Sequential versus upfront oxaliplatin-based therapy in metastatic colorectal cancer: long-term outcomes of a randomized phase 3 trial.

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. Colorectal cancer is common, particularly in older adults. The standard treatment, chemotherapy, often combines several drugs, which can cause serious side effects, such as nerve damage, which can reduce quality of life. We conducted a clinical trial to compare two treatment strategies. In one group, people were given drugs that were less likely to cause severe side effects, fluoropyrimidine plus bevacizumab. A drug more likely to cause severe side effects, oxaliplatin, was only added if cancer progressed. The other group started with all three drugs simultaneously. The long-term survival of people in the two groups was similar but those who were given the oxaliplatin later experienced fewer side effects and had a better quality of life. Thus using a sequential treatment strategy might improve the quality of life for people with cancer. Okawaki et al. report updated overall survival and quality-of-life results from a randomized phase III trial comparing sequential versus upfront oxaliplatin-based therapy in metastatic colorectal cancer. They show comparable overall survival, with lower early treatment burden and less neuropathy with the sequential strategy.