PURPOSE:Two phase 3 randomized controlled trials (OTT-0101, RTOG-9413) and a meta-analysis have shown an impact of sequencing of androgen deprivation therapy (ADT) and radiation therapy on oncologic outcomes in prostate cancer (PCa). However, the impact of sequencing strategy on health-related quality of life (HR-QoL) is unclear. Here, we present the patient-reported HR-QoL outcomes from the OTT-0101 study. METHODS AND MATERIALS:In this trial, patients with PCa with Gleason score ≤7, clinical stage T1b to T3a, and prostate-specific antigen level <30 ng/mL were randomly assigned to neoadjuvant and concurrent ADT for 6 months, starting 4 months before or concurrent with prostate radiation therapy, or concurrent and adjuvant ADT for 6 months, starting simultaneously with prostate radiation therapy. HR-QoL was assessed using European Organisation for Research and Treatment of Cancer QoL questionnaires. Time until definitive deterioration was defined as time from random allocation to the first deterioration of at least 10 points with no further improvement of ≥10 points or if the patient experienced progression, died, or dropped out after deterioration, resulting in missing data. Stratified log-rank tests were applied for between-group comparisons of time-to-event estimates. RESULTS:Overall, 393 patients (194 and 199 in the 2 arms, respectively) were evaluable, except 214 (101 and 113 in the 2 arms, respectively) for sexual function. Five-year rates of freedom from definitive deterioration of urinary symptoms, bowel symptoms, and sexual activity were 33.5%, 33.1%, and 38.5% in the neoadjuvant group and 34.1%, 35.4%, and 36.7% in the adjuvant group, respectively, with no significant between-group differences. The adjuvant approach was associated with a reduced risk of definitive deterioration of sexual function (hazard ratio, 0.68; 95% confidence interval, 0.49-0.94; P = .02). With respect to clinical relevance, the mean change in score for sexual function showed only a small to moderate difference favoring the adjuvant group at and beyond 3 years. CONCLUSIONS:In this study, no differences were found in the bowel or urinary symptoms between the adjuvant and neoadjuvant approach. Considering a significant likelihood of type I and type II errors and because of a lack of a persistent and clinically meaningful between-group difference in mean score changes over time, our findings do not confer a clear and conclusive picture of the impact of sequencing strategy on sexual function.

Letters28 August 2020Salivary Detection of COVID-19FREELisa Caulley, MD, MPH, Martin Corsten, MD, Libni Eapen, MD, Jonathan Whelan, BSc, Jonathan B. Angel, MD, Kym Antonation, MPH, Nathalie Bastien, PhD, Guillaume Poliquin, MD, PhD*, and Stephanie Johnson-Obaseki, MD, MPH*Lisa Caulley, MD, MPHUniversity of Ottawa and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (L.C., J.B.A.)Search for more papers by this author, Martin Corsten, MDDalhousie University, Halifax, Nova Scotia, Canada (M.C.)Search for more papers by this author, Libni Eapen, MDUniversity of Ottawa, Ottawa, Ontario, Canada (L.E., J.W., S.J.)Search for more papers by this author, Jonathan Whelan, BScUniversity of Ottawa, Ottawa, Ontario, Canada (L.E., J.W., S.J.)Search for more papers by this author, Jonathan B. Angel, MDUniversity of Ottawa and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (L.C., J.B.A.)Search for more papers by this author, Kym Antonation, MPHNational Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada (K.A., N.B.)Search for more papers by this author, Nathalie Bastien, PhDNational Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada (K.A., N.B.)Search for more papers by this author, Guillaume Poliquin, MD, PhD*National Microbiology Laboratory, Public Health Agency of Canada, and University of Manitoba, Winnipeg, Manitoba, Canada (G.P.)Search for more papers by this author, and Stephanie Johnson-Obaseki, MD, MPH*University of Ottawa, Ottawa, Ontario, Canada (L.E., J.W., S.J.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M20-4738 SectionsSupplemental MaterialAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Background: Standard testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires a nasopharyngeal or oropharyngeal swab but is limited by modest sensitivity, the need for health care human resources and personal protective equipment, and the potential for transmission in transit to or at the testing center. An urgent need exists for innovative testing strategies to expedite identification of cases and facilitate mass testing.Objective: To determine the detection rate of SARS-CoV-2 using a novel, self-administered kit for saliva collection compared with standard swab testing.Methods: We prospectively enrolled consecutive, asymptomatic, high-risk persons and those with mild symptoms suggestive of coronavirus disease 2019 (COVID-19) at a centralized testing center in Ottawa, Canada. Eligible adults provided 1 saliva specimen using a self-collection kit (OMNIgene•ORAL, OM-505 [DNA Genotek]) concurrent with their standard swab test. These kits are designed for self-collection without expert assistance and can preserve viral material at room temperature for transport and analysis (1). Total nucleic acid extraction and polymerase chain reaction analysis for SARS-CoV-2 were done at the Eastern Ontario Regional Laboratory in Ottawa for swabs and at the National Microbiology Laboratory in Winnipeg for saliva. Outcomes were reported for detection of the SARS-CoV-2 envelope (E) gene with a cycle threshold value less than 37. The Supplement provides additional methodological details.Findings: Of the 1939 paired swab and saliva samples analyzed (Figure), SARS-CoV-2 E gene was detected in 70 samples (Table), 80.0% with swabs and 68.6% with saliva. Thirty-four participants (48.6%) tested positive for SARS-CoV-2 on both swab and saliva samples. Discordant test results were seen in 22 participants (31.4%) who tested positive with swab alone and in 14 (20%) who tested positive with saliva alone. Swabs were obtained from the nasopharynx in 35.7% of participants who tested positive with saliva alone, compared with 9.1% of participants who tested positive with swab alone.Figure. Study flow diagram.Standard swab and saliva sample collection during the study period. COVID-19 = coronavirus disease 2019.* Inclusion criteria were age ≥18 y, provision of informed consent, and being high-risk asymptomatic or having mild symptoms of COVID-19. Patients were screened before entry by a physician. Those with severe symptoms were redirected to an emergency department for formal clinical evaluation.† Eight participants were tested twice at the testing center (for both standard swab and saliva sample). Two tested positive on their initial oropharyngeal swab and negative on a saliva sample. These participants' results remained positive on an oropharyngeal swab and negative on a saliva sample on repeated testing (5 d and 8 d later). One participant tested positive on the initial oropharyngeal swab and negative on the saliva sample. This participant tested negative on both specimens 7 d later. The remaining 6 participants tested negative on initial and repeated testing for both specimens. Download figure Download PowerPoint Table. Characteristics of Population That Tested Positive for SARS-CoV-2Discussion: Our study found that standard diagnostic methods of nasopharyngeal and oropharyngeal swabs detected more COVID-19 cases than saliva testing among patients who were asymptomatic but at high risk or who were mildly symptomatic. Salivary detection of SARS-CoV-2 has been proposed as an alternative to standard swab diagnostic methods. Saliva testing presents potential advantages: Collection does not require trained staff or personal protective equipment, can be done outside testing centers, and may be better tolerated in challenging or pediatric populations.Because of RNA instability, use of raw saliva necessitates rapid transportation to a laboratory for extraction of viral material and polymerase chain reaction analysis. This study is unique in that it used a novel collection kit containing a preservative and viricidal fluid, allowing for safe and stable storage and transport of the samples. Our findings add to those of previous studies, which have focused on salivary tests of symptomatic or hospitalized patients (2); these studies have suggested that saliva tests may be more sensitive. By design, we included asymptomatic and mildly symptomatic persons to simulate mass screening for COVID-19.Our study has important limitations. First, evaluating the performance of a novel diagnostic test in the absence of a true gold standard reference is challenging. The reported false-negative rate of reverse transcriptase polymerase chain reaction–based testing for SARS-CoV-2 using swabs is approximately 38% at symptom onset and as high as 100% shortly after exposure (3). In our study, 20% of COVID-19 cases were detected by saliva alone, further supporting the notion that standard swab testing may be an unreliable reference standard. Second, nasopharyngeal or oropharyngeal swabbing was done according to swab availability at the testing center even though nasopharyngeal swabs are preferred in symptomatic persons and those later in the illness course (4), which may have affected our results. Analyses of the influence of swab site on study results were not done because of limited sample size. Third, analysis of swab and saliva samples was split between 2 laboratories to accommodate the demand for testing resources in a pandemic. The potential effect of assay differences was mitigated by a targeted evaluation of the E gene, a widely accepted and sensitive target gene for SARS-CoV-2 (5). Finally, more than half of eligible patients declined participation.Nonetheless, our study shows the feasibility of a simple, safe collection tool for salivary detection of SARS-CoV-2 in the setting of a COVID-19 testing center. Despite a lower estimated rate of detection relative to swab testing, saliva testing may be of particular benefit for remote, vulnerable, or challenging populations.References1. Wasserman JK, Rourke R, Purgina B, et al. HPV DNA in saliva from patients with SCC of the head and neck is specific for p16-positive oropharyngeal tumours. J Otolaryngol Head Neck Surg. 2017;46:3. [PMID: 28061890] doi:10.1186/s40463-016-0179-6 CrossrefMedlineGoogle Scholar2. Czumbel LM, Kiss S, Farkas N, et al. Saliva as a candidate for COVID-19 diagnostic testing: a meta-analysis. Front Med (Lausanne). 2020;7:465. doi:10.3389/fmed.2020.00465 CrossrefMedlineGoogle Scholar3. Kucirka LM, Lauer SA, Laeyendecker O, et al. Variation in false-negative rate of reverse transcriptase polymerase chain reaction–based SARS-CoV-2 tests by time since exposure. Ann Intern Med. 2020;173:262-267. doi:10.7326/M20-1495 LinkGoogle Scholar4. Patel MR, Carroll D, Ussery E, et al. Performance of oropharyngeal swab testing compared to nasopharyngeal swab testing for diagnosis of COVID-19—United States, January-February 2020. Clin Infect Dis. 2020. [PMID: 32548635] doi:10.1093/cid/ciaa759 CrossrefGoogle Scholar5. Corman VM, Landt O, Kaiser M, et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill. 2020;25. [PMID: 31992387] doi:10.2807/1560-7917.ES.2020.25.3.2000045 CrossrefMedlineGoogle Scholar Comments 0 Comments Sign In to Submit A Comment Burton AbramsNo institutional affiliation28 August 2020 Discrimination of swab analysis Can processing of either the nasal swabs or saliva swabs discriminate between RNA from active viruses vs. inactive viruses? Emmah StevensonNo institutional affiliation20 March 2021 Selection of Participants How were subjects selected for this study? Author, Article, and Disclosure InformationAuthors: Lisa Caulley, MD, MPH; Martin Corsten, MD; Libni Eapen, MD; Jonathan Whelan, BSc; Jonathan B. Angel, MD; Kym Antonation, MPH; Nathalie Bastien, PhD; Guillaume Poliquin, MD, PhD; Stephanie Johnson-Obaseki, MD, MPHAffiliations: University of Ottawa and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (L.C., J.B.A.)Dalhousie University, Halifax, Nova Scotia, Canada (M.C.)University of Ottawa, Ottawa, Ontario, Canada (L.E., J.W., S.J.)National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada (K.A., N.B.)National Microbiology Laboratory, Public Health Agency of Canada, and University of Manitoba, Winnipeg, Manitoba, Canada (G.P.)Acknowledgment: The authors thank Jill Allan, RN, BN, of the Ottawa Hospital Research Institute for her clinical and methodological assistance to the investigators as a clinical research assistant; John Trickett, RN, for facilitating the research study as Clinical Director of The Ottawa Hospital and the COVID-19 Assessment Center; H. Chaim Birnboim, MD, MSc, former Chief Scientific Officer at DNA Genotek, for his expertise in the functionality of the saliva collection kits; Karamchand Ramotar, PhD, Associate Professor of Pathology and Laboratory Medicine at the University of Ottawa, for his guidance and collaboration in comparing saliva samples with the swab reference standard from the Eastern Ontario Regional Laboratory Association; Rafal Iwasiow, PhD, of DNA Genotek for his vital contribution of saliva collection kits and expertise in their functionality; and Stephanie Burke Schinkel, MSc, of the Ottawa Hospital Research Institute for her valuable assistance to the investigators.Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-4738.Reproducible Research Statement: Study protocol: Not available. Statistical code and data set: Available from Dr. Johnson-Obaseki (e-mail, stjohnson@toh.ca).Corresponding Author: Stephanie Johnson-Obaseki, MD, MPH, Ottawa Hospital Research Institute, Department of Otolaryngology - Head and Neck Surgery, University of Ottawa, S3, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada; e-mail, stjohnson@toh.ca.This article was published at Annals.org on 28 August 2020.* Drs. Poliquin and Johnson-Obaseki contributed equally to this work. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byFully Integrated Ratiometric Fluorescence Enrichment Platform for High-Sensitivity POC Testing of Salivary Cancer BiomarkersSalivary SARS-CoV-2 RNA for diagnosis of COVID-19 patients: A systematic review and meta-analysis of diagnostic accuracyA novel strategy to avoid sensitivity loss in pooled testing for SARS-CoV-2 surveillance: validation using nasopharyngeal swab and saliva samplesPeptide nucleic acid and antifouling peptide based biosensor for the non-fouling detection of COVID-19 nucleic acid in salivaRespiratory virus detection in the upper respiratory tract of asymptomatic, community-dwelling older peopleDevelopment of a high sensitivity RT-PCR assay for detection of SARS-CoV-2 in individual and pooled nasopharyngeal samplesPerformance evaluation of a non-invasive one-step multiplex RT-qPCR assay for detection of SARS-CoV-2 direct from salivaValidation of RT-qPCR test for SARS-CoV-2 in saliva specimensSalivary testing for SARS-CoV-2 in the pediatric population: a diagnostic accuracy studySaliva testing among teachers during the COVID-19 pandemic: Effects on health concerns, well-being, and precautionary behaviorCOVID‐19 detection with severity level analysis using the deep features, and wrapper‐based selection of ranked featuresUser acceptability of saliva and gargle samples for identifying COVID-19 positive high-risk workers and household contactsSaliva versus Upper Respiratory SwabsSaliva as an alternative specimen to nasopharyngeal swabs for COVID-19 diagnosis: ReviewIs saliva collected passively without forceful coughing sensitive to detect SARS-CoV-2 in ambulatory cases? 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PURPOSE There remains a lack of clarity regarding the influence of sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) on outcomes in prostate cancer (PCa). Herein, we evaluate the optimal sequencing of ADT with prostate-directed RT in localized PCa. METHODS MEDLINE (1966-2018), Embase (1982-2018), ClinicalTrials.gov, and conference proceedings (1990-2018) were searched to identify randomized trials evaluating the sequencing, but not duration, of ADT with RT. Two randomized phase III trials were identified, and individual patient data were obtained: Ottawa 0101 and NRG Oncology's Radiation Therapy Oncology Group 9413. Ottawa 0101 randomly assigned patients to neoadjuvant or concurrent versus concurrent or adjuvant short-term ADT. Radiation Therapy Oncology Group 9413, a 2 × 2 factorial trial, included a random assignment of neoadjuvant or concurrent versus adjuvant short-term ADT. The neoadjuvant or concurrent ADT arms of both trials were combined into the neoadjuvant group, and the arms receiving adjuvant ADT were combined into the adjuvant group. The primary end point of this meta-analysis was progression-free survival (PFS). RESULTS The median follow-up was 14.9 years. Overall, 1,065 patients were included (531 neoadjuvant and 534 adjuvant). PFS was significantly improved in the adjuvant group (15-year PFS, 29% v 36%, hazard ratio [HR], 1.25 [95% CI, 1.07 to 1.47], P = .01). Biochemical failure (subdistribution HR [sHR], 1.37 [95% CI, 1.12 to 1.68], P = .002), distant metastasis (sHR, 1.40 [95% CI, 1.00 to 1.95], P = .04), and metastasis-free survival (HR, 1.17 [95% CI, 1.00 to 1.37], P = .050) were all significantly improved in the adjuvant group. There were no differences in late grade ≥ 3 gastrointestinal (2% v 3%, P = .33) or genitourinary toxicity (5% v 5%, P = .76) between groups. CONCLUSION The sequencing of ADT with prostate-directed RT has significant association with long-term PFS and MFS in localized PCa. Our findings favor use of an adjuvant over a neoadjuvant approach, without any increase in long-term toxicity.

5584 Background: The timing of systemic therapy in relation to radiotherapy (RT) is important in most malignancies. In contrast, androgen deprivation therapy (ADT) has largely been investigated in relation to its duration rather than its sequencing with RT. Herein, we conduct the first combined individual patient analysis of two phase III randomized trials to determine the optimal timing of ADT with RT in localized prostate cancer (PCa). Methods: Individual patient data was obtained from the Malone et al trial (JCO 2019), which randomized patients to receive neoadjuvant/concurrent or concurrent/adjuvant ADT for 6 months with prostate only RT. This was combined with the prostate only RT arms of RTOG 9413 that randomized patients to 4 months of neoadjuvant/concurrent or adjuvant ADT. The neoadjuvant/concurrent arms of both trials were combined into the “neoadjuvant” group, and the concurrent/adjuvant (Malone) and adjuvant arm (RTOG 9413) were combined in the “adjuvant” group. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Cumulative incidence of distant metastasis (DM), PCa-specific mortality (PCSM) and biochemical failure (BF) were calculated using the Fine-Gray method with non-PCa deaths as competing events. Late genitourinary (GU) and gastrointestinal (GI) toxicity are also reported. Results: The median follow-up was 14.9 years (yrs) and 1065 patients were included (n=531 neoadjuvant, 534 adjuvant). Groups were well balanced for all baseline characteristics. Adjuvant ADT was superior to neoadjuvant ADT in terms of BF (15yr: 33% vs 43%, HR: 1.37 (95%CI: 1.12-1.68), p=0.002), DM (15yr: 12% vs 18%, HR: 1.40 (95%CI: 1.00-1.95), p=0.04), and PFS (15yr: 36% vs 29%, HR: 1.25 (95%CI: 1.07-1.47), p=0.01). Adjuvant ADT yielded lower PCSM (15yr: 15% vs 20%, HR: 1.29 (95%CI: 0.95-1.75), p=0.10), but did not reach statistical significance. This approached statistical significance in high risk PCa (HR 1.39 (95%CI 1.00-1.93), p=0.053). OS was not significantly different between arms (15yr: 39% vs 34%, HR: 1.11 (95%CI: 0.95-1.30), p=0.20). There was no significant difference in either late grade ≥3 GI (p=0.21) or GU (p=0.98) toxicity. Conclusions: We demonstrate for the first time that sequencing of ADT with RT significantly impacts long-term oncologic outcomes in localized PCa, favoring an adjuvant rather than neoadjuvant approach, without increasing late toxicity. This data has important implications to ongoing and future clinical trial design. Clinical trial information: NCT00769548 .

Bladder Cancer Canada (BCC), Canadian Urologic Oncology Group (CUOG), and Canadian Urological Association (CUA)". 1 This was a summary and report of the committee's consensus deliberations during the first twoday BCC-CUA-CUOG Bladder Cancer Quality of Care Meeting (BCQCM) held in late 2014.One of the recommendations from the report was to perform a Delphi process to establish a set of quality indicators across important categories of bladder cancer care. 1 This process was undertaken, and led to a 2017 publication listing 60 quality indicators for consideration. 2 In November 2016, another multidisciplinary committee consisting largely of the same members met at a second BCQCM, which focused on the patient journey and optimizing management.The report of this second BCQCM was published in 2018. 3The following is a summary of the third national BCQCM.The objectives for the meeting were the following:-To provide an update on the status of the Canadian Bladder Cancer Information System (CBCIS) and its potential future impact; -To set benchmarks for the core quality indicators selected at the 2 nd BCQCM; -To discuss the desirability and feasibility of an annual Canadian Bladder Cancer Forum; -To review barriers and enablers of bladder preservation for invasive bladder cancer; -To examine and discuss the future of bladder cancer research, with a focus on patient engagement and their priorities; and -To review issues and concerns from the patient perspective and Bladder Cancer Canada.

315 Background: Dose-escalated prostate radiotherapy (PRT) with androgen deprivation therapy (ADT) is a standard curative treatment for localized prostate cancer (LPCa). The optimal sequencing of these therapies is unclear. We report the patient-reported health related quality of life (HR-QoL) outcomes from a phase III study exploring optimal sequencing of PRT with ADT in LPCa. Methods: Newly diagnosed LPCa patients with Gleason score ≤7, clinical stage T1b-T3a, and PSA < 30 ng/mL were randomized to receive PRT (76 Gy/38 fractions) with 6 months (mos) of ADT starting 4 mos prior to RT (NAHT arm) or concurrently with RT (CAHT arm). HR-QoL was assessed using EORTC QLQ-C30 and PR25 at baseline, q2 mos while on ADT, q4 mos for year 1 and 2 after ADT, q6 mos from year 3 to 5 and annually thereafter. Linear mixed modelling was applied to compare change in score (relative to baseline) over time. Wilcoxon rank-sum test was used to identify between-group difference in absolute scores, at 18, 36 and 60 mos. The statistical and clinical significance was set at p≤0.01 and 10-point threshold, respectively. Results: Overall 432 men were enrolled in the study and 393 (194 in NAHT and 199 in CAHT arm) were eligible for HR-QoL evaluation. There was a significant difference in the change in score of sleep disturbance due to urinary bother (least-squared mean: 3.9 vs. 7.6, P = 0.001) between the two arms. Although there were statistically significant differences in absolute scores of global QoL (18, 60 mos), cognitive (18, 60 mos), social and emotional functions (60 mo), sexual intimacy (18 mo) and fatigue (60 mo) favoring NAHT, the only clinically meaningful difference was noted in ejaculatory dysfunction at 18 (mean: 52.5 vs. 64.6), 36 (60.2 vs. 49.2) & 60 mos (61.4 vs. 50.9), respectively. Conclusions: We did not find any notable difference between the two arms with respect to score change over time in any of the HR-QoL metrics except sleep disturbance due to urinary bother. Clinically meaningful difference was noted only in the late absolute ejaculatory dysfunction score which favored the NAHT arm. Based on these findings, both NAHT and CAHT with PRT are reasonable standards of care for LPCa. Clinical trial information: DC-990-0082.

Background Patients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) have substantially better treatment response and overall survival (OS) than patients with HPV-negative disease. Treatment options for HPV+ OPC can involve either a primary radiotherapy (RT) approach (± concomitant chemotherapy) or a primary surgical approach (± adjuvant radiation) with transoral surgery (TOS). These two treatment paradigms have different spectrums of toxicity. The goals of this study are to assess the OS of two de-escalation approaches (primary radiotherapy and primary TOS) compared to historical control, and to compare survival, toxicity and quality of life (QOL) profiles between the two approaches. Methods This is a multicenter phase II study randomizing one hundred and forty patients with T1–2 N0–2 HPV+ OPC in a 1:1 ratio between de-escalated primary radiotherapy (60 Gy) ± concomitant chemotherapy and TOS ± de-escalated adjuvant radiotherapy (50–60 Gy based on risk factors). Patients will be stratified based on smoking status (< 10 vs. ≥ 10 pack-years). The primary endpoint is OS of each arm compared to historical control; we hypothesize that a 2-year OS of 85% or greater will be achieved. Secondary endpoints include progression free survival, QOL and toxicity. Discussion This study will provide an assessment of two de-escalation approaches to the treatment of HPV+ OPC on oncologic outcomes, QOL and toxicity. Results will inform the design of future definitive phase III trials. Trial Registration Clinicaltrials.gov identifier: NCT03210103 . Date of registration: July 6, 2017, Current version: 1.3 on March 15, 2019.

Purpose: We performed a secondary analysis of a phase 3 randomized trial to determine the influence of sequencing of radiation therapy and androgen deprivation therapy (ADT) on posttreatment testosterone recovery and implications of testosterone recovery on subsequent relapse. Methods and Materials: Patients with localized prostate cancer with Gleason score <= 7, clinical stage T1b to T3a, and prostate-specific antigen <30 ng/mL were randomized to neoadjuvant and concurrent ADT for 6 months starting 4 months before prostate radiation therapy (NHT arm) or concurrent and adjuvant ADT for 6 months starting simultaneously with radiation therapy (CAHT arm). Full testosterone recovery (FTR) was defined as recovery of testosterone to >10.5 nmol/L in patients with baseline similar to 10.5 nmol/L or to baseline level in patients with baseline <10.5 nmol/L. Restricted mean survival time (RMST) since ADT initiation to supra-castrate testosterone level (>1.7 nmol/L), and to FTR was compared between the arms using a truncation time point of 36 months. Results: The adjusted difference in RMST to supracastrate testosterone between the CAHT and NHT arm was 1.5 months (95% confidence interval [CI], 0.5-2.5; P=.005). No difference was noted in RMST to FTR between the arms (18.7 vs 18.5 months, adjusted difference: 0.5; 95% CI, -1.4 to 2.4; P=.61). There was no evidence of heterogeneity of treatment effect (interaction P=.76) on risk of relapse over subgroups stratified by testosterone recovery to supracastrate level at 15 months after start of ADT. Based on a multistate Markov model, no independent effect of time to FTR on risk of subsequent relapse was observed (adjusted hazard ratio: 1.02; 95% CI, 0.96-1.08). Conclusions: Patients should be counseled that an additional 12 months on average is needed for FTR to occur after treatment with prostate radiation therapy and 6 months of ADT. This is independent of the sequencing of ADT and radiation therapy. Furthermore, recovery of testosterone does not appear to affect the risk of subsequent relapse. (C) 2020 Elsevier Inc. All rights reserved.

PURPOSE Dose-escalated radiotherapy (RT) with androgen-deprivation therapy (ADT) is a standard definitive treatment of localized prostate cancer (LPCa). The optimal sequencing of these therapies is unclear. Our phase III trial compared neoadjuvant versus concurrent initiation of ADT in combination with dose-escalated prostate RT (PRT). PATIENTS AND METHODS Patients with newly diagnosed LPCa with Gleason score ≤ 7, clinical stage T1b to T3a, and prostate-specific antigen < 30 ng/mL were randomly allocated to neoadjuvant and concurrent ADT for 6 months starting 4 months before RT (neoadjuvant group) or concurrent and adjuvant ADT for 6 months starting simultaneously with RT (concurrent group). The primary end point was biochemical relapse-free survival (bRFS). Stratified log-rank test was used to compare bRFS and overall survival (OS). Incidence of grade ≥ 3 late RT-related toxicities was compared by log-rank test. RESULTS Overall, 432 patients were randomly assigned to the neoadjuvant (n = 215) or concurrent group (n = 217). At 10 years, bRFS rates for the two groups were 80.5% and 87.4%, respectively. Ten-year OS rates were 76.4% and 73.7%, respectively. There was no significant difference in bRFS ( P = .10) or OS ( P = .70) between the two groups. Relative to the neoadjuvant group, the hazard ratio for the concurrent group was 0.66 (95% CI, 0.41 to 1.07) for bRFS and 0.94 (95% CI, 0.68 to 1.30) for OS. No significant difference was observed in the 3-year incidence of late RT-related grade ≥ 3 GI (2.5% v 3.9%) or genitourinary toxicity (2.9% v 2.9%). CONCLUSION In our study, there was no statistically significant difference in bRFS between the two treatment groups. Similarly, no difference was seen in OS or late RT-related toxicities. On the basis of these results, both neoadjuvant and concurrent initiations of short-term ADT with dose-escalated PRT are reasonable standards of care for LPCa.

An approach is described for estimating future dose rates to Waste Isolation Pilot Plant workers processing remote handled transuranic waste. The waste streams will come from the entire U.S. Department of Energy complex and can take on virtually any form found from the processing sequences for defense-related production, radiochemistry, activation and related work. For this reason, the average waste matrix from all generator sites is used to estimate the average radiation fields over the facility lifetime. Innovative new techniques were applied to estimate expected radiation fields. Non-linear curve fitting techniques were used to predict exposure rate profiles from cylindrical sources using closed form equations for lines and disks. This information becomes the basis for Safety Analysis Report dose rate estimates and for present and future ALARA design reviews when attempts are made to reduce worker doses.

In Canada, bladder cancer ranks as the fifth most common cancer, with an estimated 8900 new cases and 2400 deaths in 2018.1 Approximately 15% of patients have locally advanced or metastatic disease at presentation. A further 40–50% of those with muscle-invasive, early-stage disease will relapse after initial treatment. The majority of patients with advanced-stage disease will succumb to their disease. Cancers of the ureter, renal pelvis, and proximal urethra constitute approximately 5–10% of cases of urothelial carcinoma and are treated with similar systemic therapy as bladder cancer. GUMOC (Genitourinary Medical Oncologists of Canada) is comprised of Canadian medical oncologists who specialize in the treatment of genitourinary cancers. With recent advances in systemic therapy, especially due to the emergence of immunotherapy as a therapeutic option, a consensus opinion has become necessary to guide the management of unresectable, locally advanced and metastatic urothelial carcinoma.

6006 Background: The incidence of OPSCC has risen rapidly, due to an epidemic of human papillomavirus (HPV) infection. Radiation therapy (RT) has historically been the standard treatment, but transoral robotic surgery (TORS) has surpassed RT in the US as the most common approach, based on assumptions of reduced toxicity or improved quality of life (QOL). No randomized trials have previously compared these treatments. Methods: The ORATOR trial (NCT01590355) enrolled patients with T1-T2 N0-2(≤4 cm) OPSCC amenable to TORS. We randomly assigned patients, stratified by p16 status, to RT (70 Gy/35 fractions, with chemotherapy if N1-2) vs. TORS (± adjuvant [chemo]RT based on pathology). The primary endpoint was a definitive comparison of swallowing QOL at 1-year using the MD Anderson Dysphagia Inventory (MDADI), powered to detect a 10-point improvement (a clinically-meaningful change [CMC]) in the TORS arm. Secondary endpoints included adverse events (AEs), other QOL outcomes [including EORTC scales, the Voice Handicap Index-10, Neck Dissection Impairment Index, and Patient Neurotoxicity Questionnaire], overall- and progression-free survival (OS, PFS). All analyses were pre-specified and intention-to-treat. Results: Between 2012 and 2017, 68 patients were randomized (n = 34 in each arm), in Canada and Australia. Median age was 59 years; 87% were male. Primary tumor sites were palatine tonsil (74%) or base of tongue (26%). Arms were well-balanced for baseline factors, including p16 status (88% in each arm). Median follow-up was 27 months. MDADI scores at 1-year were statistically superior in the RT arm (mean ± SD: 86.9 ± 11.4 vs. 80.1 ± 13.0 in the TORS arm; p = 0.042), but not meeting the definition of a CMC. For the other QOL metrics, outcomes were similar at 1-year. Feeding tube rates at 1-year were 3% (n = 1) vs. 0% respectively. Rates of treatment-related grade ≥2 AEs were similar (91% vs. 100%, p = 0.24), with more neutropenia, constipation and tinnitus in the RT arm and more trismus in the TORS arm (all p < 0.05). There was one TORS bleeding-related death. OS and PFS were similar. Conclusions: RT had superior swallowing QOL scores at 1 year compared to TORS, but the difference was not a CMC. Toxicities differed between the arms. This study provides the first level 1 evidence to inform patients of the QOL impact of both approaches. Clinical trial information: NCT01590355.

Background Transoral robotic surgery (TORS) with concurrent neck dissection has supplanted radiotherapy in the USA as the most common treatment for oropharyngeal squamous cell carcinoma (OPSCC), yet no randomised trials have compared these modalities. We aimed to evaluate differences in quality of life (QOL) 1 year after treatment. Methods The ORATOR trial was an investigator-initiated, multicentre, international, open-label, parallel-group, phase 2, randomised study. Patients were enrolled at six hospitals in Canada and Australia. We randomly assigned (1:1) patients aged 18 years or older, with Eastern Cooperative Oncology Group scores of 0-2, and with T1-T2, N0-2 ( <= 4 cm) OPSCC tumour types to radiotherapy (70 Gy, with chemotherapy if N1-2) or TORS plus neck dissection (with or without adjuvant chemoradiotherapy, based on pathology). Following stratification by p16 status, patients were randomly assigned using a computer-generated randomisation list with permuted blocks of four. The primary endpoint was swallowing-related QOL at 1 year as established using the MD Anderson Dysphagia Inventory (MDADI) score, powered to detect a 10-point improvement (a clinically meaningful change) in the TORS plus neck dissection group. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov (NCT01590355) and is active, but not currently recruiting. Findings 68 patients were randomly assigned (34 per group) between Aug 10, 2012, and June 9, 2017. Median followup was 25 months (IQR 20-33) for the radiotherapy group and 29 months (23-43) for the TORS plus neck dissection group. MDADI total scores at 1 year were mean 86.9 (SD 11.4) in the radiotherapy group versus 80.1 (13.0) in the TORS plus neck dissection group (p=0 - 042). There were more cases of netttropenia (six [18%] of 34 patients vs none of 34), hearing loss (13 [38%] vs five 115%1), and tinnitus (12 [35%] vs two [6%]) reported in the radiotherapy group than in the TORS plus neck dissection group, and more cases of trismus in the TORS plus neck dissection group (nine [26%] vs one [3%]). The most common adverse events in the radiotherapy group were dysphagia (n=6), hearing loss (n=6), and mucositis (n=4), all grade 3, and in the TORS plus neck dissection group, dysphagia (n=9, all grade 3) and there was one death caused by bleeding after TORS. Interpretation Patients treated with radiotherapy showed superior swallowing-related QOL scores 1 year after treatment, although the difference did not represent a clinically meaningful change. Toxicity patterns differed between the groups. Patients with OPSCC should be informed about both treatment options. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

In Canada, bladder cancer ranks as the fifth most common cancer, with an estimated 8900 new cases and 2400 deaths in 2018.1 Approximately 15% of patients have locally advanced or metastatic disease at presentation. A further 40–50% of those with muscle-invasive, early-stage disease will relapse after initial treatment. The majority of patients with advanced-stage disease will succumb to their disease. Cancers of the ureter, renal pelvis, and proximal urethra constitute approximately 5‒10% of cases of urothelial carcinoma and are treated with similar systemic therapy as bladder cancer. GUMOC (Genitourinary Medical Oncologists of Canada) is comprised of Canadian medical oncologists who specialize in the treatment of genitourinary cancers. With recent advances in systemic therapy, especially due to the emergence of immunotherapy as a therapeutic option, a consensus opinion has become necessary to guide the management of unresectable, locally advanced and metastatic urothelial carcinoma.

5017 Background: In patients presenting with metastatic prostate cancer (mPCa), the role of local therapy is undefined. Recent registry analyses have suggested, however, that external beam radiotherapy (RT) directed at the prostate may improve overall survival (OS). We reviewed the experience of primary tumor-directed RT in this setting at our center. Methods: The study population consisted of men with newly-diagnosed mPCa referred to a comprehensive cancer center between 2005 and 2015 and treated initially with androgen deprivation therapy. Patients were eligible for inclusion if they received 1) prostate RT with biologically effective dose at least that of a course of 40 Gy in 15 fractions or 2) no prostate RT. The association between receipt of prostate RT and OS was studied. OS was estimated using the Kaplan-Meier method while univariate and multivariate Cox regression were used to identify factors associated with OS. Results: A total of 304 cases were eligible. Prostate RT was received in 105 cases. Median age at diagnosis was 75 years (IQR, 67-82 years). Median follow-up was 72.2 months. On univariate analysis, prostate RT was associated with improved OS (HR 0.62, 95% CI 0.46-0.84, p = 0.002). 2-year and 5-year OS was 74.7% and 41.8% respectively in those receiving prostate RT and 56.9% and 27.6% respectively in those not receiving RT. Median OS in those receiving RT was 48.3 months versus 29.2 months in those not receiving RT. In a multivariate Cox model taking account of age at diagnosis, year of diagnosis, presenting PSA, T stage, N stage, and M1 subdivision, RT remained associated with improved survival (HR 0.64, 95% CI 0.43-0.96, p = 0.033). Conclusions: This cohort represents the largest single-center experience of primary tumor-directed RT in mPCa reported to date. In this population, receipt of prostate RT was associated with improved OS. The observed 19-month absolute difference in median OS is clinically significant. This analysis could not account for performance status, volume of metastatic disease, comorbidities, receipt of systemic therapies, and other potential confounders. Only large-scale RCTs will be able to definitively assess the value of prostate RT in this setting.

The OTT0101 Phase III Trial evaluated the optimal sequencing of Dose Escalated XRT (76Gy) in combination with 6 mo ADT. Trial hypothesis was that early (day 1) XRT will improve PSA Disease Free Survival (DFS) compared to XRT after 4 months ADT. Four hundred thirty-eight patients were entered on the Phase 3 trial evaluating optimal timing of XRT in combination with 6 months ADT (goserelin + bicalutamide). Inclusion criteria were cT1-T3, GL < 8, PSA < 30. Low risk prostate cancer patients were excluded. Patients were randomized to XRT after 4 months ADT (arm A) or to XRT day 1 of ADT (arm B). Overall Survival (OS), PSA DFS, Local DFS and Distant DFS were estimated using the Kaplan-Meier method. Treatment arms were compared using log rank tests. Clinical characteristics: mean age 69; 69 % cT1-T2A, 31 % cT2B-T3; 75 % Gleason 7; mean PSA = 10. Median follow-up is > 12 yrs. There was no stat sig difference between Rx arms. 5 & 10 year PSA DFS (Arm A vs B): 89 vs 93% and 81% vs 86 %. There were no differences in local control, OS or distant metastases by Rx arm. The pooled 5 & 10-year results are the following: PSA DFS 91 % & 83 %; Local DFS 96 % and 94 %; Distant DFS 99% & 96 %; OS 92 % & 72%. The sequencing of XRT in combination with ADT did not influence clinical outcomes. The durable local control and PSA DFS support the benefit of ADT in combination with Dose Escalated XRT.

Kassouf et alBladder cancer quality of care result of consensus deliberations during a two-day meeting that took place in late 2014.In November 2016, another multidisciplinary committee consisting largely of the same members convened the "2nd BCC-CUA-CUOG Bladder Cancer Quality of Care Meeting 2016".The focus was on patient journey and optimizing management.The following document is a summary of the proceedings of this meeting.The objectives for the meeting were the following: I Patient journey:• To discuss unmet needs in bladder cancer care from the patient perspective. II Optimizing management:• To select the top 10 indicators of bladder cancer quality of care and establish benchmarks; • To develop a score card for measurement of bladder cancer quality of care;• To address complex bladder cancer management from a training perspective; • To identify bladder cancer centres of expertise across Canada using refined criteria; • To discuss the establishment of a bladder cancer research network of excellence; I -Unmet needs in bladder cancer: The patient perspectivePatient representatives from Bladder Cancer Canada (BCC) presented their perspective on unmet needs in bladder cancer care.These perspectives were gathered by patients from Bladder Cancer Canada through the BCC website / discussion forum, BCC patient-to-patient emails and phone calls, as well as a patient needs survey conducted at the Princess Margaret Hospital in Toronto.Patient needs were subdivided into four timeframes across the patient journey: 1) beginning the journey with signs/symptoms (pre-diagnosis); 2) from diagnosis to treatment; 3) during treatment; and, 4) after treatment: living "the new normal".

Background: Radical cystectomy (RC) associated with pelvic lymph node dissection (PLND) is the most common local therapy in the management of non-metastatic muscle invasive bladder cancer (MIBC). Loco-regional recurrence (LRR), however, remains a common and important therapeutic challenge associated with poor oncologic outcomes. We aimed to systematically review evidence regarding factors associated with LRR and to propose a framework for adjuvant radiotherapy (RT) in patients with MIBC. Methods: We performed this systematic review in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. We searched the PubMed database for articles related to MIBC and associated treatments, published between January 1980 and June 2015. Articles identified by searching references from candidate articles were also included. We retrieved 1383 publications from PubMed and 34 from other sources. After an initial screening, a review of titles and abstracts, and a final comprehensive full text analysis of papers assessed for eligibility, a final consensus on 32 studies was obtained. Results: LRR is associated with specific patient-, tumor-, center- or treatment-related variables. LRR varies widely, occurring in as many as 43% of the cases and is strongly related to survival outcomes. While perioperative treatment does not impact on LRR, pathological factors such as pT, pN, positive margins status, extent of PLND, number of lymph nodes removed and/or invaded are correlated with LRR. Patients with pT3-T4a and/or positive lymph-nodes and/or limited pelvic lymph-node dissection and/or positive surgical margins have been distributed in LRR risk groups with accuracy. Conclusions: LRR patterns are well-known and for selected patients, adjuvant treatments could target this event. Intrinsic tumor subtype may guide future criteria to define a personalized treatment strategy. Prospective trials evaluating safety and efficacy of adjuvant RT are ongoing in several countries.

INTRODUCTION:Muscle-invasive bladder cancer (MIBC) is associated with high recurrence and mortality rates. The role of radiotherapy as an adjunct to radical cystectomy is not well-defined. We sought to evaluate the efficacy and safety of radiotherapy preoperatively or postoperatively for patients with MIBC receiving cystectomy compared to cystectomy alone. The primary outcome was overall survival. The secondary outcome was adverse effects. METHODS:MEDLINE, EMBASE, and CENTRAL were searched on August 30, 2016 for randomized controlled trials (RCTs) of patients undergoing cystectomy for bladder cancer. A control group receiving cystectomy alone and an intervention group with radiotherapy and cystectomy were required. The Jadad score was used to assess for bias. Fifteen studies representing 10 RCTs met eligibility criteria. RESULTS:A total of 996 patients were randomized in seven trials included in a meta-analysis of neoadjuvant radiotherapy. Insufficient data were available to complete a pooled analysis for adjuvant radiotherapy. There was a non-statistically significant improvement in overall survival for patients who received neo-adjuvant radiotherapy and cystectomy. At three years and five years, the odds ratios were 1.23 (95% confidence interval [CI] 0.72-2.09) and 1.26 (95% CI 0.76-2.09), respectively, in favour of neoadjuvant radiotherapy. Subgroup analyses including higher doses of radiotherapy showed greater effect on survival. CONCLUSIONS:These data suggest that radiotherapy prior to cystectomy may improve overall survival. This review was limited by old studies, heterogeneous patient populations, and radiotherapy treatment techniques that may not meet current standards. There is a need for current RCTs to further evaluate this effect.