Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial
Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial
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DOI：
10.1158/1940-6207.capr-08-0042
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发表时间：
2008-06-01
影响因子：
3.3
通讯作者：
Gerner, Eugene W.
中科院分区：
文献类型：
--
作者：
Meyskens, Frank L., Jr.;McLaren, Christine E.;Gerner, Eugene W.
低剂量联合给予化学预防药物的临床前研究显示在预防腺瘤方面具有显著的疗效，几乎没有额外的毒性，这表明了一种改善预防复发性腺瘤的风险受益比的策略。375例有腺瘤切除史（>= 3 mm）的患者被随机分配接受口服二氟甲基鸟氨酸（DFMO）500 mg和舒林酸150 mg，每日一次或匹配的安慰剂治疗36个月，根据基线和临床部位使用低剂量阿司匹林（81 mg）分层。在随机化或退出研究后3年进行随访结肠镜检查。采用对数二项回归分析比较各组结直肠腺瘤复发率。比较接受安慰剂治疗的患者和接受积极干预的患者的结果，（a）一个或多个腺瘤的复发率分别为41.1%和12.3%，（风险比，0.30; 95%置信区间，0.18-0.49; P < 0.001）;（B）8.5%的患者有一个或多个晚期腺瘤，而0.7%的患者有一个或多个晚期腺瘤，（风险比，0.085; 95%可信区间，0.011-0.65; P < 0.001）;（c）17例（13.2%）患者在最后一次结肠镜检查时有多发性腺瘤（>1个），而1例（0.7%;风险比，0.055; 0.0074-0.41; P < 0.001）。安慰剂组8.2%的患者发生严重不良事件（≥ 3级），而积极干预组为11%（P = 0.35）。报告听力较基线变化的患者比例无显著差异。低剂量口服DFMO和舒林酸可显著减少复发性腺瘤性息肉，且副作用少。
Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (>= 3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18-0.49; P < 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011-0.65; P < 0.001); and (c) 17 (13.2%) patients had multiple adenomas (>1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074-0.41; P < 0.001). Serious adverse events (grade >= 3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.