Publications by authors named "Srikala S Sridhar"

115 Publications

Avelumab first-line maintenance in locally advanced or metastatic urothelial carcinoma: Applying clinical trial findings to clinical practice.

Cancer Treat Rev 2021 Mar 22;97:102187. Epub 2021 Mar 22.

Beth Israel Deaconess Medical Center and IMIM-PSMAR Lab, Harvard Medical School, Boston, MA, USA.

Although urothelial carcinoma (UC) is considered a chemotherapy-sensitive tumor, progression-free survival and overall survival (OS) are typically short following standard first-line (1L) platinum-containing chemotherapy in patients with locally advanced or metastatic disease. Immune checkpoint inhibitors (ICIs) have antitumor activity in UC and favorable safety profiles compared with chemotherapy; however, trials of 1L ICI monotherapy or chemotherapy + ICI combinations have not yet shown improved OS vs chemotherapy alone. In addition to direct cytotoxicity, chemotherapy has potential immunogenic effects, providing a rationale for assessing ICIs as switch-maintenance therapy. In the JAVELIN Bladder 100 phase 3 trial, avelumab administered as 1L maintenance with best supportive care (BSC) significantly prolonged OS vs BSC alone in patients with locally advanced or metastatic UC that had not progressed with 1L platinum-containing chemotherapy (median OS, 21.4 vs 14.3 months; hazard ratio, 0.69 [95% CI, 0.56-0.86]; P = 0.001). Efficacy benefits were seen across various subgroups, including recipients of 1L cisplatin- or carboplatin-based chemotherapy, patients with PD-L1+ or PD-L1- tumors, and patients with diverse characteristics. Results from JAVELIN Bladder 100 led to the approval of avelumab as 1L maintenance therapy for patients with locally advanced or metastatic UC that has not progressed with platinum-containing chemotherapy. Avelumab 1L maintenance is also included as a standard of care in treatment guidelines for advanced UC with level 1 evidence. This review summarizes the data that supported these developments and discusses practical considerations for administering avelumab maintenance in clinical practice, including patient selection and treatment management.
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http://dx.doi.org/10.1016/j.ctrv.2021.102187DOI Listing
March 2021

Lack of Evidence Does Not Equal Lack of Benefit: Neoadjuvant Chemotherapy and Trimodality Therapy in Selected Patients with Muscle-Invasive Bladder Cancer : In response to: Dirk Böhmer and Arne Grün. Lacking Evidence to Recommend Neoadjuvant Chemotherapy and Definitive Radiotherapy in Muscle-Invasive Bladder Cancer.

Curr Oncol Rep 2021 Mar 3;23(3):36. Epub 2021 Mar 3.

Department of Medicine, Division of Medical Oncology, Princess Margaret Cancer Center, University Health Network, University of Toronto, 700 University Avenue, Toronto, Ontario, M5G 6M9, Canada.

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http://dx.doi.org/10.1007/s11912-021-01035-9DOI Listing
March 2021

Evaluation of Efficacy and Safety of Nab-Paclitaxel vs Paclitaxel in Platinum-Refractory Metastatic Urothelial Cancer-Reply.

JAMA Oncol 2021 Feb 11. Epub 2021 Feb 11.

Canadian Clinical Trials Group (CCTG), Queen's University, Kingston, Ontario, Canada.

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http://dx.doi.org/10.1001/jamaoncol.2020.8017DOI Listing
February 2021

Significantly Minimizing Drug Wastage and the Cost of Cabazitaxel Used to Treat Metastatic Castration-Resistant Prostate Cancer.

Eur Urol 2021 Feb 21;79(2):177-179. Epub 2020 Oct 21.

Division of Medical Oncology, Department of Medicine, Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Cabazitaxel is used to treat patients with metastatic castration-resistant prostate cancer progressing after docetaxel. It is prepackaged in 60 mg single-dose vials, a quantity much higher than the average prescribed dose, which leads to, substantial drug wastage (DW) and associated costs. To minimize DW we implemented a cost-saving, cohorting strategy where multiple patients scheduled to receive cabazitaxel (at a dose of 20mg/m every 3 wks) were cohorted and treated on a single weekday whenever possible. Excess drug from each vial was then saved and used for subsequent patients treated on the same day. The drug cost with cohorting was calculated from the actual number of vials used, and the drug cost without cohorting was estimated by assumingthat one vial was used per treatment. The cost of DW was determined based on the amount of drug that was discarded. All cost calculations also accounted for the discount incentives offered by Sanofi-Aventis. Over a 3-yr period, 74 patients received 402 treatments of cabazitaxel. Multiple patients were treated on 67.4% of the treatment days, and grouping of three patients on one day saved one vial. The estimated total drug cost saved was $394 536 CAD (21.1%). Pending further studies on safety and efficacy, this strategy could potentially be adopted to mitigate DW for cabazitaxel and similarly for other oncology drugs. This would significantly decrease the overall financial burden on patients, institutions, and stakeholders. PATIENT SUMMARY: Cabazitaxel chemotherapy is associated with substantial drug wastage and associated costs. By cohorting patients scheduled to receive cabazitaxel on a single weekday, the total drug cost was decreased by $394 536 CAD (21.1%) over a 3-yr period. Similar strategies could be considered to overcome the prohibitory costs associated with drug wastage for cabazitaxel and other cancer drugs.
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http://dx.doi.org/10.1016/j.eururo.2020.09.048DOI Listing
February 2021

Recent Advances in the Management of Penile Cancer: A Contemporary Review of the Literature.

Oncol Ther 2021 Jan 16. Epub 2021 Jan 16.

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Penile cancer is a rare condition, which mostly affects men in their sixth decade of life. The most common histology is squamous cell carcinoma (SCC), with about half of the cases linked to human papilloma virus (HPV) infection. The lack of awareness and significant social and psychological stigma associated with penile cancer often leads to delays in presentation, diagnosis and management. Timely multidisciplinary care at experienced centers is therefore critical for improving outcomes. For patients with advanced disease, treatment options are limited and prognosis remains poor. Large international efforts are underway to further define the optimal standards of care. Targeted therapies and immune checkpoint inhibitors could potentially play a role in advanced disease and are under evaluation in clinical trials. In this review, we discuss the current management of penile cancer and future directions.
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http://dx.doi.org/10.1007/s40487-020-00135-zDOI Listing
January 2021

Enfortumab Vedotin in urothelial cancer.

Ther Adv Urol 2020 Jan-Dec;12:1756287220980192. Epub 2020 Dec 27.

Associate Professor, Department of Medicine, Medical Oncologist, Princess Margaret Cancer Center, Chair, GU Medical Oncologists of Canada, 7-625 OPG, 610 University Avenue, Toronto, ON M5G 2M9, Canada.

The treatment landscape for metastatic urothelial cancer (mUC) beyond first-line platinum-based chemotherapy has changed significantly over the last 5 years with the recent approvals of the immune checkpoint inhibitors (ICIs), fibroblast growth factor receptor (FGFR) inhibitors and most recently Enfortumab Vedotin (EV). EV is a novel antibody-drug conjugate (ADC), that delivers monomethyl auristatin E (MMAE), a microtubule-disrupting agent, inside cells harboring the cell surface nectin-4 receptor. In mUC, EV has shown encouraging response rates and received accelerated approval from the Food and Drug Administration (FDA) in December 2019 in the post-platinum and ICI setting. EV is generally well tolerated, with the main toxicities being neuropathy, skin rash, alopecia and fatigue. Notably EV can also be administered to patients with renal dysfunction, which is commonly a concern in this patient population. EV is now being tested in combination strategies and in earlier disease settings in urothelial cancers. In this review, we will discuss its mechanism of action, clinical trials leading to FDA approval as well as ongoing trials and future directions.
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http://dx.doi.org/10.1177/1756287220980192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780177PMC
December 2020

Defining cisplatin eligibility in patients with muscle-invasive bladder cancer.

Nat Rev Urol 2021 Feb 11;18(2):104-114. Epub 2021 Jan 11.

Division of Medical Oncology, Department of Medicine, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.

The current treatment paradigm for muscle-invasive bladder cancer (MIBC) consists of cisplatin-based neoadjuvant chemotherapy followed by local definitive therapy, or local definitive therapy alone for cisplatin-ineligible patients. Given that MIBC has a high propensity for distant relapse and is a chemotherapy-sensitive disease, under-utilization of chemotherapy is associated with suboptimal cure rates. Cisplatin eligibility criteria are defined for patients with metastatic bladder cancer by the Galsky criteria, which include creatinine clearance ≥60 ml/min. However, consensus is still lacking regarding cisplatin eligibility criteria in the neoadjuvant, curative MIBC setting, which continues to represent a substantial barrier to the standardization of patient care and clinical trial design. Jiang and colleagues accordingly suggest an algorithm for assessing cisplatin eligibility in patients with MIBC. Instead of relying on an absolute renal function threshold, their algorithm emphasizes a multidisciplinary and patient-centred approach. They also propose mitigation strategies to minimize the risk of cisplatin-induced nephrotoxicity in selected patients with impaired renal function. This new framework is aimed at reducing the inappropriate exclusion of some patients from cisplatin-based neoadjuvant chemotherapy (which leads to under-treatment) and harmonizing clinical trial design, which could lead to improved overall outcomes in patients with MIBC.
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http://dx.doi.org/10.1038/s41585-020-00404-6DOI Listing
February 2021

Systemic therapy in bladder preservation.

Urol Oncol 2020 Nov 19. Epub 2020 Nov 19.

Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. Electronic address:

Bladder cancer is an aggressive and lethal disease. Even when presenting as localized muscle-invasive disease, the 5-year survival rate is about 70%, and the recurrence rate after radical cystectomy is approximately 50%. Neoadjuvant chemotherapy (NAC) has the potential to downstage the primary tumor and treat micrometastases, leading to a decrease in recurrence rates and an increase in cure rates. There is level 1 evidence in favor of neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy. However, data from clinical trials evaluating NAC for patients undergoing bladder-sparing treatments are less robust, so this strategy remains controversial. The response to NAC is prognostic and patients with favorable pathological response have better overall survival. Strategies to select patients based on molecular biomarkers have the potential to guide treatment decisions and even de-intensify treatment, avoiding local treatment for those with complete responses to systemic therapy. This review outlines the current literature on the use of NAC in the context of bladder preservation for muscle-invasive bladder cancer, highlights neoadjuvant studies in patients ineligible for cisplatin-based NAC, and discusses novel bladder-preservation strategies, including multimodality combinations and biomarker-driven studies of definitive chemotherapy.
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http://dx.doi.org/10.1016/j.urolonc.2020.10.006DOI Listing
November 2020

Neoadjuvant chemotherapy plus radical cystectomy versus radical cystectomy alone in clinical T2 bladder cancer without hydronephrosis.

BJU Int 2020 Nov 5. Epub 2020 Nov 5.

Division of Urology, Department of Surgical Sciences, Torino School of Medicine, Torino, Italy.

Objectives: To assess the efficacy of neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) in a retrospective multicentre cohort of patients with cT2N0M0 bladder cancer (BCa) without preoperative hydronephrosis.

Patients And Methods: This was a propensity-based analysis of 619 patients. Of these, 316 were treated with NAC followed by RC and 303 with upfront RC. After multiple imputations, inverse probability of treatment weighting (IPTW) was used to account for potential selection bias. Multivariable logistic regression analysis was performed to evaluate the impact of NAC on pathological complete response and downstaging at RC, while IPTW-adjusted Kaplan-Meier curves and Cox regression models were built to evaluate the impact of NAC on overall survival (OS).

Results: After IPTW-adjusted analysis, standardised differences between groups were <15%. A complete response (pT0N0) at final pathology was achieved in 94 (30%) patients receiving NAC and nine (3%) undergoing upfront RC. Downstaging to non-muscle-invasive disease (
Conclusions: In patients with cT2N0 BCa and no preoperative hydronephrosis, NAC increased the rate of pathological complete response and downstaging.
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http://dx.doi.org/10.1111/bju.15289DOI Listing
November 2020

Comparative effectiveness of neoadjuvant chemotherapy in bladder and upper urinary tract urothelial carcinoma.

BJU Int 2020 Sep 27. Epub 2020 Sep 27.

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

Objective: To assess the differential response to neoadjuvant chemotherapy (NAC) in patients with urothelial carcinoma of the bladder (UCB) compared to upper tract urothelial carcioma (UTUC) treated with radical surgery.

Patients And Methods: Data from 1299 patients with UCB and 276 with UTUC were obtained from multicentric collaborations. The association of disease location (UCB vs UTUC) with pathological complete response (pCR, defined as a post-treatment pathological stage ypT0N0) and pathological objective response (pOR, defined as ypT0-Ta-Tis-T1N0) after NAC was evaluated using logistic regression analyses. The association with overall (OS) and cancer-specific survival (CSS) was evaluated using Cox regression analyses.

Results: A pCR was found in 250 (19.2%) patients with UCB and in 23 (8.3%) with UTUC (P < 0.01). A pOR was found in 523 (40.3%) patients with UCB and in 133 (48.2%) with UTUC (P = 0.02). On multivariable logistic regression analysis, patients with UTUC were less likely to have a pCR (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.27-0.70; P < 0.01) and more likely to have a pOR (OR 1.57, 95% CI 1.89-2.08; P < 0.01). On univariable Cox regression analyses, UTUC was associated with better OS (hazard ratio [HR] 0.80, 95% CI 0.64-0.99, P = 0.04) and CSS (HR 0.63, 95% CI 0.49-0.83; P < 0.01). On multivariable Cox regression analyses, UTUC remained associated with CSS (HR 0.61, 95% CI 0.45-0.82; P < 0.01), but not with OS.

Conclusions: Our present findings suggest that the benefit of NAC in UTUC is similar to that found in UCB. These data can be used as a benchmark to contextualise survival outcomes and plan future trial design with NAC in urothelial cancer.
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http://dx.doi.org/10.1111/bju.15253DOI Listing
September 2020

Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma.

N Engl J Med 2020 09 18;383(13):1218-1230. Epub 2020 Sep 18.

From Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary University of London, St. Bartholomew's Hospital, London (T.P.); Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Centre Jean Bernard Clinique Victor Hugo, Le Mans (E.V.), and Gustave Roussy, INSERM Unité 981, Université Paris-Saclay, Villejuif (Y.L.) - both in France; the Medical Oncology Unit, Azienda Ospedaliera S. Maria, Terni (C.C.), and Pfizer, Milan (C.F., A.P.) - both in Italy; the Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Seville, Spain (B.P.V.); the Department of Clinical Medicine, Macquarie University, Sydney (H.G.); the Division of Oncology, Department of Medicine, University General Hospital of Patras, Patras, Greece (H.K.); the Institute for Oncology and Radiology of Serbia, Belgrade (S.R.); the Department of Medical Oncology, Algemeen Ziekenhuis Klina, Brasschaat, Belgium (W.D.); Patient Area Pelvic Cancer, Theme Cancer, Karolinska University Hospital, and the Department of Oncology-Pathology, Karolinska Institute, Solna, Sweden (A.U.); Princess Margaret Cancer Centre, University Health Network, Toronto (S.S.S.); the Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan (N.T.); the State Institution of Healthcare Regional Clinical Oncology Dispensary, Omsk, Russia (E.K.); the Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York (C.N.S.); the Department of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston (J.B.), and Pfizer, Cambridge (R.L., J.W.) - both in Massachusetts; Inova Schar Cancer Institute, Fairfax, VA (J.B.A.-C.); Yale Cancer Center, New Haven (D.P.P.), and Pfizer, Groton (B.H.) - both in Connecticut; Pfizer, La Jolla, CA (C.D., J.A.B.-H.); Pfizer, Porto Salvo, Portugal (N.C.); and the Department of Medicine, Division of Oncology, University of Washington, and the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle (P.G.).

Background: Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance.

Methods: In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival, assessed among all patients who underwent randomization (overall population) and among those with tumors positive for programmed cell death ligand 1 (PD-L1). Secondary end points included progression-free survival and safety.

Results: Among all 700 patients who underwent randomization, the addition of maintenance avelumab to best supportive care significantly prolonged overall survival as compared with best supportive care alone (control). Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.86; P = 0.001). Avelumab also significantly prolonged overall survival in the PD-L1-positive population; overall survival at 1 year was 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% CI, 0.40 to 0.79; P<0.001). The median progression-free survival was 3.7 months in the avelumab group and 2.0 months in the control group in the overall population (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75) and 5.7 months and 2.1 months, respectively, in the PD-L1-positive population (hazard ratio, 0.56; 95% CI, 0.43 to 0.73). The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively.

Conclusions: Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Bladder 100 ClinicalTrials.gov number, NCT02603432.).
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http://dx.doi.org/10.1056/NEJMoa2002788DOI Listing
September 2020

Efficacy and Safety of nab-Paclitaxel vs Paclitaxel on Survival in Patients With Platinum-Refractory Metastatic Urothelial Cancer: The Canadian Cancer Trials Group BL.12 Randomized Clinical Trial.

JAMA Oncol 2020 Sep 17. Epub 2020 Sep 17.

Canadian Cancer Trials Group (CCTG), Queen's University, Kingston, Ontario, Canada.

Importance: Treatment options for platinum-refractory metastatic urothelial cancer (mUC) are limited, and outcomes remain poor. Nab-paclitaxel is an albumin-bound formulation of paclitaxel showing promising activity and tolerability in a prior single-arm trial.

Objectives: To evaluate the efficacy and safety of nab-paclitaxel vs paclitaxel in platinum-refractory mUC.

Design, Setting, And Participants: In this investigator-initiated, open-label, phase 2 randomized clinical trial conducted across Canada and Australia from January 2014 to April 2017, eligible patients had histologically confirmed, radiologically evident mUC of the urinary tract. Mixed histologic findings, except small cell, were permitted provided UC was the predominant histologic finding. All patients had received platinum-based chemotherapy either in the metastatic setting or were within 12 months of perioperative chemotherapy. Patients with prior taxane chemotherapy were not included. Patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 2 and adequate organ function.

Interventions: Patients were randomized to nab-paclitaxel, 260 mg/m2, or paclitaxel, 175 mg/m2, every 3 weeks.

Main Outcomes And Measures: The primary end point was progression-free survival (PFS).

Results: Among 199 patients, median age was 67 (range, 24-88) years; 144 (72%) were men; 167 (84%) were ECOG PS 0-1; 59 (30%) had liver metastases; and 110 (55%) were within 6 months of prior platinum-based chemotherapy. At a median follow-up of 16.4 months, there was no significant difference between nab-paclitaxel vs paclitaxel for median PFS (3.4 months vs 3.0 months; hazard ratio [HR], 0.92; 90% CI, 0.68-1.23; 1-sided P = .31). Median overall survival was 7.5 months for nab-paclitaxel vs 8.8 months for paclitaxel (HR, 0.95; 90% CI, 0.70-1.30; 1-sided P = .40); and objective response rate (ORR) was 22% for nab-paclitaxel vs 25% for paclitaxel (P = .97). Grade 3/4 adverse events were more frequent with nab-paclitaxel (64/97 [66%]) compared with paclitaxel (45/97 [46%]), P = .009; but peripheral sensory neuropathy was similar (all grades, 72/97 [74%] vs 64/97 [66%]; grade 3/4, 7/97 [7%] vs 3/97 [3%]; P = .27). There were no apparent differences in scores for health-related quality of life.

Conclusions And Relevance: In this open-label, phase 2 randomized clinical trial of patients with platinum-refractory mUC, nab-paclitaxel had similar efficacy to paclitaxel; but worse toxic effects. The ORR with either taxane, however, was higher than previously reported and similar to those reported for the immune checkpoint inhibitors, suggesting that the taxanes remain a reasonable option in this setting.

Trial Registration: ClinicalTrials.gov Identifier: NCT02033993.
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http://dx.doi.org/10.1001/jamaoncol.2020.3927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499236PMC
September 2020

Canadian experience of neoadjuvant chemotherapy on bladder recurrences in patients managed with trimodal therapy for muscle-invasive bladder cancer.

Can Urol Assoc J 2020 Dec;14(12):404-410

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

Introduction: Bladder preservation with trimodal therapy (TMT) has emerged as a feasible alternative to radical cystectomy in patients with muscle-invasive bladder cancer. Neoadjuvant chemotherapy (NAC) was proven to cause pathological downstaging. For this reason, we evaluated whether receipt of NAC decreases local bladder recurrences in TMT patients.

Methods: We retrospectively analyzed our TMT database for all patients treated between 2003 and 2017. Patients were treated with maximal transurethral resection of bladder tumor (TURBT) followed by chemotherapy/radiotherapy with or without NAC. Baseline demographic and tumor characteristics were recorded. Rates of local and systemic recurrence were analyzed per receipt of NAC. Overall recurrence-free survival (RFS) and bladder (b)RFS were analyzed using the Kaplan-Meier method and Cox proportional hazards modelling.

Results: Median age and followup periods were 72 years and 3.6 years, respectively. Fifty-four patients had NAC and concurrent chemoradiation (NAC-TMT) vs. 70 patients who had concurrent chemoradiation only (TMT). Carcinoma in situ (CIS) was present in 31% of the patients in NAC-TMT group compared to 24% in TMT group (p=0.40). After treatment, 24 (44%) and 31 (44%) patients in NAC-TMT and TMT groups, respectively, had bladder tumor recurrence. Overall RFS at three years was 46% and 50% in NAC-TMT and TMT groups, respectively (p=0.70). BRFS at three years was 55% and 69% in NAC-TMT and TMT groups, respectively (p=0.27). Multivariable analyses found that the presence of concomitant CIS (hazard ratio [HR] 2.13; 95% confidence interval CI 1.06-4.27; p=0.0036) was the primary factor associated with local bladder recurrence.

Conclusions: Receipt of NAC does not obviate the risk of bladder recurrence post-TMT. Patients with CIS should be monitored especially closely for local recurrence.
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http://dx.doi.org/10.5489/cuaj.6459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704086PMC
December 2020

Transitioning to a New Normal in the Post-COVID Era.

Curr Oncol Rep 2020 06 22;22(7):73. Epub 2020 Jun 22.

Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 6M9, Canada.

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http://dx.doi.org/10.1007/s11912-020-00956-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306409PMC
June 2020

Key Perspectives on Managing Older Patients with Prostate Cancer: What We Know About the Fit and What We Need to Know About the Frail.

Eur Urol Oncol 2020 08 16;3(4):410-411. Epub 2020 Jun 16.

Department of Medicine, University Health Network, University of Toronto, Toronto, Canada.

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http://dx.doi.org/10.1016/j.euo.2020.05.006DOI Listing
August 2020

Eligibility Criteria and Endpoints in Metastatic Renal Cell Carcinoma Trials.

Am J Clin Oncol 2020 08;43(8):559-566

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre.

Objectives: Treatments for metastatic renal cell carcinoma (mRCC) are often compared across trials, but trial eligibility criteria and endpoints differ. In an effort to better align trials, the Definition for the Assessment of Time to event Endpoints in CANcer trials (DATECAN) project published recommendations in 2015 to be used in mRCC clinical trial design. We analyzed mRCC trial criteria to determine if DATECAN's recommendations were followed.

Materials And Methods: We compared eligibility criteria across 29 phase 3 mRCC trials conducted between 2003 and 2019. We then evaluated endpoints used in 10 phase 3 trials activated between 2015 and 2019 to determine their compliance with DATECAN's recommendations.

Results: Among the 29 trials, performance status, renal function, and disease characteristics differed in terms of requirements and measures used. In terms of endpoints, the 10 trials did not entirely follow DATECAN's recommendations. In total, 7/10 trials' primary endpoint was progression-free survival (PFS) as recommended; 4/9 trials used PFS as an endpoint but did not publish their definition of PFS, and the 5 that did, included "death from any cause" instead of DATECAN's recommendation of "death from kidney cancer."

Conclusions: Key eligibility criteria were somewhat inconsistent across the phase 3 mRCC trials studied. Endpoints in the newer trials did not align with DATECAN's recommendations. Not only is greater standardization needed to facilitate meta-analyses and cross-trial comparisons, but as evident from lack of adherence to DATECAN's recommendations, greater promotion and adoption of recommendations are needed to better harmonize trial design.
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http://dx.doi.org/10.1097/COC.0000000000000705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515769PMC
August 2020

Optimizing management of advanced urothelial carcinoma: A review of emerging therapies and biomarker-driven patient selection.

Can Urol Assoc J 2020 Aug;14(8):E373-E382

Division of Medical Oncology, University of Alberta, Edmonton, AB, Canada.

Introduction: Advanced urothelial carcinoma has been challenging to treat due to limited treatment options, poor response rates, and poor long-term survival. New treatment options hold the promise of improved outcomes for these patients.

Methods: A multidisciplinary working group drafted a management algorithm for advanced urothelial carcinoma using "consensus development conference" methodology. A targeted literature search identified new and emerging treatments for inclusion in the management algorithm. Published clinical data were considered during the algorithm development process, as well as the risks and benefits of the treatment options. Biomarkers to guide patient selection in clinical trials for new treatments were incorporated into the algorithm.

Results: The advanced urothelial carcinoma management algorithm includes newly approved first-line anti-programmed death receptor-1 (PD1)/ programmed death-ligand 1 (PD-L1) therapies, a newly approved anti-fibroblast growth factor receptors (FGFR) therapy, and an emerging anti-Nectin 4 therapy, which have had encouraging results in phase 2 trials for second-line and third-line therapy, respectively. This algorithm also incorporates suggestions for biomarker testing of PD-L1 expression and FGFR gene alterations.

Conclusions: Newly approved and emerging therapies are starting to cover an unmet need for more treatment options, better response rates, and improved overall survival in advanced urothelial carcinoma. The management algorithm provides guidance on how to incorporate these new options, and their associated biomarkers, into clinical practice.
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http://dx.doi.org/10.5489/cuaj.6458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402696PMC
August 2020

Unfavorable Cancer-specific Survival After Neoadjuvant Chemotherapy and Radical Cystectomy in Patients With Bladder Cancer and Squamous Cell Variant: A Multi-institutional Study.

Clin Genitourin Cancer 2020 10 8;18(5):e543-e556. Epub 2020 Feb 8.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Nonurothelial carcinoma (UC) malignancies have traditionally been considered to have a more aggressive clinical course, and little is known about their response to neoadjuvant therapy. We examined the effect of neoadjuvant chemotherapy (NAC) on a large population of patients with bladder cancer (BCa) with different histologic variants (HVs).

Patients And Methods: We relied on a retrospective, multicenter database of 2858 patients with BCa who had undergone radical cystectomy with or without NAC from 1990 to 2017. Pure and mixed HVs were grouped into 6 categories: squamous cell carcinoma (SCC; n = 283; 45%), other subtypes (n = 95; 15%), micropapillary (n = 85; 14%), adenocarcinoma (n = 65; 10%), small cell (n = 54; 8.6%), and sarcomatous (n = 47; 7.6%). Kaplan-Meier and Cox regression analyses were used to examine cancer-specific survival (CSS) according to the HV, using pure UC as the reference. Logistic regression models were used to examine the odds of clinical-to-pathologic downstaging after NAC according to the HV.

Results: Overall, we identified 2229 cases of pure UC and 629 cases of BCa with HVs at radical cystectomy. Of the 450 NAC-treated patients, only those patients with SCC (n = 44; 9.8%) had had worse CSS (median CSS, 33 vs. 116 months; P < .001) and higher mortality rates (hazard ratio, 2.1; P = .03) compared with those with pure UC (n = 328; 72.9%). The results of the analyses were also confirmed when the pure and mixed cases were considered separately. After adjusting for NAC, only SCC showed a lower rate of clinical-to-pathologic downstaging (odds ratio, 0.4; P = .03) compared with UC.

Conclusions: SCC was the HV exhibiting the lowest effect of NAC in terms of activity and CSS. Compared with pure UC, SCC seemed to be insensitive to traditional NAC regimens.
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http://dx.doi.org/10.1016/j.clgc.2020.01.007DOI Listing
October 2020

Impact of sex on response to neoadjuvant chemotherapy in patients with bladder cancer.

Urol Oncol 2020 07 11;38(7):639.e1-639.e9. Epub 2020 Feb 11.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX; Departments of Urology, Weill Cornell Medical College, New York, New York; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow, Russia. Electronic address:

Objective: To assess the effect of patient's sex on response to neoadjuvant chemotherapy (NAC) in patients with clinically nonmetastatic muscle-invasive bladder cancer (MIBC).

Methods: Complete pathologic response, defined as ypT0N0 at radical cystectomy, and downstaging were evaluated using sex-adjusted univariable and multivariable logistic regression modeling. We used interaction terms to account for age of menopause and smoking status. The association of sex with overall survival and cancer-specific survival was evaluated using Cox regression analyses.

Results: A total of 1,031 patients were included in the analysis, 227 (22%) of whom were female. Female patients had a higher rate of extravesical disease extension (P = 0.01). After the administration of NAC, ypT stage was equally distributed between sexes (P = 0.39). On multivariable logistic regression analyses, there was no difference between the sexes or age of menopause with regards to ypT0N0 rates or downstaging (all P > 0.5). On Cox regression analyses, sex was associated with neither overall survival (hazard ratio 1.04, 95% confidence interval 0.75-1.45, P = 0.81) nor cancer-specific survival (hazard ratio 1.06, 95% confidence interval 0.71-1.58, P = 0.77).

Conclusion: Our study generates the hypothesis that NAC equalizes the preoperative disparity in pathologic stage between males and females suggesting a possible differential response between sexes. This might be the explanation underlying the comparable survival outcomes between sexes despite females presenting with more advanced tumor stage.
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http://dx.doi.org/10.1016/j.urolonc.2020.01.010DOI Listing
July 2020

Application of the ASCO Value Framework and ESMO Magnitude of Clinical Benefit Scale to Assess the Value of Abiraterone and Enzalutamide in Advanced Prostate Cancer.

JCO Oncol Pract 2020 02 21;16(2):e201-e210. Epub 2020 Jan 21.

Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Purpose: As novel hormonal therapies, such as abiraterone and enzalutamide, move into earlier stages of treatment of advanced prostate cancer, there are significant cost implications. We used the ASCO Value Framework (AVF) and European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) to quantify and compare the incremental clinical benefit and costs of these agents in the metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC) settings.

Methods: We searched PubMed for randomized phase III trials of abiraterone and enzalutamide in mCRPC and mCSPC. Incremental clinical benefit was quantified using the AVF and ESMO-MCBS by 2 independent assessors. Incremental drug costs were calculated using average wholesale prices (AWPs) from the RED BOOK Online.

Results: In mCRPC, 2 abiraterone trials (COU-AA-301 and COU-AA-302) and 2 enzalutamide trials (AFFIRM and PREVAIL) met search criteria. AVF scores ranged from 46.3 to 66.6, suggesting clinical benefit; ESMO-MCBS scores ranged from 3 to 5, with lower clinical benefit in the mCRPC predocetaxel setting. The overall incremental AWP ranged from $83,460.94 to $205,128.85. In mCSPC, 4 trials met criteria (LATITUDE, STAMPEDE, ENZAMET, and ARCHES; AVF scores were 79.8, 33.3, 59, and 17, respectively). All of the studies showed benefit except ARCHES. By ESMO-MCBS, both LATITUDE and STAMPEDE showed benefit (score for 4 for both studies); ENZAMET and ARCHES were not evaluable. The overall cost of treatment was significantly higher in the mCSPC setting.

Conclusion: The AVF and ESMO-MCBS frameworks generated slightly different results but suggested that abiraterone and enzalutamide show clinical benefit in both mCRPC and mCSPC but trended to lower clinical benefit and increased costs in earlier disease stages. Further refinement of the AVF and ESMO-MCBS is needed to facilitate their use and their ability to inform clinical practice in a rapidly changing treatment landscape.
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http://dx.doi.org/10.1200/JOP.19.00421DOI Listing
February 2020

EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4-Positive Solid Tumors, Including Metastatic Urothelial Carcinoma.

J Clin Oncol 2020 04 7;38(10):1041-1049. Epub 2020 Feb 7.

Yale School of Medicine, New Haven, CT.

Purpose: To assess the safety/tolerability and antitumor activity of enfortumab vedotin (EV), a novel investigational antibody-drug conjugate that delivers the microtubule-disrupting agent, monomethyl auristatin E, to cells that express Nectin-4.

Methods: EV-101 is a phase I dose escalation/expansion study that enrolled patients with Nectin-4-expressing solid tumors (eg, metastatic urothelial carcinoma [mUC]) who progressed on ≥ 1 prior chemotherapy regimen and/or programmed death-1 receptor/programmed death ligand-1 [PD-(L)1] inhibitor, including a cohort of patients with mUC who received prior anti-PD-(L)1 therapy. Patients received escalating doses of EV up to 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. Primary objectives were evaluation of safety/tolerability and pharmacokinetics; antitumor activity was a secondary objective.

Results: Enrolled patients with mUC (n = 155) were heavily pretreated, with 96% having prior platinum-based chemotherapy and 29% receiving ≥ 3 lines of prior treatment. Maximum tolerated dose of EV was not established; however, the recommended phase II dose was identified as 1.25 mg/kg. Rash, peripheral neuropathy, fatigue, alopecia, and nausea were the most common treatment-related adverse events (TRAEs); the most common TRAEs were grade 1-2 in severity. Among the 112 patients with mUC treated with single-agent EV 1.25 mg/kg, the investigator-assessed confirmed objective response rate (ORR) was 43%, and duration of response was 7.4 months. Median overall survival (OS) was 12.3 months, and the OS rate at 1 year was 51.8%. Similar ORR and estimated median OS were observed in patients ≥ 75 years of age with and without prior anti-PD-(L)1 treatment, liver metastases, or upper-tract disease.

Conclusion: Single-agent EV was generally well tolerated and provided clinically meaningful and durable responses in patients with mUC; survival data are encouraging. A pivotal phase II and a confirmatory phase III study are ongoing.
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http://dx.doi.org/10.1200/JCO.19.02044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106979PMC
April 2020

Is it time to redefine cisplatin ineligibility in metastatic urothelial cancer?

Eur J Cancer 2020 03 31;127:158-159. Epub 2020 Jan 31.

Princess Margaret Cancer Center, University of Toronto, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2019.12.019DOI Listing
March 2020

Trimodality Therapy for Muscle-Invasive Bladder Cancer: Recent Advances and Unanswered Questions.

Curr Oncol Rep 2020 02 1;22(2):14. Epub 2020 Feb 1.

Department of Medicine, Division of Medical Oncology, Princess Margaret Cancer Center, University Health Network, University of Toronto, Canada, 700 University Avenue, Toronto, ON, Canada.

Purpose Of Review: Bladder-sparing trimodality therapy (TMT) has become an accepted alternative to cystectomy for selected muscle invasive bladder cancer (MIBC) patients unfit for cystectomy or opting for bladder preservation. This review will summarize recent advances in TMT for MIBC.

Recent Findings: A growing body of literature has emerged which supports the use of TMT. However, its delivery is yet to be standardized. The role of chemotherapy and predictive biomarkers remain to be elucidated. Novel bladder-sparing approaches, drug combinations including immunotherapy and targeted therapies are under investigation in clinical trials, with the goal of ultimately enhancing survival and quality of life outcomes. Recent advances in TMT have made bladder preservation possible for MIBC patients seeking an alternative local therapy to cystectomy. With careful patient selection, TMT offers comparable survival outcomes to cystectomy, and improved quality of life as patients are able to successfully retain their bladder.
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http://dx.doi.org/10.1007/s11912-020-0880-5DOI Listing
February 2020

Development of the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM): A toxicity subscale to measure quality of life in patients with cancer who are treated with ICMs.

Cancer 2020 04 8;126(7):1550-1558. Epub 2020 Jan 8.

Applied Health Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.

Background: Patients with cancer who are treated with immune checkpoint modulators (ICMs) have their health-related quality of life (HRQOL) measured using general patient-reported outcome (PRO) tools. To the authors' knowledge, no instrument has been developed to date specifically for patients treated with ICMs. The objective of the current study was to develop a toxicity subscale PRO instrument for patients treated with ICMs to assess HRQOL.

Methods: Input was collected from a systematic review as well as patients and physicians experienced with ICM treatment. Descriptive thematic analysis was used to evaluate the qualitative data obtained from patient focus groups and interviews, which informed an initial list of items that described ICM side effects and their impact on HRQOL. These inputs informed item generation and/or reduction to develop a toxicity subscale.

Results: Focus groups and individual interviews with 37 ICM-treated patients generated an initial list of 176 items. After a first round of item reduction that produced a shortened list of 76 items, 16 physicians who care for patients who are treated with ICMs were surveyed with a list of 49 patient-reported side effects and 11 physicians participated in follow-up interviews. A second round of item reduction was informed by the physician responses to produce a list of 25 items.

Conclusions: To the authors' knowledge, this 25-item list is the first HRQOL-focused toxicity subscale for patients treated with ICMs and was developed in accordance with US Food and Drug Administration guidelines, which prioritize patient input in developing PRO tools. The subscale will be combined with the Functional Assessment of Cancer Therapy-General (FACT-G) to form the FACT-ICM. Prior to recommending the formal use of this PRO instrument, the authors will evaluate its validity and reliability in longitudinal studies involving substantially more patients.
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http://dx.doi.org/10.1002/cncr.32692DOI Listing
April 2020

Impact of age at diagnosis of de novo metastatic prostate cancer on survival.

Cancer 2020 03 26;126(5):986-993. Epub 2019 Nov 26.

Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Background: An older age at the diagnosis of prostate cancer has been linked to worse prostate cancer-specific survival (PCSS). However, these studies were conducted before the approval of many life-prolonging drugs. This study was aimed at describing outcomes in a contemporary cohort of men diagnosed with de novo metastatic prostate cancer (mPCa) and assessing associations with the age at diagnosis while controlling for known prognostic factors.

Methods: The Surveillance, Epidemiology, and End Results registry was used to identify men diagnosed with mPCa from 2004 to 2014. Men were classified by 4 age groups: ≤54, 55 to 64, 65 to 74, and ≥75 years. The median overall survival, PCSS, and restricted mean survival times for any-cause mortality and prostate cancer-specific mortality (PCSM) were calculated. Multivariable and subdistribution hazard ratios for PCSM according to age group and with controlling for race, marital status, and income were estimated.

Results: Compared with men aged ≤54 years, men aged ≥75 years experienced a mean PCSS at 5 years that was 6.7 months shorter (95% confidence interval [CI], 5.5-7.8 months). In multivariable analyses, men aged ≥75 years had a 49% increase in the rate of PCSM in comparison with those aged ≤54 years (95% CI, 1.39-1.60). The subdistribution hazard ratio for PCSM between these groups was 1.41 (95% CI, 1.32-1.50).

Conclusions: Age was found to be an independent predictor of shorter PCSS in men diagnosed with de novo mPCa even in an era with more effective therapies. Further work is needed to determine the reason for poor outcomes in older men with mPCa.
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http://dx.doi.org/10.1002/cncr.32630DOI Listing
March 2020

The prognostic value of the neutrophil-to-lymphocyte ratio in patients with muscle-invasive bladder cancer treated with neoadjuvant chemotherapy and radical cystectomy.

Urol Oncol 2020 01 31;38(1):3.e17-3.e27. Epub 2019 Oct 31.

Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Introduction: The neutrophil-to-lymphocyte ratio (NLR) is an attractive marker because it is derived from routine bloodwork. NLR has shown promise as a prognostic factor in muscle invasive bladder cancer (MIBC) but its value in patients receiving neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) is not yet established. Since NLR is related to an oncogenic environment and poor antitumor host response, we hypothesized that a high NLR would be associated with a poor response to NAC and would remain a poor prognostic indicator in patients receiving NAC.

Methods: A retrospective analysis was performed on patients with nonmetastatic MIBC (cT2-4aN0M0) who received NAC prior to RC between 2000 and 2013 at 1 of 19 centers across Europe and North America. The pre-NAC NLR was used to split patients into a low (NLR ≤ 3) and high (NLR > 3) group. Demographic and clinical parameters were compared between the groups using Student's t test, chi-squared, or Fisher's exact test. Putative risk factors for disease-specific and overall survival were analyzed using Cox regression, while predictors of response to NAC (defined as absence of MIBC in RC specimen) were investigated using logistic regression.

Results: Data were available for 340 patients (199 NLR ≤ 3, 141 NLR > 3). Other than age and rate of lymphovascular invasion, demographic and pretreatment characteristics did not differ significantly. More patients in the NLR > 3 group had residual MIBC after NAC than the NLR ≤ 3 group (70.8% vs. 58.3%, P = 0.049). NLR was the only significant predictor of response (odds ratio: 0.36, P = 0.003) in logistic regression. NLR was a significant risk factor for both disease-specific (hazard ratio (HR): 2.4, P = 0.006) and overall survival (HR:1.8, P = 0.02).

Conclusion: NLR > 3 was associated with a decreased response to NAC and shorter disease-specific and overall survival. This suggests that NLR is a simple tool that can aid in MIBC risk stratification in clinical practice.
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http://dx.doi.org/10.1016/j.urolonc.2019.09.023DOI Listing
January 2020