IntroductionProstate cancer (PCa) is the most frequent diagnosed malignancy in male patients in Europe and radiation therapy (RT) is a main treatment option. However, current RT concepts for PCa have an imminent need to be rectified in order to modify the radiotherapeutic strategy by considering (i) the personal PCa biology in terms of radio resistance and (ii) the individual preferences of each patient.MethodsTo this end, a mechanistic multiscale model of prostate tumor response to external radiotherapeutic schemes, based on a discrete entity and discrete event simulation approach has been developed. Following technical verification, an adaptation to clinical data approach is delineated. Multiscale data has been provided by the University of Freiburg. Additionally, a sensitivity analysis has been performed.ResultsThe impact of model parameters such as cell cycle duration, dormant phase duration, apoptosis rate of living and progenitor cells, fraction of dormant stem and progenitor cells that reenter cell cycle, number of mitoses performed by progenitor cells before becoming differentiated, fraction of stem cells that perform symmetric division, fraction of cells entering the dormant phase following mitosis, alpha and beta parameters of the linear-quadratic model and oxygen enhancement ratio has been studied. The model has been shown to be particularly sensitive to the apoptosis rate of living stem and progenitor cells, the fraction of dormant stem and progenitor cells that reenter cell cycle, the fraction of stem cells that perform symmetric division and the fraction of cells entering the dormant phase following mitosis. A qualitative agreement of the model behavior with experimental and clinical knowledge has set the basis for the next steps towards its thorough clinical validation and its eventual certification and clinical translation. The paper showcases the feasibility, the fundamental design and the qualitative behavior of the model in the context of in silico experimentation.DiscussionFurther data is being collected in order to enhance the model parametrization and conduct extensive clinical validation. The envisaged digital twin or OncoSimulator, a concept and technologically integrated system that our team has previously developed for other cancer types, is expected to support both patient personalized treatment and in silico clinical trials.

We prospectively evaluated the effects of stereotactic body radiotherapy (SBRT) on circulating immune cells. Patients with oligo-metastatic and oligo-progressive pulmonary lesions were treated with SBRT with (cSBRT) or without (SBRT group) concurrent systemic treatment (chemotherapy or immune checkpoint blockade) using different fractionation regimes. Immunoprofiling of peripheral blood cells was performed at baseline, during, at the end of SBRT, and at the first and second follow-ups. The study accrued 100 patients (80 with evaluable samples). The proportion of proliferating CD8+ T-cells significantly increased after treatment. This increase remained significant at follow-up in the SBRT group, but not in the cSBRT group and was not detected with doses of >10Gy per fraction indicating that lower doses are necessary to increase proliferating T-cells' frequency. We detected no favorable impact of concurrent systemic treatment on systemic immune responses. The optimal timing of systemic treatment may be post-SBRT to leverage the immune-modulating effects of SBRT.

PURPOSE:Stereotactic body radiotherapy (SBRT) is emerging as a valuable treatment modality for localized prostate cancer, with promising biochemical progression-free survival rates. Longitudinal assessment of prostate-specific antigen (PSA) is the mainstay of follow-up after treatment. PSA kinetics and dynamics are well-established in the context of brachytherapy and conventionally fractionated radiotherapy, yet little is known in the context of prostate SBRT. METHODS:A review of available literature in MEDLINE, Scopus, and Embase was performed, focusing on studies reporting PSA slope, nadir, bounce, and biochemical failure after prostate SBRT. RESULTS:Thirty-three records (45 % prospective) encompassing 9949 patients were included. SBRT dose ranged from 32-50 Gy in 4-5 fractions and overall median follow-up time (range) was 41 (15-74) months. Use of androgen deprivation therapy ranged from 0-38 %. SBRT was characterized by a steep initial decline of PSA, slowing down over time and ultimately yielding a lower nadir in comparison with conventional radiotherapy, with a median value (range) of 0.24 (0.1-0.6) ng/mL after a median time (range) of 33.1 (6-54) months. There was an inverse correlation between the highest SBRT dose in a trial and PSA nadir (r = - 0.59; p < 0.001). Benign PSA bounce occurred in 30 % of patients across all studies, after a median time (range) of 14.8 (9-36) months and with a median size (range) of 0.5 (0.3-1.1) ng/mL. There was no significant correlation between bounce and dose, nadir nor biochemical failure. There was, however, a significant inverse correlation between ADT use and PSA bounce frequency (r = -0.49; p = 0.046). CONCLUSION:PSA kinetics and dynamics after SBRT for localized prostate cancer are different from those in other established radiotherapy modalities. Benign PSA bounce is very common. Clinicians should be aware of these factors and patients should be counseled accordingly, preventing unnecessary distress or salvage treatment.

Introduction The combination of immunotherapy (IO) with radiation therapy might provide a clinical benefit to our patients due to a synergistic effect. Radiation therapy of the location of recurrence might lead to an increase in the immunogenic potential and;a systemic immunological reaction is described that leads to an increased activity of the immune system against cancerous tissue (abscopal effect). The goal of our study is to evaluate the efficacy and safety of immunotherapy in combination with standard salvage radiation therapy (SRT) in patients with biochemical recurrence (BCR) of prostate-specific antigen (PSA) persistence after radical prostatectomy (RP). Primary endpoint is complete biochemical response (PSA level below detection level) 60 weeks after start of trial treatment, which further defines prognosis of patients and the further course of disease. Further explorative endpoints like radiographic progression-free survival, PSA-nadir level and time to PSA-nadir, time to initiation of subsequent therapy (secondary ADT or NHA). Methods The trial is as a phase II, open-label, single arm monocenter trial which evaluates the combination of pembrolizumab;in combination with SRT. Pembrolizumab will be administered in a three-weekly scheme up to one year of treatment. A concomitant ADT is administered in high-risk patients only (PSA >0.7ng/ml or cN+ in imaging studies). All patients will be staged with PSMA PET-CT, if applicable. Additionally, blood and urine samples will be collected for correlative biomarker studies.Imaging within 30 days prior to study inclusion is mandatory (([68Ga] or [18F] PSMA PET-CT as standard imaging modality, alternatively CT abdomen and full-body bone scan) is one of the important inclusion crtieria.Prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to registration (like neo-adjuvant androgen deprivation therapy (ADT), secondary hormone ablation or taxan-based chemotherapy) and distant metastases or suspicious lymph nodes outside the lower pelvis;are important exclusion criteria.Results:Conclusions:

TPS212 Background: Goal of our study is to evaluate the efficacy and safety of immunotherapy in combination with standard salvage radiation therapy (SRT) in patients with biochemical recurrence (BCR) or prostate-specific antigen (PSA) persistence after radical prostatectomy (RP). The combination of immunotherapy (IO) with radiation therapy might provide a clinical benefit to patients with recurrent prostate cancer due to an induction of increased activity of the immune system against cancerous tissue (abscopal effect). Primary endpoint is complete biochemical response (PSA level below detection level) 60 weeks after start of trial treatment, which further defines prognosis of patients. Further explorative endpoints like radiographic progression-free survival, PSA-nadir level and time to PSA-nadir, time to initiation of subsequent therapy (secondary ADT or NHA) and quality of life as well as adverse events will be evaluated. Methods: The trial is as a phase II, open-label, single arm monocenter trial which evaluates the combination of pembrolizumab as study medication in combination with SRT. Pembrolizumab will be administered in a three-weekly scheme up to one year of treatment. A concomitant ADT is administered in high-risk patients only (PSA > 0.7ng/ml or cN+ in imaging studies). All patients will be staged with PSMA PET-CT, if applicable. Additionally, blood and urine samples will be collected for correlative biomarker studies. A total of 49 patients are planned to be enrolled in this explorative study within 2 years. INCLUSION CRITERIA (excerpt) Histologically confirmed diagnosis of an adenocarcinoma of the prostate and a BCR or PSA persistence after RP. Histology of the RP specimen needs to fulfill the following criteria: adenocarcinoma of the prostate, Gleason score 7-10; pNX or pN0 or pN1 (max. 2 lymph nodes involved). Imaging within 30 days prior to study inclusion is mandatory (([68Ga] or [18F] PSMA PET-CT as standard imaging modality, alternatively CT abdomen and full-body bone scan). PSA value between ≥0.2 and ≤1.0 ng/ml, measured at least six weeks postoperatively. EXCLUSION CRITERIA (excerpt) Prior-therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137). Prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to registration (like neo-adjuvant androgen deprivation therapy (ADT), secondary hormone ablation or taxan-based chemotherapy). Distant metastases or suspicious lymph nodes outside the lower pelvis in imaging with PSMA PET-CT (patients with PET positive bone lesions that are morphologically not clearly suspicious of metastases and would not change clinical practice can be included). Clinical trial information: NCT04931979.

ObjectivesThe 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.MethodsA 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.ResultsA 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/m2 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.ConclusionTreatment 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.

Abstract 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_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.

Introduction68Ga-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 MethodsThis 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.ResultsMedian 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).ConclusionThis 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.

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 68Ga-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: 68Ga-PSMA PET, n = 18 and cohort 2: 18F-PSMA PET, n = 19) and 1 external (cohort 3: 68Ga-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 68Ga-PSMA and 18F-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.

Background/Aim: We examined the prognostic value of intraprostatic gross tumour volume (GTV) as measured by multiparametric MRI (mpMRI) in patients with prostate cancer following (primary) external beam radiation therapy (EBRT). Patients and Methods: In a retrospective monocentric study, we analysed patients with prostate cancer (PCa) after EBRT. GTV was delineated in pre-treatment mpMRI (GTV-MRI) using T2-weighted images. Cox-regression analyses were performed considering biochemical failure recurrence-free survival (BRFS) as outcome variable. Results: Among 131 patients, after a median follow-up of 57 months, biochemical failure occurred in 27 (21%). GTV-MRI was not correlated with % of positive biopsy cores, Gleason score and initial PSA (all r<0.2) and only moderately correlated with cT stage (r=0.32). In univariate analysis, cT stage, Gleason score and GTV-MRI were higher in subjects with shorter BRFS (p<0.05). GTV-MRI remained a significant predictor for BRFS in multivariate analyses, independent of Gleason score and cT stage. Conclusion: GTV, defined using mpMRI, provides incremental prognostic value for BRFS, independent of established risk factors. This supports the implementation of imaging-based GTV for risk-stratification, although further validation is needed.

Accurate delineation of the intraprostatic gross tumour volume (GTV) is a prerequisite for treatment approaches in patients with primary prostate cancer (PCa). Prostate-specific membrane antigen positron emission tomography (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 tumour (GTV-CNN) in PSMA-PET. Methods: The CNN (3D U-Net) was trained on [68Ga]PSMA-PET images of 152 patients from two different institutions and the training labels were generated manually using a validated technique. The CNN was tested on two independent internal (cohort 1: [68Ga]PSMA-PET, n=18 and cohort 2: [18F]PSMA-PET, n=19) and one external (cohort 3: [68Ga]PSMA-PET, n=20) test-datasets. Accordance between manual contours and GTV-CNN was assessed with Dice-Sørensen coefficient (DSC). Sensitivity and specificity were calculated for the two internal test-datasets by using whole-mount histology. Results: 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 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 seconds for a standard dataset. Conclusion: The application of a CNN for automated contouring of intraprostatic GTV in [68Ga]PSMA- and [18F]PSMA-PET images resulted in a high concordance with expert contours and in high sensitivities and specificities in comparison with histology reference. This robust, accurate and fast technique may be implemented for treatment concepts in primary PCa. The trained model and the study's source code are available in an open source repository.

The purpose of this analysis was primarily to analyze biochemical-recurrence free survival (BRFS) after positron emission tomography (PET)-guided salvage radiotherapy (sRT) in a large cohort, and to further compare BRFS after PSMA vs. choline PET/ computer tomography (CT)-based sRT. This retrospective analysis is based on 421 patients referred for PSMA or choline PET/CT after radical prostatectomy due to biochemically recurrent or persistent disease. BRFS (PSA: 0.2 ng/mL) was defined as the study endpoint. Cox regression analyses were performed to assess the impact of different clinical parameters on BRFS. Additionally, propensity score matching was performed to adjust patient cohorts (PSMA vs. choline PET/CT-based sRT). The median follow-up time was 30 months. BRFS at three years after sRT was 58%. In the multivariate analysis, only PSA before PET imaging and PSA before sRT were significantly associated with BRFS (p < 0.05). After propensity score matching, 272 patients were further analyzed; there was no significant difference in three-year BRFS between patients with PSMA PET-based vs. choline PET-based sRT (55% vs. 63%, p = 0.197). The present analysis confirmed the overall high BRFS rates after PET-based sRT and the strong prognostic effect of PSA level prior to sRT. PSMA PET-based sRT did not have superior BRFS rates when compared with choline PET-based sRT.

BACKGROUND AND PURPOSE:Focal therapies are a promising approach to treat prostate cancer (PCa) more precisely instead of conventional whole gland treatment. Nowadays, multiparametric MRI (mpMRI) is routinely used for gross tumor volume (GTV) delineation. The aim of our study was to compare PSMA-PET/CT and mpMRI for the delineation of intraprostatic tumor burden by using whole mount histopathology as a reference standard.MATERIAL AND METHODS:17 prospectively enrolled patients with primary PCa underwent [68Ga-]PSMA-11 PET/CT and mpMRI before radical prostatectomy. PSMA-PET/CT, mpMRI and histopathology of the resected specimens were co-registered. Two teams of experts generated GTV contours for mpMRI and PET, respectively. The imaging was validated on a lesion level and slice by slice in quadrants based on the distribution of PCa in histopathology. Overall, 772 quadrants were analyzed with 414 being true positive for tumor (53.6%).RESULTS:Median tumor volumes were 10.4 ml for GTV-histo, 10.8 ml for PSMA-PET and 4.5 ml for mpMRI. Median tumor volume in mpMRI was significant (p < 0.05) smaller than GTV-PET and GTV-histo, respectively. The sensitivity and specificity were 86% and 87% for PSMA-PET, 58% and 94% for mpMRI and 91% and 84% for their GTV-union. In 133 quadrants PSMA-PET/CT correctly identified tumor where mpMRI found none. MpMRI identified 19 true positive quadrants exclusively.CONCLUSION:Our investigation demonstrates an increased consensus of PSMA-PET with histopathology compared to mpMRI for intraprostatic GTV delineation, especially with a higher sensitivity. Additionally mpMRI contours underestimate tumor volume significantly. Thus PSMA-PET may be a complementary augmentation for GTV delineation in focal therapies.