Table 4.
Treatments which require further validation or are not currently recommended for the treatment or prevention of chemotherapy-induced peripheral neuropathy
| Treatment | Author and study design | Number of patients | Antineoplastic agent | Study outcome(s) | Notes |
|---|---|---|---|---|---|
| α-Lipoic acid | Gedlicka et al. 2002 [353]: Pilot study | Total (n = 15) | Oxaliplatin, raltitrexed | 53% of participants developed less severe OIPN symptoms | No control group, small sample population. High-dose α-lipoic acid associated with nausea and gastric pain |
| α-Lipoic acid | Gedlicka et al. 2003 [354]: Pilot study | Total (n = 14) | Docetaxel, cisplatin | Six participants improved CIPN symptoms by at least one WHO grade score. Seven participants with severe CIPN did not respond to treatment | No control group, small sample population |
| α-Lipoic acid | Guo et al. 2014 [236]: Randomised, double-blind, placebo-controlled trial | Participants randomised (n = 243) to α-lipoic acid (n = 122) or placebo (n = 121). Participants who did not complete the 24-week treatment were: α-lipoic acid (n = 88) and placebo (n = 85), leaving a final total (n = 173) for analysis of: α-lipoic acid (n = 88) placebo (n = 85) | Oxaliplatin, cisplatin | No statistically significant difference in FACT/GOG-Ntx scores between α-lipoic acid-treated or placebo-treated groups | High drop-out rate and poor α-lipoic acid treatment compliance |
| OPERA (α-lipoic acid, Boswellia serrata, methylsulfonylmethane, bromelain) |
Desideri et al. 2017 [237]: Prospective study |
Total (n = 25) | Cisplatin, carboplatin, vinca alkaloid, taxanes and eribulin | Changes identified in patient-reported pain scores after 12 weeks of therapy compared to baseline | No placebo, small sample size |
| Neuronorm (docosahexaenoic acid, α-lipoic acid, vitamin C and vitamin E) | Maschio et al. 2019 [355]: Phase II prospective study | Total (n = 31) | Bortezomib | 12 participants reported no BIPN, with 13 participants progressing to painful BIPN (grade 1). Five participants developed BIPN grade ≥ 2, which is fewer than the proposed 40% expected by the primary end-point | No comparator group. Small sample size |
| ORG 2766 | van der Hoop et al. 1990 [332]: Prospective study |
Total (n = 67) Placebo (n = 25) Low-dose ORG 2766 (n = 22) High-dose ORG 2766 (n = 20) (Participants received either 4 or 6 cycles of chemotherapy) |
Cisplatin | Vibration perception threshold after six cycles of cisplatin chemotherapy was preserved in the high-dose ORG 2766 group compared to placebo (5.87 ± 1.97 µm vs 0.88 ± 0.17 µm; p < 0.005) | - |
| ORG 2766 | Roberts et al. 1997 [356]: Randomised, multicentre, double-blind, placebo-controlled trial |
Total (n = 174) Placebo (n = 67) ORG 2766 2 mg (n = 63) ORG 2766 4 mg (n = 66) |
Cisplatin, cyclophosphamide | ORG 2766 increased the rate and severity of CisPN (p < 0.05) | - |
| ORG 2766 | Koeppen et al. 2004 [357]: Randomised, double-blind, placebo-controlled study |
Total (n = 147) ORG 2766 (n = 73) Placebo (n = 74) |
Vincristine | No significant differences observed between placebo and ORG 2766 groups | - |
| ACL | Hershman et al. 2013 [234]: Randomised double-blind placebo-controlled Trial |
Total (n = 409) ALC (n = 201) Placebo (n = 194) |
Paclitaxel | ACL significantly worsened CIPN symptoms after 24 weeks | - |
| Curcumin | Howells et al. 2019 [238]: Randomised, standard-of-care comparator study |
Total (n = 27) FOLFOX (n = 9) FOLFOX + curcumin (n = 18) |
Oxaliplatin | No significant difference between treatment arms in OIPN | - |
| Venlafaxine (prevention) | Zimmerman et al. 2016 [297]: Pilot, randomised, placebo-controlled, double-blind study |
Total (n = 43) Venlafaxine (n = 22) Placebo (n = 21) |
Oxaliplatin | No significant effect of venlafaxine in the prevention of acute or chronic OIPN | OINS scores indicated improvement in cold hyperalgesia of the throat |
| Glutamine (prevention) | Wang et al. 2007 [247]: Randomised, standard-of-care-controlled trial |
Total (n = 86) Glutamine (n = 42) Control (n = 44) |
Oxaliplatin, 5-FU | The incidence of acute OIPN was lower in the glutamine group compared to the control group (33.3% vs 56.8%; p = 0.03) | No difference in NCS abnormalities (p = NS) |
| Glutamine (prevention) | Vahdat et al. 2001 [248]: Non-randomised, standard-of-care-controlled trial |
Total (n = 55) Glutamine (n = 12) Control (n = 33) |
Paclitaxel | Significant reduction in TIPN severity such as dysaesthesia (p < 0.05), motor weakness (p = 0.04) and interference with daily functioning (p < 0.001) | No objective nerve function measures |
| Glutamine (prevention) | Stubblefield et al. 2005 [249]: Non-randomised, standard-of-care-controlled trial |
Total (n = 36) Glutamine (n = 12) Control (n = 24) |
Paclitaxel | The glutamine group reported lower incidence of weakness (p = 0.02), vibration perception (p = 0.02) and numbness (p = 0.004) compared to controls | No difference in NCS abnormalities (p = NS) |
| Glutathione (prevention) | Cascinu et al. 1995 [245]: Randomised, placebo-controlled, double-blind trial |
Total (n = 43) Glutathione (n = 25) Placebo (n = 18) |
Cisplatin | After 15 weeks, glutathione resulted in fewer incidents of clinically confirmed CisPN compared to the placebo group (16% vs 88%; p = 0.0001) | - |
| Glutathione (prevention) | Cascinu et al. 2002 [244]: Randomised, placebo-controlled, double-blind trial |
Total (n = 40) Glutathione (n = 21) Placebo (n = 19) |
Oxaliplatin | Fewer participants developed grade 2–4 OIPN in the glutathione group compared to placebo (p = 0.004) | - |
| Vitamin E (prevention) | Pace et al. 2003 [240]: Randomised, standard-of-care-controlled trial |
Total (n = 27) Vitamin E + cisplatin (n = 13) Cisplatin alone (n = 14) |
Cisplatin | The incidence of CisPN was lower in the vitamin E-supplemented group compared to standard of care (30.7% vs 85.7%; p < 0.01) | No objective nerve function measures. Not placebo- or active-comparator-controlled |
| Vitamin E (prevention) | Pace et al. 2007 [241]: Multicentre randomised, placebo-controlled, double blind trial |
Total (n = 25) Vitamin E + cisplatin (n = 11) Cisplatin alone (n = 14) |
Cisplatin | Preliminary analysis of the first 25 eligible participants indicated median difference between vitamin E and placebo groups (p < 0.05) | – |
| Vitamin E (prevention) | Kottschade et al. 2011 [242]: Randomised, placebo-controlled, double blind phase III trial |
Total (n = 185) Vitamin E (n = 94) Placebo (n = 91) |
Taxanes and platinum | No significant effect of vitamin E in the prevention of sensory CIPN | – |
| Vitamin E (prevention) | Argyriou et al. 2005 [243]: Pilot, randomised, standard-of-care-controlled, open-label, single-blind trial |
Total (n = 31) Vitamin E (n = 16) Control (n = 15) |
Cisplatin, paclitaxel | CIPN incidence was reduced in the vitamin E group compared to controls (25% vs 73.3%; p = 0.019). NDS scores were lower in participants treated with vitamin E compared to controls (3.4 ± 6.3 vs 11.5 ± 10.6; p = 0.026) | – |
| Glutathione (prevention) | Milla et al. 2009 [358]: Randomised, placebo-controlled phase I trial |
Total (n = 27) Glutathione (n = 14) Placebo (n = 13) |
Oxaliplatin | Grade 1–2 OIPN occurred in 50% of participants compared to 69% of participants treated with placebo (p = 0.0037) | – |
| Calcium and magnesium (prevention) | Loprinzi et al. 2014 [258]: Randomised, placebo-controlled, double-blind phase III trial |
Total (n = 353) Calcium and magnesium infusion before and after chemotherapy (n = 118) Calcium and magnesium infusion before and placebo after chemotherapy (n = 116) Placebo (n = 119) |
Oxaliplatin | No significant effect of calcium magnesium infusion in the prevention of acute OIPN | – |
| Calcium and magnesium (prevention) | Knijn et al. 2011 [254]: Retrospective analysis of a randomised, standard-of-care-controlled phase III trial |
Total (n = 732) Calcium and magnesium (n = 551) Standard-of-care (n = 181) |
Oxaliplatin | Incidence of OIPN (all grades) was reduced in the calcium and magnesium group compared to controls (85% vs 92%; p = 0.02). Incidence of ≥ 2 OIPN was similarly reduced (40% vs 45%; p = 0.22) | – |
| Calcium and magnesium (prevention) | Han et al. 2013 [259]: Prospective randomised, placebo-controlled, double-blind phase I, crossover trial |
Total (n = 19) Calcium and magnesium (n = 10) Placebo (n = 9) |
Oxaliplatin | No significant difference in self-reported acute OIPN symptoms | NCS abnormalities higher in calcium and magnesium compared to controls (p = ns) |
| Calcium and magnesium (prevention) | Gamelin et al. 2004 [255]: Retrospective analysis of a cohort study |
Total (n = 161) Calcium and magnesium (n = 96) Standard-of-care (n = 65) |
Oxaliplatin | At the end of treatment all grade OIPN was reduced in the calcium and magnesium compared to standard of care (4% vs 31%; p < 0.001). (20% vs 45%; p = 0.003). OIPN severity (grade ≥ 3) occurred at a lower incidence in participants treated with calcium and magnesium compared to standard of care (7% vs 26%; p = 0.001) | – |
| Calcium and magnesium (prevention) | Ao et al. 2012 [256]: Meta-analysis | Total (n = 202) | Oxaliplatin | Fixed effects model identified calcium and magnesium has no effect on acute OIPN (OR = 0.41, 95% CI 0.11–1.49; p = 0.70, I2, 0) | – |
| Amifostine (prevention) | Leong et al. 2003 [250]: Randomised, placebo-controlled, double-blind trial |
Total (n = 58) Amifostine (n = 21) Placebo (n = 27) |
Paclitaxel and carboplatin | No significant difference in neuropathy incidence of amifostine treatment between groups was identified | – |
| Amifostine (prevention) | Hilpert et al. 2005 [251]: Randomised, placebo-controlled, double-blind phase II trial |
Total (n = 72) Amifostine (n = 37) Placebo (n = 34) |
Paclitaxel, carboplatin and epirubicin | Amifostine improved self-reported sensory CIPN symptoms (NCI-CTC) compared to controls (p = 0.0046) | Amifostine caused worsening of nausea (p = 0.0005) and vomiting (p = 0.0083) |
| Amifostine (Ages 3–21) (prevention) | Gurney et al. 2014 [252]: Cohort study |
Total (n = 379) Average-risk (n = 263) High-risk (n = 116) |
Cisplatin | Participants with average risk of hearing loss reduced the risk of hearing loss (OR, 0.30; 95% CI: 0.14–0.64). High risk participants did not prevent hearing loss (OR, 0.89; 95% CI: 0.31–2.54) | – |
| DDTC | Gandara et al. 1995 [253]: Randomised placebo-controlled multicentre trial |
Total (n = 214) DDTC (n = 106) Placebo (n = 108) |
Cisplatin | Participants receiving DDTC with lower cumulative doses of cisplatin were more likely to cease chemotherapy treatment | – |
| Massage (prevention) | Izgu et al. 2019 [359]: Randomised, standard-of-care-controlled trial |
Total (n = 40) Massage (n = 19) Control (n = 21) |
Paclitaxel | Reduced pain reported by massage group compared to controls at week 12 (p < 0.05) | – |
| Electro-acupuncture (prevention) | Greenlee et al. 2016 [360]: Randomised sham-controlled pilot trial |
Total (n = 48) Electro-acupuncture (n = 25) Sham electro-acupuncture (n = 23) |
Paclitaxel, oxaliplatin | No difference between groups. Also, participants in receipt of electro-acupuncture recovered at a slower rate after chemotherapy treatment stopped | – |
| Calmangafodipir (prevention) | Glimelius et al. 2018 [361]: Randomised, placebo-controlled, double-blind phase II trial |
Total (n = 173) Placebo (n = 60) Calmangafodipir (n = 113) |
Oxaliplatin | Participants treated with calmangafodipir reported fewer sensory symptoms (p < 0.01) and fewer incidents of physician-graded OIPN (p = 0.016) compared to controls | Due to promising results, currently ongoing phase III trials |
| Pregabalin (prevention) | de Andrade et al. 2017 [283]: Randomised, placebo-controlled, double-blind phase II trial |
Total (n = 143) Pregabalin (n = 78) Placebo (n = 65) |
Oxaliplatin | Pregabalin did not decrease the incidence of chronic OIPN or neuropathic pain compared to placebo (p = NS) | – |
| Oxcarbazepine (prevention) | Argyriou et al. 2006 [362]: Randomised, open-label, standard-of-care-controlled trial |
Total (n = 40) Oxcarbazepine (n = 20) Control (n = 20) |
Oxaliplatin | The incidence of OIPN was reduced in the oxcarbazepine group compared to controls (31.2% vs 75%; p = 0.033) | – |
| Carbamazepine (treatment) | Wilson et al. 2002 [363]: Phase I trial | Total (n = 12) | Oxaliplatin | No impact on the symptoms or impaired NCS of OIPN | Small, non-randomised trial |
| Exercise (treatment) | Kleckner et al. 2018 [269]: Secondary analysis of multicentre, randomised, standard-of-care-controlled phase III trial |
Total (n = 355) Exercise (n = 170) Control (n = 185) |
Taxanes, platinums and vinca alkaloids | Exercise reduced self-reported sensory CIPN symptoms of thermal sensation in the hands or feet (p = 0.045), paraesthesia (p = 0.061) which was more pronounced in older (p = 0.086), male (p = 0.028) or participants with breast cancer (p = 0.076) | – |
| Aromatherapy massage (treatment) | Izgu et al. 2019 [364]: Randomised, standard-of-care-controlled trial |
Total (n = 46) Massage (n = 22) Control (n = 24) |
Oxaliplatin | Reduction in self-reported painful OIPN symptoms at week 6 in treated participants compared to standard of care | – |
| Acupuncture (treatment) | Molassiotis et al. 2019 [365]: Randomised, single-blind, standard-of-care-controlled trial |
Total (n = 87) Acupuncture (n = 44) Control (n = 43) |
Platinum, taxane, bortezomib | TNS scores improved after 20 weeks of treatment in participants treated with acupuncture compared to standard of care (p < 0.05). Sensory NCI-CTC-AE scores improved (p < 0.05) but not the motor subset items | – |
| Laser-acupuncture (treatment) | Hsieh et al. 2016 [267]: Prospective cohort study | Total (n = 17) | Oxaliplatin | Laser acupuncture reduced the severity of OIPN symptoms in both the hands and feet of participants (p < 0.05) | – |
| Acupuncture and methylcobalamin (treatment) | Han et al. 2017 [264]: Randomised, methylcobalamin controlled, prospective study |
Total (n = 98) Acupuncture + methylcobalamin (n = 49) Methylcobalamin alone (n = 49) |
– | After 84 days both groups improved pain scores, with reduced pain scores in the acupuncture group (p < 0.01) | – |
| Electro-acupuncture (treatment) | Rostock et al. 2013 [265]: Randomised placebo-controlled trial |
Total (n = 59) Electro-acupuncture (n = 14) Hydroelectric baths (n = 13) Vitamin B (n = 15) Placebo (n = 17) |
– | Electro-acupuncture demonstrated a worse effect in the treatment of CIPN symptoms (0.8 ± 1.2), with a group difference of –0.3 (95% CI −1.4 to 0.8; p = 0.705) | – |
| Electro-acupuncture | Garcia et al. 2014 [268]: Pilot study | Total (n = 19) | Thalidomide, bortezomib | At weeks 9–13, pain severity, fine motor functioning and walking all improved according to FACT/GOG-Ntx scores. No improvements in NCS were identified | – |
| Lidocaine (treatment) | Van den Heuvel et al. 2017 [366]: Prospective case series | Total (n = 9) | Platinum, taxanes, capecitabine, cyclophosphamide, trastuzumab, cyclophosphamide, capecitabine, imatinib, bevacizumab, etoposide and cytarabine | A significant analgesic effect in 88% of patients (p = 0.01). Pain reduction was maintained for 23 days in five participants | – |
| Lamotrigine | Rao et al. 2008 [367]: Randomised, double-blind, placebo-controlled phase III trial | Total (n = 131) | Paclitaxel, docetaxel, carboplatin, cisplatin, oxaliplatin, vincristine and vinblastine | No significant relief of CIPN symptoms identified using lamotrigine | – |
| Oral mucosal spray containing delta-9 tetrahydrocannabinol and cannabidiol (treatment) | Lynch et al. 2014 [368]: randomised, placebo-controlled crossover pilot study patients | Total (n = 16) | Cisplatin, oxaliplatin, paclitaxel, vincristine | No significant relief of pain intensity in participants with CIPN | – |
| Topical amitriptyline and ketamine | Gewandter et al. 2014 [271]: Multicentre, randomised, placebo-controlled, double-blind phase III trial | Total (n = 462) | Taxane, non-taxane | No significant difference in self-reported sensory CIPN symptoms using topical amitriptyline and ketamine compared to placebo (p = NS) | Short 5-week study |
| Topical baclofen, amitriptyline and ketamine | Barton et al. 2011 [369]: Randomised, placebo-controlled, double-blind trial | Total (n = 150) | Taxanes, platinums, vinca alkaloids and thalidomides | Improvement in sensory (p = 0.053) and motor (p = 0.021) subscales of the EORTC QLQ-CIPN20 in the topical baclofen, amitriptyline and ketamine group compared to controls | – |
| Topical amitriptyline | Rossignol et al. 2019 [272]: open-label, non-comparative, uncontrolled, prospective pilot clinical trial | Total (n = 44) | Oxaliplatin, bortezomib, vinca alkaloids, lenalidomide, bendamustine | A reduction in pain score of at least 3 points was observed after 1 week in all participants. After 4 weeks, pain scores were reduced to 2 (p < 0.0001) | – |
| Topical menthol 1% (treatment) | Fallon et al. 2015 [370]: Prospective study | Total (n = 38) | Oxaliplatin, cisplatin, carboplatin, paclitaxel and bortezomib | 82% of participants had improvement in pain scores (p < 0.001). Improvements in HADS scores and QST were also identified (p < 0.001) | – |
| Capsaicin 8% patch | Anand et al. 2019 [275]: single-centre, open-label, longitudinal study | Total (n = 16) | Bortezomib, platinum, and or taxane | Self-reported measures indicated reduced spontaneous pain (p = 0.02), touch-evoked pain (p = 0.03), cold-evoked pain (p = 0.03), neuropathic pain (p = 0.0007), and continuous (p = 0.01) and overall pain (p = 0.004) | Potential disease modification as IENFD identified regenerative nerve markers |
5-FU Fluorouracil, CIPN Chemotherapy-induced peripheral neuropathy, DDTC Diethyldithiocarbamate, EORTC QLQ-CIPN20 European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-CIPN twenty-item scale, FACT/GOG-Ntx Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity, IENFD Intraepidermal nerve fibre density, OIPN Oxaliplatin-induced peripheral neuropathy, NCI-CTC-AE Common Terminology Criteria for Adverse Events, NS not significant, NCS Nerve conduction studies, TIPN Taxane-induced peripheral neuropathy