BACKGROUND:Inconsistent, varied, and selective outcome reporting is problematic in localized renal cell cancer (RCC) research. Core outcome sets (COSs) offer a solution by defining a standardized minimum set of outcomes that should be measured and reported in all trials in a specific area of health or health care. OBJECTIVE:We aimed to develop a COS for localized RCC (L-RCC). DESIGN, SETTING AND PARTICIPANTS:COS development was conducted over three phases. Phase 1 identified potentially relevant outcomes via a systematic review and patient interviews. In Phase 2, Phase 1 outcomes were entered into a 2-round online Delphi study, whereby patients, health care professionals (HCPs), and researchers scored each outcome's importance. In Phase 3, a series of meetings were conducted to reach a consensus on defining outcomes and selecting appropriate measurements. RESULTS AND LIMITATIONS:Phase 1 identified 200 outcomes. The outcome list was deduplicated and refined before the Delphi study. Round one of the Delphi was completed by 168 participants, of whom 140 completed Round 2. The consensus meeting series was attended by 20 participants (HCPs, researchers, and patients). The L-RCC-COS consists of 21 agreed-upon outcomes, of which 10 apply to all treatments and 11 are intervention-specific. Consensus meeting participants were exclusively based in Europe; future validation work should determine if the L-RCC-COS outcomes are conceptually transferable to other languages and cultures. CONCLUSIONS:There is a broad agreement from HCPs, researchers, and patients on which outcomes are important and how they should be defined in L-RCC. We developed the L-RCC-COS suitable for effectiveness trials, observational studies, and routine practice. Use of the L-RCC-COS to standardize outcome reporting in clinical trials and real-world evidence data collection will enable more precise and powerful evidence syntheses and reduce research waste.

PURPOSE:The Clinical Genome Resource (ClinGen) Von Hippel-Lindau (VHL) Variant Curation Expert Panel (VCEP) has created variant classification specifications tailored to the VHL gene, including phenotype-driven and evidence-based criteria, utilizing somatic and germline mutational hotspots, along with functional and in silico data. METHODS:Using the American College of Medical Genetics and Genomics guidance and the ClinGen Sequence Variant Interpretation recommendations, the VCEP made substantial modifications to 8 evidence codes (PVS1, PS3, PS4, PM1, BS2, BS3, BS4, and BP5), whereas 14 had minor changes, and 6 were not used (PM3, PP2, BP1, PP4, PP5/BP6). The VHL VCEP applied 2 literature sets of over >428 articles in Clinical Interpretations of Variants in Cancer and >8700 structured annotations using Hypothesis. RESULTS:From 31 pilot variants, 15 remained pathogenic/likely pathogenic, and 9 resolved to benign through the stand-alone benign evidence code, whereas 7 variants with initial uncertain classifications lacking additional evidence, remained uncertain. CONCLUSION:The versioned VHL VCEP Specifications are publicly available in the ClinGen Criteria Specifications Registry and will enhance the transparency and consistency of variant classifications for this highly sequenced hereditary cancer gene.

ObjectiveTo explore patients’ experience of decision making regarding treatment of localised kidney cancer.MethodsA total of 21 patients with localised kidney cancer, across three countries, participated in either four focus groups or seven semi‐structured interviews that lasted on average 2 h. Focus groups and interviews were all conducted in the participants' native language, recorded, transcribed and (if applicable) translated into English. Thematic analysis was used to develop a codebook and identify themes.ResultsAll participants expressed a desire to be actively involved in the treatment decision‐making process. However, due to the emotional toll of the cancer journey, which often necessitates quick decisions, actively engaging in the decision‐making process was described as challenging. The study revealed 12 key themes. These themes included the impact of diagnostic paths, patient characteristics, patient empowerment, health literacy, source of support, fear of recurrence, trust in treatment and healthcare providers, shared decision making (SDM), professional interaction, personal belief system, and organisational and administrative issues.ConclusionsThe findings highlight the complexity of decision making, underscoring the desire for patient involvement, SDM, and clear communication. We reveal a significant gap between research recommendations and clinical practice, emphasising the need to translate research findings to clinical application to enhance patient‐centred care.

Context Immune-oncology strategies are revolutionising the perioperative treatment in several tumour types. The perioperative setting of renal cell carcinoma (RCC) is an evolving field, and the advent of immunotherapy is producing significant advances. Objective To critically review the potential pros and cons of adjuvant and neoadjuvant immune-based therapeutic strategies in RCC, and to provide insights for future research in this field. Evidence acquisition We performed a collaborative narrative review of the existing literature. Evidence synthesis Adjuvant immunotherapy with pembrolizumab is a new standard of care for patients at a higher risk of recurrence after nephrectomy, demonstrating a disease-free survival and overall survival benefit in the phase 3 KEYNOTE-564 trial. Current data do not support neoadjuvant therapy use outside clinical trials. While both adjuvant and neoadjuvant immune-based approaches are driven by robust biological rationale, neoadjuvant immunotherapy may enable a stronger and more durable antitumour immune response. If neoadjuvant single-agent immune checkpoint inhibitors demonstrated limited activity on the primary tumour, immune-based combinations may show increased activity. Overtreatment and a risk of relevant toxicity for patients who are cured by surgery alone are common concerns for both neoadjuvant and adjuvant strategies. Biomarkers helping patient selection and treatment deintensification are lacking in RCC. No results from randomised trials comparing neoadjuvant or perioperative immune-based therapy with adjuvant immunotherapy are available. Conclusions Adjuvant immunotherapy is a new standard of care in RCC. Both neoadjuvant and adjuvant immunotherapy strategies have potential advantages and disadvantages. Optimising perioperative treatment strategies is nuanced, with the role of neoadjuvant immune-based therapies yet to be defined. Given strong biological rationale for a pre/perioperative approach, there is a need for prospective clinical trials to determine clinical efficacy. Research investigating biomarkers aiding patient selection and treatment deintensification strategies is needed. Patient summary Immunotherapy is transforming the treatment of kidney cancer. In this review, we looked at the studies investigating immunotherapy strategies before and/or after surgery for patients with kidney cancer to assess potential pros and cons. We concluded that both neoadjuvant and adjuvant immunotherapy strategies may have potential advantages and disadvantages. While immunotherapy administered after surgery is already a standard of care, immunotherapy before surgery should be better investigated in future studies. Future trials should also focus on the selection of patients in order to spare toxicity for patients who will be cured by surgery alone.

384 Background: Cabozantinib plus nivolumab (CN) is a 1L therapy for aRCC. In the CM9ER trial CN had superior efficacy to sunitinib (SUN) and showed HRQoL benefit. We investigated the relationship between clinical outcomes, treatment and early deterioration in HRQoL dimensions in the CM9ER population. Methods: Using the CM9ER intention-to-treat (ITT) population (median follow-up 32.9 months) we: (a) explored time-to-event outcomes for CN vs SUN (b) identified determinants of HRQoL benefit by performing ordinal regression using the 19-item Functional Assessment of Cancer Therapy – Kidney Symptom Index (FKSI-19) item scores at week 13 (c) investigated relationships between early (week 13) deterioration in FKSI-19 items and clinical outcomes using a cox proportional modeling framework. First, univariate Cox proportional hazard modeling assessed the predictiveness of early FKSI-19 item deterioration (sig. threshold p ≤ 0.20). Items with significant univariate associations with the outcome were included in multivariate regression modeling (sig. threshold p ≤ 0.10). Treatment and baseline stratification factors (geographic region, baseline IMDC score, PD-L1 status) remained in all models. Results: All CM9ER ITT patients (N = 651; CN, 323; SUN, 328) were included. Compared with SUN, CN patients had a longer median duration of treatment (94.6 wks vs 36.5 wks), time to disease progression (83.1 wks vs 42.1 wks) and time to first grade 3/4 adverse event (16.3 wks vs 12.0 wks). FKSI-19 items with early deterioration favoring CN vs SUN ( p ≤ 0.05) were: lack of energy; pain; fatigue; bone pain; weak all over; nausea; bothered by treatment side effects; able to work. The table reports variables significantly associated with clinical outcomes ( p ≤ 0.05). Conclusions: Early deterioration in bone pain and sleep were associated with increased risk of mortality, and early deterioration in pain with reduced risk of toxicity-related discontinuation. We found no association between early FKSI-19 item deterioration and risk of progression or tumor shrinkage. Controlling for other variables, CN (vs SUN) treatment was positively and significantly associated with increased chance of tumor shrinkage, survival and progression-free survival, independent of early HRQoL deterioration. Clinical trial information: NCT03141177 . [Table: see text]

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.

he von Hippel-Lindau (VHL) tumor suppressor gene encodes an adaptor protein that regulates an array of transcription-dependent and -independent cellular and physiological processes. Mutations in this gene cause VHL disease, congenital polycythemia, renal cell carcinoma (RCC), and several other sporadic tumor types. Although different animal models for VHL disease have been adapted, the zebrafish VHL model offers distinct opportunities. Zebrafish vhl mutants develop key aspects of the human disease condition, including activation of the hypoxia-inducible factor (HIF) signaling pathway, polycythemia, excessive neovascularization, macular edema, and pronephric abnormalities resembling early stages of RCC. The zebrafish vhl model offers a platform for the identification of genetic pathways, modifiers, and interactors involved in the development of VHL-associated neoplasms. Vhl mutants represent a unique and clinically relevant in vivo model for studying genotype-phenotype correlations and the identification of prognostic biomarkers. The amenability of zebrafish for chemical genetic screens will not only be helpful to identify novel therapeutic agents but may also reveal novel processes that require regulation by VHL. Citation Format: Ellen van Rooijien, Stefan Schulte-Merker, Ive Logister, Emile Voest, Rachel Giles. A zebrafish model for VHL and hypoxia signaling [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA013.

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 rec-ommended. Pembrolizumab remains the only immune checkpoint inhibitor currently recommended in this setting. Overall survival data are immature and biomarkers to pre-dict 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 kid-ney cancer to reduce the risk of recurrence showed no improvement with these treat-ments. 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.(c) 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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.

CIVIC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC's functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIVIC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications.

653 Background: Kidney cancer (renal cell carcinoma, RCC) has shown a sustained increase in its global prevalence thereby presenting increasing burden to health systems, and most of all, to individual patients and their families. Little is known about the variations in the patient experience and best practices among countries. Although individual national surveys have been held, no conclusions could be drawn about country-level variation in patient experience or best practice. Here, we report on the 3rd biennial Global Patient Survey on the diagnosis, management, and burden of Renal Cell Carcinomas conducted by the International Kidney Coalition (IKCC) and involving its Affiliate Organisations worldwide in 15 languages. The aim of the survey was to improve collective understanding and to contribute toward the reduction of the burden of kidney cancer around the world. Methods: A 35-question survey on the diagnosis, management, and burden of RCC was designed by a multi-country steering committee of patient leaders to identify geographic variations in 6 key dimensions: patient education, experience and awareness, access to care and clinical trials, best practices, quality of life, and unmet psychosocial needs. EAU, ESMO, ASCO and NCCN Guidelines committees provided topics of interest to support evidence-based medicine (eg patient perspective on active surveillance, biopsies, etc) . The survey was distributed to patients with kidney cancer and their caregivers in 15 languages, through social media and IKCC’s 49 Affiliate Organizations and/or allied organizations who are not formal affiliates. It was completed online or in paper form between 26 September 2022 and 31 October 2022. At the time of this abstract submission, the survey was still open for completion. Results: We will present the top-line results of the 2022 survey for the very first time. Survey results will be analyzed using cross-tabulations by an independent third-party organization, and multi-variate analysis of predetermined variable will be performed. The full global report will be presented, as well as individual country reports where at least 100 responses were received. Conclusions: The IKCC and its global affiliates will be using the results to ensure that patients’ voices are heard. Actionable points will suggest future projects. Furthermore, individual countries can use their reports to advance their understanding of patient experiences and to drive improvements in care provision locally.

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.

The International Kidney Cancer Coalition, representing 1·2 million patients with kidney cancer globally, and its medical advisory board commend the comprehensive analysis by David Cella and colleagues 1 Cella D Motzer RJ Suarez C et al. Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open-label, randomised, phase 3 trial. Lancet Oncol. 2022; 23: 292-303 Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar of patient-reported outcomes (PROs) and quality of life (QOL) among patients diagnosed with metastatic renal cell carcinoma that was published in The Lancet Oncology. However, the patient community would like to raise a few additional points of discussion. Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open-label, randomised, phase 3 trialPROs were maintained or improved with nivolumab plus cabozantinib versus sunitinib. Compared with sunitinib, nivolumab plus cabozantinib significantly delayed time to deterioration of patient-reported outcome scores. These results suggest a benefit for nivolumab plus cabozantinib compared with sunitinib in the treatment of patients with advanced renal cell carcinoma. Full-Text PDF Patient-reported outcomes: what really matters to patients? – Authors' replyWe very much appreciate Elshad Hasanov and colleagues' interest in our Article1 and the input from the international community of patients with kidney cancer. We involve the patient community when designing patient-reported outcome (PRO) measures. The points raised by Hasanov and colleagues are important to bear in mind when planning to evaluate new drug treatments for advanced kidney cancer. Late effects of new treatments, including immune checkpoint inhibitors, are important to monitor, particularly when considering long-term benefit. Full-Text PDF

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.

Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome where individuals are predisposed to tumor development in the brain, adrenal gland, kidney, and other organs. It is caused by pathogenic variants in the VHL tumor suppressor gene. Standardized disease information has been difficult to collect due to the rarity and diversity of VHL patients. Over 4100 unique articles published until October 2019 were screened for germline genotype-phenotype data. Patient data were translated into standardized descriptions using Human Genome Variation Society gene variant nomenclature and Human Phenotype Ontology terms and has been manually curated into an open-access knowledgebase called Clinical Interpretation of Variants in Cancer. In total, 634 unique VHL variants, 2882 patients, and 1991 families from 427 papers were captured. We identified relationship trends between phenotype and genotype data using classic statistical methods and spectral clustering unsupervised learning. Our analyses reveal earlier onset of pheochromocytoma/paraganglioma and retinal angiomas, phenotype co-occurrences and genotype-phenotype correlations including hotspots. It confirms existing VHL associations and can be used to identify new patterns and associations in VHL disease. Our database serves as an aggregate knowledge translation tool to facilitate sharing information about the pathogenicity of VHL variants.