Chemotherapy-induced peripheral neuropathy is a common adverse event which affects the sensory, motor and autonomic nerves. |
The diagnosis of chemotherapy-induced peripheral neuropathy lacks a gold standard. |
There are currently no proven strategies or interventions to prevent or limit the development of chemotherapy-induced peripheral neuropathy. |
A mechanistic approach is needed to address strategies for prevention and treatment of chemotherapy-induced peripheral neuropathy. |
Introduction
Study and design | Participants | Agent(s) studied | Cancer types | Diagnostic methodology | Grading criteria used | Study duration/length of follow-up | Incidence |
---|---|---|---|---|---|---|---|
Platinum agents | |||||||
Leonard et al. [298]: Phase I trial | Oxaliplatin (n = 86) | Oxaliplatin | Colorectal | Questionnaire asked by clinical staff (SRO) | OSNS, based on the NCI-CTC | Up to 12 cycles | Grade 1 dysaesthesia: 70.9%, paraesthesia: 66.3%, grade 2 dysaesthesia: 11.6%, paraesthesia: 19.8%, grade 3 dysaesthesia: 4.7%, paraesthesia: 7%, grade 4 dysaesthesia: 0%, paraesthesia: 1.2% |
Alejandro et al. [299]: Retrospective review of cohort study | FOLFOX6 (n = 50) | FOLFOX6 | Colorectal | NCI-CTC | NCI-CTC | Up to 12 cycles | 84% reported at least one episode of acute neuropathy, 74% reported acute OIPN. 48% reported persistent OIPN. 12% reported grade 3 neuropathy > 8 cycles of FOLFOX |
Rothenberg et al. [300]: Phase III trial | Total (n = 445), Oxaliplatin (n = 153), FOLFOX4 (n = 150) fluorouracil and leucovorin (n = 142) | Oxaliplatin, FOLFOX, fluorouracil and leucovorin | Metastatic colorectal | Questionnaire asked by clinical staff (SRO) | OSNS, based on the NCI-CTC | 14 months (maximum) | Acute OIPN (all grades): 53–58%, acute OIPN grade 3–4: 3–10%, cumulative OIPN: 51%, cumulative OIPN grade 3–4: 3% |
Yamada et al. [301]: Phase III trial | Total (n = 685) S-1 and Oxaliplatin (n = 318), S-1 and Cisplatin (n = 324) | S-1 and oxaliplatin S-1 and cisplatin | Advanced gastric | SRO | NCI-CTC-AE | 25.9 (median) | Oxaliplatin—sensory neuropathy (any grade): 85.5%, grade ≥ 3: 16%, cisplatin sensory neuropathy (any grade): 23.6%, grade ≥ 3: 0% |
Bando et al. [302]: Phase III trial | Total (n = 685) S-1 and oxaliplatin (n = 343) S-1 and cisplatin (n = 342) | S-1 and oxaliplatin S-1 and cisplatin | Advanced gastric | SRO | NCI-CTC-AE | 17.5 months for oxaliplatin, 13.5 months for cisplatin (median) | OIPN grade ≥ 3 4.5–5.3%, CisPN grade ≥: 0% |
Lonardi et al. [303]: Phase III multicentre trial | Total (n = 3715) 3 months FOLFOX/XELOX treatment (n = 1848) 6 months FOLFOX/XELOX treatment (n = 1867) | FOLFOX4 (64%) or XELOX (36%) | Stage II/III colorectal | NCI-CTC (SRO) | NCI-CTC | 3 Years | 3 months treatment with either FOLFOX or XELOX, grade 0: 49.9%, grade 1–2: 41.3%, grade 3–4: 8.8%, 6 months treatment with either FOLFOX or XELOX, grade 0: 31.6%, grade 1–2: 37.2%, grade 3–4: 31.2% |
Al-Batran et al. [304]: Phase III trial | Total (n = 220) Oxaliplatin (n = 112) Cisplatin (n = 102) | Fluorouracil, leucovorin, and oxaliplatin Fluorouracil, leucovorin, and cisplatin | Advanced gastro-oesophageal | NCI-CTC (SRO) | WHO toxicity criteria | 14 months (median) | Oxaliplatin (all grades): 62.5%, oxaliplatin grade 3–4: 14.3%, cisplatin (all grades): 21.6%, cisplatin grade 3-4: 2% |
Cassidy et al. [305]: Two-arm, open-label, randomised phase III trial | Total = (n = 1304) FOLFOX4 ± placebo (n = 649) XELOX ± placebo (n = 655) | FOLFOX4, XELOX | Colorectal | NCI-CTC (SRO) | NCI-CTC | 29.7 months (median) | FOLFOX4, grade 1: 11%, grade 2: 5%, grade 3: 4%, grade 4: 0%, XELOX, grade 1: 11%, grade 2: 5%, grade 3: 4%, grade 4: 0% |
Tournigand et al. [306]: Randomised FOLFOX comparator trial | Total (n = 620) FOLFOX4 (n = 311) FOLFOX7 + simplified leucovorin and fluorouracil (n = 309) | FOLFOX4, FOLFOX7, leucovorin, fluorouracil | Advanced colorectal | NCI-CTC (SRO) | NCI-CTC | 31 months (median) | FOLFOX4, grade 1: 34%, grade 2: 37%, grade 3: 18%, grade 4: 0%, FOLFOX7, grade 1: 36%, grade 2: 42%, grade 3: 13%, grade 4: 0% |
Andre et al. [307]: International phase III trial | Total (n = 2246) Oxaliplatin + fluorouracil and leucovorin (n = 1123) Fluorouracil and leucovorin (n = 1123) | Oxaliplatin, fluorouracil, leucovorin, | Stage II/III colorectal | NCI-CTC (SRO) | NCI-CTC (version 1.0) | - | Oxaliplatin + fluorouracil and leucovorin, paraesthesia, all grades: 92%, grade 3: 12.4%, fluorouracil and leucovorin, all grades: 15.6%, grade 3: 0.2% |
Gebremedhn et al. [42]: Systematic review | Total participants treated with oxaliplatin (n = 6211) | FOLFOX, FOLFOX3, FOLFOX4, oxaliplatin, XELOX | - | NCI-CTC version 1, 2 and 3, TNSc, WHO toxicity criteria, FACT, OSNS | - | - | Acute OIPN: most common AE of all grades 4–98% |
Beijers et al. [308]: Systematic review | Total participants treated with oxaliplatin (n = 3869) | FOLFOX, FOLFOX4, XELOX | - | NCI-CTC version 1, 2 and 3, TNSc, WHO toxicity criteria, FACT, OSNS, NCS | - | 12 months–8 years | No definitive conclusions drawn for the incidence and risk factors for chronic OIPN |
Land et al. [309]: Phase III trial | Total (n = 395) Oxaliplatin, fluorouracil and leucovorin (n = 189) Fluorouracil and leucovorin (n = 206) | Oxaliplatin, fluorouracil and leucovorin | Stage II/III colorectal | FACT, OSNS, NCI-CTC | 18 months | OIPN at 12 months, grade 1: 25%, grade 2: 4.5%, grade 3: 0.4% | |
De Gramont et al. [46]: Phase III trial | Total (n = 420) Oxaliplatin, fluorouracil and leucovorin (n = 210) Fluorouracil and leucovorin (n = 210) | Oxaliplatin, fluorouracil and leucovorin | Colorectal | NCI-CTC | NCI-CTC | 27.7 months (median) | Painless paraesthesia: 65.1%, painful paraesthesia: 10.5%, pharyngolaryngeal dysaesthesia: 22.5% |
Briani et al. [47]: Longitudinal cohort study | Total (n = 91) | FOLFOX4, FOLFOX6, XELOX | Colorectal | NCI-CTC, neurological examination, TNSc and NCS | TNSc | 25 months (median) after treatment cessation | After 2 years treatment cessation: OIPN, grade 1: 85.2%, grade 2: 14.8%, grade 3: 0% |
Park et al. [43]: Longitudinal cohort study | Total (n = 24) | FOLFOX4, FOLFOX6, XELOX | Colorectal | Clinical examination, TNSc, NSS, NCI-CTC (Sensory subscale), NCS | TNSc, NCI-CTC (Sensory subscale) | 29 ± 4 months after treatment cessation | After 2.4 years treatment cessation: persistent OIPN symptoms: 79.2% (upper limbs 45.8%, 79.2% in the lower limbs), grade 0: 20.8%, grade 1: 37.5%, grade 2: 29.2%, grade 3: 12.5%, 66.7% reported minor improvements of 1 grade during time to follow-up > 40% reported fine motor deficits, walking difficulties and significant functional impairments |
Ibrahim et al. [310]: multicentre randomised trial enrolled | Total (n = 445) Oxaliplatin, fluorouracil and leucovorin (n = 150) Fluorouracil and leucovorin (n = 142) Oxaliplatin (n = 153) | Oxaliplatin, fluorouracil and leucovorin | - | WHO toxicity criteria, NCI-CTC | NCI-CTC | - | Oxaliplatin (all grades), total: 76%, acute: 65%, chronic: 43%, oxaliplatin (grade 3/4), acute: 5%, chronic: 3%, oxaliplatin, fluorouracil and leucovorin (all grades), total: 74%, acute: 56%, chronic: 48%, oxaliplatin, fluorouracil and leucovorin (grade 3/4), acute: 2%, chronic: 6% |
Taxanes | |||||||
Argyriou et al. [311]: Prospective study | Total (n = 21) | Paclitaxel, carboplatin | Lung, breast, ovarian | NSS, NDS, NCS | PNP, WHO toxicity criteria | 3 months | Neuropathy (all grades): 66.5%, none: 33.3%, mild: 19%, moderate: 33.3%, severe: 14.2% |
Peng et al. [312]: Meta-analysis | Total (n = 2878) | Nab-paclitaxel | Gastric, urothelial, pancreatic, lung, breast, cervix, ovarian, melanoma and prostate | - | NCI-CTC (version 4.0) | - | Nab-paclitaxel TIPN, total (all grades): 51.0% (95% CI 45.1–57.6%), high-grade: 12.4% (9.8–15.7%) |
Socinski et al. [313]: Phase III trial | Total (n = 1052) Nab-paclitaxel + carboplatin (n = 521) Paclitaxel + carboplatin (n = 531) | Nab-paclitaxel, paclitaxel, carboplatin | Advanced non-small cell lung | ECOG, NCI-CTC (version 3.0) | NCI-CTC (version 3.0) | Nab-paclitaxel group, TIPN (all grades): 46%, grade 3: 3%, grade 4: 0%, paclitaxel group TIPN (all grades): 62%, grade 3: 11%, grade 4 : < 1% | |
Pace et al. [241]: Pilot study | Total (n = 14) | Paclitaxel | Advanced breast | Neurological examination (VPT, pinprick, muscle strength, deep tendon reflexes), TNS, NCS | - | 24 weeks, for 11 participants, a further follow-up examination was conducted 4–17 months after cessation of treatment | TIPN (all grades), 12 weeks: 71% (paraesthesia ± impaired tendon reflexes), 14 weeks: 96% (signs ± symptoms ± significant NCS abnormalities), non-significant improvement in all patients at follow-up |
Baldwin et al. [314]: Prospective cohort study | Total (n = 1940) | Paclitaxel | Breast | NCI-CTC (version 2.0) | NCI-CTC (version 2.0) | - | TIPN grade ≥ 2, 4 cycles of paclitaxel: 17%, 6 cycles of paclitaxel: 33% |
Dorling et al. [315]: Secondary case–control study of four chemotherapy trials | Total (n = 2354) Participants analysed according to NCI-CTC-AE (n = 1279) | Paclitaxel, gemcitabine, cyclophosphamide, methotrexate, 5-fluorouracil, epirubicin | Breast | NCI-CTC-AE (version 2.0 & 3.0), TNS | NCI-CTC-AE (version 2.0 & 3.0) | 1 month after treatment cessation | TIPN, grade 0: 21.2%, grade 1: 50.7%, grade 2: 23.7%, grade 3: 4.4%, TIPN grade ≥ 2: 28.1% |
Shimozuma et al. [84]: Phase III trial | Total (n = 300) Anthracycline + cyclophosphamide + paclitaxel (n = 74) Anthracycline + cyclophosphamide + docetaxel (n = 75), Paclitaxel (n = 76) Docetaxel (n = 75) | Anthracycline, cyclophosphamide paclitaxel, docetaxel | Breast | PNQ, FACT, NCI-CTC (version 2.0) | PNQ | 1 year | Incidence of PNQ grade D or E (equivalent to NCI-CTC grade 3–4) for: paclitaxel: > 10%, docetaxel: > 10%, both worsened after cycles 3–7, with an incidence of 16–21% |
Scagliotti et al. [316]: Phase III trial | Total (n = 926) Paclitaxel + carboplatin + sorafenib (n = 464) Paclitaxel + carboplatin + placebo (n = 462) | Paclitaxel, carboplatin, sorafenib | Advanced non-small cell lung | NCI-CTC-AE (version 3.0) | NCI-CTC-AE (version 3.0) | ~ 10 months | Paclitaxel, carboplatin, sorafenib group, all grades: 14%, grade 3: 3%, paclitaxel, carboplatin, placebo group, all grades: 13%, grade 3: 2% |
Bonomi et al. [83]: Phase III trial | Total (n = 574) High-dose paclitaxel and cisplatin (n = 193) Low-dose paclitaxel and cisplatin (n = 191) Etoposide and cisplatin (n = 190) | Paclitaxel, etoposide, cisplatin, | Advanced non-small cell lung | ECOG, FACT | ECOG | 28.5 months (median) | Grade 3 TIPN, high-dose paclitaxel and cisplatin: 40%, low-dose paclitaxel and cisplatin: 23%, etoposide and cisplatin: 21% |
Scagliotti et al. [317]: Phase III trial | Total (n = 607) Paclitaxel + carboplatin (n = 201) Gemcitabine + cisplatin (n = 205) Vinorelbine + cisplatin (n = 201) | Paclitaxel, carboplatin, gemcitabine, cisplatin, vinorelbine | Advanced non-small cell lung | NCI-CTC (version 2.0) | NCI-CTC (version 2.0) | 8–10 months | CIPN in paclitaxel and carboplatin group, grade 1: 22.8%, grade 2: 7%, grade 3: 0%, CIPN in the cisplatin and gemcitabine, grade 1: 4%, grade 2: 0%, grade 3: 0%, CIPN in the vinorelbine and cisplatin, grade 1: 4%, grade 2: 2.5%, grade 3: 0.5% |
Gao et al. [318]: Meta-analysis | Total (n = 940) | Paclitaxel | Advanced, non-small cell lung | – | – | – | Weekly paclitaxel treatment grade 3–4: 10%, once every 3 weeks paclitaxel treatment, grade 3–4: 17.92% |
Vinca alkaloids | |||||||
Ness et al. [107]: Cohort study (children) | Total (n = 531) | Vincristine, vinblastine, carboplatin, cisplatin | Skin, brain, bone, muscle and kidney | mTNS, SOT | mTNS | Participants underwent testing ≥ 10 years after treatment | Sensory neuropathy (all grades): 20.4%, motor neuropathy (all grades): 20.8% |
Andersson et al. [108]: Cohort study | Total (n = 107) | Vinorelbine | Advanced or metastatic breast | MedRA (version 18.1) | MedRA (version 18.1) | 26.5 months (median) | Any grade: 21.5%, grade 3–4: 1.9% |
Ramchandren et al. [319]: Cohort study (children) | Total (n = 37) | Vincristine | Acute lymphoblastic leukaemia | NIS, NCS, TNSr | NIS, NCS, TNSr | Participants underwent testing 7.4 years after treatment (mean) | TNSr score of 1 indicated a VIPN prevalence of 100%, TNSr score of ≥ 2 indicated a VIPN prevalence of 94.6%. Participants had impaired NCS |
Smith et al. [320]: Cohort study (children) | Total (n = 128) | Vincristine | Acute lymphoblastic leukaemia | NCI-CTC-AE (version 4.0) | NCI-CTC-AE (version 4.0) | 1 year from start of treatment | VIPN (all grades): 78%, sensory VIPN: grade 1: 31%, grade 2: 3.2%, grade 3: 1.6%, grade 4: 0%, motor VIPN: grade 1: 18%, grade 2: 4.4%, grade 3: 1.9%, grade 4: 0% |
Immunomodulatory agents | |||||||
Glasmacher et al. [133]: Systematic review and pooled analysis | Total (n = 1674) | Thalidomide | Multiple myeloma | WHO toxicity criteria | WHO toxicity criteria | - | 50–200 mg/day of bortezomib: 16% BIPN (all grades), > 200 mg/d of bortezomib: 31% BIPN (all grades) |
Mileshkin et al. [125]: Cohort study | Total (n = 75) | Thalidomide | Refractory/relapsed multiple myeloma | NCI-CTC (version 2.0), NCS | NCI-CTC (version 2.0) | 24 weeks | Grade ≥ 2 ThIPN: 31% SNAP impairment (> 50%): 53% |
Dimopoulos et al. [321]: Multicentre phase II Trial | Total (n = 44) | Thalidomide, dexamethasone | Refractory multiple myeloma | WHO toxicity criteria | WHO toxicity criteria | 23.3 months (median) | ThIPN (all grades): 23% |
Prince et al. [322]: Multicentre phase II Trial | Total (n = 66) | Thalidomide | Relapsed/resistant multiple myeloma | NCI-CTC (version 2.0), NCS | NCI-CTC (version 2.0), NCS | 20 months (median) | ThIPN (all grades): sensory: 70%, motor: 35%, ThiPN grade 3: sensory: 11%, motor: 3% |
von Lilienfeld-Toal et al. [323]: Systematic review and pooled analysis | Total (n = 451) | Thalidomide, dexamethasone | Refractory/relapsed multiple myeloma | ThIPN (all grades): 27% (95% CI 23–32) | |||
Briani et al. [121]: Case–control study | Total (n = 14) | Thalidomide | Systemic lupus erythematosus | Neurological examination, NSS, NCS | Neurological examination, NSS, NCS | Up to 35 months | ThiPN (all grades): 71.4% |
Grover et al. [325]: Case–control study | Total (n = 23) | Thalidomide, cyclophosphamide, vincristine | Refractory/relapsed multiple myeloma | - | - | Up to 15 months | ThIPN (all grades): 13% |
Tosi et al. [130]: Longitudinal Cohort study | Total (n = 40) | Thalidomide | Refractory/relapsed multiple myeloma | WHO toxicity criteria | WHO Toxicity Criteria | 1 year | ThIPN at 6 months, grade 0: 47.5%, grade 1: 35%, grade 2: 17.5%, grade 3: 0%, ThIPN at 1 year, grade 0: 25%, grade 1: 15%, grade 2: 32.5%, grade 3: 27.5% |
Facon et al. [326]: Randomised controlled trial | Total (n = 447) Melphalan + prednisone (n = 196) Melphalan + predispose + thalidomide (n = 125) Stem cell transplant + melphalan (n = 126) | Thalidomide, melphalan, prednisone | Multiple myeloma | – | – | 30 months | ThIPN (all grades): 55%, grade 3 – 5% |
Bastuji-Garin et al. [122]: Prospective Cohort Study | Total (n = 135) | Thalidomide | Dermatological disorder | Signs and symptoms, NCS | Signs and symptoms, NCS | 30 months | ThIPN (all grades): 25.2% (95% CI 17.9–32.5%) |
Bramuzzo et al. [120]: Multicentre cohort study (children) | Total (n = 142) | Thalidomide | Pediatric inflammatory bowel disease | NCI-CTC (version 4.0), NCS | NCI-CTC (version 4.0) | 24 months | ThIPN (all grades): 72.5%, NCS impairment: 49.1% |
Dimopoulos et al. [135]: Phase III trial | Total (n = 351) Lenalidomide (n = 176) Placebo (n = 175) | Lenalidomide | Refractory/relapsed multiple myeloma | NCI-CTC (version 2.0) | NCI-CTC (version 2.0) | 11.3 months (median) | Grade 3 lenalidomide-related neuropathy occurred at < 10% |
Briani et al. [136]: Prospective Cohort Study | Total (n = 30) | Lenalidomide | Refractory/relapsed multiple myeloma | TNS, ECOG | TNS, ECOG | 12 months | At baseline 53.3% of patients had BIPN/ThiPN; these patients remained stable. No lenalidomide-related neuropathy was identified after 12 months |
Miguel et al. [137]: Multicentre phase III trial | Total (n = 455), Pomalidomide + low-dose dexamethasone (n = 302), high-dose dexamethasone (n = 153) | Pomalidomide, dexamethasone | Refractory/relapsed multiple myeloma + intolerant to bortezomib, lenalidomide or thalidomide | ECOG | ECOG | 18 months | Pomalidomide-related neuropathy (any grade): 15%, dexamethasone-related neuropathy (any grade): 11%, pomalidomide or dexamethasone-related neuropathy (grade ≥ 3): 1% |
Richardson et al. [327]: Multicentre phase II trial | Total (n = 102) 15 mg of lenalidomide twice daily (n = 35) 30 mg of lenalidomide once daily (n = 67) | Lenalidomide | Refractory/relapsed multiple myeloma | NCI-CTC (version 2.0) | NCI-CTC (version 2.0) | 28 months | Lenalidomide-related neuropathy observed in 10% of patients in the once-daily group, lenalidomide-related neuropathy observed in 23% of patients in the twice-daily group |
Katodritou et al. [132]: Cohort study | Total (n = 211) | Lenalidomide, dexamethasone | Refractory/relapsed multiple myeloma | - | - | 13 months (median) | Lenalidomide-related neuropathy observed in 8% of patients |
Proteasome inhibitors | |||||||
Peng et al. [328]: Meta-analysis | Total (n = 6492) | Bortezomib | Multiple myeloma, mantle cell lymphoma | - | - | - | BIPN (all grades): 33.9% (95% CI 29.9–38.5%), BIPN grade 3/4: 8.1% (95% CI 6.9–9.4%) |
Richardson et al. [153]: Phase II trial | Total (n = 193) | Bortezomib | Multiple myeloma | NCI-CTC (version 2.0) | NCI-CTC (version 2.0) | BIPN (all grades): 31%, BIPN grade 3: 12% | |
Richardson et al. [129]: Cohort study | Total (n = 256) Bortezomib at 1 mg/m2 (n = 28) Bortezomib at (1.3 mg/m2) (n = 228) | Bortezomib | Advanced multiple myeloma | FACT, GOG-Ntx | FACT, GOG-Ntx | - | BIPN (1 mg/m2), grade 1: 11% grade 2: 4%, grade 3: 4% grade 4: 4%, all grades: 21%, BIPN (1.3 mg/m2), grade 1: 7%, grade 2: 16%, grade 3: 14%, grade 4: 0%, All grades: 37% |
Richardson et al. [329]: Phase III trial | Total (n = 669) Bortezomib (n = 331)dexamethasone (n = 332) | Bortezomib, dexamethasone | Advanced multiple myeloma | NCI-CTC (version 2.0) | NCI-CTC (version 2.0) | - | BIPN (all grades): 36%, BIPN grade 3): 7%, BIPN grade 4): 1% |
Richardson et al. [330]: Cohort study | Total (n = 64) | Bortezomib | Multiple myeloma | FACT, GOG-Ntx, NCS | NCI-CTCAE (version NS) | 29 months (median) | BIPN (all grades): 64%, grade 1: 36%, grade 2: 25%, grade 3: 3% |
Kropff et al. [154]: Phase II trial | Total (n = 54) | Bortezomib, dexamethasone, cyclophosphamide | Multiple myeloma | NCI-CTC (version 3.0) | NCI-CTC (version 3.0) | 20 months (median) | BIPN, grade 1: 17%, grade 2: 28%, grade 3: 17% |
Aguiar et al. [331]: Systematic review and meta-analysis | - | Bortezomib, thalidomide, lenalidomide | Multiple myeloma | - | - | - | Peripheral neuropathy incidence was significantly higher when thalidomide was added to chemotherapy regimens compared to control arms |
Chaudhry et al. [127]: Prospective cohort study | Total (n = 27) | Bortezomib, thalidomide | Multiple myeloma | TNS, NCS | TNS | 2 months (median) | All grades: 96%, grade 1: 42%, grade 2: 38%, grade 3: 19% |
Antineoplastic agent | Approval | Cumulative toxic dose | Symptoms/Signs | Progression |
---|---|---|---|---|
Oxaliplatin (acute) | 2002a | ≥ 85 mg/m2 | Predominantly sensory acute: Cold-induced allodynia, throat discomfort, tingling, numbness ± pain in the hands and feet | Acute (may lead to dose reduction or stopping treatment) |
Does not resolve between cycles | ||||
Predominantly sensory chronic: Distal and symmetrical loss of sensation in the hands and feet ± pain | Severity of acute OIPN is predictive of chronic and higher grade | |||
Oxaliplatin (chronic) | ≥ 510 mg/m2 | Coasting phenomenon | ||
Symptoms are predominantly in the hands, which become more predominant in the feet after ~ 18 months of chronic OIPN symptoms | Participants continue to report symptoms for years after treatment has stopped | |||
Cisplatin | 1985a | ≥ 600 mg/m2 | Cisplatin implicated in ototoxicity | A proportion of participants recover although not back to pre-chemotherapy baseline |
Motor: Muscle cramps, neuromyotonia, muscle weakness, fine motor impairment | ||||
Reduction and/or loss of deep tendon reflexes | ||||
≥ 780 mg/m2 | Autonomic: Orthostatic hypotension | |||
Carboplatin | 1986a | ≥ 400 mg/m2 | Sensory: Distal and symmetrical loss of sensation in the hands and feet: | Acute (may lead to dose reduction or stopping treatment) |
Motor: | Can progress to chronic | |||
Large fibre involvement leading to ataxia | Coasting effect | |||
Reduction or loss of deep tendon reflexes | ||||
Taxanes | Paclitaxel acute pain syndrome: | Acute pain syndrome | ||
Aching pain, arthralgia, myalgia and muscle cramps in the lower extremities | Acute symptoms may not resolve between cycles | |||
Paclitaxel | 1992a | ≥ 100 mg/m2 | Predominantly sensory: | Severity of acute TIPN may lead to dose reduction or stopping treatment and is predictive of chronic and higher-grade neuropathy |
Docetaxel | 1995a | ≥ 300 mg/m2 | Acute, length-dependent distal sensory neuropathy characterised by numbness and tingling ± pain in a stocking-and-glove distribution | Recovery or improvement once treatment is stopped is expected in a majority of patients |
Neuropathic pain in the hands and feet is frequent | Participants recover although rarely back to pre-chemotherapy baseline | |||
Motor: | A number continue to persist with low-grade symptoms | |||
Reduction and/or loss of deep tendon reflexes | ||||
Possible proprioceptive loss leading to an unsteady gait | ||||
Facial nerve palsy | ||||
Rare autonomic: | ||||
Orthostatic hypotension | ||||
Paralytic ileus | ||||
Arrhythmia | ||||
Optic neuropathy | ||||
Vinca alkaloids | Predominantly sensorimotor: | Acute (may lead to dose reduction or stopping treatment) | ||
Distal and symmetrical loss of sensation in the hands and feet characterised by numbness and tingling ± pain | Progression to chronic has established genetic risk factors | |||
Vincristine | 1984a | ≥ 4 mg/m2 | Motor: | Children and adolescents tolerate higher cumulative doses than adults |
Distal symmetric weakness in lower legs | Coasting effect | |||
Vinblastine | 1992a | Walking difficulties | ||
Muscle cramps | ||||
Vinorelbine | 1994a | Foot drop | ||
Impaired fine motor skills | ||||
Autonomic: | ||||
Orthostatic hypotension | ||||
Paralytic ileus | ||||
Constipation | ||||
Urogenital dysfunction | ||||
Walking difficulties | ||||
Foot drop | ||||
Impaired fine motor skills | ||||
Thalidomide | 2003a | ≥ 50 mg/day | Sensory | Acute can progress to chronic |
Distal and symmetrical loss of sensation in the hands and feet characterised by hyperaesthesia, hypoaesthesia and paraesthesia | Long-term neurotoxic sequelae are not uncommon | |||
Numbness, tingling, burning pain, sensitivity to touch and heat in the hands and feet | Treatment duration may be more neurotoxic than dose | |||
Motor | ||||
Distal weakness, tremor | ||||
Muscle cramps | ||||
Reduction or loss of deep tendon reflexes | ||||
Loss of proprioception | ||||
Gait ataxia | ||||
Bortezomib | 2008a | ≥ 1 mg/m2 | Sensory: Distal symmetrical, length-dependent axonal sensorimotor neuropathy, mild to moderate sensory loss, mild to severe neuropathic pain in a glove-and-stocking distribution. Burning sensations, tingling, hyperaesthesia, hypoaesthesia and weakness in the distal extremities, which may advance proximally | Acute can progress to chronic, although a majority of participants improve or completely resolve BIPN |
Motor: Mild to moderate motor weakness in the distal lower extremities | ||||
Rare autonomic: Orthostatic hypotension |
Literature Search Methodology
Toxicity Versus Benefit
Oxaliplatin-Induced Peripheral Neuropathy
Pathogenesis of Platinum-Induced Peripheral Neuropathy
Taxane-Induced Peripheral Neuropathy
Pathogenesis of TIPN
Vinca Alkaloids
Pathogenesis of VIPN
Thalidomide-Induced Peripheral Neuropathy
Pathogenesis of ThiPN
Bortezomib
Pathogenesis of BIPN
Diagnostic Methods
Identification of CIPN and Grading
CTCAE term | Grade 1 | Grade 2 | Grade 3 | Grade 4 | Grade 5 |
---|---|---|---|---|---|
Peripheral motor neuropathy | Asymptomatic; clinical or diagnostic observations only | Moderate symptoms; limiting instrumental ADL | Severe symptoms; limiting self-care ADL | Life-threatening consequences; urgent intervention indicated | Death |
Peripheral sensory neuropathy | Asymptomatic | Moderate symptoms; limiting instrumental ADL | Severe symptoms; limiting self-care ADL | Life-threatening consequences; urgent intervention indicated | – |
Nerve Conduction Studies (NCS)
Quantitative Sensory Testing (QST)
Skin Biopsy
Corneal Confocal Microscopy
Chemotherapy and Neuropathic Pain
Preventative Treatment
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 |
Nutraceuticals
Calcium and Magnesium Infusion
Symptomatic Treatments
Treatment | Author and study design | Number of patients | Antineoplastic agent | Study outcome | Guideline |
---|---|---|---|---|---|
Duloxetine | Yang et al. 2012 [291]: Open-label pilot study | 30 | Oxaliplatin | OIPN improved in 47.4% of participants by one grade, with 62.6% maintaining on a steady grade | ASCO, ONS, NCI |
Smith et al. 2013 [290]: Randomised, placebo-controlled, double-blind, phase III crossover trial | 141 | Paclitaxel, oxaliplatin | Duloxetine statistically significantly reduced average pain score after 5 weeks compared to placebo (1.06 [95% CI, 0.72–1.40] vs 0.34 [95% CI, 0.01–0.66]; p = 0.003) | ||
Hirayama et al. 2015 [292]: Randomised, vitamin B12-controlled, open-label crossover pilot trial | 32 | Oxaliplatin, paclitaxel, vincristine and bortezomib | Duloxetine changed pain scores pain (p = 0.04) and numbness (p = 0.03) compared to placebo | ||
Otake et al. 2015 [376]: Retrospective cohort study | 25 | Paclitaxel, carboplatin, epirubicin | Duloxetine improved CIPN symptoms in 56% of participants | ||
Farshchian et al. 2018 [294]: Randomised, placebo-controlled, double-blind trial | 156 | Taxane and platinum | Both duloxetine and venlafaxine reduced neuropathic pain and CIPN grade at week 4 compared to controls (p < 0.05). Duloxetine was more effective compared to venlafaxine (p < 0.05) | ||
Anti-depressants | Kus et al. 2016 [296]: Retrospective case–control study | 199 | Taxanes, platinums | An improvement of 75% in pain score was reported in 53.5%, 58.3% and 45.2% in the first three visits compared to 0% in the control group (p < 0.001) | ESMO, NCCN |
Özdoǧan et al. 2004 [377]: Pilot study | 12 | Platinums, vinca alkaloids, 5-FU, etoposide | Reduced pain scores were statistically significant compared to baseline (p ≤ 0.001). Increase in drowsiness reported (p = 0.041) | ||
Durand et al. 2005 [378]: Case study | 2 | Oxaliplatin | Anecdotal functional improvements reported | ||
Durand et al. 2012 [295]: Randomised, double-blind, placebo-controlled phase III trial | 42 | Oxaliplatin | Pain relief reported at a higher frequency in participants treated with venlafaxine compared to controls (31.3% vs 5.3%; p = 0.03) | ||
Hammack et al. 2002 [284]: Randomised, double-blind, placebo-controlled, crossover trial | 51 | Cisplatin | No significant impact on CiSPN pain or paraesthesia severity from baseline | ||
Kautio et al. 2008 [285]: Randomised, double-blind, placebo-controlled trial | 33 | Vinca alkaloids, platinums and taxanes | No significant impact on CIPN pain | ||
Gabapentinoids | Mishra et al. 2012 [279]: Prospective, randomised, double-blind, placebo-controlled trial | 120 | - | Number of participants requiring morphine was significantly lower in the amitriptyline, gabapentin and pregabalin treatment groups compared to placebo (56.7%, 33.3% and 16.7% vs 100%). Pregabalin appeared to outperform gabapentin in reducing lancinating pain (p = 0.026) and dysaesthesia (p = 0.021) | ESMO, ASCO, NCCN |
Rao et al. 2007 [282]: Randomised, double-blind, placebo-controlled, crossover, phase III trial | 84 | Paclitaxel, docetaxel, carboplatin, cisplatin, oxaliplatin, vincristine or vinblastine | No benefit identified in reducing pain scores in participants with CIPN | ||
Tsavaris et al. 2008 [280]: Pilot study | 110 | Docetaxel, paclitaxel, vinorelbine, oxaliplatin, | Approximately half of participants had no response to gabapentin therapy, whilst the other half had a decrease in chemotherapy dose self-reported to be managed by gabapentin pharmacotherapy | ||
Magnowska et al. 2018 [281]: Prospective study | 61 | Paclitaxel, carboplatin | Participants receiving gabapentin report improved symptoms (p = 0.027), pain (p = 0.027 and neurological deficit (p = 0.019) | ||
Saif et al. 2010 [379]: Prospective study | 23 | Pregabalin pharmacotherapy improved OIPN severity by 1–2 grades in 48% of participants | |||
Opioids | Cartoni et al. 2012 [277]: Pilot study | 46 | Bortezomib | Reduction in the intensity and frequency of pain reported in 47.8% of participants after 2 weeks compared to baseline (mean numeric rating scale = 3.65; p < 0.01) | ESMO, NCCN |
Kim et al. 2018 (276): Multicentre, interventional, single-arm phase IV study | 66 | Taxanes, epothilones platinums, bortezomib, thalidomide, vinca alkaloid | A 21.4% reduction in pain score in participants at week 4 (1.29 ± 1.84; p < 0.0001 |