Search Results (161)

Background: Renal cell carcinoma (RCC) is a common malignancy with a rising global incidence. While cytoreductive nephrectomy (CRN) was historically a cornerstone in the management of metastatic RCC (mRCC), its role has been questioned following pivotal trials such as CARMENA and SURTIME. With the advent of immune checkpoint inhibitors (ICIs) and targeted therapies, the contemporary relevance of CRN coupled with first-line immunotherapy and targeted therapy combination regimens warrants re-evaluation. Methods: This retrospective cohort study utilized the TriNetX research network to identify patients aged 18–90 years diagnosed with mRCC between 2005 and 2024 who received first-line systemic therapies. Patients were stratified into two cohorts based on receipt of CRN status within one year of diagnosis. Propensity score matching (1:1) was done to adjust baseline characteristics. Kaplan–Meier survival analysis and Cox proportional hazards modeling were used to compare five-year overall survival between the groups. Results: Among 5960 eligible patients, 1776 (888 CRN matched to 888 who did not) formed the cohort of analysis. The CRN group demonstrated significantly higher five-year survival (57.7% vs. 45.0%, p < 0.0001) with a hazard ratio of 1.56 (95% CI: 1.33–1.83). Subgroup analyses showed consistent survival benefits across all four NCCN-recommended first-line regimens—Axitinib + Pembrolizumab: 64.0% (CRN) vs. 53.3% (no CRN), p = 0.01; Cabozantinib + Nivolumab: 50.1% vs. 40.4%, p = 0.004; Lenvatinib + Pembrolizumab: 37.4% vs. 22.8%, p = 0.012; Nivolumab + Ipilimumab: 56.4% vs. 46.1%, p = 0.005. Conclusions: In the era of modern immunotherapy and targeted agents, CRN remains associated with improved survival in patients with mRCC receiving NCCN-recommended first-line regimens. These findings support the continued evaluation of CRN as a component of multimodal therapy, particularly in patients with favorable risk profiles. Full article

Background: Despite recent advances in the management of metastatic renal cell carcinoma (mRCC), real-world outcomes remain heterogeneous, and early treatment failure is common. Predictive biomarkers for time to treatment failure (TTF) outside clinical trials are poorly characterized. Objective: To identify clinical and laboratory predictors associated with early treatment failure in a real-world cohort of mRCC patients treated with immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitors (TKIs), or combination regimens. Methods: We conducted a retrospective, single-center analysis of patients with metastatic non-urothelial RCC treated between 2018 and 2023. Cox proportional hazards regression was used to evaluate the association between baseline biological parameters and TTF for each treatment regimen. Results: Among 137 patients receiving first-line therapy, 50 received Ipilimumab + Nivolumab, 49 Sunitinib, and 17 Avelumab + Axitinib. For Ipilimumab + Nivolumab, elevated AST was significantly associated with shorter TTF. For Avelumab + Axitinib, shorter TTF was associated with lymph node metastases, low lymphocyte count, low creatinine, low BMI, and low hemoglobin. For Cabozantinib in subsequent lines, a higher platelet count, ALT, and presence of liver metastases were associated with shorter TTF. No statistically significant predictors were found for Nivolumab used in the second-line setting. Conclusions: Routine, accessible biomarkers such as AST, hemoglobin, lymphocyte count, and creatinine may serve as predictors of treatment failure in specific therapeutic contexts. These findings support risk-adapted strategies and individualized monitoring in real-world clinical practice, though further validation in larger cohorts is warranted. Full article

This study aimed to clarify the alterations in gene expression in metastatic renal cell carcinoma (mRCC) during disease progression and in response to treatment with immune checkpoint inhibitors using a syngeneic mouse mRCC model. RENCA cells were orthotopically implanted in BALB/c mice. Mice received first-line treatment with cabozantinib, anti-PD-1 antibody, or a combination. Tumor progression was monitored using serial micro-computed tomography. Lung metastasis samples were collected, and RNA sequencing was performed. Mice with apparent disease progression received second-line treatment with axitinib, everolimus, or lenvatinib after combination therapy. The median overall survival was 28, 34, 34, and 49 days in untreated mice and those treated with cabozantinib, anti-PD-1, or their combination, respectively (p < 0.05). RNA sequencing revealed upregulation of the fibroblast growth factor pathway in lung metastases after monotherapy, whereas mTOR pathway activation was observed only after combination therapy. Treatment-specific gene expression changes occur in mRCC, suggesting that the optimal target for sequential therapy in mRCC varies depending on prior treatment. Full article

Background/Objectives: Alterations in long non-protein-coding RNAs (lncRNAs) are known to influence cellular proliferation, apoptosis, and metastasis in human cancers, including renal cell carcinoma (RCC). Methods: Using pyrosequencing, we analyzed DNA methylation (DNAm) at 23 loci within the LINC00404 CpG island across 28 human cancer cell line models, 181 RCC tumor tissues, 154 paired tumor-adjacent normal tissues (adNs), and 194 metastatic tissue samples. Results: Our analysis revealed that all CpG sites exhibited tumor-specific hypermethylation (all p ≤ 1.4 × 10⁻⁵). Moreover, primary RCC tissues with distant metastases (M1) and metastatic tissue samples (Mtx) showed significant hypermethylation compared to RCC without distant metastases (M0). Notably, DNAm in Mtx displayed a significant increase in 22 CpG sites, compared to 12 CpG sites in the M1/M0 comparison, suggesting that DNAm in Mtx differs both qualitatively and quantitatively. Conclusions: Given that elevated levels of DNAm were also observed in the majority of cell line models, our findings suggest that LINC00404 may play a pivotal role in the malignant development and progression of RCC metastasis, as well as in other human cancers. Full article

Background/Objectives: Kidney transplantation is associated with an increased risk of renal cell carcinoma (RCC). This study aimed to evaluate the outcomes of de novo RCC in kidney transplant recipients (KTRs). Methods: We retrospectively identified 50 de novo RCC cases among 4012 KTRs transplanted from 2005 to 2024. Data on patient characteristics and outcomes were collected. Propensity score matching (PSM) compared 34 localized RCC cases in KTRs with 34 non-transplant RCC cases. The statistical analyses used Kaplan–Meier estimates, the log-rank test, and the Cox regression. Results: The RCC incidence was 0.64 per 1000 person-years, with a standardized incidence ratio of 4.40 (95% CI: 3.33–5.80). In the KTR cohort, clear cell RCC was present in 42%, and papillary RCC was present in 42%. RCC developed predominantly in native kidneys (92%). UICC stage I was present in 74%. The treatment for the non-metastatic RCC was nephrectomy in the majority of cases (91%). For the metastatic RCC, 71% received a tyrosine kinase inhibitor (TKI). In the KTR cohort, the 3- and 5-year overall survival (OS) rates were 85% and 72%, respectively, with a median OS of 199 months; the synchronous metastasized (M1) patients had a median OS of 14 months. Rejection, age, advanced UICC stage, higher pT stage, clinical positive lymph nodes, M1, and higher grade were significantly associated with poor OS. The 5-year OS (96% vs. 84%, p = 0.72) and MFS (92% vs. 93%, p = 0.61) were comparable in the PSM cohort between the KTRs and the non-KTRs in the localized RCC. Conclusions: KTRs have a higher risk of RCC and present at a localized stage with comparable OS rates to non-transplant RCC patients. Adverse tumor characteristics, including synchronous metastases, significantly affect the prognosis, highlighting the need for surveillance and individualized treatment, particularly for metastatic RCC. Full article

Background/Objectives: Early treatment assessment in metastatic renal cell carcinoma (mRCC) remains challenging due to the limited accuracy of current imaging methods. Given prostate-specific membrane antigen (PSMA) overexpression in mRCC, PSMA PET is a promising approach. Despite numerous studies on PSMA imaging in mRCC, data on PSMA uptake changes during systemic therapy are scarce. We analyzed PSMA uptake on PET after treatment initiation in mRCC patients. Methods: A retrospective single-center analysis of mRCC patients who underwent [¹⁸F]PSMA-1007 PET/CT before (PET₁) and at a mean of 9.5 weeks after (PET₂) starting systemic therapy was conducted. PSMA uptake in metastatic lesions was compared by region and RCC subtype. Uptake differences between PET₁ and PET₂ were analyzed using an unpaired t-test. Results: This study included 25 patients (mean age 65.2 ± 14.7 years; 20 male) with mRCC. A total of 113 (PET₁) and 48 (PET₂) metastases were assessed. Lymph node metastases showed stable PSMA uptake (median SUV_max) after treatment (7.8 vs. 7.7, p = 0.77), while uptake by bone (6.4 vs. 12.4, p = 0.03) and lung metastases (4.5 vs. 8.1, p = 0.004) increased significantly. SUV stability in lymph nodes was independent of RCC subtype (ccRCC: p = 0.48, pRCC: p > 0.99). Bone (6.6 vs. 15.9, p = 0.008) and lung metastases (4.8 vs. 8.1, p = 0.02) had higher PSMA uptake in ccRCC, unlike pRCC (bone: 6.2 vs. 6.0, p = 0.86). Conclusions: Alterations of PSMA-radioligand uptake are seen in bone and pulmonary metastases but not in lymph node metastases after initiation of systemic treatment in patients with mRCC. ccRCC has a higher PSMA uptake than other RCC subtypes. Full article

Background/Objectives: The precise role of volumetric body composition (VBC) parameters, visceral adipose tissue index (VATI), subcutaneous adipose tissue index (SATI), and skeletal muscle index (SMI) on the survival of metastatic renal cell carcinoma (mRCC) is not fully elucidated. Herein, the present study investigated the clinical significance of baseline VBC parameters and their changes after 3–4 months from treatment initiation in patients with mRCC treated with first-line targeted therapy. Methods: A total of 108 patients were enrolled. VBC parameters were depicted from computerized tomography (CT) images at the third lumbar vertebra level. Kaplan–Meier curves were used to estimate survival probability, and the differences between prognostic subgroups were compared with the log-rank test. The association of baseline VBC variables and their change values (First CT value minus baseline CT value) with progression-free survival (PFS) and overall survival (OS) was evaluated in univariate and multivariate analyses. Results: The median PFS and OS of the whole patients were 11 and 46 months, respectively. Patients with increased VATI and SATI change values had poorer OS than those with decreased values. However, patients with higher SMI change values had superior OS than those with lower values. Among VBC variables, the independent predictors of worse OS were high VATI change (HR 5.10, p = 0.001) and low SMI change values (HR 2.66, p = 0.007), in addition to International Metastatic Renal Cell Carcinoma Database Consortium prognostic stratification (p = 0.001). Conclusions: Our findings showed that high VATI and low SMI changes were associated with worse OS in mRCC patients treated with first-line targeted therapy. Full article

Background: The treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved rapidly with the introduction of various immune-oncology (IO) agents and tyrosine kinase inhibitors (TKIs). We aimed to describe real-world treatment patterns and clinical outcomes of mRCC patients in post-IO and TKI settings. Methods: Using data from The US Oncology Network electronic health record database, iKnowMed, this retrospective cohort study included adult mRCC patients receiving subsequent treatments (index treatment) post-IO and TKI in combination or sequence between 1 January 2018 and 30 September 2020 and followed them until 30 April 2022. Treatment patterns were summarized descriptively. Overall survival (OS) and progression-free survival (PFS) from the index date was described using Kaplan–Meier analysis. Results: We identified 239 patients diagnosed with mRCC who received anticancer treatment post-IO and TKI therapies. The median age was 67 (range: 58, 73) years, 73.6% were male, and 61.5% had an intermediate/poor International Metastatic Renal Cell Carcinoma Database Consortium risk score. Among these, 29 (12.1%) received subsequent therapy at the line of therapy 2 (LOT2), 167 (69.8%) at LOT3, and 43 (18.0%) at LOT4+. The most common subsequent treatments were cabozantinib (38.5%) and axitinib (10.5%). The median OS for LOT2, LOT3, and LOT4+ was 18.0, 17.0, and 26.9 months, respectively. The median PFS for LOT2, LOT3, and LOT4+ was 6.1, 5.0, and 4.0 months, respectively. Conclusions: In mRCC patients treated with IO and TKI in combination/sequence, subsequent LOT choice is diverse, with TKI-based treatments being the most preferred. There is a need for considering treatment sequencing studies and studies with a new mode of action in this population. Full article

Background: Increased expression of MET and hepatocyte growth factor (HGF)-related molecules has been positively correlated with poor prognosis in renal cell carcinoma (RCC). In the current study, the expression and phosphorylation of MET in metastatic RCC (mRCC) are determined by immunohistochemistry, and the therapeutic effect of MET and HGF activation-targeting agents for RCC cell lines is analyzed. Methods: Immunohistochemistry was performed for 76 formalin-fixed paraffin-embedded specimens (primary tumor: 32, metastatic site: 44). The therapeutic effect of capmatinib (MET-I) and SRI-31215 (inhibitor of HGF-activating proteases: HGFA-I) was determined based on the inhibition of MET phosphorylation, cell proliferation, and cell migration in 786-O and caki-1 cell lines. Results: Increased expression and phosphorylation of MET were observed in both primary tumor and metastatic sites; however, phosphorylation was significantly upregulated in metastatic sites (p = 0.0001). In an assay of RCC cell lines, the strongest inhibition of MET phosphorylation, cell proliferation, and migration was confirmed with the combined used of MET-I and HGFA-I. Conclusions: Phosphorylation of MET was significantly upregulated in metastasis, which suggested the importance of downregulation in the treatment of mRCC. Our findings suggest that dual inhibition of MET and HGF activation may offer a promising strategy for mRCC treatment, warranting further clinical validation. Full article

Background/Objectives: Nivolumab has been shown to be an effective treatment for metastatic renal cell carcinoma (mRCC); however, patient responses vary considerably. The objective of this study is to evaluate the prognostic value of the C-PLAN index in predicting survival outcomes for patients with mRCC treated with nivolumab. Methods: This retrospective cohort study included 81 mRCC patients previously treated with tyrosine kinase inhibitors who subsequently received nivolumab. The C-PLAN index, which includes C-reactive protein, performance status, lactate dehydrogenase, albumin, and derived neutrophil-to-lymphocyte ratio, was used to classify patients into “good” and “poor” prognostic groups. Results: The median overall survival (OS) was 22 months, and the median progression-free survival (PFS) was 6.7 months. Patients in the “poor” C-PLAN group exhibited significantly shorter OS and PFS than those in the “good” group (median OS: 13 vs. 31 months, p = 0.003; median PFS: 3 vs. 10 months, p = 0.007). The C-PLAN index was identified as an independent predictor of both OS (HR = 1.19, 95% CI: 1.11–3.43, p = 0.020) and PFS (HR = 1.71, 95% CI: 1.04–2.78, p = 0.032) in multivariate analysis. Conclusions: These findings suggest that the C-PLAN index may serve as a valuable prognostic tool, offering insights into survival outcomes for patients undergoing nivolumab therapy. Further prospective and multicenter studies are warranted to validate its clinical utility. Full article

Background/Objectives: Metastatic renal cell carcinoma (mRCC) is a heterogeneous disease requiring precise risk stratification for optimal treatment selection. The International Metastatic RCC Database Consortium (IMDC) model classifies patients into favorable-, intermediate-, and poor-risk groups; however, emerging evidence suggests that the favorable-risk category encompasses patients with distinct prognoses. This study aims to evaluate whether subclassifying favorable-risk mRCC into “very favorable” and “favorable” subgroups improves prognostic accuracy and informs treatment strategies. Methods: This retrospective cohort study analyzed 189 patients diagnosed with mRCC at a single tertiary center between 2017 and 2023. Based on IMDC criteria, 75 patients were classified as favorable risk and included in the final analysis. These patients were further stratified into very favorable (n = 29) and favorable (n = 46) groups based on time from diagnosis to systemic therapy, Karnofsky performance status, and presence of metastases at specific sites. Kaplan–Meier analysis and Cox proportional hazards regression models were used to assess progression-free survival (PFS) and overall survival (OS). Results: Patients in the very favorable group demonstrated significantly longer median PFS (22.8 vs. 13.8 months, HR: 0.55, p = 0.020) and OS (74.4 vs. 42.7 months, HR: 0.38, p = 0.013) compared to the favorable group. In multivariate analysis, very-favorable-risk classification remained an independent prognostic factor for OS (p = 0.014) but not for PFS (p = 0.071). Conclusions: Stratifying favorable-risk mRCC patients into very favorable and favorable subgroups enhances prognostic assessment, potentially guiding more tailored treatment strategies. These findings highlight the need for refined risk models to improve personalized management in mRCC. Full article

Despite advances in the management of advanced clear cell renal cell carcinoma (ccRCC), robust biomarkers for prognosis and therapeutic response prediction remain elusive. Dysregulation of the intrarenal renin–angiotensin system (RAS) has been implicated in renal carcinogenesis but little explored, particularly regarding biomarker discovery and therapeutic innovation. Consequently, this study investigates the immunohistochemical expression and clinical relevance of the Mas-related G-protein-coupled receptor D (MrgD) in patients with ccRCC who developed metastatic disease (mccRCC). A cohort of 132 patients treated between 2008 and 2018 with nephrectomy and tyrosine kinase inhibitor (TKI)-based sequential therapy was analyzed. Treatment response was assessed using both the MASS and RECIST scoring systems. High MrgD expression in primary tumors was significantly associated with larger size, advanced stage, higher histological grade, and worse overall survival. Among 81 patients with metachronous metastases, high MrgD expression independently predicted shorter disease-free survival. High MrgD staining intensity correlated with poorer TKI responses in first-line therapy but improved outcomes with second-line mTORC1 inhibitors. These findings suggest that MrgD may be a useful biomarker of RAS linked to tumor aggressiveness in ccRCC. MrgD holds potential for identifying high-risk patients and guiding treatment selection in advanced disease. Further research is needed to unlock its clinical potential. Full article

Background: Ipilimumab and nivolumab (ipi/nivo) improved overall survival (OS) compared to sunitinib in the pivotal Checkmate 214 trial of metastatic renal cell carcinoma (mRCC) with International Metastatic RCC Database Consortium (IMDC) intermediate/poor risk disease. We evaluated the efficacy and toxicity of ipi/nivo in older and frailer populations in a real-world mRCC cohort. Methods: Analysis was conducted on a real-world cohort with mRCC (N = 551) treated with first-line ipi/nivo from the Canadian Kidney Cancer information system (CKCis) database from January 2014 to December 2021. A comparison was made between outcomes and toxicity in patients 1. <70 versus (vs.) ≥70 yo, 2. <75 vs. ≥75 yo, and 3. KPS ≥70 vs. <70 yo. OS, progression-free survival (PFS), and time to treatment failure (TTF) were calculated by Kaplan–Meier analysis. Log-rank tests were used for comparison between groups. Results: Ipi/nivo treatment had no impact on survival outcomes or toxicity for patients >70 yo and >75 yo when controlled for IMDC. However, when comparing patients with KPS > 70 vs. KPS < 70, patients with a poor performance status had decreased median OS at 54.5 m vs. 10.8 m (p-value < 0.0001) and PFS at 11.6 vs. 3.1 m (p-value < 0.0001). Conclusions: The use of ipi/nivo in mRCC demonstrated similar survival outcomes and toxicity in an older patient population. In patients with a poor performance status, it was associated with inferior OS and PFS. We believe that ipi/nivo is a reasonable treatment option for these patient populations, particularly in older patients. Full article

Background: The RAVE-Renal study was conducted to evaluate the real-world efficacy and safety of avelumab plus axitinib as a first-line therapy for patients with metastatic renal cell carcinoma (mRCC). Methods: RAVE-Renal was a multicenter, noninterventional, ambispective study with both retrospective and prospective components. The study included adult patients with histologically confirmed mRCC, measurable disease per RECIST version 1.1, and no prior systemic therapy. Patients received avelumab (800 mg intravenously every 2 weeks) plus axitinib (5 mg orally twice daily). The primary endpoints were median progression-free survival (PFS) and objective response rate (ORR). The secondary endpoints included median OS, 1-year overall survival (OS) rate, and safety. Results: A total of 125 patients from 13 sites were enrolled, with a median follow-up of 16.1 months. The median age was 61.0 years. The study population comprised 35.3% favorable, 49% intermediate, and 15.7% poor IMDC risk patients. The median PFS was 14.9 months (95% CI, 11.72–19.08). The ORR was 44.3% (95% CI, 32.5–56.1). The clinical benefit rate was 93.4%. The 1-year OS rate was 71.2%, with the median OS not reached. Any-grade treatment-related adverse events (TRAEs) occurred in 99 (79.2%) cases, including grade ≥3 TRAEs in 24 (19.2%). Conclusions: Avelumab in combination with axitinib showed clinical benefits in a real-world setting, consistent with findings from a pivotal trial. The regimen was effective and well tolerated across various patient subgroups. Full article

A combination of nivolumab and ipilimumab (NIVO + IPI) is the only approved combination of two immune checkpoint inhibitors for metastatic or advanced renal cell carcinoma (mRCC). Inadequate evidence of treatment with NIVO + IPI has been reported in Japanese cohorts. We evaluated the clinical efficacy of NIVO + IPI treatment. Patients with mRCC who received NIVO + IPI at nine Japanese facilities between August 2018 and March 2023 were enrolled in this study. The primary endpoint in this study was the assessment of oncological outcomes in patients with mRCC who received NIVO + IPI. Eighty-four patients with mRCC were enrolled. The median follow-up period was 18.3 months, and median progression-free and overall survival were 13.3 and 50.9 months, respectively. The objective response rate was 47.6%, and the disease control rate was 78.6%. To our knowledge, this is the largest study that evaluates Japanese patients with mRCC receiving NIVO + IPI treatment. In this study, the real-world oncological outcomes after NIVO + IPI treatment were comparable to those in the CheckMate 214 study. Full article