Combined chemoradiotherapy with gemcitabine in patients with locally advanced inoperable transitional cell carcinoma of the urinary bladder and/or in patients ineligible for surgery : a phase I trial

Background 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 and methods 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/m2, 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. Results 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/m2 gem twice weekly. At DL 6 with 40 mg/m2, 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. Conclusions 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/m2 twice weekly with concurrent radiation