Antioxidants During Chemotherapy: One Step Forward, Two Steps Back?

By Dónal P. O'Mathúna, PhD. Dr. O'Mathúna is Senior Lecturer in Ethics, Decision- Making & Evidence, School of Nursing, Dublin City University, Ireland; he reports no financial relationship to this field of study.

Source: Greenlee H, et al. Use of antioxidant supplements during breast cancer treatment: A comprehensive review. Breast Cancer Res Treat 7 Oct 2008; Epub ahead of print.

An estimated 45-80% of breast cancer patients use antioxidant supplements after diagnosis, and use of antioxidant supplements during breast cancer treatment is common. Dietary supplements with antioxidant effects include vitamins, minerals, phytonutrients, and other natural products. These investigators conducted a comprehensive review of literature on the associations between antioxidant supplement use during breast cancer treatment and patient outcomes.

Repeated literature searches were carried out on PubMed between July 2006 and October 2007. The search was limited to articles published in English, French, or German. Numerous search terms were selected to obtain articles involving observational studies and clinical trials of any antioxidant dietary supplement during treatment for breast cancer. Using the general search term "antioxidant supplement" revealed studies involving vitamin C, vitamin E, antioxidant combinations, multivitamins, glutamine, glutathione, melatonin, and soy isoflavones. Each of these terms was used in subsequent searches of the same database. The reference lists from review articles were also examined for studies.

Twenty-two articles met inclusion criteria; the findings did not support any conclusions regarding the effects of individual antioxidant supplements during conventional breast cancer treatment on toxicities, tumor response, recurrence, or survival. A few studies suggested that antioxidant supplements might decrease side effects associated with treatment, including vitamin E for hot flashes due to hormonal therapy and glutamine for oral mucositis during chemotherapy. Underpowered trials suggest that melatonin may enhance tumor response during treatment.

The evidence is currently insufficient to inform clinician and patient guidelines on the use of antioxidant supplements during breast cancer treatment. Thus, well-designed clinical trials and observational studies are needed to determine the short- and long-term effects of such agents.

Commentary

An estimated 182,460 women were diagnosed with breast cancer in the United States in 2008.1 Various studies have found that between 45% and 80% of these women use antioxidant supplements after diagnosis of or during treatment for breast cancer. The impact of these supplements on prognosis, treatment, or toxicity is largely unknown, and recommendations vary. This study systematically reviewed the literature available on antioxidant supplement use after breast cancer diagnosis.

Antioxidant supplements are readily available over the counter. Many cancer patients believe that antioxidants are beneficial for their general health or to counteract the oxidative damage that can accompany cancer treatment. Many cancer treatments induce oxidative stress, which can disrupt growth of cancer cells. However, such oxidative stress can also harm normal tissue and lead to various side effects and toxicities of chemotherapy. Some have alleged that antioxidants can protect normal tissues from these toxicities. Others claim that antioxidant supplements may protect cancer cells and thus counteract the effectiveness of the treatments. Still others have suggested that antioxidants can potentiate chemotherapy or radiation therapy through some poorly understood mechanisms. While various and contradictory theories are proposed, very few clinical data are available to guide decision-makers.

This review sought to summarize the available literature from clinical trials and observational studies in this area. The supplements most commonly considered to be antioxidants are vitamin C, vitamin E, selenium, and zinc, although others were included in the abstract above. Literature searching was limited to PubMed and the reference lists of identified studies. It is possible that other studies might have been identified in other databases, such as the Cochrane Database or EMBASE. The search was also limited to English, French, or German articles, which may have missed studies published in other languages.

Nevertheless, 22 articles were identified reporting on three observational studies and 19 clinical trials. The latter clinical trials included nine randomized controlled trials, four non-randomized controlled trials, and six single-arm trials. The three observational studies were retrospective cohort studies. The studies were published between 1980 and 2007. They included one on vitamin C, six on vitamin E, five on antioxidant combinations, one on multivitamins, two on glutamine, one on glutathione, three on melatonin, and three on soy isoflavones. In all cases, these studies were conducted with breast cancer patients.

Thirteen of the studies examined the use of antioxidants to reduce the toxicities of chemotherapy, radiation therapy, or tamoxifen therapy. Vitamin E was examined in six trials as a means to reduce cardiotoxicity, alopecia, or hot flashes. No clinical benefits were found, except for reduced incidence of hot flashes in one trial. Another trial found participants taking multivitamins were more fatigued than those taking a placebo. No benefits were found in trials of glutamine, glutathione, or soy isoflavones to reduce side effects.

Nine studies examined the effect of antioxidants on tumor response, recurrence, or survival. One trial found no benefit from vitamin C in five-year survival rates, but many details were omitted from the publication. Five studies examined high-dose combination antioxidant therapy. Most of the studies had significant methodological limitations. One well-designed retrospective cohort study suggested that women using megadoses of antioxidants fared worse than the control group. A series of three studies by the same research group examined 20 g/d melatonin during chemotherapy. Some beneficial effects were reported, but not for all outcomes. These trials enrolled small numbers of participants leading to concerns that they were underpowered.

Overall, the authors concluded that there is insufficient evidence to support firm recommendations about any of the antioxidant supplements commonly used during treatment for breast cancer. All of the studies had methodological limitations of one sort or another. None of them examined other factors that impact total antioxidant intake, such as other dietary supplements or intake from fruits and vegetables. Physical activity patterns can also influence oxidative stress levels and these were not taken into account.

Caution is warranted with these antioxidants. The only large-scale observational study of breast cancer patients taking large doses of antioxidants found a trend towards decreased survival. A recent review examined the use of antioxidants during chemotherapy and radiation therapy for numerous cancer sites.2 It found some evidence of reduced toxicity with chemotherapy, but harm with radiation therapy. Studies are urgently needed in this area for breast cancer patients in particular. The review noted that two observational studies of the effects of antioxidants on breast cancer treatment are currently under way. In addition, four clinical trials are currently being conducted examining the effects of antioxidants on treatment-related toxicities during breast cancer treatment. Given the widespread use of antioxidants in general, and during breast cancer treatment in particular, the results of these studies are eagerly awaited. Meanwhile, patients and clinicians have little reliable evidence to guide them.

References

1. Greenlee H, et al. Complementary and alternative therapy use before and after breast cancer diagnosis: The Pathways Study. Breast Cancer Res Treat 31 Jan 2009; Epub ahead of print.

2. Block KI, et al. Impact of antioxidant supplementation on chemotherapeutic toxicity: A systematic review of the evidence from randomized controlled trials. Int J Cancer 2008;123:1227-1239.