Clinical testing of supplementation therapy in early stage breast cancer: pitfalls and opportunities.

The professional and research oncology community has done a poor job of serving patients when it comes to providing quality information about alternative and complementary, or integrative approaches to cancer care. Even in areas that are now becoming more accepted by patients and physicians, such as the use of psychological and nutritional support, very little data have been generated that are really useful to patients. Mega-dose vitamin supplementation is a commonly sought approach in cancer care, and this is based in part on extrapolations of the activity of vitamin cofactors in disease and health as well as laboratory data that support both direct anticancer effects and effects on the immune function. However, clinical effects of vitamins, minerals, and antioxidant supplementation (hereafter referred to in aggregate as supplementation therapy) in early stage breast cancer have never been studied in a controlled randomized trial, despite the common use and interest in this setting. Hence, most medical oncologists have been reluctant to make any recommendations in this area and even tend to advise against the use of such supplements out of concern that it may interfere with the activity of conventional hormonal and chemotherapeutic drugs. On the other hand, supplementation therapy remains of great interest to patients and is also embraced by many naturopathic and holistic physicians and care providers. It is clear that laboratory and other preclinical models of cancer are not very predictive of clinical effects. The genetic and cellular complexities, the individual diversity seen across human tumors of the same type, and the intricacies of tumor host interaction dictate that clinical trials must ultimately confirm laboratorybased hypotheses. Oftentimes, clinical effects are overestimated. Nevertheless, clinical trials involve some human risk and thus a high priority must be given to those trials that have a physiological basis or a strong clinical experience to support the experimental arm. Supplementation therapy meets both these criteria with some laboratory data suggesting an effect from vitamins and antioxidants, as well from small patient case series, case-control studies showing lower risk of breast cancer, and large cohort studies suggesting lower risk of breast cancer with vitamin A supplementation, especially if the diet is vitamin Adeficient. However, in the breast cancer preventive setting, most other vitamin and micronutrient cohort studies or even randomized trials have failed to show a significant effect. Many investigators in the burgeoning field of integrative medical research rely on evidence from the laboratory as well as cohort or case-control studies prior to proposing a large-scale randomized trial just as would be the case in any other field. This is necessary to assume that there is a basis for a positive clinical effect, that the modality is relatively safe and feasible, and to estimate a magnitude of the effect size to determine the appropriate sample size. However, in the field of integrative medicine, the modalities are often complex rather than “single agent” and are often individualized. Case series or cohort studies provide some information about safety and feasibility of specific approaches but are often criticized because of patient selectivity, which make outcome very difficult to interpret in a heterogeneous disease such as breast cancer. Case-control studies, in which patients are matched for characteristics that are known to influence outcome, can correct for some of these biases, but the problem of unanticipated biases still is problematic. This is especially true for lifestyle studies since many factors such as the use of alcohol and tobacco can be linked to other factors such as motivation and likelihood to seek medical care at an early juncture. The study by Lesperance and colleagues at the British Columbia Cancer Agency (BCCA) stands out as a noteworthy example of the power of a well-designed case-control study. Supplementation therapy was assessed using a reasonably uniformly prescribed regimen of beta-carotene, vitamin C, selenium, niacin, Tripathy