Patterns of Failure After Definitive Chemoradiation for Muscle-Invasive Bladder Cancer.

Purpose/objective(s) Outcomes for muscle-invasive bladder cancer (MIBC) treated with definitive chemoradiation (CRT) have largely remained stagnant in recent decades. To understand how best to improve outcomes for this population, we investigated patterns of failure after CRT for MIBC within the national Veterans Affairs' (VA) database. Materials/methods In the VA database, we identified patients diagnosed between 2000 and 2018 with urothelial histology, MIBC (T2-4a/N0-3/M0) who underwent CRT (defined as at least 50% of an intended definitive radiation regimen in conjunction with at least 1 cycle of chemotherapy). All patients' electronic health records were chart reviewed to obtain detailed clinical, pathologic, treatment (radiation dose, type of chemotherapy), and outcomes (dates and locations of recurrences, cause-specific death) data. Median times to recurrence are reported along with 25th-75th percentiles. Endpoints of local recurrence (LR, defined as recurrence in the bladder or upper tract), distant recurrence (DR, defined as recurrence beyond regional lymph nodes), overall mortality (OM), and bladder cancer-specific mortality (BCM) were evaluated in multivariable Cox and Fine-Gray models. Results Overall, 356 patients were included: median age 76, T2 disease 85%, lymph node positive (LN+) disease 5%. 12% of patients had carcinoma in situ, 32% had multifocal disease, and 33% had pretreatment hydronephrosis. Median follow up time was 77 months. 5-year OM was 69% (95% CI 64-74%) and 5-year BCM was 39% (95% CI 34-44%). 155 (44%) patients had no recurrence. In the 135 (38%) patients that developed DR, the median time to DR was 12.1 mo (8.0-23.4 mo). 106 (79%) patients of the DR group developed DR as a first recurrence with either DR only (n = 73) or DR and LR simultaneously (n = 33). In the 123 (35%) patients that developed LR, median time to LR was 11.1 mo (7.3-20.9 mo). Of the 92 patients who developed LR first without a simultaneous DR, 26 (28%) went on to develop DR. Median time from LR to DR in this group was 12.4 mo (3.0-27.0 mo). In multivariable models, LN+ disease, pretreatment hydronephrosis, and creatinine clearance (CrCl) ≤ 50 were associated with higher rates of DR, inferior OM, and inferior BCM. No patient, tumor, or treatment variables were associated with LR. Conclusion 44% of patients with MIBC treated with CRT had no recurrence while 35% developed LR and 38% developed DR. These results highlight the need for continued local surveillance after CRT as over a third of patients developed LR. Given the high proportion of DR and the advent of novel agents (antibody drug conjugates, immunotherapy, etc.) for advanced urothelial carcinoma, these data emphasize the need for clinical trials exploring such agents to improve outcomes for patients with MIBC undergoing definitive intent CRT. Our identified clinical markers (LN+ disease, hydronephrosis, decreased CrCl) as well as novel biomarkers (e.g., circulating tumor DNA) may help delineate populations most likely to benefit from additional therapy.