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Departments of Gynecologic Oncology [M. F., L. W., C. Z.], Biomathematics [E. N. A.], Pathology [A. M.], Experimental Therapeutics [W. N. H.], Cell Biology [R. L.], and Head and Neck Thoracic Oncology [S. L., W. K. H.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Department of Obstetrics, Gynecology, and Reproductive Biology, The University of Texas Health Science Center; Houston, Texas [M. F., L. W., C. Z.]; and Department of Epidemiology, The University of Michigan, School of Public Health I, Ann Arbor, Michigan 48104 [D. S.]
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.
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F. Formelli Correspondence re: M. Follen et al., A Randomized Clinical Trial of 4-Hydroxyphenylretinamide for High-Grade Squamous Intraepithelial Lesions of the Cervix. Clin. Cancer Res., 7: 3356-3365, 2001 Clin. Cancer Res., May 1, 2002; 8(5): 1310 - 1312. [Full Text] [PDF]
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M. Follen and H. A. Fritsche Reply Clin. Cancer Res., May 1, 2002; 8(5): 1313 - 1313. [Full Text] [PDF]
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