The effect of tumor downsizing on surgical complexity during nephrectomy after immune checkpoint inhibitors for metastatic renal cell carcinoma

Purpose: Immune Checkpoints Inhibitors (ICI) have changed the therapeutic landscape of metastatic renal cell carcinoma first-line treatment with complete response (CR) at metastatic sites observed in 10 to 15% of cases. Delayed nephrectomy could be discussed for patients having a clinical benefit from immunotherapy-based treatment. However, it is unclear whether prior immunotherapy exposure adversely influences the complexity of surgery. The aim of this study was to assess oncological outcomes of differed nephrectomy after immunotherapy, and to identify predictive factors associated with surgical complexity. Methods: This is a multicenter retrospective study from a national cohort of 102 patients treated between March 2015 and March 2023 by differed nephrectomy after complete response (CR) or major partial response (mPR defined as > 80% according to RECIST criteria) on metastatic sites following immunotherapy-based combination treatment. Tumor downsizing was assessed by calculating the percentage reduction from the largest measured tumor diameter, comparing before and after immunotherapy. Results: A total of 102 patients (median age 63.3 years) were included. ICI was administered as first-line in 84.3% of cases, with an ICI-ICI (74.5%) or ICI-TKI combination (25.5%), and with a median duration of treatment of 10 [1–57] months. The majority of procedures are radical nephrectomies (n = 85, 83.3%) with an open approach performed in 52.9% of cases (n = 54). Median operative time was 180 [90–563] minutes and median blood loss was 300 cc [0-4000] cc. Surgeons experienced difficulties due to adhesions and inflammatory reactions at the kidney and the surrounding tissue in 65.7% of cases (n = 67), more frequently in case of partial nephrectomy compared to radical surgery (85% vs. 61%, p = 0.04). In 15 cases (14.7%), the surgical approach changed during the procedure due to these intraoperative difficulties (including 10 patients with open conversion and 3 partial nephrectomies finally converted to radical). We highlighted a relationship between primary renal tumor downsizing and intraoperative complexity. Tumor downsizing > 10% is more likely to induce surgical difficulties (76.1% vs. 45.7%, p = 0.002), but without any impact on postoperative complications rate. Pathology reports show a complete response in 13.7% (n = 14), a pT1-pT2 stage in 29.4% (n = 30) and a pT3-pT4 stage in 56.9% (n = 58), a median ISUP grade 3 and a clear cell carcinoma histology in 95.1% (n = 97). After a median follow-up of 29.6 months, 48% of patients were free from progression and without systemic treatment. Patients with a complete response at the metastatic sites had a better prognosis in terms of recurrence-free survival (82.1% vs. 37.9% at 3 years, p = 0.001). Conclusion: Delayed nephrectomy after immunotherapy could be a challenging surgical procedure but offers encouraging oncological outcomes.