PURPOSE:Ultra-hypofractionation (UHF) has emerged as a safe and effective strategy; however, its role in prostate cancer (PCa) pelvic nodal irradiation combined with high-dose-rate brachytherapy (HDR-BT) and androgen deprivation therapy (ADT) remains insufficiently defined. PCS-XI (NCT05820633) is a multicentre, phase III randomized trial evaluating pelvic UHF versus conventionally fractionated (CF) radiotherapy. We report a prespecified interim analysis focusing on toxicity and patient-reported outcomes (PROs). METHODS:Men with unfavorable-intermediate to very-high-risk prostate adenocarcinoma were enrolled. Patients were randomized 1:1 to CF (43 Gy/20 fractions, 44 Gy/22 fractions, or 46 Gy/23 fractions) or UHF (25 Gy in 5 fractions delivered every other day) whole pelvis radiotherapy, combined with single-fraction 15 Gy HDR-BT to the prostate with concomitant ADT. Genitourinary and gastrointestinal toxicities (CTCAE v5.0) and PROs (IPSS, SHIM, EPIC-26) were collected longitudinally. RESULTS:At interim analysis, 142 patients were randomized (CF = 73; UHF = 69), with a median follow-up of 17.6 months. Baseline clinicopathologic characteristics, ADT exposure, and treatment volumes were well balanced between arms. Grade 2-3 GU and GI toxicity rates were low and comparable between arms. No grade 4-5 toxicities were observed. Longitudinal PRO analyses demonstrated parallel trajectories. Clinically meaningful differences favoring UHF were observed for urinary incontinence at 12 months and bowel function at 18 months. Conversely, the CF arm demonstrated superior early hormonal function at 3 and 9 months. CONCLUSIONS:Pelvic UHF combined with HDR-BT and ADT was well tolerated compared to CF. These findings support its short-term safety and tolerability. Longer follow-up is required to prove non-inferiority and assess oncologic outcomes.

Radiobiological indices can provide insights into treatment efficacy beyond traditional physical dose metrics and potentially facilitate the comparison between various radiotherapy plans. This study investigates the integration of radiobiological indices with standard physical dose criteria to improve high-dose-rate (HDR) brachytherapy plan evaluation and selection process for the treatment of prostate cancers in a multicriteria optimization (MCO) framework. This is accomplished within the framework of a graphics processing unit-based multicriteria optimization algorithm, gMCO. 2000 Pareto-optimal plans for 200 patients were optimized for a 15 Gy HDR brachytherapy boost after external beam radiation therapy (44 Gy in 22 fractions). Tumour control probability (TCP), normal tissue complication probability (NTCP), and uncomplicated tumour control probability (UTCP) were calculated for each plan. Maximizing UTCP alone resulted in insufficient target coverage (target $$V_{100} < 90\%$$) according to clinical guidelines. Conversely, maximizing target coverage while meeting institutional criteria compromised UTCP significantly (reduction of about 0.09). Selecting plans that met all institutional criteria first, then maximizing UTCP, achieved a balanced compromise between tumour control and normal tissue safety. While combining UTCP and standard dose metrics based on dose-volume histogram (i.e., absorbed dose or physical dose constraints) with MCO can enhance brachytherapy plan optimization, exclusive reliance on standard TCP and NTCP models, using recommended parameters, yields clinically unacceptable plans.

BACKGROUND:Accurate delineation of the prostate and intraprostatic gross tumor volume (GTV) on multiparametric MRI (mpMRI) is critical for radiation therapy planning, particularly for focal dose escalation strategies. However, interpretation of mpMRI can be challenging and prone to inter-observer variability, especially among radiation oncologists (ROs) who may have limited training in prostate MRI interpretation. In addition, because many patients do not undergo diagnostic mpMRI before treatment, radiologist input is often absent during treatment planning, which can compromise accurate GTV delineation. PURPOSE:To evaluate approaches for improving focal prostate GTV delineation on mpMRI for radiotherapy planning, by assessing the impact of radiology reports on ROs contours, and comparing the performance of an automated segmentation tool (AIRC) with radiologists' contours as a potential replacement when radiologist input is unavailable. METHODS:Twenty patients underwent mpMRI at our institution. Delineation of the prostate gland and GTV was performed by ROs in two phases. In the first phase, ROs segmented both structures with access only to biopsy results, indicating positive core locations. In the second phase, they repeated the segmentation with access to the radiology report. AIRC segmented both structures as well, using the same images as made available to the ROs. Lesion detection performance was evaluated using sensitivity and positive predictive value (PPV). Segmentations were compared to consensus contours from two radiologists using the STAPLE algorithm. Similarity metrics computed included Dice similarity coefficient (DSC), Hausdorff distance (HD), distance from center, and relative volume difference. RESULTS:Prostate gland segmentation showed minimal inter-observer variability and high agreement with the reference, with a mean DSC of 0.89 ± 0.02 $0.89 \pm 0.02$ for ROs and 0.90 ± 0.03 $0.90 \pm 0.03$ for AIRC. In contrast, GTV segmentation demonstrated substantial variability and a high number of false positives and missed lesions when ROs lacked access to the radiology report. PPV significantly improved during the second attempt with access to the radiology report ( p = 0.03 $p=0.03$ ), and similarity metrics improved significantly across all measures ( p < 0.01 $p<0.01$ ). Sensitivity also increased in the second attempt, although not significantly ( p = 0.0625 $p=0.0625$ ). AIRC performance was comparable to the ROs' first attempt. CONCLUSIONS:High inter-observer variability in GTV segmentation was observed when ROs lacked access to the radiology report, underscoring the difficulty of mpMRI interpretation. Providing radiology reports and establishing standardized guidelines for mpMRI interpretation may improve segmentation accuracy and consistency. An Automated segmentation tool could facilitate the first step in the planning workflow by assisting ROs in target definition.

Androgen deprivation therapy (ADT) is regularly used to treat locally advanced and metastatic prostate cancer (PCa) with toxicities, including metabolic syndrome (MS) and associated adverse hormonal changes. This study evaluated whether metformin mitigates changes in laboratory biomarkers associated with MS and type II diabetes mellitus (T2DM) in PCa patients receiving ADT. PRIME is a phase III double-blind, randomized controlled trial in which 166 normoglycemic patients with PCa receiving ADT were randomized to receive metformin or placebo. For this study, 47 patients from the metformin arm and 32 patients from the placebo arm underwent serum collection and analysis of the following analytes at baseline, 9, and 12 months: IGF-1, IGFBP1, IGFBP2, IGFBP3, IGFBP7, leptin, adiponectin, GDF15, insulin, C-peptide, GIP, GLP-1, and IL-6. Independent t-tests were used to determine whether significant changes in analytes were evident in patients receiving metformin vs placebo and to evaluate analyte changes from baseline for the metformin and placebo groups separately. Mean leptin values increased markedly in the placebo group and significantly less in the metformin group across all time points. Significant improvements were also observed in IGFBP1, IL-6, C-peptide, and GLP-1 with metformin compared with placebo. GDF15 and IGFBP3 significantly increased compared with baseline with ADT alone. This study demonstrates that metformin can mitigate biomarker changes induced by ADT associated with an increased risk of T2DM and MS. In addition, the attenuated increase in leptin signals a potential for improved PCa outcomes, as high leptin values have been correlated with aggressive disease and worse prognosis.

Radiotherapy has achieved substantial progress often attributed to accelerated technological innovation over decades. However, randomized controlled trials (RCTs) are costly, difficult to fund and to conduct, such that the generation of quality evidence is outpaced by changes in practice. We sought to evaluate the implementation performance of a platform approach to the conduct of pragmatic RCTs in radiation oncology. We implemented PERa, a platform consisting of a prospective registry of patients receiving standard-of-care radiation therapy, designed to support pragmatic registry-based RCT (rRCT) methods and staged informed consent. Implementation performance metrics included rate of registry enrollment, acceptability of re-contact and/or serving as controls for interventional trials, activation and recruitment of embedded comparative effectiveness rRCTs, compliance to study arms, and completeness of ePRO data acquired at scale. Between January 1, 2018 and December 31, 2023, the registry accrued 1415 participants across 5 participating institutions. At time of stage 1 consent, 93

Importance Patients with prostate cancer have a high burden of cardiovascular risk factors, often suboptimally controlled, and adverse cardiovascular outcomes. Objective To determine whether the routine referral of patients with prostate cancer to a cardiovascular specialist to implement a systematic risk factor strategy is more likely to reduce adverse cardiovascular outcomes and improve risk factor control than usual care. Design, Settings, and Participants This randomized clinical trial included patients with prostate cancer from 55 sites in 8 countries between 2015 and 2025. Eligible patients were diagnosed with prostate cancer during the past 12 months; had received treatment with androgen deprivation therapy (ADT) for the first time within the past 6 months; or planned to start ADT in the next month. Patients taking a statin with a systolic blood pressure of 130 mm Hg or lower were ineligible. Data were analyzed from May 25 to August 7, 2026. Intervention Patients were allocated in a 1:1 ratio to receive usual care alone or usual care plus routine referral to an internist or cardiologist. The specialists provided a systematic intervention, including a target of systolic blood pressure of 130 mm Hg or lower and a statin medication, irrespective of the patient’s cholesterol levels (even if not usual or guideline-driven practice); encourage smoking cessation; and provide guidance on diet and exercise. Main Outcomes and Measures Hierarchical composite of cardiovascular death, myocardial infarction, stroke, heart failure, suboptimal cholesterol (total cholesterol, >155 mg/dL [to convert to mmol/L, multiply by 0.0259]) and suboptimal blood pressure (systolic blood pressure, >130 mm Hg) as evaluated by the win ratio. Results The analysis included 2487 patients with prostate cancer (mean [SD] age, 68 [8] years). During median (IQR) follow-up of 5.8 (2.7-8.2) years, the win ratio in favor of the intervention was 1.60 (95% CI, 1.42-1.81), mostly attributable to lower cholesterol in the intervention group (mean difference, 12 mg/dL; 95% CI, 9-15 mg/dL) as a consequence of greater protocol-mandated statin use. Mean (SD) close-out systolic blood pressure values were 131.1 (16.9) mm Hg in the intervention group and 132.9 (18.3) mm Hg in the control group. There was no difference in time to cardiovascular death, myocardial infarction, stroke, or heart failure between groups (subdistribution hazard ratio, 1.08; 95% CI, 0.79-1.49). Conclusions and Relevance In this randomized clinical trial, routine referral of patients with prostate cancer to a cardiovascular specialist lead to improved outcomes, specifically through better cholesterol control. However, it is uncertain whether this reduced clinical cardiovascular events. Trial Registration ClinicalTrials.gov Identifier: NCT03127631

Purpose Over the past decade there has been an expansion of brachytherapy (BT) education and practice in Canada including recognition of several BT fellowship programs as eligible for Area of Focused Competence (AFC) designation by the Royal College of Physicians and Surgeons of Canada. This study aims to characterize the extent of BT availability, expertise and utilization after implementation of these initiatives. Materials and Methods A 68-question survey covering expertise, training, resources and future challenges to BT programs was created and sent to a single representative at each of the 36 centers in Canada identified to have an active BT program. Absolute count (proportions) and medians (inter-quartile-range) were used to describe the data. Results 30 responses (response rate 83%) representing all provinces with at least one available BT program (9) were obtained. Twelve (40%) serviced catchment areas with populations >1 million. The median number of radiation oncologists practicing BT in each centre was 5 (3-6); this represented 33% (23%-43%) of overall workforce at each centre. 9 (30%) centers had at least one AFC trained brachytherapist on site while 27 (90%) had at least one non-AFC fellowship trained brachytherapist on site. Of the 10 respondent centers offering BT fellowship programs, 6 (60%) are AFC accredited. All 30 respondents (100%) offered BT treatment for endometrial cancer, 26 (87%) for cervical cancer, 25 (83%) for prostate cancer and 20 (67%) for vaginal cancer. Breast, penile and anal canal BT was offered at 4 (13%), 3 (10%) and 2 (7%) centers, respectively. No center offered lymph node/metastases or bladder BT. In 2024, the median number of endometrial, cervical, prostate and vaginal cancers cases treated were 38 (22-50), 19 (7-33), 66 (41-138) and 1 (0-3), respectively. Sixteen, (62%) respondents anticipated an increase in demand for BT resources within the next 5 years. Conclusions BT programs in Canada are supported by highly trained brachytherapists. BT programs most commonly treat gynecologic cancers (endometrial, cervical and vaginal); while case loads are highest for prostate cancer. These survey results will allow comprehensive assessment of BT access and utilization across the country, and allow strategic planning where there is an anticipated increase in BT demand.

PURPOSE/OBJECTIVE:Brachytherapy (BT) techniques, skillsets and resource requirements have advanced over the past decade. This study aimed to characterize the current extent of BT availability, expertise and utilization in Canada. MATERIALS AND METHODS:A 68-question survey covering expertise, training, resources and future challenges to BT programs was created and sent to a single representative at each of the 36 of 49 radiotherapy centers in Canada identified to have an active BT program. Responses were then analyzed in aggregate. RESULTS:Thirty-one responses (response rate 86%) representing all provinces with at least 1 available BT program (9) were obtained. The median number of radiation oncologists practicing BT in each center was 5 (3-6); this represented 33% (24%-43%) of the workforce at each center. Thirty (97%) centers had at least 1 fellowship trained brachytherapist on site. Eleven (35%) respondent centers offered BT fellowship programs and 7 (64%) of those offered the nationally accredited brachytherapy designations at the end of training. All 30 respondents (100%) offered BT treatment for endometrial cancer, 26 (87%) for cervical cancer, 25 (83%) for prostate cancer and 20 (67%) for vaginal cancer. In 2024, the median number of endometrial, cervical, prostate and vaginal cancers cases treated were 38 (22-50), 19 (7-33), 66 (41-138) and 1 (0-3), respectively. Sixteen (62%) respondents anticipated an increase in demand for BT resources within the next 5 years. CONCLUSION:BT programs across Canada are supported by highly trained brachytherapists. BT programs most commonly treat gynecologic and genitourinary malignancies.

PURPOSE/OBJECTIVES:Low Dose-Rate Brachytherapy (LDR) and High Dose-Rate Brachytherapy (HDR) are options for favorable risk prostate cancer. We hypothesized that HDR provides comparable disease control with less urinary toxicity. Primary objective was to determine prostate cancer control at 48 months, defined as a PSA < 0.4 ng/ml. MATERIALS/METHODS:Eligible patients had low and intermediate risk diseases. Randomization was to Arm 1 LDR with I-125 to 144 Gy, or Arm 2 HDR with 19 Gy x1 + intraprostatic boost. Follow-up included PSA, toxicity (CTCAE v 4.0), and Quality of Life (EPIC 26). Arm 2 was closed in May 2019 due to evidence of inferior outcomes, and a third arm (HDR 13.5 Gy x 2) was opened. We report outcomes of Arms 1 (LDR) and 2 (HDR single fraction) prior to study amendment. RESULTS:103 patients were randomized: 51 to LDR (Arm 1) and 52 to HDR (Arm 2). Median age 65 years; 76 % had Gleason 3 + 4, 90 % PSA < 10, and 80 % stage T1c. Median follow-up 53 months. PSA control at 4 years was 78.4 % for LDR, and 21.2 % for HDR. Local progression rates: 2 % LDR, 13.5 % HDR. Grade 3 toxicity occurred in 6 patients for LDR and 2 patients Arm 2. Urinary irritative and bowel symptoms were worse in the first 6 months for LDR. CONCLUSIONS:LDR brachytherapy has high prostate cancer disease control rate at 4 years, although with worse impact on urinary symptoms in the first 6 months. Single fraction HDR was associated with unacceptable cancer control.

PURPOSE:This study aims to clinically implement eb_gui, a user-friendly toolkit for Monte Carlo simulations utilizing egs_brachy, in the context of low-dose-rate (LDR) brachytherapy for prostate and breast cancers. METHODS:A set of test cases, ranging from simple to complex scenarios including single- and multi-seed patient models, was developed for LDR brachytherapy of both breast (103Pd) and prostate (125I). Utilizing Digital Imaging and Communications in Medicine (DICOM) files, the open-source interface eb_gui was employed to compute doses. The commissioning process involved comparing eb_gui results against clinical TG-43 treatment planning system (TG43-TPS) calculations, encompassing point-by-point differences across 3D dose distributions, dose volume histograms, and dose metrics. Additionally, patient-specific dose distributions were computed using eb_gui's full-tissue models (TG186-MC) and compared against TG-43 Monte Carlo calculations (TG43-MC) across multiple cancer centers. RESULTS:Excellent agreement was observed between TG43-TPS and TG43-MC calculated doses, with point-to-point differences of less than 1 Gy (∼1% of prescription dose) for breast and prostate cases. Comparisons between multicenter TG186-MC and TG43-MC doses highlighted discrepancies that underscore the limitations of the TG-43 formalism and affirming the necessity for a model-based dose calculation algorithm (MBDCA). CONCLUSION:This study successfully developed a series of test cases and a commissioning workflow for implementing eb_gui in LDR brachytherapy across multiple centers. The findings underscore the potential of TG-186 MBDCA to enhance the precision of patient dosimetry and improve the accuracy of treatment outcome predictions in LDR brachytherapy. This work represents a significant step toward broader adoption of advanced dose calculation methodologies in clinical practice.

Purpose Over the past decade there has been an expansion of brachytherapy (BT) education and practice in Canada including recognition of several BT fellowship programs as eligible for Area of Focused Competence (AFC) designation by the Royal College of Physicians and Surgeons of Canada. This study aims to characterize the extent of BT availability, expertise and utilization after implementation of these initiatives. Materials and Methods A 68-question survey covering expertise, training, resources and future challenges to BT programs was created and sent to a single representative at each of the 36 centers in Canada identified to have an active BT program. Absolute count (proportions) and medians (inter-quartile-range) were used to describe the data. Results 30 responses (response rate 83%) representing all provinces with at least one available BT program (9) were obtained. Twelve (40%) serviced catchment areas with populations >1 million. The median number of radiation oncologists practicing BT in each centre was 5 (3-6); this represented 33% (23%-43%) of overall workforce at each centre. 9 (30%) centers had at least one AFC trained brachytherapist on site while 27 (90%) had at least one non-AFC fellowship trained brachytherapist on site. Of the 10 respondent centers offering BT fellowship programs, 6 (60%) are AFC accredited. All 30 respondents (100%) offered BT treatment for endometrial cancer, 26 (87%) for cervical cancer, 25 (83%) for prostate cancer and 20 (67%) for vaginal cancer. Breast, penile and anal canal BT was offered at 4 (13%), 3 (10%) and 2 (7%) centers, respectively. No center offered lymph node/metastases or bladder BT. In 2024, the median number of endometrial, cervical, prostate and vaginal cancers cases treated were 38 (22-50), 19 (7-33), 66 (41-138) and 1 (0-3), respectively. Sixteen, (62%) respondents anticipated an increase in demand for BT resources within the next 5 years. Conclusions BT programs in Canada are supported by highly trained brachytherapists. BT programs most commonly treat gynecologic cancers (endometrial, cervical and vaginal); while case loads are highest for prostate cancer. These survey results will allow comprehensive assessment of BT access and utilization across the country, and allow strategic planning where there is an anticipated increase in BT demand.

PURPOSE:We investigated whether metformin decreases metabolic syndrome (MS) risk in patients with prostate cancer (PCa) receiving androgen deprivation therapy (ADT). MATERIALS AND METHODS:In this phase 3, multicenter, double-blind, randomized controlled trial, normoglycemic patients with PCa planned for at least 9 months of ADT were randomized 2:1 to receive metformin 850 mg or placebo twice daily orally for 18 months. The primary objective was to compare proportions of MS at 18 months between the study arms. RESULTS:Between July 2018 and November 2023, 166 patients were randomized. The trial closed prematurely on November 24, 2023, because of drug supply cessation and the planned enrollment numbers (n = 300) were not met. A total of 90 (metformin) and 45 patients (placebo) were analyzed in the final analysis. The median follow-up was 24 months (IQR: 19.5-36 months). Proportions of MS between metformin and placebo arms were 38/90 (42%) vs 26/45 (58%) at baseline (P = .09) and 40/73 (55%) vs 23/34 (68%) at 18 months (P = .2). Significant reductions in mean (SD) body weight occurred with metformin at 9 (-0.9 [4] vs +1.8 [3.8] kg; P < .001) and 12 months (-0.33 [3.9] vs +1.8 [3.9] kg; P = .004). Mean (SD) hemoglobin A1c was lowered with metformin at 9% (-0.02% [0.23%] vs +0.08% [0.26%]; P = .02) and 12 months (+0.03% [0.27%] vs +0.08% [0.27%]; P = .03). Significantly smaller increments in mean (SD) waist circumferences were noted with metformin at 9 (+0.8 [4.3] vs +2.9 [5.7] cm; P = .03), 12 (+1.9 [5.1] vs +3.3 [6] cm; P = .15), and 18 months (+1.8 [3.8] vs +3.8 [6.1] cm; P = .03). CONCLUSIONS:Metformin did not reduce the risk of MS in patients with PCa on ADT. However, significant improvements in body weight, waist circumference, and hemoglobin A1c suggest a potential role for metformin in reducing ADT-related complications.