NCCN Task Force Report: Management of Neuropathy in Cancer

S-1

Supplement

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 Neuropathy is most common in people over age NCCN Task Force, neuropathy, cancer treatment 55, with a prevalence of 3% to 4%. Among the general population, about a third of cases are caused by diabe- Abstract tes, while another third is termed idiopathic (cause un- Neuropathy is a common, often debilitating complication of cancer known). Neuropathy can also result from a variety of and its treatment. Effective management of this disorder depends on early diagnosis and an understanding of its underlying causes factors, including medications (such as chemotherapeu- in the individual patient. In January 2009, NCCN gathered a mul- tic agents), genetics, autoimmune disorders, infections, tidisciplinary group to review the literature and discuss interven- nutritional deficiencies, and metabolic imbalances. tion strategies currently available to patients as well as areas that Neuropathy is a common complication of cancer and its require research efforts. The task force, which comprised experts treatment that can lead to serious clinical consequences in anesthesiology, medical oncology, neurology, neuro-oncology, neurophysiology, nursing, pain management, and rehabilitation, for the patient. This report presents the views of the was charged with the goal of outlining recommendations for the NCCN Task Force on the assessment and management possible prevention, diagnosis, and management of neuropathy. of neuropathy in cancer patients as discussed at the This report documents the proceedings of this meeting with a gen- meeting in January 2009. eral background on neuropathy and neuropathy in oncology, followed by discussions on challenges and research issues, evaluation Signs and Symptoms criteria, and management of different symptoms associated with The severity of neuropathy ranges from discomfort to this disorder. (JNCCN 2009;7[Suppl 5]:S1-S26) being severely debilitating, and the onset of symptoms can be sudden or slowly progress over time. Initially, pa- Overview tients often feel abnormal sensations like tingling, pain, or numbness. Many complain of difficulty in walking, What Is Neuropathy? dropping things, or feeling like they are wearing gloves Neuropathy, or peripheral neuropathy, is defined as the and stockings when they are not. If internal organs are condition arising from the damage and dysfunction of the affected, patients may experience diarrhea or constipa- peripheral nerves—the motor, sensory and autonomic tion, low blood pressure, irregular heartbeat, or even nerves that connect the brain and spinal cord to the rest of difficulty breathing. the body. The major anatomic demarcations of the periph- Neuropathy in Cancer eral nervous system include the nerve root, plexus, and Consequences of neuropathy can be severe for patients peripheral nerves. Although the terms neuropathy and pe- with cancer and may result in reduced quality of life, in- ripheral neuropathy generally refer to the part of the nervous terference with activities of daily living, disability, and system distal to the plexus, it should be noted that any potentially shorter survival. Neuropathic symptoms re- or all levels of the peripheral nervous system may be af- sulting from therapeutic interventions such as the che- fected depending on the etiology of insult. There are more motherapy can cause treatment delays, dose reductions, than 100 known types of neuropathy, each with its specific or even discontinuation of therapy, which can affect prognosis, set of symptoms, and progressive pattern. outcomes and compromise survival.

NCCN Task Force Report

Patients with cancer have a heightened risk • Onset after administration of chemotherapy, of developing neuropathy. Cancer-related causes which may be progressive, rapid, or “coasting” include: • Dose-dependent • Neurotoxicity of cancer treatment, such as sur- Table 1 is a general but not exhaustive list of gery, radiotherapy, and chemotherapy (addressed chemotherapeutic drugs and anticancer biologics further in detail) frequently reported as associated with symptomatic • Tumor pathology: direct compression or infiltra- neuropathy.1,4 These include platinum-containing tion of nerves by primary or metastatic lesions agents, vinca alkaloids, taxanes, bortezomib, thalido- • Nutritional deficiencies mide, lenalidomide, and ixabepilone. Many of these • Metabolic disturbances drugs (e.g., paclitaxel and cisplatin) are widely used • Opportunistic infections in a variety of cancers. The onset dose is an approxi- • Paraneoplastic neurologic disorders (PND), or mation of the cumulative dose when neuropathy nervous dysfunction caused by the remote effects typically starts to occur. For most regimens, sever- of cancer ity of neuropathy increases with dose and duration Chemotherapy-Induced Peripheral Neuropathy until cessation of treatment. A notable exception is Neuropathy is a major dose-limiting toxicity of many the platinum agents, for which symptoms may prog- chemotherapeutic regimens.1 Among the various ress for weeks to months after treatment completion. 5 types of neuropathies seen in cancer patients, che- This is called the coasting effect. motherapy-induced peripheral neuropathy (CIPN) Another exception to the typical pattern of CIPN is the most widely reported and has been the focus of is oxaliplatin, which is unique in that 2 patterns have research efforts. For these reasons, much of the panel been observed: acute transient (cold-induced) and 6,7 discussion and conclusions is focused on CIPN. cumulative persistent (dose-limiting) neuropathy. CIPN usually manifests as sensory symptoms Symptoms of CIPN usually subside with time for such as paresthesia and dysesthesia (numbness, tin- most drugs, although long-term sequelae can occur. gling, abnormal touch sensations), or cold sensitiv- Challenges in Oncology and Research Issues ity. Pain is often reported and may be described as Despite the high overall reported occurrence across burning, freezing, lancination, shock-like, or elec- different cancers, data on neuropathic toxicity ap- tric. Normal touch can be perceived as painful (al- pears scattered and at times confusing, especially for lodynia), with sensations that would normally be older drugs such as cisplatin or vincristine. Histori- painful experienced as excruciating (hyperpathia). cally, CIPN has not been a research focus in che- Motor symptoms are uncommon and usually milder. motherapeutic medicine. Neurotoxicity is typically These may manifest as mild weakness in the lower reported as one of many adverse events in clinical tri- limbs. Reflexes at the ankles may be diminished or als the goal of which is to test other health outcomes absent. Some patients experience altered proprio- (e.g., response or survival), and this broadly defined ception, which can lead to accidents or falls. Auto- term renders comparison across studies difficult. nomic impairment is thought to be rare, although As shown in Table 1, the frequency of docu- this has not been systematically studied. Evidence of mented neuropathic events ranges widely for many this impairment might include constipation after use agents. One main reason is that the severity and of vinca alkaloids,2,3 orthostasis, urinary dysfunction, frequency of the adverse effects heavily depends on and sexual dysfunction. the dose, duration, and schedule. This can be illus- CIPN has a number of diagnostic features that trated using paclitaxel given to breast cancer pa- can help physicians distinguish it from other neurop- tients: a dose of 175 mg/m2 is associated with 2% to athies (e.g., PND, carpal tunnel syndrome, diabetic 12%25,28,30,31 grade 3 to 4 sensory neuropathy (based neuropathy, metabolic neuropathy). These are: on the National Cancer Institute Common Termi- • Symmetrical, distal, length-dependent “glove nology Criteria for Adverse Events [NCI-CTCAE]), and stocking” distribution compared with 22% to 33%29,30 for a dose of 250 mg/ • Predominantly sensory symptoms (especially m2 (infusion over 3 hours every 3 weeks for either pain), both in frequency and severity, rather dose). Within the same trial, increasing the infusion than motor symptoms period from 3 to 24 hours at the 250 mg/m2 dose re-

Management of Neuropathy in Cancer Recovery Partial, symptoms may progress for months after discontinuation Similar to cisplatin Resolution within a week Resolution in 3 months, may persist long-term Resolution usually within 3 months, may persist for vincristine Resolution usually within 3 months, may persist Resolution usually within 3 weeks Resolution usually within 3 months, may persist Resolution usually within 3 months, may persist Resolution in 4–6 weeks May persist for over 1 year Unclear Clinical Manifestation Symmetrical painful paresthesia or numbness in a stocking-glove distribution, sensory ataxia with gait dysfunction Similar to cisplatin but milder Cold-induced painful dysesthesia Similar to cisplatin Symmetrical tingling paresthesia, loss of ankle stretch reflexes, constipation, occasionally weakness, and gait dysfunction Symmetrical painful paresthesia or numbness in stocking-glove distribution, decreased vibration or proprioception, occasionally weakness, sensory ataxia, and gait dysfunction Similar to paclitaxel Similar to paclitaxel Painful paresthesia, burning sensation, occasionally weakness, sensory ataxia, and gait dysfunction. Rare autonomic dysfunction including orthostatic hypotension Painful paresthesia, burning sensation Symmetrical tingling or numbness, pain. Occasionally weakness, sensory ataxia, and gait dysfunction Similar to thalidomide 2 2 2 2 2 2 2 Onset Dose 300 mg/m 800–1600 mg/m any 750–850 mg/m 4–10 mg 100–300 mg/m unclear 75–100 mg/m 1.3 mg/m 40–120 mg/m 20 g unclear

4%–16%

7%–8% 4%–9% (severe) 4%–9% 7%–8% (severe) 10%–18% (severe) Incidence 28%–100% (overall) + paclitaxel: (severe*) 6%–42% (overall) paclitaxel: + 85%–95% (overall) FOLFOX: 30%–47% (overall) 57%–83% (overall), 2%–33% (severe) + Cisplatin: + Carboplatin: (severe) 73% (overall) 10%–15% (severe) 11%–64% (overall) 3%–14% (severe) 31%–55% (overall) 9%–22% (severe) 63% (overall), 14% (severe) + capecitabine: 67% (overall), 21% (severe) 25%–83% (overall), 15%– 28% (severe) 10%–23% (overall), 1%–3% (severe) 21–24 54,55 1,15,16 31,35 47–53 1,9–14 45,46 39–44 Common Antineoplastic Agents Known to Induce Neuropathy 1,25,34,36–38 10–12,25–34 1,8–11 17–20 Table 1 Table Drug Platinum compounds Cisplatin Carboplatin Oxaliplatin (acute) Oxaliplatin (persistent/ chronic) Vinca alkaloids Vincristine, vinblastine, vinorelbine, vindesine Taxanes Paclitaxel Abraxane (albumin- bound paclitaxel) Docetaxel Others Bortezomib Ixabepilone Thalidomide Lenalidomide (thalidomide analog) * Dose-limiting or grade 3 or 4 neuropathy according to the grading scale used by the study authors. study the by used scale grading the to according neuropathy 4 or 3 grade or Dose-limiting *

NCCN Task Force Report

duced the incidence of severe neuropathy from 22% report of symptoms rather than active query by the to 13%,29 while the increasingly adopted weekly evaluator. Such voluntary symptom reporting can be schedule of 1-hour infusion (80 mg/m2) increased influenced by patient personality, physician-patient neuropathic events compared with the conventional relationship, and the medical system in which the 3-hour infusion (175 mg/m2) every 3 weeks (24% vs. study is conducted. The subjective nature of CIPN 12%).28 Also, chemotherapy regimens often include symptoms adds to the variability of reported inci- more than one potentially neurotoxic drug, and the dence and severity. Underestimation and underre- potential additive or synergistic effects of different porting of CIPN are also suggested by studies that drug combinations remain largely elusive. show that physician evaluation results in lower pain In addition, cancer patients may have pre- assessments than invited patient questionnaire.57–59 existing peripheral nervous system dysfunction such Admittedly, most existing evaluation tools are de- as radiculopathy from degenerative disease or neu- signed to measure neuropathy in other settings (e.g., ropathy from diabetes or other causes. This can pre- diabetes) and have not been validated for CIPN. dispose them to manifesting earlier and more severe More sensitive and comprehensive assessment sys- neuropathic symptoms when challenged with a neu- tems are needed for the chemotherapy setting. rotoxic chemotherapeutic or other cancer-related Terminology clarification is also important for insult.56 By the nature of the modern medical system, differential diagnosis. Panelists noted that health most cancer patients enrolling in a clinical trial have professionals and patients are often confused about advanced disease and have already been exposed to the various medical terms describing pain (pain, a number of chemotherapeutic drugs, many of which neuropathy, paresthesia, dysesthesia), and with the may be neurotoxins. This poses significant difficulty different clinical conditions associated with pain. A in properly attributing subsequent neuropathy to patient experiencing paclitaxel-induced arthralgia is the agent or regimen tested. For example, in a trial a classic example. Arthralgia is a transient, inflam- of 113 advanced breast cancer patients who have matory joint pain that typically develops 24 to 48 been heavily pretreated, mild peripheral neuropathy hours after infusion and persisting for 3 to 5 days, (grade 1–2) was already evident in 27% of the wom- as opposed to the symmetrical glove-stocking distri- en before administration of the neurotoxic ixabepi- bution of numbness, tingling, or burning related to lone.45 Similarly, Richardson et al.44 documented an CIPN that progresses with accumulating dose. How- 81% and 83% baseline incidence of symptomatic ever, the patient may only complain of a generic neuropathy before bortezomib treatment based on “pain” during a doctor visit. Becoming familiar with patient questionnaires and neurologist examination the clinical diagnostic features of CIPN and asking reports, respectively, in a group of 256 patients with specific questions will help the evaluator identify the recurrent/relapsed myeloma. In the group, 11% also condition and implement proper intervention, such had a history of diabetes, which may have contrib- as dose reduction. uted to the development of CIPN. Quality assessment and reporting leading to ac- Unfortunately, these 2 studies are among the few curate diagnosis is a crucial step that must precede that include such complete information. The Task clinical decisions regarding treatment. Unfortunate- Force panelists expressed concern about the lack of ly, CIPN presents a diagnostic dilemma because, to standardization in quality reporting of CIPN. Across date, approved, effective treatment options are lack- clinical trials, neuropathic cases have been recorded ing. Although many therapeutic agents to treat or in a number of formats: specific symptoms (e.g., pain), prevent CIPN have been proposed over the years, development of functional impairment resulting from few are supported by adequate data. As opposed to symptoms, neurophysiologic testing, and prevalence studies investigating drug efficacy, conducting clini- by grade or incidence of only severe cases according cal trials to test strategies for lowering toxicity may to different scoring systems. Even when the same scale be difficult because of financial support, physician is used, grading can vary due to differences in training perception, and public concern. Because some treat- and experience in patient assessment. ments for neuropathy are over-the-counter supple- Compounding the problem is the issue of under- ments (e.g., glutamine), obtaining financial support reporting. Most clinical trials rely on patient self- for a large, robust clinical trial may be difficult.

Management of Neuropathy in Cancer

Also, the balance between lowering or prevent- ity of the platinum drugs seems to occur at the dor- ing neurologic toxicity and maintaining drug efficacy sal root ganglion (DRG), resulting in neuronopathy. may be fine, because the 2 may be closely related. Small sensory fibers are affected early and most fre- Randomized studies on preventative agents have quently by chemotherapeutic agents. Because these been closed prematurely because of preliminary con- nerves have little capacity for regeneration, damage cerns on their negative impact on the efficacy of che- to them is responsible for the predominance of sen- motherapy, although retrospective review did not sory symptoms found in CIPN. Also, the cell bodies support these concerns (see Prevention, page S-11). of the peripheral sensory neurons are located in the Other clinical trials are still ongoing, but these DRG, where they are outside the protective blood- studies will need to show reduced neurotoxicity with- brain barrier and thus more vulnerable. out compromise of antineoplastic toxicity. This poses The DRG also has a rich supply of capillaries that a major challenge, because large patient numbers are are highly permeable to toxic compounds circulating needed to provide sufficient power for proving non- in the blood. Motor nerves are generally less frequent- inferiority. However, the persistent pattern of CIPN ly or seriously affected by neurotoxic chemotherapy. may present the opportunity to use a crossover de- Motor nerves that have survived a chemotherapeutic sign on intervention strategies, in which patients are insult have the capacity for distal sprouting and re- randomized to 2 treatment sequences: placebo-agent innervation of muscle fibers that have lost their in- or agent-placebo.60 Provided that carry-over effects nervation. Clinically, this capacity for regeneration are carefully considered, within-patient comparisons results in the recovery of the patient’s strength and of crossovers can significantly enhance the statisti- function. Autonomic nerves are also usually less sensi- cal power by eliminating between-patient variation. tive to the effects of neurotoxic chemotherapy. This study approach has been effectively applied to The exact mechanism of damage remains to be polyneuropathic pain management,61 as well as can- fully elucidated for each class of chemotherapy drugs, cer supportive care strategies.62–64 but various mechanisms based on in vitro and in animal models have been proposed. The platinum compounds have been reported to accumulate in the Mechanisms of Neuropathy DRG and exert direct damage to the DRG neurons, Neurotoxicity Mechanisms of Chemotherapeutic inducing DNA derangement, morphologic changes, and Biologic Agents and subsequent apoptosis.65,66 Cisplatin can also Neuropathy arises from damage to the peripheral disrupt axonal microtubule growth that is essential nerves. Within the peripheral nervous system, the for axonal transport.67 Studies suggest that the acute motor axons (nerve fibers) are large and myelinated, form of oxaliplatin toxicity may be associated with and the sensory and autonomic axons are mostly calcium chelation by oxalate released from the drug, small and unmyelinated or thinly myelinated. The adversely affecting�� ion�� channels and synaptic�� trans- type of neuropathic symptom experienced depends mission.68,69 Like cisplatin, taxanes and vinca alkaloids on the type of nerve affected: have also been found to disrupt axonal transport via • Sensory nerves affect sensation, such as with microtubule damage.70–73 Of note, vinca alkaloids painful paresthesia, dysesthesia, cold-sensitivity, are known to induce severe acute neurotoxicity tingling, numbness, alteration in vibration and in patients with Charcot-Marie-Tooth disease, a proprioception, or a change in reflexes. hereditary sensorimotor neuropathy.74 ��Correspond- • Motor nerves affect muscles and motion, such as ingly, the genetic mutations involved in this disorder with muscle weakness. are also linked to malfunction in microtubules and • Autonomic nerves affect internal organs, such axonal transport.75,76 as with orthostatic hypotension, constipation, Among newer agents, a role in neuronal urinary retention, irregular heart rate, and degeneration has been attributed to thalidomide.77 sexual dysfunction. Bortezomib, a novel proteasome inhibitor, may Most neurotoxic drugs (taxanes and vinca alka- induce neuronal injury via multiple mechanisms such loids) used in chemotherapy cause axonal damage, a as cytoskeletal change, mitochondrial disturbance, condition termed axonopathy. Primary nerve toxic- and disruption in tubulin polymerization.78–80

NCCN Task Force Report

The extent of nerve damage affects the distribu- acute motor sensory axonal neuropathy, and Miller tion of symptoms. One useful classification of neu- Fisher syndrome. Chronic idiopathic demyelinating ropathy is as follows: polyneuropathy and multifocal motor neuropathy can • Mononeuropathy: damage to a single peripheral also be seen with greater frequency in cancer patients. nerve In these cases, the body’s immune system mistargets • Mononeuropathy multiplex: involvement of sev- the nerve tissues, causing inflammation or injury. Au- eral isolated nerves toimmune mechanisms should be considered in HIV • Polyneuropathy: simultaneous malfunction of patients with cancer and transplant patients with many peripheral nerves neuromuscular symptoms, including neuropathy. • Autonomic neuropathy: damage to nerves affect- Diabetes is a common pre-existing comorbidity ing internal organs in cancer patients and is associated with a high in- CIPN is primarily polyneuropathic, with sym- cidence of peripheral neuropathy. The neuropathy- metric stocking-glove “dying back” distribution, inducing mechanism of diabetes is still not fully with the earliest symptoms developing at the finger understood, but it is widely attributed to hypergly- tips and toes�� (Figure 1)��. The length-dependent, dis- cemia. Impaired glucose tolerance is seen in many tal pattern seems to indicate distal involvement of non-diabetic cancer patients and can cause symp- the longest peripheral axons, followed by progression toms that are clinically similar to those of early of the symptoms proximally along the limbs as the diabetic neuropathy. neuropathy worsens. One explanation is that these Systemic factors like weight loss predispose pa- longest fibers have the greatest surface area exposed tients to focal compression neuropathies. The most to a CIPN drug and hence are subject to greater common is peroneal nerve compression at the fibu- toxicity. Existing mononeuropathy such as median lar head resulting in foot drop and sensory distur- nerve damage found in carpal tunnel syndrome can bance along the lateral aspect of the leg and over worsen as CIPN polyneuropathy develops. the foot. Patients with head and neck or gastroin- Neuropathic Mechanisms From Other Conditions testinal cancers are examples of patients who may As previously discussed, PND is a rare condition experience significant weight loss within a short that typically precedes tumor diagnosis and can time period. lead to neuropathic symptoms in cancer patients. Patients with paraproteinemia such as mono- PND is thought to arise from autoimmune response clonal gammopathy of unknown significance; mul- directed against tumor antigens, which also cross- tiple myeloma; Waldenström’s macroglobulinemia; react with proteins normally found in the nervous and polyneuropathy, organomegaly, endocrinopathy, system. A number of paraneoplastic antibodies monoclonal gammopathy, and skin changes syn- have been characterized, many of which are com- drome can develop neuropathy from various mecha- monly found in lung cancer patients (reviewed nisms. Patients may have antibodies against the by Darnell and Posner81). Examples are the anti- nerve, develop secondary amyloid nerve deposition, CV2/CRMP5 and the anti-Hu antibodies associ- or have circulating cryoglobulins causing vasculitis. ated with peripheral neuropathy and autonomic However, even in these patients, neuropathy mostly dysfunction. Detecting a paraneoplastic antibody is secondary to chemotoxicity. can aid in the diagnosis of a previously unknown tumor, tumor recurrence, or rarely, a new second malignancy. In cancer patients with known PND, Evaluation the most common etiology of CIPN, however, is CIPN is typically evaluated under 2 settings. First, still neurotoxic treatment. it is commonly assessed during a clinical trial, either A slightly greater incidence of other autoimmune as part of the toxicity profile of a newantineoplastic neuropathies is found in cancer patients compared drug or as the end point to determine the efficacy of with the general population. These neuropathies in- a neuroprotective agent. Evaluation is also required clude Guillain-Barré syndrome, an acute onset neu- during routine oncology practice, when patients ropathy that includes acute inflammatory demyelinat- complain of symptoms during the course of treating polyneuropathy, acute motor axonal neuropathy, ment. The following questions must be addressed:

Management of Neuropathy in Cancer

• Are the symptoms due to neuropathy? • If so, is the neuropathy a re- Pinprick, temperature, vibration, motor strength sult of cancer treatment, cancer pathology, or other causes Normal unrelated to cancer? • Are the symptoms severe Diminished enough to require intervention? • If so, what are the options Lost 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 AQ-X currently available include clini- Hyperesthesia, cal evaluation (grading systems), contact sensitivity objective testing, and patient questionnaires. However, standardization is lacking across these modalities. The largely subjective Normal or decreased nature of pain and other neuro- knee reflexes pathic symptoms render objective measurement inherently difficult. Poor correlation between objective findings or physician evaluation and patient-reported symptom severity is frequently noted. Decreased ankle Neurophysiologic and Other reflexes Decreased or normal Objective Testing strength Neurophysiologic tests such as elec- tromyography (EMG), nerve conduction studies (NCS), and quantitative sensory tests (QST) are objective quantitative assessments Decreased pin, temperature, vibration of the function of the peripheral nervous system. Limitations to ob- Figure 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, may not be readily accessible at all NJ: Current Medicine Group LLC; 2007; with permission. medical sites. Some of these tests are also invasive, leading to low patient adherence. in a study of 38 cancer patients receiving second-line Also, reports�� of the added value to physician exami- paclitaxel, 71% of patients reported symptoms of nation or patient questionnaires for CIPN have been paresthesias and numbness in a questionnaire, but only inconsistent.82–85 In general, objective�� neurophysiolog��- 48% showed an increase in the vibration perception 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.

NCCN Task Force Report

A series of laboratory and imaging tests is neurologists disagreed on at least one scale; complete available to help evaluate for other possible causes agreement on all 4 scales was noted in only 20% of neuropathy, such as the paraneoplastic panel of patients. Interobserver agreement ranged from (anti-Hu, anti-Yo, anti-Mag) for PND diagnosis, 46% (NCIC-CTC) to 84% (WHO), and interscale blood tests for metabolic or nutritional deficiency- agreement for the dichotomy grade 2 and under; grade mediated neuropathy, or MRI for identifying 3 varied from 68% (WHO and NCIC-CTCAE) to compressive radiculopathy. However, these are 100% (WHO and ECOG). This study highlights the usually only conducted on outlier cases in the cancer disparity in interpretation among physicians, as well setting. In-office skin biopsy at proximal and distal as the substantial variation in grading when using anatomic sites is performed for density measurement different grading systems. of intra-epidermal nerve fibers to evaluate small fiber The significant problem of variability is in part neuropathies. Although highly specific, it has low caused by the lack of clearly defined evaluation pa- sensitivity ��and the same limitations as neurophysi- rameters. For instance, the phrase “interfering with ological testing (cost, pain, inadequate correlation function but not interfering�� with ��activities of daily liv- with patient reports). ing” in grade 2 of the NCI-CTCAE specifies neither Clinical Assessment the function nor activity and thus is open to interpre- As opposed to specialized neurophysiologic testing, tation. Other criticisms include mixing of objective clinical assessment (history and physical examination) parameters (e.g., loss of reflex) with subjective symp- is performed by the treating oncologist and typically toms (e.g., paresthesias), lack of pain assessment, and the first-line evaluation of CIPN. Patient history failure to account for chronic toxicity and changes in should include associated comorbidity, personal and symptoms.91 More recently, a newer tool, Total Neurop- family history of neuropathy, alcohol use and other athy Score (TNS),92 was developed that was reported to toxic exposures, and any CIPN experienced during be more sensitive than the NCI-CTCAE in detecting previous treatment. The temporal profile should be changes in CIPN.93 described in detail (regimen dosage, duration, schedule, Patient-Based Evaluation coasting), as well as the characteristics and distribution As previously discussed, underestimation and of signs and symptoms. Physical examination should underreporting�� of CIPN using�� physician-based meth- describe clinical features of the neuropathy, such as ods is substantial.57–59 Neuropathic symptoms such as sensory abnormalities, deep tendon reflex dysfunc- pain and paresthesias are predominantly subjective, tion, motor weakness, pain characteristics, autonomic and individuals may have different thresholds of tol- symptoms, and most importantly, functional impair- erance for these symptoms. Direct input from the pa- ment. For individuals with pre-existing or hereditary tient is therefore critical in the evaluation, because neuropathy, related musculoskeletal findings should the requirement for intervention is largely based be documented. Such abnormalities can include foot on patient preference. Patient-based instruments deformities such as high arches, flat fee, or hammer- that have been developed to address this need in- toes (deformity of the proximal interphalangeal joint clude the Functional Assessment of Cancer Therapy of the second, third, or fourth toe causing them to be (FACT)/Gynecology Oncology Group-Neurotox- permanently bent). icity,94 FACT-Taxane,95 and Patient Neurotoxicity A number of physician-based grading systems have Questionnaire (PNQ).1 These are self-administered been developed for CIPN assessment. The most widely questionnaires designed to determine the level and used are the NCI-CTCAE, Ajani Sensory, WHO, and incidence of clinically significant functional impair- ECOG systems (Table 2).86–89 These systems grade ment resulting from CIPN. CIPN from grade 0 (normal) to 4 (severe) or 5 (death). However, variability is apparent among examiners and Recommendations different scoring systems. In a key study conducted For routine oncology practice, the Task Force panel by Postma et al.,90 2 neurologists independently rated strongly encourages physicians to actively query can��- the severity of CIPN in 37 patients using the NCIC- cer patients on signs and symptoms of neuropathy. CTCAE (adapted from the NCI-CTC), WHO, Before neurotoxic therapy is administered, a baseline ECOG, and Ajani scales. In 80% of the cases, the assessment should be performed and recorded. Iden-

Management of Neuropathy in Cancer

Table 2 Commonly Used Physician-Based Grading Scales for Evaluation of CIPN Scale Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 WHO87 Paresthesias and/ Severe Intolerable Paralysis NA or decreased paresthesias paresthesias and/or tendon reflexes and/or mild marked motor loss weakness ECOG88 Decreased deep Absent deep Disabling sensory Respiratory NA tendon reflexes, tendon loss, severe dysfunction mild paresthesias reflexes, severe peripheral secondary to or constipation paresthesias or neuropathic pain, weakness, constipation, obstipation, severe obstipation mild weakness weakness, bladder requiring dysfunction surgery, paralysis confining patient to bed/ wheelchair NCI-CTCAE (v3.0)89 Neuropathy-sensory Asymptomatic: Sensory Sensory alteration Disabling Death loss of deep alteration or or paresthesia tendon reflexes paresthesia interfering with or pasresthesia (including ADL (including tingling), tingling) but not interfering with interfering with function but function not with ADL Neuropathy-motor Asymptomatic, Symptomatic Weakness Life- Death weakness by weakness interfering with threatening: exam/testing interfering with ADL: bracing or disabling only function but assistance to walk (e.g.,paralysis) not interfering indicated with ADL Ajani86 Sensory Paresthesia, Mild objective Severe paresthesia, Complete NA decreased deep abnormality, moderate objective sensory loss, loss tendon reflexes absence of abnormality, of function deep tendon severe functional reflexes, mild abnormality to moderate functional abnormality Motor Mild or transient Persistent Unable to ambulate Complete NA muscle weakness moderate paralysis weakness but ambulatory

Abbreviations: ADL, activities of daily living; CIPN, chemotherapy-induced peripheral neuropathy; NA, not applicable; NCI- CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events. tifying pre-existing conditions that may predispose dose accumulation, early report of mild cases is im- patients to and potentially exacerbate CIPN is important for detecting the onset of neuropathy dur- perative. Of special concern are patients with hered- ing continuous monitoring. For a list of diagnostic itary motor and sensory neuropathies, such as Char- features of CIPN that distinguishes it from other cot-Marie-Tooth disease, who may develop severe types of neuropathy��, see Chemotherapy��-Induced�� Pe��- neuropathic paralysis when receiving vincristine. ripheral Neuropathy (page S-2). Routine assessment should continue during The main goal of routine clinical assessment is therapy. Because most cases of CIPN progress with to determine whether the patient is experiencing

NCCN Task Force Report

significant neuropathic symptoms that require inter- nosis. Similarly, the need for additional laboratory vention. For this purpose, the use of grading systems testing, imaging, or biopsying depends on the initial is helpful but not sufficient alone. In particular, pain clinical assessment. The decision to order these tests is a major symptom that is not well addressed by ex- is usually made by the specialist. isting scales. The panel suggests the following pain For clinical trials, multimodality assessment is assessment tools commonly used under other clini- preferable. Simple QST like the Von Frey or Neuro- cal settings: Brief Pain Inventory,96,97 Neuropathic pen may be easier for standardization than tests that Pain Scale,98,99 and Leeds Assessment of Neuropath- require extensive setup or equipment. Given the ic Symptoms and Signs Pain Scale (LANSS).100,101 high variability of commonly used physician-based Whether to intervene with the neuropathic symp- scoring systems, multicenter studies must reach a toms that arise depends on patient preference and consensus on the grading scale as well as interpreta- the medical judgment of the physician. tion of the chosen scale. As pointed out by panel- Table 3 lists recommendations by the NCCN ists, pain assessment and functional impairment are Task Force panel on the key points to include dur- critical endpoints, and the integration of pain scales ing assessment of neuropathy on a cancer patient. (Brief Pain Inventory, LANSS, Neuropathic Pain In addition to a history and physical examination, Scale), patient-based questionnaires (FACT, PNQ) functional assessment is critical. Simple skill tests and skill tests (timed pellet retrieval, pegboard test) and questions about activities of daily living provide is strongly encouraged. important information. Physicians can also refer to existing patient questionnaires.1,94,95 Panelists agree that referral to a specialist can Prevention also be helpful. This may be a neurologist or phys- Many agents have been proposed for preventing neu- iatrist (specialist in physical medicine and rehabili- ropathy caused by antineoplastic drugs. The mecha- tation) experienced in managing neuromuscular nisms by which most of these drugs might minimize disorders in the cancer setting. When pain is a pre- neuropathy are based on limited preclinical data and dominant issue, referral to a supportive care or pain informed opinion. Most of these agents have been management specialist may improve overall patient studied in clinical trials with designs inadequate for management. The exact point of referral will de- definitive assessment of the impact on neuropathy. pend on physician discretion and the infrastructure A few have been evaluated in randomized controlled of individual medical centers, but it is important trials. Most have been assessed during platinum- that such a system be in place. In general, oncolo- based chemotherapy. Table 4 lists these agents, the gists should consider referral when the patient case proposed mechanism for preventing CIPN, and find- is out of their usual clinical experience, such as ings from clinical trials.121 when a patient has atypical signs, severe symptoms, Vitamin E may mitigate neuropathy associated or underlying neuropathic disorders. with platinum-based chemotherapy. Three small, Specialists can help delineate the neuropathic open-labeled studies randomized 30 to 47 cancer etiology, which may affect decisions about cancer patients receiving chemotherapy mostly consisting treatment, suggest treatment, or point to resources of cisplatin to vitamin E or control.102–104 The ac- for patient support and rehabilitation (see Manage- tive arms were consistently associated with a lower ment of Functional Deficits, page S-17). However, incidence of CIPN (21%–31%) compared with the the panel emphasized that specialist scheduling control arm (69%–86%), with statistical significance should be in parallel with ongoing oncologist vis- (P < .03). The severity of neuropathy as measured by its so that logistics do not delay appropriate anti- toxicity scores was also reduced. neoplastic treatment. Communication between the A double-blinded, randomized, placebo-con- treating physician and specialist is essential. trolled study of 81 patients undergoing cisplatin Objective neurophysiologic testing is not suffi- - therapy is ongoing. Interim analysis of the first 50 ciently reliable to be used alone for decision making. patients showed a significantly lower median toxic- But such testing may be used as an adjunct to clini- ity score in the supplement group.105 Because vita- cal assessment for confirming or ruling out a- diag min E is an antioxidant, concerns have been raised

Management of Neuropathy in Cancer about the possibility that it may suppress chemo- Table 3 Key Points to Report During Clinical therapeutic efficacy by interfering with the oxida- Assessment of CIPN tive breakdown of DNA and membranes of cancer History cells. Preclinical models have shown no difference in • Personal history of neuropathy and CIPN from previous cisplatin-induced tumor inhibition with or without cancer treatment vitamin E.104,122 In a randomized study of 136 lung • Personal and family history of hereditary neuropathy (patients with Charcot-Marie Tooth disease should cancer patients receiving paclitaxel and carboplatin, avoid vincristine-based chemotherapy) multiple high-dose antioxidant supplementation • Related comorbid conditions (e.g., diabetes, HIV, including vitamin E affected neither the response Guillain-Barré syndrome, CIDP, radiculopathy) rate nor survival.123 These results are reassuring, but • Alcohol use a well-designed, adequately-powered trial to con- • Temporal profile: regimen dosage, duration, schedule, “coasting” effects firm the safety of vitamin E is important before its • Symptoms general adoption. • Type: sensory, motor, or autonomic Intravenous administration of calcium and mag- • Distribution: distal symmetric or asymmetric nesium (CaMg) has been proposed as prophylaxis • Severity against neurologic damage induced by oxaliplatin, • Pain assessment: BPI, LANSS, NPS on the basis that heightened extracellular calcium • Time course of CIPN, including onset and resolution of symptoms could facilitate closing of sodium channels, thereby • Treatment delays or discontinuation related to CIPN decreasing the hyperexcitability of neurons exposed Physical Examination 124 to oxaliplatin. Two concurrent randomized con- • Sensory assessment: light touch, vibration, trolled trials, N04C7 and CONcePT, were initiated proprioception, pin-prick, temperature to test the effect of CaMg on oxaliplatin-related neu- • Deep tendon reflex: presence, absence, diminishment ropathy. Both trials were terminated after CONcePT • Motor weakness investigators reported diminished response to che- • Autonomic symptoms (e.g., constipation, orthostatic hypotension, urinary dysfunction, sexual dysfunction) 125 motherapy in the CaMg arm. After study termina- • Related musculoskeletal abnormalities (e.g., tion, however, a subsequent independent radiology hammertoes, high or flattened arches) review suggested the opposite finding with respect to Sample Questions for Patient tumor response.121,126 • Do you feel numbness or tingling in your hands or Despite early termination, the N04C7 study re- feet? • Do you feel pain in your hands and feet? (Rate it on a vealed a reduction in CIPN incidence in the active scale of 0 to 10.) 106 127 arm. Gamelin et al. released an interim report • Do you feel like having gloves and stockings on? on their multicenter, double-blind trial (Neuroxa) • Do these sensations bother you? Are they getting randomizing patients on the FOLFOX4 regimen. worse? There was no difference in the response or survival • Do you feel weakness in your arms and legs? rates between the arms, but significantly lower fre- • Do you drop things often? • Have you fallen recently? quency and severity of neuropathy were seen in one • Do you have difficulty walking or climbing stairs? group (blind not yet broken). Future updates should • Do these sensations interfere with your work or daily clarify the effectiveness and safety of CaMg. activities? Despite various rationales for their evaluation, Examples of Functional Assessment Skill Tests other drugs such as amifostine, nimodipine, Org • Getting up and straight-line walking (observe gait and 2766, and rhuLIF have all failed to show clinical balance) benefit in randomized trials. Recently, new agents, • Name writing including acetyl-L-carnitine, alpha lipoic acid, and • Buttoning • Timed pellet retrieval (for clinical trials) vitamin B12/B6, have entered phase III randomized • Pegboard test (for clinical trials) clinical testing. Abbreviations: BPI, Brief Pain Inventory; CIDP, chronic Conclusions idiopathic demyelinating polyneuropathy; CIPN, Although several agents have shown potentially chemotherapy-induced peripheral neuropathy; LANSS, Leeds encouraging results as mitigators of neuropathy, Assessment of Neuropathic Symptoms and Signs Pain Scale; NPS, Neuropathic Pain Scale. current data are inadequate to recommend any for

NCCN Task Force Report

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 CIPN incidence reduced (104)106 oxalate (metabolite of oxaliplatin) Glutamine Upregulation of nerve growth factor CIPN incidence reduced (86)107 Glutathione Hampers accumulation of platinum adducts CIPN incidence reduced/trend towards reduction in DRG (50-151)108–110 N-acetylcysteine Antioxidant; increases blood concentrations Incidence of grade 2-4 neuropathy reduced (14)111 of glutathione Oxcarbazepine Inhibits high-frequency firing of nerves; Neuropathy incidence reduced (32)112 modulates ion channels 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 Not effective (66)114 repair 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, Vibration perception maintained (55)117 adrenocorticotrophic hormone analog 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 New trial: NCT00775645* regeneration 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 en- mendations for cancer patients is unclear. Larger dorse any of the existing agents. This lack of en- randomized controlled studies specifically in cancer dorsement reflects the small sample size and vari- are needed to delineate the safety and efficacy of able treatment regimens, modest observed effects, neuropathy prophylaxis, although these may be met and lingering concerns over impairment of efficacy with several challenges, as discussed previously. for anti-cancer therapy. In 2007, Albers et al.128 The panel was concerned by the inconsistency of performed a systematic review of 16 randomized end points used among the various trials examining controlled studies of neuroprotective agents (ami- neuropathy and potential interventions. Frequently, fostine, metal chelator diethyldithiocarbamate, discordance is apparent between symptom reports glutathione, Org 2766, and vitamin E) and found and objective measures, and satisfactory neuropathy the data inconclusive. Separate literature on the evaluation tools are currently lacking, as discussed use of neuron-protective agents has developed from previously. Panelists agreed that multimodal mea- the evaluation and treatment of non-cancer–relat- surement of functionality is of primary importance ed neuropathy, predominantly diabetic neuropathy. and the incorporation of simple skill tests (e.g., the Whether experience from non-chemotherapy–re- pegboard test) will add valuable information at a rela- lated neuropathies is relevant for clinical recom- tively low cost.

Management of Neuropathy in Cancer

Treatment sion. Radiation therapy and chemotherapy may also be of benefit when treating tumors responsive to Non-Cancer–Related Neuropathy these therapeutic modalities. Steroids or intravenous Treatment of neuropathy in cancer patients remains immunoglobulin may be effective against specific a challenge and depends on etiology. As discussed, subtypes of PND such as Lambert-Eaton myasthenic a main complication is that an individual patient syndrome and paraneoplastic dermatomyositis.130 may experience neuropathic symptoms caused by a Randomized trials have shown brief efficacy of combination of factors. Distinguishing CIPN from intravenous immunoglobulin in treating anti-MAG other types of neuropathy is important in deciding neuropathy.131,132 Current treatment schema also in- whether the antineoplastic treatment needs to be cludes rituximab133 and apheresis. For the rare poly- modified. Damage to the peripheral nervous system neuropathy, organomegaly, endocrinopathy, monoclo- at other levels, including the nerve root and plexus, nal gammopathy, and skin changes syndrome, surgery may mimic peripheral neuropathy. Care should be and radiation against the plasmaproliferative disorder taken in evaluation and exclusion of such disorders, is the mainstay of treatment; steroids are also effective. particularly in patients with a history of degenerative spine disease or radiation therapy that affects CIPN the nerve root or plexus. Identifying underlying neu- To date, no approved effective treatment is avail- ropathy is essential, because specific treatment or able for CIPN, although a number of medications management strategies are available for certain non- are useful for pain control (see subsequent sections). cancer–related neuropathies: Because CIPN symptoms may progress with cumu- • Hereditary: cancer patients with Charcot-Marie- lating exposure, close monitoring is necessary dur- Tooth disease should avoid vincristine-based ing chemotherapy. In severe cases, dose reduction or chemotherapy74 treatment discontinuation may be indicated at the • Diabetes: control of glucose level and weight, discretion of the treating oncologist, but this must be exercise, and pain relief can be helpful weighed against the oncologic risks. • Alcohol: avoiding alcohol, improving nutrition Symptom Management: Pain Medications (vitamin supplement), and pain relief can be Various pharmacologic agents have been tested in helpful symptom control trials to alleviate established neu- • HIV: controlling HIV and selecting medication ropathy. Drugs that have been approved by the FDA that has a low risk of contributing to neuropathy have been so based on their efficacy in reducing pain • Guillain-Barré syndrome: intravenous immuno- intensity for other types of neuropathic pain disor- 129 globulin (IVIg) and apheresis ders, mainly diabetic neuropathy and post-herpetic • Chronic idiopathic demyelinating polyneuropa- neuralgia. Most clinical trials on the use of other thy (CIDP): steroids, intravenous immunoglob- drugs to moderate CIPN have failed to yield posi- ulin, and apheresis tive findings,134–137 although results from 2 recent • Mononeuropathy (i.e., median mononeuropathy studies are more encouraging.138,139 To date, no agent causing carpel tunnel syndrome, ulnar mono- has been approved specifically for treating CIPN. neuropathy): resting hand splints, physical or Table 5 lists the medications that are currently be- occupational therapy, corticosteroid injection, ing used off-label to relieve the positive symptoms surgical decompression (it should be noted that of CIPN (pain, paresthesias, dysesthesias, allodynia). surgical decompression in patients on active an- It should be noted that none of these agents are ef- tineoplastic treatment was thought to be rela- fective in the treatment of negative neuropathic tively contraindicated by the panel) symptoms such as weakness or the loss of sensory Cancer-Related Neuropathy modalities, including light touch or proprioception. In most instances, control of the tumor remains a Many of these agents should be administered at a priority for stabilizing or improving cancer-related low starting dose and slowly titrated to the dose that neuropathic conditions. Surgery remains the most confers the best efficacy with limited side effects. efficient way to relieve symptoms, particularly when Specifications for administration and side effects are the neuropathy is the result of direct tumor compres- listed. Readers can also refer to the NCCN Clinical

NCCN Task Force Report

Table 5 Common Agents for Pain Management in Neuropathy

Duration of Drug Starting Dose Titration Maximum Dose Adequate Trial Potential Side Effects Duloxetine 20–30 mg/d No evidence that 120 mg/d 2 wk Nausea, xerostomia, higher dose is constipation, diarrhea more effective Gabapentin* 100–300 mg increase by 3600 mg 1–2 wk at max Somnolence, dizziness, GI nightly or 100–300 mg 3 (depending on tolerated dose symptoms, mild edema, 100–300 mg 3 times/day, every absorption) cognitive impairment times/d 1–7 days (elderly), exacerbation of gait problems 5% Lidocaine Maximum of 3 Non-applicable 3 patches 2 wk Rash/erythema patch patches daily

Opioids 5–15 mg every Convert to long- No ceiling effect 4–6 wk Constipation, nausea, (oxycodone, 4 h acting after 1 wk, vomiting (self-limited), morphine, titrate based on sedation, confusion, methadone) breakthrough use respiratory depression Pregabalin 25–50 mg 3 Increase by 50 mg/ 200 mg 3 times/d Unclear (likely Dizziness, somnolence, times/d dose after 1 wk 2–4 wk) xerostomia, edema, blurred vision, decreased concentration Tramadol 50 mg 1–2/d Increase by 50-100 400 mg/d (100 4 wk Dizziness, constipation, mg/d, individual mg 4 times/d); nausea, somnolence, doses every 3-7 elderly 300 mg/d orthostatic hypotension, days increased risk of seizure, serotonin syndrome Tricyclic Starting dose: Increase by 10-25 75–150 mg; may 6-8 wk; 1-2 wk Cardiovascular disease antidepressants 10-25 mg mg every 3-7 days increase if blood at max dose (needs screening), (amitriptyline,* nightly level of drug anticholinergic nortriptyline,* plus metabolite effects, interact with desipramine) <100 ng/mL drugs metabolized by cytochrome P450 2D6 (e.g., cimetidine, phenothiazine)

*Negative results in randomized controlled clinical trials on chemotherapy-induced peripheral neuropathy

Practice Guidelines in Oncology: Adult Cancer Pain of pregabalin (NCT00380874) in advanced colorec- (to view the most recent version of these guidelines, tal cancer patients was terminated due to insufficient visit the NCCN Web site at www.nccn.org) for pain conditional power to detect differences. Nonethe- management strategies in cancer patients. less, panelists reported from their clinical experience Antiepileptic Drugs: Gabapentin is an anti-epileptic that both pregabalin and gabapentin may be helpful drug widely used for neuropathic pain. In randomized in treating pain associated with CIPN. Compared controlled trials involving mixed populations, gaba- with gabapentin, pregabalin has similar and perhaps pentin was found to relieve pain and improve sleep, milder side effects, faster onset of action, better ab- mood, and quality of life.140–144 However, in a double- sorption, and less need for dosage titration. blinded, controlled, crossover trial (n = 115) gabap- Local Anesthetics: The 5% lidocaine patch has the entin was no better than placebo in reducing CIPN.137 advantage of minimal side effects (local rash) and Pregabalin has the same mechanism of action ease of administration. It has been shown to alleviate as gabapentin and is approved for the treatment of allodynia (a form of dysesthesia) mainly in patients diabetic neuropathy and post-herpetic neuralgia. with post-herpetic neuropathy,151 but has not been Its efficacy in reducing neuropathic pain has been shown to have a significant impact on pain intensity shown in 6 randomized trials.145–150 A phase IV trial in cancer patients with postsurgical pain.152

Management of Neuropathy in Cancer

Antidepressants: Duloxetine is a serotonin and agent. It has shown efficacy in relieving painful dia- norepinephrine reuptake inhibitor (SNRI) that betic neuropathy and improving patients’ quality of is effective in reducing pain in patients with dia- life.157,158 The maximum dose is 400 mg per day for betic neuropathy.153–155 It has the advantage of be- most adults and 300 mg per day for elderly patients. ing fast-acting, with rapid onset of action within The opioids morphine and oxycodone provide the first few doses. However, duloxetine should be analgesia and lessened sleep interference for dia- avoided in patients on tamoxifen because it will betic neuropathy when used alone or in combina- decrease the concentration of endoxifen, an active tion with gabapentin.141,159–161 Task Force members metabolite of tamoxifen. As a serotonin reuptake pointed out that although the opioid methadone is inhibitor, duloxetine is relatively contraindicated used frequently, its use is complicated by a very long when used with other drugs that affect serotonin half-life, effect on QT intervals, and many drug– reuptake, including the selective serotonin reup- drug interactions that can result in serious adverse take inhibitors, tricyclic antidepressants, tramadol, events. Current recommendations suggest that only and triptans commonly used to treat migraines for clinicians with experience administering methadone fear of causing the potentially fatal serotonin syn- should prescribe this medication. Other opioids (tra- drome. A randomized, placebo-controlled trial of madol, morphine, oxycodone) that have been tested duloxetine in cancer patients with CIPN is ongo- for neuropathy may be considered safer alternatives ing (NCT00489411). Another SNRI, venlafaxine, in treating CIPN. has recently been reported to reduce the incidence Other medications that have been studied in- of acute oxaliplatin-induced neuropathic pain com- clude lamotrigine,136 selective serotonin reuptake pared with placebo (35% vs. 76%) in a small trial inhibitors, mexiletine, 0.75% capsaicin, and intra- of 54 patients.139 venous lidocaine. However, these are not recom- Tricyclic antidepressants (TCAs; amitripty- mended for routine use because of mixed results or line, nortriptyline, and desipramine) are FDA-ap- safety issues. proved for relieving symptoms of depression, not Recommendations: Currently, the general approach neuropathic pain. Despite this, they were the first to pain medication for CIPN is to choose an agent class of nonopioid medications to gain widespread based on the clinician’s experience and expectation use in the treatment of neuropathic pain, based of efficacy and safety, and titrate that agent to the on benefits seen primarily in diabetic patients.156 maximal tolerated dose. If a single agent is effective, Unfortunately, studies of these agents are limited then it should be continued. If a single agent con- by substantial side effects (high drop-out rates) fers partial but incomplete benefit, then a second and their pharmacologic interactions with drugs agent with a different mechanism of action should metabolized by cytochrome P450 2D6. Their po- be chosen and added. If the first agent is ineffective tential negative impact on cardiovascular func- or poorly tolerated, then it should be discontinued tion necessitates screening, especially in elderly and another agent chosen and titrated. Often many patients. Despite TCA’s efficacy on diabetic neu- agents will be needed for adequate analgesia. Panel- ropathy, 2 randomized, placebo-controlled trials ists agreed that the clinical context of the treatment (n = 44 and 51, respectively) of amitriptyline and will determine the choice of medication. For exam- nortriptyline yielded negative results in patients ple, a fast-acting agent with low risk of nausea will with CIPN.134,135 Given these limitations, TCAs be most suitable for a patient going through active are not typically used as a first-line pain medica- adjuvant chemotherapy before surgery. Unfortunate- tion for CIPN. More recently, a topical gel formu- ly, there is inadequate evidence on the best order of lation BAK-PLO (baclofen, amitriptyline, and ket- administration and combination. Two randomized, amine in pluronic lecithin organogel) moderately double-blinded trials in 41 to 338 patients, primar- improved CIPN symptoms in a randomized trial of ily with diabetic neuropathy, showed more effective 208 cancer patients.138 pain reduction with the combination of an opioid Opioids: Tramadol is a centrally acting analgesic. It (morphine or oxycodone) and gabapentin compared is often considered a mild opioid but has other an- with gabapentin alone, with little exacerbation of algesic properties and may be considered a novel side effects.141,160

NCCN Task Force Report

Symptom Management: Neurostimulation the scalp. There is evidence that it alleviates pain for Therapies post-stroke central pain syndromes, but its effects are Medication is often insufficient to mitigate neuro- short-lived and moderate.163 pathic pain, and alternative nonpharmacological Electrical nerve stimulation, either transcutane- therapies have been investigated. In particular, elec- ous (TENS) or percutaneous, originally developed trical stimulation therapies, typically administered in the 1960s for treating nociceptive and muscu- by a specialist, have elicited some benefits. They are loskeletal syndromes, uses portable skin patches to generally considered reversible, although they vary pass electrical current through the cutaneous tissues. widely in their degree of invasiveness. These neuro- Nine small trials involving an aggregate of approxi- stimulation techniques are generally based on the mately 200 patients with neuropathic pain generally gate control theory proposed by Melzack and Wall;162 associate TENS with a positive effect on pain con- they are designed to relieve pain by somatotopically trol (reviewed by Cruccu et al.163). “masking” the affected area with non-painful stimu- One randomized study involving 41 diabetic lation of A-beta afferent fibers, thereby blocking patients showed a higher response rate with high- out the painful stimuli. Hence these modalities are frequency muscle stimulation (69%) than with seldom effective towards patients with deafferented TENS (25%). However, the study had no placebo.173 nerves leading to numbness or tingling. The Euro- Other studies have shown that acupuncture-like low pean Federation of Neurological Forces (EFNS)163 frequency TENS is better than sham stimulations. recently produced a detailed review and recom- An emerging technique called anodyne therapy mendations on these techniques for neuropathic uses monochromatic near-infrared photo energy pain. As with pain medications, most evidence sup- to increase circulation to nerves and reduce pain. porting neurostimulation came from studies on dia- Small studies (n = 21–27) have shown a benefit for betic or other types of neuropathy. Data on CIPN diabetic patients,174,175 but a strong placebo effect are anecdotal. was present in 2 randomized, sham-controlled tri- Spinal cord stimulation (SCS) involves the sur- als.174,176 Several panelists noted that burns are a gical placement of electrodes into the epidural space potential risk in patients with sensory deficits and that can send non-noxious electrical stimulation that no efficacy studies have been performed in on- across the spine to displace the painful sensation. cology patients. SCS has been shown to provide good pain relief in Recommendations: Current literature is inconclu- small case series of patients with refractory CIPN sive on the benefits of neurostimulation in treating (n = 2–4)164,165 and other types of neuropathy (n = CIPN, and more rigorous studies are needed. Despite 6–19).166–169 Long-term effects up to 8 years are re- a lack of evidence, panelists generally agreed that ported. Of note, SCS is an invasive technique that TENS can be a helpful adjuvant therapy for CIPN includes the risks and costs of surgery, although a patients with contraindications to or for whom pain temporary lead is typically tested for a trial period medication is ineffective, considering its ease of ap- before permanent implantation. There were initial plication, reversibility, and relatively low cost. concerns that cancer patients with SCS may suffer Complementary and Alternative Medicine neurologic injury during an MRI, but published case Therapies reports as well as panelists’ experience indicate that According to the National Center for Complemen- it is safe to perform MRI with the SCS temporarily tary and Alternative medicine, complementary and turned off.170–172 alternative medicine (CAM) is a group of diverse Similar techniques include motor cortex stimu- medical and health care systems, practices, and prod- lation and deep brain stimulation, which require ucts that are not generally considered part of con- surgical implantation into the brain. These proce- ventional medicine. CAM therapies have achieved dures are highly invasive and have little evidence widespread use among patients with neurologic dis- to support their use for treating neuropathic pain. orders. A questionnaire-based study found that 77 of High frequency (5–20 Hz) repetitive transcranial 180 (43%) patients with peripheral neuropathy used magnetic stimulation is a noninvasive technique CAM, such as megavitamins (35%) and acupunc- that applies the coil of a magnetic stimulator above ture (30%).177 In another report of 450 patients, pa-

Management of Neuropathy in Cancer tients indicated massage (35%), meditation (18%), Conclusions: The increasingly widespread use of and acupuncture (10%) as common self-care strate- CAM therapies among patients and the current gies for HIV-related peripheral neuropathy.178 paucity of evidence on their safety and efficacy in Clinical studies investigating natural products treating CIPN raise the need for more controlled, as prophylactics for neuropathy and neurostimula- sufficiently powered studies. Acupuncture is a more tion techniques for pain management have been promising approach supported by scientific plausibil- discussed in previous sections. Among other CAM ity, although the technique lacks standardization. As approaches, most research focused on acupuncture. with TENS, it is noninvasive and relatively inexpen- Originally from Chinese traditional medicine, mod- sive, and it may be considered as an adjunct option ern acupuncture is based on the theory that insertion in treating patients with medication-resistant CIPN. and manipulation of a needle at specific acupuncture Several natural products available to the public as points in the body induces signals in afferent nerves dietary supplements also showed promise, although that subsequently regulate spinal signal transmission their definitive efficacy has not been established. and neural pain perception. This theory is supported Management of Functional Deficits by preclinical studies and animal models (reviewed Cancer patients with CIPN often present with sig- 179 by Wang et al. ). nificant functional deficits especially as their condi- 180 Alimi et al. randomized 90 cancer patients tion worsens. These deficits may include decreased with mainly neuropathic pain to auricular acupunc- balance, gait abnormalities, muscle weakness, and ture and 2 placebo groups (acupuncture or auricular sensory loss, which can lead to an increased fall seeds at placebo points). At 2 months, pain inten- risk, difficulties in performing activities of daily liv- sity decreased by 36% from baseline with acupunc- ing, safety concerns, and diminished participation. ture versus 2% with placebo (P < .0001). Another Rehabilitation specialists, particularly physical and randomized controlled trial enrolling 250 patients occupational therapists, are uniquely qualified to as- with HIV-related neuropathy found that both acu- sess patients with CIPN and provide interventional puncture and amitriptyline reduced symptoms, with strategies (both remedial and compensatory) to help a favorable trend over placebo that did not reach patients either reverse or safely deal with these inter- statistical significance.181 A non-randomized trial related deficits. of 47 patients with idiopathic neuropathy reported The brain requires sensory and proprioceptive improvement both in symptoms and objective NCS information from the periphery to maintain balance; measurements for 76% of patients receiving acu- therefore, the sensory losses associated with CIPN puncture compared with only 15% receiving best can result in balance deficits. For example, Visovsky medical care.182 For CIPN, only one pilot, single- and Daly186 recorded a slight decline of 12% in bal- arm, prospective case series of 5 patients was per- ance over the course of 12-week carboplatin treat- formed. The pain scores were lowered in all patients ment in cancer patients. Similarly, Wampler et al.187 (average 8 points reduced to average 3 points) after significantly correlated increasing balance deficits two 6-week courses of acupuncture.183 with increasing CIPN severity in 20 breast cancer Evidence is scarce on the efficacy of other CAM patients who had received taxane chemotherapy. therapies on neuropathic symptoms. Case series of Clinical assessments of balance can be made using successful treatment of neuropathic pain by biofeed- simple tests such as the Single Limb Stance Test (time back have been reported,184 but no data from pro- patient can stand on one leg), Tandem Standing Test spective trials are available. Dietary supplements (time patient can stand heel to toe), or the Timed Up have also been studied for prevention and treat- and Go test (the patient stands up, walks 10 feet, returns ment of neuropathy. They include alpha-lipoic acid, and sits down), or more complex tests such as the Berg acetyl-L-carnitine, benfotiamine, methylcobala- balance test or the Rhomberg balance test. Computer- min, topical capsaicin, vitamin E, glutathione, fo- based biomechanical analysis of balance, which pro- late, pyridoxine, biotin, myo-inositol, omega-3 and vides quantitative assessment, is increasingly available -6 fatty acids, L-arginine, L-glutamine, taurine, N- for use in a clinical setting.188 Questionnaires like the acetylcysteine, zinc, magnesium, chromium, and St. Activities-Specific Balance Confidence Scale are also John’s wort.185 used clinically to evaluate balance.

NCCN Task Force Report

Therapeutic interventions aimed at improving trasts), and increasing diligence when the patient balance typically involve progressive task training is in a novel environment should be provided. For starting with static standing activities (firm and hard patients with CIPN who also have cognitive, vi- surfaces) and then advancing first to static standing sual, or auditory deficits, caregiver education is of coupled with simple manipulation activities (e.g., particular importance. holding a glass of water, passing a basketball), then The presence of peripheral neuropathy can also to walking (different surfaces) and finally to walk- contribute to detrimental changes in gait patterns. ing coupled with simple manipulation activities.189 In a study of 24 older women, those with peripheral Modification or elimination of visual input can also neuropathy showed a gait pattern that was slower be included to make these tasks more demanding. and less efficient as measured by various gait param- In a case report discussing a patient with stage III eters (e.g., increased step time) than the control breast cancer with docetaxel-associated neuropathy, group, with differences magnified under challenging such a program (45–60 minutes per session, 2 times walking environments.194 Clinical gait assessment per week, 4 weeks total) improved the patient’s sense involves visual and auditory observation of gait pat- of balance.190 tern, shoe wear (e.g., marred shoe top may indicate Gait training and lower extremity strengthening foot drag), foot slap, and toe dragging. Biomechani- exercises are important therapeutic activities that cal analysis systems are available that provide sophis- improve balance, as shown by a study (n = 20) of ticated quantitative analysis of specific gait param- diabetic patients undergoing intense daily strength- eters. Gait training typically incorporates balance ening exercises (e.g., toe raises, heel raises, wall training, lower extremity strengthening, endurance slides). Compared with a control exercise regimen, activities, and walking under simple (smooth, level these strengthening exercise significantly enhanced surface) and complex conditions (time constraints, balance.191 Assistive devices including canes, walk- physical load, and terrain obstacles). Labor-intensive ers, wheelchairs, and ankle-foot orthoses may also be programs, such as training with body weight support recommended, less to reverse this deficit and more to systems, are more widely used for stroke patients compensate for it. but may be useful for patients with CIPN. Appro- Although the incidence of falls in patients with priate assistive devices (canes, walkers, and ankle- CIPN has not been reported, the risk for falls is 5 foot orthoses) can also be helpful for improving times greater in older patients with peripheral neu- gait characteristics.195 ropathy than in healthy age-matched controls.192 Identifying muscle weakness caused specifically Therefore, rehabilitation staff must be particularly by CIPN is difficult because this condition can be the alert to an increased fall risk in patients with CIPN. result of a variety of factors already present in many Asking cancer patients whether they have fallen re- cancer patients, including deconditioning, fatigue, cently is a simple screening question for determining nutritional deficiency, sleep disorders, depression, heightened fall risk. Impaired gait and balance are medication regimens, and pre-existing neurologic the most reliable predictors of this serious medical disorders. Chemotherapeutic agents that cause CIPN problem.193 Results from clinical tests such as the damage sensory neurons much more frequently than timed up and go, single limb stance, gait analysis, motor neurons, reducing the likelihood that muscle and sensory assessment also provide further assess- weakness is associated with CIPN. Of note, many ment of fall risk in CIPN patients. cancer patients receive corticosteroids, a drug well- Therapeutic interventions aimed at reducing known for its muscle-wasting effects, particularly on fall risk typically include lower extremity strength- respiratory and proximal lower extremity muscles. ening exercises and gait training combined with Regardless of the cause of muscle weakness, balance training and issuance of assistive devices. muscle function must be assessed in these patients. Patient and caregiver education regarding issues Manual muscle testing of specific muscles or muscle such as recognizing potential environmental haz- groups is the most frequently used method of assess- ards, performing necessary home and environmen- ing muscle strength. Hand-held dynamometers can tal modifications (removing throw rugs, installing be used to directly measure specific muscle strength adequate lighting, and maximizing visual con- or infer muscle strength such as grip strength. Ul-

Management of Neuropathy in Cancer trasound is used to image skeletal muscle for archi- Table 6 Safety Notes and Tips in the tectural changes consistent with decreases in muscle Management of Functional Deficits strength. Therapeutic management schemes for in- Avoid or Discontinue Physical Training If: 197 creasing muscle strength are similar whether muscle • Resting diastolic blood pressure > 115 mm Hg or loss is attributable directly to CIPN or indirectly to resting systolic blood pressure > 200 mm Hg other cancer-related causes. Resistance training is • Diastolic pressure rises > 10 mm Hg above resting value consistently shown to be effective in improving mus- and systolic pressure > 250 mm Hg cle strength. For example, a 9-hour weekly training • Heart rate to increase with increasing exertional program over 6 weeks increased muscular strength demand by an average of 41% in 70 cancer patients undergo- • Signs of poor perfusion (light-headedness, confusion, 196 pallor, cyanosis, or cold and clammy skin) are present ing chemotherapy. One key to a successful exercise or become present program is to distinguish patients who require super- • Angina or angina like symptoms are present or begin vision in an inpatient or outpatient training program • Body temperature > 38°C from self-motivated patients who often derive com- • Hemoglobin < 8.0 g/dL parable or greater benefit from participating in a self- • Ongoing bleeding or fresh petechiae or bruises are directed exercise program. presnt; sample question: “Do you bleed often while Special attention must be paid to safety for can- brushing your teeth?” cer patients engaging in exercise and physical train- Footwear ing (Table 6). Physicians and rehabilitation thera- • Avoid heels pists should observe contraindications for training • Insoles should not be too soft 196 to avoid injury and symptom exacerbation. Atten- • Grip surface on shoes tion must also be paid to the use of proper footwear, • Loafer-style, Velcro straps if having difficulty with daily foot inspections, and reporting foot injury. shoelaces As with muscle weakness, cancer patients with • Examine feet for signs of injury including abrasions, CIPN may have difficulties performing activities of blisters, etc. daily living because of sensory and motor loss. Suc- Orthosis cessful rehabilitation of these deficits requires that • Watch out for skin abrasion they first be identified. Then strategies must be -de • Wear protective clothing underneath the orthosis veloped to either correct or compensate for the defi- • Select good shoes with proper support, have a closed cit and maximize patient independence. Therapeutic back and toe, come up over the top of the feet and interventions may include musculoskeletal therapies have a slightly wider width to accommodate the (strengthening, range of motion), environmental orthoses modification, teaching energy conservation - tech • Remove if pain occurs, see the orthotist if pain persists niques, and providing adaptive equipment. Practical Household Environment adaptive approaches adopted by occupational thera- • Avoid or protect against thermal stress (reduce hot water temperature, wear gloves, use potholders) pists are very helpful: • Modifying tasks, such as switching to loafer-style • Keep rooms well-lit, use night lights shoes or using Velcro shoe laces • Remove or tack down loose rugs • Providing adaptive equipment, such as enlarged • Tidy loose wires across hallways handles on eating utensils, buttonhooks, Velcro • Use non-skid bath mats on computer keys to stimulate sensation • Employ energy conservation • Teaching increased use of vision and attention when performing household tasks Recommendations: The Task Force panel empha- • Increasing proprioceptive input, such as sized the importance of physicians integrating the putting weights on the patient’s arm for better identification and assessment of functional deficits proprioception into the evaluation of patients with CIPN. Sample • Educating patients on protective household questions and simple skill tests that oncologists can adaptation use to accomplish this are listed in Table 3. Overall, • Strengthening panelists strongly recommend referring patients with

NCCN Task Force Report

CIPN that interferes with functioning to a physical terization (reviewed by Selius and Subedi200). Low- or occupational therapist. Therapeutic interven- friction, hydrophilic-coated catheters are preferable tions, education, and practical advice provided by over regular catheters for the prevention of urinary these rehabilitation specialists can prove invalu- tract infection. Use of urethral indwelling catheters able in helping patients to both correct CIPN-in- is not recommended due to possible complications duced functional deficits and to cope with the dif- such as sepsis, stones, prostatitis, urethral erosions, ficulties and challenges these deficits cause in their and development of squamous cell carcinoma. everyday life. Constipation can also be related to underlying Management of Autonomic Symptoms medical disorders, including obstruction by tumor, Although CIPN primarily affects sensory nerves, au- electrolyte abnormalities, and endocrine dysfunc- tonomic impairment is sometimes seen after the use tion such as hypothyroidism, and worsened by treat- of antineoplastic agents such as vincristine, cisplatin, ment with medications, particularly opioids. A well carboplatin, paclitaxel, and bortezomib. For exam- thought-out bowel program may include adequate ple, in a phase II study of bortezomib in patients with water and fiber intake, stool softeners, and, when metastatic neuroendocrine tumors, 6 of 10 patients needed, cathartic agents. The timing of cathartic with moderate sensory neuropathy also experienced agents should be deliberate, with the goal of produc- grade 2 to 3 dizziness, orthostasis, syncope, ileus, or ing bowel movement at a specific time of day. For abdominal cramping.198 As discussed, it is difficult instance, the use of agents before sleep coupled with to specifically attribute neuropathic symptoms to a the ingestion of breakfast and warm liquid may help single drug because other cancer-related factors may reliably produce a morning bowel movement in some also be involved. Autonomic neuropathy induced patients. Methylnaltrexone is an effective medica- 201,202 by chemotherapy has not been well documented tion for opioid-induced constipation, but its ef- or studied. ficacy is unclear when constipation is related to au- Recommendations: Autonomic dysfunction can tonomic neuropathy from chemotherapy. manifest with a wide variety of symptoms. The more common symptoms seen in patients undergoing chemotherapy are dizziness or lightheadedness related to Conclusions orthostatic hypotension, bloating, urinary retention, With the continued use of neurotoxic drugs, emer- constipation or diarrhea, and impotence. The EFNS gence of newer neuropathy-inducing antineoplastic developed guidelines on the management of ortho- agents, and the adoption of dose-dense regimens, the static hypotension.199 Advice for mild cases include problem of CIPN is more relevant than ever in on- getting up slowly (supine position to sitting, sitting cology. In reviewing the current literature, panelists to standing) as well as maintaining adequate salt in- noted a paucity of rigorous studies on the assessment, take and hydration. Abdominal binders or graded prevention, and management of cancer treatment– compression stockings decrease venous pooling and related neuropathy. More well-designed, sufficiently may be helpful for some patients. For more severe powered trials specifically on patients with CIPN are cases, midodrine, fludrocortisone, or their combina- necessary to validate evaluation tools, explore differ- tion may be prescribed. ent combinations and sequence of pain medications, Urinary retention can often be related to un- and test the efficacy and safety of therapeutic meth- derlying medical disorders such as benign prostatic ods and preventative supplements. hyperplasia or an obstructive tumor and worsened by In the interim, improving education and aware- treatment with medications that have anticholiner- ness within both the medical and general commu- gic properties such as TCAs and opioids. In such cas- nity will be an essential primer in efforts to over- es, discontinuation of the offending agent may result come neuropathy. Physician and patient education in resolution of symptoms. The addition of alpha- are required to address the issues of underdiagnosis, blocking medications may be indicated in patients underassessment, and failure of intervention. Patient with benign prostatic hyperplasia. Chronic urinary participation in clinical trials is strongly encouraged. retention from neurogenic bladder can be effectively While the community awaits more study data, managed using hygienic, intermittent self-cathe- existing measures can aid patients with CIPN. A

Management of Neuropathy in Cancer number of medications are available to mitigate neu- 15. Park SB, Goldstein D, Lin CS, et al. Acute abnormalities of sensory nerve function associated with oxaliplatin-induced ropathic pain, as are various interventional measures neurotoxicity. J Clin Oncol 2009;27:1243–1249. and devices to improve or compensate for functional 16. Becouarn Y, Ychou M, Ducreux M, et al. Phase II trial of deficits. For patients for whom pain medications are oxaliplatin as first-line chemotherapy in metastatic colorectal ineffective, noninvasive techniques such as TENS or cancer patients. Digestive Group of French Federation of Cancer Centers. J Clin Oncol 1998;16:2739–2744. acupuncture may be considered. 17. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938–2947. References 18. Giacchetti S, Perpoint B, Zidani R, et al. Phase III multicenter 1. Hausheer FH, Schilsky RL, Bain S, et al. Diagnosis, management, randomized trial of oxaliplatin added to chronomodulated and evaluation of chemotherapy-induced peripheral neuropathy. fluorouracil-leucovorin as first-line treatment of metastatic Semin Oncol 2006;33:15–49. colorectal cancer. J Clin Oncol 2000;18:136–147. 19. Maindrault-Goebel F, de Gramont A, Louvet C, et al. High-dose 2. Langkjer ST, Ejlertsen B, Mouridsen H, et al. Vinorelbine as first- intensity oxaliplatin added to the simplified bimonthly leucovorin line or second-line therapy for advanced breast cancer: a phase and 5-fluorouracil regimen as second-line therapy for metastatic I-II trial by the Danish Breast Cancer Co-operative Group. Acta colorectal cancer (FOLFOX 7). Eur J Cancer 2001;37:1000–1005. Oncol 2008;47:735–739. 20. Maindrault-Goebel F, Louvet C, Andre T, et al. Oxaliplatin 3. Pal PK. Clinical and electrophysiological studies in vincristine added to the simplified bimonthly leucovorin and 5-fluorouracil induced neuropathy. Electromyogr Clin Neurophysiol regimen as second-line therapy for metastatic colorectal cancer 1999;39:323–330. (FOLFOX6). GERCOR. Eur J Cancer 1999;35:1338–1342. 4. Park SB, Krishnan AV, Lin CS, et al. Mechanisms underlying 21. Windebank AJ, Grisold W. Chemotherapy-induced neuropathy. J chemotherapy-induced neurotoxicity and the potential for Peripher Nerv Syst 2008;13:27–46. neuroprotective strategies. Curr Med Chem 2008;15:3081–3094. 22. Pace A, Bove L, Nistico C, et al. Vinorelbine neurotoxicity: 5. Siegal T, Haim N. Cisplatin-induced peripheral neuropathy: clinical and neurophysiological findings in 23 patients. J Neurol Frequent off-therapy deterioration, demyelinating syndromes, and Neurosurg Psychiatry 1996;61:409–411. muscle cramps. Cancer 1990;66:1117–1123. 23. Postma TJ, Benard BA, Huijgens PC, et al. Long-term effects 6. Cassidy J, Misset JL. Oxaliplatin-related side effects: characteristics of vincristine on the peripheral nervous system. J Neurooncol and management. Semin Oncol 2002;29:11–20. 1993;15:23–27. 7. Gamelin E, Gamelin L, Bossi L, Quasthoff S. Clinical aspects and 24. Verstappen CC, Koeppen S, Heimans JJ, et al. Dose-related molecular basis of oxaliplatin neurotoxicity: current management vincristine-induced peripheral neuropathy with unexpected off- and development of preventive measures. Semin Oncol therapy worsening. Neurology 2005;64:1076–1077. 2002;29:21–33. 25. Jones SE, Erban J, Overmoyer B, et al. Randomized phase III study 8. Platinol label information. Available at: http://dailymed.nlm.nih. of docetaxel compared with paclitaxel in metastatic breast cancer. gov/dailymed/drugInfo.cfm?id=4915#nlm34084-4. Accessed: July J Clin Oncol 2005;23:5542–5551. 1, 2009. 26. Lee JJ, Swain SM. Peripheral neuropathy induced by microtubule- 9. Carboplatin label information. Available at: http://dailymed.nlm. stabilizing agents. J Clin Oncol 2006;24:1633–1642. nih.gov/dailymed/drugInfo.cfm?id=4325#nlm34084-4. Accessed: 27. Paridaens R, Biganzoli L, Bruning P, et al. Paclitaxel versus July 1, 2009. doxorubicin as first-line single-agent chemotherapy for metastatic 10. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin breast cancer: a European Organization for Research and and paclitaxel compared with cisplatin and paclitaxel in patients Treatment of Cancer randomized study with cross-over. J Clin Oncol 2000;18:724–733. with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2003;21:3194–3200. 28. Seidman AD, Berry D, Cirrincione C, et al. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel 11. Rosell R, Gatzemeier U, Betticher DC, et al. Phase III randomised for metastatic breast cancer, with trastuzumab for all HER-2 trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in overexpressors and random assignment to trastuzumab or not in patients with advanced non-small-cell lung cancer: a cooperative HER-2 nonoverexpressors: final results of Cancer and Leukemia multinational trial. Ann Oncol 2002;13:1539–1549. Group B protocol 9840. J Clin Oncol 2008;26:1642–1649. 12. Lilenbaum R, Axelrod R, Thomas S, et al. Randomized phase 29. Smith RE, Brown AM, Mamounas EP, et al. Randomized trial of II trial of erlotinib or standard chemotherapy in patients with 3-hour versus 24-hour infusion of high-dose paclitaxel in patients advanced non-small-cell lung cancer and a performance status of with metastatic or locally advanced breast cancer: National 2. J Clin Oncol 2008;26:863–869. Surgical Adjuvant Breast and Bowel Project protocol B-26. J Clin 13. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus Oncol 1999;17:3403–3411. platinum-based chemotherapy versus conventional platinum- 30. Winer EP, Berry DA, Woolf S, et al. Failure of higher-dose based chemotherapy in women with relapsed ovarian cancer: the paclitaxel to improve outcome in patients with metastatic breast ICON4/AGO-OVAR-2.2 trial. Lancet 2003;361:2099–2106. cancer: Cancer and Leukemia Group B trial 9342. J Clin Oncol 14. Pfisterer J, Vergote I, Du Bois A, Eisenhauer E. Combination 2004;22:2061–2068. therapy with gemcitabine and carboplatin in recurrent ovarian 31. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial cancer. Int J Gynecol Cancer 2005;15(Suppl 1):36–41. of nanoparticle albumin-bound paclitaxel compared with

NCCN Task Force Report

polyethylated castor oil-based paclitaxel in women with breast 49. Tosi P, Zamagni E, Cellini C, et al. Neurological toxicity of cancer. J Clin Oncol 2005;23:7794–7803. long-term (>1 yr) thalidomide therapy in patients with multiple 32. Perez EA, Vogel CL, Irwin DH, et al. Multicenter phase II trial of myeloma. Eur J Haematol 2005;74:212–216. weekly paclitaxel in women with metastatic breast cancer. J Clin 50. von Lilienfeld-Toal M, Hahn-Ast C, Furkert K, et al. A Oncol 2001;19:4216–4223. systematic review of phase II trials of thalidomide/dexamethasone 33. Fountzilas G, Tsavdaridis D, Kalogera-Fountzila A, et al. Weekly combination therapy in patients with relapsed or refractory paclitaxel as first-line chemotherapy and trastuzumab in patients multiple myeloma. Eur J Haematol 2008;81:247–252. with advanced breast cancer. A Hellenic Cooperative Oncology 51. Mileshkin L, Stark R, Day B, et al. Development of neuropathy Group phase II study. Ann Oncol 2001;12:1545–1551. in patients with myeloma treated with thalidomide: patterns of 34. Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the occurrence and the role of electrophysiologic monitoring. J Clin adjuvant treatment of breast cancer. N Engl J Med 2008;358:1663– Oncol 2006;24:4507–4514. 1671. 52. Molloy FM, Floeter MK, Syed NA, et al. Thalidomide neuropathy 35. Rizvi NA, Riely GJ, Azzoli CG, et al. Phase I/II trial of weekly in patients treated for metastatic prostate cancer. Muscle Nerve intravenous 130-nm albumin-bound paclitaxel as initial 2001;24:1050–1057. chemotherapy in patients with stage IV non-small-cell lung 53. Richardson P, Schlossman R, Jagannath S, et al. Thalidomide cancer. J Clin Oncol 2008;26:639–643. for patients with relapsed multiple myeloma after high-dose 36. Burstein HJ, Manola J, Younger J, et al. Docetaxel administered chemotherapy and stem cell transplantation: results of an open- on a weekly basis for metastatic breast cancer. J Clin Oncol label multicenter phase 2 study of efficacy, toxicity, and biological 2000;18:1212–1219. activity. Mayo Clin Proc 2004;79:875–882. 37. Hilkens PH, Verweij J, Stoter G, et al. Peripheral neurotoxicity 54. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus induced by docetaxel. Neurology 1996;46:104–108. dexamethasone for relapsed or refractory multiple myeloma. N 38. New PZ, Jackson CE, Rinaldi D, et al. Peripheral neuropathy Engl J Med 2007;357:2123–2132. secondary to docetaxel (Taxotere). Neurology 1996;46:108–111. 55. Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 39. Badros A, Goloubeva O, Dalal JS, et al. Neurotoxicity of 2 study of lenalidomide therapy for patients with relapsed or bortezomib therapy in multiple myeloma: a single-center relapsed and refractory multiple myeloma. Blood 2006;108:3458– experience and review of the literature. Cancer 2007;110:1042– 3464. 1049. 56. Stubblefield MD, Slovin S, MacGregor-Cortelli B, et al. 40. Jagannath S, Barlogie B, Berenson J, et al. A phase 2 study of An electrodiagnostic evaluation of the effect of pre-existing two doses of bortezomib in relapsed or refractory myeloma. Br J peripheral nervous system disorders in patients treated with the Haematol 2004;127:165–172. novel proteasome inhibitor bortezomib. Clin Oncol (R Coll 41. Jagannath S, Durie BG, Wolf J, et al. Bortezomib therapy alone Radiol) 2006;18:410–418. and in combination with dexamethasone for previously untreated 57. Basch E, Iasonos A, McDonough T, et al. Patient versus symptomatic multiple myeloma. Br J Haematol 2005;129:776– clinician symptom reporting using the National Cancer Institute 783. Common Terminology Criteria for Adverse Events: results of a 42. Mateos MV, Hernandez JM, Hernandez MT, et al. Bortezomib questionnaire-based study. Lancet Oncol 2006;7:903–909. plus melphalan and prednisone in elderly untreated patients with 58. Shimozuma K, Ohashi Y, Takeuchi A, et al. Feasibility and multiple myeloma: results of a multicenter phase 1/2 study. Blood validity of the Patient Neurotoxicity Questionnaire during taxane 2006;108:2165–2172. chemotherapy in a phase III randomized trial in patients with 43. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study breast cancer: N-SAS BC 02. Support Care Cancer 2009; in press. of bortezomib in relapsed, refractory myeloma. N Engl J Med 59. Stephens RJ, Hopwood P, Girling DJ, Machin D. Randomized 2003;348:2609–2617. trials with quality of life endpoints: are doctors’ ratings of patients’ 44. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, physical symptoms interchangeable with patients’ self-ratings? characteristics, and reversibility of peripheral neuropathy during Qual Life Res 1997;6:225–236. treatment of advanced multiple myeloma with bortezomib. J Clin 60. Louis TA, Lavori PW, Bailar JC III, Polansky M. Crossover Oncol 2006;24:3113–3120. and self-controlled designs in clinical research. N Engl J Med 45. Perez EA, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone 1984;310:24–31. (BMS-247550) in a phase II study of patients with advanced breast 61. Sindrup SH, Andersen G, Madsen C, et al. Tramadol relieves pain cancer resistant to an anthracycline, a taxane, and capecitabine. J and allodynia in polyneuropathy: a randomised, double-blind, Clin Oncol 2007;25:3407–3414. controlled trial. Pain 1999;83:85–90. 46. Thomas ES, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine 62. Loprinzi CL, Kugler JW, Sloan JA, et al. Lack of effect of coumarin for metastatic breast cancer progressing after anthracycline and in women with lymphedema after treatment for breast cancer. N taxane treatment. J Clin Oncol 2007;25:5210–5217. Engl J Med 1999;340:346–350. 47. Offidani M, Corvatta L, Marconi M, et al. Common and rare 63. Loprinzi CL, Sloan JA, Perez EA, et al. Phase III evaluation of side-effects of low-dose thalidomide in multiple myeloma: focus fluoxetine for treatment of hot flashes. J Clin Oncol 2002;20:1578– on the dose-minimizing peripheral neuropathy. Eur J Haematol 1583. 2004;72:403–409. 64. Pockaj BA, Gallagher JG, Loprinzi CL, et al. Phase III double- 48. Plasmati R, Pastorelli F, Cavo M, et al. Neuropathy in multiple blind, randomized, placebo-controlled crossover trial of black myeloma treated with thalidomide: a prospective study. Neurology cohosh in the management of hot flashes: NCCTG trial N01CC1. 2007;69:573–581. J Clin Oncol 2006;24:2836–2841.

Management of Neuropathy in Cancer

65. Cavaletti G, Fabbrica D, Minoia C, et al. Carboplatin toxic 83. du Bois A, Schlaich M, Luck HJ, et al. Evaluation of neurotoxicity effects on the peripheral nervous system of the rat. Ann Oncol induced by paclitaxel second-line chemotherapy. Support Care 1998;9:443–447. Cancer 1999;7:354–361. 66. McDonald ES, Windebank AJ. Cisplatin-induced apoptosis 84. Forsyth PA, Balmaceda C, Peterson K, et al. Prospective study of DRG neurons involves bax redistribution and cytochrome c of paclitaxel-induced peripheral neuropathy with quantitative release but not fas receptor signaling. Neurobiol Dis 2002;9:220– sensory testing. J Neurooncol 1997;35:47–53. 233. 85. Chaudhry V, Rowinsky EK, Sartorius SE, et al. Peripheral 67. Tulub AA, Stefanov VE. Cisplatin stops tubulin assembly into neuropathy from taxol and cisplatin combination chemotherapy: microtubules. A new insight into the mechanism of antitumor clinical and electrophysiological studies. Ann Neurol activity of platinum complexes. Int J Biol Macromol 2001;28:191– 1994;35:304–311. 198. 86. Ajani JA, Welch SR, Raber MN, et al. Comprehensive criteria 68. Benoit E, Brienza S, Dubois JM. Oxaliplatin, an anticancer for assessing therapy-induced toxicity. Cancer Invest 1990;8:147– agent that affects both Na+ and K+ channels in frog peripheral 159. myelinated axons. Gen Physiol Biophys 2006;25:263–276. 87. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting 69. Grolleau F, Gamelin L, Boisdron-Celle M, et al. A possible results of cancer treatment. Cancer 1981;47:207–214. explanation for a neurotoxic effect of the anticancer agent 88. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response oxaliplatin on neuronal voltage-gated sodium channels. J criteria of the Eastern Cooperative Oncology Group. Am J Clin Neurophysiol 2001;85:2293–2297. Oncol 1982;5:649–655. 70. Cavaletti G, Tredici G, Braga M, Tazzari S. Experimental 89. National Cancer Institute. National Cancer Institute-Common peripheral neuropathy induced in adult rats by repeated Terminology Criteria for Adverse Events (NCI-CTCAE), version intraperitoneal administration of taxol. Exp Neurol 1995;133:64– 3.0. Available at: http://ctep.cancer.gov/protocolDevelopment/ 72. electronic_applications/docs/ctcaev3.pdf. Accessed July 8, 2009. 71. Macfarlane BV, Wright A, Benson HA. Reversible blockade of 90. Postma TJ, Heimans JJ, Muller MJ, et al. Pitfalls in grading retrograde axonal transport in the rat sciatic nerve by vincristine. severity of chemotherapy-induced peripheral neuropathy. Ann J Pharm Pharmacol 1997;49:97–101. Oncol 1998;9:739–744. 72. Sahenk Z, Brady ST, Mendell JR. Studies on the pathogenesis of 91. Postma TJ, Heimans JJ. Grading of chemotherapy-induced vincristine-induced neuropathy. Muscle Nerve 1987;10:80–84. peripheral neuropathy. Ann Oncol 2000;11:509–513. 73. Topp KS, Tanner KD, Levine JD. Damage to the cytoskeleton 92. Cavaletti G, Jann S, Pace A, et al. Multi-center assessment of of large diameter sensory neurons and myelinated axons in the Total Neuropathy Score for chemotherapy-induced peripheral neurotoxicity. J Peripher Nerv Syst 2006;11:135–141. vincristine-induced painful peripheral neuropathy in the rat. J Comp Neurol 2000;424:563–576. 93. Cavaletti G, Frigeni B, Lanzani F, et al. The Total Neuropathy Score as an assessment tool for grading the course of chemotherapy- 74. Weimer LH, Podwall D. Medication-induced exacerbation induced peripheral neurotoxicity: comparison with the National of neuropathy in Charcot Marie Tooth disease. J Neurol Sci Cancer Institute-Common Toxicity Scale. J Peripher Nerv Syst 2006;242:47–54. 2007;12:210–215. 75. Fabrizi GM, Cavallaro T, Angiari C, et al. Charcot-Marie- 94. Calhoun EA, Welshman EE, Chang CH, et al. Psychometric Tooth disease type 2E, a disorder of the cytoskeleton. Brain evaluation of the Functional Assessment of Cancer Therapy/ 2007;130:394–403. Gynecologic Oncology Group-Neurotoxicity (Fact/GOG-Ntx) 76. Zhao C, Takita J, Tanaka Y, et al. Charcot-Marie-Tooth disease questionnaire for patients receiving systemic chemotherapy. Int J type 2A caused by mutation in a microtubule motor KIF1Bbeta. Gynecol Cancer 2003;13:741–748. Cell 2001;105:587–597. 95. Cella D, Peterman A, Hudgens S, et al. Measuring the side effects 77. Chaudhry V, Cornblath DR, Corse A, et al. Thalidomide-induced of taxane therapy in oncology: the functional assesment of cancer neuropathy. Neurology 2002;59:1872–1875. therapy-taxane (FACT-taxane). Cancer 2003;98:822–831. 78. Cavaletti G, Gilardini A, Canta A, et al. Bortezomib-induced 96. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief peripheral neurotoxicity: a neurophysiological and pathological Pain Inventory. Ann Acad Med Singapore 1994;23:129–138. study in the rat. Exp Neurol 2007;204:317–325. 97. Tittle MB, McMillan SC, Hagan S. Validating the brief pain 79. Csizmadia V, Raczynski A, Csizmadia E, et al. Effect of an inventory for use with surgical patients with cancer. Oncol Nurs experimental proteasome inhibitor on the cytoskeleton, cytosolic Forum 2003;30:325–330. protein turnover, and induction in the neuronal cells in vitro. 98. Galer BS, Jensen MP. Development and preliminary validation of Neurotoxicology 2008;29:232–243. a pain measure specific to neuropathic pain: the Neuropathic Pain 80. Poruchynsky MS, Sackett DL, Robey RW, et al. Proteasome Scale. Neurology 1997;48:332–338. inhibitors increase tubulin polymerization and stabilization 99. Jensen MP, Friedman M, Bonzo D, Richards P. The validity of the in tissue culture cells: a possible mechanism contributing to neuropathic pain scale for assessing diabetic neuropathic pain in a peripheral neuropathy and cellular toxicity following proteasome clinical trial. Clin J Pain 2006;22:97–103. inhibition. Cell Cycle 2008;7:940–949. 100. Bennett M. The LANSS Pain Scale: the Leeds Assessment of 81. Darnell RB, Posner JB. Paraneoplastic syndromes involving the Neuropathic Symptoms and Signs. Pain 2001;92:147–157. nervous system. N Engl J Med 2003;349:1543–1554. 101. Potter J, Higginson IJ, Scadding JW, Quigley C. Identifying 82. Berger T, Malayeri R, Doppelbauer A, et al. Neurological neuropathic pain in patients with head and neck cancer: use of monitoring of neurotoxicity induced by paclitaxel/cisplatin the Leeds Assessment of Neuropathic Symptoms and Signs Scale. chemotherapy. Eur J Cancer 1997;33:1393–1399. J R Soc Med 2003;96:379–383.

NCCN Task Force Report

102. Argyriou AA, Chroni E, Koutras A, et al. Vitamin E for 116. Cassidy J, Paul J, Soukop M, et al. Clinical trials of nimodipine as prophylaxis against chemotherapy-induced neuropathy: a a potential neuroprotector in ovarian cancer patients treated with randomized controlled trial. Neurology 2005;64:26–31. cisplatin. Cancer Chemother Pharmacol 1998;41:161–166. 103. Argyriou AA, Chroni E, Koutras A, et al. A randomized 117. van der Hoop RG, Vecht CJ, van der Burg ME, et al. Prevention of controlled trial evaluating the efficacy and safety of vitamin cisplatin neurotoxicity with an ACTH(4-9) analogue in patients E supplementation for protection against cisplatin-induced with ovarian cancer. N Engl J Med 1990;322:89–94. peripheral neuropathy: final results. Support Care Cancer 118. Koeppen S, Verstappen CC, Korte R, et al. Lack of neuroprotection 2006;14:1134–1140. by an ACTH (4-9) analogue. A randomized trial in patients 104. Pace A, Savarese A, Picardo M, et al. Neuroprotective effect treated with vincristine for Hodgkin’s or non-Hodgkin’s of vitamin E supplementation in patients treated with cisplatin lymphoma. J Cancer Res Clin Oncol 2004;130:153–160. chemotherapy. J Clin Oncol 2003;21:927–931. 119. Roberts JA, Jenison EL, Kim K, et al. A randomized, multicenter, 105. Pace A, Carpano S, Galie E, et al. Vitamin E in the neuroprotection double-blind, placebo-controlled, dose-finding study of ORG of cisplatin induced peripheral neurotoxicity and ototoxicity 2766 in the prevention or delay of cisplatin-induced neuropathies [abstract]. J Clin Oncol 2007;25(Suppl 18S):Abstract 9114. in women with ovarian cancer. Gynecol Oncol 1997;67:172–177. 106. Nikcevich DA, Grothey A, Sloan JA, et al. Effect of intravenous 120. Davis ID, Kiers L, MacGregor L, et al. A randomized, double- calcium and magnesium (IV CaMg) on oxaliplatin-induced blinded, placebo-controlled phase II trial of recombinant human sensory neurotoxicity (sNT) in adjuvant colon cancer: results leukemia inhibitory factor (rhuLIF, emfilermin, AM424) to of the phase III placebo-controlled, double-blind NCCTG trial prevent chemotherapy-induced peripheral neuropathy. Clin N04C7 [abstract]. J Clin Oncol 2008;26(Suppl 18S):Abstract Cancer Res 2005;11:1890–1898. 4009. 121. Wolf S, Barton D, Kottschade L, et al. Chemotherapy-induced 107. Wang WS, Lin JK, Lin TC, et al. Oral glutamine is effective for peripheral neuropathy: prevention and treatment strategies. Eur J preventing oxaliplatin-induced neuropathy in colorectal cancer Cancer 2008;44:1507–1515. patients. Oncologist 2007;12:312–319. 122. Leonetti C, Biroccio A, Gabellini C, et al. Alpha-tocopherol 108. Cascinu S, Catalano V, Cordella L, et al. Neuroprotective effect protects against cisplatin-induced toxicity without interfering of reduced glutathione on oxaliplatin-based chemotherapy in with antitumor efficacy. Int J Cancer 2003;104:243–250. advanced colorectal cancer: a randomized, double-blind, placebo- 123. Pathak AK, Bhutani M, Guleria R, et al. Chemotherapy alone controlled trial. J Clin Oncol 2002;20:3478–3483. vs. chemotherapy plus high dose multiple antioxidants in patients 109. Cascinu S, Cordella L, Del Ferro E, et al. Neuroprotective effect with advanced non small cell lung cancer. J Am Coll Nutr of reduced glutathione on cisplatin-based chemotherapy in 2005;24:16–21. advanced gastric cancer: a randomized double-blind placebo- 124. Armstrong CM, Cota G. Calcium block of Na+ channels and its controlled trial. J Clin Oncol 1995;13:26–32. effect on closing rate. Proc Natl Acad Sci U S A 1999;96:4154– 4157. 110. Smyth JF, Bowman A, Perren T, et al. Glutathione reduces the toxicity and improves quality of life of women diagnosed with 125. Hochster HS, Grothey A, Childs BH. Use of calcium and ovarian cancer treated with cisplatin: results of a double-blind, magnesium salts to reduce oxaliplatin-related neurotoxicity. J randomised trial. Ann Oncol 1997;8:569–573. Clin Oncol 2007;25:4028–4029. 111. Lin PC, Lee MY, Wang WS, et al. N-acetylcysteine has 126. Hochster H, Grothey A, Shpilsky A, Childs BH. Effect of neuroprotective effects against oxaliplatin-based adjuvant intravenous calcium and magnesium versus placebo on response chemotherapy in colon cancer patients: preliminary data. Support to FOLFOX4 + bevacizumab in the CONcePT trial [abstract]. Care Cancer 2006;14:484–487. Presented at ASCO Gastrointestinal Cancers Symposium; January 25–27, 2009; Orlando, Florida. Abstract 280. 112. Argyriou AA, Chroni E, Polychronopoulos P, et al. Efficacy of oxcarbazepine for prophylaxis against cumulative oxaliplatin- 127. Gamelin L, Boisdron-Celle M, Morel A, et al. Oxaliplatin-related induced neuropathy. Neurology 2006;67:2253–2255. neurotoxicity: interest of calcium-magnesium infusion and no impact on its efficacy. J Clin Oncol 2008;26:1188–1189; author 113. Cassidy J, Bjarnason G, Hickish T. Randomized double blind reply 1189–1190. placebo controlled phase III study assessing the efficacy of xaliproden in reducing the cumulative peripheral sensory 128. Albers J, Chaudhry V, Cavaletti G, Donehower R. Interventions for preventing neuropathy caused by cisplatin and related neuropathy induced by the oxaliplatin and 5-FU/LV combination compounds. Cochrane Database Syst Rev 2007:CD005228. (FOLFOX4) in first line treatment of patients with metastatic colorectal cancer [abstract]. J Clin Oncol 2006;24(Suppl 129. Hughes RA, Swan AV, Raphael JC, et al. Immunotherapy 18S):Abstract 229. for Guillain-Barre syndrome: a systematic review. Brain 2007;130:2245–2257. 114. Leong SS, Tan EH, Fong KW, et al. Randomized double-blind trial of combined modality treatment with or without amifostine in 130. de Beukelaar JW, Sillevis Smitt PA. Managing paraneoplastic unresectable stage III non-small-cell lung cancer. J Clin Oncol neurological disorders. Oncologist 2006;11:292–305. 2003;21:1767–1774. 131. Comi G, Roveri L, Swan A, et al. A randomised controlled trial 115. Hilpert F, Stahle A, Tome O, et al. Neuroprotection with of intravenous immunoglobulin in IgM paraprotein associated amifostine in the first-line treatment of advanced ovarian cancer demyelinating neuropathy. J Neurol 2002;249:1370–1377. with carboplatin/paclitaxel-based chemotherapy--a double- 132. Dalakas MC, Quarles RH, Farrer RG, et al. A controlled study of blind, placebo-controlled, randomized phase II study from the intravenous immunoglobulin in demyelinating neuropathy with Arbeitsgemeinschaft Gynakologische Onkologoie (AGO) IgM gammopathy. Ann Neurol 1996;40:792–795. Ovarian Cancer Study Group. Support Care Cancer 2005;13:797– 133. Dalakas MC, Rakocevic G, Salajegheh M, et al. Placebo- 805. controlled trial of rituximab in IgM anti-myelin-associated

Management of Neuropathy in Cancer

glycoprotein antibody demyelinating neuropathy. Ann Neurol 150. Tolle T, Freynhagen R, Versavel M, et al. Pregabalin for relief 2009;65:286–293. of neuropathic pain associated with diabetic neuropathy: a 134. Hammack JE, Michalak JC, Loprinzi CL, et al. Phase III randomized, double-blind study. Eur J Pain 2008;12:203–213. evaluation of nortriptyline for alleviation of symptoms of cis- 151. Meier T, Wasner G, Faust M, et al. Efficacy of lidocaine patch 5% platinum-induced peripheral neuropathy. Pain 2002;98:195–203. in the treatment of focal peripheral neuropathic pain syndromes: 135. Kautio AL, Haanpaa M, Saarto T, Kalso E. Amitriptyline in the a randomized, double-blind, placebo-controlled study. Pain treatment of chemotherapy-induced neuropathic symptoms. J 2003;106:151–158. Pain Symptom Manage 2008;35:31–39. 152. Cheville AL, Sloan JA, Northfelt DW, et al. Use of a lidocaine 136. Rao RD, Flynn PJ, Sloan JA, et al. Efficacy of lamotrigine in the patch in the management of postsurgical neuropathic pain in patients with cancer: a phase III double-blind crossover study management of chemotherapy-induced peripheral neuropathy: (N01CB). Support Care Cancer 2009;17:451–460. a phase 3 randomized, double-blind, placebo-controlled trial, N01C3. Cancer 2008;112:2802–2808. 153. Quilici S, Chancellor J, Lothgren M, et al. Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of 137. Rao RD, Michalak JC, Sloan JA, et al. Efficacy of gabapentin in the diabetic peripheral neuropathic pain. BMC Neurol 2009;9:6. management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled, crossover 154. Raskin J, Pritchett YL, Wang F, et al. A double-blind, randomized trial (N00C3). Cancer 2007;110:2110–2118. multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med 138. Barton D, Wos E, Qin R, et al. A randomized controlled trial 2005;6:346–356. evaluating a topical treatment for chemotherapy-induced 155. Wernicke JF, Pritchett YL, D’Souza DN, et al. A randomized neuropathy: NCCTG trial N06CA [abstract]. J Clin Oncol controlled trial of duloxetine in diabetic peripheral neuropathic 2009;27(Suppl 15S):Abstract 9531. pain. Neurology 2006;67:1411–1420. 139. Durand JP, Deplanque G, Gorent J, et al. Efficacy of venlafaxine 156. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, for the prevention and relief of acute neurotoxicity of amitriptyline, and fluoxetine on pain in diabetic neuropathy. N oxaliplatin: results of EFFOX, a randomized, double-blinded, Engl J Med 1992;326:1250–1256. placebo-controlled prospective study [abstract]. J Clin Oncol 2009;27(Suppl 15S):Abstract 9533. 157. Freeman R, Raskin P, Hewitt DJ, et al. Randomized study of tramadol/acetaminophen versus placebo in painful diabetic 140. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for peripheral neuropathy. Curr Med Res Opin 2007;23:147–161. the symptomatic treatment of painful neuropathy in patients 158. Harati Y, Gooch C, Swenson M, et al. Double-blind randomized with diabetes mellitus: a randomized controlled trial. JAMA trial of tramadol for the treatment of the pain of diabetic 1998;280:1831–1836. neuropathy. Neurology 1998;50:1842–1846. 141. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their 159. Gimbel JS, Richards P, Portenoy RK. Controlled-release combination for neuropathic pain. N Engl J Med 2005;352:1324– oxycodone for pain in diabetic neuropathy: a randomized 1334. controlled trial. Neurology 2003;60:927–934. 142. Hahn K, Arendt G, Braun JS, et al. A placebo-controlled trial 160. Hanna M, O’Brien C, Wilson MC. Prolonged-release oxycodone of gabapentin for painful HIV-associated sensory neuropathies. J enhances the effects of existing gabapentin therapy in painful Neurol 2004;251:1260–1266. diabetic neuropathy patients. Eur J Pain 2008;12:804–813. 143. Ho TW, Backonja M, Ma J, et al. Efficient assessment of 161. Watson CP, Moulin D, Watt-Watson J, et al. Controlled-release neuropathic pain drugs in patients with small fiber sensory oxycodone relieves neuropathic pain: a randomized controlled neuropathies. Pain 2009;141:19–24. trial in painful diabetic neuropathy. Pain 2003;105:71–78. 144. Simpson DA. Gabapentin and venlafaxine for the treatment of 162. Melzack R, Wall PD. Pain mechanisms: a new theory. Science painful diabetic neuropathy. J Clin Neuromuscul Dis 2001;3:53– 1965;150:971–979. 62. 163. Cruccu G, Aziz TZ, Garcia-Larrea L, et al. EFNS guidelines on 145. Arezzo JC, Rosenstock J, Lamoreaux L, Pauer L. Efficacy and safety neurostimulation therapy for neuropathic pain. Eur J Neurol of pregabalin 600 mg/d for treating painful diabetic peripheral 2007;14:952–970. neuropathy: a double-blind placebo-controlled trial. BMC Neurol 164. Cata JP, Cordella JV, Burton AW, et al. Spinal cord stimulation 2008;8:33. relieves chemotherapy-induced pain: a clinical case report. J Pain 146. Freynhagen R, Strojek K, Griesing T, et al. Efficacy of pregabalin Symptom Manage 2004;27:72–78. in neuropathic pain evaluated in a 12-week, randomised, double- 165. Bruel BM, Burton A, Are M, et al. Dorsal column stimulation for blind, multicentre, placebo-controlled trial of flexible- and fixed- severe chemotherapy-induced peripheral neuropathy [abstract]. dose regimens. Pain 2005;115:254–263. Presented at the NANS 2006 Annual Meeting; December 8, 147. Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves 2006. symptoms of painful diabetic neuropathy: a randomized controlled 166. Daousi C, Benbow SJ, MacFarlane IA. Electrical spinal cord trial. Neurology 2004;63:2104–2110. stimulation in the long-term treatment of chronic painful diabetic 148. Richter RW, Portenoy R, Sharma U, et al. Relief of painful neuropathy. Diabet Med 2005;22:393–398. diabetic peripheral neuropathy with pregabalin: a randomized, 167. Kumar K, Toth C, Nath RK. Spinal cord stimulation for chronic placebo-controlled trial. J Pain 2005;6:253–260. pain in peripheral neuropathy. Surg Neurol 1996;46:363–369. 149. Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin 168. Tesfaye S, Watt J, Benbow SJ, et al. Electrical spinal-cord for the treatment of painful diabetic peripheral neuropathy: a stimulation for painful diabetic peripheral neuropathy. Lancet double-blind, placebo-controlled trial. Pain 2004;110:628–638. 1996;348:1698–1701.

NCCN Task Force Report

169. de Vos CC, Rajan V, Steenbergen W, et al. Effect and safety of 186. Visovsky C, Daly BJ. Clinical evaluation and patterns of spinal cord stimulation for treatment of chronic pain caused by chemotherapy-induced peripheral neuropathy. J Am Acad Nurse diabetic neuropathy. J Diabetes Complications 2009;23:40–45. Pract 2004;16:353–359. 170. Roebling R, Huch K, Kassubek J, et al. Cervical spinal MRI in 187. Wampler MA, Miaskowski C, Hamel K, et al. The modified a patient with a vagus nerve stimulator (VNS). Epilepsy Res total neuropathy score: a clinically feasible and valid measure of 2009;84:273–275. taxane-induced peripheral neuropathy in women in breast cancer. 171. Shah RV, Smith HK, Chung J, et al. Cervical spinal cord neoplasm J Support Oncol 2006;4:W9–W16. in a patient with an implanted cervical spinal cord stimulator: the 188. Nardone A, Galante M, Pareyson D, Schieppati M. Balance control controversial role of magnetic resonance imaging. Pain Physician in sensory neuron disease. Clin Neurophysiol 2007;118:538–550. 2004;7:273–278. 189. Silsupadol P, Siu KC, Shumway-Cook A, Woollacott MH. 172. De Andres J, Valia JC, Cerda-Olmedo G, et al. Magnetic Training of balance under single- and dual-task conditions in resonance imaging in patients with spinal neurostimulation older adults with balance impairment. Phys Ther 2006;86:269– systems. Anesthesiology 2007;106:779–786. 281. 173. Reichstein L, Labrenz S, Ziegler D, Martin S. Effective treatment 190. Wampler MA, Hamolsky D, Hamel K, et al. Case report: painful of symptomatic diabetic polyneuropathy by high-frequency peripheral neuropathy following treatment with docetaxel for external muscle stimulation. Diabetologia 2005;48:824–828. breast cancer. Clin J Oncol Nurs 2005;9:189–193. 174. Leonard DR, Farooqi MH, Myers S. Restoration of sensation, reduced pain, and improved balance in subjects with diabetic 191. Richardson JK, Sandman D, Vela S. A focused exercise regimen peripheral neuropathy: a double-blind, randomized, placebo- improves clinical measures of balance in patients with peripheral controlled study with monochromatic near-infrared treatment. neuropathy. Arch Phys Med Rehabil 2001;82:205–209. Diabetes Care 2004;27:168–172. 192. Richardson JK, Hurvitz EA. Peripheral neuropathy: a true risk 175. Prendergast JJ, Miranda G, Sanchez M. Improvement of sensory factor for falls. J Gerontol A Biol Sci Med Sci 1995;50:M211–215. impairment in patients with peripheral neuropathy. Endocr Pract 193. Ganz DA, Bao Y, Shekelle PG, Rubenstein LZ. Will my patient 2004;10:24–30. fall? JAMA 2007;297:77–86. 176. Lavery LA, Murdoch DP, Williams J, Lavery DC. Does 194. Richardson JK, Thies SB, DeMott TK, Ashton-Miller JA. A anodyne light therapy improve peripheral neuropathy in comparison of gait characteristics between older women with diabetes? A double-blind, sham-controlled, randomized trial to and without peripheral neuropathy in standard and challenging evaluate monochromatic infrared photoenergy. Diabetes Care environments. J Am Geriatr Soc 2004;52:1532–1537. 2008;31:316–321. 195. Richardson JK, Thies SB, DeMott TK, Ashton-Miller JA. 177. Brunelli B, Gorson KC. The use of complementary and alternative Interventions improve gait regularity in patients with peripheral medicines by patients with peripheral neuropathy. J Neurol Sci neuropathy while walking on an irregular surface under low light. 2004;218:59–66. J Am Geriatr Soc 2004;52:510–515. 178. Nicholas PK, Kemppainen JK, Canaval GE, et al. Symptom 196. Quist M, Rorth M, Zacho M, et al. High-intensity resistance management and self-care for peripheral neuropathy in HIV/ and cardiovascular training improve physical capacity in cancer AIDS. AIDS Care 2007;19:179–189. patients undergoing chemotherapy. Scand J Med Sci Sports 179. Wang SM, Kain ZN, White P. Acupuncture analgesia: I. The 2006;16:349–357. scientific basis. Anesth Analg 2008;106:602–610. 197. Thompson WR, Gordon NF, Pescatello LS. ACSM’s Guidelines 180. Alimi D, Rubino C, Pichard-Leandri E, et al. Analgesic effect for Exercise Testing and Prescription, 8th ed. Philadelphia: of auricular acupuncture for cancer pain: a randomized, blinded, Lippincott Williams & Wilkins; 2009. controlled trial. J Clin Oncol 2003;21:4120–4126. 198. Shah MH, Young D, Kindler HL, et al. Phase II study of 181. Shlay JC, Chaloner K, Max MB, et al. Acupuncture and the proteasome inhibitor bortezomib (PS-341) in patients amitriptyline for pain due to HIV-related peripheral neuropathy: with metastatic neuroendocrine tumors. Clin Cancer Res a randomized controlled trial. Terry Beirn Community Programs 2004;10:6111–6118. for Clinical Research on AIDS. JAMA 1998;280:1590–1595. 182. Schroder S, Liepert J, Remppis A, Greten JH. Acupuncture 199. Lahrmann H, Cortelli P, Hilz M, et al. EFNS guidelines on the treatment improves nerve conduction in peripheral neuropathy. diagnosis and management of orthostatic hypotension. Eur J Eur J Neurol 2007;14:276–281. Neurol 2006;13:930–936. 183. Wong R, Sagar S. Acupuncture treatment for chemotherapy- 200. Selius BA, Subedi R. Urinary retention in adults: diagnosis and induced peripheral neuropathy—a case series. Acupunct Med initial management. Am Fam Physician 2008;77:643–650. 2006;24:87–91. 201. Slatkin N, Thomas J, Lipman AG, et al. Methylnaltrexone for 184. Haythornthwaite JA, Benrud-Larson LM. Psychological treatment of opioid-induced constipation in advanced illness assessment and treatment of patients with neuropathic pain. Curr patients. J Support Oncol 2009;7:39–46. Pain Headache Rep 2001;5:124–129. 202. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for 185. Head KA. Peripheral neuropathy: pathogenic mechanisms and opioid-induced constipation in advanced illness. N Engl J Med alternative therapies. Altern Med Rev 2006;11:294–329. 2008;358:2332–2343.