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Results of a Phase II Double-Blinded Randomized Clinical Trial of Difluoromethylornithine for Cervical Intraepithelial Neoplasia Grades 2 to 3

Departments of ¹ Gynecologic Oncology, ² Biostatistics and Applied Mathematics, ³ Pathology, ⁴ Division of Medicine, and ⁵ Center for Biomedical Engineering, ⁶ Obstetrics and Reproductive Sciences, The University of Texas M.D. Anderson Cancer Center; and ⁷ Department of Pathology, The University of Texas Health Science Center at Houston, Houston, Texas

Requests for reprints: M. Follen, The University of Texas M.D. Anderson Cancer Center, Unit 193, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-2564; Fax: 713-792-4856; E-mail: mfollen{at}mdanderson.org, rzwelling{at}mdanderson.org.

Purpose: Our purpose was to conduct a double-blinded randomized trial of difluoromethylornithine (DFMO) at 0.125, 0.5 gm/m², versus placebo in the treatment of cervical intraepithelial neoplasia (CIN) grades 2 to 3. A promising phase I study has shown histopathologic responses at these dose levels.

Experimental Design: Patients with histopathologically confirmed CIN 2-3 lesions were recruited from a colposcopy clinic and underwent Papanicolaou testing, human papillomavirus testing, and colpophotography. They took oral contraception and DFMO or placebo elixir for 28 days and filled out the National Cancer Institute common toxicity calendars. They returned for follow-up and a repeat Papanicolaou smear, colpophotograph, and loop excision of the cervix.

Results: There were no statistically significant differences among the arms in histopathologic response. This could no be explained by any biases in risk factors. The prominent toxicities were diarrhea, dizziness, nausea, and headaches. There were no differences in the toxicities among arms. The Papanicolaou smear was a poor biomarker of response and correlated poorly with the histopathology.

Conclusions: DFMO is no active at 0.125 and 0.5 gm/m² for 28 days when given orally in CIN 2-3. Higher oral doses or longer administration is necessary, supporting data from breast trials. Alternatively, a trial of topical DFMO might merit attention as activity has been noed in trials of actinic keratoses.

Key Words: HPV • chemoprevention • biomarkers • ornithine decarboxylase

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