Saliba F, Hagipantelli R, Misset J L, Bastian G, Vassal G, Bonnay M, Herait P, Cote C, Mahjoubi M, Mignard D, Cvitkovic E
Paul Brousse Hospital, Villejuif, France.
J Clin Oncol. 1998 Aug;16(8):2745-51. doi: 10.1200/JCO.1998.16.8.2745.
Irinotecan (CPT-11), a camptothecin derivative, has shown efficacy against colorectal cancer. Delayed-onset diarrhea is its main limiting toxicity. The aim of this study was to determine the pathophysiology of CPT-11-induced delayed-onset diarrhea and assess the efficacy of combined antidiarrheal medication in a phase II, prospective, successive-cohorts, open study.
Twenty-eight patients with advanced colorectal cancer refractory to fluorouracil (5-FU) therapy received CPT-11 350 mg/m2 every 3 weeks. The first cohort of 14 consecutive patients explored for the mechanism of diarrhea received acetorphan (a new enkephalinase inhibitor) 100 mg three times daily; the second 14-patient cohort received, in addition to acetorphan, loperamide 4 mg three times daily. Before treatment, and if late diarrhea occurred, patients underwent colon mucosal biopsies for CPT-11 and topoisomerase I levels; intestinal transit time; fecalogram; fat and protein excretion; alpha1-antitrypsin clearance; D-xylose test; blood levels for vasoactive intestinal polypeptide, glucagon, gastrin, somatostatin, prostaglandin E2, and carboxylesterase; CPT-11/SN-38 and SN-38 glucuronide pharmacokinetics; and stool cultures.
Delayed-onset diarrhea occurred during the first three treatment cycles in 23 patients (82%). Electrolyte fecal measurements showed a negative or small osmotic gap in nine of nine patients and an increased alpha1-antitrypsin clearance in six of six patients. There were no modifications in stool cultures or hormonal dysfunction. Four of 11 patients (36%) with delayed-onset diarrhea in the first cohort responded to acetorphan, whereas nine of 10 patients (90%) responded to the combination of acetorphan and loperamide (P < .02).
CPT-11-induced delayed-onset diarrhea is caused by a secretory mechanism with an exudative component. Early combined treatment with loperamide and acetorphan seems effective in controlling the diarrheal episodes.
伊立替康（CPT-11）是一种喜树碱衍生物，已显示出对结直肠癌有效。迟发性腹泻是其主要的限制毒性。本研究的目的是确定CPT-11诱导的迟发性腹泻的病理生理学，并在一项II期、前瞻性、连续队列、开放性研究中评估联合止泻药物的疗效。
28例对氟尿嘧啶（5-FU）治疗难治的晚期结直肠癌患者每3周接受350mg/m²的CPT-11治疗。连续14例患者的第一组探索腹泻机制，每天3次接受100mg阿醋托芬（一种新的脑啡肽酶抑制剂）；第二组14例患者除阿醋托芬外，每天3次接受4mg洛哌丁胺。治疗前，以及如果发生晚期腹泻，患者进行结肠黏膜活检以检测CPT-11和拓扑异构酶I水平；肠道转运时间；粪便造影；脂肪和蛋白质排泄；α1-抗胰蛋白酶清除率；D-木糖试验；血管活性肠肽、胰高血糖素、胃泌素、生长抑素、前列腺素E2和羧酸酯酶的血药浓度；CPT-11/SN-38和SN-38葡糖苷酸的药代动力学；以及粪便培养。
23例患者（82%）在最初三个治疗周期中出现迟发性腹泻。粪便电解质测量显示，9例患者中有9例的渗透压差为负或较小，6例患者中有6例的α1-抗胰蛋白酶清除率增加。粪便培养或激素功能障碍无变化。第一组中11例迟发性腹泻患者中有4例（36%）对阿醋托芬有反应，而10例患者中有9例（90%）对阿醋托芬和洛哌丁胺的联合用药有反应（P<0.02）。
CPT-11诱导的迟发性腹泻是由一种伴有渗出成分的分泌机制引起的。洛哌丁胺和阿醋托芬的早期联合治疗似乎对控制腹泻发作有效。
