Evaluating longitudinal toxicity and adverse event in cetuximab-treated metastatic colorectal cancer: a pooled analysis from 1,302 patients in ARCAD database.

Abstract

Traditional adverse event (AE) reporting in oncology trials focuses on the single worst CTCAE grade, which may underrepresent chronic or recurrent toxicity burden. We applied a longitudinal toxicity framework to compare toxicity profiles of chemotherapy with or without cetuximab in metastatic colorectal cancer. We pooled two randomized first-line trials in the ARCAD database. AEs examined were diarrhea, rash, hand-foot syndrome (HFS), fatigue, anorexia, and mucositis. Outcomes included grade ≥3 AE, time to first occurrence of maximum grade, early onset (≤6 weeks), and AEL, a normalized measure of cumulative toxicity burden over treatment. Analyses were adjusted for chemotherapy backbone, ECOG performance status, sex, primary tumor location, dose reduction, and treatment duration. Compared with Chemotherapy alone (n = 564), Chemotherapy plus cetuximab (n = 738) was associated with higher grade ≥3 rash (21% vs 0.5%; adjusted odds ratio [OR] 49.89, 95% CI 15.8-157.4), higher rash AEL (0.257 vs 0.069; adjusted mean difference 0.22, 95% CI 0.21-0.23), and more frequent early-onset maximum rash (67% vs 34%; adjusted OR 4.28, 95% CI 2.72-6.74). Rash AEL remained higher with cetuximab within maximum-grade strata. HFS showed higher grade ≥3 risk and overall AEL with cetuximab, but no within-grade AEL difference, indicating higher overall HFS burden reflected grade distribution rather than within-grade chronicity. No consistent differences were observed for other AEs. Incorporating onset timing and AEL distinguished persistent toxicity burden from isolated peak events. This framework may support comparative tolerability assessment when chronic toxicity burden is central to decision-making.