Introduction:

Despite advancements in the management of high-risk, locally advanced clear cell renal cell carcinoma (ccRCC), nearly half of affected patients will experience disease recurrence following surgical resection of the primary tumor. The KEYNOTE-564 trial has demonstrated a significant overall survival (OS) benefit to adjuvant immune checkpoint blockade (ICB) with pembrolizumab with extended follow up. However, the risk of recurrence is variable amongst patients who meet KEYNOTE criteria, and adjuvant ICB carries significant risk of high-grade adverse immune related events that could lead to permanent morbidity. While patients with metastatic and regional disease at diagnosis likely stand the most to gain from adjuvant therapy, the optimal patient selection amongst non-metastatic patients is less clear. This study examines the clinical and pathologic factors associated with early cancer-specific mortality (CSM) in patients with non-metastatic ccRCC to help better inform adjuvant treatment selection and neoadjuvant ICB clinical trial design. 

Methods:

A retrospective review of consecutive patients with RCC who underwent surgical resection at Moffitt Cancer Center and Tampa General Hospital was conducted. Patients with pathologic staging meeting KEYNOTE-564 inclusion criteria (clear cell histology, pT2G4 or sarcomatoid N0M0, pT3+ N0M0, or pTany N+M0, ECOG 0-1) were included. Patients who had adjuvant ICB, metastatic disease at diagnosis, clinically node positive disease, inadequate follow up (<24 months after surgery), incomplete data, or unknown CSM were excluded. Clinicopathologic data was abstracted by chart review and supplemented with Cancer Registry data. The primary outcome was cancer specific death within 24 months of nephrectomy. Univariable logistic regression was used to assess the prognostic value of preoperative variables regarding early CSM. Kaplan Meier (KM) analysis was implemented to generate survival curves of different patient populations. Statistical analysis was completed in R © (version 4.3.1) using the survival package, with a level of significance set at 0.05.     

Results:

In total, 134 patients who underwent surgery from 2000-2019 met inclusion criteria. 70% of patients were male, with a median age of 66 years (interquartile range [IQR]: 58-72) and median follow up of 72 months (IQR: 29-116). Pathologically, 32% of patients had an IVC tumor thrombus, 34% had a tumor greater than 10 cm in size, and 74% had grade 3-4 tumors. Large tumors greater than 10 cm in size (p=0.035) and grade 4 disease (p=0.046) were associated with early CSM (Table 1). Tumor thrombus level was not associated with early CSM. In total, 41% of patients with large (> 10 cm) grade 4 tumors experienced early CSM. In comparison, only 14% of all other patients succumbed to early CSM (Figure 1).   

Conclusion:

The present study identified large tumor size (>10 cm) and grade 4 disease as clinicopathologic factors associated with early CSM following nephrectomy for high-risk, non-metastatic ccRCC. These findings could provide additional risk stratification for early CSM in shared decision making regarding the benefits of adjuvant therapy in similar patients. 

Funding: N/A