Ongoing advances in systemic therapy for metastatic renal cell carcinoma (mRCC) have left the role of surgical resection in this setting uncertain. In this mini review, we examine historical data and ongoing clinical trials evaluating the role of cytoreductive nephrectomy and metastasectomy in mRCC. We note that patients undergoing upfront nephrectomy may have a delayed opportunity to receive systemic therapy, which poses a significant risk, particularly for individuals with poor-risk or actively progressing disease. Although patients undergoing resection after response to systemic therapy have favorable outcomes, ongoing randomized trials will provide clarity regarding the role of deferred nephrectomy and metastasectomy in the context of current systemic regimens. PATIENT SUMMARY: In this mini review, we assess data on surgery to remove the primary tumor and its metastatic sites in kidney cancer. Drug options for metastatic kidney cancer have greatly improved, so there is a need to evaluate how surgery is used for these patients.

Since the advent of targeted therapy, deferred cytoreductive nephrectomy (dCN) has been offered to patients with metastatic renal cell carcinoma (mRCC) who respond to systemic therapy. Transition to the immunotherapy (IO) era necessitates a re-evaluation of the role of upfront CN (uCN) in mRCC management. Our aim was to determine whether uCN improves overall survival (OS) in patients with mRCC receiving IO in comparison to tyrosine kinase inhibitor (TKI) therapy.

This nationwide historical cohort study included patients with synchronous mRCC diagnosed in the Netherlands between 2018 and 2020 who were treated with IO or TKI agents. We used propensity score-based inverse probability of treatment weighting (IPTW) to adjust for prognostic differences in Kaplan-Meier and Cox regression analyses. OS was compared for patients with versus without uCN. Analyses were stratified for IO and TKI therapy.

Of 872 patients, 433 received IO (63 uCN + IO, 370 IO ± dCN) and 439 received TKI (67 uCN + TKI, 372 TKI ± dCN) therapy. The uCN treatment arms had more favourable prognostic factors than those starting with systemic therapy. In the IO cohort, the IPTW-adjusted median OS was 33 mo for uCN + IO versus 24 mo for IO ± dCN (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.40-0.97). There was no significant difference in median OS in the TKI cohort (19 mo for uCN + TKI versus 17 mo for TKI ± dCN; HR 0.76, 95% CI 0.52-1.12). Limitations include the observational nature of the study and the risk of residual confounding.

In the absence of randomised controlled trials (RCTs), our results indicate a preference for uCN in patients with mRCC with favourable prognostic factors in the IO era. Owing to the risk of residual confounding, strong evidence from RCTs is needed.

Cytoreductive nephrectomy following immune checkpoint blockade (ICB) in metastatic renal cell carcinoma remains controversial, with limited data on its clinical and pathological outcomes. This study evaluated the outcomes of patients undergoing deferred cytoreductive nephrectomy (dCN) after ICB-based treatment, focusing on the radiologic and pathological responses, and postoperative clinical outcomes.

We retrospectively reviewed 24 patients with metastatic or locally advanced RCC who underwent dCN after ICB at a single institution between April 2018 and May 2024. We assessed the radiological response to ICB, pathological findings (presence and extent of necrosis) in resected primary tumors, and postoperative clinical outcomes, including the rate of patients without measurable disease and those who discontinued systemic therapy.

Median ICB exposure prior to surgery was 11.3 months. Radiologically, 67% of patients had partial response, 29% had stable disease, and 4% had a complete response. Pathology showed 96% of specimens with necrosis, 21% of specimens showing no residual disease (pT0), and 21% exhibiting ≥95% necrosis. Postoperatively, 50% of patients had nonmeasurable disease of first follow-up scans, and 54% discontinued systemic therapy, with 9 patients remaining on surveillance at last follow-up. Limitations include the small sample size and retrospective design.

Deferred CN following ICB therapy is feasible. Extensive necrosis in the resected surgical specimen after ICB-based therapy requires further investigation as a prognostic marker for durable responses off systemic therapy.

Surgical removal of primary tumors reverses tumor-mediated immune suppression in pre-clinical models with metastatic disease. However, how cytoreductive surgery in the metastatic setting modulates the immune responses in patients, especially in the context of immune checkpoint therapy (ICT), is not understood. We report the first prospective, pilot, non-comparative clinical trial (NCT02210117) to evaluate the feasibility, clinical benefits, and immunologic changes of combining three different ICT-containing strategies with cytoreductive surgery or biopsy for patients with metastatic clear cell renal cell carcinoma. Primary safety endpoint of this trial has been met, with 43 patients completing cytoreductive surgery, 36 patients undergoing post-ICT biopsy, and 25 patients without either procedure due to progressive disease or toxicities or withdrawal of consent (total N = 104). Patients receiving ICT with cytoreductive surgery or biopsy, did not experience additional ICT- or procedure-related toxicities. The median overall survival was 54.7 months for patients who received ICT plus cytoreductive surgery. Immune-monitoring studies demonstrated that cytoreductive surgery increased antigen-presenting dendritic cell population and decreased KDM6B-expressing immune-suppressive myeloid cells in the peripheral blood. This study highlighted the feasibility of combining ICT with cytoreductive surgery in a metastatic setting and demonstrated the potential enhancement of immune responses following ICT plus cytoreductive surgery.

Kidney renal clear cell carcinoma (KIRC), a therapy-resistant aggressive kidney cancer, exhibits resistance to immune checkpoint inhibitors. Altered sialylation is involved in tumor development, affecting immune microenvironment dynamics. In the study, through systematic bioinformatics analysis and experimental verification, we demonstrated that ST3Gal5 expression was elevated in tumor tissues of KIRC patients, correlating with poor prognosis, and ST3Gal1 was downregulated and associated with a better prognosis. Immunohistochemistry analysis confirmed the expression patterns of ST3Gal1 and ST3Gal5 in 30 KIRC patients. Furthermore, KIRC patients were stratified into two clusters based on ST3Gal1 and ST3Gal5 levels using consensus clustering to investigate their roles in KIRC tumorigenesis, immune characteristics and treatment sensitivity. KIRC patients in Cluster 2, characterized by increased ST3Gal5 and downregulated ST3Gal1 expression, exhibited increased expression of immune checkpoints, immune cell infiltration, immune escape scores, and worse prognosis. Knockdown of ST3Gal5 in KIRC cell lines (786-O and 769-P) resulted in reduced tumor proliferation, migration, and invasion in vivo and in vitro. Together, the dysregulation of sialyltransferases (ST3Gal1 and ST3Gal5) in KIRC influences tumorigenesis and immune responses. These findings underscore the potential of ST3Gal1 and ST3Gal5 as prognostic factors and immunotherapy targets for KIRC.

The study aims to evaluate the survival impact of primary tumor resection (PTR) on thoracic esophageal cancer with distant metastasis(TECDM). Data of patients with TECDM was collected from the Surveillance, Epidemiology, and End Results database(SEER) from 2010 to 2020. A 1:1 propensity-score matching(PSM) analysis was employed to minimize heterogeneity between the groups. Total 7733 patients with TECDM were included in the analysis, of which 121 underwent primary tumor resection and 7612 did not. Patients who underwent primary tumor resection exhibited better median overall survival(OS) and median cancer-specific survival(CSS) compared to those who did not, in both the overall and PSM cohort. In the PSM cohort, the median OS was 11 months (95% CI, 9 to 13 months) for TECDM patients who underwent PTR, compared to 7 months (95% CI, 5 to 9 months) for those who did not. Furthermore, Cox proportional hazards models indicated that PTR was a significantly protective factor for TECDM patients in OS (HR: 0.5529; 95% CI, 0.5196 to 0.7730, P < 0.001) and CSS (HR:0.5869 ; 95% CI, 0.479 to 0.7192, P < 0.001). In conclusion, primary tumor resection is associated with improved overall survival and cancer-specific survival in thoracic esophageal cancer patients with distant metastasis.

Renal cell carcinoma (RCC) was diagnosed in over 400 000 individuals globally in 2020, making it a significant global health concern. The incidence of RCC varies by region and overall mortality rates have been declining. This decline is attributed in part to advancements in early cancer detection through imaging and the development of more effective systemic therapies. Cytoreductive nephrectomy (CN) was adopted as a standard treatment for metastatic RCC (mRCC) based on clinical experience and early clinical trials. However, the treatment landscape has shifted with the introduction of tyrosine kinase inhibitors (TKI) in 2007 and, more recently, immune checkpoint inhibitors (ICIs). Dual ICI therapy and combinations of ICIs with TKIs are collectively referred to as immuno-combination therapies and have become standard first-line treatments. This review examines the evolving role of CN in the era of immuno-combination therapies, with a focus on patient selection and the timing of surgery. The immunogenic nature of RCC, characterized by spontaneous tumor regression and immune cell infiltration, suggests a potential benefit from combining CN with ICI therapy to enhance treatment outcomes. This is supported by several clinical studies that reported improved outcomes; however, these were limited by their retrospective nature. Ongoing clinical trials, such as NORDIC-SUN, PROBE, and SEVURO-CN, are expected to provide critical insights into the role of CN in the ICI era. Their findings will ultimately guide future clinical decision-making and further refine treatment strategies for mRCC.

The role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) in the era of immune checkpoint inhibitors (ICIs) is controversial. We aimed to investigate the survival benefit of CN in patients with mRCC treated with ICIs.

We searched the EMBASE, MEDLINE, and Web of Science databases up to August 26, 2023 to identify studies comparing overall survival (OS) for patients with mRCC treated with ICIs with or without CN. We reconstructed individual patient data using published Kaplan-Meier curves and performed one- and two-stage meta-analyses using 6-mo and 12-mo landmarks to control for immortal time bias. We also performed subgroup analyses for patients treated with first-line ICI or upfront CN.

We identified eight eligible studies involving a total of 2319 patients. There were statistically significant differences in baseline characteristics (age, clear cell histology, International mRCC Database Consortium scores) between the ICI + CN and ICI-alone groups. Combined CN + ICI therapy was associated with superior OS in the primary analysis (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.37-0.54) and secondary analyses, and in subgroup analyses for patients receiving first-line ICI therapy (HR 0.39, 95% CI 0.30-0.48) and upfront CN (HR 0.52, 95% CI 0.40-0.69).

CN combined with ICI therapy in mRCC may be associated with superior OS. Further studies are needed to confirm this finding and identify the patients most likely to benefit from CN in this setting.

We compared outcomes after immune checkpoint inhibitor (ICI) therapy, which boosts the immune system to fight cancer, with or without nephrectomy (surgical removal of the kidney) in patients with metastatic kidney cancer. We found that the combination of nephrectomy and ICI therapy was associated with better survival than just ICI therapy.

Historically, patients with metastatic renal cell carcinoma (mRCC) have been offered upfront cytoreductive nephrectomy (CN) followed by systemic therapy. Currently, CN is no longer the standard of care (SOC) based on the randomised phase 3 CARMENA study performed in the vascular endothelial growth factor receptor tyrosine kinase inhibitor era. With the advent of immune checkpoint inhibitor (ICI) combination therapy in first line, the role of CN needs to be reassessed. There is indirect evidence from small retrospective series that deferred CN after ICI combination therapy may lead to better outcomes. To reassess the role of CN, we designed PrimerX, a randomised controlled trial following the Trial within Cohorts (TwiCs) study design. The primary objective of this study is to re-evaluate the benefit of deferred local treatment in the current era of immunotherapy.

This PrimerX study has been designed as a TwiCs study within the Dutch Prospective Renal Cell Carcinoma (PRO-RCC) cohort. The PRO-RCC cohort includes patients with mRCC and nonmetastatic RCC, and has been set up for prospective collection of long-term clinical data and as an infrastructure for initiating TwiCs studies. The PrimerX TwiCs trial follows a Bayesian adaptive multistage design to allow for early discontinuation due to futility or efficacy. PrimerX has appropriate ethics approval and is registered at clinical.trials.gov (NCT05941169).

The primary clinical endpoint is overall survival, defined as the time from randomisation to death from any cause. The secondary endpoint is the objective response rate within the primary tumour prior to local therapy, as assessed by a computed tomography scan.

A maximum of 700 patients with synchronous mRCC and absence of progression at metastatic sites following at least 6 mo of standard first-line ICI combination therapy will be assigned randomly to receive local treatment of the primary tumour (experimental arm) or SOC (control arm). The experimental intervention consists of (partial) CN, any form of ablative local therapy, or magnetic resonance imaging guided ablative stereotactic radiotherapy, performed within 6 mo and 1.5 yr after the start of systemic treatment.

The primary tumor resection (PTR) of de novo stage IV breast cancer (DnIV BC) is controversial, and previous studies have suggested that the neutrophil-to-lymphocyte ratio (NLR) could be a poor-prognosis factor for BC. We investigated PTR's surgical advantage related to clinical outcomes, the surgery timing in responders to systemic therapy, and whether the NLR can predict the benefit of surgery for DnIV BC.

We retrospectively analyzed the cases of the DnIV BC patients who received systemic therapies and/or underwent PTR at our institution between January 2004 and December 2022. Blood tests and NLR measurement were performed before and after each systematic therapy and/or surgery.

Sixty patients had undergone PTR local surgery (Surgery group); 81 patients had not undergone surgical treatment (Non-surgery group). In both groups, systemic treatment was performed as chemotherapy (95%) and/or endocrine therapy (92.5%) (p < 0.0001). The groups' respective median progression-free survival (PFS) durations were 88 and 30.3 months (p = 0.004); their overall survival (OS) durations were 100.1 and 31.8 months (p = 0.0002). The Surgery-group responders to systemic therapy lasting > 8.1-months showed significantly longer OS (p = 0.044). The PFS and OS were significantly associated with the use of postoperative systemic therapy (p = 0.0012) and the NLR (p = 0.018). A low NLR (≤ 3) was associated with significantly better prognoses (PFS and OS; p < 0.0001).

A longer effective duration of systemic therapy (> 8.1 months) and a low pre-surgery NLR (≤ 3.0) could predict PTR's surgical advantage for DnIV BC. These variables may help guide decisions regarding the timing of surgery for DnIV BC.

Stereotactic ablative body radiotherapy (SABR) is an effective treatment for localized renal cell carcinoma (RCC). However, the role of primary site SABR for locally recurrent or metastatic RCC is unclear. Here, we report outcomes of primary SABR across a diverse cohort of localized, recurrent, and metastatic RCC patients treated at our institution.

RCC patients treated with SABR to lesions of the kidney or nephrectomy bed at our institution with at least 6 months of follow-up were included for analysis. Local control, overall survival, and freedom from distant failure were estimated using the Kaplan-Meier method. Estimated glomerular filtration rate (eGFR) was assessed at baseline and following SABR.

Fifty-three patients received primary site SABR. Thirty-seven (70 %) patients had localized RCC, and 16 (30 %) had metastatic RCC. Seven (13 %) had locally recurrent RCC after prior surgery or ablation. The median tumor size was 4.5 cm (IQR 3.7-6.3). At a median follow-up of 23 months (IQR 12-35), 2-year local control was 100 %, and 3-year local control was 94.4 % (95 % CI 84.4 %-100 %). Among patients with initially localized disease, the 2-year freedom from distant failure was 94.6 % (95 % CI 87.6 %-100 %), and the 2-year overall survival was 66.5 % (95 % CI 51.9 %-85.2 %). Twelve (23 %) patients experienced acute grade 1-2 treatment-related toxicity (nausea, vomiting, or small bowel). There were no acute grade 3-4 toxicities. Two (3.8 %) patients developed late grade 3 gastrointestinal toxicity. The median baseline eGFR was 51 mL/min/1.73 m2 (IQR 38-77). At 1-year post-SABR, the median eGFR decline was 5 mL/min/1.73 m2 (IQR -3 to 9). One patient required dialysis following SABR.

This analysis demonstrates excellent local control rates across patients with localized, recurrent, and metastatic RCC treated with SABR. Treatment was associated with minimal eGFR decline.

Renal cell carcinoma (RCC) is the seventh most common cancer in the United States; clear cell RCC (ccRCC) is the most common subtype. We report a case of spontaneous regression of metastatic ccRCC and discuss possible underlying mechanisms informed by a literature review. While regression of metastatic RCC has been described following nephrectomy or treatment of the primary tumor, spontaneous regression is rare. Postulated underlying causes include tumor necrosis and immune-mediated responses. Of 29 identified cases of spontaneous regression, only ours occurred after only a biopsy. Better understanding of the pathophysiology of spontaneous regression in RCC will improve its management.

To assess survival differences between non-extensive surgery (NES) and extensive surgery (ES) in International Federation of Gynecology and Obstetrics (FIGO) stage IVB cervical cancer patients receiving chemotherapy from a population-based database, the Surveillance, Epidemiology and End Results.

Propensity matching was conducted to minimize heterogeneity. Survival analysis was performed by the Kaplan-Meier method, log-rank test, and Cox proportional hazards model.

A total of 154 patients met screening criteria, among whom 84 patients (84/154) underwent NES while 70 patients (70/154) underwent ES. After matching, no survival advantage was observed in ES group compared with NES group (p=0.066; hazard ratio [HR]=1.54; 95% confidence interval [CI]=0.97-2.42). Stratified analyses suggested ES prolonged overall survival in patients with histology other than squamous cell carcinoma and adenocarcinoma (p=0.028; HR=0.36; 95% CI=0.15-0.89) and American Joint Committee on Cancer (AJCC) T stage T1 (p=0.009; HR=0.18; 95% CI=0.05-0.66). Despite no survival benefit after regional lymph node surgery (p=0.629; HR=0.88; 95% CI=0.53-1.47), subgroup analyses demonstrated that patients younger than 50 (p=0.006; HR=0.21; 95% CI=0.07-0.64), with AJCC T stage T1 (p=0.002; HR=0.09; 95% CI=0.02-0.42), T3 (p=0.001; HR=0.02; 95% CI=0.00-0.21), hematogenous metastasis (p=0.036; HR=0.27; 95% CI=0.08-0.92) and without surgery of other sites (p=0.040; HR=0.01; 95% CI=0.00-0.79) might achieve longer survival after regional lymph node surgery.

In conclusion, ES or regional lymph node surgery may provide survival advantage for certain subgroup of FIGO IVB cervical cancer patients receiving chemotherapy. However, it deserves large scale prospective clinical trials to confirm.

Interleukin-12 (IL-12) is considered to be a promising cytokine for enhancing an antitumor immune response; however, recombinant IL-12 has shown significant toxicity and limited efficacy in early clinical trials. Recently, many strategies for delivering IL-12 to tumor tissues have been developed, such as modifying IL-12, utilizing viral vectors, non-viral vectors, and cellular vectors. Previous studies have found that the fusion of IL-12 with extracellular matrix proteins, collagen, and immune factors is a way to enhance its therapeutic potential. In addition, studies have demonstrated that viral vectors are a good platform, and a variety of viruses such as oncolytic viruses, adenoviruses, and poxviruses have been used to deliver IL-12-with testing previously conducted in various cancer models. The local expression of IL-12 in tumors based on viral delivery avoids systemic toxicity while inducing effective antitumor immunity and acting synergistically with other therapies without compromising safety. In addition, lipid nanoparticles are currently considered to be the most mature drug delivery system. Moreover, cells are also considered to be drug carriers because they can effectively deliver therapeutic substances to tumors. In this article, we will systematically discuss the anti-tumor effects of IL-12 on its own or in combination with other therapies based on different delivery strategies.

Even though cytoreductive nephrectomy (CN) was once the standard of care for patients with advanced renal cell carcinoma (RCC), its role in treatment has not been well analyzed or defined in the era of immunotherapy (IO).

This study analyzed pathological outcomes in patients with advanced or metastatic RCC who received IO prior to CN. This was a multi-institutional, retrospective study of patients with advanced or metastatic RCC. Patients were required to receive IO monotherapy or combination therapy prior to radical or partial CN. The primary endpoint assessed surgical pathologic outcomes, including American Joint Committee on Cancer (AJCC) staging and frequency of downstaging, at the time of surgery. Pathologic outcomes were correlated to clinical variables using a Wald-chi squared test from Cox regression in a multi-variable analysis. Secondary outcomes included objective response rate (ORR) defined by response evaluation criteria in solid tumors (RECIST) version 1.1 and progression-free survival (PFS), which were estimated using the Kaplan-Meier method with reported 95% CIs.

Fifty-two patients from 9 sites were included. Most patients were male (65%), 81% had clear cell histology, 11% had sarcomatoid differentiation. Overall, 44% of patients experienced pathologic downstaging, and 13% had a complete pathologic response. The ORR immediately prior to nephrectomy was stable disease in 29% of patients, partial response in 63%, progressive disease in 4%, and 4% unknown. Median follow-up for the entire cohort was 25.3 months and median PFS was 3.5 years (95% CI, 2.1-4.9).

IO-based interventions prior to CN in patients with advanced or metastatic RCC demonstrates efficacy, with a small fraction of patients showing a complete response. Additional prospective studies are warranted to investigate the role of CN in the modern IO-era.

Renal cell carcinoma (RCC) is the most common solid tumour of the kidney and accounts for 3% of all cancers. While immune checkpoint inhibitor (ICI)-based combination therapies have emerged as the first-line treatment for metastatic renal cell carcinoma (mRCC), the role of surgery has become more controversial. This review summarizes the evidence, current role and future directions for surgery in mRCC management. The survival benefits of cytoreductive nephrectomy (CN) shown in the interferon era have encountered increasing disputes in the tyrosine-kinase inhibitor (TKI) and ICI eras. Undoubtedly, several systematic reviews based on retrospective data have supported the survival benefits of CN. Nevertheless, 2 prospective trials, CARMENA and SURTIME, proved that sunitinib as the upfront therapy resulted in noninferior survival outcomes compared with immediate CN. The safety of CN does have solid ground in the current literature. Several studies suggested that preoperative systemic therapy did not seem to aggravate perioperative complications or mortality rates, in experienced centres. Meticulous patient selection is the rule of thumb in the modern management of mRCC patients. The limitations of the existing prognostication models, however, must be acknowledged. Clinicians should adopt a multidisciplinary and holistic approach and contemplate all patient, disease, surgeon and socio-economical factors, before deciding who should go for surgery. The advent of metastasis-directed therapy (MDT) and survival benefits of adjuvant pembrolizumab shown in the oligometastatic subgroup, where complete metastasectomy could be achieved (M1 NED), calls for more comparative studies against upfront ICI combinations. In summary, CN brings survival benefits to well-selected good-to-intermediate-risk mRCC patients. Individualized and multidisciplinary care is pivotal.

Background: This study aimed to investigate the effect of cytoreductive nephrectomy (CN) on the survival outcomes of nivolumab used as a subsequent therapy after the failure of at least one anti-vascular endothelial growth factor (VEGF) agent in patients with metastatic clear-cell renal-cell carcinoma (ccRCC). Methods: We included 106 de novo metastatic ccRCC patients who received nivolumab after progression on at least one anti-VEGF agent. Multivariate Cox regression analysis was performed to investigate the factors affecting survival in patients receiving nivolumab. Results: Of the 106 de novo metastatic ccRCC patients, 83 (78.3%) underwent CN. There were no statistical differences between the two groups in terms of age, gender, Eastern Cooperative Oncology Group (ECOG) score, tumor size, International Metastatic RCC Database Consortium (IMDC) risk group, number of previous treatment lines, first-line anti-VEGF therapy, or metastasis sites (p = 0.137, p = 0.608, p = 0.100, p = 0.376, p = 0.185, p = 0.776, p = 0.350, and p = 0.608, respectively). The patients who received nivolumab with CN had a longer time to treatment discontinuation (TTD) [14.5 months, 95% confidence interval (CI): 8.6-20.3] than did those without CN 6.7 months (95% CI: 3.9-9.5) (p = 0.001). The median overall survival (OS) was 22.7 months (95% CI: 16.1-29.4). The patients with CN had a median OS of 22.9 months (95% CI: 16.3-29.4), while those without CN had a median OS of 8.1 months (95% CI: 5.6-10.5) (p = 0.104). In the multivariate analysis, CN [hazard ratio (HR): 0.521; 95% CI: 0.297-0.916; p = 0.024] and the IMDC risk score (p = 0.011) were statistically significant factors affecting TTD; however, the IMDC risk score (p = 0.006) was the only significant factor for overall survival. Conclusions: Our study showed that the TTD of nivolumab was longer in metastatic ccRCC patients who underwent cytoreductive nephrectomy.

Renal cell carcinoma (RCC) accounts for nearly 2% of cancers diagnosed worldwide. For metastatic RCC, targeted therapy is one of the most common treatment methods. It can include approaches that target vascular endothelial growth factor (VEGFR) or rely on immune checkpoint inhibitors or mTOR inhibitors. Adenosine A2A receptor (A2AR) is a type of widely distributed G-protein-coupled receptor (GPCR). Recently, an increasing number of studies suggest that the activation of A2AR can downregulate anti-tumor immune responses and prevent tumor growth. Currently, the data on A2AR antagonists in RCC treatment are still limited. Therefore, in this article, we further investigate the clinical trials investigating A2AR drugs in RCC. We also describe the epidemiology and current treatment of RCC, along with the physiological role of A2AR, and the types of A2AR drugs that are associated with tumor treatment.

Approximately 15 000 people receive a diagnosis of renal cell carcinoma (RCC) in Germany each year; in 20-30% of cases, metastatic RCC (mRCC) is already present at the time of diagnosis. This disease in the metastatic stage is still mainly treated palliatively, yet the multimodal therapeutic landscape has changed markedly over the past 15 years, with the approval of many new treatments for patients with mRCC.

This review is based on prospective studies retrieved by a selective search in PubMed and the ASCO and ESMO databases and on the German and European oncological and urological guidelines for RCC.

Drugs are the mainstay of treatment. mRCC can be treated with a combination of two immune checkpoint inhibitors (CPIs), a CPI and a tyrosine-kinase inhibitor (TKI) (evidence level IA), or a TKI as monotherapy (evidence level IIC-IC). With prognosis-based sequential drug treatment, a mean progressionfree survival of 12 to 24 months and an overall survival of approximately 50 months can be achieved from the time of initiation of first-line therapy. Aside from pharmacotherapy, the multidisciplinary tumor board should evaluate the indications for local treatments such as cytoreductive nephrectomy, metastasectomy, and radiotherapy, depending on the individual prognostic constellation and the patient's present condition.

Optimal individualized decisions require a high level of expertise and the collabo - ration of a multidisciplinary tumor board. Older prognostic parameters currently play a leading role in decision-making, while predictive parameters and molecular markers are not yet adequately validated.

Immunotherapy-based systemic treatment (ST) is the standard of care for most patients diagnosed with metastatic renal cell carcinoma (mRCC). Cytoreductive nephrectomy (CN) has historically shown benefit for select patients with mRCC, but its role and timing are not well understood in the era of immunotherapy. The primary objective of this study is to assess outcomes in patients who received ST only, CN followed by ST (CN-ST), and ST followed by CN (ST-CN). The Canadian Kidney Cancer information system (CKCis) database was queried to identify patients with de novo mRCC who received immunotherapy-based ST between January 2014 and June 2023. These patients were classified into three categories as described above. Cox proportional hazards models were used to assess the impact of the timing of ST and CN on overall survival (OS) and progression-free survival (PFS), after adjusting for the International Metastatic RCC Database Consortium (IMDC) risk group, age, and comorbidities. Best overall response and complications of ST and CN for these cohorts were collected. A total of 588 patients were included in this study: 331 patients received ST only, 215 patients received CN-ST, and 42 patients received ST-CN. Patient and disease characteristics including age, gender, performance status, IMDC risk category, comorbidity, histology, type of ST, and metastatic sites are reported. OS analysis favored patients who received ST-CN (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.13-0.68) and CN-ST (HR 0.68, CI 0.47-0.97) over patients who received ST only. PFS analysis showed a similar trend for ST-CN (HR 0.45, CI 0.26-0.77) and CN-ST (HR 0.9, CI 0.68-1.17). This study examined baseline features and outcomes associated with the use and timing of CN and ST using real-world data via a large Canadian real-world cohort. Patients selected to receive CN after ST demonstrated improved outcomes. There were no appreciable differences in perioperative complications across groups. Limitations include the small number of patients in the ST-CN group and residual confounding and selection biases that may influence the outcomes in patients undergoing CN.

Systemic and local therapies for patients with metastatic renal cell carcinoma (mRCC) are often challenging despite the evolution of multimodal cancer therapies in the last decade. In this review, we will focus on recent multidisciplinary approaches for patients with mRCC.

Systemic therapies for patients with mRCC have been garnering attention particularly after the approval of immuno-oncology (IO) agents, including anti-programmed death 1/programmed death-ligand 1. IO combinations have significantly prolonged overall survival in patients with mRCC in the first-line setting. Regarding local therapies, cytoreductive nephrectomy (CN) has become less common in the post-Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques (CARMENA) trial era, even though CN may still benefit selected patients with mRCC. In addition, metastasis-directed local therapies, namely metastasectomy or stereotactic radiotherapy, particularly for oligo-metastatic lesions or brain metastases, may have a prognostic impact. Several ablative techniques are also evolving while maintaining high local control rates with acceptable safety.

Multimodal cancer therapies are essential for conquering complex cases of mRCC. Modern systemic therapies including IO-based combination therapy as well as local therapies including CN, metastasectomy, stereotactic radiotherapy, and ablative techniques appear to improve oncologic outcomes of patients with mRCC, although appropriate patient selection is indispensable.

The treatment paradigm for high risk localized and advanced kidney cancer has been characterized by ongoing changes, with the introduction of vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) and later with immune checkpoint blockade. In this article, we review how current evidence informs our decision-making on post-checkpoint inhibitor systemic therapies, the role of adjuvant and/or neoadjuvant therapies, and the role of cytoreductive nephrectomy in the evolving systemic therapy landscape. While some studies support a post-checkpoint inhibitor benefit from the VEGFR TKIs cabozantinib or axitinib, the benefit of doublet therapies including a VEGF receptor inhibitor and a checkpoint inhibitor remains an area of active investigation, with the combination of lenvatinib plus pembrolizumab showing promise but with a Phase III trial of the combination of atezolizumab plus cabozantinib showing no benefit over cabozantinib alone. The role of adjuvant therapy in patients with high-risk disease who have undergone cytoreductive nephrectomy and potentially metastasectomy is also an area of continuing interest. While the S-TRAC study demonstrated a disease-free survival benefit for adjuvant sunitinib, no overall survival benefit was shown, and multiple other studies of adjuvant VEGFR TKI therapy have been negative. Subsequently, adjuvant pembrolizumab has shown a benefit in overall survival, whereas trials of neoadjuvant and adjuvant nivolumab, adjuvant atezolizumab, and adjuvant ipilimumab plus nivolumab have all been negative. Finally, the role for cytoreductive nephrectomy continues to be an area of active debate. The CARMENA study raised important questions about the role of cytoreductive nephrectomy given the advances in VEGFR TKI therapy but was characterized by accrual difficulties and a significant number of patients not receiving treatment according to the study protocol. Two ongoing studies (NORDIC-SUN and PROBE) seek to further address the role of cytoreductive nephrectomy in the doublet therapy era.

The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) remains unclear in the immuno-oncology (IO) era. The results of two randomized trials, CARMENA and SURTIME, questioned the role and timing of CN. However, despite the latest advances in the systemic treatment of mRCC, previous trials have only used targeted therapy, and no studies have fully investigated the role of CN in immune checkpoint inhibitor (CPI) settings, and there is an urgent need for future studies to better define the role and timing of CN.

This study is an open-label, multi-center, parallel, prospective, randomized, interventional clinical study to evaluate the efficacy of CN in combination with CPIs in mRCC patients with International mRCC Database Consortium (IMDC) intermediate- and poor-risk. Synchronous mRCC patients with ≤ 3 IMDC risk features will be randomly allocated to three groups (1, upfront CN; 2, deferred CN; and 3, systemic therapy [ST] only). For ST, the nivolumab plus ipilimumab combination regimen, one of the standard regimens for intermediate- and poor-risk mRCC, is chosen. The primary endpoint is overall survival. The secondary endpoints are progression-free survival, objective response rate, number of participants with treatment-related adverse events, and number of participants with surgical morbidity. We will analyze the genetic mutation profiles of the tumor tissue, circulating tumor DNA, urine tumor DNA, and tumor-infiltrating lymphocytes. The gut and urine microbial communities will be analyzed. The study will begin in 2022 and will enroll 55 patients.

This study is one of the few prospective randomized trials to evaluate the benefit of CN in the treatment of synchronous mRCC in the IO era. The SEVURO-CN trial will help identify the role and timing of CN, thereby rediscovering the value of CN.

ClinicalTrials.gov, NCT05753839. Registered on 3 March 2023.

About 20% of patients with renal cell carcinoma present with non-clear cell histology (nccRCC), encompassing various histological types. While surgery remains pivotal for localized-stage nccRCC, the role of cytoreductive nephrectomy (CN) in metastatic nccRCC is contentious. Limited data exist on the role of CN in metastatic nccRCC under current standard of care.

This retrospective study focused on the impact of upfront CN on metastatic nccRCC outcomes with first-line immune checkpoint inhibitor (IO) combinations or tyrosine kinase inhibitor (TKI) monotherapy.

The study included 221 patients with nccRCC and synchronous metastatic disease, treated with IO combinations or TKI monotherapy in the first line. Baseline clinical characteristics, systemic therapy, and treatment outcomes were analyzed. The primary objective was to assess clinical outcomes, including progression-free survival (PFS) and overall survival (OS). Statistical analysis involved the Fisher exact test, Pearson's correlation coefficient, analysis of variance, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models.

Median OS for patients undergoing upfront CN was 36.8 (95% confidence interval [CI] 24.9-71.3) versus 20.8 (95% CI 12.6-24.8) months for those without CN (p = 0.005). Upfront CN was significantly associated with OS in the multivariate Cox regression analysis (hazard ratio 0.47 [95% CI 0.31-0.72], p < 0.001). In patients without CN, the median OS and PFS was 24.5 (95% CI 18.1-40.5) and 13.0 months (95% CI 6.6-23.5) for patients treated with IO+TKI versus 7.5 (95% CI 4.3-22.4) and 4.9 months (95% CI 3.0-8.1) for those receiving the IO+IO combination (p = 0.059 and p = 0.032, respectively).

Our study demonstrates the survival benefits of upfront CN compared with systemic therapy without CN. The study suggests that the use of IO+TKI combination or, eventually, TKI monotherapy might be a better choice than IO+IO combination for patients who are not candidates for CN regardless of IO eligibility. Prospective trials are needed to validate these findings and refine the role of CN in current mRCC management.

This pooled analysis of patient-level data from trials evaluated the clinical outcomes of patients with metastatic renal cell carcinoma with or without cytoreductive nephrectomy before a combination of immune checkpoint inhibitor and antiangiogenic therapy.

Data from 5 trials of immune checkpoint inhibitors plus antiangiogenic therapy were pooled. Only patients with stage 4 disease at initial diagnosis were included to ensure that nephrectomy was performed for cytoreductive purposes and not to previously treat an earlier stage of disease. The effect of cytoreductive nephrectomy before immune checkpoint inhibitor therapy on outcomes was evaluated using the Kaplan-Meier method and a Cox proportional hazards regression model, adjusted for age, sex, risk group, performance status, and the presence of sarcomatoid differentiation.

A total of 981 patients were included. The estimated median progression-free survival with and without nephrectomy was 15 and 11 months, respectively; the adjusted hazard ratio was 0.71 (95% confidence interval = 0.59 to 0.85). The estimated median overall survival with and without nephrectomy was 46 and 28 months, respectively; the adjusted hazard ratio was 0.63 (95% confidence interval = 0.51 to 0.77). Objective response was 60% of patients with vs 46% of patients without cytoreductive nephrectomy.

Patients with metastatic renal cell carcinoma who undergo cytoreductive nephrectomy before immune checkpoint inhibitor plus antiangiogenic therapy had improved outcomes compared with patients without cytoreductive nephrectomy. Selection factors for cytoreductive nephrectomy may be prognostic and could not be fully controlled for in this retrospective analysis. Prospective determination of and stratification by prior cytoreductive nephrectomy may be considered when designing clinical trials to assess the impact of this factor on prognosis.

Nephrectomy is the surgical removal of all or part of a kidney. When the aim of nephrectomy is to reduce tumor burden in people with established metastatic disease, the procedure is called cytoreductive nephrectomy (CN). CN is typically combined with systemic anticancer therapy (SACT). SACT can be initiated before or immediately after the operation or deferred until radiological signs of disease progression. The benefits and harms of CN are controversial.

To assess the effects of cytoreductive nephrectomy combined with systemic anticancer therapy versus systemic anticancer therapy alone or watchful waiting in newly diagnosed metastatic renal cell carcinoma.

We performed a comprehensive search in the Cochrane Library, MEDLINE, Embase, Scopus, two trial registries, and other gray literature sources up to 1 March 2024. We applied no restrictions on publication language or status.

We included randomized controlled trials (RCTs) that evaluated SACT and CN versus SACT alone or watchful waiting.

Two review authors independently selected studies and extracted data. Primary outcomes were time to death from any cause and quality of life. Secondary outcomes were time to disease progression, treatment response, treatment-related mortality, discontinuation due to adverse events, and serious adverse events. We performed statistical analyses using a random-effects model. We rated the certainty of evidence using the GRADE approach.

Our search identified 10 records of four unique RCTs that informed two comparisons. In this abstract, we focus on the results for the two primary outcomes. Cytoreductive nephrectomy plus systemic anticancer therapy versus systemic anticancer therapy alone Three RCTs informed this comparison. Due to the considerable heterogeneity when pooling across these studies, we decided to present the results of the prespecified subgroup analysis by type of systemic agent. Cytoreductive nephrectomy plus interferon immunotherapy versus interferon immunotherapy alone CN plus interferon immunotherapy compared with interferon immunotherapy alone probably increases time to death from any cause (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.51 to 0.89; I²= 0%; 2 studies, 326 participants; moderate-certainty evidence). Assuming 820 all-cause deaths at two years' follow-up per 1000 people who receive interferon immunotherapy alone, the effect estimate corresponds to 132 fewer all-cause deaths (237 fewer to 37 fewer) per 1000 people who receive CN plus interferon immunotherapy. We found no evidence to assess quality of life. Cytoreductive nephrectomy plus tyrosine kinase inhibitor therapy versus tyrosine kinase inhibitor therapy alone We are very uncertain about the effect of CN plus tyrosine kinase inhibitor (TKI) therapy compared with TKI therapy alone on time to death from any cause (HR 1.11, 95% CI 0.90 to 1.37; 1 study, 450 participants; very low-certainty evidence). Assuming 574 all-cause deaths at two years' follow-up per 1000 people who receive TKI therapy alone, the effect estimate corresponds to 38 more all-cause deaths (38 fewer to 115 more) per 1000 people who receive CN plus TKI therapy. We found no evidence to assess quality of life. Immediate cytoreductive nephrectomy versus deferred cytoreductive nephrectomy One study evaluated CN followed by TKI therapy (immediate CN) versus three cycles of TKI therapy followed by CN (deferred CN). Immediate CN compared with deferred CN may decrease time to death from any cause (HR 1.63, 95% CI 1.05 to 2.53; 1 study, 99 participants; low-certainty evidence). Assuming 620 all-cause deaths at two years' follow-up per 1000 people who receive deferred CN, the effect estimate corresponds to 173 more all-cause deaths (18 more to 294 more) per 1000 people who receive immediate CN. We found no evidence to assess quality of life.

CN plus SACT in the form of interferon immunotherapy versus SACT in the form of interferon immunotherapy alone probably increases time to death from any cause. However, we are very uncertain about the effect of CN plus SACT in the form of TKI therapy versus SACT in the form of TKI therapy alone on time to death from any cause. Immediate CN versus deferred CN may decrease time to death from any cause. We found no quality of life data for any of these three comparisons. We also found no evidence to inform any other comparisons, in particular those involving newer immunotherapy agents (programmed death receptor 1 [PD-1]/programmed death ligand 1 [PD-L1] immune checkpoint inhibitors), which have become the backbone of SACT for metastatic renal cell carcinoma. There is an urgent need for RCTs that explore the role of CN in the context of contemporary forms of systemic immunotherapy.

In this study, we aimed to determine the utility of cytoreductive nephrectomy (CN) in real-world clinical practice and investigate whether CN contributes to improved oncological outcomes in patients with metastatic renal cell carcinoma (mRCC). This retrospective multicenter cohort study enrolled patients with mRCC who received systemic therapy at six institutions between May 2005 and May 2023. The patients were divided into those who did not undergo CN (Group I) and those who underwent CN (Group II). The primary endpoints were oncological outcomes, including cancer-specific survival (CSS) and progression-free survival (PFS). Altogether, 137 patients with mRCC were included in this study. The median CSS was 14 months in Group I and 32 months in Group II (p < 0.001). Additionally, the median PFS in Groups I and II was 5 and 13 months, respectively (p = 0.006). A multivariate analysis showed that CN was an independent prognostic factor for CSS and PFS. Hence, CN is a potential treatment modality that can improve oncological outcomes in patients with mRCC.

In this review, we aim to provide a comprehensive assessment of the evolving landscape of the perioperative management in renal cell carcinoma (RCC), emphasizing its dynamic and intricate nature. We explore academic and clinical insights into the perioperative treatment paradigm of RCC. Up-to-date treatment options are discussed and the evolving role of neoadjuvant and adjuvant therapy in RCC is highlighted.

The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) has been called into question on the basis of clinical trial data from the tyrosine kinase inhibitor (TKI) era. Comparative analyses of CN for patients treated with immuno-oncology (IO) versus TKI agents are sparse. Our objective was to compare CN timing and outcomes among patients who received TKI versus IO therapy.

This was a multicenter retrospective analysis of patients who underwent CN using data from the REMARCC (Registry of Metastatic RCC) database. The cohort was divided into TKI versus IO first-line therapy groups. The primary outcome was all-cause mortality (ACM). Secondary outcomes included cancer-specific mortality (CSM). Multivariable analysis was used to identify factors predictive for ACM and CSM. The Kaplan-Meier method was used to analyze 5-yr overall survival (OS) and cancer-specific survival (CSS) with stratification by primary systemic therapy and timing in relation to CN.

We analyzed data for 189 patients (148 TKI + CN, 41 IO +CN; median follow-up 23.2 mo). Multivariable analysis revealed that a greater number of metastases (hazard ratio [HR] 1.06; p = 0.015), greater primary tumor size (HR 1.10; p = 0.043), TKI receipt (HR 2.36; p = 0.015), and initiation of systemic therapy after CN (HR 1.49; p = 0.039) were associated with worse ACM. A greater number of metastases at diagnosis (HR 1.07; p = 0.011), greater primary tumor size (HR 1.12; p = 0.018), TKI receipt (HR 5.43; p = 0.004), and initiation of systemic therapy after CN (HR 2.04; p < 0.001) were associated with worse CSM. Kaplan-Meier analyses revealed greater 5-yr rates for OS (51% vs 27%; p < 0.001) and CSS (83% vs 30%; p < 0.001) for IO +CN versus TKI + CN. This difference persisted in a subgroup analysis for patients with intermediate or poor risk, with 5-yr OS rates of 50% for IO + CN versus 30% for TKI + CN (p < 0.001). A subanalysis stratified by CN timing revealed better 5-yr rates for OS (50% vs 30%; p = 0.042) and CSS (90% vs 30%, p = 0.019) for delayed CN after IO therapy, but not after TKI therapy.

For patients who underwent CN, systemic therapy before CN was associated with better outcomes. In addition, IO therapy was associated with better survival outcomes in comparison to TKI therapy. Our findings question the applicability of clinical trial data from the TKI era to CN in the IO era for mRCC.

For patients with metastatic kidney cancer treated with surgery, better survival outcomes were observed for those who also received immunotherapy in comparison to therapy targeting specific proteins in the body (tyrosine kinase inhibitors, TKIs). Immunotherapy or TKI treatment resulted in better outcomes if it was received before rather than after surgery.

To evaluate the current role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) within the context of evolving treatment paradigms, focusing on implications for patient selection.

Two randomized trials failed to show significant benefits from CN for intermediate and poor-risk patients undergoing targeted therapy. Despite this, subgroup analysis and retrospective data suggest potential benefits for a subset of good and intermediate-risk patients. Although currently used risk stratification tools guide CN eligibility, they have limitations, including, subjectivity, perioperative variability, and missing validation. Deferred CN may benefit patients responding to systemic treatment, whereas other patients may benefit from upfront CN. Emerging data supports the value of CN with immune checkpoint inhibitors (ICI) in selected patients, emphasizing the need for ongoing trials in the ICI era.

The role and timing of CN in mRCC have evolved across therapeutic eras. Although awaiting prospective evidence in the current era of ICI, CN still has a role in the therapeutic approach for a subset of patients. The decision to recommend CN must be personalized and involve multidisciplinary discussions considering both patient- and tumor-related factors.

There is a controversy about whether surgery should proceed among metastatic pancreatic cancer (mPC) patients. A survival benefit was observed in mPC patients who underwent primary tumor resection; however, determining which patients would benefit from surgery is complex. For this purpose, we created a model to identify mPC patients who may benefit from primary tumor excision.

Patients with mPC were extracted from the Surveillance, Epidemiology, and End Results database, and separated into surgery and nonsurgery groups based on whether the primary tumor was resected. Propensity score matching (PSM) was applied to balance confounding factors between the two groups. A nomogram was developed using multivariable logistic regression to estimate surgical benefit. Our model is evaluated using multiple methods.

About 662 of 14,183 mPC patients had primary tumor surgery. Kaplan-Meier analyses showed that the surgery group had a better prognosis. After PSM, a survival benefit was still observed in the surgery group. Among the surgery cohort, 202 patients survived longer than 4 months (surgery-beneficial group). The nomogram discriminated better in training and validation sets under the receiver operating characteristic (ROC) curve (AUC), and calibration curves were consistent. Decision curve analysis (DCA) revealed that it was clinically valuable. This model is better at identifying candidates for primary tumor excision.

A helpful prediction model was developed and validated to identify ideal candidates who may benefit from primary tumor resection in mPC.