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Treatment intensification with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPi) have led to improved survival in advanced prostate cancer. However, ADT is linked to significant cardiovascular toxicity, and ARPi also negatively impacts cardiovascular health. Together with a higher prevalence of baseline cardiovascular risk factors reported among prostate cancer survivors at diagnosis, there is a pressing need to prioritise and optimise cardiovascular health in this population. Firstly, While no dedicated cardiovascular toxicity risk calculators are available, other tools such as SCORE2 can be used for baseline cardiovascular risk assessment. Next, selected patients on combination therapy may benefit from de-escalation of ADT to minimise its toxicities while maintaining cancer control. These patients can be characterised by an exceptional PSA response to hormonal treatment, favourable disease characteristics and competing comorbidities that warrant a less aggressive treatment regime. In addition, emerging molecular and genomic biomarkers hold the potential to identify patients who are suited for a de-escalated treatment approach either with ADT or with ARPi. One such biomarker is AR-V7 splice variant that predicts resistance to ARPi. Lastly, optimization of modifiable cardiovascular risk factors for patients through a coherent framework (ABCDE) and exercise therapy is equally important. This article aims to comprehensively review the cardiovascular impact of hormonal manipulation in metastatic hormone-sensitive prostate cancer, propose overarching strategies to mitigate cardiovascular toxicity associated with hormonal treatment, and, most importantly, raise awareness about the detrimental cardiovascular effects inherent in our current management strategies involving hormonal agents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Chen, Wong, Tan, Tay, Tan, Chan, Ho, Cheng, Teoh, Chiu, Wang, Saad, Kanesvaran, Li, Ng, Tuan and Yuen.)

Objective. The validation of deformable image registration (DIR) for contour propagation is often done using contour-based metrics. Meanwhile, dose accumulation requires evaluation of voxel mapping accuracy, which might not be accurately represented by contour-based metrics. By fabricating a deformable anthropomorphic pelvis phantom, we aim to (1) quantify the voxel mapping accuracy for various deformation scenarios, in high- and low-contrast regions, and (2) identify any correlation between dice similarity coefficient (DSC), a commonly used contour-based metric, and the voxel mapping accuracy for each organ. Approach . Four organs, i.e. pelvic bone, prostate, bladder and rectum (PBR), were 3D printed using PLA and a Polyjet digital material, and assembled. The latter three were implanted with glass bead and CT markers within or on their surfaces. Four deformation scenarios were simulated by varying the bladder and rectum volumes. For each scenario, nine DIRs with different parameters were performed on RayStation v10B. The voxel mapping accuracy was quantified by finding the discrepancy between true and mapped marker positions, termed the target registration error (TRE). Pearson correlation test was done between the DSC and mean TRE for each organ. Main results . For the first time, we fabricated a deformable phantom purely from 3D printing, which successfully reproduced realistic anatomical deformations. Overall, the voxel mapping accuracy dropped with increasing deformation magnitude, but improved when more organs were used to guide the DIR or limit the registration region. DSC was found to be a good indicator of voxel mapping accuracy for prostate and rectum, but a comparatively poorer one for bladder. DSC > 0.85/0.90 was established as the threshold of mean TRE ⩽ 0.3 cm for rectum/prostate. For bladder, extra metrics in addition to DSC should be considered. Significance . This work presented a 3D printed phantom, which enabled quantification of voxel mapping accuracy and evaluation of correlation between DSC and voxel mapping accuracy., (© 2024 Institute of Physics and Engineering in Medicine.)

Widespread adoption of mpMRI has led to a decrease in the number of patients requiring prostate biopsies. 68 Ga-PSMA-11 PET/CT has demonstrated added benefits in identifying csPCa. Integrating the use of these imaging techniques may hold promise for predicting the presence of csPCa without invasive biopsy. A retrospective analysis of 42 consecutive patients who underwent mpMRI, 68 Ga-PSMA-11 PET/CT, prostatic biopsy, and radical prostatectomy (RP) was carried out. A lesion-based model ( n = 122) using prostatectomy histopathology as reference standard was used to analyze the accuracy of 68 Ga-PSMA-11 PET/CT, mpMRI alone, and both in combination to identify ISUP-grade group ≥ 2 lesions. 68 Ga-PSMA-11 PET/CT demonstrated greater specificity and positive predictive value (PPV), with values of 73.3% (vs. 40.0%) and 90.1% (vs. 82.2%), while the mpMRI Prostate Imaging Reporting and Data System (PI-RADS) 4-5 had better sensitivity and negative predictive value (NPV): 90.2% (vs. 78.5%) and 57.1% (vs. 52.4%), respectively. When used in combination, the sensitivity, specificity, PPV, and NPV were 74.2%, 83.3%, 93.2%, and 51.0%, respectively. Subgroup analysis of PI-RADS 3, 4, and 5 lesions was carried out. For PI-RADS 3 lesions, 68 Ga-PSMA-11 PET/CT demonstrated a NPV of 77.8%. For PI-RADS 4-5 lesions, 68 Ga-PSMA-11 PET/CT achieved PPV values of 82.1% and 100%, respectively, with an NPV of 100% in PI-RADS 5 lesions. A combination of 68 Ga-PSMA-11 PET/CT and mpMRI improved the radiological diagnosis of csPCa. This suggests that avoidance of prostate biopsy prior to RP may represent a valid option in a selected subgroup of high-risk patients with a high suspicion of csPCa on mpMRI and 68 Ga-PSMA-11 PET/CT.

Background and Purpose: This study aimed to investigate the feasibility of safe-dose escalation to dominant intraprostatic lesions (DILs) and assess the clinical impact using dose-volume (DV) and biological metrics in photon and proton therapy. Biological parameters defined as late grade ≥ 2 gastrointestinal (GI) and genitourinary (GU) derived from planned ( D P ) and accumulated dose ( D A ) were utilized., Materials and Methods: In total, 10 patients with high-risk prostate cancer with multiparametric MRI-defined DILs were investigated. Each patient had two plans with a focal boost to the DILs using intensity-modulated proton therapy (IMPT) and volumetric-modulated arc therapy (VMAT). Plans were optimized to obtain DIL coverage while respecting the mandatory organ-at-risk constraints. For the planning evaluation, DV metrics, tumor control probability (TCP) for the DILs and whole prostate excluding the DILs (prostate-DILs), and normal tissue complication probability (NTCP) for the rectum and bladder were calculated. Wilcoxon signed-rank test was used for analyzing TCP and NTCP data., Results: IMPT achieved a higher D mean for the DILs compared to VMAT (IMPT: 68.1 GyRBE vs. VMAT: 66.6 Gy, p < 0.05). Intermediate-high rectal and bladder doses were lower for IMPT ( p < 0.05), while the high-dose region (V60 Gy) remained comparable. IMPT-TCP for prostate-DIL were higher compared to VMAT (IMPT: 86%; α/β = 3, 94.3%; α/β = 1.5 vs. VMAT: 84.7%; α/β = 3, 93.9%; α/β = 1.5, p < 0.05). Likewise, IMPT obtained a moderately higher DIL TCP (IMPT: 97%; α/β = 3, 99.3%; α/β = 1.5 vs. VMAT: 95.9%; α/β = 3, 98.9%; α/β = 1.5, p < 0.05). Rectal D A -NTCP displayed the highest GI toxicity risk at 5.6%, and IMPT has a lower GI toxicity risk compared to VMAT-predicted Quantec-NTCP ( p < 0.05). Bladder D P -NTCP projected a higher GU toxicity than D A -NTCP, with VMAT having the highest risk ( p < 0.05)., Conclusion: Dose escalation using IMPT is able to achieve a high TCP for the DILs, with the lowest rectal and bladder DV doses at the intermediate-high-dose range. The reduction in physical dose was translated into a lower NTCP ( p < 0.05) for the bladder, although rectal toxicity remained equivalent., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ong, Knight, Panettieri, Dimmock, Tuan, Tan and Wright.)

Purpose: To report outcomes of using image-guided hybrid intra-cavitary/interstitial applicators under moderate sedation for locally advanced cervical cancer patients in our institution., Material and Methods: A total of 69 fractions of brachytherapy with hybrid applicators were performed in 33 patients from January 2017 to April 2021. All patients underwent MRI pelvis 1 week pre-brachytherapy to determine suitability for interstitial brachytherapy and pre-plan needle placement. All insertion of applicators were performed under moderate sedation with midazolam and/or fentanyl. Fifty-eight (84.1%) fractions were planned with CT alone. Clinical outcomes, dose volume parameters, and toxicities were analyzed., Results: The median follow-up was 28 months. A total of 320 needles (median, 5 needles per fraction) were implanted, with a median insertion depth of 3 cm (range, 1.5-4 cm). The median high-risk clinical target volume (HR-CTV) during initial brachytherapy was 34.5 cc (range, 17.8-74.7 cc). The median total EQD 2 D 2cc of the rectum, bladder, sigmoid, and small intestine colon was 71.8 Gy, 81.5 Gy, 69 Gy, and 58.3 Gy, respectively. The 2-year local control and overall survival were 80.7% and 77.7%, respectively. Larger volume HR-CTV was significantly associated with worse local control (HR = 1.08, p = 0.005) and overall survival (HR = 1.04, p = 0.015). None of the patients required in-patient admission or blood transfusion post-procedure. Late grade 3 gastrointestinal and genitourinary toxicities were observed in 4 patients (12.2%)., Conclusions: Hybrid applicators inserted under moderate sedation are feasible and safe. Image-guided interstitial brachytherapy with CT planning aided by MRI performed 1 week pre-brachytherapy is associated with favorable outcomes and modest toxicities., Competing Interests: The authors report no conflict of interest., (Copyright © 2023 Termedia.)

Objective . Automatic deformable image registration (DIR) is a critical step in adaptive radiotherapy. Manually delineated organs-at-risk (OARs) contours on planning CT (pCT) scans are deformably registered onto daily cone-beam CT (CBCT) scans for delivered dose accumulation. However, evaluation of registered contours requires human assessment, which is time-consuming and subjects to high inter-observer variability. This work proposes a deep learning model that allows accurate prediction of Dice similarity coefficients (DSC) of registered contours in prostate radiotherapy. Approach . Our dataset comprises 20 prostate cancer patients with 37-39 daily CBCT scans each. The pCT scans and planning contours were deformably registered to each corresponding CBCT scan to generate virtual CT (vCT) scans and registered contours. The DSC score, which is a common contour-based validation metric for registration quality, between the registered and manual contours were computed. A Siamese neural network was trained on the vCT-CBCT image pairs to predict DSC. To assess the performance of the model, the root mean squared error (RMSE) between the actual and predicted DSC were computed. Main results . The model showed promising results for predicting DSC, giving RMSE of 0.070, 0.079 and 0.118 for rectum, prostate, and bladder respectively on the holdout test set. Clinically, a low RMSE implies that the predicted DSC can be reliably used to determine if further DIR assessment from physicians is required. Considering the event where a registered contour is classified as poor if its DSC is below 0.6 and good otherwise, the model achieves an accuracy of 92% for the rectum. A sensitivity of 0.97 suggests that the model can correctly identify 97% of poorly registered contours, allowing manual assessment of DIR to be triggered. Significance . We propose a neural network capable of accurately predicting DSC of deformably registered OAR contours, which can be used to evaluate eligibility for plan adaptation., (Creative Commons Attribution license.)

Introduction: We report herein the impact of focal therapy (FT) on multi-domain functional outcomes in a Phase II prospective clinical trial (NCT04138914) in focal cryotherapy for clinically significant prostate cancer (csPCa)., Methods: The primary outcome was the detection of a ≥5 point deterioration in any of the four main expanded prostate index composite (EPIC) functional domains. Pretreatment multiparametric magnetic resonance imaging (mpMRI) and transperineal targeted and systematic saturation biopsy were used to select patients with prostate-specific antigen (PSA)≤20 ng/mL, Gleason grade group (GG) ≤4, mpMRI lesion volume ≤ 3 mL (for a single lesion) or ≤1.5 mL (where two lesions were present). Focal cryotherapy was performed with a minimum 5 mm margin around each target lesion. EPIC scores were obtained at baseline and posttreatment at 1, 3, 6, and 12 months. Mandatory repeat mpMRI and prostate biopsy were performed at 12 months to determine the infield and outfield recurrence., Results: Twenty-eight patients were recruited. The mean age was 68 years, with PSA of 7.3 ng/mL and PSA density of 0.19 ng/mL 2 . No Clavien-Dindo ≥3 complications occurred. Transient worsening of EPIC urinary (mean diff 16.0, p < 0.001, 95% confidence interval [CI]: 8.8-23.6) and sexual function scores (mean diff 11.0, p:0.005, 95% CI: 4.0-17.7) were observed at 1-month posttreatment, with recovery by Month 3. A subgroup who had ablation extending to the neurovascular bundle had a trend to delayed recovery of sexual function to Month 6. At 12-month repeat mpMRI and biopsy, 22 patients (78.6%) had no detectable csPCa. Of the six patients (21.4%) who had csPCa recurrences, four were GG2, one GG3, and one GG4. Four patients underwent repeat FT, one underwent radical prostatectomy, while the remaining one patient with low-volume GG2 cancer opted for active surveillance., Conclusion: FT using cryotherapy was associated with a transient deterioration of urinary and sexual function with resolution at 3 months posttreatment and with reasonable early efficacy in well-selected csPCa patients., (© 2023 The Authors. The Prostate published by Wiley Periodicals LLC.)

Regional hyperthermia therapy (RHT) is a treatment that applies moderate heat to tumours in an attempt to potentiate the effects of oncological treatments and improve responses. Although it has been used for many years, the mechanisms of action are not fully understood. Heterogenous practices, poor quality assurance, conflicting clinical evidence and lack of familiarity have hindered its use. Despite this, several centres recognise its potential and have adopted it in their standard treatment protocols. In recent times, significant technical improvements have been made and there is an increasing pool of evidence that could revolutionise its use. Our narrative review aims to summarise the recently published prospective trial evidence and present the clinical effects of RHT when added to standard cancer treatments. In total, 31 studies with higher-quality evidence across various subsites are discussed herein. Although not all of these studies are level 1 evidence, benefits of moderate RHT in improving local tumour control, survival outcomes and quality of life scores were observed across the different cancer subsites with minimal increase in toxicities. This paper may serve as a reference when considering this technique for specific indications.

Background and Purpose: Normal tissue complication probability (NTCP) parameters derived from traditional 3D plans may not be ideal in defining toxicity outcomes for modern radiotherapy techniques. This study aimed to derive parameters of the Lyman-Kutcher-Burman (LKB) NTCP model using prospectively scored clinical data for late gastrointestinal (GI) and genitourinary (GU) toxicities for high-risk prostate cancer patients treated using volumetric-modulated-arc-therapy (VMAT). Dose-volume-histograms (DVH) extracted from planned (D P ) and accumulated dose (D A ) were used., Material and Methods: D P and D A obtained from the DVH of 150 prostate cancer patients with pelvic-lymph-nodes irradiation treated using VMAT were used to generate LKB-NTCP parameters using maximum likelihood estimations. Defined GI and GU toxicities were recorded up to 3-years post RT follow-up. Model performance was measured using Hosmer-Lemeshow goodness of fit test and the mean area under the receiver operating characteristics curve (AUC). Bootstrapping method was used for internal validation., Results: For mild-severe (Grade ≥1) GI toxicity, the model generated similar parameters based on D A and D P DVH data (D A -D 50 :71.6 Gy vs D P -D 50 :73.4; D A -m:0.17 vs D P -m:0.19 and D A/P -n 0.04). The 95% CI for D A -D 50 was narrower and achieved an AUC of >0.6. For moderate-severe (Grade ≥2) GI toxicity, D A -D 50 parameter was higher and had a narrower 95% CI (D A -D 50 :77.9 Gy, 95% CI:76.4-79.6 Gy vs D P -D 50 :74.6, 95% CI:69.1-85.4 Gy) with good model performance (AUC>0.7). For Grade ≥1 late GU toxicity, D 50 and n parameters for D A and D P were similar (D A -D 50 : 58.8 Gy vs D P -D 50 : 59.5 Gy; D A -n: 0.21 vs D P -n: 0.19) with a low AUC of<0.6. For Grade ≥2 late GU toxicity, similar NTCP parameters were attained from D A and D P DVH data (D A -D 50 :81.7 Gy vs D P -D 50 :81.9 Gy; D A -n:0.12 vs D P -n:0.14) with an acceptable AUCs of >0.6., Conclusions: The achieved NTCP parameters using modern RT techniques and accounting for organ motion differs from QUANTEC reported parameters. D A -D 50 of 77.9 Gy for GI and D A /D P -D 50 of 81.7-81.9 Gy for GU demonstrated good predictability in determining the risk of Grade ≥2 toxicities especially for GI derived D 50 and are recommended to incorporate as part of the DV planning constraints to guide dose escalation strategies while minimising the risk of toxicity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ong, Knight, Panettieri, Dimmock, Tuan, Tan and Wright.)

Aims: Ultra-hypofractionated radiotherapy (UHF-RT) is widely utilized in men with localized prostate cancer (PCa). There are limited data in Asian cohorts. We report the outcomes of a single-arm, phase II trial of UHF-RT from an Asian center., Methods: We recruited men with histologically confirmed, nonmetastatic localized PCa. UHF-RT regimens were 36.25 Gy (Cohort A) and 37.5 Gy (Cohort B) delivered in five fractions every other day over 1.5-2.5 weeks. Primary endpoint was physician-scored late genitourinary (GU) and gastrointestinal (GI) adverse events (AEs). Quality-of-life (QoL) was assessed by Expanded Prostate Cancer Index Composite (EPIC) at baseline, 1- and 2-year post-UHF-RT., Results: Between March 2014 and August 2019, 105 men were recruited; four were subsequently excluded from analysis. Median age was 68.0 (Interquartile range (IQR): 63.8-73.0) years. 26 (24.8%) and 68 (64.8%) men had NCCN-defined low-and intermediate-risk PCa, respectively. No late ≥G3 GU or GI toxicities were reported in both cohorts. Peak incidence of acute ≥G2 GU AEs at 14 days post-UHF-RT was 23.6% (17/72) and 24.0% (6/25) in Cohorts A and B, respectively; ≥G2 GI AEs were observed in 9.7% (7/72) and 36.0% (9/25), respectively. Late ≥G2 GU and GI AEs occurred in 4.7% and 3.1% of Cohort A patients, and 5.0% in Cohort B at 12 months, with no AEs at 24 months. EPIC scores changed minimally across all domains. At a median follow-up of 44.9 months, we recorded one (1.3%) biochemical relapse by the Phoenix criteria (Cohort A)., Conclusion: UHF-RT is well tolerated in Asian men and can be a recommended fractionation schema for localized PCa., (© 2021 The Authors. Asia-Pacific Journal of Clinical Oncology published by John Wiley & Sons Australia, Ltd.)

Background and Purpose: Significant dose deviations have been reported between planned (D P ) and accumulated (D A ) dose in prostate radiotherapy. This study aimed to develop multivariate analysis (MVA) models associating Grade 1 and 2 gastrointestinal (GI) toxicity with clinical and D P or D A dosimetric variables separately., Materials and Methods: Dose volume (DV) metrics were compared between D A and D P for 150 high-risk prostate cancer patients. MV models were generated from significant clinical and dosimetric variables (p < 0.05) at univariate level. Dose-based-region of interest (DB-ROI) metrics were included. Model performance was measured, and additional subgroup analysis were performed., Results: Rectal D A demonstrated a higher intermediate-high dose (V 30-65 Gy and DB-ROI at 15-50 mm) compared to D P . Conversely, at the very high dose region, rectal D A (V 75 Gy and DB-ROI at 5-10 mm) were significantly lower. In MVA, rectal DB-ROI at 10 mm was predictive for Grade ≥ 1 GI toxicity for D A and D P . Age, rectal D A for D 0.03 cc , and rectal D P for DB-ROI 10 mm were predictors for Grade 2 GI toxicity. Subgroup analysis revealed that patients ≥ 72 years old and a rectal D A of ≥ 78.2 Gy were highly predictive of Grade 2 GI toxicity., Conclusions: The dosimetric impact of a higher dose rectal dose in D A due to volumetric changes was minimal and was not predictive of detrimental clinical toxicity apart from rectal D 0.03 cc  ≥ 78.2 Gy for Grade 2 GI toxicity. The use of the DB-ROI method can provide equivalent predictive power as the DV method in toxicity prediction., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: This study aims to explore the role of four-dimensional (4D) transperineal ultrasound (TPUS) in the contouring of prostate gland with planning computed tomography (CT) images, in the absence of magnetic resonance imaging (MRI)., Materials and Methods: Five radiation oncologists (ROs) performed two rounds of prostate gland contouring (single-blinded) on CT-alone and CT/TPUS datasets obtained from 10 patients who underwent TPUS-guided external beam radiotherapy. Parameters include prostate volume, DICE similarity coefficient (DSC) and centroid position. Wilcoxon signed-rank test assessed the significance of inter-modality differences, and the intraclass correlation coefficient (ICC ) reflected inter- and intra-observer reliability of parameters., Results: Inter-modality analysis revealed high agreement (based on DSC and centroid position) of prostate gland contours between CT-alone and CT/TPUS. Statistical significant difference was observed in the superior-inferior direction of the prostate centroid position (p = 0.011). All modalities yielded excellent inter-observer reliability of delineated prostate volume with ICC > 0.9, mean DSC > 0.8 and centroid position: CT-alone (ICC = 1.000) and CT/TPUS (ICC = 0.999) left-right (L/R); CT-alone (ICC = 0.999) and CT/TPUS (ICC = 0.998) anterior-posterior (A/P); CT-alone (ICC = 0.999) and CT/TPUS (ICC = 1.000) superior-inferior (S/I). Similarly, all modalities yielded excellent intra-observer reliability of delineated prostate volume, ICC > 0.9 and mean DSC > 0.8. Lastly, intra-observer reliability was excellent on both imaging modalities for the prostate centroid position, ICC > 0.9., Conclusion: TPUS does not add significantly to the amount of anatomical information provided by CT images. However, TPUS can supplement planning CT to achieve a higher positional accuracy in the S/I direction if access to CT/MRI fusion is limited., Competing Interests: Conflict of interest The authors do not have any conflict of interest to declare., (© 2022 Greater Poland Cancer Centre.)

Background: Androgen deprivation therapy (ADT) and radiotherapy (RT) are the mainstay treatment for localized prostate cancer and recurrence after surgery. Cardiovascular (CV) toxicity of ADT is increasingly recognized, and the risk relates to pre-existing risk factors and ADT modalities. Despite ethnic differences in the prevalence of CV risk factors and variations of CV mortality, data on ADT-related cardiotoxicities in the Asian population remain inconclusive. Our registry-based study investigated ADT-related major adverse cardiovascular events (MACE) after primary or salvage RT., Methods: Our study combined two prospectively established registry databases from National Cancer Center Singapore and National Heart Center Singapore. The primary endpoint is time to first MACE after treatment. MACE is defined as myocardial infarction, stroke, unstable angina, or cardiovascular death. Two types of propensity score adjustments, including ADT propensity score as a covariate in the multivariable regression model and propensity score weighting, were applied to balance baseline features and CV risk factors between RT alone and RT + ADT groups., Results: From 2000 to 2019, 1940 patients received either RT alone (n = 494) or RT + ADT (n = 1446) were included. After a median follow-up of 10 years (RT) and 7.2 years (RT+ ADT), the cumulative incidence of MACE at 1, 3 and 9 years was 1.2, 5 and 16.2% in RT group, and 1.1, 5.2 and 17.6% in RT + ADT group, respectively. There were no differences in the incidence of MACE between 2 groups (HR 1.01, 95% CI 0.78-1.30, p = 0.969). Pre-treatment CV risk factors were common (80%), and CV disease (15.9%) was the second leading cause of death after prostate cancer (21.1%). On univariate analysis, older age, Indians and Malays, pre-existing CV risk factors, and history of MACE were associated with higher MACE risk. After propensity score adjustments, there remained no significant differences in MACE risk between RT + ADT and RT group on multivariable analysis., Conclusions: In our registry-based study, ADT is not associated with increased risk of major cardiovascular events among Southeast Asian men with prostate cancer after curative radiotherapy., (© 2022. The Author(s).)

Inter-fraction organ variations cause deviations between planned and delivered doses in patients receiving radiotherapy for prostate cancer. This study compared planned (D P ) vs accumulated doses (D A ) obtained from daily cone-beam computed tomography (CBCT) scans in high-risk- prostate cancer with pelvic lymph nodes irradiation. An intensity-based deformable image registration algorithm used to estimate contours for D A was validated using geometrical agreement between radiation oncologist's and deformable image registration algorithm propagated contours. Spearman rank correlations (r s ) between geometric measures and changes in organ volumes were evaluated for 20 cases. Dose-volume (DV) differences between D A and D P were compared (Wilcoxon rank test, p < 0.05). A novel region-of-interest (ROI) method was developed and mean doses were analyzed. Geometrical measures for the prostate and organ-at-risk contours were within clinically acceptable criteria. Inter-group mean (± SD) CBCT volumes for the rectum were larger compared to planning CT (pCT) (51.1 ± 11.3 cm 3 vs 46.6 ± 16.1 cm 3 ), and were moderately correlated with variations in pCT volumes, rs = 0.663, p < 0.01. Mean rectum DV for D A was higher at V30-40 Gy and lower at V70-75 Gy, p < 0.05. Mean bladder CBCT volumes were smaller compared to pCT (198.8 ± 55 cm 3 vs 211.5 ± 89.1 cm 3 ), and was moderately correlated with pCT volumes, rs = 0.789, p < 0.01. Bladder D A was higher at V30-65 Gy and lower at V70-75 Gy (p < 0.05). For the ROI method, rectum and bladder D A were lower at 5 to 10 mm (p < 0.01) as compared to D P , whilst bladder D A was higher than D P at 20 to 50 mm (p < 0.01). Generated D A demonstrated significant differences in organ-at-risk doses as compared to D P . A well-constructed workflow incorporating a ROI DV-extraction method has been validated in terms of efficiency and accuracy designed for seamless integration in the clinic to guide future plan adaptation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The relevance of continuous testosterone (TT) monitoring in castration-resistant prostate cancer (CRPC) remains in question., Objective: To determine if TT levels before and during novel anti-androgen therapies (NAAT), and the TT 'bounce' phenomenon may predict treatment response in CRPC., Materials and Methods: From 2014 through 2018, we identified 92 CRPC patients treated with either Abiraterone or Enzalutamide from a prospectively maintained cancer registry. The TT levels measured before and during NAAT were correlated with the oncological outcomes, determined by PSA response (% change), PSA progression-free survival (PFS) and overall survival (OS)., Results and Limitations: At CRPC, 58 (63.0%) and 34 (37.0%) patients opted for Abiraterone and Enzalutamide respectively. Median TT levels at CRPC status before and during NAAT were 10.37 ng/dl and 20.46 ng/dl respectively. PSA response was superior in patients with a higher TT before NAAT (P:0.048, median difference: 18.22%, 95% CI 0.70 - 40.37) and longer time to CRPC (P: 0.041, median difference: 15.31%, 95% CI 1.84 -34.84), with a trend towards lower TT during NAAT (P: 0.062). Over a follow up of 33.0 months, 65 patients (70.7%) developed PSA progression. PSA PFS was longer in patients with higher TT before NAAT (16.3 vs. 10.8 months; P: 0.023), lower TT during NAAT (17.0 vs. 9.1 months; P: 0.001), and longer time to CRPC (13.4 vs. 8.0 months; P: 0.032). Importantly, better OS was observed in lower TT during NAAT (45.0 vs. 33.0 months; P:0.029) and longer time to CRPC (43.0 vs. 31.0 months; P: 0.025). The TT 'bounce' phenomenon was observed in 28 patients (33.3%), and was associated with a poorer PSA response (P: 0.029, median difference: 18.90%, 95% CI 3.83 - 41.45), shorter PSA PFS (8.6 vs 15.2 months, P: 0.002) and shorter OS (29.0 vs. 45.0 months, P: 0.012)., Conclusion: In CRPC patients, TT behaviors before and during NAAT, and the 'bounce' phenomenon continue to predict treatment response and could guide clinical decisions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

An automated dose accumulation and contour propagation workflow using daily cone beam computed tomography (CBCTs) images for prostate cases that require pelvic lymph nodes irradiation (PLNs) was developed. This workflow was constructed using MIM® software with the intention to provide accurate dose transformations for plans with two different isocentres, whereby two sequential treatment phases were prescribed. The pre-processing steps for data extractions from treatment plans, CBCTs, determination of couch shift information and management of missing CBCTs are described. To ensure that the imported translational couch shifts were in the correct orientation and readable in MIM, phantom commissioning was performed. For dose transformation, rigid registration with corrected setup shifts and scaled fractional dose was performed for pCT to daily CBCTs, which were then deformed onto CBCT 1 . Fractional dose summation resulted in the final accumulated dose for the patient allowing differences in dosimetry between the planned and accumulated dose to be analysed. Contour propagations of the prostate, bladder and rectum were performed within the same workflow. Transformed contours were then deformed onto daily CBCTs to generate trending reports for analysis, including Dice Similarity Coefficient (DSC) and Mean Distance to Agreement (MDA). Results obtained from phantom commissioning (DSC = 0.96, MDA = 0.89 mm) and geometrical analysis of the propagated contours for twenty patients; prostate (DSC: 0.9 ± 0.0, MDA: 1.0 ± 0.3 mm), rectum (DSC: 0.8 ± 0.1, mm, MDA: 1.7 ± 0.6 mm) and bladder (DSC: 0.8 ± 0.1, MDA: 2.8 ± 1.0 mm) were within clinically accepted tolerances for both DSC (>0.8) and MDA (< 0.3 mm). The developed workflow is being performed on a larger patient cohort for predictive model building, with the goal of correlating observed toxicity with the actual accumulated dose received by the patient., (© 2020 The Authors. Journal of Medical Radiation Sciences published by John Wiley & Sons Australia, Ltd on behalf of Australian Society of Medical Imaging and Radiation Therapy and New Zealand Institute of Medical Radiation Technology.)

This technical evaluation aims to provide practice 'how to' guidelines for radiation therapists (RTs) when positioning a transperineal ultrasound (TPUS) probe during prostate radiotherapy. Recommendations and practical tips will be provided for the best practice in TPUS-guided workflow to obtain optimal ultrasound images for accurate interpretation and registration of the prostate gland. This will assist the RTs in making consistent and accurate clinical decision in an ultrasound-guided radiotherapy workflow for prostate treatment. The implementation process and the associated successes and challenges will also be described to assist institutions who may be investigating the potential of implementing this system., (© 2020 The Authors. Journal of Medical Radiation Sciences published by John Wiley & Sons Australia, Ltd on behalf of Australian Society of Medical Imaging and Radiation Therapy and New Zealand Institute of Medical Radiation Technology.)

Background/purpose: The optimal dose fractionation for palliative radiotherapy (RT) in patients with symptomatic advanced bladder cancer is unclear. This study aimed to determine if a higher dose of RT was associated with improved symptoms response rates., Methods: We searched PubMed, Central and Embase for eligible studies published from 1990 to 2019. The primary outcomes were symptoms response rates for hematuria, dysuria and frequency. Secondary outcomes included treatment-related adverse events and quality of life., Results: We found one randomized, four prospective and eight retrospective non-comparative observational studies including 1320 patients who received palliative bladder radiotherapy for symptom relief. The dose fractionation schedules varied across studies ranging from 8 Gy single fraction to 60 Gy in 2 to 8 Gy per fraction. The pooled response rates for hematuria, dyuria and frequency symptoms were 74%, 58% and 71% respectively. A higher dose of RT was not associated with improved response rates of hematuria and frequency. However, a higher dose of RT was associated with a longer duration of hematuria response and reduced response of dysuria. Grade 3 gastrointestinal and genitourinary toxicity occurred in up to 26% of patients. Health-related quality of life (HRQOL) outcomes were reported in one study., Conclusion: This systematic review demonstrates that a higher dose of bladder RT was not associated with improved response rates of hematuria and frequency symptoms but was associated with reduced response of dysuria. Higher doses of bladder RT was associated with more durable hematuria response. Prospective studies to determine the effects of palliative bladder radiotherapy on HRQOL outcomes are warranted.

Background: The exploration of Advanced Practiced Radiation Therapists (APRTs) development in Singapore started in 2011. This study aims to provide an overview of the development of the APRT roles, and to discuss the approaches used to develop and implement these roles in Singapore., Materials and Methods: A mixed methods approach was used in the development of the APRT program. A literature review was carried out to define the APRT scope of practice and core responsibilities. A competency and assessment framework were setup to assess the core competency areas. With this framework, a structured 1-year residency training program was developed., Results: The scope of practice and core responsibilities of APRTs were defined with five proposed advanced practice profiles being successfully validated. A competency framework was set up to assess the core competency domains: clinical, technical and professional competencies, research, education and leadership. A 4-point scoring system was developed for the competency assessment based on two criteria; the frequency with which RTTs would demonstrate competency, and the ability of performing the task competently. A 1-year structured APRT residency program was developed and implemented. The programme consisted of structured lectures, and clinical practice-based modules where APRT residents receive structured mentoring under a mentorship program., Conclusion: The APRT program in Singapore employed an evidence-based implementation process that tested the feasibility of a new practice model. Multidisciplinary involvements, mentorship and clinical training were important factors for the success of the APRT program., Competing Interests: The authors of this article report no conflict of interest., (© 2021 The Authors.)

A commercial deep learning (DL)-based automated segmentation tool (AST) for computed tomography (CT) is evaluated for accuracy and efficiency gain within prostate cancer patients. Thirty patients from six clinics were reviewed with manual- (MC), automated- (AC) and automated and edited (AEC) contouring methods. In the AEC group, created contours (prostate, seminal vesicles, bladder, rectum, femoral heads and penile bulb) were edited, whereas the MC group included empty datasets for MC. In one clinic, lymph node CTV delineations were evaluated for interobserver variability. Compared to MC, the mean time saved using the AST was 12 min for the whole data set (46%) and 12 min for the lymph node CTV (60%), respectively. The delineation consistency between MC and AEC groups according to the Dice similarity coefficient (DSC) improved from 0.78 to 0.94 for the whole data set and from 0.76 to 0.91 for the lymph nodes. The mean DSCs between MC and AC for all six clinics were 0.82 for prostate, 0.72 for seminal vesicles, 0.93 for bladder, 0.84 for rectum, 0.69 for femoral heads and 0.51 for penile bulb. This study proves that using a general DL-based AST for CT images saves time and improves consistency.

In December 2019, pneumonia of unknown cause was reported by China to WHO. The outbreak was found to be caused by a coronavirus which was officially named "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), and the disease caused by it was named 'COVID-19'. The first case in Singapore was confirmed on 23rd January 2020. With lessons learnt from the SARS epidemic in 2003 and the H1N1 flu pandemic in 2009, Singapore was much better prepared to deal with the virus outbreak. The government has taken swift measures to contain and break the chain of transmission. Healthcare workers face the challenge of keeping patients and staff safe from the disease. There is a higher risk of mortality of COVID-19 in cancer patients and hence unique considerations for a radiation oncology department operating in an infectious disease outbreak. This article is the recommendations and adapted workflow from the two National Cancer Centres in Singapore with the endorsement by the working committee of the Chapter of Radiation Oncology, Academy of Medicine, Singapore. It highlights the challenges that radiation oncology departments in Singapore face and the appropriate recommended responses. This includes interventions, business continuity plans and workflow in managing a COVID-19 positive patient on radiotherapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Objective: The magnitude of intra-fractional prostate displacement (change from initial position over time) is associated with the duration of the patient lying on the radiotherapy treatment couch. This study reports a minute-by-minute association and calculates the impact of this displacement on duration-dependent margins using real-time intra-fractional position data monitored by four-dimensional transperineal ultrasound (4D TPUS)., Materials and Methods: A total of 55 patients were recruited prospectively. Intra-fractional position of the prostate was monitored in real-time using a 4D TPUS Clarity® system. A total of 1745 monitoring sessions were analysed. Van Herk's margin recipe (2.5∑ + 1.64((σ 2  + σ p 2 ) 1/2  - σ p )) was used to estimate the duration-dependant margins for every minute, up to the 15th minute. Linear regression analysis was then performed on the overall margins against time and direction., Results: The mean intra-fractional position was 0.76 mm Inferior (Inf), 0 mm Lateral (Lat) and 0.94 mm Posterior (Post) at the 15th minute. A minimum margin expansion of 2.42 mm (Superior/Inf), 1.02 mm (Left/Right) and 2.65 mm (Anterior/Post) was required for an 8‑minute treatment compared to 4.29 mm (Sup/Inf), 1.84 mm (Lt/Rt) and 4.63 mm (Ant/Post) for a 15-minute treatment. The required margin expansion increased linearly (R 2  = 0.99) in all directions (p < 0.01). However, while there was no statistically significant difference (p = 0.10) in the required margin expansion in the Sup/Inf and Ant/Post directions respective of the time duration, the margins were much bigger compared to those in the Lt/Rt direction (p < 0.01)., Conclusion: We report our experience in deriving the minimum duration-dependant margin to generate the required planning target volume for prostate radiotherapy. The required margin increases linearly in all directions within the 15-min duration; thus, the margin will depend on the duration of the technique chosen (IMRT/VMAT/3DCRT/proton).

Objective: Prostate cancers (PCa) in Asian individuals are molecularly distinct from those found in their Caucasian counterparts. There is no risk stratification tool for Asian men with rapid biochemical recurrence (BCR) following radical prostatectomy (RadP). This study aims to assess the detection rate of 68 Ga-prostate-specific membrane antigen-positron emission tomography/computed tomography (PSMA-PET/CT) for diagnosis of clinical recurrence and as a treatment decision making tool in Asian patients with BCR post-RadP., Methods: 68 Ga PSMA-PET and CT body with/without bone scan [conventional workup (CWU)] were performed in 55 Asian patients with BCR within 36 months post-RadP. Two blinded reviewers assessed the images. Detection rates of 68 Ga PSMA-PET/CT were evaluated, and impact on management was reviewed by comparison with CWU., Results: Median time to BCR post-RadP was 8.1 months. Detection rate for 68 Ga PSMA-PET/CT was 80% (44/55). A positive scan was significantly associated with increasing prostate-specific antigen (PSA) level [odds ratio (OR) = 1.13 (95% CI 1.05-1.30), P = 0.017], but not with higher Gleason grade or shorter PSA doubling time. Compared to CWU, 68 Ga PSMA-PET/CT detected an additional 106 lesions in 33/44 patients with a positive scan, resulting in a change in management in 25/44 (56.8%) patients: 10 to hormonal therapy (HT) and whole pelvis radiotherapy (RT) in addition to bed RT, and 15 to palliative HT alone., Conclusions: In the present report, we demonstrated the diagnostic and treatment decision utility of 68 Ga PSMA-PET/CT in Asian men with rapid BCR. Detection of small volume nodal and systemic recurrences at low PSA levels (< 1.0 ng/mL) highlights the role of the tool in assigning patients to treatment intensification with HT-RT or palliative HT in polymetastatic disease.

Purpose: To evaluate the dosimetric impact and plan robustness of using Pencil Beam Scanning (PBS) in patients that requires prophylactic pelvic lymph nodes (PLNs) irradiation for prostate cancer., Material and Methods: Five intermediate to high-risk prostate patients previously treated using volumetric modulated arc therapy (VMAT), were selected for this study. Comparative proton radiotherapy plans were generated, where a three-field intensity modulated proton therapy (IMPT) plan was for the phase 1 planning target volume (PTV1) with PLNs. A technique with two posterior oblique fields using single field uniform dose (SFUD) was used for phase 2 (PTV2) volume, that comprises of the prostate and proximal seminal vesicles (Pro + proxSVs). Plan evaluation was performed on PTV coverage and dose to the organs at risk (OARs) using VMAT plans as a baseline (BL). Robust analysis on clinical target volume (CTV) coverage for the PBS plans was simulated with a 3 and 5 mm setup errors and a 3.5% range uncertainty., Results: For target coverage, PTV1 and PTV2 showed negligible differences with a comparable homogeneity index (HI) values for both modalities. Proton plans produced a statistically significant lower mean dose to the bladder (32.5 Gy(RBE) vs. 46.5 Gy) and rectum (33.6 Gy(RBE) vs. 42.7 Gy). Dose to the bladder and rectum was equivalent at the high dose region. For the bowel cavity, the mean dose for proton plans were 45% lower compared to VMAT plans. Similarly, proton plans were able to achieve an overall reduction in integral dose for both treatment phase. CTV coverage remained high with all the simulated setup and range errors., Conclusions: Proposed beam geometries for PTV1 and PTV2 proton plans presented good treatment accuracy with similar target coverage as the VMAT plans. Better sparing of OARs was achieved at the low-medium dose region for the proton plans., (© 2018 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy & Oncology.)

Background and Purpose: During radiotherapy, prostate motion changes over time. Quantifying and accounting for this motion is essential. This study aimed to assess intra-fraction prostate motion and derive duration-dependent planning margins for two treatment techniques., Material and Methods: A four-dimension (4D) transperineal ultrasound Clarity® system was used to track prostate motion. We analysed 1913 fractions from 60 patients undergoing volumetric-modulated arc therapy (VMAT) to the prostate. The mean VMAT treatment duration was 3.4 min. Extended monitoring was conducted weekly to simulate motion during intensity-modulated radiation therapy (IMRT) treatment (an additional seven minutes). A motion-time trend analysis was conducted and the mean intra-fraction motion between VMAT and IMRT treatments compared. Duration-dependent margins were calculated and anisotropic margins for VMAT and IMRT treatments were derived., Results: There were statistically significant differences in the mean intra-fraction motion between VMAT and the simulated IMRT duration in the inferior (0.1 mm versus 0.3 mm) and posterior (-0.2 versus -0.4 mm) directions respectively (p ≪ 0.01). An intra-fraction motion trend inferiorly and posteriorly was observed. The recommended minimum anisotropic margins are 1.7 mm/2.7 mm (superior/inferior); 0.8 mm (left/right), 1.7 mm/2.9 mm (anterior/posterior) for VMAT treatments and 2.9 mm/4.3 mm (superior/inferior), 1.5 mm (left/right), 2.8 mm/4.8 mm (anterior/posterior) for IMRT treatments. Smaller anisotropic margins were required for VMAT compared to IMRT (differences ranging from 1.2 to 1.6 mm superiorly/inferiorly, 0.7 mm laterally and 1.1-1.9 mm anteriorly/posteriorly)., Conclusions: VMAT treatment is preferred over IMRT as prostate motion increases with time. Larger margins should be employed in the inferior and posterior directions for both treatment durations. Duration-dependent margins should be applied in the presence of prolonged imaging and verification time., (© 2018 The Authors.)

Background and Purpose: Inconsistent bladder and rectal volumes have been associated with motion uncertainties during prostate radiotherapy. This study investigates the impact of these volumes to determine the optimal bladder volume., Materials and Methods: 60 patients from two Asian hospitals were recruited prospectively. 1887 daily cone-beam computed tomography (CBCT) images were analysed. Intra-fraction motion of the prostate was monitored real-time using a four-dimension transperineal ultrasound (4D TPUS) Clarity® system. The impact of planned bladder volume, adequacy of daily bladder filling, and rectum volume on mean intra-fraction motion of the prostate was analysed. Patients' ability to comply with the full bladder hydration protocol and level of frustration was assessed using a questionaire. Acute side effects were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and quality of life (QoL) assessed using the International Prostate Symptom Score (IPSS)., Results: The mean (SD) bladder and rectum volumes achieved during daily treatment were 139.7 cm 3 (82.4 cm 3 ) and 53.3 cm 3 (18 cm 3 ) respectively. Mean (SD) percentage change from planned CT volumes in bladder volume was reduced by 8.2% (48.7%) and rectum volume was increased by 12.4% (42.2%). Linear Mixed effect model analysis revealed a reduction in intra-fraction motion in both the Sup/Inf ( p  = 0.008) and Ant/Post ( p  = 0.0001) directions when the daily bladder was filled between 82 and 113% (3rd Quartiles) of the planned CT volumes. A reduction in intra-fraction motion of the prostate in the Ant/Post direction (z-plane) ( p  = 0.03) was observed when the planned bladder volume was greater than 200 ml. Patients complied well with the hydration protocol with minimal frustration (mean (SD) scores of 2.1 (1.4) and 1.8 (1.2) respectively). There was a moderate positive correlation (0.496) between mean bladder volume and IPSS reported post-treatment urinary straining ( p  = 0.001)., Conclusions: A planned bladder volume >200 cm 3 and daily filling between 82 and 113%, reduced intra-fraction motion of the prostate. The hydration protocol was well tolerated., (© 2018 The Authors.)

Purpose: Our purpose was to investigate interfraction setup error of the immobilization device required to implement transperineal ultrasound compared with the current, standard immobilization device. Patient comfort and radiation therapist (RT) satisfaction were also assessed., Methods and Materials: Cone beam computed tomography images were acquired before 4069 fractions from 111 patients (control group, n = 56; intervention group, n = 55) were analyzed. The intervention group was immobilized using the Clarity Immobilization System (CIS), comprising a knee rest with autoscan probe kit and transperineal ultrasound probe (n = 55), and control group using a leg immobilizer (LI) (n = 56). Interfraction setup errors were compared for both groups. Weekly questionnaires using a 10-point visual analog scale were administered to both patient groups to measure and compare patient comfort. RT acceptance for both devices was also compared using a survey., Results: There was no significant difference in the magnitude of interfraction cone beam computed tomography-derived setup shifts in the lateral and anteroposterior direction between the LI and CIS ( P = .878 and .690, respectively). However, a significant difference ( P = .003) was observed in the superoinferior direction between the 2 groups of patients. Patient-reported level of comfort and stability demonstrated no significant difference between groups ( P = .994 and .132). RT user acceptance measures for the LI and CIS were ease of handling (100% vs 53.7%), storage (100% vs 61.1%), and cleaning of the devices (100% vs 64.8%), respectively., Conclusions: The CIS demonstrated stability and reproducibility in prostate treatment setup comparable to LI. The CIS device had no impact on patient comfort; however, RTs indicated a preference for LI over the CIS mainly because of its weight and bulkiness.