Ryan David P, Puchalski Thomas, Supko Jeffrey G, Harmon David, Maki Robert, Garcia-Carbonero Rocio, Kuhlman Caroline, Winkelman Jennifer, Merriam Priscilla, Quigley Travis, Jimeno Jose, Manola Judith, Demetri George D
Division of Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, 100 Blossom Street, Boston, MA 02114, USA.
Oncologist. 2002;7(6):531-8. doi: 10.1634/theoncologist.7-6-531.
To assess the efficacy, tolerability, and pharmacokinetics of ecteinascidin 743 (ET-743) in patients with advanced gastrointestinal stromal tumors (GISTs).
The study was confined to adult patients with radiographically measurable GISTs. ET-743 was administered as a 24-hour continuous i.v. infusion at a dose of 1.5 mg/m(2) repeated every 3 weeks. Pharmacokinetic blood sampling was performed during the first cycle of therapy. Tumors were restaged after every second cycle of therapy.
A total of 20 patients was enrolled in the study, 19 of whom were treated with 47 cycles of ET-743 (median 2, range 1-10). Severe toxicities were limited to reversible grade 3 transaminitis in 10 patients and grade 3 fatigue in one patient. There were no objective responses, and disease stabilization occurred in two patients lasting for periods of 4 and 10 months. The 1-year survival rate was 71.1%. Mean +/- standard deviation values of the maximum plasma concentration and total plasma clearance were 1.1 +/- 0.4 ng/ml and 44 +/- 16 l/h/m(2), respectively, for 19 of the 20 patients.
This study is the first report of a prospective phase II trial to evaluate a cytotoxic agent in patients with GISTs. This study underscores the primary resistance of GISTS to chemotherapy and stands in stark contrast to the encouraging results recently achieved with STI571. The lack of response may be associated with a therapeutically ineffective exposure to the drug based upon the lower incidence of severe toxicities and greater clearance than described in phase I and II trials of ET-743.
评估埃博霉素743（ET-743）治疗晚期胃肠道间质瘤（GISTs）患者的疗效、耐受性及药代动力学。
本研究纳入成年、影像学可测量GISTs患者。ET-743以1.5mg/m²剂量进行24小时持续静脉输注，每3周重复一次。在治疗的第一个周期进行药代动力学血样采集。每两个治疗周期后对肿瘤进行重新分期。
共20例患者入组本研究，其中19例接受了47个周期的ET-743治疗（中位数2个周期，范围1 - 10个周期）。严重毒性反应仅限于10例患者出现可逆性3级转氨酶升高和1例患者出现3级疲劳。未观察到客观缓解，2例患者疾病稳定，持续时间分别为4个月和10个月。1年生存率为71.1%。20例患者中的19例，其最大血浆浓度和总血浆清除率的平均值±标准差分别为1.1±0.4ng/ml和44±16l/h/m²。
本研究是评估细胞毒性药物治疗GISTs患者的前瞻性II期试验的首次报告。本研究强调了GISTs对化疗的原发性耐药，这与最近使用STI571取得的令人鼓舞的结果形成鲜明对比。基于严重毒性反应发生率较低以及清除率高于ET-743的I期和II期试验中所描述的情况，缺乏反应可能与药物治疗无效的暴露有关。
