Modulation of irinotecan with cyclosporine: a phase II trial in advanced colorectal cancer
Modulation of irinotecan with cyclosporine: a phase II trial in advanced colorectal cancer
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DOI：
10.1007/s00280-005-1020-5
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发表时间：
2005-10-01
影响因子：
3
通讯作者：
Vokes, EE
中科院分区：
文献类型：
--
作者：
Desai, AA;Kindler, HL;Vokes, EE
引言：尽管伊立替康具有广泛的临床经验，但其毒性仍存在重大问题。在一项I期试验中，我们通过使用环孢菌素抑制SN-38（伊立替康的活性代谢产物）的胆汁排泄来调节伊立替康的药代动力学。该调节似乎降低了伊立替康的胃肠道毒性，并表明伊立替康活性也可能保留。因此，我们在结直肠癌（CRC）患者中进行了这项II期试验，以进一步评估环孢霉素调节的伊立替康的毒性和活性。患者和方法：16例5-氟尿嘧啶难治性结直肠癌患者接受了治疗。环孢霉素（5 mg/kg）输注6小时，伊立替康（60 mg/m2/天，90分钟输注）在环孢霉素开始后3小时开始。两种药物每周给药一次，共4周，每6周给药一次。每12周评估一次反应，每周监测一次毒性。结果：16例患者可评价毒性，11例可评价反应。有1例部分缓解（6%）。5例患者的SD持续时间中位数为12周。仅在13%的患者中观察到3/4级腹泻。结论：肠外环孢霉素调节伊立替康的药代动力学似乎可降低CRC患者腹泻的发生率。鉴于伊立替康单药治疗的活性中等，需要进行更大规模的研究，以评估该调节是否在不影响该活性的情况下改善毒性。现有临床数据表明，应进一步评价伊立替康的药代动力学调节，以确定其最佳临床效用。
Introduction: Despite the extensive clinical experience with irinotecan, significant concerns remain regarding its toxicity. In a phase I trial, we modulated irinotecan pharmacokinetics by inhibiting biliary excretion of SN-38, the active metabolite of irinotecan, using cyclosporine. The modulation appeared to decrease the gastrointestinal toxicity of irinotecan and suggested that irinotecan activity might also be retained. Hence, we conducted this phase II trial in patients with colorectal cancer (CRC) to further evaluate the toxicity and activity of irinotecan modulated with cyclosporine. Patients and Methods: Sixteen patients with 5-fluorouracil refractory CRC were treated. Cyclosporine (5 mg/kg) was administered as a 6-h infusion and irinotecan (60 mg/m(2)/day, 90-min infusion) was started 3 h after initiation of the Cyclosporine. Both agents were given weekly for 4 weeks, every 6 weeks. Responses were assessed every 12 weeks, and toxicity was monitored weekly. Results: Sixteen patients were evaluable for toxicity and 11 for response. There was 1 partial response (6%). Five patients had SD lasting a median of 12 weeks. Grade 3/4 diarrhea was observed in only 13% of the patients. Conclusion: Pharmacokinetic modulation of irinotecan using parenteral cyclosporine appears to decrease the incidence of diarrhea in CRC patients. Given the modest activity of irinotecan monotherapy, a larger study would be required to assess if the modulation improves the toxicity without compromising this activity. The available clinical data suggest that pharmacokinetic modulation of irinotecan should be evaluated further to define its optimal clinical utility.