Long-Term Survival Outcomes of Cytoreductive Nephrectomy Combined with Targeted Therapy for Metastatic Renal Cell Carcinoma: A Systematic Review and Individual Patient Data Meta-Analysis

Abstract

The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) remains controversial during the targeted therapy era. To reconcile the current literature, we analyzed the reported survival data at the individual patient level and compared the long-term survival outcomes of CN combined with targeted therapy vs. targeted therapy alone in patients with mRCC. We performed a systematic review of the literature using the MEDLINE, Scopus, and Cochrane Library databases (end-of-search date: 21 July 2020). We recuperated individual patient data from the Kaplan-Meier curves for overall (OS), progression-free (PFS), and cancer-specific survival (CSS) from each study. We subsequently performed one-stage frequentist and Bayesian random-effects meta-analyses using both Cox proportional hazards and restricted mean survival time (RMST) models. Two-stage random-effects meta-analyses were also performed as sensitivity analyses. A subgroup analysis was also performed to determine the effect of CN timing. Fifteen studies fulfilling our inclusion criteria were identified, including fourteen retrospective cohort studies and one randomized controlled trial. In the one-stage frequentist meta-analysis, the CN group had superior OS (hazard ratio [HR]: 0.58, 95% confidence interval [CI]: 0.54-0.62, p < 0.0001) and CSS (HR: 0.63, 95% CI: 0.53-0.75, p < 0.0001). No meaningful clinical difference was observed in PFS (HR: 0.90, 95% CI: 0.80-1.02, p = 0.09). One-stage Bayesian meta-analysis also revealed superior OS (HR: 0.59, 95% credibility interval [CrI]: 0.55-0.63) and CSS (HR: 0.63, 95% CrI: 0.53-0.75) in the CN group, while no meaningful clinical difference was detected in PFS (HR: 0.91, 95% CrI: 0.80-1.02). Similar results were obtained with the RMST models. The OS benefit was also noted in the two-stage meta-analyses models, and in the subgroup of patients who received upfront CN. The combination of CN and targeted therapy for mRCC may lead to superior long-term survival outcomes compared to targeted therapy alone. Careful patient selection based on prognostic factors is required to optimize outcomes.

Keywords: VEGF inhibitors; cytoreductive nephrectomy; mammalian target of rapamycin inhibitors; renal cell carcinoma; targeted therapy; tyrosine kinase inhibitors.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of the study selection process.

Figure 2

Risk of bias assessment for observational studies using the ROBINS-I tool (A,B) and randomized controlled trials using the RoB2 tool (C,D).

Figure 3

Kaplan–Meier plots of the pooled cohorts for overall survival (A), progression-free survival (B), and cancer-specific survival (C), derived from the one-stage frequentist random-effects survival meta-analysis using reconstructed individual patient data.

Figure 4

Kaplan–Meier plots in the upfront cytoreductive nephrectomy (CN) subgroup for overall survival (A), progression-free survival (B), and cancer-specific survival (C), derived from the one-stage frequentist random-effects survival meta-analysis using reconstructed individual patient data.