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Antioxidants in the News

A recent article in the Journal of Clinical Oncology has surely caught the eyes of many in the world of integrative and alternative medicine. Isabel Bairati and colleagues report on a randomized trial in which they gave head and neck cancer patients in their experimental group supplemental vitamin E and β-carotene during and after radiation therapy. Patients receiving the supplements had lower rates of side effects from radiation therapy than the control group did, as might be expected with the use of antioxidants. When information about the prooxidant effects of β-carotene in presumably oxidizing environments was published a few years into the trial, β-carotene supplements were eliminated from the study and only vitamin E was given. Vitamin E alone did not protect against radiationinduced side effects. By the end of the study, it was found that patients who had received both β-carotene and vitamin E, as well as those who received vitamin E alone, had a nonsignificantly higher risk of local recurrence. An earlier publication on the same study found that while the overall risk of second primary cancers after 8 years was similar between the control and supplemented groups, the supplemented groups (with or without β-carotene) had higher rates of second primaries during the supplementation period, which extended for 3 years beyond the end of radiation therapy. Both studies imply a negative effect of these antioxidants on head and neck cancer. An editorial comment by Camphausen et al in the same issue as the more recent study makes several interesting points: they acknowledge that the phytochemical antioxidants probably are not present in sufficient concentration and are not sufficiently powerful free radical scavengers to be able to counteract the primary and secondary free radical species produced directly by radiation therapy. They speculate that the antioxidants may suppress continued free radical production arising from the inflammatory response that follows radiation therapy, which could perhaps impede antitumor activity, although it is not known if this inflammatory response actually occurs in tumor tissue. The effects of antioxidants are certainly complicated by the fact that, as Camphausen et al acknowledge, most “antioxidants,” particularly the phytochemical antioxidants, are not simply antioxidants but also trigger complex signal transduction pathways, which may ultimately result in tumor cell death, though a few promote tumor cell survival. The editorial warns that patients should “avoid unnecessary supplementation during and after radiotherapy.” Camphausen et al go on to conclude that improving the therapeutic index of radiation therapy through use of antioxidants is a reasonable and, in fact, commendable goal, suggesting that further attempts in this area should be carried out in cancers in which there is effective salvage therapy. This strategy would guarantee that if particular antioxidants should result in protection of tumor tissue, patients will not have a decrement in survival as a result of a therapy that may reduce treatment regimen side effects to a manageable level. We discuss this idea and other topics related to tumor protection in a commentary in this issue, based on the history and current research on the pharmacological antioxidant and normal tissue cytoprotectant amifostine. We especially emphasize the need to adapt the harsh modern regimens of chemoradiation and high-dose chemotherapy for bone marrow transplant to the needs of patients unable or unwilling to tolerate their side effects, by improving their therapeutic index with the use of amifostine and, potentially, phytochemical antioxidants. These may offer alternatives to amifostine, which, although it is definitely efficacious in a number of chemo and radiation side effects, is also expensive, logistically difficult, and frequently toxic. An article in the current issue of Integrative Cancer Therapies by Sunila and Kuttan explores the potential of a botanical as a radioprotectant, taking the initial step of evaluating its radioprotective effects on normal tissue in an animal model. One concern that we have with the Journal of Clinical Oncology editorial by Camphausen et al is that the main message that many physicians will take away from it is not the idea that exploration of the cytoprotectant effects of phytochemical antioxidants can be reasonably conducted in human trials and that it is a reasonable goal to explore management of radiation’s side effects with natural agents that are low in toxicity. Rather, we suspect that many physicians will stop at the sentence that urges people to avoid unnecessary supplementation and generalize it to urge all cancer patients to avoid all supplemental and food-based antioxidants at all times. This is not a reasonable response. There are many natural antioxidants, and they have many effects. No reasonable integrative physician today would counsel a patient to take β-carotene and vitamin E—or even vitamin E alone—to help in dealing with the side effects of radiation therapy or to Editorial