Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most disabling and demoralizing problems that arise for cancer survivors. When investigating symptoms of numbness, tingling, or pain in the extremities, it is critical to determine whether the problem is neuropathic, somatic, or mixed. If the diagnosis is CIPN, it is important to weigh the potential benefits and harms of possible treatment options, and to devise an evidence-based multimodality treatment program. Such programs may include mixtures of opioid and nonopioid adjunctive medications, based on evidence from CIPN trials, and also extrapolation from trials in patients with other neuropathic pain syndromes—although such extrapolating must be done with caution, since other syndromes sometimes respond to agents that CIPN does not respond to. Other components of a successful program might include exercise; and possibly neuromodulation via acupuncture, spinal cord electrical stimulation, or neurocutaneous stimulation. There is good randomized trial evidence that most of the anticonvulsants and tricyclic antidepressants typically prescribed for neuropathic pain have little or no effect on CIPN, but there is some evidence of efficacy for duloxetine—however, clinical practice with regard to pharmacologic treatment of CIPN often does not reflect these data. We review here the recommendations of the American Society of Clinical Oncology, as well as some new and promising approaches to neuropathy, including new neuromodulation techniques.
Chemotherapy-induced peripheral neuropathy (CIPN) pain can greatly diminish quality of life; create or worsen depression, insomnia, fatigue, and other symptom clusters; and lead to unwanted dose modification and even failure of treatment. The proportion of cancer patients who experience neuropathic pain at some point in their survivorship ranges from 40% to 70%. A quick glance at the evidence reveals many aspects of CIPN treatment where improvement is needed, with a recent systematic review finding “insufficient evidence to confirm the efficacy” of central nervous system (CNS) drugs for CIPN. There are no known preventatives, and for many patients, control of the pain requires opioids. However, use of opioids in this setting has become problematic nationwide, given the new Centers for Disease Control guidelines instructing practitioners to reduce the use of opioids.[4,5] Duloxetine is the only nonopioid that has proven to be helpful. The drugs usually used to treat neuropathic pain, such as amitriptyline, gabapentin, and pregabalin, do not appear to be better than placebos in CIPN. Some antidepressants and anticonvulsants work somewhat, but the number needed to treat ranges from 3 to 7 (we must treat 3 to 7 people—for at least 1 or 2 weeks in order to assess effectiveness—but only 1 benefits), and all these agents have side effects. We explore here the known effective treatments, and suggest some alternatives that appear to be beneficial and not harmful, offering the perspective of practicing oncologists throughout. We will focus specifically on CIPN; other recent reviews cover the full gamut of all cancer-related pain, or all types of neuropathic pain.[7,8]
Incidence and Natural History
We now have a better understanding of how neuropathic pain resulting from chemotherapy starts, is sustained, and resolves.[9,10] The different causes and manifestations of CIPN are shown in Table 1. The patterns of occurrence vary substantially from drug to drug. Researchers at the Mayo Clinic have studied the relationship between early and late CIPN pain, and found that early truncal pains, which previously had been thought to be myalgias but now are hypothesized to be a form of acute neuropathy,[11,12] partly predict the occurrence of later disabling neuropathy. As an example, paclitaxel neuropathy may start with an acute pain syndrome that resolves, with a more severe and more chronic neuropathy developing later. We have also learned to distinguish the various clinical components of CIPN—ie, to separate pain, numbness, and tingling (all measurable on a scale of 0 to 10)—and have now modified our clinical trials to record all three components.
Another example of a distinctive neuropathy is that caused by oxaliplatin; this is characterized clinically by early cold sensitivity that then transforms into long-lasting pain, numbness, and tingling. In our own practice, and as documented by comparative studies, this is often the most difficult CIPN to treat. Our understanding of CIPN caused by oxaliplatin, and the way we explain it to patients, has been clarified by small studies that showed a progressive loss of nerve conduction amplitude and velocity with each cycle of oxaliplatin, and cumulative decreases in the epidermal nerve fiber density. We explain to patients that this means that oxaliplatin first damages their nerves, then causes them to actually disappear. Whether the nerve fibers can reappear in time is not yet known.
Another recently recognized syndrome is that in which CIPN worsens after chemotherapy has finished, and long after there is an ability to combat the problem by reducing the dose. This phenomenon has been referred to as “coasting” and is classically associated with platinum agents. Of note, the rate at which and the degree to which neuropathy worsens with oxaliplatin are equal in the 2 to 3 months after treatment completion to what is seen in the last few weeks prior to treatment completion, consistent with the hypothesis that the complete damage from a dose of chemotherapy may not be manifest for about 2 to 3 months after the dose.
A surprising fact for many oncologists is that CIPN never seems to remit in a substantial number of patients. In our own practices, we have seen patients still suffering from CIPN 10 or more years after they received paclitaxel or bortezomib or thalidomide. While these patients are often functional, they may still be receiving chronic opioids, with side effects of constipation, fatigue, and hypogonadism—or still suffering from other drug side effects, such as sleepiness or edema. When we have finally been able to effect pain relief for these patients (eg, through use of duloxetine or neuromodulation, as described further on), they have been extremely grateful, a reflection of the degree to which CIPN had limited their lives.
Recognition of CIPN in Clinical Practice
We have all learned to ask, “Are you having any pain, numbness, or tingling since you started chemotherapy?” Further, most oncologists do attempt to roughly grade CIPN, based on whether it interferes with everyday tasks, such as typing or buttoning buttons, and on whether it resolves completely between cycles. Current National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) guidelines[16,17] do not recommend any more specific assessment, such as might be used in a clinical trial, but both do recommend assessment before each treatment. Current guidelines do not agree on when to reduce or stop chemotherapy because of CIPN. Nevertheless, if a patient develops significant neuropathy during treatment, consideration of stopping the offending drug(s) or reducing the dose is appropriate.
Prevention of CIPN
There are no agents that have demonstrated efficacy in the prevention of CIPN, despite evaluation of many therapies traditionally used in the treatment of neuropathic pain. Various vitamins, minerals, herbs, and nonpharmacologic strategies have also been studied, with limited success. A summary of the literature pertaining to each CIPN prevention measure follows.
Vitamins, minerals, and other ‘natural’ approaches with no evidence of efficacy
Goshajinkigan. This is a traditional Japanese medicine that is produced from a specific formulation of 10 distinct herbs used to treat diabetic neuropathy. The first study of goshajinkigan in cancer patients involved 45 patients with unresectable colorectal cancer who were receiving oxaliplatin, fluorouracil, and folinic acid (FOLFOX) chemotherapy, with 22 assigned to receive goshajinkigan. The incidence of grade 3 peripheral neuropathy was markedly reduced in the goshajinkigan group, at 33% vs 75% after 20 courses of treatment. A phase II randomized double-blind placebo-controlled trial evaluating 89 patients who were receiving oxaliplatin-based chemotherapy showed a statistically significant reduction in grade 2 and grade 3 neuropathy in the goshajinkigan arm. However, a larger, more definitive phase III randomized double-blind placebo-controlled trial evaluating this agent in patients receiving FOLFOX was stopped after accrual of 142 of the planned 310 patients when grade 2 or greater neurotoxicity was found to be significantly higher in the treatment arm. Based on these results, goshajinkigan has not been recommended for the prevention of CIPN, and its trial results should serve as a cautionary tale about little-tested products.
Calcium and magnesium. A definitive phase III randomized placebo-controlled double-blind study of intravenous calcium and magnesium as a preventive strategy in colon cancer patients receiving adjuvant oxaliplatin-based therapy showed no reduction in neuropathy with calcium and magnesium supplementation; therefore, use of these agents is not recommended for CIPN prevention. A recent report illustrates substantial waxing and waning of the use of calcium and magnesium infusions in patients receiving oxaliplatin over a 10-year period prior to the question having been put to rest by the phase III trial results.
Acetyl-L-carnitine. This modified amino acid showed promise in animal models and in pilot studies[23,24] for the prevention of platinum- and taxane-associated neuropathy. However, a randomized placebo-controlled trial of prevention of taxane-induced neuropathy in women undergoing adjuvant chemotherapy for breast cancer found it to be associated with an increased rate of CIPN. The use of this supplement for CIPN prevention has been discouraged, based on these negative findings.
Alpha-lipoic acid. This antioxidant was evaluated in a randomized double-blind placebo-controlled trial as a preventive agent in patients receiving platinum-based chemotherapy. Only 70 of 243 enrolled patients (29%) completed the study, although the dropout rate was comparable in both arms (the high attrition rate was attributed in part to the high frequency of dosing required for alpha-lipoic acid administration); there were no significant differences in pain scores between the two groups.
Vitamin E. The largest randomized placebo-controlled double-blind trial evaluating use of vitamin E, which involved 207 patients treated with taxanes or platinum agents, failed to show significant differences in incidence of neuropathy, time to neuropathy onset, or need for chemotherapy dose reduction. Without any strong evidence available to support its use, vitamin E is not recommended for CIPN prevention.
Vitamins, minerals, and other ‘natural’ approaches that appear promising but for which more evidence is required
Omega-3 fatty acids. One small trial in Iran randomized 60 patients starting paclitaxel to placebo or omega-3 fatty acid pearls, 640 mg TID (10% eicosapentaenoic acid and 54% docosahexaenoic acid), during and for 1 month after chemotherapy. The incidence of CIPN was 30% with omega-3 fatty acids vs 59% with placebo, as measured by the reduced Total Neuropathy Score, and with confirmatory preserved sural nerve conduction, ascertained by peak-to-peak amplitude measurement of sensory action potentials. To our knowledge, this trial has not been replicated, but the toxicity is extremely low, and omega-3 fatty acids are both widely available and inexpensive. One replication trial (ClinicalTrials.gov identifier: NCT01821833) is currently recruiting participants.
TO PUT THAT INTO CONTEXT
Nanna B. Finnerup, MD, DrMedSc
Chemotherapy-induced peripheral neuropathy (CIPN) is a serious and common side effect resulting from treatment with neurotoxic chemotherapeutic agents. The type of neuropathy may vary, but the chronic form is often a length-dependent, mainly sensory, axonal polyneuropathy. Most patients with CIPN complain of symptoms related to sensory loss—eg, numbness—while only a subgroup of patients develop neuropathic pain.
What New Developments in the Management of CIPN Does This Review Highlight?
This comprehensive review by Majithia and colleagues provides an excellent overview of studies on the prevention and treatment of CIPN. Although there is limited evidence from randomized controlled trials, possible promising approaches include exercise and omega-3 fatty acids for the prevention of CIPN, and neuromodulation and topical agents for its treatment. One randomized double-blind trial has shown an effect for the antidepressant duloxetine in painful CIPN.
What Issues Still Need to Be Addressed?
Many patients with painful CIPN are cancer-free; thus, opioids are not recommended as first- or second-line treatments. Unfortunately, trials assessing neuropathic pain drugs in CIPN have not been properly designed to test the drugs’ effect on pain: they have included patients with other, nonpain neuropathy symptoms, such as sensory loss, and/or have not separately assessed the drugs’ effect on pain. However, until appropriate trials have been carried out, I think there is a good rationale for using treatments for which there is evidence in other types of neuropathic pain—eg, pregabalin, gabapentin, tricyclic antidepressants, and serotonin-noradrenaline reuptake inhibitors—to treat the pain of CIPN. Nonetheless, there is an unmet need for high-quality placebo- or sham-controlled trials in CIPN that clearly distinguish between pain and nonpain symptoms. Such trials are essential if we are to improve the prevention and treatment of CIPN and CIPN-related neuropathic pain.
Financial Disclosure: Dr. Finnerup has received honoraria for consulting and/or travel support from Grünenthal, Novartis, and Teva Pharmaceutical.
Exercise. Emerging data support the notion that exercise protects against CIPN and may help repair damaged nerves after CIPN develops. These data include information regarding patients who were exercising more prior to receiving neurotoxic chemotherapy, patients randomized to more exercise while receiving neurotoxic chemotherapy,[30,31] and patients who exercised more following neurotoxic chemotherapy.[32,33] The largest randomized trial of exercise for CIPN prevention enrolled 314 patients who were scheduled to receive chemotherapy and randomized them to usual care or usual care plus Exercise for Cancer Patients, a standardized, individualized, moderate-intensity, home-based, 6-week progressive walking and resistance exercise program. The exercise group reported a 0.26-point reduction (on a 0-to-10 scale) in CIPN, which was significant (P = .0432) compared with the effect of duloxetine (0.53 effect size, with an observed mean difference—compared with placebo—of 0.72 on a 0-to-10 scale). In addition, exercise had other major benefits and no harms. Exact exercise prescriptions have not yet been developed, but the more hours spent in moderate-to-vigorous activity, the less CIPN. Again, the toxicity is minimal and the benefits with regard to other aspects of survivorship are well established. In our own practice, we ask patients to do at least 20 minutes of walking every day.
Pharmacologic agents with no evidence of efficacy
Anticonvulsants. Several anticonvulsants have been evaluated for the prevention of CIPN. An open-label non–placebo-controlled trial randomized 36 patients with advanced colorectal cancer to receive chemotherapy with or without carbamazepine. There were no differences between the groups in neuropathy symptoms. The findings from this trial contrasted with those from another open-label non–placebo-controlled trial that randomized 32 patients to receive oxaliplatin-based chemotherapy with or without oxcarbazepine. The oxcarbazepine arm experienced a significantly reduced incidence of CIPN (31.2% vs 75%). These findings have not been confirmed in larger, phase III trials, however, and the 2014 ASCO guidelines indicate that there was insufficient evidence to support use of these agents for CIPN prevention. Pregabalin is another agent in this category; it has been studied in a phase II trial, with results that failed to support its use for CIPN prevention.
Antidepressants. Three trials have been conducted in which antidepressants were given for the prevention of CIPN, with varying results. Amitriptyline was studied in a randomized placebo-controlled double-blind manner in patients receiving chemotherapy with vinca alkaloids, platinum agents, or taxanes. There were no significant differences in neuropathic symptoms between the groups. Venlafaxine was found to be helpful in one placebo-controlled double-blind trial involving 48 patients receiving oxaliplatin-based chemotherapy. However, another randomized pilot trial, which was similarly designed to evaluate the neuroprotective role of venlafaxine in patients receiving oxaliplatin-based chemotherapy, failed to support its use as a preventive agent, and did not support initiation of further phase III investigation. Based on the present data, antidepressants are not recommended for CIPN prevention.
Chemoprotectants: no good evidence of efficacy
Amifostine. This agent is an organic thiophosphate that has been studied in several randomized trials as an agent that might prevent neurotoxicity resulting from both taxanes and platinum agents.[40-50] Results of these trials have been mixed, and while a Cochrane meta-analysis that considered results from some of these trials suggested significant reduction in the risk of CIPN with the use of amifostine, the quality of data collected from these studies was not considered strong enough to recommend amifostine for this purpose. A 2014 ASCO systematic review arrived at a similar conclusion, noting that the inconsistency of the data, as well as the increased risk of side effects, made amifostine an inappropriate choice for CIPN prevention.
Nimodipine. While this calcium channel blocker showed promise in animal models as a protective agent for platinum-related neuropathy, it failed to show benefit in a randomized double-blind placebo-controlled trial involving 51 patients treated with cisplatin for ovarian cancer. Patients who received nimodipine had significantly inferior outcomes with respect to neurotoxicity, leading to premature discontinuation of the trial.
Neurotropin. This extract of small peptides from the skin of rabbits injected with the vaccinia virus was tested in a phase II pilot trial involving 80 colon cancer patients treated with oxaliplatin-based chemotherapy; the results have suggested protection against grade 2 or greater neurotoxicity. However, there have been no large phase III trials to provide confirmation of these results.
Diethyldithiocarbamate (DDTC). This agent showed promise in animal models but failed to perform as well in a randomized placebo-controlled trial of 221 patients treated with cisplatin for ovarian cancer. Patients who received DDTC were more likely to be withdrawn from treatment early due to toxicity, raising safety concerns for this agent.
ACTH analog ORG 2766. There have been six trials evaluating the use of ACTH analog ORG 2766 for CIPN prevention in patients receiving either cisplatin or vincristine.[54-59] A Cochrane meta-analysis considering four of these trials concluded that this agent was not beneficial for the prevention of CIPN. Similarly, the systematic review from ASCO, which considered all six trials, found mixed results that did not support the use of this agent for CIPN prevention.
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