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

Abstract

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 due to reduced kidney function. Other treatment options include split-dose cisplatin, carboplatin and non-platinum-based regimens. We compared the incidence of acute kidney injury (AKI) and cancer outcomes within 3 chemotherapy regimens. Methods: We conducted a single-center retrospective study of mUC patients who received first-line chemotherapy from 2005-2019. We compared standard gemcitabine-cisplatin (gem-cis) to two alternative regimens: 1) gemcitabine-cisplatin 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 KDIGO-defined AKI. Secondary outcomes included overall survival (OS) and progression free survival (PFS). 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/1.73m2 (IQR: 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, ECOG, baseline eGFR, hypertension, diabetes and visceral disease. The adjusted hazard ratios (aHR) were 1.31 (95%CI: 0.61-2.78; p=0.49) and 0.98 (95%CI:0.46-2.07; 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 aHR of 1.54 (95%CI: 1.02-2.33; p=0.04) and 1.96 (95%CI: 1.31-2.95; p<0.01) respectively. Median PFS was 8.1 (IQR: 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. Conclusion s: 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 mUC patients with kidney disease.

Cancer Treatment in CKD: Time to Move Beyond Renalism

“…3 There was no difference in the occurrence of AKI among the three groups. 3 When AKI occurred, it was most commonly mild (Kidney Disease Improving Global Outcomes stage 1). Patients who did not receive full-dose cisplatin had a lower eGFR than those who received standard therapy, and lower kidney function was a frequent reason for not receiving standard therapy.…”

“…In this retrospective study, the authors compared outcomes for patients with mUC treated with standard-dose gemcitabine-cisplatin, split-dose cisplatin, and a noncisplatin-based regimen. 3 There was no difference in the occurrence of AKI among the three groups. 3 When AKI occurred, it was most commonly mild (Kidney Disease Improving Global Outcomes stage 1).…”

“…Unfortunately, patients who did not receive the standard regimen had significantly worse survival compared with those who did receive standard treatment. 3 This study has various limitations as noted by the authors. It was a retrospective study, and there is a risk of selection bias, and the unaccounted confounders, such as patient comorbidities or poorer functional status, associated with CKD may have affected treatment selection and results.…”

“…As reported by Cote et al , ineligibility to access the best therapy for mUC on the basis of concerns about reduced kidney function was associated with higher risk of progressive disease and reduced patient survival. 3 There is clearly a need to revisit cisplatin eligibility criteria and develop new strategies such as immunotherapy, targeted treatments, and other novel therapies for patients with mUC and kidney disease. 11 Moreover, there is an opportunity to revise the broad restrictions on access to cancer therapies in general for patients with CKD.…”

“…An interesting observation from the study by Cote et al , is that a small but significant number of patients in the standard treatment arm received full-dose cisplatin despite an eGFR <60 ml/min per m 2 . 3 This represents some deviation by some of the oncologists from conventional practice. Did these providers make the decision unilaterally?…”