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Low-Dose Topical Delivery of All-Trans Retinoic Acid for Cervical Intraepithelial Neoplasia II and III

Departments of ¹ Family Medicine, ² Radiation Oncology, ³ Pathology, and ⁴ Internal Medicine-Hematology/Oncology, University of Michigan, Ann Arbor, Michigan; ⁵ Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan; and ⁶ Centers for Disease Control and Prevention, Atlanta, Georgia

Requests for reprints: M.T. Ruffin, Department of Family Medicine, University of Michigan, 1018 Fuller Street, Ann Arbor, MI 48109-0708. Phone: 737-998-7120; Fax: 734-998-7335. E-mail: mruffin{at}umich.edu

Objective: The objective of this study was to determine an effective dose for all-trans retinoic acid (atRA) delivered with a cervical cap and sponge for 4 days to women with cervical intraepithelial neoplasia (CIN) II/III.

Methods: Study participants made up of 175 women with biopsy-proven CIN II/III were randomized to four consecutive days of atRA at one of three doses (0.16%, 0.28%, and 0.36%) or placebo. All subjects underwent a repeat colposcopy evaluation and biopsy of the cervix at 12 weeks.

Results: The study participants mean ages were 27.6 years. The racial distribution was 63% Caucasian, 27% African American, and 8% other. Among participants, 93% were human papillomavirus-positive at baseline with 68% positive for high-risk types. The disease response at 12 weeks to atRA or placebo was not significantly different (P = 0.49) among the four dose groups. Participants with CIN II at baseline were more likely to be free of disease at 12 weeks than participants with CIN III at baseline (P = 0.003). There were no reported systemic adverse events related to drug or placebo exposure and only mild local self-reported and clinician-detected toxicities.

Conclusion: Lower concentrations of atRA applied with a cervical cap for 4 days were no more effective than placebo. However, the rate of histologic regression in biopsied CIN II/III patients was high even over a short time interval, and emphasizes the importance of having a placebo arm and an adequate sample size.

Key Words: Gynecological cancers: cervical • Premalignant lesions • Drug Design and Optimization • Phase I-III Clinical Trials • Retinoids and receptors