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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]

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 [18F] 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 [18F] PSMA-1007-PET/CT and MRI (Freiburg) or [18F] 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. [ABSTRACT FROM AUTHOR]

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 ([18F]PSMA-1007/PET) has not been examined yet. Patients and Methods: Ten Patients with primary PCa who underwent [18F]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 [18F]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. [ABSTRACT FROM AUTHOR]

Purpose: The European Association of Urology (EAU) proposed a risk stratification (high vs. low risk) for patients with biochemical recurrence (BR) following radical prostatectomy (RP). Here we investigated whether this stratification accurately predicts outcome, particularly in patients staged with PSMA-PET., Methods: For this study, we used a retrospective database including 1222 PSMA-PET-staged prostate cancer patients who were treated with salvage radiotherapy (SRT) for BR, at 11 centers in 5 countries. Patients with lymph node metastases (pN1 or cN1) or unclear EAU risk group were excluded. The remaining cohort comprised 526 patients, including 132 low-risk and 394 high-risk patients., Results: The median follow-up time after SRT was 31.0 months. The 3-year biochemical progression-free survival (BPFS) was 85.7 % in EAU low-risk versus 69.4 % in high-risk patients (p = 0.002). The 3-year metastasis-free survival (MFS) was 94.4 % in low-risk versus 87.6 % in high-risk patients (p = 0.005). The 3-year overall survival (OS) was 99.0 % in low-risk versus 99.6 % in high-risk patients (p = 0.925). In multivariate analysis, EAU risk group remained a statistically significant predictor of BPFS (p = 0.003, HR 2.022, 95 % CI 1.262-3.239) and MFS (p = 0.013, HR 2.986, 95 % CI 1.262-7.058)., Conclusion: Our data support the EAU risk group definition. EAU risk grouping for BCR reliably predicted outcome in patients staged lymph node-negative after RP and with PSMA-PET before SRT. To our knowledge, this is the first study validating the EAU risk grouping in patients treated with PSMA-PET-planned SRT., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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).)

Purpose: The number of older adults with head and neck squamous cell carcinoma (HNSCC) is increasing, and treatment of these patients is challenging. Although cisplatin-based chemotherapy concomitantly with radiation therapy is considered the standard regimen for patients with locoregionally advanced HNSCC, there is substantial real-world heterogeneity regarding concomitant chemotherapy in older patients with HNSCC., Methods and Materials: The SENIOR study is an international multicenter cohort study including older patients (≥65 years) with HNSCC treated with definitive radiation therapy at 13 academic centers in the United States and Europe. Patients with concomitant chemoradiation were analyzed regarding overall survival (OS) and progression-free survival (PFS) via Kaplan-Meier analyses. Fine-Gray competing risk regressions were performed regarding the incidence of locoregional failures and distant metastases., Results: Six hundred ninety-seven patients with a median age of 71 years were included in this analysis. Single-agent cisplatin was the most common chemotherapy regimen (n = 310; 44%), followed by cisplatin plus 5-fluorouracil (n = 137; 20%), carboplatin (n = 73; 10%), and mitomycin C plus 5-fluorouracil (n = 64; 9%). Carboplatin-based regimens were associated with diminished PFS (hazard ratio [HR], 1.39 [1.03-1.89]; P < .05) and a higher incidence of locoregional failures (subdistribution HR, 1.54 [1.00-2.38]; P = .05) compared with single-agent cisplatin, whereas OS (HR, 1.15 [0.80-1.65]; P = .46) was comparable. There were no oncological differences between single-agent and multiagent cisplatin regimens (all P > .05). The median cumulative dose of cisplatin was 180 mg/m 2 (IQR, 120-200 mg/m 2 ). Cumulative cisplatin doses ≥200 mg/m 2 were associated with increased OS (HR, 0.71 [0.53-0.95]; P = .02), increased PFS (HR, 0.66 [0.51-0.87]; P = .003), and lower incidence of locoregional failures (subdistribution HR, 0.50 [0.31-0.80]; P = .004). Higher cumulative cisplatin doses remained an independent prognostic variable in the multivariate regression analysis for OS (HR, 0.996 [0.993-0.999]; P = .009)., Conclusions: Single-agent cisplatin can be considered in the standard chemotherapy regimen for older patients with HNSCC who can tolerate cisplatin. Cumulative cisplatin doses are prognostically relevant in older patients with HNSCC., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: With the increased use of focal radiation dose escalation for primary prostate cancer (PCa), accurate delineation of gross tumor volume (GTV) in prostate-specific membrane antigen PET (PSMA-PET) becomes crucial. Manual approaches are time-consuming and observer dependent. The purpose of this study was to create a deep learning model for the accurate delineation of the intraprostatic GTV in PSMA-PET., Methods: A 3D U-Net was trained on 128 different 18 F-PSMA-1007 PET images from three different institutions. Testing was done on 52 patients including one independent internal cohort (Freiburg: n = 19) and three independent external cohorts (Dresden: n = 14 18 F-PSMA-1007, Boston: Massachusetts General Hospital (MGH): n = 9 18 F-DCFPyL-PSMA and Dana-Farber Cancer Institute (DFCI): n = 10 68 Ga-PSMA-11). Expert contours were generated in consensus using a validated technique. CNN predictions were compared to expert contours using Dice similarity coefficient (DSC). Co-registered whole-mount histology was used for the internal testing cohort to assess sensitivity/specificity., Results: Median DSCs were Freiburg: 0.82 (IQR: 0.73-0.88), Dresden: 0.71 (IQR: 0.53-0.75), MGH: 0.80 (IQR: 0.64-0.83) and DFCI: 0.80 (IQR: 0.67-0.84), respectively. Median sensitivity for CNN and expert contours were 0.88 (IQR: 0.68-0.97) and 0.85 (IQR: 0.75-0.88) (p = 0.40), respectively. GTV volumes did not differ significantly (p > 0.1 for all comparisons). Median specificity of 0.83 (IQR: 0.57-0.97) and 0.88 (IQR: 0.69-0.98) were observed for CNN and expert contours (p = 0.014), respectively. CNN prediction took 3.81 seconds on average per patient., Conclusion: The CNN was trained and tested on internal and external datasets as well as histopathology reference, achieving a fast GTV segmentation for three PSMA-PET tracers with high diagnostic accuracy comparable to manual experts., 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 Authors. Published by Elsevier B.V. All rights reserved.)

Current risk-stratification systems for prostate cancer (PCa) do not sufficiently reflect the disease heterogeneity. Genomic classifiers (GC) enable improved risk stratification after surgery, but less data exist for patients treated with definitive radiation therapy (RT) or RT in oligo-/metastatic disease stages. To guide future perspectives of GCs for RT, we conducted (1) a systematic review on the evidence of GCs for patients treated with RT and (2) a survey of experts using the Delphi method, addressing the role of GCs in personalized treatments to identify relevant fields of future clinical and translational research. We performed a systematic review and screened ongoing clinical trials on ClinicalTrials.gov. Based on these results, a multidisciplinary international team of experts received an adapted Delphi method survey. Thirty-one and 30 experts answered round 1 and round 2, respectively. Questions with ≥75% agreement were considered relevant and included in the qualitative synthesis. Evidence for GCs as predictive biomarkers is mainly available to the postoperative RT setting. Validation of GCs as prognostic markers in the definitive RT setting is emerging. Experts used GCs in patients with PCa with extensive metastases (30%), in postoperative settings (27%), and in newly diagnosed PCa (23%). Forty-seven percent of experts do not currently use GCs in clinical practice. Expert consensus demonstrates that GCs are promising tools to improve risk-stratification in primary and oligo-/metastatic patients in addition to existing classifications. Experts were convinced that GCs might guide treatment decisions in terms of RT-field definition and intensification/deintensification in various disease stages. This work confirms the value of GCs and the promising evidence of GC utility in the setting of RT. Additional studies of GCs as prognostic biomarkers are anticipated and form the basis for future studies addressing predictive capabilities of GCs to optimize RT and systemic therapy. The expert consensus points out future directions for GC research in the management of PCa., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background/purpose: The present study aimed to assess whether SRT to the prostatic fossa should be initiated in a timely manner after detecting biochemical recurrence (BR) in patients with prostate cancer, when no correlate was identified with prostate-specific membrane antigen positron emission tomography (PSMA-PET)., Materials and Methods: This retrospective, multicenter analysis included 1222 patients referred for PSMA-PET after a radical prostatectomy due to BR. Exclusion criteria were: pathological lymph node metastases, prostate-specific antigen (PSA) persistence, distant or lymph node metastases, nodal irradiation, and androgen deprivation therapy (ADT). This led to a cohort of 341 patients. Biochemical progression-free survival (BPFS) was the primary study endpoint., Results: The median follow-up was 28.0 months. The 3-year BPFS was 71.6% in PET-negative cases and 80.8% in locally PET-positive cases. This difference was significant in univariate (p = 0.019), but not multivariate analyses (p = 0.366, HR: 1.46, 95%CI: 0.64-3.32). The 3-year BPFS in PET-negative cases was significantly influenced by age (p = 0.005), initial pT3/4 (p < 0.001), pathology scores (ISUP) ≥ 3 (p = 0.026), and doses to fossa > 70 Gy (p = 0.027) in univariate analyses. In multivariate analyses, only age (HR: 1.096, 95%CI: 1.023-1.175, p = 0.009) and PSA-doubling time (HR: 0.339, 95%CI: 0.139-0.826, p = 0.017) remained significant., Conclusion: To our best knowledge, this study provided the largest SRT analysis in patients without ADT that were lymph node-negative on PSMA-PET. A multivariate analysis showed no significant difference in BPFS between locally PET-positive and PET-negative cases. These results supported the current EAU recommendation to initiate SRT in a timely manner after detecting BR in PET negative patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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.

Purpose: Prostate-specific membrane antigen positron emission tomography (PSMA-PET) is increasingly used to guide salvage radiation therapy (sRT) in patients with prostate cancer and biochemical recurrence/persistence after prostatectomy. This work examined (1) metastasis-free survival (MFS) after PSMA-PET guided sRT and (2) the metastatic patterns on PSMA-PET images after sRT., Methods and Materials: This retrospective, multicenter (9 centers, 5 countries) study included patients referred for PSMA-PET due to recurrent/persistent disease after prostatectomy. Patients with distant metastases (DM) on PSMA-PET before sRT were excluded. Cox regression was performed to assess the effect of clinical parameters on MFS. The distribution of PSMA-PET detected DM after sRT and their respective risk factors were analyzed., Results: All (n = 815) patients received intensity modulated RT to the prostatic fossa. In the case of PET-positive pelvic lymph nodes (PLN-PET) (n = 275, 34%), pelvic lymphatics had been irradiated. Androgen deprivation therapy had been given in 251 (31%) patients. The median follow-up after sRT was 36 months. The 2-/4-year MFS after sRT were 93%/81%. In multivariate analysis, the presence of PLN-PET was a strong predictor for MFS (hazard ratio, 2.39; P < .001). After sRT, DM were detected by PSMA-PET in 128/198 (65%) patients, and 2 metastatic patterns were observed: 43% had DM in sub-diaphragmatic para-aortic LNs (abdominal-lymphatic), 45% in bones, 9% in supra-diaphragmatic LNs, and 6% in visceral organs (distant). Two distinct signatures with risk factors for each pattern were identified., Conclusions: MFS in our study is lower compared with previous studies, obviously due to the higher detection rate of DM in PSMA-PET after sRT. Thus, it remains unclear whether MFS is a surrogate endpoint for overall survival in PSMA PET-staged patients in the post-sRT setting. PLN-PET may be proposed as a new surrogate parameter predictive of MFS. Analysis of recurrence patterns in PET after sRT revealed risk factor signatures for 2 metastatic patterns (abdominal-lymphatic and distant), which may allow individualized sRT concepts in the future., (Copyright © 2022 Elsevier Inc. All rights reserved.)