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

Randomized, multicenter trial in adults 18 years or older with stage I or II head and neck squamous cell carcinoma receiving radiation therapy in Quebec, Canada. Active intervention arms included 156 participants randomized to α-tocopherol plus β-carotene and 384 randomized to α-tocopherol alone, each with placebo comparison.

Oral dl-α-tocopherol 400 IU daily was given during radiation therapy and continued for 3 years afterward. One active arm also received oral β-carotene 30 mg daily on the same schedule; both active regimens were compared with placebo, and β-carotene was later discontinued during the trial.

The supplementation strategy did not improve cancer outcomes and was associated with worse cancer-free outcomes during the supplementation period. For second primary cancers in the first 3.5 years, hazard ratios were 2.42 (1.45 to 4.04) for any supplementation and 2.88 (1.56 to 5.31) for α-tocopherol alone; beyond 3.5 years, the estimates were 0.57 (0.31 to 1.07) and 0.41 (0.16 to 1.03), respectively. Cancer-free survival was also worse during supplementation, with HR 1.65 (1.21 to 2.25) for any supplementation and 1.86 (1.27 to 2.72) for α-tocopherol alone. The authors concluded that high-dose α-tocopherol should not be used for cancer prevention in this setting because no overall benefit was observed and adverse effects during use were possible.

Interpretation is limited by the trial population being restricted to early-stage head and neck cancer patients treated with radiation therapy, which limits generalizability. The β-carotene arm was discontinued, and the effect estimates showed time-varying results, making the overall clinical interpretation more complex. Arm-level sex and ethnicity data were not reported, and some outcome and adherence details were incomplete.