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.

Whole pelvis vs. hemi pelvis elective nodal radiotherapy in patients with PSMA-positive nodal recurrence after radical prostatectomy - a retrospective multi-institutional propensity score analysis.

PURPOSE: Despite growing evidence for bilateral pelvic radiotherapy (whole pelvis RT, WPRT) there is almost no data on unilateral RT (hemi pelvis RT, HPRT) in patients with nodal recurrent prostate cancer after prostatectomy. Nevertheless, in clinical practice HPRT is sometimes used with the intention to reduce side effects compared to WPRT. Prostate-specific membrane antigen positron emission tomography / computed tomography (PSMA-PET/CT) is currently the best imaging modality in this clinical situation. This analysis compares PSMA-PET/CT based WPRT and HPRT. METHODS: A propensity score matching was performed in a multi-institutional retrospective dataset of 273 patients treated with pelvic RT due to nodal recurrence (214 WPRT, 59 HPRT). In total, 102 patients (51 in each group) were included in the final analysis. Biochemical recurrence-free survival (BRFS) defined as prostate specific antigen (PSA) < post-RT nadir + 0.2ng/ml, metastasis-free survival (MFS) and nodal recurrence-free survival (NRFS) were calculated using the Kaplan-Meier method and compared using the log rank test. RESULTS: Median follow-up was 29 months. After propensity matching, both groups were mostly well balanced. However, in the WPRT group there were still significantly more patients with additional local recurrences and biochemical persistence after prostatectomy. There were no significant differences between both groups in BRFS (p = .97), MFS (p = .43) and NRFS (p = .43). After two years, BRFS, MFS and NRFS were 61%, 86% and 88% in the WPRT group and 57%, 90% and 82% in the HPRT group, respectively. Application of a boost to lymph node metastases, a higher RT dose to the lymphatic pathways (> 50 Gy EQD2α/ß=1.5 Gy) and concomitant androgen deprivation therapy (ADT) were significantly associated with longer BRFS in uni- and multivariate analysis. CONCLUSIONS: Overall, this analysis presents the outcome of HPRT in nodal recurrent prostate cancer patients and shows that it can result in a similar oncologic outcome compared to WPRT. Nevertheless, patients in the WPRT may have been at a higher risk for progression due to some persistent imbalances between the groups. Therefore, further research should prospectively evaluate which subgroups of patients are suitable for HPRT and if HPRT leads to a clinically significant reduction in toxicity.

Metastases-directed stereotactic body radiotherapy in combination with targeted therapy or immunotherapy: systematic review and consensus recommendations by the EORTC-ESTRO OligoCare consortium.

Stereotactic body radiotherapy (SBRT) for patients with metastatic cancer, especially when characterised by a low tumour burden (ie, oligometastatic disease), receiving targeted therapy or immunotherapy has become a frequently practised and guideline-supported treatment strategy. Despite the increasing use in routine clinical practice, there is little information on the safety of combining SBRT with modern targeted therapy or immunotherapy and a paucity of high-level evidence to guide clinical management. A systematic literature review was performed to identify the toxicity profiles of combined metastases-directed SBRT and targeted therapy or immunotherapy. These results served as the basis for an international Delphi consensus process among 28 interdisciplinary experts who are members of the European Society for Radiotherapy and Oncology (ESTRO) and European Organisation for Research and Treatment of Cancer (EORTC) OligoCare consortium. Consensus was sought about risk mitigation strategies of metastases-directed SBRT combined with targeted therapy or immunotherapy; a potential need for and length of interruption to targeted therapy or immunotherapy around SBRT delivery; and potential adaptations of radiation dose and fractionation. Results of this systematic review and consensus process compile the best available evidence for safe combination of metastases-directed SBRT and targeted therapy or immunotherapy for patients with metastatic or oligometastatic cancer and aim to guide today's clinical practice and the design of future clinical trials.

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.

Stereotactic radiotherapy combined with immunotherapy or targeted therapy for metastatic renal cell carcinoma.

OBJECTIVES: To evaluate the safety and efficacy of stereotactic radiotherapy (SRT) in patients with metastatic renal cell carcinoma (mRCC) concurrently receiving targeted therapy (TT) or immunotherapy. PATIENTS AND METHODS: Data on patients with mRCC were extracted from a retrospective international multicentre register study (TOaSTT), investigating SRT concurrent (≤30 days) with TT/immune checkpoint inhibitor (ICI) therapy. Overall survival (OS), progression-free survival (PFS), local metastasis control (LC) and time to systemic therapy switch were analysed using Kaplan-Meier curves and log-rank testing. Clinical and treatment factors influencing survival were analysed using multivariate Cox regression. Acute and late SRT-induced toxicity were defined according to the Common Terminology Criteria for Adverse Events v.4.03. RESULTS: Fifty-three patients who underwent 128 sessions of SRT were included, of whom 58% presented with oligometastatic disease (OMD). ICIs and TT were received by 32% and 68% of patients, respectively. Twenty patients (37%) paused TT for a median (range) of 14 (2-21) days. ICI therapy was not paused in any patient. A median (range) of 1 (1-5) metastatic tumour was treated per patient, with a median (range) SRT dose of 65 (40-129.4) Gy (biologically effective dose). The OS, LC and PFS rates at 1 year were 71%, 75% and 25%, respectively. The median OS and PFS were not significantly different among patients receiving TT vs those receiving ICIs (P = 0.329). New lesions were treated with a repeat radiotherapy course in 46% of patients. After 1 year, 62% of patients remained on the same systemic therapy as at the time of SRT; this was more frequent for ICI therapy compared to TT (83% vs 36%; P = 0.035). OMD was an independent prognostic factor for OS (P = 0.004, 95% confidence interval [CI] 0.035-0.528) and PFS (P = 0.004; 95% CI 0.165-0.717) in multivariate analysis. Eastern Cooperative Oncology Group performance status (ECOG-PS) was the other independent prognostic factor for OS (P = 0.001, 95% CI 0.001-0.351). Acute grade 3 toxicity was observed in two patients, and late grade 3 toxicity in one patient. No grade 4 or 5 toxicity was observed. CONCLUSION: Combined treatment with TT or immunotherapy and concurrent SRT was safe, without signals of increased severe toxicity. As we observed no signal of excess toxicity, full-dose SRT should be considered to achieve optimal metastasis control in patients receiving TT or immunotherapy. Favourable PFS and OS were observed for patients with oligometastatic RCC with a good ECOG-PS, which should form the basis for prospective testing of this treatment strategy in properly designed clinical trials.

Prognostic risk classification for biochemical relapse-free survival in patients with oligorecurrent prostate cancer after [68Ga]PSMA-PET-guided metastasis-directed therapy.

PURPOSE: Since the success of prostate-specific membrane antigen-positron emission tomography (PSMA-PET) imaging for patients with oligorecurrent prostate cancer (ORPC), it is increasingly used for radiotherapy as metastasis-directed therapy (MDT). Therefore, we developed a prognostic risk classification for biochemical relapse-free survival (bRFS) for patients after PSMA-PET-guided MDT after radical prostatectomy. METHODS: We analyzed 292 patients with local recurrence (LR) and/or pelvic lymph node (LN) lesions and/or up to five distant LN, bone (BM), or visceral metastases (VM) detected with [68Ga]PSMA-PET imaging. Median follow-up was 16 months (range 0-57). The primary endpoint was bRFS after MDT. Cox regression analysis for risk factors was incorporated into a recursive partitioning analysis (RPA) with classification and regression tree method. RESULTS: PSA at recurrence ≥ 0.8 ng/mL, BM, and VM was significantly associated with biochemical relapse. RPA showed five groups with tenfold cross-validation of 0.294 (SE 0.032). After building risk classes I to IV (p < 0.0001), mean bRFS was 36.3 months (95% CI 32.4-40.1) in class I (PSA < 0.8 ng/mL, no BM) and 25.8 months (95% CI 22.5-29.1) in class II (PSA ≥ 0.8 ng/mL, no BM, no VM). LR and/or pelvic LNs caused relapse in classes I and II. Mean bRFS was 16.0 months (95% CI 12.4-19.6) in class III (PSA irrelevant, present BM) and 5.7 months (95% CI 2.7-8.7) in class IV (PSA ≥ 0.8 ng/mL, no BM, present VM). CONCLUSION: We developed and internally validated a risk classification for bRFS after PSMA-PET-guided MDT. Patients with PSA < 0.8 ng/mL and local relapse only (LR and/or pelvic LNs) had the most promising bRFS. PSA ≥ 0.8 ng/mL and local relapse only (LR and/or pelvic LNs) indicated intermediate risk for failure. Patients with BM were at higher risk regardless of the PSA. However, those patients still show satisfactory bRFS. In patients with VM, bRFS is heavily decreased. MDT in such cases should be discussed individually.

Efficacy of PSMA ligand PET-based radiotherapy for recurrent prostate cancer after radical prostatectomy and salvage radiotherapy.

BACKGROUND: A substantial number of patients will develop further biochemical progression after radical prostatectomy (RP) and salvage radiotherapy (sRT). Recently published data using prostate-specific membrane antigen ligand positron emission tomography (PSMA - PET) for re-staging suggest that those recurrences are often located outside the prostate fossa and most of the patients have a limited number of metastases, making them amenable to metastasis-directed treatment (MDT). METHODS: We analyzed 78 patients with biochemical progression after RP and sRT from a retrospective European multicenter database and assessed the biochemical recurrence-free survival (bRFS; PSA < nadir + 0.2 ng/ml or no PSA decline) as well as the androgen deprivation therapy- free survival (ADT-FS) using Kaplan-Meier curves. Log-rank test and multivariate analysis was performed to determine influencing factors. RESULTS: A total of 185 PSMA - PET positive metastases were detected and all lesions were treated with radiotherapy (RT). Concurrent ADT was prescribed in 16.7% (13/78) of patients. The median PSA level before RT was 1.90 ng/mL (range, 0.1-22.1) and decreased statistically significantly to a median PSA nadir level of 0.26 ng/mL (range, 0.0-12.25; p < 0.001). The median PSA level of 0.88 ng/mL (range, 0.0-25.8) at the last follow-up was also statistically significantly lower (p = 0.008) than the median PSA level of 1.9 ng/mL (range, 0.1-22.1) before RT. The median bRFS was 17.0 months (95% CI, 14.2-19.8). After 12 months, 55.3% of patients were free of biochemical progression. Multivariate analyses showed that concurrent ADT was the most important independent factor for bRFS (p = 0.01). The median ADT-FS was not reached and exploratory statistical analyses estimated a median ADT-FS of 34.0 months (95% CI, 16.3-51.7). Multivariate analyses revealed no significant parameters for ADT-FS. CONCLUSIONS: RT as MDT based on PSMA - PET of all metastases of recurrent prostate cancer after RP and sRT represents a viable treatment option for well-informed and well-selected patients.

Outcomes of adolescents and young adults treated for brain and skull base tumors with pencil beam scanning proton therapy.

BACKGROUND: The use of proton therapy (PT) in adolescents and young adults (AYAs) is becoming increasingly popular. This study aims to assess the outcomes and late toxicity consequences in AYAs (15-39 years) with brain/skull base tumors treated with pencil beam scanning proton therapy. METHODS: One hundred seventy six AYAs treated curatively at the Paul Scherrer Institute (PSI) were identified. Median age was 30 years (range 15-39) and median prescribed dose was 70.0 Gy (relative biological effectiveness [RBE]) (range 50.4-76.0). The most common tumors treated were chordomas/chondrosarcomas (61.4%), followed by gliomas (15.3%), and meningiomas (14.2%). RESULTS: After a median follow up of 66 months (range 12-236), 24 (13.6%) local only failures and one (0.6%) central nervous system (CNS) distant only failure were observed. The 6-year local control, distant progression-free survival, and overall survival were 83.2%, 97.4%, and 90.2%, respectively. The 6-year high-grade (≥grade [G] 3) PT-related late toxicity-free survival was 88.5%. Crude late toxicity rates were 26.2% G1, 37.8% G2, 12.2% G3, 0.6% G4, and 0.6% G5. The one G4 toxicity was a retinopathy and one G5 toxicity was a brainstem hemorrhage. The 6-year cumulative incidences for any late PT-related pituitary, ototoxicity, and neurotoxicity were 36.3%, 18.3%, and 25.6%; whilst high-grade (≥G3) ototoxicity and neurotoxicity were 3.4% and 2.9%, respectively. No secondary malignancies were observed. The rate of unemployment was 9.5% pre-PT, increasing to 23.8% post-PT. Sixty-two percent of survivors were working whilst 12.7% were in education post-PT. CONCLUSIONS: PT is an effective treatment for brain/skull base tumors in the AYA population with a reasonable late toxicity profile. Despite good clinical outcomes, around one in four AYA survivors are unemployed after treatment.

Clinical impact of 68Ga-PSMA-11 PET on patient management and outcome, including all patients referred for an increase in PSA level during the first year after its clinical introduction.

PURPOSE: The fast-increasing use of positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) ligand for the imaging of prostate cancer (PCA) biochemical recurrence has led to a rapid change in treatment concepts. Since the superiority of 68Ga-PSMA-11 PET in detecting recurrent PCA is well established, the aim of our study was to assess its effect on management and outcome in all patients imaged during the first year after its introduction into clinical routine. METHODS: Of 327 patients imaged, 223 were referred for recurrent PCA and gave written informed consent for further analysis of their data for this retrospective consecutive cohort analysis. Twenty patients were lost to further follow-up. The rate of detection of recurrence by 68Ga-PSMA-11 PET was based on the clinical reports. Management before the availability of PET diagnostic information was assessed according to guidelines (therapy option without 68Ga-PSMA-11 PET). In the 203 patients with follow-up 6 months after 68Ga-PSMA-11 PET, the therapies effectively implemented as well as follow-up PSA levels were evaluated, with a PSA value of <0.2 ng/ml representing a complete response and a decrease in PSA value of at least 50% from baseline representing a partial response. RESULTS: 68Ga-PSMA-11 PET was positive and identified recurrence in 166 of the 223 patients (74%), with a detection rate of 50% for recurrent disease at low PSA values of <0.5 ng/ml. 68Ga-PSMA-11 PET led to a change in management in 122 of the 203 patients (60%). A substantial increase in the use of metastasis-targeted treatment and a reduction in the use of systemic treatment were observed, with 59 of the 203 patients (29%) undergoing targeted radiotherapy (RTXa) only, and 20 patients (10%) undergoing RTXa with hormonal therapy as the two most frequently selected therapy options. The proportion of patients in whom systemic therapy was selected decreased from 60% (133 of 223 patients) to 34% (70 of 203 patients) on the basis of the information provided by the 68Ga-PSMA-11 PET scan. PSMA PET-directed metastasis-targeted treatment led to a complete response after 6 months in 45% of patients. CONCLUSION: The high rate of recurrence detection by PSMA PET was confirmed and PSMA PET led to a change in management in 60% of patients. Focal therapy for PSMA-positive lesions is a promising approach with complete responses in 45% of patients.

Current and potential future role of PSMA-PET in patients with castration-resistant prostate cancer.

PURPOSE: To review the current literature and discuss potential future roles of the novel positron emission tomography (PET) tracers targeting the prostate-specific membrane antigen (PSMA) in patients with castration-resistant prostate cancer (CRPC). METHODS: A literature search on February 19th 2018 was conducted using the Medline database and www.clinicaltrials.gov . Additionally, illustrative cases of CRPC patients from our own institution who were restaged and treated based on PSMA-PET scan results are provided. RESULTS: 11 Studies met the inclusion criteria. PSMA-PET detected more metastatic lesions compared to conventional bone scan. Several patients were up-staged from non-metastatic CRPC (nmCRPC) to metastatic CRPC (mCRPC). Currently, no clear consensus exists regarding treatment response assessment in PSMA-PET scans for mCRPC patients undergoing treatment. Also, the role of PSMA-PET as a gatekeeper for systemic therapy or radioligands is currently undefined. PSMA-guided metastasis-directed radiotherapy may not only alleviate local symptoms but has the potential to defer systemic treatment in patients with oligoprogressive CRPC. CONCLUSION: Compared to bone scan, PSMA-PET is more sensitive and specific to detect metastases but the therapeutic consequences of PSMA-PET results in the setting of CRPC remain unclear. Until future studies define the role of PSMA-PET in patients with CRPC, the current standard for imaging remains bone scan and computerized tomography.

The blind spots in follow-up after nephrectomy or nephron-sparing surgery for localized renal cell carcinoma.

PURPOSE: This study was conducted to identify time to and type of recurrence in relation to scheduled follow-up (FU) imaging after nephrectomy or nephron-sparing surgery for localized renal cell carcinoma (RCC). Using this information, future guidelines could improve the early detection of metastases. METHODS: Measured from moment of treatment, all recurrences after (partial) nephrectomy performed between 2000 and 2010 were categorized as being detected early (<6 months), late (>5 year for T1/T2 and >10 year for T3/T4), or intermediate (time within those two) based on European Association of Urology (EAU) guidelines. Also symptomatic presentation was screened. RESULTS: Recurrent disease developed in 80 of 396 patients after (partial) tumor nephrectomy. Mean time to recurrence in months was 56 (n = 21) for T1, 24 (n = 18) for T2, 21 (n = 38) for T3, and 11 (n = 2) for T4 tumors. Detection of early recurrence occurred in 22 patients (28%), of which 20 (91%) were T2-T4 tumors. In 10 (48%) of T1 tumors, late recurrence was found. Of the patients with symptoms due to recurrence, 65% (17/26) were detected outside the FU surveillance protocol (P = 0.01). CONCLUSION: A more intensive FU the first 6 months after nephrectomy for T2-T4 and FU imaging ≥5 years after surgery for T1 tumors might improve early and asymptomatic detection of recurrent disease after nephrectomy for RCC.

Multi-institutional Analysis of Metastasis-directed Therapy with or Without Androgen Deprivation Therapy in Oligometastatic Castration-sensitive Prostate Cancer.

BACKGROUND: Metastasis-directed therapy (MDT) is increasingly being used in oligometastatic castration-sensitive prostate cancer (omCSPC). However, it is currently unclear how to optimally integrate MDT with the standard of care of systemic hormonal therapy. OBJECTIVE: To report long-term outcomes of MDT alone versus MDT and a defined course of androgen deprivation therapy (ADT) in omCSPC. DESIGN, SETTING, AND PARTICIPANTS: Here, a multicenter, international retrospective cohort of omCSPC as defined by conventional imaging was reported. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical progression-free survival (bPFS), distant progression-free survival (dPFS), and combined biochemical or distant progression-free survival (cPFS) were evaluated with Kaplan-Meier and multivariable Cox proportional hazard regression models. RESULTS AND LIMITATIONS: A total of 263 patients were included, 105 with MDT + ADT and 158 with MDT alone. The majority of patients had metachronous disease (90.5%). Five-year bPFS, dPFS, and cPFS were, respectively, 24%, 41%, and 19% in patients treated with MDT + ADT and 11% (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.36-0.64), 29% (HR 0.56, 95% CI 0.40-0.78), and 9% (HR 0.50, 95% CI 0.38-0.67) in patients treated with MDT alone. On a multivariable analysis adjusting for pretreatment variables, the use of ADT was associated with improved bPFS (HR 0.43, p < 0.001), dPFS (HR 0.45, p = 0.002), and cPFS (HR 0.44, p < 0.001). CONCLUSIONS: In this large multi-institutional report, the addition of concurrent ADT to MDT appears to improve time to prostate-specific antigen progression and distant recurrence, noting that about 10% patients had durable control with MDT alone. Ongoing phase 3 studies will help further define treatment options for omCSPC. PATIENT SUMMARY: Here, we report a large retrospective review evaluating the outcomes of metastasis-directed therapy with or without a limited course of androgen deprivation for patients with oligometastatic castration-sensitive prostate cancer. This international multi-institutional review demonstrates that the addition of androgen deprivation therapy to metastasis-directed therapy (MDT) improves progression-free survival. While a proportion of patients appear to have long-term disease control with MDT alone, further work in biomarker discovery is required to better identify which patients would be appropriate for de-escalated therapy.

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.

Can PSMA PET/CT help in dose-tailoring in post-prostatectomy radiotherapy?

There are few randomized trials to evaluate the use of PSMA-PET in the planning of post-prostatectomy radiotherapy. There are two unresolved questions 1) should we increase the dose to lesions visible on PSMA-PET 2) can we reduce dose in the case of a negative PSMA-PET. In this review, we summarize and discuss the available evidence in the literature. We found that in general, there seems to be an advantage for dose-increase, but ta large recent study from the pre-PSMA era didn't show an advantage for dose escalation. Retrospective studies have shown that conventional doses to PSMA-PET-positive lesions seem sufficient. On the other hand, in the case of a negative PSMA-PET, there is no evidence that dose-reduction is possible. In the future, the combination of PSMA-PET with genomic classifiers could help in better identify patients who might benefit from either dose- de-or -increase. We further need to identify intraindividual references to help identify lesions with higher aggressiveness.

Interdisciplinary Swiss consensus recommendations on staging and treatment of advanced prostate cancer.

The management of prostate cancer is undergoing rapid changes in all disease settings. Novel imaging tools for diagnosis have been introduced, and the treatment of high-risk localized, locally advanced and metastatic disease has changed considerably in recent years. From clinical and health-economic perspectives, a rational and optimal use of the available options is of the utmost importance. While international guidelines list relevant pivotal trials and give recommendations for a variety of clinical scenarios, there is much room for interpretation, and several important questions remain highly debated. The goal of developing a national consensus on the use of these novel diagnostic and therapeutic strategies in order to improve disease management and eventually patient outcomes has prompted a Swiss consensus meeting. Experts from several specialties, including urology, medical oncology, radiation oncology, pathology and nuclear medicine, discussed and voted on questions of the current most important areas of uncertainty, including the staging and treatment of high-risk localized disease, treatment of metastatic hormone-sensitive prostate cancer (mHSPC) and use of new options to treat metastatic castration-resistant prostate cancer (mCRPC).

Definition and Diagnosis of Oligometastatic Bladder Cancer: A Delphi Consensus Study Endorsed by the European Association of Urology, European Society for Radiotherapy and Oncology, and European Society of Medical Oncology Genitourinary Faculty.

BACKGROUND: In contrast to other cancers, the concept of oligometastatic disease (OMD) has not been investigated in bladder cancer (BC). OBJECTIVE: To develop an acceptable definition, classification, and staging recommendations for oligometastatic BC (OMBC) spanning the issues of patient selection and the roles of systemic therapy and ablative local therapy. DESIGN, SETTING, AND PARTICIPANTS: A European consensus group of 29 experts, led by the European Association of Urology (EAU), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Medical Oncology (ESMO), and including members from all other relevant European societies, was established. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A modified Delphi method was used. A systematic review was used to build consensus questions. Consensus statements were extracted from two consecutive surveys. The statements were formulated during two consensus meetings. Agreement levels were measured to determine if consensus was achieved (≥75% agreement). RESULTS AND LIMITATIONS: The first survey included 14 questions and the second survey had 12. Owing to a considerable lack of evidence, which was the major limitation, definition was limited in the context of de novo OMBC, which was further classified as synchronous OMD, oligorecurrence, and oligoprogression. A maximum of three metastatic sites, all resectable or amenable to stereotactic therapy, was proposed as the definition of OMBC. Pelvic lymph nodes represented the only "organ" not included in the definition of OMBC. For staging, no consensus on the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography was reached. A favourable response to systemic treatment was proposed as the criterion for selection of patients for metastasis-directed therapy. CONCLUSIONS: A consensus statement on the definition and staging of OMBC has been formulated. This statement will help to standardise inclusion criteria in future trials, potentiate research on aspects of OMBC for which consensus was not achieved, and hopefully will lead to the development of guidelines on optimal management of OMBC. PATIENT SUMMARY: As an intermediate state between localised cancer and disease with extensive metastasis, oligometastatic bladder cancer (OMBC) might benefit from a combination of systemic treatment and local therapy. We report the first consensus statements on OMBC drawn up by an international expert group. These statements can provide a basis for standardisation of future research, which will lead to high-quality evidence in the field.

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.

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.

Photodynamic therapy as novel nephron sparing treatment option for small renal masses.

PURPOSE: Photodynamic therapy has great potential as nephron sparing therapy for small renal masses. Using mTHPC [meso-tetra(hydroxyphenyl)chlorin] (BioLitec Pharma, Dublin, Ireland), a photosensitizer that targets vasculature and tissue, we determined whether renal tumors could be ablated using mTHPC mediated photodynamic therapy in a translational renal carcinoma mouse model. MATERIALS AND METHODS: We administered mTHPC intravenously in kidney tumor bearing mice. Tumor diameter was about 7 mm. At several drug-light intervals a cylindrical laser fiber was placed intratumorally for interstitial illumination using a wavelength of 652 nm. We determined mTHPC biodistribution up to 48 hours after administration and tumor destruction after mTHPC mediated photodynamic therapy. In vitro mTHPC uptake and photodynamic therapy induced cytotoxicity were studied in human endothelial, renal and renal cell carcinoma cell lines. RESULTS: Ablated regions with a maximum diameter of 9.3 mm and complete loss of cell viability were observed at a drug-light interval of 4 hours, when mTHPC was increased in blood and tissue. Viable renal tissue remained detectable outside the illuminated area. In endothelial cells mTHPC uptake and sensitivity to photodynamic therapy were increased compared to those in renal cell carcinoma and renal cells. CONCLUSIONS: mTHPC mediated photodynamic therapy is a nephron sparing therapy. The extent of renal tumor destruction is adequate for clinical translation. Localization of mTHPC in tumor vasculature and tissue produces a strong combined effect. Our findings justify further preclinical studies of the applicability of photodynamic therapy for renal cell carcinoma before photodynamic therapy can become a valuable addition to current minimally invasive treatments of small renal masses.