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.
Introduction
Chemotherapy-induced peripheral neuropathy (CIPN) pain can greatly diminish quality of life; create or worsen depression, insomnia, fatigue, and other symptom clusters[1]; 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%.[2] 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.[3] 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.[6] 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.[7] 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,[13] 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.[14]
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.[15]
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,[18] 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[19] 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.[20] 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.[21] 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.[15]
Acetyl-L-carnitine. This modified amino acid showed promise in animal models[22] 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.[25] 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.[26] 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.[27] Without any strong evidence available to support its use, vitamin E is not recommended for CIPN prevention.[17]
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.[28] 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
[[{"type":"media","view_mode":"media_crop","fid":"54023","attributes":{"alt":"","class":"media-image","id":"media_crop_1155370336481","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"6760","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"height: 144px; width: 144px;","title":"","typeof":"foaf:Image"}}]]
Nanna B. Finnerup, MD, DrMedSc
Aarhus University
Aarhus, Denmark
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,[29] 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.[34] 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.[35] 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.[17] 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.[36]
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.[37] 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.[38] 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.[39] 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.[17]
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.[51] 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.[52] 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.[53] 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.[60] 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.[17]
Treatment of Established CIPN
There are limited therapeutic options for patients with established CIPN, mirroring the situation for CIPN prevention. In the acute setting, the decision to dose-reduce or discontinue chemotherapeutic agents should be made with consideration of the severity of symptoms. When patients experience chronic neurotoxicity that necessitates intervention beyond dose reduction or discontinuation, the strongest evidence supports the use of duloxetine. Several additional agents have been studied, but with regard to efficacy, results have been mixed. Established and possibly active modalities are shown in Table 2 and Table 3.
The one nonopioid pharmacologic agent with reliable efficacy: duloxetine
Duloxetine was studied in a multicenter randomized double-blind crossover trial involving 231 patients with taxane- or platinum-associated CIPN.[6] Patients were randomly assigned to receive duloxetine (30 mg daily for 1 week, then 60 mg daily for 4 weeks) or placebo for 5 weeks, followed by a washout period, then a crossover to the opposite arm. Patients who received duloxetine as initial therapy experienced a mean decrease in average pain of 1.06, compared with 0.34 for those receiving placebo (a reduction of 0.72; P = .003), as measured by the Brief Pain Inventory–Short Form. Of those who received duloxetine, 59% experienced a decrease in pain of any amount, compared with 38% of those who received placebo. Another smaller randomized controlled trial of duloxetine yielded similar results.[61] Other antidepressants, by contrast, have not shown a similar benefit. The tricyclic antidepressants nortriptyline and amitriptyline each were studied in small trials,[62,63] but failed to significantly reduce pain symptoms compared with placebo.
Nonopioid agents not better than placebo in randomized trials, but which may help individual patients: anticonvulsants
Although anticonvulsants, such as gabapentinoids, are utilized for treatment of other neuropathic pain states, they have not been proven effective for patients with CIPN. In a double-blind placebo-controlled crossover trial involving 115 patients with CIPN, gabapentin did not change symptom severity any more than did a placebo after 6 weeks, on multiple measures.[64] Lamotrigine was similarly studied in 131 patients and failed to provide a statistically significant decrease in pain reduction after 10 weeks of therapy.[65]
The combination of nortriptyline and gabapentin was additive compared with either alone in other types of neuropathic pain. Gilron et al added nortriptyline at a target dose of 100 mg nightly to a stable dose of gabapentin of at least 300 mg 3 times a day.[66] Thus, patients who want to avoid opioids may want to try this combination.
Agents for which there is insufficient evidence to be strongly recommended, but that have limited toxicity
Topical baclofen, amitriptyline, and ketamine (BAK). Topical BAK was studied in a randomized placebo-controlled trial, and a small but statistically insignificant (P = .053) benefit was seen in the BAK arm after 4 weeks of therapy, as measured by the European Organisation for Research and Treatment of Cancer CIPN20 quality-of-life questionnaire.[67] Notably, statistically significant (P = .021) improvement was seen in the motor subscale of this survey with use of BAK. A related combination of ketamine and amitriptyline was studied in a randomized double-blind placebo-controlled manner but failed to show similar benefit after 6 weeks of treatment.[68] However, toxicity was minimal, so BAK gel may be worth trying in individual patients; the prescription is available from the authors of this review.
Topical low-concentration menthol. One person with significant CIPN from bortezomib treatment[69] and one with CIPN from carboplatin therapy[70] found relief with topical 1% menthol and were able to continue treatment.[69] A subsequent phase II trial of 1% menthol applied to the affected area in 51 patients with neuropathic pain (35 with CIPN) showed substantial relief with minimal toxicity: 31 of 38 evaluable patients had improvement in their pain scores (P < .001), with improvements also noted in mood, walking, and catastrophizing.[69] No toxicity was noted. Plausible mechanisms of action include occupation of the receptor for transient receptor potential melastatin 8 (a surface receptor ion channel that gives signals to pain fibers) and replacement of the “pain” impulse with a soothing sensation. While randomized controlled trials are certainly needed, the lack of toxicity and low cost (less than $3 for a tube of 1%–2% menthol backrub at any drugstore) make this an attractive option.
Topical gabapentin. This agent has been reported to relieve the pain of vulvodynia,[71] postherpetic neuropathy, and other local pain problems in most patients in whom it has been tried, with minimal toxicity. In a recent series, 20 of 23 benefited, with pain scores falling from 8.2 to 5.6 at 1 month, and 11 of 23 achieving a clinically meaningful 30% reduction in pain.[72] Most centers use 6% w/w gabapentin, compounded, applied 3 times daily. The topical preparation penetrates deep enough to affect local nociception,[73] so there is a rationale for its working. The typical side effects associated with gabapentin-sedation, fatigue, and edema-have been minimal, since application even to a large area would result in absorption of only 100 mg/d. There have been no randomized trials of topical gabapentin, although we will be starting one soon.
Opioids
There is no published evidence that opioids help with CIPN, but our own experience tells us that sometimes they are the only drugs that do help. In other non-CIPN neuropathic pain syndromes, when neurotropic drugs are given in combination with an opioid, the effect is additive. The best example that proves benefit is a randomized trial of gabapentin, an opioid (morphine or hydromorphone), or the combination vs placebo for neuropathic pain. The combination was significantly more effective than either agent alone when tested in patients with non-CIPN neuropathic pain.[74] The only other drug proven to show benefit in combination with an opioid is nortriptyline, which reduced average pain scores by about 1 point on a 10-point scale when added to morphine[75]; however, this combination was not tested specifically in CIPN. The side effects of dry mouth, constipation, and sedation were more common with the combination, as expected, but were manageable. In our practice, we start nortriptyline at 10 mg at night and increase the dose by 10-mg increments every 3 to 5 nights, as tolerated (either with or without an opioid).
There are no compelling data to suggest that one opioid is better than another for neuropathic pain. The best available trial showing equivalence of morphine and methadone was underpowered to detect small but possibly clinically meaningful differences.[76]
Neuromodulation: techniques that send alternative signals along the pain fibers
Neuropathy, including CIPN, involves nerve signals that no longer serve a purpose-unlike the nerve signals from a compressed vertebra, for example. Unless pain is protecting a person from a compression fracture or from keeping his or her hand on a hotplate, the pain signal is not serving any useful purpose. What if it were possible to reverse or reset purposeless pain signals, either at the damaged nerve endings or along the pathways to the brain? Neuromodulation is the broad term used to describe techniques that disrupt pain signals and allow the transmission of more normal impulses.
Spinal cord stimulation (SCS). An exciting development has been the application of an established treatment modality, SCS, to CIPN. First reported in 2004 to provide substantial relief of truly refractory CIPN, SCS has now been reported to be highly successful in at least a dozen cases.[77-79] All of these case reports have demonstrated long-lasting reduction in pain of at least 50%, with acceptable side effects. The problem with SCS is mechanical: the electrodes must be inserted along the dorsal re-entry zone of the spinal cord, then connected to a pulse generator implanted under the skin like a pacemaker. This is expensive (over $100,000 for insertion and trial), is invasive, and can cause hematomas and infection. The technique also requires coordination with an expert SCS team, and insurance may not cover it.
Scrambler therapy. There may be effective ways to deliver an alternative “nonpain” signal to damaged nerve pathways, but the evidence is still limited. Transcutaneous electrical nerve stimulation may work for superficial pain, but it has not been used successfully for CIPN or serious cancer pain.[80] However, there is some promising preliminary evidence of efficacy (although no randomized trial results as yet) for a different type of stimulation that uses a rapidly changing electrical impulse designed to send a nonpain signal along CIPN-damaged pathways. Using scrambler therapy (Calmare), Smith et al reported pain relief in 16 of 18 patients with refractory CIPN, including 4 whose pain resolved to 0 (on a scale of 0 to 10), and an overall average reduction in pain of around 60%.[81] Function improved in most patients, including less interference with walking and sleeping, for at least 3 months.[82] Pachman et al at the Mayo Clinic replicated this study and reported about a 50% reduction in pain, numbness, and tingling lasting at least 3 months.[83] Of note, there appeared to be a learning curve for practitioners, with the patients who were treated later experiencing better and longer-lasting pain relief.[83] A recent review of at least 20 scientific reports noted no harm in any trial of scrambler therapy, and with most reporting a substantial relief of pain, including CIPN, postherpetic neuropathy, cancer pain, and noncancer pain.[84] The two randomized trials that have compared sham to real scrambler therapy showed a 50% reduction in back pain and a 91% reduction in the pain of failed back syndrome or postherpetic neuropathy at 3 to 4 weeks, respectively, with the relief lasting several months.[85,86] Since the publication of Majithia’s review,[84] there have been continued reports of success with the use of scrambler therapy in cancer somatic pain, including bone and visceral metastases, pediatric cancer chest wall pain, and other types of pain. The US military has 17 scrambler therapy machines in current use.
We have been using scrambler therapy routinely at our centers, and we believe this treatment modality has benefit in some patients. At the same time, we are humbled by the many therapies that have shown promise in phase II trials only to prove no better than placebo or sham in phase III trials.
Acupuncture. This is another safe method of neuromodulation, which has recently been reviewed in depth.[87] Several small nonrandomized trials have shown benefit, and one randomized sham-controlled trial failed to show benefit, perhaps because patients’ baseline pain scores were so low that showing benefit was not possible. Thus, the evidence is inconclusive at best.
Discussion and Conclusions
CIPN is increasingly recognized as a problem that can be devastating, refractory, and hard to treat. Some promising modalities are in development, but much more work is needed before it is possible to help the majority of patients. There are no proven preventive drugs; omega-3 fatty acids have shown some promise, but the one small trial clearly needs replication, given the history of failed drug trials in this setting. For treatment of established CIPN, we urge oncologists to first use the only drug with proven benefit, duloxetine, and to not routinely prescribe drugs that have not been shown to work for CIPN, such as gabapentin and pregabalin, even though they work for other types of neuropathic pain and may work in individual patients. It is important to have a sequence of drugs to try, since the number of people who benefit from each neuropathic pain drug is only about 1 in 3; it is also important to give each drug for at least 2 weeks to fully evaluate whether it works before moving on.[7,8]
For truly refractory pain, a trial of spinal cord stimulation may make sense, although the evidence for this modality is limited by small numbers and lack of randomized trials. Scrambler therapy is a promising noninvasive treatment being tested in randomized sham or alternative treatment trials. Acupuncture appears to help some patients, but the trial data are conflicting. Moderate-to-vigorous exercise before, during, and after chemotherapy has a multitude of benefits, including less CIPN.
Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
References:
1. Hwang KH, Cho OH, Yoo YS. Symptom clusters of ovarian cancer patients undergoing chemotherapy, and their emotional status and quality of life. Eur J Oncol Nurs. 2016;21:215-22.
2. Smith TJ, Temin S, Alesi ER, et al. American Society of Clinical Oncology provisional clinical opinion: the integration of palliative care into standard oncology care. J Clin Oncol. 2012;30:880-7.
3. Chu SH, Lee YJ, Lee ES, et al. Current use of drugs affecting the central nervous system for chemotherapy-induced peripheral neuropathy in cancer patients: a systematic review. Support Care Cancer. 2015;23:513-24.
4. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain-United States, 2016. JAMA. 2016;315:1624-45.
5. Olsen Y. The CDC guideline on opioid prescribing: rising to the challenge. JAMA. 2016;315:1577-9.
6. Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013;309:1359-67.
7. Smith TJ, Saiki CB. Cancer pain management. Mayo Clin Proc. 2015;90:1428-39.
8. Gilron I, Baron R, Jensen T. Neuropathic pain: principles of diagnosis and treatment. Mayo Clin Proc. 2015;90:532-45.
9. Grisold W, Cavaletti G, Windebank AJ. Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention. Neuro Oncol. 2012;14(suppl 4):iv45-iv54.
10. Carozzi VA, Canta A, Chiorazzi A. Chemotherapy-induced peripheral neuropathy: What do we know about mechanisms? Neurosci Lett. 2015;596:90-107.
11. Reeves BN, Dakhil SR, Sloan JA, et al. Further data supporting that paclitaxel-associated acute pain syndrome is associated with development of peripheral neuropathy: North Central Cancer Treatment Group trial N08C1. Cancer. 2012;118:5171-8.
12. Loprinzi CL, Reeves BN, Dakhil SR, et al. Natural history of paclitaxel-associated acute pain syndrome: prospective cohort study NCCTG N08C1. J Clin Oncol. 2011;29:1472-8.
13. Kroigard T, Schroder HD, Qvortrup C, et al. Characterization and diagnostic evaluation of chronic polyneuropathies induced by oxaliplatin and docetaxel comparing skin biopsy to quantitative sensory testing and nerve conduction studies. Eur J Neurol. 2014;21:623-9.
14. Burakgazi AZ, Messersmith W, Vaidya D, et al. Longitudinal assessment of oxaliplatin-induced neuropathy. Neurology. 2011;77:980-6.
15. Pachman DR, Qin R, Seisler DK, et al. Clinical course of oxaliplatin-induced neuropathy: results from the randomized phase III trial N08CB (Alliance). J Clin Oncol. 2015;33:3416-22.
16. National Comprehensive Cancer Network. National Comprehensive Clinical Practice Guidelines in Oncology. Survivorship. Version 2.2016. http://www.nccn.org/professionals/physician_gls/pdf/survivorship.pdf. Accessed October 7, 2016.
17. Hershman DL, Lacchetti C, Dworkin RH, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32:1941-67.
18. Nishioka M, Shimada M, Kurita N, et al. The kampo medicine, goshajinkigan, prevents neuropathy in patients treated by FOLFOX regimen. Int J Clin Oncol. 2011;16:322-7.
19. Kono T, Hata T, Morita S, et al. Goshajinkigan oxaliplatin neurotoxicity evaluation (GONE): a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of goshajinkigan to prevent oxaliplatin-induced neuropathy. Cancer Chemother Pharmacol. 2013;72:1283-90.
20. Oki E, Emi Y, Kojima H, et al. Preventive effect of goshajinkigan on peripheral neurotoxicity of FOLFOX therapy (GENIUS trial): a placebo-controlled, double-blind, randomized phase III study. Int J Clin Oncol. 2015;20:767-75.
21. Loprinzi CL, Qin R, Dakhil SR, et al. Phase III randomized, placebo-controlled, double-blind study of intravenous calcium and magnesium to prevent oxaliplatin-induced sensory neurotoxicity (N08CB/Alliance). J Clin Oncol. 2014;32:997-1005.
22. Pisano C, Pratesi G, Laccabue D, et al. Paclitaxel and cisplatin-induced neurotoxicity: a protective role of acetyl-L-carnitine. Clin Cancer Res. 2003;9:5756-67.
23. Bianchi G, Vitali G, Caraceni A, et al. Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl-L-carnitine. Eur J Cancer. 2005;41:1746-50.
24. Maestri A, De Pasquale Ceratti A, Cundari S, et al. A pilot study on the effect of acetyl-L-carnitine in paclitaxel- and cisplatin-induced peripheral neuropathy. Tumori. 2005;91:135-8.
25. Hershman DL, Unger JM, Crew KD, et al. Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. J Clin Oncol. 2013;31:2627-33.
26. Guo Y, Jones D, Palmer JL, et al. Oral alpha-lipoic acid to prevent chemotherapy-induced peripheral neuropathy: a randomized, double-blind, placebo-controlled trial. Support Care Cancer. 2014;22:1223-31.
27. Kottschade LA, Sloan JA, Mazurczak MA, et al. The use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: results of a randomized phase III clinical trial. Support Care Cancer. 2011;19:1769-77.
28. Ghoreishi Z, Esfahani A, Djazayeri A, et al. Omega-3 fatty acids are protective against paclitaxel-induced peripheral neuropathy: a randomized double-blind placebo controlled trial. BMC Cancer. 2012;12:355.
29. Greenlee H, Hershman DL, Shi Z, et al. Body mass index, lifestyle factors, and taxane-induced neuropathy in women with breast cancer: the Pathways Study. J Clin Oncol. 2016;34(suppl):abstr 10002.
30. Kleckner I, Kamen CS, Peppone LJ, et al. A URCC NCORP nationwide randomized controlled trial investigating the effect of exercise on chemotherapy-induced peripheral neuropathy in 314 cancer patients. J Clin Oncol. 2016;34(suppl):abstr 10000.
31. Streckmann F, Kneis S, Leifert JA, et al. Exercise program improves therapy-related side-effects and quality of life in lymphoma patients undergoing therapy. Ann Oncol. 2014;25:493-9.
32. Ezendam NP, Pijlman B, Bhugwandass C, et al. Chemotherapy-induced peripheral neuropathy and its impact on health-related quality of life among ovarian cancer survivors: results from the population-based PROFILES registry. Gynecol Oncol. 2014;135:510-7.
33. Stevinson C, Steed H, Faught W, et al. Physical activity in ovarian cancer survivors: associations with fatigue, sleep, and psychosocial functioning. Int J Gynecol Cancer. 2009;19:73-8.
34. von Delius S, Eckel F, Wagenpfeil S, et al. Carbamazepine for prevention of oxaliplatin-related neurotoxicity in patients with advanced colorectal cancer: final results of a randomised, controlled, multicenter phase II study. Invest New Drugs. 2007;25:173-80.
35. Argyriou AA, Chroni E, Polychronopoulos P, et al. Efficacy of oxcarbazepine for prophylaxis against cumulative oxaliplatin-induced neuropathy. Neurology. 2006;67:2253-5.
36. Shinde SS, Seisler D, Soori G, et al. Can pregabalin prevent paclitaxel-associated neuropathy?-an ACCRU pilot trial. Support Care Cancer. 2016;24:547-53.
37. Kautio AL, Haanpaa M, Leminen A, et al. Amitriptyline in the prevention of chemotherapy-induced neuropathic symptoms. Anticancer Res. 2009;29:2601-6.
38. Durand JP, Deplanque G, Montheil V, et al. Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial. Ann Oncol. 2012;23:200-5.
39. Zimmerman C, Atherton PJ, Pachman D, et al. MC11C4: a pilot randomized, placebo-controlled, double-blind study of venlafaxine to prevent oxaliplatin-induced neuropathy. Support Care Cancer. 2016;24:1071-8.
40. Kemp G, Rose P, Lurain J, et al. Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol. 1996;14:2101-12.
41. Planting AS, Catimel G, de Mulder PH, et al. Randomized study of a short course of weekly cisplatin with or without amifostine in advanced head and neck cancer. EORTC Head and Neck Cooperative Group. Ann Oncol. 1999;10:693-700.
42. Gelmon K, Eisenhauer E, Bryce C, et al. Randomized phase II study of high-dose paclitaxel with or without amifostine in patients with metastatic breast cancer. J Clin Oncol. 1999;17:3038-47.
43. Gallardo D, Mohar A, Calderillo G, et al. Cisplatin, radiation, and amifostine in carcinoma of the uterine cervix. Int J Gynecol Cancer. 1999;9:225-30.
44. Moore DH, Donnelly J, McGuire WP, et al. Limited access trial using amifostine for protection against cisplatin- and three-hour paclitaxel-induced neurotoxicity: a phase II study of the Gynecologic Oncology Group. J Clin Oncol. 2003;21:4207-13.
45. Kanat O, Evrensel T, Baran I, et al. Protective effect of amifostine against toxicity of paclitaxel and carboplatin in non-small cell lung cancer: a single center randomized study. Med Oncol. 2003;20:237-45.
46. Glover D, Ibrahim J, Kirkwood J, et al. Phase II randomized trial of cisplatin and WR-2721 versus cisplatin alone for metastatic melanoma: an Eastern Cooperative Oncology Group Study (E1686). Melanoma Res. 2003;13:619-26.
47. Leong SS, Tan EH, Fong KW, et al. Randomized double-blind trial of combined modality treatment with or without amifostine in unresectable stage III non-small-cell lung cancer. J Clin Oncol. 2003;21:1767-74.
48. De Vos FY, Bos AM, Schaapveld M, et al. A randomized phase II study of paclitaxel with carboplatin +/- amifostine as first line treatment in advanced ovarian carcinoma. Gynecol Oncol. 2005;97:60-7.
49. Hilpert F, Stahle A, Tome O, et al. Neuroprotection with amifostine in the first-line treatment of advanced ovarian cancer with carboplatin/paclitaxel-based chemotherapy-a double-blind, placebo-controlled, randomized phase II study from the Arbeitsgemeinschaft Gynakologische Onkologoie (AGO) Ovarian Cancer Study Group. Support Care Cancer. 2005;13:797-805.
50. Lorusso D, Ferrandina G, Greggi S, et al. Phase III multicenter randomized trial of amifostine as cytoprotectant in first-line chemotherapy in ovarian cancer patients. Ann Oncol. 2003;14:1086-93.
51. Cassidy J, Paul J, Soukop M, et al. Clinical trials of nimodipine as a potential neuroprotector in ovarian cancer patients treated with cisplatin. Cancer Chemother Pharmacol. 1998;41:161-6.
52. Zhang RX, Lu ZH, Wan DS, et al. Neuroprotective effect of neurotropin on chronic oxaliplatin-induced neurotoxicity in stage II and stage III colorectal cancer patients: results from a prospective, randomised, single-centre, pilot clinical trial. Int J Colorectal Dis. 2012;27:1645-50.
53. Gandara DR, Nahhas WA, Adelson MD, et al. Randomized placebo-controlled multicenter evaluation of diethyldithiocarbamate for chemoprotection against cisplatin-induced toxicities. J Clin Oncol. 1995;13:490-6.
54. van der Hoop RG, Vecht CJ, van der Burg ME, et al. Prevention of cisplatin neurotoxicity with an ACTH(4-9) analogue in patients with ovarian cancer. N Engl J Med. 1990;322:89-94.
55. Hovestadt A, van der Burg ME, Verbiest HB, et al. The course of neuropathy after cessation of cisplatin treatment, combined with Org 2766 or placebo. J Neurol. 1992;239:143-6.
56. van Kooten B, van Diemen HA, Groenhout KM, et al. A pilot study on the influence of a corticotropin (4-9) analogue on Vinca alkaloid-induced neuropathy. Arch Neurol. 1992;49:1027-31.
57. van Gerven JM, Hovestadt A, Moll JW, et al. The effects of an ACTH (4-9) analogue on development of cisplatin neuropathy in testicular cancer: a randomized trial. J Neurol. 1994;241:432-5.
58. Roberts JA, Jenison EL, Kim K, et al. A randomized, multicenter, double-blind, placebo-controlled, dose-finding study of ORG 2766 in the prevention or delay of cisplatin-induced neuropathies in women with ovarian cancer. Gynecol Oncol. 1997;67:172-7.
59. Koeppen S, Verstappen CC, Korte R, et al. Lack of neuroprotection by an ACTH (4-9) analogue. A randomized trial in patients treated with vincristine for Hodgkin’s or non-Hodgkin’s lymphoma. J Cancer Res Clin Oncol. 2004;130:153-60.
60. Albers JW, Chaudhry V, Cavaletti G, Donehower RC. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev. 2014;(3):CD005228.
61. Hirayama Y, Ishitani K, Sato Y, et al. Effect of duloxetine in Japanese patients with chemotherapy-induced peripheral neuropathy: a pilot randomized trial. Int J Clin Oncol. 2015;20:866-71.
62. Hammack JE, Michalak JC, Loprinzi CL, et al. Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy. Pain. 2002;98:195-203.
63. Kautio AL, Haanpaa M, Saarto T, Kalso E. Amitriptyline in the treatment of chemotherapy-induced neuropathic symptoms. J Pain Symptom Manage. 2008;35:31-9.
64. Rao RD, Michalak JC, Sloan JA, et al. Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled, crossover trial (N00C3). Cancer. 2007;110:2110-8.
65. Rao RD, Flynn PJ, Sloan JA, et al. Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled trial, N01C3. Cancer. 2008;112:2802-8.
66. Gilron I, Bailey JM, Tu D, et al. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet. 2009;374:1252-61.
67. Barton DL, Wos EJ, Qin R, et al. A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA. Support Care Cancer. 2011;19:833-41.
68. Gewandter JS, Mohile SG, Heckler CE, et al. A phase III randomized, placebo-controlled study of topical amitriptyline and ketamine for chemotherapy-induced peripheral neuropathy (CIPN): a University of Rochester CCOP study of 462 cancer survivors. Support Care Cancer. 2014;22:1807-14.
69. Fallon MT, Storey DJ, Krishan A, et al. Cancer treatment-related neuropathic pain: proof of concept study with menthol-a TRPM8 agonist. Support Care Cancer. 2015;23:2769-77.
70. Storey DJ, Colvin LA, Mackean MJ, et al. Reversal of dose-limiting carboplatin-induced peripheral neuropathy with TRPM8 activator, menthol, enables further effective chemotherapy delivery. J Pain Symptom Manage. 2010;39:e2-e4.
71. Boardman LA, Cooper AS, Blais LR, Raker CA. Topical gabapentin in the treatment of localized and generalized vulvodynia. Obstet Gynecol. 2008;112:579-85.
72. Hiom S, Patel GK, Newcombe RG, et al. Severe postherpetic neuralgia and other neuropathic pain syndromes alleviated by topical gabapentin. Br J Dermatol. 2015;173:300-2.
73. Bryson E, Asbill S, Sweitzer S. Skin permeation and antinociception of topical gabapentin formulations. Int J Pharm Compd. 2014;18:504-11.
74. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352:1324-34.
75. Gilron I, Tu D, Holden RR, et al. Combination of morphine with nortriptyline for neuropathic pain. Pain. 2015;156:1440-8.
76. Bruera E, Palmer JL, Bosnjak S, et al. Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study. J Clin Oncol. 2004;22:185-92.
77. Cata JP, Cordella JV, Burton AW, et al. Spinal cord stimulation relieves chemotherapy-induced pain: a clinical case report. J Pain Symptom Manage. 2004;27:72-8.
78. Abd-Elsayed A, Schiavoni N, Sachdeva H. Efficacy of spinal cord stimulators in treating peripheral neuropathy: a case series. J Clin Anesth. 2016;28:74-7.
79. Lamer TJ, Deer TR, Hayek SM. Advanced innovations for pain. Mayo Clin Proc. 2016;91:246-58.
80. Kim JH, Dougherty PM, Abdi S. Basic science and clinical management of painful and non-painful chemotherapy-related neuropathy. Gynecol Oncol. 2015;136:453-9.
81. Smith TJ, Coyne PJ, Parker G, Dodson P. Pilot trial of a patient-specific cutaneous electro-stimulation device (MC5-A Calmare®) for chemotherapy-induced peripheral neuropathy. J Pain Symptom Manage. 2010;40:883-91.
82. Coyne PJ, Wan W, Dodson P, et al. A trial of scrambler therapy in the treatment of cancer pain syndromes and chronic chemotherapy-induced peripheral neuropathy. J Pain Palliat Care Pharmacother. 2013;27:359-64.
83. Pachman DR, Ruddy K, Sangaralingham LR, et al. Calcium and magnesium use for oxaliplatin-induced neuropathy: a case study to assess how quickly evidence translates into practice. J Natl Compr Canc Netw. 2015;13:1097-101.
84. Majithia N, Smith TJ, Coyne PJ, et al. Scrambler therapy for the management of chronic pain. Support Care Cancer. 2016;24:2807-14.
85. Starkweather AR, Coyne P, Lyon DE, et al. Decreased low back pain intensity and differential gene expression following Calmare(R): results from a double-blinded randomized sham-controlled study. Res Nurs Health. 2015;38:29-38.
86. Marineo G, Iorno V, Gandini C, et al. Scrambler therapy may relieve chronic neuropathic pain more effectively than guideline-based drug management: results of a pilot, randomized, controlled trial. J Pain Symptom Manage. 2012;43:87-95.
87. Brami C, Bao T, Deng G. Natural products and complementary therapies for chemotherapy-induced peripheral neuropathy: a systematic review. Crit Rev Oncol Hematol. 2016;98:325-34.
88. Bird TD. Charcot-Marie-Tooth hereditary neuropathy overview. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993-2016. https://www.ncbi.nlm.nih.gov/books/NBK1358/. Accessed October 8, 2016.
89. Frederiks CN, Lam SW, Guchelaar HJ, Boven E. Genetic polymorphisms and paclitaxel- or docetaxel-induced toxicities: a systematic review. Cancer Treat Rev. 2015;41:935-50.
90. Boora GK, Kanwar R, Kulkarni AA, et al. Testing of candidate single nucleotide variants associated with paclitaxel neuropathy in the trial NCCTG N08C1 (Alliance). Cancer Med. 2016;5:631-9.
91. de la Morena Barrio P, Conesa MA, Gonzalez-Billalabeitia E, et al. Delayed recovery and increased severity of paclitaxel-induced peripheral neuropathy in patients with diabetes. J Natl Compr Canc Netw. 2015;13:417-23.
