Patient selection for cytoreductive nephrectomy in 2025

In 2025, cytoreductive nephrectomy (CN) remains an integral part of the multidisciplinary management of metastatic renal cell carcinoma (mRCC). Rapid advances in systemic therapies—particularly immune checkpoint inhibitors (ICI)—have reshaped the treatment landscape and triggered debate regarding the optimal patient selection criteria and timing of surgery. Current studies emphasize the importance of refining selection criteria to maximize benefits and reduce risks in the context of newer systemic therapies. This article describes optimal CN patient selection for urologists in 2025.

A Brief Historical Context

Daniel D. Shapiro, MD, FACS

Landmark randomized trials conducted in the early 2000s demonstrated a survival advantage for up-front cytoreductive surgery in combination with interferon alfa compared with interferon alpha alone, solidifying up-front CN as an integral part of the treatment of selected patients with mRCC.^1-3 During the 2000s and early 2010s, systemic therapies continued to improve with the development of targeted therapies, including tyrosine kinase inhibitors and mTOR inhibitors. During this time, the debate regarding the role of CN
was revisited following the publication of 2 randomized phase 3
trials in 2018: CARMENA (NCT00930033)⁴ and SURTIME (NCT01099423).⁵ Although CARMENA and SURTIME challenged the necessity of up-front CN, these trials suffered from severe limitations hindering clinically meaningful results, including both trials failing to enroll their targeted enrollment and closing because of slow accrual, more than 20% crossover from the nonsurgical to the surgical arm, and inclusion of a large proportion of known poor-risk surgical candidates (substandard patient selection when compared with published criteria during that era).

E. Jason Abel, MD, FACS

Starting in 2015, with the publication of the phase 3 CheckMate 025 trial (NCT01668784),⁶ ICI therapies transformed the mRCC systemic treatment landscape and became first-line therapy for most patients with mRCC. These therapies have resulted in substantially longer median overall survival. For example, the phase 3 CheckMate 214 trial (NCT02231749) demonstrated a median overall survival of 56 months for patients receiving nivolumab (Opdivo) plus ipilimumab (Yervoy) compared with 26 months with sunitinib (Sutent), with similar findings for patients receiving pembrolizumab (Keytruda) plus axitinib (Inlyta) in the phase 3 KEYNOTE-426 trial (NCT02853331).^7,8 Given that patients are responding better and living longer, the question is raised again regarding the proper role for CN.

Current Landscape of Cytoreductive Nephrectomy

When addressing the question of CN utility, it is critical to realize that the majority of patients included in prior phase 3 trials evaluating systemic therapies for mRCC received prior nephrectomy. The rate of nephrectomy before systemic therapy in phase 3 trials ranges from 74% to 96%, so it is difficult to estimate how well systemic therapies work in the absence of a prior nephrectomy.⁹ Additionally, a biological rationale continues to support the utilization of CN in appropriately selected patients. A recent pilot study evaluated the impact of CN on the immune microenvironment of individuals treated with delayed CN. The trial demonstrated surgical safety (14% 90-day complication rate) and median overall survival (OS) of 55 months among patients who received ICI plus deferred CN. Interestingly, patients who received CN were found to have increased numbers of antitumor
dendritic cells and decreased number of immune-suppressive myeloid cells in the peripheral blood, suggesting an improved immune-mediated antitumor response that was not observed among patients who did not receive CN.¹⁰ This study is supported by many observational studies demonstrating safety and improved outcomes among appropriately selected patients who received CN.^11,12 These studies have consistently advocated for a nuanced approach to CN that requires multidisciplinary input weighing patient-, tumor-, and system-related factors to select optimal candidates and improve outcomes.

Patient Selection for Cytoreductive Nephrectomy

The treatment team must first decide the indication for CN. The major goal of CN is to improve patient survival. Additionally, CN with or without metastasectomy may delay the need for additional systemic therapy. Other indications for nephrectomy in the metastatic setting would be for symptom relief (eg, pain or hematuria). If the goal is to improve patient survival, we advocate for a selection approach developed and validated using a population of patients who underwent CN. This selection system, known as the Selection for Cytoreductive Nephrectomy (SCREEN) score, integrates risk factors and groups patients into favorable (0-1 risk factors), intermediate (2-3 risk factors), and poor (≥4 risk factors) risk groups.¹³ The risk factors included in the SCREEN score fall into 3 categories: radiographic risk factors, patient symptoms, and laboratory risk factors (Figure). They are designed to identify optimal candidates for up-front CN and minimize mortality risk within 12 months after surgery.

The SCREEN score has several advantages over prior selection criteria traditionally used to select patients for CN, such as the International Metastatic RCC Database Consortium (IMDC) risk score. First, the SCREEN score was developed using a large, multi-institutional population of patients who underwent up-front CN. Second, the SCREEN risk groups better discriminate among poor-, intermediate-, and favorable-risk groups compared with IMDC risk groups (Table).¹³ Using the IMDC classification, most patients within this study were either intermediate or poor risk, and both intermediate- and poor-risk patients had similar median OS, limiting the ability to differentiate between these 2 groups of patients. Using the SCREEN scoring system, patients were evenly distributed among risk groups, and the median OS in each risk group was significantly different. Third, the SCREEN score integrates not only patient symptoms and labs but also radiographic features, which is traditionally a critical aspect of a multidisciplinary tumor group approach to CN decision-making (ie, can most of the disease burden be removed with CN?). Fourth, the SCREEN score was designed to minimize mortality risk within 1 year of surgery. Lastly, the SCREEN score has been validated in independent cohorts of patients using ICI therapy. For these reasons, the SCREEN score is a useful method to risk-stratify patients and select for CN. Patients in the favorable- and intermediate-risk groups should be considered for up-front CN. Patients classified as poor risk should be considered for initial systemic therapy. Deferred CN would be considered if patients respond to initial systemic therapy without progressive disease.

It is critically important that patients are treated by an experienced multidisciplinary team. Patients with mRCC in 2025 are treated by specialists including urologists, medical oncologists, radiologists, pathologists, radiation oncologists, and interventional radiologists. Patients with oligometastatic disease are increasingly being rendered disease-free using a combination of systemic therapy, surgery, radiation, and ablative therapy, allowing patients to achieve treatment-free intervals.^14,15 A coordinated and experienced team is critical to achieving these results and minimizing patient morbidity. Regarding surgical intervention, surgeon experience is important for improving surgical outcomes. Modern series show CN is safe with low morbidity at high-volume centers, even in the post-ICI setting.^11,16

Conclusion

In 2025, CN is part of the standard of care management for patients with mRCC, especially those with favorable or intermediate risk. CN is safe and well tolerated and may improve patient symptoms. Appropriate patient selection for CN is a highly individualized process that is improved with a multidisciplinary approach. Further investigations into circulating and molecular biomarkers, advanced imaging, and systemic therapies may redefine the roles of surgery and systemic therapies; however, current validated risk stratification strategies, such as the SCREEN score, can be easily incorporated into clinical practice and improve patient outcomes.

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