Neoadjuvant Gemcitabine/Cisplatin in High-Risk Upper Tract Urothelial Carcinoma

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In a phase II trial reported in the Journal of Clinical Oncology, Coleman et al found that neoadjuvant split-dose gemcitabine and cisplatin produced a high rate of pathologic response in patients with high-risk localized upper tract urothelial carcinoma. The investigators also showed that pathologic response was associated with improved survival outcomes.

Study Details

In the study, 57 patients enrolled from four U.S. centers between December 2010 and April 2019 were to receive four cycles of gemcitabine at 1,000 mg/m2 and cisplatin at 35 mg/m2 once daily on days 1 and 8 of a 21-day cycle prior to surgical resection and lymph node dissection. As noted by the investigators, the modification of conventional gemcitabine/cisplatin by removal of day 15 of gemcitabine and use of split-dose cisplatin has been shown to improve the toxicity profile and tolerability. The primary endpoint was rate of pathologic response, defined as < ypT2N0.  

Pathologic Response

A total of 51 patients (89%) completed at least three cycles of chemotherapy, and 27 (47%) completed four cycles. Pathologic response was observed in 36 (63%, 95% confidence interval [CI] = 49%–76%) of 57 patients, with complete pathologic response (ypT0N0) observed in 11 (19%). All patients underwent surgery.


  • Pathologic response was observed in 63% of patients.
  • Pathologic response was associated with improved survival outcomes.

At a median follow up of 3.1 years (interquartile range = 2.0–6.1 years), 2- and 5-year progression-free survival rates among all patients were 89% (95% CI = 81%–98%) and 72% (95% CI = 59%–87%). Overall survival at 2 and 5 years was 93% (95% CI = 86%–100%) and 79% (95% CI = 67%–94%).  

Compared with nonresponders (≥ ypT2N any; n = 21), patients with pathologic complete response and those with partial response had improved 2-year progression-free survival (100% and 95% vs 76%, P < .001) and 2-year overall survival (100% and 100% vs 80%, P < .001).

Adverse Events

Grade ≥ 3 adverse events occurred in 42 patients (74%), most commonly decreased lymphocytes (33%), decreased neutrophils (32%), and hyperglycemia (14%). Febrile neutropenia occurred in four patients (7%). Adverse events led to dose delays in 5 patients (9%), dose reductions in 12 (21%), and discontinuation of treatment in 8 (14%); those leading to discontinuation were thromboembolic events in 3 patients, renal dysfunction in 2, and a cardiovascular event in 1. No treatment-related deaths occurred.

The authors concluded, “Neoadjuvant chemotherapy with split-dose gemcitabine/cisplatin for high-risk upper tract urothelial carcinoma 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 neoadjuvant chemotherapy as a standard of care for high-risk upper tract urothelial carcinoma, and split-dose gemcitabine/cisplatin is a viable option for neoadjuvant chemotherapy.”

Jonathan A. Coleman, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute, Thompson Family Foundation, and Ruth L. Kirschstein National Research Service Award. For full disclosures of the study authors, visit

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