The ability of physicians and patients to make confident assessments of the risk–benefit ratio of concomitant use of dietary antioxidants with conventional cancer therapies is limited by many factors including the presence of significant gaps in clinical trial results. Clinical trials examining the potential benefit of these combinations have been conducted since the late 1980s. However, despite many trials demonstrating positive effects of combined therapies, none of the combinations has yet gained widespread acceptance in clinical practice. Many of these trials were small and thus lack sufficient statistical power to provide robust answers. Meta-analyses have not been done and would be unlikely to provide more clarity for the reasons stated below.
Our investigation identified trials studying a diverse selection of antioxidants, including glutathione, vitamin E, NAC, vitamin C, selenium, coenzyme Q10, and zinc as well as some combinations. This variety of types of dietary antioxidants investigated in these studies contributes to a significant heterogeneity in the research and clinical questions asked.
Differences in formulations or descriptions of an antioxidant can also cause confusion in comparison between studies of, ostensibly, the same antioxidant. Perhaps, this is best illustrated with vitamin E, a term that can be used to refer to single isomers, racemic mixtures, or mixtures of any of several tocopherols (e.g., α
-tocopherols). Studies identified in this review reported using several different forms of tocopherols and one simply described the compound as “vitamin E.” When α
-tocopherol was specified, often the specific salt was not. Preclinical research has demonstrated differences in the bioavailability of different stereoisomers of α
-tocopherol and in biological activity of the acetate and succinate salts of α-tocopherol
The dosage and schedule of administration for antioxidants of the same type often differed between the studies we reviewed. These studies generally did not provide a rationale for the dosage, formulation, or schedule used.
The selection and specifics of the conventional cancer therapy protocol also often differed between studies, as did the cancer type and stage. Among the 52 clinical trials we reviewed, only five studies of glutathione and two studies of NAC used exactly the same antioxidant and conventional cancer therapy doses and regimens in the same cancer types.
A search of Clinicaltrials.gov identified 38 ongoing trials of antioxidant and chemotherapy or radiotherapy combinations (80
). Several steps are needed to optimize the chance for ongoing and future research endeavors to lead to a satisfactory evidence base for development of clinical practice guidelines of the concurrent use of dietary antioxidants and conventional cancer therapies. First, a community of interested researchers must come to consensus and focus efforts on one, or a small number of antioxidant and conventional cancer therapy combinations and specific clinical research questions. This has been accomplished to a limited degree with the combination of glutathione and cisplatin-based chemotherapy for treatment of gastric cancer (30
). Initial efforts should focus on a rational approach to selection of the antioxidant and chemotherapy or radiotherapy partner. Both results from well-designed and conducted preclinical studies and findings from previous clinical trials can provide a basis for these choices.
Second, studies are needed that reveal the mechanism(s) of action of specific combinations of antioxidants and conventional cancer therapies. Several review articles and reports of animal studies (81
) have speculated about the mechanism of action for the combination of cisplatin and reduced glutathione, but the involved pathways remain unknown. The identification of biomarkers that reflect these mechanisms of action may also help guide clinical trial design (84
). Recent evidence pointing to differences in survival after treatment of patients associated with a polymorphism of the glutathione S-transferase gene may suggest possibilities for such useful markers (86
Next, a concerted effort should be made to determine the optimal formulation, dose, and schedule of the antioxidant under investigation in combination with a specific chemotherapy regimen through appropriately designed, dose-escalation studies. In the early trials of glutathione, the dose of 1.5 g/m2
was selected without determining an optimal dose, out of concern for possibly reducing the effectiveness of CDDP (43
). While some subsequent studies adopted this dose, others used various doses, generally without providing a rationale in the final paper. We found no study that attempted to determine the optimal doses of an antioxidant–chemotherapy combination.
Finally, given these important inconsistencies between reports, we suggest that journals considering future articles on this topic require authors to adhere to a few basic criteria, which would improve future summary analyses on this topic ().
Recommendations for reporting of clinical research with combinations of antioxidants and chemotherapy or radiotherapy.
An example from colorectal cancer therapy illustrates the successful accomplishment of some of these proposed steps. Folinic acid was found to significantly augment the therapeutic index of fluorouracil (5-FU) through meta-analysis of clinical trials and is currently accepted as a standard treatment (87
). Folinic acid may not have gone through a full dose-finding process, but low and high doses were tested in at least one study (78
Despite some encouraging findings regarding possible benefits of antioxidant and chemotherapy combinations, few comparative phase III studies have been done and none have demonstrated an effect of the magnitude of adding folinic acid to 5-FU (77
). However, folinic acid increases the toxicity of 5-FU (88
), whereas various antioxidants either diminish toxicity [e.g., glutathione and cisplatin (22
)] or have no effect on toxicity [e.g., selenium and irinotecan (72
)]. The mechanism of action by which folinic acid modulates the activity of fluorinated pyrimidines, such as 5-FU, has been well elucidated. Perhaps, the lack of understanding regarding the pathways involved in the cytoprotective and therapeutic augmentation effects of dietary antioxidants with specific cancer therapeutics may be one reason the combinations have not been more thoroughly studied.
The US NCI’s Division of Cancer Treatment and Diagnosis has established some areas of special interest with regard to the development of its grant portfolio (89
). One of these topics is the identification of complementary approaches that augment the therapeutic index of conventional anticancer therapeutics. Research proposals assessing the combined use of antioxidants and conventional cancer therapies would address this topic and thus would be eligible via either of two program announcements (90
A potential limitation of our review is selection bias. We only searched and included publications with their full text written in English, possibly overlooking some relevant clinical trials in non-English language journals. Although we only searched through MEDLINE via PubMed, EMBASE, and Cochrane Library, additional clinical trials from the bibliographies of retrieved articles and OCCAM’s archives were added to get as complete a list as possible.