Adjei A A, Klein C E, Kastrissios H, Goldberg R M, Alberts S R, Pitot H C, Sloan J A, Reid J M, Hanson L J, Atherton P, Rubin J, Erlichman C
Department of Oncology, Mayo Clinic and Foundation, Rochester, MN, USA.
J Clin Oncol. 2000 Mar;18(5):1116-23. doi: 10.1200/JCO.2000.18.5.1116.
The goals of this study were to determine the maximum-tolerated dose and describe the toxicities of the combination of irinotecan and docetaxel administered every 3 weeks to patients with advanced malignancies and, also, to evaluate the effect of irinotecan on the disposition of docetaxel and describe preliminary evidence of antitumor activity.
Eighteen patients received 85 courses (median, two courses; range, one to 15 courses) of treatment with irinotecan, administered over 90 minutes by intravenous infusion, followed by docetaxel, administered over 60 minutes by intravenous infusion. Four escalating dose levels of irinotecan/docetaxel (160/50 mg/m(2), 160/65 mg/m(2), 200/65 mg/m(2), and 200/75 mg/m(2)) were studied. Pharmacokinetic analyses were performed to evaluate the effect of irinotecan on the disposition of docetaxel.
The most common and dose-limiting toxicity was myelosuppression, which consisted of neutropenia that was severe (National Cancer Institute common toxicity criteria [NCI CTC] grade 4) but brief (< 5 days) in 11 patients, with three episodes of febrile neutropenia. Nonhematologic toxicities of anorexia, nausea, and stomatitis were mild to moderate (NCI CTC grades 1 and 2), but there was one incidence each of both CTC grade 3 anorexia and nausea. All patients had total alopecia. Diarrhea was dose-dependent and severe in four patients who failed to take adequate antidiarrhea therapy. Five out of 16 assessable patients, one with cholangiocarcinoma, one with leiomyosarcoma, and three with non-small-cell lung cancer, achieved partial remissions.
The combination of irinotecan and docetaxel causes significant reversible myelosuppression, which was dose limiting but led to no serious sequelae. There was no evidence of a clinically significant interaction using these two agents in this sequence. The combination showed antitumor activity at all the dose levels tested and should be further studied in a number of tumor types. The recommended phase II dose on this schedule is irinotecan 160 mg/m(2) and docetaxel 65 mg/m(2).
本研究的目的是确定晚期恶性肿瘤患者每3周接受一次伊立替康和多西他赛联合治疗的最大耐受剂量并描述其毒性，同时评估伊立替康对多西他赛药代动力学的影响，并描述抗肿瘤活性的初步证据。
18例患者接受了85个疗程（中位值为2个疗程；范围为1至15个疗程）的治疗，先静脉输注伊立替康90分钟，然后静脉输注多西他赛60分钟。研究了伊立替康/多西他赛的四个递增剂量水平（160/50mg/m²、160/65mg/m²、200/65mg/m²和200/75mg/m²）。进行了药代动力学分析以评估伊立替康对多西他赛药代动力学的影响。
最常见的剂量限制性毒性是骨髓抑制，表现为11例患者出现严重（美国国立癌症研究所通用毒性标准 [NCI CTC] 4级）但短暂（<5天）的中性粒细胞减少，伴有3次发热性中性粒细胞减少发作。厌食、恶心和口腔炎等非血液学毒性为轻度至中度（NCI CTC 1级和2级），但各有1例出现3级厌食和恶心。所有患者均出现完全脱发。腹泻具有剂量依赖性，4例未采取充分止泻治疗的患者腹泻严重。16例可评估患者中有5例实现部分缓解，其中1例为胆管癌，1例为平滑肌肉瘤，3例为非小细胞肺癌。
伊立替康和多西他赛联合使用会导致显著的可逆性骨髓抑制，这是剂量限制性的，但未导致严重后遗症。按此顺序使用这两种药物未发现有临床显著相互作用的证据。该联合方案在所有测试剂量水平均显示出抗肿瘤活性，应在多种肿瘤类型中进一步研究。该方案推荐的II期剂量为伊立替康160mg/m²和多西他赛65mg/m²。
