Split-dose cisplatin in patients with locally advanced or metastatic urothelial carcinoma: a systematic literature review and network meta-analysis

Abstract

Background: Gemcitabine plus cisplatin (GC) is a highly active and commonly used regimen in locally advanced/metastatic urothelial carcinoma (la/mUC). With GC, cisplatin is dosed at 70 mg/m2 on day 1 of a 3-week cycle; however, for many patients, impaired renal or cardiac function, neuropathy, or poor performance status (PS) can preclude use of cisplatin. A promising alternative is split-dose GC, in which the cisplatin dose is divided over 2 days. Methods: We conducted a systematic literature review (SLR) and network meta-analysis (NMA) to better understand treatment patterns and comparative effectiveness and safety of split-dose GC vs gemcitabine plus carboplatin (GCa) and GC and methotrexate plus vinblastine, doxorubicin, and cisplatin (MVAC), respectively. Results: Among 120 identified studies, 16 studies representing 1767 patients included split-dose GC. Common reasons for choosing split-dose GC were impaired renal function, age >70 years, comorbidities, and physician preference. Split-dose GC had ORRs of 39% to 80%, median PFS of 3.5 to 9.9 months, and median OS of 8.5 to 18.1 months. Discontinuation rates due to adverse events were 5% to 38%. In the NMA, ORR with split-dose GC was significantly higher than that observed with GCa but similar to that seen with GC and MVAC. PFS and OS for split-dose GC was also similar to that observed with the other regimens (GCa, GC, and MVAC). Conclusions: This is the first SLR and NMA of split-dose GC in la/mUC. Despite heterogeneity in the limited studies included, split-dose GC demonstrated comparable effectiveness and safety profile to those seen with other regimens. Split-dose GC thus has the potential to extend the la/mUC population eligible to receive cisplatin-based regimens and warrants further prospective study. Micro abstractSplit-dose cisplatin (dose divided over 2 days) + gemcitabine is a potential chemotherapy regimen for patients with locally advanced/metastatic urothelial carcinoma unable to tolerate conventional 1-day cisplatin dosing, but clinical studies are limited. Here, data from all reported clinical studies of split-dose cisplatin + gemcitabine were reviewed and analyzed. Overall, the effectiveness of split-dose cisplatin appears comparable to standard regimens.