Publications by authors named "Axel Bex"

215 Publications

Perioperative impact of body mass index on upper urinary tract and renal robot-assisted surgery: a single high-volume centre experience.

J Robot Surg 2021 Jul 27. Epub 2021 Jul 27.

Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, Hampstead, London, UK.

To assess the impact of body mass index (BMI) on peri-operative outcomes of kidney and upper tract robot-assisted surgery. Medical audit of patients who underwent robot-assisted kidney and upper tract cancer surgery at a single institution between 2017 and 2019, categorized on BMI into obese patients with a BMI ≥ 30 kg/m and a control group with BMI < 25 kg/m. Patient and tumour characteristics, surgery time, intraoperative blood loss, intraoperative adverse events (AE) according to the European Association of Urology Intraoperative Adverse Incidents Classification (EAUiaiC), conversion- to-open/radical rate as well as 30-day postoperative AE according to Clavien-Dindo (CD) and length of inpatient stay were analyzed. 366 patients were identified, 141 with a BMI < 25 (normal-weight) and 225 BMI ≥ 30 (obesity). There were no significant differences between the groups in terms of age, gender, comorbidities, tumour size, TNM stage and type of surgery. Obese patients had a higher estimated blood loss (198.05 ml), surgery time (171.75 min), intraoperative AE (all grades) (14.67%, 95% CI (0.10-0.19) as well as adherent perinephric fat (APF) (14.22%, 95% CI (0.09-0.19)) in contrast to the control group (86.85 ml, 148.29 min, 7.04% and 2.12%, respectively). Hospital stay, major intraoperative AE (≥ 3) and major postoperative AE (CD > 2) distributed equally between groups. Robotic kidney and upper tract surgery in obese patients showed an increase in surgery time and blood loss potentially related to APF. However, obesity was not associated with conversion to open surgery or radical nephrectomy in nephron-sparing procedures, length of stay, major intraoperative AE or postoperative complications.
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http://dx.doi.org/10.1007/s11701-021-01285-6DOI Listing
July 2021

High-risk Surgically Resected Renal Cell Carcinoma: Is There a Role for Adjuvant VEGF-TKI Inhibitors?

Curr Probl Cancer 2021 Jun 5:100759. Epub 2021 Jun 5.

Urological Research Institute (URI), Unit of Urology, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Milan, Italy.

The indications for adjuvant vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) agents after curative intent nephrectomy for renal cell carcinoma are still a matter of debate. The ASSURE, PROTECT and ATLAS trials have failed to meet their primary end-points. Conversely, S-TRAC has shown a disease free survival (DFS) benefit. To date, meta-analyses have repeatedly proved the absence of a clinical benefit, in term of DFS and overall survival (OS). Nevertheless, the results of the SORCE trial have been recently released and might add valuable information. We pooled the results of all five reported trials testing for any potential DFS and OS benefits associated with VEGF-TKI use. Interestingly, for pooled DFS we found a marginal positive hazard ratio (HR) of 0.92 (95% confidence interval [CI] 0.85-1.00; P-value = 0.049) in favor of adjuvant VEGF-TKI agents. This benefit was more pronounced for DFS in the sub-groups of only high-risk patients (HR: 0.89, 95% CI 0.80-0.99; P-value = 0.026), but less pronounced in clear-cell only subgroup (HR 0.92, 95% CI: 0.85-1.00; P-value = 0.044). Overall survival benefit was instead not reached. However, pooled relative risk for high-grade (grade ≥3 according to CTCAE classification) adverse events was irremediably high, 2.56 (95% CI: 2.15-3.04; P-value < 0.001). Given the marginal benefit in terms of DFS and the drawback of high-grade adverse events, even after the SORCE trial publication, adjuvant VEGF-TKIs therapy cannot be considered in the whole group of patients with non-metastatic high-risk renal cell carcinoma after surgery.
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http://dx.doi.org/10.1016/j.currproblcancer.2021.100759DOI Listing
June 2021

The 2021 Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibitor-based Combination Therapies for Treatment-naive Metastatic Clear-cell Renal Cell Carcinoma Are Standard of Care.

Eur Urol 2021 Oct 29;80(4):393-397. Epub 2021 May 29.

The Royal Free London NHS Foundation Trust, London, UK; UCL Division of Surgery and Interventional Science, London, UK; Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address:

The recent randomized controlled phase III CLEAR trial results are the last to complement immune checkpoint inhibitor (ICI)-based doublet combination therapies for treatment-naïve 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.
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http://dx.doi.org/10.1016/j.eururo.2021.04.042DOI Listing
October 2021

Growth and renal function dynamics of renal oncocytomas in patients on active surveillance.

BJU Int 2021 May 28. Epub 2021 May 28.

Division of Surgery and Interventional Science, University College London, London, UK.

Objectives: To study the natural history of renal oncocytomas and address indications for intervention by determining how growth is associated with renal function over time, the reasons for surgery and ablation, and disease-specific survival.

Patients And Methods: The study was conducted in a retrospective cohort of consecutive patients with renal oncocytoma on active surveillance reviewed at the Specialist Centre for Kidney Cancer at the Royal Free London NHS Foundation Trust (2012 to 2019). Comparison between groups was performed using Mann-Whitney U-tests and chi-squared tests. A mixed-effects model with a random intercept for patient was used to study the longitudinal association between tumour size and estimated glomerular filtration rate (eGFR).

Results: Longitudinal data from 98 patients with 101 lesions were analysed. Most patients were men (68.3%) and the median (interquartile range [IQR]) age was 69 (13) years. The median (IQR) follow-up was 29 (26) months. Most lesions were small renal masses, and 24% measured over 4 cm. Over half (64.4%) grew at a median (IQR) rate of 2 (4) mm per year. No association was observed between tumour size and eGFR over time (P = 0.871). Nine lesions (8.9%) were subsequently treated. Two deaths were reported, neither were related to the diagnosis of renal oncocytoma.

Conclusion: Natural history data from the largest active surveillance cohort of renal oncocytomas to date show that renal function does not seem to be negatively impacted by growing oncocytomas, and confirms clinical outcomes are excellent after a median follow-up of over 2 years. Active surveillance should be considered the 'gold standard' management of renal oncocytomas up to 7cm.
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http://dx.doi.org/10.1111/bju.15499DOI Listing
May 2021

The European Association of Urology COVID Intermediate-priority Group is Poorly Predictive of Pathological High Risk Among Patients with Renal Tumours.

Eur Urol 2021 Aug 20;80(2):265-267. Epub 2021 May 20.

UCL Medical School, University College London, London, UK; Specialist Centre For Kidney Cancer, Royal Free London NHS Foundation Trust, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2021.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136273PMC
August 2021

How to Cost the Implementation of Major System Change for Economic Evaluations: Case Study Using Reconfigurations of Specialist Cancer Surgery in Part of London, England.

Appl Health Econ Health Policy 2021 May 19. Epub 2021 May 19.

Research Department of Primary Care and Population Health, University College London, London, UK.

Background: Studies have been published regarding the impact of major system change (MSC) on care quality and outcomes, but few evaluate implementation costs or include them in cost-effectiveness analysis (CEA). This is despite large potential costs of MSC: change planning, purchasing or repurposing assets, and staff time. Implementation costs can influence implementation decisions. We describe our framework and principles for costing MSC implementation and illustrate them using a case study.

Methods: We outlined MSC implementation stages and identified components, using a framework conceived during our work on MSC in stroke services. We present a case study of MSC of specialist surgery services for prostate, bladder, renal and oesophagogastric cancers, focusing on North Central and North East London and West Essex. Health economists collaborated with qualitative researchers, clinicians and managers, identifying key reconfiguration stages and expenditures. Data sources (n = approximately 100) included meeting minutes, interviews, and business cases. National Health Service (NHS) finance and service managers and clinicians were consulted. Using bottom-up costing, items were identified, and unit costs based on salaries, asset costs and consultancy fees assigned. Itemised costs were adjusted and summed.

Results: Cost components included options appraisal, bidding process, external review; stakeholder engagement events; planning/monitoring boards/meetings; and making the change: new assets, facilities, posts. Other considerations included hospital tariff changes; costs to patients; patient population; and lifetime of changes. Using the framework facilitated data identification and collection. The total adjusted implementation cost was estimated at £7.2 million, broken down as replacing robots (£4.0 million), consultancy fees (£1.9 million), staff time costs (£1.1 million) and other costs (£0.2 million).

Conclusions: These principles can be used by funders, service providers and commissioners planning MSC and researchers evaluating MSC. Health economists should be involved early, alongside qualitative and health-service colleagues, as retrospective capture risks information loss. These analyses are challenging; many cost factors are difficult to identify, access and measure, and assumptions regarding lifetime of the changes are important. Including implementation costs in CEA might make MSC appear less cost effective, influencing future decisions. Future work will incorporate this implementation cost into the full CEAs of the London Cancer MSC.

Trial Registration: Not applicable.
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http://dx.doi.org/10.1007/s40258-021-00660-6DOI Listing
May 2021

Radical Nephrectomy: The Widening Gap Between Evolution of Technique and Evidence.

Eur Urol 2021 Oct 13;80(4):440-441. Epub 2021 May 13.

Department of Urology, The Royal Free London NHS Foundation Trust, London, UK; Division of Surgery and Interventional Science, University College London, London, UK.

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http://dx.doi.org/10.1016/j.eururo.2021.04.038DOI Listing
October 2021

Impact of the first surge of the COVID-19 pandemic on a tertiary referral centre for kidney cancer.

BJU Int 2021 May 8. Epub 2021 May 8.

Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, London, UK.

Objective: To analyse the impact of the COVID-19 pandemic on a centralized specialist kidney cancer care pathway.

Materials And Methods: We conducted a retrospective analysis of patient and pathway characteristics including prioritization strategies at the Specialist Centre for Kidney Cancer located at the Royal Free London NHS Foundation Trust (RFH) before and during the surge of COVID-19.

Results: On 18 March 2020 all elective surgery was halted at RFH to redeploy resources and staff for the COVID-19 surge. Prioritizing of patients according to European Association of Urology guidance was introduced. Clinics and the specialist multidisciplinary team (SMDT) meetings were maintained with physical distancing, kidney surgery was moved to a COVID-protected site, and infection prevention measurements were enforced. During the 7 weeks of lockdown (23 March to 10 May 2020), 234 cases were discussed at the SMDT meetings, 53% compared to the 446 cases discussed in the 7 weeks pre-lockdown. The reduction in referrals was more pronounced for small and asymptomatic renal masses. Of 62 low-priority cancer patients, 27 (43.5%) were deferred. Only one (4%) COVID-19 infection occurred postoperatively, and the patient made a full recovery. No increase in clinical or pathological upstaging could be detected in patients who underwent deferred surgery compared to pre-COVID practice.

Conclusion: The first surge of the COVID-19 pandemic severely impacted diagnosis, referral and treatment of kidney cancer at a tertiary referral centre. With a policy of prioritization and COVID-protected pathways, capacity for time-sensitive oncological interventions was maintained and no immediate clinical harm was observed.
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http://dx.doi.org/10.1111/bju.15441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239749PMC
May 2021

Pattern, timing and predictors of recurrence after surgical resection of chromophobe renal cell carcinoma.

World J Urol 2021 Apr 13. Epub 2021 Apr 13.

Division of Surgery and Interventional Science, University College London, London, UK.

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1007/s00345-021-03683-9DOI Listing
April 2021

Should patients with low-risk renal cell carcinoma be followed differently after nephron-sparing surgery vs radical nephrectomy?

BJU Int 2021 Sep 26;128(3):386-394. Epub 2021 Apr 26.

UCL Division of Surgical and Interventional Science, Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, London, UK.

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.
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http://dx.doi.org/10.1111/bju.15415DOI Listing
September 2021

Editorial: Standard and future in the treatment of renal cell carcinoma.

Curr Opin Urol 2021 05;31(3):226-227

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1097/MOU.0000000000000877DOI Listing
May 2021

Increasing the evidence for surveillance of metastatic renal cancer.

Authors:
Axel Bex

Cancer 2021 Jul 25;127(13):2184-2186. Epub 2021 Mar 25.

Specialist Center for Kidney Cancer, Royal Free London National Health Service Foundation Trust, London, United Kingdom.

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http://dx.doi.org/10.1002/cncr.33490DOI Listing
July 2021

Perioperative therapy in renal cancer in the era of immune checkpoint inhibitor therapy.

Curr Opin Urol 2021 05;31(3):262-269

Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust.

Purpose Of Review: Immune checkpoint inhibitor (ICI) combination therapy has revolutionized therapy of metastatic renal cancer. The success of immunotherapy has renewed an interest to study these agents in adjuvant and neoadjuvant settings and prior to cytoreductive nephrectomy. This narrative review will give an overview of ongoing trials and early translational research outcomes.

Recent Findings: In nonmetastatic renal cell carcinoma (RCC), five phase 3 adjuvant and neoadjuvant trials with ICI monotherapy or combinations are ongoing with atezolizumab (IMmotion 010; NCT03024996), pembrolizumab (KEYNOTE-564; NCT03142334), nivolumab (PROSPER; NCT03055013), nivolumab with or without ipilimumab (CheckMate 914; NCT03138512) and durvalumab with or without tremelimumab (RAMPART; NCT03288532). Phase 1b/2 neoadjuvant trials demonstrate safety, efficacy and dynamic changes of immune infiltrates and provide rationales for neoadjuvant trial concepts as well as prediction of response to therapy. In primary metastatic RCC, two phase 3 trials investigate the role of deferred cytoreductive nephrectomy following pretreatment with ICI combination (NORDICSUN; NCT03977571 and PROBE; NCT04510597).

Summary: The outcomes of the major phase 3 trials are awaited as early as 2023. Meanwhile, translational data from phase 1b/2 studies enhance our understanding of the tumour immune microenvironment and its dynamic changes.
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http://dx.doi.org/10.1097/MOU.0000000000000868DOI Listing
May 2021

Outcome after resection of occult and non-occult lymph node metastases at the time of nephrectomy.

World J Urol 2021 Feb 25. Epub 2021 Feb 25.

Department of Urology, Renal Cancer Unit, Royal Free Hospital, London, UK.

Purpose: There is sparse evidence on outcomes of resected occult LN metastases at the time of nephrectomy (synchronous disease). We sought to analyse a large international cohort of patients and to identify clinico-pathological predictors of long-term survival.

Materials And Methods: We collected data of consecutive patients who underwent nephrectomy and LND for T cN0-1pN1 and cM0-1 RCC at 7 referral centres between 1988 and 2019. Patients were stratified into four clinico-pathological groups: (1) cN0cM0-pN1, (2) cN1cM0-pN1(limited, 1-3 positive nodes), (3) cN1cM0-pN1(extensive, > 3 positive nodes), and (4) cM1-pN1. Overall survival (OS) was estimated using the Kaplan-Meier method, and associations with all-cause mortality (ACM) were evaluated using Cox models with multiple imputations.

Results: Of the 4370 patients with LND, 292 patients with pN1 disease were analysed. Median follow-up was 62 months, during which 171 patients died. Median OS was 21 months (95% CI 17-30 months) and the 5-year OS rate was 24% (95% CI 18-31%). Patients with cN0cM0-pN1 disease had a median OS of 57 months and a 5-year OS rate of 43%. 5-year OS (median OS) decreased to 29% (33 months) in cN1cM0-pN1(limited) and to 23% (23 months) in cN1cM0-pN1(extensive) patients. Those with cM1-pN1 disease had the worst prognosis, with a 5-year OS rate of 13% (9 months). On multivariable analysis, age (p = 0.034), tumour size (p = 0.02), grade (p = 0.02) and clinico-pathological group (p < 0.05) were significant predictors of ACM.

Conclusion: Depending on clinico-pathological group, grade and tumour size, 5-year survival of patients with LN metastases varies from 13 to 43%. Patients with resected occult lymph node involvement (cN0/pN1 cM0) have the best prognosis with a considerable chance of long-term survival.
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http://dx.doi.org/10.1007/s00345-021-03633-5DOI Listing
February 2021

T cells expanded from renal cell carcinoma display tumor-specific CD137 expression but lack significant IFN-γ, TNF-α or IL-2 production.

Oncoimmunology 2021 01 21;10(1):1860482. Epub 2021 Jan 21.

Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Metastatic renal cell carcinoma (RCC) has a poor prognosis. Recent advances have shown beneficial responses to immune checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies. As only a subset of RCC patients respond, alternative strategies should be explored. Patients refractory to anti-PD-1 therapy may benefit from autologous tumor-infiltrating lymphocyte (TIL) therapy. Even though efficient TIL expansion was reported from RCC lesions, it is not well established how many RCC TIL products are tumor-reactive, how well they produce pro-inflammatory cytokines in response to autologous tumors, and whether their response correlates with the presence of specific immune cells in the tumor lesions. We here compared the immune infiltrate composition of RCC lesions with that of autologous kidney tissue of 18 RCC patients. Tcell infiltrates were increased in the tumor lesions, and CD8 Tcell infiltrates were primarily of effector memory phenotype. Nine out of 16 (56%) tested TIL products we generated were tumor-reactive, as defined by CD137 upregulation after exposure to autologous tumor digest. Tumor reactivity was found in particular in TIL products originating from tumors with ahigh percentage of infiltrated Tcells compared to autologous kidney, and increased CD25 expression on CD8 Tcells. Importantly, although TIL products had the capacity to produce the key effector cytokines IFN-γ, TNF-α or IL-2, they failed to produce significant amounts in response to autologous tumor digests. In conclusion, TIL products from RCC lesions contain tumor-reactive Tcells. Their restricted tumor-specific cytokine production requires further investigation of immunosuppressive factors in RCC and subsequent optimization of RCC-derived TIL culture conditions.
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http://dx.doi.org/10.1080/2162402X.2020.1860482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833735PMC
January 2021

Prevalence, Disease-free, and Overall Survival of Contemporary Patients With Renal Cell Carcinoma Eligible for Adjuvant Checkpoint Inhibitor Trials.

Clin Genitourin Cancer 2021 04 7;19(2):e92-e99. Epub 2021 Jan 7.

Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, UCL Division of Surgical and Interventional Science, London, UK; Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address:

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.
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http://dx.doi.org/10.1016/j.clgc.2020.12.005DOI Listing
April 2021

Radiomics to better characterize small renal masses.

World J Urol 2021 Aug 26;39(8):2861-2868. Epub 2021 Jan 26.

Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, London, UK.

Purpose: Radiomics is a specific field of medical research that uses programmable recognition tools to extract objective information from standard images to combine with clinical data, with the aim of improving diagnostic, prognostic, and predictive accuracy beyond standard visual interpretation. We performed a narrative review of radiomic applications that may support improved characterization of small renal masses (SRM). The main focus of the review was to identify and discuss methods which may accurately differentiate benign from malignant renal masses, specifically between renal cell carcinoma (RCC) subtypes and from angiomyolipoma without visible fat (fat-poor AML) and oncocytoma. Furthermore, prediction of grade, sarcomatoid features, and gene mutations would be of importance in terms of potential clinical utility in prognostic stratification and selecting personalised patient management strategies.

Methods: A detailed search of original articles was performed using the PubMed-MEDLINE database until 20 September 2020 to identify the English literature relevant to radiomics applications in renal tumour assessment. In total, 42 articles were included in the analysis in 3 main categories related to SRM: prediction of benign versus malignant SRM, subtypes, and nuclear grade, and other features of aggressiveness.

Conclusion: Overall, studies reported the superiority of radiomics over expert radiological assessment, but were mainly of retrospective design and therefore of low-quality evidence. However, it is clear that radiomics is an attractive modality that has the potential to improve the non-invasive diagnostic accuracy of SRM imaging and prediction of its natural behaviour. Further prospective validation studies of radiomics are needed to augment management algorithms of SRM.
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http://dx.doi.org/10.1007/s00345-021-03602-yDOI Listing
August 2021

Major Urological Cancer Surgery for Patients is Safe and Surgical Training Should Be Encouraged During the COVID-19 Pandemic: A Multicentre Analysis of 30-day Outcomes.

Eur Urol Open Sci 2021 Mar 9;25:39-43. Epub 2021 Jan 9.

Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, London, UK.

COVID-19 has resulted in the deferral of major surgery for genitourinary (GU) cancers with the exception of cancers with a high risk of progression. We report outcomes for major GU cancer operations, namely radical prostatectomy (RP), radical cystectomy (RC), radical nephrectomy (RN), partial nephrectomy (PN), and nephroureterectomy performed at 13 major GU cancer centres across the UK between March 1 and May 5, 2020. A total of 598 such operations were performed. Four patients (0.7%) developed COVID-19 postoperatively. There was no COVID-19-related mortality at 30 d. A minimally invasive approach was used in 499 cases (83.4%). A total of 228 cases (38.1%) were described as training procedures. Training case status was not associated with a higher American Society of Anesthesiologists (ASA) score ( =  0.194) or hospital length of stay (LOS;  >  0.05 for all operation types). The risk of contracting COVID-19 was not associated with longer hospital LOS ( =  0.146), training case status ( =  0.588), higher ASA score ( =  0.295), or type of hospital site ( =  0.303). Our results suggest that major surgery for urological cancers remains safe and training should be encouraged during the ongoing COVID-19 pandemic provided appropriate countermeasures are taken. These real-life data are important for policy-makers and clinicians when counselling patients during the current pandemic.

Patient Summary: We collected outcome data for major operations for prostate, bladder, and kidney cancers during the COVID-19 pandemic. These surgeries remain safe and training should be encouraged during the ongoing pandemic provided appropriate countermeasures are taken. Our real-life results are important for policy-makers and clinicians when counselling patients during the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.euros.2021.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796655PMC
March 2021

Novel Liquid Biomarkers and Innovative Imaging for Kidney Cancer Diagnosis: What Can Be Implemented in Our Practice Today? A Systematic Review of the Literature.

Eur Urol Oncol 2021 Feb 3;4(1):22-41. Epub 2021 Jan 3.

European Association of Urology (EAU) Young Academic Urologists (YAU) Renal Cancer Working Group; Department of Urology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Division of Experimental Oncology, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.

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.
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http://dx.doi.org/10.1016/j.euo.2020.12.011DOI Listing
February 2021

Summary from the Kidney Cancer Association's Inaugural Think Thank: Coalition for a Cure.

Clin Genitourin Cancer 2021 04 14;19(2):167-175. Epub 2020 Nov 14.

Urologic Oncology Branch, Center for Cancer Research, Mayo Clinic, Rochester, MN.

Close to 74,000 cases of renal cell carcinoma (RCC) are diagnosed each year in the United States. The past 2 decades have shown great developments in surgical techniques, targeted therapy and immunotherapy agents, and longer complete response rates. However, without a global cure, there is still room for further advancement in improving patient care in this space. To address some of the gaps restricting this progress, the Kidney Cancer Association brought together a group of 27 specialists across the areas of clinical care, research, industry, and advocacy at the inaugural "Think Tank: Coalition for a Cure" session. Topics addressed included screening, imaging, rarer RCC subtypes, combination drug therapy options, and patient response. This commentary summarizes the discussion of these topics and their respective clinical challenges, along with a proposal of projects for collaboration in overcoming those needs and making a greater impact on care for patients with RCC moving forward.
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http://dx.doi.org/10.1016/j.clgc.2020.10.005DOI Listing
April 2021

Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Nivolumab plus Cabozantinib Joins Immune Checkpoint Inhibition Combination Therapies for Treatment-naïve Metastatic Clear-Cell Renal Cell Carcinoma.

Eur Urol 2021 03 24;79(3):339-342. Epub 2020 Dec 24.

The Royal Free London NHS Foundation Trust, London, UK; UCL Division of Surgery and Interventional Science, University College London, London, UK; Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address:

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.
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http://dx.doi.org/10.1016/j.eururo.2020.12.005DOI Listing
March 2021

Real-world Data of Nivolumab for Patients With Advanced Renal Cell Carcinoma in the Netherlands: An Analysis of Toxicity, Efficacy, and Predictive Markers.

Clin Genitourin Cancer 2021 06 14;19(3):274.e1-274.e16. Epub 2020 Oct 14.

Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, London, United Kingdom.

Background: Nivolumab, a programmed death 1 inhibitor, has been approved as second-line treatment for advanced renal cell carcinoma (RCC) in Europe since 2016. We investigated the toxicity and efficacy of nivolumab as well as potential predictive biomarkers in the Dutch population.

Patients And Methods: This was a retrospective, multicenter study of the Dutch national registry of nivolumab for the treatment of advanced RCC. The main outcome parameters included toxicity, objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and time to treatment failure (TTF). In addition, potential predictive and prognostic biomarkers for outcomes were evaluated.

Results: Data on 264 patients were available, of whom 42% were International Metastatic RCC Database Consortium (IMDC) poor risk at start of nivolumab, 16% had ≥ 3 lines of previous therapy, 7% had non-clear-cell RCC, 11% had brain metastases, and 20% were previously treated with everolimus. Grade 3/4 immune-related adverse events occurred in 15% of patients. The median OS was 18.7 months (95% confidence interval, 13.7-23.7 months). Progression occurred in 170 (64.4%) of 264 patients, with a 6-and 12-months TTP of 49.8% and 31.1%, respectively. The ORR was 18.6% (49 of 264; 95% confidence interval, 14%-23%). Elevated baseline lymphocytes were associated with improved PFS (P = .038) and elevated baseline lactate dehydrogenase with poor OS, PFS, and TTF (P = .000). On-treatment increase in eosinophils by week 8 predicted improved OS (P = .003), PFS (P = .000), and TTF (P = .014), whereas a decrease of neutrophils was associated with significantly better TTF (P = .023).

Conclusions: The toxicity and efficacy of nivolumab for metastatic RCC after previous lines of therapy are comparable with the results in the pivotal phase III trial and other real-world data. On-treatment increase in eosinophil count is a potential biomarker for efficacy and warrants further investigation.
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http://dx.doi.org/10.1016/j.clgc.2020.10.003DOI Listing
June 2021

A cohort study of 30 day mortality after NON-EMERGENCY surgery in a COVID-19 cold site.

Int J Surg 2020 Dec 24;84:57-65. Epub 2020 Oct 24.

Department of Urology, University College London Hospital NHS Foundation Trust, London, UK; Division of Surgery and Interventional Science, University College London, London, UK.

Background: Two million non-emergency surgeries are being cancelled globally every week due to the COVID-19 pandemic, which will have a major impact on patients and healthcare systems.

Methods: During the peak of the pandemic in the United Kingdom, we set up a multicentre cancer network amongst 14 National Health Service institutions, performing urological, thoracic, gynaecological and general surgical urgent and cancer operations at a central COVID-19 cold site. This is a cohort study of 500 consecutive patients undergoing surgery in this network. The primary outcome was 30-day mortality from COVID-19. Secondary outcomes included all-cause mortality and post-operative complications at 30-days.

Results: 500 patients underwent surgery with median age 62.5 (IQR 51-71). 65% were male, 60% had a known diagnosis of cancer and 61% of surgeries were considered complex or major. No patient died from COVID-19 at 30-days. 30-day all-cause mortality was 3/500 (1%). 10 (2%) patients were diagnosed with COVID-19, 4 (1%) with confirmed laboratory diagnosis and 6 (1%) with probable COVID-19. 33/500 (7%) of patients developed Clavien-Dindo grade 3 or higher complications, with 1/33 (3%) occurring in a patient with COVID-19.

Conclusion: It is safe to continue cancer and urgent surgery during the COVID-19 pandemic with appropriate service reconfiguration.
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http://dx.doi.org/10.1016/j.ijsu.2020.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584883PMC
December 2020

The Impact of Histological Subtype on the Incidence, Timing, and Patterns of Recurrence in Patients with Renal Cell Carcinoma After Surgery-Results from RECUR Consortium.

Eur Urol Oncol 2021 Jun 24;4(3):473-482. Epub 2020 Oct 24.

Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, UCL Division of Surgical and Interventional Science, London, UK; Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

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 nonmetastatic 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.
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http://dx.doi.org/10.1016/j.euo.2020.09.005DOI Listing
June 2021

Targeted therapy for metastatic renal cell carcinoma.

Cochrane Database Syst Rev 2020 10 14;10:CD012796. Epub 2020 Oct 14.

Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden.

Background: Several comparative randomised controlled trials (RCTs) have been performed including combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors since the publication of a Cochrane Review on targeted therapy for metastatic renal cell carcinoma (mRCC) in 2008. This review represents an update of that original review.

Objectives: To assess the effects of targeted therapies for clear cell mRCC in patients naïve to systemic therapy.

Search Methods: We performed a comprehensive search with no restrictions on language or publication status. The date of the latest search was 18 June 2020.

Selection Criteria: We included randomised controlled trials, recruiting patients with clear cell mRCC naïve to previous systemic treatment. The index intervention was any TKI-based targeted therapy.

Data Collection And Analysis: Two review authors independently assessed the included studies and extracted data for the primary outcomes: progression-free survival (PFS), overall survival (OS) and serious adverse events (SAEs); and the secondary outcomes: health-related quality of life (QoL), response rate and minor adverse events (AEs). We performed statistical analyses using a random-effects model and rated the certainty of evidence according to the GRADE approach.

Main Results: We included 18 RCTs reporting on 11,590 participants randomised across 18 comparisons. This abstract focuses on the primary outcomes of select comparisons. 1. Pazopanib versus sunitinib Pazopanib may result in little to no difference in PFS as compared to sunitinib (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.90 to 1.23; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 18 fewer participants experiencing PFS (95% CI 76 fewer to 38 more) per 1000 participants. Pazopanib may result in little to no difference in OS compared to sunitinib (HR 0.92, 95% CI 0.80 to 1.06; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 27 more OSs (95% CI 19 fewer to 70 more) per 1000 participants. Pazopanib may result in little to no difference in SAEs as compared to sunitinib (risk ratio (RR) 1.01, 95% CI 0.94 to 1.09; 1 study, 1102 participants; low-certainty evidence). Based on the control event risk of 734 per 1000 in this trial, this corresponds to 7 more participants experiencing SAEs (95% CI 44 fewer to 66 more) per 1000 participants. 2. Sunitinib versus avelumab and axitinib Sunitinib probably reduces PFS as compared to avelumab plus axitinib (HR 1.45, 95% CI 1.17 to 1.80; 1 study, 886 participants; moderate-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 130 fewer participants experiencing PFS (95% CI 209 fewer to 53 fewer) per 1000 participants. Sunitinib may result in little to no difference in OS (HR 1.28, 95% CI 0.92 to 1.79; 1 study, 886 participants; low-certainty evidence). Based on the control event risk of 890 per 1000 in this trial at 12 months, this would result in 29 fewer OSs (95% CI 78 fewer to 8 more) per 1000 participants. Sunitinib may result in little to no difference in SAEs (RR 1.01, 95% CI 0.93 to 1.10; 1 study, 873 participants; low-certainty evidence). Based on the control event risk of 705 per 1000 in this trial, this corresponds to 7 more SAEs (95% CI 49 fewer to 71 more) per 1000 participants.  3. Sunitinib versus pembrolizumab and axitinib Sunitinib probably reduces PFS as compared to pembrolizumab plus axitinib (HR 1.45, 95% CI 1.19 to 1.76; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 590 per 1000 in this trial at 12 months, this corresponds to 125 fewer participants experiencing PFS (95% CI 195 fewer to 56 fewer) per 1000 participants. Sunitinib probably reduces OS (HR 1.90, 95% CI 1.36 to 2.65; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 880 per 1000 in this trial at 12 months, this would result in 96 fewer OSs (95% CI 167 fewer to 40 fewer) per 1000 participants. Sunitinib may reduce SAEs as compared to pembrolizumab plus axitinib (RR 0.90, 95% CI 0.81 to 1.02; 1 study, 854 participants; low-certainty evidence) although the CI includes the possibility of no effect. Based on the control event risk of 604 per 1000 in this trial, this corresponds to 60 fewer SAEs (95% CI 115 fewer to 12 more) per 1000 participants.  4. Sunitinib versus nivolumab and ipilimumab Sunitinib may reduce PFS as compared to nivolumab plus ipilimumab (HR 1.30, 95% CI 1.11 to 1.52; 1 study, 847 participants; low-certainty evidence). Based on the control event risk of 280 per 1000 in this trial at 30 months' follow-up, this corresponds to 89 fewer PFSs (95% CI 136 fewer to 37 fewer) per 1000 participants. Sunitinib reduces OS (HR 1.52, 95% CI 1.23 to 1.89; 1 study, 847 participants; high-certainty evidence). Based on the control event risk 600 per 1000 in this trial at 30 months, this would result in 140 fewer OSs (95% CI 219 fewer to 67 fewer) per 1000 participants. Sunitinib probably increases SAEs (RR 1.37, 95% CI 1.22 to 1.53; 1 study, 1082 participants; moderate-certainty evidence). Based on the control event risk of 457 per 1000 in this trial, this corresponds to 169 more SAEs (95% CI 101 more to 242 more) per 1000 participants.

Authors' Conclusions: Based on the low to high certainty of evidence, several combinations of immune checkpoint inhibitors appear to be superior to single-agent targeted therapy in terms of PFS and OS, and with a favourable AE profile. Some single-agent targeted therapies demonstrated a similar or improved oncological outcome compared to others; minor differences were observed for AE within this group. The certainty of evidence was variable ranging from high to very low and all comparisons were based on single trials.
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http://dx.doi.org/10.1002/14651858.CD012796.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094280PMC
October 2020

Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial.

J Clin Oncol 2020 12 14;38(34):4064-4075. Epub 2020 Oct 14.

Medical Research Council Clinical Trials Unit at University College London (UCL), Institute of Clinical Trials and Methodology, London, United Kingdom.

Purpose: SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence.

Patients And Methods: We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo.

Results: Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, -0.49 to 0.48 year; = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib.

Conclusion: Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.
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http://dx.doi.org/10.1200/JCO.20.01800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768344PMC
December 2020

Trends in urologic oncology clinical practice and medical education under COVID-19 pandemic: An international survey of senior clinical and academic urologists.

Urol Oncol 2020 12 7;38(12):929.e1-929.e10. Epub 2020 Oct 7.

Department of Urology, Chaim Sheba Medical Center, Ramat Gan, Israel, The Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel.

Objective: Ad-hoc guidelines for managing the COVID-19 pandemic are published worldwide. We investigated international applications of such policies in the urologic-oncology community.

Methods: A 20-item survey was e-mailed via SurveyMonkey to 100 international senior urologic-oncology surgeons. Leaders' policies regarding clinical/surgical management and medical education were surveyed probing demographics, affiliations, urologic-oncologic areas of interest, and current transportation restrictions. Data on COVID-19 burden were retrieved from the ECDC. Statistical analyses employed non-parametric tests (SPSS v.25.0, IBM).

Results: Of 100 leaders from 17 countries, 63 responded to our survey, with 58 (92%) reporting university and/or cancer-center affiliations. Policies on new-patient visits remained mostly unchanged, while follow-up visits for low-risk diseases were mostly postponed, for example, 83.3% for small renal mass (SRM). Radical prostatectomy was delayed in 76.2% of cases, while maintaining scheduled timing for radical cystectomy (71.7%). Delays were longer in Europe than in the Americas for kidney cancer (SRM follow-up, P = 0.014), prostate cancer (new visits, P = 0.003), and intravesical therapy for intermediate-risk bladder cancer (P = 0.043). In Europe, COVID-19 burden correlated with policy adaptation, for example, nephrectomy delays for T2 disease (r = 0.5, P =0.005). Regarding education policies, trainees' medical education was mainly unchanged, whereas senior urologists' planned attendance at professional meetings dropped from 6 (IQR 1-11) to 2 (IQR 0-5) (P < 0.0001).

Conclusion: Under COVID-19, senior urologic-oncology surgeons worldwide apply risk-stratified approaches to timing of clinical and surgical schedules. Policies regarding trainee education were not significantly affected. We suggest establishment of an international consortium to create a directive for coping with such future challenges to global healthcare.
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http://dx.doi.org/10.1016/j.urolonc.2020.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539173PMC
December 2020

Integrating Phenotypic Search and Phosphoproteomic Profiling of Active Kinases for Optimization of Drug Mixtures for RCC Treatment.

Cancers (Basel) 2020 Sep 21;12(9). Epub 2020 Sep 21.

Molecular Pharmacology Group, School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland.

Combined application of multiple therapeutic agents presents the possibility of enhanced efficacy and reduced development of resistance. Definition of the most appropriate combination for any given disease phenotype is challenged by the vast number of theoretically possible combinations of drugs and doses, making extensive empirical testing a virtually impossible task. We have used the streamlined-feedback system control (s-FSC) technique, a phenotypic approach, which converges to optimized drug combinations (ODC) within a few experimental steps. Phosphoproteomics analysis coupled to kinase activity analysis using the novel INKA (integrative inferred kinase activity) pipeline was performed to evaluate ODC mechanisms in a panel of renal cell carcinoma (RCC) cell lines. We identified different ODC with up to 95% effectivity for each RCC cell line, with low doses (ED) of individual drugs. Global phosphoproteomics analysis demonstrated inhibition of relevant kinases, and targeting remaining active kinases with additional compounds improved efficacy. In addition, we identified a common RCC ODC, based on kinase activity data, to be effective in all RCC cell lines under study. Combining s-FSC with a phosphoproteomic profiling approach provides valuable insight in targetable kinase activity and allows for the identification of superior drug combinations for the treatment of RCC.
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http://dx.doi.org/10.3390/cancers12092697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564658PMC
September 2020

Clinical outcome of robot-assisted residual mass resection in metastatic nonseminomatous germ cell tumor.

World J Urol 2021 Jun 21;39(6):1969-1976. Epub 2020 Sep 21.

Department of Oncological Urology, University Medical Center Utrecht, Utrecht, The Netherlands.

Purpose: To evaluate the outcome of robot-assisted residual mass resection (RA-RMR) in nonseminomatous germ cell tumor (NSGCT) patients with residual tumor following chemotherapy.

Patients And Methods: Retrospective medical chart analysis of all patients with NSGCT undergoing RA-RMR at two tertiary referral centers between January 2007 and April 2019. Patients were considered for RA-RMR in case of a residual tumor between 10 and 50 mm at cross-sectional computed tomography (CT) imaging located ventrally or laterally from the aorta or vena cava, with normalized tumor markers following completion of chemotherapy, and no history of retroperitoneal surgery.

Results: A total of 45 patients were included in the analysis. The Royal Marsden stage before chemotherapy was IIA in 13 (28.9%), IIB in 16 (35.6%), IIC in 3 (6.7%) and IV in 13 patients (28.9%). The median residual tumor size was 1.9 cm (interquartile range [IQR] 1.4-2.8; range 1.0-5.0). Five procedures (11.1%) were converted to an open procedure due to a vascular injury (n = 2), technical difficulty (n = 2) or tumor debris leakage (n = 1). A postoperative adverse event occurred in two patients (4.4%). Histopathology showed teratoma, necrosis and viable cancer in 29 (64.4%), 14 (31.1%), and two patients (4.4%), respectively. After a median follow-up of 41 months (IQR 22-70), one patient (2.2%) relapsed in the retroperitoneum. The one- and 2-year recurrence-free survival rate was 98%.

Conclusion: RA-RMR is an appropriate treatment option in selected patients, potentially providing excellent cure rates with minimal morbidity. Long-term outcome data are needed to further support this strategy and determine inclusion and exclusion criteria.
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http://dx.doi.org/10.1007/s00345-020-03437-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217018PMC
June 2021
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