The biennial Advanced Prostate Cancer Consensus Conference (APCCC) provides expert-based recommendations on clinical topics for which high-level evidence is lacking. These consensus statements reflect the views of a worldwide panel of more than 100 specialists. There may be discrepancies in local implementation because of context-specific factors. To explore this for the Dutch situation, a national multidisciplinary panel of 34 specialists used a stepwise approach to evaluate selected APCCC 2024 questions. After individual voting, results were discussed in a plenary meeting with partial revoting. Discordance with APCCC consensus was observed for 35% of the questions. Items with the greatest disagreement were revisited in an online follow-up meeting. National deviations were largely regarded justified because of several contextual factors, including wider clinical adoption of prostate-specific membrane antigen positron emission tomography/computed tomography in the Netherlands. Our approach may provide an adequate means of identifying barriers for local compliance with the international consensus recommendations. Patient summary: International experts established consensus statements on the treatment of advanced prostate cancer for topics with unclear evidence. Dutch specialists reviewed these recommendations to determine which ones fit best with local care.

With the heterogeneous use and interpretation of next-generation molecular imaging and approval of new treatment strategies, therapeutic decision-making for de novo metastatic hormone-sensitive prostate cancer (mHSPC) is becoming increasingly challenging. It is conceivable that patients are treated differently in another country, hospital or by another clinician. Here, we aim to provide insights into the clinical practices, challenges, and unmet needs in the management of de novo mHSPC.In this explorative mixed-method study, a survey was sent to urologists and oncologists in 13 Dutch hospitals from the TripleAiM1 network. Additionally, four patient cases were discussed in multi-disciplinary team consultations in four of these hospitals. Results from the survey and patient cases were then discussed in focus group sessions. Three sessions were held with the same expert panel, comprising urologists, medical oncologists, a nuclear medicine physician and radiation oncologist. Major themes were identified and analysed using the Matrix method. Of the 91 surveys distributed, 27 urologists and 19 oncologists responded. Patients with low-volume (LV) disease showed most practice variation; ranging from curative to palliative intent and from single to triplet therapies. Reasons given for this variation include the heterogeneous aspect of LV disease, ambiguous definitions, varying interpretations of study data, lead-time in adoption of novel treatment strategies, and guideline gaps. Adding to this divergence are differences in interpretation of metastatic volume. As the majority of physicians (36/46) use PSMA-PET/CT for staging, while LV and high-volume per CHAARTED criteria are defined on conventional imaging. On a scale of 0-10, metastatic volume (8.5), performance score (8.6), and patient preferences (9.0) were considered the most important factors for selecting treatments. This did not differ significantly between specialties, but showed large dispersion within specialties, suggesting variation at the individual physician level. In conclusion, this study provides insights into clinical practices and challenges in the management of de novo mHSPC. By elucidating the perspectives of Dutch physicians, our findings contribute to a better understanding of the complexities involved in treatment decision-making. Moving forward, there is a need for consensus on definitions, imaging modalities for staging, and treatment selection given the altered diagnostic and therapeutic landscape.

PURPOSE:Medical imaging is crucial in modern radiotherapy, aiding diagnosis, treatment planning, and monitoring. The development of synthetic imaging techniques, particularly synthetic computed tomography (sCT), continues to attract interest in radiotherapy. The SynthRAD2025 dataset and the accompanying SynthRAD2025 Grand Challenge aim to stimulate advancements in synthetic CT generation algorithms by providing a platform for comprehensive evaluation and benchmarking of synthetic CT generation algorithms based on cone-beam CTs (CBCT) and magnetic resonance images (MRI). ACQUISITION AND VALIDATION METHODS:The dataset comprises 2362 cases, including 890 MRI-CT pairs and 1472 CBCT-CT pairs of head-and-neck, thoracic, and abdominal cancer patients treated at five European university medical centers [UMC Groningen, UMC Utrecht, Radboud UMC (Netherlands), LMU University Hospital Munich, and University Hospital of Cologne (Germany)]. Images were acquired using a wide range of acquisition protocols and scanners. Pre-processing, including rigid and deformable image registration methods, was performed to ensure high-quality image datasets and alignment between modalities. Extensive quality assurance was performed to validate image consistency and usability. DATA FORMAT AND USAGE NOTES:All imaging data is provided using the MetaImage (.mha) file format, ensuring compatibility with common medical image processing tools. Metadata, including acquisition parameters and registration details, is available in structured comma-separated value (CSV) files. To ensure dataset integrity, SynthRAD2025 is split into training (65%), validation (10%), and test (25%) sets. The dataset is accessible through https://doi.org/10.5281/zenodo.14918088 under the SynthRAD2025 collection. POTENTIAL APPLICATIONS:This dataset enables benchmarking and development of synthetic imaging techniques for radiotherapy applications. Potential use cases include sCT generation for MRI-only and MR-guided photon and proton radiotherapy, CBCT-based dose calculations, and adaptive radiotherapy workflows. By incorporating data from diverse acquisition settings, SynthRAD2025 supports the advancement of robust and generalizable image synthesis algorithms for clinical implementation, ultimately promoting personalized cancer care and improving adaptive radiotherapy workflows.

Background and objective: Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) and new treatment modalities have expanded the possibilities for diagnosing and managing metastatic prostate cancer, but have also raised questions about their implementation in daily clinical practice. We sought consensus on definitions, preferred imaging modality for staging, and treatment selection in the era of next-generation imaging. Methods: A modified Delphi method involved two voting rounds and a face-to-face multidisciplinary meeting with 40 Dutch prostate cancer (PCa) experts. Consensus was reached if ≥75% of the panellists chose the same option. Appropriateness was assessed by the RAND Corporation/University of California Los Angeles appropriateness method. Key findings and limitations: There was consensus on performing metastatic screening with PSMA-PET/CT for unfavourable intermediate- or high-risk PCa. PSMA-PET/CT findings were considered feasible for determining treatment in synchronous metastatic hormone-sensitive prostate cancer, but there was no agreement on the validity of the CHAARTED criteria for interpreting the PSMA-PET/CT findings. If the PSMA-PET/CT findings led to upstaging after conventional imaging, 76% of panellists would opt for treatment intensification. In case of downstaging, 71% would choose for deintensification. Panellists would generally treat patients based on metastatic disease volume as per the CHAARTED criteria, except for bulky low-volume disease (LVD) and LVD with multiple (more than ten) bone metastases, all within the axial skeleton. This would be classified as LVD but treated as high-volume disease. Limitations are that the statements are largely consensus based and originate from a national (Dutch) perspective. Conclusions and clinical implications: PSMA-PET/CT was considered the preferred modality for initial PCa staging, which is nowadays the standard of care in The Netherlands. The majority of panellists would incorporate PSMA-PET/CT findings for treatment planning, including intensification and deintensification, but the criteria for interpreting metastatic disease volume on PSMA-PET/CT are still uncertain. Patient summary: A group of Dutch medical specialists discussed on how to diagnose metastatic hormone-sensitive prostate cancer and choose the most appropriate treatment for patients with this condition. It was concluded that imaging based on Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) helps determine appropriate treatment options, with most experts supporting treatment adjustments based on PSMA-PET/computed tomography (CT) results. However, there is still some uncertainty about the criteria for interpreting the extent of metastatic disease with PSMA-PET/CT.

Purpose A high radiation dose (≥ 75 Gy EQD2) is required to achieve tumor control in intermediate / high-risk prostate cancer (PCa). Brachytherapy (BT) provides a steep dose gradient, resulting in a higher dose to the tumor while minimizing dose to surrounding organs. Therefore, a combination of external beam radiotherapy (EBRT) and a BT boost may potentially result in less gastrointestinal (GI) and genitourinary (GU) toxicity. This multicenter, randomized trial was designed to compare the toxicity of EBRT alone with that of EBRT plus a BT boost. Here we present the primary endpoint: the 3 years late GI and GU toxicity. Overall survival (OS), biochemical disease-free survival (bDFS) and relapse-free survival (RFS) were analyzed as secondary endpoints. Materials and Methods Patients with PCa, stage T1c-T3a, N0, M0, PSA ≤ 60 ug/l and Gleason ≤ 8, were randomized to: EBRT alone (35 × 2.2 Gy) or EBRT (20 × 2.2 Gy) + BT boost (HDR: 1 × 13 Gy or PDR: 24 × 1.27 Gy, 2.2 hour interval). Both arms received an EQD2 of 79 Gy. EBRT was given using intensity modulated radiotherapy. The toxicity was assessed with the RTOG Late Radiation Morbidity Scoring criteria from both physicians’ records (clinical record form) and patients’ self-assessment questionnaires, at baseline, every 6 months for the first 3 years, and at 4 and 5 years post treatment. For both GI and GU toxicity, the highest score and the earliest date corresponding to the occurrence of grade ≥2 toxicity was registered for analysis. For the cumulative incidence of grade ≥ 2 late GI / GU toxicity, a competing risk regression analysis was performed considering death without toxicity as the competing event. First a univariate regression analysis was performed, followed by a multivariate regression analysis with adjustment for significant univariable prognostic factors. With age, PSA, Gleason, T-stage, risk classification, smoking, urinary flow, hormonal therapy, diabetes, abdominal surgery, GI comorbidity, prostate volume and overall GI/GU at baseline considered as candidate prognostic factors. OS, bDFS and RFS were assessed from randomization using the Kaplan-Meier method and univariate / multivariate Cox regression. Results From March 2013 to March 2019, 196 evaluable patients were enrolled. Baseline patient and tumor characteristics as well as baseline toxicity were well balanced between arms. The 3-year cumulative incidence of grade ≥ 2 GI toxicity (Fig. 1a) was 22% (EBRT+BT) vs 31% (EBRT), not statistically different in univariate (HR 0.67; 95% CI 0.41 - 1.12; p=0.129). Since no factor seem to have prognostic value for grade ≥ 2 GI toxicity based on the univariate analysis, no multivariate analysis was conducted. The 3-year cumulative incidence of grade ≥ 2 GU toxicity (Fig. 1b) was 43% (EBRT+BT) vs 29% (EBRT), not statistically different in univariate (HR 1.49; 95% CI 0.98 - 2.27; p=0.064) nor multivariate analysis adjusted for diabetes mellitus (yes/no) (HR 1.44; 95% CI 0.94 - 2.20; p=0.090). At 3 years, OS was 95% vs 98%, bDFS 97% vs 98% and RFS 97% vs 97%, in EBRT+BT vs EBRT, respectively. No significant differences between the arms were found. Conclusions In this multicenter, randomized trial that investigated the added value of a BT boost compared to EBRT alone, the observed decrease in grade ≥ 2 late GI and increase in grade ≥ 2 late GU toxicity did not reach statistical significance.

Purpose: The PERYTON trial is a multicenter randomized controlled trial that will investigate whether the treatment outcome of salvage external beam radiation therapy (sEBRT) will be improved with hypofractionated radiation therapy. A pretrial quality assurance (QA) program was undertaken to ensure protocol compliance within the PERYTON trial and to assess variation in sEBRT treatment protocols between the participating centers. Methods and Materials: Completion of the QA program was mandatory for each participating center (N = 8) to start patient inclusion. The pretrial QA program included (1) a questionnaire on the center-specific sEBRT protocol, (2) a delineation exercise of the clinical target volume (CTV) and organs at risk, and (3) a treatment planning exercise. All contours were analyzed using the pairwise dice similarity coefficient (DSC) and the 50th and 95th percentile Hausdorff distance (HD50 and HD95, respectively). The submitted treatment plans were reviewed for protocol compliance. Results: The results of the questionnaire showed that high-quality, state-of-the-art radiation therapy techniques were used in the participating centers and identified variations of the sEBRT protocols used concerning the position verification and preparation techniques. The submitted CTVs showed significant variation, with a range in volume of 29 cm3 to 167 cm3, a mean pairwise DSC of 0.52, and a mean HD50 and HD95 of 2.3 mm and 24.4 mm, respectively. Only in 1 center the treatment plan required adaptation before meeting all constraints of the PERYTON protocol. Conclusions: The pretrial QA of the PERYTON trial demonstrated that high-quality, but variable, radiation techniques were used in the 8 participating centers. The treatment planning exercise confirmed that the dose constraints of the PERYTON protocol were feasible for all participating centers. The observed variation in CTV delineation led to agreement on a new (image-based) delineation guideline to be used by all participating centers within the PERYTON trial. (c) 2023 The Authors. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background and purpose: Stereotactic body radiotherapy (SBRT) is increasingly applied for pelvic lymph node recurrence. Thus far, knowledge on pelvic lymph node motion during CBCT-guided SBRT is lacking and the applied margins vary between institutions. This study evaluated pelvic lymph node motion during CBCT-guided SBRT and assessed the currently applied PTV margins of 3 and 5 mm. Material and methods: In total, 45 pelvic lymph node metastases were included. One observer delineated 45 GTVs on planning CT, 224 GTVs on pre-fraction and 216 on post-fraction CBCT. The GTV centroid coordinates were derived from all images for inter- and intrafraction motion analysis. Additionally, we assessed the influence of treatment time and lesion location on lesion motion. The expected coverage of a 3-mm and 5-mm PTV margin was assessed using the inclusiveness index for GTVs on pre- and post-fraction CBCT. Results: Lymph node interfraction motion was limited to 5 mm in 96-97 % of fractions for all translational directions and intrafraction lesion motion was limited to 3 mm in 97-100 % of fractions. Para-rectal lesions (11 %) were associated with significantly larger inter- and intrafraction motion compared to other pelvic locations and treatment duration showed no correlation with lesion motion. The mean (sd) lesion inclusiveness index was 99 % (5 %) for the 5-mm PTV margin and 96 % (9 %) for the 3-mm margin. Conclusion: Pelvic lymph node motion during CBCT-guided stereotactic radiotherapy was within the widely applied PTV margin of 5 mm, providing an opportunity to reduce this margin for pelvic lymph node SBRT.

Background and Purpose Over the past decade, tools for automation of various sub-tasks in radiotherapy planning have been introduced, such as auto-contouring and auto-planning. The purpose of this study was to benchmark what degree of automation is possible. Materials and Methods A challenge to perform automated treatment planning for prostate and prostate bed radiotherapy was set up. Participants were provided with simulation CTs and a treatment prescription and were asked to use automated tools to produce a deliverable radiotherapy treatment plan with as little human intervention as possible. Plans were scored for their adherence to the protocol when assessed using consensus expert contours. Results Thirteen entries were received. The top submission adhered to 81.8% of the minimum objectives across all cases using the consensus contour, meeting all objectives in one of the ten cases. The same system met 89.5% of objectives when assessed with their own auto-contours, meeting all objectives in four of the ten cases. The majority of systems used in the challenge had regulatory clearance (Auto-contouring: 82.5%, Auto-planning: 77%). Despite the ‘hard’ rule that participants should not check or edit contours or plans, 69% reported looking at their results before submission. Conclusions Automation of the full planning workflow from simulation CT to deliverable treatment plan is possible for prostate and prostate bed radiotherapy. While many generated plans were found to require none or minor adjustment to be regarded as clinically acceptable, the result indicated there is still a lack of trust in such systems preventing full automation.

Samenvatting Deze studie onderzocht het patroon van lokaal recidief (LR) na prostatectomie met behulp van prostaatspecifieke membraanantigeen (PSMA) positronemissietomografie/computertomografie (PET/CT)-scans. In totaal werden retrospectief 103 PSMA PET/CT-scans verzameld van patiënten met verdenking op LR in negen behandelcentra. Een ervaren nucleaire geneeskundige beoordeelde de geanonimiseerde scans opnieuw en identificeerde op 83 PSMA PET/CT-scans 93 laesies als verdacht voor LR. De meest voorkomende locatie van LR (56%) was binnen 2 cm craniaal van de bulbus. Daarnaast werden 24 LR (26%) waargenomen > 2 cm craniaal van de bulbus en caudaal van de top van de symfyse. Slechts 17 LR (18%) werden craniaal van de symfyse gezien. Deze bevindingen dragen bij aan de kennis van het patroon van LR na prostatectomie en kunnen in de toekomst leiden tot gerichtere bestraling van de prostaatloge.

Background and purpose: Introducing moderately hypofractionated salvage radiotherapy (SRT) following prostatectomy obligates investigation of its effects on clinical target volume (CTV) coverage and organ-at-risk (OAR) doses. This study assessed interfractional volume and dose changes in OARs and CTV in moderately hypofractionated SRT and evaluated the 8 -mm planning target volume (PTV) margin. Materials and methods: Twenty patients from the PERYTON-trial were included; 10 received conventional SRT (35 x 2 Gy) and 10 hypofractionated SRT (20 x 3 Gy). OARs were delineated on 539 pre-treatment Cone Beam CT (CBCT) scans to compare interfractional OAR volume changes. CTVs for the hypofractionated group were delineated on 199 CBCTs. Dose distributions with 4 and 6 mm PTV margins were generated using voxel-wise minimum robustness evaluation of the original 8 -mm PTV plan, and dose changes were assessed. Results: Median volume changes for bladder and rectum were -26 % and -10 %, respectively. OAR volume changes were not significantly different between the two treatment schedules. The 8 -mm PTV margin ensured optimal coverage for prostate bed and vesicle bed CTV (V95 = 100 % in >97 % fractions). However, bladder V60 <25 % was not achieved in 5 % of fractions, and rectum V60 <5 % was unmet in 33 % of fractions. A 6 -mm PTV margin resulted in CTV V95 = 100 % in 92 % of fractions for prostate bed, and in 86 % for vesicle bed CTV. Conclusions: Moderately hypofractionated SRT yielded comparable OAR volume changes to conventionally fractionated SRT. Interfractional changes remained acceptable with a PTV margin of 6 mm for prostate bed and 8 mm for vesicle bed.

Background/objectives: Accurate and uniform interpretation and reporting of metastatic prostate cancer (PCa) lesions on prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) are indispensable. 18F-PSMA-1007 is increasingly used because of its favorable imaging characteristics. However, increased non-specific skeletal uptake may be an important pitfall of this radioligand. Therefore, we aimed to assess the interobserver variation in reporting skeletal 18F-PSMA-1007 uptake on PET/CT. Design/methods: In total, 33 18F-PSMA-1007 PET/CT scans of 21 patients with primary PCa and 12 patients with biochemical recurrence were included, and a total of 85 skeletal lesions were evaluated by three independent observers. The primary endpoint was the interobserver variability of the likelihood of malignancy of the skeletal lesions on both patient and lesion level (kappa analysis). Results: Observers qualified most lesions as not malignant (81–91%) and the overall mean interobserver agreement was moderate on both patient (κ: 0.54) and lesion level (κ: 0.55). In 52 lesions without corresponding CT substrate, the rating resulted in not malignant in 95–100%. Availability of additional imaging (60% of lesions) did not improve interobserver agreement (κ: 0.39 on lesion level) and resulted in unchanged rating for all observers in 78%. Conclusion: This interobserver analysis of skeletal 18F-PSMA-1007 uptake resulted in moderate agreement, in line with rates reported in literature. Importantly, the presence of non-specific skeletal uptake without CT substrate, as a potential shortcoming of 18F-PSMA-1007, did not impair interobserver agreement.

Stereotactic body radiotherapy (SBRT) is increasingly applied for pelvic oligometastases of prostate cancer, and currently no simple immobilization method is available for cone beam computed tomography (CBCT)-guided treatment. We assessed patient set-up and intrafraction motion using simple immobilization during CBCT-guided pelvic SBRT. Forty patients were immobilized with basic arm- head-and knee support and either a thermoplastic cushion or a foam cushion. Analysis of 454 CBCTs showed mean intrafraction translation <3.0 mm in 94% of fractions and mean intrafraction rotation <1.5 degrees in 95% of fractions. Therefore, simple immobilization ensured stable patient positioning during CBCT-guided pelvic SBRT.

PURPOSE:Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) scan is the standard imaging procedure for biochemical recurrent prostate cancer postprostatectomy because of its high detection rate at low serum prostate-specific antigen levels. However, existing guidelines for clinical target volume (CTV) in prostate bed salvage external beam radiation therapy (sEBRT) are primarily based on experience-based clinical consensus and have been validated using conventional imaging modalities. Therefore, this study aimed to optimize CTV definition in sEBRT by using PSMA PET/CT-detected local recurrences (LRs). METHODS AND MATERIALS:Patients with suspected LR on PSMA PET/CT postprostatectomy were retrospectively enrolled in 9 Dutch centers. Anonymized scans were centrally reviewed by an expert nuclear medicine physician. Each boundary of the CTV guideline from the Groupe Francophone de Radiothérapie en Urologie (GFRU) was evaluated and adapted to improve the accuracy and coverage of the area at risk of LR (CTV) on PSMA PET/CT. The proposed CTV adaptation was discussed with the radiation oncologists of the participating centers, and final consensus was reached. To assess reproducibility, the participating centers were asked to delineate 3 new cases according to the new PERYTON-CTV, and the submitted contours were evaluated using the Dice similarity coefficient (DSC). RESULTS:After central review, 93 LRs were identified on 83 PSMA PET/CTs. The proposed CTV definition improved the coverage of PSMA PET/CT-detected LRs from 67% to 96% compared with the GFRU-CTV, while reducing the GFRU-CTV by 25%. The new CTV was highly reproducible, with a mean DSC of 0.82 (range, 0.81-0.83). CONCLUSIONS:This study contributes to the optimization of CTV definition in postprostatectomy sEBRT by using the pattern of LR detected on PSMA PET/CT. The PERYTON-CTV is highly reproducible across the participating centers and ensures coverage of 96% LRs while reducing the GFRU-CTV by 25%.

Background:Germline and tumour genetic testing in prostate cancer (PCa) is becoming more broadly accepted, but testing indications and clinical consequences for carriers in each disease stage are not yet well defined. Objective:To determine the consensus of a Dutch multidisciplinary expert panel on the indication and application of germline and tumour genetic testing in PCa. Design setting and participants:The panel consisted of 39 specialists involved in PCa management. We used a modified Delphi method consisting of two voting rounds and a virtual consensus meeting. Outcome measurements and statistical analysis:Consensus was reached if ≥75% of the panellists chose the same option. Appropriateness was assessed by the RAND/UCLA appropriateness method. Results and limitations:Of the multiple-choice questions, 44% reached consensus. For men without PCa having a relevant family history (familial PCa/BRCA-related hereditary cancer), follow-up by prostate-specific antigen was considered appropriate. For patients with low-risk localised PCa and a family history of PCa, active surveillance was considered appropriate, except in case of the patient being a BRCA2 germline pathogenic variant carrier. Germline and tumour genetic testing should not be done for nonmetastatic hormone-sensitive PCa in the absence of a relevant family history of cancer. Tumour genetic testing was deemed most appropriate for the identification of actionable variants, with uncertainty for germline testing. For tumour genetic testing in metastatic castration-resistant PCa, consensus was not reached for the timing and panel composition. The principal limitations are as follows: (1) a number of topics discussed lack scientific evidence, and therefore the recommendations are partly opinion based, and (2) there was a small number of experts per discipline. Conclusions:The outcomes of this Dutch consensus meeting may provide further guidance on genetic counselling and molecular testing related to PCa. Patient summary:A group of Dutch specialists discussed the use of germline and tumour genetic testing in prostate cancer (PCa) patients, indication of these tests (which patients and when), and impact of these tests on the management and treatment of PCa.