Genitourinary Radiation Oncologists Of Canada Research Articles

Application of a novel machine learning framework for predicting non-metastatic prostate cancer-specific mortality in men using the Surveillance, Epidemiology, and End Results (SEER) database

Accurate prognostication is crucial in treatment decisions made for men diagnosed with non-metastatic prostate cancer. Current models rely on prespecified variables, which limits their performance. We aimed to investigate a novel machine learning approach to develop an improved prognostic model for predicting 10-year prostate cancer-specific mortality and compare its performance with existing validated models. We derived and tested a machine learning-based model using Survival Quilts, an algorithm that automatically selects and tunes ensembles of survival models using clinicopathological variables. Our study involved a US population-based cohort of 171 942 men diagnosed with non-metastatic prostate cancer between Jan 1, 2000, and Dec 31, 2016, from the prospectively maintained Surveillance, Epidemiology, and End Results (SEER) Program. The primary outcome was prediction of 10-year prostate cancer-specific mortality. Model discrimination was assessed using the concordance index (c-index), and calibration was assessed using Brier scores. The Survival Quilts model was compared with nine other prognostic models in clinical use, and decision curve analysis was done. 647 151 men with prostate cancer were enrolled into the SEER database, of whom 171 942 were included in this study. Discrimination improved with greater granularity, and multivariable models outperformed tier-based models. The Survival Quilts model showed good discrimination (c-index 0·829, 95% CI 0·820-0·838) for 10-year prostate cancer-specific mortality, which was similar to the top-ranked multivariable models: PREDICT Prostate (0·820, 0·811-0·829) and Memorial Sloan Kettering Cancer Center (MSKCC) nomogram (0·787, 0·776-0·798). All three multivariable models showed good calibration with low Brier scores (Survival Quilts 0·036, 95% CI 0·035-0·037; PREDICT Prostate 0·036, 0·035-0·037; MSKCC 0·037, 0·035-0·039). Of the tier-based systems, the Cancer of the Prostate Risk Assessment model (c-index 0·782, 95% CI 0·771-0·793) and Cambridge Prognostic Groups model (0·779, 0·767-0·791) showed higher discrimination for predicting 10-year prostate cancer-specific mortality. c-indices for models from the National Comprehensive Cancer Care Network, Genitourinary Radiation Oncologists of Canada, American Urological Association, European Association of Urology, and National Institute for Health and Care Excellence ranged from 0·711 (0·701-0·721) to 0·761 (0·750-0·772). Discrimination for the Survival Quilts model was maintained when stratified by age and ethnicity. Decision curve analysis showed an incremental net benefit from the Survival Quilts model compared with the MSKCC and PREDICT Prostate models currently used in practice. A novel machine learning-based approach produced a prognostic model, Survival Quilts, with discrimination for 10-year prostate cancer-specific mortality similar to the top-ranked prognostic models, using only standard clinicopathological variables. Future integration of additional data will likely improve model performance and accuracy for personalised prognostics. None.

Current topics in radiotherapy for genitourinary cancers: Consensus statements of the Genitourinary Radiation Oncologists of Canada

The biennial meeting of the Genitourinary Radiation Oncologists of Canada (GUROC) took place November 22-23, 2019. A consensus-building session was held during the meeting addressing topics of emerging interest or controversy in the management of genitourinary malignancies. Draft statements were debated among all meeting attendees in an open forum with anonymous live voting. Statements for which there was at least 75% agreement among attendees were adopted as GUROC consensus. Four evidence-based consensus statements were developed. First, the use of prostate radiotherapy is recommended in the setting of de novo low-volume metastatic hormone-sensitive prostate cancer to improve overall survival. Second, the support of ongoing randomized trials evaluating metastasis-directed ablative local therapy in oligometastatic prostate cancer is recommended; where such trials are available, off-trial use of oligometastasis-directed ablative radiotherapy at this time is strongly discouraged. Third, routine use of prostate-rectal hydrogel spacer devices in patients with localized prostate cancer planned to receive external beam radiotherapy is not recommended; instead, selective use in patients at highest risk of rectal toxicity may be considered. Finally, multidisciplinary consultation is recommended for all patients with newly diagnosed localized muscle-invasive bladder cancer. The GUROC consensus statements provide practical guidance to clinicians in areas of current controversy in the management of prostate and bladder cancer, and it is hoped that their implementation will contribute to improved outcomes in real-world practice and greater support of clinical trials.

Predicting Prostate Cancer Death with Different Pretreatment Risk Stratification Tools: A Head-to-head Comparison in a Nationwide Cohort Study

BackgroundNumerous pretreatment risk classification tools are available for prostate cancer. Which tool is best in predicting prostate cancer death is unclear. ObjectiveTo systematically compare the prognostic performance of the most commonly used pretreatment risk stratification tools for prostate cancer. Design, setting, and participantsA nationwide cohort study was conducted, including 154 811 men in Prostate Cancer data Base Sweden (PCBaSe) 4.0 diagnosed with nonmetastatic prostate cancer during 1998–2016 and followed through 2016. Outcome measurements and statistical analysisWe compared the D’Amico, National Institute for Health and Care Excellence (NICE), European Association of Urology (EAU), Genito-Urinary Radiation Oncologists of Canada (GUROC), American Urological Association (AUA), National Comprehensive Cancer Network (NCCN), and Cambridge Prognostic Groups (CPG) risk group systems; the Cancer of the Prostate Risk Assessment (CAPRA) score; and the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram in predicting prostate cancer death by estimating the concordance index (C-index) and the observed versus predicted cumulative incidences at different follow-up times. Results and limitationsA total of 139 515 men were included in the main analysis, of whom 15 961 died from prostate cancer during follow-up. The C-index at 10 yr of follow-up ranged from 0.73 (95% confidence interval [CI]: 0.72–0.73) to 0.81 (95% CI: 0.80–0.81) across the compared tools. The MSKCC nomogram (C-index: 0.81, 95% CI: 0.80–0.81), CAPRA score (C-index: 0.80, 95% CI: 0.79–0.81), and CPG system (C-index: 0.78, 95% CI: 0.78–0.79) performed the best. The order of performance between the tools remained in analyses stratified by primary treatment and year of diagnosis. The predicted cumulative incidences were close to the observed ones, with some underestimation at 5 yr. It is a limitation that the study was conducted solely in a Swedish setting (ie, case mix). ConclusionsThe MSKCC nomogram, CAPRA score, and CPG risk grouping system performed better in discriminating prostate cancer death than the D’Amico and D’Amico-derived systems (NICE, GUROC, EAU, AUA, and NCCN). Use of these tools may improve clinical decision making. Patient summaryThere are numerous pretreatment risk classification tools that can aid treatment decision for prostate cancer. We systematically compared the prognostic performance of the most commonly used tools in a large cohort of Swedish men with prostate cancer. The Memorial Sloan Kettering Cancer Center nomogram, Cancer of the Prostate Risk Assessment score, and Cambridge Prognostic Groups performed best in predicting prostate cancer death. The use of these tools may improve treatment decisions.

External validation of the ProCaRS nomograms and comparison of existing risk-stratification tools for localized prostate cancer.

The purpose of this study was to perform a direct comparison of several existing risk-stratification tools for localized prostate cancer in terms of their ability to predict for biochemical failure-free survival (BFFS). Two large databases were used and an external validation of two recently developed nomograms on an independent cohort was also performed in this analysis. Patients who were treated with external beam radiotherapy (EBRT) and/or brachytherapy for localized prostate cancer were selected from the multi-institutional Genitourinary Radiation Oncologists of Canada (GUROC) Prostate Cancer Risk Stratification (ProCaRS) database (n=7974) and the Centre Hospitalier de l'Université de Montréal (CHUM) validation database (n=2266). The primary outcome was BFFS using the Phoenix definition. Concordance index (C-index) reported from Cox proportional hazards regression using 10-fold cross validation and decision curve analysis (DCA) were used to predict BFFS. C-index identified Cancer of the Prostate Risk Assessment (CAPRA) score and ProCaRS as superior to the historical GUROC and National Comprehensive Cancer Network (NCCN) risk-stratification systems. CAPRA modeled as five and three categories were superior to GUROC and NCCN only for the CHUM database. C-indices for CAPRA score, ProCaRS, GUROC, and NCCN were 0.72, 0.72, 0.71, and 0.72, respectively, for the ProCaRS database, and 0.66, 0.63, 0.57, and 0.60, respectively, for the CHUM database. However, many of these comparisons did not demonstrate a clinically meaningful difference. DCA identified minimal differences across the different risk-stratification systems, with no system emerging with optimal net benefit. External validation of the ProCaRS nomograms yielded favourable calibrations of R2=0.778 (low-dose rate [LDR]-brachytherapy) and R2=0.868 (EBRT). This study externally validated two ProCaRS nomograms for BFFS that may help clinicians in treatment selection and outcome prediction. A direct comparison between existing risk-stratification tools demonstrated minimal clinically significant differences in discriminative ability between the systems, favouring the CAPRA and ProCaRS systems. The incorporation of novel prognostic variables, such as genomic markers, is needed.

Assessing guideline impact on referral patterns of postprostatectomy patients to radiation oncologists

Adjuvant radiotherapy (aRT) can improve biochemical progression-free survival in patients with high-risk features (HRF) after radical prostatectomy (RP). Guidelines from Alberta and the Genitourinary Radiation Oncologists of Canada (GUROC) recommend that patients with HRF be referred to radiation oncologists (RO) based on the findings from three randomized, controlled trials (RCT). Our study examines the impact of these recommendations both pre- (2005) and post- (2012) publication of RCT and GUROC guideline establishment. Patients undergoing RP during 2005 and 2012 were identified from the provincial cancer registry. Charts were retrospectively reviewed and variables of interest were linked to the registry data. RO referral patterns for each year were determined and variables influencing referral (extracapsular extension, positive margin, seminal vesicle invasion, and post-RP prostate-specific antigen [PSA]) were compared. Median time to referral was 26.4 months in 2005 compared to 3.7 months 2012 (p<0.001). Among patients referred post-RP, a higher proportion was referred within six months in 2012 (21%) as compared to 2005 (13%) (p=0.003). Among eligible patients in 2012, 30% were referred for discussion of aRT compared to 24% in 2005 (p=0.003). There was a marked drop in patients referred for salvage radiation therapy beyond six months and a rise in the number of patients who are never referred. Despite an increase in referral rates to RO post-RP from 2005-2012, more than 50% of those patients with HRF did not receive a referral. Initiatives aimed at improving multidisciplinary care and guideline adherence should be undertaken.

Development of ProCaRS Clinical Nomograms for Biochemical Failure-free Survival Following Either Low-Dose Rate Brachytherapy or Conventionally Fractionated External Beam Radiation Therapy for Localized Prostate Cancer.

Purpose: Although several clinical nomograms predictive of biochemical failure-free survival (BFFS) for localized prostate cancer exist in the medical literature, making valid comparisons can be challenging due to variable definitions of biochemical failure, the disparate distribution of prognostic factors, and received treatments in patient populations. The aim of this investigation was to develop and validate clinically-based nomograms for 5-year BFFS using the ASTRO II “Phoenix” definition for two patient cohorts receiving low-dose rate (LDR) brachytherapy or conventionally fractionated external beam radiation therapy (EBRT) from a large Canadian multi-institutional database.Methods and Materials: Patients were selected from the GUROC (Genitourinary Radiation Oncologists of Canada) Prostate Cancer Risk Stratification (ProCaRS) database if they received (1) LDR brachytherapy ≥ 144 Gy (n=4208) or (2) EBRT ≥ 70 Gy (n=822). Multivariable Cox regression analysis for BFFS was performed separately for each cohort and used to generate clinical nomograms predictive of 5-year BFFS. Nomograms were validated using calibration plots of nomogram predicted probability versus observed probability via Kaplan-Meier estimates.Results: Patients receiving LDR brachytherapy had a mean age of 64 ± 7 years, a mean baseline PSA of 6.3 ± 3.0 ng/mL, 75% had a Gleason 6, and 15% had a Gleason 7, whereas patients receiving EBRT had a mean age of 70 ± 6 years, a mean baseline PSA of 11.6 ± 10.7 ng/mL, 30% had a Gleason 6, 55% had a Gleason 7, and 14% had a Gleason 8-10. Nomograms for 5-year BFFS included age, use and duration of androgen deprivation therapy (ADT), baseline PSA, T stage, and Gleason score for LDR brachytherapy and an ADT (months), baseline PSA, Gleason score, and biological effective dose (Gy) for EBRT.Conclusions: Clinical nomograms examining 5-year BFFS were developed for patients receiving either LDR brachytherapy or conventionally fractionated EBRT and may assist clinicians in predicting an outcome. Future work should be directed at examining the role of additional prognostic factors, comorbidities, and toxicity in predicting survival outcomes.

Impact of Race on Both Pathologic Extent of Disease and Administration of Adjuvant Radiation Therapy in a Cohort With Clinical Low-Risk Prostate Cancer Undergoing Radical Prostatectomy

Purpose/Objective(s): Androgen deprivation therapy (ADT) and standard dose external beam radiation therapy ( 70 Gy) have improved biochemical outcomes in intermediate risk (IR) prostate cancer. It is not known whether ADT improves outcomes in patients treated with brachytherapy. Our purpose is to evaluate the impact of ADT on biochemical failure free survival (bFFS) and overall survival (OS) in a multi-institutional database of IR prostate cancer patients treated with low dose rate prostate brachytherapy (LDR BT). Materials/Methods: From the Genitourinary Radiation Oncologists of Canada (GUROC) Prostate Cancer Risk Stratification (ProCaRS) database, a cohort of 859 patients with IR prostate cancer treated with LDR BTwith or without ADT was identified. Propensity scores were generated using multivariate regression based on age, baseline PSA, Gleason score and clinical stage. Patients treated with LDR alone were each matched to 2 patients who received the combination of LDR and ADT. Results: A 1:2 matching scenario (175 LDR BT : 350 LDR BT+ADT) provided the best balance of adjusted prognostic factors, a larger sample size than obtained with 1:1 matching, and standardized differences< 0.1 for prognostic factors used for matching. The 2 groups were balanced for age, baseline PSA, Gleason score and clinical stage. Median follow-up was longer in the LDR BT+ADT group (7.15 vs 4.21 years). After matching, there was no difference in bFFS (relative risk LDRBT+ADTZ 0.87, 95%CIZ 0.50-1.53); however, OS was worse in the group receiving ADT (relative risk LDR BT+ADT Z 2.83, 95%CIZ 1.00-7.98). Furthermore, a trend towardsworse cancer-related survival was observed for the LDR BT+ADT group (p Z 0.095). Conclusions: These results suggest that ADT does not benefit bFFS or OS in IR patients treated with LDR BT. Prospective studies are needed to investigate the role of ADT in IR prostate cancer patients treated with LDR BT. Author Disclosure: J. Rose: None. J.M. Crook: None. Y. Yang: None. A. Warner: None. J. Morris: None. T. Pickles: None. A. Martin: None. E. Vigneault: None. C. Catton: None. G. Rodrigues: None.

The Prostate Cancer Risk Stratification Project: Database Construction and Risk Stratification Outcome Analysis

This investigation reports on the biochemical and clinical outcomes of a newly created pan-Canadian Prostate Cancer Risk Stratification (ProCaRS) database developed by the Genitourinary Radiation Oncologists of Canada (GUROC). GUROC ProCaRS template-compliant data on 7974 patients who underwent radiotherapy were received from 7 unique databases. Descriptive analysis, Cox proportional hazards, and Kaplan-Meier analyses were performed using American Society for Radiation Oncology (ASTRO) biochemical failure-free survival (BFFS), prostate cancer-specific survival, and overall survival. Multivariable modeling for the primary ASTRO BFFS end point showed that age, prostate-specific antigen, T stage, and Gleason score and components such as hormonal therapy, and radiation treatment (brachytherapy with better outcome than external-beam) were predictive of outcome. Kaplan-Meier analysis of the existing GUROC and new NCCN classification system both showed good separation of all clinical outcome curves. The construction of a pan-Canadian database has informed important prostate cancer radiotherapy outcomes and risk stratification.

The prostate cancer risk stratification (ProCaRS) project: Recursive partitioning risk stratification analysis

BackgroundThe Genitourinary Radiation Oncologists of Canada (GUROC) published a three-group risk stratification (RS) system to assist prostate cancer decision-making in 2001. The objective of this project is to use the ProCaRS database to statistically model the predictive accuracy and clinical utility of a proposed new multi-group RS schema. MethodsThe RS analyses utilized the ProCaRS database that consists of 7974 patients from four Canadian institutions. Recursive partitioning analysis (RPA) was utilized to explore the sub-stratification of groups defined by the existing three-group GUROC scheme. 10-fold cross-validated C-indices and the Net Reclassification Index were both used to assess multivariable models and compare the predictive accuracy of existing and proposed RS systems, respectively. ResultsThe recursive partitioning analysis has suggested that the existing GUROC classification system could be altered to accommodate as many as six separate and statistical unique groups based on differences in BFFS (C-index 0.67 and AUC 0.70). GUROC low-risk patients would be divided into new favorable-low and low-risk groups based on PSA ⩽6 and PSA >6. GUROC intermediate-risk patients can be subclassified into low-intermediate and high-intermediate groups. GUROC high-intermediate-risk is defined as existing GUROC intermediate-risk with PSA >=10 AND either T2b/c disease or T1T2a disease with Gleason 7. GUROC high-risk patients would be subclassified into an additional extreme-risk group (GUROC high-risk AND (positive cores ⩾87.5% OR PSA >30). ConclusionsProposed RS subcategories have been identified by a RPA of the ProCaRS database.

Clarifying the role of salvage radiotherapy

In this issue of CUAJ, the Genito-Urinary Radiation Oncologists of Canada (GUROC) group addresses several very important issues relating to salvage radiotherapy following biochemical relapse after radical prostatectomy.1 With the published results from the EORTC (European Organisation for Research and Treatment of Cancer) 229112 and SWOG (Southwest Oncology Group) 8794 (NCIC PR-2)3 studies and the recent update of the latter trial showing metastasis-free and overall survival benefit for adjuvant radiotherapy for pT3 disease,4 the questions relating to salvage radiotherapy deserve more discussion. A fundamental issue is the attitude of urologists toward the use of local salvage radiotherapy. There is a wide range of opinions among practitioners in various countries about whether radiotherapy should be recommended for prostate-specific antigen (PSA) relapse after radical prostatectomy, with those in favour ranging from 13% to 91%. A safe assumption is that the Canadian position is more moderate and intermediate. The dichotomy in practice pattern stems largely from the lack of evidence from randomized controlled trials. The GUROC consensus meeting included a discussion on 2 retrospective multi-institutional analyses by Stephenson and colleagues5,6 that revealed some surprising results. The 6-year progression-free probability was 32% for all participants, and even the most unfavourable group (those with a Gleason score of 8–10, negative margins or a serum PSA level doubling time of < 10 mo, i.e., those with a high probability of distant metastatic disease) had a 1 in 5 chance of achieving sustained progression-free response provided the local salvage radiotherapy was delivered when the serum PSA level was less than 2.0 μg/L. Remarkably, when such patients were treated when the serum PSA level was less than 0.5 μg/L, 41% were disease-free at 6 years. These findings have led to the very reasonable recommendation by the GUROC for much earlier referral for salvage radiation consideration, even for patients with high-risk features. Another potential consequence of earlier radiotherapy may be obviation or deferral of androgen ablation (demonstrated in the SWOG 8794, NCIC PR-2 adjuvant radiotherapy trial3,4), with the inherent benefits of avoiding hormonal therapy. Although multivariable analysis from the retrospective multicentre study suggested a benefit for neoadjuvant androgen ablation6 the role of adjunctive hormonal therapy with salvage radiotherapy remains unsettled. The upcoming MRC (Medical Research Council) (NCIC PR-13) study hopes to answer some of the questions, including the timing and duration of hormonal therapy. The trial design appears somewhat complicated and imposing at first glance, but is in fact very logical and straightforward, and by providing an opportunity for most radical prostatectomy patients to participate at some point in the variable clinical course, the MRC will hopefully maximize accrual and eventually provide some valuable answers. Sia and colleagues referred to the potential role of endorectal magnetic resonance imaging in guiding and planning salvage radiotherapy. Another imaging modality is the ProstaScint (Cytogen Corporation) capromab pendetide scan.7 More promising would be the fusion or coregistration of ProstaScint with another imaging modality such as CT.8,9 Ongoing studies with newer imaging techniques will assist radiation oncologist with making decisions about and fine-tuning salvage radiotherapy for the patient with biochemical relapse after radical prostatectomy. The recommendations by GUROC, with acceptance and participation from urologists, should clarify the role of salvage radiotherapy after radical prostatectomy.

Salvage radiotherapy following biochemical relapse after radical prostatectomy: proceedings of the Genito-Urinary Radiation Oncologists of Canada consensus meeting

For patients with recurrent prostate cancer after radical prostatectomy, salvage radiotherapy is the only potentially curative treatment option. However, until recently there has been a paucity of data on the effectiveness of this approach. In light of recently published studies, the Genito-Urinary Radiation Oncologists of Canada (GUROC) met and crafted a consensus statement regarding the current place of salvage radiotherapy. GUROC also identified gaps in current knowledge and identified ongoing study protocols that will advance our knowledge in this area.This report summarizes the main conclusions of the meeting and the commentary provided during the consensus-building process, and outlines the consensus statement that was subsequently adopted.

Adjuvant radiotherapy following radical prostatectomy: Genito-Urinary Radiation Oncologists of Canada Consensus Statement

Until the results of 3 randomized trials became known in 2005, the role of adjuvant postoperative radiation therapy following radical prostatectomy was poorly defined. After the publication of these trials, the Genito-Urinary Radiation Oncologists of Canada (GUROC) met and crafted a consensus statement regarding the current place of adjuvant radiation therapy. GUROC also identified gaps in current knowledge and strongly supports ongoing study protocols to further quantify the benefit of postoperative radiotherapy.This report summarizes the main trial findings and the commentary provided during the consensus-building process. It also outlines the subsequent consensus statement.

The management of high-risk, locally advanced, prostate cancer radiation therapy

The management of high-risk, locally advanced, prostate cancer radiation therapy

Standing on Your Own Feet

The Genitourinary Radiation Oncologists of Canada (GUROC) published a three-group risk stratification (RS) system to assist prostate cancer decision-making in 2001. The objective of this project is to use the ProCaRS database to statistically model the predictive accuracy and clinical utility of a proposed new multi-group RS schema.The RS analyses utilized the ProCaRS database that consists of 7974 patients from four Canadian institutions. Recursive partitioning analysis (RPA) was utilized to explore the sub-stratification of groups defined by the existing three-group GUROC scheme. 10-fold cross-validated C-indices and the Net Reclassification Index were both used to assess multivariable models and compare the predictive accuracy of existing and proposed RS systems, respectively.The recursive partitioning analysis has suggested that the existing GUROC classification system could be altered to accommodate as many as six separate and statistical unique groups based on differences in BFFS (C-index 0.67 and AUC 0.70). GUROC low-risk patients would be divided into new favorable-low and low-risk groups based on PSA ⩽6 and PSA >6. GUROC intermediate-risk patients can be subclassified into low-intermediate and high-intermediate groups. GUROC high-intermediate-risk is defined as existing GUROC intermediate-risk with PSA >=10 AND either T2b/c disease or T1T2a disease with Gleason 7. GUROC high-risk patients would be subclassified into an additional extreme-risk group (GUROC high-risk AND (positive cores ⩾87.5% OR PSA >30).Proposed RS subcategories have been identified by a RPA of the ProCaRS database.