Ludwig Boltzmann Institute for Applied Cancer Research (LBI-ACR VIEnna)-LB Cluster Translational Oncology (LB-CTO), Kaiser Franz Josef-Spital, Vienna; Applied Cancer Research-Institution for Translational Research Vienna (ACR-ITR VIEnna)/CEADDP, Vienna.
Ludwig Boltzmann Institute for Applied Cancer Research (LBI-ACR VIEnna)-LB Cluster Translational Oncology (LB-CTO), Kaiser Franz Josef-Spital, Vienna; Applied Cancer Research-Institution for Translational Research Vienna (ACR-ITR VIEnna)/CEADDP, Vienna.
Ann Oncol. 2014 Sep;25(9):1789-1794. doi: 10.1093/annonc/mdu209. Epub 2014 Jun 16.
We conducted a phase I trial of gemcitabine (gem) with concurrent radiotherapy in patients with muscle-invasive bladder cancer (BC) ineligible for surgery or cisplatin or refusing organ loss.
Patients with urothelial cancer, cT2-T4, cN0-1, M0, ineligible for surgery due to local tumor extension, PS, age or co-morbidities or who refused surgery were included. After maximal transurethral resection, the treatment schedule included: twice-weekly i.v. infusion of gem [dose levels (DL) 1-6: 20, 27, 30, 33, 50 and 40 mg/m(2), respectively] for 30 min and concurrent radiotherapy (RT) to the bladder with 55.5 Gy. The primary end point was to determine the maximum-tolerated dose (MTD) and the dose recommended (RD) for further studies of this gem schedule. The secondary end point was late toxicity. The MTD was defined by dose-limiting toxicity (DLT) in 2 or more of 6 patients, discontinuation of RT and/or gem for >1 week in 2 or more of 6 patients due to grade (G) 3/4 acute and/or late toxicity in more than 2 of 18 patients.
Thirty-five of 44 patients were assessable for toxicity and thus the primary end point. DLTs occurred in two of five patients at dose level 5: one G3 alanine aminotransferase elevation and one G3 fatigue. The MTD, therefore, was 50 mg/m(2) gem twice weekly. At DL 6 with 40 mg/m(2), the RD was established: only one of six patients developed G3 fatigue and diarrhea. Late toxicity was rare and of low grade (only G1-2). The 2-year locoregional failure rate was 32% (9/28); 10 of 28 patients (38%) were alive with an intact bladder and no evidence of recurrent disease, 9 patients developed distant metastases and 6 died of their disease.
Gemcitabine in combination with RT is well tolerated in BC patients ineligible for surgery and/or cisplatin. The RD of gemcitabine for subsequent trials is 40 mg/m(2) twice weekly with concurrent radiation.
我们进行了一项吉西他滨（gem）联合放化疗治疗肌层浸润性膀胱癌（BC）患者的 I 期临床试验，这些患者不适宜手术或不能耐受顺铂治疗，或拒绝接受器官丧失。
纳入患有尿路上皮癌、cT2-T4、cN0-1、M0，由于局部肿瘤扩散、PS、年龄或合并症而不适宜手术，或拒绝手术的患者。在最大程度经尿道切除术后，治疗方案包括：每周两次静脉输注 gem [剂量水平（DL）1-6：分别为 20、27、30、33、50 和 40mg/m(2)]，持续 30 分钟，同时对膀胱进行 55.5Gy 的放疗。主要终点是确定最大耐受剂量（MTD）和进一步研究该 gem 方案的推荐剂量（RD）。次要终点是晚期毒性。MTD 通过 6 例患者中有 2 例或更多例出现剂量限制毒性（DLT）、6 例患者中有 2 例或更多例因 3/4 级急性和/或晚期毒性而停止 RT 和/或 gem 治疗超过 1 周来定义，超过 18 例患者中有 2 例或更多例发生毒性。
44 例患者中有 35 例可评估毒性，因此达到了主要终点。5 例患者中有 2 例在剂量水平 5 时出现 DLT：1 例丙氨酸氨基转移酶升高 3 级，1 例疲劳 3 级。因此，MTD 为每周两次 gem 50mg/m(2)。在 DL6 时，用 40mg/m(2)，确定 RD：仅有 1 例患者出现 3 级疲劳和腹泻。晚期毒性罕见且程度较低（仅 1-2 级）。2 年局部区域失败率为 32%（28 例中的 9 例）；28 例患者中有 10 例（38%）膀胱完整且无疾病复发，9 例患者发生远处转移，6 例患者死于疾病。
吉西他滨联合放疗在不适合手术和/或顺铂治疗的 BC 患者中耐受良好。随后试验的 gem 推荐剂量为每周两次 40mg/m(2)，同时进行放疗。
