title: Phase I study of gemcitabine and radiotherapy plus cisplatin after transurethral resection as conservative treatment for infiltrating bladder cancer.
abstract: OBJECTIVE
  Although the use of radical transurethral resection followed by concurrent radiochemotherapy leads to a similar survival rate to that achieved after cystectomy, the number of long-term survivors is low in both cases. An improvement may be obtained by adding a new drug, such as gemcitabine, which is active in bladder cancer and acts as a radiosensitizer. However, because gemcitabine may be very toxic when associated with radiotherapy, we designed this dose-finding study in an attempt to find the dose that can be safely added to radiotherapy and concurrent cisplatin in patients treated with transurethral resection for infiltrating bladder cancer.
  
  
  METHODS
  After undergoing macroscopically complete transurethral resections for transitional carcinoma of the bladder, patients staged pT2 or higher and without distant metastases concurrently received 54 Gy of fractionated radiotherapy over 6 weeks with cisplatin (100 mg/m(2) q.3 w), starting on Day 1 of radiotherapy. Concomitant gemcitabine was administered on Days 1, 8, and 15 q.3 w for 2 cycles at a dose of 200 mg/m(2), escalated to 500 mg/m(2), with a 100 mg/m(2) increase at each dose level. The maximum tolerated dose was defined as the dose of gemcitabine associated with dose-limiting toxic effects (febrile neutropenia, Grade 4 thrombocytopenia, Grade 3 or 4 enteric toxicity, or Grade 4 nonhematologic toxicity) in 33% of the patients treated at that dose level. Six to 8 weeks after completing the therapy, the patients underwent cystoscopic reevaluation with multiple biopsies of the initial tumor site.
  
  
  RESULTS
  Of our consecutive series of 16 patients, 5 received a gemcitabine dose of 200 mg/m(2)/week, 3 a dose of 300 mg/m(2)/week, 3 a dose of 400 mg/m(2)/week, and 5 a dose of 500 mg/m(2)/week for 6 weeks. No dose-limiting toxicity was observed at doses of up to 400 mg/m(2)/week. At the dose 500 mg/m(2)/week, 1 patient experienced an intestinal perforation that recovered after surgery, and another suddenly died after developing Grade 3 untreated diarrhea in the last treatment week. All of the 15 evaluable patients were microscopically disease free at the cystoscopic reevaluation; furthermore, the posttreatment computed tomography scans did not reveal any distant metastases.
  
  
  CONCLUSIONS
  After transurethral resection for the conservative treatment of infiltrating bladder cancer, gemcitabine doses of up to 400 mg/m(2)/week seem to be safe in combination with cisplatin and radiotherapy in organ-sparing management. On the basis of the promising results of this Phase I study, we are currently conducting a Phase II trial to verify the possible improvement in local control resulting from the addition of gemcitabine.
authors: Department of Medical Oncology, Santa Chiara Hospital, Trento, Italy. caffo@tn.apss.tn.it
authors: Orazio
authors: O
authors: Caffo
authors: Gianni
authors: G
authors: Fellin
authors: Umberto
authors: U
authors: Graffer
authors: Francesco
authors: F
authors: Valduga
authors: Andrea
authors: A
authors: Bolner
authors: Lucio
authors: L
authors: Luciani
authors: Luigi
authors: L
authors: Tomio
authors: Enzo
authors: E
authors: Galligioni
mesh_terms: D000368:Aged; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000532:radiotherapy* / Q000601:surgery; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011788:Quality of Life; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000532:radiotherapy* / Q000601:surgery; D000093542:Gemcitabine
chemical_list: D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine