Table 3.
Chemotherapy-induced peripheral neuropathy Phase III prevention and treatment evidence
| Year | Author | Design | Type of study | Population | Drug and dosage | Measurement tool | Measurement time points | Results |
|---|---|---|---|---|---|---|---|---|
| 2013 | Hershman | Phase III, randomized, double-blind, placebo-controlled, multicenter | Preventative (n=409) | Stage I-III breast cancer patients receiving taxanes; stratified based on chemotherapy regimen | Acetyl-L-carnitine 3000 mg daily for 24 weeks | FACT-Ntx NCI CTCAE v3.0 |
Baseline (before taxane); weeks 12, 24, 36, 52, 104 | No difference in CIPN at 12 weeks using the 11 item neurotoxicity subscale of the FACT-taxane scale; CIPN was significantly increased at 24 weeks |
| 2014 | Guo | Phase III, randomized, double-blind, placebo-controlled, multicenter | Preventative (n=70) | Patients receiving cisplatin or oxaliplatin; stratified according to their exposure to platinums | Alpha-lipoic acid 600 mg daily three times a day for 24 weeks | FACT/GOG-Ntx; BPI score NCI CTCAE v3.0 |
Baseline, and then at 24, 36, and 48 weeks of treatment | No difference in FACT-NTX, BPI score, pain or functional testing at 24 weeks 71% attrition rate |
| 1996 | Kemp | Phase III, randomized, double-blind | Preventative (n=242) | Stage III-IV ovarian cancer patients receiving 100 mg/m2 cisplatin | Amifostine 910 mg/m2 reconstituted with 9.5 mL NS IV over 15 min before each chemotherapy infusion for 6 cycles of chemotherapy (every 3 weeks) | NCI CTCAE | Baseline, before cycles 4, 5, 6, and monthly for 3 months following completion of protocol | A statistically significant difference in the NCI CTCAE was demonstrated between the treatment arm and control arm by cycle 5 (P=0.15) |
| 2003 | Lorusso | Phase III, randomized, double-blind | Preventative (n=187) | Stage 1-4 ovarian cancer patients scheduled to receive carboplatinum and paclitaxel | Amifostine 910 mg/m2 reconstituted with 9.5 mL NS IV over 15 min before each chemotherapy infusion for 6 cycles of chemotherapy (every 3 weeks) | NCI CTCAE v2.0 | Baseline, weekly, posttreatment | A statistically significant difference in the NCI CTCAE was demonstrated against severe neurotoxicity (Grade 3-4) (P=0.0.02) |
| 2008 | Grothey | Phase III 4-arm randomized, double-blind, placebo-controlled | Preventative (n=139) | Metastatic colorectal cancer patients receiving mFOLFOX7 (85 mg/m2 q2 weeks; CO) or mFOLFOX7 with and without oxaliplatin every round of 8 cycles (IO) | Calcium and magnesium 1 g of magnesium and calcium before and after each infusion | Unknown | Unknown | Study aborted due to errant concern regarding detrimental effects of calcium/magnesium. Preliminary results were positive |
| 2010 | Ishibashi | Phase III, randomized, double-blind, placebo-controlled | Preventative (n=33) | Metastatic colorectal cancer patients receiving mFOLFOX6 (85 mg/m2 every 2 weeks) | Calcium and magnesium 850 mg calcium gluconate and 720 mg magnesium sulfate in 100 mL dextrose 5% water infused over 15 min before and after oxaliplatin | NCI CTCAE v3.0 DEB-NTS |
Base (before oxaliplatin); with each cycle of oxaliplatin and after completion of 6 cycles | There was no difference in the NCI CTCAE v3.0 and DEB Neurotoxicity Scale (DEB-NTS) after the completion of 6 cycles |
| 2011 | Grothey | Phase III, randomized, double-blind, placebo-controlled, 4-arm study | Preventative (n=102) | Stage II or III colon cancer patients scheduled to receive FOLFOX4 or mFOLFOX6 (85 mg/m2 q2 weeks) × 6 months; stratified by age, sex, chemotherapy regimen | Calcium and magnesium 1 g of magnesium and calcium in 100 mL dextrose 5% water infused over 30 min before and after chemotherapy compared to before chemotherapy only | NCI CTCAE v3.0 | Base; q2 weeks (prior to each cycle); 18 weeks | A statistically significant difference was demonstrated in the percentage of patients with Grade 2 or greater chronic sensory neurotoxicity based on the NCI CTCAE v3.0 (P=0.038) and the oxaliplatin-specific scale (P=0.018) during treatment or at the completion of treatment |
| 2013 | Gobran | Phase III, randomized, double-blind, placebo-controlled | Preventative (n=60) | Colorectal cancer patients scheduled to receive an oxaliplatin-based regimen (85 mg/m2) | Calcium and magnesium 1 g of magnesium and calcium in 250 mL IV fluid infused over 30 min before and after oxaliplatin infusion | NCI CTCAE v3.0 | Baseline; within 5 days of each chemotherapy cycle; monthly postchemotherapy completion for those who had developed CIPN | No statistically significant difference was demonstrated at the completion of treatment based on the NCI CTCAE v3.0 |
| 2013 | Loprinzi | Phase III, randomized, double-blind, placebo-controlled, 4-arm study | Preventative (n=353) | Colorectal cancer patients receiving adjuvant FOLFOX or mFOLFOX 85 mg/m2 every 2 weeks for 6 months (12 cycles) | Calcium and magnesium 1 g of magnesium and calcium in 100 mL dextrose 5% water infused over 30 min before and after chemotherapy compared to before chemotherapy only | EORTC QLQ-CIPN20 | Baseline (likely prior to first cycle); q2 weeks (before each cycle of chemotherapy); acute symptoms were monitored before each FOLFOX dose and 5 consecutive days after | No statistically significant differences at the completion of 12 cycles using the EORTC QLQ-CIPN 20 |
| 2013 | Smith | Phase III, randomized, double-blind, placebo-controlled, multicenter, cross-over | Treatment (n=220) | Cancer patients with Grade 1 or higher NCI-CTCAE sensory neuropathy with CIPN pain 4/10 or higher. Patients with diabetes, PVD, and stable analgesic regimens allowed | Duloxetine 60 mg daily×5 weeks (30 mg daily for 1 week - then 30 mg twice daily for 4 weeks) followed by 2 weeks washout period between duloxetine and placebo | BPI-SF; FACT/GOG-Ntx | Baseline; weekly; 6 weeks (end of Phase I), 8 weeks (after wash-out), 13 weeks (after Phase II) | There was a statistically significant decrease in the pain score in the duloxetine group as measured by the brief pain inventory short form compared to those receiving placebo at 6 weeks (P=0.003) |
| 2007 | Rao | Phase III, randomized, double-blind, placebo-controlled cross-over | Treatment (n=115) | Cancer patients with average daily pain scores of either (1) >4/10 on NRS or (2) >1 on the 0-3 ENS. Currently receiving neurotoxic chemotherapy (stratified by chemo type) or posttreatment | Gabapentin 300 mg daily increased over 3 weeks to maximum dose of 2700 mg for 3 weeks (6 weeks treatment each phase); 2 weeks washout between study phases | NRS BPI-SF; 24 h average pain on NRS; ENS | Primary - base; weekly. Secondary - base; 6, 8, and 14 weeks | No difference in pain or CIPN scores measured by the NRS and the ENS at 6 and 14 weeks |
| 1995 | Cascinu | Phase III, randomized, double-blind, placebo-controlled | Preventative (n=50) | Stage III-IV gastric cancer patients receiving cisplatin (40 mg/m2 weekly) | Glutathione 1.5 g/m2 in 100 mL normal saline IV over 15 min before each weekly chemo infusion and 600 mg intermuscularly on days 2-5 after each infusion | WHO grading scale | Baseline (before cisplatin); after 9 and 15 weeks of cisplatin tx | A statistically significant difference was demonstrated in the glutathione arm at 9 and 15 weeks based on the WHO neurotoxicity scale (P=0.0001) |
| 1997 | Smyth | Phase III, randomized, double-blind, placebo-controlled multi-center | Preventative (n=151) | Stage I-IV ovarian cancer patients receiving cisplatin (100 mg/m2 q3 weeks×6 cycles) | Glutathione3 g/m2 in 200 mL normal saline infused over 20 min before chemotherapy infusion every 3 weeks | NCI CTCAE Nerve conduction studies | Baseline (before cisplatin); after 3 and 6 cycles | No difference was demonstrated in CIPN at the completion of 6 cycles based on the NCI CTCAE |
| 2002 | Cascinu | Phase III, randomized, double-blind, placebo-controlled | Preventative (n=52) | Colorectal cancer patients receiving 100 mg/m2 (high dose) oxaliplatin every 2 weeks | Glutathione1.5 g/m2 IV over 15 min before each infusion | NCI CTCAE; neurological examination; nerve conduction studies | Base (before oxaliplatin); after cycles 4, 8, and 12 | A statistically significant difference was detected in the glutathione arm after 8 and 12 cycles based on the NCI CTCAE. (P=0.003 and P=0.004, respectively) |
| 2013 | Leal | Phase III, randomized, double-blind, placebo-controlled multicenter | Preventative (n=122) | Cancer patients receiving paclitaxel (150-200 mg/m2)/carboplatin (AUC 5-7) q3-4 weeks or paclitaxel 80 mg/m2 weekly for 12 weeks (mixed regimens - no stratification but subgroup analyses) | Glutathione1.5 g/m2 IV over 15 min prior to chemotherapy, starting their first or second cycle | EORTC QLQ-CIPN20; NCI CTCAE | Base (before chemotherapy); 1 week after each cycle; within 6 cycles of tx | No difference in CIPN measured by the EORTC QLQ-CIPN20 sensory subscale and the NCI CTCAE v4.0 after 6 cycles; increased time to development of CIPN favored the placebo group |
| 2015 | Oki | Phase III, randomized, double-blind, placebo-controlled | Preventative (n=182) | Stage III colorectal cancer patients receiving mFOLFOX6 | Goshajinkigan7.5 g/day orally before or in between meals starting on the first day of mFOLFOX6; Stopped after 12 cycles (~26 weeks) | NCI CTCAE v3.0 DEB-NTS | Base (before first chemotherapy cycle); 12th cycle of chemotherapy (24 weeks) | The incidence of Grade 2 or greater neurotoxicity based on the NCI CTCAE v3.0 was statistically significantly higher for the group receiving goshajinkigan (P=0.007) |
| 2008 | Rao | Phase III, randomized, double-blind, placebo-controlled | Treatment (n=131) | Cancer patients with CIPN >1 month duration that could be receiving chemotherapy or posttreatment with average daily pain >4/10 NRS or >1 ENS | Lamotrigine Escalating dosing until patient reaches max dose of 300 mg for 2 weeks then tapered off | NRS - average daily pain score; ECOG neuropathy scale | Baseline and weekly | No difference in pain as measured by the NRS and ENS at 10 weeks |
| 2002 | Hammack | Phase III, randomizeddouble-blind, placebo-controlled, cross-over | Treatment (n=51) | Cancer patient receiving cisplatin or posttreatment with painful CIPN >1 month; stratified by age, cumulative dose, severity of CIPN, and whether cisplatin administration was ongoing or completed | NortriptylineEscalating doses until patient reaches max dose of 100 mg daily | VAS; VDS | Base; weekly until 9 weeks (end of Phase II) | No significant differences were demonstrated in quality of life measures or symptoms affecting daily life |
| 2011 | Barton | Phase III, randomized, double-blind, placebo-controlled | Treatment (n=150) | Cancer patients with >1 month CIPN numbness, tingling, or pain and >4/10 pain severity only in hands or feet, currently or have received neurotoxic chemotherapy | Topical amitriptyline ketamine baclofen Apply gel twice daily for 4 weeks; 10 mg baclofen, 40 mg amitriptyline, 20 mg ketamine | EORTC QLQ-CIPN20; BPI; NCI CTCAE v3.0 | Base (before intervention), 4 weeks follow-up | The motor neuropathy subscale had a significant effect size of 0.38 over placebo (P=0.021) measured by the EORTC QLQ-CIPN20. The sensory neuropathy subscale showed a trend favoring the intervention arm (P=0.053) |
| 2014 | Gewandter | Phase III, randomized double-blind, placebo-controlled, multicenter | Treatment (n=462) | Cancer patients posttreatment for 1 month with >4/10 pain, numbness, tingling over the past 24 h | Topical 4% amitriptyline and 2% ketamine Apply gel twice daily to areas with pain, numbness, or tingling; 40 mg amitriptyline, 20 mg ketamine | NRS | Daily diary using NRS 11 point scale rating pain numbness tingling starting 1 week before topical AK started and at week 3, 6 after enrollment | No significant treatment effect for numbness, tingling, or pain was noted at 6 weeks measured by the NRS |
| 2011 | Durand | Phase III, randomized, double-blind, placebo-controlled, multi-site | Treatment (n=42) | Cancer patients that reported “distressing” CIPN and still receiving oxaliplatin every 2 weeks | Venlafaxine50 mg 1 h before infusion and 37.5 mg extended release twice a day from day 2 to day 11 until the end of chemotherapy treatment | NPSI; oxaliplatin-specific Levi’s scale | Base; days 1-5 after each chemotherapy infusion; completion of chemotherapy; 3 months postchemotherapy completion | A significant treatment effect was noted in the proportion of patients experiencing a complete relief of acute neurotoxicity compared to placebo measured by the NPSI (P=0.03) |
| 2015 | Zimmerman | Phase III, randomized, double-blind, placebo-controlled, multisite | Preventative (n=48) | Stage II-IV colorectal cancer patients receiving adjuvant FOLFOX or mFOLFOX for 6 months (12 cycles) | Venlafaxine XR37.5 mg×twice daily started the 1st or 2nd weeks of chemotherapy until 1 week posttreatment | EORTC QLQ-CIPN20; NCI CTCAE v4.0Oxaliplatin acute symptom questionnaire | Base (likely before the 2nd cycle of chemotherapy); before each chemo infusion (oxali-acute sx questionnaire also filled out for 6 consecutive days beginning the day of the infusion); 1, 3, 6, and 12 months postchemotherapy completion | No significant treatment effect was noted between placebo arm and venlafaxine arm for sensory neuropathy measured by the EORTC QLQ-CIPN20 |
| 2010 | Pace | Phase III, randomized, double-blind, placebo-controlled | Preventative (n=41) | Cancer patients with solid tumor malignancies scheduled to receive cisplatin | Vitamin E400 mg per day orally started 1-8 days before chemotherapy through 3 months after cisplatin completion | TNS; NCS | Base, after 3 cycles; after cisplatin completion; 1 month after cisplatin completion | The incidence of neuropathy was significantly lower in the Vitamin E group compared to the placebo group measured by the TNS after six cycles of cisplatin (P=0.01) |
| 2011 | Kottschade | Phase III, randomized, double-blind, placebo-controlled, multi-site | Preventative (n=189) | Cancer patients scheduled to receive taxanes or platinums (stratified by type of chemo, gender, and age) | Vitamin E300 mg twice daily starting within 4 days of first chemotherapy infusion, through 1 month postchemotherapy completion | NCI CTCAE v3.0 | Base, before each chemotherapy cycle, and at 1 and 6 months follow-up | No significant treatment effect was noted in sensory neuropathy of the NCI CTCAE v3.0 between the treatment arm and the placebo arm |
AUC: Area under the curve, BPI: Brief pain inventory, CIPN: Chemotherapy-induced peripheral neuropathy, EORTC QLQ-CIPN 20: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20, DEB-NTS: Neurotoxicity criteria of DEBiopharm, ECOG ENS: Eastern Cooperative Oncology Group Neuropathy scale, FACT/GOG-Ntx: Functional assessment of cancer therapy/Gynecologic Oncology Group Neuropathy scale, mFOLFOX: Fluorouracil, leucovorin, and oxaliplatin, NCI CTCAE: National Cancer Institute Common Terminology Criteria Adverse Effects Scale, NCS: Nerve conduction study, NPSI: Neuropathic pain symptom inventory, NRS: Numeric rating scale, PRO: Patient-reported outcome measure, PVD: Peripheral vascular disease, TNS: Total neuropathy score, VAS: Visual analog scale, VDS: Visual descriptive scale, XR: Extended release, WHO: World Health Organization, VDS: Verbal descriptor scale