One small randomized, sham-controlled trial of weekly electro-acupuncture for the prevention of taxane-induced peripheral neuropathy in 63 patients did not show any differences in neuropathy between groups.¹³ In this trial, the electro-acupuncture arm actually had a slower recovery of neuropathy than was seen in the sham group, after chemotherapy was stopped.

Two trials evaluating acetyl-l-carnitine were identified. Campone et al¹⁴ reported data on the use of acetyl-l-carnitine for preventing sagopilone-induced neuropathy in 150 patients randomly assigned to receive acetyl-l-carnitine or placebo. There were no significant differences between the 2 treatment arms for peripheral neuropathy overall, and the median duration of neuropathy was similar.¹⁴ These data are consistent with older data from a previously reported trial in patients receiving paclitaxel, where neuropathy was actually worse in the patients who received acetyl-l-carnitine.^15,16 In a recent long-term follow-up analysis⁷ of that trial, 24 weeks of acetyl-l-carnitine therapy resulted in statistically significantly worse CIPN (P = .01) over 2 years, as measured by the Functional Assessment of Cancer Therapy-Neurotoxicity (FACT-Ntx) Questionnaire.

One randomized, double-blinded clinical trial that evaluated oral alpha-lipoic acid (ALA) for the prevention of platinum-induced peripheral neuropathy was identified. Patients received 600 mg ALA acid 3 times daily for 24 weeks while receiving chemotherapy. This trial enrolled 243 patients, but only 70 of them (29%) completed the trial. The study authors reported that the high dropout rate may have been related, in part, to the requirement that patients take the drug 3 times per day. Data indicated that neuropathy scores increased significantly from baseline for both groups at 24 weeks (P < .001 for each group), with no statistically significant ameliorating effect from ALA in the treatment arm being observed from the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) tool, from pain scores, or from functional test scores. The study results suggest that ALA is not tolerated well and does not prevent neuropathy.¹⁷

One systematic review and 1 pilot trial not included in the systematic review evaluating the utility of intravenous calcium and magnesium were identified. The systemic review, which included 694 patients from 5 trials published between 2010 and 2014, confirmed that there was no beneficial effect in terms of the incidence of grade ≥ 2 neuropathy (relative risk [RR], 0.81; 95% CI, 0.60 to 1.11) or chronic neurotoxicity (RR, 0.95; 95% CI, 0.69 to 1.32) from CaMg infusions for the prevention of oxaliplatin-induced peripheral neuropathy.¹⁸ Two older pooled analyses identified from Xu et al¹⁹ and Wen et al²⁰, which did not come to the same conclusion, should be discounted, as they did not include data from the largest and most recent definitive trial.

A small randomized, placebo-controlled, crossover trial of calcium/magnesium for prevention of oxaliplatin-induced acute neuropathy involved 20 patients and evaluated EMG motor nerve hyperexcitability scores.²¹ The authors reported that there were no differences between those who received calcium and magnesium versus placebo in EMG outcomes (mean EMG score Ca/Mg, 6.5; standard deviation [SD], 4.31; and mean placebo score, 6.2; SD, 4.34) or for patient-reported acute neurotoxicity symptoms.²¹

Calmangafodipir was studied in a placebo-controlled 3-arm phase II trial in patients receiving oxaliplatin-based chemotherapy.²² This trial provided promising enough data to initiate 2 phase III, placebo-controlled clinical trials (ClinicalTrials.gov identifiers: NCT04034355 and NCT04034355), with results forthcoming.

A 61-patient randomized trial evaluated a nutraceutical product, l-carnosine, as an agent to try to decrease oxaliplatin-induced neuropathy.²³ Although the study reported remarkably positive results for the study agent over the control arm, there was no placebo used in this trial and it was not double-blinded. Clinicians judged neuropathy severity, as opposed to using patient-reported outcomes. Thus, additional data are necessary to understand the potential utility of this agent.

The first publication suggesting that cryotherapy was helpful for decreasing taxane-induced neuropathy came from Danish investigators, who noted that patients who received distal-extremity cryotherapy for decreasing onycholysis appeared to have reduced amounts of docetaxel-induced neuropathy by approximately 50%.²⁴ Five trials evaluating cryotherapy were identified. One prospective, self-controlled trial in 36 patients with breast cancer treated weekly with paclitaxel, who wore frozen gloves (FGs) and socks on the dominant side for 90 minutes but not the other side, reported that the development of subjective CIPN symptoms was clinically and statistically significantly delayed during the course of the paclitaxel treatment; the occurrence of subjective CIPN at a cumulative dose of 960 mg/m² was reported to be almost completely prevented (severe CIPN; hand: 2.8% v 41.7%; odds ratio [OR], infinite; 95% CI, 3.32 to infinite; P < .001; foot: 2.8% v 36.1%; OR, infinite; 95% CI, 2.78 to infinite; P < .001), and the CIPN incidence, as assessed by other objective modalities, was lower on the intervention side.²⁵ In a larger unblinded RCT, 180 patients started treatment with oxaliplatin, docetaxel, or paclitaxel and were randomly assigned to FGs on both hands during treatment or to usual care.²⁶ Self-reported CIPN and QOL were measured. Overall neuropathy scores, the primary outcome measure, were not significantly different between the groups, in part because the feet were not treated, and neuropathy in lower extremities is oftentimes more problematic than it is in upper extremities. This study’s results did support that FGs reduced neuropathy symptoms in patients’ hands and improved some QOL measures. A recently published randomized phase II trial, involving 42 patients, compared cryotherapy (performed with ice packs on hands and feet) to an untreated control group who was not treated with cryotherapy.²⁷ The area under the curve of the CIPN20 sensory scores over 12 weeks of paclitaxel was not found to differ between the study arms (mean difference, 3.45; 95% CI, −3.13 to 10.02; P = .26). However, when the cryotherapy arm was compared with a control arm made up of controls combined from 3 previous trials, the cryotherapy arm had less neuropathy (Wilcoxon rank-sum P = .01). The authors of this study reported that the data supported phase III trial testing of this approach.

In a trial that evaluated a unilateral FG in 53 patients receiving docetaxel, 60% of the patients stopped the cryotherapy, and there were no differences between the hands that were randomly assigned to receive it versus not.²⁸ Likewise, another study described similarly high drop-out rates and did not report positive findings.²⁹

One trial evaluated continuous-flow limb hypothermia as a neuroprotective strategy in 20 patients receiving paclitaxel chemotherapy compared with usual care. Patients who received continuous limb hypothermia had less self-reported paclitaxel-induced neuropathy symptoms and had better nerve conduction studies.³⁰ The same group of researchers also conducted a subsequent proof-of-concept study in patients with cancer receiving taxane chemotherapy.³¹ In this study, both cryotherapy and compression therapy (ie, cryo-compression therapy) were given to all 4 limbs in 13 subjects with each dose of paclitaxel. An analysis of nerve conduction studies with cryo-compression, administered at 16°C and a cyclic pressure of 5-15 mm Hg, illustrated preservation of motor amplitudes compared with baseline.³² In a cross-study comparison with their previous group of patients who had been treated with cryotherapy alone, patients appeared to do better with the combination therapy.³²

One trial evaluated compression therapy using a tight surgical glove during taxane chemotherapy infusion.³³ The intervention hand side was randomized within 43 patients. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 sensory neuropathies were reported in 21% of the hands that wore the gloves versus 76% of hands that were not gloved.

A recently published small trial (38 patients) compared cryotherapy to compression therapy. This trial had patients use cryotherapy on one hand and compression therapy on the other and reported that similar results were seen with each approach.³⁴ Additional randomized trials investigating cryotherapy and cryo-compression are ongoing.

Three RCTs that evaluated various exercise interventions for the prevention of CIPN were identified. In a large trial of patients with cancer receiving taxane-, platinum-, or vinca alkaloid–based chemotherapy,³⁵ 355 patients were randomly assigned to chemotherapy or chemotherapy plus Exercise for Cancer Patients (EXCAP), a standardized, individualized, moderate-intensity, home-based, 6-week progressive walking and resistance exercise program. This unblinded trial was developed to evaluate the effectiveness of exercise on fatigue. As a secondary analysis, data regarding CIPN were also collected; these results supported that, compared with the control, exercise significantly reduced CIPN symptoms of hot/coldness in hands/feet (P = .045) and numbness and tingling, although the latter was not statistically significantly reduced compared with the control arm (P = .06). The intervention group still developed neuropathy, but less than the control group—a difference of approximately half a point on a 0-10 scale. On the basis of these findings and other preliminary supportive evidence,^36,37 the NCI has recently approved a concept for a randomized cooperative oncology group trial to prospectively address the utility of exercise in this setting.

GM-1 is a monosialo-glycosphingolipid that performs an important function in the processes of neurogenesis, nerve development and differentiation, cell recognition, and signal transduction.³⁸ Two randomized trials investigating GM-1 for CIPN prevention were identified. In the first trial, Zhu et al³⁹ reported on 120 patients with GI cancers who were treated with oxaliplatin-based chemotherapy randomly assigned to receive intravenous ganglioside-monosialic acid or to a control group that received no neuroprotective agents. Although the grade of neurotoxicity in the experimental group was significantly lower than in the control group (P < .05, Mann-Whitney U test), the lack of placebo control and the lack of patient-reported outcome data decrease the confidence of this finding.³⁹

The second trial was a placebo-controlled, double-blinded study of intravenous GM-1, given to prevent taxane-induced CIPN in 183 patients with early-stage breast cancer. The study reported that treatment with GM-1 resulted in a statistically significant reduction in the severity and incidence of CIPN after 4 cycles of taxane-containing chemotherapy (P < .001).³⁸ A peculiar aspect of this trial is that the neuropathy appeared to be totally reversed in the placebo arm 3 months after chemotherapy completion, which is quite unusual in Western populations.⁴⁰ Despite this very positive report, a confirmatory trial is needed.

Our systematic review found a meta-analysis that pooled data from 5 trials and included 397 patients. The review reported that goshajinkigan was not associated with a reduced incidence of CIPN when assessed with the CTCAE (RR, 0.99; 95% CI, 0.53 to 1.85 for CIPN ≥ grade 2).⁴¹ Our systemic review did not find additional studies with goshajinkigan that were not included in this meta-analysis.

One small randomized study (N = 40) that evaluated metformin as a means of preventing oxaliplatin-induced neuropathy compared with a control group was identified.⁴² The authors reported that, at the end of the 12th FOLFOX-4 (fluorouracil, leucovorin, and oxaliplatin) regimen cycle, grade 2-3 neuropathy was lower in the metformin arm compared with the control arm (60% v 95%; P = .009), and the metformin arm had better NTX-12 scores (24.0 v 19.2; P < .001). Given the small sample size, more confirmatory studies are needed before recommending this approach for oxaliplatin-induced neuropathy.

Two randomized placebo-controlled trials investigating pregabalin were identified. On the basis of pilot study information, which suggested that gabapentinoids could decrease paclitaxel-associated acute pain and chronic neuropathy, investigators developed a phase II placebo-controlled clinical trial (N = 46) to look at pregabalin for preventing these neuropathic problems. The results did not support that pregabalin was helpful for preventing the paclitaxel-associated acute pain syndrome or paclitaxel-induced peripheral neuropathy.⁴³

In another double-blind, placebo-controlled trial, 143 pain-free, chemotherapy-naive patients with colorectal cancer receiving at least 1 cycle of modified FLOX (ie, fluorouracil, leucovorin, and oxaliplatin) were randomly assigned to receive either pregabalin or placebo for 3 days before and 3 days after each oxaliplatin infusion. After following patients for up to 6 months, the authors reported that preemptive use of pregabalin during oxaliplatin infusions did not decrease the incidence of chronic pain related to oxaliplatin, measured by pain intensity and QOL scales.⁴⁴ An additional randomized, double-blinded, placebo-controlled trial of pregabalin involving 64 patients who were receiving oxaliplatin chemotherapy was terminated early, as an interim analysis found that there were not sufficiently positive data to continue the trial.¹⁵

A small study (20 patients per arm) evaluating gabapentin 300 mg 3 times a day in a double-blind, randomized trial in patients receiving paclitaxel was identified.⁴⁵ Although the authors reported a significant reduction in CIPN, confirmation of this is needed in a subsequent trial.

One trial investigating the efficacy of venlafaxine on prevention of CIPN was identified. Pursuant to data from Durand et al⁴⁶ discussed in the initial ASCO CIPN guideline, this phase II randomized, placebo-controlled clinical trial was conducted to look at venlafaxine as a drug to decrease neuropathy associated with oxaliplatin.⁴⁷ Fifty patients were randomly assigned to venlafaxine or placebo, given continuously with initiation of the first or second cycle of oxaliplatin. The trial results did not support the use of venlafaxine in this setting, dampening enthusiasm for proceeding with a phase III trial.⁴⁷ Notably, the Durand et al⁴⁶ study started venlafaxine/placebo after patients had received some oxaliplatin, in contrast to at oxaliplatin initiation. Given that there are now data that support that venlafaxine may decrease symptoms in patients with established neuropathy (although not as well as duloxetine),⁴⁸ it may be that in the Durand et al⁴⁶ trial venlafaxine was potentially acting as an agent that treated established neuropathy, as opposed to acting as a prevention agent.

A 71-patient placebo-controlled 2-arm trial evaluated an oral vitamin B product in patients who were receiving a variety of neurotoxic drugs (taxanes, oxaliplatin, or vincristine).⁴⁹ Data were only available for 47 patients and, understandably with this small sample size and the variety of chemotherapy drugs, there was no suggestion that the primary end point was improved in the vitamin B arm.

One systemic review and meta-analysis plus another trial not included in the meta-analysis were identified. The systematic review and meta-analysis of 6 studies that included 353 patients reported that the administration of vitamin E (at doses that included 300 mg daily, 300 mg twice daily, and 400 mg daily) did not decrease the incidence of CIPN (RR, 0.55; 95% CI, 0.29 to 1.05; P = .07.⁵⁰ The small study published subsequently to the meta-analysis⁵¹ also concluded that vitamin E did not help to prevent oxaliplatin-induced peripheral neuropathy.

The current review did not find studies supporting the recommendation of any neuropathy-preventative agent. Unlike the promising original guideline commentary regarding venlafaxine as a preventative agent, the updated guideline does not recommend it. A negative follow-up study with a similar number of patients, which treated patients for a longer time period and used a more accepted chemotherapy neuropathy patient-reported outcome measurement tool, backs this.⁴⁷

Given the dearth of effective established agents for preventing chemotherapy-induced neuropathy and the limited effective therapy for treating established CIPN, patients/clinicians should weigh the benefits of using neuropathy-inducing agents against the risks of developing long-term, irreversible CIPN.

Although proof of benefit has not been established, available data support that exercise, cryotherapy, compression therapy, and/or cryo-compression therapy may, in part, prevent CIPN symptoms and appear to be reasonably safe, although clinicians and patients should be aware of frostbite risk. Ganglioside-monosialic acid seemed to be effective in preventing taxane-induced peripheral neuropathy in Chinese patients, but this should be confirmed in a large trial in a different ethnic group. Ongoing trials are attempting to better define whether one or more of these methods will safely prevent CIPN.

Although there are limited clinical trial data available to guide practice when patients develop CIPN during the course of neurotoxic chemotherapy, this is a common clinical practice situation. Scenarios vary from patients who are being treated with curative intent versus palliative-intent chemotherapy for advanced cancer. Clinicians and patients may make different decisions for continuing neurotoxic chemotherapy in patients suffering from significant neuropathy, based on whether the patient is receiving adjuvant chemotherapy that might improve survival probabilities by a percentage point or two, versus a patient receiving adjuvant chemotherapy expected to improve survival probabilities by many percentage points, versus a patient with metastatic disease. In these individual situations, clinicians may determine whether to reasonably use alternative chemotherapy regimens that do not cause neurotoxicity. Clinicians should obtain individual patient perspectives in all these situations.

Current data from an RCT mildly suggest that exercise is a feasible, safe, and promising supportive measure for patients with cancer experiencing CIPN. The trial randomly assigned 45 patients with established CIPN to a 10-week home-based muscle strengthening and balancing exercise program versus usual care. The patients in the exercise group experienced a significant reduction in neuropathic pain scores (P < .0001) and improvement in Functional QOL (P = .0002), Symptom QOL (P = .0003) and Global Health Status QOL (P = .004) compared with those randomly assigned to the usual-care group.⁵² The lack of an active control group diminishes the strength of the findings. Another small trial evaluated patients with metastatic colorectal cancer randomly assigned to an exercise program versus a wait-list control group.³⁶ Those receiving exercise had relatively stable CIPN scores over time, while the wait-list control group’s CIPN worsened.

Five trials evaluating the efficacy of acupuncture for the treatment of CIPN were identified,^53-55 including 1 trial that evaluated electro-acupuncture⁵⁶ and another that evaluated acupuncture combined with methylcobalamin.⁵⁷ A randomized assessor-only–blinded controlled trial of acupuncture twice weekly for 8 weeks versus a wait-list control group involving 87 patients with cancer reported significant changes at 8 weeks in pain measured using the Brief Pain Inventory (BPI).⁵³ Significant improvements in clinical neurologic assessment, QOL domains, and symptom distress were also reported (all P < .05). Improvements in pain interference, neurotoxicity-related symptoms, and functional aspects of QOL were sustained in a 14-week assessment (P < .05), as were physical and functional well-being at a 20-week assessment (P < .05).

A pilot trial involving 40 women with stage I-III breast cancer and grade ≥ 1 CIPN after taxane-containing adjuvant chemotherapy investigated immediate acupuncture versus a wait-list control.⁵⁴ At 8 weeks, participants in the treatment arm experienced significant improvements in the Patient Neurotoxicity Questionnaire (PNQ) sensory score (P = .01), FACT-NTX summary score (P = .002), and BPI–Short Form pain severity score P = .03) compared with those in the control arm. No serious adverse effects were observed.

Another pilot trial randomly assigned 33 adult patients with cancer and CIPN into 2 groups (control and acupuncture: treated with 10 sessions, twice a week).⁵⁵ Statistically significant differences were reported in physical (P = .03) and function (P = .04) domains of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 when comparing between control and acupuncture groups. NCI CTCAE Scale and neuropathy sensory symptoms were also improved in the acupuncture group between pretreatment and 5 weeks post-treatment (P = .01), whereas no such differences were detected in the control group (P = .11).

The use of electro-acupuncture was not superior to placebo in a randomized trial of 59 patients with CIPN.⁵⁶ The trial failed to show efficacy compared with placebo, as determined by using a predefined statistical threshold at the first interim analysis.

Another trial in 98 patients compared acupuncture combined with methylcobalamin to methylcobalamin alone and found that after 3 cycles of therapy the pain was significantly mitigated in the methylcobalamin plus acupuncture group.⁵⁷ Visual analogue scale (VAS) pain scores decreased more in the methylcobalamin plus acupuncture group than the methylcobalamin control group (P < .01).

Two duloxetine trials were published after the initial ASCO CIPN guideline publication.^48,58 One trial randomly assigned patients with CIPN to 3 pharmacotherapy groups: venlafaxine, duloxetine, and placebo.⁴⁸ The authors reported decreased neuropathy in the venlafaxine and duloxetine groups, with a better reduction in the duloxetine group compared with venlafaxine group (P < .05). In another open-label, randomized, crossover study, 34 patients with cancer were randomly assigned to receive duloxetine (20 mg/d orally for the first week and 40 mg/d for the next 3 weeks) or vitamin B12 (1.5 mg/d orally for 4 weeks).⁵⁸ After a 2- to 4-week washout period, treatment was crossed over for another 4 weeks. Decreases in the mean VAS scores for numbness and pain were seen during the periods of duloxetine administration. Significant differences were observed between the duloxetine-first and the vitamin B12-first groups with respect to numbness (P = .03) and pain (P = .04) at 4 weeks after administration.

In January 2020, a trial was published that randomly assigned patients with paclitaxel- or docetaxel-associated CIPN to receive duloxetine versus pregabalin, with 40-42 patients per arm. They reported a ≥ 33% improvement of visual analog scores in the duloxetine and pregabalin arms at 6 weeks of 38% and 93%, respectively (P < .001).⁵⁹ The majority of the patients in both arms started their treatment while they were receiving chemotherapy, and some of this improvement may have been related to chemotherapy discontinuation.

Two randomized trials evaluating scrambler therapy, an electrocutaneous treatment approach, were found.^60,61 One randomized sham-controlled phase II trial in 33 patients who received 30-minute sessions of scrambler therapy (ST) or sham treatment found no significant differences between the sham and the experimental ST group for BPI average pain or the EORTC CIPN-20.⁶⁰

The second phase II trial randomly assigned patients with CIPN symptoms for at least 3 months to receive ST or transcutaneous electrical nerve stimulation (TENS) for 2 weeks. In 46 evaluable patients, twice as many ST-treated patients had at least a 50% documented improvement during the 2 treatment weeks from their baseline pain, tingling, and numbness scores when compared with the TENS-treated patients (from 36%-56% compared with 16%-28% for each symptom).⁶¹ Global Impression of Change scores for “neuropathy symptoms,” pain, and QOL improved similarly. Moreover, patients in the ST group were more likely than those in the TENS group to recommend their treatment to other patients, during both the 2-week treatment period and the 8-week follow-up period (P < .0001).⁶¹ The publication did not report any substantial adverse events.⁶²

A small, randomized, placebo-controlled clinical trial of 18 patients evaluated the role of nabiximols, an oral mucosal cannabinoid spray, for chemotherapy-induced neuropathic pain.⁶³ In this crossover clinical trial, 16 of the 18 randomly assigned patients completed the study. Noting the small number of patients, there was no suggestion of differential benefits in neuropathy scores between the active and placebo agents. Yet, there was more evidence of toxicity (fatigue, dry mouth, dizziness, and nausea) in the patients receiving the cannabinoid preparation, decreasing interest in this approach.

A topical 4% amitriptyline/2% ketamine preparation was studied as a treatment of established chemotherapy neuropathy in a randomized, placebo-controlled trial involving 462 patients.⁶⁴ Patients with average 7-day pain, numbness, and tingling ratings of at least 4 on an 11-point numeric rating scale were eligible for enrollment in the study. Topical amitriptyline/ketamine showed no effect on 6-week CIPN scores (adjusted mean difference, −0.17; P = .363), and this trial did not support that using this topical preparation alleviated chemotherapy-induced pain, numbness, or tingling.

Additional data, which have become available since the previous ASCO CIPN guideline, further support the utility of duloxetine for treating established painful CIPN. Conversely, there have not been any further clinical trials to strongly support the utility of tricyclic antidepressants, gabapentinoids, or topical amitriptyline/ketamine/baclofen, decreasing the tepid support that was provided for these 3 therapeutic approaches in the initial ASCO CIPN guideline. In addition, newer published reports do not provide support for a topical amitriptyline/ketamine preparation or an oral mucosal cannabinoid product.

Although proof of benefit has not been provided, data suggestive of benefit support that 3 approaches (scrambler therapy, acupuncture, and exercise) may diminish established CIPN symptoms and appear to be reasonably safe. Further research is needed to better delineate the utility, or its lack thereof, of these approaches in treating established CIPN.