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Introduction: Prostate cancer (PCa) is a prevalent malignancy in European men, often treated with radiotherapy (RT) for localized disease. While modern RT achieves high success rates, concerns about late gastrointestinal (GI) toxicities persist. This retrospective study aims to identify predictors for late GI toxicities following definitive conventionally fractionated external beam RT (EBRT) for PCa, specifically exploring the dose to the rectal wall., Materials and Methods: A cohort of 96 intermediate- to high-risk PCa patients underwent EBRT between 2008 and 2016. Rectum and rectum wall contours were delineated, and 3D dose matrices were extracted. Volumetric and dosimetric indices were computed, and statistical analyses were performed to identify predictors using the Mann-Whitney U-rank test, logistic regression, and recursive feature elimination., Results: In our cohort, 15 out of 96 patients experienced grade II late proctitis. Our analysis reveals distinct optimal predictors for rectum and rectum wall (RW) structures varying with α/β values (3.0 and 2.3 Gy) across prescribed doses of 68 to 76 Gy. Despite variability, RW predictors demonstrate greater consistency, notably V68Gy[%] to V74Gy[%] for α/β 3.0 Gy, and V68Gy[%] to V70Gy[%] for α/β 2.3 Gy. The model with α/β 2.3 Gy, featuring RW volume receiving 70 Gy (V70Gy[%]), stands out with a BIC value of 62.92, indicating its superior predictive effectiveness. Finally, focusing solely on the rectum structure, the V74Gy[%] emerges the best predictor for α/β 3.0 Gy, with a BIC value of 66.73., Conclusion: This investigation highlights the critical role of V70Gy[%] in the rectum wall as a robust predictor for grade II late gastrointestinal (GI) toxicity following external beam radiation therapy (EBRT) for prostate cancer (PCa). Furthermore, our findings suggest that focusing on the rectum wall specifically, rather than the entire rectum, may offer improved accuracy in assessing proctitis development. A V70Gy (in EQD2 with α/β 2.3 Gy ) of ≤5% and if possible ≤1% for the rectal wall should be achieved to minimize the risk of late grade II proctitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Spohn, Radicioni, Eisfelder, Zamboglou, Baltas, Grosu and Sachpazidis.)

Background: Currently, there are no data from randomized trials on the use of intraoperative radiotherapy (IORT) as a tumor bed boost in women at high risk of local recurrence. The aim of this retrospective analysis was to compare the toxicity and oncological outcome of IORT or simultaneous integrated boost (SIB) with conventional external beam radiotherapy (WBI) after breast conserving surgery (BCS)., Methods: Between 2009 and 2019, patients were treated with a single dose of 20 Gy IORT with 50 kV photons, followed by WBI 50 Gy in 25 or 40.05 in 15 fractions or WBI 50 Gy with SIB up to 58.80-61.60 Gy in 25-28 fractions. Toxicity was compared after propensity score matching. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method., Results: A 1:1 propensity-score matching resulted in an IORT + WBI and SIB + WBI cohort of 60 patients, respectively. The median follow-up for IORT + WBI was 43.5 vs. 32 months in the SIB + WBI cohort. Most women had a pT1c tumor: IORT group 33 (55%) vs. 31 (51.7%) SIB group (p = 0.972). The luminal-B immunophenotype was most frequently diagnosed in the IORT group 43 (71.6%) vs. 35 (58.3%) in the SIB group (p = 0.283). The most reported acute adverse event in both groups was radiodermatitis. In the IORT cohort, radiodermatitis was grade 1: 23 (38.3%), grade 2: 26 (43.3%), and grade 3: 6 (10%) vs. SIB cohort grade 1: 3 (5.1%), grade 2: 21 (35%), and grade 3: 7 (11.6%) without a meaningful difference (p = 0.309). Fatigue occurred more frequently in the IORT group (grade 1: 21.7% vs. 6.7%; p = 0.041). In addition, intramammary lymphedema grade 1 occurred significantly more often in the IORT group (11.7% vs. 1.7%; p = 0.026). Both groups showed comparable late toxicity. The 3- and 5-year local control (LC) rates were each 98% in the SIB group vs. 98% and 93% in the IORT group (LS: log rank p = 0.717)., Conclusion: Tumor bed boost using IORT and SIB techniques after BCS shows excellent local control and comparable late toxicity, while IORT application exhibits a moderate increase in acute toxicity. These data should be validated by the expected publication of the prospective randomized TARGIT-B study., Competing Interests: DK has received honoraria from Merck Sharp & Dome, Onkowissen, and Pfizer as well as research funding from Merck KGaA outside the submitted work. 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 © 2023 Stoian, Exner, Gainey, Erbes, Gkika, Popp, Spohn, Krug, Juhasz-Böss, Grosu and Sprave.)

Introduction: Accurate detection and segmentation of the intraprostatic gross tumor volume (GTV) is pivotal for radiotherapy (RT) in primary prostate cancer (PCa) since it influences focal therapy target volumes and the patients' cT stage. The study aimed to compare the performance of multiparametric resonance imaging (mpMRI) with [ 18 F] PSMA-1007 positron emission tomography (PET) for intraprostatic GTV detection as well as delineation and to evaluate their respective influence on RT concepts., Materials and Methods: In total, 93 patients from two German University Hospitals with [ 18 F] PSMA-1007-PET/CT and MRI (Freiburg) or [ 18 F] PSMA-1007-PET/MRI (Dresden) were retrospectively enrolled. Validated contouring techniques were applied for GTV-PET and -MRI segmentation. Absolute tumor volume and cT status were determined for each imaging method. The PCa distribution from histopathological reports based on biopsy cores and surgery specimen was used as reference in terms of laterality (unilateral vs . bilateral)., Results: In the Freiburg cohort ( n = 84), mpMRI and PET detected in median 2 (range: 1-5) and 3 (range: 1-8) GTVs, respectively ( p < 0.01). The median GTV-MRI was significantly smaller than the GTV-PET, measuring 2.05 vs . 3.65 ml ( p = 0.0005). PET had a statistically significant higher concordance in laterality with surgery specimen compared to mpMRI ( p = 0.04) and biopsy ( p < 0.01), respectively. PSMA PET led to more cT2c and cT3b stages, whereas cT3a stage was more pronounced in mpMRI. Based on the cT stage derived from mpMRI and PET information, 21 and 23 as well as 59 and 60 patients, respectively, were intermediate- and high-risk according to the National Comprehensive Cancer Network (NCCN) v1.2022 criteria. In the Dresden cohort ( n = 9), similar results were observed., Conclusion: Intraprostatic GTV segmentation based on [18F] PSMA-1007 PET results in more and larger GTVs compared to mpMRI. This influences focal RT target volumes and cT stage definition, but not the NCCN risk group., Competing Interests: CZ received funding from the German Cancer Consortium (DKTK), Naslund Medical, and the Klaus Tschira foundation, as well as honoraria from Johnson and Johnson and Novocure, outside the submitted work. 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 © 2022 Marinescu, Spohn, Kiefer, Bronsert, Ceci, Holzschuh, Sigle, Jilg, Rühle, Sprave, Nicolay, Winzer, Rehm, Kotzerke, Hölscher, Grosu, Ruf, Benndorf and Zamboglou.)

Introduction: The National Comprehensive Cancer Network recommends external beam radiotherapy (EBRT) combined with androgen deprivation therapy (ADT) as the preferred treatment option for newly diagnosed node-positive (cN1) prostate cancer (PCa) patients. However, implementation of positron emission tomography targeting prostate-specific membrane antigen (PSMA-PET) in the staging of primary PCa patients has a significant impact on RT treatment concepts. This study aims to evaluate outcomes and their respective risk factors on patients with PSMA-PET-based cN1 and/or cM1a PCa receiving primary RT and ADT., Methods: Forty-eight patients with cN0 and/or cM1a PCa staged by [ 18 F]PSMA-1007-PET ( n = 19) or [ 68 Ga]PSMA-11-PET ( n = 29) were retrospectively included. All patients received EBRT to the pelvis ± boost to positive nodes, followed by boost to the prostate. The impact of different PET-derived characteristics such as maximum standard uptake value (SUVmax) and number of PET-positive lymph nodes on biochemical recurrence-free survival (BRFS) (Phoenix criteria) and metastasis-free survival (MFS) was determined using Kaplan-Meier and Cox proportional hazard regression analyses., Results: Median follow-up was 24 months. Median initial serum prostate-specific antigen was 20.2 ng/ml (IQR 10.2-54.2). Most patients had cT stage ≥ 3 (63%) and ISUP grade ≥ 3 (85%). Median dose to the prostate, elective nodes, and PET-positive nodes was 75 Gy, 45 Gy, and 55 Gy, respectively. Ninety percent of patients received ADT with a median duration of 9 months (IQR 6-18). In univariate analysis, cM1a stage ( p = 0.03), number of >2 pelvic nodes ( p = 0.01), number of >1 abdominal node ( p = 0.02), and SUVmax values ≥ median (8.1 g/ml for 68 Ga-PSMA-11 and 7.9 g/ml for 18 F-PSMA-1007) extracted from lymph nodes were significantly associated with unfavorable BRFS, but classical clinicopathological features were not. Number of >2 pelvic nodes ( n = 0.03), number of >1 abdominal node ( p = 0.03), and SUVmax values ≥ median extracted from lymph nodes were associated with unfavorable MFS. In multivariate analysis, number of >2 pelvic lymph nodes was significantly associated with unfavorable BRFS (HR 5.2, p = 0.01) and SUVmax values ≥ median extracted from lymph nodes had unfavorable MFS (HR 6.3, p = 0.02)., Conclusion: More than 2 PET-positive pelvic lymph nodes are associated with unfavorable BRFS, and high SUVmax values are associated with unfavorable MFS. Thus, the number of PET-positive lymph nodes and the SUVmax value might be relevant prognosticators to identify patients with favorable outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Spohn, Birkenmaier, Ruf, Mix, Sigle, Haehl, Adebahr, Sprave, Gkika, Rühle, Nicolay, Kirste, Grosu and Zamboglou.)

Purpose: Multiparametric magnetic resonance tomography (mpMRI) and prostate specific membrane antigen positron emission tomography (PSMA-PET/CT) are used to guide focal radiotherapy (RT) dose escalation concepts. Besides improvements of treatment effectiveness, maintenance of a good quality of life is essential. Therefore, this planning study investigates whether urethral sparing in moderately hypofractionated RT with focal RT dose escalation influences tumour control probability (TCP) and normal tissue complication probability (NTCP)., Patients and Methods: 10 patients with primary prostate cancer (PCa), who underwent 68Ga PSMA-PET/CT and mpMRI followed by radical prostatectomy were enrolled. Intraprostatic tumour volumes (gross tumor volume, GTV) based on both imaging techniques (GTV-MRI and -PET) were contoured manually using validated contouring techniques and GTV-Union was created by summing both. For each patient three IMRT plans were generated with 60 Gy to the whole prostate and a simultaneous integrated boost up to 70 Gy to GTV-Union in 20 fractions by (Plan 1) not respecting and (Plan 2) respecting dose constraints for urethra as well as (Plan 3) respecting dose constraints for planning organ at risk volume for urethra (PRV = urethra + 2mm expansion). NTCP for urethra was calculated applying a Lyman-Kutcher-Burman model. TCP-Histo was calculated based on PCa distribution in co-registered histology (GTV-Histo). Complication free tumour control probability (P+) was calculated. Furthermore, the intrafractional movement was considered., Results: Median overlap of GTV-Union and PRV-Urethra was 1.6% (IQR 0-7%). Median minimum distance of GTV-Histo to urethra was 3.6 mm (IQR 2 - 7 mm) and of GTV-Union to urethra was 1.8 mm (IQR 0.0 - 5.0 mm). The respective prescription doses and dose constraints were reached in all plans. Urethra-sparing in Plans 2 and 3 reached significantly lower NTCP-Urethra (p = 0.002) without significantly affecting TCP-GTV-Histo (p = p > 0.28), NTCP-Bladder (p > 0.85) or NTCP-Rectum (p = 0.85), resulting in better P+ (p = 0.006). Simulation of intrafractional movement yielded even higher P+ values for Plans 2 and 3 compared to Plan 1., Conclusion: Urethral sparing may increase the therapeutic ratio and should be implemented in focal RT dose escalation concepts., 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 © 2021 Spohn, Sachpazidis, Wiehle, Thomann, Sigle, Bronsert, Ruf, Benndorf, Nicolay, Sprave, Grosu, Baltas and Zamboglou.)

Purpose: Accurate contouring of intraprostatic gross tumor volume (GTV) is pivotal for successful delivery of focal therapies and for biopsy guidance in patients with primary prostate cancer (PCa). Contouring of GTVs, using 18-Fluor labeled tracer prostate specific membrane antigen positron emission tomography ([ 18 F]PSMA-1007/PET) has not been examined yet., Patients and Methods: Ten Patients with primary PCa who underwent [ 18 F]PSMA-1007 PET followed by radical prostatectomy were prospectively enrolled. Coregistered histopathological gross tumor volume (GTV-Histo) was used as standard of reference. PSMA-PET images were contoured on two ways: (1) manual contouring with PET scaling SUVmin-max: 0-10 was performed by three teams with different levels of experience. Team 1 repeated contouring at a different time point, resulting in n = 4 manual contours. (2) Semi-automatic contouring approaches using SUVmax thresholds of 20-50% were performed. Interobserver agreement was assessed for manual contouring by calculating the Dice Similarity Coefficient (DSC) and for all approaches sensitivity, specificity were calculated by dividing the prostate in each CT slice into four equal quadrants under consideration of histopathology as standard of reference., Results: Manual contouring yielded an excellent interobserver agreement with a median DSC of 0.90 (range 0.87-0.94). Volumes derived from scaling SUVmin-max 0-10 showed no statistically significant difference from GTV-Histo and high sensitivities (median 87%, range 84-90%) and specificities (median 96%, range 96-100%). GTVs using semi-automatic segmentation applying a threshold of 20-40% of SUVmax showed no significant difference in absolute volumes to GTV-Histo, GTV-SUV50% was significantly smaller. Best performing semi-automatic contour (GTV-SUV20%) achieved high sensitivity (median 93%) and specificity (median 96%). There was no statistically significant difference to SUVmin-max 0-10., Conclusion: Manual contouring with PET scaling SUVmin-max 0-10 and semi-automatic contouring applying a threshold of 20% of SUVmax achieved high sensitivities and very high specificities and are recommended for [ 18 F]PSMA-1007 PET based focal therapy approaches. Providing high specificities, semi-automatic approaches applying thresholds of 30-40% of SUVmax are recommend for biopsy guidance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer TZ declared a past co-authorship with several of the authors WS-S, CJ, and AG to the handling editor., (Copyright © 2020 Spohn, Kramer, Kiefer, Bronsert, Sigle, Schultze-Seemann, Jilg, Sprave, Ceci, Fassbender, Nicolay, Ruf, Grosu and Zamboglou.)

Introduction: An accurate delineation of the intraprostatic gross tumor volume (GTV) is of importance for focal treatment in patients with primary prostate cancer (PCa). Multiparametric MRI (mpMRI) is the standard of care for lesion detection but has been shown to underestimate GTV. This study investigated how far the GTV has to be expanded in MRI in order to reach concordance with the histopathological reference and whether this strategy is practicable in clinical routine., Patients and Methods: Twenty-two patients with planned prostatectomy and preceded 3 Tesla mpMRI were prospectively examined. After surgery, PCa contours delineated on histopathological slides (GTV-Histo) were superimposed on MRI using ex-vivo imaging as support for co-registration. According to the PI-RADSv2 classification, GTV was manually delineated in MRI (GTV-MRI) by two experts in consensus. For volumetric analysis, we compared GTV-MRI and GTV-Histo. Subsequently, we isotropically enlarged GTV-MRI in 1 mm increments within the prostate and also compared those with GTV-Histo regarding the absolute volumes. For evaluating the spatial accuracy, we considered the coverage ratio of GTV-Histo, the Sørensen-Dice coefficient (DSC), as well as the contact with the urethra., Results: In 19 of 22 patients MRI underestimated the intraprostatic tumor volume compared to histopathological reference: median GTV-Histo (4.7 cm 3 , IQR: 2.5-18.8) was significantly (p<0.001) lager than median GTV-MRI (2.6 cm 3 , IQR: 1.2-6.9). A median expansion of 1 mm (range: 0-4 mm) adjusted the initial GTV-MRI to at least the volume of GTV-Histo (GTV exp -MRI). Original GTV-MRI and expansion with 1, 2, 3, and 4 mm covered in median 39% (IQR: 2%-78%), 62% (10%-91%), 70% (15%-95%), 80% (21-100), 87% (25%-100%) of GTV-Histo, respectively. Best DSC (median: 0.54) between GTV-Histo and GTV-MRI was achieved by median expansion of 2 mm. The urethra was covered by initial GTVs-MRI in eight patients (36%). After applying an expansion with 2 mm the urethra was covered in one more patient by GTV-MRI., Conclusion: Using histopathology as reference, we demonstrated that MRI underestimates intraprostatic tumor volume. A 2 mm-expansion may improve accurate GTV-delineation while respecting the balance between histological tumor coverage and overtreatment., 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 © 2020 Kramer, Spohn, Kiefer, Ceci, Sigle, Oerther, Schultze-Seemann, Gratzke, Bock, Bamberg, Grosu, Benndorf and Zamboglou.)