One of the most debilitating toxicities related to chemotherapy is peripheral neuropathy. Neuropathy is defined as a condition arising from the damage and dysfunction of the peripheral nerves (motor, sensory, autonomic) that connect the brain and spinal cord to the rest of the body.1 Chemotherapy-induced peripheral neuropathy (CIPN) is defined as toxic neuropathy that results from the direct injury of the peripheral nervous system by chemotherapeutic agents.2 The incidence of CIPN is variable (30%-40%) and is largely dependent on several factors, including patient age, dose intensity, cumulative dose, duration of therapy, use of regimens containing multiple neurotoxic chemotherapy agents, and any preexisting conditions that are associated with peripheral neuropathy, such as diabetes and alcohol abuse.3 When symptoms are severe or irreversible, CIPN can lead to serious clinical and quality-of-life (QOL) consequences for patients. This article presents an overview of the current strategies for assessment, prevention, and management of CIPN.
Chemotherapeutic and biologic agents associated with symptomatic neuropathy include the platinum compounds, vinca alkaloids, taxanes, and others such as bortezomib, ixabepilone, and thalidomide. Agents associated with CIPN cause structural damage to peripheral nerves that result in abnormal sensory processing of the peripheral and/or central nervous systems.4,5 CIPN can affect both small fiber axons (temperature, pinpricks) and large sensory axons (vibrations, proprioception).3 CIPN typically manifests as sensory symptoms, such as paresthesia and dysesthesia (numbness and tingling). Patients often describe the neuropathic pain as burning, shock-like, or electric. Other sensations, such as allodynia (normal touch perceived as painful) and hyperpathia (normal painful sensations perceived as excruciating), may occur. In general, motor symptoms are uncommon and may manifest as weakness of the lower limbs. On examination, reflexes may be diminished or absent, and some patients may present with abnormal proprioception, which can lead to falls and other safety concerns. Several diagnostic features can aid clinicians in the differential diagnosis of CIPN, including predominant sensory symptoms and onset after chemotherapy administration (Table 1). With platinum agents, a “coasting” effect may be present, which is characterized by progressive symptoms for weeks to months after treatment completion.6
A notable exception to symptom characterization for CIPN can be found with the platinum agent oxaliplatin. Peripheral neuropathy in colorectal cancer (CRC) is primarily related to oxaliplatin. The dose-limiting toxicity of this agent is a neurotoxicity that induces two distinct neuropathies: a transient acute syndrome and a cumulative chronic neurotoxicity. Acute oxaliplatin-induced peripheral nerve hyperexcitability, referred to as “acute ch an nel opathy,” is characterized by an increased excitability of nerve and muscle cells triggered by exposure to cold.7 The acute neuropathy observed with oxaliplatin occurs in 85% to 95% of all patients.7 Symptoms include distal or perioral paresthesias or dysesthesias that peak within the first 24 to 48 hours after treatment.8 These symptoms can occur during or immediately after the first oxaliplatin infusion but are generally mild, short-lived, and completely reversible within hours or days. Between 1% and 2% of patients also report a pharyngolaryngeal dysesthesia, which they describe as the sensation of difficulties in breathing or swallowing.8 Symptoms related to oxaliplatinassociated chronic neurotoxicity are gradually prolonged and eventually persist be tween treatments and increase with cumulative doses of greater than 1000 mg/m2.9 The chronic neurotoxicity may lessen over time, with partial recoveries seen at 13 weeks after treatment.7,10
The onset of symptoms of CIPN can be sudden or progressive. Symptom severity ranges from mild discomfort to severe disabilities that result in significant loss of function and diminishing QOL. In severe cases, CIPN can be extremely painful, and can result in dose reductions, treatment delays, and discontinuation of treatment. These represent significant limitations to the successful treatment of cancer and directly impact patient outcomes and overall survival.
The assessment of CIPN continues to be a clinical challenge for healthcare professionals because of great variability in symptom characteristics and lack of empirical evidence on optimal evaluation methods. The first step in assessing CIPN is to take a comprehensive history that includes information such as neuropathic symptom characteristics, duration and onset of symptoms, comorbidities, and history of chemotherapeutic/ medication administration. A physical examination that includes as sessment of reflexes (ankle jerks) and sensory evaluation (vibrations, proprioception, pinpricks, temperature) should also be performed. The clinician should assess whether symptoms are severe enough to mandate intervention and which options for intervention are optimal based on symptom severity. The need for modification or discontinuation of present cancer treatments should also be determined.1
Several grading systems have been developed in recent years for CIPN assessment, including the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCICTCAE), Ajani Sensory Neuropathy, World Health Organization Toxicity Criteria, and that of the Eastern Cooperative Oncology Group.1,11,12 Data comparing these scales in the assessment of CIPN show great variability in interobserver agreement, which highlights variations in grading and interpretation disparities.13 A new tool, the Total Neuro pathy Score, was recently reported to be more sensitive in detecting changes in CIPN compared with the NCI-CTCAE.14,15 The Chemotherapy-Induced Peripheral Neuropathy Outcome Measures Study (CI-PERINOMS) is a current international collaborative effort that is aiming to identify the best methods to assess and monitor CIPN.16 Objective, quantitative measures such as electromyography, nerve-conduction studies, and sensory-threshold testing have also been used in the assessment of CIPN. To date, these measures have not been completely adopted into clinical settings because of concerns such as cost, need for subspecialty expertise, invasiveness, and potential low patient adherence.1,17 Research also shows that objective neurophysiologic findings correlate poorly with subjective, patient-reported outcomes, with a trend toward underassessment.18-21
Table 2 provides a list of agents that have been tested for prevention of CIPN. A calcium plus magnesium (Ca/Mg) infusion has been tested as a neuroprotectant for oxaliplatin-induced neuropathy in two randomized controlled trials, the North Central Cancer Treatment Group’s N04C7 and the Combined Oxaliplatin Neurotoxicity Prevention Trial (CONcePT). Unfortunately, both trials were terminated early after reports of diminished re sponse to chemotherapy in the CONcePT study,22 although subsequent radiology review suggested no effect on tumor response.3,23 The N04C7 trial reported a reduction in CIPN incidence in the arm that received the Ca/Mg infusions.24 Results from a randomized trial testing the efficacy of xaliproden, a nonpeptideneurotrophic agent, show a lower incidence of grade 3 neuropathy in patients treated with 5-fluorouracil/leucovorin/ oxaliplatin (FOLFOX4), but without reductions in overall neurotoxicity incidence.25 A double-blind, multicenter trial, NEUROXA, is currently randomizing patients on a FOLFOX4 regimen.1
Vitamin E has been tested as a neuroprotectant in patients receiving cisplatin- based chemotherapy. Three small, open-label studies randomized patients receiving cisplatin-based chemo therapy to vitamin E or control. The incidence of CIPN was significantly lower in the active arms (21%-31%) than in the control group (69%-86%). Toxicity severity scores were also reduced in the active arms.26-28 An interim report from an ongoing double-blind, randomized, placebo-controlled trial of patients receiving cisplatin therapy showed a significantly reduced median toxicity score in the active arm. At the 2009 annual meeting of the American Society of Clinical Oncology, Kotts chade and colleagues presented findings from a phase 3 double-blind, placebo-controlled study, N05C3, of vitamin E in the prevention of CIPN in patients receiving therapy with taxanes and/or platinum compounds.29 The primary end point was incidence of grade 2+ sensory neuropathy as measured by NCI-CTCAE. Although vitamin E was well-tolerated, it did not appear to reduce the incidence of sensory neuropathy. Other agents, such as amifostine, nimodipine, and rHuLIF, did not show clinical benefits in randomized trials.30-32 Newer agents, such as glutamine, acetyl L-carnitine, alpha-lipoic acid, and vitamins B12/B6, are currently being tested in large-scale, phase 3, randomized trials.33-35
Despite the growing number of clinical trials testing various therapeutic options, currently there is no standard, evidence-based treatment to specifically manage CIPN.36 Numerous pharmacologic agents have been tested to eliminate symptomatic neuropathy associated with chemotherapy. Table 3 lists pharmacologic agents being used as offlabel treatments for symptomatic CIPN. Gabapentin, an antiepileptic agent, is probably one of the most widely used drugs for neuropathic pain. In several randomized trials involving mixed disease populations, gabapentin was effective in relieving pain and improving QOL.37-39 In a double-blind, controlled, crossover trial, however, gabapentin was no better than placebo for treatment of CIPN.32 Pregabalin, another antiepileptic agent with similar mechanisms of action as gabapentin, is approved for diabetic neuropathy and postherpetic neuralgia.40-44 Lamotrigine was tested in a multicenter, double-blind, placebocontrolled, randomized trial for the treatment of pain and other neuropathic symptoms due to CIPN. However, there were no differences in average pain scores for the lamotrigine and placebo arms.45
Antidepressants have also been tested for the treatment of CIPN. Dulo x - etine, a serotonin and norepinephrine reuptake inhibitor (SNRI), has been shown to reduce pain associated with diabetic neuropathy.46 Another SNRI, venlafaxine, was recently shown to reduce the incidence of acute oxaliplatin- induced neuropathic pain compared with placebo (35% vs 67%).47 SNRIs, however, have contraindications for patients taking tamoxifen as well as other drugs that affect serotonin reuptake.48,49 Tricyclic antidepressants (TCAs) such as amitriptyline, nortriptyline, and desipramine also are commonly used for the treatment of diabetic neuropathy. Negative results were reported in two small randomized, placebo-controlled trials that tested the efficacy of amitriptyline and nortriptyline for CIPN.30,31 TCAs have substantial side effects (anticholinergic, cardiac) as well as pharmacologic in - teractions with drugs metabolized by cytochrome P450, further limiting their potential use. As a rule, TCAs are not recommended for the first-line treatment of CIPN.1
Recently, a topical gel formulation of baclofen, amitriptyline, and ketamine (BAK-PLO) yielded moderate improvements in CIPN symptoms in a randomized trial in patients with CIPN.50
Opioids such as tramadol, morphine, and oxycodone (in combination with gabapentin) have shown efficacy in diabetic neuropathy.51-53 The lidocaine patch (5%) was shown to alleviate allodynia in patients with postherpetic neuralgia, but it did not have a significant impact for postsurgical pain in cancer patients.54,55 Complementary and alternative therapies such as acupuncture have also been tested for CIPN,56,57 and preliminary results are encouraging, with pain intensity decreased by 36% with acupuncture versus 2% with placebo.56
Understanding the relationship between CIPN and QOL in cancer is important not only for patients but also for healthcare practitioners caring for individuals with cancer. To thoroughly understand how CIPN affects the QOL of patients, it is necessary to capture the overall experience of living with CIPN from the patient’s perspective. Few qualitative studies have been conducted in recent years that attempted to understand CIPN from the subjective perspective. Bakitas conducted an excellent qualitative study that described the CIPN symptom experience and the effect of symptoms on everyday life.58 Patients described CIPN as “background noise” that can be overshadowed by other treatment- and diseaserelated issues, but the unpleasantness of CIPN can interfere with daily activities and socialization.58 Patients’ awareness of CIPN was often inaccurate and its occurrence surprising, because most did not recall being educated about CIPN or advised to anticipate the symptoms. When monitoring CIPN, clinicians primarily focused on how the symptoms affected motor functionality (dexterity, gait) but rarely asked about the effect on daily living.58 CIPN caused disruptions in daily living, leisure, work, and family roles.58 Patients who reported a pain component to their CIPN often experienced functional difficulties, fatigue, sleep disturbance, and mood disturbances.58 Patients also described the use of multiple processes in learning to live with CIPN.58
Similar results have been described in another qualitative study conducted by Closs and colleagues59 as well as in our work at City of Hope, where we explored the impact of CIPN on QOL in a cohort (n = 53) of CRC patients.60 In our study, significant differences in QOL were found after initiation of treatment with an oxaliplatin-based regimen. Patterns for neuropathy and toxicity grading also suggested that patients may notice symptoms of neuropathy as early as 24 hours after treatment initiation, with temporary relief at 1 week, and then noticeable symptoms again at the 1- and 2-month assessments. By 2 months after treatment initiation, more grade 2 and 3 neurotoxicities were observed.60 Although subjects did not find the dysesthesias and coldrelated allodynia distressing, they found the acute sensations surprising when first experienced, and made adjustments in eating and drinking habits related to cold foods and beverages to cope with these neuropathic symptoms.60
Based on the current evidence available in the literature, it is clear that much work needs to be done to determine the most effective methods for assessment and treatment of CIPN. The prompt assessment of symptoms related to CIPN is essential for determining appropriate and effective management strategies. The assessment of CIPN should continue throughout treatment and beyond, because chronic CIPN canoccur months and years beyond treatment.4 It is important to understand that many agents may be needed for adequate treatment of CIPN and that the clinical context should be used to guide the choice of medications.1 The general approach should be to choose an agent based on clinical context, efficacy, and safety, and to titrate the agent to maximum tolerated dose.1
Patients need to be educated on what to expect with CIPN. It is evident from some of the current evidence that clinicians are not doing an optimal job of providing patients with timely information on CIPN. Beyond pharmacologic treatments, it may also be helpful to discuss nonpharmacologic supportive care strategies to cope with CIPN, such as personal safety measures to prevent burns or falls that may be related to sensory motor deficits.10 Functional deficits, such as decreased balance, gait abnormalities, and muscle weakness, can occur with CIPN.61,62 Rehabilitation experts, such as physical and occupational therapists if available, should be included in the interdisciplinary care of cancer patients with CIPN. When functional deficits are a concern, patient and family caregivers should be educated on potential environmental hazards and the need for home and environmental modifications. These include installing adequate light, removing hazardous items such as throw rugs, modifying tasks, providing adaptive equipment, ensuring protection against extreme temperatures (hot and cold), and wearing proper footwear.1 Finally, studies that characterize the time of onset, duration, and resolution or persistence of symptoms are needed to develop a more comprehensive and subjective understanding of CIPN.63
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