Background and purposeChemotherapy-induced peripheral neuropathy (CIPN) is a major side-effect of many commonly used cancer drugs, affecting up to 90% of patients treated with oxaliplatin. This systematic review and meta-analysis analysed randomised controlled trials (RCTs) to determine if any pharmacological agents or traditional medicines can prevent oxaliplatin-induced peripheral neuropathy (OIPN) in colorectal cancer (CRC) patients.Materials and methodsWe 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.Results20 studies were included in the systematic review with a median sample size of 61 (range 14-2450). Meta-analysis was conducted for two treatments: first, agents with anti-oxidative stress properties and second, Ca2+/Mg2+ infusions. Anti-oxidative stress treatments 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.ConclusionsWhilst the existing published RCTs included small numbers of patients, the meta-analysis indicates that anti-oxidative stress therapies can prevent severe OIPN developing at the end of treatment in CRC patients. A large, randomised, placebo-controlled trial assessing OIPN using CTCAE grades and patient-reported outcomes is warranted to confirm these findings.

Supplementary Figure S14. Alpha and beta diversity measures of stool samples collected at screening were compared with samples collected at the end of treatment (EOT). Violin plots represent the lack of significant differences in Shannon’s diversity and Chao1’s richness (A-B), while the principal coordinate analysis charts are used to plot Bray-Curtis’s diversity and Jaccard’s richness (C-D) The volcano plot in Panel E represents the different gut microbiota composition at a genus level across timepoints. Abbreviation: NS, non significant; EOT, end of treatment.

Supplementary Figure S10. Bar graphs showing the absence of association between entropy and response prior to the start of pembrolizumab (A) and at the end of treatment (B). Abbreviations: ICI, immune checkpoint inhibitor; ns, not significant; EOT, end of treatment.

Supplementary Methods 1: Analysis of health-related quality of life.

Supplementary Figure S3. Manual gating scheme used for analysis of peripheral immune landscape. Live singlet CD45+ were gated on CD3+CD19- and CD3-CD19+ cells. T cells were further gated on CD4 T cells, CD8 T cells, MAIT cells, gd T cells and NKT cells.

Supplementary Table 3. Mass cytometry panels.

Supplementary Figure S2. Custom-developed bioinformatic variant calling pipeline to identify somatic SNVs and indels

Supplementary Figure S6. Changes from baseline in global health status (GHS)/quality of life (QoL) and functioning domains on EORTC QLQ-C30 questionnaire.

Supplementary Figure S8. The Variant Allele Frequency (VAF) of specific mutations changes during the course of the treatment. For instance, the VAF of ARID1a increases at treatment failure in patients 025 and 022 (both responders, Panel A). Furthermore, within the same patient, the VAF of different mutations changes coherently with the course of the treatment, as showed for patient 022 (B) and 002 (C), where the VAF increases at treatment discontinuation. Abbreviation: EOT, end of treatment.

Supplementary Methods 5. Complete list of the targeted genes profiled using the NanoString PanCancer Immune panel.

Supplementary Table 1. Inclusion and exclusion criteria.

Supplementary Figure S7. Radar chart of symptom scales according to EORTC QLQ-C30 (Top Panel) and EORTC QLQ-HCC18 (Bottom Panel) symptom scales. Values are reported as means and scale score range is 0-100. Higher scores indicate more symptoms.

Supplementary Figure S12. A. Volcano plot of differentially regulated genes identified by Nanostring analysis. The Benjamini–Hochberg P-values are correlated to fold-changes in transcripts identified in samples from responders (n = 4) versus non-responders (n = 6). Transcripts achieving the highest statistical significance (p value <0.05) are highlighted by the presence of the corresponding gene name and are highlighted in the Heat Map shown in Panel B.

Supplementary Methods 3: Circulating Free DNA

Supplementary Table 5. Full list of serum metabolites analysed.

Supplementary Figure S9. The productive Simpson clonality did not show any significant TACE-induced change when considering all samples analysed (A), and even after a further breakdown in responders (B) and non-responders (C). We did not observe any change in productive Simpson clonality when comparing samples collected before the start of pembrolizumab and at the end of treatment in the whole cohort (D), in responders (E) and non-responders (F). Abbreviations: TACE, trans-arterial chemoembolisation; ns, not significant; ICI, immune checkpoint inhibitor.

Purpose: Transarterial chemoembolization (TACE) may prime adaptive immunity and enhance immunotherapy efficacy. PETAL evaluated safety, preliminary activity of TACE plus pembrolizumab and explored mechanisms of efficacy.Patients and Methods: Patients with liver-confined hepatocellular carcinoma (HCC) were planned to receive up to two rounds of TACE followed by pembrolizumab 200 mg every 21 days commencing 30 days post-TACE until disease progression or unacceptable toxicity for up to 1 year. Primary endpoint was safety, with assessment window of 21 days from pembrolizumab initiation. Secondary endpoints included progression-free survival (PFS) and evaluation of tumor and host determinants of response.Results: Fifteen patients were included in the safety and efficacy population: 73% had nonviral cirrhosis; median age was 72 years. Child-Pugh class was A in 14 patients. Median tumor size was 4 cm. Ten patients (67%) received pembrolizumab after one TACE; 5 patients after two (33%). Pembrolizumab yielded no synergistic toxicity nor dose-limiting toxicities post-TACE. Treatment-related adverse events occurred in 93% of patients, most commonly skin rash (40%), fatigue, and diarrhea (27%). After a median follow-up of 38.5 months, objective response rate 12 weeks post-TACE was 53%. PFS rate at 12 weeks was 93% and median PFS was 8.95 months [95% confidence interval (CI): 7.30-NE (not estimable)]. Median duration of response was 7.3 months (95% CI: 6.3-8.3). Median overall survival was 33.5 months (95% CI: 11.6-NE). Dynamic changes in peripheral T-cell subsets, circulating tumor DNA, serum metabolites, and in stool bacterial profiles highlight potential mechanisms of action of multimodal therapy.Conclusions: TACE plus pembrolizumab was tolerable with no evidence of synergistic toxicity, encouraging further clinical development of immunotherapy alongside TACE.

Supplementary Methods 2: Overview of Biomarker analysis.

Supplementary Table 4. List of antibodies used for mass cytometry

Supplementary Methods 6. Functional categories and related numbers of genes profiled using the NanoString PanCancer Immune panel.