High-dose vitamin C for colorectal cancer patients with RAS/BRAF mutations

Results of a phase III study analysing the effect of adding high-dose vitamin C to FOLFOX in previously untreated patients with metastatic colorectal cancer (mCRC) failed to show a survival benefit. Furthermore, the addition of vitamin C slightly increased the adverse event rate, with a marked increase in the incidence of vomiting and nausea. Interestingly, the trial did reveal a PFS improvement in the subgroup of patients with RAS mutations, a finding that is currently under further investigation.

Previous studies have suggested a potential anticancer effect of intravenously high dose vitamin C. In fact, preclinical data show that high dose vitamin C selectively kills human colorectal cancer cells harbouring KRAS or BRAF mutations. To date, however, high-quality placebo-controlled trials are missing to support the use of ascorbate (vitamin C) during cancer treatment. In a subsequent phase I study adding high-dose ascorbic acid to mFOLFOX or FOLFIRI in patients with metastatic colorectal cancer (mCRC) or gastric cancer revealed an objective response rate of 58% with a disease control rate of 96%. During the 2022 World congress on gastrointestinal cancer, results were presented of a phase III trial evaluating the addition of high-dose vitamin C to FOLFOX +/- bevacizumab in the first-line treatment of patients with mCRC,

Study design

The presented randomised, open-label, phase III study enrolled 442 patients with unresectable mCRC who did not receive prior treatment for metastatic disease. Patients with mCRC were randomized 1:1 to the control (chemotherapy only, n=221) or the experimental cohort (chemotherapy plus high-dose vitamin C, n=221). Patients in the control group were treated with FOLFOX with or without bevacizumab every two weeks, while patients in the experimental group also received vitamin C intravenously (1.5g/kg/day, d1-3). The primary endpoint was progression-free survival (PFS), with secondary objectives including overall survival (OS), ORR, assessment of treatment-related adverse events (TRAEs), and PFS and OS in RAS or BRAF mutant patients.

Results

After a median follow-up of 24.5 months, chemotherapy + high dose vitamin C was not superior to chemotherapy-only in terms of PFS (8.6 vs. 8.3 months; p=0.1). In addition, also the median OS did not differ between both arms (20.7 vs. 19.7 months; p=0.7). An overall response was observed in 44.3% of the patients in the experimental group as compared to 42.1% in the control group. Disease control rates (DCR) were 84.2 vs. 81.4%.  In a prespecified subgroup analysis, patients with RAS mutation were found to have a better PFS in the experimental group than in the control group  (9.2 vs. 7.8 months; p = 0.01). A further multivariable analysis showed that high-dose vitamin C added to chemotherapy was an independent factor that could prolong the PFS of patients with RAS mutation (HR[95%CI]: 0.64[0.47-0.87; p=0.004]). All grade treatment related adverse events were reported in 86.9% of patients in the experimental group as compared to 81.9% in the control group. TRAEs of grade 3 or higher were found in 33.5% and 30.3% in the experimental and control arm, respectively. A marked difference between both arms was seen in the incidence of nausea and vomiting with rates of 24.4 vs. 14.9% and 21.3 vs. 10.4% in the experimental and control arm, respectively.

Conclusions

Adding high-dose vitamin C to FOLFOX with or without bevacizumab failed to induce a superior OS or PF in the first line treatment of patients with mCRC. Furthermore, the addition of vitamin C did lower the toxicity, but in fact increased the incidence of vomiting and nausea. Interestingly, the study did show a PFS benefit in patients harbouring a RAS mutation. Currently, a phase 2 trial is ongoing to further investigate the potential benefit of vitamin C in patients with RAS/BRAF mutant resectable or metastatic solid tumours.

Reference

Wang F, He M-M, Xiao J, et al. A randomized, open-label, multicenter, phase 3 study of high-dose vitamin C plus FOLFOX +/- bevacizumab versus FOLFOX +/- bevacizumab in unresectable untreated metastatic colorectal cancer. Presented at ESMO WGCI 2022; Abstract SO17.