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/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. 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/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. 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/m(2) twice weekly with concurrent radiation.

Auto-masked 2D/3D image registration and its validation with clinical cone-beam computed tomography.

Image-guided alignment procedures in radiotherapy aim at minimizing discrepancies between the planned and the real patient setup. For that purpose, we developed a 2D/3D approach which rigidly registers a computed tomography (CT) with two x-rays by maximizing the agreement in pixel intensity between the x-rays and the corresponding reconstructed radiographs from the CT. Moreover, the algorithm selects regions of interest (masks) in the x-rays based on 3D segmentations from the pre-planning stage. For validation, orthogonal x-ray pairs from different viewing directions of 80 pelvic cone-beam CT (CBCT) raw data sets were used. The 2D/3D results were compared to corresponding standard 3D/3D CBCT-to-CT alignments. Outcome over 8400 2D/3D experiments showed that parametric errors in root mean square were <0.18° (rotations) and <0.73 mm (translations), respectively, using rank correlation as intensity metric. This corresponds to a mean target registration error, related to the voxels of the lesser pelvis, of <2 mm in 94.1% of the cases. From the results we conclude that 2D/3D registration based on sequentially acquired orthogonal x-rays of the pelvis is a viable alternative to CBCT-based approaches if rigid alignment on bony anatomy is sufficient, no volumetric intra-interventional data set is required and the expected error range fits the individual treatment prescription.