Similar to treatment paradigms in patients with stage IV disease with most malignancies, before 2001 the removal of the affected renal unit in patients with metastatic kidney cancer was largely reserved for those in need of palliation. Yet after a report of 2 landmark trials in 2001 that demonstrated an approximately 6-month overall survival advantage, cytoreductive nephrectomy (CN) seized the therapeutic scene and became an essential element of metastatic kidney cancer management.

Yet the last 2 decades have seen the introduction of a number of novel agents into the kidney cancer space, which include vascular endothelial growth factor pathway targeted therapeutics, immune checkpoint inhibitors and more recently combinations of the 2 (fig. 1). As the efficacy of systemic therapy has improved, the role of CN has undergone a major and rapid evolution (fig. 2).

Figure 1.

Patients who enrolled into the 2001 SWOG and the European Platform of Cancer Research (EORTC) randomized trials received either upfront nephrectomy followed by interferon-alpha (INF) or INF alone without surgery. It is important to note that in these trials, nearly all patients (331) received systemic therapy. For instance, only 3 of 163 (1.8%) in the INF only arms and 9 of 161 (5.6%) in the CN+INF arms did not get INF. Yet in real world clinical practice far from every patient ended up receiving systemic therapy after CN. For instance, in one series 30% of patients did not receive systemic therapy for a variety of reasons with nearly half succumbing soon after CN without INF or targeted therapy due to rapid disease progression or perioperative mortality.¹ In other words, in clinical practice CN at times prevented patients from receiving systemic therapy. As such, as systemic therapy became more effective over the years, the question regarding the harms of CN was appropriately raised.

Figure 2. Male patient who presented with gross hematuria and weight loss found to have locally advanced and oligometastatic sarcomatoid clear cell RCC to lung. Patient underwent CN with concurrent distal pancreatomy, splenectomy and left colectomy followed by treatment with chemotherapy/TKI combination and then checkpoint inhibitor for 2 years. Currently, NED × 2 years. Today’s clinical trials are seeking to establish appropriateness and sequencing of CN in such patients.

In this context, the CARMENA trial was launched in 2009 to explore the continued role of CN in the targeted therapy era.² The trial enrolled and randomized 450 patients to nephrectomy followed by the targeted agent sunitinib vs sunitinib alone. Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) risk groups with the primary end point being overall survival. At a median followup of 50.9 months and at that time of analysis in 2017, patients in the sunitinib alone group exhibited a longer median overall survival than those in the CN + targeted therapy group (18.4 months vs 13.9 months).

Figure 3.

Overall, the trial demonstrated noninferiority of sunitinib without surgery and demonstrated that some patients appear to be harmed by upfront CN. However, the study’s findings have been interpreted with a degree of caution, as CARMENA was enriched with poor risk patients, who made up 43% of the overall cohort. Also, unlike the 2001 SWOG and EORTC trials, a large proportion of patients did not receive systemic therapy (17.7% in CN+sunitinib arm) or nephrectomy (7.1% in the CN+sunitinib arm). Indeed, when one compares median overall survival (OS) of patients in the sunitinib only arm of CARMENA (18.4 months) to median OS in sunitinib only arms of other recent trials such as CABOSUN (21.8 months), CheckMate 214 (26 months), and KEYNOTE-426 (median OS not reached >18 months), the severity of disease for patients who were enrolled into CARMENA becomes apparent.

Given CARMENA’s poor risk disease case mix, clinicians have questioned whether patients who were most likely to benefit from CN never enrolled into CARMENA. To that end, the updated results presented at the 2019 annual meeting of the American Society of Clincal Oncology (ASCO) focused on the intermediate risk patient group (low risk patients are those who metastasize following treatment of localized disease and therefore do not undergo CN by definition). Intention-to-treat analysis again demonstrated a clear survival benefit of sunitinib alone vs CN for patients who had 2 risk factors (31.2 months vs 17.6 months, p=0.033). However, this benefit was no longer evident for patients who harbored only 1 risk factor, with a trend favoring CN (31.4 months vs 25.2 months, p=0.232). Furthermore, 29% of patients in the sunitinib only arm underwent an interval nephrectomy, with those patients experiencing the highest magnitude of a survival benefit (48.5 months vs 15.7 months, HR 0.34 [0.22–0.54]), supporting the idea of systemic therapy as a litmus test to guide CN patient selection.³

Concurrently, the EORTC conducted the SURTIME trial, which evaluated immediate vs delayed CN after a trial of 3 cycles of sunitinib.⁴ Given poor recruitment, this treatment sequencing trial was unable to meet its primary end point, and the results were presented as exploratory. While there was no difference in 28-week progression-free survival, the deferred CN approach resulted in more patients receiving sunitinib and indexing a higher overall survival rate. As such, pretreatment with sunitinib allowed for identification of patients who either would not benefit from or be harmed by surgery.

In view of CARMENA and SURTIME results, is upfront CN ever appropriate in 2021? In the opinion of many the answer is a resounding “yes,” but for a very select group of patients. Indeed, not all patients with stage IV disease require immediate systemic therapy. A previously published phase II trial of patients with oligometastatic disease who underwent CN demonstrated that patients can stay off systemic therapy for a median time of 14.9 months with a significant proportion of patients being able to avoid treatment for 2 years.⁵ Therefore, in those patients with stage IV disease who present with oligometastatic disease and for whom observation off of systemic therapy is appropriate, upfront CN should be strongly considered (fig. 3).

As therapeutic options for kidney cancer patients continue to evolve, checkpoint inhibitors have become the gold standard for metastatic renal cell carcinoma (RCC), requiring a further appraisal of CN. Therefore, prospective clinical investigations continue. The PROBE trial (SWOG 1931) and NORDIC-SUN trial (NCT03977571) are phase III randomized clinical trials designed to evaluate the role of CN in the era of checkpoint inhibitors (see Appendix). While we await results from these studies, retrospective reports appear to be following the trends established in the targeted therapy era. Bakouny and colleagues recently presented a retrospective analysis of survival in patients receiving checkpoint inhibitors with (143) and without surgery (55) at the 2020 GU ASCO.⁶ In this cohort, investigators identified improvement in overall survival associated with CN (HR 0.369 [0.19–0.83]), suggesting that CN may continue to play a role in properly selected patients. Nevertheless, as we have learned, such retrospective reports from preselected cohorts can be a self-fulfilling prophecy and must be validated via prospective trials.

In conclusion, patients who require systemic therapy should forgo upfront CN in order to avoid patient harm. CN should then be deployed as necessary based on systemic therapy response and patient clinical course. In patients with oligometastatic disease who do not require urgent systemic therapy, CN should still be strongly considered.