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

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.