Publications by authors named "Naveen S Basappa"

27 Publications

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Results from a Canadian consensus forum of key controversial areas in the management of advanced prostate cancer: Recommendations for Canadian healthcare providers.

Can Urol Assoc J 2021 Jun 8. Epub 2021 Jun 8.

Medical Affairs, Janssen Inc, Toronto, ON, Canada.

Introduction: Rapid progress in diagnostics and therapeutics for the management of prostate cancer (PCa) have created areas where high-level evidence to guide practice is lacking. The Genitourinary Research Consortium (GURC) conducted its second Canadian consensus forum to address areas of controversy in the management of PCa and provide recommendations to guide treatment.

Methods: A panel of PCa specialists discussed topics related to the management of PCa. The core scientific committee finalized the design, questions and the analysis of the consensus results. Attendees then voted to indicate their management choice regarding each statement/topic. Questions for voting were adapted from the 2019 Advanced Prostate Cancer Consensus Conference. The thresholds for agreement were set at ≥ 75% for 'consensus agreement', > 50% for "near-consensus", and ≤ 50% for "no consensus".

Results: The panel was comprised of 29 PCa experts including urologists (n=12), medical oncologists (n= 12), and radiation oncologists (n= 5). Voting took place for 65 pre-determined questions and three ad hoc questions. Consensus was reached for 34 questions, spanning a variety of areas including biochemical recurrence, treatment of metastatic castration-sensitive PCa, management of non-metastatic and metastatic castration-resistant PCa, bone health, and molecular profiling.

Conclusion: The consensus forum identified areas of consensus or near-consensus in more than half of the questions discussed. Areas of consensus typically aligned with available evidence, and areas of variability may indicate a lack of high-quality evidence and point to future opportunities for further research and education.
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http://dx.doi.org/10.5489/cuaj.7347DOI Listing
June 2021

Outcomes of patients with solid tumour malignancies treated with first-line immuno-oncology agents who do not meet eligibility criteria for clinical trials.

Eur J Cancer 2021 Jul 8;151:115-125. Epub 2021 May 8.

Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada. Electronic address:

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 <70%/Eastern Cooperative Oncology Group 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 <40 mL/min (15%, 61 of 395). Between the ineligible vs. eligible groups, the median OS, ORR, median TD and median TTNT were 10.2 vs. 39.7 months (p < 0.01), 36% vs. 47% (p < 0.01), 2.7 vs. 6.9 months (p < 0.01) and 6.0 vs. 16.8 months (p < 0.01), respectively. Subgroup analyses showed statistically significant inferior OS, TD and TTNT for trial-ineligible vs. -eligible patients across all tumour types. Adjusted hazard ratios for death in RCC, NSCLC and melanoma were 1.84 (95% confidence interval [CI] 1.22-2.77), 2.21 (95% CI 1.58-3.11) and 1.82 (95% CI 1.21-2.74), respectively..

Conclusions: Thirty-two percent of real-world patients treated with contemporary 1L IO-based therapies were ineligible for clinical trials. Although one-third of the trial-ineligible patients responded to treatment, the overall trial-ineligible population had inferior outcomes than trial-eligible patients. These data may guide patient counselling and temper expectations of benefit.
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http://dx.doi.org/10.1016/j.ejca.2021.04.004DOI Listing
July 2021

Determining generalizability of the Canadian Kidney Cancer information system (CKCis) to the entire Canadian kidney cancer population.

Can Urol Assoc J 2020 Oct;14(10):E499-E506

Department of Medicine and Urology, Dalhousie University, Halifax, NS, Canada.

Introduction: The Canadian Kidney Cancer information system (CKCis) has prospectively collected data on patients with renal tumors since January 1, 2011 from 16 sites within 14 academic centers in six 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 December 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 vs. urban via postal code information (2 digit=0) and by Canadian urban boundary files. To determine the proportion of renal cell carcinoma (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 1250 patients per year, which represents approximately 20% of the total kidney cancer incidence. The proportion of patients captured per province did vary from 13-43%. 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 vs. urban areas.
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http://dx.doi.org/10.5489/cuaj.6716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716824PMC
October 2020

Prognostic impact of paraneoplastic syndromes on patients with non-metastatic renal cell carcinoma undergoing surgery: Results from Canadian Kidney Cancer information system.

Can Urol Assoc J 2021 Apr;15(4):132-137

Department of Surgery, University of Manitoba, Winnipeg, MB, Canada.

Introduction: The impact of paraneoplastic syndromes (PNS) on survival in patients with renal cell carcinoma (RCC) is uncertain. This study was conducted to analyze the association of PNS with recurrence and survival of patients with non-metastatic RCC undergoing nephrectomy.

Methods: The Canadian Kidney Cancer information system is a multi-institutional cohort of patients started in January 2011. Patients with nephrectomy for non-metastatic RCC were identified. PNS included anemia, polycythemia, hypercalcemia, and weight loss. Associations between PNS and recurrence or death were assessed using Kaplan-Meier curves and multivariable analysis.

Results: Of 4337 patients, 1314 (30.3%) had evidence of one or more PNS. Patients with PNS were older, had higher comorbidity, and had more advanced clinical and pathological tumor characteristics as compared to patients without PNS (all p<0.05). Kaplan-Meier five-year estimated recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were significantly worse in patients with PNS (63.7%, 84.3%, and 79.6%, respectively, for patients with PNS vs. 73.9%, 90.8%, and 90.1%, respectively, for patients without PNS, all p<0.005). On univariable analysis, presence of PNS increased risk of recurrence (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.48-1.90, p<0.0001) and cancer-related death (HR 1.85, 95% CI 1.34-2.54, p=0.0002). Adjusting for known prognostic factors, PNS was not associated with recurrence or survival.

Conclusions: In non-metastatic RCC patients undergoing surgery, presence of PNS is associated with older age, higher Charlson comorbidity index score, advanced tumor stage, and aggressive tumor histology. Following surgery, baseline PNS is not strongly independently associated with recurrence or death.
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http://dx.doi.org/10.5489/cuaj.6833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021432PMC
April 2021

Outcomes of complete metastasectomy in metastatic renal cell carcinoma patients: The Canadian Kidney Cancer information system experience.

Urol Oncol 2020 10 7;38(10):799.e1-799.e10. Epub 2020 Aug 7.

Faculty of Medicine, McGill University, Montreal, QC, Canada.

Background: Surgical resection of metastasis can be integrated in the management of metastatic renal cell carcinoma (mRCC) as it can contribute to delay disease progression and improve survival.

Objective: This study assessed the impact of complete metastasectomy in mRCC patients using real-world pan-Canadian data.

Design, Setting And Participants: The Canadian Kidney Cancer information system (CKCis) database was used to select patients who were diagnosed with mRCC between January 2011 and April 2019. To minimize selection bias, each patient having received a complete metastasectomy was matched with up to 4 patients not treated with metastasectomy.

Outcome Measurements And Statistical Analysis: Overall survival (OS) was calculated from the date of metastasectomy or selection, to death from any cause. A Cox proportional hazards model was used to assess the impact of the metastasectomy while adjusting for potential confounding variables.

Results: A total of 229 patients undergoing complete metastasectomy were matched with 803 patients not treated with metastasectomy. After matching, baseline characteristics were well balanced between groups. After 12 months, the proportion of patients that were still alive was 96.0% and 89.8% in the complete metastasectomy and its matched group, respectively; the 5-year OS were 63.2% and 51.4%, respectively. Multivariate analysis performed in the matched cohort revealed that patients who underwent complete metastasectomy had a lower risk of mortality compared to patients who did not undergo metastasectomy (hazard ratio: 0.41, 95% confidence interval:0.27-0.63).

Conclusion: Our study found that patients who underwent complete metastasectomy have a longer overall survival and a longer time to initiation of targeted therapy compared to patients not receiving metastasectomy. These findings should support aggressive resection of metastasis in selected patients.
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http://dx.doi.org/10.1016/j.urolonc.2020.07.021DOI Listing
October 2020

Deferred Cytoreductive Nephrectomy in Patients with Newly Diagnosed Metastatic Renal Cell Carcinoma.

Eur Urol 2020 10 30;78(4):615-623. Epub 2020 Apr 30.

Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada.

Background: The use of cytoreductive nephrectomy (CN) selectively for patients who show a favorable response to upfront systemic therapy may be an approach to select optimal candidates with metastatic renal cell carcinoma (mRCC) who are most likely to benefit.

Objective: We sought to characterize outcomes of deferred CN (dCN) after upfront sunitinib, outcomes relative to sunitinib alone, and outcomes of CN followed by sunitinib.

Design, Setting, And Participants: We used the prospectively maintained International mRCC Database Consortium (IMDC) database to identify patients with newly diagnosed mRCC (2006-2018).

Intervention: Sunitinib alone, upfront CN followed by sunitinib, sunitinib followed by dCN.

Outcome Measurements And Statistical Analysis: Outcomes were overall survival (OS) and time to sunitinib treatment failure (TTF). Kaplan-Meier and multivariable Cox regression analyses were performed; dCN was analyzed as a time-varying covariate to account for immortal time bias.

Results And Limitations: We evaluated 1541 patients, of whom 651 (42%) received sunitinib alone, 805 (52%) underwent CN followed by sunitinib, and 85 (5.5%) received sunitinib followed by dCN, at a median of 7.8 mo from diagnosis. Median OS periods for patients treated with sunitinib alone, CN followed by sunitinib, and sunitinib followed by dCN were 10, 19, and 46 mo, respectively, while the median TTF values were 4, 8, and 13 mo, respectively. In multivariable regression analyses, sunitinib followed by dCN was significantly associated with improved OS (hazard ratio [HR] = 0.45, 95% confidence interval [CI] 0.33-0.60, p < 0.001) and TTF (HR = 0.62, 95% CI 0.46-0.85, p = 0.003) versus sunitinib alone. Among CN-treated patients, sunitinib followed by dCN was associated with improved OS (HR = 0.52, 95% CI 0.39-0.70, p < 0.001) and TTF (HR = 0.71, 95% CI 0.56-0.90, p = 0.005) compared with upfront CN followed by sunitinib. In various sensitivity analyses, dCN remained significantly associated with improved OS and TTF.

Conclusions: Patients who received dCN were carefully selected and achieved long OS. With these benchmark outcomes, optimal selection criteria need to be identified and confirmation of the role of dCN in a clinical trial is warranted.

Patient Summary: We characterized benchmark survival outcomes for patients with metastatic kidney cancer treated with sunitinib alone, nephrectomy (kidney removal) followed by sunitinib, and sunitinib followed by nephrectomy. Patients who had their nephrectomy after an initial course of sunitinib had prolonged survival.
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http://dx.doi.org/10.1016/j.eururo.2020.04.038DOI Listing
October 2020

Controversial issues in the management of patients with advanced prostate cancer: Results from a Canadian consensus forum.

Can Urol Assoc J 2020 Apr 5;14(4):E137-E149. Epub 2019 Nov 5.

BC Cancer Agency, University of British Columbia, Vancouver, BC, Canada.

Introduction: The management of advanced prostate cancer (PCa) continues to evolve with the emergence of new diagnostic and therapeutic strategies. As a result, there are multiple areas in this landscape with a lack of high-level evidence to guide practice. Consensus initiatives are an approach to establishing practice guidance in areas where evidence is unclear. We conducted a Canadian-based consensus forum to address key controversial areas in the management of advanced PCa.

Methods: As part of a modified Delphi process, a core scientific group of PCa physicians (n=8) identified controversial areas for discussion and developed an initial set of questions, which were then reviewed and finalized with a larger group of 29 multidisciplinary PCa specialists. The main areas of focus were non-metastatic castration-resistant prostate cancer (nmCRPC), metastatic castration-sensitive prostate cancer (mCSPC), metastatic castration-resistant prostate cancer (mCRPC), oligometastatic prostate cancer, genetic testing in prostate cancer, and imaging in advanced prostate cancer. The predetermined threshold for consensus was set at 74% (agreement from 20 of 27 participating physicians).

Results: Consensus participants included uro-oncologists (n=13), medical oncologists (n=10), and radiation oncologists (n=4). Of the 64 questions, consensus was reached in 30 questions (n=5 unanimously). Consensus was more common for questions related to biochemical recurrence, sequencing of therapies, and mCRPC.

Conclusions: A Canadian consensus forum in PCa identified areas of agreement in nearly 50% of questions discussed. Areas of variability may represent opportunities for further research, education, and sharing of best practices. These findings reinforce the value of multidisciplinary consensus initiatives to optimize patient care.
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http://dx.doi.org/10.5489/cuaj.6082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7124178PMC
April 2020

Rapid atrophy of cardiac left ventricular mass in patients with non-small cell carcinoma of the lung.

J Cachexia Sarcopenia Muscle 2019 10 10;10(5):1070-1082. Epub 2019 Jul 10.

Department of Oncology, Division of Palliative Care Medicine, University of Alberta, Edmonton, Canada.

Background: Cancer is a systemic catabolic condition affecting skeletal muscle and fat. We aimed to determine whether cardiac atrophy occurs in this condition and assess its association with cardiac function, symptoms, and clinical outcomes.

Methods: Treatment naïve metastatic non-small cell lung cancer patients (n = 50) were assessed prior to and 4 months after commencement of carboplatin-based palliative chemotherapy. Methods included echocardiography for left ventricular mass (LVM) and LV function [LV ejection fraction, global longitudinal strain (GLS), diastolic function], computed tomography to quantify skeletal muscle and total adipose tissue, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), validated questionnaires for dyspnoea and fatigue, plasma biomarkers, tumour response to therapy, and overall survival.

Results: During 112 ± 6 days, the median change in LVM was -8.9% [95% confidence interval (95% CI) -10.8 to -4.8, P < 0.001]. Quartiles of LVM loss were -20.1%, -12.9%, -4.8%, and +5.5%. Losses of muscle, adipose tissue, and LVM were frequently concurrent; LVM loss > median value was associated with loss of skeletal muscle [odds ratio (OR) = 4.5, 95% CI: 1.4-14.8, P=0.01] and loss of total adipose tissue (OR = 10.0, 95% CI: 2.7-36.7, P < 0.001). LVM loss was associated with decreased GLS (OR = 6.6, 95% CI: 1.9-22.7, P=0.003) but not with LV ejection fraction or diastolic function. In the population overall, plasma levels of C-reactive protein (P=0.008), high sensitivity troponin T (hs-TnT) (P=0.03), and galectin-3 (P=0.02) increased over time, while N-terminal pro B-type natriuretic peptide and hs-cTnI did not change over time. C-reactive protein was the only biomarker associated with LVM loss but at the univariate level only. Independent predictors of LVM loss were prior weight loss (adjusted OR = 10.2, 95% CI: 2.2-46.9, P=0.003) and tumour progression (adjusted OR = 14.6, 95% CI: 1.4-153.9, P=0.02). LVM loss was associated with exacerbations of fatigue (OR = 6.6, 95% CI: 1.9-22.7, P=0.003), dyspnoea (OR = 9.3, 95% CI: 2.4-35.8, P<0.001), and deterioration of performance status (OR = 4.8, 95% CI: 1.3-18.3,P=0.02). Patients with concurrent loss of LVM, skeletal muscle, and fat were more likely to deteriorate in all three symptom domains and to have reduced survival (P=0.05).

Conclusions: Intense LVM atrophy is associated with non-small cell lung cancer-induced cachexia. Loss of LVM was associated with emerging alterations of GLS, indicating subtle changes in left ventricular function. Longer term studies are needed to assess the full scope of cardiac atrophy and its impact. LVM atrophy arises in conjunction with losses of fat and skeletal muscle and is temporally associated with meaningful declines in performance status, worsening of fatigue, and dyspnoea, as well as poorer tumour response and decreased survival. The specific contribution of LVM atrophy to these outcomes requires further study.
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http://dx.doi.org/10.1002/jcsm.12451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818459PMC
October 2019

Diabetes and kidney cancer survival in patients undergoing nephrectomy: A Canadian multi-center, propensity score analysis.

Urol Oncol 2019 09 5;37(9):576.e11-576.e16. Epub 2019 Jul 5.

Division of Urology, University of Toronto, Toronto, Canada. Electronic address:

Introduction: Diabetes has been associated with worse survival outcomes in various malignancies; however, there are conflicting data in kidney cancer. Determining whether diabetes is associated with survival in kidney cancer may help guide treatment in a comorbid patient population.

Methods: We used the Canadian Kidney Cancer information system database to identify patients undergoing partial or radical nephrectomy between 1989 and 2017 for localized renal cell carcinoma at 16 institutions across Canada. We derived inverse probability of treatment weights (IPTW) from a propensity score model based on various clinical, surgical, and pathological characteristics. We used Cox proportional hazard models to evaluate the association between diabetes and cancer-specific and overall survival, in the sample weighted by the IPTW.

Results: 4828 patients met inclusion criteria, of whom 948 (19.6%) were diabetic. Median follow-up in those without death was 26.6 months (interquartile range 9.7-53.8). Among the entire cohort, 901 deaths were from any cause, and 299 deaths from kidney cancer. Before propensity score methods, diabetics were older, more likely to have comorbidities and clear cell histopathology. After propensity score adjustment, all characteristics were balanced between groups (standardized difference <0.10). IPTW-adjusted Cox proportional hazard models demonstrated no significant association between diabetes and cancer-specific (hazard ratio 1.13, 95% confidence interval 0.78-1.62), or overall survival (hazard ratio 1.14, 95% confidence interval 0.94-1.38).

Conclusions: Our multi-centre study found that diabetes and nondiabetics have similar survival following nephrectomy for kidney cancer.
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http://dx.doi.org/10.1016/j.urolonc.2019.06.006DOI Listing
September 2019

A Phase II Study of PX-866 in Patients With Recurrent or Metastatic Castration-resistant Prostate Cancer: Canadian Cancer Trials Group Study IND205.

Clin Genitourin Cancer 2019 06 15;17(3):201-208.e1. Epub 2019 Mar 15.

Canadian Cancer Trials Group, Kingston, ON, Canada.

Background: In PTEN-loss models, the phosphatidylinositol 3-kinase (PI3K)/AKT and androgen receptor signaling pathways cross-regulate by reciprocal feedback whereby inhibition of one activates the other, creating a rationale for co-targeting. We studied the irreversible, pan-isoform inhibitor of Class I PI-3K PX-866 singly (part A) and with abiraterone acetate (AA) in patients on AA with rising prostate-specific antigen (PSA) (part B).

Patients And Methods: The primary endpoint was lack of progression at 12 weeks. Exploratory endpoints included changes in circulating tumor cells (CTC), pharmacodynamic studies on platelets (part A), and archival tumor exploration of PTEN as predictor of response (part B).

Results: A total of 43 and 25 patients accrued to parts A and B, respectively. In part A, 14 (33%) patients were progression-free at 12 weeks, with 2 partial objective responses and 1 confirmed PSA response. Favorable CTC conversion (< 5 CTC/7.5 mL) occurred in 6 (24%) of 25 evaluable patients. In part B, 11 of 25 patients had measurable disease. Six (24%) patients were progression-free at 12 weeks. No objective or PSA responses were observed. For all 68 patients, the most common toxicities were diarrhea (53 patients), nausea (36), anorexia (24), fatigue (22), and vomiting (20). Among 17 patients for whom PTEN testing was possible, 3 had PTEN homozygous deletion and 14 had no change. No correlation between PTEN status and response was seen.

Conclusions: PX-866 had modest single agent activity. Adding AA to PX-866 showed no evidence of resistance reversal. Strategies to combine PI3K inhibition with androgen receptor-targeted therapies could consider initiation earlier, combination with other agents, and/or recruiting a selected population.
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http://dx.doi.org/10.1016/j.clgc.2019.03.005DOI Listing
June 2019

Management algorithms for metastatic prostate cancer.

Can Urol Assoc J 2019 Apr 26:50-60. Epub 2019 Apr 26.

University of Calgary, Calgary, AB, Canada.

Introduction: Prostate cancer poses a significant lifetime risk to Canadian men. Treatment for metastatic prostatic cancer (mPCa) is an area of ongoing research with a lack of up-to-date clinical guidance. The multidisciplinary Canadian Genitourinary Research Consortium (GURC) determined that additional guidance focusing on management of mPCa was warranted.

Methods: The most up-to-date guidelines, consensus statements, and emerging phase 3 trials were identified and used to inform development of algorithms by a multidisciplinary genitourinary oncology panel outlining recommendations for the management of mPCa.

Results: A single pan-Canadian guideline and five national and international guidelines or consensus statements published since 2015 were identified, along with two new phase 3 trials and one additional randomized comparison. Iterative GURC discussions led to the development of two mPCa algorithms: the first addressing management of newly diagnosed metastatic castration-sensitive prostate cancer (mCSPC) patients and the second addressing treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). For newly diagnosed mCSPC patients with high-volume/high-risk disease, either docetaxel or abiraterone acetate and prednisone (AAP) added to androgen-deprivation therapy (ADT) is recommended. The addition of radiotherapy to ADT is suggested for those with low-volume disease and/or AAP to ADT for low-volume or low-risk disease. For first-line mCRPC, androgen receptor-axis-targeted (ARAT) therapy is recommended for most patients, while sequencing with docetaxel, radium-223, ARAT therapy, and/or cabazitaxel is recommended for later lines of therapy.

Conclusions: Two treatment algorithms were developed for the management of mPC and can be used by multidisciplinary specialist teams to guide treatment.
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http://dx.doi.org/10.5489/cuaj.5840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012295PMC
April 2019

Hydroxychloroquine is a safe and effective steroid-sparing agent for immune checkpoint inhibitor-induced inflammatory arthritis.

Clin Rheumatol 2019 May 30;38(5):1513-1519. Epub 2019 Jan 30.

Division of Rheumatology, Department of Medicine, University of Alberta, 8-120 Clinical Sciences Building, 8440 112 St NW, Edmonton, AB, T6G 2G3, Canada.

Immunotherapy for cancer treatment continues to evolve, and immune checkpoints have proven successful therapeutic targets. With success has come the challenge of managing the commonly associated immune-related toxicities. Arthralgias and arthritis are a common immune-related adverse event (IrAE), well described in the literature (Pardoll Nat Rev Cancer 12:252-264, 2012; Diesendruck and Benhar Drug Resist Updat 30:39-47, 2017; Cappelli et al. Arthritis Care Res 69:1751-1763, 2017; Brahmer et al. J Clin Oncol 36:1714-1768, 2018; Smith and Bass (2017). The optimal management of immune checkpoint inhibitor (ICI)-induced arthritis remains unclear. We describe the first series using hydroxychloroquine as a first-line disease-modifying antirheumatic drug (DMARD) for patients without pre-existing autoimmune disease, who developed arthritis secondary to ICI's. This was a single-center retrospective observational study reporting all patients evaluated by rheumatologists affiliated with the University of Alberta, a large tertiary health care center in Northern Alberta, Canada, deemed to have inflammatory arthritis (IA) following ICIs. We identified 11 patients, without pre-existing autoimmune disease, who developed IA following ICIs. Most patients presented with a symmetrical polyarthritis with both large and small joint involvement. All patients were treated according to the outlined treatment protocol with hydroxychloroquine as a first-line steroid-sparing agent: either as monotherapy or in combination with tapering doses of systemic corticosteroids (3) or intra-articular steroid injections (6). One patient required the addition of methotrexate to control symptoms and none required biologic therapy. There were no reported adverse effects from hydroxychloroquine. Inflammatory arthritis is an important complication of ICIs leading to significant impact on patient quality of life. In our experience, in patients without pre-existing autoimmune disease, hydroxychloroquine is an effective first-line therapy for IA secondary to ICI therapy.
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http://dx.doi.org/10.1007/s10067-019-04451-2DOI Listing
May 2019

The efficacy and safety of sunitinib given on an individualised schedule as first-line therapy for metastatic renal cell carcinoma: A phase 2 clinical trial.

Eur J Cancer 2019 02 14;108:69-77. Epub 2019 Jan 14.

Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada.

Background: Sunitinib is administered on a rigid schedule that may not be optimal for all patients. We hypothesised that toxicity-driven dose and schedule changes would optimise drug exposure and outcome for each patient.

Materials And Methods: In a phase 2 trial, 117 patients with metastatic clear cell renal cell cancer were started on sunitinib 50 mg/day with the aim to treat for 28 days. Treatment breaks were reduced to 7 days. Sunitinib dose and the number of days on therapy were individualised based on toxicity aiming for ≤ grade II toxicity with dose escalation in patients with minimal toxicity. The null hypothesis for the primary end-point was a progression-free survival (PFS) of 8.5 months based on a study with similar eligibility criteria.

Results: The null hypothesis was rejected (p < 0.001) with a median PFS of 12.5 months (95% confidence interval [CI]: 9.6-16.5). The median overall survival was 38.5 months (95% CI: 28.3-not reached). The objective response rate (46.1%) and stable disease rate (38.5%) translated into a clinical benefit for 84.6% of patients with no decline in quality of life scores during therapy. Fewer patients were dose reduced (26.5% vs. 50%) or discontinued due to toxicity (7.7 vs. 18-20%) compared to standard sunitinib dosing, and 20 (18.4%) patients were dose escalated to 62.5 mg (12) and 75 mg (8) with a wide individual variation in the optimal dose and treatment duration.

Conclusions: Individualised sunitinib therapy is feasible, safe and an effective method to manage toxicity with one of the best efficacy seen for oral vascular endothelial growth factor inhibitors in metastatic renal cell carcinoma. CLINICALTRIALS.

Gov Identifier: NCT01499121.
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http://dx.doi.org/10.1016/j.ejca.2018.12.006DOI Listing
February 2019

Undiagnosed cardiac deficits in non-small cell carcinoma patients in the candidate population for anti-cachexia clinical trials.

Support Care Cancer 2019 Apr 13;27(4):1551-1561. Epub 2018 Dec 13.

Department of Oncology, Division of Palliative Care Medicine, University of Alberta, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada.

Purpose: Currently, there is no approved therapy for cancer cachexia. According to European and American regulatory agencies, physical function improvements would be approvable co-primary endpoints of new anti-cachexia medications. As physical functioning is in part dependent on cardiac functioning, we aimed to explore the cardiac status of a group of patients meeting current criteria for inclusion in cachexia clinical trials.

Methods: Seventy treatment-naive patients with metastatic NSCLC [36 (51.4%) male; 96% ECOG 0-1; eligible for carboplatin-based therapy and meeting eligibility criteria for cachexia clinical trials] were recruited before the start of first-line carboplatin-based chemotherapy. Patients were evaluated by echocardiography, electrocardiography, and scales for fatigue and dyspnea. Computed tomography cross-sectional images were utilized for body composition analysis.

Results: In 9/70 patients (12.8%), echocardiography allowed discovery of clinically relevant cardiac disorders [seven patients with left ventricular ejection fraction (LVEF) 32%-47%; one patient with severe right ventricular dilation and severe pulmonary hypertension and one patient with severe pericardial effusion warranted hospitalization and drainage]. Another 10/70 (14.3%) patients had diastolic dysfunction with preserved LVEF. The cardiac conditions were associated with aggravated fatigue (p < 0.05), dyspnea (p < 0.05), and anemia (p = 0.06). Five out of seven patients with LVEF < 50% were sarcopenic and one was borderline sarcopenic.

Conclusion: Baseline cardiac status of the metastatic NSCLC patients adds potential heterogeneity for anti-cachexia clinical trials. Detailed cardiac screening data might be useful for inclusion/exclusion criteria, randomization, and post hoc analysis.
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http://dx.doi.org/10.1007/s00520-018-4561-yDOI Listing
April 2019

Checkpoint inhibitors in patients with metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

Cancer 2018 09 11;124(18):3677-3683. Epub 2018 Oct 11.

Department of Medical Oncology, Tom Baker Cancer Center, Calgary, Alberta, Canada.

Background: To the authors' knowledge, outcomes and prognostic tools have yet to be clearly defined in patients with metastatic renal cell carcinoma (mRCC) who are treated with immuno-oncology (IO) checkpoint inhibitors (programmed death-ligand 1 [PD-L1] inhibitors). In the current study, the authors aimed to establish IO efficacy benchmarks in patients with mRCC and update patient outcomes in each International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic class.

Methods: A retrospective analysis was performed using the IMDC database with data from 38 centers. It included patients with mRCC who were treated with ≥1 line of IO. Overall response rates (ORRs), duration of treatment (DOT), and overall survival (OS) were calculated. Patients were stratified using IMDC prognostic factors.

Results: A total of 687 patients (90% with clear cell and 10% with non-clear cell) were included. The ORR was 27% in evaluable patients (461 patients). In patients treated with first-line nivolumab and ipilimumab (49 patients), the combination of PD-L1 inhibitor and vascular endothelial growth factor inhibitor (72 patients), and PD-L1 inhibitor (51 patients), the ORR was 31%, 39%, and 40%, respectively, and the median DOT was 8.3 months, 14.7 months, and 8.3 months, respectively. The ORR for second-line, third-line, and fourth-line nivolumab was 22%, 24%, and 26%, respectively. The median DOT was 5.7 months, 6.2 months, and 8.3 months, respectively, in the second-line, third-line, and fourth-line settings. When segregated into IMDC favorable-risk, intermediate-risk, and poor-risk groups, the median OS rates for the first-line, second-line, third-line, and fourth-line treatment settings were not reached (NR), NR, and NR, respectively (P = .163); NR, 26.7 months, and 7.4 months, respectively (P < 0. 0001); 36.1 months, 28.2 months, and 11.1 months, respectively (P = .016); and NR, NR, and 6.7 months, respectively (P = .047).

Conclusions: The ORR was not found to deteriorate from the first-line to the fourth-line of IO therapy. In the second line through fourth line, the IMDC criteria appropriately stratified patients into favorable-risk, intermediate-risk, and poor-risk groups for OS.
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http://dx.doi.org/10.1002/cncr.31595DOI Listing
September 2018

Kidney Cancer Research Network of Canada consensus statement on the role of adjuvant therapy after nephrectomy for high-risk, non-metastatic renal cell carcinoma: A comprehensive analysis of the literature and meta-analysis of randomized controlled trials.

Can Urol Assoc J 2018 Jun;12(6):173-180

Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Centre, Montreal, QC, Canada.

Introduction: The Kidney Cancer Research Network of Canada (KCRNC) collaborated to prepare this consensus statement about the use of target agents as adjuvant therapy in patients with non-metastatic renal cell carcinoma (nmRCC) after nephrectomy. We reviewed the published data and performed a meta-analysis of studies that focused on vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs).

Methods: A systematic literature search identified seven trials on adjuvant target therapy in nmRCC. Three trials, the ASSURE, S-TRAC, and PROTECT, focused on VEGFR TKIs and represented the focus of the study, including a meta-analysis combining their data on disease-free survival (DFS) and overall survival (OS).

Results: The ASSURE trial showed no DFS or OS benefit of TKIs over placebo after one year of adjuvant sorafenib or sunitinib. In contrast, the S-TRAC trial showed improved DFS after one year of adjuvant sunitinib using central review process, but not using investigator review process. No OS benefit was recorded in either study. Recently, the PROTECT trial also showed no DFS or OS benefit when one year of adjuvant pazopanib was compared to placebo. Meta-analyses of the pooled DFS and OS estimates from all three trials resulted in DFS and OS hazard ratios of 0.87 (95% confidence interval [CI] 0.73-1.04) and 1.04 (95% CI 0.89-1.22), respectively.

Conclusions: Data from three available clinical trials of adjuvant VEGFR TKIs vs. placebo do not currently support the use of adjuvant TKI therapy as standard of care after nephrectomy for nmRCC. At this time, adjuvant TKI-based adjuvant therapy is not recommended for routine use after nephrectomy for high-risk nmRCC, but highly motivated patients may benefit from a discussion with their oncologist regarding the risks and benefits of adjuvant TKI.
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http://dx.doi.org/10.5489/cuaj.5187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994982PMC
June 2018

Disparity in public funding of therapies for metastatic castrate-resistant prostate cancer across Canadian provinces.

Can Urol Assoc J 2018 Oct 16;12(10):328-336. Epub 2018 Jul 16.

Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.

Introduction: Treatment using abiraterone acetate plus prednisone, enzalutamide, cabazitaxel, and radium-223 (Ra-223) improves overall survival (OS) and quality of life for patients with metastatic castrate-resistant prostate cancer (mCRPC). Despite their proven benefits, access to these therapies is not equal across Canada.

Methods: We describe provincial differences in access to approved mCRPC therapies. Data sources include the pan-Canadian Oncology Drug Review database, provincial cancer care resources, and correspondence with pharmaceutical companies.

Results: Both androgen receptor-axis-targeted therapies (ARATs), abiraterone acetate plus prednisone and enzalutamide, are funded by provinces in the pre-and post-chemotherapy setting, however, sequential ARAT use is not funded. "Sandwich" therapy, where one ARAT is used pre-chemotherapy and a second is used upon progression on chemotherapy, is funded in six provinces: Ontario (ON), Alberta, New Brunswick, Prince Edward Island (PEI), Nova Scotia (NS), and Newfoundland and Labrador. Ra-223 is funded in five provinces: ON, Quebec (QC), British Columbia (BC), Saskatchewan, and Manitoba to varying degrees; ON allows Ra-223 either pre- or post-chemo (not both); QC allows Ra-223 post-chemo unless chemo is not tolerated; BC allows Ra-223 if other life-prolonging mCRPC therapies have been received or ineligible. Cabazitaxel is funded in all provinces post-docetaxel, except QC and PEI. Cabazitaxel is not funded as fist-line treatment for mCPRC or in combination with other agents. In ON, BC, QC, and PEI, cabazitaxel is not funded after progression on an ARAT in the post-chemotherapy setting.

Conclusions: While all provinces have access to docetaxel and ARATs, sandwiching sequential ARATs with docetaxel is funded only in select provinces. Ra-223 and cabazitaxel access is not ubiquitous across Canada. Such inequalities in access to life-prolonging therapies could lead to disparities in survival and quality of life among patients with mCRPC. Further research should quantify interprovincial variation in outcomes and cost that may result from variable access.
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http://dx.doi.org/10.5489/cuaj.5378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192749PMC
October 2018

First-line sunitinib or pazopanib in metastatic renal cell carcinoma: The Canadian experience.

Can Urol Assoc J 2017 Mar-Apr;11(3-4):112-117

Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada.

Introduction: Clinical trial data has shown pazopanib to be non-inferior in overall survival (OS) compared to sunitinib as first-line treatment for metastatic renal cell carcinoma (mRCC). The purpose of this study was to evaluate outcomes and compare dose-modifying toxicities of mRCC patients treated with suntinib or pazopanib in the real-world setting.

Methods: Data were collected on mRCC patients using the prospective Canadian Kidney Cancer Information System (CKCis) database from January 2011 to November 2015. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method.

Results: We identified 670 patients treated with sunitinib (n=577) and pazopanib (n=93). There were no significant differences in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups (p=0.807). Patients treated with sunitinib had improved OS compared with pazopanib (median 31.7 vs. 20.6 months, p=0.028; adjusted hazard ratio [aHR] 0.60; 95% confidence interval [CI] 0.380.94). Time to treatment failure (TTF) was numerically, but not statistically, improved with sunitinib (medians 11.0 vs. 8.4 months, p=0.130; aHR 0.87; 95% CI 0.591.28). Outcomes with individualized dosing on sunitinib were unavailable for this analysis. Patients treated with sunitinib had a higher incidence of mucositis, hand-foot syndrome, and gastroesophageal reflux disease; patients treated with pazopanib had a higher incidence of hepatotoxicity.

Conclusions: In Canadian patients with mRCC, treatment with sunitinib appears to be associated with an improved OS compared to pazopanib in the first-line setting. Patient selection factors and the contemporary practice of individualized dosing with sunitinib may contribute to these real-world outcomes and warrant further investigation.
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http://dx.doi.org/10.5489/cuaj.4398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434501PMC
May 2017

Setting Research Priorities for Kidney Cancer.

Eur Urol 2017 12 8;72(6):861-864. Epub 2017 May 8.

Departments of Surgery and Surgical Oncology (Division of Urology), Princess Margaret Cancer Centre, University Health Network, and the University of Toronto, Toronto, Canada.

Defining disease-specific research priorities in cancer can facilitate better allocation of limited resources. Involving patients and caregivers as well as expert clinicians in this process is of value. We undertook this approach for kidney cancer as an example. The Kidney Cancer Research Network of Canada sponsored a collaborative consensus-based priority-setting partnership that identified ten research priorities in the management of kidney cancer. These are discussed in the context of current initiatives and gaps in knowledge.
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http://dx.doi.org/10.1016/j.eururo.2017.04.011DOI Listing
December 2017

Treatment options in advanced renal cell carcinoma after first-line treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors.

Authors:
Naveen S Basappa

Can Urol Assoc J 2016 Nov-Dec;10(11-12Suppl7):S242-S244

Department of Medical Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada.

Targeted therapy for metastatic renal cell carcinoma (mRCC) was introduced a decade ago and since then, a number of therapeutic options have been developed. Vascular endothelial growth factor-targeted therapy is the widely accepted first-line option for mRCC. After progression, treatment in the second-line setting has typically been with either axitinib or everolimus. However, with the advent of several new agents demonstrating efficacy in the second-line setting, including nivolumab, cabozantinib, and the combination of lenvatinib and everolimus, the treatment paradigm has shifted toward these novel therapies with improved patient outcomes.
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http://dx.doi.org/10.5489/cuaj.4292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215301PMC
January 2017

Perioperative chemotherapy for muscle invasive bladder cancer.

Curr Opin Support Palliat Care 2015 Sep;9(3):249-54

aDivision of Urology, Department of Surgery bDivision of Medical Oncology, Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.

Purpose Of Review: Radical cystectomy with or without systemic chemotherapy is considered a standard of care for patients with muscle invasive bladder cancer (MIBC). The purpose of this review is to provide an update on current and recent literature published within the last 12 months reviewing the evidence for use of perioperative chemotherapy for patients with MIBC.

Recent Findings: In the neoadjuvant chemotherapy (NAC) setting, the evidence demonstrates clinical efficacy and lower rate of toxicity with the use of high-dose methotrexate, vinblastine, doxorubicin, and cyclophosphamide (MVAC) compared with standard MVAC. Higher quality evidence for the use of gemcitabine with cisplatin is not yet available. Meta-analysis of cisplatin-based regimens in the adjuvant setting demonstrates significant benefit in overall survival and disease-free survival specifically in patients with lymph-node-positive disease.

Summary: The available evidence suggests that along with radical cystectomy, cisplatin-based perioperative chemotherapy should be the standard of care in patients with MIBC with a higher quality and quantity of literature in support of the NAC approach. Adoption of perioperative chemotherapy for MIBC is on the rise in North America, which is reassuring. Novel therapeutic approaches for cisplatin-ineligible patients are currently being investigated.
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http://dx.doi.org/10.1097/SPC.0000000000000148DOI Listing
September 2015

The impact of tumor burden characteristics in patients with metastatic renal cell carcinoma treated with sunitinib.

Cancer 2011 Mar 19;117(6):1183-9. Epub 2010 Oct 19.

Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio 44195, USA.

Background: An important goal of noncurative therapy for metastatic renal cell carcinoma (mRCC) is tumor burden (TB) control. However, to the authors' knowledge, the impact of TB characteristics on clinical outcome has not been studied in patients with mRCC who were treated with vascular endothelial growth factor-targeted therapy.

Methods: Patients with clear cell mRCC who were treated with sunitinib between June 2004 and October 2007 were retrospectively identified. Computed tomography scans were re-reviewed from baseline, at the time of maximal TB shrinkage (TS) while receiving sunitinib, and at the time of progressive disease (PD). Measurements were recorded as per Response Evaluation Criteria In Solid Tumors (RECIST).

Results: A total of 69 patients were identified. The majority (54%) were classified as being of favorable risk using Cleveland Clinic Foundation Tyrosine Kinase Inhibitor (CCF TKI) risk group criteria. All patients underwent prior nephrectomy and 77% received prior systemic therapy. There were a median of 8 metastatic deposits across all organs (range, 1-27 deposits). The median TB at the initiation of therapy was 14.0 cm (range, 3.0 cm-42.2 cm). On multivariable analysis, baseline characteristics of disease confined to above the diaphragm (P = .03) and a total TB <13 cm (P = .09) were found to be independent positive predictors of progression-free survival. A+ baseline, total number of metastases <10 (P < .001) and TB above the diaphragm <6.5 cm (P = .05) were found to be independent positive predictors of overall survival (OS). Increased TS while receiving sunitinib was found to be significantly associated with OS (P < .001). At the time of PD, tumor location and pattern of disease progression were not found to be associated with survival as measured from the date of PD. However, total TB (P = .003) and total number of metastatic deposits (≤12 vs >12; P < .001) were found to be significant predictors of survival after PD.

Conclusions: The results of the current study indicate that TB characteristics are associated with clinical outcome in patients with mRCC who are treated with sunitinib.
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http://dx.doi.org/10.1002/cncr.25713DOI Listing
March 2011