Originally published as JCO Early Release 10.1200/JCO.2005.05.903 on July 18 2005

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Implications for Tumor Control During Protection of Normal Tissues With Antioxidants

Radiation Oncology Branch and Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD

The use of antioxidants during antineoplastic radiation therapy has long been a controversial topic. Antioxidants are known for their ability to scavenge free radicals, potentially reducing the damage caused by ionizing radiation to treated tissues. Reduction of normal tissue injury from radiotherapy with antioxidant supplementation is intriguing; however, it raises significant concerns about the possible inadvertent simultaneous protection of tumor tissues. This issue is not limited to the clinical trial setting, given that increasing numbers of the American public take vitamin supplements and naturopathic remedies during therapy.

DNA damage is the most lethal form of cellular damage caused by ionizing radiation. With the types of ionizing radiation used in clinical practice today, approximately two thirds of DNA damage is caused by short-lived (nanoseconds to microseconds) high-energy primary and secondary free radicals.¹ To act as a radioprotector by scavenging these free radicals, an antioxidant needs to be present in sufficient concentrations and have efficient radical scavenging capabilities in proximity to the target (DNA) during the radiation exposure. -tocopherol and ß-carotene would not be expected to provide significant protection against radiation-induced primary and secondary reactive species compared with conventional radioprotectors. However, free-radical generation in tissues may continue after the radiation exposure as a consequence of an inflammatory response, with the generation of cytokines and sustained production of longer lived free radicals.² In this setting, particularly in normal tissues, -tocopherol and ß-carotene may in fact be quite effective toward protecting against sustained free-radical damage. Interestingly, it is now becoming clear that free radicals can also serve as initiators (triggers) for complex signal transduction and gene expression pathways governing pro- and antisurvival responses. For example, -tocopherol can modulate transcriptional and post-transcriptional regulation of protein kinase C, cyclooxigenase, and lipoxygenase. Whether radiation induces a similar inflammatory response in tumors is less clear, given their markedly different redox status.³ To further complicate the issue of supplementation, the concentration of the agent or the surrounding environment can alter the antioxidant effects of many molecules. As for the microenvironment, ß-carotene is an antioxidant at low oxygen concentrations; however, it acts as a pro-oxidant at high oxygen concentrations.⁴

To illustrate this complex relationship of dose, agent, and microenvironment, consider the following two large randomized studies that have assessed the efficacy of ß-carotene as a preventative agent in patients at high risk of malignancy. The Alpha-Tocopherol, Beta-Carotene cancer prevention trial randomly assigned 29,133 male smokers to supplementation with -tocopherol, ß-carotene, both, or placebo, and unexpectedly found an increased risk of lung cancer in participants who received ß-carotene supplementation. Supplementation with -tocopherol alone in this study appeared to have no adverse effect on lung cancer incidence.⁵ In addition, the ß-Carotene and Retinol Efficacy trial randomly assigned 18,314 men and women at high risk of developing lung cancer to the combination of daily ß-carotene and retinyl palmitate (vitamin A) or placebo. This large study was stopped early because of evidence of a significant increase in the risk of lung cancer and lung cancer mortality in the treatment group compared with the placebo group.⁶ It is hypothesized that the increased incidence of lung cancers seen in both of these large, randomized studies is at least partially due to the pro-oxidant nature of ß-carotene when used at high doses or in oxygen-rich environments, such as the lung.⁴

How do the preclinical findings that antioxidants improve the efficacy of radiotherapy translate into clinical outcomes? Numerous clinical studies investigating the effects of antioxidants in combination with radiotherapy or after radiotherapy have now been completed, with various degrees of success. In the adjuvant setting, antioxidants have been used to manage a wide range of radiation-induced normal tissue toxicities with varying success. Clinical studies of antioxidants delivered concurrent with radiotherapy have also been completed with the hopes of reducing normal tissue toxicity in a variety of settings, including head and neck cancers,^7,8 bladder cancers,⁹ and in the prevention of alopecia and radiation dermatitis during brain radiotherapy.^10,11

Although promising efficacy in the prevention of normal tissue toxicity has been reported with antioxidant supplementation, it is important to consider the effects of this treatment on the ability to achieve the primary goal of radiotherapy: the local cure of the tumor. In this issue of the Journal of Clinical Oncology, Bairati et al¹² report the results of a randomized trial evaluating -tocopherol and ß-carotene supplementation during and after radiotherapy for head and neck cancer. This double-blind, placebo-controlled, randomized study was initiated to determine the effect of antioxidant supplementation on the development of second cancers and to determine if concurrent administration of these agents with radiotherapy reduces normal tissue toxicity. A total of 540 patients were included in this trial and observed for evidence of acute toxicity. Adherence to the assigned treatment was assessed with pill counting and assays of plasma -tocopherol and ß-carotene levels. ß-carotene supplementation was discontinued after the results of the Alpha-Tocopherol, Beta-Carotene trial and ß-Carotene and Retinol Efficacy trial became available. To assess the effects of supplementation on normal tissue toxicity, acute toxicity and quality of life were measured in each study participant during, at the completion of, and 1 month after radiotherapy. With regard to outcomes, supplementation with -tocopherol and ß-carotene appeared to reduce the toxicity encountered by study participants significantly. Of significant concern is the finding of an increased risk of local recurrence in the supplemented group, suggesting decreased efficacy of radiotherapy with supplementation.

A smaller randomized trial evaluating daily mouth rinsing with -tocopherol solution during radiotherapy to prevent mucositis in head and neck cancer patients has been published recently.⁷ This study included 54 patients with oral cavity and oropharynx cancers and found a significant improvement in symptomatic mucositis. The rates of local recurrence are not discussed in the report of this trial; however, a trend toward a decrease in survival in the experimental arm is reported at a median follow-up of 12 months. The authors attribute this trend toward decreased survival in patients receiving -tocopherol mouth rinse to the higher number of patients with advanced disease in that arm.

Where do these findings leave us? With the results of Bairati et al,¹² it appears that supplementation with ß-carotene is not justified for reduction in mucositis given the concerns for a decrease in the efficacy of radiotherapy for head and neck cancers in addition to the concerns of increasing the risk of lung cancers in a group of patients who are already at an elevated risk. Similarly, the results of Bairati et al¹² with -tocopherol in combination with the results observed by Ferreira et al⁷ suggest that additional randomized trials using antioxidants for normal tissue cytoprotection in patients with head and neck cancers are not warranted. Furthermore, the issue of patient self-supplementation with antioxidants during radiotherapy must also be addressed in more detail given the results of this study. Without any definitive data on this issue, a reasonable approach would be to avoid unnecessary supplementation during and after radiotherapy.

Bairati et al¹² are to be commended for their work in attempting to increase the therapeutic ratio of radiation therapy for head and neck cancers. However, what should be apparent from these data is the difficulty in determining from preclinical data which agents will be protectors of normal tissue without providing protection to tumor tissue in clinical trials. These issues are of primary concern for future trials designed to test a potential radiation protector. Perhaps future investigations of antioxidant supplementation and radioprotectors to prevent normal tissue toxicity should be performed initially in patients with diseases with high rates of salvage. In these participants, the possible unintentional tumor protection and resultant recurrence may not lead to significant decrements in survival if effective salvage therapy was available.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. von Sontag C: The Chemical Basis of Radiation Biology. Philadelphia, Taylor and Francis, 1987

2. Robbins ME, Zhao W: Chronic oxidative stress and radiation-induced late normal tissue injury: A review. Int J Radiat Biol 80:251-259, 2004[CrossRef][Medline]

3. Cook JA, Gius D, Wink DA, et al: Oxidative stress, redox, and the tumor microenvironment. Semin Radiat Oncol 14:259-266, 2004[CrossRef][Medline]

4. Palozza P, Serini S, Di Nicuolo F, et al: Prooxidant effects of beta-carotene in cultured cells. Mol Aspects Med 24:353-362, 2003[CrossRef][Medline]

5. The alpha-tocopherol, beta-carotene lung cancer prevention study: Design, methods, participant characteristics, and compliance—The ATBC Cancer Prevention Study Group. Ann Epidemiol 4:1-10, 1994[Medline]

6. Omenn GS, Goodman GE, Thornquist MD, et al: Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst 88:1550-1559, 1996[Abstract/Free Full Text]

7. Ferreira PR, Fleck JF, Diehl A, et al: Protective effect of alpha-tocopherol in head and neck cancer radiation-induced mucositis: A double-blind randomized trial. Head Neck 26:313-321, 2004[CrossRef][Medline]

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

9. Sanchiz F, Milla A, Artola N, et al: Prevention of radioinduced cystitis by orgotein: A randomized study. Anticancer Res 16:2025-2028, 1996[Medline]

10. Metz JM, Smith D, Mick R, et al: A phase I study of topical Tempol for the prevention of alopecia induced by whole brain radiotherapy. Clin Cancer Res 10:6411-6417, 2004[Abstract/Free Full Text]

11. Halperin EC, Gaspar L, George S, et al: A double-blind, randomized, prospective trial to evaluate topical vitamin C solution for the prevention of radiation dermatitis: CNS Cancer Consortium. Int J Radiat Oncol Biol Phys 26:413-416, 1993[Medline]

12. 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

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