Introduction:

Neoadjuvant chemotherapy (NAC) in upper tract urothelial carcinoma (UTUC) currently remains underused compared to other cancers, partly due to a lack of high-quality evidence.  We sought to examine pathologic complete response (pCR) rates (pT0 N0/X) and pathologic downstaging (pDS) rates (pT1 N0/X or less) at nephroureterectomy, as well as predictors of pCR and pDS.  We further sought to determine the effects of pCR and pDS on overall survival (OS) and examine prognosticators of OS after NAC for high risk UTUC.

Methods:

A large national hospital-based database (The National Cancer Database) was used to identify all patients from 2004 to 2016 with nonmetastatic high grade UTUC who received NAC followed by nephroureterectomy.  Overall, 32701 patients with high grade UTUC were identified from 2004 to 2016.  791 of these patients had high grade nonmetastatic UTUC and received NAC followed by nephroureterectomy.  Complete pathological response rates and downstaging rates were examined, with subgroup analysis performed for node positive (N+) disease and N0/NX disease.  Univariate linear regression and multivariate logistic regression was performed to identify clinical variables that predict complete response and pathological downstaging.  Kaplan-Meier methods and log-rank testing were used for survival analysis for patients with complete response and downstaging.  Cox proportional hazard methods were used to estimate overall survival.

Results:

791 patients were identified with high grade nonmetastatic UTUC who received NAC followed by nephroureterectomy.  46 patients (5.82%) had pCR, and 255 (32.24%) had pDS.  pCR and pDS rates for N+ subgroup were 5.35% and 15.51% respectively, and for N0/NX subgroup, 5.96% and 37.42% respectively.  

In multivariate analysis, predictors of pCR were year of diagnosis, female sex, and clinical T1 disease.  The only predictor of pDS was clinical Tis disease.  Adverse predictors of pDS were cT2, cT3, cT4, and cTX disease.  Age, time from diagnosis to treatment, Charlson comorbidity index, facility type (academic/community), tumor location, histology, and grade were not predictive of pCR/pDS.

The median OS for all patients was 48.2 months.  pCR and pDS were both associated with improved OS (p=0.003 and <0.001 respectively) with a median not reached for pCR and 99.1 months for pDS.  Pathological downstaging was the strongest prognostic factor for OS (HR 0.26, p<0.001).

Conclusion:

In the largest retrospective series examined to date, pathological complete response and downstaging rates for nonmetastatic high risk upper tract urothelial carcinoma were 5.82% and 32.24% respectively after neoadjuvant chemotherapy.  Node negative and node positive disease had equivalent rates of complete response, but node negative disease had a significantly higher rate of downstaging compared to node positive.

Predictors of complete response were year of diagnosis, female sex, and clinical T1 disease.  The only predictor of downstaging was clinical Tis disease.  Adverse predictors of pDS were cT2, cT3, cT4, and cTX disease.  Age, time from diagnosis to treatment, Charlson comorbidity index, facility type, tumor location, histology, and grade were not predictive of pCR/pDS.

Pathologic complete response and downstaging were both significantly associated with improved overall survival, and pathological downstaging was the strongest prognostic factor for overall survival. 

Although neoadjuvant chemotherapy appears to be effective, prospective studies are further needed to evaluate.

Funding: Dr. S. Venkat supported by the Ferdinand C. Valentine Fellowship Award from the New York Academy of Medicine