Table 4.
Summary of findings and limitations by agent
| Agent | Results | Limitations |
|---|---|---|
| Prevention | ||
| Acetyl-L-carnitine (n=1) | The administration of acetyl-L-carnitine had no effect on CIPN severity in comparison to placebo 12 weeks following randomization. At 24 weeks following randomization, CIPN symptoms worsened in the group randomized to receive acetyl-L-carnitine[7] | These results were limited by small sample size, lack of a valid and reliable measurement tool, and heterogeneity of the chemotherapy regimen |
| Alpha-lipoic acid (n=1) | There were no differences in CIPN severity (FACT/GOG-Ntx and BPI) 24 weeks following study initiation between the group randomized to receive alpha-lipoic acid and the group randomized to receive placebo | The results were limited by small sample size (underpowered) and a high attrition rate in both the control and intervention groups (e.g., 71%). In addition, the statistical methods did not control for imbalances in the amount of neurotoxic chemotherapy received between groups[15] |
| Amifostine (n=2) | Two studies demonstrated that individuals randomized to receive amifostine experienced reduced CIPN incidence (NCI CTCAE) in comparison to individuals randomized to receive placebo[16,17 | Results were limited by lack of a valid and reliable measurement tool, lack of control for confounding variables (i.e., DM, Vitamin B deficiencies, PAD), and small sample size |
| Calcium and magnesium (n=5) | Three studies demonstrated a neuroprotective effect of calcium and magnesium.[18,19,20] No difference in CIPN was found at the completion of 12 cycles of chemotherapy in two additional studies, using the EORTC QLQ-CIPN 20[8] and the NCI CTCAE.[18] One study[19] was aborted due to concern for detrimental effects of calcium and magnesium on tumor response based on the Concept study;[21] however, preliminary data indicated a neuroprotective effect. Later, this was found not to be the case[8] | Study results were limited by malapropos timing of the outcome measure,[19] heterogeneity of chemotherapy regimens,[19] and lack of control for cumulative oxaliplatin doses.[18] All studies except one[8] lacked control for confounding variables, all studies lacked a valid and reliable measurement tool, and three studies had small sample sizes[19,20,22] |
| Glutathione (n=4) | Two[23,24] of four[25,26] reviewed studies demonstrated that individuals randomized to receive glutathione experienced less CIPN in comparison to individuals randomized to receive placebo based on the WHO scale[24] and the NCI CTCAE.[23,25,26] Measurement time points varied between 6 and 12 cycles of chemotherapy | Results were limited by a lack of valid and reliable measurement tool in all four studies, lack of control for confounding variables,[23,24,25] suboptimal statistical validity,[26] and malapropos timing of the outcome measurement[26] |
| Goshajinkigan (n=1) | An interim analysis in a study authored by Oki et al.[27] revealed that randomization to goshajinkigan worsened CIPN incidence (NCI CTCAE) in comparison to randomization to placebo 24 weeks postbaseline | The results are limited by a small sample size, lack of a valid and reliable measurement tool, and lack of control for confounding variables |
| Venlafaxine XR (n=1) | There were no differences in CIPN incidence (NCI CTCAE and QLQ-CIPN 20) between individuals randomized to receive venlafaxine or placebo after 12 cycles of oxaliplatin[28] | Results were limited by a lack of control for confounding variables, lack of valid and reliable measurement tool, and small sample size (underpowered) |
| Vitamin E (n=2) | One study found the incidence of neuropathy (TNS) was significantly lower in the intervention group compared to the control group after six cycles of cisplatin.[29] On the other hand, an additional study revealed that there were no differences in CIPN incidence (NCI CTCAE) between the group randomized to receive Vitamin E and the group randomized to receive placebo during taxane/platinum chemotherapy receipt[30] | Results were limited due to underpowered statistical analyses,[29,30] lack of reliable and valid measurement tools,[30] and lack of control for confounding variables |
| Treatment | ||
| Duloxetine (n=1) | A study by Smith et al. demonstrated that duloxetine 60 mg/day was superior to placebo in reducing chronic painful CIPN symptom severity 5 weeks following randomization (BPI)[6] | Changes in concurrent analgesic medications were not assessed throughout the study thus findings could be the result of increased analgesic use. This trial completed an intent-to-treat analysis which statistically provides a conservative estimate of efficacy |
| Gabapentin (n=1) | Gabapentin (up to 2700 mg/day) was not superior to placebo in reducing CIPN symptom severity (ECOG ENS) in individuals who received taxanes, platinum compounds, and vinca alkaloids 6 and 14 weeks following study initiation, respectively | A major limitation of this trial was that the administered dose of gabapentin may have been inadequate.[31] Gabapentin has been shown to be effective to treat neuropathic pain symptoms in doses up to 3600 mg/day.[32] Another major limitation was that individuals were still receiving neurotoxic chemotherapy during the trial, which may have worsened CIPN severity and subsequently confounded the effect of gabapentin on CIPN severity. Results were also limited by lack of a valid and reliable measurement tool, small sample size, and high attrition rate (25% attrition in the treatment arm) |
| Lamotrigine (n=1) | Lamotrigine (escalating dose up to 300 mg/day) was not effective in reducing CIPN severity in patients receiving taxanes, platinum compounds, vinca alkaloids, or combination therapy based on the ECOG ENS at 10 weeks[33] for acute and chronic CIPN | Although patients had CIPN for over 1 month at baseline, patients could still receive chemotherapy throughout the study. Additionally, results were limited by a lack of a valid and reliable measurement tool, small sample size, and 46% attrition rate in the treatment arm |
| Nortriptyline (n=1) | Nortriptyline (escalating dose up to 100 mg/day) was not effective in treating patients for painful CIPN receiving cisplatin measured by a visual analog scale and visual descriptor scale at 4 weeks[34] | Results were limited by a malapropos mechanism of action, lack of a valid and reliable measurement tool, concurrent chemotherapy which may result in unstable CIPN, and insufficient washout period in a crossover design. Evidence suggests nortriptyline should be gradually tapered (decreasing dose) over several weeks to minimize withdrawal symptoms which can include muscle pain.[35] In addition, the eligibility criteria did not specify a minimum baseline pain (at least a four out of 10-pain severity score), which is essential for pain trials[36] |
| Topical 4% amitriptyline, 2% ketamine, and 1% baclofen (BAK) (n=1) | Randomization to receive topical baclofen 10 mg, amitriptyline 40 mg, and ketamine 20 mg (applied as one spoonful twice daily to affected areas) led to marginally significant improvements in CIPN severity (QLQ-CIPN 20) in comparison to placebo in patients receiving a variety of neurotoxic agents.[37] Study participants included patients who had received or were currently receiving neurotoxic chemotherapy that reported CIPN symptoms | Although BAK targets acute pain mechanisms, the primary outcome was nonspecific to pain, and patients were enrolled if they had numbness, tingling, or pain at baseline for any duration (some participants may have had chronic nonpainful CIPN). Results were limited by a lack of control for confounding variables and concomitant pain medications |
| Topical 4% amitriptyline and 2% ketamine (AK) (n=1) | Individuals with established CIPN symptoms (1 month postneurotoxic chemotherapy treatment) randomized to receive 6 weeks of topical amitriptyline 40 mg and ketamine 20 mg (applied to affected areas twice daily) experienced similar CIPN symptom severity in comparison to individuals randomized to receive placebo[38] | Results were limited by a malapropos mechanism of action and malapropos intervention dose. The trial focused on all symptoms of CIPN yet measured sensory CIPN over the past week with an NRS of mean pain, numbness, or tingling. Topical AK’s mechanism of action may also only be appropriate for treating acute painful CIPN instead of chronic painful CIPN. In clinical trials for polyneuropathy in diabetic and nondiabetic patients, amitriptyline 75 mg active substance over 4 weeks significantly reduced neuropathic pain.[39] A dose of 40 mg topically twice daily may not have reached a therapeutic level to reduce neuropathic pain |
| Venlafaxine (n=1) | Venlafaxine immediate (50 mg) and XR (37.5 mg twice daily for 10 days) was superior to placebo for the treatment of oxaliplatin-associated acute sensory CIPN (NPSI).[40] The primary endpoint was the percentage of patients with 100% relief of symptoms during venlafaxine treatment | A limitation of this trial was the poor enrollment rate. Investigators stopped the study before reaching their targeted number of patients because the venlafaxine capsules reached the expiration date |
BPI: Brief Pain Inventory, CIPN: Chemotherapy-induced peripheral neuropathy, QLQ-CIPN 20: Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20, EORTC QLQ-CIPN 20: European Organisation for Research and Treatment of Cancer QLQ-CIPN 20, ECOG ENS: Eastern Cooperative Oncology Group Neuropathy scale, FACT/GOG-Ntx: Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neuropathy scale, NCI CTCAE: National Cancer Institute Common Terminology Criteria Adverse Effects Scale, NPSI: Neuropathic Pain Symptom Inventory, NRS: Numeric rating scale, TNS: Total neuropathy score, XR: Extended release, DM: Diabetes mellitus, PAD: Peripheral arterial disease, WHO: World Health Organization, BAK: Baclofen amitriptyline ketamine, AK: Amitriptyline ketamine