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.