Renal cell carcinoma (RCC) is the most common solid tumor of the kidney, responsible for approximately 3% of all cancers worldwide. Each year over 430,000 people receive a kidney tumor diagnosis globally, and roughly 179,000 die from the disease. Epidemiological studies using the GLOBOCAN database indicate that kidney cancer incidence is rising, particularly in Europe and among people aged 50 or younger.
Metastatic RCC (mRCC) encompasses several distinct clinical scenarios: de novo disease that presents with metastases at the outset, oligometastatic disease with five or fewer metastatic sites, and oligoprogressive disease where new metastases develop after treatment of initially localized cancer. According to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model, median overall survival varies dramatically from 43 months for favorable-risk patients down to fewer than 8 months for poor-risk patients.
The emergence of immune checkpoint inhibitor (ICI)-based combination therapies as first-line treatment for mRCC has transformed the therapeutic landscape. However, this breakthrough raises two fundamental clinical questions: whether surgery still has a meaningful role alongside modern systemic therapy, and how clinicians should select which patients benefit most from surgery versus systemic treatment alone.
This review synthesizes evidence on cytoreductive nephrectomy (CN) across three distinct eras of systemic therapy for mRCC: the interferon era, the targeted therapy (tyrosine kinase inhibitor) era, and the current immune checkpoint inhibitor era. The authors examine both prospective randomized controlled trials and retrospective studies to evaluate the survival benefits and safety of CN in each treatment context.
Key landmark trials analyzed include CARMENA, a noninferiority trial of 450 patients comparing sunitinib alone versus CN followed by sunitinib, and SURTIME, which randomized 99 patients to either upfront or deferred CN with sunitinib. Retrospective data from large databases including the IMDC cohort (4,639 patients) and the REMARCC registry are also evaluated.
The review further examines evidence on metastasis-directed therapy (MDT), the safety profile of CN in various treatment settings, prognostication models such as the MSKCC, IMDC, and the newer SCREEN score, and the optimal sequencing of surgery relative to systemic therapy. Ongoing phase 2 and 3 clinical trials are identified to address current knowledge gaps.
In the interferon era, the survival benefit of CN was well established. A randomized controlled trial of 241 patients demonstrated that CN followed by interferon alpha-2b yielded longer overall survival than interferon alone (median 11.1 vs 8.1 months). A combined analysis of two prospective trials (331 patients) confirmed this advantage with a median OS of 13.6 versus 7.8 months for CN-plus-interferon versus interferon alone.
In the targeted therapy era, retrospective studies continued to support CN. IMDC data showed median OS of 20.6 versus 9.5 months for CN versus no CN, and a systematic review of 10 non-randomized studies also associated CN with improved OS. However, these retrospective findings were subject to significant selection bias, as patients with better performance status were more likely to undergo surgery.
Prospective data from the TKI era challenged this narrative. The CARMENA trial demonstrated that sunitinib alone was noninferior to CN followed by sunitinib (median OS 18.4 vs 13.9 months) in intermediate-to-poor risk patients. The SURTIME trial found that deferred CN after initial sunitinib yielded better median OS than upfront surgery (32.4 vs 15 months), though both trials had limitations including poor accrual and high metastatic burden populations.
In the current ICI era, only retrospective evidence is available. An analysis of 4,639 IMDC patients found that CN was associated with significantly longer overall survival in both TKI-treated and ICI-treated populations. A separate multi-center study of 367 mRCC patients treated with ICI reported a 67% reduction in the risk of all-cause mortality for patients who received CN.
However, important caveats exist. Approximately 20% of patients who underwent CN in the CARMENA and SURTIME trials never received systemic therapy due to surgical complications or deconditioning, highlighting the risk that upfront surgery may preclude beneficial systemic treatment. Selection bias in retrospective ICI-era studies must also be acknowledged.
For non-clear cell RCC subtypes, including papillary and chromophobe variants, the evidence is even more limited. Retrospective SEER registry data suggest that combining CN with systemic therapy improves OS compared to systemic therapy alone, but these data predate the widespread use of ICI combinations. Newer agents such as pembrolizumab, cabozantinib, and savolitinib show promise for papillary RCC specifically, making further study of CN in this context imperative.
The MSKCC and IMDC models are currently the most widely used tools for prognosticating mRCC patients. European Association of Urology guidelines recommend immediate CN for patients with good performance status who do not require systemic therapy and for those with oligometastases amenable to complete metastasis-directed therapy. Delayed CN is recommended for good responders to systemic therapy, while CN is discouraged for poor-risk and certain intermediate-risk patients.
These models have important limitations: they were derived from pre-ICI data and do not account for metastatic burden characteristics such as volume, sites, and number of lesions. The SCREEN score, a newer 7-item tool incorporating radiographic features like total metastatic tumor burden and bone metastasis, outperformed the IMDC model in predicting first-year mortality after CN (ROC 0.76 vs 0.55).
Multidisciplinary team discussions involving urologists, radiologists, oncologists, radiotherapists, pathologists, and specialist nurses have been associated with improved survival outcomes for mRCC patients. The development of better prognostication methods and coordinated multidisciplinary care are essential for optimizing individualized treatment decisions.
Concerns about desmoplastic reactions from presurgical systemic therapy potentially increasing perioperative complications have been investigated in multiple studies. A cohort of 173 CN patients found that presurgical systemic therapy was not predictive of increased severe (Clavien-Dindo grade 3 or higher) complications, though it did predict more wound complications compared to immediate CN.
Data from the SURTIME trial showed comparable complication profiles regardless of whether CN was performed upfront or after systemic therapy. Severe adverse events, 30-day readmission, and in-hospital mortality rates were similar between the two groups. For post-ICI CN specifically, one study reported that only 3% experienced severe complications and none had 90-day mortality.
Overall, the contemporary evidence suggests that CN carries an acceptable complication profile in both treatment-naive and post-systemic therapy settings when performed at experienced centers. This safety data supports the consideration of CN as a viable option within a multimodal treatment strategy for appropriately selected mRCC patients.
Metastasis-directed therapy (MDT), which targets confined metastatic sites using surgery, radiotherapy, or ablation, has emerged as an important strategy for oligometastatic RCC. Systematic reviews have shown that complete MDT improves both survival and local symptom relief compared to incomplete or no MDT, while stereotactic ablative radiotherapy achieves local control rates above 90%.
The KEYNOTE-564 trial is the only positive study demonstrating both disease-free survival and overall survival benefits from adjuvant pembrolizumab after nephrectomy for high-risk clear cell RCC. Notably, the subgroup rendered disease-free by both CN and complete metastasectomy (M1 NED, 5.8% of the trial population) showed an even more pronounced benefit, with a 71% reduction in the risk of recurrence or death.
Regarding treatment sequencing, a multi-center retrospective study from the REMARCC registry found that systemic therapy after CN was associated with worse cancer-specific and overall survival compared to systemic therapy before CN. Subgroup analysis showed that delayed CN after ICI led to better 5-year overall survival and cancer-specific survival than upfront CN, although this finding did not hold true in the TKI subgroup.
Several knowledge gaps persist regarding prognostication, treatment sequencing, and patient selection for CN and MDT in the ICI era. Genetics and biomarkers are potential tools for improving clinical decision-making, though concrete clinical benefits remain to be demonstrated. Researchers are encouraged to work toward defining oligometastatic RCC and refining prognostication models.
Three ongoing clinical trials aim to address these gaps. The NORDIC-SUN phase 3 trial compares nivolumab/ipilimumab with or without CN, while the PROBE phase 3 trial evaluates standard-of-care systemic therapy with or without surgery. The CYTO-KIK phase 2 trial investigates the effect of upfront cabozantinib and nivolumab on subsequent CN outcomes. All use overall survival as their primary endpoint.
A particularly promising future direction is the comparison of upfront ICI combination therapies against a treatment bundle of CN plus complete MDT followed by adjuvant pembrolizumab. Through coordinated research efforts, the field aims to optimize treatment pathways and individualize patient selection for mRCC management in the coming years.
Cytoreductive nephrectomy can optimize survival outcomes for metastatic RCC, but careful patient selection and surgical timing are critical. Upfront CN is no longer the standard of care for unselected intermediate-risk and all poor-risk patients, marking a significant shift from previous treatment paradigms.
A deferred CN approach, where systemic therapy is administered first, is generally favored to maximize the likelihood of receiving systemic treatment and to identify patients most likely to benefit from surgery. For patients with oligometastatic disease, nephrectomy with complete MDT to achieve M1 NED status, followed by adjuvant pembrolizumab, represents a promising treatment strategy.
Individualized, multidisciplinary care is essential in making treatment decisions for mRCC patients. Clinicians must consider patient factors, disease characteristics, surgeon expertise, and socioeconomic circumstances when determining optimal management. The results of ongoing prospective trials will provide crucial guidance for defining the role of CN in the ICI era.