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Volume 7 Supplement 5

JNCCN

Journal of the National Comprehensive Cancer Network

NCCN Task Force Report: Management of Neuropathy in Cancer Michael D. Stubblefield, MD; Harold J. Burstein, MD, PhD; Allen W. Burton, MD; Christian M. Custodio, MD; Gary E. Deng, MD, PhD; Maria Ho, PhD; Larry Junck, MD; G. Stephen Morris, PT, PhD; Judith A. Paice, PhD, RN, FAAN; Sudhakar Tummala, MD; and Jamie H. Von Roenn, MD

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JNCCN

Volume 7 Supplement 5 Journal of the National Comprehensive Cancer Network Masthead

Postal and Contact Information

Editorial Editor-in-Chief: Harold J. Burstein, MD, PhD National Comprehensive Cancer Network Senior Director, Professional and Patient Publications: Kimberly A. Callan, MS, ELS Assistant Managing Editor: Kerrin Robinson, MA Editorial Associate: Genevieve Emberger Hartzman, MA National Comprehensive Cancer Network Chairman of the Board: Al B. Benson III, MD Vice Chair of the Board: Thomas A. D’Amico, MD Chief Executive Officer: William T. McGivney, PhD Executive Vice President/Chief Operating Officer: Patricia J. Goldsmith Senior VP, Finance/Chief Financial Officer: Lisa Kimbro, CPA, MBA Clinical Practice Guidelines Senior VP, Clinical Information and Publications: Joan S. McClure, MS VP, Clinical Information Operations: Kristina M. Gregory, RN, MSN, OCN Associate Director, Clinical Information: Dorothy A. Shead, MS Guidelines Coordinators: Nicole R. McMillian, MS Mary Dwyer Rosario, MS Oncology Scientists/Sr. Medical Writers: Miranda Hughes, PhD Hema Sundar, PhD Susan J. Moench, PhD Rashmi Kumar, PhD Maria Ho, PhD Administrative Coordinators: Mary Anne Bergman Jean Marie Dougherty Business Development and Marketing Director, Pharma/Biotech: C. Lyn Fitzgerald Senior Manager, Communications and Marketing: Jennifer Tredwell, MBA Advertising Cold Spring Publishing Director of Business Development: David Horowitz Publishing and Design Cold Spring Publishing Executive Editor: Conor Lynch Editorial Assistant: Sarah McGullam Production Coordinator: Wendy McGullam President: Anthony Cutrone Publisher: John A. Gentile, Jr.

JNCCN (ISSN 1540-1405), the official journal of the National Comprehensive Cancer Network, is published 10 times annually by Cold Spring Publishing, 147 Main Street, Suite C, Cold Spring Harbor, NY 11724. Copyright © 2009 by the National Comprehensive Cancer Network. All rights reserved. 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 information storage and retrieval system, without permission in writing from NCCN. Subscriptions: Prices for yearly subscriptions (10 issues plus supplements) are: Individual: Print only or online only, US $440; Can/Mex + Int’l $545; print and online, US $485; Can/Mex + Int’l $610. Institutional: Print only or online only, US $685; Can/Mex + Int’l $790; print and online, US $750; Can/ Mex + Int’l $865. Single Copy: US $70.00; Can/Mex $85.00; Int’l $95.00. Subscription Inquiries should be directed to Wendy McGullam, Cold Spring Publishing, at: 631-692-0800 x303 or [email protected]. Online access is available to subscribers through IngentaConnect (www.ingentaconnect.com). Contact Information Editorial Office: Manuscripts, correspondence, and commentaries to be considered for publication should be sent to Kimberly Callan, Senior Director, Professional and Patient Publications, JNCCN, 275 Commerce Drive, Suite 300, Fort Washington, PA 19034; or e-mail [email protected]. Correspondence can also be faxed: 215-690-0283 (attn: JNCCN). Questions about requirements for publication or topic suitability can be directed as above or to Harold J. Burstein, MD, PhD, Editor-in-Chief, JNCCN, 275 Commerce Drive, Suite 300, Fort Washington, PA 19034; or e-mail [email protected]. Instructions for authors are published in JNCCN as space allows and can be found on-line at www.nccn. org/jnccn. They can also be requested by calling 215-690-0270 or e-mailing [email protected]. Advertising To purchase advertising space: Contact David Horowitz, Director of Business Development, Cold Spring Publishing, 147 Main Street, Suite C, Cold Spring Harbor, NY 11724; phone 631-692-0800 x304; fax 631692-0805; or e-mail [email protected]. To send film or digital ad materials: Ship to Cold Spring Publishing, Attn: Wendy McGullam, (JNCCN, Vol ___ Issue ___), 147 Main Street, Suite C, Cold Spring Harbor, NY 11724; phone 631-692-0800 x303; fax 631-692-0805; or e-mail [email protected]. To send pre-printed inserts: Ship to Publishers Press, Inc., Attn: Tammy Baugh, 13487 South Preston Highway, Lebanon Junction, KY 40150. Production Reprints: Reprints of individual articles are available. Orders must be for a minimum of 100 copies. Please contact David Horowitz, Director of Business Development, Cold Spring Publishing, 147 Main Street, Suite C, Cold Spring Harbor, NY 11724; phone 631-692-0800 x304; fax 631-692-0805; or e-mail [email protected]. Permissions For information about photocopying, republishing, reprinting, or adapting material, please go online to www.nccn.org/about/permissions/default.asp. Indexing JNCCN is indexed by MEDLINE/PUBMED®, Chemical Abstracts, EMBASE, EmCare, and Scopus. This paper meets the requirements of ANSI/NISO Z39.48-1992 (Permanence of Paper) effective with Volume 1, Issue 1, 2003. JNCCN is a member of the Medscape Publisher’s Circle®, an alliance of leading medical publishers whose content is featured on Medscape (http://www.medscape.com). Medscape is part of the WebMD Medscape Health Network, a leading online healthcare resource for professionals and consumers.

Disclaimer The treatment algorithms presented in JNCCN and its supplements are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual circumstances to determine any patient’s care or treatment. The research articles, reviews, and other individually authored papers presented herein are the work of the authors listed. Furthermore, the reader is advised that, except where specifically stated, all of the ideas and opinions expressed in JNCCN are the authors’ own and do not necessarily reflect those of NCCN, the member organizations, the editor, or the publisher. Publication of an advertisement or other product mention in JNCCN should not be construed as an endorsement of the product or the manufacturer’s claims. The information contained in JNCCN is presented for the purpose of educating our readership on cancer treatment and management. The information should not be relied on as complete or accurate, nor should it be relied on to suggest a course of treatment for a particular individual. It should not be used in place of a visit, call, consultation, or the advice of a licensed physician or other qualified health care provider. Patients with health care-related questions or concerns are advised to contact a physician or other qualified health care provider promptly. Although every attempt has been made to verify that information presented within is complete and accurate, the information is provided “AS IS” without warranty, express or implied. NCCN hereby excludes all implied warranties of merchantability and fitness for a particular use or purpose with respect to the Information. Furthermore, NCCN makes no warranty as to the reliability, accuracy, timeliness, usefulness, adequacy, completeness, or suitability of the information.

JNCCN

Volume 7 Supplement 5 Journal of the National Comprehensive Cancer Network Mission Statement NCCN Member Institutions City of Hope Comprehensive Cancer Center Los Angeles, California Dana-Farber/Brigham and Women’s Cancer Center| Massachusetts General Hospital Cancer Center Boston, Massachusetts Duke Comprehensive Cancer Center Durham, North Carolina Fox Chase Cancer Center Philadelphia, Pennsylvania Huntsman Cancer Institute at the University of Utah Salt Lake City, Utah Fred Hutchinson Cancer Research Center/ Seattle Cancer Care Alliance Seattle, Washington The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland Robert H. Lurie Comprehensive Cancer Center of Northwestern University Chicago, Illinois Memorial Sloan-Kettering Cancer Center New York, New York H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute Columbus, Ohio Roswell Park Cancer Institute Buffalo, New York Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine St. Louis, Missouri St. Jude Children’s Research Hospital/University of Tennessee Cancer Institute Memphis, Tennessee Stanford Comprehensive Cancer Center Stanford, California University of Alabama at Birmingham Comprehensive Cancer Center Birmingham, Alabama UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan UNMC Eppley Cancer Center at The Nebraska Medical Center Omaha, Nebraska The University of Texas M. D. Anderson Cancer Center Houston, Texas Vanderbilt-Ingram Cancer Center Nashville, Tennessee For more information, visit www.nccn.org

JNCCN is dedicated to improving the quality of cancer care locally, nationally, and internationally while enhancing the collaboration between academic medicine and the community physician. JNCCN is further committed to disseminating information across the cancer care continuum by publishing clinical practice guidelines and reporting rigorous outcomes data collected and analyzed by experts from the world’s leading care centers. JNCCN also provides a forum for original research and review papers focusing on clinical and translational research and applications of the NCCN Guidelines in everyday practice, as well as correspondence and commentary.

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About the NCCN The National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 21 of the world’s leading cancer centers, is dedicated to improving the quality and effectiveness of care provided to patients with cancer. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The primary goal of all NCCN initiatives is to improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives. For more information, visit www.nccn.org.

Volume 7 Supplement 5

JNCCN

Journal of the National Comprehensive Cancer Network

NCCN Task Force: Management of Neuropathy in Cancer *C,PMichael D. Stubblefield, MDÞτ Memorial Sloan-Kettering Cancer Center *PHarold J. Burstein, MD, PhD† Dana-Farber Cancer Institute *PAllen W. Burton, MD£ϕ The University of Texas M. D. Anderson Cancer Center *PChristian M. Custodio, MDτ Memorial Sloan-Kettering Cancer Center *PGary E. Deng, MD, PhDδ Memorial Sloan-Kettering Cancer Center

*Maria Ho, PhD National Comprehensive Cancer Network *PLarry Junck, MDΨ University of Michigan Medical School *PG. Stephen Morris, PT, PhDτ The University of Texas M. D. Anderson Cancer Center *PJudith A. Paice, PhD, RN, FAAN#£ Robert H. Lurie Comprehensive Cancer Center of Northwestern University *PSudhakar Tummala, MDÞΨ The University of Texas M. D. Anderson Cancer Center

*PJamie H. Von Roenn, MD‡ Robert H. Lurie Comprehensive Cancer Center of Northwestern University KEY: *Writing Committee Member; CChair; P Presenter Specialties: ÞInternal Medicine; τPhysical Medicine, Including Physical Therapy and Rehabilitation Medicine; †Medical Oncology; £Pain Management; ϕAnesthesiology; δIntegrative Medicine; ΨNeurology/Neuro-Oncology; #Nursing; ‡Hematology/Hematology Oncology

Disclosure of Affiliations and Significant Relationships Dr. Stubblefield has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. He is on the speakers’ bureau for Pfizer Inc. (that total $10,000 or more) and Allergan, Inc. Dr. Burstein has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. Dr. Burton has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. He is on the speakers’ bureau for Pfizer Inc. Dr. Custodio has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. Dr. Deng has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. Dr. Ho has disclosed that she has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. She is an employee of the National Comprehensive Cancer Network. Dr. Junck has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. Dr. Morris has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. Dr. Paice has disclosed that she has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. Dr. Tummala has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. Dr. Von Roenn has disclosed that she has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity.

JNCCN

Volume 7 Supplement 5 Journal of the National Comprehensive Cancer Network Continuing Education Information CME Acceditation The National Comprehensive Cancer Network (NCCN) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The NCCN designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation on the activity. The NCCN adheres to the ACCME Standards for Commercial Support of Continuing Medical Education. This activity is approved for 1.0 contact hours. NCCN is an approved provider of continuing nursing education by the PA State Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. Approval as a provider refers to recognition of educational activities only and does not imply ANCC Commission Accreditation of PA Nurses approval or endorsement of any product. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

Target Audience This educational program is designed to meet the needs of oncologists, advanced practice nurses, and other clinical professionals who treat and manage patients with cancer. Educational Objectives After completion of this CME activity, participants should be able to: • Explain the etiology of neuropathy in cancer patients. • Describe the manifestations of chemotherapy-induced peripheral neuropathy. • List agents associated with neuropathy. • Describe tools to assess neuropathy in cancer patients. • Outline strategies to manage peripheral neuropathy associated with chemotherapy. The opinions expressed in this publication are those of the participating faculty and not those of the National Comprehensive Cancer Network, Bristol-Myers Squibb Company, sanofi-aventis U.S., or the manufacturers of any products mentioned herein. This publication may include the discussion of products for indications not approved by the FDA. Participants are encouraged to consult the package inserts for updated information and changes regarding indications, dosages, and contraindications. This recommendation is particularly important with new or infrequently used products. Activity Instructions Participants will read all portions of this monograph, including all tables, figures, and references. A post-test and an evaluation form follow this activity, both of which require completion. To receive your continuing education certificate, you will need a score of at least 70% on the post-test. The post-test and evaluation form must be completed and returned by September 14, 2010. It should take approximately 1.0 hours to complete this activity as designed. There are no registration fees for this activity. Certificates will be e-mailed within 4 to 6 weeks of receipt of the post-test. Copyright 2009, National Comprehensive Cancer Network (NCCN). All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from the NCCN.

S-1 Supplement

NCCN Task Force Report: Management of Neuropathy in Cancer Michael D. Stubblefield, MD; Harold J. Burstein, MD, PhD; Allen W. Burton, MD; Christian M. Custodio, MD; Gary E. Deng, MD, PhD; Maria Ho, PhD; Larry Junck, MD; G. Stephen Morris, PT, PhD; Judith A. Paice, PhD, RN, FAAN; Sudhakar Tummala, MD; and Jamie H. Von Roenn, MD

Key Words NCCN Task Force, neuropathy, cancer treatment Abstract Neuropathy is a common, often debilitating complication of cancer and its treatment. Effective management of this disorder depends on early diagnosis and an understanding of its underlying causes in the individual patient. In January 2009, NCCN gathered a multidisciplinary group to review the literature and discuss intervention strategies currently available to patients as well as areas that require research efforts. The task force, which comprised experts in anesthesiology, medical oncology, neurology, neuro-oncology, neurophysiology, nursing, pain management, and rehabilitation, was charged with the goal of outlining recommendations for the possible prevention, diagnosis, and management of neuropathy. This report documents the proceedings of this meeting with a general background on neuropathy and neuropathy in oncology, followed by discussions on challenges and research issues, evaluation criteria, and management of different symptoms associated with this disorder. (JNCCN 2009;7[Suppl 5]:S1-S26)

Overview What Is Neuropathy?

Neuropathy, or peripheral neuropathy, is defined as the condition arising from the damage and dysfunction of the peripheral nerves—the motor, sensory and autonomic nerves that connect the brain and spinal cord to the rest of the body. The major anatomic demarcations of the peripheral nervous system include the nerve root, plexus, and peripheral nerves. Although the terms neuropathy and peripheral neuropathy generally refer to the part of the nervous system distal to the plexus, it should be noted that any or all levels of the peripheral nervous system may be affected depending on the etiology of insult. There are more than 100 known types of neuropathy, each with its specific prognosis, set of symptoms, and progressive pattern.

Neuropathy is most common in people over age 55, with a prevalence of 3% to 4%. Among the general population, about a third of cases are caused by diabetes, while another third is termed idiopathic (cause unknown). Neuropathy can also result from a variety of factors, including medications (such as chemotherapeutic agents), genetics, autoimmune disorders, infections, nutritional deficiencies, and metabolic imbalances. Neuropathy is a common complication of cancer and its treatment that can lead to serious clinical consequences for the patient. This report presents the views of the NCCN Task Force on the assessment and management of neuropathy in cancer patients as discussed at the meeting in January 2009. Signs and Symptoms

The severity of neuropathy ranges from discomfort to being severely debilitating, and the onset of symptoms can be sudden or slowly progress over time. Initially, patients often feel abnormal sensations like tingling, pain, or numbness. Many complain of difficulty in walking, dropping things, or feeling like they are wearing gloves and stockings when they are not. If internal organs are affected, patients may experience diarrhea or constipation, low blood pressure, irregular heartbeat, or even difficulty breathing. Neuropathy in Cancer

Consequences of neuropathy can be severe for patients with cancer and may result in reduced quality of life, interference with activities of daily living, disability, and potentially shorter survival. Neuropathic symptoms resulting from therapeutic interventions such as the chemotherapy can cause treatment delays, dose reductions, or even discontinuation of therapy, which can affect outcomes and compromise survival.

© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 5 | September 2009

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NCCN Task Force Report

Patients with cancer have a heightened risk of developing neuropathy. Cancer-related causes include: • Neurotoxicity of cancer treatment, such as surgery, radiotherapy, and chemotherapy (addressed further in detail) • Tumor pathology: direct compression or infiltration of nerves by primary or metastatic lesions • Nutritional deficiencies • Metabolic disturbances • Opportunistic infections • Paraneoplastic neurologic disorders (PND), or nervous dysfunction caused by the remote effects of cancer Chemotherapy-Induced Peripheral Neuropathy

Neuropathy is a major dose-limiting toxicity of many chemotherapeutic regimens.1 Among the various types of neuropathies seen in cancer patients, chemotherapy-induced peripheral neuropathy (CIPN) is the most widely reported and has been the focus of research efforts. For these reasons, much of the panel discussion and conclusions is focused on CIPN. CIPN usually manifests as sensory symptoms such as paresthesia and dysesthesia (numbness, tingling, abnormal touch sensations), or cold sensitivity. Pain is often reported and may be described as burning, freezing, lancination, shock-like, or electric. Normal touch can be perceived as painful (allodynia), with sensations that would normally be painful experienced as excruciating (hyperpathia). Motor symptoms are uncommon and usually milder. These may manifest as mild weakness in the lower limbs. Reflexes at the ankles may be diminished or absent. Some patients experience altered proprioception, which can lead to accidents or falls. Autonomic impairment is thought to be rare, although this has not been systematically studied. Evidence of this impairment might include constipation after use of vinca alkaloids,2,3 orthostasis, urinary dysfunction, and sexual dysfunction. CIPN has a number of diagnostic features that can help physicians distinguish it from other neuropathies (e.g., PND, carpal tunnel syndrome, diabetic neuropathy, metabolic neuropathy). These are: • Symmetrical, distal, length-dependent “glove and stocking” distribution • Predominantly sensory symptoms (especially pain), both in frequency and severity, rather than motor symptoms

• Onset after administration of chemotherapy, which may be progressive, rapid, or “coasting” • Dose-dependent Table 1 is a general but not exhaustive list of chemotherapeutic drugs and anticancer biologics frequently reported as associated with symptomatic neuropathy.1,4 These include platinum-containing agents, vinca alkaloids, taxanes, bortezomib, thalidomide, lenalidomide, and ixabepilone. Many of these drugs (e.g., paclitaxel and cisplatin) are widely used in a variety of cancers. The onset dose is an approximation of the cumulative dose when neuropathy typically starts to occur. For most regimens, severity of neuropathy increases with dose and duration until cessation of treatment. A notable exception is the platinum agents, for which symptoms may progress for weeks to months after treatment completion. This is called the coasting effect.5 Another exception to the typical pattern of CIPN is oxaliplatin, which is unique in that 2 patterns have been observed: acute transient (cold-induced) and cumulative persistent (dose-limiting) neuropathy.6,7 Symptoms of CIPN usually subside with time for most drugs, although long-term sequelae can occur. Challenges in Oncology and Research Issues

Despite the high overall reported occurrence across different cancers, data on neuropathic toxicity appears scattered and at times confusing, especially for older drugs such as cisplatin or vincristine. Historically, CIPN has not been a research focus in chemotherapeutic medicine. Neurotoxicity is typically reported as one of many adverse events in clinical trials the goal of which is to test other health outcomes (e.g., response or survival), and this broadly defined term renders comparison across studies difficult. As shown in Table 1, the frequency of documented neuropathic events ranges widely for many agents. One main reason is that the severity and frequency of the adverse effects heavily depends on the dose, duration, and schedule. This can be illustrated using paclitaxel given to breast cancer patients: a dose of 175 mg/m2 is associated with 2% to 12%25,28,30,31 grade 3 to 4 sensory neuropathy (based on the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]), compared with 22% to 33%29,30 for a dose of 250 mg/ m2 (infusion over 3 hours every 3 weeks for either dose). Within the same trial, increasing the infusion period from 3 to 24 hours at the 250 mg/m2 dose re-


75–100 mg/m2

11%–64% (overall) 3%–14% (severe)

Docetaxel1,25,34,36–38

* Dose-limiting or grade 3 or 4 neuropathy according to the grading scale used by the study authors.

Lenalidomide (thalidomide analog)54,55

unclear

20 g

10%–23% (overall), 1%–3% (severe)

Symmetrical tingling or numbness, pain. Occasionally weakness, sensory ataxia, and gait dysfunction Similar to thalidomide

40–120 mg/m2

63% (overall), 14% (severe) + capecitabine: 67% (overall), 21% (severe) 25%–83% (overall), 15%– 28% (severe)

Ixabepilone45,46

Thalidomide47–53

Painful paresthesia, burning sensation

1.3 mg/m2

31%–55% (overall) 9%–22% (severe)

Painful paresthesia, burning sensation, occasionally weakness, sensory ataxia, and gait dysfunction. Rare autonomic dysfunction including orthostatic hypotension

Similar to paclitaxel

Similar to paclitaxel

Symmetrical painful paresthesia or numbness in stocking-glove distribution, decreased vibration or proprioception, occasionally weakness, sensory ataxia, and gait dysfunction

Symmetrical tingling paresthesia, loss of ankle stretch reflexes, constipation, occasionally weakness, and gait dysfunction

Similar to cisplatin

Bortezomib39–44

Others

unclear

100–300 mg/m2

4–10 mg

73% (overall) 10%–15% (severe)

+ Carboplatin: 4%–16% (severe)

57%–83% (overall), 2%–33% (severe) + Cisplatin: 7%–8% (severe)

30%–47% (overall)

750–850 mg/m

Abraxane (albuminbound paclitaxel)31,35

Paclitaxel10–12,25–34

Taxanes

Vincristine, vinblastine, vinorelbine, vindesine21–24

Vinca alkaloids

Oxaliplatin (persistent/ chronic)17–20

FOLFOX: 10%–18% (severe)

Cold-induced painful dysesthesia 2

any

Oxaliplatin (acute)1,15,16

Similar to cisplatin but milder

800–1600 mg/m2

6%–42% (overall) + paclitaxel: 4%–9% (severe) 85%–95% (overall)

Carboplatin1,9–14

Symmetrical painful paresthesia or numbness in a stocking-glove distribution, sensory ataxia with gait dysfunction

Clinical Manifestation

300 mg/m2

Onset Dose

28%–100% (overall) + paclitaxel: 7%–8% (severe*)

Incidence

Cisplatin1,8–11

Platinum compounds

Drug

Table 1 Common Antineoplastic Agents Known to Induce Neuropathy

Unclear

May persist for over 1 year

Resolution in 4–6 weeks

Resolution usually within 3 months, may persist


Resolution usually within 3 weeks


Resolution usually within 3 months, may persist for vincristine

Resolution in 3 months, may persist long-term

Resolution within a week

Similar to cisplatin

Partial, symptoms may progress for months after discontinuation

Recovery

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Management of Neuropathy in Cancer


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duced the incidence of severe neuropathy from 22% to 13%,29 while the increasingly adopted weekly schedule of 1-hour infusion (80 mg/m2) increased neuropathic events compared with the conventional 3-hour infusion (175 mg/m2) every 3 weeks (24% vs. 12%).28 Also, chemotherapy regimens often include more than one potentially neurotoxic drug, and the potential additive or synergistic effects of different drug combinations remain largely elusive. In addition, cancer patients may have preexisting peripheral nervous system dysfunction such as radiculopathy from degenerative disease or neuropathy from diabetes or other causes. This can predispose them to manifesting earlier and more severe neuropathic symptoms when challenged with a neurotoxic chemotherapeutic or other cancer-related insult.56 By the nature of the modern medical system, most cancer patients enrolling in a clinical trial have advanced disease and have already been exposed to a number of chemotherapeutic drugs, many of which may be neurotoxins. This poses significant difficulty in properly attributing subsequent neuropathy to the agent or regimen tested. For example, in a trial of 113 advanced breast cancer patients who have been heavily pretreated, mild peripheral neuropathy (grade 1–2) was already evident in 27% of the women before administration of the neurotoxic ixabepilone.45 Similarly, Richardson et al.44 documented an 81% and 83% baseline incidence of symptomatic neuropathy before bortezomib treatment based on patient questionnaires and neurologist examination reports, respectively, in a group of 256 patients with recurrent/relapsed myeloma. In the group, 11% also had a history of diabetes, which may have contributed to the development of CIPN. Unfortunately, these 2 studies are among the few that include such complete information. The Task Force panelists expressed concern about the lack of standardization in quality reporting of CIPN. Across clinical trials, neuropathic cases have been recorded in a number of formats: specific symptoms (e.g., pain), development of functional impairment resulting from symptoms, neurophysiologic testing, and prevalence by grade or incidence of only severe cases according to different scoring systems. Even when the same scale is used, grading can vary due to differences in training and experience in patient assessment. Compounding the problem is the issue of underreporting. Most clinical trials rely on patient self-

report of symptoms rather than active query by the evaluator. Such voluntary symptom reporting can be influenced by patient personality, physician-patient relationship, and the medical system in which the study is conducted. The subjective nature of CIPN symptoms adds to the variability of reported incidence and severity. Underestimation and underreporting of CIPN are also suggested by studies that show that physician evaluation results in lower pain assessments than invited patient questionnaire.57–59 Admittedly, most existing evaluation tools are designed to measure neuropathy in other settings (e.g., diabetes) and have not been validated for CIPN. More sensitive and comprehensive assessment systems are needed for the chemotherapy setting. Terminology clarification is also important for differential diagnosis. Panelists noted that health professionals and patients are often confused about the various medical terms describing pain (pain, neuropathy, paresthesia, dysesthesia), and with the different clinical conditions associated with pain. A patient experiencing paclitaxel-induced arthralgia is a classic example. Arthralgia is a transient, inflammatory joint pain that typically develops 24 to 48 hours after infusion and persisting for 3 to 5 days, as opposed to the symmetrical glove-stocking distribution of numbness, tingling, or burning related to CIPN that progresses with accumulating dose. However, the patient may only complain of a generic “pain” during a doctor visit. Becoming familiar with the clinical diagnostic features of CIPN and asking specific questions will help the evaluator identify the condition and implement proper intervention, such as dose reduction. Quality assessment and reporting leading to accurate diagnosis is a crucial step that must precede clinical decisions regarding treatment. Unfortunately, CIPN presents a diagnostic dilemma because, to date, approved, effective treatment options are lacking. Although many therapeutic agents to treat or prevent CIPN have been proposed over the years, few are supported by adequate data. As opposed to studies investigating drug efficacy, conducting clinical trials to test strategies for lowering toxicity may be difficult because of financial support, physician perception, and public concern. Because some treatments for neuropathy are over-the-counter supplements (e.g., glutamine), obtaining financial support for a large, robust clinical trial may be difficult.


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Also, the balance between lowering or preventing neurologic toxicity and maintaining drug efficacy may be fine, because the 2 may be closely related. Randomized studies on preventative agents have been closed prematurely because of preliminary concerns on their negative impact on the efficacy of chemotherapy, although retrospective review did not support these concerns (see Prevention, page S-11). Other clinical trials are still ongoing, but these studies will need to show reduced neurotoxicity without compromise of antineoplastic toxicity. This poses a major challenge, because large patient numbers are needed to provide sufficient power for proving noninferiority. However, the persistent pattern of CIPN may present the opportunity to use a crossover design on intervention strategies, in which patients are randomized to 2 treatment sequences: placebo-agent or agent-placebo.60 Provided that carry-over effects are carefully considered, within-patient comparisons of crossovers can significantly enhance the statistical power by eliminating between-patient variation. This study approach has been effectively applied to polyneuropathic pain management,61 as well as cancer supportive care strategies.62–64

Mechanisms of Neuropathy Neurotoxicity Mechanisms of Chemotherapeutic and Biologic Agents

Neuropathy arises from damage to the peripheral nerves. Within the peripheral nervous system, the motor axons (nerve fibers) are large and myelinated, and the sensory and autonomic axons are mostly small and unmyelinated or thinly myelinated. The type of neuropathic symptom experienced depends on the type of nerve affected: • Sensory nerves affect sensation, such as with painful paresthesia, dysesthesia, cold-sensitivity, tingling, numbness, alteration in vibration and proprioception, or a change in reflexes. • Motor nerves affect muscles and motion, such as with muscle weakness. • Autonomic nerves affect internal organs, such as with orthostatic hypotension, constipation, urinary retention, irregular heart rate, and sexual dysfunction. Most neurotoxic drugs (taxanes and vinca alkaloids) used in chemotherapy cause axonal damage, a condition termed axonopathy. Primary nerve toxic-

ity of the platinum drugs seems to occur at the dorsal root ganglion (DRG), resulting in neuronopathy. Small sensory fibers are affected early and most frequently by chemotherapeutic agents. Because these nerves have little capacity for regeneration, damage to them is responsible for the predominance of sensory symptoms found in CIPN. Also, the cell bodies of the peripheral sensory neurons are located in the DRG, where they are outside the protective bloodbrain barrier and thus more vulnerable. The DRG also has a rich supply of capillaries that are highly permeable to toxic compounds circulating in the blood. Motor nerves are generally less frequently or seriously affected by neurotoxic chemotherapy. Motor nerves that have survived a chemotherapeutic insult have the capacity for distal sprouting and reinnervation of muscle fibers that have lost their innervation. Clinically, this capacity for regeneration results in the recovery of the patient’s strength and function. Autonomic nerves are also usually less sensitive to the effects of neurotoxic chemotherapy. The exact mechanism of damage remains to be fully elucidated for each class of chemotherapy drugs, but various mechanisms based on in vitro and in animal models have been proposed. The platinum compounds have been reported to accumulate in the DRG and exert direct damage to the DRG neurons, inducing DNA derangement, morphologic changes, and subsequent apoptosis.65,66 Cisplatin can also disrupt axonal microtubule growth that is essential for axonal transport.67 Studies suggest that the acute form of oxaliplatin toxicity may be associated with calcium chelation by oxalate released from the drug, adversely affecting �� ion�� channels and synaptic �� trans68,69 mission. Like cisplatin, taxanes and vinca alkaloids have also been found to disrupt axonal transport via microtubule damage.70–73 Of note, vinca alkaloids are known to induce severe acute neurotoxicity in patients with Charcot-Marie-Tooth disease, a Correspondhereditary sensorimotor neuropathy.74 �� ingly, the genetic mutations involved in this disorder are also linked to malfunction in microtubules and axonal transport.75,76 Among newer agents, a role in neuronal degeneration has been attributed to thalidomide.77 Bortezomib, a novel proteasome inhibitor, may induce neuronal injury via multiple mechanisms such as cytoskeletal change, mitochondrial disturbance, and disruption in tubulin polymerization.78–80


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The extent of nerve damage affects the distribution of symptoms. One useful classification of neuropathy is as follows: • Mononeuropathy: damage to a single peripheral nerve • Mononeuropathy multiplex: involvement of several isolated nerves • Polyneuropathy: simultaneous malfunction of many peripheral nerves • Autonomic neuropathy: damage to nerves affecting internal organs CIPN is primarily polyneuropathic, with symmetric stocking-glove “dying back” distribution, with the earliest symptoms developing at the finger tips and toes�� (Figure 1)�� . The length-dependent, distal pattern seems to indicate distal involvement of the longest peripheral axons, followed by progression of the symptoms proximally along the limbs as the neuropathy worsens. One explanation is that these longest fibers have the greatest surface area exposed to a CIPN drug and hence are subject to greater toxicity. Existing mononeuropathy such as median nerve damage found in carpal tunnel syndrome can worsen as CIPN polyneuropathy develops. Neuropathic Mechanisms From Other Conditions

As previously discussed, PND is a rare condition that typically precedes tumor diagnosis and can lead to neuropathic symptoms in cancer patients. PND is thought to arise from autoimmune response directed against tumor antigens, which also crossreact with proteins normally found in the nervous system. A number of paraneoplastic antibodies have been characterized, many of which are commonly found in lung cancer patients (reviewed by Darnell and Posner81). Examples are the antiCV2/CRMP5 and the anti-Hu antibodies associated with peripheral neuropathy and autonomic dysfunction. Detecting a paraneoplastic antibody can aid in the diagnosis of a previously unknown tumor, tumor recurrence, or rarely, a new second malignancy. In cancer patients with known PND, the most common etiology of CIPN, however, is still neurotoxic treatment. A slightly greater incidence of other autoimmune neuropathies is found in cancer patients compared with the general population. These neuropathies include Guillain-Barré syndrome, an acute onset neuropathy that includes acute inflammatory demyelinating polyneuropathy, acute motor axonal neuropathy,

acute motor sensory axonal neuropathy, and Miller Fisher syndrome. Chronic idiopathic demyelinating polyneuropathy and multifocal motor neuropathy can also be seen with greater frequency in cancer patients. In these cases, the body’s immune system mistargets the nerve tissues, causing inflammation or injury. Autoimmune mechanisms should be considered in HIV patients with cancer and transplant patients with neuromuscular symptoms, including neuropathy. Diabetes is a common pre-existing comorbidity in cancer patients and is associated with a high incidence of peripheral neuropathy. The neuropathyinducing mechanism of diabetes is still not fully understood, but it is widely attributed to hyperglycemia. Impaired glucose tolerance is seen in many non-diabetic cancer patients and can cause symptoms that are clinically similar to those of early diabetic neuropathy. Systemic factors like weight loss predispose patients to focal compression neuropathies. The most common is peroneal nerve compression at the fibular head resulting in foot drop and sensory disturbance along the lateral aspect of the leg and over the foot. Patients with head and neck or gastrointestinal cancers are examples of patients who may experience significant weight loss within a short time period. Patients with paraproteinemia such as monoclonal gammopathy of unknown significance; multiple myeloma; Waldenström’s macroglobulinemia; and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome can develop neuropathy from various mechanisms. Patients may have antibodies against the nerve, develop secondary amyloid nerve deposition, or have circulating cryoglobulins causing vasculitis. However, even in these patients, neuropathy mostly is secondary to chemotoxicity.

Evaluation CIPN is typically evaluated under 2 settings. First, it is commonly assessed during a clinical trial, either as part of the toxicity profile of a new antineoplastic drug or as the end point to determine the efficacy of a neuroprotective agent. Evaluation is also required during routine oncology practice, when patients complain of symptoms during the course of treatment. The following questions must be addressed:


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• Are the symptoms due to neuropathy? • If so, is the neuropathy a result of cancer treatment, cancer pathology, or other causes unrelated to cancer? • Are the symptoms severe enough to require intervention? • If so, what are the options for intervention or symptom management? • Is modification or discontinuation of the present cancer treatment necessary? To date, a gold standard for evaluating CIPN has not been defined. The assessment methods currently available include clinical evaluation (grading systems), objective testing, and patient questionnaires. However, standardization is lacking across these modalities. The largely subjective nature of pain and other neuropathic symptoms render objective measurement inherently difficult. Poor correlation between objective findings or physician evaluation and patient-reported symptom severity is frequently noted. Neurophysiologic and Other Objective Testing

Pinprick, temperature, vibration, motor strength Normal Diminished Lost

AQ-X Hyperesthesia, contact sensitivity

Normal or decreased knee reflexes

Decreased or normal strength

Decreased ankle reflexes

Neurophysiologic tests such as electromyography (EMG), nerve conduction studies (NCS), and quantitative sensory tests (QST) are Decreased pin, temperature, objective quantitative assessments vibration of the function of the peripheral nervous system. Limitations to obFigure 1 Symptoms of chemotherapy-induced peripheral neuropathy. jective testing include cost and the Adapted from: Simpson DA, Tagliati M, Gonzales-Duarte A, Mongello S. Neurologic need for subspecialty expertise that manifestations. In: Mildvan D, ed. International Atlas of AIDS, 4th edition. Hoboken, NJ: Current Medicine Group LLC; 2007; with permission. may not be readily accessible at all medical sites. Some of these tests in a study of 38 cancer patients receiving second-line are also invasive, leading to low patient adherence. paclitaxel, 71% of patients reported symptoms of Also, reports�� of the added value to physician examiparesthesias and numbness in a questionnaire, but only nation or patient questionnaires for CIPN have been 82–85 48% showed an increase in the vibration perception In general, objective �� neurophysiolog�� inconsistent. ic findings correlate poorly with subjective reports by threshold (QST).83 Changes on EMG and NCS may patients, with a tendency to underassess. For example, also lag behind the onset of symptoms. © Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 5 | September 2009

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A series of laboratory and imaging tests is available to help evaluate for other possible causes of neuropathy, such as the paraneoplastic panel (anti-Hu, anti-Yo, anti-Mag) for PND diagnosis, blood tests for metabolic or nutritional deficiencymediated neuropathy, or MRI for identifying compressive radiculopathy. However, these are usually only conducted on outlier cases in the cancer setting. In-office skin biopsy at proximal and distal anatomic sites is performed for density measurement of intra-epidermal nerve fibers to evaluate small fiber neuropathies. Although highly specific, it has low sensitivity�� and the same limitations as neurophysiological testing (cost, pain, inadequate correlation with patient reports). Clinical Assessment

As opposed to specialized neurophysiologic testing, clinical assessment (history and physical examination) is performed by the treating oncologist and typically the first-line evaluation of CIPN. Patient history should include associated comorbidity, personal and family history of neuropathy, alcohol use and other toxic exposures, and any CIPN experienced during previous treatment. The temporal profile should be described in detail (regimen dosage, duration, schedule, coasting), as well as the characteristics and distribution of signs and symptoms. Physical examination should describe clinical features of the neuropathy, such as sensory abnormalities, deep tendon reflex dysfunction, motor weakness, pain characteristics, autonomic symptoms, and most importantly, functional impairment. For individuals with pre-existing or hereditary neuropathy, related musculoskeletal findings should be documented. Such abnormalities can include foot deformities such as high arches, flat fee, or hammertoes (deformity of the proximal interphalangeal joint of the second, third, or fourth toe causing them to be permanently bent). A number of physician-based grading systems have been developed for CIPN assessment. The most widely used are the NCI-CTCAE, Ajani Sensory, WHO, and ECOG systems (Table 2).86–89 These systems grade CIPN from grade 0 (normal) to 4 (severe) or 5 (death). However, variability is apparent among examiners and different scoring systems. In a key study conducted by Postma et al.,90 2 neurologists independently rated the severity of CIPN in 37 patients using the NCICCTCAE (adapted from the NCI-CTC), WHO, ECOG, and Ajani scales. In 80% of the cases, the

neurologists disagreed on at least one scale; complete agreement on all 4 scales was noted in only 20% of patients. Interobserver agreement ranged from 46% (NCIC-CTC) to 84% (WHO), and interscale agreement for the dichotomy grade 2 and under; grade 3 varied from 68% (WHO and NCIC-CTCAE) to 100% (WHO and ECOG). This study highlights the disparity in interpretation among physicians, as well as the substantial variation in grading when using different grading systems. The significant problem of variability is in part caused by the lack of clearly defined evaluation parameters. For instance, the phrase “interfering with function but not interfering �� with �� activities of daily living” in grade 2 of the NCI-CTCAE specifies neither the function nor activity and thus is open to interpretation. Other criticisms include mixing of objective parameters (e.g., loss of reflex) with subjective symptoms (e.g., paresthesias), lack of pain assessment, and failure to account for chronic toxicity and changes in symptoms.91 More recently, a newer tool, Total Neuropathy Score (TNS),92 was developed that was reported to be more sensitive than the NCI-CTCAE in detecting changes in CIPN.93 Patient-Based Evaluation

As previously discussed, underestimation and underreport�� ing�� of CIPN using �� physician-based methods is substantial.57–59 Neuropathic symptoms such as pain and paresthesias are predominantly subjective, and individuals may have different thresholds of tolerance for these symptoms. Direct input from the patient is therefore critical in the evaluation, because the requirement for intervention is largely based on patient preference. Patient-based instruments that have been developed to address this need include the Functional Assessment of Cancer Therapy (FACT)/Gynecology Oncology Group-Neurotoxicity,94 FACT-Taxane,95 and Patient Neurotoxicity Questionnaire (PNQ).1 These are self-administered questionnaires designed to determine the level and incidence of clinically significant functional impairment resulting from CIPN. Recommendations

For routine oncology practice, the Task Force panel strongly encourages physicians to actively query can�� cer patients on signs and symptoms of neuropathy. Before neurotoxic therapy is administered, a baseline assessment should be performed and recorded. Iden-


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Table 2 Commonly Used Physician-Based Grading Scales for Evaluation of CIPN Scale

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

87

WHO

Paresthesias and/ or decreased tendon reflexes

Severe paresthesias and/or mild weakness

Intolerable paresthesias and/or marked motor loss

Paralysis

NA

ECOG88

Decreased deep tendon reflexes, mild paresthesias or constipation

Absent deep tendon reflexes, severe paresthesias or constipation, mild weakness

Disabling sensory loss, severe peripheral neuropathic pain, obstipation, severe weakness, bladder dysfunction

Respiratory dysfunction secondary to weakness, obstipation requiring surgery, paralysis confining patient to bed/ wheelchair

NA

Neuropathy-sensory

Asymptomatic: loss of deep tendon reflexes or pasresthesia (including tingling) but not interfering with function

Sensory alteration or paresthesia (including tingling), interfering with function but not with ADL

Sensory alteration or paresthesia interfering with ADL

Disabling

Death

Neuropathy-motor

Asymptomatic, weakness by exam/testing only

Symptomatic weakness interfering with function but not interfering with ADL

Weakness interfering with ADL: bracing or assistance to walk indicated

Lifethreatening: disabling (e.g.,paralysis)

Death

Sensory

Paresthesia, decreased deep tendon reflexes

Mild objective abnormality, absence of deep tendon reflexes, mild to moderate functional abnormality

Severe paresthesia, moderate objective abnormality, severe functional abnormality

Complete sensory loss, loss of function

NA

Motor

Mild or transient muscle weakness

Persistent moderate weakness but ambulatory

Unable to ambulate

Complete paralysis

NA

NCI-CTCAE (v3.0)89

Ajani86

Abbreviations: ADL, activities of daily living; CIPN, chemotherapy-induced peripheral neuropathy; NA, not applicable; NCICTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.

tifying pre-existing conditions that may predispose patients to and potentially exacerbate CIPN is imperative. Of special concern are patients with hereditary motor and sensory neuropathies, such as Charcot-Marie-Tooth disease, who may develop severe neuropathic paralysis when receiving vincristine. Routine assessment should continue during therapy. Because most cases of CIPN progress with

dose accumulation, early report of mild cases is important for detecting the onset of neuropathy during continuous monitoring. For a list of diagnostic features of CIPN that distinguishes it from other types of neuropathy�� , see Chemotherapy�� -I�� nduced �� P�� eripheral Neuropathy (page S-2). The main goal of routine clinical assessment is to determine whether the patient is experiencing


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significant neuropathic symptoms that require intervention. For this purpose, the use of grading systems is helpful but not sufficient alone. In particular, pain is a major symptom that is not well addressed by existing scales. The panel suggests the following pain assessment tools commonly used under other clinical settings: Brief Pain Inventory,96,97 Neuropathic Pain Scale,98,99 and Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale (LANSS).100,101 Whether to intervene with the neuropathic symptoms that arise depends on patient preference and the medical judgment of the physician. Table 3 lists recommendations by the NCCN Task Force panel on the key points to include during assessment of neuropathy on a cancer patient. In addition to a history and physical examination, functional assessment is critical. Simple skill tests and questions about activities of daily living provide important information. Physicians can also refer to existing patient questionnaires.1,94,95 Panelists agree that referral to a specialist can also be helpful. This may be a neurologist or physiatrist (specialist in physical medicine and rehabilitation) experienced in managing neuromuscular disorders in the cancer setting. When pain is a predominant issue, referral to a supportive care or pain management specialist may improve overall patient management. The exact point of referral will depend on physician discretion and the infrastructure of individual medical centers, but it is important that such a system be in place. In general, oncologists should consider referral when the patient case is out of their usual clinical experience, such as when a patient has atypical signs, severe symptoms, or underlying neuropathic disorders. Specialists can help delineate the neuropathic etiology, which may affect decisions about cancer treatment, suggest treatment, or point to resources for patient support and rehabilitation (see Management of Functional Deficits, page S-17). However, the panel emphasized that specialist scheduling should be in parallel with ongoing oncologist visits so that logistics do delay appropriate antineoplastic treatment. Communication between the treating physician and specialist is essential. Objective neurophysiologic testing �� is�� not sufficiently reliable to be used alone for decision making. But such testing may be used as an adjunct to clinical assessment for confirming or ruling out a diag-

nosis. Similarly, the need for additional laboratory testing, imaging, or biopsying depends on the initial clinical assessment. The decision to order these tests is usually made by the specialist. For clinical trials, multimodality assessment is preferable. Simple QST like the Von Frey or Neuropen may be easier for standardization than tests that require extensive setup or equipment. Given the high variability of commonly used physician-based scoring systems, multicenter studies must reach a consensus on the grading scale as well as interpretation of the chosen scale. As pointed out by panelists, pain assessment and functional impairment are critical endpoints, and the integration of pain scales (Brief Pain Inventory, LANSS, Neuropathic Pain Scale), patient-based questionnaires (FACT, PNQ) and skill tests (timed pellet retrieval, pegboard test) is strongly encouraged.

Prevention Many agents have been proposed for preventing neuropathy caused by antineoplastic drugs. The mechanisms by which most of these drugs might minimize neuropathy are based on limited preclinical data and informed opinion. Most of these agents have been studied in clinical trials with designs inadequate for definitive assessment of the impact on neuropathy. A few have been evaluated in randomized controlled trials. Most have been assessed during platinumbased chemotherapy. Table 4 lists these agents, the proposed mechanism for preventing CIPN, and findings from clinical trials.121 Vitamin E may mitigate neuropathy associated with platinum-based chemotherapy. Three small, open-labeled studies randomized 30 to 47 cancer patients receiving chemotherapy mostly consisting of cisplatin to vitamin E or control.102–104 The active arms were consistently associated with a lower incidence of CIPN (21%–31%) compared with the control arm (69%–86%), with statistical significance (P < .03). The severity of neuropathy as measured by toxicity scores was also reduced. A double-blinded, randomized, placebo-controlled study of 81 patients undergoing cisplatin therapy is ongoing. Interim analysis of the first 50 patients showed a significantly lower median toxicity score in the supplement group.105 Because vitamin E is an antioxidant, concerns have been raised


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about the possibility that it may suppress chemotherapeutic efficacy by interfering with the oxidative breakdown of DNA and membranes of cancer cells. Preclinical models have shown no difference in cisplatin-induced tumor inhibition with or without vitamin E.104,122 In a randomized study of 136 lung cancer patients receiving paclitaxel and carboplatin, multiple high-dose antioxidant supplementation including vitamin E affected neither the response rate nor survival.123 These results are reassuring, but a well-designed, adequately-powered trial to confirm the safety of vitamin E is important before its general adoption. Intravenous administration of calcium and magnesium (CaMg) has been proposed as prophylaxis against neurologic damage induced by oxaliplatin, on the basis that heightened extracellular calcium could facilitate closing of sodium channels, thereby decreasing the hyperexcitability of neurons exposed to oxaliplatin.124 Two concurrent randomized controlled trials, N04C7 and CONcePT, were initiated to test the effect of CaMg on oxaliplatin-related neuropathy. Both trials were terminated after CONcePT investigators reported diminished response to chemotherapy in the CaMg arm.125 After study termination, however, a subsequent independent radiology review suggested the opposite finding with respect to tumor response.121,126 Despite early termination, the N04C7 study revealed a reduction in CIPN incidence in the active arm.106 Gamelin et al.127 released an interim report on their multicenter, double-blind trial (Neuroxa) randomizing patients on the FOLFOX4 regimen. There was no difference in the response or survival rates between the arms, but significantly lower frequency and severity of neuropathy were seen in one group (blind not yet broken). Future updates should clarify the effectiveness and safety of CaMg. Despite various rationales for their evaluation, other drugs such as amifostine, nimodipine, Org 2766, and rhuLIF have all failed to show clinical benefit in randomized trials. Recently, new agents, including acetyl-L-carnitine, alpha lipoic acid, and vitamin B12/B6, have entered phase III randomized clinical testing. Conclusions

Although several agents have shown potentially encouraging results as mitigators of neuropathy, current data are inadequate to recommend any for

Table 3 Key Points to Report During Clinical Assessment of CIPN History • Personal history of neuropathy and CIPN from previous cancer treatment • Personal and family history of hereditary neuropathy (patients with Charcot-Marie Tooth disease should avoid vincristine-based chemotherapy) • Related comorbid conditions (e.g., diabetes, HIV, Guillain-Barré syndrome, CIDP, radiculopathy) • Alcohol use • Temporal profile: regimen dosage, duration, schedule, “coasting” effects • Symptoms • Type: sensory, motor, or autonomic • Distribution: distal symmetric or asymmetric • Severity • Pain assessment: BPI, LANSS, NPS • Time course of CIPN, including onset and resolution of symptoms • Treatment delays or discontinuation related to CIPN Physical Examination • Sensory assessment: light touch, vibration, proprioception, pin-prick, temperature • Deep tendon reflex: presence, absence, diminishment • Motor weakness • Autonomic symptoms (e.g., constipation, orthostatic hypotension, urinary dysfunction, sexual dysfunction) • Related musculoskeletal abnormalities (e.g., hammertoes, high or flattened arches) Sample Questions for Patient • Do you feel numbness or tingling in your hands or feet? • Do you feel pain in your hands and feet? (Rate it on a scale of 0 to 10.) • Do you feel like having gloves and stockings on? • Do these sensations bother you? Are they getting worse? • Do you feel weakness in your arms and legs? • Do you drop things often? • Have you fallen recently? • Do you have difficulty walking or climbing stairs? • Do these sensations interfere with your work or daily activities? Examples of Functional Assessment Skill Tests • Getting up and straight-line walking (observe gait and balance) • Name writing • Buttoning • Timed pellet retrieval (for clinical trials) • Pegboard test (for clinical trials) Abbreviations: BPI, Brief Pain Inventory; CIDP, chronic idiopathic demyelinating polyneuropathy; CIPN, chemotherapy-induced peripheral neuropathy; LANSS, Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale; NPS, Neuropathic Pain Scale.


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Table 4 Proposed Agents for Preventing CIPN Drug

Mechanism of Action

Findings From Randomized Controlled Trials (N)

Agents with Positive Findings in Randomized Controlled Trials Vitamin E

Antioxidant/minimizes neuronal damage

CIPN incidence and severity reduced (30-47)102–104 CIPN severity reduced (81)105 Ongoing trial: NCT00363129*

Ca++/Mg++

Facilitates Na channel function; binds oxalate (metabolite of oxaliplatin)

CIPN incidence reduced (104)106

Glutamine

Upregulation of nerve growth factor

CIPN incidence reduced (86)107

Glutathione

Hampers accumulation of platinum adducts in DRG

CIPN incidence reduced/trend towards reduction (50-151)108–110

N-acetylcysteine

Antioxidant; increases blood concentrations of glutathione

Incidence of grade 2-4 neuropathy reduced (14)111

Oxcarbazepine

Inhibits high-frequency firing of nerves; modulates ion channels

Neuropathy incidence reduced (32)112

Xaliproden

Non-peptide neurotrophic agent

Shift of CIPN from grade 3 to grade 2 (649)113 Ongoing trial: NCT00603577*

Agents With Negative Findings in Randomized Controlled Trials Amifostine

Detoxifies chemotherapy; facilitates DNA repair

Not effective (66)114 Improvement on NCI-CTC scale but not on patient questionnaire (72)115

Nimodipine

Calcium channel antagonist

Not effective; randomized trial closed early (51)116

Org 2766

Nerve growth factor family, adrenocorticotrophic hormone analog

Vibration perception maintained (55)117 Not effective (150-196)118,119

rhuLIF

Neuroprotective cytokine

Not effective (117)120

Additional Agents Being Tested in Ongoing Phase III Randomized Controlled Trials Vitamin B12/B6

Essential for nerve function

Ongoing trial: NCT00659269*

Acetyl-L-carnitine

Oxidation of free fatty acids/nerve regeneration

New trial: NCT00775645*

Alpha lipoic acid

Antioxidant

Ongoing trial: NCT00705029*

Abbreviations: CIPN, chemotherapy-induced peripheral neuropathy; DRG, dorsal root ganglion; NCI- CTC, National Cancer Institute Common Toxicity Criteria. *ClinicalTrials.gov identification number

ordinary use in patients, and the panel did not endorse any of the existing agents. This lack of endorsement reflects the small sample size and variable treatment regimens, modest observed effects, and lingering concerns over impairment of efficacy for anti-cancer therapy. In 2007, Albers et al.128 performed a systematic review of 16 randomized controlled studies of neuroprotective agents (amifostine, metal chelator diethyldithiocarbamate, glutathione, Org 2766, and vitamin E) and found the data inconclusive. Separate literature on the use of neuron-protective agents has developed from the evaluation and treatment of non-cancer–related neuropathy, predominantly diabetic neuropathy. Whether experience from non-chemotherapy–related neuropathies is relevant for clinical recom-

mendations for cancer patients is unclear. Larger randomized controlled studies specifically in cancer are needed to delineate the safety and efficacy of neuropathy prophylaxis, although these may be met with several challenges, as discussed previously. The panel was concerned by the inconsistency of end points used among the various trials examining neuropathy and potential interventions. Frequently, discordance is apparent between symptom reports and objective measures, and satisfactory neuropathy evaluation tools are currently lacking, as discussed previously. Panelists agreed that multimodal measurement of functionality is of primary importance and the incorporation of simple skill tests (e.g., the pegboard test) will add valuable information at a relatively low cost.


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Treatment Non-Cancer–Related Neuropathy

Treatment of neuropathy in cancer patients remains a challenge and depends on etiology. As discussed, a main complication is that an individual patient may experience neuropathic symptoms caused by a combination of factors. Distinguishing CIPN from other types of neuropathy is important in deciding whether the antineoplastic treatment needs to be modified. Damage to the peripheral nervous system at other levels, including the nerve root and plexus, may mimic peripheral neuropathy. Care should be taken in evaluation and exclusion of such disorders, particularly in patients with a history of degenerative spine disease or radiation therapy that affects the nerve root or plexus. Identifying underlying neuropathy is essential, because specific treatment or management strategies are available for certain noncancer–related neuropathies: • Hereditary: cancer patients with Charcot-MarieTooth disease should avoid vincristine-based chemotherapy74 • Diabetes: control of glucose level and weight, exercise, and pain relief can be helpful • Alcohol: avoiding alcohol, improving nutrition (vitamin supplement), and pain relief can be helpful • HIV: controlling HIV and selecting medication that has a low risk of contributing to neuropathy • Guillain-Barré syndrome: intravenous immunoglobulin (IVIg) and apheresis129 • Chronic idiopathic demyelinating polyneuropathy (CIDP): steroids, intravenous immunoglobulin, and apheresis • Mononeuropathy (i.e., median mononeuropathy causing carpel tunnel syndrome, ulnar mononeuropathy): resting hand splints, physical or occupational therapy, corticosteroid injection, surgical decompression (it should be noted that surgical decompression in patients on active antineoplastic treatment was thought to be relatively contraindicated by the panel) Cancer-Related Neuropathy

In most instances, control of the tumor remains a priority for stabilizing or improving cancer-related neuropathic conditions. Surgery remains the most efficient way to relieve symptoms, particularly when the neuropathy is the result of direct tumor compres-

sion. Radiation therapy and chemotherapy may also be of benefit when treating tumors responsive to these therapeutic modalities. Steroids or intravenous immunoglobulin may be effective against specific subtypes of PND such as Lambert-Eaton myasthenic syndrome and paraneoplastic dermatomyositis.130 Randomized trials have shown brief efficacy of intravenous immunoglobulin in treating anti-MAG neuropathy.131,132 Current treatment schema also includes rituximab133 and apheresis. For the rare polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome, surgery and radiation against the plasmaproliferative disorder is the mainstay of treatment; steroids are also effective. CIPN

To date, no approved effective treatment is available for CIPN, although a number of medications are useful for pain control (see subsequent sections). Because CIPN symptoms may progress with cumulating exposure, close monitoring is necessary during chemotherapy. In severe cases, dose reduction or treatment discontinuation may be indicated at the discretion of the treating oncologist, but this must be weighed against the oncologic risks. Symptom Management: Pain Medications

Various pharmacologic agents have been tested in symptom control trials to alleviate established neuropathy. Drugs that have been approved by the FDA have been so based on their efficacy in reducing pain intensity for other types of neuropathic pain disorders, mainly diabetic neuropathy and post-herpetic neuralgia. Most clinical trials on the use of other drugs to moderate CIPN have failed to yield positive findings,134–137 although results from 2 recent studies are more encouraging.138,139 To date, no agent has been approved specifically for treating CIPN. Table 5 lists the medications that are currently being used off-label to relieve the positive symptoms of CIPN (pain, paresthesias, dysesthesias, allodynia). It should be noted that none of these agents are effective in the treatment of negative neuropathic symptoms such as weakness or the loss of sensory modalities, including light touch or proprioception. Many of these agents should be administered at a low starting dose and slowly titrated to the dose that confers the best efficacy with limited side effects. Specifications for administration and side effects are listed. Readers can also refer to the NCCN Clinical


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Table 5 Common Agents for Pain Management in Neuropathy Drug

Starting Dose

Titration

Maximum Dose

Duration of Adequate Trial

Duloxetine

20–30 mg/d

No evidence that higher dose is more effective

120 mg/d

2 wk

Nausea, xerostomia, constipation, diarrhea

Gabapentin*

100–300 mg nightly or 100–300 mg 3 times/d

increase by 100–300 mg 3 times/day, every 1–7 days

3600 mg (depending on absorption)

1–2 wk at max tolerated dose

Somnolence, dizziness, GI symptoms, mild edema, cognitive impairment (elderly), exacerbation of gait problems

5% Lidocaine patch

Maximum of 3 patches daily

Non-applicable

3 patches

2 wk

Rash/erythema

Opioids (oxycodone, morphine, methadone)

5–15 mg every 4h

Convert to longacting after 1 wk, titrate based on breakthrough use

No ceiling effect

4–6 wk

Constipation, nausea, vomiting (self-limited), sedation, confusion, respiratory depression

Pregabalin

25–50 mg 3 times/d

Increase by 50 mg/ dose after 1 wk

200 mg 3 times/d

Unclear (likely 2–4 wk)

Dizziness, somnolence, xerostomia, edema, blurred vision, decreased concentration

Tramadol

50 mg 1–2/d

Increase by 50-100 mg/d, individual doses every 3-7 days

400 mg/d (100 mg 4 times/d); elderly 300 mg/d

4 wk

Dizziness, constipation, nausea, somnolence, orthostatic hypotension, increased risk of seizure, serotonin syndrome

Tricyclic antidepressants (amitriptyline,* nortriptyline,* desipramine)

Starting dose: 10-25 mg nightly

Increase by 10-25 mg every 3-7 days

75–150 mg; may increase if blood level of drug plus metabolite 115 mm Hg or resting systolic blood pressure > 200 mm Hg • Diastolic pressure rises > 10 mm Hg above resting value and systolic pressure > 250 mm Hg • Heart rate to increase with increasing exertional demand • Signs of poor perfusion (light-headedness, confusion, pallor, cyanosis, or cold and clammy skin) are present or become present • Angina or angina like symptoms are present or begin • Body temperature > 38°C • Hemoglobin < 8.0 g/dL • Ongoing bleeding or fresh petechiae or bruises are presnt; sample question: “Do you bleed often while brushing your teeth?” Footwear • Avoid heels • Insoles should not be too soft • Grip surface on shoes • Loafer-style, Velcro straps if having difficulty with shoelaces • Examine feet for signs of injury including abrasions, blisters, etc. Orthosis • Watch out for skin abrasion • Wear protective clothing underneath the orthosis • Select good shoes with proper support, have a closed back and toe, come up over the top of the feet and have a slightly wider width to accommodate the orthoses • Remove if pain occurs, see the orthotist if pain persists Household Environment • Avoid or protect against thermal stress (reduce hot water temperature, wear gloves, use potholders) • Keep rooms well-lit, use night lights • Remove or tack down loose rugs • Tidy loose wires across hallways • Use non-skid bath mats • Employ energy conservation

Recommendations: The Task Force panel emphasized the importance of physicians integrating the identification and assessment of functional deficits into the evaluation of patients with CIPN. Sample questions and simple skill tests that oncologists can use to accomplish this are listed in Table 3. Overall, panelists strongly recommend referring patients with


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CIPN that interferes with functioning to a physical or occupational therapist. Therapeutic interventions, education, and practical advice provided by these rehabilitation specialists can prove invaluable in helping patients to both correct CIPN-induced functional deficits and to cope with the difficulties and challenges these deficits cause in their everyday life. Management of Autonomic Symptoms

Although CIPN primarily affects sensory nerves, autonomic impairment is sometimes seen after the use of antineoplastic agents such as vincristine, cisplatin, carboplatin, paclitaxel, and bortezomib. For example, in a phase II study of bortezomib in patients with metastatic neuroendocrine tumors, 6 of 10 patients with moderate sensory neuropathy also experienced grade 2 to 3 dizziness, orthostasis, syncope, ileus, or abdominal cramping.198 As discussed, it is difficult to specifically attribute neuropathic symptoms to a single drug because other cancer-related factors may also be involved. Autonomic neuropathy induced by chemotherapy has not been well documented or studied. Recommendations: Autonomic dysfunction can manifest with a wide variety of symptoms. The more common symptoms seen in patients undergoing chemotherapy are dizziness or lightheadedness related to orthostatic hypotension, bloating, urinary retention, constipation or diarrhea, and impotence. The EFNS developed guidelines on the management of orthostatic hypotension.199 Advice for mild cases include getting up slowly (supine position to sitting, sitting to standing) as well as maintaining adequate salt intake and hydration. Abdominal binders or graded compression stockings decrease venous pooling and may be helpful for some patients. For more severe cases, midodrine, fludrocortisone, or their combination may be prescribed. Urinary retention can often be related to underlying medical disorders such as benign prostatic hyperplasia or an obstructive tumor and worsened by treatment with medications that have anticholinergic properties such as TCAs and opioids. In such cases, discontinuation of the offending agent may result in resolution of symptoms. The addition of alphablocking medications may be indicated in patients with benign prostatic hyperplasia. Chronic urinary retention from neurogenic bladder can be effectively managed using hygienic, intermittent self-cathe-

terization (reviewed by Selius and Subedi200). Lowfriction, hydrophilic-coated catheters are preferable over regular catheters for the prevention of urinary tract infection. Use of urethral indwelling catheters is not recommended due to possible complications such as sepsis, stones, prostatitis, urethral erosions, and development of squamous cell carcinoma. Constipation can also be related to underlying medical disorders, including obstruction by tumor, electrolyte abnormalities, and endocrine dysfunction such as hypothyroidism, and worsened by treatment with medications, particularly opioids. A well thought-out bowel program may include adequate water and fiber intake, stool softeners, and, when needed, cathartic agents. The timing of cathartic agents should be deliberate, with the goal of producing bowel movement at a specific time of day. For instance, the use of agents before sleep coupled with the ingestion of breakfast and warm liquid may help reliably produce a morning bowel movement in some patients. Methylnaltrexone is an effective medication for opioid-induced constipation,201,202 but its efficacy is unclear when constipation is related to autonomic neuropathy from chemotherapy.

Conclusions With the continued use of neurotoxic drugs, emergence of newer neuropathy-inducing antineoplastic agents, and the adoption of dose-dense regimens, the problem of CIPN is more relevant than ever in oncology. In reviewing the current literature, panelists noted a paucity of rigorous studies on the assessment, prevention, and management of cancer treatment– related neuropathy. More well-designed, sufficiently powered trials specifically on patients with CIPN are necessary to validate evaluation tools, explore different combinations and sequence of pain medications, and test the efficacy and safety of therapeutic methods and preventative supplements. In the interim, improving education and awareness within both the medical and general community will be an essential primer in efforts to overcome neuropathy. Physician and patient education are required to address the issues of underdiagnosis, underassessment, and failure of intervention. Patient participation in clinical trials is strongly encouraged. While the community awaits more study data, existing measures can aid patients with CIPN. A


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number of medications are available to mitigate neuropathic pain, as are various interventional measures and devices to improve or compensate for functional deficits. For patients for whom pain medications are ineffective, noninvasive techniques such as TENS or acupuncture may be considered.

15. Park SB, Goldstein D, Lin CS, et al. Acute abnormalities of sensory nerve function associated with oxaliplatin-induced neurotoxicity. J Clin Oncol 2009;27:1243–1249.

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118. Koeppen S, Verstappen CC, Korte R, et al. Lack of neuroprotection by an ACTH (4-9) analogue. A randomized trial in patients treated with vincristine for Hodgkin’s or non-Hodgkin’s lymphoma. J Cancer Res Clin Oncol 2004;130:153–160. 119. Roberts JA, Jenison EL, Kim K, et al. A randomized, multicenter, double-blind, placebo-controlled, dose-finding study of ORG 2766 in the prevention or delay of cisplatin-induced neuropathies in women with ovarian cancer. Gynecol Oncol 1997;67:172–177. 120. Davis ID, Kiers L, MacGregor L, et al. A randomized, doubleblinded, placebo-controlled phase II trial of recombinant human leukemia inhibitory factor (rhuLIF, emfilermin, AM424) to prevent chemotherapy-induced peripheral neuropathy. Clin Cancer Res 2005;11:1890–1898. 121. Wolf S, Barton D, Kottschade L, et al. Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. Eur J Cancer 2008;44:1507–1515. 122. Leonetti C, Biroccio A, Gabellini C, et al. Alpha-tocopherol protects against cisplatin-induced toxicity without interfering with antitumor efficacy. Int J Cancer 2003;104:243–250. 123. Pathak AK, Bhutani M, Guleria R, et al. Chemotherapy alone vs. chemotherapy plus high dose multiple antioxidants in patients with advanced non small cell lung cancer. J Am Coll Nutr 2005;24:16–21. 124. Armstrong CM, Cota G. Calcium block of Na+ channels and its effect on closing rate. Proc Natl Acad Sci U S A 1999;96:4154– 4157. 125. Hochster HS, Grothey A, Childs BH. Use of calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol 2007;25:4028–4029. 126. Hochster H, Grothey A, Shpilsky A, Childs BH. Effect of intravenous calcium and magnesium versus placebo on response to FOLFOX4 + bevacizumab in the CONcePT trial [abstract]. Presented at ASCO Gastrointestinal Cancers Symposium; January 25–27, 2009; Orlando, Florida. Abstract 280. 127. Gamelin L, Boisdron-Celle M, Morel A, et al. Oxaliplatin-related neurotoxicity: interest of calcium-magnesium infusion and no impact on its efficacy. J Clin Oncol 2008;26:1188–1189; author reply 1189–1190. 128. Albers J, Chaudhry V, Cavaletti G, Donehower R. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev 2007:CD005228. 129. Hughes RA, Swan AV, Raphael JC, et al. Immunotherapy for Guillain-Barre syndrome: a systematic review. Brain 2007;130:2245–2257. 130. de Beukelaar JW, Sillevis Smitt PA. Managing paraneoplastic neurological disorders. Oncologist 2006;11:292–305. 131. Comi G, Roveri L, Swan A, et al. A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy. J Neurol 2002;249:1370–1377. 132. Dalakas MC, Quarles RH, Farrer RG, et al. A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy. Ann Neurol 1996;40:792–795. 133. Dalakas MC, Rakocevic G, Salajegheh M, et al. Placebocontrolled trial of rituximab in IgM anti-myelin-associated


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Management of Neuropathy in Cancer glycoprotein antibody demyelinating neuropathy. Ann Neurol 2009;65:286–293. 134. Hammack JE, Michalak JC, Loprinzi CL, et al. Phase III evaluation of nortriptyline for alleviation of symptoms of cisplatinum-induced peripheral neuropathy. Pain 2002;98:195–203. 135. Kautio AL, Haanpaa M, Saarto T, Kalso E. Amitriptyline in the treatment of chemotherapy-induced neuropathic symptoms. J Pain Symptom Manage 2008;35:31–39. 136. Rao RD, Flynn PJ, Sloan JA, et al. Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled trial, N01C3. Cancer 2008;112:2802–2808. 137. Rao RD, Michalak JC, Sloan JA, et al. Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled, crossover trial (N00C3). Cancer 2007;110:2110–2118. 138. Barton D, Wos E, Qin R, et al. A randomized controlled trial evaluating a topical treatment for chemotherapy-induced neuropathy: NCCTG trial N06CA [abstract]. J Clin Oncol 2009;27(Suppl 15S):Abstract 9531. 139. Durand JP, Deplanque G, Gorent J, et al. Efficacy of venlafaxine for the prevention and relief of acute neurotoxicity of oxaliplatin: results of EFFOX, a randomized, double-blinded, placebo-controlled prospective study [abstract]. J Clin Oncol 2009;27(Suppl 15S):Abstract 9533. 140. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998;280:1831–1836. 141. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 2005;352:1324– 1334. 142. Hahn K, Arendt G, Braun JS, et al. A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. J Neurol 2004;251:1260–1266. 143. Ho TW, Backonja M, Ma J, et al. Efficient assessment of neuropathic pain drugs in patients with small fiber sensory neuropathies. Pain 2009;141:19–24. 144. Simpson DA. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. J Clin Neuromuscul Dis 2001;3:53– 62. 145. Arezzo JC, Rosenstock J, Lamoreaux L, Pauer L. Efficacy and safety of pregabalin 600 mg/d for treating painful diabetic peripheral neuropathy: a double-blind placebo-controlled trial. BMC Neurol 2008;8:33. 146. Freynhagen R, Strojek K, Griesing T, et al. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, doubleblind, multicentre, placebo-controlled trial of flexible- and fixeddose regimens. Pain 2005;115:254–263. 147. Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology 2004;63:2104–2110. 148. Richter RW, Portenoy R, Sharma U, et al. Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain 2005;6:253–260. 149. Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain 2004;110:628–638.

150. Tolle T, Freynhagen R, Versavel M, et al. Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: a randomized, double-blind study. Eur J Pain 2008;12:203–213. 151. Meier T, Wasner G, Faust M, et al. Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain 2003;106:151–158. 152. Cheville AL, Sloan JA, Northfelt DW, et al. Use of a lidocaine patch in the management of postsurgical neuropathic pain in patients with cancer: a phase III double-blind crossover study (N01CB). Support Care Cancer 2009;17:451–460. 153. Quilici S, Chancellor J, Lothgren M, et al. Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain. BMC Neurol 2009;9:6. 154. Raskin J, Pritchett YL, Wang F, et al. A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med 2005;6:346–356. 155. Wernicke JF, Pritchett YL, D’Souza DN, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology 2006;67:1411–1420. 156. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 1992;326:1250–1256. 157. Freeman R, Raskin P, Hewitt DJ, et al. Randomized study of tramadol/acetaminophen versus placebo in painful diabetic peripheral neuropathy. Curr Med Res Opin 2007;23:147–161. 158. Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998;50:1842–1846. 159. Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology 2003;60:927–934. 160. Hanna M, O’Brien C, Wilson MC. Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. Eur J Pain 2008;12:804–813. 161. Watson CP, Moulin D, Watt-Watson J, et al. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain 2003;105:71–78. 162. Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150:971–979. 163. Cruccu G, Aziz TZ, Garcia-Larrea L, et al. EFNS guidelines on neurostimulation therapy for neuropathic pain. Eur J Neurol 2007;14:952–970. 164. Cata JP, Cordella JV, Burton AW, et al. Spinal cord stimulation relieves chemotherapy-induced pain: a clinical case report. J Pain Symptom Manage 2004;27:72–78. 165. Bruel BM, Burton A, Are M, et al. Dorsal column stimulation for severe chemotherapy-induced peripheral neuropathy [abstract]. Presented at the NANS 2006 Annual Meeting; December 8, 2006. 166. Daousi C, Benbow SJ, MacFarlane IA. Electrical spinal cord stimulation in the long-term treatment of chronic painful diabetic neuropathy. Diabet Med 2005;22:393–398. 167. Kumar K, Toth C, Nath RK. Spinal cord stimulation for chronic pain in peripheral neuropathy. Surg Neurol 1996;46:363–369. 168. Tesfaye S, Watt J, Benbow SJ, et al. Electrical spinal-cord stimulation for painful diabetic peripheral neuropathy. Lancet 1996;348:1698–1701.


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NCCN Task Force Report 169. de Vos CC, Rajan V, Steenbergen W, et al. Effect and safety of spinal cord stimulation for treatment of chronic pain caused by diabetic neuropathy. J Diabetes Complications 2009;23:40–45.

186. Visovsky C, Daly BJ. Clinical evaluation and patterns of chemotherapy-induced peripheral neuropathy. J Am Acad Nurse Pract 2004;16:353–359.

170. Roebling R, Huch K, Kassubek J, et al. Cervical spinal MRI in a patient with a vagus nerve stimulator (VNS). Epilepsy Res 2009;84:273–275.

187. Wampler MA, Miaskowski C, Hamel K, et al. The modified total neuropathy score: a clinically feasible and valid measure of taxane-induced peripheral neuropathy in women in breast cancer. J Support Oncol 2006;4:W9–W16.

171. Shah RV, Smith HK, Chung J, et al. Cervical spinal cord neoplasm in a patient with an implanted cervical spinal cord stimulator: the controversial role of magnetic resonance imaging. Pain Physician 2004;7:273–278. 172. De Andres J, Valia JC, Cerda-Olmedo G, et al. Magnetic resonance imaging in patients with spinal neurostimulation systems. Anesthesiology 2007;106:779–786. 173. Reichstein L, Labrenz S, Ziegler D, Martin S. Effective treatment of symptomatic diabetic polyneuropathy by high-frequency external muscle stimulation. Diabetologia 2005;48:824–828. 174. Leonard DR, Farooqi MH, Myers S. Restoration of sensation, reduced pain, and improved balance in subjects with diabetic peripheral neuropathy: a double-blind, randomized, placebocontrolled study with monochromatic near-infrared treatment. Diabetes Care 2004;27:168–172. 175. Prendergast JJ, Miranda G, Sanchez M. Improvement of sensory impairment in patients with peripheral neuropathy. Endocr Pract 2004;10:24–30. 176. Lavery LA, Murdoch DP, Williams J, Lavery DC. Does anodyne light therapy improve peripheral neuropathy in diabetes? A double-blind, sham-controlled, randomized trial to evaluate monochromatic infrared photoenergy. Diabetes Care 2008;31:316–321. 177. Brunelli B, Gorson KC. The use of complementary and alternative medicines by patients with peripheral neuropathy. J Neurol Sci 2004;218:59–66. 178. Nicholas PK, Kemppainen JK, Canaval GE, et al. Symptom management and self-care for peripheral neuropathy in HIV/ AIDS. AIDS Care 2007;19:179–189. 179. Wang SM, Kain ZN, White P. Acupuncture analgesia: I. The scientific basis. Anesth Analg 2008;106:602–610. 180. Alimi D, Rubino C, Pichard-Leandri E, et al. Analgesic effect of auricular acupuncture for cancer pain: a randomized, blinded, controlled trial. J Clin Oncol 2003;21:4120–4126. 181. Shlay JC, Chaloner K, Max MB, et al. Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: a randomized controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS. JAMA 1998;280:1590–1595. 182. Schroder S, Liepert J, Remppis A, Greten JH. Acupuncture treatment improves nerve conduction in peripheral neuropathy. Eur J Neurol 2007;14:276–281. 183. Wong R, Sagar S. Acupuncture treatment for chemotherapyinduced peripheral neuropathy—a case series. Acupunct Med 2006;24:87–91. 184. Haythornthwaite JA, Benrud-Larson LM. Psychological assessment and treatment of patients with neuropathic pain. Curr Pain Headache Rep 2001;5:124–129. 185. Head KA. Peripheral neuropathy: pathogenic mechanisms and alternative therapies. Altern Med Rev 2006;11:294–329.

188. Nardone A, Galante M, Pareyson D, Schieppati M. Balance control in sensory neuron disease. Clin Neurophysiol 2007;118:538–550. 189. Silsupadol P, Siu KC, Shumway-Cook A, Woollacott MH. Training of balance under single- and dual-task conditions in older adults with balance impairment. Phys Ther 2006;86:269– 281. 190. Wampler MA, Hamolsky D, Hamel K, et al. Case report: painful peripheral neuropathy following treatment with docetaxel for breast cancer. Clin J Oncol Nurs 2005;9:189–193. 191. Richardson JK, Sandman D, Vela S. A focused exercise regimen improves clinical measures of balance in patients with peripheral neuropathy. Arch Phys Med Rehabil 2001;82:205–209. 192. Richardson JK, Hurvitz EA. Peripheral neuropathy: a true risk factor for falls. J Gerontol A Biol Sci Med Sci 1995;50:M211–215. 193. Ganz DA, Bao Y, Shekelle PG, Rubenstein LZ. Will my patient fall? JAMA 2007;297:77–86. 194. Richardson JK, Thies SB, DeMott TK, Ashton-Miller JA. A comparison of gait characteristics between older women with and without peripheral neuropathy in standard and challenging environments. J Am Geriatr Soc 2004;52:1532–1537. 195. Richardson JK, Thies SB, DeMott TK, Ashton-Miller JA. Interventions improve gait regularity in patients with peripheral neuropathy while walking on an irregular surface under low light. J Am Geriatr Soc 2004;52:510–515. 196. Quist M, Rorth M, Zacho M, et al. High-intensity resistance and cardiovascular training improve physical capacity in cancer patients undergoing chemotherapy. Scand J Med Sci Sports 2006;16:349–357. 197. Thompson WR, Gordon NF, Pescatello LS. ACSM’s Guidelines for Exercise Testing and Prescription, 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2009. 198. Shah MH, Young D, Kindler HL, et al. Phase II study of the proteasome inhibitor bortezomib (PS-341) in patients with metastatic neuroendocrine tumors. Clin Cancer Res 2004;10:6111–6118. 199. Lahrmann H, Cortelli P, Hilz M, et al. EFNS guidelines on the diagnosis and management of orthostatic hypotension. Eur J Neurol 2006;13:930–936. 200. Selius BA, Subedi R. Urinary retention in adults: diagnosis and initial management. Am Fam Physician 2008;77:643–650. 201. Slatkin N, Thomas J, Lipman AG, et al. Methylnaltrexone for treatment of opioid-induced constipation in advanced illness patients. J Support Oncol 2009;7:39–46. 202. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 2008;358:2332–2343.


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Post-test

Please circle the correct answer on the enclosed answer sheet.

1. Cancer-related causes of neuropathy include: a. Myelosuppressive chemotherapy b. Tumor pathology c. Nutritional deficiency d. Radiotherapy e. All of the above 2. Which of the following is NOT a diagnostic feature of CIPN? a. Dose-dependent symptoms b. Progressive onset following drug administration c. Concomitant sensory, motor, and autonomic impairment of comparable severity d. “Glove and stocking”, “dying back” distribution of abnormal sensations 3. Which of the following is/are TRUE regarding chemotherapeutic agents known to induce neuropathy? a. In most cases, CIPN aggravates with the accumulation of dose and duration. b. Neuropathy is only associated with older, traditional chemotherapy such as cisplatin and is not a reported side effect of newer antineoplastic agents. c. Neuropathic symptoms disappear almost immediately upon completion of the chemotherapy cycle. d. All of the above 4. Which of the following represents significant challenges in the management of neuropathy in cancer patients? a. Patients often have underlying neuropathy or pre-existing conditions that increase their risk of developing CIPN when exposed to a neurotoxic drug. b. CIPN is underestimated and underreported. c. No effective treatment has been approved for CIPN. d. All of the above 5. Which of the following is/are a patient-based tool for evaluation of neuropathic symptoms? a. NCI-CTCAE b. FACT-Taxane c. TNS d. ECOG e. All of the above

6. Which of the following is a pain assessment tool that can complement existing neuropathy grading systems? a. PND b. PNQ c. NPS d. NCI-CTCAE 7. Which statement(s) accurately describes the current status of prevention therapy for CIPN? a. Larger randomized controlled studies are still needed to confirm the safety and efficacy of preventative agents. b. Vitamin E is the only approved neuropathyprophylactic agent. c. CaMg injection is showing promise in reducing the incidence of paclitaxel-related neuropathy. d. All of the above 8. Which of the following is FALSE regarding pain medications for CIPN? a. No pain-killing drug has been specifically approved for CIPN. b. Gabapentin, pregabalin, duloxetine, and oxycodone are medications commonly used for CIPN. c. There is no consensus on the best order of administration and combination of drugs to relieve neuropathic pain in cancer patients. d. All are true 9. Use of electrical neurostimulation and acupuncture to relieve neuropathic pain in cancer patients should be avoided due to their invasiveness and excessive side effects. a. True b. False 10. Which of the following is NOT useful in managing functional deficits related to CIPN? a. Consult a physical therapist or occupational therapist. b. Wear tight-fitting orthosis and ensure direct skin contact. c. Enroll in exercise programs to improve gait and balance. d. Modify the household environment for safety, such as removing loose rugs and enhancing lighting.


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Please circle the correct answer below. Post-Test Answer Sheet Please circle one answer per question. A score of at least 70% on the post-test is required. 1.

a

b

c

d

2.

a

b

c

3.

a

b

4.

a

5.

a

e

6.

a

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d

7.

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d

8.

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b

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d

9.

a

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d

10.

a

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e

The activity content helped me to achieve the following objectives: (1 = Strongly disagree; 3 = Not sure; 5 = Strongly agree) Explain the etiology of neuropathy in cancer patients

1

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5

Describe the manifestations of chemotherapy-induced peripheral neuropathy

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List agents associated with neuropathy

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Describe tools to assess neuropathy in cancer patients

1

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Outline strategies to manage peripheral neuropathy associated with chemotherapy

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5

Please indicate the extent to which you agree or disagree with the following statements: You were satisfied with the overall quality of this activity.

Strongly agree

Agree

Undecided

Disagree

Strongly disagree

This activity addressed issues that will help me improve my professional competence and/or performance.

Strongly agree

Agree

Undecided

Disagree

Strongly disagree

You will make a change in your practice as a result of participation in this activity.

Strongly agree

Agree

Undecided

Disagree

Strongly disagree

The activity presented scientifically rigorous, unbiased, and balanced information.

Strongly agree

Agree

Undecided

Disagree

Strongly disagree

Disagree

Strongly disagree

Individual presentations were free of commercial bias.

Strongly agree

Agree

Undecided


S-993

Registration for Credit

NCCN Task Force Report: Management of Neuropathy in the Treatment of Cancer Release Date: September 14, 2009 Expiration Date: September 14, 2010

To receive credit, please complete this page, the post-test, and the evaluation, and mail to the following address: Continuing Education Department NCCN 275 Commerce Drive, Suite 300 Fort Washington, PA 19034 There is no fee for participating in this activity.

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