Tolerability of concurrent external beam radiotherapy and [177Lu]Lu-PSMA-617 for node-positive prostate cancer in treatment naïve patients, phase I study (PROQURE-I trial).

BACKGROUND: Prostate cancer patients with locoregional lymph node disease at diagnosis (N1M0) still have a limited prognosis despite the improvements provided by aggressive curative intent multimodal locoregional external beam radiation therapy (EBRT) with systemic androgen deprivation therapy (ADT). Although some patients can be cured and the majority of patients have a long survival, the 5-year biochemical failure rate is currently 29-47%. [177Lu]Lu-PSMA-617 has shown impressive clinical and biochemical responses with low toxicity in salvage setting in metastatic castration-resistant prostate cancer. This study aims to explore the combination of standard EBRT and ADT complemented with a single administration of [177Lu]Lu-PSMA-617 in curative intent treatment for N1M0 prostate cancer. Hypothetically, this combined approach will enhance EBRT to better control macroscopic tumour localizations, and treat undetected microscopic disease locations inside and outside EBRT fields. METHODS: The PROQURE-I study is a multicenter prospective phase I study investigating standard of care treatment (7 weeks EBRT and 3 years ADT) complemented with one concurrent cycle (three, six, or nine GBq) of systemic [177Lu]Lu-PSMA-617 administered in week two of EBRT. A maximum of 18 patients with PSMA-positive N1M0 prostate cancer will be included. The tolerability of adding [177Lu]Lu-PSMA-617 will be evaluated using a Bayesian Optimal Interval (BOIN) dose-escalation design. The primary objective is to determine the maximum tolerated dose (MTD) of a single cycle [177Lu]Lu-PSMA-617 when given concurrent with EBRT + ADT, defined as the occurrence of Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grade three or higher acute toxicity. Secondary objectives include: late toxicity at 6 months, dosimetric assessment, preliminary biochemical efficacy at 6 months, quality of life questionnaires, and pharmacokinetic modelling of [177Lu]Lu-PSMA-617. DISCUSSION: This is the first prospective study to combine EBRT and ADT with [177Lu]Lu-PSMA-617 in treatment naïve men with N1M0 prostate cancer, and thereby explores the novel application of [177Lu]Lu-PSMA-617 in curative intent treatment. It is considered likely that this study will confirm tolerability as the combined toxicity of these treatments is expected to be limited. Increased efficacy is considered likely since both individual treatments have proven high anti-tumour effect as mono-treatments. TRIAL REGISTRATION: ClinicalTrials, NCT05162573 . Registered 7 October 2021.

Neurovascular-Sparing MR-Guided Adaptive Radiotherapy in Prostate Cancer; Defining the Potential Population for Erectile Function-Sparing Treatment.

BACKGROUND: Magnetic resonance-guided adaptive radiotherapy (MRgRT) enables neurovascular-sparing treatment for localized prostate cancer (PCa). The aim of this treatment is preservation of erectile function by sparing the neurovascular bundles, the internal pudendal arteries, the corpora cavernosa, and the penile bulb. Internal pudendal arteries, corpora cavernosa, and penile bulb sparing can generally be achieved in all patients, but NVB sparing can be challenging due to its proximity to the prostate and is therefore dependent on tumor location. PCa patients that have sufficient erectile function at baseline and favorable tumor characteristics might benefit from this treatment. Currently, it is unclear what proportion of patients are eligible for neurovascular-sparing treatment and to what extent this is technically feasible. AIM: To define the eligibility and technical feasibility for neurovascular-sparing MRgRT in intermediate-risk localized PCa patients. METHODS: A consecutive series of men that received 5 × 7.25 gray (Gy) MRgRT for localized PCa were included. Baseline erectile function was assessed using the International Index of Erectile Function (IIEF)-5 questionnaire. Additionally, the ability of sparing the neurovascular bundles was assessed in all patients. Per neurovascular-sparing protocol, the dominant intraprostatic lesion with a 4 mm isotropic margin should receive 34.44 Gy in ≥ 99% of the volume (i.e., high-dose area). When the high-dose area directly borders or overlaps the NVB because of a dorsolateral position of the dominant intraprostatic lesion, sparing of the NVB was considered not feasible on that side. OUTCOMES: Patient-reported IIEF-5 baseline questionnaires and the technical feasibility of NVB sparing were assessed. RESULTS: Of the 102 men that completed the IIEF-5 questionnaire at baseline, 49.0% of patients reported to have an IIEF-5 score of ≥ 17. In those patients, the NVB could technically have been spared bilaterally in 20.0% and unilaterally in 68.0%. CLINICAL IMPLICATIONS: Our findings define the potential population for neurovascular-sparing MRgRT for localized PCa and indicate the proportion in which the NVB can technically be spared. STRENGTH & LIMITATIONS: The major strength of this study is the prospective collection of data. The limitations include that the neurovascular-sparing feasibility definition is based on pre-clinical planning data. CONCLUSION: A substantial group of 49.0% of patients in our study had mild or no erectile dysfunction at baseline. Of these patients, the NVB could technically have been spared bilaterally in 20.0% and unilaterally in 68.0% during MRgRT. Trials need to assess the effect of neurovascular-sparing MRgRT on erectile function. Teunissen FR, van der Voort van Zyp JRN, Verkooijen HM, et al., Neurovascular-Sparing MR-Guided Adaptive Radiotherapy in Prostate Cancer; Defining the Potential Population for Erectile Function-Sparing Treatment. J Sex Med 2022;19:1196-1200.

The first patient-reported outcomes from the Utrecht Prostate Cohort (UPC): the first platform facilitating 'trials within cohorts' (TwiCs) for the evaluation of interventions for prostate cancer.

PURPOSE: To describe the development and first outcomes of the Utrecht Prostate Cohort (UPC): the first 'trials within cohorts' (TwiCs) platform for prostate cancer (PCa). METHODS: All non-metastasized, histologically proven PCa patients who are planned to receive standard of care are eligible for inclusion in UPC. Patients provide informed consent for the collection of clinical and technical patient data, physician-reported outcomes, and patient-reported outcomes (PROs) up to 10 years post-treatment. Additionally, patients may provide broad consent for future randomization for experimental-intervention trials (TwiCs). Changes in PROs (EPIC-26 questionnaire domains) of the participants who received standard of care were analyzed using Wilcoxon signed-rank tests. RESULTS: In two years, 626 patients were enrolled, 503 (80.4%) of whom provided broad consent for future randomization. Among these, 293 (46.8%) patients underwent magnetic resonance-guided adaptive radiotherapy (MRgRT), 116 (18.5%) CT-guided external beam radiation therapy (EBRT), 109 (17.4%) robot-assisted radical prostatectomy (RARP), and 65 (10.4%) patients opted for active surveillance. Patients treated with MRgRT and CT-guided EBRT showed a transient but significant decline in urinary irritative/obstructive and bowel domain scores at 1-month follow-up. RARP patients showed a significant deterioration of urinary incontinence domain scores between baseline and all follow-up moments and significant improvement of urinary irritative/obstructive domain scores between baseline and 9- and 12-month follow-up. All radical treatment groups showed a significant decline in sexual domain scores during follow-up. Active surveillance patients showed no significant deterioration over time in all domains. CONCLUSION: The first results from the UPC study show distinct differences in PROs between treatment options for PCa. REGISTRATION NO: NCT04228211.

The accuracy of patients' perceptions of the risks associated with localised prostate cancer treatments.

OBJECTIVES: To assess the accuracy of patients' perceptions of the risks associated with localised prostate cancer treatments (radical prostatectomy [RP], radiotherapy [RT], and active surveillance [AS]), and to identify correlates of misperceptions. PATIENTS AND METHODS: We used baseline data (questionnaires completed after treatment information was provided but before treatment) of 426 patients with newly diagnosed localised prostate cancer who participated (87% response rate) in a prospective, longitudinal, multicentre study. Patients' pretreatment perceptions of differences in adverse outcomes of treatments were compared to those based on the literature. We used univariate and multivariate linear regression to identify correlates of misperceptions. RESULTS: About two-thirds (68%, n = 211) of the patients did not understand that the risk of disease recurrence is comparable between RP and RT. More than half of the patients did not comprehend that RP patients are at greater risk of urinary incontinence (65%, n = 202) and erectile dysfunction (61%, n = 190), and less at risk of bowel problems (53%, n = 211) compared to RT patients. Many patients overestimated the risk of requiring definitive treatment following AS (45%, n = 157) and did not understand that mortality rates following AS, RP, and RT are comparable (80%, n = 333). Consulting a radiotherapist or a clinical nurse specialist was positively associated with, and emotional distress was negatively associated with, better understanding of the risks (P < 0.05), although effect sizes were small. CONCLUSION: Prior to choosing treatment, most patients with prostate cancer poorly understood the differences in treatment risks. Greater efforts should be made to better understand why these misperceptions occur and, most importantly, how they can be corrected.

Overall survival benefit of androgen suppression in addition to dose-escalated external beam radiotherapy for high-risk prostate cancer: Nationwide real-world data indicates a shift in men that benefit.

OBJECTIVE: To evaluate the real-world added value of androgen deprivation therapy (ADT) in addition to external beam radiotherapy (EBRT) in men with high-risk non-metastatic prostate cancer, in view of advances in radiotherapy and diagnostics. METHODS: All Dutch men diagnosed with high-risk non-metastatic prostate cancer (defined as: ≥cT2c-T3b N0M0, PSA ≥20-50 ng/ml, and/or Gleason score ≥8 (International Society of Urological Pathology [ISUP] grade ≥4)) from 2009 through 2019 and treated with EBRT with or without ADT were identified in the population-based Netherlands Cancer Registry. Propensity scores were used to match (1:1) men that received ADT to men that did not receive ADT. Subsequently, OS was compared. Analyses were also stratified by number of high-risk features, 1 (either ≥cT2c, PSA >20 ng/ml or Gleason score ≥8) versus ≥2 (out of ≥cT2c, PSA >20 ng/ml and Gleason score ≥8). RESULTS: A total of 14,773 men with high-risk non-metastatic prostate cancer were identified, 3,958 (27%) of which received EBRT alone. After matching, 3,427 men remained in both groups and baseline characteristics were well-balanced. After a median follow-up of 92 months, OS was better in men treated with EBRT and ADT compared to men treated with EBRT alone (10-year OS: 66.4% versus 61.8%; HR 0.88 [95%CI: 0.80-0.96]). There was no statistically significant difference in OS in the subgroup of men with only 1 high-risk feature (10-year OS 67.7% versus 64.9%; HR 0.95 [95%CI: 0.85-1.07]). CONCLUSIONS: In a contemporary cohort of men treated for high-risk non-metastatic prostate cancer with EBRT, an OS benefit of adding ADT was only observed in men with at least 2 high-risk features. These results suggest that improvements in diagnostics and treatment in recent decades have resulted in a stage shift of men benefiting from the addition of ADT to EBRT.

Deep-learning-based joint rigid and deformable contour propagation for magnetic resonance imaging-guided prostate radiotherapy.

BACKGROUND: Deep learning-based unsupervised image registration has recently been proposed, promising fast registration. However, it has yet to be adopted in the online adaptive magnetic resonance imaging-guided radiotherapy (MRgRT) workflow. PURPOSE: In this paper, we design an unsupervised, joint rigid, and deformable registration framework for contour propagation in MRgRT of prostate cancer. METHODS: Three-dimensional pelvic T2-weighted MRIs of 143 prostate cancer patients undergoing radiotherapy were collected and divided into 110, 13, and 20 patients for training, validation, and testing. We designed a framework using convolutional neural networks (CNNs) for rigid and deformable registration. We selected the deformable registration network architecture among U-Net, MS-D Net, and LapIRN and optimized the training strategy (end-to-end vs. sequential). The framework was compared against an iterative baseline registration. We evaluated registration accuracy (the Dice and Hausdorff distance of the prostate and bladder contours), structural similarity index, and folding percentage to compare the methods. We also evaluated the framework's robustness to rigid and elastic deformations and bias field perturbations. RESULTS: The end-to-end trained framework comprising LapIRN for the deformable component achieved the best median (interquartile range) prostate and bladder Dice of 0.89 (0.85-0.91) and 0.86 (0.80-0.91), respectively. This accuracy was comparable to the iterative baseline registration: prostate and bladder Dice of 0.91 (0.88-0.93) and 0.86 (0.80-0.92). The best models complete rigid and deformable registration in 0.002 (0.0005) and 0.74 (0.43) s (Nvidia Tesla V100-PCIe 32 GB GPU), respectively. We found that the models are robust to translations up to 52 mm, rotations up to 15 ∘ $^\circ$ , elastic deformations up to 40 mm, and bias fields. CONCLUSIONS: Our proposed unsupervised, deep learning-based registration framework can perform rigid and deformable registration in less than a second with contour propagation accuracy comparable with iterative registration.

MRI-guided radiotherapy in twenty fractions for localised prostate cancer; results from the MOMENTUM study.

Background and purpose: MRI-guided radiotherapy (MRIgRT) offers multiple potential advantages over CT-guidance. This study examines the potential clinical benefits of MRIgRT for men with localised prostate cancer, in the setting of moderately hypofractionated radiotherapy. We evaluate two-year toxicity outcomes, early biochemical response and patient-reported outcomes (PRO), using data obtained from a multicentre international registry study, for the first group of patients with prostate cancer who underwent treatment on a 1.5 T MR-Linac. Materials and methods: Patients who were enrolled within the MOMENTUM study and received radical treatment with 60 Gy in 20 fractions were identified. PSA levels and CTCAE version 5.0 toxicity data were measured at follow-up visits. Those patients who consented to PRO data collection also completed EQ-5D-5L, EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires. Results: Between November 2018 and June 2022, 146 patients who had MRIgRT for localised prostate cancer on the 1.5 T MR-Linac were eligible for this study. Grade 2 and worse gastro-intestinal (GI) toxicity was reported in 3 % of patients at three months whilst grade 2 and worse genitourinary (GU) toxicity was 7 % at three months. There was a significant decrease in the median PSA at 12 months. The results from both the EQ-5D-5L data and EORTC global health status scale indicate a decline in the quality of life (QoL) during the first six months. The mean change in score for the EORTC scale showed a decrease of 11.4 points, which is considered clinically important. QoL improved back to baseline by 24 months. Worsening of hormonal symptoms in the first six months was reported with a return to baseline by 24 months and sexual activity in all men worsened in the first three months and returned to baseline at 12 months. Conclusion: This study establishes the feasibility of online-MRIgRT for localised prostate on a 1.5 T MR-Linac with low rates of toxicity, similar to that published in the literature. However, the clinical benefits of MRIgRT over conventional radiotherapy in the setting of moderate hypofractionation is not evident. Further research will focus on the delivery of ultrahypofractionated regimens, where the potential advantages of MRIgRT for prostate cancer may become more discernible.

Automated pelvic MRI measurements associated with urinary incontinence for prostate cancer patients undergoing radical prostatectomy.

BACKGROUND: Pelvic morphological parameters on magnetic resonance imaging (MRI), such as the membranous urethral length (MUL), can predict urinary incontinence after radical prostatectomy but are prone to interobserver disagreement. Our objective was to improve interobserver agreement among radiologists in measuring pelvic parameters using deep learning (DL)-based segmentation of pelvic structures on MRI scans. METHODS: Preoperative MRI was collected from 167 prostate cancer patients undergoing radical prostatectomy within our regional multicentric cohort. Two DL networks (nnU-Net) were trained on coronal and sagittal scans and evaluated on a test cohort using an 80/20% train-test split. Pelvic parameters were manually measured by three abdominal radiologists on raw MRI images and with the use of DL-generated segmentations. Automated measurements were also performed for the pelvic parameters. Interobserver agreement was evaluated using the intraclass correlation coefficient (ICC) and the Bland-Altman plot. RESULTS: The DL models achieved median Dice similarity coefficient (DSC) values of 0.85-0.97 for coronal structures and 0.87-0.98 for sagittal structures. When radiologists used DL-generated segmentations of pelvic structures, the interobserver agreement for sagittal MUL improved from 0.64 (95% confidence interval 0.28-0.83) to 0.91 (95% CI 0.84-0.95). Furthermore, there was an increase in ICC values for the obturator internus muscle from 0.74 (95% CI 0.42-0.87) to 0.86 (95% CI 0.75-0.92) and for the levator ani muscle from 0.40 (95% CI 0.05-0.66) to 0.61 (95% CI 0.31-0.78). CONCLUSIONS: DL-based automated segmentation of pelvic structures improved interobserver agreement in measuring pelvic parameters on preoperative MRI scans. RELEVANCE STATEMENT: The implementation of deep learning segmentations allows for more consistent measurements of pelvic parameters by radiologists. Standardized measurements are crucial for incorporating these parameters into urinary continence prediction models. KEY POINTS: • DL-generated segmentations improve interobserver agreement for pelvic measurements among radiologists. • Membranous urethral length measurement improved from substantial to almost perfect agreement. • Artificial intelligence enhances objective pelvic parameter assessment for continence prediction models.

Safety and Tolerability of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy.

Importance: In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy. Objective: To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach). Design, Setting, and Participants: This cohort study included adults with solid tumors treated with a 1.5-T MR-Linac enrolled in Multi Outcome Evaluation for Radiation Therapy Using the MR-Linac (MOMENTUM), a large prospective international study of MRgRT between February 2019 and October 2021. Included were adults with solid tumors treated with a 1.5-T MR-Linac. Data were collected in Canada, Denmark, The Netherlands, United Kingdom, and the US. Data were analyzed in August 2023. Exposure: All patients underwent MRgRT using a 1.5-T MR-Linac. Radiation prescriptions were consistent with institutional standards of care. Main Outcomes and Measures: Patterns of care, tolerability, and technical feasibility (ie, treatment completed as planned). Acute high-grade radiotherapy-related toxic effects (ie, grade 3 or higher toxic effects according to Common Terminology Criteria for Adverse Events version 5.0) occurring within the first 3 months after treatment delivery. Results: In total, 1793 treatment courses (1772 patients) were included (median patient age, 69 years [range, 22-91 years]; 1384 male [77.2%]). Among 41 different treatment sites, common sites were prostate (745 [41.6%]), metastatic lymph nodes (233 [13.0%]), and brain (189 [10.5%]). ATS was used in 1050 courses (58.6%). MRgRT was completed as planned in 1720 treatment courses (95.9%). Patient withdrawal caused 5 patients (0.3%) to discontinue treatment. The incidence of radiotherapy-related grade 3 toxic effects was 1.4% (95% CI, 0.9%-2.0%) in the entire cohort and 0.4% (95% CI, 0.1%-1.0%) in the subset of patients treated with ATS. There were no radiotherapy-related grade 4 or 5 toxic effects. Conclusions and Relevance: In this cohort study of patients treated on a 1.5-T MR-Linac, radiotherapy was safe and well tolerated. Online adaptation of the radiation plan at each treatment session to account for anatomic variations was associated with a low risk of acute grade 3 toxic effects.

Patient preferences for treatment modalities for localised prostate cancer.

Objectives: To assess the patient preferences and utility scores for the different conventional and innovative treatment modalities for localised prostate cancer (PCa). Subjects and Methods: Patients treated for localised PCa and healthy volunteers were invited to fill out a treatment-outcome scenario questionnaire. Participants ranked six different treatments for localised PCa from most to least favourable, prior to information. In a next step, treatment procedures, toxicity, risk of biochemical recurrence and follow-up regimen were comprehensibly described for each of the six treatments (i.e. treatment-outcome scenarios), after which patients re-ranked the six treatments. Additionally, participants gave a visual analogue scale (VAS) and time trade-off (TTO) score for each scenario. Differences between utility scores were tested by Friedman tests with post hoc Wilcoxon signed-rank tests. Results: Eighty patients and twenty-nine healthy volunteers were included in the study. Before receiving treatment-outcome scenario information, participants ranked magnetic resonance-guided adaptive radiotherapy most often as their first choice (35%). After treatment information was received, active surveillance was most often ranked as the first choice (41%). Utility scores were significantly different between the six treatment-outcome scenarios, and active surveillance, non- and minimal-invasive treatments received higher scores. Conclusions: Active surveillance and non-invasive treatment for localised PCa were the most preferred options by PCa patients and healthy volunteers and received among the highest utility scores. Treatment preferences change after treatment information is received.

Recurrence characteristics after focal salvage HDR brachytherapy in prostate cancer.

BACKGROUND AND PURPOSE: Radiorecurrent prostate cancer is often confined to the prostate, predominantly near the index lesion. The purpose of this study was to look at recurrence characteristics in patients treated with focal salvage high dose-rate (HDR) brachytherapy. MATERIALS AND METHODS: Patients treated with MRI-guided HDR brachytherapy, with a single fraction of 19 Gy from July 2013 to October 2021 as focal salvage treatment, were prospectively included in the current study. Imaging data were collected regarding the occurrence of local, regional and distant recurrences, including location of local recurrences (LR) in relation to the HDR radiotherapy field. RESULTS: One hundred seventy-five patients were included after focal salvage HDR brachytherapy (median follow-up 36 months (IQR 23-50)). Three-years biochemical recurrence-free survival, LR-free survival, in-field LR-free survival, out-of-field LR-free survival, any-recurrence-free survival and ADT-free survival were 43% (95%CI 34%-52%), 51% (41%-61%), 70% (61%-80%), 92% (88%-97%), 42% (32%-52%) and 86% (80%-92%), respectively. Larger GTV-size and shorter PSA doubling time were associated with in-field LR in multivariable analysis. CONCLUSION: After focal salvage HDR brachytherapy with a dose of 1x19 Gy for local prostate cancer recurrence, subsequent recurrences are mostly local and in-field.

Deep learning for automated contouring of neurovascular structures on magnetic resonance imaging for prostate cancer patients.

Background and purpose: Manual contouring of neurovascular structures on prostate magnetic resonance imaging (MRI) is labor-intensive and prone to considerable interrater disagreement. Our aim is to contour neurovascular structures automatically on prostate MRI by deep learning (DL) to improve workflow and interrater agreement. Materials and methods: Segmentation of neurovascular structures was performed on pre-treatment 3.0 T MRI data of 131 prostate cancer patients (training [n = 105] and testing [n = 26]). The neurovascular structures include the penile bulb (PB), corpora cavernosa (CCs), internal pudendal arteries (IPAs), and neurovascular bundles (NVBs). Two DL networks, nnU-Net and DeepMedic, were trained for auto-contouring on prostate MRI and evaluated using volumetric Dice similarity coefficient (DSC), mean surface distances (MSD), Hausdorff distances, and surface DSC. Three radiation oncologists evaluated the DL-generated contours and performed corrections when necessary. Interrater agreement was assessed and the time required for manual correction was recorded. Results: nnU-Net achieved a median DSC of 0.92 (IQR: 0.90-0.93) for the PB, 0.90 (IQR: 0.86-0.92) for the CCs, 0.79 (IQR: 0.77-0.83) for the IPAs, and 0.77 (IQR: 0.72-0.81) for the NVBs, which outperformed DeepMedic for each structure (p < 0.03). nnU-Net showed a median MSD of 0.24 mm for the IPAs and 0.71 mm for the NVBs. The median interrater DSC ranged from 0.93 to 1.00, with the majority of cases (68.9%) requiring manual correction times under two minutes. Conclusions: DL enables reliable auto-contouring of neurovascular structures on pre-treatment MRI data, easing the clinical workflow in neurovascular-sparing MR-guided radiotherapy.

Magnetic Resonance-Guided Adaptive Radiation Therapy for Prostate Cancer: The First Results from the MOMENTUM study-An International Registry for the Evidence-Based Introduction of Magnetic Resonance-Guided Adaptive Radiation Therapy.

PURPOSE: Magnetic resonance (MR)-guided radiation therapy (MRgRT) is a new technique for treatment of localized prostate cancer (PCa). We report the 12-month outcomes for the first PCa patients treated within an international consortium (the MOMENTUM study) on a 1.5T MR-Linac system with ultrahypofractionated radiation therapy. METHODS AND MATERIALS: Patients treated with 5 × 7.25 Gy were identified. Prostate specific antigen-level, physician-reported toxicity (Common Terminology Criteria for Adverse Events [CTCAE]), and patient-reported outcomes (Quality of Life Questionnaire PR25 and Quality of Life Questionnaire C30 questionnaires) were recorded at baseline and at 3, 6, and 12 months of follow-up (FU). Pairwise comparative statistics were conducted to compare outcomes between baseline and FU. RESULTS: The study included 425 patients with localized PCa (11.4% low, 82.0% intermediate, and 6.6% high-risk), and 365, 313, and 186 patients reached 3-, 6-, and 12-months FU, respectively. Median prostate specific antigen level declined significantly to 1.2 ng/mL and 0.1 ng/mL at 12 months FU for the nonandrogen deprivation therapy (ADT) and ADT group, respectively. The peak of genitourinary and gastrointestinal CTCAE toxicity was reported at 3 months FU, with 18.7% and 1.7% grade ≥2, respectively. The QLQ-PR25 questionnaire outcomes showed significant deterioration in urinary domain score at all FU moments, from 8.3 (interquartile range [IQR], 4.1-16.6) at baseline to 12.4 (IQR, 8.3-24.8; P = .005) at 3 months, 12.4 (IQR, 8.3-20.8; P = .018;) at 6 months, and 12.4 (IQR, 8.3-20.8; P = .001) at 12 months. For the non-ADT group, physician- and patient-reported erectile function worsened significantly between baseline and 12 months FU. CONCLUSIONS: Ultrahypofractionated MR-guided radiation therapy for localized PCa using a 1.5T MR-Linac is effective and safe. The peak of CTCAE genitourinary and gastrointestinal toxicity was reported at 3 months FU. Furthermore, for patients without ADT, a significant increase in CTCAE erectile dysfunction was reported at 12 months FU. These data are useful for educating patients on expected outcomes and informing study design of future comparative-effectiveness studies.

The Development and External Validation of Artificial Intelligence-Driven MRI-Based Models to Improve Prediction of Lesion-Specific Extraprostatic Extension in Patients with Prostate Cancer.

Adequate detection of the histopathological extraprostatic extension (EPE) of prostate cancer (PCa) remains a challenge using conventional radiomics on 3 Tesla multiparametric magnetic resonance imaging (3T mpMRI). This study focuses on the assessment of artificial intelligence (AI)-driven models with innovative MRI radiomics in predicting EPE of prostate cancer (PCa) at a lesion-specific level. With a dataset encompassing 994 lesions from 794 PCa patients who underwent robot-assisted radical prostatectomy (RARP) at two Dutch hospitals, the study establishes and validates three classification models. The models were validated on an internal validation cohort of 162 lesions and an external validation cohort of 189 lesions in terms of discrimination, calibration, net benefit, and comparison to radiology reporting. Notably, the achieved AUCs ranged from 0.86 to 0.91 at the lesion-specific level, demonstrating the superior accuracy of the random forest model over conventional radiological reporting. At the external test cohort, the random forest model was the best-calibrated model and demonstrated a significantly higher accuracy compared to radiological reporting (83% vs. 67%, p = 0.02). In conclusion, an AI-powered model that includes both existing and novel MRI radiomics improves the detection of lesion-specific EPE in prostate cancer.

[Experiences with MRI-guided brachytherapy for radiorecurrent prostate cancer]. / Ervaringen met MRI-geleide brachytherapie bij prostaatkankerrecidief.

MR-guided brachytherapy offers a focal salvage treatment for the local recurrence in case of isolated locally recurrent prostate cancer in the prostate and/or seminal vesicles after primary radiotherapy. By focusing on only the local recurrence instead of the whole prostate, chances of additional toxicity of the bladder, urethra and rectum can be minimized. In almost all patients, the treatment leads to a good initial treatment response that persists in about half of patients, while others will develop progressive disease later on. For selecting suitable patients, factors such as preexistent urinary- and bowel complaints, localization and size of the recurrence, PSA doubling time and time between primary radiotherapy and development of the recurrence are relevant. MR-guided brachytherapy can provide a suitable salvage strategy, with the aims of deferring androgen deprivation therapy and a chance of cure.

Accumulated bladder wall dose is correlated with patient-reported acute urinary toxicity in prostate cancer patients treated with stereotactic, daily adaptive MR-guided radiotherapy.

BACKGROUND AND PURPOSE: Magnetic resonance (MR)-guided linear accelerators (MR-Linac) enable accurate estimation of delivered doses through dose accumulation using daily MR images and treatment plans. We aimed to assess the association between the accumulated bladder (wall) dose and patient-reported acute urinary toxicity in prostate cancer (PCa) patients treated with stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: One-hundred-and-thirty PCa patients treated on a 1.5 T MR-Linac were included. Patients filled out International Prostate Symptom Scores (IPSS) questionnaires at baseline, 1 month, and 3 months post-treatment. Deformable image registration-based dose accumulation was performed to reconstruct the delivered dose. Dose parameters for both bladder and bladder wall were correlated with a clinically relevant increase in IPSS (≥ 10 points) and/or start of alpha-blockers within 3 months using logistic regression. RESULTS: Thirty-nine patients (30%) experienced a clinically relevant IPSS increase and/or started with alpha-blockers. Bladder D5cm3, V10-35Gy (in %), and Dmean and Bladder wall V10-35Gy (cm3 and %) and Dmean were correlated with the outcome (odds ratios 1.04-1.33, p-values 0.001-0.044). Corrected for baseline characteristics, bladder V10-35Gy (in %) and Dmean and bladder wall V10-35Gy (cm3 and %) and Dmean were still correlated with the outcome (odds ratios 1.04-1.30, p-values 0.001-0.028). Bladder wall parameters generally showed larger AUC values. CONCLUSION: This is the first study to assess the correlation between accumulated bladder wall dose and patient-reported urinary toxicity in PCa patients treated with MR-guided SBRT. The dose to the bladder wall is a promising parameter for prediction of patient-reported urinary toxicity and therefore warrants prospective validation and consideration in treatment planning.

Fast and accurate deformable contour propagation for intra-fraction adaptive magnetic resonance-guided prostate radiotherapy.

To facilitate full intra-fraction adaptive MR-guided radiotherapy, accurate contour propagation is needed. We aimed to assess the clinical usability of intra-fraction propagated contours by a deformable image registration algorithm in ten prostate cancer patients. Two observers judged the contours on need for manual adaptation and feasibility of adapting contours within 3 min. CTV and bladder contours needed none or only minor editing in most cases (≥ 97%), whereas rectum contours needed more extensive editing in 12-23%. Nevertheless, adaptation times were < 3 min for ≥ 93% of the cases. This paves the way for exploring adaptive workflows using intra-fraction deformable contour propagation.

Clinical application of a sub-fractionation workflow for intrafraction re-planning during prostate radiotherapy treatment on a 1.5 Tesla MR-Linac: A practical method to mitigate intrafraction motion.

BACKGROUND: Intrafraction motion during radiotherapy limits margin reduction and dose escalation. Magnetic resonance (MR)-guided linear accelerators (MR-Linac) have emphasised this issue by enabling intrafraction imaging. We present and clinically apply a new workflow to counteract systematic intrafraction motion during MR-guided stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: With the sub-fractionation workflow, the daily dose is delivered in multiple sequential parts (sub-fractions), each adapted to the latest anatomy. As each sub-fractionation treatment plan complies with the dose constraints, no online dose accumulation is required. Imaging and treatment planning are executed in parallel with dose delivery to minimise dead time, enabling an efficient workflow. The workflow was implemented on a 1.5 T MR-Linac and applied in 15 prostate cancer (PCa) patients treated with 5 × 7.25 Gy in two sub-fractions of 3.625 Gy (10 × 3.625 Gy in total). Intrafraction clinical target volume (CTV) motion was determined and compared to a workflow with single-plan delivery. Furthermore, required planning target volume (PTV) margins were determined. RESULTS: Average on-table time was 42.7 min. Except for two fractions, all fractions were delivered within 60 min. Average intrafraction 3D CTV displacement (±standard deviation) was 1.1 mm (± 0.7) with the sub-fractionation workflow, whereas this was up to 3.5 mm (± 2.4) without sub-fractionation. Calculated PTV margins required with sub-fractionation were 1.0 mm (left-right), 2.4 mm (cranial-caudal), and 2.6 mm (anterior-posterior). CONCLUSION: Feasibility of the sub-fractionation workflow was demonstrated in 15 PCa patients treated with two sub-fractions on a 1.5 T MR-Linac. The workflow allows for significant PTV margin reduction in these patients by reducing systematic intrafraction motion during SBRT.