Introduction:

An estimated 10% of people with renal cell carcinoma (RCC) are diagnosed with a concurrent tumor thrombus (RCC-TT). TT presents a potential challenge to RCC treatment by necessitating a radical nephrectomy and tumor thrombectomy (RN-TT), a more complex and morbid procedure than radical nephrectomy. Surgical resection remains the mainstay of treatment, but recent advances in systemic therapy (ST) may be beneficial such as decreasing TT size prior to RN-TT. Chemotherapy is not standard of care for most cases of RCC, but platinum-based treatments have shown a role in collecting duct carcinoma, renal medullary carcinomas, and SMARCB1-deficient RCC. Whether chemotherapy is beneficial for patients with RCC-TT is unknown as the current literature is sparse. More evidence is available for targeted and immune therapies, which have recently gained popularity as components of multimodal therapy for RCC. Several case reports and case series of multimodal neoadjuvant therapy have demonstrated utility for patients with RCC-TT (i.e., reduced thrombus size, downstaging of tumor). Nevertheless, combined-data analyses have yielded mixed results and remain inconclusive, especially with respect to oncologic outcomes. High-powered studies are required to fill this gap in the existing literature and provide more information on whether ST interventions are beneficial for patients with RCC-TT. This study aimed to answer three separate questions on ST for RCC-TT patients. The first was for non-mRCC-TT patients, examining if preoperative ST effected overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival (MFS). The second analysis focused on patients diagnosed with metastatic RCC-TT (mRCC-TT) preoperatively, aiming to assess if ST prior to cytoreductive RN-TT (CN-TT) impacted OS or CSS. The last analysis assessed the effect of postoperative ST after RN-TT on OS, CSS, and MFS.

Methods:

This was a multi-institutional analysis conducted across North America, Central/South America, Europe, and South Korea using data from the Intercontinental Collaboration on Renal Cell Carcinoma (ICORCC) database. All patient information was retrospectively reviewed via the electronic medical record at each participating institution and stored on a master database for statistical analysis. To be included, all patients required a diagnosis of RCC-TT and were required to have undergone RN-TT for their disease. The range for the analysis window was 1999-present. ST was defined as chemotherapy, immunotherapy, targeted therapy (drugs used to specifically identify cancer cells and attack/alter them), or any combination of these. ST regimens were not standardized in the analysis and were at the discretion of providers. There was the most heterogeneity in the chemotherapy cohort, but regimens were most often platinum based. Immunotherapy was most often sunitinib, axitinib, cabozanitinib, or pazopanib. Targeted therapy was most often mammalian target of rapamycin inhibitors, nivolumab, or pembrolizumab. All administration of ST was done secondary to oncologic control. Any patients who received ST >12 months from RN-TT were excluded from analysis to limit inclusion of patients receiving ST after RN-TT due to disease progression. Pre-, peri-, and postoperative variables collected included age, gender, race, body mass index (BMI), diabetes mellitus (DM), chronic kidney disease (CKD), Karnofsky performance score, Charlson Comorbidity Index (CCI), creatinine, tumor size (both preoperatively and postoperatively), tumor stage and grade, OS, CSS, and MFS. Preoperative tumor size was defined as the greatest tumor dimension seen on computerized tomography (CT) scan and/or magnetic resonance imaging (MRI) scan measured in centimeters (cm). Metastases were diagnosed with radiographic imaging, most often CT or MRI scan. MFS was the time to radiographic evidence of metastasis after RN-TT. Patients with mRCC-TT prior to RN-TT were excluded from analysis one entirely. For analysis two, only patients with mRCC-TT who underwent cytoreductive RN-TT were included, and thus no MFS was calculated. In analysis three, all patients were included, but patients with mRCC-TT preoperatively were excluded from calculations on MFS.  Independent samples t-test and chi-squared test were run to compare variables between systemic therapy and no systemic therapy patients for each analysis. Kaplan-Meier survival analysis with log-rank test was also conducted for OS, CSS, and MFS. Some patients had incomplete survival data and so they were excluded from survival analysis where applicable. Analysis of variance (ANOVA) was conducted to compare OS, CSS, and MFS by specific systemic therapy regimen for each of the three analyses. There were a minority of patients who were confirmed to have received systemic therapy, but whose regimen was not properly documented (unknown regimen). These patients were included for all analyses aside from ANOVA comparisons between specific ST types on OS, CSS, and MFS, where they were excluded. Statistical significance was set to p<0.05 and was carried out using SPSS Statistics Version 28 (Armonk, NY) and SAS Statistics Version 9.4 (Cary, NC).

Results:

Of all RN-TT, 75% of all patients had their RN-TT performed in the year 2011 or beyond.

146 (70.9%) non-mRCC-TT patients did not receive ST and 60 (29.1%) did preoperatively. Age was greater in those without ST (64.7 years) than with ST (59.7 years; p=0.007). BMI was significantly smaller in the ST cohort (26.7 versus 29.7; p=0.009). No other demographic differences were appreciated. Postoperative tumor size was significantly greater in the ST group (9.8 cm versus 8.6 cm; p=0.039). No other oncologic variables differed. The median number of cycles used for ST was 5 (4-7.25). On Kaplan-Meier survival analysis, median OS was 6.1 years in the ST group and 5 years in the non-ST group which was not significantly different (Figure 1A; p>0.05). Median CSS was not different based on ST (median not reached; at four years 64% of the cohort was alive) versus no ST administration (7.8 years; p>0.05). Median MFS was significantly greater in the non-ST grouping (Median not reached; at 6.7 years 52.6% of the cohort had not experienced a metastatic event) versus ST (1.1 years; p<0.0001). 

84 (71.8%) patients with mRCC-TT received preoperative ST before CN-TT, and 33 (28.2%) patients had mRCC-TT and did not receive ST before CN-TT. Preoperative tumor size was significantly smaller in the ST cohort (8.8 cm versus 10.8 cm; p=0.002). No other demographic differences were appreciated. Operative time was significantly shorter in the ST group (264.2 minutes versus 336.2 minutes; p=0.049). No other oncologic variables differed. The median number of ST cycles used was 6.5 (4.75-8.25). On Kaplan-Meier survival analysis, median OS was 2 years in the ST group and 0.5 years in the non-ST group which was significantly different (Figure 1B; p=0.0007). Median CSS was 2.3 years in the ST grouping and 0.5 years in the non-ST grouping (p=0.0007).

119 (37.8%) patients received postoperative ST after RN-TT, and 196 (62.2%) patients did not. The median time to ST administration after RN-TT was 2.7 months. Race was different between the two cohorts, with the ST grouping having a greater proportion of Asian patients (20.2% versus 7.2%; p=0.006). No other demographic differences were appreciated. Tumor grade was different, and the non-ST cohort had a greater proportion of grade 2 disease (17.1% versus 5.3%; p=0.013). No other oncologic variables differed. The median number of ST cycles used was 6 (4-7). On Kaplan-Meier survival analysis, OS was 2.5 years in the ST group and 3.8 years in the non-ST group which was not significantly different (Figure 1C; p>0.05). CSS was 3 years in the ST grouping and the median survival was not reached in the non-therapy grouping with 55.9% of the cohort not experiencing death at four years (p>0.05). MFS was 0.4 years in the ST group and 1.25 years in the non-ST group which was similar (p>0.05).

Chemotherapy plus immunotherapy was associated with the greatest OS and CSS in analysis 2, but no other differences were noted. (Table 1a,b,c-3a,b,c; p=0.003, p=0.028).   

Conclusion:

Strengths of our study include a robust sample size from a multitude of institutions across the globe from the ICORCC database. Additionally, inclusion of multiple categories and combinations of systemic therapies makes our results broadly applicable, especially in countries where newer and more expensive systemic therapies are not necessarily readily available to practitioners for use. Nevertheless, there are several limitations to acknowledge, notably the analysis’s retrospective nature. The primary aim of our study was to analyze ST's effect overall for patients’ with RCC-TT, not specific therapeutic regimens, which we cannot comment on. We attempted to account for this by running ANOVA sub analysis on OS, CSS, and MFS based on therapeutic regimen, where some significant differences were appreciated. However, we recognize this is not optimal. Moreover, the specific agents used were not standardized and there is significant heterogeneity in the way RCC has been treated over time given that we include patient data spanning over 25 years. The majority of patients had their RN-TT performed in the year 2011 and beyond though. Despite these shortcomings, we feel the data presented is strong and can impact practice patterns and additionally can guide prospective study to confirm its results.

In this multi-center retrospective study of ST for RCC-TT patients from the ICORCC database, we sought to answer three different questions about ST for RCC-TT. These were regarding tole role of preoperative ST for non-mRCC-TT patients, preoperative ST for mRCC-TT patients before CN-TT, and postoperative ST after RN-TT. A key takeaway was our ability to demonstrate that there does appear to be an OS and CSS benefit to preoperative ST for mRCC-TT patients prior to CN-TT. Additionally, we observed that MFS was worse in non-mRCC-TT patients receiving preoperative ST, with no benefit to postoperative ST after RN-TT. The literature is sparse in examining ST for RCC-TT patients, with mixed results, making our series one of the largest to ever be reported on. The multi-institutional and multi-continental nature also increases the external validity of our findings. The findings noted in this study require prospective trials for validation, with a focus on specific therapeutic regimens, cycles, and dosages. We present an exciting avenue for further research on an important understudied patient population.

Funding: N/A