Sequential versus upfront oxaliplatin-based therapy in metastatic colorectal cancer: long-term outcomes of a...

Whether oxaliplatin should be given sequentially or upfront in metastatic colorectal cancer remains clinically relevant, especially for older patients often underrepresented in trials.

We report updated overall survival and prespecified quality-of-life outcomes from the open-label, randomized, multicenter phase 3 C-cubed trial in Japan. This trial was registered in the University Hospital Medical Information Network Clinical Trials Registry UMIN000015405 (October 14, 2014) and UMIN000036690 (May 10, 2019). The primary endpoint was reported previously. Of 311 randomized patients with previously untreated metastatic colorectal cancer, 300 were included in the full analysis set. Patients received fluoropyrimidine plus bevacizumab, with oxaliplatin added at progression, or received fluoropyrimidine, oxaliplatin, and bevacizumab from the start. Overall survival was analyzed using Cox regression and time-restricted survival methods. Quality of life was assessed prospectively using patient-reported questionnaires.

Here we show that overall survival is similar between strategies. Median overall survival is 27.2 months with sequential treatment and 27.4 months with upfront treatment (hazard ratio, 1.00; 95% confidence interval, 0.76-1.33; p = 0.98). Additional time-restricted and milestone analyses show no between-group differences. There is no evidence that age modifies the relative treatment effect. Patient-reported outcomes indicate a lower early treatment burden with sequential treatment, including smaller early declines in physical functioning and less sensory neuropathy.

Updated overall survival is comparable between sequential and upfront oxaliplatin-based strategies, while sequential treatment is associated with lower early treatment burden. These findings support individualized selection of first-line treatment based on age, vulnerability, and treatment goals.