Background and Purpose Chemotherapy-induced peripheral neuropathy (CIPN) is a major side-eaect of many commonly used cancer drugs, aaecting up to 90% of patients treated with oxaliplatin. This systematic review and meta-analysis aimed to analyse randomised controlled trials (RCTs) to determine if any pharmacological agents can prevent or reduce oxaliplatin-induced peripheral neuropathy (OIPN) in colorectal cancer (CRC) patients.

Materials and Methods We searched PubMed, EMBASE and Web of Science for RCTs published before March 2025 that included patients with CRC who received oxaliplatin-based chemotherapy and had peripheral neuropathy quantified using Common Toxicity Criteria for Adverse Events (CTCAE). Meta-analysis was performed for agents tested in three or more RCTs with a minimum combined sample size of 100 patients.

Results 20 studies were included with a median sample size of 61 (range 14-2450). Meta-analysis was used for two treatments. Anti-oxidative stress treatments were not associated with reduced incidence of grade ≥2 OIPN when assessed mid-treatment but were associated with a significant reduction of grade ≥2 OIPN at the end of treatment (OR:0.04, 95%CI:0.01-0.12; p<0.00001). No reduction of grade ≥2 OIPN was observed for Ca2+/Mg2+ infusions. 35% of studies had potential high risk of bias and 45% of studies showed low risk of bias.

Conclusions Whilst the existing published RCTs included small numbers of patients, the meta-analysis indicates that anti-oxidative stress therapies reduce the end of treatment severe OIPN incidence in CRC patients. A large, randomised, placebo-controlled trial assessing OIPN using CTCAE grades and patient-reported outcomes is warranted to confirm these findings.

The authors have declared no competing interest.

Cancer Research UK

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present work are contained in the manuscript