Baseline creatinine clearance as an indicator of severe adverse events associated with oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer: Safety analysis of the phase III Japanese ACHIEVE trial.

Abstract

667 Background: The phase III ACHIEVE trial (JFMC47), a project of the International Duration Evaluation of Adjuvant Chemotherapy (IDEA), was established to prospectively analyze data from several randomized trials to test whether 3-month (arm 3) oxaliplatin-based adjuvant (FOLFOX4, mFOLFOX6, or XELOX) treatment is non-inferior to 6-month (arm 6) treatment in terms of disease-free survival in patients (pts) with stage III colon cancer. It aims to reveal the association between baseline characteristics and ≥ grade 3 adverse events (AEs) related to XELOX and mFOLFOX6, particularly focusing on the role of baseline creatinine clearance (CCr) on ≥ grade 3 AEs. Methods: This association was assessed using the Cox proportional hazards model. Results: During 2012–2014, 1,313 pts were randomized from 244 centers; 1,301 were included in the intention-to-treat population. Among the safety population (N = 1,277; 642, arm 3; 635, arm 6), the overall incidence of ≥ grade 3 AEs was 29% in arm 3 and 43% in arm 6 (p < 0.0001). Neuropathy of ≥ grade 2 was more frequent in arm 6 than in arm 3 (37% vs. 14%; p < 0.0001). Regarding the fluoropyrimidine backbone, grade 3–4 neutropenia was more with mFOLFOX6 than XELOX (30% vs. 12%), whereas grade 3–4 anorexia (2% vs. 5%) and grade 3–4 diarrhea (1% vs. 6%) were more with XELOX. Multivariate analysis, including treatment duration, regimen, CCr ( < 50 vs. > 50 mL/min), age, and sex, showed that CCr had a statistically significant impact on the occurrence of ≥ grade 3 AEs (hazard ratio = 0.44, p < 0.0001). Pts with CCr < 50 may have had more frequent ≥ grade 3 AEs independent of other factors, such as age. Conclusions: Grade 3 or higher AEs related to XELOX or mFOLFOX6 may be associated with the degree of CCr. Clinical trial information: UMIN 000008543.