title: Randomized trial of 13-cis retinoic acid compared with retinyl palmitate with or without beta-carotene in oral premalignancy.
abstract: OBJECTIVE
  To investigate whether retinyl palmitate (RP) alone or plus beta-carotene (BC) would be as effective and less toxic than low-dose 13-cis retinoic acid (13cRA) in treating oral premalignant lesions (OPLs) and reducing the risk of oral cancer.
  
  
  METHODS
  Initially, patients were randomly assigned to receive low-dose 13cRA or BC plus RP for 3 years (plus 2 years follow-up). After other randomized trials established an adverse effect of BC on lung cancer incidence/mortality, BC was dropped (patients randomly assigned to 13cRA or RP alone). The primary end point was OPL clinical response at 3 months.
  
  
  RESULTS
  We randomly assigned 162 eligible patients. The 3-month clinical response rate of the combined BC plus RP and RP alone arm (32.5%) was not statistically equivalent to that of 13cRA (48.1%). The clinical response rate of RP alone (20.0%) was significantly lower than that of BC plus RP (42.9%; P = .03). Similar oral cancer-free survival rates were observed across all arms. There was no significant association between 3-month OPL response and subsequent oral cancer development (P = .11). Grades 2 and higher adverse events were more common in the 13cRA than other groups (P < .0001).
  
  
  CONCLUSIONS
  This large chemoprevention trial did not establish the equivalence of RP plus BC or RP alone with low-dose 13cRA in reducing the long-term risk of oral cancer. At present, 13cRA, BC plus RP, and RP alone cannot be recommended for chemoprevention, and new, better agents are needed in this setting. Our results did not establish short-term OPL response as a surrogate end point for oral cancer-free survival.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. vpapadim@mdanderson.org
authors.forename: Vassiliki A
authors.initials: VA
authors.lastname: Papadimitrakopoulou
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: William N
authors.initials: WN
authors.lastname: William
authors.forename: Jack W
authors.initials: JW
authors.lastname: Martin
authors.forename: Margaret
authors.initials: M
authors.lastname: Thomas
authors.forename: Edward S
authors.initials: ES
authors.lastname: Kim
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.forename: Lei
authors.initials: L
authors.lastname: Feng
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016588:Anticarcinogenic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004224:Diterpenes; D005260:Female; D006801:Humans; D015474:Isotretinoin / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000517:prevention & control*; D011230:Precancerous Conditions / Q000188:drug therapy*; D000084562:Retinyl Esters; D016896:Treatment Outcome; D014801:Vitamin A / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D014815:Vitamins / Q000008:administration & dosage* / Q000009:adverse effects; D019207:beta Carotene / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D016588:Anticarcinogenic Agents; D004224:Diterpenes; D000084562:Retinyl Esters; D014815:Vitamins; D019207:beta Carotene; D014801:Vitamin A; C014794:retinol palmitate; D015474:Isotretinoin