Introduction:

Inaccurate clinical staging of upper tract urothelial carcinoma (UTUC) can confound the role of neoadjuvant chemotherapy (NAC) prior to radical nephroureterectomy (RNU).  Renal insufficiency induced by radical nephroureterectomy (RNU) and peri-operative chemotherapy for upper tract urothelial carcinoma (UTUC) dictates sequencing and eligibility for definitive therapy.  We investigate fluctuations in glomerular filtration rate (GFR) before and after NAC in association with post-therapy pathologic stage and survival outcomes.

Methods:

An IRB-approved retrospective review of patients treated with adequate NAC (≥3 cycles) prior to RNU for UTUC at our institution from 2000-2019 was performed from a prospectively maintained database.  GFR was calculated before and 4-6 weeks after NAC (prior to RNU) using the CKD-EPI equation.  Kruskal-Wallis and ANOVA tests were used to analyze non-categorical data and the chi-square test was used to analyze categorical variables. Kaplan Meier (KM) analysis was performed for survival outcomes. 

Results:

152 patients received adequate NAC and 121 patients (79.6%) were treated with cisplatin-based regimens.   Percent change from baseline GFR favored non-cisplatin regimens at all follow-up time intervals.  Patients managed with non-cisplatin regimens experienced mean 14.2% GFR rise after completion of their NAC while those treated with cisplatin exhibited a mean 1.8% decline from baseline GFR (P>0.001).  At 12-month follow-up after RNU, patients receiving cisplatin-based NAC experienced a 34.7% decline from baseline GFR compared to just 17.1% decline in those receiving non-cisplatin NAC (P=0.004). 

Post-NAC improvement of GFR >10% relative to baseline was associated with residual invasive disease (P=0.018).  Final pathologic stage for patients achieving >10% improvement in GFR during NAC was 16.7% ypT0, 24.0% for ypTa-is, 40.4% for ypT1-2, 43.1% for and ypT3-4.  Overall survival was similarly stratified by GFR response to NAC (P=0.049), with patients experiencing a GFR gain of >10% after NAC exhibiting worse overall survival. 

Conclusion:

Low baseline GFR was an independent predictor of poor survival in patients receiving adequate NAC prior to RNU, and cisplatin-based regimens induced greater renal insufficiency compared to non-cisplatin NAC.  Improvement in GFR during NAC predicted high pathologic stage and poor survival- likely reflective of cortical destruction by locally-invasive tumors, a finding which requires further investigation and may be used to risk-stratify patients for therapeutic intensification.

Funding: Urology Care Foundation Research Scholars Award to PJH (IRG 85-001-25)