A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients.
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.
Bairati
Isabelle
I
Centre de Recherche en Cancérologie de L'Université Laval, Québec City, Québec, Canada.
Meyer
François
F
Gélinas
Michel
M
Fortin
André
A
Nabid
Abdenour
A
Brochet
François
F
Mercier
Jean-Philippe
JP
Têtu
Bernard
B
Harel
François
F
Mâsse
Benoît
B
Vigneault
Eric
E
Vass
Sylvie
S
del Vecchio
Pierre
P
Roy
Jean
J
D000328:Adult; D000368:Aged; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000975:Antioxidants / Q000008:administration & dosage* / Q000009:adverse effects*; D015986:Confounding Factors, Epidemiologic; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006258:Head and Neck Neoplasms / Q000532:radiotherapy*; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D009381:Neoplasms, Radiation-Induced / Q000453:epidemiology / Q000517:prevention & control*; D016609:Neoplasms, Second Primary / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control*; D016017:Odds Ratio; D016016:Proportional Hazards Models; D011878:Radiotherapy / Q000009:adverse effects; D016019:Survival Analysis; D017211:Treatment Failure; D024502:alpha-Tocopherol / Q000008:administration & dosage* / Q000009:adverse effects*; D019207:beta Carotene / Q000008:administration & dosage* / Q000009:adverse effects*
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D019207:beta Carotene; D024502:alpha-Tocopherol