Combined chemo-radiotherapy 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
Mené sur 44 patients atteints d'un carcinome à cellules transitionnelles de la vessie de stade localement avancé et ne pouvant ou ne souhaitant pas être opérés, cet essai de phase I évalue la dose maximale tolérée, la dose recommandée et la toxicité à long terme d'une chimiothérapie par gemcitabine en combinaison avec une radiothérapie concomitante
Background : We conducted a phase I trial of gemcitabine (gem) with concurrent radiotherapy in patients (pts) 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 minutes and concurrent radiotherapy (RT) to the bladder with 55.5 Gy. The primary endpoint was to determine the MTD and the dose recommended (RD) for further studies of this gem-schedule. The secondary endpoint was late toxicity. The MTD was defined by dose limiting toxicity (DLT) in≥2/6 pts, discontinuation of RT and/or gem for >1 week in≥2/6 pts due to grade (G) 3/4 acute and/or late toxicity in>2/18 pts. Results : 35 out of 44 pts were evaluable for toxicity and thus the primary endpoint. DLTs occurred in 2/5 pts at dose level 5: one G3 ALT 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 1/6 pts 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); 10/28 pts (38%) were alive with an intact bladder and no evidence of recurrent disease, 9 pts 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.