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Purpose: Convolutional Neural Networks (CNNs) have emerged as transformative tools in the field of radiation oncology, significantly advancing the precision of contouring practices. However, the adaptability of these algorithms across diverse scanners, institutions, and imaging protocols remains a considerable obstacle. This study aims to investigate the effects of incorporating institution-specific datasets into the training regimen of CNNs to assess their generalization ability in real-world clinical environments. Focusing on a data-centric analysis, the influence of varying multi- and single center training approaches on algorithm performance is conducted. Methods: nnU-Net is trained using a dataset comprising 161 18F-PSMA-1007 PET images collected from four distinct institutions (Freiburg: n = 96, Munich: n = 19, Cyprus: n = 32, Dresden: n = 14). The dataset is partitioned such that data from each center are systematically excluded from training and used solely for testing to assess the model's generalizability and adaptability to data from unfamiliar sources. Performance is compared through a 5-Fold Cross-Validation, providing a detailed comparison between models trained on datasets from single centers to those trained on aggregated multi-center datasets. Dice Similarity Score, Hausdorff distance and volumetric analysis are used as primary evaluation metrics. Results: The mixed training approach yielded a median DSC of 0.76 (IQR: 0.64–0.84) in a five-fold cross-validation, showing no significant differences (p = 0.18) compared to models trained with data exclusion from each center, which performed with a median DSC of 0.74 (IQR: 0.56–0.86). Significant performance improvements regarding multi-center training were observed for the Dresden cohort (multi-center median DSC 0.71, IQR: 0.58–0.80 vs. single-center 0.68, IQR: 0.50–0.80, p < 0.001) and Cyprus cohort (multi-center 0.74, IQR: 0.62–0.83 vs. single-center 0.72, IQR: 0.54–0.82, p < 0.01). While Munich and Freiburg also showed performance improvements with multi-center training, results showed no statistical significance (Munich: multi-center DSC 0.74, IQR: 0.60–0.80 vs. single-center 0.72, IQR: 0.59–0.82, p > 0.05; Freiburg: multi-center 0.78, IQR: 0.53–0.87 vs. single-center 0.71, IQR: 0.53–0.83, p = 0.23). Conclusion: CNNs trained for auto contouring intraprostatic GTV in 18F-PSMA-1007 PET on a diverse dataset from multiple centers mostly generalize well to unseen data from other centers. Training on a multicentric dataset can improve performance compared to training exclusively with a single-center dataset regarding intraprostatic 18F-PSMA-1007 PET GTV segmentation. The segmentation performance of the same CNN can vary depending on the dataset employed for training and testing. [ABSTRACT FROM AUTHOR]

This retrospective, multi-centered study aimed to improve high-quality radiation treatment (RT) planning workflows by training and testing a Convolutional Neural Network (CNN) to perform auto segmentations of organs at risk (OAR) for prostate cancer (PCa) patients, specifically the bladder and rectum. The objective of this project was to develop a clinically applicable and robust artificial intelligence (AI) system to assist radiation oncologists in OAR segmentation. The CNN was trained using manual contours in CT-datasets from diagnostic 68 Ga-PSMA-PET/CTs by a student, then validated (n = 30, PET/CTs) and tested (n = 16, planning CTs). Further segmentations were generated by a commercial artificial intelligence (cAI) software. The ground truth were manual contours from expert radiation oncologists. The performance was evaluated using the Dice-Sørensen Coefficient (DSC), visual analysis and a Turing test. The CNN yielded excellent results in both cohorts and OARs with a DSC median  > 0.87, the cAI resulted in a DSC > 0.78. In the visual assessment, 67% (bladder) and 75% (rectum) of the segmentations were rated as acceptable for treatment planning. With a misclassification rate of 45.5% (bladder) and 51.1% (rectum), the CNN passed the Turing test. The metrics, visual assessment and the Turing test confirmed the clinical applicability and therefore the support in clinical routine., (© 2024. The Author(s).)

High dose-rate brachytherapy presents a promising therapeutic avenue for prostate cancer management, involving the temporary implantation of catheters which deliver radioactive sources to the cancerous site. However, as catheters puncture and penetrate the prostate, tissue deformation is evident which may affect the accuracy and efficiency of the treatment. In this work, a data-driven in silico modelling procedure is proposed to simulate brachytherapy while accounting for prostate biomechanics. Comprehensive magnetic resonance and transrectal ultrasound images acquired prior, during and post brachytherapy are employed for model personalisation, while the therapeutic procedure is simulated via sequential insertion of multiple catheters in the prostate gland. The medical imaging data are also employed for model evaluation, thus, demonstrating the potential of the proposed in silico procedure to be utilised pre- and intra-operatively in the clinical setting., 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 Hadjicharalambous, Roussakis, Bourantas, Ioannou, Miller, Doolan, Strouthos, Zamboglou and Vavourakis.)

Background: In the era of personalized cancer treatment, understanding the intrinsic heterogeneity of tumors is crucial. Despite some patients responding favorably to a particular treatment, others may not benefit, leading to the varied efficacy observed in standard therapies. This study focuses on the prediction of tumor response to chemo-immunotherapy, exploring the potential of tumor mechanics and medical imaging as predictive biomarkers. We have extensively studied "desmoplastic" tumors, characterized by a dense and very stiff stroma, which presents a substantial challenge for treatment. The increased stiffness of such tumors can be restored through pharmacological intervention with mechanotherapeutics., Methods: We developed a deep learning methodology based on shear wave elastography (SWE) images, which involved a convolutional neural network (CNN) model enhanced with attention modules. The model was developed and evaluated as a predictive biomarker in the setting of detecting responsive, stable, and non-responsive tumors to chemotherapy, immunotherapy, or the combination, following mechanotherapeutics administration. A dataset of 1365 SWE images was obtained from 630 tumors from our previous experiments and used to train and successfully evaluate our methodology. SWE in combination with deep learning models, has demonstrated promising results in disease diagnosis and tumor classification but their potential for predicting tumor response prior to therapy is not yet fully realized., Results: We present strong evidence that integrating SWE-derived biomarkers with automatic tumor segmentation algorithms enables accurate tumor detection and prediction of therapeutic outcomes., Conclusions: This approach can enhance personalized cancer treatment by providing non-invasive, reliable predictions of therapeutic outcomes., (© 2024. The Author(s).)

Background: Salvage radiation therapy (sRT) is often the sole curative option in patients with biochemical recurrence after radical prostatectomy. After sRT, we developed and validated a nomogram to predict freedom from biochemical failure., Objective: This study aims to evaluate prostate-specific membrane antigen-positron emission tomography (PSMA-PET)-based sRT efficacy for postprostatectomy prostate-specific antigen (PSA) persistence or recurrence. Objectives include developing a random survival forest (RSF) model for predicting biochemical failure, comparing it with a Cox model, and assessing predictive accuracy over time. Multinational cohort data will validate the model's performance, aiming to improve clinical management of recurrent prostate cancer., Methods: This multicenter retrospective study collected data from 13 medical facilities across 5 countries: Germany, Cyprus, Australia, Italy, and Switzerland. A total of 1029 patients who underwent sRT following PSMA-PET-based assessment for PSA persistence or recurrence were included. Patients were treated between July 2013 and June 2020, with clinical decisions guided by PSMA-PET results and contemporary standards. The primary end point was freedom from biochemical failure, defined as 2 consecutive PSA rises >0.2 ng/mL after treatment. Data were divided into training (708 patients), testing (271 patients), and external validation (50 patients) sets for machine learning algorithm development and validation. RSF models were used, with 1000 trees per model, optimizing predictive performance using the Harrell concordance index and Brier score. Statistical analysis used R Statistical Software (R Foundation for Statistical Computing), and ethical approval was obtained from participating institutions., Results: Baseline characteristics of 1029 patients undergoing sRT PSMA-PET-based assessment were analyzed. The median age at sRT was 70 (IQR 64-74) years. PSMA-PET scans revealed local recurrences in 43.9% (430/979) and nodal recurrences in 27.2% (266/979) of patients. Treatment included dose-escalated sRT to pelvic lymphatics in 35.6% (349/979) of cases. The external outlier validation set showed distinct features, including higher rates of positive lymph nodes (47/50, 94% vs 266/979, 27.2% in the learning cohort) and lower delivered sRT doses (<66 Gy in 57/979, 5.8% vs 46/50, 92% of patients; P<.001). The RSF model, validated internally and externally, demonstrated robust predictive performance (Harrell C-index range: 0.54-0.91) across training and validation datasets, outperforming a previously published nomogram., Conclusions: The developed RSF model demonstrates enhanced predictive accuracy, potentially improving patient outcomes and assisting clinicians in making treatment decisions., (©Ali Janbain, Andrea Farolfi, Armelle Guenegou-Arnoux, Louis Romengas, Sophia Scharl, Stefano Fanti, Francesca Serani, Jan C Peeken, Sandrine Katsahian, Iosif Strouthos, Konstantinos Ferentinos, Stefan A Koerber, Marco E Vogel, Stephanie E Combs, Alexis Vrachimis, Alessio Giuseppe Morganti, Simon KB Spohn, Anca-Ligia Grosu, Francesco Ceci, Christoph Henkenberens, Stephanie GC Kroeze, Matthias Guckenberger, Claus Belka, Peter Bartenstein, George Hruby, Louise Emmett, Ali Afshar Omerieh, Nina-Sophie Schmidt-Hegemann, Lucas Mose, Daniel M Aebersold, Constantinos Zamboglou, Thomas Wiegel, Mohamed Shelan. Originally published in JMIR Cancer (https://cancer.jmir.org), 20.09.2024.)

Background: In this work, we compare input level, feature level and decision level data fusion techniques for automatic detection of clinically significant prostate lesions (csPCa)., Methods: Multiple deep learning CNN architectures were developed using the Unet as the baseline. The CNNs use both multiparametric MRI images (T2W, ADC, and High b-value) and quantitative clinical data (prostate specific antigen (PSA), PSA density (PSAD), prostate gland volume & gross tumor volume (GTV)), and only mp-MRI images (n = 118), as input. In addition, co-registered ground truth data from whole mount histopathology images (n = 22) were used as a test set for evaluation., Results: The CNNs achieved for early/intermediate / late level fusion a precision of 0.41/0.51/0.61, recall value of 0.18/0.22/0.25, an average precision of 0.13 / 0.19 / 0.27, and F scores of 0.55/0.67/ 0.76. Dice Sorensen Coefficient (DSC) was used to evaluate the influence of combining mpMRI with parametric clinical data for the detection of csPCa. We compared the DSC between the predictions of CNN's trained with mpMRI and parametric clinical and the CNN's trained with only mpMRI images as input with the ground truth. We obtained a DSC of data 0.30/0.34/0.36 and 0.26/0.33/0.34 respectively. Additionally, we evaluated the influence of each mpMRI input channel for the task of csPCa detection and obtained a DSC of 0.14 / 0.25 / 0.28., Conclusion: The results show that the decision level fusion network performs better for the task of prostate lesion detection. Combining mpMRI data with quantitative clinical data does not show significant differences between these networks (p = 0.26/0.62/0.85). The results show that CNNs trained with all mpMRI data outperform CNNs with less input channels which is consistent with current clinical protocols where the same input is used for PI-RADS lesion scoring., Trial Registration: The trial was registered retrospectively at the German Register for Clinical Studies (DRKS) under proposal number Nr. 476/14 & 476/19., (© 2024. The Author(s).)

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.)

Management of prostate cancer (PC) might be improved by combining external beam radiotherapy (EBRT) and prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with lutetium-177 ( 177 Lu)-labeled PSMA inhibitors. We hypothesized a higher efficacy of the combination due to augmentation of the radiation dose to the tumor and interactions of EBRT with PSMA expression potentially increasing radiopharmaceutical uptake. Therefore, this study analyzed the influence of radiation on PSMA expression levels in vitro . The results were translated to evaluate the efficacy of the combination of photon EBRT and [ 177 Lu]Lu-PSMA-617 in a murine PC xenograft model. Finally, a clinical case report on a combined elective field EBRT with RLT dose escalation illustrates a proof-of-concept. Methods: PSMA gene and protein expression were assessed in human PSMA-overexpressing LNCaP cells after irradiation using reverse transcription quantitative polymerase chain reaction (RT-qPCR), flow cytometry and On-Cell Western assays. In the in vivo therapy study, LNCaP tumor-bearing BALB/c nu/nu mice were irradiated once with 2 Gy X-ray EBRT and injected with 40 MBq [ 177 Lu]Lu-PSMA-617 after 4 h or received single or no treatment (n = 10 each). Tumor-absorbed doses by [ 177 Lu]Lu-PSMA-617 were calculated according to the Medical Internal Radiation Dosimetry (MIRD) formalism after deriving time-activity curves using a gamma probe. An exemplified patient case is demonstrated where fractionated EBRT (54 Gy to prostate; 45 Gy to pelvic lymphatics) and three cycles of [ 177 Lu]Lu-PSMA-617 (3.4-6.0 GBq per cycle) were sequentially combined under concurrent androgen deprivation for treating locally advanced PC. Results: At 4 h following irradiation with 2-8 Gy, LNCaP cells displayed a PSMA protein upregulation by around 18% relative to non-irradiated cells, and a stronger upregulation on mRNA level (up to 2.6-fold). This effect was reversed by 24 h when PSMA protein levels were downregulated by up to 22%. Mice treated with the combination therapy showed significantly improved outcomes regarding tumor control and median survival (p < 0.0001) as compared to single or no treatment. Relative to monotherapy with PSMA-RLT or EBRT, the tumor doubling time was prolonged 1.7- or 2.7-fold and the median survival was extended by 24% or 60% with the combination, respectively. Additionally, tumors treated with EBRT exhibited a 14% higher uptake of the radiopharmaceutical as evident from the calculated tumor-absorbed dose, albeit with high variability in the data. Concerning the patient case, the tri-modality treatment was well tolerated and the patient responded with a long-lasting complete biochemical remission for five years following end of PSMA-RLT. The patient then developed a biochemical relapse with oligo-recurrent disease on follow-up imaging. Conclusion: The present preclinical and clinical data demonstrate that the combination of EBRT with dose escalation by PSMA-RLT improves tumor control and potentially prolongs survival. This may pave the way for further clinical investigations of this approach to explore the curative potential of the combination therapy., Competing Interests: Competing Interests: This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - grant BA 6696/2-1 and DFG - grant 423813989/GRK2606. ME and ACE hold patent rights on PSMA-targeting inhibitors., (© The author(s).)

Introduction: Despite radical prostatectomy (RP) and radiotherapy (RT) being established treatments for localised prostate cancer, a significant number of patients experience recurrent disease. While conventionally fractionated RT is still being used as a standard treatment in the postoperative setting, ultra-hypofractionated RT has emerged as a viable option with encouraging results in patients with localised disease in the primary setting. In addition, recent technological advancements in RT delivery and precise definition of isolated macroscopic recurrence within the prostate bed using prostate-specific membrane antigen-positron emission tomography (PSMA-PET) and multiparametric MRI (mpMRI) allow the exploration of ultra-hypofractionated schedules in the salvage setting using five fractions., Methods and Analysis: In this single-arm prospective phase II multicentre trial, 36 patients with node-negative prostate adenocarcinoma treated with RP at least 6 months before trial registration, tumour stage pT2a-3b, R0-1, pN0 or cN0 according to the UICC TNM 2009 and evidence of measurable local recurrence within the prostate bed detected by PSMA PET/CT and mpMRI within the last 3 months, will be included. The patients will undergo focal ultra-hypofractionated salvage RT with 34 Gy in five fractions every other day to the site of local recurrence in combination with 6 months of androgen deprivation therapy. The primary outcome of this study is biochemical relapse-free survival at 2 years. Secondary outcomes include acute side effects (until 90 days after the end of RT) of grade 3 or higher based on Common Terminology Criteria for Adverse Events V.5, progression-free survival, metastasis-free survival, late side effects and the quality of life (based on European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, QLQ-PR25)., Ethics and Dissemination: The study has received ethical approval from the Ethics Commission of the Canton of Bern (KEK-BE 2022-01026). Academic dissemination will occur through publications and conference presentations., Trial Registration Number: NCT05746806., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose/objectives: Auto-segmentation with artificial intelligence (AI) offers an opportunity to reduce inter- and intra-observer variability in contouring, to improve the quality of contours, as well as to reduce the time taken to conduct this manual task. In this work we benchmark the AI auto-segmentation contours produced by five commercial vendors against a common dataset., Methods and Materials: The organ at risk (OAR) contours generated by five commercial AI auto-segmentation solutions (Mirada (Mir), MVision (MV), Radformation (Rad), RayStation (Ray) and TheraPanacea (Ther)) were compared to manually-drawn expert contours from 20 breast, 20 head and neck, 20 lung and 20 prostate patients. Comparisons were made using geometric similarity metrics including volumetric and surface Dice similarity coefficient (vDSC and sDSC), Hausdorff distance (HD) and Added Path Length (APL). To assess the time saved, the time taken to manually draw the expert contours, as well as the time to correct the AI contours, were recorded., Results: There are differences in the number of CT contours offered by each AI auto-segmentation solution at the time of the study (Mir 99; MV 143; Rad 83; Ray 67; Ther 86), with all offering contours of some lymph node levels as well as OARs. Averaged across all structures, the median vDSCs were good for all systems and compared favorably with existing literature: Mir 0.82; MV 0.88; Rad 0.86; Ray 0.87; Ther 0.88. All systems offer substantial time savings, ranging between: breast 14-20 mins; head and neck 74-93 mins; lung 20-26 mins; prostate 35-42 mins. The time saved, averaged across all structures, was similar for all systems: Mir 39.8 mins; MV 43.6 mins; Rad 36.6 min; Ray 43.2 mins; Ther 45.2 mins., Conclusions: All five commercial AI auto-segmentation solutions evaluated in this work offer high quality contours in significantly reduced time compared to manual contouring, and could be used to render the radiotherapy workflow more efficient and standardized., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Doolan, Charalambous, Roussakis, Leczynski, Peratikou, Benjamin, Ferentinos, Strouthos, Zamboglou and Karagiannis.)

Background: Statins are widely used due to their ability to lower plasma cholesterol and offer protection from the effects of atherosclerosis. However, their role in urology and specifically bladder cancer remains unclear. We aimed to systematically address this issue in the literature and determine any possible effects of statin therapy on bladder cancer., Methods: We searched MEDLINE (PubMed) and Cochrane Library databases for records up to 26 March 2023, for studies evaluating the effects of statins on urinary bladder cancer (UBC). We included all randomized controlled trials (RCTs), cohorts, and case-control studies that were conducted on the adult population. PROSPERO registration number: CRD42023407795., Results: Database searches returned 2251 reports, and after thorough investigation and assessment for eligibility, 32 reports were included in the analysis. Of them, 4 were RCTs, 6 were case-control studies, and 22 were cohort studies. Our qualitative analysis demonstrated no association between statin administration and UBC local control, recurrence, survival, or mortality, or between statin administration and bacille Calmette-Guérin (BCG) immunotherapy effectiveness. A meta-analysis of 10 trials revealed a non-significant reduction of 11% in UBC risk among users compared with non-users in RCTs (RR: 0.89, 95% CI 0.68-1.16, p = 0.37) and a non-significant increase of 32% of UBC risk among statin users compared with non-users in the analysis of the cohort studies (RR: 1.32, 95% CI 0.76-2.30, p = 0.33)., Conclusions: Our results provide strong evidence to support the neutral effect of statins on UBC local control, recurrence, survival, and mortality, and on BCG immunotherapy. Our meta-analysis revealed a non-significant effect on UBC risk among statin users when compared with non-users, indicating no statin effect on UBC incidence and overall prognosis.

In healthcare, a growing number of physicians and support staff are striving to facilitate personalized radiotherapy regimens for patients with prostate cancer. This is because individual patient biology is unique, and employing a single approach for all is inefficient. A crucial step for customizing radiotherapy planning and gaining fundamental information about the disease, is the identification and delineation of targeted structures. However, accurate biomedical image segmentation is time-consuming, requires considerable experience and is prone to observer variability. In the past decade, the use of deep learning models has significantly increased in the field of medical image segmentation. At present, a vast number of anatomical structures can be demarcated on a clinician's level with deep learning models. These models would not only unload work, but they can offer unbiased characterization of the disease. The main architectures used in segmentation are the U-Net and its variants, that exhibit outstanding performances. However, reproducing results or directly comparing methods is often limited by closed source of data and the large heterogeneity among medical images. With this in mind, our intention is to provide a reliable source for assessing deep learning models. As an example, we chose the challenging task of delineating the prostate gland in multi-modal images. First, this paper provides a comprehensive review of current state-of-the-art convolutional neural networks for 3D prostate segmentation. Second, utilizing public and in-house CT and MR datasets of varying properties, we created a framework for an objective comparison of automatic prostate segmentation algorithms. The framework was used for rigorous evaluations of the models, highlighting their strengths and weaknesses., 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 Ltd.. All rights reserved.)

Importance: Prostate-specific antigen membrane positron-emission tomography (PSMA-PET) is increasingly used to guide salvage radiotherapy (sRT) after radical prostatectomy for patients with recurrent or persistent prostate cancer., Objective: To develop and validate a nomogram for prediction of freedom from biochemical failure (FFBF) after PSMA-PET-based sRT., Design, Setting, and Participants: This retrospective cohort study included 1029 patients with prostate cancer treated between July 1, 2013, and June 30, 2020, at 11 centers from 5 countries. The initial database consisted of 1221 patients. All patients had a PSMA-PET scan prior to sRT. Data were analyzed in November 2022., Exposures: Patients with a detectable post-radical prostatectomy prostate-specific antigen (PSA) level treated with sRT to the prostatic fossa with or without additional sRT to pelvic lymphatics or concurrent androgen deprivation therapy (ADT) were eligible., Main Outcomes and Measures: The FFBF rate was estimated, and a predictive nomogram was generated and validated. Biochemical relapse was defined as a PSA nadir of 0.2 ng/mL after sRT., Results: In the nomogram creation and validation process, 1029 patients (median age at sRT, 70 years [IQR, 64-74 years]) were included and further divided into a training set (n = 708), internal validation set (n = 271), and external outlier validation set (n = 50). The median follow-up was 32 months (IQR, 21-45 months). Based on the PSMA-PET scan prior to sRT, 437 patients (42.5%) had local recurrences and 313 patients (30.4%) had nodal recurrences. Pelvic lymphatics were electively irradiated for 395 patients (38.4%). All patients received sRT to the prostatic fossa: 103 (10.0%) received a dose of less than 66 Gy, 551 (53.5%) received a dose of 66 to 70 Gy, and 375 (36.5%) received a dose of more than 70 Gy. Androgen deprivation therapy was given to 325 (31.6%) patients. On multivariable Cox proportional hazards regression analysis, pre-sRT PSA level (hazard ratio [HR], 1.80 [95% CI, 1.41-2.31]), International Society of Urological Pathology grade in surgery specimen (grade 5 vs 1+2: HR, 2.39 [95% CI, 1.63-3.50], pT stage (pT3b+pT4 vs pT2: HR, 1.91 [95% CI, 1.39-2.67]), surgical margins (R0 vs R1+R2+Rx: HR, 0.60 [95% CI, 0.48-0.78]), ADT use (HR, 0.49 [95% CI, 0.37-0.65]), sRT dose (>70 vs ≤66 Gy: HR, 0.44 [95% CI, 0.29-0.67]), and nodal recurrence detected on PSMA-PET scans (HR, 1.42 [95% CI, 1.09-1.85]) were associated with FFBF. The mean (SD) nomogram concordance index for FFBF was 0.72 (0.06) for the internal validation cohort and 0.67 (0.11) in the external outlier validation cohort., Conclusions and Relevance: This cohort study of patients with prostate cancer presents an internally and externally validated nomogram that estimated individual patient outcomes after PSMA-PET-guided sRT.

Importance: The number of older adults with head and neck squamous cell carcinoma (HNSCC) is increasing, and these patients are underrepresented in clinical trials. It is unclear whether the addition of chemotherapy or cetuximab to radiotherapy is associated with improved survival in older adults with HNSCC., Objective: To examine whether the addition of chemotherapy or cetuximab to definitive radiotherapy is associated with improved survival in patients with locoregionally advanced (LA) HNSCC., Design, Setting, and Participants: The Special Care Patterns for Elderly HNSCC Patients Undergoing Radiotherapy (SENIOR) study is an international, multicenter cohort study including older adults (≥65 years) with LA-HNSCCs of the oral cavity, oropharynx/hypopharynx, or larynx treated with definitive radiotherapy, either alone or with concomitant systemic treatment, between January 2005 and December 2019 at 12 academic centers in the US and Europe. Data analysis was conducted from June 4 to August 10, 2022., Interventions: All patients underwent definitive radiotherapy alone or with concomitant systemic treatment., Main Outcomes and Measures: The primary outcome was overall survival. Secondary outcomes included progression-free survival and locoregional failure rate., Results: Among the 1044 patients (734 men [70.3%]; median [IQR] age, 73 [69-78] years) included in this study, 234 patients (22.4%) were treated with radiotherapy alone and 810 patients (77.6%) received concomitant systemic treatment with chemotherapy (677 [64.8%]) or cetuximab (133 [12.7%]). Using inverse probability weighting to attribute for selection bias, chemoradiation was associated with longer overall survival than radiotherapy alone (hazard ratio [HR], 0.61; 95% CI, 0.48-0.77; P < .001), whereas cetuximab-based bioradiotherapy was not (HR, 0.94; 95% CI, 0.70-1.27; P = .70). Progression-free survival was also longer after the addition of chemotherapy (HR, 0.65; 95% CI, 0.52-0.81; P < .001), while the locoregional failure rate was not significantly different (subhazard ratio, 0.62; 95% CI, 0.30-1.26; P = .19). The survival benefit of the chemoradiation group was present in patients up to age 80 years (65-69 years: HR, 0.52; 95% CI, 0.33-0.82; 70-79 years: HR, 0.60; 95% CI, 0.43-0.85), but was absent in patients aged 80 years or older (HR, 0.89; 95% CI, 0.56-1.41)., Conclusions and Relevance: In this cohort study of older adults with LA- HNSCC, chemoradiation, but not cetuximab-based bioradiotherapy, was associated with longer survival compared with radiotherapy alone.

Background and Purpose: Tumor-infiltrating lymphocytes (TILs) are associated with locoregional control (LRC) in head-and-neck squamous cell carcinoma (HNSCC) patients undergoing (chemo)radiotherapy. As immunosenescence results in reduced immune activity, the role of TILs in elderly HNSCC patients may differ compared to younger patients, providing a rationale to study the prognostic role of TILs and immune checkpoints (ICs) in this population., Material and Methods: Sixty-three HNSCC patients aged ≥ 65 years undergoing definitive (chemo)radiotherapy between 2010 and 2019 with sufficient material from pre-treatment biopsies were included in the analysis. Immunohistochemical stainings of CD3, CD4, CD8, PD-L1, TIM3, LAG3, TIGIT and CD96, and of osteopontin as an immunosenescence-associated protein were performed. Overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan-Meier method, and Fine-Gray's models were used for locoregional failure (LRF) analyses., Results: While there was no correlation between patient age and IC expression, osteopontin levels correlated with increasing age (r = 0.322, p < 0.05). Two-year OS, PFS, and LRC were 44%, 34%, and 71%, respectively. Increased LAG3 expression, both intraepithelial (SHR = 0.33, p < 0.05) and stromal (SHR = 0.38, p < 0.05), and elevated stromal TIM3 expression (SHR = 0.32, p < 0.05) corresponded with reduced LRFs. Absent tumoral PD-L1 expression (TPS = 0%) was associated with more LRFs (SHR = 0.28, p < 0.05). There was a trend towards improved LRF rates in elderly patients with increased intraepithelial CD3 + (SHR = 0.52, p = 0.07) and CD8 + (SHR = 0.52, p = 0.09) TIL levels., Conclusion: LAG3, TIM3 and TPS are promising biomarkers in elderly HNSCC patients receiving (chemo)radiotherapy. Considering the frequency of non-cancer related deaths in this population, the prognostic value of these biomarkers primarily relates to LRC., (© 2022. The Author(s).)

Backround: Accurate surrogate parameters for radio resistance are warranted for individualized radiotherapy (RT) concepts in prostate cancer (PCa). The purpose of this study was to assess intertumoral heterogeneity in terms of radio resistance using an ex-vivo γH2AX assay after irradiation of prostate biopsy cores and to investigate its correlation with clinical features of respective patients as well as imaging and genomic features of tumor areas., Methods: Twenty one patients with histologically-proven PCa and pre-therapeutic multiparametric resonance imaging and prostate-specific membrane antigen positron emission tomography were included in the study. Biopsy cores were collected from 26 PCa foci. Residual γH2AX foci were counted 24 h after ex-vivo irradiation (with 0 and 4 Gy) of biopsy specimen and served as a surrogate for radio resistance. Clinical, genomic (next generation sequencing) and imaging features were collected and their association with the radio resistance was studied., Results: In total 18 PCa lesions from 16 patients were included in the final analysis. The median γH2AX foci value per PCa lesion was 3.12. According to this, the patients were divided into two groups (radio sensitive vs. radio resistant) with significant differences in foci number (p < 0.0001). The patients in the radio sensitive group had significantly higher prostate specific antigen serum concentration (p = 0.015), tumor areas in the radio sensitive group had higher SUV (standardized uptake values in PSMA PET)-max and -mean values (p = 0.0037, p = 0.028) and lower ADC (apparent diffusion coefficient-mean values, p = 0.049). All later parameters had significant (p < 0.05) correlations in Pearson's test. One patient in the radio sensitive group displayed a previously not reported loss of function frameshift mutation in the NBN gene (c.654&#95;658delAAAAC) that introduces a premature termination codon and results in a truncated protein., Conclusion: In this pilot study, significant differences in intertumoral radio resistance were observed and clinical as well as imaging parameters may be applied for their prediction. After further prospective validation in larger patient cohorts these finding may lead to individual RT dose prescription for PCa patients in the future., (© 2022. The Author(s).)

Background: Accompanied by the demographic change, the number of octogenarian cancer patients with bone metastases will increase in the future. Palliative radiotherapy constitutes an effective analgesic treatment; however, as pain perception and bone metabolism change with increasing age, the analgesic efficacy of radiotherapy may be altered in elderly patients. We therefore investigated the treatment outcomes of palliative radiotherapy for bone metastases in octogenarians., Methods: Patients between 80 and 89 years undergoing radiotherapy for bone metastases between 2009 and 2019 at a tertiary cancer center were analyzed for patterns-of-care, pain response and overall survival (OS). Logistic regression analyses were carried out to examine parameters associated with pain response, and Cox analyses were conducted to reveal prognostic parameters for OS., Results: A total of 288 patients with 516 irradiated lesions were included in the analysis. The majority (n = 249, 86%) completed all courses of radiotherapy. Radiotherapy led to pain reduction in 176 patients (61%) at the end of treatment. Complete pain relief at the first follow-up was achieved in 84 patients (29%). Bisphosphonate administration was significantly associated with higher rates of pain response at the first follow-up (p < 0.05). Median OS amounted to 9 months, and 1-year, 2-year and 3-year OS were 43%, 28% and 17%. In the multivariate analysis, ECOG (p < 0.001), Mizumoto score (p < 0.01) and Spinal Instability Neoplastic Score (SINS) (p < 0.001) were independent prognosticators for OS., Conclusion: Palliative radiotherapy for bone metastases constitutes a feasible and effective analgesic treatment in octogenarian patients. ECOG, Mizumoto score and SINS are prognosic variables for survival and may aid treatment decisions regarding radiotherapy fractionation in this patient group. Single-fraction radiotherapy with 8 Gy should be applied for patients with uncomplicated bone metastases and poor prognosis. Prospective trials focusing on quality of life of these very old cancer patients with bone metastases are warranted to reveal the optimal radiotherapeutic management for this vulnerable population., (© 2022. The Author(s).)

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.)

Automatic prostate tumor segmentation is often unable to identify the lesion even if multi-parametric MRI data is used as input, and the segmentation output is difficult to verify due to the lack of clinically established ground truth images. In this work we use an explainable deep learning model to interpret the predictions of a convolutional neural network (CNN) for prostate tumor segmentation. The CNN uses a U-Net architecture which was trained on multi-parametric MRI data from 122 patients to automatically segment the prostate gland and prostate tumor lesions. In addition, co-registered ground truth data from whole mount histopathology images were available in 15 patients that were used as a test set during CNN testing. To be able to interpret the segmentation results of the CNN, heat maps were generated using the Gradient Weighted Class Activation Map (Grad-CAM) method. The CNN achieved a mean Dice Sorensen Coefficient 0.62 and 0.31 for the prostate gland and the tumor lesions -with the radiologist drawn ground truth and 0.32 with whole-mount histology ground truth for tumor lesions. Dice Sorensen Coefficient between CNN predictions and manual segmentations from MRI and histology data were not significantly different. In the prostate the Grad-CAM heat maps could differentiate between tumor and healthy prostate tissue, which indicates that the image information in the tumor was essential for the CNN segmentation., (© 2022. The Author(s).)

Objectives: The number of elderly head-and-neck squamous cell carcinoma (HNSCC) patients is increasing, and clinical trials defining the standard of care either excluded or underrepresented elderly patients. This leaves physicians with a challenging and highly individual treatment decision largely lacking clinical evidence., Methods: A tri-national patterns-of-care survey was sent to all members of the German (DEGRO), Austrian (ÖGRO), and Swiss (SRO/SSRO) national societies of radiation oncology. The online questionnaire consisted of 27 questions on the treatment of elderly HNSCC patients, including 6 case-based questions. Frequency distributions and subgroup comparisons were calculated using SPSS statistics software., Results: A total of 132 answers were collected, including 46(35%) form universities, 52(39%) from non-university-hospitals and 34(26%) from private practices. 83(63%) treat 1-5 and 42(32%) >5 elderly HNSCC patients per month. Target volumes are defined analog current guidelines by 65(50%) of responders and altered based on age/comorbidities or tumor stage by 36(28%) and 28(22%), respectively. Chemotherapy is routinely administered by 108(84%) if indicated, with weekly 40mg/m 2 of cisplatin being the favored regimen by 68(53%) in the definitive situation and 60(47%) in the adjuvant setting. Hypofractionation and hyperfractionation/acceleration are used by 26(20%) and 11(9%), respectively. Only 7(5%) clinicians routinely recommend inpatient treatment for elderly HNSCC patients. In a typical definitive patient case, 73(63%) responders recommended chemoradiation with bilateral elective node irradiation analog current guidelines. In an adjuvant example case recommendations regarding elective volume and chemotherapy were heterogeneous. Differences between responders' institutions concern the frequency of PET-CT in staging, preventive port-catheter and PEG implantation, the choice of chemotherapy regimens and the use of alternative fractionations., Conclusion: Treatment of elderly HNSCC-patients in the German-speaking countries mainly follows guidelines established for younger patients. Algorithms for patient stratification and treatment de-escalation for "unfit" elderly patients are needed., 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 Haehl, Rühle, Spohn, Sprave, Gkika, Zamboglou, Grosu and Nicolay.)

Technical advances in radiotherapy (RT) treatment planning and delivery have substantially changed RT concepts for primary prostate cancer (PCa) by (i) enabling a reduction of treatment time, and by (ii) enabling safe delivery of high RT doses. Several studies proposed a dose-response relationship for patients with primary PCa and especially in patients with high-risk features, as dose escalation leads to improved tumor control. In parallel to the improvements in RT techniques, diagnostic imaging techniques like multiparametric magnetic resonance imaging (mpMRI) and positron-emission tomography targeting prostate-specific-membrane antigen (PSMA-PET) evolved and enable an accurate depiction of the intraprostatic tumor mass for the first time. The HypoFocal-SBRT study combines ultra-hypofractionated RT/stereotactic body RT, with focal RT dose escalation on intraprostatic tumor sides by applying state of the art diagnostic imaging and most modern RT concepts. This novel strategy will be compared with moderate hypofractionated RT (MHRT), one option for the curative primary treatment of PCa, which has been proven by several prospective trials and is recommended and carried out worldwide. We suspect an increase in relapse-free survival (RFS), and we will assess quality of life in order to detect potential changes.

The effects of radiotherapy on systemic immunity remain to be fully characterized in a disease-specific manner. The aim of the study was to examine potential biomarkers of systemic immunomodulation when using radiotherapy for thoracic malignancies. Serial blood samples were collected from 56 patients with thoracic malignancies prior (RTbaseline), during (RTduring) and at the end of radiotherapy (RTend), as well as at the first (FU1) and second follow-up (FU2). The changes in serum levels of IL-10, IFN-γ, IL-12p70, IL-13, IL-1β, IL-4, IL-6, IL-8, TNF-α, bFGF, sFlt-1, PlGF, VEGF, VEGF-C, VEGF-D and HGF were measured by multiplexed array and tested for associations with clinical outcomes. We observed an increase in the levels of IL-10, IFN-γ, PlGF and VEGF-D and a decrease in those of IL-8, VEGF, VEGF-C and sFlt-1 during and at the end of radiotherapy. Furthermore, baseline concentration of TNF-α significantly correlated with OS. IL-6 level at RTend and FU1,2 correlated with OS (RTend: p = 0.039, HR: 1.041, 95% CI: 1.002-1.082, FU1: p = 0.001, HR: 1.139, 95% CI: 1.056-1.228, FU2: p = 0.017, HR: 1.101 95% CI: 1.018-1.192), while IL-8 level correlated with OS at RTduring and RTend (RTduring: p = 0.017, HR: 1.014, 95% CI: 1.002-1.026, RTend: p = 0.004, HR: 1.007, 95% CI: 1.061-1.686). In conclusion, serum levels of TNF-α, IL-6 and IL-8 are potential biomarkers of response to radiotherapy. Given the recent implementation of immunotherapy in lung and esophageal cancer, these putative blood biomarkers should be further validated and evaluated in the combination or sequential therapy setting.

Introduction: 68Ga-PSMA PET/CT is associated with unprecedented sensitivity for localization of biochemically recurrent prostate cancer at low PSA levels prior to radiotherapy. Aim of the present analysis is to examine whether patients undergoing postoperative, salvage radiotherapy (sRT) of the prostatic fossa with no known nodal or distant metastases on conventional imaging (CT and/or MRI) and on positron emission tomography/computed tomography (68Ga-PSMA PET/CT) will have an improved biochemical recurrence-free survival (BRFS) compared to patients with no known nodal or distant metastases on conventional imaging only., Material and Methods: This retrospective analysis is based on 459 patients (95 with and 364 without 68Ga-PSMA PET/CT). BRFS (PSA < post-sRT Nadir + 0.2 ng/ml) was the primary study endpoint. This was first analysed by Kaplan-Meier and uni- and multivariate Cox regression analysis for the entire cohort and then again after matched-pair analysis using tumor stage, Gleason score, PSA at time of sRT and radiation dose as matching parameters., Results: Median follow-up was 77.5 months for patients without and 33 months for patients with 68Ga-PSMA PET/CT. For the entire cohort, tumor stage (pT2 vs. pT3-4; p= <0.001), Gleason score (GS ≤ 7 vs. GS8-10; p=0.003), pre-sRT PSA (<0.5 vs. ≥0.5ng/ml; p<0.001) and sRT dose (<70 vs. ≥70Gy; p<0.001) were the only factors significantly associated with improved BRFS. This was not seen for the use of 68Ga-PSMA PET/CT prior to sRT (p=0.789). Matched-pair analysis consisted of 95 pairs of PCa patients with or without PET/CT and no significant difference in BRFS based on the use of PET/CT was evident (p=0.884)., Conclusion: This analysis did not show an improvement in BRFS using 68Ga-PSMA PET/CT prior to sRT neither for the entire cohort nor after matched-pair analysis after excluding patients with PET-positive lymph node or distant metastases a priori. As no improved BRFS resulted with implementation of 68Ga-PSMA PET in sRT planning, sRT should not be deferred until the best "diagnostic window" for 68Ga-PSMA PET/CT., 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 Schmidt-Hegemann, Zamboglou, Thamm, Eze, Kirste, Spohn, Li, Stief, Bolenz, Schultze-Seemann, Bartenstein, Prasad, Ganswindt, Grosu, Belka, Mayer and Wiegel.)

Tumor hypoxia is associated with radiation resistance and can be longitudinally monitored by 18 F-fluoromisonidazole ( 18 F-FMISO)-PET/CT. Our study aimed at evaluating radiomics dynamics of 18 F-FMISO-hypoxia imaging during chemo-radiotherapy (CRT) as predictors for treatment outcome in head-and-neck squamous cell carcinoma (HNSCC) patients. We prospectively recruited 35 HNSCC patients undergoing definitive CRT and longitudinal 18 F-FMISO-PET/CT scans at weeks 0, 2 and 5 (W0/W2/W5). Patients were classified based on peritherapeutic variations of the hypoxic sub-volume (HSV) size (increasing/stable/decreasing) and location (geographically-static/geographically-dynamic) by a new objective classification parameter (CP) accounting for spatial overlap. Additionally, 130 radiomic features (RF) were extracted from HSV at W0, and their variations during CRT were quantified by relative deviations (∆ RF ). Prediction of treatment outcome was considered statistically relevant after being corrected for multiple testing and confirmed for the two 18 F-FMISO-PET/CT time-points and for a validation cohort. HSV decreased in 64% of patients at W2 and in 80% at W5. CP distinguished earlier disease progression (geographically-dynamic) from later disease progression (geographically-static) in both time-points and cohorts. The texture feature low grey-level zone emphasis predicted local recurrence with AUC W2 = 0.82 and AUC W5 = 0.81 in initial cohort ( N = 25) and AUC W2 = 0.79 and AUC W5 = 0.80 in validation cohort. Radiomics analysis of 18 F-FMISO-derived hypoxia dynamics was able to predict outcome of HNSCC patients after CRT.

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies of men in the world. Due to a variety of treatment options in different risk groups, proper diagnostic and risk stratification is pivotal in treatment of PCa. The development of precise medical imaging procedures simultaneously to improvements in big data analysis has led to the establishment of radiomics - a computer-based method of extracting and analyzing image features quantitatively. This approach bears the potential to assess and improve PCa detection, tissue characterization and clinical outcome prediction. This article gives an overview on the current aspects of methodology and systematically reviews available literature on radiomics in PCa patients, showing its potential for personalized therapy approaches. The qualitative synthesis includes all imaging modalities and focuses on validated studies, putting forward future directions., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: To examine treatment patterns, oncological outcomes and toxicity rates in elderly patients receiving radiotherapy for cutaneous squamous cell carcinoma (cSCC) of the head-and-neck region., Material and Methods: In this retrospective single-center analysis, locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) of elderly patients > 65 years with cSCC of the head-and-neck region undergoing radiotherapy between 2010 and 2019 were calculated. The prognostic value of clinicopathological parameters on radiotherapy outcomes was analyzed using the Cox proportional hazards model. In addition, both acute and chronic toxicities were retrospectively quantified according to CTCAE version 5.0., Results: A total of 69 elderly patients with cSCC of the head-and-neck region with a median age of 85 years were included in this analysis, of whom 21.7% (15 patients) presented with nodal disease. The majority of patients exhibited a good performance status, indicated by a median Karnofsky performance status (KPS) and Charlson Comorbidity Index (CCI) of 80% and 6 points, respectively. Radiotherapy was administered as primary (48%), adjuvant (32%) or palliative therapy (20%). 55 patients (79.7%) completed treatment and received the scheduled radiotherapy dose. Median EQD2 radiation doses were 58.4 Gy, 60 Gy and 51.3 Gy in the definitive, adjuvant and palliative situation, respectively. 2-year LRC, PFS and OS ranged at 54.2%, 33.5 and 40.7%, respectively. Survival differed significantly between age groups with a median OS of 20 vs. 12 months (p < 0.05) for patients aged 65-80 or above 80 years. In the multivariate analysis, positive lymph node status remained the only significant prognostic factor deteriorating OS (HR 3.73, CI 1.54-9.03, p < 0.01). Interestingly, neither KPS nor CCI impaired survival in this elderly patient cohort. Only 3 patients (4.3%) experienced acute CTCAE grade 3 toxicities, and no chronic CTCAE grade 2-5 toxicities were observed in our cohort., Conclusion: Radiotherapy was feasible and well-tolerated in this distinct population, showing the general feasibility of radiotherapy for cSCC of the head-and-neck region also in the older and oldest olds. The very mild toxicities may allow for moderate dose escalation to improve LRC.

Accurate delineation of the intraprostatic gross tumor volume (GTV) is a prerequisite for treatment approaches in patients with primary prostate cancer (PCa). Prostate-specific membrane antigen PET (PSMA PET) may outperform MRI in GTV detection. However, visual GTV delineation underlies interobserver heterogeneity and is time consuming. The aim of this study was to develop a convolutional neural network (CNN) for automated segmentation of intraprostatic tumor (GTV-CNN) in PSMA PET. Methods: The CNN (3D U-Net) was trained on the 68 Ga-PSMA PET images of 152 patients from 2 different institutions, and the training labels were generated manually using a validated technique. The CNN was tested on 2 independent internal (cohort 1: 68 Ga-PSMA PET, n = 18 and cohort 2: 18 F-PSMA PET, n = 19) and 1 external (cohort 3: 68 Ga-PSMA PET, n = 20) test datasets. Accordance between manual contours and GTV-CNN was assessed with the Dice-Sørensen coefficient (DSC). Sensitivity and specificity were calculated for the 2 internal test datasets (cohort 1: n = 18, cohort 2: n = 11) using whole-mount histology. Results: The median DSCs for cohorts 1-3 were 0.84 (range: 0.32-0.95), 0.81 (range: 0.28-0.93), and 0.83 (range: 0.32-0.93), respectively. Sensitivities and specificities for the GTV-CNN were comparable with manual expert contours: 0.98 and 0.76 (cohort 1) and 1 and 0.57 (cohort 2), respectively. Computation time was around 6 s for a standard dataset. Conclusion: The application of a CNN for automated contouring of intraprostatic GTV in 68 Ga-PSMA and 18 F-PSMA PET images resulted in a high concordance with expert contours and in high sensitivities and specificities in comparison with histology as a reference. This robust, accurate and fast technique may be implemented for treatment concepts in primary prostate cancer. The trained model and the study's source code are available in an open source repository., (COPYRIGHT © 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

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.)

Background: In case of oligo-recurrent prostate cancer (PC) following prostatectomy, 68 Ga-PSMA-PET/CT can be used to detect a specific site of recurrence and to initiate metastasis-directed radiation therapy (MDT). However, large heterogeneities exist concerning doses, treatment fields and radiation techniques, with some studies reporting focal radiotherapy (RT) to PSMA-PET/CT positive lesions only and other studies using elective RT strategies. We aimed to compare oncological outcomes and toxicity between PET/CT-directed RT (PDRT) and PDRT plus elective RT (eRT; i.e. prostate bed, pelvic or paraaortal nodes) in a large retrospective multicenter study., Methods: Data of 394 patients with oligo-recurrent 68 Ga-PSMA-PET/CT-positive PC treated between 04/2013 and 01/2018 in six different academic institutions were evaluated. Primary endpoint was biochemical-recurrence-free survival (bRFS). bRFS was analyzed using Kaplan-Meier survival curves and log rank testing. Uni- and multivariate analyses were performed to determine influence of treatment parameters., Results: In 204 patients (51.8%) RT was directed only to lesions seen on 68 Ga-PSMA-PET/CT (PDRT), 190 patients (48.2%) received PDRT plus eRT. PDRT plus eRT was associated with a significantly improved 3-year bRFS compared to PDRT alone (53 vs. 37%; p = 0.001) and remained an independent factor in multivariate analysis (p = 0.006, HR 0.29, 95% CI 0.12-0.68). This effect was more pronounced in the subgroup of patients who were treated with PDRT and elective prostate bed radiotherapy (ePBRT) with a 3-year bRFS of 61% versus 22% (p <0.001). Acute and late toxicity grade ≥3 was 0.8% and 3% after PDRT plus eRT versus no toxicity grade ≥3 after PDRT alone., Conclusions: In this large cohort of patients with oligo-recurrent prostate cancer, elective irradiation of the pelvic lymphatics and the prostatic bed significantly improved bRFS when added to 68 Ga-PSMA-PET/CT-guided focal radiotherapy. These findings need to be evaluated in a randomized controlled trial., 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 Kirste, Kroeze, Henkenberens, Schmidt-Hegemann, Vogel, Becker, Zamboglou, Burger, Derlin, Bartenstein, Ruf, la Fougère, Eiber, Christiansen, Combs, Müller, Belka, Guckenberger and Grosu.)

The effects of radiotherapy on the long-term quality of life (QoL) of surviving elderly HNSCC patients are not well understood, therefore, we analyzed QoL in this population. A cross-sectional analysis was performed at a tertiary cancer center to assess long-term QoL in elderly HNSCC patients. Eligible patients were ≥65 years at the time of treatment who had to be alive for ≥1 year after radiotherapy and without current anti-cancer treatment. QoL and patient satisfaction were assessed using the EORTC QLQ-C30, QLQ-H&N35 and ZUF-8 questionnaires, respectively, and treatment-related toxicities were graded according to CTCAE (Common Terminology Criteria of Adverse Effects) v.5.0. Seventy-four patients met the inclusion criteria, of which 50 consented to participate. Median time between radiotherapy and QoL assessment was 32 months (range 12-113). The QLQ-C30 global QoL median amounted to 66.7 points (interquartile range (IQR) 50.0-83.3), which was comparable to the age- and gender-adjusted German population (median 65.3). Median global QoL was similar between patients undergoing definitive (75.0, IQR 50.0-83.3) and adjuvant (chemo)radiotherapy (66.7, IQR 41.7-83.3, p = 0.219). HPV-positive HNSCC patients had superior global QoL after radiotherapy than their HPV-negative counterparts ( p < 0.05), and concomitant chemotherapy did not influence the long-term QoL ( p = 0.966). Median global QoL did not correspond with physician-assessed highest-graded chronic toxicities ( p = 0.640). The ZUF-8 ranged at 29 points in median (IQR 27-31), showing high patient satisfaction. Surviving elderly HNSCC patients treated by radiotherapy exhibit a relatively high long-term global QoL which is a relevant information for clinicians treating elderly HNSCC patients.

Comparison studies using histopathology as standard of reference enable a validation of the diagnostic performance of imaging methods. This study analysed (1) the impact of different image-histopathology co-registration pathways, (2) the impact of the applied data analysis method and (3) intraindividually compared multiparametric magnet resonance tomography (mpMRI) and prostate specific membrane antigen positron emission tomography (PSMA-PET) by using the different approaches. Ten patients with primary PCa who underwent mpMRI and [ 18 F]PSMA-1007 PET/CT followed by prostatectomy were prospectively enrolled. We demonstrate that the choice of the intermediate registration step [(1) via ex-vivo CT or (2) mpMRI] does not significantly affect the performance of the registration framework. Comparison of analysis methods revealed that methods using high spatial resolutions e.g. quadrant-based slice-by-slice analysis are beneficial for a differentiated analysis of performance, compared to methods with a lower resolution (segment-based analysis with 6 or 18 segments and lesions-based analysis). Furthermore, PSMA-PET outperformed mpMRI for intraprostatic PCa detection in terms of sensitivity (median %: 83-85 vs. 60-69, p < 0.04) with similar specificity (median %: 74-93.8 vs. 100) using both registration pathways. To conclude, the choice of an intermediate registration pathway does not significantly affect registration performance, analysis methods with high spatial resolution are preferable and PSMA-PET outperformed mpMRI in terms of sensitivity in our cohort.

Background: Radiotherapy (RT) is an established, potentially curative treatment option for all risk constellations of localized prostate cancer (PCA). Androgen deprivation therapy (ADT) and dose-escalated RT can further improve outcome in high-risk (HR) PCA. In recent years, shorter RT schedules based on hypofractionated RT have shown equal outcome. Stereotactic body radiotherapy (SBRT) is a highly conformal RT technique enabling ultra-hypofractionation which has been shown to be safe and efficient in patients with low- and intermediate-risk PCA. There is a paucity of data on the role of SBRT in HR PCA. In particular, the need for pelvic elective nodal irradiation (ENI) needs to be addressed. Therefore, we conducted a systematic review to analyze the available data on observed toxicities, ADT prescription practice, and oncological outcome to shed more light on the value of SBRT in HR PCA., Methods: We searched the PubMed and Embase electronic databases for the terms "prostate cancer" AND "stereotactic" AND "radiotherapy" in June 2020. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations., Results: After a rigorous selection process, we identified 18 individual studies meeting all selection criteria for further analyses. Five additional studies were included because their content was judged as relevant. Three trials have reported on prostate SBRT including pelvic nodes; 2 with ENI and 1 with positive pelvic nodes only. The remaining studies investigated SBRT of the prostate only. Grade 2+ acute genitourinary (GU) toxicity was between 12% and 46.7% in the studies investigating pelvic nodes irradiation and ranged from 0% to 89% in the prostate only studies. Grade 2+ chronic GU toxicity was between 7% and 60% vs. 2% and 56.7%. Acute gastrointestinal (GI) grade 2+ toxicity was between 0% to 4% and 0% to 18% for studies with and without pelvic nodes irradiation, respectively. Chronic GI grade 2+ toxicity rates were between 4% and 50.1% vs. 0% and 40%. SBRT of prostate and positive pelvic nodes only showed similar toxicity rates as SBRT for the prostate only. Among the trials that reported on ADT use, the majority of HR PCA patients underwent ADT for at least 2 months; mostly neoadjuvant and concurrent. Biochemical control rates ranged from 82% to 100% after 2 years and 56% to 100% after 3 years. Only a few studies reported longer follow-up data., Conclusion: At this point, SBRT with or without pelvic ENI cannot be considered the standard of care in HR PCA, due to missing level 1 evidence. Treatment may be offered to selected patients at specialized centers with access to high-precision RT. While concomitant ADT is the current standard of care, the necessary duration of ADT in combination with SBRT remains unclear. Ideally, all eligible patients should be enrolled in clinical trials.

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.)