The Association Between Small Primary Tumor Size and Prognosis in Metastatic Renal Cell Carcinoma: Insights from Two Independent Cohorts of Patients Who Underwent Cytoreductive Nephrectomy

Abstract

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 ≤4cm were compared with larger masses. Secondary analyses were performed to assess the robustness of these findings.

Results and limitations: Clear cell tumors ≤4cm 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 ≤4cm 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.

Patient summary: We evaluated the impact of small tumor size on prognosis in patients with metastatic kidney cancer who undergo removal of the primary tumor. Very small masses (≤4cm) were associated with better prognosis in patients with clear cell tumors.

Keywords: Cytoreductive surgical procedures; Metastasis; Nephrectomy; Renal cell carcinoma.

Fig. 1 –

Association between primary tumor size and number of metastatic sites. Scatterplot showing the positive correlation between primary tumor size (cm) and the number of metastatic sites. The marginal plots show the distribution of each variable. Smaller tumors were found to have fewer metastatic sites affected; the finding was specific to clear cell renal cell carcinoma.

Fig. 2 –

Survival estimates of individuals with small primary tumors (≤4 cm) compared with their larger counterparts. Kaplan-Meier curves showing the association between small primary tumor size (≤4 cm) and prolonged survival in both the (A–C) MSK and (D–E) IMDC cohorts. Results are shown separately for all individuals and broken down by primary histology (clear cell vs non–clear cell). The effect of size on survival seems to be exclusive to patients with clear cell renal cell carcinoma. HR = hazard ratio; IMDC = International Metastatic Database Consortium; MSK = Memorial Sloan Kettering; NR = not reported.

Fig. 3 –

Most common sites of metastasis and their impact on survival. Summary of the most common sites of disease and their association with overall survival (right). Univariate Cox regressions were used to test the association between the presence of metastasis in these locations and survival. Only central nervous system (CNS) involvement was associated with worse prognosis after correction for multiple testing (q < 0.05). HR = hazard ratio.

Fig. 4 –

Multivariable (adjusted) Cox regression estimates of the association between small primary tumor size (≤4 cm) and survival after accounting for other prognostic factors. Forest plot showing the results of multivariable Cox regressions in both (A) the MSK and (B) the IMDC cohorts. Small tumor size (≤4 cm) was independently associated with survival after accounting for other known prognostic factors. CI = confidence interval; CN = cytoreductive nephrectomy; CNS = central nervous system; IMDC = International Metastatic Database Consortium; KPS = Karnofsky performance status; MSK = Memorial Sloan Kettering.

Fig. 5 –

Relative effect of primary tumor size on survival across the size spectrum accounting for other prognostic factors. Results of the univariate and multivariable Cox regression analyses using sequential size cutoffs (0.1 cm increments). The top panels represent the distribution of tumor size in the (A) MSK and (B) IMDC cohorts. (C and D) The bottom panels show the hazard ratios and 95% confidence intervals for a small tumor compared with a large one at each size cutoff. Smaller tumor size seems to be associated with better survival in both cohorts. CI = confidence interval; HR = hazard ratio; IMDC = International Metastatic Database Consortium; MSK = Memorial Sloan Kettering; MSKCC = Memorial Sloan Kettering Cancer Center.