The role of online MR-guided multi-fraction stereotactic ablative radiotherapy in lung tumours.

Background: The aim of this prospective observational study was to evaluate the dosimetry benefits, changes in pulmonary function, and clinical outcome of online adaptive MR-guided SBRT. Methods: From 11/2020-07/2022, 45 consecutive patients with 59 lesions underwent multi-fraction SBRT (3-8 fractions) at our institution. Patients were eligible if they had biopsy-proven NSCLC or lung cancer/metastases diagnosed via clinical imaging. Endpoints were local control (LC) and overall survival (OS). We evaluated PTV/GTV dose coverage, organs at risk exposure, and changes in pulmonary function (PF). Acute toxicity was classified per the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0. Results: The median PTV was 14.4 cm3 (range: 3.4 - 96.5 cm3). In total 195/215 (91%) plans were reoptimised. In the reoptimised vs. predicted plans, PTV coverage by the prescribed dose increased in 94.6% of all fractions with a median increase in PTV VPD of 5.6% (range: -1.8 - 44.6%, p < 0.001), increasing the number of fractions with PTV VPD ≥ 95% from 33% to 98%. The PTV D95% and D98% (BED10) increased in 93% and 95% of all fractions with a median increase of 7.7% (p < 0.001) and 10.6% (p < 0.001). The PTV D95% (BED10) increased by a mean of 9.6 Gy (SD: 10.3 Gy, p < 0.001). At a median follow-up of 21.4 months (95% CI: 12.3-27.0 months), 1- and 2-year LC rates were 94.8% (95% CI: 87.6 - 100.0%) and 91.1% (95% CI: 81.3 - 100%); 1- and 2-year OS rates were 85.6% (95% CI: 75.0 - 96.3%) and 67.1 % (95% CI: 50.3 - 83.8%). One grade ≥ 3 toxicity and no significant reduction in short-term PF parameters were recorded. Conclusions: Online adaptive MR-guided SBRT is an effective, safe and generally well tolerated treatment option for lung tumours achieving encouraging local control rates with significantly improved target volume coverage.

European association of urology risk stratification predicts outcome in patients receiving PSMA-PET-planned salvage radiotherapy for biochemical recurrence following radical prostatectomy.

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.

Differentiation of benign and metastatic lymph nodes in soft tissue sarcoma.

Lymph node metastasis (LNM) occurs in less than 5% of soft tissue sarcoma (STS) patients and indicates an aggressive course of disease. Suspicious lymph nodes (LN) in staging imaging are a frequent topic of discussion in multidisciplinary tumor boards. Predictive markers are needed to facilitate stratification and improve treatment of STS patients. In this study, 56 STS patients with radiologically suspicious and subsequently histologically examined LN were reviewed. Patients with benign (n = 26) and metastatic (n = 30) LN were analyzed with regard to clinical, laboratory and imaging parameters. Patients with LNM exhibited significantly larger short axis diameter (SAD) and long axis diameter (LAD) vs. patients with benign LN (median 22.5 vs. 14 mm, p < 0.001 and median 29.5 vs. 21 mm, p = 0.003, respectively). Furthermore, the presence of central necrosis and high maximal standardized uptake value (SUVmax) in FDG-PET-CT scans were significantly associated with LNM (60 vs. 11.5% of patients, p < 0.001 and median 8.59 vs. 3.96, p = 0.013, respectively). With systemic therapy, a slight median size regression over time was observed in both metastatic and benign LN. Serum LDH and CRP levels were significantly higher in patients with LNM (median 247 vs. 187.5U/L, p = 0.005 and 1.5 vs. 0.55 mg/dL, p = 0.039, respectively). This study shows significant associations between LNM and imaging features as well as laboratory parameters of STS patients. The largest SAD, SUVmax in FDG-PET-CT scan, the presence of central necrosis, and high serum LDH level are the most important parameters to distinguish benign from metastatic LNs.

The prognostic significance of a negative PSMA-PET scan prior to salvage radiotherapy following radical prostatectomy.

AIM: The optimal management for early recurrent prostate cancer following radical prostatectomy (RP) in patients with negative prostate-specific membrane antigen positron-emission tomography (PSMA-PET) scan is an ongoing subject of debate. The aim of this study was to evaluate the outcome of salvage radiotherapy (SRT) in patients with biochemical recurrence with negative PSMA PET finding. METHODS: This retrospective, multicenter (11 centers, 5 countries) analysis included patients who underwent SRT following biochemical recurrence (BR) of PC after RP without evidence of disease on PSMA-PET staging. Biochemical recurrence-free survival (bRFS), metastatic-free survival (MFS) and overall survival (OS) were assessed using Kaplan-Meier method. Multivariable Cox proportional hazards regression assessed predefined predictors of survival outcomes. RESULTS: Three hundred patients were included, 253 (84.3%) received SRT to the prostate bed only, 46 (15.3%) additional elective pelvic nodal irradiation, respectively. Only 41 patients (13.7%) received concomitant androgen deprivation therapy (ADT). Median follow-up after SRT was 33 months (IQR: 20-46 months). Three-year bRFS, MFS, and OS following SRT were 73.9%, 87.8%, and 99.1%, respectively. Three-year bRFS was 77.5% and 48.3% for patients with PSA levels before PSMA-PET ≤ 0.5 ng/ml and > 0.5 ng/ml, respectively. Using univariate analysis, the International Society of Urological Pathology (ISUP) grade > 2 (p = 0.006), metastatic pelvic lymph nodes at surgery (p = 0.032), seminal vesicle involvement (p < 0.001), pre-SRT PSA level of > 0.5 ng/ml (p = 0.004), and lack of concomitant ADT (p = 0.023) were significantly associated with worse bRFS. On multivariate Cox proportional hazards, seminal vesicle infiltration (p = 0.007), ISUP score >2 (p = 0.048), and pre SRT PSA level > 0.5 ng/ml (p = 0.013) remained significantly associated with worse bRFS. CONCLUSION: Favorable bRFS after SRT in patients with BR and negative PSMA-PET following RP was achieved. These data support the usage of early SRT for patients with negative PSMA-PET findings.

ESTRO ACROP consensus recommendation on the target volume definition for radiation therapy of macroscopic prostate cancer recurrences after radical prostatectomy.

Background: The European Society for Radiotherapy & Oncology (ESTRO) Advisory Committee for Radiation Oncology Practice (ACROP) panel on prostate bed delineation reflected on macroscopic local recurrences in patients referred for postoperative radiotherapy (PORT), a challenging situation without standardized approach, and decided to propose a consensus recommendation on target volume selection and definition. Methods: An ESTRO ACROP contouring consensus panel consisting of 12 radiation oncologists and one radiologist, all with subspecialty expertise in prostate cancer, was established. Participants were asked to delineate the prostate bed clinical target volumes (CTVs) in two separate clinically relevant scenarios: a local recurrence at the seminal vesicle bed and one apically at the level of the anastomosis. Both recurrences were prostate-specific membrane antigen (PSMA)-avid and had an anatomical correlate on magnetic resonance imaging (MRI). Participants also answered case-specific questionnaires addressing detailed recommendations on target delineation. Discussions via electronic mails and videoconferences for final editing and consensus were performed. Results: Contouring of the two cases confirmed considerable variation among the panelists. Finally, however, a consensus recommendation could be agreed upon. Firstly, it was proposed to always delineate the entire prostate bed as clinical target volume and not the local recurrence alone. The panel judged the risk of further microscopic disease outside of the visible recurrence too high to safely exclude the rest of the prostate bed from the CTV. A focused, "stereotactic" approach should be reserved for re-irradiation after previous PORT. Secondly, the option of a focal boost on the recurrence was discussed. Conclusion: Radiation oncologists are increasingly confronted with macroscopic local recurrences visible on imaging in patients referred for postoperative radiotherapy. It was recommended to always delineate and irradiate the entire prostate bed, and not the local recurrence alone, whatever the exact location of that recurrence. Secondly, specific dose-escalation on the macroscopic recurrence should only be considered if an anatomic correlate is visible. Such a focal boost is probably feasible, provided that OAR constraints are prioritized. Possible dose is also dependent on the location of the recurrence. Its potential benefit should urgently be investigated in prospective clinical trials.

Is PSMA PET/CT cost-effective for the primary staging in prostate cancer? First results for European countries and the USA based on the proPSMA trial.

PURPOSE: The proPSMA trial at ten Australian centers demonstrated increased sensitivity and specificity for PSMA PET/CT compared to conventional imaging regarding metastatic status in primary high-risk prostate cancer patients. A cost-effectiveness analysis showed benefits of PSMA PET/CT over conventional imaging for the Australian setting. However, comparable data for other countries are lacking. Therefore, we aimed to verify the cost-effectiveness of PSMA PET/CT in several European countries as well as the USA. METHODS: Clinical data on diagnostic accuracy were derived from the proPSMA trial. Costs for PSMA PET/CT and conventional imaging were taken from reimbursements of national health systems and individual billing information of selected centers in Belgium, Germany, Italy, the Netherlands, and the USA. For comparability, scan duration and the decision tree of the analysis were adopted from the Australian cost-effectiveness study. RESULTS: In contrast to the Australian setting, PSMA PET/CT was primarily associated with increased costs in the studied centers in Europe and the USA. Mainly, the scan duration had an impact on the cost-effectiveness. However, costs for an accurate diagnosis using PSMA PET/CT seemed reasonably low compared to the potential consequential costs of an inaccurate diagnosis. CONCLUSION: We assume that the use of PSMA PET/CT is appropriate from a health economic perspective, but this will need to be verified by a prospective evaluation of patients at initial diagnosis.

TIM-3 Qualifies as a Potential Immunotherapeutic Target in Specific Subsets of Patients with High-Risk Soft Tissue Sarcomas (HR-STS).

(1) Background: The expression of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), an immune checkpoint receptor on T cells, has been associated with dismal outcomes and advanced tumor stages in various solid tumors. The blockade of TIM-3 is currently under examination in several clinical trials. This study examines TIM-3 expression in high-risk soft tissue sarcomas (HR-STS). (2) Methods: Tumor cell expression of TIM-3 on protein level was analyzed in pre-treatment biopsies of patients with HR-STS. TIM-3 expression was correlated with clinicopathological parameters including tumor-infiltrating lymphocyte (TIL) counts, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PDL-1) expression in patients with HR-STS. Survival dependent on the expression of TIM-3 was analyzed. (3) Results: TIM-3 expression was observed in 101 (56%) out of 179 pre-treatment biopsies of patients with HR-STS. TIM-3 expression was significantly more often observed in undifferentiated pleomorphic sarcomas (UPS) compared to other histological subtypes (p < 0.001), high TIL counts (p < 0.001), and high PD-1 (p < 0.001) and PD-L1 expression (p < 0.001). TIM-3 expression did not have a prognostic impact on survival in patients with HR-STS. (4) Conclusions: This is the first study to demonstrate a significant tumor cell expression of TIM-3 in specific subsets of patients with HR-STS. TIM-3 qualifies as a potential immunotherapeutic target in HR-STS.

Salvage radiotherapy is effective in patients with PSMA-PET-negative biochemical recurrence- results of a retrospective study.

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.

Development and Validation of a Multi-institutional Nomogram of Outcomes for PSMA-PET-Based Salvage Radiotherapy for Recurrent Prostate Cancer.

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.

DNA-methylation and genomic copy number in primary tumors and corresponding lymph node metastases in prostate cancer from patients with low and high Gleason score.

Purpose: In prostate cancer, the indication to irradiate the pelvic lymphatic pathways in clinical node-negative patients is solely based on clinical nomograms. To define biological risk patterns of lymphatic spread, we studied DNA-methylation and genomic copy number in primary tumors and corresponding lymph nodes metastases. Methods/Patients: DNA-methylation and genomic copy number profiles of primary tumors (PT) and paired synchronous lymph node metastases (LN) from Gleason Score (GS)-6/7a (n = 20 LN-positive, n = 20 LN-negative) and GS-9/10 patients (LN-positive n = 20) after prostatectomy and lymphonodectomy were analyzed. Results: GS-6/7a pN0 PTs and GS-6/7a pN1 PTs differed in histone H3K27me3/H3K9me3 mediated methylation. PTs compared to LNs, in both, GS-6/7a pN1 and GS-9/10 pN1 patients showed large differences in DNA-methylation mediated by histones H3K4me1/2, in addition to copy number changes of chromosomal regions 11q13.1, 14q11.2 and 15q26.1. Between GS-6/7a pN1 and GS-9/10 pN1 patients, methylation levels differed more when comparing LNs than PTs. 16q21-22.1 was specifically lost in GS-9/10 pN0 PTs. Immune system-related pathways characterized the differences between PTs and LNs in both GS-6/7a pN1 and GS-9/10 pN1 patients. Comparing PTs and LKs between GS-6/7a pN1 and GS-9/10 pN1 patients revealed altered transmembrane and G-protein-coupled receptor signaling. Conclusions: Our data suggest that progression of prostate cancer, including lymphatic spread, is associated with histone-mediated DNA-methylation and we hypothesize a methylation signature predicting lymphatic spread in GS-6/7a patients from primary tumors. Lymphatic spread in GS-6/7a patients, flanked by DNA-methylation and CNA alterations, appears to be more complex than in GS-9/10 patients, in whom the primary tumors already appear to bear lymph node metastasis-enabling alterations.

PSMA-PET/CT-guided salvage radiotherapy in recurrent or persistent prostate cancer and PSA < 0.2 ng/ml.

PURPOSE: The purpose of this retrospective, multicenter study was to assess efficacy of PSMA-PET/CT-guided salvage radiotherapy (sRT) in patients with recurrent or persistent PSA after primary surgery and PSA levels < 0.2 ng/ml. METHODS: The study included patients from a pooled cohort (n = 1223) of 11 centers from 6 countries. Patients with PSA levels > 0.2 ng/ml prior to sRT or without sRT to the prostatic fossa were excluded. The primary study endpoint was biochemical recurrence-free survival (BRFS) and BR was defined as PSA nadir after sRT + 0.2 ng/ml. Cox regression analysis was performed to assess the impact of clinical parameters on BRFS. Recurrence patterns after sRT were analyzed. RESULTS: The final cohort consisted of 273 patients; 78/273 (28.6%) and 48/273 (17.6%) patients had local or nodal recurrence on PET/CT. The most frequently applied sRT dose to the prostatic fossa was 66-70 Gy (n = 143/273, 52.4%). SRT to pelvic lymphatics was delivered in 87/273 (31.9%) patients and androgen deprivation therapy was given to 36/273 (13.2%) patients. After a median follow-up time of 31.1 months (IQR: 20-44), 60/273 (22%) patients had biochemical recurrence. The 2- and 3-year BRFS was 90.1% and 79.2%, respectively. The presence of seminal vesicle invasion in surgery (p = 0.019) and local recurrences in PET/CT (p = 0.039) had a significant impact on BR in multivariate analysis. In 16 patients, information on recurrence patterns on PSMA-PET/CT after sRT was available and one had recurrent disease inside the RT field. CONCLUSION: This multicenter analysis suggests that implementation of PSMA-PET/CT imaging for sRT guidance might be of benefit for patients with very low PSA levels after surgery due to promising BRFS rates and a low number of relapses within the sRT field.

Development of PSMA-PET-guided CT-based radiomic signature to predict biochemical recurrence after salvage radiotherapy.

PURPOSE: To develop a CT-based radiomic signature to predict biochemical recurrence (BCR) in prostate cancer patients after sRT guided by positron-emission tomography targeting prostate-specific membrane antigen (PSMA-PET). MATERIAL AND METHODS: Consecutive patients, who underwent 68Ga-PSMA11-PET/CT-guided sRT from three high-volume centers in Germany, were included in this retrospective multicenter study. Patients had PET-positive local recurrences and were treated with intensity-modulated sRT. Radiomic features were extracted from volumes of interests on CT guided by focal PSMA-PET uptakes. After preprocessing, clinical, radiomics, and combined clinical-radiomic models were developed combining different feature reduction techniques and Cox proportional hazard models within a nested cross validation approach. RESULTS: Among 99 patients, median interval until BCR was the radiomic models outperformed clinical models and combined clinical-radiomic models for prediction of BCR with a C-index of 0.71 compared to 0.53 and 0.63 in the test sets, respectively. In contrast to the other models, the radiomic model achieved significantly improved patient stratification in Kaplan-Meier analysis. The radiomic and clinical-radiomic model achieved a significantly better time-dependent net reclassification improvement index (0.392 and 0.762, respectively) compared to the clinical model. Decision curve analysis demonstrated a clinical net benefit for both models. Mean intensity was the most predictive radiomic feature. CONCLUSION: This is the first study to develop a PSMA-PET-guided CT-based radiomic model to predict BCR after sRT. The radiomic models outperformed clinical models and might contribute to guide personalized treatment decisions.

ESTRO-ACROP recommendations for evidence-based use of androgen deprivation therapy in combination with external-beam radiotherapy in prostate cancer.

BACKGROUND AND PURPOSE: There is no consensus concerning the appropriate use of androgen deprivation therapy (ADT) during primary and postoperative external-beam radiotherapy (EBRT) in the management of prostate cancer (PCa). Thus, the European Society for Radiotherapy and Oncology (ESTRO) Advisory Committee for Radiation Oncology Practice (ACROP) guidelines seeks to present current recommendations for the clinical use of ADT in the various indications of EBRT. MATERIAL AND METHODS: A literature search was conducted in MEDLINE PubMed that evaluated EBRT and ADT in prostate cancer. The search focused on randomized, Phase II and III trials published in English from January 2000 to May 2022. In case topics were addressed in the absence of Phase II or III trials, recommendations were labelled accordingly based on the limited body of evidence. Localized PCa was classified according to D'Amico et al. classification in low-, intermediate and high risk PCa. The ACROP clinical committee identified 13 European experts who discussed and analyzed the body of evidence concerning the use of ADT with EBRT for prostate cancer. RESULTS: Key issues were identified and are discussed: It was concluded that no additional ADT is recommended for low-risk prostate cancer patients, whereas for intermediate- and high-risk patients four to six months and two to three years of ADT are recommended. Likewise, patients with locally advanced prostate cancer are recommended to receive ADT for two to three years and when ≥ 2 high-risk factors (cT3-4, ISUP grade ≥ 4 or PSA ≥ 40 ng/ml) or cN1 is present ADT for three years plus additional Abiraterone for two years is recommended. For postoperative patients no ADT is recommended for adjuvant EBRT in pN0 patients whereas for pN1 patients adjuvant EBRT with long-term ADT is performed for at least 24 to 36 months. In the setting of salvage EBRT ADT is performed in biochemically persistent PCa patients with no evidence of metastatic disease. Long-term ADT (24 months) is recommended in pN0 patients with high risk of further progression (PSA ≥ 0.7 ng/ml and ISUP grade group ≥ 4) and a life expectancy of over ten years, whereas short-term ADT (6 months) is recommended in pN0 patients with lower risk profile (PSA < 0.7 ng/ml and ISUP grade group 4). Patients considered for ultra-hypofractionated EBRT as well as patients with image based local recurrence within the prostatic fossa or lymph node recurrence should participate in appropriate clinical trials evaluating the role of additional ADT. CONCLUSION: These ESTRO-ACROP recommendations are evidence-based and relevant to the use of ADT in combination with EBRT in PCa for the most common clinical settings.

An Analysis of the Distribution of PSMA PET/CT-Positive Lymph Nodes and Their Coverage by Different Elective Nodal Radiation Volumes in Postoperative Prostate Cancer Patients.

Salvage elective nodal radiotherapy (ENRT) is a treatment option for patients with biochemically persistent or recurrent prostate cancer who have lymph node metastases (LNs) after prostatectomy. Possible ENRT templates were proposed by the Radiation Therapy Oncology Group (RTOG; 2009), the PIVOTAL trialists (2015), and the NRG Oncology Group (2021). The goal of this study was to analyze the distribution of prostate-specific membrane antigen (PSMA) PET/CT-positive LNs and to compare the templates regarding their LN coverage. Methods: We analyzed the PSMA PET/CT scans of 105 patients with PET-positive LNs treated with salvage ENRT from 2014 to 2019. All LNs were mapped in an exemplary dataset, classified by region, and assessed with regard to their potential coverage by the 3 ENRT templates. The primary endpoint was the number of missed LNs. The secondary endpoint was the number of patients with full coverage. To compare the templates, a t test and McNemar test were used. Results: Three hundred thirty-five LNs were contoured (3.19 per patient; 95% CI, 2.43-3.95). Most frequently, LNs were seen in the internal iliac (n = 94, 28.1%), external iliac (n = 60, 17.9%), periaortic (n = 58, 17.3%), common iliac (n = 55, 16.4%), perirectal (n = 26, 7.8%), and presacral (n = 19, 5.7%) regions. The NRG template missed fewer LNs per patient (1.01, 31.7%) than the RTOG (1.28, 40.1%, P < 0.001) and PIVOTAL templates (1.19, 37.3%, P = 0.003). No difference was observed in the number of patients with full coverage of all LNs: 52 (49.5%) with the NRG template versus 50 (47.6%) with the RTOG (P = 0.625) and 49 (46.7%) with the PIVOTAL template (P = 0.250). Conclusion: The NRG template showed better coverage than the RTOG and PIVOTAL templates. Nevertheless, in this cohort, it would have missed almost one third of all contoured LNs and would have resulted in incomplete coverage in half the patients. This result underlines the importance of advanced imaging, such as PSMA PET/CT scans, before salvage ENRT and shows the need for further individualization of ENRT fields.

Elective nodal radiotherapy with a gapless radiation field junction for oligorecurrent prostate cancer after previous radiotherapy.

Purpose: To evaluate the feasibility of subsequent elective nodal radiotherapy (ENRT) for nodal recurrences after previous radiotherapy with a defined planning approach for a gapless radiation field junction. Methods: Patients with 1) previous radiotherapy of prostate or prostatic fossa and subsequent pelvic ENRT or 2) previous pelvic radiotherapy and subsequent ENRT to paraaortic lymph nodes (LN) and gapless junction of both radiation fields were analyzed. The cumulative maximum dose (Dmax-cum) and the maximum cumulative dose in 1 cc (D1cc-cum) were estimated. Absolute toxicity and the toxicity exceeding baseline were evaluated. Results: Twenty-two patients with PSMA-PET/CT-staged nodal oligorecurrence after prior radiotherapy were treated with pelvic (14 patients) or paraaortic ENRT (9 patients). One patient was treated sequentially at both locations. Median time between first and second RT was 20.2 months. Median doses to the lymphatic pathways and to PET-positive LN were 47.5 Gy and 64.8 Gy, respectively. The planning constraint of an estimated Dmax-cum ≤ 95 Gy and of D1cc-cum < 90 Gy were achieved in 23/23 cases and 22/23 cases, respectively. Median follow-up was 33.5 months. There was no additional acute or late toxicity ≥ grade 3. Worst acute toxicity exceeding baseline was grade 1 in 68.2% and grade 2 in 22.7% of patients. Worst late toxicity exceeding baseline was grade 1 in 31.8% and grade 2 in 18.2% of patients. Conclusion: ENRT for nodal recurrences after a previous radiotherapy with gapless junction of radiation fields seems to be feasible, applying the dose constraints Dmax-cum ≤ 95 Gy and D1cc-cum < 90 Gy without grade 3 acute or late toxicities exceeding baseline.

Cost-Effectiveness Analysis of 177Lu-PSMA-617 Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer poses a therapeutic challenge with poor prognosis. The VISION trial showed prolonged progression-free and overall survival in patients treated with lutetium Lu 177 vipivotide tetraxetan (177Lu-PSMA-617) radioligand therapy compared with using the standard of care (SoC) alone. The objective of this study was to determine the cost-effectiveness of 177Lu-PSMA-617 treatment compared with SoC therapy. METHODS: A partitioned survival model was developed using data from the VISION trial, which included overall and progression-free survival and treatment regimens for 177Lu-PSMA-617 and SoC. Treatment costs, utilities for health states, and adverse events were derived from public databases and the literature. Because 177Lu-PSMA-617 was only recently approved, costs for treatment were extrapolated from 177Lu-DOTATATE. Outcome measurements included the incremental cost, effectiveness, and cost-effectiveness ratio. The analysis was performed in a US setting from a healthcare system perspective over the lifetime horizon of 60 months. The willingness-to-pay threshold was set to $50,000, $100,000, and $200,000 per quality-adjusted life years (QALYs). RESULTS: The 177Lu-PSMA-617 group was estimated to gain 0.42 incremental QALYs. Treatment using 177Lu-PSMA-617 led to an increase in costs compared with SoC ($169,110 vs $85,398). The incremental cost, effectiveness, and cost-effectiveness ratio for 177Lu-PSMA-617 therapy was $200,708/QALYs. Sensitivity analysis showed robustness of the model regarding various parameters, which remained cost-effective at all lower and upper parameter bounds. In probabilistic sensitivity analysis using Monte Carlo simulation with 10,000 iterations, therapy using 177Lu-PSMA-617 was determined as the cost-effective strategy in 37.14% of all iterations at a willingness-to-pay threshold of $200,000/QALYs. CONCLUSIONS: Treatment using 177Lu-PSMA-617 was estimated to add a notable clinical benefit over SoC alone. Based on the model results, radioligand therapy represents a treatment strategy for patients with metastatic castration-resistant prostate cancer with cost-effectiveness in certain scenarios.

Genomic Classifiers in Personalized Prostate Cancer Radiation Therapy Approaches: A Systematic Review and Future Perspectives Based on International Consensus.

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.

The maximum standardized uptake value in patients with recurrent or persistent prostate cancer after radical prostatectomy and PSMA-PET-guided salvage radiotherapy-a multicenter retrospective analysis.

PURPOSE: This study aims to evaluate the association of the maximum standardized uptake value (SUVmax) in positron-emission tomography targeting prostate-specific membrane antigen (PSMA-PET) prior to salvage radiotherapy (sRT) on biochemical recurrence free survival (BRFS) in a large multicenter cohort. METHODS: Patients who underwent 68 Ga-PSMA11-PET prior to sRT were enrolled in four high-volume centers in this retrospective multicenter study. Only patients with PET-positive local recurrence (LR) and/or nodal recurrence (NR) within the pelvis were included. Patients were treated with intensity-modulated-sRT to the prostatic fossa and elective lymphatics in case of nodal disease. Dose escalation was delivered to PET-positive LR and NR. Androgen deprivation therapy was administered at the discretion of the treating physician. LR and NR were manually delineated and SUVmax was extracted for LR and NR. Cox-regression was performed to analyze the impact of clinical parameters and the SUVmax-derived values on BRFS. RESULTS: Two hundred thirty-five patients with a median follow-up (FU) of 24 months were included in the final cohort. Two-year and 4-year BRFS for all patients were 68% and 56%. The presence of LR was associated with favorable BRFS (p = 0.016). Presence of NR was associated with unfavorable BRFS (p = 0.007). While there was a trend for SUVmax values ≥ median (p = 0.071), SUVmax values ≥ 75% quartile in LR were significantly associated with unfavorable BRFS (p = 0.022, HR: 2.1, 95%CI 1.1-4.6). SUVmax value in NR was not significantly associated with BRFS. SUVmax in LR stayed significant in multivariate analysis (p = 0.030). Sensitivity analysis with patients for who had a FU of > 12 months (n = 197) confirmed these results. CONCLUSION: The non-invasive biomarker SUVmax can prognosticate outcome in patients undergoing sRT and recurrence confined to the prostatic fossa in PSMA-PET. Its addition might contribute to improve risk stratification of patients with recurrent PCa and to guide personalized treatment decisions in terms of treatment intensification or de-intensification. This article is part of the Topical Collection on Oncology-Genitourinary.

Radiotherapy for hormone-sensitive prostate cancer with synchronous low burden of distant metastases.

PURPOSE: The DEGRO Expert Commission on Prostate Cancer has revised the indication for radiation therapy of the primary prostate tumor in patients with synchronous distant metastases with low metastatic burden. METHODS: The current literature in the PubMed database was reviewed regarding randomized evidence on radiotherapy of the primary prostate tumor with synchronous low metastatic burden. RESULTS: In total, two randomized trials were identified. The larger study, the STAMPEDE trial, demonstrated an absolute survival benefit of 8% after 3 years for patients with low metastatic burden treated with standard of care (SOC) and additional radiotherapy (RT) (EQD2 ≤ 72 Gy) of the primary tumor. Differences in the smaller Horrad trial were not statistically significant, although risk reduction in the subgroup (< 5 bone metastases) was equal to STAMPEDE. The STOPCAP meta-analysis of both trials demonstrated the benefit of local radiotherapy for up to 4 bone lesions and an additional subanalysis of STAMPEDE also substantiated this finding in cases with M1a-only metastases. CONCLUSION: Therefore, due to the survival benefit after 3 years, current practice is changing. New palliative SOC is radiotherapy of the primary tumor in synchronously metastasized prostate cancer with low metastatic burden (defined as ≤ 4 bone metastases, with or without distant nodes) or in case of distant nodes only detected by conventional imaging.

Metastasis-Free Survival and Patterns of Distant Metastatic Disease After Prostate-Specific Membrane Antigen Positron Emission Tomography (PSMA-PET)-Guided Salvage Radiation Therapy in Recurrent or Persistent Prostate Cancer After Prostatectomy.

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.