Previous animal and in vitro studies have indicated that free radicals such as reactive oxygen species (ROS) can cause cellular damage and lead to cancer by altering cellular regulatory pathways.^1,2) Vitamin C has been considered an antioxidant that can prevent ROS-induced cellular damage.^3,4) However, the efficacy of vitamin C supplements for prevention of cancer has been controversial for decades.

In 1976, a possible therapeutic effect of high-dose vitamin C supplementation in 100 patients with advanced cancer was reported in a non-randomized clinical trial by Cameron and Pauling,^5,6) compared to a control group of 1,000 untreated and matched patients. However, two subsequent randomized placebo-controlled trials (RCTs) by Creagan et al.⁷⁾ and Moertel et al.⁸⁾ in 1979 and 1985 reported no beneficial effect of high-dose vitamin C therapy in patients with advanced cancer.

Since then, several RCTs have shown inconsistent findings regarding the effects of vitamin C supplementation on the risk of cancer. In 2006, a systematic review of four RCTs indicated that vitamin C supplements did not increase survival in cancer patients.⁹⁾ Similarly, a meta-analysis of several RCTs published in 2008 reported that vitamin C supplementation given singly or in combination with other antioxidant supplements had no effect on the prevention of gastrointestinal cancers.¹⁰⁾ Additionally, a meta-analysis by Jiang et al.¹¹⁾ indicated that vitamin C supplementation had no significant effect on prevention of prostate cancer. Although additional large RCTs have been published, no comprehensive meta-analysis on this issue has been reported so far.

The aim of this study was to perform a meta-analysis of RCTs in order to assess the efficacy of vitamin C supplements for cancer prevention. Subgroup meta-analyses were also performed by vitamin C supplement dose, follow-up period, methodological quality, outcome, funding source, gender, smoking status, country, and type of cancer.

In this meta-analysis of seven RCTs, we found no significant association between vitamin C supplementation and cancer risk. In addition, no efficacy of vitamin C supplements was found for the prevention of cancer in subgroup analyses according to vitamin C dose administered singly or in combination with other supplements, follow-up period, methodological quality, cancer mortality, gender, smoking status, country, and type of cancer.

Vitamin C is an electron donor that non-enzymatically stabilizes ROS by reducing them; in this process, vitamin C is oxidized to an ascorbyl radical. Unlike other dangerous free radicals, the ascorbyl radical is short-lived, with a half-life of 10^-5 seconds, and is relatively unreactive.²⁰⁾ Shortly after donating an electron, the ascorbyl radical donates another electron and is further oxidized to dehydroascorbic acid. These two oxidized forms of vitamin C can be reduced back to the original state by at least three different enzyme pathways and reducing biological compounds.²¹⁾ However, not all oxidized ascorbic acid is recovered. Some dehydroascorbic acid is metabolized by hydrolysis and is lost to other biological compounds.²²⁾ Therefore, the stability, reducibility, and reusability of oxidized ascorbic acid explain why vitamin C is a preferred antioxidant.

The findings of our analysis were consistent with those of previous meta-analyses of RCTs, which concluded no association between vitamin C and prostate, colorectal, and gastrointestinal cancers.^9,10,23) Our findings, however, were inconsistent with those of previously published preclinical in vivo or in vitro studies on this issue.^24,25,26) In 2005, an in vitro experiment conducted by Abdel-Latif et al.²⁷⁾ suggested the efficacy of vitamin C supplements in facilitating apoptosis of esophageal cancer cells when used in conjunction with chemotherapy. Also, in 2010, Pollard et al.²⁴⁾ showed that pharmacological doses of ascorbic acid could greatly reduce both tumor growth and cancer metastases in the prostate and lungs of rats.

This discrepancy in findings between preclinical in vivo or in vitro studies and RCTs might be due to the fact that preclinical studies may not represent biological responses in the human body.²⁸⁾ Anti-carcinogenic antioxidants in animals could be carcinogenic to humans. For instance, experimental studies indicated that beta-carotene reduces the risk of cancer incidence,²⁹⁾ but may act as a pro-oxidant under chronic oxidative stress such as tobacco exposure in humans and lead to lung cancer.^30,31)

In 2009, Bandera et al.³²⁾ reported a meta-analysis of 12 case-control studies, indicating a strong inverse association between antioxidant vitamins and the risk of endometrial cancer. Another meta-analysis of 13 cohort studies conducted by Park et al.³³⁾ showed a slight inverse association between vitamin C supplementation and the risk of colon cancer.

A similar discrepancy in findings between observational epidemiologic studies and RCTs might be explained by recall and selection biases common in retrospective studies such as case-control studies. As for recall bias, recollection of diet may differ between cancer patients and healthy controls; cancer patients are prone to report an unhealthy diet, while healthy controls report otherwise.^34,35)

In evaluating the association between use of antioxidant supplements and risk of cancer, cohort studies are less biased than case-control studies, but causation cannot be sufficiently supported.^36,37) The diet assessment tools used in cohort studies might not precisely evaluate participants' long-term vitamin C consumption. In addition, use of vitamin C supplements in trials differs from the intake of fruit and vegetables rich in vitamin C in cohort studies, which contain other vitamins and micronutrients in addition to vitamin C. That is, vitamin C might have beneficial effects when administered in combination with other nutrients.

It is noteworthy that our findings are similar to those of the previously published meta-analysis of RCTs on the association between antioxidant supplementation and cancer and mortality. In 2007, Bjelakovic et al.³⁸⁾ reported the results of meta-analysis of 47 high-quality trials involving 180,938 participants. Their findings showed that vitamin A, vitamin E, or beta-carotene supplementation increased mortality while vitamin C and selenium were not significantly associated with mortality.³⁸⁾ The authors proposed that removing free radicals through antioxidant supplementation might impede some major defensive mechanisms such as apoptosis, phagocytosis, and detoxification, thus increasing mortality. Similarly, in 2010, Myung et al.³⁹⁾ reported that antioxidant supplements showed no significant effect on primary and secondary cancer prevention. Furthermore, in subgroup meta-analysis of four RCTs by type of cancer revealed increased risk of bladder cancer.³⁹⁾

Regarding the efficacy of high-dose vitamin C therapy, the different findings between Cameron and Pauling^5,6) and Creagan et al.⁷⁾ and Moertel et al.⁸⁾ have marked an ongoing controversy. There are two important differences between the two trials. First, Cameron and Pauling^5,6) used both intravenous and oral administrations of vitamin C, while Creagan et al.⁷⁾ and Moertel et al.⁸⁾ only used oral administration. In general, the concentration of ascorbic acid was much higher when administered intravenously than orally. Furthermore, higher concentrations of vitamin C have been found to accumulate in tumors compared to normal tissues.^40,41,42) Likewise, laboratory data suggested the toxicity of high-dose vitamin C in cancer cell lines.^43,44,45) Chen et al.⁴⁶⁾ suggested that elevated concentrations of ascorbic acid might increase formation of hydrogen peroxide (H₂O₂), which may be toxic to tumor cells. This suggests a possible explanation for why Cameron and Pauling^5,6) found high-dose vitamin C supplementation to be therapeutic, while Moertel et al.⁸⁾ did not. The other difference is that the studies by Cameron and Pauling^5,6) were not RCTs, while those by Creagan and Moertel were RCTs. Cameron and Pauling^5,6) used matched controls without randomization. Additional large randomized, double-blind, placebo-controlled trials are necessary to investigate the effects of oral or intravenous administration of high-dose vitamin C therapy on cancer risk.

Our study has several limitations. First, we were unable to investigate the beneficial effects of vitamin C supplements on cancer in patients with vitamin C deficiency because few RCTs included these populations. Further trials are needed to explore this association. Second, our findings should not be directly translated to the effects of fruit and vegetables rich in vitamin C. Last, the participants included in our meta-analysis were mostly 50-60 years of age. Thus, our findings cannot be generalized to younger populations. Further RCTs in younger participants are therefore necessary.

In summary, our meta-analyses of RCTs showed no efficacy of vitamin C supplementation for prevention of cancer. Further large-scale, randomized controlled trials are necessary to confirm our findings.