A randomized clinical trial of 4-hydroxyphenylretinamide for high-grade squamous intraepithelial lesions of the cervix.

Abstract

PURPOSE:

Previous trials of topical trans-retinoic acid treatment of cervical intraepithelial neoplasia (CIN) grades 2 and 3 led to a statistically significant regression of CIN 2, but not CIN 3. We tested N-(4-hydroxyphenyl)retinamide (4-HPR), a promising oral retinoid that has been shown to induce apoptosis through nonretinoic receptor acid-mediated pathways, for its toxicity and efficacy against CIN 2/3.

EXPERIMENTAL DESIGN:

In a blinded randomized trial, 4-HPR at 200 mg/day for 6 months (with a 3-day/month drug holiday) was compared with placebo in patients with biopsy-proven CIN-2/3 [high-grade squamous intraepithelial lesions (HGSILs)]. Patients were treated with placebo or 4-HPR for 6 months, biopsied, and then followed for an additional 6 months. At the 12-month end point, they underwent either loop excision if a histological lesion was present or a biopsy from the original area of the lesion if no lesion was present.

RESULTS:

An interim analysis of blinded data showed a significantly worse prognosis at 12 months for one group. When the code was broken because of the poorer outcomes, we discovered that the 4-HPR treatment arm was performing more poorly than was the placebo at 6 and 12 months (25 versus 44% response rates at 6 months; 14 versus 50% at 12 months). Toxicity was not significant in either arm.

CONCLUSIONS:

4-HPR at 200 mg/day with a 3-day/month drug holiday is not active compared with placebo in the treatment of HGSIL. Because 4-HPR is active in the laboratory, the lack of effect in our trial may indicate that higher doses are needed in patients to achieve comparable results.

• Authors: M Follen, E N Atkinson, D Schottenfeld, A Malpica, L West, S Lippman, C Zou, W N Hittelman, R Lotan, W K Hong
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 7 Issue 11 Pg. 3356-65 (Nov 2001) ISSN: 1078-0432 [Print] United States
• PMID: 11705848 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial)

Chemical References

• Antineoplastic Agents
• Fenretinide

Topics

• Adult
• Antineoplastic Agents (adverse effects, therapeutic use)
• Cheilitis (chemically induced)
• Cross-Over Studies
• Exanthema (chemically induced)
• Female
• Fenretinide (adverse effects, blood, therapeutic use)
• Humans
• Medical Futility
• Patient Compliance
• Photosensitivity Disorders (chemically induced)
• Time Factors
• Treatment Outcome
• Uterine Cervical Neoplasms (drug therapy, pathology)
• Uterine Cervical Dysplasia (drug therapy, pathology)