Refining the Characterization and Outcome of Pathological Complete Responders after Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: Lessons from the Randomized Phase III VESPER (GETUG-AFU V05) Trial

SIMPLE SUMMARY: On the basis of a deep analysis of data collected in a randomized trial of perioperative chemotherapy in muscle-invasive bladder cancer, we refined the characterization and outcome of patients whose cystectomy specimens were pathologically free of cancer (pCR) after neoadjuvant chemotherapy. Nested variant and lymphovascular invasion were identified as adverse predictive factors of pCR. We confirm that these patients portend a better outcome as compared to patients with invasive disease at cystectomy, with a progression-free survival probability three years after pCR on cystectomy of about 85%. A lower creatinine clearance and the delivery of less than four cycles were associated with a higher risk of relapse. ABSTRACT: Neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy and pelvic lymph node dissection is the optimal treatment for patients with muscle-invasive bladder cancer. In recent years, the VESPER trial showed a statistically significant higher progression-free survival with dd-MVAC (dose dense methotrexate, vinblastine, doxorubicin, and cisplatin) compared to GC (gemcitabine and cisplatin). In the present report, we refine the characterization and outcome of patients whose cystectomy specimens were pathologically free of cancer (pathological complete response, pCR). We confirm that these patients portend a better outcome as compared to patients with invasive disease (≥pT1N0) at cystectomy. Nested variant and lymphovascular invasion were identified as adverse predictive factors of pCR. Progression-free survival probability three years after pCR on cystectomy was about 85%, regardless of the NAC regimen. A lower creatinine clearance and the delivery of less than four cycles were associated with a higher risk of relapse. Predicting the efficacy of NAC remains a major challenge. The planned analysis of molecular subtypes in the VESPER trial could help predict which patients may achieve complete response and better outcome.