Randomized trial of 13-cis retinoic acid compared with retinyl palmitate with or without beta-carotene in oral premalignancy.
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.
Papadimitrakopoulou
Vassiliki A
VA
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
Lee
J Jack
JJ
William
William N
WN
Martin
Jack W
JW
Thomas
Margaret
M
Kim
Edward S
ES
Khuri
Fadlo R
FR
Shin
Dong M
DM
Feng
Lei
L
Hong
Waun Ki
WK
Lippman
Scott M
SM
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
D016588:Anticarcinogenic Agents; D004224:Diterpenes; D000084562:Retinyl Esters; D014815:Vitamins; D019207:beta Carotene; D014801:Vitamin A; C014794:retinol palmitate; D015474:Isotretinoin