Winde G, Schmid K W, Schlegel W, Fischer R, Osswald H, Bünte H
Department of General Surgery, Westfalische Wilhelms-Universität Münster, Germany.
Dis Colon Rectum. 1995 Aug;38(8):813-30. doi: 10.1007/BF02049838.
This nonrandomized, controlled Phase II pilot study aims at the lowest effective dose of rectally applied sulindac to achieve and maintain adenoma reversion in colectomized patients with familial adenomatous polyposis (FAP).
The study group (n = 15) underwent proctoscopic and laboratory follow-up for polyp reversion every 6 to 12 weeks. Polyp reversion was followed by dose reduction in predefined steps. Proliferating cell nuclear antigen/cyclin (PCNA) and KI-67 proliferation indices (PI) were performed by point counting. Prostaglandin (PG)E2 and PGF2 alpha were quantified by time-resolved competitive fluorescence immunoassay.
All patients responded to therapy within 6 to 24 weeks. Sixty and 87 percent of patients achieved complete adenoma reversion after 48 weeks at 53 and 67 mg of sulindac per day per patient on average, respectively. Reversion was evident compared with the control group. Dose reduction by one-sixth to one-eighth of the usual oral dose was significant (Mann's trend test, P < 0.05). PCNA and KI-67 PIs of adenomatous and flat mucosa were significantly reduced (Wilcoxon's test, P < 0.05). Correlation of PCNA and KI-67 PIs indicate similar reaction of different tissue structures (Spearman's rank correlation test, P < 0.01). Nonsteroidal anti-inflammatory drug-induced redifferentiation from high-grade to low-grade dysplasia occurred in all but two patients. Tissue-PGE2 levels were greatly reduced. Unwanted, curable side effects were rare (gastritis, n = 2), and laboratory controls are within detection limits.
Low-dose rectal sulindac maintenance therapy is highly effective in achieving complete adenoma reversion without relapse in 87 percent of patients after 33 months. Rectal FAP phenotype should be crucial for the surgical decision. Colectomy with ileorectal anastomosis and regular chemoprevention might proceed to be a promising alternative to pouch procedures. Chemoprevention with lower incidence of FAP-related tumors via dysplasia reversion may be possible in the future.
本项非随机对照的II期试点研究旨在确定直肠应用舒林酸的最低有效剂量，以实现并维持家族性腺瘤性息肉病（FAP）结肠切除患者的腺瘤逆转。
研究组（n = 15）每6至12周接受直肠镜检查和实验室随访以观察息肉逆转情况。息肉逆转后按预定步骤减少剂量。通过点计数法检测增殖细胞核抗原/细胞周期蛋白（PCNA）和KI-67增殖指数（PI）。通过时间分辨竞争性荧光免疫测定法定量前列腺素（PG）E2和PGF2α。
所有患者在6至24周内对治疗有反应。平均每日每例患者分别给予53毫克和67毫克舒林酸治疗48周后，分别有60%和87%的患者实现了腺瘤完全逆转。与对照组相比，逆转情况明显。将剂量减至通常口服剂量的六分之一至八分之一具有显著意义（曼恩趋势检验，P < 0.05）。腺瘤性和平坦黏膜的PCNA和KI-67 PI显著降低（威尔科克森检验，P < 0.05）。PCNA和KI-67 PI的相关性表明不同组织结构的反应相似（斯皮尔曼等级相关检验，P < 0.01）。除两名患者外，所有患者均发生了非甾体抗炎药诱导的从高级别发育异常向低级别发育异常的再分化。组织PGE2水平大幅降低。不良但可治愈的副作用很少见（胃炎，n = 2），实验室检查结果在检测限内。
低剂量直肠舒林酸维持治疗在33个月后能使87%的患者有效实现完全腺瘤逆转且无复发。直肠FAP表型对于手术决策应至关重要。回肠直肠吻合术联合结肠切除术及定期化学预防可能成为袋形手术的一种有前景的替代方案。未来通过发育异常逆转降低FAP相关肿瘤发生率的化学预防可能成为现实。
