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In metastatic hormone sensitive prostate cancer (mHSPC), treatment intensification with either docetaxel or an androgen-receptor-axis targeted therapy (ARAT), added to androgen deprivation therapy (ADT) is the new standard of care. To better understand patterns of treatment intensification in Canada and specifically how it has been influenced by the COVID-19 pandemic, we conducted a national survey of genitourinary medical oncologists from across Canada.Using SurveyMonkey, we conducted an online survey of 119 medical oncologists in Canada from January 15 to January 27, 2021. The survey consisted of 16 questions, including demographics, and asked specifically about their approach to managing mHSPC before and during the pandemic.Overall there were 50/119 (42%) respondents. Most were male (65%), from Ontario (35%), practicing in academic centers (71%), with 45% reporting their practices focused primarily on genitourinary malignancies and one other tumor site. The majority were in practice 1 to 5 years (34%). Overall 65% indicated their practice patterns had changed since the pandemic, with 51% offering more ARATs and less docetaxel chemotherapy. In low volume mHSPC, the use of ARATs increased from 73% to 79%, while the use of docetaxel remained unaltered at 2%. In high volume disease, the use of ARATs increased from 63% to 84%, while the use of docetaxel decreased from 37% to 14%. Use of granulocyte colony stimulating factor (G-CSF) with docetaxel chemotherapy increased by 35%. Post-pandemic, 45% reported they intend to maintain these changes. Only 18% reported they had prostate cancer patients test positive for COVID-19, and all patients recovered.Management of patients with mHSPC in Canada has changed during the pandemic, with increased uptake of ARATs and reduced use of docetaxel, a trend expected to continue beyond the pandemic. How this trend will impact uptake of triplet therapy (ADT + ARAT + Docetaxel), downstream treatment choices and overall outcomes remains to be seen.

The role of upfront cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) in the era of immune checkpoint inhibitors is unclear.To evaluate the relationship between upfront CN and clinical outcomes in the setting of mRCC treated with immune checkpoint inhibitors or targeted therapy.Using the International Metastatic RCC Database Consortium, we retrospectively identified patients diagnosed with de novo mRCC treated with immune checkpoint inhibitors or targeted therapy.Overall survival (OS) was compared between the two groups using the Kaplan-Meier method and multivariable Cox regressions adjusting for known prognostic factors.We identified a total of 4639 eligible patients with mRCC. Among the 4202 patients treated with targeted therapy and 437 patients treated with immune checkpoint inhibitors, 2326 (55%) and 234 (54%) patients received upfront CN prior to treatment start. In multivariable analyses, CN was associated with significantly better OS in both the immune checkpoint inhibitor-treated (hazard ratio [HR]: 0.61; 95% confidence interval [CI], 0.41-0.90, p = 0.013) and the targeted therapy treatment (HR: 0.72; 95% CI, 0.67-0.78, p 0.001) group. There was no difference in OS benefit of CN between the immune checkpoint inhibitor and targeted therapy treatment groups (interaction p = 0.6). Limitations include selection of patients from large academic centers and the retrospective nature of the study.Upfront CN is associated with a significant OS benefit in selected patients treated by either immune checkpoint inhibitors or targeted therapy, and still has a role in selected patients in the era of immune checkpoint inhibitors.Before effective systemic therapies were available for metastatic kidney cancer, surgical removal of the primary (kidney) tumor was the mainstay of treatment. The role of removing the primary tumor has recently been called into question given that more effective systemic therapies have become available. In this study, we find that removal of the primary kidney tumor still has a benefit for selected patients treated with highly effective modern systemic therapies, including targeted therapies and immune checkpoint inhibitors.

Background Treatment options for metastatic renal cell carcinoma (mRCC) include cytoreductive nephrectomy (CN) and systemic therapy (ST). Results from the CARMENA and SURTIME trials suggest that CN before ST may not be the optimal treatment strategy for mRCC. Objective To use real-world data to evaluate and compare outcomes for patients with mRCC who underwent CN before, after, or without ST to those patients who only received ST. Design, setting, and participants The Canadian Kidney Cancer information system (CKCis) database was used to identify patients diagnosed with mRCC between January 2011 and April 2020. Only patients with synchronous disease, treated within 12 mo from their initial RCC diagnosis, with International Metastatic Renal Cell Carcinoma Database Consortium intermediate/high risk, and confirmed RCC histology were included. Outcome measurements and statistical analysis Patients were classified into four groups according to the initial treatment received for mRCC. Inverse probability of treatment weighting using propensity scores was used to balance the treatment groups. Cox proportional hazards models were used to assess the impact of CN after adjusting for potential confounding variables in the weighted cohorts. Results and limitations A total of 788 patients were included in the study cohort. Of these 383 patients underwent CN before ST, 73 underwent CN after ST, 80 underwent CN only, and 252 patients received ST only. The median patient age was 63 yr and 73% of the cohort were men. In weighted analysis, the groups undergoing CN before ST (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.52–0.82) and CN after ST (HR 0.41, 95% CI 0.28–0.60) both had better survival compared to the ST only group. No survival benefit was observed for CN only compared to ST only, or for CN before ST compared to CN after ST. Conclusions We evaluated the association between different sequences of treatment with CN and survival in patients with mRCC using CKCis real world data. The results demonstrate that the selected patients who undergo CN, whether performed before or after ST, have an associated improvement in survival. Patient summary Two of the treatment options for metastatic kidney cancer are surgery and systemic therapy (chemotherapy or immunotherapy). We used data from the Canadian Kidney Cancer information system to determine whether there are differences in survival according to the sequencing of these treatments. Patients who had both surgery and systemic therapy, regardless of which treatment was first, had better survival than patients who only received systemic therapy.

Background: Although metastatic germ cell tumor (GCT) is highly curable with initial cisplatin-based chemotherapy (CT), 20–30% of patients relapse. Salvage CT options include conventional (CDCT) and high dose chemotherapy (HDCT), however definitive comparative data remain lacking. We aimed to characterize the contemporary practice patterns of salvage CT across Canada. Methods: We conducted a 30-question online survey for Canadian medical and hematological oncologists with experience in treating GCT, assessing treatment availability, patient selection, and management strategies used for relapsed GCT patients. Results: There were 30 respondents from 18 cancer centers across eight provinces. The most common CDCT regimens used were TIP (64%) and VIP (25%). HDCT was available in 13 centers (70%). The HDCT regimen used included carboplatin and etoposide for two cycles (76% in 7 centers), three cycles (6% in 2 centers), and the TICE protocol (11%, in 2 centers). “Bridging” CDCT was used by 65% of respondents. Post-HDCT treatments considered include surgical resection for residual disease (87.5%), maintenance etoposide (6.3%), and surveillance only (6.3%). Conclusions: HDCT is the most commonly used GCT salvage strategy in Canada. Significant differences exist in the treatment availability, selection, and delivery of HDCT, highlighting the need for standardization of care for patients with relapsed testicular GCT.

Pembrolizumab plus axitinib improved efficacy over sunitinib in treatment-naive advanced renal cell carcinoma in the KEYNOTE-426 (NCT02853331) study. However, a relatively high incidence of grade 3/4 aminotransferase elevations was observed.To further characterize treatment-emergent aminotransferase elevations in patients treated with pembrolizumab-axitinib.Patients enrolled in KEYNOTE-426 were included in this study.Three Standardized MedDRA Queries for potential hepatic disorders were used to identify patients for the hepatic event analysis subpopulation (HEAS). Alanine aminotransferase events were characterized for time to onset, time to recovery, corticosteroid use, and rechallenge with study treatment(s).The HEAS comprised 189/429 (44%) pembrolizumab-axitinib patients and 128/425 (30%) sunitinib patients. Grade 3/4 hepatic adverse events were more common in the combination arm: 22% (94/429) versus 7% (29/425); 3% (13/429) discontinued the combination due to hepatic adverse events. In the pembrolizumab-axitinib arm, 125/426 patients (29%) had alanine aminotransferase (ALT) ≥3× upper limit of normal (ULN), with median time to onset of 84 d (range, 7-840 d). Among patients with ALT ≥3× ULN, 120/125 (96%) recovered to3× ULN following study treatment interruption/discontinuation, with a median time to recovery of 15 d (3-176 d): 68/120 (57%) received corticosteroids. One hundred patients were rechallenged with one or both study treatment(s): 45/100 (45%) had ALT ≥3× ULN recurrence, and all 45 recovered to ALT3× ULN following study treatment interruption/discontinuation. No fatal hepatic events occurred.A higher incidence of grade 3/4 aminotransferase elevations occurs with pembrolizumab-axitinib. These events should be carefully evaluated and managed with prompt study treatment interruption or discontinuation, with or without corticosteroid treatment. The decision to rechallenge with one or both drugs should be based on severity of event and thorough causality assessment.Renal cell carcinoma patients receiving pembrolizumab-axitinib are at a higher risk of liver enzyme elevations, which could be reversed with appropriate management.

Purpose: Sunitinib and sorafenib are used widely in the treatment of renal cell carcinoma (RCC). These agents are associated with a significant incidence of cardiovascular (CV) dysfunction and left ventricular ejection fraction (LVEF) declines, observed largely in the metastatic setting. However, in the adjuvant population, the CV effects of these agents remain unknown. We prospectively defined the incidence of cardiotoxicity among resected, high-risk RCC patients treated with these agents.Experimental Design: Sunitinib, sorafenib, or placebo was administered for up to 12 months in patients with high-risk, resected RCC. LVEF was measured by multigated acquisition (MUGA) scans at standard intervals. Additional CV adverse events were reported according to NCI Common Terminology Criteria for Adverse Events (CTCAE).Results: Among 1,943 patients randomized, 1,599 had at least 1 post-baseline MUGA. Within 6 months, 21 patients (1.3%) experienced a cardiac event, defined as an LVEF decline from baseline that was >15% and below the institutional lower limit of normal. Nine of 513 patients (1.8%) were on sunitinib, 7 of 508 (1.4%) on sorafenib, and 5 of 578 (0.9%) on placebo (P = 0.28 and 0.56 comparing sunitinib and sorafenib to placebo, respectively). With dose interruption or adjustment, 16 of the 21 recovered their LVEF to >50%. The incidence of symptomatic heart failure, arrhythmia, or myocardial ischemia did not differ among groups.Conclusions: In the adjuvant setting, we prospectively define low incidence of cardiotoxicity with sunitinib and sorafenib. These findings may be related to close CV monitoring, or potentially to fewer CV comorbidities in our nonmetastatic population. Clin Cancer Res; 21(18); 4048–54. ©2015 AACR.

Supplementary Figure: Consort diagram of patients participating in cardiac sub study

Supplementary Tables 1-5, Figures 1-3. Supplemental Table 1: Events per person-year of follow-up Supplemental Table 2: Event rates among patients randomized to sorafenib or sunitinib who started at reduced vs. full dose Supplemental Table 3a. Event rates among patients who did or did not discontinue treatment due to adverse events, and among patients with ECOG PS 0 vs. 1 Supplemental Table 3b: Baseline LVEF and change in LVEF among patients who did or did not discontinue treatment due to adverse events Supplemental Table 4: Relationship among treatment duration, baseline LVEF by MUGA, and probability of an event by any definition Supplemental Table 5: Relationship among treatment duration, baseline LVEF by MUGA, and probability of an event by the definition "Per Protocol Including Other" Supplemental Figure 1: Relationship among baseline LVEF by MUGA, treatment duration, and event status, where event is defined by any of the criteria Supplemental Figure 2: Relationship among baseline LVEF by MUGA, treatment duration, and event status, where event is defined as a decline in LVEF of 16% or more to below the lower limit of normal, or a grade 3 or higher cardiac adverse event Supplemental Figure 3: Algorithm for management of study drug-induced hypertension

Brain metastases (BM) in metastatic renal cell carcinoma (mRCC) have been reported to be present in up to 25% of patients diagnosed with mRCC. There is limited published literature evaluating the role of routine intra-cranial imaging for the screening of asymptomatic BM in mRCC.To evaluate the potential utility of routine intra-cranial imaging, a retrospective cohort study was conducted to characterize the outcomes of mRCC patients who presented with asymptomatic BM, as compared to symptomatic BM.The Canadian Kidney Cancer Information System (CKCis) database was used to identify mRCC patients diagnosed with BM. This cohort was divided into two groups based on the presence or absence of BM symptoms. Details regarding patient demographics, disease characteristics, systemic treatments, BM characteristics and survival outcomes were extracted. Statistical analysis was through chi-square tests, analysis of variance, and Kaplan-Meier method to characterize survival outcomes. A p-value of0.05 was considered statistically significant for all analyses. A total of 267 mRCC patients with BM were identified of which 106 (40%) presented with asymptomatic disease. The majority of patients presented with multiple (i.e.,1) BM (75%) with no significant differences noted in number of BM or BM-directed therapy received in symptomatic, as compared to asymptomatic BM patients. Median [95% confidence interval (CI)] overall survival (OS) from mRCC diagnosis was 42 months (95% CI: 32-62) for patients with asymptomatic BM, and 39 months (95% CI: 29-48) with symptomatic BM (p = 0.10). OS from time of BM diagnosis was 28 months (95% CI: 18-42) for the asymptomatic BM group, as compared to 13 months (95% CI: 10-21) in the symptomatic BM group (p = 0.04).Given a substantial proportion of patients may present with asymptomatic BM, limiting intra-cranial imaging to patients with symptomatic BM, may be associated with a missed opportunity for timely diagnosis and treatment. The utility of routine intra-cranial imaging in patients with renal cell carcinoma, warrants further prospective evaluation.

Contains fulltext : 251789.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To analyse if exposure to sunitinib in the Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients With Metastatic Kidney Cancer (SURTIME) trial, which investigated opposite sequences of cytoreductive nephrectomy (CN) and systemic therapy, is associated with the overall survival (OS) benefit observed in the deferred CN arm. PATIENTS AND METHODS: A post hoc analysis of SURTIME trial data. Variables analysed included number of patients receiving sunitinib, time from randomisation to start sunitinib, overall response rate by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, and duration of drug exposure and dose in the intention-to-treat population of the immediate and deferred arm. Descriptive methods and 95% confidence-intervals (CI) were used. RESULTS: In the deferred arm, 97.7% (95% CI 89.3-99.6%; n = 48) received sunitinib vs 80% (95% CI 66.9-88.7%, n = 40) in the immediate arm. Following immediate CN, 19.6% progressed 4 weeks after CN and the median time to start sunitinib was 39.5 vs 4.5 days in the deferred arm. At week 16, 46.0% had progressed at metastatic sites in the immediate CN arm vs 32.7% in the deferred arm. Sunitinib dose reductions, escalations and interruptions were not statistically significantly different between arms. Among patients who received sunitinib in the immediate or deferred arm the median total sunitinib treatment duration was 172.5 vs 248 days. Reduction of target lesions was more profound in the deferred arm. CONCLUSIONS: In comparison to the deferred CN approach, immediate CN impairs administration, onset, and duration of sunitinib. Starting with systemic therapy leads to early and more profound disease control and identification of progression prior to planned CN, which may have contributed to the observed OS benefit.

BACKGROUND: Cabozantinib is an oral multitargeted tyrosine kinase inhibitor (TKI) that has demonstrated efficacy in metastatic renal-cell carcinoma (mRCC) randomized trials. OBJECTIVE: To explore the real-world effectiveness of cabozantinib in pretreated patients with mRCC, including patients who progressed on immune-oncology checkpoint inhibitor (ICI) therapy. METHODS: Using the Canadian Kidney Cancer information system (CKCis), patients with mRCC treated with cabozantinib monotherapy as second-line or later from January 1, 2011 to September 1, 2019 were identified. Patients were stratified based on line of cabozantinib received. We reported overall survival (OS), time to treatment failure (TTF) and disease control rate (DCR). Prognostic variables were analyzed using multivariable analysis. RESULTS: 157 patients received cabozantinib (median TTF 8.0 months; median OS 15.8 months): 37 (24%) in the second line (median TTF 10.4 months; median OS 18.9 months) 66 (42%) in third line (median TTF 5.9 months; median OS 13.3 months) and 54 (34%) in either 4th or 5th line (median TTF 9.4 months; median OS 16.8 months). One hundred sixteen patients (74%) received cabozantinib after prior ICI therapy (median TTF of 7.6 months; median OS of 15.8 months). DCR in all patients was 63% with 46%, 65% and 72% in 2nd line, 3rd line and 4th/5th line patients respectively. DCR in patients who received cabozantinib after prior ICI therapy was 64%. CONCLUSIONS: Cabozantinib is effective in a real-world, unselected population of mRCC patients, including in those who have progressed on prior ICI therapy, and in those exposed to multiple lines of therapy.

Objective: To evaluate the role of incomplete metastasectomy (IM) for patients with metastatic renal cell carcinoma (mRCC) on overall survival (OS) and time to introduction of first-line systemic therapy. Methodology: Patients diagnosed with mRCC between Jan 2011 and Apr 2019 in 16 centers were selected from the Canadian Kidney Cancer information system database. We included mRCC patients who had prior nephrectomy and had received an IM (resection of at least 1 metastasis) or no metastasectomy (NM). A propensity score matching was performed to minimize selection bias. Cox proportional hazards analysis was used to assess the impact of the metastasectomy while adjusting for potential confounders. OS was assessed by Kaplan-Meier analysis. Results: A total of 138 patients with mRCC underwent IM, while 1221 patients did not. On multivariate analysis, IM did not improve OS (hazard ratio [HR] 0.96, 95% CI 0.63 to 1.45, P = 0.836) However, subgroup analyses revealed IM improved OS compared with NM when lungs were the only site involved (median time to OS not reached versus 66 months, respectively; P = 0.014). Additionally, lung metastasectomy delayed the systemic therapy compared with NM (median 41 and 13 months, respectively, P = 0.014). IM of endocrine organs (thyroid, pancreas, adrenals) or bone metastases did not impact OS. Conclusion: The role of IM for mRCC is limited. Incomplete resection of lung metastases was associated with improved OS and delayed time to introduction of systemic therapy when lungs were the sole location of metastatic disease. Despite case-matching, unknown unadjusted confounders may explain the relationship between IM and survival in this analysis.

Purpose:The time between radiographic identification of a renal tumor and surgery can be concerning for patients and clinicians due to fears of tumor progression while awaiting treatment. This stud...

PURPOSE Patients with GI cancers in Nepal often present with advanced disease and poor outcomes. The purpose of the study was to determine the time to presentation, diagnosis, and treatment of GI cancer and the baseline factors that may be associated with delays. PATIENTS AND METHODS An institutional review board–approved study was performed in Kathmandu, Nepal, from July 2018 to June 2019. Patients with newly diagnosed GI cancers were asked to fill out a standardized questionnaire. Baseline factors such as residence, literacy, and use of self-medication were recorded. Patients were asked to report the time from first symptom to presentation, time from primary care visit to pathologic diagnosis, and time from diagnosis to surgery and/or treatment. Baseline factors were analyzed using 2-tailed t tests (Prism 8.0; GraphPad, La Jolla, CA) to determine whether any factors were associated with longer time delays in these 3 intervals. RESULTS The cohort comprised of 104 patients with a median age of 53.5 years (range, 22-77 years); 61.5% were men, 46.2% had upper GI cancers, and 83.7% presented with stage III or IV disease. The median time to presentation was 150 days, time to diagnosis was 220 days, and time to treatment was 50 days. There was no statistically significant difference in time intervals between upper and lower GI cancers. Use of self-medication (88.5%) was the only factor associated with longer time intervals to presentation, diagnosis, and treatment. CONCLUSION Patients in Nepal have long time intervals to presentation, diagnosis, and treatment of GI cancer. Self-medication led to longer delays. Reasons for self-medication and other potential barriers will be explored in future studies in the hopes of improving outcomes.

Squamous cell carcinoma of the upper urinary tract is a rare entity associated with rapidly progressive disease and poor outcomes. Here, we describe a case of a squamous cell carcinoma of the upper urinary tract associated with significant progression and paraneoplastic syndrome. Post-operatively, the patient had near complete resolution of her paraneoplastic syndromes with significant improvements in her functional status.

BACKGROUND: Despite recent advances in the management of muscle-invasive bladder cancer (MIBC), treatment outcomes remain suboptimal, and variability exists across current practice patterns. OBJECTIVE: To promote standardization of care for MIBC in Canada by developing a consensus guidelines using a multidisciplinary, evidence-based, patient-centered approach who specialize in bladder cancer. METHODS: A comprehensive literature search of PubMed, Medline, and Embase was performed; and most recent guidelines from national and international organizations were reviewed. Recommendations were made based on best available evidence, and strength of recommendations were graded based on quality of the evidence. RESULTS: Overall, 17 recommendations were made covering a broad range of topics including pathology review, staging investigations, systemic therapy, local definitive therapy and surveillance. Of these, 10 (59% ) were level 1 or 2, 7 (41% ) were level 3 or 4 recommendations. There were 2 recommendations which did not reach full consensus, and were based on majority opinion. This guideline also provides guidance for the management of cisplatin-ineligible patients, variant histologies, and bladder-sparing trimodality therapy. Potential biomarkers, ongoing clinical trials, and future directions are highlighted. CONCLUSIONS: This guideline embodies the collaborative expertise from all disciplines involved, and provides guidance to further optimize and standardize the management of MIBC.

Background: Immune checkpoint inhibitors (CPIs) have come to the forefront as a major component of the management of metastatic renal cell carcinoma ( mRCC). Over a short period of time, several studies have shown benefit in using these agents in the first-line setting. Objective: In this systematic review, the available evidence regarding the use of CPI-based regimens in previously untreated mRCC was reviewed. Methods: A systematic search for phase II and III studies was conducted of the PubMed and Embase databases as per the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The search retrieved abstracts to February 1, 2020. Data was compiled and summarized in narrative and tabular formats. Results: Fifty-five abstracts from 11 clinical trials were included, including four phase III clinical trials and seven phase II trials. The most recent phase III data demonstrates overall survival (OS) benefit for ipilimumab plus nivolumab (for intermediate and poor risk patients) and pembrolizumab plus axitinib combination regimens over sunitinib. Two other regimens (avelumab plus axitinib and atezolizumab plus bevacizumab) have shown benefits in progression free survival, but not in OS to date. Toxicity data shows varying patterns of adverse events between the four treatments. Phase II data indicate CPI has activity as a single agent, and in patients with non-clear cell subtypes of RCC. Conclusions: CPI-based regimens improve outcomes in virtually all subgroups of mRCC patients when used as front-line therapy. This is certain to change the landscape of mRCC treatment.

Aims To evaluate the clinical impact of the Canadian criteria for identifying patients and families at risk for hereditary renal cell carcinoma (RCC). Materials and methods The Canadian hereditary RCC risk criteria were applied to patients from 16 centres in the Canadian Kidney Cancer information system (CKCis) prospective database. The primary end point was the proportion of patients who met at least one criterion. Results Between January 2011 and May 2017, 8388 patients were entered in the database; 291 had inadequate risk data; 2827 (35%) met at least one criterion for genetic testing (at-risk population). Most (83%) met just one criterion. The criterion of non-clear cell histology contributed the largest proportion of at-risk patients (59%), followed by age ≤ 45 years (28%). Sixty-one patients had documentation of genetic testing, with 56 being classified at-risk (2% of at-risk). Twenty patients (35%) of the patients at risk and tested for hereditary RCC were found to harbour a germline mutation. Conclusions Application of the Canadian hereditary RCC risk criteria to a large prospective database resulted in 35% of patients being identified at risk for hereditary RCC who could qualify for genetic testing. However, the true incidence of hereditary RCC in this population is unknown as most patients did not have documented genetic testing carried out and, thus, the sensitivity and specificity of the criteria cannot be determined. The low proportion of at-risk patients who underwent genetic testing is disappointing and highlights that there may be gaps in reporting, knowledge and/or barriers in access to genetic testing.

Treatment options for clear-cell metastatic renal cell carcinoma (mRCC) have increased significantly. Clinical practice guidelines aim to aid with decision-making about treatment selection through evidence-based recommendations. In this article, recommendations on first-line treatment for clear-cell mRCC in guidelines from three international organizations are reviewed and summarized. Future guideline development should focus on dynamic updates based on practice-changing data and guidance regarding therapy selection. PATIENT SUMMARY: International guidelines for first-line treatment of metastatic renal cell carcinoma are reviewed in this article. The main differences between guidelines appear to be how quickly the newest evidence is included.

600 Background: The outcomes of patients with brain metastases from renal cell carcinoma (RCC) are not well characterized due to exclusion of these patients from clinical trials. Methods: Using the IMDC, patients with brain metastases from RCC at the initiation of first-line therapy were analyzed. Baseline patient characteristics, brain-directed local therapies, clinician assessment of best overall response as per RECIST 1.1, and overall survival (OS) were compared across first-line therapies, namely immuno-oncology (IO)-based combination therapy (IO/IO or IO/vascular endothelial growth factor (VEGF)) and anti-VEGF monotherapy (sunitinib or pazopanib). Results: The overall cohort of patients with brain metastases included 775 patients, consisting of 78/1298 (6.0%) and 697/8633 (8.1%) in the IO-based and anti-VEGF cohorts, respectively (p = 0.009). Among the baseline patient characteristics, only the proportion of patients receiving whole-brain radiotherapy differed significantly across the IO-based and anti-VEGF cohorts with proportions of 25.0% and 55.7%, respectively (p < 0.001). Best overall response in all disease sites was 3.4% complete response (CR), 25.9% partial response (PR), 39.7% stable disease (SD), and 31% progressive disease (PD) in the IO-based cohort, whereas it was 0.7% CR, 29.6% PR, 36.7% SD, and 33.0% PD in the anti-VEGF cohort (p = 0.223). The following factors were significantly associated with longer OS on multivariable analysis: IMDC favourable-/intermediate-risk (HR 0.49, 95% CI 0.37–0.65; p < 0.001), IO-based combination therapy (HR 0.51, 95% CI 0.29–0.92; p = 0.026), neurosurgery (HR 0.62, 95% CI 0.47–0.83; p = 0.001), and stereotactic radiosurgery (HR 0.64, 95% CI 0.49–0.84; p = 0.001). Conclusions: Patients with brain metastases receiving IO-based combination therapy may have longer OS than those receiving anti-VEGF monotherapy. Brain-directed local therapies including neurosurgery and stereotactic radiosurgery were associated with longer OS. [Table: see text]

Background: Immuno-oncology (IO)–based therapies have been approved based on randomised clinical trials, yet a significant proportion of real-world patients are not represented in these trials. We sought to compare the outcomes of trial-ineligible vs. -eligible patients with advanced solid tumours treated with first-line (1L) IO therapy. Patients and methods: Using the International Metastatic Renal Cell Carcinoma (RCC) Database Consortium and the Alberta Immunotherapy Database, patients with advanced RCC, non–small-cell lung cancer (NSCLC) or melanoma treated with 1L PD-(L)1 inhibition–based therapy were included. Trial eligibility was retrospectively determined as per commonly used exclusion criteria. The outcomes of interest were overall survival (OS), overall response rate (ORR), treatment duration (TD) and time to next treatment (TTNT). Results: A total of 395 of 1241 (32%) patients were deemed trial-ineligible. The main reasons for ineligibility based on preselected exclusion criteria were Karnofsky performance status 1 (40%, 158 of 395), brain metastases (32%, 126 of 395), haemoglobin < 9 g/dL (16%, 63 of 395) and estimated glomerular filtration rate

The European Organisation for Research and Treatment of Cancer SURTIME trial explored timing of sunitinib, a tyrosine kinase inhibitor (TKI), and cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma. Previous retrospective studies suggest increased surgeryrelated adverse events (AEs) after presurgical TKI. We report surgical safety from a randomised comparison of CN before or after sunitinib. In-hospital mortality, 30-d readmission rate, and intraoperative and 30-d postoperative AEs according to Common Terminology Criteria for Adverse Events version 4 and Clavien-Dindo (CD) were analysed. Patients were randomised 1:1 to immediate CN followed by sunitinib versus sunitinib followed by deferred CN 24 h after the last dose of sunitinib. None of the tumours in the deferred arm became unresectable, and only two patients had a sunitinib-related delay of CN of >2 wk. AEs related to surgery (all grades) in the immediate and deferred arms occurred in 52% and 53% after CN, respectively, although the number of intraoperative surgery-related AEs was higher in the immediate arm. Postoperative AEs (CD >= 3), 30-d readmission, and in-hospital mortality rates were 6.5%, 13%, and 4.3% in the immediate arm and 2.5%, 7.5%, and 2.5% in the deferred arm, respectively. There were no differences in surgery time, blood loss, and hospital stay.Patient summary: Patients with metastatic kidney cancer do not have more surgical complications irrespective of whether they are treated with systemic therapy before or after surgery. (C) 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.

In the present study, we explored the real-world efficacy of the immuno-oncology checkpoint inhibitor nivolumab and the tyrosine kinase inhibitor cabozantinib in the second-line setting. Using the International Metastatic Renal Cell Carcinoma Database Consortium (imdc) dataset, a retrospective analysis of patients with metastatic renal cell carcinoma (mrcc) treated with nivolumab or cabozantinib in the second line after prior therapy targeted to the vascular endothelial growth factor receptor (vegfr) was performed. Baseline characteristics and imdc risk factors were collected. Overall survival (os) and time to treatment failure (ttf) were calculated using Kaplan&ndash, Meier curves. Overall response rates (orrs) were determined for each therapy. Multivariable Cox regression analysis was performed to determine survival differences between cabozantinib and nivolumab treatment. The analysis included 225 patients treated with nivolumab and 53 treated with cabozantinib. No significant difference in median os was observed: 22.10 months [95% confidence interval (ci): 17.18 months to not reached] with nivolumab and 23.70 months (95% ci: 15.52 months to not reached) with cabozantinib (p = 0.61). The ttf was also similar at 6.90 months (95% ci: 4.60 months to 9.20 months) with nivolumab and 7.39 months (95% ci: 5.52 months to 12.85 months) with cabozantinib (p = 0.20). The adjusted hazard ratio (hr) for nivolumab compared with cabozantinib was 1.30 (95% ci: 0.73 to 2.3), p = 0.38. When adjusted by imdc criteria and age, the hr was 1.32 (95% ci: 0.74 to 2.38), p = 0.35. Real-world imdc data indicate comparable os and ttf for nivolumab and cabozantinib. Both agents are reasonable therapeutic options for patients progressing after initial first-line vegfr-targeted therapy.

Importance: In clinical practice, patients with primary metastatic renal cell carcinoma (mRCC) have been offered cytoreductive nephrectomy (CN) followed by targeted therapy, but the optimal sequence of surgery and systemic therapy is unknown. Objective: To examine whether a period of sunitinib therapy before CN improves outcome compared with immediate CN followed by sunitinib. Design, Setting, and Participants: This randomized clinical trial began as a phase 3 trial on July 14, 2010, and continued until March 24, 2016, with a median follow-up of 3.3 years and a clinical cutoff date for this report of May 5, 2017. Patients with mRCC of clear cell subtype, resectable primary tumor, and 3 or fewer surgical risk factors were studied. Interventions: Immediate CN followed by sunitinib therapy vs treatment with 3 cycles of sunitinib followed by CN in the absence of progression followed by sunitinib therapy. Main Outcomes and Measures: Progression-free survival was the primary end point, which needed a sample size of 458 patients. Because of poor accrual, the independent data monitoring committee endorsed reporting the intention-to-treat 28-week progression-free rate (PFR) instead. Overall survival (OS), adverse events, and postoperative progression were secondary end points. Results: The study closed after 5.7 years with 99 patients (80 men and 19 women; mean [SD] age, 60 [8.5] years). The 28-week PFR was 42% in the immediate CN arm (n = 50) and 43% in the deferred CN arm (n = 49) (P =.61). The intention-to-treat OS hazard ratio of deferred vs immediate CN was 0.57 (95% CI, 0.34-0.95; P =.03), with a median OS of 32.4 months (95% CI, 14.5-65.3 months) in the deferred CN arm and 15.0 months (95% CI, 9.3-29.5 months) in the immediate CN arm. In the deferred CN arm, 48 of 49 patients (98%; 95% CI, 89%-100%) received sunitinib vs 40 of 50 (80%; 95% CI, 67%-89%) in the immediate arm. Systemic progression before planned CN in the deferred CN arm resulted in a per-protocol recommendation against nephrectomy in 14 patients (29%; 95% CI, 18%-43%). Conclusions and Relevance: Deferred CN did not improve the 28-week PFR. With the deferred approach, more patients received sunitinib and OS results were higher. Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN. This evidence complements recent data from randomized clinical trials to inform treatment decisions in patients with primary clear cell mRCC requiring sunitinib. Trial Registration: ClinicalTrials.gov identifier: NCT01099423., SCOPUS: cp.j, info:eu-repo/semantics/published

Most studies indicate no benefit of adjuvant therapy with VEGFR tyrosine kinase inhibitors in advanced renal cell carcinoma (RCC). PROTECT (NCT01235962) was a randomized, double-blind, placebo-controlled phase 3 study to evaluate adjuvant pazopanib in patients with locally advanced RCC at high risk of relapse after nephrectomy (pazopanib, n = 769; placebo, n = 769). The results of the primary analysis showed no difference in disease-free survival between pazopanib 600 mg and placebo. Here we report the final overall survival (OS) analysis (median follow-up: pazopanib, 76 mo, interquartile range [IQR] 66-84; placebo, 77 mo, IQR 69-85). There was no significant difference in OS between the pazopanib and placebo arms (hazard ratio 1.0, 95% confidence interval 0.80-1.26; nominal p > 0.9). OS was worse for patients with T4 disease compared to those with less advanced disease and was better for patients with body mass index (BMI) >= 30 kg/m(2) compared to those with lower BMI. OS was significantly better for patients who remained diseasefree at 2 yr after treatment compared with those who relapsed within 2 yr. These findings are consistent with the primary outcomes from PROTECT, indicating that adjuvant pazopanib does not confer a benefit in terms of OS for patients following resection of locally advanced RCC.Patient summary: In the randomized, double-blind, placebo-controlled phase 3 PROTECT study, overall survival was similar for patients with locally advanced renal cell carcinoma (RCC) at high risk of relapse after nephrectomy who received adjuvant therapy with pazopanib or placebo. Pazopanib is not recommended as adjuvant therapy following resection of locally advanced RCC. (C) 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Active surveillance (AS) is a commonly used strategy in patients with slow-growing disease. We aimed to assess the outcomes and safety of AS in patients with metastatic renal cell carcinoma (mRCC).We used the Canadian Kidney Cancer information system (CKCis) to identify patients with mRCC diagnosed between January 1, 2011, and December 31, 2016. The AS strategy was defined as (1) the start of systemic therapy ≥ 6 months after diagnosis of mRCC, or (2) never receiving systemic therapy for mRCC with an overall survival (OS) of ≥1 year. Patients starting systemic treatment6 months after diagnosis of mRCC were defined as receiving immediate systemic treatment. OS and time until first-line treatment failure (TTF) were compared between the two cohorts.A total of 853 patients met the criteria for AS (cohort A). Of these, 364 started treatment6 months after their initial diagnosis (cohort A1) and 489 never started systemic therapy (cohort A2); 827 patients received immediate systemic treatment (cohort B). The 5-year OS probability was significantly greater for cohort A than for cohort B (70% vs. 33.6%; P.0001). After adjusting for International Metastatic RCC Database Consortium risk criteria and age, both OS (hazard ratio [HR] = 0.58; 95% confidence interval [CI], 0.47-0.70; P.0001) and TTF (HR = 0.72; 95% CI, 0.60-0.85; P = .0002) were greater in cohort A1 compared with B. For cohort A1, the median time on AS was 14.2 months (range, 6-71).Based on the largest analysis of AS in mRCC to date, our data suggest that a subset of patients may be safely observed without immediate initiation of systemic therapy.

At the Canadian Testis Cancer Workshop, the multidisciplinary management of testis cancer care was discussed. The two-day workshop involved urologists, medical and radiation oncologists, pathologists, radiologists, physician’s assistants, residents, fellows, nurses, patients, and patient advocacy group members. This review summarizes the discussion regarding clinical dilemmas in local and regional testis cancer. We present cases that highlight the need for a coordinated approach to individualize care. Overarching themes include the importance of a multidisciplinary approach to testis cancer, willingness to involve a high-volume experienced center, and given that the oncological outcomes are excellent, a reminder that clinical decisions need to prioritize selecting a strategy with the least treatment-related morbidity when safe to do so.

Background: Concomitant chemo-radiation for pelvic cancers remains challenging to be delivered at full doses. We hypothesized that fewer delays in chemotherapy would occur if the sequence of radiotherapy would be reversed, starting with the boost volume followed by the elective nodal volume. We report the result of a Phase II randomized study for high risk prostate cancer. Patients and Method: The study was a double-blinded phase II randomized trial. Patients were eligible if they had non-metastatic high-risk prostate cancer. All patients received 2.5 years of hormonal therapy and 46.5 Gy in 25 fractions to the pelvic lymph nodes. Patients received a radiation boost to the prostate, either before or after whole pelvic irradiation. Concurrent (20 mg/m2) Docetaxel was given on the first day of radiotherapy and weekly thereafter for a total of eight treatments until predefined toxicity stopping rules. Results: Ninety patients were included and randomized. Four were ineligible for the analysis. In total, 42 patients were randomized to the standard sequence, 44 patients to the experimental sequence. There were statistically fewer GI or GU toxicities leading to a docetaxel dose reduction or omission in the experimental sequence compared to the standard sequence, 5 vs. 15 events (p = 0.027). There was no difference in overall survival, cause-specific survival, or biochemical-relapse free survival between the two sequences. Conclusions: This is the first study to test sequence inversion for pelvic radio-chemotherapy in a randomized double-blind trial. Less chemotherapy interruptions or dose reductions occurred by inverting the radiation sequence of the large field and the boost. The trial was registered with Clinicaltrials.gov: NCT00452556.

Single-cell RNA sequencing provides new insights into pathologic epithelial and mesenchymal remodeling in the human lung., Pulmonary fibrosis (PF) is a form of chronic lung disease characterized by pathologic epithelial remodeling and accumulation of extracellular matrix (ECM). To comprehensively define the cell types, mechanisms, and mediators driving fibrotic remodeling in lungs with PF, we performed single-cell RNA sequencing of single-cell suspensions from 10 nonfibrotic control and 20 PF lungs. Analysis of 114,396 cells identified 31 distinct cell subsets/states. We report that a remarkable shift in epithelial cell phenotypes occurs in the peripheral lung in PF and identify several previously unrecognized epithelial cell phenotypes, including a KRT5−/KRT17+ pathologic, ECM-producing epithelial cell population that was highly enriched in PF lungs. Multiple fibroblast subtypes were observed to contribute to ECM expansion in a spatially discrete manner. Together, these data provide high-resolution insights into the complexity and plasticity of the distal lung epithelium in human disease and indicate a diversity of epithelial and mesenchymal cells contribute to pathologic lung fibrosis.

In November 2018, The Canadian Testis Cancer Workshop was convened. The two-day workshop involved urologists, medical and radiation oncologists, pathologists, radiologists, physician’s assistants, residents and fellows, nurses, patients and patient advocacy groups. One of the goals of the workshop was to discuss the challenging areas of testis cancer care where guidelines may not be specific. The objective was to distill through discussion around cases, expert approach to working through these challenges. Herein we present a summary of discussion from the workshop around controversies in the management of clinical stage 1 (CS1) disease. CS1 represents organ confined non-metastatic testis cancer that represents approximately 70-80% of men at presentation. Regardless of management, CS1 has an excellent prognosis. However, without adjuvant treatment, approximately 30% of CS1 nonseminomatous germ cell tumors (NSGCT) and 15% of CS1 seminoma relapse. The workshop reviewed that while surveillance has become the standard for the majority of patients with CS1 disease there remains debate in the management of patients at high-risk of relapse. The controversy in the management of CS1 testis cancer surrounds the optimal balance between the morbidity of overtreatment and the identification of patients who may derive most benefit from adjuvant treatment. The challenge lies in a shared decision process where discussion of options extends beyond the simple risk of relapse but to include the long-term toxicities of adjuvant treatments and the favorable cancer-specific survival.

INTRODUCTION: The Canadian Kidney Cancer information system (CKCis) has prospectively collected data on patients with renal tumors since Jan 1st, 2011 from 16 sites within 14 academic centers in 6 provinces. Canadian kidney cancer experts have used CKCis data to address several research questions. The goal of this study was to determine if the CKCis cohort is representative of the entire Canadian kidney cancer population, specifically regarding demographic and geographic distributions. METHODS: The CKCis prospective cohort was analyzed up to Dec 31, 2018. Baseline demographics and tumor characteristics were analyzed including location of patients’ residence at the time of CKCis entry. Geographic data is presented by province, rural versus urban via postal code info (2nd digit=0) and by Canadian urban boundary files. To determine the proportion of RCC patients that CKCis captures, CKCis accruals were compared to projected Canadian Cancer Society RCC incidence in 2016-2017 and the incidence from the 2016 Canadian Cancer Registry. To determine if the CKCis baseline data is representative it was compared to Registry data and other published data when Registry data was not available. RESULTS: This CKCis cohort includes 10,298 eligible patients: 66.6% male, median age 62.6 years, 14.6% had metastatic disease at the time of diagnosis and 70.4% had clear cell carcinomas. The CKCis cohort captures about 1,250 patients per year, which represents approximately 20% of the total kidney cancer incidence. The proportion of patients captured per province did vary from 13% to 43%. Rural patients make up 17% of patients with some baseline differences between rural and urban patients. There appears to be no major differences between CKCis patient demographics and disease characteristics compared to national data sources. Canadian heat maps detailing patient location are presented. CONCLUSIONS: CKCis contains prospective data on >10,000 Canadian kidney cancer patients making it a valuable resource for kidney cancer research. The baseline demographic and geographic data do appear to include a broad cross section of patients and seem to be highly representative of the Canadian kidney cancer population. Moving forward, future projects will include determining if CKCis cancer outcomes are also representative of the entire Canadian kidney cancer population, and studying variations across provinces and within rural versus urban areas.

At the Canadian Testis Cancer Workshop, the rationale and feasibility of regionalization of testis cancer care were discussed. The two-day workshop involved urologists, medical and radiation oncologists, pathologists, radiologists, physician’s assistants, residents and fellows, and nurses, as well as patients and patient advocacy groups. This review summarizes the discussion and recommendations of one of the central topics of the workshop — the centralization of testis cancer in Canada. It was acknowledged that non-guideline-concordant care in testis cancer occurs frequently, in the range of 18–30%. The National Health Service in the U.K. stipulates various testis cancer care modalities be delivered through supra-regional network. All cases are reviewed at a multidisciplinary team meeting and aspects of care can be delivered locally through the network. In Germany, no such network exists, but an insurance-supported online second opinion network was developed that currently achieves expert case review in over 30% of cases. There are clear benefits to regionalization in terms of survival, treatment morbidity, and cost. There was agreement at the workshop that a structured pathway for diagnosis and treatment of testis cancer patients is required. Regionalization may be challenging in Canada because of geography; independent administration of healthcare by each province; physicians fearing loss of autonomy and revenue; patient unwillingness to travel long distances from home; and the inability of the larger centers to handle the ensuing increase in volume. We feel the first step is to identify the key performance indicators and quality metrics to track the quality of care received. After identifying these metrics, implementation of a “networks of excellence” model, similar to that seen in sarcoma care in Ontario, could be effective, coupled with increased use of health technology, such as virtual clinics and telemedicine.

Although immune-mediated therapies have been used in genitourinary (gu) malignancies for decades, recent advances with monoclonal antibody checkpoint inhibitors (cpis) have led to a number of promising treatment options. In renal cell carcinoma (rcc), cpis have been shown to have benefit over conventional therapies in a number of settings, and they are the standard of care for many patients with metastatic disease. Based on recent data, combinations of cpis and antiangiogenic therapies are likely to become a new standard approach in rcc. In urothelial carcinoma, cpis have been shown to have a role in the second-line treatment of metastatic disease, and a number of clinical trials are actively investigating cpis for other indications. In other gu malignancies, such as prostate cancer, results to date have been less promising. Immunotherapies continue to be an area of active study for all gu disease sites, with several clinical trials ongoing. In this review, we summarize the current evidence for cpi use in rcc, urothelial carcinoma, prostate cancer, testicular germ-cell tumours, and penile carcinoma. Ongoing clinical trials of interest are highlighted, as are the challenges that clinicians and patients will potentially face as immune cpis become a prominent feature in the treatment of gu cancers.