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


METHODS
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.
Follen
M
M
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. mfollen@mdanderson.org.
Atkinson
E N
EN
Schottenfeld
D
D
Malpica
A
A
West
L
L
Lippman
S
S
Zou
C
C
Hittelman
W N
WN
Lotan
R
R
Hong
W K
WK
D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002613:Cheilitis / Q000139:chemically induced; D018592:Cross-Over Studies; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D017313:Fenretinide / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D006801:Humans; D018447:Medical Futility; D010349:Patient Compliance; D010787:Photosensitivity Disorders / Q000139:chemically induced; D013997:Time Factors; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; D017313:Fenretinide