JOMCC | January/February 2009 Volume 2 Issue 1 by Green Hill Healthcare Communications, LLC

January/February 2009 • Volume 2 • Number 1

CLINICAL Clinical Advances in the Treatment of Myelodysplastic Syndromes: Reasons for Hope Sandra E. Kurtin, RN, MS, AOCN, ANP-C

NCCN Guidelines on Management of Multiple Myeloma: Transplant-eligible and Transplant-ineligible Patients Beth Faiman, RN, MSN, CNP, AOCN

REGULATORY Cancer Drug Compendia and the Quest for Value-based Cancer Care An interview with John V. Cox, DO, MBA, FACP, and Samuel M. Silver, MD, PhD

The NCCN Compendium: Unique Resource for Value-based Cancer Drugs Coverage Decisions Al B. Benson, III, MD, FACP

Hematology/Oncology: Medications, Indications, and ICD-9 Codes

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TABLE OF CONTENTS

Publisher Philip Pawelko phil@greenhillhc.com

INTRODUCTION 6

Clinical Economics in Oncology Care Philip Pawelko

CLINICAL 19

Clinical Advances in the Treatment of Myelodysplastic Syndromes: Reasons for Hope Sandra E. Kurtin, RN, MS, AOCN, ANP-C

NCCN Guidelines on Management of Multiple Myeloma: Transplant-eligible and Transplant-ineligible Patients Beth Faiman, RN, MSN, CNP, AOCN

Editorial Director Karen Rosenberg karen@greenhillhc.com Managing Editor Dawn Lagrosa Production Manager Marie RS Borrelli Directors, Client Services John W. Hennessy john@greenhillhc.com Russell Hennessy russell@greenhillhc.com Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrators Thiel Hennessy Lisa Russo

Mission Statement Multidisciplinary Cancer Care is a forum that provides oncologists, nurses, pharmacists, and their respective cancer care team members insights into the diverse aspects of oncology management. As an authoritative resource on the clinical, business, and regulatory changes affecting the oncology care community, this journal offers expert analysis of the dynamic nature and practical implications of current treatment, legislative, and reimbursement issues in the field.

Multidisciplinary Cancer Care

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TABLE OF CONTENTS

EDITORIAL BOARD Anna M. Butturini, MD University of Southern California Pediatrics

REGULATORY

An interview with John V. Cox, DO, MBA, FACP, and Samuel M. Silver, MD, PhD

Beth Faiman, RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Institute Oncology Nursing

The NCCN Compendium: Unique Resource for Value-based Cancer Drugs Coverage Decisions

Mehra Golshan, MD Dana-Farber Cancer Institute Breast Cancer

Cancer Drug Compendia and the Quest for Value-based Cancer Care

Al B. Benson, III, MD, FACP 40

Scott E. Eggener, MD University of Chicago Genitourinary Cancer

Hematology/Oncology: Medications, Indications, and ICD-9 Codes

Susan Goodin, PharmD, FCCP, BCOP Cancer Institute of New Jersey Oncology Pharmacy Shaji K. Kumar, MD Mayo Clinic Hematologic Malignancies Theodore F. Logan, MD Indiana University Melanoma Beryl McCormick, MD Memorial Sloan-Kettering Cancer Center Radiation Oncology

EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Multidisciplinary Cancer Care, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: karen@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in Multidisciplinary Cancer Care, do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in Multidisciplinary Cancer Care, 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. Multidisciplinary Cancer Care is published by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2009 by Green Hill Healthcare Communications, LLC. All rights reserved. Multidisciplinary Cancer Care 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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Patrick Medina, PharmD, BCOP Oklahoma University College of Pharmacy Oncology Pharmacy Laura L. Morris, MD Goshen Center for Cancer Care Surgical Oncology Ritu Salani, MD Ohio State University Medical Center Gynecologic Malignancies

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Clinical Economics in Oncology Care: Making Sure Costs Never Become Larger Than Life

he launch of Multidisciplinary Cancer Care reflects the importance of mastering the eternal triangle of healthcare delivery, Cost/Quality/Access. The rise in oncology drug costs so far outpaces the rest of pharmaceutical product costs (21.6% vs 1.3% in 2005) that oncology patients are increasingly at risk not only from the disease itself, but also from runaway costs that impede access to care. With insurers, payers, and patients struggling to afford the costly new treatment options coming out of pharma and biotech companies, progressive new coverage models are arising to keep pace with them. The bottom line of this publication is simple: management of drug costs is essential to optimal clinical outcomes. Pace is the operative consideration. The US Food and Drug Administration is approving new cancer drugs faster than any other medications. Approvals are based on product quality, not commercial viability, which is giving rise to evidence-based assurance of the drugsâ&#x20AC;&#x2122; value propositions. Multidisciplinary Cancer Care was founded to illuminate this econometrics aspect of cancer treatment and reconcile the new kind of value proposition with affordability. Each issue of Multidisciplinary Cancer Care will feature interviews with key opinion leaders, highlights of major medical meetings, drug compendia updates, clinically themed review sections, and coding updates as they come together to drive oncology healthcare delivery. The impact of new guidelines, Medicare regulations, demographic shifts, and the economy on cancer treatment reimbursement is now a full-time object of study by healthcare professionals. We intend to bring a coherent picture of the trends dominating this field in each successive issue. We hope to shed light on the incentives of all parties participating in the process, with the singular strategy of helping you succeed in this remarkable new era of oncology care. We hope to hear from you and integrate your ideas in the dialog guiding this process.

â&#x20AC;&#x201D;Philip Pawelko Publisher

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January/February 2009

Cancer Drug Compendia and the Quest for Value-based Cancer Care An Interview with John V. Cox, DO, MBA, FACP, and Samuel M. Silver, MD, PhD

Two oncology experts explain their approaches to the current oncology compendia and their benefits for the various stakeholders involved in cancer care. Issues of cost, access, and quality comprise value in cancer care. The high cost of cancer agents complicates questions of long-term versus short-term survival and quality-of-life issues. The current compendia help access mainly. Lack of clinical trials for many drug uses complicate payment decisions for payers, purchasers, and physicians, since much of current cancer therapy involves off-label uses. Unlike John V. Cox Samuel M. Silver some cancer treatment guidelines that are strictly based on clinical trial evidence, the National Comprehensive Cancer Network guidelines provide experts’ decisions based on variable levels of evidence, offering physicians necessary information in the absence of evidence. Oncologists often need guidance to questions for which no clinical trials are available. In contrast to treatment guidelines, compendia are designed to help in coverage and reimbursement decisions, including off-label drug use, an essential issue for physicians, who cannot prescribe treatment that is not covered by payers or purchasers because of the high price tag attached to cancer drugs. Reaching consensus among the different stakeholders is therefore particularly critical in cancer care; compendia enhance and facilitate such consensus.

ultidisciplinary Cancer Care (MCC): We hope this discussion will highlight points in compendia yet to be designed to help payers and providers meet the quality, access, and cost issues that together comprise value for the patient.

Samuel M. Silver: Seven years ago, when I was director of bone marrow transplant at the University of Michigan, I remember saying that the cost for bone marrow transplant will be minor compared with the treatment of more common diseases, owing to more expensive therapies. This is quite true now. In dealing with the treatment of some common malignancies, the benefit is measured in weeks, and the 1 year of life saved is measured in hundreds of thousands of dollars. Comparative effectiveness appears to be a current catch phrase, and the American Society of Clinical

Dr Cox is a practicing oncologist at Methodist Hospital, Dallas, TX; Dr Silver is Assistant Dean for Research, Professor of Internal Medicine/Hematology-Oncology, University of Michigan Medical School, and Director of University of Michigan Cancer Center Network, Ann Arbor, MI.

Oncology (ASCO) is talking about this very issue and forming committees to examine it. MCC: This appears to be a case of incremental gains at anything but incremental increases in cost. Silver: It appears to be. John V. Cox: I agree. Your suggestion of quality and access over cost and how it defines value reminded me of the internal challenge our profession is going through: we are seeing all these “me-too” agents, even new and innovative drugs, which only push the rock up the hill a very short distance. This is interesting from a scientific point of view but not so exciting from a clinical point of view. When these agents come wrapped in these huge bills, it is frankly shocking. This is really a challenge for us. I cannot imagine running an insurance company or trying to set public policy related to these issues. I think comparative effectiveness and this type of evaluation is going to have to become a part of our system. Would you feel comfortable offering a very expensive drug that provides only marginal benefit? If I were a patient, I don’t think I would buy it.

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MCC: In 1990, Professor Richard Peto (now Sir Richard Peto), codirector of the Clinical Trial Service Unit at Oxford University, presented results from his 10-year study on breast cancer treatment, noting the nominal improvements in mortality with the available treatments at that time. Professor Peto said he and his colleagues had embarked on their study expecting that patients would not be very interested in going through the ordeal of chemotherapy for nominal gains. Their analysis, however, showed that patients were eager to do anything that would extend their lives even just a little longer. Of course, the costs associated with minimal gains from new cancer drugs are anything but minimal or incremental.

The language of the NCCN compendium is more restrictive than the FDA language and perhaps more restrictive than some of the other compendia. Cox: From time to time we are reminded of the gains gauged from a cancer patient’s perspective and how that affects our perception of what value is. Those extra 2 or 3 months or even few weeks can be a sizable amount of time to a patient, even though we may perceive it as a very minimal gain. Patients with cancer are seeing time through a lens that we cannot see. I certainly walk this economic and business side, but I can only imagine that this conversation would be a completely different context if I had the illness and was struggling to make decisions. MCC: When you must look through so many different lenses—from government to patient to payer to caregiver— it is amazing to arrive at a consensus at all. But it is healthy to have these perspectives; it’s better for a payer, for example, to not pretend that he is a patient or vice versa. But how do cancer compendia represent the payers’ expertise, for example? Silver: This is a difficult question. Certainly the payer seeks a reasonable solution. They don’t want to pay for things that clearly are not beneficial. So that is the red line. The gray line now deals with comparative effectiveness. One of the recommendations from the National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium for first-line treatment of patients with locally advanced or metastatic pancreatic adenocarcinoma is erlotinib—which is indicated by the US Food and Drug Administration (FDA) as mono-

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therapy for the treatment of locally advanced non– small-cell lung cancer—in combination with gemcitabine. It has been assigned a category 2A, meaning that the decision was not based on results from a randomized clinical trial but from less rigorous studies in the literature. Even though the decision cannot be backed by the highest level of evidence, it remained the overwhelming consensus of the committee. The language of the NCCN compendium is more restrictive than the FDA language and perhaps more restrictive than some of the other compendia. We do have “compendia wars” with regard to language and a payer’s decisions about the use of an agent and whether performance of an agent is evidence based. Because the NCCN guidelines are not purely evidence based, they have been criticized. Dr Roger Winn, who shepherded the NCCN guidelines, agreed that we need evidencebased guidelines, but adhering only to the highest-level evidence would leave us with guidelines that are full of holes and not very useful for the total practice of oncology. Clinicians need answers and guidance for multiple treatment decision points where no randomized clinical trials are available. In such cases, we need to know whether a group of experts think a decision is reasonable. If so, we need to know what level of agreement there is on a decision. So the NCCN categorizes their experts’ decisions—whether it is 2A or 2B, and so on. Clinicians actually use these guidelines, and I think that a lot of payers have been using them too. Compendia do not slavishly adhere to evidence-based guidelines, because these do not always exist. MCC: Is it more of an imperative for payers than for clinicians to drive the development of protocols into guidelines and guidelines into compendia? And is it more an imperative in terms of cost management or quality-of-care management? Silver: Clinicians want to know what source to go to for a particular patient, and they want to understand what constitutes a reasonable therapy. Consider all the diseases we take care of. We want to know what’s best for our patients, what’s reasonable for them. Payers want to know if a therapy is reasonable and if it has credible consensus behind it. The issue of therapeutic comparisons, so far as costs are concerned, is on the payers’ minds, and I think the clinician is becoming cognizant of this and is conflicted. The Centers for Medicare & Medicaid Services (CMS) states that cost is not a driving issue. CMS is seeking options that are “reasonable and necessary.” However, when you are dealing with purchasers, you

know that they seek solutions that are cost-effective. This is sometimes an elusive preoccupation. MCC: We currently know very little about the longterm effects of a cancer intervention or combination of interventions or no intervention. The burden for this is extended to all stakeholders, including caregivers. The more we know, the more health economists realize that they still have a lot to learn before they can define cost-effectiveness. Meanwhile, decisions have to be made immediately. Silver: A study not related to cancer recently calculated the lifetime medical costs of fit, thin members of the population, which turned out to be higher than the costs of smokers and people who are overweight, who end up dying early and therefore do not populate chronic care facilities with neurodegenerative disorders for years. People often die before there are long-term consequences associated with medical therapy. But what we are doing with radiation or with other chemotherapy drugs is associated with long-term consequences. I see more and more women who were treated 20 years ago with radiation for Hodgkin’s disease and who now have triple-negative breast cancer. So, we are finding out things that we just did not know 20 years ago when we treated these people. MCC: Payers and purchasers are interested in knowing if compendia offer practical guidance to payers via their coverage decisions. Cox: Sam said it well early in his comments. There is this interesting intersect with compendia providing a collection of guidelines but of an evidence-based nature. So I think clinicians who want to do the right thing for their patients will often reference compendia or guidelines that are using the compendia to determine what the best thing is for their patients. They want to make sure they have not missed something. I myself am impressed about the urgency of compendia and guidelines. I am not sure that my colleagues are seeking out those guidelines and the compendia entirely for the altruistic reason of wanting to know their patients or what is best for their patients. This is an area where cost and the payer’s demand for more evidencebased care, and wanting to have documentation, is causing greater awareness of the need to be evidence based in our treatment, patient by patient. I think that has been a good thing. Paying attention to evidencebased practice and treatment is good. So my encourage-

ment to readers of the journal and to payers, as well as to the purchasers of employee-based insurance plans, is to make sure that those companies are using compendia and guidelines (such as the NCCN guideline) as a base, to ensure that patients and employees have access to good expert-based oncology care. I would be fearful if insurance plans let cost be the arbiter here. I am making a plea for them to use the compendia, hold us accountable for these evidence-based decisions. I can say this a little more vigorously now than I could have 6 months ago, knowing that CMS has at least acknowledged the NCCN compendium. Now we also have Thomson Micromedex’s DRUGDEX System and other private compendia getting their feet on the ground. Having several resources provides a good evidence source for purchasers of insurance and health plans on which they base oncology decisions.

Having several resources provides a good evidence source for purchasers of insurance and health plans on which they base oncology decisions. MCC: You have made an important point. Compendia are holding in proper dynamic tension the balance between cost management and quality management. And it is not serving as just a cost-management or a quality-management tool, but it is protecting the balance of cost and quality. Cox: I see compendia as arbiters of that tension. Many times doctors and institutions are quite egocentric. We tend to march to our own drummers. And these third-party issues for compendia and guidelines processes help provide a necessary external measure of accountability regarding how we treat our patients. I would have loved this to have been completely grown out of our professionalism. Sam may argue that the NCCN process may be an expression of that professionalism. Silver: There are two ongoing projects: one is ASCO’s Quality Oncology Practice Initiative, which deals with private practices and institutions so that they can compare what they do with what their colleagues do. The second is the NCCN guidelines outcome project. This project deals mainly with breast cancer patients treated in academic institutions, but some community hospitals have joined this project, allowing those providers to compare what they do against the national norm to improve outcomes. They

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take a look at what evidence provides. I believe people are modifying their practices based on evidence, but it takes hard work. It takes time to examine data and compare oneself with others. If you do not adopt the best practices, the payers and purchasers will descend with a vengeance. That may happen anyway, but if you have a sort-of grassroots swell to this from community practice and academic practice, we will have some say in the game. How does this fit in with compendia? I think that John is right. By and large, physicians do not consult compendia to see what the next best therapy is. They seek out compendia to see whether the therapy will be covered. That is how compendia are used, and that is how we think of them. We don’t think of compendia as sources for what to do. We use them as validation that we are going to get paid for what we are about to do.

the USP-DI. Those two compendia are slavishly evidence driven. So, they are not drawn from a treatment guideline or from a professional consensus. They are drawn literally from the perspective of either a pharmaceutical company or a clinician who wants to use a particular drug for a particular cancer. So they conduct a literature review and see how their premises are expressed in the data that exist in published literature, and a slavish determination is made on the strength of evidence. So, these compendia arise from two different ways. I do agree with Sam that we use compendia for confirmation of payment, and that’s why I keep coming back to the purchasers of healthcare. MCC: How does the difference between the way data are obtained and analyzed affect the way payers use various compendia? Silver: I don’t think we know yet.

By and large, physicians do not consult compendia to see what the next best therapy is. They seek out compendia to see whether the therapy will be covered. MCC: Should this be changed? Silver: I don’t think so; that’s what compendia are designed for. The way they are presented, they are not good for determining care. Guidelines are, but not necessarily compendia. I think of compendia as more of telephone directories of where you are allowed to go. MCC: That’s a very interesting point. In the case of NCCN, which started with its guidelines and now has its compendium, can you describe how this evolution occured? Silver: There are guidelines, and there are compendia. NCCN has combined the two. I don’t believe the other compendia have been derived from guidelines. Cox: Right. The guideline process, complete with algorithms that help you make treatment decisions, is what the NCCN compendium has been drawn from. Two other compendia are the American Society of Health-System Pharmacists’ AHFS DI and Micromedex’s DRUGDEX System, the successor to

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Cox: I agree. We really have only had this robust group of compendia for a few months. Before that we were worried because our compendia system was not robust; it was practically broke. So, I don’t think we know yet what effect they will have. MCC: NCCN is leading the pack in terms of what influences payers’ decision-making process, but what payers want is a cross of all the guidelines and the supporting evidence. What appears to be missing is a decision-making tool, something that would guide the process rather than offer a number of treatments for a specific cancer. Silver: We should also note that CMS has just announced that it is adding another compendium— Elsevier’s Gold Standard’s Clinical Pharmacology. MCC: Do you see the compendia being used as a mechanism for aligning the activities and the interests of clinicians with those of payers? Silver: I think the compendia are going to have to use discretion. There may be interventions that are quite costly, and the jury is still out on drugs with a lower level of evidence that are not approved for a given indication, even though they are listed in a compendium. MCC: We talked about the importance of having purchasers and providers use compendia. What about regulatory agencies such as the FDA and patient advocacy groups?

Silver: Compendia are not part of the purview of the FDA. Compendia are not their responsibility; they are totally independent of the FDA. Cox: I worry that the FDA may monitor compendia only to watch the off-label promotions, but they are not involved in any of the systems of how compendia are developed or how they are deemed. MCC: With the FDA starting to consider surrogate end points as criteria for drug approvals, do you see this as having an impact on what we are talking about? Is there a difference in utilization or a different perspective between the two prongs of the oncology group, the community-based oncologists versus those in academia? Silver: Well, honestly I don’t see any of my colleagues in academia talking about the compendia until they are denied payment for a drug. People who are writing clinical trials may want to look at compendia with regard to the insurers that are predominant among their patient population and the state laws that deal with offlabel use of anticancer drugs. That’s a whole different aspect, but I don’t see academic physicians generally using the word “compendia” in their discussions. At the University of Michigan, we have standard order sets for most of the oncology diseases we treat. These are time tested and as far as insurability is concerned—at least as more agents are added—it is going to become more difficult. But compendia are not a topic of general discussion in the academic community. Cox: The difference is only the insulation that possibly an institution-based physician may have from the budgetary issues that affect the business of a community-based physician. I think most communitybased oncologists are very aware of the compendia or at least their practice managers, who are giving advice, are. Usually there is no degree of separation between those individuals. So, in academia, we are a little more cognizant than we were 10 years ago about giving a drug that was not covered. Then you were able to absorb the cost or easily find a replacement drug. Today, there is no such thing as easy drug replacement, and there is no way you could absorb the cost of one of these drugs if you fail to be aware of whether it is going to be covered. MCC: And to that end are diagnostics a big part of the compendium? Cox: By diagnostics, do you mean whether I con-

duct a computed tomography (CT) scan for a given situation? MCC: Or qualify patients before putting them on an expensive biologic agent. Cox: No, compendia are not that detailed. MCC: Do you think that’s something that may be added to improve them?

Compendia are not part of the purview of the FDA. Compendia are not their responsibility; they are totally independent of the FDA. Silver: That is where guidelines come in. Actually, the NCCN guidelines are often not that detailed either, even though they will say you may consider a CT scan versus a positive emission tomography (PET) scan. The wording would be to “consider” versus it being a recommendation. They may not necessarily recommend CT scans or PET scans every 4 months for follow-up purposes. It gets vague when it comes to survival and maintenance issues. So, we have a long way to go for that. I know that in dealing with the standard of care in issues of clinical trial design, it becomes important to determine what the standard of care is as opposed to what the protocol pays as far as diagnostic tests. Investigators have a lot of trouble with that, because these issues are not clearly defined. As we get into more expensive ways of staging someone with breast cancer, for example, we need to determine if we can use magnetic resonance imaging scans. There is tremendous debate about what is helpful or whether we are causing patients to have more mastectomies. These are very hot topics. Cox: Yes. Imaging is a driving issue, and we do overuse it. Silver: To the larger question of diagnostics as an integral part of obtaining value in the use of cancer drugs, this is an area of growing concern. The September 2006 issue of Health Affairs had several articles that examined biologics. Much of the discussion was related to cancer care. One of the articles pointed out that conventional drug cost-management tools do not work for biologics. At best, they are punitive. They do not really reduce costs or resource utilization over-

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all, but they certainly manage to hurt a lot of patients who need the care. So, the industry is looking for ways to do cost management of biologics, while targeting the right patient with the right drug. Good diagnostics, it would seem to me, are going to be an essential component of trying to provide optimal use of the great new cancer agents that are coming down the pipeline. These are costly drugs, but they are doing some great things for patients.

Good diagnostics are going to be essential to provide optimal use of the great new cancer agents that are coming down the pipeline. Cox: You bring up an issue that is beyond the scope of this discussion, but what you have just described is where ideally there will be a tight-knit relationship between those who are paying the bills and those who are providing the care. To capture that, to know how I am dealing with my diagnostics and how that is concerned with a choice for an expensive biologic drug, you must have a good handle on the whole trajectory of care for that patient; you must be part of this case management team. And since most of our relationships with the payer are simply through the billing code, it does not capture whether we are using a first-line or second-line drug. I am sure there are sophisticated algorithms that Aetna or UnitedHealthcare use, but I think those are going to have to be another step up of the discussion or information that is shared, and it may present as an opportunity for institutions such as the University of Michigan, or large groups such as Texas Oncology, of which I am a member, to develop case management relationships with Aetna or with UnitedHealthcare. Transplant communities may be used to this, but small community oncologists are not. MCC: If you had to identify one key factor that’s driving cancer care today, what would that be? Silver: That’s a very complex question, because cancer care is so multifaceted. I don’t think there is one single issue that drives cancer care. I think there are many things, and some are totally independent of compendia—issues of survival; the complications and consequences of therapy; what to do with the increasing numbers of patients who have finished their therapy but certainly have not finished their assessment for dis-

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ease, who should be taking care of these patients, and where they should be cared for; and use of the new expensive drugs on the market, at what cost for what little effect. These questions are almost impossible to answer. MCC: What do you consider to be some of the top priorities in cancer care? Cox: Every year you are in practice you begin to realize the schism between the wonderful science and the interesting things that are going on, and where it is taking us. Wonderful things are happening on every side of the triangle of clinical, business, and regulatory, but it is not necessarily pushing us all in the same direction. It goes back to Lewis Thomas, a wonderful essayist who wrote a lot for the New England Journal of Medicine. One of his essays was on the contrasting care of polio and the cost of polio and how this whole industry existed in the 1920s, 1930s, and 1940s, including specialist surgeons and fancy machines, and all this mechanism of taking care of the poor sufferers of the disease. And this entire problem was solved with a simple vaccine. Cancer does not lend itself to a simple solution. We are stuck with a huge mechanism that will continually challenge our viability as physicians and the viability of payers to cover all these mechanisms of care until science finds an elegant solution. Silver: The other side of the coin is that we are constantly changing the care of cancer, and patients’ families and anyone who sees me reading something about cancer on an airplane, for example, will ask, “So, when is cancer going to be cured? I understand it may be in about 10 years or so.” And then you launch into a discussion about there being so many different cancers and even though we have done well with some, we are still struggling with many. The fact that we are changing many cancers from an acute disease to a chronic condition is good. But it is like diabetes, and we have not found a cure for diabetes yet. Cox: I agree. The cure for cancer will not be similar to that found for polio. MCC: Which point on the value triangle of cancer care—cost, quality, or access—do you think compendia are going to enhance? Silver: Right now, I don’t think compendia are helping cost. They could help quality, and I think they have helped with access. The bottom line is—how many

cancer drugs do we use that are off-label, and is it a huge number? We and the payers do not have a bible to consult. If we were restricted to the label indications, we would be left with a markedly diminished armamentarium for taking care of our patients. I am not even talking about the planned new drugs; I am talking about the old drugs that have been time tested for diseases that we treat every day but have never gone through the FDAindication process and associated expenses. Cox: I agree with Sam. I think that of the three parts of your triangle, access is the major point that a compendia could help. We already said that as the ability to know that when I prescribe something that is listed in the compendia I can get it, I can provide that service to a patient. Now, the other two arms are affected, and what we are saying is the payer knows that it has something to do with quality, because it has an exterior benchmark that says it belongs to that disease and for that particular patient. It also helps payers modestly to control costs, because they can ask for more information or get a better handle on a drug that may be very expensive, and that may not be provided for a diagnosis that is not included in the compendium. MCC: Do you think that compendia will ever address end-of-life and palliative care issues? And when could that dialogue begin?

Cox: So far the compendia as we know them today do not deal with these issues. What I see is a case-management discussion regarding changing the physician’s relationship with the payer. It brings that triangle right into my own backyard. I do not know how we could do that otherwise, or how we are going to have to find the right leverage. Our oncology group is talking with a couple of the big payers. We deal with these very issues, because these are huge drivers for them.

We and the payers do not have a bible to consult. If we were restricted to the label indications, we would be left with a markedly diminished armamentarium for taking care of our patients. Silver: I agree, especially because when dealing with areas of care or hospice, we need to be specific about what palliative care is—for example, whether it is 10 years’ worth of low-grade therapy but not curative care. Definitions are indeed interesting and important and certainly are issues that we talk about with regard to erythropoiesis-stimulating agents (ESAs) these days; this is something about which we will talk more when the FDA makes its decision about ESAs. ■

Cancer Compendia The Centers for Medicare & Medicaid Services currently recognizes four cancer compendia for reimbursement purposes: 1. American Society of Health-System Pharmacists’ AHFS DI www.ahfsdruginformation.com/ 2. Elsevier’s Gold Standard’s Clinical Pharmacology www.goldstandard.com/ViewPress.aspx?ID=110 3. NCCN Drug & Biologics Compendium www.nccn.org/professionals/drug_compendium/content/contents.asp 4. Thomson Micromedex’s DRUGDEX System www.micromedex.com/products/drugdex/

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Colorectal Cancer Update: New Strategies in Supportive Care

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INTRODUCTION

Circulation Department n the United States, colorectal cancer cases, chemotherapy can be used to shrink circulation@coexm.com (CRC) is estimated to be the third most unresectable tumors to facilitate surgery. diagnosed cancer and the third It also remains the mainstay of treatment Business November/December 2008Manager • Volume 1 • Numbercommonly 5 most common cause of cancer death for patients with inoperable CRC. Blanche Marchitto among both men and women.1 The inciOver the past decade, therapeutic dence rates of CRC have declined by near- options for patients with metastatic colExecutive Administrators ly 26% from 1984 to 2004, mainly due to orectal cancer (MCRC) have expanded, Thiel Hennessy early detection of polyps before progres- due in large part to the development and Lisa Russo sion to cancer.2 Surgery can cure about 90% approval of more effective chemotheraof CRCs when the disease is found early, peutic agents and new biologic therapies. and 5-year survival rates have risen from However, these novel treatments are asso51% (1975-1977) to 65% (1996-2003).1 ciated with unique toxicity profiles that About 50% to 60% of patients diagnosed pose distinct nursing management chalwith CRC will develop metastatic disease, lenges. As integral members of the cancer Supported by most commonly in the liver or lung.3 Five- care team, oncology nurses must remain year survival rates in patients with cognizant of effective strategies for managan educational grant from metastatic liver disease who do not under- ing specific treatment-related toxicities, so go surgery approach zero. With resection that patients with MCRC are better able to of liver metastases, 5-year survival rates are continue with appropriate treatments Editor in Chief approximately 25% to 50%.3,4 In some while maintaining quality of life. Sagar Lonial, MD Jointly sponsored by M edical L earning Institute, Inc. and Center of Excellence M edia, L L C Emory University

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Considerations in Multiple Myeloma: Side Effect Management

MULTIDISCIPLINARY TEAM PRESENTATIONS BY Lillian Chou, PharmD NewYork-Presbyterian Hospital

Charise Gleason, MSN, ANP-BC, AOCNP Emory University

Cindy Ippoliti, PharmD Cornell Medical Center

Lisa C. Smith, MSN, FNP, AOCN Cancer Center of the Carolinas

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LETTER TO OUR READERS D ear Colleague: It is my distinct pleasure to offer this newsletter entitled “ Considerations in M ultiple M yeloma: Side Effect M anagement,” the fifth issue in a series of newsletters featuring topics relevant to your multidisciplinary team approach to caring for patients with multiple myeloma (M M ). Together with a faculty of hematologists/oncologists, oncology nurses, and oncology pharmacists, we focus our discussion on one topic for each newsletter. Previous issues focused on patients with renal dysfunction, treatment-naive patients, difficult-to-treat populations of M M patients, and health economics. T his issue will focus on the side effects associated with various agents and treatment regimens used to treat M M . It is our sincere hope that the information presented here is of value to you in your care of patients with M M . Sincerely, Sagar L onial, M D Associate Professor of H ematology and Oncology Emory U niversity

Supported by an educational grant from

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Oncology

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The NCCN Compendium: Unique Resource for Value-based Cancer Drugs Coverage Decisions Al B. Benson, III, MD, FACP

he National Comprehensive Cancer Network (NCCN) has brought a new level of value to payers in a continued attempt to manage healthcare resource allocation. The NCCN is unique in that it develops guidelines directly linked to practice—NCCN Clinical Practice Guidelines in Oncology— which are reviewed and updated continually. The NCCN’s structure encourages rapid integration of new developments for a particular disease site, which then can be immediately integrated into the NCCN Drug & Biologics Compendium. Both the treatment guidelines and the compendium are kept current. This provides a unique resource for decision makers, because most compendia have not been able to respond even remotely rapidly to changes in cancer care. The NCCN compendium provides sound, scientific, evaluative information to the oncology community and is designed to inform decision-making and improve outcomes. It offers the unique feature of being linked to practice guidelines and timeliness with regard to integrating new advances into the compendium. Balancing population-based research with personalized medicine considerations can be challenging for the development of cancer treatment strategies. One of the problems with cancer-related clinical trials has been using empiric design strategies rather than identifying patients most likely to benefit from therapy (enriched populations). The development of biologic therapies has encouraged alternative trial designs that explore human biological profiles as important parameters. Since most cancers are heterogeneous, an individualized or personalized approach to cancer treatment is very desirable. Dr Benson is Professor of Medicine, Associate Director for Clinical Investigations, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, and Chairman of the Board of the National Comprehensive Cancer Network.

Although we are far from a universal personalized approach to cancer care, considerable progress has been made. Wherever prognostic and/or predictive tumor markers are important in treatment selection, these markers are integrated into the NCCN guidelines and the compendium. For example, there is evidence that patients with the Kras (Kirsten rat sarcoma 2 viral oncogene homolog) mutation will not benefit from antiepithelial growth factor receptor therapy for metastatic colon cancer with either cetuximab or pan-

Balancing population-based research with personalized medicine considerations can be challenging for the development of cancer treatment strategies. itumumab. After the American Society of Clinical Oncology (ASCO) 2008 presentations and review of other retrospective reports, the NCCN Colorectal Cancer Panel met to alter the guidelines reflecting the use of Kras to determine treatment considerations. A personalized approach will be helpful in the case of rare diseases, where it is extremely difficult to conduct randomized phase 3 trials with sufficient numbers of patients in an acceptable time frame. By defining biologic profiles for treatment selection, it should be possible to conduct much smaller trials that will benefit patients with rare diseases.

Key Challenges to Cancer Treatment Challenges to cancer treatments remain, including a demographic shift (ie, aging of the baby boomers), the high cost of biologics, and ensuring therapeutic success of new treatment regimens, and the turning of acute conditions into chronic conditions. The treatment

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Table. NCCN Member Institutions • City of Hope Cancer Center, Los Angeles, CA • Dana-Farber/Brigham & Women’s Cancer Center/ Massachusetts General Hospital Cancer Center, Boston, MA • Duke Comprehensive Cancer Center, Durham, NC • Fox Chase Cancer Center, Philadelphia, PA • Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT • Fred Hutchinson Cancer Research Center/ Seattle Cancer Care Alliance, Seattle, WA • Arthur G. James Cancer Hospital & Richard J. Solove Research Institute, Ohio State University, Columbus, OH • The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD • Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL • Memorial Sloan-Kettering Cancer Center, New York, NY • H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, FL • Roswell Park Cancer Institute, Buffalo, NY • Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO • St. Jude Children’s Research Hospital/University of Tennessee Cancer Institute, Memphis, TN • Stanford Comprehensive Cancer Center, Stanford, CA • University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL • UCSF Comprehensive Cancer Center, San Francisco, CA • University of Michigan Comprehensive Cancer Center, Ann Arbor, MI • UNMC Eppley Cancer Center, Nebraska Medical Center, Omaha, NE • The University of Texas M.D. Anderson Cancer Center, Houston, TX • Vanderbilt-Ingram Cancer Center, Nashville, TN NCCN indicates National Comprehensive Cancer Network.

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guidelines do provide detail about how to manage patients over time, including appropriate follow-up procedures. Furthermore, the NCCN plans to address important survival issues. The NCCN is considering creating a list to include the cost of anticancer agents; however, the focus will remain on the level of evidence to support the use of biologics and chemotherapy agents for specific diseases. Given the breadth of the guidelines, NCCN does not have the resources to attempt cost-effectiveness analysis—a complex and very resource-intensive enterprise.

Providing Value in Cancer Care Because the guidelines are updated continually (at least annually) and represent an evidence-based approach whenever evidence is available, they offer value to providers, payers, and, ultimately, to patients. They provide evidence-based expert consensus in the absence of high-level evidence and are comprehensive across all stages and modalities, representing a multidisciplinary continuum of care. The guidelines focus on treatment, risk reduction, early detection, and supportive care. With 44 panels representing more than 800 multidisciplinary cancer specialists, the guidelines also receive institutional review providing invaluable feedback to each panel. Thus, the guidelines provide a tool for improving the quality of care that should benefit payers and providers, and, most important, the patient. The NCCN strongly supports clinical trials, which are critical to proving outcomes data and achieving the goal of providing personalized medicine. By encouraging appropriate cancer care, the hope is that institutions across the country will be better able to provide it, while referring patients with complex and rare cancers for care that is not available locally. We hope this strategy will improve access to better cancer care across the country. Framing the Expectations of Payers and Providers The great advantage of the NCCN structure is that the information is provided free online and in other formats. Therefore, all payers and providers presumably have ready access to the NCCN guidelines and compendium. The guidelines provide comprehensive information that is not restricted simply to drug therapy but also includes important diagnostic information (eg, surveillance, surgical, and radiation approaches). As a derivative product, the NCCN compendium makes recommendations about the use of drugs and biologics in the full context of care. The compendium offers a list of appropriate agents for a disease, including the brand name, pharmacologic class, US Food and Drug

Administration (FDA) indication, histology, NCCN recommended use, route of administration, NCCN category level of evidence, and the International Classification of Diseases, Ninth Revision (ICD-9) code. It is important for payers to recognize that guidelines are not prescriptive. The payer can be assured that if the guidelines are being followed for a particular patient, optimal care is being delivered. However, there are circumstances where alternatives may represent the individual patient’s best interest. Such instances are usually handled on a case-by-case basis. Private payers, such as the BlueCross BlueShield plans, UnitedHealthcare, Cigna, Aetna, and Humana, use the NCCN guidelines to make coverage determinations for drugs and biologics used in an anticancer chemotherapy regimen. UnitedHealthcare was the first payer to base its benefit coverage for chemotherapy drugs used in outpatient settings on the NCCN compendium, effective March 15, 2008. Cigna plans to synthesize the compendium into its clinical coverage materials. Discussions are ongoing with Humana and several BlueCross BlueShield plans about officially recognizing the compendium for coverage determinations.

Obligations of the NCCN Panel Clinical experts and NCCN member institutions (Table) review the literature for evidence to support updates to the NCCN guidelines and reach a consensus regarding the quality of evidence of their findings. For rare diseases, there is often a dearth of published randomized clinical trials; however, the panel does review phase 2 trials to determine if a particular use appears appropriate. It is also important to acknowledge that the use of many oncology agents is not indicated by the FDA. Offlabel medication use is often determined by evidence from clinical trials. Lacking published clinical trials, the panel must avail itself of presentations and abstracts at national and international meetings, including ASCO and the American Society of Hematology. The NCCN membership includes 21 of the leading cancer centers in the world, with multidisciplinary experts covering the broad spectrum of cancer and related diseases. Because each member institution provides a review of the guideline, the level of expertise in the process is automatically expanded. Approval of the NCCN Compendium The NCCN compendium is a tool designed to provide value by balancing quality, access, and effectiveness. The NCCN worked closely with the Centers for Medicare & Medicaid Services and UnitedHealthcare

to enhance the electronic functionality of the NCCN compendium. The NCCN expanded the compendium’s search capabilities and established an alphabetized listing of all drugs and biologics on the compendium homepage, with links to the complete information for each drug and biologic. NCCN also linked the drugs and biologics individually to their corresponding FDA labels, which provide extensive information on clinical pharmacology, warnings, cautions, adverse reactions, and drug interactions. An additional feature is electronic linking of the drugs with specific indications in the compendium to the relevant NCCN Chemotherapy Order Templates that contain references to support the indication and dosing. NCCN has also mapped the J-codes of the drugs and biologics found in the compendium to the corresponding ICD-9 codes.

To promote the safe use of potentially toxic agents and combinations of agents, the NCCN is linking each of the agents listed in the compendium to relevant chemotherapy orders templates. NCCN Chemotherapy Order Templates To promote the safe use of potentially toxic agents and combinations of agents, the NCCN is linking each of the agents listed in the compendium to relevant chemotherapy orders templates. Because so much of oncology treatment consists of using agents in combination, it is important that clinicians understand the special requirements of multidrug, multiday, multicycle chemotherapy. The NCCN Chemotherapy Order Templates provide directions for using these regimens appropriately. The templates provide the dose and schedule of administration of each agent and any supportive care measures that are required. They also list any monitoring or doseholding recommendations associated with the regimen. Each order template lists the appropriate citation of data supporting the regimen’s use and thus provides the user of the compendium with the evidence that supports the use of each agent listed in it. The compendium also provides links to the most recent FDAapproved product label for each agent. ■ For more information, visit www.nccn.org.

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Clinical Advances in the Treatment of Myelodysplastic Syndromes: Reasons for Hope Sandra E. Kurtin, RN, MS, AOCN, ANP-C

trategies for the treatment of hematologic diseases, including myelodysplastic syndromes (MDS), have expanded at an unparalleled rate, offering improved response rates, overall survival, and disease control for patients. Three new active therapies have received US Food and Drug Administration (FDA) approval since 2004 for the treatment of MDS. Numerous clinical trials are ongoing that offer promising therapies for future use either as single agents or in combinations. Refinement of the diagnostic evaluation and application of prognostic criteria for MDS has allowed more specific treatment selection for each individual patient. Integrating the rapidly expanding treatment arsenal into an organized and evidence-based treatment approach for patients with MDS presents an ongoing challenge to oncology clinicians. Understanding novel mechanisms of antitumor activity, associated toxicities, and clinical management strategies for these new therapies is critical to safe and effective management of patients receiving them. An overview of the historical background for MDS (Table 1) and an update on the most current clinical trials will be provided, with specific information on management of patients receiving active therapies or supportive care.

Epidemiology and Etiology

Before 1973, only 143 cases of MDS had been reported. Today, there are 10,000 to 15,000 new cases of MDS annually in the United States, and the prevalence is estimated to be 35,000 to 55,000 cases based on typical life expectancy. There is an increase in incidence with advancing age, highest at ages 80 to 84 Ms Kurtin is Hematology Oncology Nurse Practitioner, Arizona Cancer Center, and Clinical Assistant Professor of Medicine and Nursing, University of Arizona, Tucson, AZ.

Table 1. Scientific Developments in MDS: A Historical Perspective • Classified as preleukemia until the late 1970s • 1976: First French-American-British (FAB) classification system • 1982: First publication using the term myelodysplastic • 1986: First indexed by the National Library of Medicine • 1986: Modification of the FAB classification system • 1997: WHO modification of the FAB criteria • 1997: International Prognostic Scoring System riskstratification criteria • 2000: International Working Group response criteria, revised 2006 • 2004: First National Comprehensive Cancer Network treatment guidelines • 2004: First FDA-approved agent for treatment of MDS (azacitidine) • 2005: Two additional agents FDA approved for MDS (lenalidomide, decitabine) • 2007: WHO Prognostic Scoring System risk-stratification criteria • 2008: First data indicating improved overall survival in the treatment of MDS (azacitidine) MDS indicates myelodysplastic syndromes; WHO, World Health Organization; FDA, US Food and Drug Administration. Sources: Reference 10; Steensma DP, Tefferi A. Risk-based management of myelodysplastic syndrome. Oncology (Williston Park). 2007;21:43-54; Lyons RM, Cosgriff T, Modi S, et al. Results of the initial treatment phase of a study of three alternative dosing schedules of azacitidine (Vidaza) in patients with myelodysplastic syndromes (MDS). Abstract presented at the 49th Annual Meeting of the American Society of Hematology; December 8-11, 2007; Atlanta, Georgia. Abstract 819.

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years, then decreasing dramatically at age 85. Epidemiologic data specific to MDS have been collected in the United States only since 2001.1,2 As the clinical and pathobiologic features of MDS become more familiar to clinicians, MDS becomes a part of the differential diagnosis and is detected more often in patients presenting with cytopenias, particularly anemia in the elderly. These patients often present first to their primary care providers. The development of therapeutic options may increase the number of patients considered for diagnostic evaluation and may prompt referral to a hematology/oncology specialist for further evaluation. In addition, increasing numbers of patients are being treated with cytotoxic therapies over extended periods of time, raising the potential for treatmentrelated MDS.

Today, there are 10,000 to 15,000 new cases of MDS annually in the United States, and the prevalence is estimated to be 35,000 to 55,000 cases based on typical life expectancy. The cause of MDS is unknown in most cases. Older age is a predisposing factor (80%-90% of patients are >60 years old), perhaps a result of hematopoietic senescence.3 Secondary MDS may develop after exposure to high doses of radiation, chemotherapy, or industrial toxins, such as benzene. Inherited genetic predisposition for developing MDS and congenital abnormalities are rare. MDS is considered an incurable disease in the absence of a successful allogeneic stem-cell transplant. Therefore, attention to quality of life, as with any chronic incurable disease, is critical. The Myelodysplastic Syndrome Foundation has conducted focus groups that have provided useful information on the management of patients with MDS.4 Biological Features of MDS

MDS represents a spectrum of clonal malignancies that originate in the bone marrow due to a myeloid stem-cell defect.5 Each subtype of MDS may have a varied clinical presentation, morphologic features, genetic instability, prognosis, and variable risk of leukemic transformation. The common features among these disorders are ineffective production of normal mature blood cells (hematopoiesis) with one or more peripheral cytopenias. More advanced disease is associated with progressive bone marrow dysfunction and/or

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leukemic transformation.6 MDS is thought to originate as a result of complex interactions between malignant progenitor cells (malignant clone), the bone marrow stroma, and the microenvironment. Both intrinsic (within the malignant clone itself) and extrinsic (bone marrow microenvironment and stroma) factors are thought to play a role in the pathogenesis of the disease. Intrinsic factors include cytogenetic abnormalities and epigenetic DNA changes.7,8 Extrinsic factors include medullary angiogenesis, stromal dysregulation, and an imbalance of progenitor cell proliferation and apoptosis. Cytogenetic abnormalities are present in approximately 40% to 50% of de novo MDS patients.9 The most common abnormalities include deletions of chromosomes 7, 5, and 20 and trisomy of chromosome 8. A primary intrinsic abnormality recognized in MDS is epigenetic DNA changes. Unlike genetic changes, such as mutations or deletions, which are irreversible (with the exception of an allogeneic stem-cell transplant), epigenetic changes represent potentially reversible modifications to DNA and chromatin. DNA methylation, the most common epigenetic abnormality in MDS, plays critical roles in the control of gene expression necessary for effective hematopoiesis. Hypermethylation is common in MDS, resulting in silencing of critical regulatory or suppressor functions (signal transduction path-

Because the process of hypomethylation can occur only when cells are actively dividing, treatment must be administered for an extended period of time before results may be achieved. ways) necessary for normal hematopoiesis (differentiation and apoptosis).9 DNA hypermethylation is also suspected of being involved in leukemogenesis. Hypomethylating agents provide an attractive strategy for the treatment of MDS for these reasons. Because the process of hypomethylation can occur only when cells are actively dividing, treatment must be administered for an extended period of time before results may be achieved, and prolonged treatment may be necessary because hypermethylation typically recurs when treatment is discontinued. Extrinsic factors are associated with the bone mar-

row microenvironment and include medullary angiogenesis, stromal dysregulation, and an imbalance between apoptosis (programmed cell death) and proliferation. These factors play an important role in the pathogenesis of MDS, including survival of the

Selection of the most effective therapy should be based on the unique characteristics of the individual patient. malignant clone and accelerated apoptosis of progenitor cells, leading to ineffective hematopoiesis and eventual bone marrow failure. Excessive apoptosis is thought to explain the common finding of peripheral cytopenias with a hypercellular bone marrow. As the disease progresses, the rate of proliferation exceeds apoptosis and the patient demonstrates increasing peripheral blasts and peripheral cytopenias characteristic of leukemic transformation. Clinical Presentation, Staging, Risk Stratification, and Treatment Selection

MDS is most common in the seventh and eighth decades of life. The only curative therapy for MDS is an allogeneic bone marrow transplant. This is not an option for most patients because of their age, comorbidities, and the lack of a healthy, living, related bone marrow donor. Thus the primary goals of therapy are to improve quality of life, minimize treatment toxicity, decrease transfusions, decrease infections, and prolong survival. Selection of the most effective therapy should be based on the unique characteristics of the individual patient, including specific MDS subtype, risk category, performance status, physiologic age, comorbid conditions, and lifestyle (Table 2).7,10,11 Chronologic age alone should never exclude treatment. Symptoms associated with one or more cytopeniasâ&#x20AC;&#x201D; such as fatigue, fever, recurrent or prolonged infections, bruising, or bleedingâ&#x20AC;&#x201D;are the most common symptoms that prompt the patient to seek medical care. These symptoms are often vague, with a gradual change in symptoms mistaken for other common changes of aging or chronic illness. The initial patient evaluation most often includes a complete blood count, which reveals normocytic or macrocytic anemia, normal to decreased neutrophils, and a variable platelet count. Anemia is observed in 90% of patients with MDS, either at initial presentation or during the course of their disease. A careful his-

tory and additional laboratory analysis should be pursued to exclude other causes of cytopenias. Baseline serum erythropoietin levels are critical to evaluate the role of erythropoiesis-stimulating proteins. A bone marrow biopsy and aspirate with specific attention to cytogenetic abnormalities is necessary to make the definitive diagnosis and allow staging. Adequate staging of the patient with MDS is critical to selection of the most appropriate therapy. Clinical trials have provided insight into several potential mechanisms for the abnormal hematopoiesis and resulting peripheral cytopenias seen in MDS and have offered novel targets for active therapies. Familiarity with the clinical and pathologic features of MDS is critical to understanding recent scientific advances in diagnostics, prognostication, drug development, and treatment selection for patients with these disorders. The primary classification systems for MDS include the French-American-British (FAB) and World Health Organization (WHO) classification criteria. These are based primarily on morphologic characteristics of the disease and the percentage of blasts and include five subtypes.12 Chromosomal aberrations are common in MDS; approximately 50% of patients with de novo MDS have one or more cytogenetic abnormalities. The development of the International Prognostic Scoring System (IPSS) provided an important prognostication and treatment selection tool. It was based on evaluation of bone marrow blasts, cytoge-

Approximately 50% of patients with de novo MDS have one or more cytogenetic abnormalities. netic patterns, and number of cytopenias (Table 3). However, the analysis was performed in 1997 using the FAB classification and included patients with 20% to 30% blasts (now considered acute myelogenous leukemia [AML]) and is only applicable to newly diagnosed patients. An international work group further refined the FAB criteria with delineation of isolated deletion of 5q, MDS-unspecified, and redefinition of AML to include >20% blasts.13 Additional studies to date have provided further refinement of cytogenetic and molecular findings with clinical significance in either prognosis or treatment selection. For example, flow cytometry has provided an additional prognostic tool, the MDS flow score, a tool not previously widely used for MDS. van de Loosdrecht and colleagues identified expression of CD7 or CD56

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Table 2. MDS Snapshot: Clinical and Pathological Features of MDS Feature Incidence (per year) Average age at diagnosis Etiology

Stem cell defect: myeloid progenitor cell

Chromosomal findings Cytogentic abnormality present in ~50% Additional prognostic factors indicating high-risk disease

Staging Response criteria Disease characteristics (all are incurable)

Clinical presentation Indication to treat Key concepts for effective treatment

FDA-approved therapies In clinical trials or used based on other approved indications Key supportive care concerns

Key Findings 15,000-20,000 new cases with 35,000-50,000 existing cases 70 years • Genetic instability • Mutagens • Chemical exposure • Autoimmune disease • Tobacco • Unknown in the majority of cases (~80%) Intrinsic factors: Extrinsic factors: malignant clone bone marrow microenvironment • Cytogenetic • Stromal dysregulation abnormalities • Cytokine abnormalities • Epigenetic DNA • Imbalance of apoptosis and proliferation modification Favorable: Intermediate risk: Poor risk: • -Y, del 5q, -20q • +8 and other • Complex (>3 abnormalities), chromosome 7 abnormalities: 7q, -7, del 7p, inv16, t(8:12)-AML • Increased transfusion burden (>2 units in 4 weeks) • CD7 or CD56 expression by flow cytometry • Atypical localization of immature precursors • Ongoing analysis of more sensitive testing for chromosomal and molecular attributes FAB/WHO (morphology) and IPSS/WPSS (risk stratification) International Working Group criteria 2006 Low-intermediate-1 risk: Intermediate-2-high risk: • Indolent course • Progressive course with early • Low probability of transformation to acute leukemia leukemic transformation • Cytopenias: anemia most common • Infection • Bleeding • Fatigue • Transfusion dependence, progressive cytopenias, increased blasts • Supportive care alone does not prevent disease progression (no effect on the underlying disease) • Active therapies for MDS generally require a minimum of 4-6 months to achieve a response. Premature discontinuation may limit the potential for an optimal response; instead patients should continue to receive treatment as long as they continue to benefit • Aggressive concurrent management of cytopenias is essential to effective therapy • Treatment goals: extended survival, reduce transfusion requirements, delay time to leukemic transformation and improve quality of life • Chromosomal abnormalities have prognostic value • Azacitidine (2004) • Decitabine (2005) • Lenalidomide (2005) • TLK199 • Src family kinase inhibitors • Clofarabine • Iron overloads • Cytopenias

• Arsenic trioxide • Valproic acid • Thalidomide • Injection site reactions • Gastrointestinal toxicities

MDS indicates myelodysplastic syndromes; AML, acute myelogenous leukemia; FAB, French-American-British classification system; WHO, World Health Organization; IPSS, International Prognostic Staging System; WPSS, World Prognostic Staging System; FDA, US Food and Drug Administration. Adapted with permission from Reference 7.

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January/February 2009

Table 3. Risk-based Stratification of MDS Score Prognostic variables Bone marrow myeloblasts <5% Karotype Normal, or del 5q, del Y, del 20q as sole abnormalities No of cytopenias* 0,1

0.5

1.5

2.0

5%-10% — 11%-20% Other del 7, or — abnormalities 3+ abnormalities

21%-30% —

2,3

—

IPSS Risk Group Assignment Risk

Total score

Median, Median time survival, years to AML evolution, years

Lifetime AML evolution, %

Low Intermediate-1 Intermediate-2 High

0 0.5-1.0 1.5-2.0 ≥2.5

5.7 3.5 1.2 0.4

19 30 33 45

9.4 3.3 1.1 0.2

*Anemia (hemoglobin <10 g/dL), neutropenia (absolute neutrophil count <1800/µL), and/or thrombocytopenia (platelets <100,000/µL). MDS indicates myelodysplastic syndromes; IPSS, International Prognostic Staging System; AML, acute myelogenous leukemia. This research was originally published in Blood. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079-2088. © The American Society of Hematology.

in 60% of patients with transfusion dependency or progressive disease in contrast to only 9% of patients who were not transfusion-dependent.14 CD7 has been correlated with a decrease in duration of transfusion dependence and overall survival. In addition, recent analysis specific to cytogenetic abnormalities has identified chromosome 7 abnormalities as an adverse prognostic finding. Importantly, recent clinic trials using azacitidine have shown particular efficacy in patients who have chromosome 7 abnormalities. More recently, the WHO Prognostic Scoring System (WPSS) was developed by an international group of MDS experts with adaptation of the WHO classification system and refinement of the IPSS criteria to include further characterization of cytogenetic abnormalities and transfusion requirements that are predictive of survival and leukemic transformation. These criteria are applicable throughout the course of diagnosis, including treatment-related MDS. Transfusion dependence was found to be an independent prognostic factor in MDS patients, reinforcing the primary criteria to initiate active therapies.15 Treatment Selection and Patient Management

The goals of therapy for MDS are based on individualized disease characteristics, patient characteristics, and risk category. Treatment guidelines are no longer

based on age and performance status. Transfusion dependence or progressive or symptomatic cytopenias generally indicate the need for active therapy. For lowrisk disease, the goals are to improve hematopoiesis, improve quality of life, and minimize toxicity. In highrisk disease, the goal is survival. These patients are at

The goals of therapy for MDS are based on individualized disease characteristics, patient characteristics, and risk category. high risk for early transformation to acute leukemia and generally require immediate and aggressive therapy. De novo MDS is associated with a more favorable outcome when compared with treatment-induced MDS, which is associated with poor response to standard therapies. Based on key clinical trials and ongoing investigation, the first treatment guidelines for MDS were developed by the National Comprehensive Cancer Network (NCCN) in 2004. They have been revised a number of times each year since then, consistent with the relatively new understanding of key aspects of this disease and strategies for treatment. Direct clinical comparison of current therapeutic strategies is limited, as each of these therapies has only

Multidisciplinary Cancer Care

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She’s still fighting after surgery, radiation, and chemotherapy. How can you respond when she asks what’s next?

ABRAXANE for Injectable Suspension (paclitaxel proteinbound particles for injectable suspension) (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. WARNING: ABRAXANE for Injectable Suspension (paclitaxel proteinbound particles for injectable suspension) (albumin-bound) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS.

IMPORTANT SAFETY INFORMATION The use of ABRAXANE has not been studied in patients with hepatic or renal dysfunction. In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL. ABRAXANE can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ABRAXANE. Men should be advised to not father a child while receiving treatment with ABRAXANE. It is recommended that nursing be discontinued when receiving ABRAXANE therapy. ABRAXANE contains albumin (human), a derivative of human blood. Caution should be exercised when administering ABRAXANE concomitantly with known substrates or inhibitors of CYP2C8 and CYP3A4. ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. It is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE.

give her

In a pivotal phase III trial 速

ABRAXANE delivered nearly double the overall response rate vs solvent-based paclitaxel1 The albumin-bound paclitaxel, ABRAXANE, eliminates the need for Cremophor 速 EL,* allowing delivery of a 49% higher dose vs solvent-based paclitaxel1

for efficacy

21.5% vs 11.1% (P=.003) for all study patients.1 95% CI, 16.2% to 26.7% for ABRAXANE.1 95% CI, 6.9% to 15.1% for solvent-based paclitaxel.1

15.5% vs 8.4% (P=NS) for study patients who failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapy.1 95% CI, 9.3% to 21.8% for ABRAXANE.1 95% CI, 3.9% to 12.9% for solvent-based paclitaxel.1

BOUND AND DETERMINED

Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses is recommended. Sensory neuropathy occurs frequently with ABRAXANE. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial. These events included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary embolism, and hypertension. In the randomized metastatic breast cancer study, the most important adverse events included alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), asthenia (any 47%; severe 8%), myalgia/arthralgia (any 44%; severe 8%), anemia (all 33%; severe 1%), infections (24%), nausea (any 30%;

severe 3%), vomiting (any 18%; severe 4%), diarrhea (any 27%; severe <1%), and mucositis (any 7%; severe <1%). Other adverse reactions have included ocular/visual disturbances (any 13%; severe 1%), fluid retention (any 10%; severe 0%), hepatic dysfunction (elevations in bilirubin 7%, alkaline phosphatase 36%, AST [SGOT] 39%), renal dysfunction (any 11%; severe 1%), thrombocytopenia (any 2%; severe <1%), hypersensitivity reactions (any 4%; severe 0%), cardiovascular reactions (severe 3%), and injection site reactions (<1%). During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE. To learn more about ABRAXANE, visit our Web site at www.abraxane.com Please see the Brief Summary of the ABRAXANE full prescribing information (including boxed WARNING) on the next page. *Cremophor EL (polyoxyethylated castor oil) is a registered trademark of BASF Aktiengesellschaft. Reference: 1. ABRAXANE [prescribing information]. Los Angeles, Calif: Abraxis Oncology, a division of Abraxis BioScience, Inc; August 2007. ABRAXANE is a registered trademark of Abraxis BioScience, LLC. Abraxis Oncology速 is a division of Abraxis BioScience, LLC. 息2008 Abraxis BioScience, LLC All Rights Reserved. AO 1127 12/08

Rx Only

Table 1: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule (Continued) Percent of Patients ABRAXANE Paclitaxel Injection 260/30minb 175/3hc,d (n=229) (n=225)

Brief Summary of Full Prescribing Information. WARNING ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. INDICATION: ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. CONTRAINDICATIONS: ABRAXANE should not be used in patients who have baseline neutrophil counts of <1,500 cells/mm3. WARNINGS: Bone marrow suppression (primarily neutropenia) is dose dependent and a dose limiting toxicity. ABRAXANE should not be administered to patients with baseline neutrophil counts of <1,500 cells/mm3. Frequent monitoring of blood counts should be instituted during ABRAXANE treatment. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. The use of ABRAXANE has not been studied in patients with hepatic or renal dysfunction. In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL. Pregnancy – Teratogenic Effects: Pregnancy Category D ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryo- and fetotoxicity, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women using ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ABRAXANE. Use in Males Men should be advised to not father a child while receiving treatment with ABRAXANE (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility for discussion of effects of ABRAXANE exposure on male fertility and embryonic viability). Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. PRECAUTIONS: Drug Interactions No drug interaction studies have been conducted with ABRAXANE. The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE (paclitaxel protein-bound particles for injectable suspension) concomitantly with known substrates or inhibitors of CYP2C8 and CYP3A4 (see CLINICAL PHARMACOLOGY). Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors (such as ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials. Hematology ABRAXANE therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses of therapy is recommended (see DOSAGE AND ADMINISTRATION). Nervous System Sensory neuropathy occurs frequently with ABRAXANE. The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose modification. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE (see DOSAGE AND ADMINISTRATION). Injection Site Reaction Injection site reactions occur infrequently with ABRAXANE and were mild in the randomized clinical trial. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of ABRAXANE has not been studied. Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). ABRAXANE was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay. Administration of paclitaxel protein-bound particles to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a mg/m2 basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females. A low incidence of skeletal and soft tissue fetal anomalies was also observed at doses of 3 and 12 mg/m2/week in this study (approximately 1% to 5% of the daily maximum recommended human exposure on a mg/m2 basis). Testicular atrophy/degeneration has also been observed in single-dose toxicology studies in rodents administered paclitaxel protein-bound particles at 54 mg/m2 and dogs administered 175 mg/m2 (see WARNINGS). Pregnancy – Teratogenic Effects: Pregnancy Category D (See WARNINGS section). Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Following intravenous administration of carbon-14 labeled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving ABRAXANE therapy. Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated. Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE, 11% were at least 65 years of age and <2% were 75 years or older. No toxicities occurred notably more frequently among elderly patients who received ABRAXANE. ADVERSE REACTIONS: The following table shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer. Table 1: Frequency a of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 175/3hc,d 260/30minb (n=225) (n=229) Bone Marrow Neutropenia < 2.0 x 109/L < 0.5 x 109/L Thrombocytopenia < 100 x 109/L < 50 x 109/L Anemia < 11 g/dL < 8 g/dL Infections Febrile Neutropenia Bleeding

80 9

82 22

2 <1

3 <1

33 1 24 2 2

25 <1 20 1 2 (Continued)

Hypersensitivity Reactione All 4 12 Severef 0 2 Cardiovascular Vital Sign Changesg Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsf 3 4 Abnormal ECG All patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsf 10 2 Myalgia/Arthralgia Any Symptoms 44 49 8 4 Severe Symptomsf Asthenia Any Symptoms 47 39 Severe Symptomsf 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsf 0 <1 Gastrointestinal Nausea Any symptoms 30 22 Severe symptomsf 3 <1 Vomiting Any symptoms 18 10 4 1 Severe Symptomsf Diarrhea Any Symptoms 27 15 Severe Symptomsf <1 1 Mucositis Any Symptoms 7 6 <1 0 Severe Symptomsf Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade b ABRAXANE dose in mg/m2/duration in minutes c 2 paclitaxel injection dose in mg/m /duration in hours d paclitaxel injection pts received premedication e Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. f Severe events are defined as at least grade 3 toxicity g During study drug dosing. Myelosuppression and sensory neuropathy were dose related. Adverse Event Experiences by Body System Unless otherwise noted, the following discussion refers to the primary safety database of 229 patients with metasttatic breast cancer treated with single-agent ABRAXANE in the randomized controlled trial. The frequency and severity of important adverse events for the study are presented above in tabular form. In some instances, rare severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hematologic Neutropenia, the most important hematologic toxicity, was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. In the randomized metastatic breast cancer study, infectious episodes were reported in 24% of the patients treated with a dose of 260 mg/m2 given as a 30-minute infusion. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications. Febrile neutropenia was reported in 2% of patients in the ABRAXANE arm and 1% of patients in the paclitaxel injection arm. Thrombocytopenia was uncommon. In the randomized metastatic breast cancer study, bleeding episodes were reported in 2% of the patients in each treatment arm. Anemia (Hb <11 g/dL) was observed in 33% of patients treated with ABRAXANE in the randomized trial and was severe (Hb <8 g/dL) in 1% of the cases. Among all patients with normal baseline hemoglobin, 31% became anemic on study and 1% had severe anemia. Hypersensitivity Reactions (HSRs) In the randomized controlled metastatic breast cancer study, Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients in the randomized metastatic breast cancer trial. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial. These events included chest pain, cardiac arrest, supraventricular tachycardia, edema,thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported rarely. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients in the metastatic breast cancer randomized trial. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Reports of dyspnea (12%) and cough (6%) were reported after treatment with ABRAXANE in the randomized trial. Rare reports (<1%) of pneumothorax were reported after treatment with ABRAXANE. Rare reports of interstitial pneumonia, lung fibrosis, and pulmonary embolism have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of radiation pneumonitis have been received in paclitaxel injection patients receiving concurrent radiotherapy. There is no experience with the use of ABRAXANE with concurrent radiotherapy. Neurologic The frequency and severity of neurologic manifestations were influenced by prior and/or concomitant therapy with neurotoxic agents. In general, the frequency and severity of neurologic manifestations were dose-dependent in patients receiving single-agent ABRAXANE. In the randomized trial, sensory neuropathy was observed in 71% of patients (10% severe) in the ABRAXANE arm and in 56% of patients (2% severe) in the paclitaxel injection arm. The frequency of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients in the randomized trial. In the randomized comparative study, 24 patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No incidences of grade 4 sensory neuropathies were reported in the clinical trial. Only one incident of motor neuropathy (grade 2) was observed in either arm of the controlled trial. Reports of autonomic neuropathy resulting in paralytic ileus have been received as part of the continuing surveillance of paclitaxel injection safety. Cranial nerve palsies have been reported during postmarketing surveillance of ABRAXANE. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established. Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE in single arm and randomized trials and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients in a single arm study who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. However, rare reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection have suggested persistent optic nerve damage. Arthralgia/Myalgia Forty-four percent of patients treated in the randomized trial experienced arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days. Hepatic Among patients with normal baseline liver function treated with ABRAXANE in the randomized trial, 7%, 36%, and 39% had elevations in bilirubin, alkaline phosphatase, and AST (SGOT), respectively. Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial.

Rare reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Gastrointestinal (GI) Nausea/vomiting, diarrhea, and mucositis were reported by 33%, 27%, and 7% of ABRAXANE treated patients in the randomized trial. Rare reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, were observed in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction Injection site reactions have occurred infrequently with ABRAXANE and were mild in the randomized clinical trial. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported rarely. Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Asthenia Asthenia was reported in 47% of patients (8% severe) treated with ABRAXANE in the randomized trial. Asthenia included reports of asthenia, fatigue, weakness, lethargy and malaise. Other Clinical Events Rare cases of cardiac ischemia/infarction and thrombosis/embolism possibly related to ABRAXANE treatment have been reported. Alopecia was observed in almost all of the patients. Nail changes (changes in pigmentation or discoloration of nail bed) were uncommon. Edema (fluid retention) was infrequent (10% of randomized trial patients); no patients had severe edema. The following rare adverse events have been reported as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment: skin abnormalities related to radiation recall as well as reports of Stevens-Johnson syndrome, toxic epidermal necrolysis, conjunctivitis, and increased lacrimation. As part of the continuing surveillance of ABRAXANE, skin reactions including generalized or maculo-papular rash, erythema, and pruritis have been observed. Additionally, there have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysaesthesiae. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established. Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. OVERDOSAGE: There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. DOSAGE AND ADMINISTRATION: After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. Hepatic Impairment The appropriate dose of ABRAXANE for patients with bilirubin greater than 1.5 mg/dL is not known. Dose Reduction Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For grade 3 sensory neuropathy hold treatment until resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE. Preparation and Administration Precautions ABRAXANE is a cytotoxic anticancer drug and, as with other potentially toxic paclitaxel compounds, caution should be exercised in handling ABRAXANE. The use of gloves is recommended. If ABRAXANE (lyophilized cake or reconstituted suspension) contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure to paclitaxel, events may include tingling, burning and redness. If ABRAXANE contacts mucous membranes, the membranes should be flushed thoroughly with water. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Limiting the infusion of ABRAXANE to 30 minutes, as directed, reduces the likelihood of infusion-related reactions (see PRECAUTIONS: Injection Site Reaction). No premedication to prevent hypersensitivity reactions is required prior to administration of ABRAXANE. Preparation for Intravenous Administration ABRAXANE is supplied as a sterile lyophilized powder for reconstitution before use. AVOID ERRORS, READ ENTIRE PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION. Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel. 1. Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP. 2. Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over minimum of 1 minute, using the sterile syringe to direct the solution flow onto the INSIDE WALL OF THE VIAL. 3. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized cake as this will result in foaming. 4. Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of the lyophilized cake/powder. 5. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any cake/powder occurs. Avoid generation of foam. 6. If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides. Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient: Dosing volume (mL) = Total dose (mg)/5 (mg/mL). The reconstituted suspension should be milky and homogenous without visible particulates. If particulates or settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. Discard any unused portion. Inject the appropriate amount of reconstituted ABRAXANE into an empty, sterile IV bag (plasticized polyvinyl chloride (PVC) containers, PVC or non PVC type IV bag). The use of specialized DEHP-free solution containers or administration sets is not necessary to prepare or administer ABRAXANE infusions. The use of an in-line filter is not recommended. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Stability Unopened vials of ABRAXANE are stable until the date indicated on the package when stored between 20°C to 25°C (68°F to 77°F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Stability of Reconstituted Suspension in the Vial Reconstituted ABRAXANE should be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) for a maximum of 8 hours if necessary. If not used immediately, each vial of reconstituted suspension should be replaced in the original carton to protect it from bright light. Discard any unused portion. Stability of Reconstituted Suspension in the Infusion Bag The suspension for infusion prepared as recommended in an infusion bag should be used immediately, but may be stored at ambient temperature (approximately 25°C) and lighting conditions for up to 8 hours. HOW SUPPLIED: Product NDC No. No. 103450 68817-134-50 100 mg of paclitaxel in a single use vial, individually packaged in a carton. Storage Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from bright light. Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. U.S. Patent Numbers: 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868; 6,753,006 REFERENCES: 1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Publication No. 83-2621. For sale by the Superintendent of Documents, US Government NIH Printing Office, Washington, DC 20402. 2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA, 1985; 253(11):1590-1592. 3. National Study Commission on Cytotoxic Exposure Recommendations for Handling Cytotoxic Agents. Available from Louis R Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences. 179 Longwood Avenue, Boston, Massachusetts 02115. 4. Clinical Oncology Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia, 1983; 1:426-428. 5. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians, 1983; (Sept/Oct) 258-263. 6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm, 1990; 47:1033-1049. 7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE GUIDELINES.) Am J Health-Syst Pharm, 1996; 53:1669-1686. 8. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41.

Figureâ&#x20AC;&#x201D;Treatment Algorithm for Patients with MDS MDS indicates myelodysplastic syndromes; HLA, human leukocyte antigen; ECOG, Eastern Cooperative Oncology Group; IPSS, International Prognostic Staging System; PRBCs, packed red blood cells. Sources: References 10 and 11.

recently been approved for use in the setting of monotherapy. In addition, definitions of response, desired primary end points (survival vs response), and

evolving recommendations for risk-adapted treatment selection based on prognostics and individual patient profiles have increased the complexity of clinical trials

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Table 4. FDA-Approved Agents for the Treatment of MDS Agent/Class approval date

FDA-approved indication(s)

Lenalidomide (Revlimid) Immunomodulatory and antiangiogenic Approved 2005

Transfusion-dependent low-Int-1 MDS with del 5q with or without additional cytogenetic abnormalities

Azacitidine (5-azacitidine, Vidaza) Demethylating agent Approved 2004

• Previously treated or untreated, de novo, and secondary MDS of all FAB subtypes • Documented improvement in OS for Int-2 or high-risk MDS

Decitabine (Dacogen) Demethylating agent Approved 2005

Previously treated or untreated, de novo, and secondary MDS of all FAB subtypes; Int-1, Int-2, and high-risk IPSS groups

Dosing

Patient management

10 mg/day continuous or D1-21 q 28 days

Myelosuppression -Generally resolved with drug holiday and dose modification -Specific dose-modification parameters in package insert -Transfuse red blood cells or platelets if indicated -Refer to NCCN guidelines for neutropenia, thrombocytopenia, and anemia Pruritus (grade 1) -Generally self-limiting Safety program for potential teratogenicity-Revasist Diarrhea (grade 1) -May require intermittent use of antidiarrheal agent Myelosuppression • 75 mg/m2/day sq D1-7 q 28 days -Patient education on infection and bleeding for a minimum of prevention and reportable signs and symptoms 4 cycles Injection site erythema • Continue until -Rotate injection sites, apply ice as needed for disease comfort, use fresh needle without priming before progression injection, avoid hot compresses • Alternative Nausea and vomiting dosing regimens -Premedicate with antiemetics in recent trials Transient elevation of transaminases Low-grade fevers Contraindicated in patients with sensitivity to mannitol or with extensive hepatic disease Myelosuppression-neutropenia, • 15 mg/m2/day IV over 3 hours q thrombocytopenia, leukopenia 8 hours days -Patient education on infection 1-3 q 6 weeks and bleeding prevention and • Alternate dosing reportable signs and symptoms regimens in Nausea and vomiting recent trials -Premedicate with antiemetics Transient elevation of transaminases Infections

FDA indicates US Food and Drug Administration; MDS, myelodysplastic syndromes; NCCN, National Comprehensive Cancer Network; FAB, FrenchAmerican-British; OS, overall survival; IV, intravenous; IPSS, International Prognostic Staging System. Adapted with permission from Reference 10.

interpretation and patient care. Drug-specific information, clinical management strategies, key supportive care issues, and management considerations are summarized in Table 4. Supportive care has been the mainstay of treatment

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for MDS over the past 20 years (Table 5). Until recently, no active therapies were available. Supportive care continues to be important in treatment of symptoms associated with the disease or toxicities of newly developed active therapies. Supportive care includes observa-

Table 5. Supportive Care Measures for MDS Clinical findings

Signs and symptoms

Management considerations

Anemia

Fatigue, dyspnea, dizziness,

Transfusion management -Patients with underlying cardiac disease are at increased risk for CHF exacerbation and may require diuresis with transfusions -Benefits are temporary and rarely restore Hct to normal -Transfusions should be based on symptoms not general Hgb or Hct parameters Monitoring for iron overload in transfusion-dependent patients and need for iron chelation therapy (initiate at ferritin >1000) Administration of erythropoietin agents for patients with serum epopoietin level <500 or who require >4 units of PRBCs every 8 weeks -Careful monitoring for safety in administration of erythropoietin agents in patients at risk for thrombotic events Initiate active therapies for transfusion-dependent patients with serum epopoietin level >500 or PRBCs >2 units/4 weeks Assist the patient in maintaining a flowsheet for laboratory results and transfusion dates, blood type, and any antibodies Early recognition of infections -Patient education on infection precautions and reportable signs and symptoms -Patients receiving active therapies may require drug holiday and dose adjustment -Monitoring of CBC, differential and platelet count weekly for the first 8 weeks is recommended Administration of recombinant granulocytic growth factors -Should not be administered on the same day as hypomethylating agents Antimicrobial therapy for active infections; prophylactic antibiotics are not generally recommended to avoid resistance

tachycardia, palpitations

Neutropenia

Fever, cough, dysuria, abdominal pain, or diarrhea

tion, quality-of-life assessment, growth factors, antibiotics, iron chelation therapies, and transfusion support. However, it is important to recognize that supportive care alone does not change the underlying disease. In addition, all forms of supportive care may have adverse effects, and these should be monitored carefully during treatment. Differentiating the cause of adverse events will be critical to making the most effective modification to treatment without compromising therapeutic benefit. Three agents have been approved by the FDA since May 2004 for the active treatment of MDS: azacitidine (Vidaza; approved May 2004) and decitabine (Dacogen; approved May 2006), which are both DNA methylation inhibitors, and lenalidomide (Revlimid; approved

December 2005), an oral agent that has several mechanisms of action and is considered an immunomodulatory agent (Table 4). Other agents that have been used

Differentiating the cause of adverse events will be critical to making the most effective modification to treatment without compromising therapeutic benefit. clinically in the treatment of MDS include thalidomide (Thalomid), arsenic trioxide (Trisenox), and antithymocyte globulin. Each agent has been shown to have some

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Table 5. Supportive Care Measures for MDS (cont.) Clinical findings

Signs and symptoms

Management considerations

Thrombocytopenia

Petechiae, ecchymosis,

Platelet transfusions based on risk of bleeding (platelets <10,000 or active bleeding) Careful monitoring of concomitant medications with antiplatelet effect Patient education on bleeding precautions, emergency management, and reportable signs and symptoms Aminocaproic acid may be used in transfusion-refractory patients Thrombopoiesis-stimulating proteins currently in clinical trials Patients receiving active therapies may require drug holiday and dose adjustment Institute iron chelation therapy for serum ferritin >1000 -Selected patients responding to active therapies may benefit from phlebotomy Safety monitoring for iron chelation therapy: renal toxicity: increase in serum creatinine, rare cases of acute renal failure reported, intermittent proteinuria -Baseline and regular monitoring of renal function Hepatotoxicity: elevated transaminase levels -Baseline and regular monitoring of hepatic function Pancytopenia: neutropenia agranulocytosis, thrombocytopenia reported in patients with MDS -Baseline and regular monitoring of CBC, differential, and platelet count Auditory: high-frequency hearing loss, decreased hearing -Baseline and yearly audiology evaluation Ocular: cataracts, lens opacities, increased pressure, retinal disorders -Baseline and yearly slit-eye and fundoscopic examination

epistaxis, hemoptysis, hematuria

Iron chelation for hemosiderosis (iron overload)

Elevated hepatic enzymes, fatigue, confusion, CHF, vague abdominal bloating and pain, MRI findings of iron overload of the liver

MDS indicates myelodysplastic syndromes; CHF, congestive heart failure; Hgb, hemoglobin; Hct, hematocrit; PRBCs, packed red blood cells; CBC, complete blood count; MRI, magnetic resonance imaging. Reprinted with permission from Kurtin SE. Myelodysplastic syndromes: diagnosis, treatment planning, and clinical management. Oncology (Williston Park). 2007;21(11 suppl Nurse Ed):41-48.

activity in the reduction of transfusions and changes in cytogenetic findings. Several other agents are being

Complete disease evaluation is necessary to select the best available therapy for the individual patient. studied in ongoing clinical trials or in combination with existing agents. Each agent has specific potential toxicities and nursing implications.

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January/February 2009

Complete disease evaluation is necessary to select the best available therapy for the individual patient (Figure). Patients with low serum erythropoietin levels and low transfusion requirements will benefit from erythropoiesis-stimulating proteins. Lenalidomide is the treatment of choice for patients with del 5q. A small subset of patients who are positive for HLA-DR15 may benefit from administration of antithymocyte globulin. Hypomethylating agents are the treatment of choice for patients with intermediate-2 or high-risk disease or in patients with intermediate-1 risk disease not meet-

ing the previous characteristics. The most common treatment-related toxicity for active therapies for MDS is myelosuppression. Most therapies require a minimum of 3 to 4 months of treatment to fully evaluate efficacy. Therefore, aggressive management of cytopenias is a critical component of effective treatment. Interestingly, in a review of the MDS-003 trial data, Sekeres and colleagues found patients with lower-risk MDS and del 5q cytogenetic abnormality had a higher probability of achieving transfusion independence with lenalidomide if they developed thrombocytopenia while receiving treatment, regardless of baseline platelet count, or developed neutropenia in the absence of baseline neutropenia.16 In addition, analysis of the data from the three lenalidomide trials in MDS suggests that lenalidomide has a different mechanism of action in patients with or without del 5q, a possible direct cytotoxic effect on the malignant clone with del 5q and an effect on the microenvironment in patients without del 5q.16-18 Cytogenetic responses have been shown to correlate with improved survival in patients with chromosome 5q deletion.19 A followup evaluation of six patients participating in the MDS001 trial indicates that the response to lenalidomide is durable with sustained transfusion independence up to 6.5 years and evidence of sustained cytogenetic remissions in some patients.20 More recently, Fenaux and colleagues evaluated 358 patients with intermediate-2 or high-risk MDS.21 The primary end point was overall survival in patients treated with azacitidine 75 mg/m2/day days 1 through 7 every 28 days compared with conventional chemotherapy (ARA-C [Cytarabine]/daunorubicin [Cerubidine] 7+3, or low-dose ARA-C). The patients treated with azacitidine had a significant improvement in overall survival compared with conventional care (P = .0001; hazard ratio, 0.58). The median survival was improved, from approximately 15 months with conventional care to 24.5 months with azacitidine treatment. Approximately 52% of patients treated with azacitidine were alive at 2 years compared with 26% of patients treated with conventional care. Considering the original survival data from the IPSS and WPSS with median survival of 1.2 years for intermediate-2 and 4 months for high-risk disease, this provides hope to patients with this disease. This is the first MDS trial to document a survival advantage for active therapies. Transfusion dependence is common in patients with MDS, and secondary iron overload is associated with several negative effects. Excess iron accumulates in the heart, liver, and adrenal glands. Symptoms are often

vague and may not be evident until the patient has developed serious organ damage. Elevated hepatic enzymes, mild symptoms of congestive heart failure, development of diabetes, or vague abdominal bloating and pain may indicate the need to evaluate the patient with imaging studies. Magnetic resonance imaging of the liver or diagnostic echocardiogram may demonstrate the presence of excess iron in these organs. Patients with MDS should have their baseline serum ferritin level checked and have this repeated periodically. Malcovoti and colleagues found transfusion-dependent MDS patients had significantly shorter survival (P

This is the first MDS trial to document a survival advantage for active therapies. <.001), the primary factor associated with shorter survival being the number of units received per month.22 Cardiac failure occurred in 51% of the patients, infections occurred in 31%, and hemorrhage (8%) and hepatic cirrhosis (8%) were also reported. Transfusion independence, cytogenetic remission, and improvement in quality of life have become the desired end points for clinical trials for MDS. Transfusion independence not only improves the quality of life for MDS patients, but decreases secondary organ effects and decreases the economic and clinical burden. Administration of iron chelation therapy is a key supportive care strategy and requires specific monitoring for safe administration. An evaluation of 170 transfusion-dependent MDS patients at 18 French treatment centers over a 1-month period showed a significant improvement in overall survival in patients who received treatment of iron overload, also known as iron chelation therapy. These results were consistent across all subgroups analyzed, including IPSS risk category, sex, or age. The median survival was 63 months for the entire group; however, among patients who received chelation therapy, the median survival was 115 months compared with 51 months in those patients who did not receive chelation therapy. This difference was highly significant (P <.0001). These findings suggest that chelation therapy may significantly improve survival in lower-risk patients who have a regular need for red blood cell transfusions.23 Phlebotomy, used to treat iron overload in other patients, is generally not an option for the MDS population because of underlying ineffective erythropoiesis.

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Chelation therapy includes two possible FDAapproved agents, deferoxamine (Desferal) and deferasirox (Exjade). Both agents bind iron in circulation and in the tissue, and the iron-bound form can be excreted efficiently in the urine and bile. A serum ferritin level >1000 ng/mL is suggested as the threshold to begin treatment in transfusion-dependent patients. Deferoxamine, for many years the only available agent, can be administered subcutaneously or intravenously. The half-life is approximately 20 minutes, so subcutaneous administration is most effective. It is most often given via an infusion pump over 8 to 12 hours. To avoid visual or auditory loss, no more than 2.5 g of deferoxamine should be used with each infusion.24 Deferasirox, an orally active chelation agent, was recently approved by the FDA. It is dispensed as an effervescent tablet with a half-life of 8 to 16 hours. It is to be taken daily on an empty stomach 30 minutes before a meal.25 Each of these agents is associated with unique potential toxicities that must be monitored closely. Conclusion

Recent scientific advances have offered promising treatment options for patients with MDS. Patient education and support, telephone triage for toxicity management, cytopenia management (including dose modification using established guidelines), and evaluation of reportable signs and symptoms are of particular importance with the newer oral therapies. The toxicities are manageable, but require an understanding of the unique mechanisms of action and associated side effects. Effective management of the treatment- or disease-related toxicities offers hope to patients with an opportunity to continue therapy long enough to achieve the optimal treatment outcome. References 1. Rollison DE, Hayat M, Smith M, et al. First report of national estimates of the incidence of myelodysplastic syndromes and chronic myeloproliferative disorders from the U.S. SEER Program. Abstract presented at the 48th Annual Meeting of the American Society of Hematology; December 9-12, 2006; Orlando, Florida. Abstract 247. 2. National Cancer Institute. Surveillance, epidemiology, and end results (SEER) cancer statistics review, 1975-2004. http://seer.cancer.gov/csr/ 1975_2004. Accessed May 25, 2008.

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3. Mufti G, List AF, Gore SD, et al. Myelodysplastic syndrome. Hematology Am Soc Hematol Educ Program. 2003:176-199. 4. Heptinstall K. Quality of life in myelodysplastic syndromes. A special report from the Myelodysplastic Syndromes Foundation, Inc. Oncology (Williston Park). 2008;22(2 suppl Nurse Ed):13-18. 5. Vardiman JW. Hematopathological concepts and controversies in the diagnosis and classification of myelodysplastic syndromes. Hematology Am Soc Hematol Educ Program. 2006:199-204. 6. Steensma D, Bennett JM. The myelodysplastic syndromes: diagnosis and treatment. Mayo Clin Proc. 2006;81:104-130. 7. Kurtin S. Updates and strategies for the management of MDS, CLL, and MM. Meniscus Educational Institute. August 2008. https://www.meniscus.com/ mds-cll-mm. Accessed September 4, 2008. 8. Corey S, Minden MD, Barber DL, et al. Myelodysplastic syndromes: the complexity of stem-cell diseases. Nat Rev Cancer. 2007;7:118-129. 9. Nimer SD. Myelodysplastic syndromes. Blood. 2008;111:4841-4851. 10. Kurtin SE. Advances in the management of low- to intermediate-risk myelodysplastic syndrome: integrating the National Comprehensive Cancer Network guidelines. Clin J Oncol Nurs. 2006;10:197-208. 11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: myelodysplastic syndromes. V.1.2009. http://www.nccn.org/profes sionals/physician_gls/PDF/mds.pdf. Accessed September 4, 2008. 12. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079-2088. 13. Alessandrino EP, Della Porta MG, Bacigalupo A, et al. WHO classification and WPSS predict posttransplantation outcome in patients with myelodysplastic syndrome: a study of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Blood. 2008;112:895-902. 14. van de Loosdrecht AA, Westers TM, Westra AH, et al. Identification of distinct prognostic subgroups in low- and intermediate-1-risk myelodysplastic syndromes by flow cytometry. Blood. 2008;111:1067-1077. 15. Malcovati L, Germing U, Kuendgen A, et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol. 2007;25:3503-3510. 16. Sekeres MA, Maciejewski JP, Giagounidis A, et al. Cytopenias correlate with response to lenalidomide in del 5q MDS patients. Leuk Res. 2007;31(suppl 1):S37-S38. 17. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456-1465. 18. Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karytoypes other than deletion 5q. Blood. 2008;111:86-93. 19. List AF. New agents in the treatment of MDS. Clin Adv Hematol Oncol. 2005;3:832-834. 20. Kurtin S, List A. Durable long-term responses in patients with MDS treated with lenalidomide. Accepted for publication. Clin Leukemia. September 2008. 21. Fenaux P, Mufti GJ, Santini V, et al. Azacitidine (AZA) treatment prolongs overall survival (OS) in higher-risk MDS patients compared with conventional care regimens (CCR): results of the AZA-001 phase III study. Blood (ASH Annual Meeting Abstracts). 2007;110:A817. 22. Malcovati L, Porta MG, Pascutto C, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol. 2005;23:7594-7603. 23. Rose C, Brechignac S, Vassilief D, et al. Positive impact of iron chelation therapy (CT) on survival in regularly transfused MDS patients: a prospective analysis by the GFM. Abstract presented at the 49th Annual Meeting of the American Society of Hematology; December 8-11, 2007; Atlanta, Georgia. Abstract 249. 24. Desferal [package insert]. East Hanover, NJ: Novartis; 2007. 25. Exjade [package insert]. East Hanover, NJ: Novartis; 2007.

Case Studies Case Study 1

n 83-year-old woman visits her primary care physician (PCP) with complaints of increasing fatigue. Her evaluation includes a complete physical examination, peripheral blood analysis including a complete blood cell count, a complete metabolic panel, and a thyroid panel. Her pertinent medical history includes hypothyroidism and osteoarthritis; both are now controlled with medication. Results of the laboratory evaluation reveal mild anemia (hemoglobin [Hb], 10.3 g/dL) with possible underlying metabolic abnormalities due to an elevated mean corpuscular volume (MCV) of 100 fL (normocytic, normochromic anemia). Further studies obtained by her PCP fail to reveal folate, vitamin B12, or iron deficiencies. Thyroid function is normal, and colonoscopy findings are also normal. The patient is referred to a hematologist for further evaluation. The hematologist repeats the hematologic analysis, with thyroid, serum erythropoietin, and hemolysis parameters. A review of the peripheral smear reveals mild dysplastic changes in the red blood cells (RBC). A bone marrow biopsy confirms mild dysplasia limited to the erythroid lineage, with 40% cellularity, 4.6% blasts, and 27% ringed sideroblasts. Cytogenetic evaluation reveals a normal female karyotype 46,XX[20]. Baseline hematologic parameters include white blood cell count (WBC), 3500/µL; absolute neutrophil count (ANC) 1050/mm3; Hb, 10.8 g/dL; and platelets, 318 x 109/L. Myelodysplastic syndrome (MDS) refractory anemia with ringed sideroblasts is diagnosed. The International Prognostic Scoring System (IPSS) score is 0.5, indicating low-risk disease. Baseline serum erythropoietin level is 27 mU/mL. The patient is started on erythropoietin, given weekly with concurrent administration of weekly filgrastim (Neupogen). She continues this treatment for 3 years with normalization of her Hb and neutropenia. She then develops progressive anemia, requiring intermittent transfusion; progressive neutropenia; and mild thrombocytopenia. A repeat bone marrow analysis shows trilineage dysplasia, increasing ringed sideroblasts of 49%, <1% myeloblasts, 80% cellularity, and a normal female karyotype. Given the progressive cytopenias (WBC, 2.8/µL; ANC,

1000/mm3; platelets, 102 x 109/L; Hb, 7.7 g/dL), transfusion dependence, and evidence of trilineage dysplasia, the patient is started on azacitidine (Vidaza), 75 mg/m2/day administered subcutaneously on days 1 to 7 every 28 days. She develops progressive but asymptomatic neutropenia (ANC, 600/mm3), which responds well to filgrastim administration, and also progressive thrombocytopenia after her initial cycle of therapy (platelets, 56 3 109/L), which did not require intervention. She was premedicated with a 5-hydroxytryptomine-3 (5HT3) antagonist with effective prevention of nausea or vomiting. No local injection site reactions were noted. Careful monitoring of blood counts and supportive care with growth factors allowed continued administration of azacitidine on a regular schedule. There has been improvement in all cell lines with normalization of the ANC (>1500/mm3), platelets of 156 3 109/L, and transfusion independence after 4 months of therapy. The patient continues on monthly azacitidine.

Case Study 2

he patient is a 78-year-old man who was originally diagnosed with MDS at age 69 due to progressive lethargy and malaise. An evaluation by his PCP reveals anemia and iron deficiency. The patient receives a trial of iron and erythropoietin with no substantial improvement. His anemia progresses and he requires his first RBC transfusion in September 2001. He is referred to a hematologist at a regional comprehensive cancer center and undergoes a bone marrow biopsy and aspirate that reveals MDS, refractory anemia with the 5q deletion abnormality, IPSS intermediate score of 1. His enrollment in a clinical trial does not improve his transfusion requirements and causes severe joint pain. A second clinical trial becomes available in early 2002, and on April 2, 2002, the patient begins treatment with CC5013 (lenalidomide), an oral immunomodulatory agent. Before starting this trial, he had received a total of 12 units of packed RBCs and had a WBC of 2700/µL (ANC, 1758/ mm3), and platelets of 197 3 109/L. The initial dose on the trial was 25 mg given once daily. Weekly blood counts are obtained, and within 3 weeks, he develops significant cytopenias (WBCs, 1000/µL; ANC, 140/mm3; platelets, 38 x 109/L; and Hb,

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Case Studies 8.5 g/dL). The drug is held and he receives a packed RBC transfusion on April 22, 2002. He remains afebrile and shows no evidence of bleeding. The cytopenias resolve without further intervention within 2 weeks of holding the drug. More importantly, during the drug holiday, the Hb rose independent of transfusion by 1 g. Within 4 weeks of holding the drug, the blood counts showed further hematologic improvement and a continued Hb response (WBC, 2600/ÂľL; ANC, 1300/mm3; Hb, 10.3; platelets, 58 x 109/L). Treatment resumes at a dose of 10 mg daily using a schedule of 3 weeks on and 1 week off (21 of 28 days) but further dose reduction to

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January/February 2009

5 mg daily 21 of 28 days is required. The patient has remained on this dose and has been transfusion-independent for 6.5 years with an excellent quality of life. He has received 3 injections of pegfilgrastim (Neulasta) for an ANC <500/mm3 in the presence of concurrent sinusitis. He continues to have moderate but asymptomatic thrombocytopenia that has not required intervention. A repeat bone marrow biopsy, aspirate, and cytogenetics 3 months after initiating therapy show no evidence of the 5q deletion abnormality, indicating some effect on the underlying disease. He did experience mild pruritus, but no other nonhematologic toxicities.

Gelclair ® can bring a smile to the face of patients with oral mucositis

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GELCLAIR ® provides soothing, long-lasting pain relief1 at the first sign of oral mucositis. Contains no alcohol and no lidocaine, so patients won’t experience drying, stinging or numbing.

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Prescribe 6 boxes of GELCLAIR® for a 30 day supply GELCLAIR® is available at your local pharmacy and at:

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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.

GEL070

NCCN Guidelines on Management of Multiple Myeloma: Transplant-eligible and Transplant-ineligible Patients Beth Faiman, RN, MSN, CNP, AOCN

atients with multiple myeloma (MM) are faced with an intriguing dilemma at diagnosis and often throughout their illness. While today we are plagued with the quandary of too many treatment options, this was not always the case. Historically, many therapeutic agents have been used in an attempt to improve responses to therapy, but they were unable to do so or to have a significant impact on overall survival. In 1962, Bergsagel and colleagues reported that oral melphalan was an effective therapy for patients with MM.1

Drugs such as thalidomide, bortezomib, pegylated liposomal doxorubicin, and lenalidomide, alone or in combination with dexamethasone, have helped to improve the prognosis for patients with MM. Unfortunately, not all individuals with MM responded to this therapy, and many experienced relapsed disease, for which there were few other options. The 1990s, however, began an exciting era of drug discovery with the advent of newer drugs that provided a novel approach to treatment. Drugs such as thalidomide, bortezomib, pegylated liposomal doxorubicin, and lenalidomide, alone or in combination with dexamethasone, have helped to improve the prognosis for patients with MM within the past decade.2

Ms Faiman is a Nurse Practitioner, Cleveland Clinic Taussig Cancer Institute,Cleveland, OH.

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What Is Best for My Patient? With all the available drugs and combinations, how does a patient determine the best therapy for himself or herself? The physician will, of course, recommend what he or she thinks will be the most effective treatment for the patient, but it is ultimately the patientâ&#x20AC;&#x2122;s decision as to what treatment he or she will undergo. Considerations at diagnosis and throughout the disease are based on many factors, including how aggressive patients want to be in the management of their illness, and whether quality or quantity of life is their greatest concern because of age and other factors. Is the goal to cure the disease at all cost, or is it simply care of the disease? How much will be required of the patient to be compliant and adherent to the regimen? Moreover, how can the nurse support the patient in the decision-making process? This is where recognized guidelines come into practice. Many established hospital systems have their own protocols and approved methods of treating patients with MM. These are based consensus of a committee of experts in the field and existing clinical trial data to support the recommendations. The National Comprehensive Cancer Network (NCCN) has developed treatment and supportive care guidelines in many areas of oncology, including MM.3 These are routinely updated, and the most up-to-date version of these practice guidelines can be found at www.nccn.org. Although clinical trials are recommended for all patients in all phases of therapy, this is not always an option, or trials may be deferred for reasons of patient preference. Here, we will review the NCCNâ&#x20AC;&#x2122;s practice guidelines with regard to newly diagnosed and relapsed MM. Options for Newly Diagnosed MM: Transplant Eligible Bortezomib is a proteasome inhibitor that has been proved to be effective in patients with relapsed MM and

Table 1. NCCN Recommendations for Primary Induction Therapy for Transplant Candidates • Bortezomib/dexamethasone (category 2B)* • Bortezomib/doxorubicin/dexamethasone (category 2B)* • Bortezomib/lenalidomide/dexamethasone (category 2B)* • Bortezomib/thalidomide/dexamethasone (category 2B)* • Dexamethasone • Lenalidomide/dexamethasone (category 2B)* • Liposomal doxorubicin/vincristine/ dexamethasone • Thalidomide/dexamethasone Treatments are listed alphabetically and are not preferential. *Category 2B is based on a lower level of evidence to support. There is no clear consensus, but no major disagreement. NCCN indicates National Comprehensive Cancer Network. Source: Reference 3.

those refractory to therapy. According to the NCCN guidelines, bortezomib-containing regimens are indicated in patients with newly diagnosed MM who are eligible for transplant (Table 1). There is a preponderance of phase 2 and emerging phase 3 clinical trial data suggesting that bortezomib given in combination with dexamethasone, doxorubicin, or thalidomide is an effective upfront regimen. One of the many benefits of bortezomib is its safety in patients with renal failure or renal insufficiency. Since in the United States the median age of patients at the time of diagnosis of MM is 62 years at least 25% to 50% of patients will present with renal insufficiency or renal failure at diagnosis or during the course of the disease. This, in turn, may negatively effect survival if it is not reversed.4 In clinical trials, bortezomib has been given to patients with severe renal impairment and, in some cases, has been effective in achieving renal recovery and improvement in kidney function.5 Therefore, the NCCN guidelines suggest that bortezomib be considered front-line therapy for MM. Dexamethasone, thalidomide, and liposomal doxorubicin are not heavily excreted by the kidney and are also safe in patients with renal dysfunction, even in those with high-risk MM. The combination of lenalidomide and low-dose dexamethasone (Rd) is another option for patients with

Table 2. NCCN Recommendations for Primary Induction Therapy for Nontransplant Candidates • Bortezomib/dexamethasone (category 2B)* • Bortezomib/doxorubicin/dexamethasone (category 2B)* • Bortezomib/lenalidomide/dexamethasone (category 2B)* • Bortezomib/thalidomide/dexamethasone (category 2B)* • Dexamethasone • Lenalidomide/Low-dose dexamethasone (category 2B)* • Liposomal doxorubicin/vincristine/ dexamethasone • Thalidomide/low-dose dexamethasone Treatments are listed alphabetically and are not preferential. *Category 2B is based on a lower level of evidence to support. There is no clear consensus, but no major disagreement. NCCN indicates National Comprehensive Cancer Network. Source: Reference 3.

newly diagnosed MM, as demonstrated in an Eastern Cooperative Oncology Group (ECOG) trial, and is also included in the NCCN guidelines.6 An oral regimen, lenalidomide/dexamethasone is attractive for patients because of the ease of administration. Other combinations, such as vincristine, doxorubicin, and dexamethasone (VAD) and thalidomide and dexamethasone (TD), as well as single-agent steroids, may also be considered. TD is approved by the US Food and Drug Administration (FDA) for newly diagnosed MM, but as with many regimens, time to progression can be as short as 2 years before another therapy must be considered. Options for Newly Diagnosed MM: Transplant Ineligible Melphalan and prednisone (MP) has long been considered the standard of care in patients with newly diagnosed MM. However, this regimen fails to achieve durable responses, and patients often relapse within a year. A phase 3 randomized, controlled trial comparing melphalan/prednisone/bortezomib (MPB) with MP alone has shown promising results.7 This trial included 682 patients older than 65 years of age (median age, 71 years) who had newly diagnosed MM and were ineligible for stem cell transplantation. The overall response rate was 71% in

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patients who received MPB compared with 35% in patients receiving MP alone. The MPB regimen is one of the options for nontransplant candidates in the NCCN guidelines (Table 2). Lenalidomide and low-dose dexamethasone is also a good option for transplant-ineligible patients with MM. Several clinical trials have suggested that elderly patients do not benefit from high doses of steroids.8 However, in the same ECOG trial in patients with newly diagnosed MM that was discussed above, patients older than 65 years of age seemed to benefit, with improved 1-year and 2-year survival rates compared with patients who received highdose dexamethasone. This may be due, in part, to the reduced cumulative amount of dexamethasone and the weekly dosing schedule. Other agents included in the NCCN guidelines for transplant-ineligible patients include TD, VAD, and melphalan/prednisone/thalidomide, and may be considered. However, in view of the established efficacy and safety of MPB and lenalidomide/dexamethasone regimens in recent trials, these two combinations are regarded by many centers as the new standard of care for patients with newly diagnosed MM. Options for Relapsed Disease In addition to the combinations mentioned above, the combination of bortezomib and doxorubicin has been approved by the FDA for the treatment of relapsed MM. This steroid-free regimen has demonstrated efficacy in phase 3 trials in patients with relapsed MM, time to disease progression being 9.3 months versus 6 months with bortezomib alone. In addition, the overall response rate of 52% makes this combination a good option for previously treated MM in either the transplant-eligible or ineligible setting.9 Conclusions With myriad options available to our patients with MM, it is essential for all healthcare providers to be aware

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January/February 2009

of the guidelines for treatment at the time of diagnosis and throughout the course of the disease. It is important to remember that each available regimen provides our patients the opportunity to participate in decision making at some point in the course of their disease. By combining immunomodulatory drugs with bortezomib, we can expect a different and hopefully a bettertolerated side effect profile and improved survival compared with previous decades. The next few years will continue to be an exciting time for those involved in the treatment of MM, given the many new drugs and combinations currently being tested. These new developments provide hope for our patients and the those who care for them. References 1. Bergsagel DE, Sprague CC, Austin C, et al. Evaluation of new chemotherapeutic agents in the treatment of multiple myeloma: IV. LPhenylalanine mustard (NSC-8806). Cancer Chemother Rep. 1962;21:87-99. 2. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520. 3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. V2.2009. September 11, 2008. www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf. Accessed November 5, 2008. 4. BladĂŠ J, FernĂĄndez-Llama P, Bosch F, et al. Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern Med. 1998;158:1889-1893. 5. Chanan-Khan AA, Kaufman JL, Mehta J, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood. 2007;15:2604-2606. 6. Rajkumar SV, Jacobus S, Callander N, et al. Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2007;25(18S):LBA8025. 7. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917. 8. Facon T, Mary JY, Pegourie B, et al. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood. 2006;107:1292-1298. 9. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25:3892-3901.

Presents The First Annual 2008 Curriculum for

CONSIDERATIONS IN MULTIPLE MYELOMA A Newsletter Series for Cancer Care Professionals Center of Excellence Media, along with Editor-in-Chief Sagar Lonial, MD, of Emory University, will proudly offer the multidisciplinary cancer team at your center a series of newsletters focusing on the challenges in treating patients with multiple myeloma.

SAGAR LONIAL, MD Associate Professor of Hematology and Oncology Emory University

H Earn Continuing Education Credits H

onal i t i d 8 Ad sletters 9 New g in 200 in Com

Clinical Topics: • Renal Dysfunction • Hard-to-Treat Patients • Treatment-Naive Patients • Health Economics • Side Effect Management

Each newsletter will feature: • Contributions from thought-leading physicians, pharmacists, and nurses • Continuing Education credits available to physicians, pharmacists, and nurses

To request free copies 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. 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.

Supported by an educational grant from Millennium Pharmaceuticals, Inc.

Pharmacists CME Consultants is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity has been designated for 1 contact hour (0.100 CEU). In order to receive credit, all participants must complete an evaluation, request for credit form, and a posttest. Statements of Credit will be mailed to participants within six weeks. ACPE #309-999-08-012-H01-P Initial Release Date: 05/07/08. Planned Expiration Date: 05/07/09. Nurses CME Consultants is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. CME Consultants designates this program for 1 contact hour. Participants should claim only those contact hours actually spent in the educational activity. In order to receive credit for this program, each participant must complete the evaluation form, posttest, and certificate request form. Certificates will be mailed to program participants in approximately four to six weeks after receipt of the completed evaluation form, posttest, and certificate request form.

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Hematology/Oncology: Medications, Indications, and ICD-9 Codes Indication Index Indications/Medications

ICD-9 Code

Acute lymphocytic leukemia 204.0_ Asparaginase (Elspar, Kidrolase), clofarabine (pediatric; Clolar), cyclophosphamide (Cytoxan, Neosar), cytarabine (Cytisar-U), daunorubicin (Cerubidine), dexamethasone, doxorubicin (Adriamycin, RUBEX), etoposide (Toposar, VePesid), idarubicin (Idamycin), ifosfamide (Ifex), imatimib mesylate (Gleevec), mercaptopurine (Purinethol, 6-MP), methotrexate (Folex, Mexate), mitoxantrone (Novantrone),1 nelarabine (Arranon), pegaspargase (Oncaspar), pentostatin (Nipent),2 prednisone (Deltasone), teniposide (Vumon), thioguanine, vincristine (Oncovin, Vincasar) 205.0_ Acute nonlymphocytic leukemia (erythroleukemia, meningeal, monocytic, myelocytic, myelomonocytic, promyelocytic) Asparaginase (Elspar, Kidrolase),2 azacitidine (AML, multilineage dysplasia; elderly who are not candidates for standard induction therapy; Vidaza),2 busulfan (Myleran), cyclophosphamide (Cytoxan, Neosar), cytarabine (Cytisar-U), daunorubicin (Cerubidine), doxorubicin (Adriamycin, RUBEX), etoposide (Toposar, VePesid), fludarabine phosphate (Fludara),2,3 gemtuzumab (Mylotarg), idarubicin (Idamycin), mercaptopurine (Purinethol, 6MP), methotrexate (Folex, Mexate), mitoxantrone (Novantrone), thioguanine, tretinoin (Vesanoid), vincristine (Oncovin, Vincasar)2,3

Acute prolymphocytic leukemia Pentostatin (Nipent)

204.1_ Chronic lymphocytic leukemia Alemtuzumab (Campath), chlorambucil (Leukeran), cladribine (Leustatin),1 cyclophosphamide (Cytoxan, Neosar), dasatinib (Sprycel), dexamethasone, doxorubicin (Adriamycin, RUBEX), fludarabine phosphate (Fludara), mechlorethamine (Mustargen), pentostatin (Nipent), prednisone (Deltasone), rituximab (Rituxan), sodium phosphate P32,1 uracil mustard, vincristine (Oncovin, Vincasar)

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ICD-9 Code

Chronic myelocytic leukemia 205.1_ Aldesleukin (Proleukin),1 busulfan (Myleran), cyclophosphamide (Cytoxan, Neosar), cytarabine (Cytosar-U), dasatinib (Sprycel), daunorubicin (Cerubidine), dexamethasone,2 etoposide (Toposar, VePesid),2 hydroxyurea (Hydrea), imatinib mesylate (Gleevec), interferon alpha2a (Roferon A), interferon alpha-2b (Intron A, Rebetron), mechlorethamine (Mustargen), melphalan (Alkeren), mercaptopurine (Purinethol, 6-MP), mitomycin (Mutamycin),1 nilotinib (Tasigna), prednisone (Deltasone),2 sodium phosphate P32,1 thioguanine, topotecan (Hycamtin),1 uracil mustard, vincristine (Oncovin, Vincasar)1 Chronic myelomonocytic leukemia 205.10 Daunorubicin (Cerubidine), mitomycin (Mutamycin), topotecan (Hycamtin)1 Cutaneous T-cell lymphoma

202.1_, 202.2_, 202.8_

Bexarotene (Targretin), carmustine (BICNU),2 chlorambucil (Leukeran),1 cladribine (Leustatin),2 denileukin diftitox (ONTAK), etoposide (Toposar, VePesid), fludarabine phosphate,2 interferon alpha-2a (Roferon A), interferon alpha-2b (Intron A, Rebetron), mechlorexthamine (Mustargen), methotrexate (Folex, Mexate),2 pentostatin (Nipent), vinblastine (Velban), vincristine (Oncovin, Vincasar),1 vorinostat (Zolinza)

204.9_

285.9, V58.114 Chronic anemia Darbepoetin alfa (Aranesp), epoetin alfa (Procrit, Epogen)

Indications/Medications

202.4_ Hairy-cell leukemia Chlorambucil (Leukeran), cladribine (Leustatin), fludarabine phosphate (Fludara),2 interferon alpha-2a (Roferon A), interferon alpha-2b (Intron A, Rebetron), pentostatin (Nipent), rituximab (Rituxan)2

Hodgkinâ&#x20AC;&#x2122;s lymphoma 201._ _ Amifostine (Ethyol), bleomycin (Blenoxane), carboplatin (Paraplatin, Paraplatin solution),1 carmustine (BICNU), chlorambucil (Leukeran), cisplatin (Platinol), cyclophosphamide (Cytoxan, Neosar), cytarabine (Cytosar-U),1 dacarbazine (DTIC-Dome), dexamethasone, doxorubicin (Adriamycin, RUBEX), epirubicin hydrochloride (Ellence),1

Indications/Medications

ICD-9 Code

etoposide (Toposar, VePesid), gemcitabine hydrochloride (Gemzar),1 ifosfamide (Ifex),1 lomustine (CeeNU), mechlorethamine (Mustargen), melphalan (Alkeran),1 mercaptopurine,2 methotrexate (Folex, Mexate),1 prednisone (Deltasone), procarbazine (Matulane, Natulan), thiotepa,1 uracil mustard,2 vinblastine (Velban), vincristine (Oncovin, Vincasar) 200.4_ Mantle-cell lymphoma Bortezomib (Velcade), rituximab (Rituxan)2

Multiple myeloma 203.0_ Bortezomib (Velcade), carmustine (BICNU), cyclophosphamide (Cytoxan, Neosar), dexamethasone, doxorubicin (Adriamycin, RUBEX), doxorubicin liposomal,1 etoposide (Toposar, VePesid),1 interferon alpha-2a (Roferon A), interferon alpha-2b (Intron A, Rebetron), lenalidomide (Revlimid),1 lomustine (CeeNU),1 melphalan (Alkeran), pamidronate disodium (Aredia), prednisone (Deltasone),1 procarbazine (Matulane, Natulan),1 thalidomide (Thalomid), vincristine (Oncovin, Vincasar), zoledronic acid (Zometa)1 Myelodysplastic syndromes

238.71 to 238.76, 238.79

Amifostine (Ethyol),1 arsenic trioxide (Trisenox), azacitidine (Vidaza), cytarabine (Cytosar-U),1 decitabine (Dacogen), epoetin alfa, filgrastim (Neupogen), imatinib mesylate (Gleevec), lenalidomide (Revlimid), sargramostim (Leukine), topotecan hydrochloride (Hycamtin)1

Indications/Medications Neutropenia

ICD-9 Code 288.00 to 288.04, 288.09, 288.4, 288.50 to 288.51, 288.59, 289.53

Filgrastim (chemotherapy-induced, associated with bone marrow transplant; Neupogen), pegfilgrastim (Neulasta), sargramostim (associated with bone marrow transplant, chemotherapy-induced, including chemotherapy associated with acute myelogenous leukemia; Leukine) 200._ _ ,202._ _ Non-Hodgkin’s lymphoma Amifostine (Ethyol), asparaginase (Elspar, Kidrolase), bleomycin (Blenoxane), carboplatin (Paraplatin, Paraplatin Solution),1 carmustine (BICNU), chlorambucil (Leukeran), cisplatin (Platinol), cladribine (Leustatin), cyclophosphamide (Cytoxan, Neosar), cytarabine (Cytosar-U), daunorubicin (Cerubidine),1 dexamethasone,2 doxorubicin (Adriamycin, RUBEX), epirubicin hydrochloride (Ellence),1 etoposide (Toposar, VePesid), fludarabine phosphate (Fludara), gemcitabine hydrochloride (Gemzar),1 ibritumomab tiuxetan (Zevalin), ifosfamide (Ifex), interferon alpha-2a (Roferon A), interferon alpha-2b (Intron A, Rebetron), leucovorin (Leucovorin Calcium, Wellcovorin),1 mechlorethamine (Mustargen), mercaptopurine (Purinethol, 6-MP), methotrexate (Folex, Mexate), mitoxantrone (Novantrone),1 prednisone (Deltasone), procarbazine (Matulane, Natulan), rituximab (Rituxan), teniposide (Vumon),1 tositumomab, iodine I-131 (Bexxar), uracil mustard, vinblastine (Velban), vincristine (Oncovin, Vincasar)

Medication Index Medications/Indications

ICD-9 Code

Aldesleukin (Proleukin) Chronic myelocytic leukemia

205.1_

Alemtuzumab (Campath) Chronic lymphocytic leukemia

204.1_

Amifostine (Ethyol) Hodgkin’s lymphoma Myelodysplastic syndromes1 Non-Hodgkin’s lymphoma

201._ _ 238.71 to 238.76, 238.79 200._ _, 202._ _

Medications/Indications

ICD-9 Code

Arsenic trioxide (Trisenox) Myelodysplastic syndromes

Asparaginase (Elspar, Kidrolase) Acute lymphocytic leukemia Acute nonlymphocytic leukemia2 Non-Hodgkin’s lymphoma Azacitidine (Vidaza) Acute nonlymphocytic leukemia2 Myelodysplastic syndromes

238.71 to 238.76, 238.79

204.0_ 205.0_ 200._ _, 202._ _

205.0_ 238.71 to 238.76, 238.79

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Medications/Indications Bexarotene (Targretin) Cutaneous T-cell lymphoma

ICD-9 Code

202.1_, 202.2_, 202.8_

Bleomycin (Blenoxane) Hodgkin’s lymphoma Non-Hodgkin’s lymphoma

201._ _ 200._ _, 202._ _

Bortezomib (Velcade) Mantle-cell lymphoma Multiple myeloma

200.4_ 203.0_

Busulfan (Myleran) Acute nonlymphocytic leukemia Chronic myelocytic leukemia

205.0_ 205.1_

Cyclophosphamide (Cytoxan, Neosar) (continued) 205.0_ Acute nonlymphocytic leukemia Chronic lymphocytic leukemia 204.1_ Chronic myelocytic leukemia 205.1_ Hodgkin’s lymphoma 201._ _ Multiple myeloma 203.0_ Non-Hodgkin’s lymphoma 200._ _, 202._ _ Cytarabine (Cytosar-U) Acute lymphocytic leukemia Acute nonlymphocytic leukemia Chronic myelocytic leukemia Hodgkin’s lymphoma1 Myelodysplastic syndromes1 Non-Hodgkin’s lymphoma

Carboplatin (Paraplatin, Paraplatin Solution) 201._ _ Hodgkin’s lymphoma1 Non-Hodgkin’s lymphoma1 200._ _, 202._ _

Dacarbazine (DTIC-Dome) Hodgkin’s lymphoma

201._ _

Carmustine (BICNU) Cutaneous T-cell lymphoma2

Darbepoetin alfa (Aranesp) Chronic anemia

285.9, V58.114

Dasatinib (Sprycel) Chronic lymphocytic leukemia Chronic myelocytic leukemia

204.1_ 205.1_

Hairy-cell leukemia Hodgkin’s lymphoma

202.1_, 202.2_, 202.8_ 202.4_ 201._ _

Daunorubicin (Cerubidine) Acute lymphocytic leukemia Acute nonlymphocytic leukemia Chronic myelocytic leukemia Chronic myelomonocytic leukemia Non-Hodgkin’s lymphoma1

204.0_ 205.0_ 205.1_ 205.10 200._ _, 202._ _

Cisplatin (Platinol) Hodgkin’s lymphoma Non-Hodgkin’s lymphoma

201._ _ 200._ _, 202._ _

Decitabine (Dacogen) Myelodysplastic syndromes

204.1_ 202.1_, 202.2_, 202.8_ 202.4_ 200._ _, 202._ _

Denileukin (ONTAK) Cutaneous T-cell lymphoma

Chlorambucil (Leukeran) Cutaneous T-cell lymphoma1

Cladribine (Leustatin) Chronic lymphocytic leukemia1 Cutaneous T-cell lymphoma2 Hairy-cell leukemia Non-Hodgkin’s lymphoma Clofarabine (Pediatric; Clolar) Acute lymphocytic leukemia

202.1_, 202.2_, 202.8_ 201._ _ 203.0_ 200._ _, 202._ _

204.0_

Cyclophosphamide (Cytoxan, Neosar) 204.0_ Acute lymphocytic leukemia

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ICD-9 Code

204.0_ 205.0_ 205.1_ 201._ _ 238.71 to 238.76, 238.79 200._ _, 202._ _

Hodgkin’s lymphoma Multiple myeloma Non-Hodgkin’s lymphoma

Medications/Indications

January/February 2009

Dexamethasone Acute lymphocytic leukemia Chronic lymphocytic leukemia Chronic myelocytic leukemia Hodgkin’s lymphoma Multiple myeloma Non-Hodgkin’s lymphoma2

238.71 to 238.76, 238.79

202.1_, 202.2_, 202.8_

204.0_ 204.1_ 205.1_ 201._ _ 203.0_ 200._ _, 202._ _

Medications/Indications

ICD-9 Code

Diftitox Cutaneous T-cell lymphoma

Doxorubicin (Adriamycin, RUBEX) Acute lymphocytic leukemia Acute nonlymphocytic leukemia Chronic lymphocytic leukemia Hodgkin’s lymphoma Multiple myeloma Non-Hodgkin’s lymphoma Doxorubicin liposomal Multiple myeloma1 Epirubicin hydrochloride (Ellence) Hodgkin’s lymphoma1 Non-Hodgkin’s lymphoma1 Epoetin alfa (Procrit, Epogen) Chronic anemia Myelodysplastic syndromes1

Etoposide (Toposar, VePesid) Acute lymphocytic leukemia1 Acute nonlymphocytic leukemia Chronic myelocytic leukemia Cutaneous T-cell lymphoma Hodgkin’s lymphoma Multiple myeloma1 Non-Hodgkin’s lymphoma

202.1_, 202.2_, 202.8_

204.0_ 205.0_ 204.1_ 201._ _ 203.0_ 200._ _, 202._ _

Fludarabine phosphate (Fludara) Acute prolymphocytic leukemia Acute nonlymphocytic leukemia2,3 Chronic lymphocytic leukemia Cutaneous T-cell lymphoma2 Hairy-cell leukemia

ICD-9 Code

Fludarabine phosphate (Fludara) (continued) 200._ _, 202._ _ Non-Hodgkin’s lymphoma Gemcitabine hydrochloride (Gemzar) 201._ _ Hodgkin’s lymphoma1 Non-Hodgkin’s lymphoma1 200._ _, 202._ _ Gemtuzumab (Mylotarg) Acute nonlymphocytic leukemia

205.0_

Hydroxyurea (Hydrea) Chronic myelocytic leukemia

205.1_

Ibritumomab tiuxetan (Zevalin) Non-Hodgkin’s lymphoma

200._ _, 202._ _

201._ _ 200._ _, 202._ _

Idarubicin (Idamycin) Acute lymphocytic leukemia Acute nonlymphocytic leukemia

204.0_ 205.0_

285.29, V58.114 238.71 to 238.76, 238.79

Ifosfamide (Ifex) Acute lymphocytic leukemia Hodgkin’s lymphoma1 Non-Hodgkin’s lymphoma

204.0_ 201._ _ 200._ _, 202._ _

204.0_ 205.0_ 205.1_ 202.1_, 202.2_, 202.8_ 201._ _ 203.0_ 200._ _, 202._ _

Imatinib mesylate (Gleevec) Acute lymphocytic leukemia1 Chronic myelocytic leukemia Myelodysplastic syndromes

203.0_

Filgrastim (chemotherapy-induced, associated with bone marrow transplant; Neupogen) 238.71 to 238.76, Myelodysplastic syndromes Neutropenia

Medications/Indications

238.79 288.00 to 288.04, 288.09, 288.4, 288.50 to 288.51, 288.59, 289.53

204.9_ 205.0_ 204.1_ 202.1_, 202.2_, 202.8_ 202.4_

Interferon alpha-2a (Roferon A) Chronic myelocytic leukemia Cutaneous T-cell lymphoma Hairy-cell leukemia Multiple myeloma Non-Hodgkin’s lymphoma

204.0_ 205.1_ 238.71 to 238.76, 238.79

205.1_ 202.1_, 202.2_, 202.8_ 202.4_ 203.0_ 200._ _, 202._ _

Interferon alpha-2b (Intron A, Rebetron) 205.1_ Chronic myelocytic leukemia Cutaneous T-cell lymphoma 202.1_, 202.2_, Hairy-cell leukemia Multiple myeloma Non-Hodgkin’s lymphoma Lenalidomide (Revlimid) Multiple myeloma1 Myelodysplastic syndromes

202.8_ 202.4_ 203.0_ 200._ _, 202._ _

203.0_ 238.71 to 238.76, 238.79

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Medications/Indications

ICD-9 Code

Leucovorin (Leucovorin Calcium, Wellcovorin) 200._ _, 202._ _ Non-Hodgkin’s lymphoma1

Pamidronate disodium (Aredia) Multiple myeloma

203.0_

Lomustine (CeeNU) Hodgkin’s lymphoma Multiple myeloma1

Pegaspargase (Oncaspar) Acute lymphocytic leukemia

204.0_

Mechlorethamine (Mustargen) Chronic lymphocytic leukemia Chronic myelocytic leukemia Cutaneous T-cell lymphoma

201._ _ 203.0_

Pegfilgrastim (Neulasta) Neutropenia

Hodgkin’s lymphoma Non-Hodgkin’s lymphoma

204.1_ 205.1_ 202.1_, 202.2_, 202.8_ 201._ _ 200._ _, 202._ _

Melphalan (Alkeren) Chronic myelocytic leukemia Hodgkin’s lymphoma1 Multiple myeloma

205.1_ 201._ _ 203.0_

Mercaptopurine (Purinethol, 6-MP) Acute lymphocytic leukemia Acute nonlymphocytic leukemia Chronic myelocytic leukemia Hodgkin’s lymphoma2 Non-Hodgkin’s lymphoma

204.0_ 205.0_ 205.1_ 201._ _ 200._ _, 202._ _

Methotrexate (Folex, Mexate) Acute lymphocytic leukemia Acute nonlymphocytic leukemia Cutaneous T-cell lymphoma Hodgkin’s lymphoma1 Non-Hodgkin’s lymphoma

ICD-9 Code

204.0_ 205.0_ 202.1_, 202.2_, 202.8_ 201._ _ 200._ _, 202._ _

Mitomycin (Mutamycin) Chronic myelocytic leukemia1 Chronic myelomonocytic leukemia

205.1_ 205.10

Mitoxantrone (Novantrone) Acute lymphocytic leukemia1 Acute nonlymphocytic leukemia Non-Hodgkin’s lymphoma

204.0_ 205.0_ 200._ _, 202._ _

Nelarabine (Arranon) Acute lymphocytic leukemia

204.0_

Nilotinib (Tasigna) Chronic myelocytic leukemia

205.1_

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January/February 2009

Pentostatin (Nipent) Acute lymphocytic leukemia2 Acute prolymphocytic leukemia Chronic lymphocytic leukemia2 Cutaneous T-cell lymphoma

288.00 to 288.04, 288.09, 288.4, 288.50 to 288.51, 288.59, 289.53

Hairy-cell leukemia

204.0_ 204.9_ 204.1_ 202.1_, 202.2_, 202.8_ 202.4_

Prednisone (Deltasone) Acute lymphocytic leukemia Chronic lymphocytic leukemia Chronic myelocytic leukemia2 Hodgkin’s lymphoma Multiple myeloma1 Non-Hodgkin’s lymphoma

204.0_ 204.1_ 205.1_ 201._ _ 203.0_ 200._ _, 202._ _

Procarbazine (Matulane, Natulan) Hodgkin’s lymphoma Multiple myeloma1 Non-Hodgkin’s lymphoma

201._ _ 203.0_ 200._ _, 202._ _

Rituximab (Rituxan) Chronic lymphocytic leukemia Hairy-cell leukemia2 Mantle-cell lymphoma2 Non-Hodgkin’s lymphoma

204.1_ 202.4_ 200.4_ 200._ _, 202._ _

Sargramostim (associated with bone marrow transplant, chemotherapy-induced, including chemotherapy associated with acute myelogenous leukemia; Leukine) 238.71 to 238.76, Myelodysplastic syndromes Neutropenia 238.79 288.00 to 288.04, 288.09, 288.4, 288.50 to 288.51, 288.59, 289.53

Medications/Indications

ICD-9 Code

Medications/Indications

ICD-9 Code

204.1_ 205.1_

Teniposide (Vumon) Acute lymphocytic leukemia Non-Hodgkin’s lymphoma1

Acute nonlymphocytic leukemia Uracil mustard Chronic lymphocytic leukemia Chronic myelocytic leukemia Hodgkin’s lymphoma2 Non-Hodgkin’s lymphoma

205.0_

Sodium phosphate P32 Chronic lymphocytic leukemia Chronic myelocytic leukemia

204.0_ 200._ _, 202._ _

Vinblastine (Velban) Cutaneous T-cell lymphoma

Thalidomide (Thalomid) Multiple myeloma

203.0_

Hodgkin’s lymphoma Non-Hodgkin’s lymphoma

Thioguanine Acute lymphocytic leukemia Acute nonlymphocytic leukemia Chronic myelocytic leukemia

204.0_ 205.0_ 205.1_

Thiotepa Hodgkin’s lymphoma1

201._ _

Vincristine (Oncovin, Vincasar) Acute lymphocytic leukemia Acute nonlymphocytic leukemia2,3 Chronic lymphocytic leukemia Chronic myelocytic leukemia1 Cutaneous T-cell lymphoma1

Topotecan (Hycamtin) Chronic myelocytic leukemia1 Chronic myelomonocytic leukemia1 Myelodysplastic syndromes1

205.1_ 205.10 238.71 to 238.76, 238.79

Hodgkin’s lymphoma Multiple myeloma Non-Hodgkin’s lymphoma Vorinostat (Zolinza) Cutaneous T-cell lymphoma

Tositumomab, iodine I-131 (Bexxar) 200._ _, 202._ _ Non-Hodgkin’s lymphoma Tretinoin (Vesanoid)

Zoledronic acid (Zometa) Multiple myeloma

204.1_ 205.1_ 201._ _ 200._ _, 202._ _

202.1_, 202.2_, 202.8_ 201._ _ 200._ _, 202._ _

204.0_ 205.0_ 204.1_ 205.1_ 202.1_, 202.2_, 202.8_ 201._ _ 203.0_ 200._ _, 202._ _

202.1_, 202.2_, 202.8_

203.0_

Note: Check with your local carrier on all indications before submitting a claim. 1. USP DI (no longer in print), formerly published by Thomson Micromedex (Thomson Reuters). 2. AHFS Drug Information. American Society of Health-System Pharmacists, Inc. 3. Check with your local Medicare carrier before submitting a claim for this indication. 4. Medicare may reimburse with this code; always check with your coding professional.

Multidisciplinary Cancer Care

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Upcoming Meetings FEBRUARY 27-28 Seventh International Symposium on Supportive Care in Oncology: Cancer Management in the Era of Targeted Agents New York, NY www.cancerlearning.com MARCH 4-7 The 26th Annual Miami Breast Cancer Conference 2009 Miami, FL www.cancerlearning.com 5-7 Palliative Medicine and Supportive Oncology 2009— The 13th Annual International Symposium Ft. Lauderdale, FL www.clevelandclinicmeded.com 7-12 2009 Society of Interventional Radiology Annual Meeting San Diego, CA www.sirweb.org 8-10 American Society of Preventive Oncology 33nd Annual Meeting Tampa, FL www.aspo.org 11-15 National Comprehensive Cancer Network 14th Annual Conference: Clinical Practice Guidelines and Quality Cancer Care Hollywood, FL www.nccn.org 13-14 Sixth International Symposium on Melanoma and Other Cutaneous Malignancies New York, NY www.cancerlearning.com 14-18 19th Annual National Interdisciplinary Breast Cancer Conference Las Vegas, NV www.breastcare.org

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January/February 2009

18-21 Association of Community Cancer Centers’ 35th Annual National Meeting Washington, DC www.accc-cancer.org 20-21 Sixth International Symposium on Ovarian Cancer and Gynecologic Malignancies New York, NY www.cancerlearning.com APRIL 3-6 The American Pharmacists Association Annual Meeting and Exposition San Antonio, TX www.pharmacist.com 15-18 Academy of Managed Care Pharmacy 21st Annual Meeting and Showcase Orlando, FL www.amcp.org MAY May 29-June 2 2009 American Society of Clinical Oncology Annual Meeting Orlando, FL www.asco.org JUNE 14-17 American Society of Health-Systems Pharmacists 2009 Summer Meeting Rosemont, IL www.ashp.org 17-20 10th International Lung Cancer Congress Kohala Coast, HI www.cancerlearning.com 25-27 Multinational Association of Supportive Care in Cancer 2009 International Symposium Rome, Italy www.mascc.org

RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information. WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse Reactions]. Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan [see Warnings and Precautions, Adverse Reactions]. Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions]. Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions].

INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) is indicated for the treatment of patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing (including stable disease), low-grade, CD20positive B-cell NHL, as a single agent, after first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, consider resumption of the infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with preexisting cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within 12–24 hours after the first infusion. Fatal TLS cases have occurred after administration of Rituxan. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. 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. Most cases of PML were diagnosed within 12 months of their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. 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 life-threatening 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 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

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 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 R-CHOP 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. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a serious condition that requires treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. 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. 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 oral ingestion of 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, activecontrolled 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 All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) greater. No overall differences in effectiveness were observed between these Respiratory System Any Adverse Events 99 57 38 4 patients and younger patients. Cardiac adverse reactions, mostly supraventricular Body as a Whole Increased Cough 13 1 86 10 Rhinitis 12 1 Fever 53 1 arrhythmias, occurred more frequently among elderly patients. Serious pulmonary Bronchospasm 8 1 Chills 33 3 adverse reactions were also more common among the elderly, including Dyspnea 7 1 Infection 31 4 Sinusitis 6 0 Asthenia 26 1 pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Metabolic and Nutritional Headache 19 1 Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, Abdominal Pain 14 1 Disorders 38 3 Pain 12 1 Angioedema 11 1 B-cell NHL did not include sufficient numbers of patients aged 65 and over to Back Pain 10 1 Hyperglycemia 9 1 Throat Irritation 9 0 Peripheral Edema 8 0 determine whether they respond differently from younger subjects. Flushing 5 0 LDH Increase 7 0 OVERDOSAGE There has been no experience with overdosage in human clinical Heme and Lymphatic System 67 Digestive System 48 37 2 Lymphopenia 48 40 Nausea 23 1 trials. Single doses of up to 500 mg/m2 have been given in dose-escalation Leukopenia 14 4 Diarrhea 10 1 Neutropenia 14 6 Vomiting 10 1 clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Thrombocytopenia 12 2 Nervous System 32 1 Impairment of Fertility No long term animal studies have been performed to Anemia 8 3 Dizziness 10 1 Skin and Appendages Anxiety 5 1 44 2 establish the carcinogenic or mutagenic potential of Rituxan or to determine Musculoskeletal System Night Sweats 15 1 26 3 Rash 15 1 Myalgia 10 1 potential effects on fertility in males or females. PATIENT COUNSELING Pruritus 14 1 Arthralgia 10 1 INFORMATION Patients should be provided the Rituxan Medication Guide and Urticaria 8 1 Cardiovascular System 25 3 Hypotension 10 1 provided an opportunity to read prior to each treatment session. Because caution Hypertension 6 1 should be exercised in administering Rituxan to patients with active infections, it is a Adverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by important that the patient’s overall health be assessed at each visit and any NCI-CTC criteria. questions resulting from the patient’s reading of the Medication Guide be In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and discussed. Rituxan is detectable in serum for up to six months following up to 6 months after Rituxan infusion. Rituxan in Combination With completion of therapy. Individuals of childbearing potential should use effective Chemotherapy Adverse reactions information below is based on 1250 patients contraception during treatment and for 12 months after Rituxan therapy. 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 infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (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 Revised 9/2008 (4835505) were reported more frequently (≥5%) in patients receiving Rituxan following CVP Jointly Marketed by: compared to patients who received no further therapy: fatigue (39% vs. 14%), Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 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 ©2008 Biogen Idec Inc. and Genentech, Inc. 7140917 October 2008

For previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens

When planning a treatment course for DLBCL

Take the essential path toward improved survival

Cumulative Cumulative Proportion Proportion Surviving Surviving

RITUXAN+CHOP is proven to prolong survival in DLBCL

47% INCREASE

1.0

in 7-year OS in GELA* trial 1,2

0.8 0.6 0.4 R-CHOP (n=202) CHOP† (n=197) p =0.0004

0.2 0 0 Years

• At 7 years, 8 cycles of RITUXAN+ CHOP increased overall survival (OS) from 36% to 53% compared with CHOP alone1 • At 5 years, 8 cycles of RITUXAN+ CHOP increased OS from 46% to 58% compared with CHOP alone 5

BOXED WARNINGS and Additional Important Safety Information The most important serious adverse reactions of RITUXAN are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.5 RITUXAN in Combination with CHOP Chemotherapy for DLBCL: The following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs 46%), lung disorder (31% vs 24%), cardiac disorder (29% vs 21%), and chills (13% vs 4%). In the GELA LNH 98-5 study, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs 1.0% for CHOP).5 The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs 7%) and lung disorder (6% vs 3%). Other Grade 3 or 4 adverse reactions reported more frequently among patients receiving R-CHOP were viral infection (GELA LNH 98-5 study), neutropenia (GELA LNH 98-5 and MInT studies), and anemia (MInT study).5

Please see brief summary of prescribing information on adjacent page. Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion. *GELA (Groupe d’Etude des Lymphomes de l’Adulte) LNH 98-5 trial: A Phase III trial of 399 previously untreated elderly (age ≥60 years) DLBCL patients.3,4 †CHOP: Cyclophosphamide, doxorubicin, vincristine, and prednisone. References: 1. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. J Clin Oncol. 2007;25(suppl 18S):443s. Abstract 8009. 2. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. Paper presented at: 43rd American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Ill. Abstract 8009. 3. Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse largeB-cell lymphoma. N Engl J Med. 2002;346:235-242. 4. Data on file, Genentech, Inc. 5. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.

PROVE N. POWE R FU L.