Search

The fifth edition of the World Health Organization (WHO) classification of urogenital tumours published in 2022 will be implemented in the European Association of Urology guidelines on renal cell carcinoma for 2023. Here we provide an update summarising changes in the new WHO classification of renal tumours from a clinician perspective.

BACKGROUND: Retrospective comparative studies suggest a survival benefit after complete local treatment of recurrence (LTR) in renal cell carcinoma (RCC), which may be largely due to an indication bias. OBJECTIVE: To determine the role of LTR in a homogeneous population characterised by limited and potentially resectable recurrence. DESIGN SETTING AND PARTICIPANTS: RECUR is a protocol-based multicentre European registry capturing patient and tumour characteristics, risk of recurrence (RoR), recurrence patterns, and survival of those curatively treated for nonmetastatic RCC from 2006 to 2011. Per-protocol resectable disease (RD) recurrence was defined as (1) solitary metastases, (2) oligometastases, or (3) renal fossa or renal recurrence after radical or partial nephrectomy, respectively. INTERVENTION: Local treatment of recurrence. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) and cancer-specific survival was compared in the RD population that underwent LTR versus no LTR. We constructed a multivariate model to predict risk factors for overall mortality and analysed the effect of LTR across RoR groups. RESULTS AND LIMITATIONS: Of 3039 patients with localised RCC treated with curative intent, 505 presented with recurrence, including 176 with RD. Of these patients, 97 underwent LTR and 79 no LTR. Patients in the LTR group were younger (64.3 [40-80] vs 69.2 [45-87] yr; p = 0.001). The median OS was 70.3 mo (95% confidence interval [CI] 58-82.6) versus 27.4 mo (95% CI 23.6-31.15) in the LTR versus no-LTR group (p

In KEYNOTE-564, adjuvant pembrolizumab, a PD-1 antibody, significantly improved disease-free survival (DFS) in localised clear-cell renal cell carcinoma (ccRCC) with a high risk of relapse. In 2021, the European Association of Urology RCC Guidelines Panel issued a weak recommendation for adjuvant pembrolizumab for high-risk ccRCC as defined by the trial until final overall survival data and results from other trials were available. Meanwhile, the primary DFS endpoints were not met for adjuvant atezolizumab (PD-L1 inhibitor; IMmotion010), adjuvant nivolumab plus ipilimumab (CheckMate 914), or perioperative nivolumab (PROSPER). Owing to heterogeneity, a meta-analysis is not recommended. Pembrolizumab remains the only immune checkpoint inhibitor currently recommended in this setting. Overall survival data are immature and biomarkers to predict outcome are lacking. Uncertainty exists and overtreatment is occurring. Treatment decisions should be made with caution and with the involvement of each patient. PATIENT SUMMARY: New results from three trials of immunotherapy after surgery for kidney cancer to reduce the risk of recurrence showed no improvement with these treatments. These results are in contrast to an earlier study that showed that the antibody pembrolizumab did extend the time before kidney cancer recurrence, even though it is not yet clear if overall survival is longer. Thus, we cautiously recommend pembrolizumab as additional treatment in high-risk kidney cancer after surgery, but patient preference should be carefully considered and the risk of overtreatment should be discussed.

Context Patients with chronic pelvic pain syndrome (CPPS) may have pain refractory to conventional management strategies. Botulinum toxin A (BTX-A) is a potential therapeutic option. Objective To evaluate the benefits and harms of BTX-A injections in the treatment of CPPS. Evidence acquisition A systematic review of the use of BTX-A in the treatment of CPPS was conducted (PROSPERO-ID: 162416). Comprehensive searches of EMBASE, PUBMED, Medline, and SCOPUS were performed for publications between January 1996 and May 2020. Identified studies were screened and selected studies assessed for quality prior to data extraction. The primary outcomes were improvement in pain and adverse events following treatment. Secondary outcomes included quality of life, global response assessment, sexual function, bowel function, and bladder function. Evidence synthesis After screening 1001 abstracts, 16 studies including 11 randomised controlled trials were identified, enrolling 858 patients and covering a range of CPPS subtypes. Most studies showed high risks of bias and confounding across all domains. A narrative synthesis was performed as heterogeneity of included studies precluded a meta-analysis and calculation of pooled effect estimates of measured outcomes. BTX-A reduced pain significantly in patients with bladder pain syndrome in two studies and in patients with prostate pain syndrome in one study, but no included studies showed benefit for patients with gynaecological pelvic pain. Adverse event reporting was variable and generally poor, but no serious adverse events were described. Conclusions Beneficial effects of BTX-A on pain, quality of life, and functional symptoms were seen in patients with certain CPPS subtypes, but the current evidence level is too weak to allow recommendations about BTX-A use for treating CPPS. Patient summary Botulinum toxin A is used to treat different pain disorders, but current studies are of insufficient quality to determine whether it reduces pain and improves quality of life in patients with chronic pelvic pain. Further research is needed.

Objective: To investigate whether pT1 renal cell carcinoma (RCC) should be followed differently after partial (PN) or radical nephrectomy (RN) based on a retrospective analysis of a multicentre database (RECUR). Subjects: A retrospective study was conducted in 3380 patients treated for nonmetastatic RCC between January 2006 and December 2011 across 15 centres from 10 countries, as part of the RECUR database project. For patients with pT1 clear-cell RCC, patterns of recurrence were compared between RN and PN according to recurrence site. Univariate and multivariate models were used to evaluate the association between surgical approach and recurrence-free survival (RFS) and cancer-specific mortality (CSM). Results: From the database 1995 patients were identified as low-risk patients (pT1, pN0, pNx), of whom 1055 (52.9%) underwent PN. On multivariate analysis, features associated with worse RFS included tumour size (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.14–1.39; P < 0.001), nuclear grade (HR 2.31, 95% CI 1.73–3.08; P < 0.001), tumour necrosis (HR 1.5, 95% CI 1.03–2.3; P = 0.037), vascular invasion (HR 2.4, 95% CI 1.3–4.4; P = 0.005) and positive surgical margins (HR 4.4, 95% CI 2.3–8.5; P < 0.001). Kaplan–Meier analysis of CSM revealed that the survival of patients with recurrence after PN was significantly better than those with recurrence after RN (P = 0.02). While the above-mentioned risk factors were associated with prognosis, type of surgery alone was not an independent prognostic variable for RFS nor CSM. Limitations include the retrospective nature of the study. Conclusion: Our results showed that follow-up protocols should not rely solely on stage and type of primary surgery. An optimized regimen should also include validated risk factors rather than type of surgery alone to select the best imaging method and to avoid unnecessary imaging. A follow-up of more than 3 years should be considered in patients with pT1 tumours after RN. A novel follow-up strategy is proposed. (Less)

Currently there are no specific guidelines for the post-operative follow-up of chromophobe renal cell carcinoma (chRCC). We aimed to evaluate the pattern, location and timing of recurrence after surgery for non-metastatic chRCC and establish predictors of recurrence and cancer-specific death. Retrospective analysis of consecutive surgically treated non-metastatic chRCC cases from the Royal Free London NHS Foundation Trust (UK, 2015–2019) and the international collaborative database RECUR (15 institutes, 2006–2011). Kaplan–Meier curves were plotted. The association between variables of interest and outcomes were analysed using univariate and multivariate Cox proportional hazards regression models with shared frailty for data source. 295 patients were identified. Median follow-up was 58 months. The five and ten-year recurrence-free survival rates were 94.3% and 89.2%. Seventeen patients (5.7%) developed recurrent disease, 13 (76.5%) with distant metastases. 54% of metastatic disease diagnoses involved a single organ, most commonly the bone. Early recurrence (

Longer follow-up and new trial data from phase 3 randomised controlled trials investigating immune checkpoint blockade (PD-1 or its ligand PD-L1) in advanced clear-cell renal cell carcinoma (RCC) have recently become available. The CheckMate 9ER trial demonstrated an improved progression-free survival (PFS) and overall survival (OS) benefit for the combination of cabozantinib plus nivolumab. A Keynote-426 update demonstrated an ongoing OS benefit for pembrolizumab plus axitinib in the intention-to-treat population, with a PFS benefit seen across all International Metastatic Database Consortium (IMDC) subgroups, while an update of CheckMate 214 confirmed the long-term benefit of ipilimumab plus nivolumab in IMDC intermediate and poor risk patients. The RCC Guidelines Panel continues to recommend these tyrosine kinase inhibitors + immunotherapy (IO) combination across IMDC risk groups in advanced first-line RCC and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate and poor risk. PATIENT SUMMARY: New data from trials of immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit with the combination of cabozantinib plus nivolumab and pembrolizumab plus axitinib and ipilimumab plus nivolumab. These combination therapies are recommended as first-line treatment for advanced kidney cancer.

Over the past decade, only minor changes have been introduced in the TNM staging system for renal cancer. Conversely, many milestones and modifications in management of the disease have been achieved, especially for patients with locally advanced and metastatic cancers. The European Association of Urology guidelines panel proposes a new TNM classification scheme for staging of renal cell carcinoma to reflect these breakthrough clinical improvements.

Objective: To report the incidence of venous thromboembolism (VTE) after nephrectomy in Denmark and explore associated risk factors. Materials and Methods: A nationwide population-based retrospective cohort study was performed. All nephrectomies from January 2010 to August 2018 were assessed for postoperative VTE events. Univariable and multivariable analyses were used to evaluate the odds ratio (OR) of clinical variables’ effect on postoperative VTEs, within 4 weeks and 4 months after nephrectomy. Results: In 5213 nephrectomized patients, postoperative VTE incidence was 1% and 2% within 4 weeks and 4 months, respectively. Multivariable analyses revealed that predictors of postoperative VTE within 4 months were: open nephrectomy (OR 2.5, P =.001), history of VTE (OR 13.3, P

The European Association of Urology (EAU) Renal Cell Carcinoma (RCC) Guideline Panel performed a protocol-driven systematic review (SR) on thermal ablation (TA) compared with partial nephrectomy (PN) for T1N0M0 renal masses, in order to provide evidence to support its recommendations. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed, and only comparative studies published between 2000 and 2019 were included. Twenty-six nonrandomised comparative studies were included, recruiting a total of 167 80 patients. Risk of bias (RoB) assessment revealed high or uncertain RoB across all studies, with the vast majority being retrospective, observational studies with poorly matched controls and short follow-up. Limited data showed TA to be safe, but its long-term oncological effectiveness compared with PN remains uncertain. A quality assessment of pre-existing SRs (n=11) on the topic, using AMSTAR, revealed that all SRs had low confidence rating, with all but two SRs being rated critically low. In conclusion, the current data are inadequate to make any strong and clear conclusions regarding the clinical effectiveness of TA for treating T1N0M0 renal masses compared with PN. Therefore, TA may be cautiously considered an alternative to PN for T1N0M0 renal masses, but patients must be counselled carefully regarding the prevailing uncertainties. We recommend specific steps to improve the evidence base based on robust primary and secondary studies. PATIENT SUMMARY: In this report, we looked at the literature to determine the effectiveness of thermoablation (TA) in the treatment of small kidney tumours compared with surgical removal. We found that TA could cautiously be offered as an option due to many remaining uncertainties regarding its effectiveness.

Context: The European Association of Urology (EAU) Renal Cell Carcinoma (RCC) Guideline Panel has prepared evidence-based guidelines and recommendations for the management of RCC. Objective: To present a summary of the 2022 RCC guideline, which is based on a standardised methodology including systematic reviews (SRs) and provides transparent and reliable evidence for the management of RCC. Evidence acquisition: For the 2022 update, a new literature search was carried out with a cutoff date of May 28, 2021, covering the Medline, EMBASE, and Cochrane databases. The data search focused on randomised controlled trials (RCTs) and retrospective or controlled comparator-arm studies, SRs, and meta-analyses. Evidence synthesis was conducted using modified GRADE criteria as outlined for all the EAU guidelines. Evidence synthesis: All chapters of the RCC guideline were updated on the basis of a structured literature assessment, and clinical practice recommendations were developed. The majority of the studies included were retrospective with matched or unmatched cohorts and were based on single- or multi-institution data or national registries. The exception was systemic treatment of metastatic RCC, for which there are several large RCTs, resulting in recommendations that are based on higher levels of evidence. Conclusions: The 2022 RCC guidelines have been updated by a multidisciplinary panel of experts using the highest methodological standards. These guidelines provide the most reliable contemporary evidence base for the management of RCC in 2022. Patient summary: The European Association of Urology panel for guidelines on kidney cancer has thoroughly evaluated the research data available to establish up-to-date international standards for the care of patients with kidney cancer.

Cancer mortality is exacerbated by late-stage diagnosis. Liquid biopsies based on genomic biomarkers can noninvasively diagnose cancers. However, validation studies have reported ~10% sensitivity to detect stage I cancer in a screening population and specific types, such as brain or genitourinary tumors, remain undetectable. We investigated urine and plasma free glycosaminoglycan profiles (GAGomes) as tumor metabolism biomarkers for multi-cancer early detection (MCED) of 14 cancer types using 2,064 samples from 1,260 cancer or healthy subjects. We observed widespread cancer-specific changes in biofluidic GAGomes recapitulated in an in vivo cancer progression model. We developed three machine learning models based on urine ( N urine = 220 cancer vs. 360 healthy) and plasma ( N plasma = 517 vs. 425) GAGomes that can detect any cancer with an area under the receiver operating characteristic curve of 0.83–0.93 with up to 62% sensitivity to stage I disease at 95% specificity. Undetected patients had a 39 to 50% lower risk of death. GAGomes predicted the putative cancer location with 89% accuracy. In a validation study on a screening-like population requiring ≥ 99% specificity, combined GAGomes predicted any cancer type with poor prognosis within 18 months with 43% sensitivity (21% in stage I; N = 121 and 49 cases). Overall, GAGomes appeared to be powerful MCED metabolic biomarkers, potentially doubling the number of stage I cancers detectable using genomic biomarkers.

Adjuvant treatment of nonmetastatic high-risk renal cell carcinoma is an unmet medical need. In the past, several tyrosine kinase inhibitor trials have failed to demonstrate an improvement of disease-free survival (DFS) in this setting. Only one trial (S-TRAC) provided evidence for improved DFS with sunitinib but without an overall survival (OS) signal. Keynote-564 is the first trial of an immune checkpoint inhibitor that significantly improved DFS with adjuvant pembrolizumab, a programmed death receptor-1 antibody, in clear cell renal cell carcinoma with a high risk of relapse. The intention-to-treat population, which included a group of patients after metastasectomy and no evidence of disease (M1 NED), had a significant DFS benefit. The OS data are not mature as yet. The Renal Cell Carcinoma Guideline Panel issues a weak recommendation for the adjuvant use of pembrolizumab for high-risk clear cell renal carcinoma, as defined by the trial until final OS data are available. However, the trial reilluminates the discussion on when and in whom metastasectomy should be performed. Here, caution is necessary not to perform metastasectomy in patients with poor prognostic features and rapid progressive disease, which must be excluded by a confirmatory scan of disease status prior to planned metastasectomy. PATIENT SUMMARY: New data from the adjuvant immune checkpoint inhibitor trial with pembrolizumab (a programmed death receptor-1 antibody) for the treatment of high-risk clear cell renal cell carcinoma (ccRCC) after surgery showed that the drug prolonged the period of being cancer free significantly, although whether it prolonged survival remained uncertain. Consequently, pembrolizumab is cautiously recommended as additional (ie, adjuvant) treatment in high-risk ccRCC after kidney cancer surgery.

INTRODUCTION AND OBJECTIVE:The impact of open or minimally invasive surgery (either laparoscopic or robotic approach) on survival and disease recurrence in the management of non-metastatic renal ce...

The impact of open versus minimally invasive surgery on recurrence pattern in the management of localized renal cell carcinoma (RCC) remains uncertain. We thus aimed to determine the impact of surgical approach on survival and recurrence pattern.This is a multi-institutional, matched cohort study on patients with pT1-3aN0M0 RCC from the RECUR database. After propensity score matching between open and minimally invasive surgery, disease-free (DFS) survival and risk of first recurrence according to recurrence site, namely local recurrence, abdominal/retroperitoneal, thoracic/mediastinal or uncommon site metastases were investigated with Cox regression analysis. Overall (OS) and Cancer Specific Survival (CSS) were also assessed.After matching, 1,019 patients who underwent open and 1,019 who underwent minimally invasive surgery were included (of which 70 robot-assisted). At 5.2 years of median follow-up, 130 patients in open and 125 in minimally invasive group experienced disease progression. A higher risk of local recurrence (HR 2.06; 95% CI 1.18-3.58, P-value = 0.01) and uncommon site metastases (HR 1.09; 95% CI 1.01-1.16; P-value = .04) was found for minimally invasive surgery relative to open surgery, while no difference was found in terms of DFS (HR 0.83; 95% CI 0.64-1.06; P-value = .14). No differences were found in terms of OS and CSS. Main limitation is the retrospective nature of the study.The risk for local recurrence and uncommon site metastases was higher for minimally invasive surgery compared to open surgery, although no differences were found for OS, CSS, and DFS.

Background: Current follow-up strategies for patients with renal cell carcinoma (RCC) after curative surgery rely mainly on risk models and the treatment delivered, regardless of the histological subtype. Objective: To determine the impact of RCC histological subtype on recurrence and to examine the incidence, pattern, and timing of recurrences to improve follow-up recommendations. Design, setting, and participants: This study included consecutive patients treated surgically with curative intention (ie, radical and partial nephrectomy) for non-metastatic RCC (cT1-4, M0) between January 2006 and December 2011 across 15 centres from 10 countries, as part of the euRopEan association of urology renal cell carcinoma guidelines panel Collaborative multicenter consortium for the studies of follow-Up and recurrence patterns in Radically treated renal cell carcinoma patients (RECUR) database project. Outcome measurements and statistical analysis: The impact of histological subtype (ie, clear cell RCC [ccRCC], papillary RCC [pRCC], and chromophobe RCC [chRCC]) on recurrence-free survival (RFS) was assessed via univariate and multivariate analyses, adjusting for potential interactions with important variables (stage, grade, risk score, etc.) Patterns of recurrence for all histological subtypes were compared according to recurrence site and risk criteria. Results and limitations: Of the 3331 patients, 62.2% underwent radical nephrectomy and 37.8% partial nephrectomy. A total of 2565 patients (77.0%) had ccRCC, 535 (16.1%) had pRCC, and 231 (6.9%) had chRCC. The median postoperative follow-up period was 61.7 (interquartile range: 47-83) mo. Patients with ccRCC had significantly poorer 5-yr RFS than patients with pRCC and chRCC (78% vs 86% vs 91%, p = 0.001). The most common sites of recurrence for ccRCC were the lung and bone. Intermediate-/high-risk pRCC patients had an increased rate of lymphatic recurrence, both mediastinal and retroperitoneal, while recurrence in chRCC was rare (8.2%), associated with higher stage and positive margins, and predominantly in the liver and bone. Limitations include the retrospective nature of the study. Conclusions: The main histological subtypes of RCC exhibit a distinct pattern and dynamics of recurrence. Results suggest that intermediate- to high-risk pRCC may benefit from cross-sectional abdominal imaging every 6 mo until 2 yr after surgery, while routine imaging might be abandoned for chRCC except for abdominal computed tomography in patients with advanced tumour stage or positive margins. Patient summary: In this analysis of a large database from 15 countries around Europe, we found that the main histological subtypes of renal cell carcinoma have a distinct pattern and dynamics of recurrence. Patients should be followed differently according to subtype and risk score. (C) 2020 Published by Elsevier B.V. on behalf of European Association of Urology.

The recent randomized controlled phase III CLEAR trial results are the last to complement immune checkpoint inhibitor (ICI)-based doublet combination therapies for treatment-naive metastatic clear-cell renal cell carcinoma. The CLEAR trial demonstrated an improved progression-free survival (PFS), overall survival (OS), and an objective response rate (ORR) benefit for the combination of lenvatinib plus pembrolizumab over sunitinib. The CheckMate-9ER trial update demonstrated an ongoing PFS, OS, and quality-of-life benefit for cabozantinib plus nivolumab over sunitinib as did the update of Keynote-426 for axitinib plus pembrolizumab in the intention-to-treat population, with a PFS benefit seen across all International Metastatic Database Consortium (IMDC) subgroups. In the IMDC intermediate- and poor-risk groups, the CheckMate-214 trial of ipilimumab plus nivolumab confirmed the OS benefit with a PFS plateauing after 30 months. The RCC Guidelines Panel recommends three tyrosine kinase inhibitors + ICI combinations of axitinib plus pembrolizumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab across all IMDC risk groups in advanced first-line RCC, and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate- and poor-risk groups. Patient summary New data from combination trials with immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit for lenvatinib plus pembrolizumab, cabozantinib plus nivolumab (with improved quality-of-life), axitinib plus pembrolizumab, and ipilimumab plus nivolumab. These combination therapies are recommended as first-line treatment for advanced kidney cancer.

Currently there are no specific guidelines for the post-operative follow-up of chromophobe renal cell carcinoma (chRCC). We aimed to evaluate the pattern, location and timing of recurrence after surgery for non-metastatic chRCC and establish predictors of recurrence and cancer-specific death.Retrospective analysis of consecutive surgically treated non-metastatic chRCC cases from the Royal Free London NHS Foundation Trust (UK, 2015-2019) and the international collaborative database RECUR (15 institutes, 2006-2011). Kaplan-Meier curves were plotted. The association between variables of interest and outcomes were analysed using univariate and multivariate Cox proportional hazards regression models with shared frailty for data source.295 patients were identified. Median follow-up was 58 months. The five and ten-year recurrence-free survival rates were 94.3% and 89.2%. Seventeen patients (5.7%) developed recurrent disease, 13 (76.5%) with distant metastases. 54% of metastatic disease diagnoses involved a single organ, most commonly the bone. Early recurrence ( 24 months) was observed in 8 cases, all staged ≥ pT2b. 30 deaths occurred, of which 11 were attributed to chRCC. Sarcomatoid differentiation was rare (n = 4) but associated with recurrence and cancer-specific death on univariate analysis. On multivariate analysis, UICC/AJCC T-stage ≥ pT2b, presence of coagulative necrosis, and positive surgical margins were predictors of recurrence and cancer-specific death.Recurrence and death after surgically resected chRCC are rare. For completely excised lesions ≤ pT2a without coagulative necrosis or sarcomatoid features, prognosis is excellent. These patients should be reassured and follow-up intensity curtailed.

Context The epidemiological signature of renal cell carcinoma (RCC) during the past decades is explained by overdetection and overtreatment of indolent cancers; furthermore, a non-negligible proportion of patients undergoing surgery for suspected RCC harbour benign renal tumours. As the gold standard for RCC diagnosis remains histopathological analysis of surgical or biopsy specimens, implementation of noninvasive diagnostic strategies to discriminate between benign and malignant renal masses is an urgent unmet need. Objective To systematically review novel liquid biomarkers and imaging modalities for RCC diagnosis. Evidence acquisition A systematic review of the recent English-language literature was conducted according to the European Association of Urology guidelines and the PRISMA statement recommendations (PROSPERO ID: CRD42020190773) using the MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov databases. Risk-of-bias assessment was performed according to the QUADAS 2 tool. Evidence synthesis Overall, 15 studies (six on biomarkers and nine on imaging) and eight clinical trials were included. None of the biomarkers or imaging modalities has been validated or shown to have a distinct clinical value for RCC. Specific combinations of urinary cell-free and exosomal miRNAs, urinary miR-15a, and specific panels of urinary metabolites assessed by metabolomics appear promising. In addition, machine/deep learning algorithms and radiomics applied to cross-sectional images may have potential to improve RCC diagnosis. Most studies are limited by the retrospective design, size, and lack of external validation. Conclusions Liquid biomarkers or imaging modalities are not ready for integration in the clinic and further well-designed studies must validate preliminary findings and explore utility in clinical decision-making. Patient summary We provide a comprehensive overview of the currently available biomarkers (measured in blood or urine) and novel imaging tests (other than conventional imaging) to discriminate kidney cancer from benign renal masses in a noninvasive fashion. None of the biomarkers or imaging modalities studied was validated or added clinical value; therefore, none of them can be implemented in the clinic. However, these approaches appear to be promising for improving the diagnosis of kidney cancer in the future.

Introduction Designing adjuvant trials is challenging because of uncertainties of prevalence and outcome of high-risk renal cell cancer (RCC) despite use of validated risk scores. Our objective is to investigate how differences in eligibility criteria may impact on potential study results in RCC adjuvant trials. Patients and Methods RECUR is a multicenter European database capturing patient and tumor characteristics, recurrence patterns, and survival of those curatively treated for non-metastatic RCC from 2006 to 2011 without any adjuvant therapy. We used RECUR to evaluate prevalence, disease-free survival (DFS), and overall survival (OS) according to eligibility criteria of immunotherapy-based adjuvant trials IMMotion 010 ( NCT03024996 ), Checkmate 914 ( NCT03138512 ), Keynote-564 ( NCT03142334 ), RAMPART ( NCT03288532 ), and PROSPER ( NCT03055013 ). Results Of 3024 relevant patients in RECUR, 408 (13.5%), 725 (24%), 609 (20.1%), 1363 (45.1%), and 1071 (35.4%) met eligibility criteria for IMMotion-010, CheckMate-914, Keynote-564, RAMPART, and PROSPER, respectively. The median and 5-year DFS Kaplan-Meier estimates in RECUR corresponding to each trial eligibility criteria were: not reached and 69.6% for RAMPART; not reached and 64.5% for PROSPER; 109.3 months (95% confidence interval [CI], 83.9-134.6 months) and 57% for CheckMate-914; 75.8 months (95% CI, 52.7-98.8 months) and 54.3% for Keynote-564; and 43.6 months (95% CI, 30.8-56.4 months) and 45% for IMMotion-010. Our analysis may be limited by the retrospective design. Conclusions RECUR provides estimated DFS and OS benchmarks for placebo arms of adjuvant checkpoint inhibitor studies and hence likely time to trial reporting. Well-documented contemporary registries rather than past risk models should be used to design future adjuvant trials.

The optimal follow-up (FU) strategy for patients treated for localised renal cell carcinoma (RCC) remains unclear. Using the RECUR database, we studied imaging intensity utilised in contemporary FU to evaluate its association with outcome after detection of disease recurrence. Consecutive patients with nonmetastatic RCC (n = 1612) treated with curative intent at 12 institutes across eight European countries between 2006 and 2011 were included. Recurrence occurred in 336 patients. Cross-sectional (computed tomography, magnetic resonance imaging) and conventional (chest X-ray, ultrasound) methods were used in 47% and 53%, respectively. More intensive FU imaging (more than twofold) than recommended by the European Association of Urology (EAU) was not associated with improved overall survival (OS) after recurrence. Overall, per patient treated for recurrence remaining alive with no evidence of disease, the number of FU images needed was 542, and 697 for high-risk patients. The study results suggest that use of more imaging during FU than that recommended in the 2017 EAU guidelines is unlikely to improve OS after recurrence. Prospective studies are needed to design optimal FU strategies for the future. Patient summary: After curative treatment for localised kidney cancer, follow-up is necessary to detect any recurrence. This study illustrates that increasing the imaging frequency during follow-up, even to double the number of follow-up imaging procedures recommended by the European Association of Urology guidelines, does not translate into improved survival for those with recurrence. After curative treatment for localised kidney cancer, a more intensive follow-up regimen than that recommended in the 2017 European Association of Urology guidelines did not improve overall survival among those experiencing recurrence, irrespective of the risk of recurrence. This suggests that an increase in follow-up imaging frequency is not cost-efficient. Prospective studies to identify more optimal follow-up strategies are needed.

Patients with localised renal cell carcinoma (RCC) receiving curative surgery, either radical or partial nephrectomy, have been shown in contemporary studies to develop recurrence within 5 years in 20–30% of case. Therefore, post-operative follow-up (FU) imaging plays a crucial role in detecting recurrent or metastatic disease. A number of prognostic scores have been developed to predict risk of recurrence. This review summarises the current knowledge on established FU protocols and their limitations. A non-systematic literature search was conducted using Medline. Furthermore, major guidelines [European Association of Urology (EAU), American Urological Association (AUA) and National Comprehensive Cancer Network (NCCN)] were reviewed and assessed. The EAU, AUA and NCCN post-operative follow-up guidelines differ in the frequency and type of imaging modalities recommended. The optimal duration of follow-up remains to be elucidated as does the impact of follow-up protocols on patient outcomes and quality of life. Established follow-up protocols do not take non-RCC-related factors, such as patient age and performance status into account. However, in the future individualised duration of FU based on competing risks of cancer recurrence and non-RCC death may be optimised, maximising resources and patient quality of life. There is a clear need to establish evidence-based follow-up protocols and to assess the impact of follow-up protocols on individual patients and society.

Background: Optimal follow-up (FU) strategy to detect potentially curable (PC) recurrences after treatment of localised clear cell renal cell carcinoma (ccRCC) is unclear. This study retrospectively analysed a large international database to determine recurrence patterns and overall survival (OS), as part of a wider project to issue recommendations on FU protocols. Objective: To analyse associations between RCC recurrences in patients with ccRCC, their risk group stratifications, treatments, and subsequent outcomes. Design, setting, and participants: Nonmetastatic ccRCC patients treated with curative intent between 1 January 2006 and 31 December 2011, with at least 4 yr of FU, were included. Patient, tumour and recurrence characteristics, Leibovich score, and management and survival data were recorded. Isolated local, solitary, and oligometastatic (three or fewer lesions at a single site) recurrences were considered PC, while all others were probably incurable (PI). Intervention: Primarily curative surgical treatment of ccRCC while at recurrence detection metastasectomy, systemic therapy, best supportive care, or observation. Outcome measurements and statistical analysis: Incidence, time to recurrence (TTR), and OS were measured. Competing risk analysis, Kaplan-Meier, and Cox regression models were used. Results and limitation: Of 1265 patients with ccRCC, 286 had a recurrence, with 131 being PC and 155 PI. Five-year cumulative risks of recurrence for low- (n = 53), intermediate- (n = 105), and high-risk (n = 128) patients were, respectively, 7.2%, 23.2%, and 61.6%, of whom 52.8%, 37.1%, and 30.5% were PC, respectively. Median TTR was 25.0 for PC patients versus 17.3 mo for PI patients (p = 0.004). Median OS was longer in PC compared with that in PI patients (p< 0.001). Competing risk analysis showed highest risk of ccRCC-related death in younger and high-risk patients. Limitations were no data on comorbidities, retrospective cohort, and insufficient data excluding 12% of cohort. Conclusions: Low-risk group recurrences are rare and develop later. Treatment of recurrences with curative intent is disappointing, especially in high-risk patients. An age- and risk score-dependent FU approach is suggested. Patient summary: We analysed data from eight European countries, and found that the incidence of the kidney cancer recurrence and patient survival correlated with clinical factors known to predict cancer recurrence reliably and age. We conclude that these factors should be used to design follow-up strategies. Renal cell carcinoma recurrences are rare in low-risk patients. Potentially curable recurrences are more frequent in high-risk patients, but local treatment is unlikely to be curative. Competing risk analyses suggest age and risk score as important factors in developing follow-up strategies.

Background: Screening for renal cell carcinoma (RCC) has been identified as a key research priority; however, no randomised control trials have been performed. Value of information analysis can determine whether further research on this topic is of value. Objective: To determine (1) whether current evidence suggests that screening is potentially cost-effective and, if so, (2) in which age/sex groups, (3) identify evidence gaps, and (4) estimate the value of further research to close those gaps. Design, setting, and participants: A decision model was developed evaluating screening in asymptomatic individuals in the UK. A National Health Service perspective was adopted. Intervention: A single focused renal ultrasound scan compared with standard of care (no screening). Outcome measurements and statistical analysis: Expected lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER), discounted at 3.5% per annum. Results and limitations: Given a prevalence of RCC of 0.34% (0.18–0.54%), screening 60-yr-old men resulted in an ICER of £18 092/QALY (€22 843/QALY). Given a prevalence of RCC of 0.16% (0.08–0.25%), screening 60-yr-old women resulted in an ICER of £37 327/QALY (€47 129/QALY). In the one-way sensitivity analysis, the ICER was

Recent randomised trials have demonstrated a survival benefit for a front-line ipilimumab and nivolumab combination therapy, and pembrolizumab and axitinib combination therapy in metastatic clear-cell renal cell carcinoma. The European Association of Urology Guidelines Panel has updated its recommendations based on these studies. PATIENT SUMMARY: Pembrolizumab plus axitinib is a new standard of care for patients diagnosed with kidney cancer spread outside the kidney and who did not receive any prior treatment for their cancer (treatment naive). This applies to all risk groups as determined by the International Metastatic Renal Cell Carcinoma Database Consortium criteria.

Objective: Modality and frequency of image-based renal cell carcinoma (R.C.C.) follow-up strategies are based on risk of recurrence. Using the R.E.C.U.R.-database, frequency of imaging was studied in regard to prognostic risk groups. Furthermore, it was investigated whether imaging modality utilized in contemporary follow-up were associated with outcome after detection of recurrence. Moreover, outcome was compared based on whether the assessment of potential curability was a pre-defined set of criteria’s (per-protocol) or stated by the investigator. Materials and methods: Consecutive non-metastatic R.C.C. patients (n = 1,612) treated with curative intent at 12 institutes across eight European countries between 2006 and 2011 were included. Leibovich or U.I.S.S. risk group, recurrence characteristics, imaging modality, frequency and survival were recorded. Primary endpoints were overall survival (O.S.) after detection of recurrence and frequency of features associated with favourable outcome (non-symptomatic recurrences and detection within the follow-up-programme). Results: Recurrence occurred in 336 patients. Within low, intermediate and high risk for recurrence groups, the frequency of follow-up imaging was highest in the early phase of follow-up and decreased significantly over time (p < 0.001). However, neither the image modality for detection nor ≥ 50% cross-sectional imaging during follow-up were associated with improved O.S. after recurrence. Differences between per protocol and investigator based assessment of curability did not translate into differences in O.S. Conclusions: As expected, the frequency of imaging was highest during early follow-up. Cross-sectional imaging use for detection of recurrences following surgery for localized R.C.C. did not improve O.S. post-recurrence. Prospective studies are needed to determine the value of imaging in follow-up.

Purpose of review Although novel targeted therapies for metastatic renal cell carcinoma (RCC) are emerging, metastasectomy still remains the only potentially curable intervention and plays an important role both in disease control, cancer-specific survival (CSS) and overall survival (OS). A systematic review was conducted in 2014 by the European Association of Urology RCC guidelines panel to summarize evidence on the subject at hand. The purpose of this review is to update the current evidence base. Recent findings A total of 17-19% of initially nonmetastatic patients with later RCC metastasis are potentially curable. Complete metastasectomy still remains the sole curative option, continues to show improved OS and CSS and is suggested to defer time to palliative targeted therapy. Resectability, long time to recurrence, good performance status and oligometastatic disease have better benefit of metastasectomy. Stereotactic radiotherapy remains an excellent option for local tumor control and symptom control in patients with RCC brain and bone metastases. Minimal-invasive options such as thermal ablation are evolving, albeit the evidence base is small. Novel trials are investigating sequencing of metastasectomy and targeted therapy with results pending. Summary Metastasectomy continues to be supported as beneficial for OS, CSS and progression-free survival in patients with good prognostic factors.

The European Association of Urology Renal Cell Carcinoma (RCC) Guideline Panel has prepared evidence-based guidelines and recommendations for the management of RCC.To provide an updated RCC guideline based on standardised methodology including systematic reviews, which is robust, transparent, reproducible, and reliable.For the 2019 update, evidence synthesis was undertaken based on a comprehensive and structured literature assessment for new and relevant data. Where necessary, formal systematic reviews adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were undertaken. Relevant databases (Medline, Cochrane Libraries, trial registries, conference proceedings) were searched until June 2018, including randomised controlled trials (RCTs) and retrospective or controlled studies with a comparator arm, systematic reviews, and meta-analyses. Where relevant, risk of bias (RoB) assessment, and qualitative and quantitative syntheses of the evidence were performed. The remaining sections of the document were updated following a structured literature assessment. Clinical practice recommendations were developed and issued based on the modified GRADE framework.All chapters of the RCC guidelines were updated based on a structured literature assessment, for prioritised topics based on the availability of robust data. For RCTs, RoB was low across studies. For most non-RCTs, clinical and methodological heterogeneity prevented pooling of data. The majority of included studies were retrospective with matched or unmatched cohorts, based on single- or multi-institutional data or national registries. The exception was for the treatment of metastatic RCC, for which there were several large RCTs, resulting in recommendations based on higher levels of evidence.The 2019 RCC guidelines have been updated by the multidisciplinary panel using the highest methodological standards. These guidelines provide the most reliable contemporary evidence base for the management of RCC in 2019.The European Association of Urology Renal Cell Carcinoma Guideline Panel has thoroughly evaluated the available research data on kidney cancer to establish international standards for the care of kidney cancer patients.

Little is known about the natural history of sporadic angiomyolipomas (AMLs); there is uncertainty regarding the indications of treatment and treatment options.To evaluate the indications, effectiveness, harms, and follow-up of different management modalities for sporadic AML to provide guidance for clinical practice.A systematic review of the literature was undertaken, incorporating Medline, Embase, and the Cochrane Library (from 1 January 1990 to 30 June 2017), in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. No restriction on study design was imposed. Patients with sporadic AML were included. The main interventions included active surveillance, surgery (nephron-sparing surgery and radical nephrectomy), selective arterial embolisation, and percutaneous or laparoscopic thermal ablations (radiofrequency, microwaves, or cryoablation). The outcomes included indications for active treatment, AML growth rate, AML recurrence rate, risk of bleeding, post-treatment renal function, adverse events of treatments, and modalities of follow-up. Risk of bias assessment was performed using standard Cochrane methods.Among 2704 articles identified, 43 were eligible for inclusion (zero randomised controlled trials, nine nonrandomised comparative retrospective studies, and 34 single-arm case series). Most studies were retrospective and uncontrolled, and had a moderate to high risk of bias.In active surveillance series, spontaneous bleeding was reported in 2% of patients and active treatment was undertaken in 5%. Active surveillance is the most chosen option in 48% of the cases, followed by surgery in 31% and selective arterial embolisation in 17% of the cases. Selective arterial embolisation appeared to reduce AML volume but required secondary treatment in 30% of the cases. Surgery (particularly nephron-sparing surgery) was the most effective treatment in terms of recurrence and need for secondary procedures. Thermal ablation was an infrequent option. The association between AML size and the risk of bleeding remained unclear; as such the traditional 4-cm cut-off should not per se trigger active treatment. In spite of the limitations and uncertainties relating to the evidence base, the findings may be used to guide and inform clinical practice, until more robust data emerge.Sporadic angiomyolipoma (AML) is a benign tumour of the kidney consisting of a mixture of blood vessels, fat, and muscle. Large tumours may have a risk of spontaneous bleeding. However, the size beyond which these tumours need to be treated remains unclear. Most small AMLs can be monitored without any active treatment. For those who need treatment, options include surgical removal of the tumour or stopping its blood supply (selective embolisation). Surgery has a lower recurrence rate and lower need for a repeat surgical procedure.

A Joint Statement from the European Association of Urology Renal Cell Cancer Guidelines Panel and the International Kidney Cancer Coalition : The Rejection of Ipilimumab and Nivolumab for Renal Cancer by the Committee for Medicinal Products for Human Use Does not Change Evidence-based Guideline Recommendations

Cytoreductive nephrectomy (CN) has been the standard of care in patients with metastatic clear-cell renal cancer who present with the tumour in place. The CARMENA trial compared systemic therapy alone with CN followed by systemic therapy. This article outlines the new guidelines based on these data. PATIENT SUMMARY: The CARMENA trial demonstrates that immediate cytoreductive nephrectomy should no longer be considered the standard of care in patients diagnosed with intermediate and poor risk metastatic renal cell carcinoma when medical treatment is required. However, the psychological burden poor risk patients experience hearing that removal of their primary tumour will not be beneficial, should be carefully considered.

To present the occurrence of metastases and local recurrences in primary non-metastatic patients with renal cell carcinoma (RCC) in a contemporary Swedish population-based cohort. Between 2005 and 2009, a total of 4527 patients were included in the prospective National Swedish Kidney Cancer Register accounting for nearly all RCC patients in Sweden. Among M0 patients, 472 (13 %) had no follow-up data registered within 5-year follow-up time and were excluded from the analysis. In total, 939 (21 %) had distant metastases at presentation with a decrease from 23 to 18 % during the inclusion period. Of 3107 patients with follow-up data and with M0 disease, 623 (20 %) were diagnosed with a tumor recurrence during 5-year follow-up. Mean time to recurrence was 24 months (SD ± 20 months). Among these, 570 patients (92 %) were at primary diagnosis treated with radical nephrectomy, 23 patients (3.7 %) with partial nephrectomy and 12 patients (1.9 %) with minimally invasive treatments. The most frequent sites of metastases were lung (54 %), lymph nodes (22 %) and bone (20 %). The treatment of recurrence was in 50 % systemic treatments, while metastasectomy was performed in 17 % of the patients, out of which 68 % were with a curative intention. In this population-based study, 21 % of the patients had metastatic disease at presentation, with a decreasing trend over the study period. During 5-year follow-up, 20 % of the primary non-metastatic patients had recurrent disease. Of the patients with recurrence, half were given systemic oncological treatment and 17 % underwent metastasectomy.

The randomised phase III clinical trial Checkmate-214 showed a survival superiority for the combination of ipilimumab and nivolumab when compared with the previous standard of care in first-line metastatic/advanced clear cell renal cell carcinoma (RCC) (Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. LBA5, ESMO 2017, 2017). These results change the frontline standard of care for this disease and have implications for the selection of subsequent therapies. For this reason the European Association of Urology RCC guidelines have been updated. Patient summary: The European Association of Urology guidelines will be updated based on the results of the phase III Checkmate-214 clinical trial. The trial showed superior survival for a combination of ipilimumab and nivolumab (IN), compared with the previous standard of care, in intermediate- and poor-risk patients with metastatic clear cell renal cell carcinoma. When IN is not safe or feasible, alternative agents such as sunitinib, pazopanib, and cabozantinib should be considered. Furthermore, at present, the data from the trial are immature in favourable-risk patients. Therefore, sunitinib or pazopanib remains the favoured agent for this subgroup of patients. Based on the Checkmate-214 trial, the European Association of Urology guidelines, which will be updated, recommend ipilimumab and nivolumab (IN) as the standard of care in intermediate- and poor-risk patients with metastatic clear cell renal cell carcinoma. Alternative agents such as sunitinib, pazopanib, and cabozantinib should be considered when IN is not safe or feasible. At present, in favourable-risk patients, the data from the trial are immature. Therefore, sunitinib or pazopanib remains the preferred agent in this subgroup of patients.

Context Extracorporeal shock wave lithotripsy (SWL) and ureteroscopy (URS), with or without intracorporeal lithotripsy, are the most common treatments for upper ureteric stones. With advances in technology, it is unclear which treatment is most effective and/or safest. Objective To systematically review literature reporting benefits and harms of SWL and URS in the management of upper ureteric stones. Evidence acquisition Databases including Medline, Embase, and the Cochrane library were searched from January 2000 to November 2014. All randomised controlled trials (RCTs), quasi-randomised controlled trials, and nonrandomised studies comparing any subtype or variation of URS and SWL were included. The primary benefit outcome was stone-free rate (SFR). The primary harm outcome was complications. Secondary outcomes included retreatment rate, need for secondary, and/or adjunctive procedures. The Cochrane risk of bias tool was used to assess RCTs, and an extended version was used to assess nonrandomised studies. Grading of Recommendations Assessment, Development, and Evaluation was used to assess the quality of evidence. Evidence synthesis Five thousand-three hundred and eighty abstracts and 387 full-text articles were screened. Forty-seven studies met inclusion criteria; 19 (39.6%) were RCTs. No studies on children met inclusion criteria. URS and SWL were compared in 22 studies (4 RCTs, 1 quasi-randomised controlled trial, and 17 nonrandomised studies). Meta-analyses were inappropriate due to data heterogeneity. SFR favoured URS in 9/22 studies. Retreatment rates were higher for SWL compared with URS in all studies but one. Longer hospital stay and adjunctive procedures (most commonly the insertion of a JJ stent) were more common when primary treatment was URS. Complications were reported in 11 out of 22 studies. In eight studies, it was possible to report this as a Clavien-Dindo Grade. Higher complication rates across all grades were reported for URS compared with SWL. For intragroup (intra-SWL and intra-URS) comparative studies, 25 met the inclusion criteria. These studies varied greatly in outcomes measured with data being heterogeneous. Conclusions Compared with SWL, URS was associated with a significantly greater SFR up to 4 wk but the difference was not significant at 3 mo in the included studies. URS was associated with fewer retreatments and need for secondary procedures, but with a higher need for adjunctive procedures, greater complication rates, and longer hospital stay. Patient summary In this paper, the relative benefits and harms of the two most commonly offered treatment options for urinary stones located in the upper ureter were reviewed. We found that both treatments are safe and effective options that should be offered based on individual patient circumstances and preferences.

755 Background: Post-operative follow-up protocols for renal cell carcinoma (RCC) are based on outcomes of the clear cell subtype and often rely on variables not applicable to chromophobe RCC (chRCC), such as Fuhrman nuclear grading. We aimed to evaluate predictors of recurrence to guide follow-up regimes in the context of chRCC. Methods: Combined retrospective analysis of non-metastatic surgical cases with a final diagnosis of chRCC from an institutional database at a UK tertiary high-volume centre (June/2013 to March/2019) and from the international collaborative database RECUR (12 institutes across 8 European countries; 2006 to 2011). TNM risk group, tumour size, histopathological features, cancer specific survival (CSS) and recurrence free survival (RFS) were analysed. Kaplan Meier plots and Cox regression analysis were performed to determine factors associated with recurrence (local or distant). Results: 295 cases were identified (57.3% male, median age 60). After a median follow up of 58 months, 17 (5.8%) recurrences were observed, the majority of which were distant recurrences (n = 13). CSS was 96.3%. Tumours staged ≥pT2b (HR 13.7; 95%CI 3 to 63.1; p = 0.001), with coagulative necrosis (HR 3.9; 95%CI 1.3 to 11.1; p = 0.012) and sarcomatoid differentiation (HR 33; 95%CI 8.1 to 134.6.1; p = 0.000) were more likely to recur during follow-up. Only two cases of pT1a lesions had local recurrence, both after a positive surgical margin. All patients with early recurrences ( < 18 months after surgery; n = 6) had tumours staged ≥pT2b with coagulative necrosis; sarcomatoid differentiation was also present in 3 cases. Conclusions: Recurrence of surgically resected chRCC is not common. For patients with pT1 lesions, negative margins, no coagulative necrosis or sarcomatoid features, prognosis is excellent. Follow up can be curtailed to avoid excess radiation exposure and patient anxiety.

Local treatment of metastases such as metastasectomy or radiotherapy remains controversial in the treatment of metastatic renal cell carcinoma. To investigate the benefits and harms of various local treatments, we did a systematic review of all types of comparative studies on local treatment of metastases from renal cell carcinoma in any organ. Interventions included metastasectomy, radiotherapy modalities, and no local treatment. The results suggest that patients treated with complete metastasectomy have better survival and symptom control (including pain relief in bone metastases) than those treated with either incomplete or no metastasectomy. Nevertheless, the available evidence was marred by high risks of bias and confounding across all studies. Although the findings presented here should be interpreted with caution, they and the identified gaps in knowledge should provide guidance for clinicians and researchers, and directions for further research.