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.
RCT Entities:
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: Cornelia L Trimble; Steven Piantadosi; Patti Gravitt; Brigitte Ronnett; Ellen Pizer; Andrea Elko; Barbara Wilgus; William Yutzy; Richard Daniel; Keerti Shah; Shiwen Peng; Chienfu Hung; Richard Roden; Tzyy Choou Wu; Drew Pardoll Journal: Clin Cancer Res Date: 2005-07-01 Impact factor: 12.531
Authors: Doris M Benbrook; Scott A Kamelle; Suresh B Guruswamy; Stan A Lightfoot; Teresa L Rutledge; Natalie S Gould; Bethany N Hannafon; S Terence Dunn; K Darrell Berlin Journal: Invest New Drugs Date: 2005-10 Impact factor: 3.850
Authors: Erin M Siegel; Jason L Salemi; Neal E Craft; Luisa L Villa; Alex S Ferenczy; Eduardo L Franco; Anna R Giuliano Journal: Cancer Prev Res (Phila) Date: 2010-07-06
Authors: M M Koeneman; A J Kruse; L F S Kooreman; A Zur Hausen; A H N Hopman; S J S Sep; T Van Gorp; B F M Slangen; H J van Beekhuizen; M van de Sande; C G Gerestein; H W Nijman; R F P M Kruitwagen Journal: BMC Cancer Date: 2016-02-20 Impact factor: 4.430