Bladder Preservation with Twice-Daily Radiation plus 5-Flourouracil/Cisplatin or Daily Radiation plus Gemcitabine for MIBC – Updated Results of NRG/RTOG 0712: A Randomized Phase 2 Trial

Abstract

5-fluorouracil/cisplatin and twice-daily radiation (FCT) is an established chemoradiation (CRT) regimen for selective bladder sparing treatment of muscle-invasive bladder cancer (MIBC). Gemcitabine and once daily radiation (GD) are a well-supported alternative. This trial evaluates these regimens. Patients with cT2-4a MIBC were randomized to FCT or GD. Patients had a transurethral resection and induction CRT to 40 Gy. Patients with a complete response (CR) received consolidation CRT to 64 Gy. Others had cystectomy. Adjuvant gemcitabine/cisplatin chemotherapy was administered. The primary endpoint was the rate of distant metastasis free at 3 years (DMF3). The trial was not statistically powered to compare regimens, but to assess whether either exceeded a DMF3 benchmark of 75%. DMF at 5 years (DMF5) was also assessed. Toxicity and efficacy endpoints, including CR and bladder intact distant metastasis free survival at 3 (BI-DMFS3) and 5 (BI-DMFS5) years, were assessed. From 12/2008 to 4/2014, 70 patients were enrolled; 66 eligible for analysis, 33 per arm. Median follow-up was 7.3 years for eligible living patients. DMF3 was 79% and 85% for FCT and GD, respectively. DMF5 was 70% and 77%. BI-DMFS3 was 67% (95% confidence interval [CI]: 56.2-87.4) and 72% (95% CI: 66.3-94.5). BI-DMFS5 was 65.1% (95% CI: 48.4-81.8) and 72.5% (95% CI: 56.0-89.0), respectively. Post induction CR rates were 88% and 76%. There was a total of 3 and 6 cystectomies for FCT and GD, respectively. Overall survival at 5 years was 74% and 71%. Of 33 patients in the FCT arm, 19 (58%) had treatment-related grade 3-4 toxicities during protocol treatment with 18 (56%), 2 (6%) and 2 (6%) experiencing grade 3-4 hematologic, gastrointestinal and genitourinary toxicity, respectively. For 33 in the GD arm, these proportions were 17 (52%) overall and 14 (43%), 3 (9%) and 2 (6%). Both regimens demonstrated DMF3 greater than 75% and maintained high rates of distant metastasis free at 5 years. Cystectomy rates were low and overall survival rates high on both arms. There were fewer toxicities observed in the GD arm. Either gemcitabine and daily radiation or a cisplatin-based regimen are effective bladder sparing therapies and could serve as a base for future trials of systemic therapy.