Kidney and Cancer Outcomes with Standard Versus Alternative Chemotherapy Regimens for First-Line Treatment of Metastatic Urothelial Carcinoma

KEY POINTS: Many patients with metastatic urothelial carcinoma are deemed cisplatin-ineligible because of reduced kidney function. Options include split-dose cisplatin or carboplatin. There was no significant association between regimen type and AKI. Alternative regimens were associated with higher risk of progressive disease. There is a need to revisit cisplatin eligibility criteria and develop strategies to optimize cancer treatment for patients with CKD. BACKGROUND: Cisplatin-based chemotherapy regimens remain the optimal first-line treatment for patients with metastatic urothelial carcinoma (mUC). However, many patients are deemed cisplatin-ineligible, predominantly because of reduced kidney function. Other treatment options include split-dose cisplatin, carboplatin, and non–platinum-based regimens. We compared the incidence of AKI and cancer outcomes within three chemotherapy regimens. METHODS: We conducted a single-center retrospective study of patients with mUC who received first-line chemotherapy from 2005 to 2019. We compared standard gemcitabine–cisplatin (gem-cis) with two alternative regimens: (1) gem-cis split-dose regimen (split) with cisplatin divided over days 1 and 8 and (2) combination of gemcitabine–carboplatin or single-agent gemcitabine (gem/gem-carbo). The primary outcome was Kidney Disease Improving Global Outcomes–defined AKI. Secondary outcomes included overall survival and progression-free survival. RESULTS: We identified 183 patients (98 gem-cis, 32 split, and 53 gem/gem-carbo). Median baseline eGFR in the gem/cis group was 78 ml/min per 1.73 m(2) (interquartile range, 66–91), in the split group 64 (48–77), and in the gem/gem-carbo 45 (33–57). There was no significant association between regimen type and incidence of AKI when adjusted for age, Eastern Cooperative Oncology Group, baseline eGFR, hypertension, diabetes, and visceral disease. The adjusted hazard ratios were 1.31 (95% confidence interval [CI], 0.61 to 2.78; P = 0.49) and 0.98 (95% CI, 0.46 to 2.07; P = 0.95) for split and gem/gem-carbo groups, respectively, versus gem-cis. Split and gem/gem-carbo regimens were associated with higher mortality and progressive disease relative to gem-cis with an adjusted hazard ratio of 1.54 (95% CI, 1.02 to 2.33; P = 0.04) and 1.96 (95% CI, 1.31 to 2.95; P < 0.01), respectively. Median progression free survival was 8.1 (interquartile range, 4.6–14.8), 6.1 (4.1–9.3), and 4.4 (2.3–8.6) months in the gem-cis, split, and gem/gem-carbo groups. CONCLUSIONS: There was no significant difference in the incidence of AKI between the three regimens studied. However, standard gem-cis was associated with improved cancer outcomes. Novel regimens and kidney protective strategies are needed for patients with mUC with kidney disease.