Introduction:

Cytoreductive nephrectomy (CN) may be recommended for patients with metastatic renal cell carcinoma who have a favorable response to immunotherapy with immune checkpoint inhibitors (ICI) and stable disease.  Patients may also be started on ICI for non-metastatic disease, as first-line therapy for locally advanced tumors that are deemed surgically unresectable, followed by deferred nephrectomy (DN) after downsizing enabled surgical resection. Emergent data suggest that nephrectomies after immunotherapy are safe, with low rates of major postoperative complications, blood loss, and intraoperative complications.  Nonetheless, tumor response to immunotherapy is unpredictable despite size reduction of the primary tumor. Multiple studies have demonstrated viable tumor in pathologic specimens, supporting the use of nephrectomy in the management of locally advanced or metastatic kidney cancer as a consolidation approach.  Whether CN or DN provides oncologic benefit in terms of overall survival (OS), progression-free survival (PFS), or allows for treatment-free intervals (TFI) still requires further research.

Methods:

We selected all patients from 2018 to 2025 who were treated with different immunotherapy regimens prior to nephrectomy at UAMS with the intent to study tumor response to systemic treatment, safety outcomes of surgery, radiological and pathologic response, and oncologic outcomes.  Specific oncologic outcomes that were analyzed include overall survival (OS), progression-free survival (PFS), and treatment-free intervals (TFI).  The entire cohort included 15 patients split into those who had DN following immunotherapy for a non-metastatic locally advanced tumors (n=5) and a CN cohort of de novo metastatic patients who did not progress on ICI and were selected for surgery (n=10). Oncologic outcomes were compared to a multicentric cohort of patients with similar characteristics.  The most common regimen consisted of Pembrolizumab with a TKI (60%). Locally unresectable patients typically had IVC thrombus and surrounding organ invasion. 

Results:

Average tumor size reduction was 36.77% and most patients (13/15; 87%) showed signs of primary tumor shrinkage, including one complete radiographic response. Viable tumor was seen in 13/15 (87%) pts, whereas tumor necrosis in 10/15 (67%) (average of 65% per tumor); neither was correlated with size reduction or oncological outcomes (p>0.05). Intraoperative complications, EBL, 30 and 90-day readmission rates did not differ from upfront nephrectomies when adjusted for primary tumor staging or presence of IVC tumor thrombus (p>0.05). No patients died within 90 d after surgery. OS for CN and DN cohorts were 467 (45-1006) and 700 (26-2204) days, respectively. PFS for CN and DN cohorts were 240 (34-901) and 647 (26-2204) days, respectively.  All DN patients stopped IO postoperatively; one CN patient was able to stop and achieve a TFI of 520 days.  To date, there is still no evidence of disease in 6/10 (60%) of the CN patients.

Conclusion:

Given the relatively recent approval of ICI, it is still not clear the role and timing of surgery after first-line therapy, or whether ICI could increase the risk of surgical complications and perioperative mortality. In our cohort, despite radiographic tumor response frequently seen after ICI, viable tumor was present in the majority of patients on pathologic evaluation, suggesting a lack of adequate biomarkers to assess for residual disease, as well as that surgery could be used as a consolidation strategy. Nephrectomy after immunotherapy was shown to be safe and feasible, and perioperative complications seem to be more related to local burden than treatment effect. Although the retrospective analysis prevents extrapolation to determine which prognostic features facilitate TFI and improve PFS and OS, metastatic patients in our cohort were able to experience a treatment break, as well as no evidence of disease progression after surgery.  

Funding: N/A