ENHANCEMENT OF REGRESSION OF CERVICAL INTRAEPITHELIAL NEOPLASIA-II (MODERATE DYSPLASIA) WITH TOPICALLY APPLIED ALL-TRANS-RETINOIC ACID - A RANDOMIZED TRIAL

Background: Retinoids enhance differentiation of most epithelial tissues. Epidemiologic studies have shown an inverse relationship between dietary intake or serum levels of vitamin A and the development of cervical dysplasia and/or cervical cancer. Pilot and phase I investigations demonstrated the feasibility of the local delivery of all-trans-retinoic acid (RA) to the cervix using a collagen sponge insert and cervical cap. A phase II trial produced a clinical complete response rate of 50%. Purpose: This randomized phase III trial was designed to determine whether topically applied RA reversed moderate cervical intraepithelial neoplasia (CIN) II or severe CIN. Methods: Analyses were based on 301 women with CIN (moderate dysplasia, 151 women; severe dysplasia, 150 women), evaluated by serial colposcopy, Papanicolaou cytology, and cervical biopsy. Cervical caps with sponges containing either 1.0 mt, of 0.372% beta-trans-RA or a placebo were inserted daily for 4 day when women entered the trial, and for 2 days at months 3 and 6. Patient receiving treatment and those receiving placebo were similar with respect to age, ethnicity, birth-control methods histologic features of the endocervical biopsy specimen and koilocytotic atypia, and percentage of involvement of the cervix at study. Treatment effects were compared using Fisher's exact test and logistic regression methods. Side effects were recorded, and differences were compared using Fisher's exact test. Results: RA increased the complete histologic regression rate of CIN II from 27% in the placebo group to 43% in the retinoic acid treatment group (P = .041). No treatment difference between the two arms was evident in the severe dysplasia group. More vaginal and vulvar side effects were seen in the patients receiving RA, but these effects were mild and reversible. Conclusions: A short course of locally applied RA can reverse CIN II, but not more advanced dysplasia, with acceptable local side effects. Implications: A derivative of vitamin A can reverse or suppress an epithelial preneoplasia, lending further support to the notion that chemoprevention of human cancer is feasible.