Background Kidney cancer is a growing public health concern. Using Global Burden of Disease (GBD) data, this study quantified its global burden from 1990 to 2021 and projected trends to guide prevention, diagnosis, and treatment. Methods The analysis of kidney cancer from 1990 to 2021 used GBD open data as a secondary dataset to examine global incidence, deaths, disability-adjusted life years (DALYs), and age-standardized rates. Spearman correlation analysis was used to assess the relationship between age-standardized rates and the Socio-demographic Index (SDI) globally and across 21 specific regions. A decomposition analysis was performed using data on aging, population dynamics, and epidemiological trends to identify factors contributing to changes in kidney-cancer DALYs and deaths from 1990 to 2021. Future projections for incidence, mortality, and DALYs were generated using the Bayesian Age-Period-Cohort model. Results The findings indicate a notable 16% increase in the age-standardized incidence rate (ASIR) for kidney cancer. Conversely, the age-standardized death rate (ASDR) decreased by approximately 4%. Additionally, there was an overall reduction of 11% in the age-standardized years of life lost (ASYR). Significant disparities in kidney cancer burden by sex and geographic location were identified. Increased body mass index and smoking were identified as the main contributors to kidney cancer. Population growth was found to play a role in the escalation of disease burden. The burden of kidney cancer is expected to diminish by 2036. Conclusions The ASIR of renal cancer increases while the ASDR and ASYR decrease. Promising indications suggest a future decrease in the burden associated with kidney cancer.
Therapeutic options for Renal Cell Carcinoma (RCC) are rapidly advancing. Systemic immune-oncology (IO) treatments, including immune checkpoint inhibitor (ICI) combination therapy and ICI with vascular endothelial growth factor tyrosine kinase inhibitors (VEGF TKIs), have shown substantial overall survival advantages. Data comparing first-line treatments for advanced RCC is limited, and second- and third-line therapies are frequently determined by approvals prior to current therapies. Pragmatic clinical trials (PCTs) are designed to inform a clinical decision by implementing evidence in a real-world setting. PCTs have increasing relevancy in oncology and offer advantages including generalizability, ease of trial execution, and can assist in evaluating whether therapies exhibit equivalent efficacy in clinical practice. Several PCTs have provided insight into metastatic RCC (mRCC) management. COMPARZ and PICSES trials compared pazopanib to sunitinib for mRCC patients and offered new insights into tolerability and patient preference. The MaRCC Registry yielded real-world data on treatment patterns and physician decision-making. The CARMENA trial demonstrated non-inferiority of sunitinib alone versus nephrectomy followed by sunitinib, while the STAR trial explored standard continuous versus intermittent VEGF-TKI therapy. Ongoing PCTs include the PROBE trial, ODYSSEY RCC, and CARE1 trials. Future opportunities for PCTs include comparing second-line treatment regimens for mRCC, examining differences in clinical responses by gender or age, the use of consolidative tumor-directed therapy in oligometastatic disease or for debulking metastases, and the impact of lifestyle variances on management. PCTs are needed to fill knowledge gaps and address patient-centered priorities that can inform our practices and improve quality care for patients with mRCC.
Background: While hereditary renal cell carcinoma (RCC) syndromes account for up to 16% of RCC cases and have screening guidelines; no screening recommendations exist for individuals with family history of RCC and negative genetic testing (familial RCC risk).Objective: This study aimed to assess current practices regarding screening recommendations for patients with familial RCC risk, evaluate the perceived need for formalized screening guidelines, and identify optimal clinician involvement for developing such guidelines.Methods: We surveyed healthcare providers who provide medical care for RCC patients, assessing current familial RCC screening practices, the need for and process of developing empiric risk guidelines, and case-based scenarios to understand current practice. This IRB-approved survey was distributed using listservs, professional connections, and snowball methods. Descriptive statistics and qualitative coding were used to analyze the data.Results: Seventy healthcare providers participated, primarily genetic counselors (n = 46; 66%) and medical oncologists (n = 11; 16%). Respondents indicated that: 1) screening guidelines are needed (n = 64; 91%) for familial RCC risk; 2) RCC patients inquired about the risk of RCC to family members after receiving negative genetic test results (n = 59; 84%, sometimes, often, or always); and 3) asked about screening recommendations for family members with similar frequency (n = 56, 80%). Respondents varied on the optimal screening mechanism and indications for screening unaffected relatives of RCC patients.Conclusions: Our findings show providers need screening guidelines to address patient inquiries, guide clinical management, and improve insurance coverage. Respondents agreed that there was a need for a multi-disciplinary team to develop standardized recommendations.
Mesenchymal neoplasms of the kidney encompass a wide range of tumor types with heterogeneous clinical, histologic, and molecular features. Given their rarity relative to renal epithelial neoplasms, diagnosis may be challenging. In this review, the clinicopathologic and molecular characteristics of selected mesenchymal neoplasms of the adult kidney are discussed, including benign entities with diverse lines of differentiation (such as juxtaglomerular cell tumor, angiomyolipoma, and anastomosing hemangioma), sarcomas (synovial sarcoma, leiomyosarcoma, Ewing sarcoma), and tumors with variable biologic potential (solitary fibrous tumor). Mesenchymal lesions that may arise in peri-nephric soft tissue (including well differentiated / dedifferentiated liposarcoma and perinephric myxoid pseudotumor of fat) are also highlighted, given their potential to present as a 'renal' mass.
Background Papillary renal cell carcinoma (pRCC) is the second most common kidney cancer subtype, yet our understanding of its tumor immune microenvironment (TIME) remains limited. Objective We utilized multiplex immunofluorescence (mIF) and spatial transcriptomics (ST) to evaluate immune cell architecture in pRCC contrasted with clear cell RCC (ccRCC). Methods Localized RCC tumors (16 pRCC, 70 ccRCC) underwent mIF using markers for T cells, B cells, and tumor-associated macrophages (TAMs). Spatial data in both tumor and stromal compartments of the TIME were collected. A post hoc recurrence free survival analysis (RFS) was performed using Cox proportional hazard models. Single-cell ST was performed on a subset of samples, utilizing probes against 960 transcripts. Cell density, cell spatial clustering, and spatially varying gene expression were analyzed. Results Immune cell density was statistically lower in pRCC amongst functional CD8T cells, while cell clustering was higher amongst M2-like macrophages. Using ST, two genes ( CCL18 , GPNMB ) were enriched in clustered M2-like macrophages in pRCC (FDR < 0.001) and are known markers of lipid-associated TAMs (LAMs). Conclusion Compared to ccRCC, pRCC has greater M2-like macrophage clustering. Using ST, M2-like macrophage clustering corresponds with lipid associated TAMs (LAMs), and therapeutics against this myeloid subset are currently being tested in pRCC.
Immune checkpoint inhibitors (ICIs) have revolutionized treatment of metastatic renal cell carcinoma (mRCC), yet the role and efficacy of ICI rechallenge after disease progression remain uncertain. Response-adaptive escalation in OMNIVORE, HCRN GU16-260, and TITAN-RCC trials showed limited efficacy. While KEYNOTE-146 reported a 56% ORR with pembrolizumab and lenvatinib rechallenge, CONTACT-03 and TiNivo-2 trials demonstrated that ICI rechallenge failed to improve progression-free survival or overall survival compared to VEGF TKI monotherapy. The mechanisms underlying ICI resistance are complex, involving tumor microenvironment and immune pathway alterations. Research is ongoing to develop novel combinations and identify biomarkers for personalized strategies following ICI resistance.
Background Accurate renal tumor anatomy description is crucial for improving surgical and oncological outcomes. CT advancements assist in surgical planning by determining renal tumor volume. Objectives To examine the accuracy and precision of CT in renal tumor volume measurement and to assess the impact of tumor volume on intra- and post-operative outcomes. Methods Data from 45 patients with renal mass who underwent partial or radical nephrectomy at our institution between December 2019 and January 2024 were analyzed. Automated CT volumetry software was used to detect and measure tumor volume from the pre-operative CT DICOM files. The volume of the retrieved specimens was re-measured using the water immersion method. Results The agreement between CT and the water immersion method was tested using Lin's concordance correlation coefficient (CCC), which yielded a value of 0.856. The bias correction factors (C b ) and Pearson's correlation coefficient (ρ) were 0.928 and 0.922, respectively. CCC was better for the partial nephrectomy group (0.943) than the radical nephrectomy group (0.799). The Bland-Altman plot indicated that CT overestimated large-sized tumors. A positive correlation was detected between tumor volume and each of the PADUA score (ρ = 0.494, p value = 0.001) and ischemia time (ρ = 0.048, p value = 0.821). Conclusions CT volumetry is an accurate tool for renal tumor volume measurement that could serve as a valuable parameter for optimizing surgical decisions.
Background:An immune checkpoint inhibitor (ICI) backbone is a standard of care for frontline metastatic clear cell renal cell carcinoma, involving either ICI doublet or tyrosine kinase inhibitor (TKI) with ICI. These phase 3 trials used a sunitinib control arm. The optimal regimen is uncertain. Objective:To compare long-term responders of these trials using extended follow-up data stratified by International Metastatic RCC Database Consortium risk group. Methods:Phase 3 trial data (CheckMate 214, KEYNOTE-426, CheckMate 9ER, and CLEAR) with a minimum follow-up of four years was used. Pseudo individual patient data (IPD) was obtained from Kaplan-Meier curves using the graph digitizer software IPDfromKM R package to extract coordinates of points on the curves and to apply a numerical algorithm to reconstruct progression-free survival (PFS) and overall survival (OS) results. Durable response (DR) was defined as PFS ≥ 24 months, extreme durable response (EDR) as PFS ≥ 36 months, and long-term OS as OS ≥ 48 months. Results:For the favorable risk group, lenvatinib-pembrolizumab had the highest DR and EDR, while ipilimumab-nivolumab had the lowest DR, and cabozantinib-nivolumab had the lowest EDR; there was no difference in long-term OS among the regimens (p = 0.11). For the intermediate/poor risk group, lenvatinib-pembrolizumab also had the highest DR and EDR compared to other regimens with similar DR and EDR; there was also no difference in long-term OS among the regimens (p = 0.22). Conclusion:TKI-ICI was overall associated with higher DR and EDR regardless of risk status compared to ICI doublet. Yet, OS at 48 months were similar when stratified by favorable versus intermediate/poor risk.
The therapeutic landscape of clear cell renal cell carcinoma (ccRCC) has dramatically evolved in the last decade. Immuno-oncology (IO) and/or tyrosine kinase inhibitor (TKI) based doublet therapies have become standard in the frontline setting for most patients with advanced ccRCC. For previously-treated advanced ccRCC, multiple agents are available including belzutifan, a hypoxia inducible factor 2 alpha (HIF2-α) inhibitor. However, the challenging goal of developing therapies with a unique mechanism of action remains. Many such promising agents are currently in development such as novel TKIs, inhibitors targeting alternative checkpoints, cellular therapies, radioligands, antibody-drug conjugates, and agents targeting fatty acid metabolism. Further, the role of microbiome is being actively investigated in advanced ccRCC, with ongoing studies evaluating its effect when combined with standard therapies. Mature data from trials with these agents is eagerly awaited.
The rise of immune-based combination therapies has revolutionized the treatment landscape for metastatic renal cell carcinoma (mRCC), offering significant improvements in response rates and survival. However, along with these advancements come challenges in managing treatment-related adverse events, particularly renal toxicities. Kidney biopsies represent the gold standard in diagnosing and managing these complications, providing insights into histopathological patterns and guiding therapeutic strategies. It is important to emphasize that in most of the cases expertise in onco-nephrology can enable accurate diagnosis and management of nephrotoxicities, and that in clinical practice, renal biopsy is often not easily feasible. Research efforts are underway to identify biomarkers and imaging techniques that can accurately detect renal damage characteristics without the need for invasive procedures. Promising candidates have been identified; however, validation studies are essential to enhance their effectiveness and integrate them into standard clinical practice. This paper underscores the importance of individualized approaches in managing renal adverse events and calls for further research to improve diagnostic capabilities for acute kidney injury in the context of immune-based combination therapies.
Background Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic renal cell carcinoma (mRCC) and combination regimens with targeted therapy are the current standard of care. Given their success in the first-line setting, re-use or continuation of ICIs in subsequent line settings has been a growing area of research interest. Objective This systematic review assesses the safety and efficacy of ICI re-challenge in patients with refractory mRCC. Methods Scopus, Embase, Cochrane, Ovid MEDLINE, and TRIP databases as well as clinicaltrials.gov were searched systematically for published prospective and upcoming clinical trials from inception to August 15, 2023. Inclusion criteria included patients with clear cell histology who had received at least one prior line of systemic therapy including an ICI. Trials with ICI as an intervention either in second-line or beyond were included and did not require a control arm. Safety and efficacy outcomes including overall response rates, overall survival, progression free survival, median duration of response, and grade 3 or higher adverse events (AEs) were extracted. Results Seven prospective studies and 49 upcoming clinical trials were identified. mPFS ranged from 3.7 to 12.2 months, with longer PFS rates being associated with ICI/VEGF combination re-challenge. However, data from the only phase III randomized controlled trial (CONTACT-03) did not support rechallenge of ICI with tyrosine kinase inhibitor (TKI) versus TKI alone. Rates of grade 3 or higher AEs ranged from 28–65%. Conclusions Given the paucity of current data regarding efficacy as well as high toxicity rates, patients with mRCC should not receive ICI-rechallenge unless as part of a prospective clinical trial.
Liquid biopsy techniques have developed rapidly in recent years and demonstrated success in cancer detection, disease characterization, and ongoing disease monitoring. These components, including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and cell-free DNA (cfDNA), offer minimally invasive diagnostic tools that provide valuable insights into the genomic landscape of tumors. Its applications have expanded to include various malignancies, including renal cell carcinoma (RCC). RCC, a heterogeneous malignancy, poses unique diagnostic and therapeutic challenges. Up to 40% of patients experience recurrence or metastasis following initial surgical resection, necessitating the need for precise diagnostic and prognostic tools. The application of liquid biopsy in RCC, particularly through CTCs and ctDNA/cfDNA, holds significant promise. This review first delves into the various methodologies of CTC and cfDNA/ctDNA detection in RCC and highlights their roles in RCC management. Next, we discuss in depth about current existing evidence for the utilization of liquid biopsy in RCC diagnosis, prognosis, treatment outcomes prediction and association with the progression of the disease. Despite advancements, RCC's biological features, including low ctDNA shedding and significant intratumoral heterogeneity, present challenges in the clinical application of liquid biopsy. The review also discusses the limitations of current techniques and emphasizes the need for standardized protocols and further validation in large, diverse cohorts. Future directions include integrating liquid biopsy with advanced imaging techniques and leveraging artificial intelligence to improve RCC diagnostics and patient management. With continued refinement, liquid biopsy could become an essential tool in personalized oncology, improving outcomes for RCC patients.
Ablation therapy is emerging as a compelling alternate approach for the management of patients with renal cell carcinoma (RCC), particularly patients who are not surgical candidates. These treatment modalities provide an excellent local control and minimal toxicity, with potential to delay systemic therapy for patients with oligometastatic RCC. This review aims to provide an overview of the role of ablative therapies in the management of patients with localized and oligometastatic RCC.
Background Sarcomatoid (and rhabdoid) dedifferentiation can occur in ∼5% of renal cell carcinomas (sRCC), a finding with significant therapeutic implications. sRCC is associated with increased aggressiveness, resistance to conventional targeted therapies, and increased sensitivity to immune checkpoint inhibitors. Objective There are no preclinical models for sRCC that can be used in research to better understand this disease. The pig has similar size, anatomy, immune system, and genetics, that can be employed to evaluate procedures or tumor specific drugs. We report on the creation of a large animal porcine model for sRCC. Materials In eight Oncopigs, a Cre-recombinase gene adenoviral vector (AdCre) was incubated with renal tissue obtained from an ultrasound (US) percutaneous biopsy and reinjected into the renal cortex. US was performed to assess growth and to obtain tumor tissue for pathologic and immunohistochemistry evaluation. Results Three weeks post inoculation renal tumors were successfully formed in 28 out of 32 sites (88%). Mean tumor size by imaging was 1.6 × 1.1 cm (range: 0.4–3.9 cm longest axis). Pigs remained clinically healthy up to 25 days after inoculation. On histology, tumors consisted of foci of infiltrating sarcomatoid and rhabdoid cells in a background of marked acute and chronic inflammation. The neoplastic cells showed positive immunoreactivity for PAX8, cytokeratin AE1/AE3 supporting a renal tubular origin. These cells were diffusely positive for p53 and showed high ki-67 (20–30%), and cleaved caspase 3 (20–30%) expression. Conclusion Rapid growing poorly differentiated neoplasms associated with a marked inflammatory reaction that have phenotypic and immunohistochemical features of sRCC were successfully developed. These may be suitable to study the response to local and systemic therapies.
Background Patients with von Hippel-Lindau syndrome (VHL) have an increased risk of developing multiple neoplasms. Recently, multiple pharmacologic interventions have been assessed for the treatment of these VHL-associated neoplasms. Objectives To identify current clinical trials evaluating pharmacological interventions in VHL-associated neoplasms, with an emphasis in renal cell carcinoma (RCC). Methods We conducted a systematic review of the literature utilising MEDLINE/PubMed and EMBASE databases. We searched for Clinical Trials in VHL and RCC to understand the current landscape of therapeutic interventions in this population. Results We identified five single-arms clinical trials assessing systemic interventions in patients with VHL and RCC. These therapeutic interventions consisted of three tyrosine kinase inhibitors (TKIs) – semaxinib, sunitinib, and pazopanib - and one hypoxia-inducible factor (HIF) inhibitor -belzutifan. Belzutifan therapy was associated with an overall response rate (ORR) of 49% in patients with VHL and RCC. Only 3% of patients experienced disease progression while on belzutifan, which resulted in an impressive 97% clinical benefit rate. Pazopanib was also associated with an ORR of 64%; no patients experienced disease progression while on therapy. Lastly, two studies investigated the role of sunitinib in patients with VHL and RCC. In these studies, sunitinib was associated with an ORR ranging from 33% to 66%. Conclusions Anti-angiogenic interventions such as TKI and HIF inhibitors have been shown to be effective in decreasing the rate of progression of VHL-associated neoplasms. Although only a few trials have evaluated different pharmaceutical interventions in VHL-associated neoplasms, understanding the molecular basis of this pathology has opened the opportunity for novel therapeutic approaches to improve outcomes in this population.
Background: Renal cell carcinoma (RCC) accounts for approximately 90% of kidney cancers, with a significant percentage of patients presenting with metastatic disease. Recent evidence suggests a notable role of the human microbiome in the onset, progression, and therapeutic outcomes of RCC. Objective: This systematic review aims to synthesise current knowledge on the association between the microbiome and RCC, focusing on pathogenesis, progression, and response to therapy. Methods: Complying with PRISMA guidelines, databases including PubMed, Embase, and Web of Science were searched for relevant studies up to December 7, 2023. The inclusion criterion was English-language articles that discussed RCC in relation to the microbiome of any body region. Screening was performed in a two-phase manner by three authors. Results: From 570 articles, 65 met the inclusion criteria. The gut microbiome (GM) emerged as a potential RCC pathogenesis driver, with certain bacteria associated with increased or decreased risk. Studies have also demonstrated that antibiotics and other medications can influence RCC therapeutic outcomes, reducing the effectiveness of immune-modulating therapies. Conclusions: While multiple bacterial species and antibiotics have been implicated in influencing RCC, further research is necessary to elucidate these relationships and investigate the efficacy of microbiome modulation on therapy effectiveness. Findings underscore the significant impact of the microbiome on RCC, suggesting the potential for microbiota-targeted therapeutics.
BACKGROUND: Checkpoint inhibitor (CPI)-based therapy is recommended for first-line treatment of advanced/metastatic renal cell carcinoma (mRCC). Cabozantinib is a tyrosine kinase inhibitor (TKI) approved in the USA for treating mRCC, including after CPI-based therapy. However, data on the benefits of subsequent TKI therapy are limited. OBJECTIVE: To study the real-world use and outcomes of cabozantinib versus other TKIs after CPI-based therapy for mRCC. METHODS: This retrospective study used data from the US Oncology Network electronic health record database supplemented by chart review. Patients initiated TKI therapy between 2016 and 2021 after CPI-based therapy. The primary endpoint was real-world response rate in the first 6 months of treatment (RR-6m; physician assessment). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Covariates were adjusted by inverse probability of treatment weighting. RESULTS: Of 485 included patients, 331 received cabozantinib and 154 another TKI. Baseline characteristics were generally similar between arms. For cabozantinib versus other TKIs, adjusted RR-6m (available for 69.3% of patients) was 62.5% versus 46.0% (rate difference: superiority, 16.5% [95% CI: 7.8–25.1], p = 0.0002), adjusted ORR was 62.4% versus 49.4% ( p = 0.0020), adjusted median OS was 19.2 versus 19.1 months ( p = 0.7353) and adjusted median PFS was 7.9 versus 9.2 months ( p = 0.8752). CONCLUSIONS: Cabozantinib following CPI-based therapy was effective for treating mRCC in the US real-world setting. Differences in adjusted RR-6m and ORR significantly favored cabozantinib versus other TKIs. The lack of OS difference may reflect differences in post-index therapy.
Background: Kidney cancer is amongst the deadliest genitourinary malignancies. Neoadjuvant systemic therapy has the potential to improve survival and overall outcomes in select patients. Enrolling patients in trials of neoadjuvant treatment for kidney cancer is challenging, which limits neoadjuvant treatment development. Objective: This study aims to develop a better understanding of the barriers patients face in kidney cancer clinical trial participation, with a particular focus on neoadjuvant trials for renal cell carcinoma. Methods: From 2022–2023, we recruited participants with a history of kidney cancer through a Qualtrics survey that was sent to the Kidney Cancer Association (KCA) and Kidney Cancer Cure (KCCure) mailing lists and social media pages. Patient responses on demographics, clinical information, and perspectives were evaluated. Results: Ninety-four individuals completed the survey. Eighty-one percent of respondents reported not participating in clinical trials due to not being informed about potential applicable trials. Importantly, many (76%) respondents reported that prevention of cancer return was a highly important reason to participate in clinical trials. Most respondents reported a willingness to undergo a kidney biopsy (59%), and/or additional appointments (58%) and surgery delays. Conclusions: Increased patient awareness about clinical trials with the potential to delay cancer recurrence may increase patient participation in clinical trials. Clinical trial design, including additional appointments or interventions and/or minor surgery delays are not major barriers to trial participation.
