Randomized Phase III Trial of Low-dose Isotretinoin for Prevention of Second Primary Tumors in Stage I and II Head and Neck Cancer Patients

Background: Isotretinoin (13-cis-retinoic acid) is a synthetic vitamin A derivative, or retinoid, widely used in the treatment of cystic acne. Preclinical and clinical studies of high-dose isotretinoin in patients with head and neck squamous cell cancer (HNSCC) have produced encouraging results. We...

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Bibliographic Details
Published in:JNCI : Journal of the National Cancer Institute 2006-04, Vol.98 (7), p.441-450
Main Authors: Khuri, Fadlo R., Lee, J. Jack, Lippman, Scott M., Kim, Edward S., Cooper, Jay S., Benner, Steven E., Winn, Rodger, Pajak, Thomas F., Williams, Brendell, Shenouda, George, Hodson, Ian, Fu, Karen, Shin, Dong M., Vokes, Everett E., Feng, Lei, Goepfert, Helmuth, Hong, Waun Ki
Format: Article
Language:English
Subjects:
Aged
Anticarcinogenic Agents - administration & dosage
Antineoplastic agents
Antineoplastic Agents - administration & dosage
Biological and medical sciences
Carcinoma, Squamous Cell - prevention & control
Carcinoma, Squamous Cell - secondary
Chemotherapy
Clinical trials
Disease-Free Survival
Drug Administration Schedule
Drugs
Female
Head & neck cancer
Head and Neck Neoplasms - pathology
Humans
Isotretinoin - administration & dosage
Male
Medical sciences
Multivariate Analysis
Neoplasm Staging
Neoplasms, Second Primary - etiology
Neoplasms, Second Primary - prevention & control
Odds Ratio
Oncology
Patient Selection
Pharmacology. Drug treatments
Proportional Hazards Models
Risk Factors
Smoking - adverse effects
Survival Analysis
Treatment Failure
Tumors
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Summary:Background: Isotretinoin (13-cis-retinoic acid) is a synthetic vitamin A derivative, or retinoid, widely used in the treatment of cystic acne. Preclinical and clinical studies of high-dose isotretinoin in patients with head and neck squamous cell cancer (HNSCC) have produced encouraging results. We conducted a phase III randomized trial of low-dose isotretinoin versus placebo in early-stage HNSCC patients to assess its effect on second primary tumor incidence and survival. Methods: We randomly assigned 1190 patients who had been treated for stage I or II HNSCC to receive either low-dose isotretinoin (30 mg/day) or placebo for 3 years. The patients were monitored for up to 4 more years. Survival was analyzed by the Kaplan–Meier method, and Cox proportional hazards models were used for multivariable survival analysis. All statistical tests were two-sided. Results: Isotretinoin did not statistically significantly reduce the rate of second primary tumors (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 0.83 to 1.35) or increase survival (HR = 1.03, 95% CI = 0.81 to 1.32) compared with placebo in patients with early-stage HNSCC. Current smokers had a higher rate of second primary tumors than that of never (HR = 1.64, 95% CI = 1.08 to 2.50) or former (HR = 1.32, 95% CI = 1.01 to 1.71) smokers. The hazard ratio of death from any cause for current smokers versus never smokers was 2.51 (95% CI = 1.54 to 4.10) and for current smokers versus former smokers was 1.60 (95% CI = 1.23 to 2.07). Major sites of second primary tumors (n = 261) included lung (31%), oral cavity (17%), larynx (8%), and pharynx (5%). Conclusions: Low-dose isotretinoin was not effective in reducing the rate of second primary tumors or death or smoking-related disease. Smoking statistically significantly increased the rate of second primary tumors and death. Ongoing trials are testing higher doses of isotretinoin as part of combination bioadjuvant therapeutic methods for patients with locally advanced HNSCC.
ISSN:0027-8874
1460-2105
DOI:10.1093/jnci/djj091