Review of high‐dose intravenous vitamin C as an anticancer agent

In the 1970s, Pauling and Cameron reported increased survival of patients with advanced cancer treated with high‐dose intravenous (IV) vitamin C (L‐ascorbate, ascorbic acid). These studies were criticized for their retrospective nature and lack of standardization of key prognostic factors including performance status. Subsequently, several well‐designed randomized controlled trials failed to demonstrate a significant survival benefit, although these trials used high‐dose oral vitamin C. Marked differences are now recognized in the pharmacokinetics of vitamin C with oral and IV administration, opening the issue of therapeutic efficacy to question. In vitro evidence suggests that vitamin C functions at low concentrations as an antioxidant but may have pro‐oxidant activity at high concentrations. The mechanism of its pro‐oxidant action is not fully understood, and both intra‐ and extracellular mechanisms that generate hydrogen peroxide have been proposed. It remains to be proven whether vitamin C‐induced reactive oxygen species occur in vivo and, if so, whether this will translate to a clinical benefit. Current clinical evidence for a therapeutic effect of high‐dose IV vitamin C is ambiguous, being based on case series. The interpretation and validation of these studies is hindered by limited correlation of plasma vitamin C concentrations with response. The methodology exists to determine if there is a role for high‐dose IV vitamin C in the treatment of cancer, but the limited understanding of its pharmacodynamic properties makes this challenging. Currently, the use of high‐dose IV vitamin C cannot be recommended outside of a clinical trial.