Comparative efficacy of immune checkpoint inhibitor combination therapies by metastatic site in metastatic renal cell carcinoma

Comparative efficacy of immune checkpoint inhibitor combination therapies by metastatic site in metastatic renal cell carcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Comparative efficacy of immune checkpoint inhibitor combination therapies by metastatic site in metastatic renal cell carcinoma Shingo Toyoda, Lan Inoki, Mamoru Hashimoto, Wataru Fukuokaya, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7434482/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Jan, 2026 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Few studies have investigated the efficacy of immuno-oncology (IO) combinations at different metastatic sites in renal cell carcinoma (RCC). We evaluated the differential efficacy of IO–IO and IO–tyrosine kinase inhibitor (TKI) combinations by metastatic site in metastatic RCC (mRCC). This retrospective multicenter study by the JK-FOOT Study Group included 579 patients with intermediate- or poor-risk mRCC (per International Metastatic RCC Database Consortium criteria) treated with first-line IO combinations between September 2018 and December 2024. Metastatic sites were lymph nodes, lungs, bones, liver, brain, and others. The primary outcomes were progression-free survival (PFS) and overall survival (OS); the secondary outcome was objective response rate. Efficacy was compared between IO–IO and IO–TKI for each site. For lymph node (n = 36), lung (n = 132), or brain (n = 16) metastases, OS or PFS was not significantly different between IO–IO and IO–TKI. In bone metastases (n = 80), OS tended to favor IO–TKI (P = 0.053). In liver metastases (n = 22), OS was significantly longer with IO–TKI (P = 0.011). IO–TKI may be a more appropriate first-line option than IO–IO for mRCC with bone or liver metastases, while efficacy is similar for other sites. Biological sciences/Cancer Health sciences/Oncology metastatic renal cell carcinoma bone metastasis liver metastasis immuno-oncology Figures Figure 1 Figure 2 Figure 3 Introduction Kidney cancer accounts for approximately 5% of all malignancies and ranks as the sixth most common cancer in men and the tenth in women [ 1 ] . Renal cell carcinoma (RCC) primarily occurs in populations in Europe and North America, whereas its incidence is relatively low in Asian countries. According to the Global Cancer Statistics 2020, there were 431,288 new cases of kidney cancer and 179,368 deaths worldwide. Metastatic RCC (mRCC) is observed in approximately 30% of patients at the time of initial diagnosis [ 2 ] . The most common sites of distant metastasis in clear cell RCC are the lungs (70%), lymph nodes (45%), bone (32%), liver (18%), adrenal glands (10%), and brain (8%) [ 3 ] . RCC can also metastasize to other sites, including the thyroid, pancreas, breast, skin, and muscle. The prognosis for patients with mRCC has significantly improved with the advent of targeted therapies, such as vascular endothelial growth factor (VEGF) inhibitors and, more recently, immune checkpoint inhibitors (ICIs) [ 4 ] . Combination therapies, such as nivolumab plus ipilimumab, pembrolizumab plus axitinib, avelumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib, are widely used as first-line systemic treatments for mRCC [ 5 – 9 ] . Immuno-oncology-tyrosine kinase inhibitor (IO–TKI) combination therapies have demonstrated favorable tumor-shrinking effects, including higher objective response rates (ORRs) and longer progression-free survival (PFS). The rate of progressive disease (PD) with IO–TKI therapy is lower than that with the ipilimumab–nivolumab combination therapy. Conversely, ipilimumab–nivolumab combination therapy showed better overall survival (OS) and durable responses [ 10 ] . However, little is known regarding how specific metastatic organ sites influence survival outcomes and responses to systemic therapy [ 3 , 11 ] . In this study, we evaluated the efficacy of IO–IO and IO–TKI combination therapies based on the metastatic site. Materials and methods Patient selection This study was approved by the Institutional Review Board of the principal institution, Osaka Medical and Pharmaceutical University in Osaka, Japan (approval number: RIN750–2571). Owing to the retrospective nature of the study, the requirement for individual informed consent was waived; instead, information about the study was disclosed, and patients were given the opportunity to opt out. All procedures were conducted in accordance with the ethical standards of the institutional and national research committees and with the 1964 Helsinki Declaration and its later amendments. We retrospectively reviewed the medical records of 579 patients with mRCC treated with first-line ICI-based combination therapy between January 2018 and December 2024 at multiple Japanese institutions (Jikei University School of Medicine, Tokyo, Japan; Okayama University, Okayama, Japan; Osaka Medical and Pharmaceutical University, Osaka, Japan; Kindai University Faculty of Medicine, Osaka, Japan; Fujita Health University School of Medicine, Aichi, Japan; and 15 affiliated hospitals). The analysis included metastatic sites such as lymph nodes, lungs, bones, liver, brain, and other distant organs. Only patients classified as intermediate or poor risk according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria were included. Outcome measurements The primary outcomes were PFS and OS, while the secondary outcome was the ORR. Efficacy outcomes were compared between the IO–IO and IO–TKI treatment groups. According to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, complete response (CR), partial response (PR), stable disease (SD), and PD were evaluated as the best responses during treatment. Disease management and follow-up methods Tumor assessments were performed at screening and every 2–3 months following the initiation of combination immunotherapy using imaging modalities such as computed tomography or magnetic resonance imaging, in accordance with the RECIST version 1.1. For each patient, demographic and clinical data at the time of treatment were collected, including age, sex, Karnofsky Performance Status (KPS), IMDC risk group, histological subtype, history of nephrectomy, neutrophil-to-lymphocyte ratio, and metastatic sites. The best response achieved during treatment (CR, PR, SD, or PD) was recorded for each patient. Treatment discontinuation due to disease progression or adverse events and the decision to resume therapy after discontinuation were made at the treating physician’s discretion in consultation with the patient, in accordance with the appropriate use guidelines for each combination regimen. Statistical analysis Patients were categorized into six groups based on the presence of metastases in the lymph nodes, lungs, bones, liver, brain, or other organs. Metastases to organs other than the lymph nodes, lungs, bones, liver, or brain were classified as “other distant metastases.” Only patients categorized as having intermediate or poor risk according to the International Metastatic RCC Database Consortium (IMDC) criteria were included in the analysis. The groups were defined as follows: Patients with lymph node metastases only. Patients with lung metastases, with or without lymph node metastases. Patients with bone metastases, with or without lung and/or lymph node metastases. Patients with liver metastases, with or without lung and/or lymph node metastases. Patients with liver and/or bone metastases, with or without lung, lymph node, or other distant metastases. Patients with brain metastases. PFS, OS, ORR, and prognostic factors were analyzed in each of the six groups, comparing patients treated with IO–IO combination therapy and those treated with IO–TKI combination therapy. Statistical analyses were conducted using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria). The ORR between the two treatment groups was compared using Fisher’s exact test. OS and PFS were estimated by the Kaplan–Meier method, with intergroup comparisons assessed using the chi-square test, Fisher’s exact test, or the Mann–Whitney U test, as appropriate. A two-sided P-value of < 0.05 was considered statistically significant. Hazard ratios for OS and PFS were calculated using Cox proportional hazards regression models. The multivariate analysis for each metastasis group included age, IMDC risk, first-line therapy, and KPS. Results Patient characteristics The sites of distant metastases were assessed in 579 patients with mRCC. The patients’ characteristics are summarized in Table 1. The number of patients in each metastatic site is depicted in Fig. 1. The prognosis of patients with mRCC stratified by metastatic site is shown in Fig. 2. Among patients treated with IO–IO therapy, PFS and OS were significantly different across metastatic sites (P = 0.04 and P = 0.002, respectively). Patients with liver metastasis treated with IO–IO therapy had a worse prognosis. Among patients treated with IO–TKI therapy, PFS and OS were not significantly different across metastatic sites (P = 0.21 and P = 0.52, respectively). Lymph n ode m etastasis A total of 36 patients with mRCC and only lymph node metastasis were identified; 21 patients were treated with IO–IO combination therapy, and 15 were treated with IO–TKI (Fig. 3a, b). The median PFS was 42.4 months in the IO–IO group and 24.5 months in the IO–TKI group, with no significant difference between the two groups (P = 0.95). The median OS was not reached in the IO–IO group and was 33.8 months in the IO–TKI group, with also no significant difference (P = 0.45). After adjustment for age, performance status, and IMDC risk, the type of first-line treatment was not significantly associated with OS (Table 2). The ORRs were as follows: in the IO–IO group, one patient had CR (4.8%), 9 PR (42.9%), 7 SD (33.3%), and 3 PD (14.3%). In the IO–TKI group, one patient had CR (6.7%), 6 PR (40%), 6 SD (40%), and one PD (6.7%). The ORR was 47.6% in the IO–IO group and 46.7% in the IO–TKI group; however, this difference was not statistically significant (P = 1) (Table 3). When comparing the prognosis among the IO–TKI group, the combination of pembrolizumab plus lenvatinib demonstrated favorable PFS and OS in patients with lymph node metastases, with a significant improvement in OS (P = 0.04) (Supplementary Fig. S1a, b). L ung m etastasis A total of 132 patients with mRCC and lung metastases, alone or with lymph node involvement, were included in this group analysis. Of these patients, 62 were treated with IO–IO combination therapy, and 70 were treated with IO–TKI (Fig. 3c, d). The median PFS was 15.0 months in the IO–IO group and 14.5 months in the IO–TKI group, with no significant difference between the groups (P = 0.37). The median OS was 42.7 months in the IO–IO group and not reached in the IO–TKI group, with no significant difference between the groups (P = 0.80). After adjustment for age, performance status, and IMDC risk, the type of first-line therapy was not significantly associated with OS (Table 2). ORRs were as follows: in the IO–IO group, 4 patients had CR (6.5%), 28 PR (45.2%), 16 SD (25.8%), and 10 PD (16.1%). In the IO–TKI group, 8 patients had CR (11.4%), 37 PR (52.9%), 11 SD (15.7%), and 10 PD (14.3%). The ORR was 51.6% in the IO–IO group and 64.3% in the IO–TKI group; however, this difference was not statistically significant (P = 0.14) (Table 3). When comparing the prognosis among the IO–TKI group, PFS was not significantly different among the treatment groups (P = 0.46). However, OS was significantly worse in patients treated with avelumab plus axitinib combination therapy than in those treated with the other IO–TKI combinations (P = 0.003) (Supplementary Fig. S1c, d). Bone m etastasis A total of 80 patients with mRCC and bone metastases, with or without lung and/or lymph node metastases, were included in this group analysis. Of these patients, 34 were treated with IO–IO combination therapy, and 46 were treated with IO–TKI (Fig. 3e, f). The median PFS was significantly longer in the IO–TKI group (35.2 months) than in the IO–IO group (6.3 months) (P = 0.01). The median OS was 56.8 months in the IO–IO group and not reached in the IO–TKI group, indicating a trend toward improved OS with IO–TKI therapy (P = 0.054). After adjustment for age, performance status, and IMDC risk, IO–TKI therapy showed a trend toward better prognosis (P = 0.055) (Table 2). ORRs were as follows: in the IO–IO group, there were no CR (0%), 12 PR (35.3%), 8 SD (23.5%), and 10 PD (29.4%). In the IO–TKI group, two patients had CR (4.3%), 17 PR (37.0%), 16 SD (34.8%), and 4 PD (8.7%). The ORR was 35.3% for the IO–IO group and 41.3% for the IO–TKI group; however, the difference was not statistically significant (P = 0.63) (Table 3). When comparing the prognosis among the IO–TKI group, no significant differences were observed in PFS (P = 0.52) or OS (P = 0.94) among the treatment groups; however, all IO–TKI combinations demonstrated relatively favorable outcomes (Supplementary Fig. S1e, f). Furthermore, a total of 89 patients with mRCC and bone metastases, with or without lung, lymph node, and/or other distant metastases, were included in the analysis (Supplementary Fig. S2a, b). Of these patients, 37 were treated with IO–IO combination therapy, and 52 were treated with IO–TKI. When comparing the prognosis among the IO–TKI group, no significant differences were found in PFS (P = 0.37) or OS (P = 0.60) among the treatment groups; however, nivolumab + cabozantinib showed relatively better results. Liver metastases A total of 22 patients with mRCC and liver metastases, with or without lung and/or lymph node metastases, were included in this group analysis. Of these patients, 11 were treated with IO–IO combination therapy, and 11 were treated with IO–TKI (Fig. 3g, h). The median PFS was significantly longer in the IO–TKI group (12.5 months) than in the IO–IO group (2.3 months) (P = 0.015). The median OS was significantly longer in the IO–TKI group (not reached) than in the IO–IO group (5.8 months) (P = 0.01). After adjustment for age, performance status, and IMDC risk, IO–TKI therapy was significantly associated with better OS (P = 0.033) (Table 2). ORRs were as follows: in the IO–IO group, there were no CR (0%), 3 PR (27.2%), 3 SD (27.2%), and 3 PD (27.2%). In the IO–TKI group, no CR (0%), 4 PR (36.4%), 3 SD (27.2%), and one PD (9.1%). The ORR was 27.2% for the IO-IO group and 36.4% for the IO–TKI group; however, the difference was not statistically significant (P = 0.64) (Table 3). When comparing the prognosis among the IO–TKI group, no significant differences in PFS (P = 0.25) or OS (P = 0.28) were observed among the treatment groups. However, the combination of nivolumab and cabozantinib demonstrated better PFS, while the nivolumab plus cabozantinib and pembrolizumab plus axitinib combination therapies showed better OS outcomes (Supplementary Fig. S1g, h). Furthermore, a total of 37 patients with mRCC and liver metastases, with or without lung, lymph node, and/or other distant metastases, were included in the analysis (Supplementary Fig. S2c, d). Furthermore, a total of 33 patients with mRCC and liver metastases, with or without lung, lymph node, and/or other distant metastases, were included in the analysis (Supplementary Fig. S2c, d). Of these patients, 16 were treated with IO–IO combination therapy, and 17 were treated with IO–TKI. When comparing the prognosis among the IO–TKI group, a significant difference was observed in PFS (P = 0.006), whereas no significant difference was observed in OS (P = 0.112). With liver and/or bone metastases A total of 145 patients with mRCC and other distant metastases and those with liver or bone metastases were included in this group. Of these patients, 63 were treated with IO–IO combination therapy, and 82 were treated with IO–TKI combination therapy (Fig. 3i, j). The median PFS was significantly longer in the IO–TKI group (35.2 months) than in the IO–IO group (4.5 months) (P = 0.00002). The median OS was also significantly longer in the IO–TKI group (not reached) than in the IO–IO group (13.3 months) (P = 0.002). After adjustment for age, performance status, and IMDC risk, IO–TKI treatment was significantly associated with better OS (P = 0.003) (Table 2). ORRs were as follows: in the IO–IO group, two patients had CR (3.1%), 18 PR (28.6%), 14 SD (22.2%), and 21 PD (33.3%). In the IO–TKI group, three patients showed CR (3.7%), 31 PR (37.8%), 26 SD (31.3%), and 8 PD (9.6%). Although the ORR was higher in the IO–TKI group (41.0%) than in the IO–IO group (31.7%), the difference was not statistically significant (P = 0.147). When comparing the prognosis among the IO–TKI group, PFS (P = 0.92) or OS (P = 0.87) was not significantly different among the treatment groups. However, all IO–TKI combinations demonstrated relatively favorable outcomes in PFS and OS compared with IO–IO combination therapy (Supplementary Fig. S1i, j). Brain metastases All patients with mRCC and brain metastases, regardless of other distant metastatic sites, were included in this group. A total of 16 patients were analyzed, of whom 10 patients were treated with IO–IO combination therapy and 6 were treated with IO–TKI combination therapy (Fig. 3k, l). The median PFS was 9.1 months in the IO–IO group and 7.5 months in the IO–TKI group, with no significant difference between the two groups (P = 0.069). The median OS was 23.5 months in the IO–IO group and 25.8 months in the IO–TKI group, also showing no significant difference (P = 0.76). After adjustment for age, performance status, and IMDC risk, the type of first-line treatment was not associated with OS (Table 2). ORRs were as follows: in the IO–IO group, 1 patient had CR (10%), 4 PR (40%), 3 SD (30%), and one PD (10%). In the IO–TKI group, there were no CR, 4 PR (66.7%), 2 SD (33.3%), and no PD. The ORR was 50% in the IO–IO group and 66.7% in the IO–TKI group; however, this difference was not statistically significant (P = 1) (Table 3). Kaplan–Meier curve analysis for PFS and OS stratified by each IO–TKI group is shown in Supplementary Fig. S1k, l. Discussion The therapeutic landscape for metastatic clear cell RCC has undergone significant advancements over the past decade [ 12 ] . Currently, ICI-based combination therapies are the standard first-line treatment for mRCC. However, the efficacy of ICIs according to metastatic site and the comparative effectiveness of different therapeutic regimens remain unclear. Patients with bone, liver, or brain metastases from mRCC have poorer prognoses than those with lung or lymph node metastases [ 3 ] . In this study, we compared the therapeutic outcomes of two combination regimens, IO–IO and IO–TKI, to determine if the efficacy varies by metastatic site. Our findings showed that IO–TKI combinations were more effective in patients with liver or bone metastases. However, no significant difference in efficacy was observed between IO–IO and IO–TKI regimens for patients with lymph node, lung, or brain metastases. Dudani et al. analyzed data from 10,105 patients with mRCC to evaluate the association between metastatic sites and OS [ 3 ] . Among 9,252 patients with clear cell RCC, the most common metastatic sites were the lung (70%), lymph nodes (45%), bone (32%), liver (18%), adrenal gland (10%), and brain (8%). 88% of patients received TKIs, 4.5% received mTOR inhibitors, and only 6.1% received ICI-based regimens. The median OS was 25.1 months for patients with clear cell RCC with lung metastases, 21.4 months for those with lymph node metastases, 19.4 months for those with bone metastases, 17.6 months for those with liver metastases, 16.5 months for those with brain metastases, and 15.6 months for those with pleural metastases. Metastases to the brain, liver, and bone were consistently associated with poorer survival outcomes [ 13 ] . In contrast, metastases to endocrine organs such as the pancreas, thyroid, and adrenal glands were associated with relatively favorable OS. Several studies have reported the clinical benefit of nivolumab for patients with lymph node metastases from RCC. Jajodia et al. reported organ-specific response rates to nivolumab in a cohort of 30 patients with mRCC [ 14 ] . The metastatic sites included the lung (n = 26), lymph nodes (n = 20), liver (n = 10), soft tissue (n = 7), brain (n = 5), adrenal glands (n = 4), and peritoneum (n = 4). Based on iRECIST criteria, the best ORRs for each site were 19% (lung), 35% (lymph nodes), 10% (liver), 0% (soft tissue), 20% (brain), 25% (adrenal glands), and 25% (peritoneum). Although limited by a small sample size, these findings suggest that lymph node metastases are more responsive to ICIs, while liver and soft tissue metastases demonstrate the poorest responses. Our results also showed that the patients with lymph node or lung metastasis treated with IO combination therapy had a better prognosis. In this study, no significant difference was observed in PFS or OS between IO–IO and IO–TKI combination therapies in patients with lung metastases. Among the IO–TKI regimens, only the avelumab plus axitinib combination was associated with poorer OS (P = 0.003). Bone metastases are associated with poor prognosis among patients with mRCC [ 3 ] . In our study, patients with bone metastases showed a trend toward improved OS with IO–TKI combination therapy compared with IO–IO therapy. Recent studies have shown the potential benefit of cabozantinib for patients with bone metastases. The phase III METEOR trial, which compared cabozantinib with everolimus as a second-line treatment, demonstrated a PFS benefit in patients with bone metastases [ 15 ] . Furthermore, recent subgroup analyses from the CheckMate 9ER trial, which evaluated the combination of nivolumab and cabozantinib, confirmed OS and PFS benefits in patients with bone metastases [ 16 ] . In the CLEAR trial, which compared lenvatinib plus pembrolizumab with sunitinib for advanced RCC, subgroup analyses showed that patients with poor prognostic factors, such as bone or liver metastases, experienced improved OS and PFS with combination therapy compared with sunitinib [ 17 ] . Cabozantinib targets multiple tyrosine kinase receptors, including VEGFR2, MET, AXL, RET, and KIT, which are important mediators of tumor cell survival, metastasis, and tumor angiogenesis [ 18 ] . Cabozantinib inhibits VEGFR and MET, affecting the function of osteoclasts and osteoblasts, thereby possibly altering the bone microenvironment. In this study, among treatments for bone and liver metastases, the IO–TKI regimen of nivolumab plus cabozantinib demonstrated better PFS. In patients with bone metastases, in addition to the better OS observed with nivolumab plus cabozantinib, the combinations of pembrolizumab plus lenvatinib and pembrolizumab plus axitinib also demonstrated better outcomes. Patients with liver metastases showed a systemic decrease in tumor-specific T cells, which limits the efficacy of immunotherapy [ 19 ] . Various hepatic-resident cell types, including Kupffer cells, liver sinusoidal endothelial cells, hepatocytes, plasmacytoid dendritic cells, NKT cells, and hepatic stellate cells, influence T cell fate and survival within the hepatic microenvironment. Through unbiased single-cell analysis, liver-derived CD11b⁺F4/80⁺ macrophages were identified as critical mediators that induce apoptosis of antigen-specific CD8⁺ T cells via the Fas–FasL pathway in the liver metastatic microenvironment. These findings suggest that for patients with liver metastases, IO–TKI combination therapy is a more suitable treatment strategy. In this study, no significant differences in OS or PFS were observed between IO–IO and IO–TKI combination therapies in patients with brain metastases. Sunitinib has not demonstrated substantial efficacy against brain metastases [ 20 ] . In a phase II trial involving 16 patients with RCC and untreated brain metastases, no intracranial objective responses were reported. SD was observed as the best intracranial response in only five patients. The median PFS was 2.3 months, and the median OS was 6.3 months, indicating poor outcomes. In contrast, cabozantinib might be effective for the brain metastasis. The efficacy of cabozantinib was evaluated in 33 patients with advanced RCC and brain metastases who received the drug in second-line or later settings, none of whom had undergone brain radiotherapy or surgery within 2 months prior to treatment initiation [ 21 ] . The ORR was 55%, including 3 CRs, 14 PRs, and 10 SDs, suggesting the potential effectiveness of cabozantinib in treating brain metastases from RCC. Cabozantinib crosses the blood-brain barrier and may have clinical activity in patients with brain metastases [ 22 ] . In whole-brain lysates of non-tumor-bearing mice, cabozantinib attained 20% of peak plasma levels, suggesting its ability to penetrate the blood-brain barrier. This finding has not been confirmed in human trials. Although the efficacy of cabozantinib for advanced RCC was confirmed by two randomized trials [ 23 , 24 ] , these studies largely excluded patients with active intracranial disease, and only a small number of patients with adequately treated and stable brain metastases were enrolled. There is no available data regarding the intracranial efficacy of other TKIs, such as axitinib or pazopanib, in this specific subgroup of patients. To date, the only clinical trial evaluating ICI in patients with mRCC and brain metastases is the GETUG-AFU 26 NIVOREN8 trial [ 25 ] . This was a phase II, single-arm trial assessing the safety and efficacy of nivolumab monotherapy in patients who had progressed after VEGF-targeted therapy. The study included 73 patients with brain metastases, of whom 39 had untreated intracranial target lesions and had not received prior local therapies such as radiotherapy or surgery. The intracranial ORR in this subgroup was 12%, indicating that nivolumab monotherapy has limited activity in untreated brain metastases. They emphasized the importance of local therapy prior to initiating systemic treatment. Our results also showed poor prognosis of patients with brain metastasis compared with other metastases, and no difference in efficacy between IO–IO and IO–TKI combination therapy. The optimal strategy for brain metastasis should be developed. A study analyzing 657 tumor samples investigated differences in molecular subtypes, genomic features, and the tumor microenvironment (TME) between primary and metastatic sites in RCC [ 26 ] . Although no significant difference in PD-L1 positivity was observed between primary and metastatic tumors overall, the expression rate in bone metastases was notably lower than that in primary tumors. While several clinical trials have reported that PD-L1 expression is not a reliable predictor of response to ICIs, the reduced expression in bone metastases may partly explain the limited efficacy of IO–IO combination therapy in such cases [ 27 ] . This study also estimated the abundance of various cell populations within the TME and identified significant differences between metastatic sites compared with primary renal tumors. Endothelial and monocytic lineage cells were more abundant in bone metastases, whereas B cell-rich microenvironments were observed in lung and skin metastases. Although not statistically significant, T cell abundance appeared higher in lymph node metastases than in the kidney, and CD8⁺ and cytotoxic T cells were enriched in endocrine metastases. Fibroblast populations were notably more abundant across metastatic sites, particularly in the liver, lung, bone, pleura, and soft tissues. Regarding immune checkpoint gene expression, RNA levels of CTLA4, TIM3, LAG3, or PD1 were not significantly different between primary and metastatic sites. However, PD-L1 expression was higher in pleural metastases, and PD-L2 expression was elevated in lung and bone metastases compared with that in the kidney. These findings suggest that site-specific differences in the TME contribute to the variation in treatment outcomes observed across different metastatic sites. In patients with lymph node, lung, and bone metastases treated with IO–IO combination therapy, the 36-month PFS and OS rates were approximately 30–40% and 50–70%, respectively, comparable to the results reported in the CheckMate 214 trial. In this study, we further compared treatment outcomes by metastatic site in patients receiving IO–IO or IO–TKI combination therapy (Fig. 2 ). Among the patients treated with IO–IO therapy, PFS and OS were significantly different across metastatic sites, indicating heterogeneous efficacy depending on the organ involved. In contrast, among those treated with IO–TKI therapy, no significant inter-site differences were observed, suggesting consistent therapeutic efficacy across metastatic sites. Notably, patients with liver or bone metastases, typically considered to have poor prognoses, demonstrated longer OS than those with lymph node or lung metastases in the IO–TKI group. These findings support the notion that the efficacy of combination immunotherapy may vary depending on the metastatic site. This study has several limitations. It was a retrospective analysis comparing the therapeutic efficacy of IO–IO and IO–TKI combination therapies. Unknown confounding factors might have influenced the choice of the first-line treatment. The IO–TKI group included four different regimens, each with a small number of cases, limiting the robustness of regimen-specific comparisons. Additionally, rare metastatic sites such as the brain had a limited number of cases. Owing to the small sample sizes, the results should be interpreted with caution. Future studies will require longer follow-up periods and the accumulation of additional cases. Conclusion The efficacy of IO combination therapy could depend on the metastatic site. IO–TKI combination therapy could be a more appropriate first-line treatment option than IO–IO therapy for patients with mRCC and bone or liver metastases. In contrast, IO–IO combination therapy may represent a more appropriate treatment option for patients with lymph node or lung metastases. These findings could help physicians decide the treatment strategy for patients with mRCC. Abbreviations ORR, objective response rate; PFS, progression-free survival; mRCC, metastatic renal cell carcinoma; IO, immuno-oncology; OS, overall survival; TKI, tyrosine kinase inhibitor; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; RECIST, Response Evaluation Criteria in Solid Tumors; iRECIST, immune-related Response Evaluation Criteria in Solid Tumors; KPS, Karnofsky Performance Status Declarations Acknowledgements Not applicable. Author contributions Shingo Toyoda contributed to the protocol and project development, data analysis, and manuscript writing and editing. Takafumi Yanagisawa and Keiichiro Mori contributed to the protocol and project development and data collection. Lan Inoki, Mamoru Hashimoto, Wataru Fukuokaya, Shingo Nishimura, Ryoichi Maenosono, Takehiro Iwata, Kensuke Bekku, Takuhisa Nukaya, and Takuya Tsujino contributed to data collection. Kiyoshi Takahara, Teruo Inamoto, Haruhito Azuma and Kazumasa Komura contributed to the protocol and project development. Kazutoshi Fujita contributed to the project development, manuscript editing, and supervision. All authors read and approved the final version of the manuscript. Funding None. Competing interests The authors declare no competing interests. Data availability Data will be made available by the corresponding author for reasonable requests. References Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68 , 394-424 (2018). Bukavina, L. et al. Epidemiology of renal cell carcinoma: 2022 update. Eur. Urol. 82 , 529–542 (2022). Dudani, S. et al. Evaluation of clear cell, papillary, and chromophobe renal cell carcinoma metastasis sites and association with survival. JAMA Netw. Open 4 , e2021869 (2021). Ivanyi, P. et al. The treatment of metastatic renal cell carcinoma. 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Lancet Oncol. 23 , 888-898 (2022). Motzer, R. et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N. Engl. J. Med. 384 , 1289–1300 (2021). Chen, Y. W., Panian, J., Rose, B., Bagrodia, A. & McKay, R. R.Recent developments in the management of renal cell cancer. JCO Oncol. Pract. 6 , OP2400875 (2025). Wei, H. et al. The prognosis and clinicopathological features of different distant metastases patterns in renal cell carcinoma: analysis based on the SEER database. Sci. Rep. 11 , 17822 (2021). Motzer, R. J. et al. NCCN Guidelines® insights: kidney cancer, version 2.2024. J. Natl Compr. Canc. Netw. 22 , 4-16 (2024). Gong, J., Maia, M. C., Dizman, N., Govindarajan, A. & Pal, S. K. Metastasis in renal cell carcinoma: biology and implications for therapy. Asian J. Urol. 3 , 286-292 (2016). Jajodia, A. et al. Analysis of spatial heterogeneity of responses in metastatic sites in renal cell carcinoma patients treated with nivolumab. Tomography 8 , 1363-1373 (2022). Choueiri, T. K. et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373 , 1814–1823 (2015). Choueiri, T. K. et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 384 , 829–841 (2021). Grünwald, V. et al. Phase 3 CLEAR study in patients with advanced renal cell carcinoma: outcomes in subgroups for the lenvatinib-plus-pembrolizumab and sunitinib arms. Front. Oncol. 13 , 1223282 (2023). Yakes, F. M. et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol. Cancer Ther. 10 , 2298-2308 (2011). Yu, J. et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat. Med. 1 , 152-164 (2021). Chevreau, C. et al. A phase II trial of sunitinib in patients with renal cell cancer and untreated brain metastases. Clin. Genitourin. Cancer 12 , 50-54 (2014). Hirsch, L. et al. Clinical activity and safety of cabozantinib for brain metastases in patients with renal cell carcinoma. JAMA Oncol. 7 , 1815-1823 (2021). Zhang, Y., Guessous, F., Kofman, A., Schiff, D. & Abounader, R. XL-184, a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and NSCLC. Idrugs 13 , 112–121 (2010). Choueiri, T. K. et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (Meteor): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 17 , 917-927 (2016). Choueiri, T. K. et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J. Clin. Oncol. 35 , 591-597 (2017). Flippot, R. et al. Safety and efficacy of nivolumab in brain metastases from renal cell carcinoma: results of the GETUG-AFU 26 NIVOREN multicenter phase II study. J. Clin. Oncol. 37 , 2008-2016 (2019). Gulati, S. et al. Molecular analysis of primary and metastatic sites in patients with renal cell carcinoma. J. Clin. Invest. 134 , e176230 (2024). Gulati, S. & Vogelzang, N. J. Biomarkers in renal cell carcinoma: are we there yet? Asian J. Urol. 8 , 362–375 (2021). Tables Table 1. Cohort characteristics by metastatic site. Lymph node Lung Bone IO–IO (n=21) IO–TKI (n=15) P-value IO–IO (n=62) IO–TKI (n=70) P-value IO–IO (n=34) IO–TKI (n=46) P-value Age, median, (range) 70 (27-87) 70 (26-85) 70 (32-86) 70 (44-89) 70 (25-86) 70 (45-85) Sex 18/3 11/4 0.24 48/14 49/21 0.43 29/5 37/9 0.77 eGFR, median, (range) 50 (5-84) 50 (16-79) 50 (4-102) 50 (5-91) 50 (4-102) 50 (5-98) Metastatic site, n (%) Lung 0 0 62 (100) 70 (100) 14 (41.2) 17 (37.0) 0.82 Bone 0 0 0 0 34 (100) 46 (100) Liver 0 0 0 0 0 0 Brain 0 0 0 0 0 0 Lymph node 21 (100) 15 (100) 14 (22.6) 21 (30) 0.43 7 (20.6) 10 (21.7) 1.0 Histology, n (%) Clear cell 9 (42.9) 6 (40) 0.71 44 (71.0) 56 (80) 0.3 24 (70.6) 33 (71.7) 0.74 Papillary 4 (19.0) 4 (26.7) 3 (4.8) 3 (4.3) 0 (0) 3 (6.5) Unclassified 4 (19.0) 0 (0) 3 (4.8) 1 (1.4) 1 (2.9) 0 (0) HD-related 1 (4.8) 0 (0) 0 2 (2.9) 1 (2.9) 0 (0) Chromophobe 0 (0) 0 (0) 0 0 0 (0) 0 (0) Others 3 (14.3) 1 (6.7) 4 (6.5) 1 (1.4) 3 (8.8) 2 (4.3) None 0 (0) 4 (26.7) 8 (12.9) 7 (0.1) 3 (8.8) 3 (6.5) Presence of sarcomatoid component 2 (9.5) 0 (0) 1.0 5 (8.1) 10 (14.3) 0.27 1 (2.9) 3 (6.5) 0.61 Confirmation of histology, n (%) Nephrectomy 11 (52.3) 7 (46.7) 1.0 29 (46.8) 41 (58.6) 0.16 13 (38.2) 15 (32.6) 0.81 Partial nephrectomy 1 (4.8) 0 (0) 1 (1.6) 5 (7.1) 4 (11.8) 4 (8.7) Biopsy 9 (42.9) 4 (26.7) 24 (38.7) 16 (22.9) 12 (35.3) 19 (41.3) IMDC at 1 st line, n (%) Intermediate/poor 14/7 11/4 0.72 38/24 55/15 0.036 23/11 28/18 0.64 Liver With liver and/or bone Brain IO–IO (n=11) IO–TKI (n=11) P-value IO–IO (n=63) IO–TKI (n=82) P-value IO–IO (n=10) IO–TKI (n=6) P-value Age, median, (range) 70 (54-74) 70 (58-80) 70 (25-86) 70 (40-88) 70 (53-79) 70 (53-83) Sex 8/3 9/2 1.0 52/11 63/19 5/5 3/3 1.0 eGFR, median, (range) 50 (8-77) 50 (32-102) 50 (4-160) 50 (5-102) 50 (42-116) 50 (35-110) Metastatic site, n (%) Lung 9 (81.8) 6 (54.5) 0.36 33 (52.4) 40 (48.8) 9 (90) 5 (83.3) 1.0 Bone 0 (0) 0 (0) 47 (74.6) 64 (78.0) 2 (20) 1 (16.7) 1.0 Liver 11 (100) 11 (100) 24 (38.1) 28 (34.1) 0 (0) 1 (16.7) 0.38 Brain 0 (0) 0 (0) 0 (0) 0 () 10 (100) 6 (100) Lymph node 8 (72.7) 5 (45.5) 0.39 20 (31.7) 27 (32.9) 0.43 4 (40) 3 (50) 1.0 Histology, n (%) Clear cell 9 (81.8) 7 (63.6) 0.47 45 (71.4) 55 (67.0) 0.3 6 (60) 5 (83.7) 0.49 Papillary 0 (0) 2 (18.2) 1 (1.6) 7 (8.5) 0 (0) 0 (0) Unclassified 0 (0) 0 (0) 3 (4.8) 2 (0) 1 (10) 0 (0) HD-related 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Chromophobe 0 (0) 0 (0) 0 (0) 1 (1.2) 0 (0) 0 (0) Others 0 (0) 0 (0) 4 (6.3) 2 (2.4) 1 (10) 0 (0) None 2 (18.2) 2 (18.2) 8 (12.7) 15 (18.3) 2 (20) 1 (16.7) Presence of sarcomatoid component 1 (9.1) 0 (0) 1.0 2 (3.2) 4 (4.9) 0.27 2 (20) 0 (0) 0.49 Confirmation of histology, n (%) Nephrectomy 5 (45.5) 4 (36.4) 1.0 23 (36.5) 28 (4.9) 0.16 4 (40) 1 (16.7) 0.59 Partial nephrectomy 0 (0) 0 (0) 5 (7.9) 5 (6.0) 0 (0) 0 (0) Biopsy 5 (45.5) 5 (45.5) 24 (38.1) 33 (40.2) 5 (50) 3 (50) IMDC at 1 st line, n (%) Intermediate/poor 6/5 6/5 1.0 37/26 47/35 5/5 4/2 0.63 eGFR, estimated glomerular filtration rate; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; IO, immuno-oncology; TKI, tyrosine kinase inhibitor. Table 2. Cox proportional hazards analysis of overall survival by metastatic site. Multivariate Lymph node Lung Bone Variables Hazard ratio (95% confidence interval) P-value Hazard ratio (95% confidence interval) P-value Hazard ratio (95% confidence interval) P-value Age 0.95 (0.91–0.99) 0.01 1.01 (0.97–1.06) 0.56 1.01 (0.96–1.05) 0.84 IMDC (poor vs intermediate) 2.51 (0.59–10.66) 0.21 2.24 (0.83–6.03) 0.11 0.94 (0.34–2.63) 0.91 1 st line therapy (IO–TKI vs IO–IO) 1.84 (0.59–5.69) 0.29 1.43 (0.52–3.94) 0.49 0.37 (0.13–1.02) 0.055 KPS (＜80 vs ≧80) 9.26 (1.79–47.9) 0.008 1.19 (0.25–5.67) 0.83 1.61 (0.55–4.74) 0.38 Multivariate Liver With liver and/or bone Brain Variables Hazard ratio (95% confidence interval) P-value Hazard ratio (95% confidence interval) P-value Hazard ratio (95% confidence interval) P-value Age 1.00 (0.89-1.12) 0.97 0.98 (0.95-1.00) 0.06 0.99 (0.90-1.09) 0.82 IMDC (poor vs intermediate) 1.89 (0.48-7.50) 0.36 2.71 (1.53-4.83) 0.0007 11.23 (0.44-283.7) 0.14 1 st line therapy (IO–TKI vs IO–IO) 0.14 (0.02-0.86) 0.033 0.40 (0.22-0.73) 0.003 3.98 (0.42-37.3) 0.23 KPS (＜80 vs ≧80) 0.65 (0.08-5.52) 0.69 0.48 (0.22-1.04) 0.06 9.42 (0.83-106.9) 0.07 IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; IO, immuno-oncology; TKI, tyrosine kinase inhibitor; KPS, Karnofsky Performance Status. Table 3. Response rate stratified by metastatic site. Lymph node (n=36) Lung (n=1 32 ) Bone (n=80) Liver (n=22) With liver and/or bone (n=145) Brain (n=16) Best response, n (%) IO–IO (n=21) IO–TKI (n=15) IO–IO (n=62) IO–TKI (n=70) IO–IO (n=34) IO–TKI (n=46) IO–IO (n=11) IO–TKI (n=11) IO–IO (n=63) IO–TKI (n=82) IO–IO (n=10) IO–TKI (n=6) CR 1 (4.8) 1 (6.7) 4 (6.5) 8 (11.4) 0 (0) 2 (4.3) 0 (0) 0 (0) 2 (3.1) 3 (3.7) 1 (10) 0 (0) PR 9 (42.9) 6 (40) 28 (45.2) 37 (52.9) 12 (35.3) 17 (37.0) 3 (27.2) 4 (36.4) 18 (28.6) 31 (37.8) 4 (40) 4 (66.7) SD 7 (33.3) 6 (40) 16 (25.8) 11 (15.7) 8 (23.5) 16 (34.8) 3 (27.2) 3 (27.2) 14 (22.2) 26 (31.3) 3 (30) 2 (33.3) PD 3 (14.3) 1 (6.7) 10 (16.1) 10 (14.3) 10 (29.4) 4 (8.7) 3 (27.2) 1 (9.1) 21 (33.3) 8 (9.6) 1 (10) 0 (0) ORR 10 (47.6) 7 (46.7) 32 (51.6) 45 (64.3) 12 (35.3) 19 (41.3) 3 (27.2) 4 (36.4) 20 (31.7) 34 (41.5) 5 (50) 4 (66.7) CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate. 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08:55:48","extension":"xml","order_by":29,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":143843,"visible":true,"origin":"","legend":"","description":"","filename":"a1fc1dd493754654b31fb1139ee4730d1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7434482/v1/745c6c47612b49c3fa7129a2.xml"},{"id":91829449,"identity":"75340324-0fe9-416a-92ba-af8b908df5cd","added_by":"auto","created_at":"2025-09-22 08:55:48","extension":"html","order_by":30,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":156851,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7434482/v1/cf0543c7f4c0278dd4e40425.html"},{"id":91829414,"identity":"74bd3e34-c6f1-455b-92f7-86ffc3b2cd43","added_by":"auto","created_at":"2025-09-22 08:55:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":46140,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patient selection for the study.\u003c/p\u003e\n\u003cp\u003eWe retrospectively reviewed the medical records of 579 patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitor (ICI)-based combination regimens. The following patients were excluded. Eighty-nine patients were classified as having a favorable risk according to the IMDC criteria, 28 received TKI monotherapy as first-line treatment, and 35 had no documented pathological diagnosis. The cohort of patients with mRCC was categorized by metastatic site.\u003c/p\u003e\n\u003cp\u003emRCC, metastatic renal cell carcinoma; ICI, immune checkpoint inhibitor; IO, immuno-oncology; TKI, tyrosine kinase inhibitor; IMDC, International Metastatic RCC Database Consortium.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7434482/v1/5c2ed23959a2d57b8962ad03.png"},{"id":91830495,"identity":"88221ca1-bbea-476e-a7ae-f567e65a6151","added_by":"auto","created_at":"2025-09-22 09:03:47","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":183548,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves for PFS and OS were stratified by metastatic site in patients with mRCC.\u003c/p\u003e\n\u003cp\u003ea, PFS in patients treated with IO–IO combination therapy. b, OS in patients treated with IO–IO combination therapy. c, PFS in patients treated with IO–TKI combination therapy. d, OS in patients treated with IO–TKI combination therapy. IO, immuno-oncology; TKI, tyrosine kinase inhibitor; OS, overall survival; PFS, progression-free survival; mRCC, metastatic renal cell carcinoma.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7434482/v1/27b21136419225247b0830bb.png"},{"id":91830497,"identity":"74307284-b7d2-4922-91c6-a26888f8bd29","added_by":"auto","created_at":"2025-09-22 09:03:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":175828,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves for PFS and OS by metastatic site in patients with mRCC treated with IO–IO or IO–TKI combination therapy.\u003c/p\u003e\n\u003cp\u003ePFS (a) and OS (b) in patients with lymph node-only metastases. PFS (c) and OS (d) in patients with lung metastases regardless of lymph node metastases. PFS (e) and OS (f) in patients with bone metastases regardless of lung and/or lymph node metastases. PFS (g) and OS (h) in patients with liver metastases regardless of lung and/or lymph node metastases. PFS (i) and OS (j) in patients with liver and/or bone metastases regardless of lung, lymph node, or other distant metastases. PFS (k) and OS (l) in patients with brain metastases.\u003c/p\u003e\n\u003cp\u003eIO, immuno-oncology; TKI, tyrosine kinase inhibitor; OS, overall survival; PFS, progression-free survival; mRCC, metastatic renal cell carcinoma.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7434482/v1/6d0556d28caf57e939ec05f8.png"},{"id":100617367,"identity":"cbe677dd-6936-4328-9cce-3a0f8aaa6917","added_by":"auto","created_at":"2026-01-19 17:51:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1577120,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7434482/v1/149b192c-8a18-4c9e-bb97-41a61e0dc7b2.pdf"},{"id":91831859,"identity":"1e77224b-693b-48e4-95fe-a322591fa99c","added_by":"auto","created_at":"2025-09-22 09:11:48","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":410596,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure.docx","url":"https://assets-eu.researchsquare.com/files/rs-7434482/v1/a16a48ee8d2d7e2b8d62f674.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparative efficacy of immune checkpoint inhibitor combination therapies by metastatic site in metastatic renal cell carcinoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eKidney cancer accounts for approximately 5% of all malignancies and ranks as the sixth most common cancer in men and the tenth in women\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Renal cell carcinoma (RCC) primarily occurs in populations in Europe and North America, whereas its incidence is relatively low in Asian countries. According to the Global Cancer Statistics 2020, there were 431,288 new cases of kidney cancer and 179,368 deaths worldwide. Metastatic RCC (mRCC) is observed in approximately 30% of patients at the time of initial diagnosis\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. The most common sites of distant metastasis in clear cell RCC are the lungs (70%), lymph nodes (45%), bone (32%), liver (18%), adrenal glands (10%), and brain (8%)\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. RCC can also metastasize to other sites, including the thyroid, pancreas, breast, skin, and muscle. The prognosis for patients with mRCC has significantly improved with the advent of targeted therapies, such as vascular endothelial growth factor (VEGF) inhibitors and, more recently, immune checkpoint inhibitors (ICIs)\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Combination therapies, such as nivolumab plus ipilimumab, pembrolizumab plus axitinib, avelumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib, are widely used as first-line systemic treatments for mRCC\u003csup\u003e[\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Immuno-oncology-tyrosine kinase inhibitor (IO\u0026ndash;TKI) combination therapies have demonstrated favorable tumor-shrinking effects, including higher objective response rates (ORRs) and longer progression-free survival (PFS). The rate of progressive disease (PD) with IO\u0026ndash;TKI therapy is lower than that with the ipilimumab\u0026ndash;nivolumab combination therapy. Conversely, ipilimumab\u0026ndash;nivolumab combination therapy showed better overall survival (OS) and durable responses\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. However, little is known regarding how specific metastatic organ sites influence survival outcomes and responses to systemic therapy\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. In this study, we evaluated the efficacy of IO\u0026ndash;IO and IO\u0026ndash;TKI combination therapies based on the metastatic site.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatient selection\u003c/h2\u003e\u003cp\u003e This study was approved by the Institutional Review Board of the principal institution, Osaka Medical and Pharmaceutical University in Osaka, Japan (approval number: RIN750\u0026ndash;2571). Owing to the retrospective nature of the study, the requirement for individual informed consent was waived; instead, information about the study was disclosed, and patients were given the opportunity to opt out. All procedures were conducted in accordance with the ethical standards of the institutional and national research committees and with the 1964 Helsinki Declaration and its later amendments. We retrospectively reviewed the medical records of 579 patients with mRCC treated with first-line ICI-based combination therapy between January 2018 and December 2024 at multiple Japanese institutions (Jikei University School of Medicine, Tokyo, Japan; Okayama University, Okayama, Japan; Osaka Medical and Pharmaceutical University, Osaka, Japan; Kindai University Faculty of Medicine, Osaka, Japan; Fujita Health University School of Medicine, Aichi, Japan; and 15 affiliated hospitals). The analysis included metastatic sites such as lymph nodes, lungs, bones, liver, brain, and other distant organs. Only patients classified as intermediate or poor risk according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria were included.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eOutcome measurements\u003c/h3\u003e\n\u003cp\u003eThe primary outcomes were PFS and OS, while the secondary outcome was the ORR. Efficacy outcomes were compared between the IO\u0026ndash;IO and IO\u0026ndash;TKI treatment groups. According to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, complete response (CR), partial response (PR), stable disease (SD), and PD were evaluated as the best responses during treatment.\u003c/p\u003e\n\u003ch3\u003eDisease management and follow-up methods\u003c/h3\u003e\n\u003cp\u003eTumor assessments were performed at screening and every 2\u0026ndash;3 months following the initiation of combination immunotherapy using imaging modalities such as computed tomography or magnetic resonance imaging, in accordance with the RECIST version 1.1. For each patient, demographic and clinical data at the time of treatment were collected, including age, sex, Karnofsky Performance Status (KPS), IMDC risk group, histological subtype, history of nephrectomy, neutrophil-to-lymphocyte ratio, and metastatic sites. The best response achieved during treatment (CR, PR, SD, or PD) was recorded for each patient. Treatment discontinuation due to disease progression or adverse events and the decision to resume therapy after discontinuation were made at the treating physician\u0026rsquo;s discretion in consultation with the patient, in accordance with the appropriate use guidelines for each combination regimen.\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003ePatients were categorized into six groups based on the presence of metastases in the lymph nodes, lungs, bones, liver, brain, or other organs. Metastases to organs other than the lymph nodes, lungs, bones, liver, or brain were classified as \u0026ldquo;other distant metastases.\u0026rdquo; Only patients categorized as having intermediate or poor risk according to the International Metastatic RCC Database Consortium (IMDC) criteria were included in the analysis. The groups were defined as follows:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePatients with lymph node metastases only.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePatients with lung metastases, with or without lymph node metastases.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePatients with bone metastases, with or without lung and/or lymph node metastases.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePatients with liver metastases, with or without lung and/or lymph node metastases.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePatients with liver and/or bone metastases, with or without lung, lymph node, or other distant metastases.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePatients with brain metastases.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003ePFS, OS, ORR, and prognostic factors were analyzed in each of the six groups, comparing patients treated with IO\u0026ndash;IO combination therapy and those treated with IO\u0026ndash;TKI combination therapy.\u003c/p\u003e\u003cp\u003eStatistical analyses were conducted using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria). The ORR between the two treatment groups was compared using Fisher\u0026rsquo;s exact test. OS and PFS were estimated by the Kaplan\u0026ndash;Meier method, with intergroup comparisons assessed using the chi-square test, Fisher\u0026rsquo;s exact test, or the Mann\u0026ndash;Whitney U test, as appropriate. A two-sided P-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant. Hazard ratios for OS and PFS were calculated using Cox proportional hazards regression models. The multivariate analysis for each metastasis group included age, IMDC risk, first-line therapy, and KPS.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sites of distant metastases were assessed in 579 patients with mRCC. The\u0026nbsp;patients’ characteristics are summarized in Table 1. The number of patients in each metastatic site is depicted in Fig. 1. The prognosis of patients with mRCC stratified by metastatic site is shown in Fig. 2. Among patients treated with IO–IO therapy, PFS and OS were significantly different across metastatic sites (P = 0.04 and P = 0.002, respectively). Patients with liver metastasis treated with IO–IO therapy had a worse prognosis. Among patients treated with IO–TKI therapy, PFS and OS were not significantly different across metastatic sites (P = 0.21 and P = 0.52, respectively).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLymph\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003en\u003c/strong\u003e\u003cstrong\u003eode\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003em\u003c/strong\u003e\u003cstrong\u003eetastasis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 36 patients with mRCC and only lymph node metastasis were identified; 21 patients were treated with IO–IO combination therapy, and 15 were treated with IO–TKI (Fig. 3a, b). The median PFS was 42.4 months in the IO–IO group and 24.5 months in the IO–TKI group, with no significant difference between the two groups (P = 0.95). The median OS was not reached in the IO–IO group and was 33.8 months in the IO–TKI group, with also no significant difference (P = 0.45). After adjustment for age, performance status, and IMDC risk, the type of first-line treatment was not significantly associated with OS (Table 2).\u003c/p\u003e\n\u003cp\u003eThe ORRs were as follows: in the IO–IO group, one patient had CR (4.8%), 9 PR (42.9%), 7 SD (33.3%), and 3 PD (14.3%). In the IO–TKI group, one patient had CR (6.7%), 6 PR (40%), 6 SD (40%), and one PD (6.7%). The ORR was 47.6% in the IO–IO group and 46.7% in the IO–TKI group; however, this difference was not statistically significant (P = 1) (Table 3). When comparing the prognosis among the IO–TKI group, the combination of pembrolizumab plus lenvatinib demonstrated favorable PFS and OS in patients with lymph node metastases, with a significant improvement in OS (P = 0.04) (Supplementary Fig. S1a, b).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eL\u003c/strong\u003e\u003cstrong\u003eung\u003c/strong\u003e\u003cstrong\u003em\u003c/strong\u003e\u003cstrong\u003eetastasis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 132 patients with mRCC and lung metastases, alone or with lymph node involvement, were included in this group analysis. Of these patients, 62 were treated with IO–IO combination therapy, and 70 were treated with IO–TKI (Fig. 3c, d). The median PFS was 15.0 months in the IO–IO group and 14.5 months in the IO–TKI group, with no significant difference between the groups (P = 0.37). The median OS was 42.7 months in the IO–IO group and not reached in the IO–TKI group, with no significant difference between the groups (P = 0.80).\u003c/p\u003e\n\u003cp\u003eAfter adjustment for age, performance status, and IMDC risk, the type of first-line therapy was not significantly associated with OS (Table 2).\u003c/p\u003e\n\u003cp\u003eORRs were as follows: in the IO–IO group, 4 patients had CR (6.5%), 28 PR (45.2%), 16 SD (25.8%), and 10 PD (16.1%). In the IO–TKI group, 8 patients had CR (11.4%), 37 PR (52.9%), 11 SD (15.7%), and 10 PD (14.3%). The ORR was 51.6% in the IO–IO group and 64.3% in the IO–TKI group; however, this difference was not statistically significant (P = 0.14) (Table 3). When comparing the prognosis among the IO–TKI group, PFS was not significantly different among the treatment groups (P = 0.46). However, OS was significantly worse in patients treated with avelumab plus axitinib combination therapy than in those treated with the other IO–TKI combinations (P = 0.003) (Supplementary Fig. S1c, d).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBone\u003c/strong\u003e\u003cstrong\u003em\u003c/strong\u003e\u003cstrong\u003eetastasis\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA total of 80 patients with mRCC and bone metastases, with or without lung and/or lymph node metastases, were included in this group analysis. Of these patients, 34 were treated with IO–IO combination therapy, and 46 were treated with IO–TKI (Fig. 3e, f). The median PFS was significantly longer in the IO–TKI group (35.2 months) than in the IO–IO group (6.3 months) (P = 0.01). The median OS was 56.8 months in the IO–IO group and not reached in the IO–TKI group, indicating a trend toward improved OS with IO–TKI therapy (P = 0.054).\u003c/p\u003e\n\u003cp\u003eAfter adjustment for age, performance status, and IMDC risk, IO–TKI therapy showed a trend toward better prognosis (P = 0.055) (Table 2).\u003c/p\u003e\n\u003cp\u003eORRs were as follows: in the IO–IO group, there were no CR (0%), 12 PR (35.3%), 8 SD (23.5%), and 10 PD (29.4%). In the IO–TKI group, two patients had CR (4.3%), 17 PR (37.0%), 16 SD (34.8%), and 4 PD (8.7%). The ORR was 35.3% for the IO–IO group and 41.3% for the IO–TKI group; however, the difference was not statistically significant (P = 0.63) (Table 3). When comparing the prognosis among the IO–TKI group, no significant differences were observed in PFS (P = 0.52) or OS (P = 0.94) among the treatment groups; however, all IO–TKI combinations demonstrated relatively favorable outcomes (Supplementary Fig. S1e, f). Furthermore, a total of 89 patients with mRCC and bone metastases, with or without lung, lymph node, and/or other distant metastases, were included in the analysis (Supplementary Fig. S2a, b). Of these patients, 37 were treated with IO–IO combination therapy, and 52 were treated with IO–TKI. When comparing the prognosis among the IO–TKI group,\u0026nbsp;no significant differences were found in PFS (P = 0.37) or OS (P = 0.60) among the treatment groups; however, nivolumab + cabozantinib showed relatively better results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLiver metastases\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 22 patients with mRCC and liver metastases, with or without lung and/or lymph node metastases, were included in this group analysis. Of these patients, 11 were treated with IO–IO combination therapy, and 11 were treated with IO–TKI (Fig. 3g, h). The median PFS was significantly longer in the IO–TKI group (12.5 months) than in the IO–IO group (2.3 months) (P = 0.015). The median OS was significantly longer in the IO–TKI group (not reached) than in the IO–IO group (5.8 months) (P = 0.01). After adjustment for age, performance status, and IMDC risk, IO–TKI therapy was significantly associated with better OS (P = 0.033) (Table 2).\u003c/p\u003e\n\u003cp\u003eORRs were as follows: in the IO–IO group, there were no CR (0%), 3 PR (27.2%), 3 SD (27.2%), and 3 PD (27.2%). In the IO–TKI group, no CR (0%), 4 PR (36.4%), 3 SD (27.2%), and one PD (9.1%). The ORR was 27.2% for the IO-IO group and 36.4% for the IO–TKI group; however, the difference was not statistically significant (P = 0.64) (Table 3). When comparing the prognosis among the IO–TKI group, no significant differences in PFS (P = 0.25) or OS (P = 0.28) were observed among the treatment groups. However, the combination of nivolumab and cabozantinib demonstrated better PFS, while the nivolumab plus cabozantinib and pembrolizumab plus axitinib combination therapies showed better OS outcomes (Supplementary Fig. S1g, h).\u003c/p\u003e\n\u003cp\u003eFurthermore, a total of 37 patients with mRCC and liver metastases, with or without lung, lymph node, and/or other distant metastases, were included in the analysis (Supplementary Fig. S2c, d).\u003c/p\u003e\n\u003cp\u003eFurthermore, a total of 33 patients with mRCC and liver metastases, with or without lung, lymph node, and/or other distant metastases, were included in the analysis (Supplementary Fig. S2c, d). Of these patients, 16 were treated with IO–IO combination therapy, and 17 were treated with IO–TKI. When comparing the prognosis among the IO–TKI group,\u0026nbsp;a significant difference was observed in PFS (P = 0.006), whereas no significant difference was observed in OS (P = 0.112).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWith liver and/or bone metastases\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 145 patients with mRCC and other distant metastases and those with liver or bone metastases were included in this group. Of these patients, 63 were treated with IO–IO combination therapy, and 82 were treated with IO–TKI combination therapy (Fig. 3i, j). The median PFS was significantly longer in the IO–TKI group (35.2 months) than in the IO–IO group (4.5 months) (P = 0.00002). The median OS was also significantly longer in the IO–TKI group (not reached) than in the IO–IO group (13.3 months) (P = 0.002). After adjustment for age, performance status, and IMDC risk, IO–TKI treatment was significantly associated with better OS (P = 0.003) (Table 2).\u003c/p\u003e\n\u003cp\u003eORRs were as follows: in the IO–IO group, two patients had CR (3.1%), 18 PR (28.6%), 14 SD (22.2%), and 21 PD (33.3%). In the IO–TKI group, three patients showed CR (3.7%), 31 PR (37.8%), 26 SD (31.3%), and 8 PD (9.6%). Although the ORR was higher in the IO–TKI group (41.0%) than in the IO–IO group (31.7%), the difference was not statistically significant (P = 0.147). When comparing the prognosis among the IO–TKI group, PFS (P = 0.92) or OS (P = 0.87) was not significantly different among the treatment groups. However, all IO–TKI combinations demonstrated relatively favorable outcomes in PFS and OS compared with IO–IO combination therapy (Supplementary Fig. S1i, j).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBrain metastases\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients with mRCC and brain metastases, regardless of other distant metastatic sites, were included in this group. A total of 16 patients were analyzed, of whom 10 patients were treated with IO–IO combination therapy and 6 were treated with IO–TKI combination therapy (Fig. 3k, l). The median PFS was 9.1 months in the IO–IO group and 7.5 months in the IO–TKI group, with no significant difference between the two groups (P = 0.069). The median OS was 23.5 months in the IO–IO group and 25.8 months in the IO–TKI group, also showing no significant difference (P = 0.76). After adjustment for age, performance status, and IMDC risk, the type of first-line treatment was not associated with OS (Table 2).\u003c/p\u003e\n\u003cp\u003eORRs were as follows: in the IO–IO group, 1 patient had CR (10%), 4 PR (40%), 3 SD (30%), and one PD (10%). In the IO–TKI group, there were no CR, 4 PR (66.7%), 2 SD (33.3%), and no PD. The ORR was 50% in the IO–IO group and 66.7% in the IO–TKI group; however, this difference was not statistically significant (P = 1) (Table 3). Kaplan–Meier curve analysis for PFS and OS stratified by each IO–TKI group is shown in Supplementary Fig. S1k, l.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe therapeutic landscape for metastatic clear cell RCC has undergone significant advancements over the past decade\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Currently, ICI-based combination therapies are the standard first-line treatment for mRCC. However, the efficacy of ICIs according to metastatic site and the comparative effectiveness of different therapeutic regimens remain unclear. Patients with bone, liver, or brain metastases from mRCC have poorer prognoses than those with lung or lymph node metastases\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. In this study, we compared the therapeutic outcomes of two combination regimens, IO\u0026ndash;IO and IO\u0026ndash;TKI, to determine if the efficacy varies by metastatic site. Our findings showed that IO\u0026ndash;TKI combinations were more effective in patients with liver or bone metastases. However, no significant difference in efficacy was observed between IO\u0026ndash;IO and IO\u0026ndash;TKI regimens for patients with lymph node, lung, or brain metastases.\u003c/p\u003e\u003cp\u003eDudani et al. analyzed data from 10,105 patients with mRCC to evaluate the association between metastatic sites and OS\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Among 9,252 patients with clear cell RCC, the most common metastatic sites were the lung (70%), lymph nodes (45%), bone (32%), liver (18%), adrenal gland (10%), and brain (8%). 88% of patients received TKIs, 4.5% received mTOR inhibitors, and only 6.1% received ICI-based regimens. The median OS was 25.1 months for patients with clear cell RCC with lung metastases, 21.4 months for those with lymph node metastases, 19.4 months for those with bone metastases, 17.6 months for those with liver metastases, 16.5 months for those with brain metastases, and 15.6 months for those with pleural metastases. Metastases to the brain, liver, and bone were consistently associated with poorer survival outcomes\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. In contrast, metastases to endocrine organs such as the pancreas, thyroid, and adrenal glands were associated with relatively favorable OS.\u003c/p\u003e\u003cp\u003eSeveral studies have reported the clinical benefit of nivolumab for patients with lymph node metastases from RCC. Jajodia et al. reported organ-specific response rates to nivolumab in a cohort of 30 patients with mRCC\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. The metastatic sites included the lung (n\u0026thinsp;=\u0026thinsp;26), lymph nodes (n\u0026thinsp;=\u0026thinsp;20), liver (n\u0026thinsp;=\u0026thinsp;10), soft tissue (n\u0026thinsp;=\u0026thinsp;7), brain (n\u0026thinsp;=\u0026thinsp;5), adrenal glands (n\u0026thinsp;=\u0026thinsp;4), and peritoneum (n\u0026thinsp;=\u0026thinsp;4). Based on iRECIST criteria, the best ORRs for each site were 19% (lung), 35% (lymph nodes), 10% (liver), 0% (soft tissue), 20% (brain), 25% (adrenal glands), and 25% (peritoneum). Although limited by a small sample size, these findings suggest that lymph node metastases are more responsive to ICIs, while liver and soft tissue metastases demonstrate the poorest responses. Our results also showed that the patients with lymph node or lung metastasis treated with IO combination therapy had a better prognosis.\u003c/p\u003e\u003cp\u003eIn this study, no significant difference was observed in PFS or OS between IO\u0026ndash;IO and IO\u0026ndash;TKI combination therapies in patients with lung metastases. Among the IO\u0026ndash;TKI regimens, only the avelumab plus axitinib combination was associated with poorer OS (P\u0026thinsp;=\u0026thinsp;0.003).\u003c/p\u003e\u003cp\u003eBone metastases are associated with poor prognosis among patients with mRCC\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. In our study, patients with bone metastases showed a trend toward improved OS with IO\u0026ndash;TKI combination therapy compared with IO\u0026ndash;IO therapy. Recent studies have shown the potential benefit of cabozantinib for patients with bone metastases. The phase III METEOR trial, which compared cabozantinib with everolimus as a second-line treatment, demonstrated a PFS benefit in patients with bone metastases\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Furthermore, recent subgroup analyses from the CheckMate 9ER trial, which evaluated the combination of nivolumab and cabozantinib, confirmed OS and PFS benefits in patients with bone metastases\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn the CLEAR trial, which compared lenvatinib plus pembrolizumab with sunitinib for advanced RCC, subgroup analyses showed that patients with poor prognostic factors, such as bone or liver metastases, experienced improved OS and PFS with combination therapy compared with sunitinib\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eCabozantinib targets multiple tyrosine kinase receptors, including VEGFR2, MET, AXL, RET, and KIT, which are important mediators of tumor cell survival, metastasis, and tumor angiogenesis\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Cabozantinib inhibits VEGFR and MET, affecting the function of osteoclasts and osteoblasts, thereby possibly altering the bone microenvironment. In this study, among treatments for bone and liver metastases, the IO\u0026ndash;TKI regimen of nivolumab plus cabozantinib demonstrated better PFS. In patients with bone metastases, in addition to the better OS observed with nivolumab plus cabozantinib, the combinations of pembrolizumab plus lenvatinib and pembrolizumab plus axitinib also demonstrated better outcomes.\u003c/p\u003e\u003cp\u003ePatients with liver metastases showed a systemic decrease in tumor-specific T cells, which limits the efficacy of immunotherapy\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Various hepatic-resident cell types, including Kupffer cells, liver sinusoidal endothelial cells, hepatocytes, plasmacytoid dendritic cells, NKT cells, and hepatic stellate cells, influence T cell fate and survival within the hepatic microenvironment. Through unbiased single-cell analysis, liver-derived CD11b⁺F4/80⁺ macrophages were identified as critical mediators that induce apoptosis of antigen-specific CD8⁺ T cells via the Fas\u0026ndash;FasL pathway in the liver metastatic microenvironment. These findings suggest that for patients with liver metastases, IO\u0026ndash;TKI combination therapy is a more suitable treatment strategy.\u003c/p\u003e\u003cp\u003eIn this study, no significant differences in OS or PFS were observed between IO\u0026ndash;IO and IO\u0026ndash;TKI combination therapies in patients with brain metastases. Sunitinib has not demonstrated substantial efficacy against brain metastases\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. In a phase II trial involving 16 patients with RCC and untreated brain metastases, no intracranial objective responses were reported. SD was observed as the best intracranial response in only five patients. The median PFS was 2.3 months, and the median OS was 6.3 months, indicating poor outcomes. In contrast, cabozantinib might be effective for the brain metastasis. The efficacy of cabozantinib was evaluated in 33 patients with advanced RCC and brain metastases who received the drug in second-line or later settings, none of whom had undergone brain radiotherapy or surgery within 2 months prior to treatment initiation\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. The ORR was 55%, including 3 CRs, 14 PRs, and 10 SDs, suggesting the potential effectiveness of cabozantinib in treating brain metastases from RCC. Cabozantinib crosses the blood-brain barrier and may have clinical activity in patients with brain metastases\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. In whole-brain lysates of non-tumor-bearing mice, cabozantinib attained 20% of peak plasma levels, suggesting its ability to penetrate the blood-brain barrier. This finding has not been confirmed in human trials. Although the efficacy of cabozantinib for advanced RCC was confirmed by two randomized trials\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e, these studies largely excluded patients with active intracranial disease, and only a small number of patients with adequately treated and stable brain metastases were enrolled.\u003c/p\u003e\u003cp\u003eThere is no available data regarding the intracranial efficacy of other TKIs, such as axitinib or pazopanib, in this specific subgroup of patients. To date, the only clinical trial evaluating ICI in patients with mRCC and brain metastases is the GETUG-AFU 26 NIVOREN8 trial\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. This was a phase II, single-arm trial assessing the safety and efficacy of nivolumab monotherapy in patients who had progressed after VEGF-targeted therapy. The study included 73 patients with brain metastases, of whom 39 had untreated intracranial target lesions and had not received prior local therapies such as radiotherapy or surgery. The intracranial ORR in this subgroup was 12%, indicating that nivolumab monotherapy has limited activity in untreated brain metastases. They emphasized the importance of local therapy prior to initiating systemic treatment. Our results also showed poor prognosis of patients with brain metastasis compared with other metastases, and no difference in efficacy between IO\u0026ndash;IO and IO\u0026ndash;TKI combination therapy. The optimal strategy for brain metastasis should be developed.\u003c/p\u003e\u003cp\u003eA study analyzing 657 tumor samples investigated differences in molecular subtypes, genomic features, and the tumor microenvironment (TME) between primary and metastatic sites in RCC\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. Although no significant difference in PD-L1 positivity was observed between primary and metastatic tumors overall, the expression rate in bone metastases was notably lower than that in primary tumors. While several clinical trials have reported that PD-L1 expression is not a reliable predictor of response to ICIs, the reduced expression in bone metastases may partly explain the limited efficacy of IO\u0026ndash;IO combination therapy in such cases\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. This study also estimated the abundance of various cell populations within the TME and identified significant differences between metastatic sites compared with primary renal tumors. Endothelial and monocytic lineage cells were more abundant in bone metastases, whereas B cell-rich microenvironments were observed in lung and skin metastases. Although not statistically significant, T cell abundance appeared higher in lymph node metastases than in the kidney, and CD8⁺ and cytotoxic T cells were enriched in endocrine metastases. Fibroblast populations were notably more abundant across metastatic sites, particularly in the liver, lung, bone, pleura, and soft tissues.\u003c/p\u003e\u003cp\u003eRegarding immune checkpoint gene expression, RNA levels of CTLA4, TIM3, LAG3, or PD1 were not significantly different between primary and metastatic sites. However, PD-L1 expression was higher in pleural metastases, and PD-L2 expression was elevated in lung and bone metastases compared with that in the kidney. These findings suggest that site-specific differences in the TME contribute to the variation in treatment outcomes observed across different metastatic sites.\u003c/p\u003e\u003cp\u003eIn patients with lymph node, lung, and bone metastases treated with IO\u0026ndash;IO combination therapy, the 36-month PFS and OS rates were approximately 30\u0026ndash;40% and 50\u0026ndash;70%, respectively, comparable to the results reported in the CheckMate 214 trial. In this study, we further compared treatment outcomes by metastatic site in patients receiving IO\u0026ndash;IO or IO\u0026ndash;TKI combination therapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Among the patients treated with IO\u0026ndash;IO therapy, PFS and OS were significantly different across metastatic sites, indicating heterogeneous efficacy depending on the organ involved. In contrast, among those treated with IO\u0026ndash;TKI therapy, no significant inter-site differences were observed, suggesting consistent therapeutic efficacy across metastatic sites.\u003c/p\u003e\u003cp\u003eNotably, patients with liver or bone metastases, typically considered to have poor prognoses, demonstrated longer OS than those with lymph node or lung metastases in the IO\u0026ndash;TKI group. These findings support the notion that the efficacy of combination immunotherapy may vary depending on the metastatic site.\u003c/p\u003e\u003cp\u003eThis study has several limitations. It was a retrospective analysis comparing the therapeutic efficacy of IO\u0026ndash;IO and IO\u0026ndash;TKI combination therapies. Unknown confounding factors might have influenced the choice of the first-line treatment. The IO\u0026ndash;TKI group included four different regimens, each with a small number of cases, limiting the robustness of regimen-specific comparisons. Additionally, rare metastatic sites such as the brain had a limited number of cases. Owing to the small sample sizes, the results should be interpreted with caution. Future studies will require longer follow-up periods and the accumulation of additional cases.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe efficacy of IO combination therapy could depend on the metastatic site. IO–TKI combination therapy could be a more appropriate first-line treatment option than IO–IO therapy for patients with mRCC and bone or liver metastases. In contrast, IO–IO combination therapy may represent a more appropriate treatment option for patients with lymph node or lung metastases. These findings could help physicians decide the treatment strategy for patients with mRCC.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eORR, objective response rate; PFS, progression-free survival; mRCC, metastatic renal cell carcinoma; IO, immuno-oncology; OS, overall survival; TKI, tyrosine kinase inhibitor; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; RECIST, Response Evaluation Criteria in Solid Tumors; iRECIST, immune-related Response Evaluation Criteria in Solid Tumors; KPS, Karnofsky Performance Status\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eShingo Toyoda contributed to the protocol and project development, data analysis, and manuscript writing and editing. Takafumi Yanagisawa and Keiichiro Mori contributed to the protocol and project development and data collection. Lan Inoki, Mamoru Hashimoto, Wataru Fukuokaya, Shingo Nishimura, Ryoichi Maenosono, Takehiro Iwata, Kensuke Bekku, Takuhisa Nukaya, and Takuya Tsujino contributed to data collection. Kiyoshi Takahara, Teruo Inamoto,\u0026nbsp;Haruhito Azuma\u0026nbsp;and Kazumasa Komura contributed to the protocol and project development. Kazutoshi Fujita contributed to the project development, manuscript editing, and supervision. All authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData will be made available by the corresponding author for reasonable requests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray, F. \u003cem\u003eet al. \u003c/em\u003eGlobal cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. \u003cem\u003eCA Cancer J. 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Urol.\u003c/em\u003e \u003cstrong\u003e8\u003c/strong\u003e, 362\u0026ndash;375 (2021). \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Cohort characteristics by metastatic site.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"737\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLymph node\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLung\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eIO\u0026ndash;IO\u003c/p\u003e\n \u003cp\u003e(n=21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eIO\u0026ndash;TKI\u003c/p\u003e\n \u003cp\u003e(n=15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eIO\u0026ndash;IO\u003c/p\u003e\n \u003cp\u003e(n=62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eIO\u0026ndash;TKI\u003c/p\u003e\n \u003cp\u003e(n=70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eIO\u0026ndash;IO\u003c/p\u003e\n \u003cp\u003e(n=34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eIO\u0026ndash;TKI\u003c/p\u003e\n \u003cp\u003e(n=46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eAge, median, (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e70 (27-87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e70 (26-85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e70 (32-86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e70 (44-89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e70 (25-86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e70 (45-85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e18/3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e11/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e48/14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e49/21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e29/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e37/9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eeGFR, median, (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e50 (5-84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e50 (16-79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e50 (4-102)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e50 (5-91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e50 (4-102)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e50 (5-98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetastatic site, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Lung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e62 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e70 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e14 (41.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e17 (37.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Bone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e34 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e46 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Liver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Brain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Lymph node\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e21 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e15 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e14 (22.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e21 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e7 (20.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e10 (21.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistology, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Clear cell\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e9 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e6 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e44 (71.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e56 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e24 (70.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e33 (71.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Papillary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e4 (19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e4 (26.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e3 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e3 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e3 (6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Unclassified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e4 (19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e3 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;HD-related\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e2 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Chromophobe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Others\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e3 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e4 (6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e3 (8.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e2 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;None\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e4 (26.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e8 (12.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e7 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e3 (8.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e3 (6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Presence of sarcomatoid component\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e2 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e5 (8.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e10 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e3 (6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.61\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConfirmation of histology, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Nephrectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e11 (52.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e7 (46.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e29 (46.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e41 (58.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e13 (38.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e15 (32.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Partial nephrectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e5 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e4 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e4 (8.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e9 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e4 (26.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e24 (38.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e16 (22.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e12 (35.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e19 (41.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIMDC at 1\u003csup\u003est\u003c/sup\u003e line, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eIntermediate/poor\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e14/7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e11/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e38/24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e55/15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.036\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e23/11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e28/18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.64\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"737\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLiver\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWith liver and/or bone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBrain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eIO\u0026ndash;IO\u003c/p\u003e\n \u003cp\u003e(n=11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eIO\u0026ndash;TKI\u003c/p\u003e\n \u003cp\u003e(n=11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eIO\u0026ndash;IO\u003c/p\u003e\n \u003cp\u003e(n=63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eIO\u0026ndash;TKI\u003c/p\u003e\n \u003cp\u003e(n=82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eIO\u0026ndash;IO\u003c/p\u003e\n \u003cp\u003e(n=10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eIO\u0026ndash;TKI\u003c/p\u003e\n \u003cp\u003e(n=6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eAge, median, (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e70 (54-74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e70 (58-80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e70 (25-86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e70 (40-88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e70 (53-79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e70 (53-83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e8/3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e9/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e52/11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e63/19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e5/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e3/3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eeGFR, median, (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e50 (8-77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e50 (32-102)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e50 (4-160)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e50 (5-102)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e50 (42-116)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e50 (35-110)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetastatic site, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Lung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e9 (81.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e6 (54.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e33 (52.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e40 (48.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e9 (90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e5 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Bone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e47 (74.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e64 (78.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e2 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Liver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e11 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e11 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e24 (38.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e28 (34.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Brain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 ()\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e10 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e6 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Lymph node\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e8 (72.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e5 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e20 (31.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e27 (32.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e4 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e3 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistology, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Clear cell\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e9 (81.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e7 (63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e45 (71.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e55 (67.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e6 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e5 (83.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Papillary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e2 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e7 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Unclassified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e3 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e2 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;HD-related\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Chromophobe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Others\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e4 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e2 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;None\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e2 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e2 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e8 (12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e15 (18.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e2 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Presence of sarcomatoid component\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e2 (3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e4 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e2 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConfirmation of histology, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Nephrectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e5 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e4 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e23 (36.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e28 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e4 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Partial nephrectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e5 (7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e5 (6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;Biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e5 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e5 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e24 (38.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e33 (40.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e5 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e3 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIMDC at 1\u003csup\u003est\u003c/sup\u003e line, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eIntermediate/poor\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e6/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e6/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e37/26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e47/35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e5/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e4/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eeGFR, estimated glomerular filtration rate; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; IO, immuno-oncology; TKI, tyrosine kinase inhibitor.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Cox proportional hazards analysis of overall survival by metastatic site.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 477px;\"\u003e\n \u003cp\u003eMultivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003eLymph node\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003eLung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003eBone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003eHazard ratio (95% confidence interval)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003eHazard ratio (95% confidence interval)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003eHazard ratio (95% confidence interval)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e0.95 (0.91\u0026ndash;0.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e1.01 (0.97\u0026ndash;1.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e1.01 (0.96\u0026ndash;1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003eIMDC (poor vs intermediate)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e2.51 (0.59\u0026ndash;10.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e2.24 (0.83\u0026ndash;6.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e0.94 (0.34\u0026ndash;2.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e1\u003csup\u003est\u003c/sup\u003e\u003csup\u003e \u003c/sup\u003eline therapy (IO\u0026ndash;TKI vs IO\u0026ndash;IO)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e1.84 (0.59\u0026ndash;5.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e1.43 (0.52\u0026ndash;3.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e0.37 (0.13\u0026ndash;1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.055\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003eKPS (＜80 vs\u0026nbsp;≧80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e9.26 (1.79\u0026ndash;47.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e1.19 (0.25\u0026ndash;5.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e1.61 (0.55\u0026ndash;4.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"605\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 482px;\"\u003e\n \u003cp\u003eMultivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eWith liver and/or bone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eBrain\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eHazard ratio (95% confidence interval)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eHazard ratio (95% confidence interval)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eHazard ratio (95% confidence interval)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e1.00 (0.89-1.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0.98 (0.95-1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0.99 (0.90-1.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eIMDC (poor vs intermediate)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e1.89 (0.48-7.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e2.71 (1.53-4.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.0007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e11.23 (0.44-283.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1\u003csup\u003est\u003c/sup\u003e\u003csup\u003e \u003c/sup\u003eline therapy (IO\u0026ndash;TKI vs IO\u0026ndash;IO)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e0.14 (0.02-0.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0.40 (0.22-0.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e3.98 (0.42-37.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eKPS (＜80 vs\u0026nbsp;≧80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e0.65 (0.08-5.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0.48 (0.22-1.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e9.42 (0.83-106.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eIMDC, International Metastatic Renal Cell Carcinoma Database Consortium; IO, immuno-oncology; TKI, tyrosine kinase inhibitor; KPS, Karnofsky Performance Status.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Response rate stratified by metastatic site.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"775\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLymph node\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=36)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLung\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=1\u003c/strong\u003e\u003cstrong\u003e32\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBone\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=80)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLiver\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=22)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWith liver and/or bone (n=145)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBrain\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=16)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eBest response, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eIO\u0026ndash;IO\u003c/p\u003e\n \u003cp\u003e(n=21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eIO\u0026ndash;TKI\u003c/p\u003e\n \u003cp\u003e(n=15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eIO\u0026ndash;IO\u003c/p\u003e\n \u003cp\u003e(n=62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eIO\u0026ndash;TKI\u003c/p\u003e\n \u003cp\u003e(n=70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eIO\u0026ndash;IO\u003c/p\u003e\n \u003cp\u003e(n=34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eIO\u0026ndash;TKI\u003c/p\u003e\n \u003cp\u003e(n=46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eIO\u0026ndash;IO\u003c/p\u003e\n \u003cp\u003e(n=11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eIO\u0026ndash;TKI\u003c/p\u003e\n \u003cp\u003e(n=11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eIO\u0026ndash;IO\u003c/p\u003e\n \u003cp\u003e(n=63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eIO\u0026ndash;TKI\u003c/p\u003e\n \u003cp\u003e(n=82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eIO\u0026ndash;IO\u003c/p\u003e\n \u003cp\u003e(n=10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eIO\u0026ndash;TKI\u003c/p\u003e\n \u003cp\u003e(n=6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e1 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e4 (6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e8 (11.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e2 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e2 (3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e3 (3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e9 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e6 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e28 (45.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e37 (52.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e12 (35.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e17 (37.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e3 (27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e4 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e18 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e31 (37.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e4 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e4 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e7 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e6 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e16 (25.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e11 (15.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e8 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e16 (34.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e3 (27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e3 (27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e14 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e26 (31.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e3 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e2 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e3 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e1 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e10 (16.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e10 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e10 (29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e4 (8.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e3 (27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e21 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e8 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eORR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e10 (47.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e7 (46.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e32 (51.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e45 (64.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e12 (35.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e19 (41.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e3 (27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e4 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e20 (31.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e34 (41.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e5 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e4 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"metastatic renal cell carcinoma, bone metastasis, liver metastasis, immuno-oncology","lastPublishedDoi":"10.21203/rs.3.rs-7434482/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7434482/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eFew studies have investigated the efficacy of immuno-oncology (IO) combinations at different metastatic sites in renal cell carcinoma (RCC). We evaluated the differential efficacy of IO–IO and IO–tyrosine kinase inhibitor (TKI) combinations by metastatic site in metastatic RCC (mRCC). This retrospective multicenter study by the JK-FOOT Study Group included 579 patients with intermediate- or poor-risk mRCC (per International Metastatic RCC Database Consortium criteria) treated with first-line IO combinations between September 2018 and December 2024. Metastatic sites were lymph nodes, lungs, bones, liver, brain, and others. The primary outcomes were progression-free survival (PFS) and overall survival (OS); the secondary outcome was objective response rate. Efficacy was compared between IO–IO and IO–TKI for each site. For lymph node (n = 36), lung (n = 132), or brain (n = 16) metastases, OS or PFS was not significantly different between IO–IO and IO–TKI. In bone metastases (n = 80), OS tended to favor IO–TKI (P = 0.053). In liver metastases (n = 22), OS was significantly longer with IO–TKI (P = 0.011). IO–TKI may be a more appropriate first-line option than IO–IO for mRCC with bone or liver metastases, while efficacy is similar for other sites.\u003c/p\u003e","manuscriptTitle":"Comparative efficacy of immune checkpoint inhibitor combination therapies by metastatic site in metastatic renal cell carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-22 08:55:43","doi":"10.21203/rs.3.rs-7434482/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-24T14:05:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-20T09:06:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"78729402088300608519717530650119834757","date":"2025-11-20T07:09:27+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-26T07:24:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"314945980779184170300509248680667990280","date":"2025-09-26T06:57:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-10T17:23:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-10T17:23:08+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-01T12:12:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-28T11:01:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-08-28T10:57:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bf1c6587-1c2a-4bfb-a970-5f3cf3bb3725","owner":[],"postedDate":"September 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":54660055,"name":"Biological sciences/Cancer"},{"id":54660056,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-01-19T17:19:43+00:00","versionOfRecord":{"articleIdentity":"rs-7434482","link":"https://doi.org/10.1038/s41598-025-33198-x","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-01-13 16:28:35","publishedOnDateReadable":"January 13th, 2026"},"versionCreatedAt":"2025-09-22 08:55:43","video":"","vorDoi":"10.1038/s41598-025-33198-x","vorDoiUrl":"https://doi.org/10.1038/s41598-025-33198-x","workflowStages":[]},"version":"v1","identity":"rs-7434482","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7434482","identity":"rs-7434482","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}