The Role of Cytoreductive Nephrectomy in Metastatic Non-Clear Cell Carcinoma in the Era of Emerging Systemic Therapy: A Retrospective Cohort Study

Background: Renal cell carcinoma accounts for nearly 15,000 deaths annually in the US, and approximately 30–40% of patients present with metastatic disease (mRCC). The advent of immune checkpoint inhibitors (IO) and tyrosine kinase inhibitors (TKI) has revolutionized the treatment paradigm of patients with mRCC. However, the role of cytoreductive nephrectomy (CN) in the IO-TKI era, particularly for rare and understudied histologies such as non-clear-cell RCC, remains poorly understood. Methods: We conducted a retrospective cohort study of patients with metastatic non-clear-cell RCC. Patients were stratified by receipt of CN. Baseline demographic, clinical, histologic, and metastatic site variables were collected. Overall survival was analyzed using Kaplan–Meier methods and compared with the log-rank test. Cox proportional hazards regression was performed to identify independent predictors of survival, including CN, systemic therapy, year of diagnosis, histology, and metastatic sites. Results: Among 2753 patients with metastatic nccRCC, 1654 (60.1%) underwent CN and 1099 (39.9%) did not undergo CN. The 2-year and 5-year OS rates were 35.52% and 19.22% in the CN group versus 18.53% and 7.47% in the non-CN group (p < 0.001). In the doubly robust IPTW-weighted multivariable Cox regression analysis, CN was associated with improved overall survival, corresponding to a 40% lower risk of death compared with no CN (HR 0.60, 95% CI 0.54–0.66; p < 0.001). Additionally, more recent treatment eras were associated with progressively improved overall survival, with patients diagnosed between 2015 and 2017 and 2018 onward demonstrating significantly improved OS compared with those diagnosed between 2004 and 2014. Conclusions: Our study demonstrates that CN was associated with improved OS in patients with non-clear-cell mRCC by reducing the risk of death by 40% after adjusting for baseline characteristics. These findings emphasize the role of CN even in the IO-TKI era for the management of patients with non-clear-cell mRCC. However, these findings should be interpreted in the context of the retrospective study design, potential selection bias, and lack of granular systemic therapy data within the NCDB.