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In Reply:

Laval University Cancer Research Center, Québec City, Québec, Canada

We read with great interest Dr Prasad and Dr Cole's critiques of our study,¹ and tried to understand why our prudent conclusion—"This trial suggests that use of high doses of antioxidants as adjuvant therapy might compromise radiation treatment efficacy" —was perceived by them as misleading and inaccurate. The studies they cite^2-6 address two separate issues examined in our trial. First, that antioxidants, such as beta-carotene and vitamin E, can protect normal cells from radiation-induced damage. In our trial, we were able to demonstrate such a protective effect when the supplementation combined alpha-tocopherol and beta-carotene. Therefore, our study confirmed the experimental data on cell lines and animal models even if we failed to use, as they claim, the proper molecules at the proper doses with the proper schedule. Second, that antioxidants, such as beta-carotene and vitamin E, can influence the efficacy of radiation therapy. Dr Prasad and Dr Cole are strong proponents of the hypothesis that high doses of antioxidants may improve the efficacy of radiation therapy.^5,6 The scientific evidence in favor of this hypothesis rests primarily on two experiments: one on neuroblastoma cells -irradiated and exposed to vitamin E succinate,⁷ and the other on breast tumor bearing mice given supplemental vitamin A or beta-carotene and treated by irradiation.² Following Dr Prasad's presentation at the conference on Synergy in Medical and Nutritional Therapy, the discussion was opened with these words: "It is appropriate to end with a discussion on neoplastic diseases and, in particular, antineoplastic treatment, because new considerations, including previously unpredicted interactions, arise when the science moves from the test tube to humans."⁵ Until recently, the clinical data directly addressing the issue of the effect of antioxidant supplementation on the efficacy of radiation therapy in human cancer patients was limited.⁸ In a small randomized study by Mills,⁹ 10 patients treated with radiation and chemotherapy for advanced carcinoma of the mouth who received beta-carotene supplements during therapy were compared with 10 patients who received standard treatment.⁹ Mills stated that the remission rate was not significantly different in the two groups of patients. However, given the extremely low statistical power of the study, this cannot be taken as evidence of lack of interference with therapy. In 2002, Dr Prasad and Dr Cole wrote, "A randomized placebo control trial on the use of antioxidants during radiation therapy has not yet been performed."⁶ Our study is the first placebo-controlled, double-blind, randomized trial assessing the effect of supplementation with antioxidant vitamins during radiation therapy. Our results do not support the hypothesis that antioxidants, such as beta-carotene and vitamin E, are able to reduce radiation therapy adverse effects without interfering with its therapeutic efficacy. On the contrary, the recurrence rate was 40% higher among patients randomly assigned to the supplementation arm of the trial. The supplements given in our trial might not be the most efficacious in laboratory experiments, but they are those found on drugstore shelves and are therefore those taken by many cancer patients. Our trial thus addressed a pragmatic question directly relevant to cancer patients and to their treating physicians. We agree with Dr Prasad and Dr Cole that other randomized, controlled trials should be conducted in order to provide clear scientific evidence regarding the efficacy and safety of antioxidant use as adjuvant therapies for cancer. However, we believe that patients and physicians should exert caution until new evidence is provided by these future trials.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Bairati I, Meyer F, Gélinas M, et al: Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer patients. J Clin Oncol 23:5805-5813, 2005[Abstract/Free Full Text]

2. Seifter E, Rettura A, Padawar J, et al: Vitamin A and ß-carotene as adjunctive therapy to tumor excision, radiation therapy and chemotherapy. In Prasad KN ed: Vitamins, Nutrition and Cancer. Basel, Switzerland, Karger, 1984, pp 1-19

3. Kennedy AR, Krinsky NI: Effects of retinoids, beta-carotene, and canthaxanthin on UV- and X-ray-induced transformation of C3H10T1/2 cells in vitro. Nutr Cancer 22:219-232, 1994[Medline]

4. Prasad KN, Edwards-Prasad J: Effects of tocopherol (vitamin E) acid succinate on morphological alterations and growth inhibition in melanoma cells in culture. Cancer Res 42:550-555, 1982[Abstract/Free Full Text]

5. Prasad KN, Cole WC, Kumar B, et al: Scientific rationale for using high-dose multiple micronutrients as an adjunct to standard and experimental cancer therapies. J Am Coll Nutr 20:450S–463S, 2001, discussion 473S-475S

6. Prasad KN, Cole WC, Kumar B, et al: Pros and cons of antioxidant use during radiation therapy. Cancer Treat Rev 28:79-91, 2002[CrossRef][Medline]

7. Sarria A, Prasad KN: DL-alpha tocopheryl succinate enhances the effect of gamma-irradiation on neuroblastoma cells in culture. Proc Soc Exp Biol Med 175:88-92, 1984[CrossRef][Medline]

8. Lamson DW, Brignall MS: Antioxidants in cancer therapy: Their actions and interactions with oncologic therapies. Altern Med Rev 4:304-329, 1999[Medline]

9. Mills EED: The modifying effect of beta-carotene on radiation and chemotherapy induced oral mucositis. Br J Cancer 57:416-417, 1988[Medline]

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Related Correspondence

• Antioxidants in Cancer Therapy
  Kedar N. Prasad and William C. Cole
  JCO 2006 24: 8-9 [Full Text]

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