CANCER CENTER PROFILE University of Texas M.D. Anderson Cancer Center
BOOKS & MEDIA Young adult patients land on Planet Cancer for support and venting
BREAST CANCER All-oral therapy of HER2-positive breast cancer a possibility
SEPTEMBER 2008 • VOL. 1, NO. 4
Recognize High-risk Patients to Prevent Fungal Infections
Current Approaches to Management of Pediatric Neuroblastoma An interview with Katherine K. Matthay, MD
euroblastoma, a solid tumor cancer that forms in the nervous system outside the brain, usually occurs in children younger than 5 years. The disease is classified as low, intermediate, or high risk; approximately 50% of children have high-risk disease, which has a poor progno-
sis. In this interview, Katherine K. Matthay, MD, chief of Pediatric Hematology-Oncology at the University of California at San Francisco Children’s Medical Center, describes the signs and symptoms and course of the disease and discusses current and emerging options for treatment.
Matthay is head of the New Approaches to Neuroblastoma Therapy (NANT) Consortium, a group of 14 academic medical centers and children’s hospitals in the United States that conducts clinical trials of new therapies for highrisk neuroblastoma.
Helping Children with Cancer Return to School BY SARAH F. DONNANGELO, MS
Older Patients with Stage III Colon Cancer Should Not be Denied Chemotherapy
hen a child or family has learned that they are facing the diagnosis of cancer, school is often the last thing to be considered. However, significant advances in the treatment of child-
CHICAGO—Patients with stage III colon cancer should not be denied chemotherapy on the basis of advanced age. An observational study reported at the 44th annual meeting of the American Society of Clinic Oncology shows that the oldest recipients of adjuvant chemotherapy suffered no more adverse events than their younger counterparts but were far less likely to
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Program #08CE059c: Treatment of Cancer Anemia with Erythropoiesis-stimulating Agents and IV Iron Supplementation
SUPPORTIVE CARE Preventing neutropenia in cancer patients
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TOMORROWS CHILDREN’S INSTITUTE FOR CANCER AND BLOOD DISORDERS, JOSEPH M. SANZARI CHILDREN’S HOSPITAL, HACKENSACK UNIVERSITY MEDICAL CENTER, HACKENSACK, NEW JERSEY
PHILADELPHIA—The incidence of invasive fungal infections (IFIs) has risen dramatically among cancer patients over the past 2 decades, mainly as a result of immunocompromise from intensive chemotherapy or hematopoietic stem cell transplantation (HSCT). With more than 1.3 million hospital patients affected by IFIs in the United States every year, oncology nurses are the point-of-care contact between physicians and patients and therefore have a critical role in identifying and managing high-risk patients.
ONCOLOGY NUTRITION Nutrition screening of oncology patients
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.
Medical Minutes BY JOHN SCHIESZER
Video Games May Help Improve Treatment Adherence in Young Cancer Patients John Schieszer is an award-winning national journalist and radio broadcaster of The Medical Minute. He can be reached at firstname.lastname@example.org.
Video games can be designed to improve adherence to treatment and treatment outcomes in adolescents and young adults with cancer, researchers from the Netherlands report in the August 2008 issue of Pediatrics (Kato PM, et al. Pediatrics. 2008;122:e305-e317). The intervention group consisted of 375 patients between 13 and 29 years old. All of the patients were undergoing treatment for malignancies such as leukemia, lymphoma, and soft-tissue sarcoma. At 3 months, the researchers found that the video game intervention, which involved playing a video game that addressed cancer care issues 1 hour per day, significantly improved treatment adherence. In addition, patients who played the video game had greater knowledge of their disease and more self-efficacy. The analyses suggested that the patient’s increased sense of con-
trol over cancer (self-efficacy) was a major driver of the game’s effect on medical treatment utilization. The authors believe that these results provide scientific evidence for a growing field of product development that taps into the positive potential of video games to improve human health. Previous studies by other researchers have shown that pain scores may be lower among young chronically ill patients who are able to play video games during their treatments. However, many researchers now believe that video games can be designed to do more than just distract young cancer patients. The hope is that games can be designed that educate cancer patients and motivate them to be more adherent to their regimens, which could ultimately lead to better patient outcomes and improved survival rates.
As oncology nurses know, the use of vitamin and mineral suppleSurvivors of breast cancer reported the highest use (75% to 87%), ments among cancer survivors is widespread. They may, however, whereas prostate-cancer survivors reported the least (26% to 35%). want to counsel their patients that there is no conclusive evidence Factors associated with the highest level of supplement use overall that such use is beneficial. included a higher level of education and being female. The researchers Investigators at the Fred Hutchinson Cancer Research Center in also found that many people initiate the use of vitamins and suppleSeattle, Washington, conducted a comprehensive review of the sci- ments after a cancer diagnosis. entific literature and found that little research has been done on use “Evidence clearly suggests the need for caution,” explained Ulrich. of vitamin and mineral supplements by cancer patients and many “Some vitamins, such as folic acid, may be involved in cancer progrespatients may be misinformed. sion while others, such as St. John’s wort, can interfere with “Can vitamin and herbal supplements reduce the adverse effects of chemotherapy. However, we really need more research to understand cancer treatment, decrease the risk of cancer recurrence, or improve whether use of these supplements can be beneficial or do more harm a patient’s chances of survival? We don’t really know. Research into than good.” these matters has been minimal,” said senior study author Cornelia She said until research studies clarify the effects of vitamin use Ulrich, PhD, who is an associate member of the Hutchinson Center’s in cancer survivors, nurses and other clinicians should commuPublic Health Sciences Division. “While supplement use may be nicate openly with their patients about using caution when takbeneficial for some patients, such as those who cannot eat a balanced ing supplements. diet, research suggests that certain supplements may actually interfere with treatment or even accelerate cancer growth.” Southern Region of the United States In reviewing 32 studies conducted Known as Cancer Belt between 1999 and 2006, Ulrich and her colleagues found that 64% to 81% of canResearchers have deemed the southern in this region of the country. They are curcer survivors overall reported using vitaregion of the United States “The Cancer rently enrolling as many as 1000 patients in mins or minerals (excluding multivitaBelt” because of the high cancer morbidity the study with the help of four other cancer mins), whereas in the general population and mortality rates they have found there. centers. only 50% of adults reported taking dietary Researchers in Tennessee say that brain “We’re asking patients about their diets, supplements. cancer (glioblastoma) is one of the most possible job-related exposure to canceralarming malignancies disproportionately causing chemicals, and we’re collecting affecting people in the southern region of DNA samples,” explained Thompson. “We the United States. “When you look at a know there are some genetic markers that map of brain cancer incidence in the are linked to other forms of cancer, and they United States, the Southeast just lights up may play a role in brain cancer as well.” in red,” said Reid Thompson, MD, who is Brain cancer is not the only cancer taking an associate professor of medicine at an unusual toll on Southern populations. Vanderbilt-Ingram Cancer Center, Nash- Topping the list is lung cancer. Despite ville, Tennessee. “When we found this hot- decades of warnings about the dangers of spot on the National Cancer Institute’s cigarette smoking, Southerners continue to mortality maps we realized something smoke more than individuals in other unusual is going on in this region.” regions of the country. Thompson said Much of this region is also already part of tobacco use may explain some of the higher what is called “The Stroke Belt” because cancer rates in this region of the country, the incidences of stroke are far above the but it may be more difficult to determine national average. Thompson, along with a why people living in the South are developteam of nurses and other researchers, has ing many other types of cancer besides lung launched a study to find clues that may cancer at higher rates than people who live explain the clusters of brain cancer found elsewhere. ©iStockphoto.com/Paul Kline
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The Truth About Vitamin and Mineral Benefits for Cancer Patients
Vol. 1, No. 4
Supportive Care Pegfilgrastim prevents neutropenia cancer patients at risk for Legionella infection
17 Continuing Education Treatment of cancer anemia with ESAs and IV Iron
22 Cancer Center Profile 23 Gastrointestinal Cancers KRAS status and skin toxicity predict response in colorectal cancer
25 Oncology Nutrition Nutrition screening of cancer patients
EDITORIAL BOARD EDITOR-IN-CHIEF
Beth Faiman, RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH
Wendy DiSalvo, BSN, MSN, FNP, AOCN Dartmouth Hitchcock Medical Center Norris Cotton Cancer Center Lebanon, NH
Denice Economou, RN, MN, AOCN City of Hope National Medical Center Duarte, CA Amy Ford, RN, BSN, OCN Creative Cancer Concepts, Inc. Rockwall, TX
Books & Media
Recent FDA Approvals
: online at
All-oral therapy of HER2-positive breast cancer a possibility
Deena Damsky Dell, RN, MSN, AOCN, BC Fox Chase Cancer Center Philadelphia, PA
Local recurrence risk greater with lumpectomy versus mastectomy
Isabell Castellano, RN Bristol-Myers Squibb Children’s Hospital Robert Wood Johnson University Hospital New Brunswick, NJ
PUBLISHING STAFF Publisher Philip Pawelko email@example.com Editorial Director Karen Rosenberg firstname.lastname@example.org Managing Editor Lara J. Reiman Senior Production Manager Stephanie Laudien Directors, Client Services John W. Hennessy email@example.com Russell Hennessy firstname.lastname@example.org Director of Human Resources Blanche Marchitto email@example.com Circulation firstname.lastname@example.org
26 Breast Cancer
The Official Newspaper of Record for the Hem/Onc Nurse
7 Your Financial Future
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The Official Newspaper of Record for the Hem/Onc Nurse
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Lori Stover, RN, BSN Western Pennsylvania Cancer Institute Pittsburgh, PA
Sharon S. Gentry, RN, MSN, AOCN Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC Marilyn L. Haas, PhD, RN, CNS, ANP-C Mountain Radiation Oncology Asheville, NC Cassandra J. Hammond, RN, MSN, CRNP Avid Education Partners, LLC Sharpsburg, MD Taline Khoukaz, NP, MSN, ACNP-C University of Southern California Norris Cancer Center & Hospital Los Angeles, CA
Joseph D. Tariman, RN, MN, ARNP-BC, OCN University of Washington School of Nursing Seattle, WA Pamela Hallquist Viale, RN, MS, CS, ANP, AOCN Saratoga, CA Connie Visovsky, RN, PhD, APRN University of Nebraska, College of Nursing Omaha, NE Jeanne Westphal, RN Meeker County Memorial Hospital Litchfield, MN Frank P. Whyte, RN, OCN Mount Carmel Hospital—St. Ann’s Westerville, OH
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OTHER SPECIALTIES Susan Goodin, PharmD, FCCP, BCOP Cancer Institute of New Jersey New Brunswick, NJ
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Melinda Oberleitner, RN, DNS, APRN, CNS College of Nursing and Allied Health Professions University of Louisiana Lafayette, LA
Amanda Saldivar, MS, RD, LD Cleveland Clinic Taussig Cancer Institute Cleveland, OH
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Patient Support Coordinator Program A dedicated, central point of contact helping providers and patients who rely on Celgene products Trained professionals providing personal assistance concerning: • Reimbursement assistance, insurance claims, and appeals • Medicare Issues • Locating co-pay assistance programs and services • Identifying pharmacies that are registered to dispense Celgene products • Determining the status of a prescription • Inquiries regarding Celgene’s patient assistance program • Providing information regarding Celgene products and their restricted distribution programs (RevAssist® or S.T.E.P.S.®) or appropriate contacts for other questions
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A Letter from the Editor S BETH FAIMAN, RN, MSN, APRN, BC, AOCN
eptember is back to school month, so it is appropriate to focus on issues related to treatment of cancer in children and young adults. In an interview, Dr Katherine K. Matthay, discusses advances in the treatment of pediatric neuroblastoma and the advantages of enrolling children with this and other malignancies in clinical trials to ensure that they receive the latest available treatments. With advances in cancer treatment, more and more children with cancer are now able to return to school. An article in the September issue of the Journal of the National Cancer Institute, for instance, shows “ongoing increases in survival for three of the four common childhood hematologic malignancies.” The article by Sarah F. Donnangelo explains how oncology nurses and other members of the healthcare team can help ease the transition back to school and normal routines by working with the student, parents, school personnel, and classmates to address their concerns and deal with the physical, educational, and emotional challenges that may arise. A multidisciplinary program instituted at her hospital involves the use of hospital-school liaisons to ensure good communication between patients, families, and school staff. For adolescents and young adults, websites such as PlanetCancer can provide support, information, and social net-
Coming Soon CE article: Does Finasteride Prevent Prostate Cancer?
Navigating the Journey of Breast Cancer Unraveling the Complexities of Non-Hodgkin’s Lymphoma Overcoming Barriers to Chemotherapy Safety in Nursing Oncology Patient Participation in Clinical Trials
New Combination Regimens for Metastatic Breast Cancer Reports from ASCO Breast Cancer Symposium, European Society for Medical Oncology
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working appropriate for their special interests and needs. When using this or any other website, however, it is important to know who is behind it and how reliable the information provided is. The review of PlanetCancer in this issue is the first in a series of website reviews that will help oncology nurses select websites to recommend to their patients. For patients of any age, effective supportive care is essential to help patients deal with the short-term and long-term effects of cancer and its treatment. The continuing education article in this issue adds more insight into the use of erythropoiesis-stimulating agents (ESAs) to treat cancer-related anemia. Several recent clinical trials indicate that intravenous iron supplementation is beneficial for cancer patients receiving ESAs. The implications of these findings for oncology nurses and pharmacists are discussed in this article. For oncology nurses, continuing education is necessary throughout one’s career to keep up with the many advances in this exciting field. So, I too am returning to school this month to earn my doctor of philosophy degree in nursing. In coming months, I will share with you my experiences in this new phase of my career! As always, we hope you too will share your experiences and ideas with us. Please write to us (Karen@greenhillhc.com) about the issues important to you and your colleagues.
EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Nurse™, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: firstname.lastname@example.org. 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 Nurse™, 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 Nurse™, 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 #1944-9798. The Oncology Nurse™, is published 6 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 Nurse™ 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 that little more than one third of adults were aware smoking increased the risk of bladder cancer; even among those with earlystage 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 smoking. (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.)
■ Exercise Testing Not Adhering to National and International Guidelines
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.)
■ Nurse-delivered Psychotherapy Beneficial for Depressed Cancer Patients
azacitidine for injection NEWS NOTES
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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 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, 04) 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 qualityadjusted life-year gained. (Strong V, et al. Lancet. 2008; 372:40-48.) September 2008
By Sylvia Maurin
ith 77 million baby boomers headed toward or just beginning retirement, retirement planning is of broad interest not only to boomers but also to all people with the goal of reaching that financial milestone. Regardless of where you are with respect to saving for retirement, a retirement plan is fundamental. In general, such a plan has certain common elements: (1) a best possible estimate of how many years you are from retirement; (2) a total of all assets/funding sources on which you intend to rely at retirement; and (3) an estimate of how much annual income you expect to need in retirement. Experts vary in their opinions of how much is enough, but the rule of thumb is at least 60% to 80% of your current income spread over 25 years. With those three data points, you can make a quick assessment of whether you are behind or on target with respect to saving for retirement. When doing your calculations, use a 5% total annual return on all investments. While this may sound very conservative, it is better to be pleasantly surprised rather than disappointed by less than hoped for returns.
money. Make a plan that puts you on track to meet or exceed your retirement savings goal and stick to it. Avoid borrowing and withdrawals from qualified plans, because depending on the circumstance and your age, heavy penalties may apply. Bear in mind that all contributions to qualified retirement plans grow tax-deferred. In addition to saving through such plans, determine a monthly amount that you can contribute to retirement savings held in taxable accounts. If you are uncertain about aspects of the retire-
full value for any match that may be available by setting your savings to at least equal to the highest possible employer contribution.
Taking action Always contribute as much as you can as soon as you can both to an IRA and to the employer-provided plan. Determine how much is enough and/or possible by using an assessment of your current retirement savings and projected retirement needs and by analyzing your monthly income and outflow of
ment planning process and/or need to gain tax planning and investment advice, seek the help of a retirement planning specialist. Lastly, many people report feeling torn between saving for their children’s college education and saving for their retirement. Put simply, there are numerous college loan programs and, to my knowledge, no lending available for retirement. Sylvia Maurin is president of Source One, LLC, a consulting services firm in Pittsburgh, Pennsylvania. Information presented in this column is general in nature. It is not intended to furnish or replace the expert guidance and/or advice of a financial planning professional familiar with your particular financial situation, goals, and objectives.
Your Financial Future: Retirement Planning
When doing your total annual return on all investments. Understanding retirement terminology There are two forms of the individual retirement account (IRA)—the traditional and the Roth. Depending on which better suits your circumstances, contributions to an IRA should be made annually. For the traditional IRA, your income determines whether contributions are tax deductible in whole, in part, or not at all; contributions to a Roth are not tax deductible. Your age determines how much you can contribute to an IRA. Importantly, this form of retirement savings is in addition to contributions to employer-sponsored plans. Most employer-sponsored plans are either 401(k) or 403(b) plans; the numbers and letters correspond to the section in the tax code where Federal regulations for such plans are found. If you work for a for-profit, you are likely to have a 401(k) plan; if you work for a taxexempt organization, then the plan is likely a 403(b) plan. Other retirement plans offered by small businesses include money purchase plans and profit-sharing plans. Of particular interest is whether your company contributes to employee savings, when they contribute, and how much such contributions may be. Be sure to get September 2008
Your subscription at NO CHARGE is just a signature away! Written by and for oncology nurses offering you the following: • Concise reviews of hot topics in the peer-reviewed literature by clinical specialists with key point ‘takeaways’ • Coverage of key research studies and on-the-scene reports from oncology medical meetings • Continuing education articles at no charge and post-tests, offering you a convenient way to obtain contact hours • Interviews with renowned thought leaders in the oncology nursing community • A “Policy Watch” column covering legislation and policy changes that affect cancer care in your areas of practice
calculations, use a 5%
• Articles of special interest to student nurses, your future colleagues
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VELCADE速 (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.
Please see Important Safety Information on reverse side and refer to full Prescribing Information available at www.VELCADE.com.
PHILADELPHIA—Pegfilgrastim, started at the first chemotherapy cycle and administered at all subsequent cycles, helps reduce the likelihood of febrile neutropenia in older cancer patients compared with the initiation of pegfilgrastim after the first cycle, researchers reported at the 33rd
filgrastim in the first and subsequent cycles of chemotherapy or pegfilgrastim started at the investigator’s discretion in later cycles. “Most cancer patients are 65 years of age or older, and this patient group accounts for 70% of all cancer deaths,” Flores pointed out. “While clinical data suggest that older cancer patients can tolerate the standard chemotherapy regimens used in younger patients, doctors often use suboptimal doses or lengthened schedules out of concern about toxicities, including febrile neutropenia.”
Important Safety Information INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS:
VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused postimplantation loss and a decreased number of live fetuses. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including eGrade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with eGrade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had eGrade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QTinterval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given highdose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (eGrade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Patients with Hepatic Impairment: Bortezomib is metabolized by liver enzymes and bortezomib clearance may decrease in patients with hepatic impairment. These patients should be closely monitored for toxicities when treated with VELCADE.
neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of eGrade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). DRUG INTERACTIONS:
Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients eage 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment.Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer's prescribing information. Patients with Hepatic Impairment: No pharmacokinetic studies were conducted with bortezomib in patients with hepatic impairment. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not been conducted with bortezomib. Bortezomib showed clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary cells. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames test) and in vivo micronucleus assay in mice. Fertility studies with bortezomib were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6-month rat toxicity study, degenerative effects in the ovary were observed at doses e0.3 mg/m2 (one-fourth of the recommended clinical dose), and degenerative changes in the testes occurred at 1.2 mg/m2. VELCADE could have a potential effect on either male or female fertility. Animal Toxicology: Cardiovascular Toxicity: Studies in monkeys showed that administration of dosages approximately twice the recommended clinical dose resulted in heart rate elevations, followed by profound progressive hypotension, bradycardia, and death 12 to 14 hours post dose. Doses e1.2 mg/m2 induced dose-proportional changes in cardiac parameters. Bortezomib has been shown to distribute to most tissues in the body, including the myocardium. In a repeated dosing toxicity study in the monkey, myocardial hemorrhage, inflammation, and necrosis were also observed. Chronic Administration: In animal studies at a dose and schedule similar to that recommended for patients (twice weekly dosing for 2 weeks followed by 1-week rest), toxicities observed included severe anemia and thrombocytopenia, and gastrointestinal, neurological and lymphoid system toxicities. Neurotoxic effects of bortezomib in animal studies included axonal swelling and degeneration in peripheral nerves, dorsal spinal roots, and tracts of the spinal cord. Additionally, multifocal hemorrhage and necrosis in the brain, eye, and heart were observed.
ADVERSE EVENT DATA:
Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral
VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Cambridge, MA 02139 Copyright © 2008, Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. All rights reserved. Printed in USA V0870R3
Older patients, she added, may benefit from the prophylactic use of colony-stimulating factors (CSFs) to decrease the risk of febrile neutropenia; however, CSFs are often used “reactively” in clinical practice at the onset of severe or febrile neutropenia. The inclusion criteria for the trial were specifically designed to be inclusive of older patients, and unlike most clinical trials, allowed patients with comorbidities to enroll, Flores noted. “This meant that our study cohort closely resembled the community practice population,” she said. Trial participants had lung, breast, or ovarian cancer or non-Hodgkin’s lymphoma (NHL). Roughly 90% of patients were white with Eastern Cooperative Oncology Group performance status of 0 or 1, and about two thirds of patients were in disease stage III or IV. The data showed a roughly 60% reduction in the incidence of febrile neutropenia across all cycles of chemotherapy for patients in the pegfilgrastim-all cycles arm compared with patients in the clinician-discretion arm. Patients in the pegfilgrastim-all cycles arm were also less likely to have febrile neutropenia in the first cycle of chemotherapy than patients in the clinician-discretion arm (3% vs 7% in solid tumor patients and 7% vs 25% in patients with NHL). Neutropenia-related hospitalizations were observed less often in the pegfilgrastim-all cycles arm than in the cliniciandiscretion arm for solid tumor patients (5% vs 9%, respectively) and all patients with NHL (17% vs 37%, respectively). “Prophylactic treatment with pegfilgrastim, beginning with the first cycle of chemotherapy, can minimize the need for dose reductions or dose delays as a result of febrile neutropenia or other neutropenia-related events,” Flores pointed out. “This, in turn, leads to improved disease outcomes for older patients, since they will be more likely to receive optimal doses of chemotherapy.” She added that the study findings are important for oncology nurses who, “as primary advocates for older cancer patients, are in a unique position to influence treatment decisions involving supportive care.” —Jill Stein
Cancer Patients at Risk for Legionella Infection from Hospital Water Sources PHILADELPHIA—Close attention to hospital water systems can lower the risk of infection with Legionella pneumophila in patients with cancer. This organism, which causes Legionnaire’s disease, is responsible for about 2000 nosocomial infections per year. Severe immunosuppression puts patients at high risk for infection. Continued on page 11
Pegfilgrastim Prevents Neutropenia in Older Cancer Patients
Annual Congress of the Oncology Nursing Society (ONS). The results from a phase 4 study in 832 patients 65 years of age and older found that first-cycle pegfilgrastim was associated with 60% fewer febrile neutropenia events and 50% fewer hospitalizations due to febrile neutropenia and neutropenia. Irene Q. Flores, RN, OCN, clinical research associate at the Institute for Advanced Studies in Aging and Geriatric Medicine in Washington, DC, presented results in older cancer patients randomized to proactive peg-
G REEN H ILL H EALTHCARE C OMMUNICATIONS
HELPING CHILDREN Continued from cover
hood allow patients and their families to focus on the future even after a diagnosis of cancer. Since the 1950s, overall survival rates have increased from less than 10% to more than 77%, although cure rates vary according to each specific type of childhood cancer.1 With this great accomplishment, children can remain focused on the normal activities of childhood, including the primary one of being a student. School is an arena for a child’s social, emotional, and physical as well as cognitive growth. The process of returning to school after a diagnosis of cancer can be daunting for a child with cancer, as well as for parents, siblings, school personnel, and peers. Advocacy in school must begin at the time of diagnosis and continue throughout a child’s academic career because of the unique educational issues associated with some childhood cancers and their treatments. The oncology nurse can play an important role in this process, either as a member of a larger multidisciplinary team or as the primary resource.
Table 1. Components of a Successful School Reintegration Program •Identification of a coordinator of services •Provide direct service to the child •Consult with family •Educate school personnel •Provide information to classmates •Involve the medical team Source: Reference 3.
Role of the oncology nurse The Association of Pediatric Hematology/ Oncology Nurses defines and promotes the highest standards of practice and care for children, adolescents, and young adults with cancer and blood disorders and their families.2 The highest standards should now include involvement in the process of a child’s return to school. When a child is first diagnosed with cancer, the primary focus of family and hospital staff is to address the existing medical issues. School and resuming a “normal routine” are often ignored because of these overriding medical needs. Focusing on school after the diagnosis of a life-threatening illness, however, can send a positive message of hope to a family, school, and, most important, to a child. Preparation for a child’s eventual return to school encourages a sense of self-worth, accomplishment, and forward thinking in a child who is being treated for cancer. Navigating the healthcare and educational systems can be confusing and frustrating for families of children newly diagnosed with cancer, and a nurse 10
within a pediatric hematology/oncology center can play a significant role in facilitating the transition. A nurse has the foresight and experience to look toward the future and begin planning for a child’s eventual return to school even when a parent may be unable to think that far ahead. A considerable amount of research has been done and articles written concerning recommended strategies for assisting children with cancer with their return to school. In fact, there are many more articles that suggest components of school reintegration programs than there are actual programs.3 Exemplary school reentry programs include six common features, as seen in Table 1. Parents often request direct involvement by hospital staff in planning a child’s educational program in conjunction with school personnel. This outreach should begin early in the treatment process and may consist of meeting with school staff and/or classmates to provide basic information and answers to questions. Using age-appropriate descriptions and learning tools, the oncology nurse can discuss medical facts, common emotions and feelings, as well as the important role that school and friends play while a child is being treated for cancer. Notably, perceived social support from teachers and peers within a school setting has been shown to serve as a potent protective factor against stress in children with cancer.4,5 In a comprehensive study, perceived social support from peers at school was found to be the most potent protective factor against stress for children with cancer.5 Subsequently, a major component of school reentry often involves the role of peers in a classmate’s return to school. Classroom visits are often conducted by hospital staff when a child is cleared to return to school after having been absent for a significant amount of time. These reentry classroom visits can help a child transition back to school and can address any concerns or fears staff, parents, children, or classmates may have. A nurse’s participation in the development of an individualized educational plan or other accommodation plan can also be helpful in planning an appropriate educational program, clarifying the educational goals of a child and family, and discussing the impact that a child’s illness has on reaching his or her educational goals. In attempting to treat the child as normally as possible while identifying and planning for specific needs within the school environment, focus must be on what the child can accomplish as opposed to the restrictions placed on him or her. The best plan for a child’s return to school is one that anticipates potential challenges for the individual child and outlines adjustments that are necessary to address the child’s specific circumstances. The overall goal is to create a seamless transition from hospital and home to school and mark this positive milestone in the child’s cancer journey. The key component in achieving this
G REEN H ILL H EALTHCARE C OMMUNICATIONS
Child Other Hospital Staff
Oncology Nurse Parents
Figure. Role of the Oncology Nurse on Multidisciplinary Team milestone is maintaining clear, open, and frequent communication among involved team members (Figure).
Tomorrows Children’s Institute The Tomorrows Children’s Institute for Cancer and Blood Disorders (TCI) at the Joseph M. Sanzari Children’s Hospital of Hackensack University Medical Center in Hackensack, New Jersey, is recognized as an outstanding pediatric cancer and blood disorders program. Our team of physicians, nurses, psychosocial professionals as well as administrative staff work with children and their family members, giving them the best possible chance for recovery. Unique to TCI is the involvement of hospital-school liaisons, who will meet new families early in the treatment process and assist them in the process of identifying a child’s specific educational needs and developing an appropriate plan along with his or her parents and school. This may include requesting home instruction services, arranging the completion of a psycho-educational assessment that may be used as a baseline for comparison after treatment has ended, contacting a school to inform staff that a student has been diagnosed with cancer, answering any immediate questions, or providing a school with appropriate medical and educational documentation or requests. TCI has two full-time hospital–school liaisons within its Liaisons for Effective Academic Resources and Networking program. These liaisons are dedicated to assisting parents, children, and school personnel in addressing educational issues that arise after the diagnosis of cancer or a serious blood disorder (Table 2). Need for intervention Considering the difficulties that a child with cancer may face either at the time of diagnosis or years after the completion of treatment and the rigid structure of many school programs, it is clear that intervention is needed to bridge the gap between the worlds of hospital, school, and home. Advocacy on behalf of children diagnosed with cancer must begin on the day of diagnosis to achieve
Table 2. Goals of the LEARN Program at TCI • Helping children and their parents navigate their school systems and establish appropriate educational programs • Demystifying the cancer experience for school staff • Clarifying misinformation or misconceptions regarding childhood cancer for classmates, teachers, and school administrators • Providing peers with information and strategies on how to continue being a good friend during the cancer experience • Explaining the potential social and cognitive effects that are associated with some diseases and treatments to staff working with these children LEARN indicates Liaisons for Effective Academic Resources and Networking; TCI, Tomorrows Children’s Institute for Cancer and Blood Disorders.
optimal quality of life. Yet, only a handful of pediatric oncology/hematology programs in the country have staff members who are solely dedicated to assisting children, families, and schools with these specifics. Therefore, the experience and dedication of the pediatric oncology nurse is essential to ensure that the needs of the children he or she follows are understood, so the children are able to do their jobs as students and look forward to the futures that lie ahead of them. References 1. CureSearch. Progress in childhood cancer. http://www.curesearch.org/our_research/index_sub. aspx?id=1527.Accessed July 16, 2008. 2. Association of Pediatric Hematology/ Oncology Nurses. http://www.apon.org/i4a/ pages/index. cfm? pageid=1. Accessed July 16, 2008. 3. Prevatt FF, Heffer RW, Lowe PA. A review of school reintegration programs for children with cancer. J School Psychology. 2000;38:447-467. 4. Hockenberry-Eaton M, Kemp V, DiIorio C. Cancer stressors and protective factors: predicators of stress experienced during treatment for childhood cancer. Res Nurs Health. 1994;17:351-361. 5. Varni JW, Katz ER, Colegrove R, et al. Perceived social support and adjustment of children with newly diagnosed cancer. J Dev Behav Pediatr. 1994;15:20-26.
At the 33rd Annual Congress of the Oncology Nursing Society in Philadelphia in May, researchers reported on two cases of Legionella in bone marrow transplant (BMT) patients at the nearly 700-bed Banner Good Samaritan Medical Center in Phoenix, Arizona, and the 1-year action plan to remediate the problem, which was traced to the water system. According to the US Centers for Disease Control and Prevention (CDC), e2 cases in a 6-month period define a nosocomial outbreak. As soon as the problem and source were identified at the Phoenix hospital, high-risk patients were immediately restricted in their exposure to water for drinking, bathing, showering, and hand washing. Camp showers and bottled water were used for an entire year in the bone marrow transplant unit. Although this intervention eliminated aerosolization of water, it decreased patient satisfaction and burdened nursing staff with finding creative ways to perform activities of daily living for their patients. Legionella is an aquatic gram-negative rod that thrives in warm environments and is spread by aerosols created from contaminated water. Patients’ respiratory tracts can be exposed through showers, faucets, respiratory equipment, and aspiration of potable water. Risk factors for infection include the kind and intensity of exposure as well as patients’ health status (eg, immunosuppression, end-stage renal disease, diabetes, smoking habit, and advanced age). Legionella does not spread by person-to-person transmission. Technical maneuvers used at Banner Good Samaritan to sanitize the water system included superheating the entire water supply, cleaning all water tanks, flushing and scrubbing all faucets, replacing all showerheads, and installing superchlorinators and copper-silver ionization equipment. Shower wands on flexible hoses were left hanging down after use so that the hoses drained and were not put back into a bracket or holder. Researcher Kerry Montefour, RN, BSN, CIC, manager of infection control at Good Samaritan, said the CDC recommends that BMT periodically check the water for Legionella. It does not recommend doing so for the entire hospital. Montefour attributes a large part of her hospital’s success in handling this matter to the formation of a cohesive, multidisciplinary team. “That was our facilities or maintenance personnel as well as our environmental services personnel, administration, infection control, and our BMT director and personnel in the BMT unit,” she said. Experts at the CDC, the state and county health departments, and a private consulting firm were consulted. A detailed action plan was drawn up, and while it is September 2008
The Official Newspaper of Record for the Hem/Onc Nurse
“For oncology nurses it’s the awareness of what the symptoms are for their patients, but in addition to that, what the risk factors are, for instance, questioning if there are aerators on a faucet, looking at the showers [to drain hoses]… looking for standing water sources, those kinds of things,” Kendrick advised. More information about preventing Legionella infections can be found at the CDC website (cdc.gov/mmwr/preview/ mmwrhtml/rr5303a1.htm) and at www. nature.com/bmt/journal/v30/n3/full/170 3628a.html (Oren I, et al. Bone Marrow Transplant. 2002;30:175-179).
The efforts were so successful that neither the Centers for Medicare and Medicaid Services nor the Joint Commission identified any deficiencies after several surveys. The cost of the year-long remediation effort was $400,000, excluding labor costs. No further cases of Legionella have been identified 9 months after lifting the year-long water restrictions. The researchers recommend that nurses caring for highly immunocompromised patients be aware of the risk from aerosolized water and educate their patients about taking shorter showers, removing aerators from faucets, and immediately reporting symptoms of pneumonia, fever, and cough.
—Daniel M. Keller
The Official Newspaper of Record for the Hem/Onc Pharmacist
Continued from page 9
specific to the Good Samaritan facility, coauthor Selma Kendrick, RN, MS, OCN, director of BMT oncology at the hospital, says it is available to anyone who wants it. Hospital public relations staff members were an important part of the team for disseminating information within the facility and to the community. The hospital made full disclosure to all patients and families by letter, to medical and other staff, and to the media about what it was doing to correct the problem. “One of the things that we wanted to make sure was that people did not lose trust in the facility or the people providing their care,” noted Kendrick.
Presents The First Annual 2008 Curriculum for
CONSIDERATIONS IN MULTIPLE MYELOMA A Newsletter Series for Cancer Care Professionals
SAGAR LONIAL, MD
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.
Associate Professor of Hematology and Oncology Emory University
★ Earn Continuing Education Credits ★ Clinical Topics:
Each newsletter will feature:
• Renal Dysfunction
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• Side Effect Management
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Call 732-656-7935 or visit www.coexm.com
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. Pharmacists
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.
Learning Objectives 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.
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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CURRENT APPROACHES Continued from cover
What is the incidence of pediatric neuroblastoma in the United States? We see about 650 new cases per year in the United States. About 90% of cases of neuroblastoma occur before age 5 years. Neuroblastoma is the most common solid tumor in children outside the brain.
What are the signs and symptoms of neuroblastoma in children? It depends on the location of the tumor (Figure). In about 50% of cases, children present with widespread disease. These children usually have symptoms, either from the primary tumor in the abdomen, such as abdominal distention or pain or loss of appetite, or bone pain from bone metastasis and fever. Occasionally, infants in the first year of life present with little bumps in their skin that are metastases of neuroblastoma. In the other 50% of cases, children present with localized disease, and often it is discovered for other reasons. Figure. Primary Distribution of Neuroblastomas in Children For instance, they have a radiograph done and a mass is seen in the medi- erogeneous. There are certain genet- For those who survive, what astinum or chest. Or they may present ic changes that confer a very poor are the long-term consewith abdominal distention since about prognosis. The most common and quences of the disease and 60% to 70% of these tumors arise in well described of these is amplifica- its treatment? It depends on where the disease was the abdomen. In other cases, the tion of the MYCN oncogene, which tumors arise next to the spine and is found in about one third of neurob- located and what treatment was used. cause compression of one of the nerves lastomas. When gene amplification is For children with low-stage disease who leaving the spine, leading to pain or present, even tumors that are not were treated with surgery, the main side weakness of an extremity. If the tumor metastatic behave in a very aggres- effects are referable to the tumor itself and the surgery. So, for instance, if they arises high in the chest or neck, the sive fashion. Children with MYCN amplification present with a paraspinal tumor, which patient may present with Horner syndrome; these patients may have a have a very poor prognosis and need compresses their nerves, they may be left droopy eyelid on one side and constric- very aggressive therapy. Those who with some neurologic deficits or with present with localized disease without some scoliosis and curvature of the tion of the pupil. MYCN amplification can be treated spine. Children who require intensive Are there any known risk fac- with surgery only, and they often have chemotherapy and transplant as well as a greater than 90% survival rate. local radiation and surgery may have tors for pediatric neuroChildren who present with metastatic multiple late effects. High-dose blastoma? Only 1% or 2% of cases are familial, disease and who are more than a year chemotherapy leads to second cancers or and nobody has identified a single gene. or a year and a half old at diagnosis leukemia later in life in about 5% of Several different genes have been iden- have a poor prognosis and require very children. Cisplatin commonly causes tified in the familial cases, and there are aggressive therapy, which includes hearing loss.1 Of high-risk patients who a few rare congenital syndromes as- myeloablative therapy with stem cell do survive, probably 20% or 30% will be sociated with neuroblastoma, such transplant; these patients have only a left with significant hearing loss. In addition, children who undergo highas Beckwith-Wiedemann syndrome, 30% to 40% long-term survival rate. dose chemotherapy and bone marrow congenital hypoventilation syndrome, stem cell transplant often have defective or Hirschsprung disease, but they are What are the current development of their teeth, and they not common themselves and are asso- approaches to treatment? When the tumor is localized, may have impaired growth. They may ciated with neuroblastoma in only a small percentage of cases. There are patients can often be treated surgically also have endocrine deficits later in life no risk factors in the environment, or with a small amount of che- or be sterile, or they may be hypothyroid. such as toxins or exposures to certain motherapy and surgery. When tumors substances, that are definitely associ- are widespread or have unfavorable What are some of the new biologic factors, intensive combina- treatments being investigated ated with neuroblastoma. tion chemotherapy, surgery, radiation in clinical trials? A number of new treatments are in therapy, and stem cell transplant are What is the typical course of the disease and the prognosis? used. After transplant, we also use iso- development. One of them is using a The course of the disease depends tretinoin or 13-cis-retinoic acid, targeted radiopharmaceutical to treat on the tumor biology and whether it is which causes maturation of the neu- the tumor, so that the radiation is metastatic at diagnosis. The In- roblastoma cells. For patients with delivered intravenously specifically to ternational Neuroblastoma Staging progressive, recurrent, or refractory the tumor rather than through the System is based on degree of tumor disease, there are no US Food and body as external radiation. That agent spread. Pediatric neuroblastoma is a Drug Administrationâ€“approved treat- is called metaiodobenzylguanidine or MIBG, and we link it to a radioactive disease that is biologically very het- ments, and options are limited. 12
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iodine molecule. MIBG is taken up by neuroblastoma cells specifically because they are derived from the sympathetic nervous system, and MIBG is very similar in structure to noradrenaline or norepinephrine, which is part of the sympathetic nervous system and made in the adrenal glands. This chemical is specifically taken up by the norepinephrine transporter and stored in neuroblastoma cells. When it is radioactive, you are basically loading the cells with radioactivity and killing them specifically. MIBG is on the market in Europe to treat neuroendocrine tumors and has been used in the United States on a compassionate use basis and in clinical trials but is not approved by the US Food and Drug Administration. We have used MIBG as a single agent in children who had relapsed disease, and we are now starting to use it earlier, before patients have relapsed in children with widespread metastatic disease that does not completely respond to chemotherapy. In addition, a potentially improved form of MIBG, Ultratrace Iobenguane I-131, has been developed, which may deliver more therapeutic radiation to neuroblastoma tumors while reducing side effects. NANT is conducting a phase 2a trial of this new form of MIBG with the developer Molecular Insight Pharmaceuticals, Inc, in patients who have relapsed or refractory high-risk neuroblastoma. What are the response rates? The response rates in children who relapsed have been excellent with MIBG, probably better than with any of Continued on page 14
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CURRENT APPROACHES Continued from page 12
the new chemotherapy drugs. We have found that 40% of children show a significant response.2 What we don’t know yet is what the long-term survival will be if we use this agent earlier in therapy; we are starting to do studies of that now. We have ongoing studies in which we are combining MIBG with chemotherapy in an attempt to cure these patients. What are the side effects of MIBG? The side effects are like the side effects of radiation, but the radiation goes through the bone marrow, so the main side effect is lowering in the blood count.3 To prevent that, we harvest some of the patient’s stem cells ahead of time and give them back after the treatment. Otherwise, if we use a lower dose, we can support them with blood transfusions as needed. Late side effects include impaired fertility, hypothyroidism, and, rarely, secondary leukemia.
What other new treatments are under investigation? We are looking at some new biologic medicines that interfere with genetic pathways in the tumor, the histone deacetylase inhibitors, for example. Ongoing trials are testing these agents in neuroblastoma because they look promising in the laboratory. Other genetic inhibitors that inhibit another part of the genetic pathway called mTOR are also being studied. A trial being conducted by NANT is studying lestaurtinib (CEP-
FUNGAL INFECTIONS Continued from cover
Speaking at the 33rd Annual Congress of the Oncology Nursing Society (ONS) in Philadelphia in May, June Eilers, PhD, APRN-CNS, BC, clinical nurse specialist in oncology/ hematology at the Nebraska Medical Center in Omaha, said prophylaxis is key since once established in high-risk patients, IFIs are extremely difficult to treat. Whereas in the past these infections were predominantly caused by yeasts such as Candida, they are increasingly caused by molds such as Aspergillus, with mortalities ranging from 50% to 90% among the high-risk population, even with treatment and per-case costs exceeding $82,000. At-risk patients are those with profound, prolonged neutropenia (absolute neutrophil count <100 for >1 week), acute leukemia, myelodysplastic syndromes, allogeneic HSCT, individuals with graft-versus-host disease, and autologous HSCT recipients with June Eilers, PhD, mucositis. Consequences of infection include deAPRN-CNS, BC 14
Table. Sources of Information on Neuroblastoma Trials Organization
National Institutes of Health
National Cancer Institute
New Approaches to Neuroblastoma Therapy
Children’s Oncology Group
701), which inhibits the Trk gene, which is highly expressed in neuroblastoma. There are also ongoing trials in children of another retinoid, fenretinide, which is different from retinoic acid and has been very promising in the laboratory. We are also testing some antiangiogenic compounds like bevacizumab. An ongoing national trial is using a monoclonal antibody that reacts with neuroblastoma cells, and in another trial we link that antibody to interleukin-2 to further activate the immune system. So we are approaching neuroblastoma from multiple angles—chemotherapy, immunotherapy, targeted radiotherapy, and genetic therapy. There is a lot going on in this field, but we have a long way to go to make these children survive.
Where can healthcare providers and patients get further information about ongoing trials? A number of websites list ongoing pediatric neuroblastoma trials, including the National Institutes of Health, NANT, and Children’s Oncology Group websites (Table). It is important for nurses and other lays in intended chemotherapy doses and respiratory depression. While the lung is the most common site of infection, Aspergillus may spread to other organs through the blood or by contiguous extension from the lungs. “The earlier we detect them, the less invasive they are to become,” Eilers advised. But a lack of adequate diagnostic tools, variable presentations, and sometimes inconclusive culture results often lead to delays in diagnosis, she said. Another complicating factor is that fever may be masked by administration of corticosteroids or other antipyretic drugs. Since fungal infections often do not present with signs and symptoms, Laura Zitella, RN, MS, NP, AOCN, who is a nurse practitioner at Stanford University Medical Center in Stanford, California, and assistant clinical professor at the University of California, San Francisco, said, “We have to have a high level of suspicion.” That would include being able to identify patients at high risk, knowing where fungal infections come from, and being aware of guidelines for preventing them. (See http://www. nccn. org/professionals/physician_gls/PDF/ infections.pdf for “Prevention and Treatment of Cancer-Related Infections” guidelines of the National Compre-
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healthcare professionals to know about these trials and to explain to parents that it is advantageous for their child to be enrolled in a clinical trial because they will be getting treatments that have been very carefully thought out and reviewed by physicians, scientists, and ethics boards all over the country at facilities that are skilled in administering treatment for high-risk neuroblastoma. It is a very complex disease, and it is important that it be handled by a center that sees a lot of these cases, where they understand the biology of the disease and know what genetic tests to do, how to handle the very intensive chemotherapy and transplant therapy, and how to find new approaches when a child is not doing as well as expected. References 1. Gurney JG, Tersak JM, Ness KK, et al. Hearing loss, quality of life, and academic problems in longterm neuroblastoma survivors. A report from the Children’s Oncology Group. Pediatrics. 2007; 120;e1229-e1236. 2. Matthay KK, Yanik G, Messina J, et al. Phase II study of the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzlguanidine therapy in refractory neuroblastoma. J Clin Oncol. 2007;25:1054-1060. 3. DuBois SG, Messina J, Maris JM, et al. Hematologic toxicity of high-dose iodine-131metaiodobenzlguanidine therapy for advanced neuroblastoma. J Clin Oncol. 2004;22:2452-2460.
hensive Cancer Network [NCCN]; also J Natl Compr Cancer Netw. 2008;6: 122). The guidelines give examples of conditions and therapies that elevate the risk of IFIs. They also list antifungal treatments, their doses, spectra of activity, and durations for use in specific situations.
Risk factors Aspergillus is a soil organism potentially acquired through inhalation if cellular immunity is impaired, so 95% of the infections occur in the lungs or sinuses, according to Zitella. Candida is normally found on the body and in body cavities. It becomes a problem when it overgrows in Laura Zitella, RN, the setting of immuno- MS, NP, AOCN suppression. “Our primary defense is the integrity of mucosal barriers,” Zitella said. “The biggest [pharmacologic] advance we’ve seen was in the 1990s with the introduction of fluconazole.” Several other effective antifungal agents have been approved since then. Indwelling catheters as well as mucositis cause breaches in natural barriers, putting patients at risk. Immunosuppressive
agents and corticosteroids are also risk factors.
Nonpharmacologic prophylaxis Physical and behavioral interventions are important for minimizing the risk of IFIs. Zitella recommends thorough and frequent hand washing, patient oral care and hygiene, proper catheter care, and attention to air quality using high-efficiency particulate air filters. Patient rooms should maintain positive air pressure with a high rate of air exchange, and showers and water systems should be well-maintained and cleaned routinely. Rooms and electrical outlets should be sealed. Patients should not have flowers or potted plants in their rooms. Nurses need to educate patients and their caregivers about hand washing, oral hygiene, and avoiding dust, such as at construction sites and from room vacuuming. Patients also need to avoid exposure to animal waste, soil, or decaying matter, and should not prepare or handle raw foods, especially cheeses containing mold cultures. Naturopathic preparations can be hazardous, and marijuana smoking risks exposure to Aspergillus. Besides the NCCN guidelines, other useful guidelines and materials are available from the Infectious Diseases Society of America (see http://www.idsociety.org/Content. aspx?id=9088), the US Centers for Disease Control and Prevention (www.cdc.gov), and the American Society for Blood and Marrow Transplantation (www.asbmt.org). The Oncology Nursing Society (www.ons.org) offers Putting Evidence into Practice cards on prevention of infection and on mucositis. Eilers and Zitella have received speaking fees from Schering-Plough Corporation, which sponsored a news conference at the ONS meeting, at which they spoke. —DMK
Know? In 2007, 14.5% of the overall US population had no health insurance. Nearly one third of working-age US adults without health insurance have at least one chronic disease. Source: Ann Intern Med. 2008;149:170-176. September 2008
Program #08CE059c • 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 NURSING 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.theoncologynurse.com. 2. Click on UNMC logo on homepage. 3. Register to participate. 4. Enter program number #08CE059c. • Complete and submit the evaluation form online (enter program number #08CE059c). Nurses must answer at least 70% of the questions on the post-test correctly. If Internet access is not available, please fax a request for an evaluation form to 402-559-6379, attn: Anji Wittman, (please include return fax number) or e-mail email@example.com • 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. 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 College of Nursing Continuing Nursing Education. While the University of Nebraska Medical Center College of Nursing Continuing
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 FACULTY/PLANNER DISCLOSURES All planners and faculty participating in continuing education activities provided by the University of Nebraska Medical Center, College of Nursing Continuing Nursing Education are expected to disclose to the audience any significant support or substantial relationship(s) with providers of commercial products and/or devices discussed in this activity and/or with any commercial supporters of the activity. In addition, all faculty are expected to openly disclose any off-label, experimental, or investigational use of drugs or devices discussed in their presentation. The planners and faculty and 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.
Nursing Education is an ANCC accredited organization, this does not imply endorsement by the UNMC or ANCC of any commercial products affiliated with this activity. PROGRAM GOAL To educate oncology nurses about recent findings about the use of iron supplementation in cancer patients receiving erythropoiesis-stimulating agents for anemia. LEARNING OBJECTIVES After completing this activity, the reader should be better able to: • Explain the how iron deficiency affects response to erythropoietic 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. TARGET AUDIENCE Advanced practice nurses, registered nurses, and other interested healthcare professionals, especially those caring for cancer patients. COST This program is complimentary for all learners.
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
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.
EDITORIAL BOARD Manuel G. Afable II, RN, BSN Taussig Cancer Institute Cleveland Clinic Cleveland, OH 44195 David Baribeault, RPh, BCOP Boston Medical Center Boston, MA 02118 Silvia Mague, OCN Divisione Oncologia Medica Falck Ospedale Niguarda Ca’Granda Milan, Italy 20162 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 REVIEWER Cass Hammond, RN, MSN, CRNP Avid Education Partners 18071 Crampton Lane Sharpsburg, MD 21782
CONTINUING NURSING EDUCATION ACCREDITATION AND CONTACT HOURS STATEMENT The University of Nebraska Medical Center College of Nursing Continuing Nursing Education is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. This activity is provided for 1.0 contact hours under ANCC criteria. Provided for 1.2 contact hours under Iowa Provider #78. Provider Approved by the California Board of Registered Nursing, Provider #13699 for 1.2 contact hours.
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Continuing Education Program #08CE059c • RELEASE DATE: September 30, 2008 • EXPIRATION DATE: September 29, 2009 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 exam-
ined different routes of iron administration (IV or oral) versus none, in conjunction with epoetin alfa use. Both studies showed that patients who received
Both studies showed that patients who received IV iron had a significant improvement in hematopoietic response compared with no-iron controls. IV iron had a significant improvement in hematopoietic response compared with no-iron 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 ironreplete 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 Continued on page 19
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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 18
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-
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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;22:731737. 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.
Continuing Education Program #08CE059c • RELEASE DATE: September 30, 2008 • EXPIRATION DATE: September 29, 2009 Continued from page 18
parameters were not considered in patient selection. Response, measured both as transfusion requirement and achievement of hematopoietic response, significantly favored the IV iron group. An Italian study,17 that included 149 iron-replete patients (defined as having a serum ferritin level of e100 ng/mL and TSAT e20%) 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 andin iron-replete patients. This issue is clinically relevant because appropriate iron supplementation, in
IV (not oral) iron supplementation in conjunction with ESA therapy should be considered a component of the management of CRA. addition to allowing more patients to benefit from ESA therapy, may represent a strategy to improve the cost-effectiveness of ESAs in oncology.18
Case Report A 51-year-old patient was referred to our hospital with a newly diagnosed metastatic breast carcinoma. 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
C O M M E N TA R Y
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,
because, 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
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 #08CE059c • 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 d450 pmol/L or d675 pmol/L with TSAT d19%
Epoetin alfa 40,000 U every week vs epoetin vs epoetin alfa + IV iron every week vs epoetin alfa + IV iron TDI
Iron dextrane 1,100 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 e12 g/dL or e2 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.
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 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 infusionwere 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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CANCER CENTER PROFILE
M.D. Anderson Cancer Center T
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 on 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 M.D. Anderson employs more than one of the largest programs of its kind in the 17,000 people at facilities that total more world. Risk assessment models have been than 9 million square feet. developed to predict an individual’s chance of developing lung and bladder cancer M.D. Anderson earned the distinction of being based on genetic, environmental, and voted the number one cancer center in the United U.S. News & World Report’s annual “Best lifestyle factors. The causes of primary States by Hospitals” survey. The 2008 recognition was the brain tumors are also being explored in fourth time in 6 years that M.D. Anderson has been the division by studying biologically ranked number one in this survey. related members diagnosed with priIn his state-of-the-institution address delivered mary brain tumors; the research will in October 2007, John Mendelsohn, MD, president also attempt to identify a panel of of M.D. Anderson, said, “We have articulated a genes that can predict who will develvision of a cancer care cycle that includes a contin- op the disease. uum involving prevention, early detection, treatA 300,000 square foot building will ment, and survivorship, and are planning expan- be devoted primarily to pathology and sion of our prevention and survivorship programs laboratory medicine, and the pharmacy both clinically and in research.” will handle the increase in diagnostic Continued on page 23 The survivorship program will provide more 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.
CANCER CENTER PROFILE 22
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Pain Nurse Champion
Carolyn Holmes, RN, BSN As one of M.D. Anderson’s pain nurse champions in the thoracic/cardiovascular unit, Carolyn Holmes, RN, BSN, takes an active role in epidural pain control in the thoracic patient population. Holmes was one of the first 16 nurses to graduate from the pain nurse champion program, which involves specialized pain management education and participation in a 3-day rotation with the acute pain management service, during which nurses engage in patient rounds and assessments, along with placement of epidural catheters. “We’re able to troubleshoot some of the problems that happen with equipment; most of our thoracic patients are on an epidural pump or PCA [patient-controlled analgesia] or both; so you have spinal analgesia and also intravenous and oral,” she said. “Each one of those brings its own array of potential problems or challenges to overcome, so it requires quite a knowledge base.” Pain control for cancer patients who undergo thoracic surgery is especially challenging, she said, because without adequate pain control, these patients have difficulty complying with breathing exercises and other rehabilitative measures vital to their recovery. After graduating from the University of Texas, Holmes did not immediately consider a career as an oncology nurse. “The core values at M.D. Anderson matched my own pretty closely. Its core values are caring, integrity, and discovery. That appealed to me, so I decided to come see what they had,” she said. “The emphasis on education appealed to me as well.” A unique feature to her unit is the “fast-track” surgery program. “This means that the patients come straight to the floor out of the PACU [postanesthesia care unit] rather than going to the ICU [intensive care unit],” she noted. “The high acuity level of our patients requires specialized training and care that we deliver best on our floor.” The fast-track program has resulted in improved patient outcomes and decreased hospital length of stay. “For example, traditionally treated esophagectomy patients with no complications stayed 10 to 14 days postop,” Holmes said. “Now, with fast-tracking, the average stay is 6 to 7 days, with our record discharge 4 days postop. Taking into account that an esophagectomy is considered higher risk than open heart surgery, this is remarkable. Producing results like this on our floor enables our surgeons and mid-level providers to place greater confidence in our ability to give complex care to these highrisk patients.” As a member of the pain team of the Transforming Care to Bedside program, Holmes was involved in the development of an educational packet for patients scheduled for surgery at M.D. Anderson. The packet describes the types of anesthesia used during surgery, pain scales employed in pain assessment, and pain management issues. She was also part of a team that created an online educational module for nurses who may be involved in caring for patients with chest tubes. “We deal with chest tubes all the time, but not all nurses have this experience,” she said.
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
STAGE III COLON CANCER Continued from cover
actually receive adjuvant chemotherapy for their colon cancer, said Katherine L. Khan, MD. The data were derived from the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) observational cohort study, in which medical record data were collected from a representative sample of 689 patients with incident stage III colon cancer from 22 clinical sites nationally. Important clinical morbid events recorded in the medical records were assessed 3 months before and 15 months after the diagnosis of cancer. Forty two percent of the patients in the sample were 75 years of age or older. Surgical resection was performed an average of 12 days after diagnosis, and when started, chemotherapy was given an average of 62 days after diagnosis. Seventy five percent of the 689 patients received adjuvant chemotherapy. “This study asks whether clinicians are too cautious in initiating adjuvant chemotherapy for elderly stage III colon cancer patients,” said Khan, professor of medicine at the University of California, Los Angeles. Chemotherapy use ranged from 89% of patients younger than 55 years to 59% of those at least 75 years old. When used, chemotherapy was initiated on average 3 weeks later for patients 75 years or older compared with the younger subgroups. On average, the duration of chemotherapy was 30 days
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 Delta24-RGD was successful at killing all four types. A clinical trial of the virus in patients is expected soon. Clinical trials in patients with lowgrade 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 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.
shorter for the oldest subgroup compared with the younger patients. Two regimens—bolus 5-fluorouracil with leucovorin and FolFox (fluorouracil, leucovorin, and oxaliplatin)— accounted for 70% of all regimens used. “The FolFox regimen was used far more often among younger patients than in those 75 years or older (35% vs 13%, respectively),” Khan said. The FolFox regimen is the preferred regimen for patients with colon cancer, she noted. Overall, beginning 31 days post-resection, one fourth of patients receiving adjuvant chemotherapy suffered one or more clinical adverse events, significantly more frequently than patients with no chemotherapy use. There was no relationship between age and the percentage of patients suffering at least one clinical morbid event or the mean number of clinical adverse events experienced per patient. In fact, the adjusted mean number of adverse events among those receiving chemotherapy was lower in the oldest age group (0.47) than in the 56- to 65-year-old group (0.54) and the 66- to 75-year-old age group (0.49). Multiple studies have documented low rates of use of adjuvant chemotherapy for colon cancer among the elderly despite evidence from randomized controlled trials that older patients experience similar benefits from treatment, she said. “This analysis does not support clinicians on a routine basis withholding adjuvant chemotherapy from older patients based on age alone,” Khan said. The study findings point out the
necessity of a comprehensive geriatric assessment for elderly cancer patients, said Cathy Eng, MD, assistant professor, Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston. “Treat physiologic age,” she advised.
Eng added that the CanCORS study adds to other data that show no negative impact on quality of life when adjuvant chemotherapy is provided to the elderly.
WEB EXCLUSIVES www.theoncologynurse.com
• Celecoxib May Have Role in Preventing Colorectal Cancer • Combination Therapy Reduces Risk of Colon Adenoma Recurrence • Investigational Vaccine Reduces Mortality Risk in Women with HER2-positive Breast Cancer • Alcohol May Increase Risk of Breast Cancer • Stress Accounts for Cognitive Impairment in Newly Diagnosed Breast Cancer Patients • Tantalizing Results from Lung Cancer Blood Test Presented • High Price Paid for EGFR Testing in Refractory Non–small-cell Lung Cancer • New Agent Showing Promise for Patients with Advanced Basal Cell Carcinoma • Cyclophosphamide Treatment of Childhood Cancers May Lead to Later Bladder Cancer September 2008
Continued from page 22
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 standardregimen 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 standard-dose 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 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 VanderbiltIngram 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.” —Walter Alexander
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For additional information, visit www.gelclair.com or call 1-877-GELCLAIR. Ingredients: Water, Maltodextrin, Propylene Glycol, Polyvinylpyrrolidone (PVP), Sodium Hyaluronate, Potassium Sorbate, Sodium Benzoate, Hydroxyethylcellulose, PEG-40 Hydrogenated Castor Oil, Disodium Edetate, Benzalkonium Chloride, Flavoring, Saccharin Sodium, Glycyrrhetinic Acid. Contents: 15 mL per single-use packet. Commercial boxes contain 15 single-use packets. (NDC 24477-010-15) Indications: GELCLAIR® has a mechanical action indicated for the management of pain and relief of pain by adhering to the mucosal surface of the mouth, soothing oral lesions of various etiologies, including oral mucositis/stomatitis (may be caused by chemotherapy or radiation therapy), irritation due to oral surgery, traumatic ulcers caused by braces or ill-fitting dentures, or disease. Also indicated for diffuse aphthous ulcers. Contraindications: The administration of GELCLAIR® is contraindicated in any patient with a known or suspected hypersensitivity to any of its ingredients. Side effects: At the time of producing this leaflet, no adverse effects have been reported in clinical trials with the use of GELCLAIR®. Postmarketing reports have included infrequent complaints of burning sensation in the mouth. Reference: 1. Innocenti M, Moscatelli G, Lopez S. Efficacy of Gelclair® in reducing pain in patients with oral lesions: preliminary findings from an open pilot study. J Pain Symptom Manage. 2002;24:455-457. GELCLAIR® is a registered trademark of Helsinn Healthcare SA, Lugano, Switzerland. Manufactured for Helsinn Healthcare SA, Lugano, Switzerland. Marketed and distributed by EKR Therapeutics, Inc., Cedar Knolls, NJ 07927.
© 2008 EKR Therapeutics, Inc. All rights reserved.
BY AMANDA SALDIVAR, MS, RD, LD TAUSSIG CANCER INSTITUTE, CLEVELAND, OHIO
Nutrition screening tools Several nutrition screening tools are available to help determine a patient’s nutrition risk. A tool that many dietitians working in oncology consider “a gold standard” is the Patient-Generated Subjective Global Assessment (PG-SGA). The PG-SGA was modified from Jeejeebhoy and colleagues’ Subjective Global Assessment (SGA) to be used specifically for oncology patients in the mid-1990s.9 The original SGA includes obtaining a medical history from the patient (weight history, changes in dietary intake, gastrointestinal [GI] symptoms, and functional capacity), determining metabolic stress from disease, and a physical examination (checking for loss of subcutaneous fat, muscle wasting, and edema).9 The modified PG-SGA includes more GI symptoms related to cancer, streamlines the process by having the medical history section completed by the patient and family, and provides a more objective scoring system to determine the need for a nutrition assessment by a dietitian.10 The PG-SGA has been tested for validity,11 but is often considered time-consuming and is perceived to have other barriers that may limit its use in the clinical setting by the oncology team. It must be noted, however, that malnutrition and cachexia may account for 5% to 25% of deaths among cancer patients,12-13 and studies have shown that early nutrition intervention is beneficial for oncology patients.14 The sensitivity of the PG-SGA allows for adequate referral of patients who appear to be nourished, but may be in serious need of nutrition intervention because of an underlying factor that may contribute to malnutrition.15 When using the PG-SGA, certain compromises may be made to help alleviate time constraints while still maintaining a screening process, but modified versions of the PG-SGA have not been tested for sensitivity and validity. This may pose a risk for patients who need to have nutrition intervention but could slip through the cracks. Training tools are available to help clinical staff use the PG-SGA (available at the American Dietetic Association’s web site, www.eatright.org). If, however, your facility decides to postpone use of the PG-SGA, work with your registered dietitian to determine what type of nutrition screening process will provide ease of use and appropriate referrals of patients. September 2008
1. Dewys WD, Begg C, Lavin PT, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med. 1980;69:491-497. 2. Andreyev HJ, Norman AR, Oates J, et al. Why do patients with weight loss have a worse outcome when undergoing chemotherapy for gastrointestinal malignancies? Eur J Cancer. 1998;34:503-509. 3. McAnena OJ, Daly JM. Impact of antitumor therapy on nutrition. Surg Clin North Am. 1986;66:1213-1228. 4. Kubrak C, Jensen L. Critical evaluation of nutrition screening tools recommended for oncology patients. Cancer Nurs. 2007;30:E1-E6. 5. Ravasco P, Monteir-Grillo I, Vidal PM, et al. Cancer: disease and nutrition are key determinants of patients’ quality of life. Support Care Cancer. 2004;12:246-252. 6. Horsley P, Bauer J, Gallagher B. Poor nutritional status prior to peripheral blood stem cell transplantation is associated with increased length of hospital stay. Bone Marrow Transplant. 2005;35:1113-1116. 7. Arrowsmith H. A critical evaluation of the use of nutrition screening tools by nurse. Br J Nurs. 19992000;8:1483-1490. 8. Baldwin C, McGough C, Norman AR, et al. Failure of dietetic referral in patients with gastrointestinal cancer and weight loss. Eur J Cancer. 2006;15:2504-2509. 9. Jeejeebhoy KN, Detsky AS, Baker JP. Assessment of nutritional status. JPEN J Parenter Enteral Nutr. 1990;14(5 suppl):193S-196S. 10. Ottery FD. Definition of standardized nutritional assessment and interventional pathways in oncology. Nutrition. 1996;12(suppl 1):S15-S19. 11. Bauer J, Capra S, Ferguson M. Use of the scored Patient-generated Subjective Global Assessment (PGSGA) as a nutrition assessment tool in patients with cancer. Eur J Clin Nutr. 2002;56:779-785. 12. Klastersky J, Daneau D, Verhest A. Causes of death in patients with cancer. Eur J Cancer. 1972;8:149-154. 13. Ambrus JL, Ambrus CM, Mink IB, et al. Causes of death in cancer patients. J Med. 1975;6:61-64. 14. Capra S, Ferguson M, Ried K. Cancer: impact of nutrition intervention outcome—nutrition issues for patients. Nutrition. 2001;17:769-772. 15. Li T, Hopkins U, Jung G, et al. A pilot assessment of nutritional needs in cancer outpatients receiving active anticancer therapy. http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?& vmview=abst_detail_view&confID=55&abstractID=32539. Accessed June 2, 2008.
U P M C S H A DYS I D E
Be Part of a Nationally Ranked Oncology Nursing Team! If you are interested in becoming part of a nationally ranked oncology team, discover your potential at UPMC Shadyside. UPMC Shadyside, a 527-bed tertiary care hospital located in beautiful Pittsburgh, Pennsylvania offers primary medical care, physician and nursing education, and a broad range of specialties such as oncology, cardiology, orthopedics, vascular medicine, endocrinology, and more. Our four oncology units include: stem cell transplant, medicine/oncology, hematology/oncology and surgical/oncology. Hallmarked by our compassionate teams and nursing excellence, we thrive in an invigorating environment of shared leadership and clinical excellence. Our nurses are supported with leadership development, multidisciplinary team meetings and education, and an engaged nursing leadership team. We partner closely with our sister facility UPMC Presbyterian with further cutting edge oncology care, and the attached nationally renowned Hillman Cancer Center. As western Pennsylvania’s largest employer, with 48,000 employees and nearly $7 billion in revenue, UPMC is transforming the economy of the region into one based on medicine, research, and technology. Western Pennsylvania provides a welcoming atmosphere that includes beautiful hills and rivers, a thriving arts district, professional sports, and affordable family living. Discover what UPMC Shadyside and western Pennsylvania have to offer you, your family, and your career.
alnutrition can contribute to many complications before and during anticancer treatment and has been shown to increase overall mortality.1-3 The weight loss that occurs in patients with cancer often results from a metabolic process involving the presence of the tumor and differs from typical weight loss. Other factors such as availability of food, depression or anxiety, a decrease in ability to complete daily activities, and side effects from treatment can further exacerbate weight loss or malnutrition. As many as 20% to 80% of patients have been shown to develop malnutrition over the course of their disease4; 15% of patients have already lost a clinically significant amount of weight (10% or more of body weight over 6 months) before diagnosis.1 This weight loss places the patient at higher risk for complications and may cause delays in treatment, more hospitalizations, and overall reduced quality of life.1,5,6 In an ideal world, a dietitian would be able to see every patient who is being treated. This may not be feasible or even practical, however, especially since many treatment facilities have limited or no access to dietitians.7 Furthermore, some patients are not at risk for nutrition-related problems and having a dietitian perform a full assessment on them would take time away from patients who are at risk. So, how is a patient’s nutritional status determined? Dietitians often rely on a referral process involving other members of the healthcare team, especially nursing staff, because they usually have primary and frequent contact with patients. Nutrition screening by nursing staff throughout the patient’s course of care is recommended by many nursing organizations.4 Often, however, nutrition status is overlooked by other members of the oncology team, especially among those working in outpatient settings, even if the patient presents with significant weight loss.8
Nutrition Screening of Oncology Patients
Join our team and become a valued oncology nurse within our compassionate, state-of-the- art environment! UPMC is an exciting place to build your career, and Pittsburgh is a wonderful place to call home. To discuss your future, contact Marie Kelly, nurse recruiter at 412-623-3027 or Krista Bragg, clinical director, Oncology/Surgical Services at Kbragg@upmc.edu. To learn more, visit www.upmc.com.
What’s YOUR vision
FOR A NEW TOMORROW? EOE
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Books & Media BOOKS & MEDIA
Young Adult Patients Land on Planet Cancer for Support and Venting
lanet Cancer (www.planetcancer.org) has less gravity than most other cancer websites. On this “planet,” young adult cancer patients and survivors support each other, commiserate, post videos, messages, and blogs, and arrange to get together in reality. According to Courtney Clark, director of development and marketing for the site, it was originally envisioned as a forum for people 18 to 40 years of age, an age group comprising almost 65,000 new cancer diagnoses per year in the United States. “And we’ve got some people in their 60s that are self-identifying as young adults because the type of cancer they’ve got generally hits older people,” she said. The site often takes a not-so-serious approach. For example, a rotating banner at the top of the opening page boldly announced, “We’ve Done Drugs Keith Richards Never Heard Of!” Among its top ten lists are “Top Ten Stupid Things People Say When You Tell Them You Have Cancer” and “Top Ten Ways to Pick Up Your Onc Nurse.”
hosts face-to-face events and weekend retreats from time to time. Heidi Adams started Planet Cancer as a support forum in 2000 when she was diagnosed with Ewing’s sarcoma. The site added a message board in 2002, and it relaunched early this year mainly as a social networking site since young adults are less likely to go to a support group with older patients. Moreover, they are used to reaching out on the Internet to find information or connect with others at all hours. “I want support at 7 o’clock in the morning on Tuesday when I wake up and my hair is left behind on the pillow,” Clark said. “I don’t want to wait until next Thursday at 6:30 when the rest of the support group meets....We’re seeing a huge up tick in the amount of time the young adults are spending on the site now that we’ve got new format.” Young adults often face different issues thisThe website features a “Cancertainment” section of book, from older patients and therefore appre- music, movie reviews, and more, including the top ten lists, cancer ciate the perspective of their peers. comics, blogs, photography, haikus, and video games. The Real A major function of Planet Cancer is social net- World Advice Section has tips, opportunities, links working. It sees itself as “MySpace on Prednisone.” to guides and resources, and a research section geared Clark, a 28-year-old melanoma urvivor herself, mainly to cancer issues specific to young adults. emphasizes that young adults often face different Oncology nurses may want to refer young adult issues from older patients and therefore appreciate patients to Planet Cancer, and they may want to take the perspective of their peers. People on the website a look at it themselves. It can give some insight into discuss personal and social issues such as fertility, what these patients think and are going through— how to date again, how to talk with one’s child the things they don’t say to their healthcare about cancer, or how to inform an employer about providers. Younger cancer patients often feel alone prior health problems. Survivors potentially have since they are not a cohesive group and may be decades of life ahead of them, looking over their spread out on an adult oncology floor, a pediatric shoulders for a recurrence. “The groups, and then ward, or in private oncology practices. “If nurses can message board, and then the blogs—those are the figure out how to get these young adults connecting three areas where people really interact with each to one another, then the isolation ends, and the feelother the most,” she says. ing of helplessness ends,” Clark said. International as well as special interest groups (eg, Yankees fans, pet lovers) have formed on their own The website Who is behind it: A registered nonprofit organizaon the website, and members have also arranged for tion, Planet Cancer is supported by individual donors in-person gatherings in their area. Planet Cancer
Oncology Nursing Society Manual for Clinical Trials Nursing (2nd ed)
BOOKS & MEDIA
Edited by A.D. Klimaszewski, M. Bacon, H.E. Deininger, B.A. Ford, and J.G. Westendorp. Pittsburgh, PA: ONS Publishing Division; 2008. 556 pages. Softcover. $85.00 ONS members; $135.00 nonmembers Reviewed by Lyssa Friedman, RN, MPA, OCN Veracyte, Inc, South San Francisco, California
he role of the oncology nurse is expanding and, concurrently, the regulatory and financial environments within which clinical tri26
als operate is becoming increasingly complex. At the intersection of these changes is the oncology clinical trials nurse (CTN), who brings both clinical acumen and research expertise to the table. The second edition of the Oncology Nursing Society Manual for Clinical Trials Nursing sets out to both define the CTN’s role and to provide practical steps for setting up and conducting a clinical trials program. The editors have convened a diverse group of authors from academia, community-based treatment centers, industry, and the National Cancer Institute, each of whom deliver thorough, evidence-based chapters that carefully examine the CTN’s expanding practice role. Chapters
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and grants from foundations to support its web presence, events, and retreats. The website employs a staff of four and has an active board and medical advisory panel. Members provide most of the content for the site. Good points: It provides an active, open community for user contributions, support, and networking. Needs improvement: The layout and navigation are a bit chaotic. But given that many users are frequent visitors, they probably learn their way around fairly quickly. Also, the left side of the home page features a column to contain videos, presumably submitted by users. Most of the spaces to hold videos are blank and merely say “no videos available.” However, the look of the website implies an informal, member-directed environment rather than a corporate feel, which is a good thing for this audience and purpose. The search engine on Planet Cancer uses Google search, and while it searches only within the website, the search results look like they have been gathered from the web until one notices that all the web addresses are from within the website. It should be made clear that Google is searching within the website, either by saying so or by displaying the results in keeping with the design of the website. —DMK
addressing patient accrual, staff and patient education, and working within a multidisciplinary team are wellsuited to viewing through a nurse’s
present information within a nursing framework seem forced. The book’s strength, however, is its comprehensiveness. The novice CTN
The second edition....sets out to both define the CTN’s role and to provide practical steps for setting up and conducting a clinical trials program. lens. However, clinical research is not exclusively a nursing function. The majority of chapters cover regulatory, program resource, or human subjects protection issues that are critical to all clinical research professionals, many of whom are not nurses. In some of these chapters, attempts to
need go no further to learn how protocols are organized, what are essential elements of an informed consent, and how to account for investigational drugs, to name a few. Likewise, the seasoned research program administrator can find useful tools to help allocate resources, Continued on page 29
Breast Cancer BREAST CANCER
Local Recurrence Risk Greater with Lumpectomy Versus Mastectomy in Women with BRCA Mutations CHICAGO—Women with early-stage breast cancer and the BRCA 1 or 2 mutations who underwent breast-conserving therapy (BCT) (ie, surgery and radiotherapy; n = 160) had more local recurrences compared with women who received mastectomy with or without postmastectomy radiotherapy (MX; n = 213). A local event was a recurrence of the initial breast cancer in the chest wall or a new contralateral breast cancer. In this retrospective, multicenter analysis performed by chart review of 373 women with invasive, nonmetastatic breast cancer, local failure as a component of first failure was greater for the BCT group than the MX group (P = .0043). The few patients with both BRCA 1 and 2 mutations were excluded from the analysis. The mean follow-up for both cohorts was 10 years. Lead investigator Lori Pierce, MD, professor of radiology at the University of Michigan in Ann Arbor, said the rates of distant failure, breast cancer-specific survival (Table), and overall survival were similar between the groups (P = .29, P = .85, P = .55, respectively). She presented her results at the 44th Annual Meeting of the American Society of Clinical Oncology in Chicago in June. The only predictors of local failure were a lack of use of adjuvant chemotherapy for BCT patients (hazard ratio [HR] = 3.4; P = .0095) or the presence of lobular histology for MX patients (HR = 15.0; P = .0009).
Radiation effects Since radiation damages DNA and the BRCA genes are active in DNA repair, the investigators were interested in the occurrence of contralateral
Table. Breast Cancer–specific Survival 5-year (%)
BCT indicates breast-conserving therapy; MX, mastectomy with or without postmastectomy radiotherapy.
Photo courtesy of ASCO
breast cancers (CBCs) from radiation scatter. “It’s a very limited area in the medial aspect of the contralateral breast, but you can still see very, very low rates of scatter even with current techniques of radiation,” Pierce noted. At 15 years of follow-up, they found equivalent rates of CBCs for the BCT and for the MX groups with or without radiotherapy (P = .77). Also for the MX cohort, the rate of CBCs was independent of the use of radiotherapy (P = .60). The investigators concluded that radiation scatter did not increase the rate of CBC. The study findings may be useful when discussing treatment options with patients. “I think this adds to the information that we have to be able to counsel women who are BRCA 1 and 2 carriers who have early-stage breast cancer,” Pierce said. “Some patients are highly desirous of breast conservation, and this study doesn’t mean that they cannot do breast conservation. It just gives us an idea of the outcomes both locally and, more importantly, systemically.” She noted that her study did not include enough events to draw any conclusions about the effects of oopherectomy or hormonal therapy, but findings from other series suggest that these interventions can reduce both ipsilateral and contralateral breast events. “In a full discussion of the BRCA 1 and 2 carriers, which is a long and very complicated discussion, oopherectomy and tamoxifen are both important to bring into the discussion,” she advised. —DMK
All-oral Therapy of HER2-positive Breast Cancer a Possibility
CHICAGO—At the 2008 annual meeting of the American Society of Clinical Oncology in Chicago in June, Dennis Slamon, MD, PhD, of the University of California at Los Angeles, stimulated vigorous discussion with his presentation of a study of a new oral drug combination for HER2-positive breast cancer. The comDennis Slamon, MD, PhD bination incorporated lapatinib and pazopanib, a development-stage inhibitor of multiple tyrosine kinases, including the one associated with the receptor for vascular endothelial growth factor (VEGF). Controversy centered on the validity of Slamon’s findings, garnering reactions from mild praise to outright ridicule. Focusing on methodological problems of the research, critics said the study was underpowered, of too short duration, and had many incomplete data sets. Others felt it was promising as a preliminary study and showed that a combination of smallmolecule VEGF and HER2 inhibitors could have activity in this disease. This 12-week study was a randomized trial of pazopanib plus lapatinib (PL) versus lapatinib alone in patients with advanced or metastatic HER2-positive breast cancer to examine the safety 28
and efficacy of so-called “dual pathway inhibition” using these oral agents. Lapatinib is an inhibitor of the tyrosine kinase of the HER2 receptor. Patients had received no prior chemotherapy or HER2directed therapy for their advanced disease. Twelve-week efficacy data were available for 69% of the pazopanib-lapatinib and 77% of the lapatinib patients. Progressive disease, the primary end point, occurred in 19% of the PL group and in 27% of the lapatinib group. The response rate was 44% for PL and 30% for lapatinib. Target lesions were reduced in 73% versus 43% of patients, respectively. The incidences of diarrhea, rash, and nausea were similar in the two arms. However, aspartate aminotransferase and bilirubin increases were about twice as common in the PL arm. “The major conclusion is that the combination of pazopanib and lapatinib is better than lapatinib alone in HER2-positive breast cancer,” Slamon said. Responding to criticisms that 37 of the 141 patient data sets were missing because of problems at some of the international trial sites, he explained that missing data were classified as progressive disease. And since more were missing for the PL group, if anything the study was biased against the combination. “And yet the combination looks better,” he said. Harold Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston, commented, “In the very preliminary incomplete data, they showed it did sug-
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gest that you increase the response rate and possibly the time to progression by using inhibition of both pathways.” He recommended a definitive study to follow up on this “biologically interesting idea.” In terms of dual-pathway inhibition, Mark Pegram, MD, of the Braman Family Breast Cancer Institute at the University of Miami in Florida, said, “The nice feature of the [PL] strategy is that it’s an all-oral regimen, whereas trastuzumab and bevacizumab is an all-[intravenous] regimen. So in terms of practicality and patient convenience, it might be an interesting option. —DMK
Americans made more than 1 billion physician or hospital outpatient or emergency department visits in 2006; 70% received at least one prescription, most often an analgesic. Source: www.CDC.gov. 8/6/08.
build budgets and project plans, and ensure program-wide adherence to Good Clinical Practices. The manual covers the gamut of clinical research content, including safety, legal and regulatory issues, working with institutional review boards, overseeing patients on active treatment, in ancillary studies, and undergoing follow-up, and data and quality management. A handy list of abbreviations and a complete index enhance the manual’s accessibility. This second edition recognizes trends in the management of clinical trials. The editors have added chapters about electronic data capture and clinical trial registries, as well as appendices with key historical and
Recent FDA Approvals • 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, activecontrol 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. • 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.
regulatory documents such as the Nuremberg Code, the Declaration of Helsinki and portions of the US Code of Federal Regulations. Additionally, the editors recognize that the conduct of clinical trials knows no borders and have included the International Committee on Harmonisation’s Good Clinical Practice mandate as well as chapters addressing country-specific regulatory information from CTN contributors throughout the world. Some readers may look to a book such as this as a template for building institutional policies and procedures. 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-Hodgkinís 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
That is not the purpose of the Oncology Nursing Society manual, which begins with general information about the history and background of clinical trials, then moves more specifically into elements of assurances and protocols. Later, the book reverts again to a general overview of good clinical practices. The editors hope that a future edition may be produced online, where it can be continuously updated. Such a format would go a long way toward bridging the gap between this highly informational book and a more practi-
cal hands-on manual. The ability to access electronic, customizable templates for policies and procedures, informed consent forms and budget worksheets would add tremendous value to an excellent resource, as would hyperlinks to web-based investigators, adverse events reporting, and drug accountability forms. Although the manual focuses on defining the CTN’s role, it has much to offer any clinical research professional. Well conceived, well organized and well written, this is a welcome addition to any clinical trials library.
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 Any Adverse Events 99 57 Respiratory System 38 4 more common among the elderly, including pneumonia and pneumonitis. LowBody as a Whole 86 10 Increased Cough 13 1 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 Adverse reactions observed up to 12 months following Rituxan. bAdverse 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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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
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MANUAL FOR CLINICAL TRIALS
Leading patients toward improved outcomes
You help patients reach their treatment goals RITUXAN is a proven path for many patients battling non-Hodgkin’s lymphoma (NHL), but they can’t complete the journey alone. Oncology nurses are central members of a cancer care team—working together to achieve improved outcomes. Your guidance and leadership help patients reach their treatment goals. We recognize your commitment and support your continued efforts with innovative patient-education materials and services.
RITUXAN 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, CD20-positive, 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
To learn more, ask a RITUXAN representative or visit
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.1
Reference: 1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.
Please see brief summary of prescribing information on adjacent page. Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.
PROVE N. POWE R FU L.
©2008 Genentech, Inc., and Biogen Idec Inc. All rights reserved. 9231900 April 2008
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