PURPOSE: Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability. METHODS: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001). CONCLUSION: NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.

Urothelial carcinoma is an aggressive entity that is associated with significant morbidity, but there have been major advances in both our understanding of and treatment options for patients with this disease. In this review, the authors focus on novel therapeutic and diagnostic approaches in the perioperative setting, with an emphasis on patient‐centered and individualized care. For urothelial carcinoma of the bladder (UCB), advances in nonplatinum‐based therapies, specifically immunotherapy and antibody–drug conjugates, have expanded the therapeutic arsenal for patients with muscle‐invasive UCB in both the neoadjuvant and adjuvant settings to improve survival outcomes. Given the significant morbidity of extirpative surgery (radical cystectomy and urinary diversion), there have also been greater efforts to evaluate bladder‐sparing protocols and improve the selection of patients for surgery and their postoperative recovery. The authors review special considerations for organ‐sparing surgery in females, geriatric co‐management, and enhanced recovery after surgery protocols. For upper tract urothelial carcinoma, there has been increasing recognition of its unique diagnostic and therapeutic challenges, including risks of renal functional loss. There have been advances in molecular profiling that have demonstrated various genomic differences between upper tract urothelial carcinoma and UCB, with treatment implications. This article reviews studies evaluating perioperative care that focused on optimizing therapeutic approaches, including neoadjuvant/adjuvant chemotherapy and immunotherapy, as well as nephron‐sparing strategies in carefully selected cases.

Purpose:Little is known regarding the prognostic implications of variant histology in upper tract urothelial carcinoma (UTUC). We sought to evaluate the impact of variant histology UTUC on patient ...