title: Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients.
abstract: 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.
authors.affiliation: Winship Cancer Institute/Emory University School of Medicine, Atlanta, GA 30322, USA. fkhuri@emory.edu
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.forename: Edward S
authors.initials: ES
authors.lastname: Kim
authors.forename: Jay S
authors.initials: JS
authors.lastname: Cooper
authors.forename: Steven E
authors.initials: SE
authors.lastname: Benner
authors.forename: Rodger
authors.initials: R
authors.lastname: Winn
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Pajak
authors.forename: Brendell
authors.initials: B
authors.lastname: Williams
authors.forename: George
authors.initials: G
authors.lastname: Shenouda
authors.forename: Ian
authors.initials: I
authors.lastname: Hodson
authors.forename: Karen
authors.initials: K
authors.lastname: Fu
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
authors.forename: Lei
authors.initials: L
authors.lastname: Feng
authors.forename: Helmuth
authors.initials: H
authors.lastname: Goepfert
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
mesh_terms: D000368:Aged; D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002294:Carcinoma, Squamous Cell / Q000517:prevention & control* / Q000556:secondary; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D015474:Isotretinoin / Q000008:administration & dosage*; D008297:Male; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D016609:Neoplasms, Second Primary / Q000209:etiology / Q000517:prevention & control*; D016017:Odds Ratio; D018579:Patient Selection; D016016:Proportional Hazards Models; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D016019:Survival Analysis; D017211:Treatment Failure
chemical_list: D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D015474:Isotretinoin