Evans T R J, Pentheroudakis G, Paul J, McInnes A, Blackie R, Raby N, Morrison R, Fullarton G M, Soukop M, McDonald A C
CRC Dept of Medical Oncology, University of Glasgow, Beatson Oncology Centre, Western Infirmary, Glasgow, UK.
Ann Oncol. 2002 Sep;13(9):1469-78. doi: 10.1093/annonc/mdf243.
The purpose of this study was to evaluate the dose-limiting toxicity (DLT) and maximum tolerated dose of capecitabine when used in combination with epirubicin and cisplatin (ECC) in patients with oesophageal or gastric adenocarcinoma. Response rate, progression-free survival (PFS) and overall survival were also determined, and the effect of previous oesophago-gastric surgery or concurrent oesophago-gastric cancer on the absorption and metabolism of capecitabine was evaluated.
Patients with inoperable oesophago-gastric adenocarcinoma received up to six cycles of epirubicin (50 mg/m(2) i.v., 3-weekly), cisplatin (60 mg/m(2) i.v., 3-weekly) and capecitabine, the latter administered orally in an intermittent schedule (14 days treatment; 7-day rest period) at 3-weekly intervals. Patients were recruited into one of four escalating dose cohorts (500, 825, 1000 and 1250 mg/m(2) bd). Dose escalation occurred after six patients had completed at least one cycle of chemotherapy at the previous dose level, with DLT assessed on the toxicity of the first cycle only. Blood sampling for pharmacokinetic analyses was performed over the first 10 h of day 1 of cycle 1.
Thirty-two patients, median age 63 years (range 32-76 years), ECOG performance status < or =2 with locally advanced (10) or metastatic (22) disease were recruited and were evaluable for toxicity. Two of five patients experienced DLT at 1250 mg/m(2) bd with grade II stomatitis (one patient) and grade III diarrhoea with febrile neutropenia (one patient). Cumulative toxicity for all cycles (n = 140) (worst grade per patient) includes grade IV oesophagitis (one patient), grade III diarrhoea (five), grade IV neutropenia with infection (seven), grade II stomatitis (four) and grade IV thrombocytopenia (one). Of 29 patients with evaluable disease, there was one complete response and six partial responses [24% response rate [95% confidence interval (CI) 10% to 44%]], a median PFS of 22 weeks (95% CI 17-27 weeks) and median overall survival of 34 weeks (95% CI 19-49 weeks). Capecitabine was rapidly absorbed after oral administration, with a t(max) of 1-2 h for capecitabine, DFCR (5'-deoxy-5-fluorocytidine) and DFUR (5'-deoxy-5-fluorouridine). The C(max) and AUC(0-)( infinity ) for capecitabine, DFCR and DFUR were similar to those observed in previous monotherapy studies of capecitabine taken after food.
A dose of 1000 mg/m(2) bd of capecitabine is recommended for use on an intermittent schedule in combination with these doses and schedule of epirubicin and cisplatin. This regimen is tolerable and active in oesophago-gastric adenocarcinoma. A randomised phase III comparison with ECF is justified.
本研究旨在评估卡培他滨与表柔比星和顺铂（ECC）联合应用于食管或胃腺癌患者时的剂量限制性毒性（DLT）和最大耐受剂量。同时确定缓解率、无进展生存期（PFS）和总生存期，并评估既往食管胃手术或同时存在的食管胃癌对卡培他滨吸收和代谢的影响。
无法手术的食管胃腺癌患者接受多达六个周期的表柔比星（50mg/m²静脉注射，每3周一次）、顺铂（60mg/m²静脉注射，每3周一次）和卡培他滨治疗，后者采用间歇给药方案（治疗14天；休息7天），每3周一次。患者被纳入四个剂量递增队列之一（500、825、1000和1250mg/m²每日两次）。在六名患者完成前一剂量水平的至少一个化疗周期后进行剂量递增，仅根据第一个周期的毒性评估DLT。在第1周期第1天的前10小时内进行药代动力学分析的血样采集。
招募了32例患者，中位年龄63岁（范围32 - 76岁），ECOG体能状态≤2，患有局部晚期（10例）或转移性（22例）疾病，且可评估毒性。五名患者中有两名在1250mg/m²每日两次剂量时出现DLT，分别为II级口腔炎（一名患者）和III级腹泻伴发热性中性粒细胞减少（一名患者）。所有周期（n = 140）的累积毒性（每位患者最严重级别）包括IV级食管炎（一名患者）、III级腹泻（五名）、IV级中性粒细胞减少伴感染（七名）、II级口腔炎（四名）和IV级血小板减少（一名）。在29例可评估疾病的患者中，有1例完全缓解和6例部分缓解[缓解率24%[95%置信区间（CI）10%至44%]]，中位PFS为22周（95%CI 17 - 27周），中位总生存期为34周（95%CI 19 - 49周）。卡培他滨口服后吸收迅速，卡培他滨及其代谢产物5'-脱氧-5-氟胞苷（DFCR）和5'-脱氧-5-氟尿苷（DFUR）的达峰时间（t(max)）为1 - 2小时。卡培他滨、DFCR和DFUR的峰浓度（C(max)）和药时曲线下面积（AUC(0 - ∞)）与既往卡培他滨餐后单药治疗研究中观察到的相似。
建议卡培他滨剂量为1000mg/m²每日两次，并采用间歇给药方案与这些剂量和给药方案的表柔比星和顺铂联合使用。该方案在食管胃腺癌中耐受性良好且具有活性。与ECF方案进行随机III期比较是合理的。
