Sex differences in efficacy and toxicity of first-line treatment of metastatic colorectal cancer: An analysis of 18,041 patients in the ARCAD CRC database.

Clinical Snapshot

Key Findings

• P Value: All p-values >0.05 for OS comparisons (0.69, 0.36, 0.67)

• Effect Size: Adjusted OS HR for females vs males: CT alone 1.01, CT+bevacizumab 0.96, CT+EGFR inhibitor 0.97

• Primary Outcome: No significant sex differences in overall survival across all treatment groups

• Nnt Or Sensitivity: Clinically significant toxicity differences: females had 11.3% higher grade 1-4 nausea, 12.2% higher vomiting, 8% higher neutropenia

• Confidence Interval: 95% CI ranges: 0.95-1.08, 0.89-1.04, 0.87-1.10 respectively

Clinical Application

Highly applicable as treatments (5-FU/oxaliplatin/irinotecan, bevacizumab, cetuximab/panitumumab) are standard PBS-funded options Findings support current RACGP and Cancer Council guidelines while highlighting need for enhanced supportive care protocols for female patients receiving chemotherapy Australian patients with metastatic colorectal cancer receiving first-line systemic therapy

Abstract

BACKGROUND: Greater toxicity of adjuvant chemotherapy in females has been reported previously, but the impact of patients' sex on chemotherapy (CT)+/-targeted therapies for non-resectable, metastatic colorectal cancer (mCRC) has remained unclear. We compared efficacy and toxicity of first-line chemotherapy, with or without targeted therapies, between male and female mCRC patients. METHODS: Twenty-seven randomized trials from the ARCAD CRC database were included. Primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate, toxicity (according to NCI-CTCAE). Analyses were performed within three treatment groups: A) CT alone, B) CT+bevacizumab, and C) CT+epidermal growth factor receptor inhibitor. OS and PFS were estimated using Kaplan-Meier method. Associations with sex were assessed using study-stratified Cox models adjusted for age, performance status, body mass index, and CT backbone. RESULTS: Baseline data from 18,041 patients were analysed; among 15,271 included in outcome analyses, no sex differences in OS or PFS were observed. Adjusted OS hazard ratios (95% confidence interval) for females versus (vs.) males were: A: 1.01 (0.95-1.08, P = .69), B: 0.96 (0.89-1.04, P = .36), C: 0.97 (0.87-1.10, P = .67). Females experienced higher toxicity, including grade 1-4 and 3-4 nausea (71.8% vs. 60.5% and 7.5% vs. 4.8%), vomiting (47.7% vs. 35.5% and 6.6% vs. 4.4%), and neutropenia (52.4% vs. 44.4% and 29.2% vs. 18.8%) (P < .001). Conversely, rash (grade 1-4 and 3-4) was more frequent in males (29.6% vs. 24.3% and 5.1% vs. 3.7%, P < .001). CONCLUSIONS: Despite higher chemotherapy-related toxicity in females, treatment efficacy was similar between sexes. Rash was more common in males, highlighting that patients' sex modulates toxicity profiles in both directions. Strategies to reduce adverse events in female patients are warranted.

References

1. 1.Wagner, A. D., Raeisi, M., Rakez, M., Diasio, R. D., Margalit, O., Zalcberg, J. R., Venook, A. P., Douillard, J.-Y., Lenz, H. J., Heinemann, V., Goldberg, R. M., van Cutsem, E., Schmoll, H.-J., Shi, Q., André, T., & de Gramont, A. (2026). Sex differences in efficacy and toxicity of first-line treatment of metastatic colorectal cancer: An analysis of 18,041 patients in the ARCAD CRC database. European Journal of Cancer, 116694. https://doi.org/10.1016/j.ejca.2026.116694