Effect of Treatment Sequencing of Cytoreductive Nephrectomy on Overall Survival Outcomes in Patients Receiving Immunotherapy for Metastatic Renal Cell Carcinoma

Introduction The evolving treatment paradigm for metastatic renal cell carcinoma (mRCC) has prompted ongoing investigation into the role and relevance of cytoreductive nephrectomy (CN). While prior studies have suggested that the sequencing of CN may impact survival in this population, the shift toward immunotherapy (IO)-based regimens limits the applicability of these findings, leaving the role of CN in the IO era incompletely understood. Therefore, we assessed survival outcomes among patients with mRCC treated with IO with or without CN. Materials and methods Using the National Cancer Database, we retrospectively identified patients with mRCC treated with IO, with or without CN. We categorized them into one of three groups based on treatment received: IO therapy alone, IO therapy followed by CN (IO/CN), or CN followed by IO therapy (CN/IO). Differences in OS were compared across groups using a multivariable Cox proportional hazards model. Secondary objectives compared postoperative readmission rates, postoperative hospital length of stay, and positive surgical margins among patients undergoing IO/CN and CN/IO. Results Among 1,981 eligible patients, 785 (40%) received IO therapy alone, 44 (2.2%) received IO/CN, and 1,152 (58%) received CN/IO. OS differed significantly across the three groups (Wald statistic, p<0.001). Pairwise comparisons demonstrated improved survival for both IO/CN and CN/IO compared with IO therapy (hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.13-0.40, p<0.001; and HR 0.35, 95% CI 0.27-0.43, p<0.001, respectively). However, there was no significant difference in OS between upfront and deferred CN (CN/IO vs IO/CN: HR 0.66, 95% CI 0.39-1.12, p=0.13). Among patients who underwent CN, treatment sequence was not associated with readmission rates (IO/CN vs CN/IO: odds ratio (OR) 1.56, 95% CI 0.16-14.9, p=0.702), hospital length of stay (IO/CN vs CN/IO: incidence rate ratio 1.22, 95% CI 0.88-1.70, p=0.237), or positive surgical margins (IO/CN vs CN/IO: OR 0.91, 95% CI 0.29-2.86, p=0.873). Conclusions Among mRCC patients receiving IO, CN was associated with improved OS compared with IO therapy alone, with no difference by treatment sequence. While these findings suggest that the addition of CN to IO may provide a survival benefit in appropriately selected patients, prospective randomized trials are needed to further elucidate and confirm this effect.