© 1994 by Oxford University Press
Journal of the National Cancer Institute, Vol. 86, No. 7, 539-543,
April 6, 1994
© 1994 Oxford University Press
Enhancement of Regression of Cervical Intraepithelial Neoplasia II (Moderate Dysplasia) With Topically Applied All-trans-Retinoic Acid: a Randomized Trial
Deparment of Medicine, Arizona Cancer Center, University of Arizona Tucson
Department of Obstetrics and Gynecology, Arizona Cancer Center, University of Arizona Tucson
Department of Family and Community Medicine, Arizona Cancer Center, University of Arizona Tucson
Davis Department of Pathology, Arizona Cancer Center, University of Arizona Tucson
Department of Pharmacology, Arizona Cancer Center, University of Arizona Tucson
Department of Medicine and Pharmacology, Arizona Cancer Center, University of Arizona Tucson
Correspondence to present address: Frank L. Meyskens, Jr., M.D., F.A.C.P., Universioty of California, Irvine Clinical Cancer Center, 101 The City Dr., Rt. 81, Orange, CA 92668.
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 demostrated 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, Papanocolaou cytology, and cervical biopsy. Cervical caps with sponges containing either 1.0 mL of 0.372% 
-trans-RA or a placebo were inserted daily for 4 days when women entered the trial, and for 2 days at months 3 and 6. Patients 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 and epithelial preneoplasia, lending further support to the notion that chemoprevention of human cancer is feasible. [J Natl Cancer Inst 86: 539–534, 1994]
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|
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