagop M. Kantarjian, MD, M.D. Anderson Cancer Center, Houston, Tex. Nilotinib was approved by the US Food and Drug Administration for patients with CPCML resistant to or intolerant of prior therapy in October 2007. It is a highly selective BCR-ABL inhibitor, binding
to ABL with higher affinity and greater selectivity than imatinib. Nilotinib inhibits most imatinib-resistant BCRABL mutants (T3151 excluded), Kantarjian said. In the phase 2 trial cohort, the ratio of imatinib-resistant to imatinib-intolerant patients was 71% to 29%. Median age was 58 years, median CML duration was 58 months, and prior imatinib therapy ranged from 400 mg to >800 mg (72% had received ≥600 mg/day). Median duration of prior imatinib therapy was 33 months, Kantarjian said at the American Society of Clinical Oncology 2008 annual meeting. Patients received nilotinib at a dose of 400 mg orally twice daily (2 hours from meals). Major cytogenetic (MCyR) response rate was the primary end point. Among 321 patients enrolled, the median dose intensity was 788 mg/day for a median of Photo courtesy of ASCO 465 days. Dose reduc-
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of those with mutations and 56% of those without. Also, PFS at 24 months was 75% with any mutation and 83% without mutation. “Dasatinib efficacy was demonstrated across subgroups, including all but one of 43 different baseline mutations,” Stone said. Cytopenias did not worsen with longer-term treatment. Rates of leukopenia at 12 months and 24 months were the same (27%), and both neutropenia rates (49% and 50%, respectively) and thrombocytopenia rates (48% and 49%, respectively) were similar at 12 and 24 months. Grade 3 to 4 nonhematologic side effects also did not increase
substantially. Pleural effusions were reported in 9% and 11% of patients for the first and second years, respectively, with no grade 4 events. Furthermore, among those intolerant to imatinib, cross-intolerance to dasatinib was not reported. Stone noted that in a subsequent phase 3 dose-optimization study in CPCML, 100 mg of dasatinib given once daily demonstrated similar efficacy to other doses, but with less frequent fluid retention and cytopenia and a more favorable risk-benefit ratio. As a result, 100 mg daily is the currently approved CP-CML dasatinib dose. —WA
tions were required in 25% of patients events were uncommon (lipase elevaand dose interruptions in 55% for a tion, 16%; hypophosphatemia, 15%; hyperglycemia, 12%; total bilirubin 7%). median of 19 days. Median time to complete hemato- Grade 3 to 4 anemia, neutropenia, and logic response (CHR) was 1 month, thrombocytopenia rates were 10%, 30%, and median time to MCyR was 2.8 and 28%, respectively. Median duration months. CHRs were reported in 77%, was 9 days for anemia, 15 days for neuwith MCyR and complete cytogenetic tropenia, and 23 days for thrombocyresponse rates (CCyRs) of 58% and topenia. Peripheral edema (grades 1 to 2) 42%, respectively. The response rates was reported in 6% of patients, and perifor imatinib-resistant and imatinib- cardial and pleural effusion were seen in intolerant patients were 56% and 63%, 2% and 4%, respectively (all grades). To date, Kantarjian said, nilotinib respectively, for MCyR and 39% and 50%, respectively, for CCyR. At 18 therapy has been discontinued in 53% of months, MCyR responses were sus- patients (23% for disease progression, tained in 84% of patients, and progres- 17% for adverse events). Kantarjian concluded that nilotinib sion-free survival was 67%. Ninety-five percent of patients were alive at 12 has significant activity in patients with months, and 91% were alive at 18 CP-CML after imatinib treatment failmonths. These survival durations ure, and responses are durable. exceeded those reported for other ther- Tolerability is excellent, and grade 3 to 4 apies and allogenetic stem cell trans- adverse event occurrence is minimal. plant, Kantarjian pointed out —WA (Kantarjian H, et al. Cancer. 2007; 109:1556-1560). The most common nonhematologic adverse events Reach us were rash (30%), pruritus (25%), and nausea (24%), but grade 3 to 4 rates were 2% or less. Although biochemical www.theoncologypharmacist.com abnormalities were seen in many patients, grade 3 to 4
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Continuing Education Program #CIK 9944 • RELEASE DATE: September 30, 2008 • EXPIRATION DATE: September 29, 2009
Treatment of Cancer Anemia with Erythropoiesisstimulating Agents and Intravenous Iron Supplementation BY GABRIELLA RASSU, OCN; ILARIA SCHIAVETTO, MD; SILVIA MAGLIE, OCN; ELENA PELEGATTA, OCN; AND PAOLO PEDRAZZOLI, MD Oncologia Medica Falck, Osperdale Niguarda Ca’Granda, Milano, Italy
HOW TO RECEIVE CREDIT To receive continuing education credit, learners must: • Read the article in its entirety. • Take the CE self-assessment test and complete the evaluation test: 1. Log onto www.theoncologypharmacist.com. 2. Click on UNMC logo on homepage. 3. Register to participate. 4. Enter program number # CIK 9944. • The learner must answer at least 70% of the questions on the post-test correctly. • The estimated time to complete this activity is 1 hour. Your continuing education certificate can be printed by following the directions online after successful completion of the post-test and evaluation. TARGET AUDIENCE Registered pharmacists and other interested healthcare professionals, especially those caring for cancer patients receiving erythropoiesis-stimulating agents for anemia.
FACULTY/PLANNER DISCLOSURES It is the policy of the University of Nebraska Medical Center, Center for Continuing Education that all planners and faculty participating in continuing education activities provided by the University of Nebraska Medical Center, Center for Continuing Education are to disclose to the audience any real or apparent conflicts of interest with providers of commercial products and/or devices relating to the topics of this educational activity and also disclose discussion of labeled/unapproved uses of drugs or devices discussed in their presentation. The planners and faculty have been advised that this activity must be free from commercial bias and based upon all the available scientifically rigorous data from research that conforms to accepted standards of experimental design, data collection, and analysis.
DISCLAIMERS The opinions or views expressed in this continuing education activity are those of the faculty and do not necessarily reflect the opinions or recommendations of the University of Nebraska Medical Center (UNMC), Center for Continuing Education. While the University of Nebraska Medical Center, Center for Continuing Education is an ACPE accredited organization, this does not imply endorsement by the UNMC or ACPE of any commercial products affiliated with this activity. LEARNING OBJECTIVES After completing this activity, the reader should be better able to: • Explain the how iron deficiency affects response to erythropoiesis-stimulating agents (ESAs) in patients with cancer. • Describe differences in safety and efficacy of available oral and intravenous (IV) iron preparations. • Discuss the potential benefits of concomitant use of IV iron supplements and ESAs in patients with cancer and anemia.
Data mostly derived from the dialysis population8 have clearly shown that an important factor that seriously limits erythropoietic response to ESA is functional iron deficiency (FID), which is an imbalance between iron needs in the erythropoietic marrow and iron supply.9 FID may be either pre-existing or may occur during ESA therapy, when red blood cells are produced at a rate that outstrips labile iron availability. As a consequence, iron supplementation may still be required to achieve or maintain an optimal response to ESAs. In routine clinical management of anemic cancer patients, transferrin saturation (TSAT) between 10% and 20% with normal or increased ferritin, is an accepted indicator of FID.9 Surprisingly, the use of iron supplementation during treatment with ESAs has not been as rigorously applied in anemic patients with cancer as it has for dialysis patients. This underuse is at least in part due to: (1) the false perception that patients with cancer do not have decreased iron stores (as measured by serum ferritin) and are therefore thought not to require iron supplementation during ESA therapy; (2) misinformation and misinterpretation of the incidence and clinical nature of serious adverse effects of intravenous (IV) iron.10 Parenteral iron is still considered a poorly tolerated medication that not infrequently causes
The following authors, reviewers, and planning committee members listed below have stated they have no significant or substantial relationship with providers of commercial products and/or devices discussed in this activity and/or with any commercial supporter of this activity. • Lisa Anzai, RN, MA • Catherine Bevil, Rn EdD • Cass Hammond, RN, MSN, CRNP • Lara J. Reiman • Karen Rosenberg • Manuel G. Afable II, RN, BSN • Silvia Mague, OCN • Paolo Pedrazzoli, MD • Elena Pelegatta, OCN • Gabriella Rassu, OCN • Ilaria Schiavetto, MD
David Baribeault, RPh, BCOP Boston Medical Center Boston, MA 02118 Silvia Mague, OCN Divisione Oncologia Medica Falck Ospedale Niguarda Ca’Granda Milan, Italy 20162
COST This program is complimentary for all learners.
nemia is frequent in patients with cancer, being an important contributor to morbidity in these patients.1 The etiology of cancer-related anemia is multifactorial, but, in most cases, it is a result of the chronic disease process associated with cancer (anemia of chronic disease or, more recently, anemia of inflammation).2 The mechanisms that lead to the anemia include impaired erythropoietin (Epo) production, an impaired response of the erythroid marrow to Epo, iron-restricted erythropoiesis, and a diminished pool of Epo-responsive cells. Chemotherapy, which inhibits erythroid marrow proliferation and further impairs erythropoietin production, exacerbates anemia in patients with cancer. The recombinant erythropoiesis-stimulating agents (ESAs), epoetin alfa and beta and darbepoetin alfa (DA), given according to evidence-based clinical practice guidelines,3 can correct cancer/ chemotherapy-related anemia (CRA), reduce the need for red blood cell transfusion, and provide clinically meaningful improvements in overall health in patients receiving chemotherapy.4,5 Although these agents represent a major advance in the treatment of CRA, approximately 30% to 50% of patients do not achieve a meaningful response to ESAs.6,7
EDITORIAL BOARD Manuel G. Afable II, RN, BSN Taussig Cancer Institute Cleveland Clinic Cleveland, OH 44195
Paolo Pedrazzoli, MD Divisione Oncologia Medica Falck Ospedale Niguarda Ca’Granda Milan, Italy 20162 Elena Pelegatta, OCN Divisione Oncologia Medica Falck Ospedale Niguarda Ca’Granda Milan, Italy 20162 Gabriella Rassu, OCN Divisione Oncologia Medica Falck Ospedale Niguarda Ca’Granda Milan, Italy 20162 Ilaria Schiavetto, MD Divisione Oncologia Medica Falck Ospedale Niguarda Ca’Granda Milan, Italy 20162 PLANNING COMMITTEE Lisa Anzai, RN, MA Nurse Planner University of Nebraska Medical Center College of Nursing 985330 Nebraska Medical Center Omaha, Nebraska 68198-5330 Catherine Bevil, RN EdD Director, Continuing Nursing Education and Evaluation University of Nebraska Medical Center College of Nursing 985330 Nebraska Medical Center Omaha, Nebraska 68198-5330 Lara J. Reiman Managing Editor Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Karen Rosenberg Editorial Director Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831
Continued on page 16 The following author has stated that he has the following financial relationships: David Baribeault, RPh, BCOP, states that he is on the speaker’s bureau for Amgen, Roche, and Valeant.
REVIEWER Cass Hammond, RN, MSN, CRNP Avid Education Partners 18071 Crampton Lane Sharpsburg, MD 21782
ACCREDITATION The University of Nebraska Medical Center, Center for Continuing Education is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. The ACPE provider number is 447-000-08-451-H04-P. To receive the 1 contact hour of continuing education credit, pharmacists should complete the activity requirements and evaluation at the conclusion of the activity. Approval is valid from the initial release date of September 30, 2008. The expiration date is September 29, 2009. A statement of credit will be available for printing online upon completion of the post-test with a score of 70% or better and the evaluation instrument.
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Continuing Education Program #CIK 9944 • RELEASE DATE: September 30, 2008 • EXPIRATION DATE: September 29, 2009 Continued from page 15
anaphylatic reactions. This opinion is erroneous, howevever. The currently available iron preparations (low-molecular-weight dextran, iron saccarate, ferric gluconate) are safe, as clearly demonstrated in patients undergoing dialysis.11
Clinical studies of iron supplementation in ESA-treated patients Until recently, a limited number of studies on use of iron supplementation during treatment with ESAs were available. A Swedish study12 demonstrated the efficacy of IV iron in improving hematopoietic response to epoetin beta in 67 patients with lymphoproliferative malignancies not receiving concurrent chemotherapy. Patients were enrolled if they had a positive stain for bone marrow hemosiderin. Two large US studies13,14 included patients with solid tumors undergoing chemotherapy, and
both examined different routes of iron administration (IV or oral) versus none, in conjunction with epoetin alfa use. Both studies showed that patients who received IV iron had a significant improve-
Both studies showed that patients who received IV iron had a significant improvement in hematopoietic response compared with no-iron controls. ment in hematopoietic response compared with noiron controls; in contrast, no difference between the no-iron and oral-iron groups were found. Results of such studies cannot be interpreted
without a close look at the iron status of enrolled patients. This crucial aspect is usually poorly discussed in the literature, and the current guidelines3,15 do not emphasize this point either. Both US studies and the Swedish study included a proportion of patients with iron deficiency (functional in most cases), and therefore did not provide a definitive answer on whether iron supplementation can increase the percentage of iron-replete patients (the majority of CRA patients) who respond to ESAs. Two recently published prospective trials have better clarified this issue. Bastit and colleagues16 randomized patients with nonmyeloid malignancies receiving DA to either IV iron 200 µg every 3 weeks (or the same dose within a 3-week period) or standard practice for iron administration (no iron or oral iron). Iron parameters were not considered in patient selection. Response, measured both as transfusion requirement and achievement of
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Treatment of Cancer Anemia with Erythropoiesis-stimulating Agents and Intravenous Iron Supplementation: A Pharmacist’s Perspective BY DAVID BARIBEAULT, RPH, BCOP Boston Medical Center, Massachusetts
he study by Rassu and colleagues discussed in this issue is a long-overdue evaluation of the literature supporting the use of parenteral iron supplementation in the management of anemia in cancer patients.1 For many years, it has been well-established that the successful management of anemia in patients with chronic kidney disease (CKD), especially when erythropoiesis-stimulating agents (ESAs) are used, requires the use of parenteral iron supplementation.2,3 Rassu and colleagues offer suggestions that potentially explain the reticence of oncologists to administer parenteral iron to anemic cancer patients: the perception that patients with cancer are not iron-deficient, based almost universally on elevated serum ferritin levels that are more than likely a result of inflammatory cytokines, and that parenteral iron administration carries with it unacceptable risks. It is important that oncology pharmacists involved in the management of anemia critically evaluate the available literature on the use of parenteral iron administration and educate other practitioners about the benefits and risks of this therapy. Although the data, when compared with that on the CKD population, are sparse, they are, nonetheless, telling. In the first trial evaluating the use of iron in combination with ESAs, two questions were asked: (1) Does the response rate in anemic cancer patients increase when iron is administered concurrently with ESAs, and (2) If iron supplementaton does help, does the route or method of administration make a difference in that response.4 The answer to the first question, of course, was a resounding “yes.” This should have been somewhat intuitive, however, be-
cause, by most definitions, patients had to be iron-deficient to be enrolled in the study. The answer to the second question sparked the interest of many oncology pharmacists involved in anemia management. It would seem from the results of this trial that it did not matter whether total requirements were fractionated or given as a total dose, but the route of administration was paramount to success.3 Not long after Auerbach’s original work was published, Henry and colleagues asked a similar question.5 They hypothesized that if iron dextran could improve response rates to ESAs, then so should ferric gluconate, which could potentially give physicians who feared iron dextran reactions an alternative that they could be comfortable with, and one that would improve response rates. The study design was very similar to Auerbach’s original trial in that patients were randomized to either receive parenteral iron (eight weekly doses of 125 mg), oral iron, or no iron at all. Not surprisingly, the results were almost identical, with patients with parenteral iron repletion having a much better chance at a hematopoietic response than either the oral-iron or no-iron groups. Interestingly, overt iron deficiency was not a strict eligibility criterion in this study, and, as such, there was a cohort of patients who were not iron deficient by standard definitions. This finding heralded for the first time that in cancer patients, as well as in CKD patients, stimulated erythropoiesis requires iron supplementation to be effective and that supplementation should not be given orally. This led to the recently published work of Rassu and colleagues, who set out to answer this question definitively by enrolling only
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iron-replete patients in a study of anemic cancer patients receiving ESAs for chemotherapyinduced anemia.1 In this open-label trial, a heterogeneous population of anemic cancer patients were randomized to receive either weekly darbepoetin alfa or weekly darbepoetin alfa coupled with weekly intravenous ferric gluconate.5 Once again, the administration of parenteral iron was shown to improve response rates and decrease transfusion requirements, but this was the first time that it was shown in patients who were not iron deficient. Although it has taken quite some time to get to the realization that stimulated erythropoeisis requires iron supplementation, clearly the data that we have before us should point us toward that conclusion. It is incumbent now on oncology pharmacists to work with their provider colleagues to ensure that anemia management for cancer patients includes the use of parenteral iron compounds. References 1. Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alfa. J Clin Oncol. 2008;26:1619-1625. 2. Fishbane S, Maesaka JK. Iron management in end-stage renal disease. Am J Kidney Dis. 1997;29:319-333. 3. National Kidney Foundation. Kidney Disease Outcomes Quality Initiative clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. http://www.kidney.org/professionals/KDOQI/guidelines_ anemia/ped32.htm. Accessed August 11, 2008. 4. Auerbach M, Ballard H, Trout JR, et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open label, randomized trial. J Clin Oncol. 2004;22:1301-1307. 5. Henry DH, Dahl NV, Auerbach M, et al. Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist. 2007;12:231-242.
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Continuing Education Program #CIK 9944 • RELEASE DATE: September 30, 2008 • EXPIRATION DATE: September 29, 2009 hematopoietic response, significantly favored the IV iron group. An Italian study,17 that included 149 ironreplete patients (defined as having a serum ferritin level of ≥100 ng/mL and TSAT ≥20%) demonstrated that IV iron supplementation significantly reduces treatment failures to DA with no additional toxicity. The percentage of responders in the no-iron group was comparable with rates reported in previous studies using DA.7 The Table summarizes published studies of iron supplementation and ESAs.
Conclusion Based on the novel evidence from phase 3 trials, IV (not oral) iron supplementation in conjunction with ESA therapy should be considered a component of the management of CRA, both in patients with FID and in iron-replete patients. This issue is clinically relevant because appropriate iron supplementation, in
addition to allowing more patients to benefit from ESA therapy, may represent a strategy to improve the cost-effectiveness of ESAs in oncology.18
IV (not oral) iron supplementation in conjunction with ESA therapy should be considered a component of the management of CRA. Case Report A 51-year-old patient was referred to our hospital with a newly diagnosed metastatic breast carcino-
ma. One month earlier, a 3-cm mass in the upper outer quadrant of the right breast had been found on physical examination. Pathologic evaluation of a through-cut biopsy showed a grade 3, triple-negative ductal carcinoma. Radiographs of the chest and findings on abdominal ultrasound were unremarkable. A bone scan and a computed tomography scan detected osteolytic lesions in the right proximal femur and dorsal column. Chemotherapy consisting of a combination of adriamycin 60 mg/m2 of body surface with paclitaxel at a dose of 175 mg/m2 of body surface was initiated. After two cycles of chemotherapy, a hemoglobin (Hb) value that was near normal at baseline (11.9 g/dL) dropped to 9.1 g/dL. At the same time, iron parameters were within normal ranges (TSAT, 24%; serum ferritin, 144 ng/dL). Subcutaneous DA 150 µg/week was started with no response (Hb, 9.5 g/dL) after 4 weeks, but
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Treatment of Cancer Anemia with Erythropoiesis-stimulating Agents and Intravenous Iron Supplementation: A Nurse’s Perspective BY MANUEL G. AFABLE II, RN, BSN Taussig Cancer Institute, Cleveland Clinic Foundation, Ohio
nemia in cancer patients has been reported in up to 75% of patients,1 and erythropoiesis-stimulating agents (ESAs) have been used to manage this condition. Although the role of ESAs is well recognized, it is estimated that 30% to 50% of patients do not achieve a significant response to ESAs.2 Moreover, the use of ESAs is also associated with a considerable cost. It is estimated that in the United States alone, $6 billion is spent per year on ESAs.3 The characterization of functional iron deficiency (FID) has helped explained why cancerrelated anemia (CRA) does not always respond to ESAs. It is believed that in various chronic diseases, including cancer, inflammatory cytokines, particularly interleukin 6 (IL-6), are released. IL-6 upregulates hepcidin, a peptide secreted in the liver by the hepatocytes. Hepcidin inhibits the release of absorbed iron into the circulation by inactivating ferroportin, a transmembrane protein.3 This results in FID, a scenario in which an individual actually has sufficient iron stores, but has a limited amount of iron available at the site of erythropoeisis. Similarly, this condition exists when using ESAs without adequate iron support.4 Hypererythropoiesis of the bone marrow exists, which outstrips the labile iron pool. Iron deficiency is diagnosed through laboratory testing for ferritin levels and transferrin saturation. As discussed in the article by Rassu and associates, at least six clinical trials have shown the effectiveness of the combination of ESAs and intravenous (IV) iron in increasing hemoglobin levels.This is indeed a welcome outcome if we are to encourage the concomitant use of IV iron with ESAs. The latest two trials were published in the April issue of the Journal of Clinical Oncology.2,5 It is interesting to note that in the study by Bastit and colleagues5 the addition of IV iron to ESAs resulted in a statistically significant difference in blood
transfusion requirement between the IV iron group (9%) and the standard group (20%) (P = .005). However, this study was not powered to detect a difference in the Functional Assessment of Cancer Therapy: Fatigue results, which was the tool used for the quality of life assessment. In general, these trials did not only show efficacy, but also safety when ESA and IV iron are combined. Despite the favorable responses seen with the ESA and IV iron combination, health practitioners treating CRA are still not routinely using it in their practice. The primary reason could be the perception that IV iron is associated with anaphylactic shock. Auerbach and colleagues,3 however, have pointed out that the anaphylactic reactions were largely caused by the high-molecular-weight iron dextrans, which are no longer used today. The IV iron preparations currently being used (ie, iron sucrose and iron gluconate) are less frequently associated with adverse events. In fact, adverse drug events (ADEs) data from the US Food and Drug Administration (2001-2003) showed absolute rates of life-threatening ADEs for iron sucrose, iron gluconate, and low-molecular-weight iron dextran of 0.6 per million doses, 0.9 per million doses, and 3.3 per million doses, respectively.1 The risk of developing cardiovascular disease due to iron’s potential capacity to increase oxidative risk is also a concern. In hemodialysis patients receiving IV iron, however, no increase in mortality was observed.1 For cancer patients being treated with chemotherapy, both iron sucrose and iron gluconate are good options considering their ADE profile. Both iron salts can be given as 200-mg, 2minute IV bolus, and no test dose is required.6 Higher doses are not recommended because of dose-dependent gastrointestinal reactions. The iron salt preparations are also given without pre-
medication. When diphenhydramine is given as a premedication, it can potentially cause vasoactive reactions, which could mistakenly be attributed to IV iron. When IV iron dextran is being considered, however, administration of IV methylprednisolone before and after IV infusion helps lessen the occurrence of myalgias and arthralgias.6 A study presented during the 2007 American College of Pharmacy meeting showed that combination therapy with ESA and IV iron can save about $100 per week for an individual patient. This estimate factored in the decreased ESA dosage required to reach the target hemoglobin level in patients who also received IV iron.7 Although the results of recent studies are encouraging, long-term trials are still needed to better assess the potential effects on survival of IV iron supplementation. Comparing the different IV iron formulations as well to determine the most cost-effective preparation will further improve the management of CRA. References 1. Hedenus M, Birgegard G. The role of iron supplementation during epoietin treatment for cancer-related anemia. Med Oncol. 2008 May 13. [Epub ahead of print.] 2. Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of intravenous iron supplementation in patients with chemotherapyrelated anemia without iron deficiency treated with darbepoetin alfa. J Clin Oncol. 2008;26:1619-1625. 3. Auerbach M, Ballard H. Intravenous iron in oncology. J Natl Compr Canc Netw. 2008;6:585-592. 4. Cavill I, Auerbach M, Bailie G, et al. Iron and the anaemia of chronic disease: a review and strategic recommendations. Curr Med Res Opin. 2006;22:731-737. 5. Bastit L, Vandebroek A, Altintas S, et al. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J Clin Oncol. 2008;26:1611-1618. 6. Auerbach M, Ballard H, Glaspy J. Clinical update: intravenous iron for anaemia. Lancet. 2007;369:1502-1504. 7. Auerbach M. Should intravenous iron be the standard of care in oncology? J Clin Oncol. 2008;26:1579-1581.
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Continuing Education Program #CIK 9944 • RELEASE DATE: September 30, 2008 • EXPIRATION DATE: September 29, 2009 Table. Published Studies of Iron Supplementation and ESAs in Cancer Anemia Patients enrolled (N)/diagnosis
Baseline iron status
Type and dose of IV iron
Hedenus, et al
Stainable iron in the bone marrow
Epoetin beta 30,000 U weekly vs epoetin beta + IV iron
Iron sucrose 1000 mg IV
Mean Hb (g/dL) at the end of treatment
PP: 11.8 vs 13.0/ P = .0001
Auerbach, et al13
157/ Nonmyeloid malignancies (19% lymphoid tumors)
Ferritin ≤450 pmol/L or ≤675 pmol/L with TSAT ≤19%
Epoetin alfa 40,000 U every week vs epoetin vs epoetin alfa + IV iron every week vs epoetin alfa + IV iron TDI
Iron dextran 1100 mg to 2400 mg (every week group) 1000 to 3000 mg (TDI group)
Mean Hb increase (g/dL)
ITT: 0.9 vs 1.5 vs 2.5 vs 2.4/P = .02 IV iron groups vs no-iron and oraliron groups
Henry, et al14
Serum ferritin >100 ng/mL or TSAT >15%
Epoetin alfa 40,000 U every week vs epoetin alfa + oral iron vs epoetin alfa + IV iron every week
Iron gluconate 1000 mg
Increase in Hb from baseline to last value (g/dL)
1.5 vs 1.6 vs 2.4/ P = .0092 vs oral iron; P = .0044 vs no iron
Bastit, et al16
Serum ferritin >10 ng/mL or TSAT >15%
Darbepoetin 500 µg every 3 weeks ± oral iron vs darbepoetin + IV iron every 3 weeks
Iron gluconate or iron sucrose 1200 mg
Hb >12 g/dL or >2 g/dL increase; RBC transfusions
73% vs 86%/ P = .011; 20% vs 9%/P = .005
Pedrazzoli, et al17
149/Solid tumors (colorectal, lung, breast, gynecologic)
Serum ferritin >100 ng/mL and TSAT >20%
Darbepoetin (150 µg every week) vs darbepoetin + IV iron every week
Iron gluconate 750 mg
Achievement of Hb ≥12 g/dL or ≥2 g/dL increase
PP, 70% vs 92.5%/P = .0033
ESAs indicates erythropoiesis-stimulating agents; TSAT, transferring saturation; IV, intravenous; TDI, total dose infusion; ITT, intention-to-treat population; PP, per-protocol population; Hb, hemoglobin; RBC, red blood cell.
there was evidence of FID (TSAT, 13%; serum ferritin, 106 ng/dL). The patient was kept on DA in conjunction with IV iron gluconate 125 mg weekly. Administration of DA plus IV iron resulted in progressive improvement of Hb up to normal values (12.3 g/dL) at week 5 of combined treatment. No toxic effects related to IV iron or DA infusion were documented. The patient is progression free with normal Hb at 10 months from completion of six cycles of chemotherapy. This patient with breast cancer developed FID in the course of ESA therapy, which is highly likely the reason for lack of hematopoietic response to DA. In fact, correction (and subsequent prevention) of iron deficiency by the addition of IV iron to ESA therapy normalized Hb values, allowing the patient to better tolerate chemotherapy while avoiding the risk of red blood cell transfusions. References 1. Ludwig H, Fritz E. Anaemia in cancer patients. Sem Oncol. 1998;25(3 suppl 7):2-6. 2. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011-1023. 3. Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol. 2008;26:132-149. 4. Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human erythropoietin and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst. 2006;98:708-714. 5. Cella D, Dobrez D, Glaspy J. Control of cancer-related anemia with erythropoietic agents: a review of evidence for improved quality of life and clinical outcomes. Ann Oncol. 2003;14:511-519. 6. Demetri GD, Kris M, Wade J, et al. Quality-of-life benefit in chemotherapy
patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. Procrit Study Group. J Clin Oncol. 1998;16:3412-3425. 7. Vansteenkiste J, Pirker R, Massuti B, et al. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst. 2002;94:1211-1220. 8. Macdougall IC, Tucker B, Thompson J, et al. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int. 1996;50:1694-1699. 9. Beguin Y. Erythropoietic agents and iron. In Bokemeyer C and Ludwig H, eds: Anaemia in Cancer: European School of Oncology Scientific Updates, 6. 2nd ed. Philadelphia, PA: Elsevier; 2005: 199-220. 10. Auerbach M. Clinical update: intravenous iron for anaemia. Lancet. 2007;369:1502-1504. 11. Chertow GM, Mason PD, Vaage-Nilsen O, et al. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant. 2006;21:378-382. 12. Hedenus M, Birgegard G, Nasman P, et al. Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study. Leukemia. 2007;21:627-632. 13. Auerbach M, Ballard H, Trout JR, et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open label, randomized trial. J Clin Oncol. 2004;22:1301-1307. 14. Henry DH, Dahl NV, Auerbach M, et al. Intravenous ferric gluconate improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist. 2007;12:231-242. 15. Bokemeyer C, Aapro MS, Courdi A, et al. EORTC guidelines for the use of erythropoietic agents in anaemic patients with cancer: 2006 update. Eur J Cancer. 2007;43:258-270. 16. Bastit L, Vandebroek A, Altintas S, et al. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alfa administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J Clin Oncol. 2008;26:1611-1618. 17. Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alfa. J Clin Oncol. 2008;26:1619-1625. 18. Besarab A, Amin N, Ahsan M, et al. Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients. J Am Soc Nephrol. 2000;1:530-538.
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Erratum In the June 2008 issue of The Oncology Pharmacist, an incorrect UPN number was stated for the activity (THE INCORRECT UPN IS 447-000-08-067-H04-P). The correct UPN is 447-000-08-467-H04-P and carries 1 credit. For those individuals that have completed this activity, new statements of credit will be sent with the correct UPN number. Sorry for the inconvenience. In the July/August 2008 issue of The Oncology Pharmacist, an incorrect UPN number was stated for the activity (THE INCORRECT UPN IS 447-000-08-150-H04-P). The correct UPN is 447-000-08-450-H04-P.
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ONCOLOGY TRENDS Continued from page 7
for ASC plus vinorelbine compared with ASC alone (HR, 0.80; P = .08). There were no between-group differences in the predefined quality-oflife subscales (physical functioning, pain, dyspnea, and global health status) at any of the assessments in the first 6 months. (Muers MF, et al. Lancet. 2008;371:1685-1694.)
>>> Standard and High-dose Pemetrexed Equivalent as Second-line Treatment in NSCLC High-dose pemetrexed does not improve efficacy measures beyond standard-dose pemetrexed when used as second-line therapy in patients with non-small-cell lung cancer (NSCLC). The finding emerged in a study of 588 patients with locally advanced or metastatic NSCLC, previously treated with platinum-based chemotherapy, who were randomly assigned to receive standard pemetrexed (500 mg/m2 [P500]) or high-dose pemetrexed (900 mg/m2 [P900]) every 3 weeks. P900 patients were permitted to continue treatment at P500. No significant differences were observed between the standard- and highdose treatment arms for median survival (6.7 vs 6.9 months; hazard ratio [HR] = 1.0132), progressionfree survival (2.6 vs 2.8 months; HR = 0.9681), or best overall tumor response (7.1% vs 4.3%; P = .16). The incidence of drug-related grade 3/4 toxicity was typically <5% in both treatment arms, but was numerically higher in the high-dose arm for most toxicity categories. Study accrual was terminated early because an interim analysis indicated a low probability of improved survival and numerically greater toxicity in the high-dose pemetrexed arm. (Cullen MH, et al. Ann Oncol. 2008;19:939-945.) >>>Immunosuppressive Therapy Improves Survival in Patients with Myelodysplastic Syndrome Immunosuppressive therapy (IST) produces significant improvement in the pancytopenia of a substantial proportion of patients with myelodysplastic syndrome (MDS) and is associated with improvements in overall and progressionfree survival. A group of 129 patients with MDS received IST using antithymocyte globulin (ATG) or cyclosporine (CsA) in combination or alone and were followed for a median of 3 years. Of the 129 patients, 12 (9%) had a complete response (CR) and 27 (21%) had a partial response. Patients with a CR achieved transfusion independence and near-norSeptember/October 2008
mal blood counts. Overall, 18 (24%) of 74 patients responded to ATG, 20 (48%) of 42 patients responded to ATG plus CsA, and one (8%) of 13 patients responded to CsA. In a multivariate analysis, younger age was the most significant factor predicting a favorable response to therapy. Other favorable factors affecting treatment response were HLA-DR15 positivity and combination ATG plus CsA treatment (P = .001 and P = .048, respectively). (Sloand EM, et al. J Clin Oncol. 2008;26:2505-2511.) RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information. WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse Reactions]. Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan [see Warnings and Precautions, Adverse Reactions]. Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions]. Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions].
INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) is indicated for the treatment of patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing (including stable disease), low-grade, CD20positive B-cell NHL, as a single agent, after first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, consider resumption of the infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with preexisting cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (>25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within 12–24 hours after the first infusion. Fatal TLS cases have occurred after administration of Rituxan. A high number of circulating malignant cells (*25,000/mm3) or high tumor burden confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases for which Rituxan has not been approved. The majority of patients with hematologic malignancies diagnosed with PML received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy and were diagnosed with PML within 12 months of their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B Virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of Rituxan and approximately one month after the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following Rituxan therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who develop viral hepatitis, and institute appropriate treatment including antiviral therapy. Insufficient data exist regarding the safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions.] Other Viral Infections The following additional serious viral infections, either new, reactivated, or exacerbated, have been identified in clinical studies or postmarketing reports. The majority of patients received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred as late as one year following discontinuation of Rituxan and have resulted in death. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or lifethreatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with hematologic malignancies. Renal toxicity has occurred in patients with high numbers of circulating malignant cells (>25,000/mm3) or high tumor burden who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an approved treatment regimen. Use extreme caution if this non-approved combination is used in clinical trials and monitor closely for signs of renal failure. Consider discontinuation of Rituxan for patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal
>>> Intensive Chemotherapy with Stem Cell Rescue Effective in Peripheral T-cell Lymphoma Intensive chemotherapy plus autologous stem cell transplantation (ASCT) is effective with manageable toxicity in patients with peripheral T-cell lymphoma (PTCL). A group of 41 patients (median age, 47 years) with PTCL received three courses of high-dose cyclophosphamide 2000 mg/m2/day, adriamycin 90 mg/m2/day, vincristine, and prednisone alternating with three courses of etopo-
side, cisplatin, cytarabine, and prednisone. Of the 41 patients, 28 (68%) responded to chemotherapy. ASCT was carried out in 17 patients. The complete response (CR) rate following ASCT was 51%. During a median follow-up of 3.2 years, five of 21 patients with CR relapsed and two died due to secondary neoplasms. At 4 years, the rates of progression-free and overall survival were 30% and 39%, respectively. The main variable predicting survival was the International Prognostic Index. (Mercadal S, et al. Ann Oncol. 2008;19:958-963.)
perforation was 6 (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and institute appropriate treatment for complaints of abdominal pain, especially early in the course of Rituxan therapy. [See Adverse Reactions.] Immunization The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live virus vaccines is not recommended. For NHL patients, the benefits of primary or booster vaccinations should be weighted against the risks of delay in initiation of Rituxan therapy. Laboratory Monitoring Because Rituxan binds to all CD20positive B lymphocytes (malignant and non-malignant), obtain complete blood counts (CBC) and platelet counts at regular intervals during Rituxan therapy and more frequently in patients who develop cytopenias [see Adverse Reactions]. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period. ADVERSE REACTIONS The most common adverse reactions of Rituxan (incidence *25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. The most important serious adverse reactions of Rituxan are infusion reactions, tumor lysis syndrome, mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML, other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation. Clinical Trials Experience Non-Hodgkin’s Lymphoma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to Rituxan in 1606 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n = 356 and n = 1250). These data were obtained in adults with low-grade, follicular, or DLBCL NHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. Single-Agent Rituxan Adverse reactions in Table 1 occurred in 356 patients with relapsed or refractory, lowgrade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. Most patients received Rituxan 375 mg/m2 weekly for 4 doses. Table 1 Incidence of Adverse Events in *5% of Patients with Relapsed or Refractory, LowGrade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b
and 4 adverse reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving RCHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia (Study 8). Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, antihuman anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in rituximab treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during postapproval use of Rituxan in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic: prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure. Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection. Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneous reactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatal bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUG INTERACTIONS Formal drug interaction studies have not been performed with Rituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. NonHodgkin’s lymphoma and severe rheumatoid arthritis are serious conditions that require treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Rituximab is a genetically engineered IgG molecule, and IgG crosses the human placenta. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Other than target B lymphocytes, rituximab is not known to bind to any normal human tissues in an ex vivo assay. However, it is not known if binding occurs to unique embryonic or fetal tissue receptors in vivo. Nursing Mothers It is not known whether Rituxan is secreted into human milk. However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from gastrointestinal or limited systemic exposure to Rituxan should be weighed against the known benefits of breastfeeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) frequently among elderly patients. Serious pulmonary adverse reactions were also Respiratory System 38 4 Any Adverse Events 99 57 more common among the elderly, including pneumonia and pneumonitis. Low86 10 Increased Cough 13 1 Body as a Whole Fever 53 1 Rhinitis 12 1 Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan in Chills 33 3 Bronchospasm 8 1 low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient Infection 31 4 Dyspnea 7 1 Asthenia 26 1 Sinusitis 6 0 numbers of patients aged 65 and over to determine whether they respond Headache 19 1 Metabolic and Nutritional Abdominal Pain 14 1 Disorders 38 3 differently from younger subjects. OVERDOSAGE There has been no experience Pain 12 1 Angioedema 11 1 with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have Back Pain 10 1 Hyperglycemia 9 1 Throat Irritation 9 0 Peripheral Edema 8 0 been given in dose-escalation clinical trials. NONCLINICAL TOXICOLOGY Flushing 5 0 LDH Increase 7 0 Heme and Lymphatic System 67 48 Digestive System 37 2 Carcinogenesis, Mutagenesis, Impairment of Fertility No long term animal Lymphopenia 48 40 Nausea 23 1 Leukopenia 14 4 Diarrhea 10 1 studies have been performed to establish the carcinogenic or mutagenic potential Neutropenia 14 6 Vomiting 10 1 of Rituxan or to determine potential effects on fertility in males or females. Thrombocytopenia 12 2 Nervous System 32 1 Anemia 8 3 Dizziness 10 1 PATIENT COUNSELING INFORMATION Patients should be provided the Rituxan Skin and Appendages 44 2 Anxiety 5 1 Night Sweats 15 1 Musculoskeletal System 26 3 Medication Guide and provided an opportunity to read prior to each treatment Rash 15 1 Myalgia 10 1 session. Because caution should be exercised in administering Rituxan to patients Pruritus 14 1 Arthralgia 10 1 Urticaria 8 1 Cardiovascular System 25 3 with active infections, it is important that the patient’s overall health be assessed Hypotension 10 1 Hypertension 6 1 at each visit and any questions resulting from the patient’s reading of the Medication Guide be discussed. Rituxan is detectable in serum for up to six a b Adverse reactions observed up to 12 months following Rituxan. Adverse reactions graded for severity by months following completion of therapy. Individuals of childbearing potential NCI-CTC criteria. In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and should use effective contraception during treatment and for 12 months after up to 6 months after Rituxan infusion. Rituxan in Combination With Rituxan therapy. Chemotherapy Adverse reactions information below is based on 1250 patients who received Rituxan in combination with chemotherapy or following chemotherapy. Rituxan in Combination With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm experienced a higher incidence of Revised 1/2008 (4835504) infusional toxicity and neutropenia compared to patients in the CVP arm. The Jointly Marketed by: following adverse reactions occurred more frequently (*5%) in patients receiving Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactions were reported more frequently (*5%) in patients receiving Rituxan following CVP compared to patients who received no further therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. ©2008 Biogen Idec Inc. and Genentech, Inc. 7140916 March 2008 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (*2%) in the Rituxan arm compared with those who received no further therapy (4% vs. 1%). Rituxan in Combination With Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions, regardless of severity, were reported more frequently (*5%) in patients age *60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3
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For previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens
When planning a treatment course for DLBCL
Take the essential path toward improved survival RITUXAN+CHOP is proven to prolong survival in DLBCL
in 7-year OS in GELA* trial 1,2
• At 7 years, 8 cycles of RITUXAN+ CHOP increased overall survival (OS) from 36% to 53% compared with CHOP alone1 • At 5 years, 8 cycles of RITUXAN+ CHOP increased OS from 46% to 58% compared with CHOP alone5
BOXED WARNINGS and Additional Important Safety Information The most important serious adverse reactions of RITUXAN are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.5 RITUXAN in Combination with CHOP Chemotherapy for DLBCL: The following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs 46%), lung disorder (31% vs 24%), cardiac disorder (29% vs 21%), and chills (13% vs 4%). In the GELA LNH 98-5 study, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs 1.0% for CHOP).5 The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs 7%) and lung disorder (6% vs 3%). Other Grade 3 or 4 adverse reactions reported more frequently among patients receiving R-CHOP were viral infection (GELA LNH 98-5 study), neutropenia (GELA LNH 98-5 and MInT studies), and anemia (MInT study).5
Please see brief summary of prescribing information on adjacent page. Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion. *GELA (Groupe d’Etude des Lymphomes de l’Adulte) LNH 98-5 trial: A Phase III trial of 399 previously untreated elderly (age ≥60 years) DLBCL patients.3,4 †CHOP: Cyclophosphamide, doxorubicin, vincristine, and prednisone. References: 1. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. J Clin Oncol. 2007;25(suppl 18S):443s. Abstract 8009. 2. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. Paper presented at: 43rd American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Ill. Abstract 8009. 3. Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-242. 4. Data on file, Genentech, Inc. 5. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.
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©2008 Genentech, Inc., and Biogen Idec Inc. All rights reserved. 3 Printed in USA on Recycled Paper 8974801 April 2008
Published on Jun 19, 2009
September/October 2008 Volume 1 Number 4 • Advancing Oncology Pharmacy to a New Level • Oral Chemotherapy Adherence Enhanced by Multiple Str...