Upfront Versus Deferred Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma: A Systematic Review and Individual Patient Data Meta-analysis

In patients with metastatic renal cell carcinoma, deferred cytoreductive nephrectomy is associated with superior overall survival compared with upfront cytoreductive nephrectomy, regardless of the type of systemic therapy used and the International Metastatic Renal Cell Carcinoma Database Consortium or Memorial Sloan Kettering Cancer Center risk subgroups. Despite its well-established role in metastatic renal cell carcinoma (mRCC), the optimal timing of cytoreductive nephrectomy (CN) is unclear. The aim of this systematic review is to compare the overall survival (OS) between upfront (uCN) and deferred (dCN) CN. The MEDLINE, EMBASE, and Web of Science databases were queried (end of search date: August 26, 2023) for studies comparing OS between uCN and dCN in mRCC patients. We reconstructed individual patient data from published Kaplan-Meier survival curves and performed one- and two-stage meta-analyses, using 6- and 12-mo landmarks to mitigate immortal time bias. We also performed subgroup analyses according to systemic therapy (ST) type and Memorial Sloan Kettering Cancer Center (MSKCC)/International Metastatic RCC Database Consortium (IMDC) risk scores. We assessed the risk of bias using the Risk of Bias in Non-randomized Studies of Interventions and Risk of Bias 2.0 tools. We identified 12 (two randomized trials and ten retrospective cohorts) eligible studies with a total of 3323 (2610 uCN and 713 dCN) patients. There were no statistically significant differences in the baseline characteristics of the two groups, other than the number of metastases and ST type. The overall risk of bias was high in nine out of 12 studies. Deferred CN was associated with superior OS in the primary analysis (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.65–0.84; 5-yr life expectancy difference 5.15 mo, 95% CI 3.23–7.08), all secondary analyses, as well as the tyrosine kinase inhibitor–treated (HR 0.61, 95% CI 0.51–0.74), immune checkpoint inhibitor–treated (HR 0.67, 95% CI 0.46–0.97), and intermediate IMDC/MSKCC risk (HR 0.73, 95% CI 0.55–0.97) subgroups. Deferred CN is associated with superior OS compared with uCN in mRCC patients treated with contemporary STs. Randomized studies are warranted to confirm these findings. Predictive models are needed to optimize the selection of patients most likely to benefit from dCN. In this report, we compared the outcomes of nephrectomy performed before (upfront) or after (deferred) starting systemic therapy for patients with