A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients.

Journal of the National Cancer Institute

Apr 2005

DOI: 10.1093/JNCI/DJI095

Citations:231

Influential Citations:9

Interventional (Human) Studies

Low RoB

Enhanced Details

Methods

Multicenter, double-blind, placebo-controlled, randomized trial among adults with stage I–II head and neck squamous cell carcinoma treated by radiation therapy; 540 participants enrolled; mean age ~63 years; ~82% men; 5 centers in Quebec; follow-up through 2003; main outcomes were incidence of second primary cancers and cancer-free survival.

Intervention

Daily supplementation started on the first day of radiation therapy and consisted of alpha-tocopherol 400 IU/day and beta-carotene 30 mg/day for 3 years after completion of radiation therapy; beta-carotene was discontinued after 156 participants, after which subsequent participants received alpha-tocopherol 400 IU/day alone for the same duration.

Results

During the supplementation period, alpha-tocopherol increased the incidence of second primary cancers (HR 2.88; 95% CI 1.56–5.31) and worsened cancer-free survival (HR 1.86; 95% CI 1.27–2.72). After supplementation was discontinued, the risk decreased (HR 0.41; 95% CI 0.16–1.03) for second primary cancers, and cancer-free survival appeared to improve (HR 0.71; 95% CI 0.33–1.53). Across the full follow-up, the first 3.5 years showed higher risk of recurrence or second primaries with supplementation (HR 1.65; 95% CI 1.21–2.25; alpha-tocopherol alone HR 1.86; 95% CI 1.27–2.72); after 3.5 years, risk was not elevated and tended lower (HR 0.57; 95% CI 0.31–1.07; alpha-tocopherol alone HR 0.71; 95% CI 0.33–1.53). Eight-year cancer-free survival was similar between arms. Conclusion: Alpha-tocopherol supplementation produced unexpected adverse effects on second primary cancers and cancer-free survival; caution advised with high-dose alpha-tocopherol in this setting.

Limitations

Beta-carotene arm halted after 156 participants; insufficient power to evaluate the combination of alpha-tocopherol and beta-carotene; results specific to head and neck cancer patients treated with radiation therapy and may not generalize to other populations or regimens; high-dose alpha-tocopherol exposure may influence cancer progression

Abstract

BACKGROUND Although low dietary intakes of antioxidant vitamins and minerals have been associated with higher risks of cancer, results of trials testing antioxidant supplementation for cancer chemoprevention have been equivocal. We assessed whether supplementation with antioxidant vitamins could reduce the incidence of second primary cancers among patients with head and neck cancer. METHODS We conducted a multicenter, double-blind, placebo-controlled, randomized chemoprevention trial among 540 patients with stage I or II head and neck cancer treated by radiation therapy between October 1, 1994, and June 6, 2000. Supplementation with alpha-tocopherol (400 IU/day) and beta-carotene (30 mg/day) or placebo began on the first day of radiation therapy and continued for 3 years after the end of radiation therapy. In the course of the trial, beta-carotene supplementation was discontinued after 156 patients had enrolled because of ethical concerns. The remaining patients received alpha-tocopherol or placebo only. Survival was evaluated by Kaplan-Meier analysis. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS After a median follow-up of 52 months, second primary cancers and recurrences of the first tumor were diagnosed in 113 and 119 participants, respectively. The effect of supplementation on the incidence of second primary cancers varied over time. Compared with patients receiving placebo, patients receiving alpha-tocopherol supplements had a higher rate of second primary cancers during the supplementation period (HR = 2.88, 95% CI = 1.56 to 5.31) but a lower rate after supplementation was discontinued (HR = 0.41, 95% CI = 0.16 to 1.03). Similarly, the rate of having a recurrence or second primary cancer was higher during (HR = 1.86, 95% CI = 1.27 to 2.72) but lower after (HR = 0.71, 95% CI = 0.33 to 1.53) supplementation with alpha-tocopherol. The proportion of participants free of second primary cancer overall after 8 years of follow-up was similar in both arms. CONCLUSIONS alpha-Tocopherol supplementation produced unexpected adverse effects on the occurrence of second primary cancers and on cancer-free survival. show less