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Background: A phase III multi-centre randomised trial (ROSEL) has been initiated to establish the role of stereotactic radiotherapy in patients with operable stage IA lung cancer. Due to rapid changes in radiotherapy technology and evolving techniques for image-guided delivery, guidelines had to be developed in order to ensure uniformity in implementation of stereotactic radiotherapy in this multi-centre study.Methods/design: A Quality Assurance Working Party was formed by radiation oncologists and clinical physicists from both academic as well as non-academic hospitals that had already implemented stereotactic radiotherapy for lung cancer. A literature survey was conducted and consensus meetings were held in which both the knowledge from the literature and clinical experience were pooled. In addition, a planning study was performed in 26 stage I patients, of which 22 were stage 1A, in order to develop and evaluate the planning guidelines. Plans were optimised according to parameters adopted from RTOG trials using both an algorithm with a simple homogeneity correction (Type A) and a more advanced algorithm (Type B). Dose conformity requirements were then formulated based on these results.Conclusion: Based on current literature and expert experience, guidelines were formulated for this phase III study of stereotactic radiotherapy versus surgery. These guidelines can serve to facilitate the design of future multi-centre clinical trials of stereotactic radiotherapy in other patient groups and aid a more uniform implementation of this technique outside clinical trials. [ABSTRACT FROM AUTHOR]

We evaluated the acute and late toxicity after high-dose intensity-modulated radiotherapy (IMRT) with fiducial marker-based position verification for prostate cancer. Between 2001 and 2004, 331 patients with prostate cancer received 76 Gy in 35 fractions using IMRT combined with fiducial marker-based position verification. The symptoms before treatment (pre-treatment) and weekly during treatment (acute toxicity) were scored using the Common Toxicity Criteria (CTC). The goal was to score late toxicity according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scale with a follow-up time of at least three years. Twenty-two percent of the patients experienced pre-treatment grade > or = 2 genitourinary (GU) complaints and 2% experienced grade 2 gastrointestinal (GI) complaints. Acute grade 2 GU and GI toxicity occurred in 47% and 30%, respectively. Only 3% of the patients developed acute grade 3 GU and no grade > or = 3 GI toxicity occurred. After a mean follow-up time of 47 months with a minimum of 31 months for all patients, the incidence of late grade 2 GU and GI toxicity was 21% and 9%, respectively. Grade > or = 3 GU and GI toxicity rates were 4% and 1%, respectively, including one patient with a rectal fistula and one patient with a severe hemorrhagic cystitis (both grade 4). In conclusion, high-dose intensity-modulated radiotherapy with fiducial marker-based position verification is well tolerated. The low grade > or = 3 toxicity allows further dose escalation if the same dose constraints for the organs at risk will be used. [ABSTRACT FROM AUTHOR]

Purpose: To determine the accuracy of four-dimensional computed tomography (4D-CT) scanning techniques in institutions participating in a Phase III trial of surgery vs. stereotactic radiotherapy (SBRT) for lung cancer. Methods and Materials: All 9 centers performed a 4D-CT scan of a motion phantom (Quasar, Modus Medical Devices) in accordance with their in-house imaging protocol for SBRT. A cylindrical cedar wood insert with plastic spheres of 15 mm (ø15) and 30 mm (ø30) diameter was moved in a cosine-based pattern, with an extended period in the exhale position to mimic the actual breathing motion. A range of motion of R = 15 and R = 25 mm and breathing period of T = 3 and T = 6 s were used. Positional and volumetric imaging accuracy was analyzed using Pinnacle version 8.1× at various breathing phases, including the mid-ventilation phase and maximal intensity projections of the spheres. Results: Imaging using eight CT scanners (Philips, Siemens, GE) and one positron emission tomography-CT scanner (Institution 3, Siemens) was investigated. The imaging protocols varied widely among the institutions. No strong correlation was found between the specific scan protocol parameters and the observed results. Deviations in the maximal intensity projection volumes averaged 1.9% (starting phase of the breathing cycle [ø]15, R = 15), 12.3% (ø15, R = 25), and -0.9% (ø30, R = 15). The end-expiration volume deviations (13.4%, ø15 and 2.5%, ø30), were, on average, smaller than the end-inspiration deviations (20.7%, ø15 and 4.5%, ø30), which, in turn, were smaller than the mid-ventilation deviations (32.6%, ø15 and 8.0%, ø30). A slightly larger variation in the mid-ventilation origin position was observed (mean, -0.2 mm; range, -3.6-4.2) than in the maximal intensity projection origin position (mean, -0.1 mm; range, -2.5-2.5). The range of motion was generally underestimated (mean, -1.5 mm; range, -5.5-1). Conclusions: Notable differences were seen in the 4D-CT imaging protocols for SBRT among centers. However, the observed deviations in target volumes were generally small. They were slightly larger for the mid-ventilation phases and smallest for the end-expiration phases. Steps to optimize and standardize the 4D-CT scanning protocols for SBRT are desirable. [ABSTRACT FROM AUTHOR]

Introduction: Prostate cancer hypoxia is a negative prognostic biomarker. A promising MRI-based tool to assess hypoxia is the 'Consumption and Supply based Hypoxia' (CSH) model based on diffusion-weighted imaging (DWI). The aim of the study was to validate the association between the CSH hypoxia fraction (HF DWI ) with pathological Grade Group (pGG) and pathological T-staging (pTstage) in an external prostatectomy cohort., Methods: Apparent diffusion coefficient (ADC) and fractional blood volume (fBV) maps were assessed from DWI data from 291 prostatectomies and combined by the CSH model. HF DWI was calculated for each lesion after median scaling of ADC and fBV to address differences in acquisition and analysis between centers. The absolute HF DWI values and the associations of HF DWI between pGG < 3 versus ≥ 3, and pTstage = 2 versus = 3 in the Netherlands Cancer Institute (NKI) cohort were compared to the obtained by original cohort (Oslo cohort). Statistical T- and Mann-Whitney tests ( p <0.05) were performed. Pearson correlation was determined between HF DWI and individual pGG groups., Results: The HF DWI showed comparable absolute values and similar metric performance as in the original published cohort. Higher HF DWI values were observed for higher pGG (Oslo: 0.27; NKI: 0.24) compared to lower pGG (Oslo: 0.11; NKI: 0.17). Similar results were obtained for pTstage. Furthermore, HF DWI demonstrated a significant positive correlation with pGG groups 1-5 (ρ = 0.41, p <0.001)., Conclusion: The CSH model exhibited sufficient robustness in the external cohort, suggesting a plausible reflection of true hypoxia and enabling the use of the HF DWI metric for further research into prostate cancer and hypoxia., 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 © 2024 Fernandez Salamanca, Hompland, Deręgowska-Cylke, Van der Poel, Bekers, Guimaraes, Lyng, Van der Heide, Schoots and Van Houdt.)

Purpose: To provide a comprehensive review of the means by which to optimize target volume definition for the purposes of treatment planning for patients with intact prostate cancer with a specific emphasis on focal boost volume definition., Methods: Here we conduct a narrative review of the available literature summarizing the current state of knowledge on optimizing target volume definition for the treatment of localized prostate cancer., Results: Historically, the treatment of prostate cancer included a uniform prescription dose administered to the entire prostate with or without coverage of all or part of the seminal vesicles. The development of prostate magnetic resonance imaging (MRI) and positron emission tomography (PET) using prostate-specific radiotracers has ushered in an era in which radiation oncologists are able to localize and focally dose-escalate high-risk volumes in the prostate gland. Recent phase 3 data has demonstrated that incorporating focal dose escalation to high-risk subvolumes of the prostate improves biochemical control without significantly increasing toxicity. Still, several fundamental questions remain regarding the optimal target volume definition and prescription strategy to implement this technique. Given the remaining uncertainty, a knowledge of the pathological correlates of radiographic findings and the anatomic patterns of tumor spread may help inform clinical judgement for the definition of clinical target volumes., Conclusion: Advanced imaging has the ability to improve outcomes for patients with prostate cancer in multiple ways, including by enabling focal dose escalation to high-risk subvolumes. However, many questions remain regarding the optimal target volume definition and prescription strategy to implement this practice, and key knowledge gaps remain. A detailed understanding of the pathological correlates of radiographic findings and the patterns of local tumor spread may help inform clinical judgement for target volume definition given the current state of uncertainty., Competing Interests: Disclosures Uulke van der Heide has collaborative agreements with Elekta AB and Philips; received grants from the Dutch Cancer Society and travel funding from Elekta AB; and is a member of the ASTRO Scientific Council. Linda Kerkmeijer received honoraria from SIU (2021), VenVN (2021), and the Dutch guideline committee renal cell carcinoma by SKMS; received travel stipend from ESTRO (2022); is a board member of the Dutch Uro-Oncology study group. Baris Turkbey received royalties from the National Institutes of Health; has multiple patents in AI (details available on request); has cooperative research and development agreements with NVIDIA and Philips. William Hall received consulting fees from Aktis oncology; received honoraria from Elekta; received travel funding from Elekta; serves a position as the Vice Chair of the MR Linac Consortium Steering Committee. Provisional Patient 63/483,252 was filed by the institution on medical devices to assess radiation readiness. The other 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, (Published by Elsevier Inc.)

Background and Purpose: Radiation-induced damage to the organs at risk (OARs) in head-and-neck cancer (HNC) patient can result in long-term complications. Quantitative magnetic resonance imaging (qMRI) techniques such as diffusion-weighted imaging (DWI), DIXON for fat fraction (FF) estimation and T 2 mapping could potentially provide a spatial assessment of such damage. The goal of this study is to validate these qMRI techniques in terms of accuracy in phantoms and repeatability in-vivo across a broad selection of healthy OARs in the HN region., Materials and Methods: Scanning was performed at a 3 T diagnostic MRI scanner, including the calculation of apparent diffusion coefficient (ADC) from DWI, FF and T 2 maps. Phantoms were scanned to estimate the qMRI techniques bias using Bland-Altman statistics. Twenty-six healthy subjects were scanned twice in a test-retest study to determine repeatability. Repeatability coefficients (RC) were calculated for the parotid, submandibular, sublingual and tubarial salivary glands, oral cavity, pharyngeal constrictor muscle and brainstem. Additionally, a linear mixed-effect model analysis was used to evaluate the effect of subject-specific characteristics on the qMRI values., Results: Bias was 0.009x10 -3 mm 2 /s for ADC, -0.7 % for FF and -7.9 ms for T 2 . RCs ranged 0.11-0.25x10 -3 mm 2 /s for ADC, 1.2-6.3 % for FF and 2.5-6.3 ms for T 2 . A significant positive linear relationship between age and the FF and T 2 for some of the OARs was found., Conclusion: These qMRI techniques are feasible, accurate and repeatable, which is promising for treatment response monitoring and/or differentiating between healthy and unhealthy tissues due to radiation-induced damage in HNC patients., 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., (© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)

Purpose: The focal radiation therapy (RT) boost technique was shown in a phase III randomized controlled trial (RCT) to improve prostate cancer outcomes without increasing toxicity. This technique relies on the accurate delineation of prostate tumors on MRI. A recent prospective study evaluated radiation oncologists' accuracy when asked to delineate prostate tumors on MRI and demonstrated high variability in tumor contours. We sought to evaluate the impact of contour variability and inaccuracy on predicted clinical outcomes. We hypothesized that radiation oncologists' contour inaccuracies would yield meaningfully worse clinical outcomes., Methods and Materials: Forty-five radiation oncologists and 2 expert radiologists contoured prostate tumors on 30 patient cases. Of these cases, those with CT simulation or diagnostic CT available were selected for analysis. A knowledge-based planning model was developed to generate focal RT boost plans for each contour per the RCT protocol. The probability of biochemical failure (BF) was determined using a model from the RCT. The primary metric evaluated was delta BF (DBF = Participant BF - Expert BF). An absolute increase in BF ≥5% was considered clinically meaningful., Results: Eight patient cases and 394 target volumes for focal RT boost planning were included in this analysis. In general, participant plans were associated with worse predicted clinical outcomes compared to the expert plan, with an average absolute increase in BF of 4.3%. Of participant plans, 37% were noted to have an absolute increase in BF of 5% or more., Conclusions: Radiation oncologists' attempts to contour tumor targets for focal RT boost are frequently inaccurate enough to yield meaningfully inferior clinical outcomes for patients., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.

Purpose: Segmentation of clinical target volumes (CTV) on medical images can be time-consuming and is prone to interobserver variation (IOV). This is a problem for online adaptive radiation therapy, where CTV segmentation must be performed every treatment fraction, leading to longer treatment times and logistic challenges. Deep learning (DL)-based auto-contouring has the potential to speed up CTV contouring, but its current clinical use is limited. One reason for this is that it can be time-consuming to verify the accuracy of CTV contours produced using auto-contouring, and there is a risk of bias being introduced. To be accepted by clinicians, auto-contouring must be trustworthy. Therefore, there is a need for a comprehensive commissioning framework when introducing DL-based auto-contouring in clinical practice. We present such a framework and apply it to an in-house developed DL model for auto-contouring of the CTV in rectal cancer patients treated with MRI-guided online adaptive radiation therapy., Methods and Materials: The framework for evaluating DL-based auto-contouring consisted of 3 steps: (1) Quantitative evaluation of the model's performance and comparison with IOV; (2) Expert observations and corrections; and (3) Evaluation of the impact on expected volumetric target coverage. These steps were performed on independent data sets. The framework was applied to an in-house trained nnU-Net model, using the data of 44 rectal cancer patients treated at our institution., Results: The framework established that the model's performance after expert corrections was comparable to IOV, and although the model introduced a bias, this had no relevant impact on clinical practice. Additionally, we found a substantial time gain without reducing quality as determined by volumetric target coverage., Conclusions: Our framework provides a comprehensive evaluation of the performance and clinical usability of target auto-contouring models. Based on the results, we conclude that the model is eligible for clinical use., Competing Interests: The Netherlands Cancer Institute receives institutional funding and research support from Elekta AB (Stockholm) and research support from Philips Healthcare. Femke Peters participated in a Data Safety Monitoring Board for a study into BioXmark fiducials for rectum boost., (© 2024 The Authors.)

Recognizing the potential of quantitative imaging biomarkers (QIBs) in radiotherapy, many studies have investigated the prognostic value of quantitative MRI (qMRI). With the introduction of MRI-guided radiotherapy systems, the practical challenges of repeated imaging have been substantially reduced. Since patients are treated inside an MRI scanner, acquisition of qMRI can be done during each fraction with limited or no prolongation of the fraction duration. In this review paper, we identify the steps that need been taken to move from MR as an imaging technique to a useful biomarker for MRI-guided radiotherapy (MRgRT)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: The FLAME trial (NCT01168479) showed that isotoxic focal boosting to the intraprostatic lesion(s) in patients with intermediate- and high-risk prostate cancer improves 5-year disease-free survival (DFS). Although the near-minimum dose to the gross tumor volume (D98%) was associated with improved outcomes, a closer look suggested that this might not be the same for all patients. Therefore, we investigated whether risk factors that are associated with a benefit of focal boosting can be identified., Methods and Materials: We described the distribution of clinical characteristics and the number of high-risk factors with respect to the D98% in 526 FLAME trial patients. We used penalized Cox regression to develop a prediction model. To investigate a potential benefit in patient subgroups, we compared the model-based predictions of 5-year DFS assuming standard whole-gland radiation therapy of 77 Gy to the predictions assuming an additional focal boost with D98% of 95 Gy., Results: Patients with high-risk factors were well represented in the group of 120 patients that received D98% > 85 Gy and showed fewer recurrences compared with the group that received 77 Gy. Applying the model simulating a standard dose of 77 Gy, we predicted a high DFS for grade group (GG) 1 patients, whereas patients with high-risk characteristics appeared to show a low DFS. All risk groups showed a high level of DFS when simulating D98% of 95 Gy., Conclusions: Our results suggest that GG 1 patients already show a low level of failure at a standard dose of 77 Gy, limiting the additional benefit of focal boosting. In contrast, patients with high-risk characteristics, especially GG 4 or 5, show a low 5-year DFS, while focal boosting might improve this substantially. This suggests that reaching a high focal boost dose may be particularly beneficial for these patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Purpose: Existing methods for quality assurance of the radiotherapy auto-segmentations focus on the correlation between the average model entropy and the Dice Similarity Coefficient (DSC) only. We identified a metric directly derived from the output of the network and correlated it with clinically relevant metrics for contour accuracy., Materials and Methods: Magnetic Resonance Imaging auto-segmentations were available for the gross tumor volume for cervical cancer brachytherapy (106 segmentations) and for the clinical target volume for rectal cancer external-beam radiotherapy (77 segmentations). The nnU-Net's output before binarization was taken as a score map. We defined a metric as the mean of the voxels in the score map above a threshold (λ). Comparisons were made with the mean and standard deviation over the score map and with the mean over the entropy map. The DSC, the 95th Hausdorff distance, the mean surface distance (MSD) and the surface DSC were computed for segmentation quality. Correlations between the studied metrics and model quality were assessed with the Pearson correlation coefficient (r). The area under the curve (AUC) was determined for detecting segmentations that require reviewing., Results: For both tasks, our metric (λ = 0.30) correlated more strongly with the segmentation quality than the mean over the entropy map (for surface DSC, r > 0.65 vs. r < 0.60). The AUC was above 0.84 for detecting MSD values above 2 mm., Conclusions: Our metric correlated strongly with clinically relevant segmentation metrics and detected segmentations that required reviewing, indicating its potential for automatic quality assurance of radiotherapy target auto-segmentations., 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., (© 2023 The Authors.)

Background and Purpose: The apparent diffusion coefficient (ADC), a potential imaging biomarker for radiotherapy response, needs to be reproducible before translation into clinical use. The aim of this study was to evaluate the multi-centre delineation- and calculation-related ADC variation and give recommendations to minimize it., Materials and Methods: Nine centres received identical diffusion-weighted and anatomical magnetic resonance images of different cancerous tumours (adrenal gland, pelvic oligo metastasis, pancreas, and prostate). All centres delineated the gross tumour volume (GTV), clinical target volume (CTV), and viable tumour volume (VTV), and calculated ADCs using both their local calculation methods and each of the following calculation conditions: b-values 0-500 vs. 150-500 s/mm 2 , region-of-interest (ROI)-based vs. voxel-based calculation, and mean vs. median. ADC variation was assessed using the mean coefficient of variation across delineations (CV D ) and calculation methods (CV C ). Absolute ADC differences between calculation conditions were evaluated using Friedman's test. Recommendations for ADC calculation were formulated based on observations and discussions within the Elekta MRI-linac consortium image analysis working group., Results: The median (range) CV D and CV C were 0.06 (0.02-0.32) and 0.17 (0.08-0.26), respectively. The ADC estimates differed 18% between b-value sets and 4% between ROI/voxel-based calculation (p-values < 0.01). No significant difference was observed between mean and median (p = 0.64). Aligning calculation conditions between centres reduced CV C to 0.04 (0.01-0.16). CV D was comparable between ROI types., Conclusion: Overall, calculation methods had a larger impact on ADC reproducibility compared to delineation. Based on the results, significant sources of variation were identified, which should be considered when initiating new studies, in particular multi-centre investigations., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: To quantify the difference in accuracy of adapt-to-position (ATP), adapt-to-rotation (ATR) and adapt-to-shape (ATS) workflows used in MRI-guided online adaptive radiotherapy for prostate carcinoma (PCa) by evaluating the margins required to accommodate intra-fraction motion of the clinical target volumes for prostate (CTVpros), prostate including seminal vesicles (CTVpros + sv) and gross tumor volume (GTV)., Materials and Methods: Clinical delineations of the CTVpros, CTVpros + sv and GTV of 24 patients with intermediate- and high-risk PCa, treated using ATS on a 1.5 T MR-Linac, were used for analysis. Delineations were available pre- and during beam-on. To simulate ATP and ATR workflows, we automatically generated the structures associated with these workflows using rigid transformations from the planning-MRI to the daily online MRIs. Clinical GTVs were analyzed as ATR GTVs and only ATP GTVs were simulated. Planning target volumes (PTVs) were generated with isotropic margins ranging 0.0-5.0 mm. The volumetric overlap was calculated between these PTVs and their corresponding clinical delineation on the MRI acquired during beam-on and averaged over all treatment fractions., Results: The PTV margin required to cover > 95% of the CTVpros was equal (2.5 mm) for all workflows. For the CTVpros + sv, this margin increased to 5.0, 4.0 and 3.5 mm in the ATP, ATR and ATS workflow, respectively. GTV coverage improved from ATP to ATR for margins up to 4.0 mm., Conclusion: ATP, ATR and ATS workflows ensure equal coverage of the CTVpros for the current clinical margins. For the CTVpros + sv, ATS showed optimal performance. GTV coverage improves by additional adaptations to prostate rotations., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: The hypo-FLAME trial showed that once-weekly (QW) focal boosted prostate stereotactic body radiotherapy (SBRT) is associated with acceptable acute genitourinary (GU) and gastrointestinal (GI) toxicity. Currently, we investigated the safety of reducing the overall treatment time (OTT) of focal boosted prostate SBRT from 29 to 15 days., Material and Methods: Patients with intermediate- and high-risk prostate cancer were treated with SBRT delivering 35 Gy in 5 fractions to the whole prostate gland with an iso-toxic boost up to 50 Gy to the intraprostatic lesion(s) in a semi-weekly (BIW) schedule. The primary endpoint was radiation-induced acute toxicity (CTCAE v5.0). Changes in quality of life (QoL) were examined in terms of proportions achieving a minimal clinically important change (MCIC). Finally, acute toxicity and QoL scores of the BIW schedule were compared with the results of the prior QW hypo-FLAME schedule (n = 100)., Results: Between August 2020 and February 2022, 124 patients were enrolled and treated BIW. No grade ≥3 GU or GI toxicity was observed. The 90-days cumulative incidence of grade 2 GU and GI toxicity rates were 47.5% and 7.4%, respectively. Patients treated QW scored significant less grade 2 GU toxicity (34.0%, p = 0.01). No significant differences in acute GI toxicity were observed. Furthermore, patients treated QW had a superior acute bowel and urinary QoL., Conclusion: Semi-weekly prostate SBRT with iso-toxic focal boosting is associated with acceptable acute GU and GI toxicity. Based on the comparison between the QW and BIW schedule, patients should be counselled regarding the short-term advantages of a more protracted schedule. Registration number ClinicalTrials.gov: NCT04045717., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Organ preservation is associated with superior functional outcome and quality of life (QoL) compared with total mesorectal excision (TME) for rectal cancer. Only 10% of patients are eligible for organ preservation following short-course radiotherapy (SCRT, 25 Gy in five fractions) and a prolonged interval (4-8 weeks) to response evaluation. The organ preservation rate could potentially be increased by dose-escalated radiotherapy. Online adaptive magnetic resonance-guided radiotherapy (MRgRT) is anticipated to reduce radiation-induced toxicity and enable radiotherapy dose escalation. This trial aims to establish the maximum tolerated dose (MTD) of dose-escalated SCRT using online adaptive MRgRT., Methods and Analysis: The preRADAR is a multicentre phase I trial with a 6+3 dose-escalation design. Patients with intermediate-risk rectal cancer (cT3c-d(MRF-)N1M0 or cT1-3(MRF-)N1M0) interested in organ preservation are eligible. Patients are treated with a radiotherapy boost of 2×5 Gy (level 0), 3×5 Gy (level 1), 4×5 Gy (level 2) or 5×5 Gy (level 3) on the gross tumour volume in the week following standard SCRT using online adaptive MRgRT. The trial starts on dose level 1. The primary endpoint is the MTD based on the incidence of dose-limiting toxicity (DLT) per dose level. DLT is a composite of maximum one in nine severe radiation-induced toxicities and maximum one in three severe postoperative complications, in patients treated with TME or local excision within 26 weeks following start of treatment. Secondary endpoints include the organ preservation rate, non-DLT, oncological outcomes, patient-reported QoL and functional outcomes up to 2 years following start of treatment. Imaging and laboratory biomarkers are explored for early response prediction., Ethics and Dissemination: The trial protocol has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht. The primary and secondary trial results will be published in international peer-reviewed journals., Trial Registration Number: WHO International Clinical Trials Registry (NL8997; https://trialsearch.who.int)., Competing Interests: Competing interests: The departments of radiotherapy of both the UMC Utrecht and the Netherlands Cancer Institute have received funding from Elekta, Sweden and Philips Healthcare. PS reports consulting fees from MSD and Bayer and fees for MEDtalks educational presentations. RF reports grants from Personal Genome Diagnostics, Delfi Diagnostics, Cergentis and Merck. HMV is a member of the European Commission and the Netherlands Organization of Health Research and Development and reports grants from the Dutch Cancer Foundation. MI has received personal fees from Elekta, Sweden., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Segmentation of the Gross Tumor Volume (GTV) is a crucial step in the brachytherapy (BT) treatment planning workflow. Currently, radiation oncologists segment the GTV manually, which is time-consuming. The time pressure is particularly critical for BT because during the segmentation process the patient waits immobilized in bed with the applicator in place. Automatic segmentation algorithms can potentially reduce both the clinical workload and the patient burden. Although deep learning based automatic segmentation algorithms have been extensively developed for organs at risk, automatic segmentation of the targets is less common. The aim of this study was to automatically segment the cervical cancer GTV on BT MRI images using a state-of-the-art automatic segmentation framework and assess its performance., Methods: A cohort of 195 cervical cancer patients treated between August 2012 and December 2021 was retrospectively collected. A total of 524 separate BT fractions were included and the axial T2-weighted (T2w) MRI sequence was used for this project. The 3D nnU-Net was used as the automatic segmentation framework. The automatic segmentations were compared with the manual segmentations used for clinical practice with Sørensen-Dice coefficient (Dice), 95th Hausdorff distance (95th HD) and mean surface distance (MSD). The dosimetric impact was defined as the difference in D98 (ΔD98) and D90 (ΔD90) between the manual segmentations and the automatic segmentations, evaluated using the clinical dose distribution. The performance of the network was also compared separately depending on FIGO stage and on GTV volume., Results: The network achieved a median Dice of 0.73 (interquartile range (IQR) = 0.50-0.80), median 95th HD of 6.8 mm (IQR = 4.2-12.5 mm) and median MSD of 1.4 mm (IQR = 0.90-2.8 mm). The median ΔD90 and ΔD98 were 0.18 Gy (IQR = -1.38-1.19 Gy) and 0.20 Gy (IQR =-1.10-0.95 Gy) respectively. No significant differences in geometric or dosimetric performance were observed between tumors with different FIGO stages, however significantly improved Dice and dosimetric performance was found for larger tumors., Conclusions: The nnU-Net framework achieved state-of-the-art performance in the segmentation of the cervical cancer GTV on BT MRI images. Reasonable median performance was achieved geometrically and dosimetrically but with high variability among patients., (© 2023. The Author(s).)

The purpose of this study was to characterize the motion and define the required treatment margins of the pathological mesorectal lymph nodes (GTV ln ) for two online adaptive MRI-guided strategies for sequential boosting. Secondly, we determine the margins required for the primary gross tumor volume (GTV prim ). Twenty-eight patients treated on a 1.5T MR-Linac were included in the study. On T2-weighted images for adaptation (MRI adapt ) before and verification after irradiation (MRI post ) of five treatment fractions per patient, the GTV ln and GTV prim were delineated. With online adaptive MRI-guided radiotherapy, daily plan adaptation can be performed through the use of two different strategies. In an adapt-to-shape (ATS) workflow the interfraction motion is effectively corrected by redelineation and the only relevant motion is intrafraction motion, while in an adapt-to-position (ATP) workflow the margin (for GTV ln ) is dominated by interfraction motion. The margin required for GTV prim will be identical to the ATS workflow, assuming each fraction would be perfectly matched on GTV prim . The intrafraction motion was calculated between MRI adapt and MRI post for the GTV ln and GTV prim separately. The interfraction motion of the GTV ln was calculated with respect to the position of GTV prim , assuming each fraction would be perfectly matched on GTV prim . PTV margins were calculated for each strategy using the Van Herk recipe. For GTV ln we randomly sampled the original dataset 20 times, with each subset containing a single randomly selected lymph node for each patient. The resulting margins for ATS ranged between 3 and 4 mm (LR), 3 and 5 mm (CC) and 5 and 6 mm (AP) based on the 20 randomly sampled datasets for GTV ln . For ATP, the margins for GTV ln were 10-12 mm in LR and AP and 16-19 mm in CC. The margins for ATS for GTV prim were 1.7 mm (LR), 4.7 mm (CC) and 3.2 mm anterior and 5.6 mm posterior. Daily delineation using ATS of both target volumes results in the smallest margins and is therefore recommended for safe dose escalation to the primary tumor and lymph nodes.

Background: Patients with colorectal liver metastases (CRLM) who undergo thermal ablation are at risk of developing new CRLM after ablation. Identification of these patients might enable individualized treatment., Purpose: To investigate whether an existing machine-learning model with radiomics features based on pre-ablation computed tomography (CT) images of patients with colorectal cancer can predict development of new CRLM., Material and Methods: In total, 94 patients with CRLM who were treated with thermal ablation were analyzed. Radiomics features were extracted from the healthy liver parenchyma of CT images in the portal venous phase, before thermal ablation. First, a previously developed radiomics model (Original model) was applied to the entire cohort to predict new CRLM after 6 and 24 months of follow-up. Next, new machine-learning models were developed (Radiomics, Clinical, and Combined), based on radiomics features, clinical features, or a combination of both., Results: The external validation of the Original model reached an area under the curve (AUC) of 0.57 (95% confidence interval [CI]=0.56-0.58) and 0.52 (95% CI=0.51-0.53) for 6 and 24 months of follow-up. The new predictive radiomics models yielded a higher performance at 6 months compared to 24 months. For the prediction of CRLM at 6 months, the Combined model had slightly better performance (AUC=0.60; 95% CI=0.59-0.61) compared to the Radiomics and Clinical models (AUC=0.55-0.57), while all three models had a low performance for the prediction at 24 months (AUC=0.52-0.53)., Conclusion: Both the Original and newly developed radiomics models were unable to predict new CLRM based on healthy liver parenchyma in patients who will undergo ablation for CRLM.

Objective . Multi-parametric magnetic resonance imaging (mpMRI) has become an important tool for the detection of prostate cancer in the past two decades. Despite the high sensitivity of MRI for tissue characterization, it often suffers from a lack of specificity. Several well-established pre-processing tools are publicly available for improving image quality and removing both intra- and inter-patient variability in order to increase the diagnostic accuracy of MRI. To date, most of these pre-processing tools have largely been assessed individually. In this study we present a systematic evaluation of a multi-step mpMRI pre-processing pipeline to automate tumor localization within the prostate using a previously trained model. Approach . The study was conducted on 31 treatment-naïve prostate cancer patients with a PI-RADS-v2 compliant mpMRI examination. Multiple methods were compared for each pre-processing step: (1) bias field correction, (2) normalization, and (3) deformable multi-modal registration. Optimal parameter values were estimated for each step on the basis of relevant individual metrics. Tumor localization was then carried out via a model-based approach that takes both mpMRI and prior clinical knowledge features as input. A sequential optimization approach was adopted for determining the optimal parameters and techniques in each step of the pipeline. Main results . The application of bias field correction alone increased the accuracy of tumor localization (area under the curve (AUC) = 0.77; p -value = 0.004) over unprocessed data (AUC = 0.74). Adding normalization to the pre-processing pipeline further improved diagnostic accuracy of the model to an AUC of 0.85 ( p -value = 0.000 12). Multi-modal registration of apparent diffusion coefficient images to T2-weighted images improved the alignment of tumor locations in all but one patient, resulting in a slight decrease in accuracy (AUC = 0.84; p -value = 0.30). Significance . Overall, our findings suggest that the combined effect of multiple pre-processing steps with optimal values has the ability to improve the quantitative classification of prostate cancer using mpMRI. Clinical trials: NCT03378856 and NCT03367702., (Creative Commons Attribution license.)

Background and Purpose: Strategies to limit the impact of intra-fraction motion during treatment are common in radiotherapy. Margin recipes, however, are not designed to incorporate these strategies. This work aimed to provide a framework to determine how motion management strategies influence treatment margins., Materials and Methods: Two models of intra-fraction motion were considered. In model 1 motion was instantaneous, before treatment starts and in model 2 motion was a continuous drift during treatment. Motion management strategies were modelled by truncating the underlying error distribution at c σ, with σ the standard deviation of the distribution and c a free parameter. Using Monte Carlo simulations, we determined how motion management changed the required margin. The analysis was performed for different number of treatment fractions and different standard deviations of the underlying random and systematic errors., Results: The required margin for a continuous drift was found to be well approximated by an average position of the target at ¾ of the drift. Introducing a truncation at c σ, the relative change in the margin was equal to 0.3 c . This result held for both models, was independent of σ or the number of fractions and naturally generalizes to the situation with a residual (systematic) error., Conclusion: Treatment margins can be determined when motion management strategies are applied. Moreover, our analysis can be used to study the potential benefit of different motion management strategies. This allows to discuss and determine the most appropriate strategy for margin reduction., 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.)

Objective. In online adaptive radiotherapy a new plan is generated every fraction based on the organ and clinical target volume (CTV) delineations of that fraction. This allows for a planning target volume margin that does not need to be constant over the whole course of treatment, as is the case in conventional radiotherapy. This work aims to introduce an approach to update the margins each fraction based on the per-patient treatment history and explore the potential benefits of such adaptive margins. Approach. We introduce a novel methodology to implement adaptive margins, isotropic and anisotropic, during a treatment course based on the accumulated dose to the CTV. We then simulate treatment histories for treatments delivered in up to 20 fractions using various choices for the standard deviations of the systematic and random errors and homogeneous and inhomogeneous dose distributions. The treatment-averaged adaptive margin was compared to standard constant margins. The change in the minimum dose delivered to the CTV was compared on a patient and a population level. All simulations were performed within the van Herk approach and its known limitations. Main results. The population mean treatment-averaged margins are down to 70% and 55% of the corresponding necessary constant margins for the isotropic and anisotropic approach. The reduction increases with longer fractionation schemes and an inhomogeneous target dose distribution. Most of the benefit can be attributed to the elimination of the effective systematic error over the course of treatment. Interpatient differences in treatment-averaged margins were largest for the isotropic margins. For the 10% of patients that would receive a lower than prescribed dose to the CTV this minimum dose to the CTV is increased using the adaptive margin approaches. Significance. Adaptive margins can allow to reduce margins in most patients without compromising patients with greater than average target motion., (Creative Commons Attribution license.)

Introduction: Prostate cancer is a common malignancy for which radiation therapy (RT) provides an excellent management option with high rates of control and low toxicity. Historically RT has been given with CT based image guidance. Recently, magnetic resonance (MR) imaging capabilities have been successfully integrated with RT delivery platforms, presenting an appealing, yet complex, expensive, and time-consuming method of adapting and guiding RT. The precise benefits of MR guidance for localized prostate cancer are unclear. We sought to summarize optimal strategies to test the benefits of MR guidance specifically in localized prostate cancer., Methods: A group of radiation oncologists, physicists, and statisticians were identified to collectively address this topic. Participants had a history of treating prostate cancer patients with the two commercially available MRI-guided RT devices. Participants also had a clinical focus on randomized trials in localized prostate cancer. The goal was to review both ongoing trials and present a conceptual focus on MRI-guided RT specifically in the definitive treatment of prostate cancer, along with developing and proposing novel trials for future consideration. Trial hypotheses, endpoints, and areas for improvement in localized prostate cancer that specifically leverage MR guided technology are presented., Results: Multiple prospective trials were found that explored the potential of adaptive MRI-guided radiotherapy in the definitive treatment of prostate cancer. Different primary areas of improvement that MR guidance may offer in prostate cancer were summarized. Eight clinical trial design strategies are presented that summarize options for clinical trials testing the potential benefits of MRI-guided RT., Conclusions: The number and scope of trials evaluating MRI-guided RT for localized prostate cancer is limited. Yet multiple promising opportunities to test this technology and potentially improve outcomes for men with prostate cancer undergoing definitive RT exist. Attention, in the form of multi-institutional randomized trials, is needed., Competing Interests: WH, EP, and AT receives research and travel support from Elekta AB, Stockholm Sweden. HN: ViewRay Ad board research funds BSci ad board and research funds Lantheus research funds Veracyte research funds. AK: ViewRay Research funding, honoraria, consulting Varian Honoraria Boston Scientific Advisory Board Janssen Research FundingPointBiopharma Research funding. EH: Prof. Hall reports grants from Accuray Inc., grants from Varian Medical Systems Inc., outside the submitted work; EH acknowledges support from a Cancer Research UK Network Accelerator Award Grant (A21993) to the ART-NET consortium; and from the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and ICR (London, UK). DV reports speaker fees from Elekta. AT acknowledges support from Cancer Research UK (C33589/A28284 and C7224/A28724) and the National Institute for Health Research (NIHR) Cancer Research Network. This project represents independent research supported by the National Institute for Health research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2022 Hall, Kishan, Hall, Nagar, Vesprini, Paulson, Van der Heide, Lawton, Kerkmeijer and Tree.)

Background: Focal dose escalation in external beam radiotherapy (EBRT) showed an increase in 5-yr biochemical disease-free survival in the Focal Lesion Ablative Microboost in Prostate Cancer (FLAME) trial., Objective: To analyze the effect of a focal boost to intraprostatic lesions on local failure-free survival (LFS) and regional + distant metastasis-free survival (rdMFS)., Design, Setting, and Participants: Patients with intermediate- or high-risk localized prostate cancer were included in FLAME, a phase 3, multicenter, randomized controlled trial., Intervention: Standard treatment of 77 Gy to the entire prostate in 35 fractions was compared to an additional boost to the macroscopic tumor of up to 95 Gy during EBRT., Outcome Measurements and Statistical Analysis: LFS and rdMFS, measured via any type of imaging, were compared between the treatment arms using Kaplan-Meier and Cox regression analyses. Dose-response curves were created for local failure (LF) and regional + distant metastatic failure (rdMF) using logistic regression., Results and Limitations: A total of 571 patients were included in the FLAME trial. Over median follow-up of 72 mo (interquartile range 58-86), focal boosting decreased LF (hazard ratio [HR] 0.33, 95% confidence interval [CI] 0.14-0.78) and rdMF (HR 0.58, 95% CI 0.35-0.93). Dose-response curves showed that a greater dose to the tumor resulted in lower LF and rdMF rates., Conclusions: A clear dose-response relation for LF and rdMF was observed, suggesting that adequate focal dose escalation to intraprostatic lesions prevents undertreatment of the primary tumor, resulting in an improvement rdMF., Patient Summary: Radiotherapy is a treatment option for high-risk prostate cancer. The FLAME trial has shown that a high dose specifically targeted at the tumor within the prostate will result in better disease outcome, with less likelihood of regional and distant disease spread. The FLAME trial is registered on ClinicalTrials.gov as NCT01168479., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Contouring oropharyngeal primary tumors in radiotherapy is currently done manually which is time-consuming. Autocontouring techniques based on deep learning methods are a desirable alternative, but these methods can render suboptimal results when the structure to segment is considerably smaller than the rest of the image. The purpose of this work was to investigate different strategies to tackle the class imbalance problem in this tumor site., Materials and Methods: A cohort of 230 oropharyngeal cancer patients treated between 2010 and 2018 was retrospectively collected. The following magnetic resonance imaging (MRI) sequences were available: T1-weighted, T2-weighted, 3D T1-weighted after gadolinium injection. Two strategies to tackle the class imbalance problem were studied: training with different loss functions (namely: Dice loss, Generalized Dice loss, Focal Tversky loss and Unified Focal loss) and implementing a two-stage approach (i.e. splitting the task in detection and segmentation). Segmentation performance was measured with Sørensen-Dice coefficient (Dice), 95th Hausdorff distance (HD) and Mean Surface Distance (MSD)., Results: The network trained with the Generalized Dice Loss yielded a median Dice of 0.54, median 95th HD of 10.6 mm and median MSD of 2.4 mm but no significant differences were observed among the different loss functions (p-value > 0.7). The two-stage approach resulted in a median Dice of 0.64, median HD of 8.7 mm and median MSD of 2.1 mm, significantly outperforming the end-to-end 3D U-Net (p-value < 0.05)., Conclusion: No significant differences were observed when training with different loss functions. The two-stage approach outperformed the end-to-end 3D U-Net., 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. Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)

MRI can help to categorize tissues as malignant or non-malignant both anatomically and functionally, with a high level of spatial and temporal resolution. This non-invasive imaging modality has been integrated with radiotherapy in devices that can differentially target the most aggressive and resistant regions of tumours. The past decade has seen the clinical deployment of treatment devices that combine imaging with targeted irradiation, making the aspiration of integrated MRI-guided radiotherapy (MRIgRT) a reality. The two main clinical drivers for the adoption of MRIgRT are the ability to image anatomical changes that occur before and during treatment in order to adapt the treatment approach, and to image and target the biological features of each tumour. Using motion management and biological targeting, the radiation dose delivered to the tumour can be adjusted during treatment to improve the probability of tumour control, while simultaneously reducing the radiation delivered to non-malignant tissues, thereby reducing the risk of treatment-related toxicities. The benefits of this approach are expected to increase survival and quality of life. In this Review, we describe the current state of MRIgRT, and the opportunities and challenges of this new radiotherapy approach., (© 2022. Springer Nature Limited.)

Purpose: To determine PTV margins for intrafraction motion in MRI-guided online adaptive radiotherapy for rectal cancer and the potential benefit of performing a 2nd adaptation prior to irradiation., Methods: Thirty patients with rectal cancer received radiotherapy on a 1.5 T MR-Linac. On T2-weighted images for adaptation (MRI adapt ), verification prior to (MRI ver ) and after irradiation (MRI post ) of 5 treatment fractions per patient, the primary tumor GTV (GTV prim ) and mesorectum CTV (CTV meso ) were delineated. The structures on MRI adapt were expanded to corresponding PTVs. We determined the required expansion margins such that on average over 5 fractions, 98% of CTV meso and 95% of GTV prim on MRI post was covered in 90% of the patients. Furthermore, we studied the benefit of an additional adaptation, just prior to irradiation, by evaluating the coverage between the structures on MRI ver and MRI post. A threshold to assess the need for a secondary adaptation was determined by considering the overlap between MRI adapt and MRI ver. RESULTS: PTV margins for intrafraction motion without 2nd adaptation were 6.4 mm in the anterior direction and 4.0 mm in all other directions for CTV meso and 5.0 mm isotropically for GTV prim . A 2nd adaptation, applied for all fractions where the motion between MRI adapt and MRI ver exceeded 1 mm (36% of the fractions) would result in a reduction of the PTV meso margin to 3.2 mm/2.0 mm. For PTV prim a margin reduction to 3.5 mm is feasible when a 2nd adaptation is performed in fractions where the motion exceeded 4 mm (17% of the fractions)., Conclusion: We studied the potential benefit of intrafraction motion monitoring and a 2nd adaptation to reduce PTV margins in online adaptive MRIgRT in rectal cancer. Performing 2nd adaptations immediately after online replanning when motion exceeded 1 mm and 4 mm for CTV meso and GTV prim respectively, could result in a 30-50% margin reduction with limited reduction of dose to the bowel., (© 2022. The Author(s).)

Purpose: Intravoxel incoherent motion (IVIM) is a promising technique that can acquire perfusion information without the use of contrast agent, contrary to the more established dynamic contrast-enhanced (DCE) technique. This is of interest for treatment response monitoring, where patients can be imaged on each treatment fraction. In this study, longitudinal correlations between IVIM- and DCE parameters were assessed in prostate cancer patients receiving radiation treatment., Materials and Methods: 20 prostate cancer patients were treated on a 1.5 T MR-linac with 20 x 3 or 3.1 Gy. Weekly IVIM and DCE scans were acquired. Tumors, the peripheral zone (PZ), and the transition zone (TZ) were delineated on a T 2 -weighted scan acquired on the first fraction. IVIM and DCE scans were registered to this scan and the delineations were propagated. Median values from these delineations were used for further analysis. The IVIM parameters D, f, D * and the product fD * were calculated. The Tofts model was used to calculate the DCE parameters K trans , k ep and v e . Pearson correlations were calculated for the IVIM and DCE parameters on values from the first fraction for each region of interest (ROI). For longitudinal analysis, the repeated measures correlation coefficient was used to determine correlations between IVIM and DCE parameters in each ROI., Results: When averaging over patients, an increase during treatment in all IVIM and DCE parameters was observed in all ROIs, except for D in the PZ and TZ. No significant Pearson correlations were found between any pair of IVIM and DCE parameters measured on the first fraction. Significant but low longitudinal correlations were found for some combinations of IVIM and DCE parameters in the PZ and TZ, while no significant longitudinal correlations were found in the tumor. Notably in the TZ, for both f and fD * , significant longitudinal correlations with all DCE parameters were found., Conclusions: The increase in IVIM- and DCE parameters when averaging over patients indicates a measurable response to radiation treatment with both techniques. Although low, significant longitudinal correlations were found which suggests that IVIM could potentially be used as an alternative to DCE for treatment response monitoring., Competing Interests: The Netherlands Cancer Institute is a member of the Elekta MR-linac consortium, which aims to coordinate international collaborative research relating to the Elekta Unity (MR-linac). Elekta and Philips are commercial partners within the consortium. Elekta financially supports consortium member institutions with research funding and travel costs for consortium meetings. 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 Kooreman, van Pelt, Nowee, Pos, van der Heide and van Houdt.)

Quantitative MRI has the potential to produce imaging biomarkers for the prediction of early response to radiotherapy treatment. In this pilot study, a potential imaging biomarker, the T 1ρ relaxation time, is assessed for this purpose. A T 1ρ sequence was implemented on a 1.5 T MR-linac system, a system that combines an MRI with a linear accelerator for radiation treatment. An agar phantom with concentrations of 1-4% w / w was constructed for technical validation of the sequence. Phantom images were assessed in terms of short-term repeatability and signal-to-noise ratio. Twelve rectal cancer patients, who were treated with 5 × 5 Gy, were imaged on each treatment fraction. Individual changes in the T 1ρ values of the gross tumor volume (GTV) showed an increase for most patients, although a paired t -test comparing values in the GTV from the first to the last treatment fraction showed no statistically significant difference. The phantom measurements showed excellent short-term repeatability (0.5-1.5 ms), and phantom T 1ρ values corresponded to the literature values. T 1ρ imaging was implemented successfully on the MR-linac, with a repeatability comparable to diagnostic systems, although clinical benefit in terms of treatment response monitoring remains to be demonstrated.

Objective: Dynamic contrast enhanced (DCE)-MRI is currently not generally used for intraocular masses as lesions are small, have an inhomogeneous T 1 and the eye is prone to motion. The aim of this paper is to address these eye-specific challenges, enabling accurate ocular DCE-MRI., Materials & Methods: DCE-MRI of 19 uveal melanoma (UM) patients was acquired using a fat-suppressed 3D spoiled gradient echo sequence with TWIST (time-resolved angiography with stochastic trajectories sequence). The analysis consisted of a two-step registration method to correct for both head and eye motion. A T 1 map was calculated to convert signal intensities to concentrations. Subsequently, the Tofts model was fitted voxel wise to obtain K trans and v e ., Results: Registration significantly improved the concentration curve quality (p < 0.001). The T 1 of melanotic lesions was significantly lower than amelanotic lesions (888 ms vs 1350 ms, p = 0.03). The average achieved B 1 + in the lesions was 91%. The average K trans was 0.46 min -1 (range 0.13-1.0) and the average v e was 0.22 (range 0.10-0.51)., Conclusion: Using this eye-specific analysis, DCE of intraocular masses is possible which might aid in the diagnosis, prognosis and follow-up of UM., (© 2021. The Author(s).)

Purpose or Objectives: The FLAME trial (NCT01168479) showed that by adding a focal boost to conventional fractionated EBRT in the treatment of localized prostate cancer, the five-year biochemical disease-free survival increased, without significantly increasing toxicity. The aim of the present study was to investigate the association between radiation dose to the bladder and urethra and genitourinary (GU) toxicity grade ≥2 in the entire cohort., Material and Methods: The dose-effect relations of the urethra and bladder dose, separately, and GU toxicity grade ≥2 (CTCAE 3.0) up to five years after treatment were assessed. A mixed model analysis for repeated measurements was used, adjusting for age, diabetes mellitus, T-stage, baseline GU toxicity grade ≥1 and institute. Additionally, the association between the dose and separate GU toxicity subdomains were investigated., Results: Dose-effect relations were observed for the dose (Gy) to the bladder D2 cm 3 and urethra D0.1 cm 3 , with adjusted odds ratios of 1.14 (95% CI 1.12-1.16, p < 0.0001) and 1.12 (95% CI 1.11-1.14, p < 0.0001), respectively. Additionally, associations between the dose to the urethra and bladder and the subdomains urinary frequency, urinary retention and urinary incontinence were observed., Conclusion: Further increasing the dose to the bladder and urethra will result in a significant increase in GU toxicity following EBRT. Focal boost treatment plans should incorporate a urethral dose-constraint. Further treatment optimization to increase the focal boost dose without increasing the dose to the urethra and other organs at risk should be a focus for future research, as we have shown that a focal boost is beneficial in the treatment of prostate cancer., Competing Interests: Conflict of interest statement All authors declare having no conflict of interest related to the content of this manuscript., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: High-field magnetic resonance-linear accelerators (MR-Linacs), linear accelerators combined with a diagnostic magnetic resonance imaging (MRI) scanner and online adaptive workflow, potentially give rise to novel online anatomic and response adaptive radiation therapy paradigms. The first high-field (1.5T) MR-Linac received regulatory approval in late 2018, and little is known about clinical use, patient tolerability of daily high-field MRI, and toxicity of treatments. Herein we report the initial experience within the MOMENTUM Study (NCT04075305), a prospective international registry of the MR-Linac Consortium., Methods and Materials: Patients were included between February 2019 and October 2020 at 7 institutions in 4 countries. We used descriptive statistics to describe the patterns of care, tolerability (the percentage of patients discontinuing their course early), and safety (grade 3-5 Common Terminology Criteria for Adverse Events v.5 acute toxicity within 3 months after the end of treatment)., Results: A total 943 patients participated in the MOMENTUM Study, 702 of whom had complete baseline data at the time of this analysis. Patients were primarily male (79%) with a median age of 68 years (range, 22-93) and were treated for 39 different indications. The most frequent indications were prostate (40%), oligometastatic lymph node (17%), brain (12%), and rectal (10%) cancers. The median number of fractions was 5 (range, 1-35). Six patients discontinued MR-Linac treatments, but none due to an inability to tolerate repeated high-field MRI. Of the 415 patients with complete data on acute toxicity at 3-month follow-up, 18 (4%) patients experienced grade 3 acute toxicity related to radiation. No grade 4 or 5 acute toxicity related to radiation was observed., Conclusions: In the first 21 months of our study, patterns of care were diverse with respect to clinical utilization, body sites, and radiation prescriptions. No patient discontinued treatment due to inability to tolerate daily high-field MRI scans, and the acute radiation toxicity experience was encouraging., (Copyright © 2021. Published by Elsevier Inc.)

Purpose/objective: Most dose-escalation trials in glioblastoma patients integrate the escalated dose throughout the standard course by targeting a specific subvolume. We hypothesize that anatomical changes during irradiation may affect the dose coverage of this subvolume for both proton- and photon-based radiotherapy., Material and Methods: For 24 glioblastoma patients a photon- and proton-based dose escalation treatment plan (of 75 Gy/30 fr) was simulated on the dedicated radiotherapy planning MRI obtained before treatment. The escalated dose was planned to cover the resection cavity and/or contrast enhancing lesion on the T1w post-gadolinium MRI sequence. To analyze the effect of anatomical changes during treatment, we evaluated on an additional MRI that was obtained during treatment the changes of the dose distribution on this specific high dose region., Results: The median time between the planning MRI and additional MRI was 26 days (range 16-37 days). The median time between the planning MRI and start of radiotherapy was relatively short (7 days, range 3-11 days). In 3 patients (12.5%) changes were observed which resulted in a substantial deterioration of both the photon and proton treatment plans. All these patients underwent a subtotal resection, and a decrease in dose coverage of more than 5% and 10% was observed for the photon- and proton-based treatment plans, respectively., Conclusion: Our study showed that only for a limited number of patients anatomical changes during photon or proton based radiotherapy resulted in a potentially clinically relevant underdosage in the subvolume. Therefore, volume changes during treatment are unlikely to be responsible for the negative outcome of dose-escalation studies., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Intro. Current radiation therapy (RT) planning guidelines handle uncertainties in RT using geometric margins. This approach is simple to use but oversimplifies complex underlying processes and is cumbersome for non-homogeneous dose prescriptions. In this work, we characterize the performance of a novel probabilistic target definition and planning (PTP) approach, which uses voxel-level tumor likelihood information in treatment plan optimization. Methods. We expanded a treatment planning system with probabilistic therapy planning functionality that utilizes non-binary target maps (TM) as voxel-level input to dose plan optimization. Different dose plans were calculated and compared for twelve prostate cancer patients with multiparametric magnetic resonance imaging derived TMs. Dose plans were created using both classical and PTP approaches for uniform and integrated dose boost prescriptions. Dose performance between the different approaches was compared using dose benchmarks on target and organ-at-risk (OAR) volumes. Results. Over all dose metrics, PTP was shown to be comparable to classical planning. For plans of uniform dose prescription, the PTP approach created plans within 1 Gy of the classical planning approach across all dose metrics, with no significant differences ( p  > 0.2). For plans with the integrated dose boost, PTP plans exhibited higher dose heterogeneity, but still showed target doses comparable to the classical approach, without increasing doses to OAR. Conclusion. In this work we introduce direct incorporation of probabilistic target definition into treatment planning. This treatment planning approach can produce both uniform dose plans and plans with integrated dose boosts that are comparable to ones created using classical dose planning. PTP is a flexible way to optimize external beam radiotherapy, as it is not limited by the use of margins. PTP can produce dose plans equivalent to classical planning, while also allows for greater versatility in dose prescription and direct incorporation of patient target definition uncertainty into treatment planning., (© 2021 Institute of Physics and Engineering in Medicine.)

External beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy is a very effective treatment for locally advanced cervical cancer (LACC). However, treatment-related toxicity is common and reduces the patient's quality of life (QoL) and ability to complete treatment or undergo adjuvant therapies. Intensity modulated proton therapy (IMPT) enables a significant dose reduction in organs at risk (OAR), when compared to that of standard intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). However, clinical studies evaluating whether IMPT consequently reduces side effects for LACC are lacking. The PROTECT trial is a nonrandomized prospective multicenter phase-II-trial comparing clinical outcomes after IMPT or IMRT/VMAT in LACC. Thirty women aged >18 years with a histological diagnosis of LACC will be included in either the IMPT or IMRT/VMAT group. Treatment includes EBRT (45 Gy in 25 fractions of 1.8 Gy), concurrent five weekly cisplatin (40 mg/m 2 ), and 3D image (MRI)-guided adaptive brachytherapy. The primary endpoint is pelvic bones D mean and mean bowel V 15Gy . Secondary endpoints include dosimetric parameters, oncological outcomes, health-related QoL, immune response, safety, and tolerability. This study provides the first data on the potential of IMPT to reduce OAR dose in clinical practice and improve toxicity and QoL for patients with LACC.

Background and Purpose: The phase III FLAME trial (NCT01168479) showed an increase in five-year biochemical disease-free survival, with no significant increase in toxicity when adding a focal boost to external beam radiotherapy (EBRT) for localized prostate cancer [Kerkmeijer et al. JCO 2021]. The aim of this study was to investigate the association between delivered radiation dose to the anorectum and gastrointestinal (GI) toxicity (grade ≥2)., Material and Methods: All patients in the FLAME trial were analyzed, irrespective of treatment arm. The dose-effect relation of the anorectal dose parameters (D2cm 3 and D50%) and GI toxicity grade ≥2 in four years of follow-up was assessed using a mixed model analysis for repeated measurements, adjusted for age, cardiovascular disease, diabetes mellitus, T-stage, baseline toxicity grade ≥1, hormonal therapy and institute., Results: A dose-effect relation for D2cm 3 and D50% was observed with adjusted odds ratios of 1.17 (95% CI 1.13-1.21, p < 0.0001) and 1.20 (95% CI 1.14-1.25, p < 0.0001) for GI toxicity, respectively., Conclusion: Although there was no difference in toxicity between study arms, a higher radiation dose to the anorectum was associated with a statistically significant increase in GI toxicity following EBRT for prostate cancer. This dose-effect relation was present for both large and small anorectal volumes. Therefore, further increase in dose to the anorectum should be weighed against the benefit of focal dose escalation for prostate cancer., Competing Interests: Conflict of interest statement All authors declare having no conflict of interest related to the content of this manuscript., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Daily quantitative MR imaging during radiotherapy of cancer patients has become feasible with MRI systems integrated with linear accelerators (MR-linacs). Quantitative images could be used for treatment response monitoring. With intravoxel incoherent motion (IVIM) MRI, it is possible to acquire perfusion information without the use of contrast agents. In this multicenter study, daily IVIM measurements were performed in prostate cancer patients to identify changes that potentially reflect response to treatment., Materials and Methods: Forty-three patients were included, treated with 20 fractions of 3 Gy on a 1.5 T MR-linac. IVIM measurements were performed on each treatment day. The diffusion coefficient (D), perfusion fraction (f), and pseudo-diffusion coefficient (D*) were calculated based on the median signal intensities in the non-cancerous prostate and the tumor. Repeatability coefficients (RCs) were determined based on the first two treatment fractions. Separate linear mixed-effects models were constructed for the three IVIM parameters., Results: In total, 726 fractions were analyzed. Pre-treatment average values, measured on the first fraction before irradiation, were 1.46 × 10 -3 mm 2 /s, 0.086, and 28.7 × 10 -3 mm 2 /s in the non-cancerous prostate and 1.19 × 10 -3 mm 2 /s, 0.088, and 28.9 × 10 -3 mm 2 /s in the tumor, for D, f, and D*, respectively. The repeatability coefficients for D, f, and D* in the non-cancerous prostate were 0.09 × 10 -3 mm 2 /s, 0.05, and 15.3 × 10 -3 mm 2 /s. In the tumor, these values were 0.44 × 10 -3 mm 2 /s, 0.16, and 76.4 × 10 -3 mm 2 /s. The mixed effects analysis showed an increase in D of the tumors over the course of treatment, while remaining stable in the non-cancerous prostate. The f and D* increased in both the non-cancerous prostate and tumor., Conclusions: It is feasible to perform daily IVIM measurements on an MR-linac system. Although the repeatability coefficients were high, changes in IVIM perfusion parameters were measured on a group level, indicating that IVIM has potential for measuring treatment response., Competing Interests: The Netherlands Cancer Institute, the Institute of Cancer Research and Royal Marsden NHS Foundation Trust, and the University of Tübingen are members of the Elekta MR-linac consortium, which aims to coordinate international collaborative research relating to the Elekta Unity (MR-linac). Elekta and Philips are commercial partners within the consortium. Elekta financially supports consortium member institutions with research funding and travel costs for consortium meetings. AT declares research funding from Elekta, Varian, and Accuray. DT declares institutional collaborations including financial and non-financial support with Elekta, Philips, Dr Sennewald, PTW Freiburg, and TheraPanacea. The Department of Radiation Oncology Tübingen (DT and AM) has research collaborations with Elekta AB (Sweden), Philips (The Netherlands), and Siemens Healthineers (Germany). The remaining 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 © 2021 Kooreman, van Houdt, Keesman, van Pelt, Nowee, Pos, Sikorska, Wetscherek, Müller, Thorwarth, Tree and van der Heide.)