Purpose: To compare the efficacy and safety of high-dose vitamin C plus FOLFOX +/- bevacizumab versus FOLFOX +/- bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC). Patients and Methods: Between 2017 and 2019, histologically confirmed mCRC patients (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for metastatic disease were randomized (1:1) into a control (FOLFOX +/- bevacizumab) and an experimental (high-dose vitamin C [1.5 g/kg/d, intravenously for 3 hours from D1 to D3] plus FOLFOX +/- bevacizumab) group. Randomization was based on the primary tumor location and bevacizumab prescription. Results: The progression-free survival (PFS) of the experimental group was not superior to the control group (median PFS, 8.6 vs 8.3 months; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.70-1.05; P = 0.1). The objective response rate (ORR) and overall survival (OS) of the experimental and control group were similar (ORR, 44.3% vs 42.1%; P = 0.9; median OS, 20.7 vs 19.7 months; P = 0.7). Grade 3 or higher treatment-related adverse events occurred in 33.5% and 30.3% of patients in the experimental and control group, respectively. In prespecified subgroup analyses, patients with RAS mutation had significantly longer PFS (median PFS, 9.2 vs 7.8 months; HR, 0.67; 95% CI, 0.50-0.91; P = 0.01) with vitamin C added to chemotherapy than with chemotherapy only. Conclusions: High-dose vitamin C plus chemotherapy failed to show superior PFS compared with chemotherapy in mCRC patients as first-line treatment but may be beneficial in mCRC patients harboring RAS mutation.

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