is a cofounder of Gritstone Oncology and holds equity in An2H. Timothy A. Chan serves as an advisor for Bristol-Myers Squibb, Illumina and AstraZeneca. Timothy A. Chan receives research support from AstraZeneca and Illumina. Timothy A. Chan holds a patent for the use of TMB to predict immunotherapy response. This is licensed to PGDx and MSK and Timothy A. Chan are entitled to receive royalties. Vladimir Makarov holds patent rights.

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Background: One of the main challenges in the management of renal cell carcinoma (RCC) is risk-stratifying patients who present with metastatic disease. Tumor size is an important predictor of survival in the localized setting; however, this feature has not been explored fully in patients presenting with M1 RCC.Objective: To assess the impact of tumor size on survival in patients with metastatic RCC who underwent cytoreductive nephrectomy (CN).Design, setting, and participants: We queried the Memorial Sloan Kettering (MSK) nephrectomy database for patients who presented with M1 disease and underwent CN between 1989 and 2016 (n = 304). Primary tumor size was obtained from pathology reports. Data from the International Metastatic Database Consortium (IMDC) were used for validation purposes (n = 778).Outcome measurements and statistical analysis: Overall survival (OS) estimates were computed using the Kaplan-Meier method. Cox regressions were used to test the association between tumor size and OS in univariate and multivariable analyses. Tumors ≤4 cm were compared with larger masses. Secondary analyses were performed to assess the robustness of these findings. Results and limitations:Clear cell tumors ≤4 cm were significantly associated with improved OS in both the MSK (hazard ratio [HR]: 0.35, 0.17-0.72, p = 0.004) and IMDC (HR 0.54, 0.36-0.83, p = 0.004) cohorts. The association was observed even after adjusting for known prognostic factors (HR 0.40, 0.14-1.14, p = 0.09 and HR: 0.54, 0.33-0.90, p = 0.02 in the MSK and IMDC cohorts, respectively). Limitations of this study include the absence of patients who were considered poor surgical candidates as well as potential selection bias. Conclusions:The primary tumor size ≤4 cm was independently associated with improved OS in patients with metastatic clear cell RCC who underwent CN. Additionally, the association between primary size and survival was found to be nonlinear. These findings suggest that there is a group of small metastatic RCCs that can convey a better overall prognosis. The potential role of primary tumor size when risk stratifying patients with M1 RCC should be explored further to determine its utility during clinical decision making.