BACKGROUND:To determine outcomes of MRI-assisted radiosurgery (MARS) for salvage brachytherapy using the radioisotope 103Pd after various upfront treatments including surgery, external beam radiotherapy, and brachytherapy. METHODS:We retrospectively reviewed data for patients who underwent salvage MARS for intraprostatic lesions or prostate bed recurrences from 2016 to 2022. Biochemical recurrence, prostate cancer-specific, and overall survival, and the cumulative incidences of toxicities, were determined by Kaplan-Meier estimates. Cox proportional hazards models were used to determine associations between clinical and treatment variables and risk of toxicity. RESULTS:Study included 31 patients with local recurrence after initial definitive treatment. Four (13%) were initially treated with prostatectomy and salvage radiation, twenty-four (77%) with external beam radiation, and three with brachytherapy. Most had intermediate- or high-risk prostate cancer at the time of diagnosis. Twenty-two patients (71%) had focal-gland and nine (29%) had whole-gland MARS LDR salvage brachytherapy. Median follow-up was 35-28 months. By last follow-up, 5 patients (16%) experienced recurrence and started ADT, 3 patients started ADT before experiencing recurrence due to physician discretion, and 23 patients (74%) remained without recurrence. No patients died of prostate cancer. Median PSA nadir for recurrence-free patients was 0.2 ng/mL (range, 0-0.9 ng/mL). Grade 3 toxicities occurred in 4 patients (13%) including 3 patients (13%) with genitourinary events only and 1 patient (3%) with both a grade 3 genitourinary and a grade 3 gastrointestinal event. CONCLUSIONS:In this modern series of patients undergoing salvage MARS with 103Pd, we observed acceptable toxicity and early, promising biochemical disease control. These findings highlight the broader applicability of salvage MARS regardless of upfront treatment modality.

799 Background: Metastasis-directed therapy (MDT) for oligometastatic cancer is a concept utilized for prostate and kidney cancer. Clinical research in MDT for oligometastatic urothelial carcinoma (UC) remains sparse especially in the modern era where systemic therapy advancements have substantially improved patient’s outcomes overall. We explored our institutional experience of patients with oligometastatic carcinoma of the bladder and upper tract undergoing MDT utilizing radiotherapy (RT). Methods: Patients were retrospectively identified with oligometastatic bladder or upper tract cancer from January 2016 to July 2024 with five or less sites of metastases. Those with equivalent dose of RT (EQD2 10 ) ≥ 45Gy to metastases were included. Progression free survival (PFS) and overall survival (OS) were evaluated using Kaplan Meier from time of diagnosis to metastatic disease. Cox proportional hazards analysis was conducted to determine covariates associated with survival endpoints. Results: 60 patients with oligometastasis were included with 8 patients excluded due to a RT dose EQD2 10 < 45Gy. 52 patients were in final analysis. Most were men (67%) with a median age 68 years (range, 35-91). Most had bladder primary (79%) with the remaining including upper tract. Majority had pure UC (85%) and the remainder were UC subtypes with variant histology including small cell (8%), squamous (6%), sarcomatoid (2%). Median number of metastases was 1 site, while 23% had 3+ sites. Bony metastases (27%) were most common site, then retroperitoneal nodes (18%) and lung (17%). Most received ≥2 systemic therapy cycles before MDT (62%) with 8% without any therapy prior to MDT. Most commonly used therapy included ddMVAC (21%), Gem/Cis (20%), pembrolizumab (15%), and EV (12%). MDT was delivered to all metastases in 71%, while the remaining had MDT to select sites. Most common MDT dose was 30Gy in 3 fractions (21%) followed by 50Gy in 4 fractions (17%). Median follow up from metastatic diagnosis was 19 months (range, 3-106 months). Median PFS and OS was 21 months (95% CI 8-33 months), and 39 months (95% CI, 14-64 months), respectively. At last follow up, 31 patients were alive (60%). Most common first recurrence was distant from site of MDT (96%) while 2 patients had in-field recurrence in pelvic bones. On univariate analysis, those with 1 vs 2+ sites had improved PFS with MDT (p=0.03, 95% CI 1.1-6.0). Univariate showed no association with MDT to all sites vs select, age, or # lines of systemic therapy. Conclusions: As systemic therapy has improved for patients with bladder and upper tract cancers, MDT may serve as an effective adjunct to improve cancer control. Baseline characteristics. Characteristic (n=52) No % Median Age (yrs) 68 Histology UC 44 85% UC subtype with variant histology 7 15% Site of Primary Bladder 41 79% Upper Tract 11 21% Lines of therapy before MDT 0 4 8% 1 17 33% 2+ 31 60%

e17153 Background: Focal therapy (FT) for prostate adenocarcinoma (PCa) aims to minimize adverse effects while achieving tumor control. While FT is becoming more prevalent, there is no consensus on treatment after FT failure. The goal of this study was to measure the toxicity and oncological outcomes of external beam radiation therapy (EBRT) after cryosurgery (CS) or high-intensity focused ultrasound (HIFU) to evaluate its role as a salvage treatment option for FT failure. Methods: Institutional databases were queried to identify patients diagnosed with PCa from 2002 to 2024 who were treated with CS or HIFU as the initial treatment. Patients who underwent intensity-modulated radiation therapy (IMRT) or proton therapy (PT) for recurrent localized PCa were included. Patients received concurrent androgen deprivation therapy (ADT) as recommended. Primary outcomes were acute and late genitourinary (GU) and gastrointestinal (GI) toxicity from EBRT using the modified Radiation Therapy Oncology Group (RTOG) scale. Acute and late toxicities were defined as events occurring during and up to 3 months after EBRT and after 3 months, respectively. Secondary outcomes were biochemical recurrence-free survival (bFS), metastasis-free survival (MFS), and overall survival (OS). Biochemical recurrence was defined as a PSA increase of ≥2 ng/mL above the nadir. Toxicity outcomes were reported using descriptive statistics, and survival outcomes were analyzed using Kaplan-Meier analysis. Results: 36 patients were included in this study (23 CS, 12 HIFU, and 1 both). 28 patients received IMRT and 8 patients proton therapy. 30 patients underwent confirmation biopsy before the radiation therapy with the following Gleason scores: 7 (3+4) in 15 patients, 7 (4+3) in 6 patients, 8 (4+4) in 10 patients, ≥9 in 3 patients. The median dose was 76 Gy (range 72-79.2 Gy) in 1.8 Gy (24 patients) or 2.0 Gy (12 patients) per fraction. 32 patients received ADT with radiation for a median duration of 6 months (range 4-24). Median follow-up period was 38 months (IQR 20.5–61.8). Acute genitourinary (GU) toxicities of grade 1 and grade 2 were observed in 11 patients (30.6%) and 7 patients (19.4%), respectively. Acute gastrointestinal (GI) toxicities of grade 1 and grade 2 were reported in 7 patients (19.4%) and 1 patient (2.8%), respectively. There were no grade 3 or higher acute GU or GI toxicities seen. Late GU toxicities included grade 1 and grade 2 in 2 patients each (8.3%), with grade 3 late GU toxicity (hematuria) occurring in 1 patient (4.2%). Grade 1 late GI toxicity was observed in 2 patients (8.3%). There was no grade 2 or higher late GI toxicity. bFS, MFS, and OS were 94.1%, 100%, and 100% at 5 years and 70.6%, 83.3%, and 75.8% at 10-years, respectively. Conclusions: Our data demonstrate that EBRT after FT failure is a safe and effective treatment. Studies with larger patient cohorts are required to further validate the use of EBRT as a salvage treatment.

Purpose/Objective(s) Trimodality therapy with radiation therapy (RT) is considered among standard of care for muscle-invasive bladder cancer, though its role in patients with locally advanced and metastatic urothelial carcinoma (LA-UC, M-UC) is less well understood. Local RT for metastatic prostate cancer has shown reduction in the incidence of severe genitourinary (GU) events. We therefore aim to evaluate the impact of RT on the rate of severe GU events in LA-UC and M-UC. Materials/Methods Patients with LA-UC, node positive, and/or M-UC receiving definitive RT with a dose threshold of 54 Gy at a single institution from June 2017 to January 2023 were assessed for severe GU events (nephrostomy, ureteral stents, catheterization, cystoscopic and/or surgical intervention) following RT. Kaplan-Meier analysis was used to estimate time-to-event outcomes. Results There were 20 patients treated with definitive RT following transurethral resection of bladder tumor. Most were men (65%) with a median age of 70.5 years. Patients had locally advanced T3-4 (80%), node positive (45%), and/or metastatic disease (30%), mostly with pure urothelial carcinoma (60%) or variant squamous cell (25%) histology. Hydronephrosis was present at diagnosis in 11 patients (27% resolved post RT; 9% PCN removed). The majority of patients were treated with concurrent systemic therapy (85%), most commonly with pembrolizumab (53%), while 15% of patients received RT alone. Induction chemotherapy therapy was delivered in 65% of patients (37% platinum-based). The predominant radiation technique used was intensity modulated RT (90%), while 10% of patient received 3D conformal RT. The median dose was 59.4 Gy (range = 50-65 Gy) with either conventional (70%) or hypofractionated (30%) regimens to the bladder (95%) or pelvis (5%), and 60% of patients received nodal RT. The median follow-up from completion of RT was 17.1 months (range = 3.9-74.9 months). There were severe GU events in 7 patient (35%) of patients with a mean time to event of 10.5 months (range = 0.4-74.9 months). Interestingly, patients who were 75 years old were significantly less likely to have a severe GU event than patients <75 years old (11% vs 54%, p = 0.029). There were no differences in severe GU events for patients stratified by RT dose/fractionation, presence of hydronephrosis, urothelial vs variant histology, use of concurrent chemotherapy, nodal RT, or M0 vs M1 disease. Conclusion Our findings suggest that RT for LA-UC and M-UC may extend time to severe GU events, particularly in elderly patients. This could potentially reduce disruptions in systemic therapy, enhance quality of life, and decrease hospitalizations. As this study is limited by sample size and potential selection bias, further validation and comparison studies are warranted to confirm these observations and guide clinical decision-making.

Purpose/Objective(s) The initial report of a prospective phase 3 randomized trial of dose-escalated, moderately hypofractionated versus conventionally fractionated radiation therapy for localized prostate cancer demonstrated superior cancer control with hypofractionated radiation. We analyzed the long-term outcomes to determine if this benefit was maintained given limited long-term data. Materials/Methods Between January 2001 and January 2010, men with localized prostate cancer were randomized to 75.6Gy in 1.8-Gy fractions delivered over 8.4 weeks (CIMRT) or 72Gy in 2.4-Gy fractions delivered over 6 weeks (HIMRT) using intensity modulated radiotherapy (IMRT) (IRB approved protocol ID00-381). Men were stratified at randomization by receipt of ADT and PSA ≤ 10 ng/mL. Modified RTOG criteria were used to grade late gastrointestinal (GI) and genitourinary (GU) toxicity. Primary outcome was failure defined as PSA failure (nadir + 2 ng/mL) or initiation of salvage therapy. Time to failure was calculated from the start of radiation while time to toxicity was measured from the end of radiation. Kaplan-Meier curves were generated to estimate rates of failure, survival, and toxicity. The log-rank test was used to compare the treatment arms. Characteristics were compared using Chi-square or Fisher’s exact test. Statistical analyses were performed using a data management and decision management software. Results Two hundred six patients with mostly NCCN intermediate risk (71%), Gleason grade group 2 (48%), and PSA ≤ 10 ng/mL (90%) prostate cancer were enrolled and randomized. One hundred two patients received CIMRT and 104 received HIMRT. Androgen deprivation therapy was administered to 24%. Median follow-up was 11 years. Patient and cancer characteristics were well balanced between treatment groups. Treatment failure occurred less frequently in men undergoing HIMRT (n = 13) compared to CIMRT (n = 22) but did not meet statistical significance (P = 0.077). The 10-year failure rate was 21% (95% CI = 13-30.5%) for CIMRT versus 11% (95% CI = 5.5-18.1%) for HIMRT. In the subgroup of men not receiving ADT, the 10-year failure rate was significantly less for HIMRT (13%) versus CIMRT (26%) (P = 0.039). Overall survival (OS) was similar between CIMRT and HIMRT (median OS, 20 years vs not reached) (P = 0.076). In addition, 15-year distant metastasis rate (DM) was similar between CIMRT (4%) and HIMRT (8%) (P = 0.22). 10-year cumulative late GU grade ≥ 2 toxicity was similar for HIMRT (26%) versus CIMRT (23%) (P = 0.54). The incidence of 10-year late GI grade ≥ 2 toxicity was similar between CIMRT (5%) and HIMRT (13%) (P = 0.08). No grade 4 toxicities were observed. Conclusion Long-term outcomes suggest a benefit in terms of treatment failure to dose-escalated, hypofractionated radiation, especially among patients not receiving ADT, without worse late toxicity.

Purpose: Trimodality therapy for muscle-invasive bladder cancer (MIBC) yields similar oncologic outcomes compared to radical cystectomy in appropriately selected patients; however, data regarding locally advanced MIBC (LA-MIBC) is limited. We explored our experience with LA-MIBC undergoing radiation therapy (RT). Methods: We retrospectively identified 30 patients from an institutional prospectively collated database with non-metastatic, LA-MIBC. Patients with T3-4 N0 or T2-4 N + treated from 2012 to 2022 with definitive-intent RT, who were not candidates for cystectomy were included. Kaplan-Meier analysis was used to estimate time-to- event outcomes, and multivariate analyses were conducted using Cox proportional hazards modeling. Results: 43 % had T3N0 disease, 30 % had T4N0 disease, and 27 % had node positive disease.. Neoadjuvant chemotherapy/systemic therapy was administered in 63 % of patients. Median dose and fractionation of RT was 60 Gy in 30 fractions. 23 % of patients received hypofractionated RT, 57 % received nodal RT. At a median follow-up of 20 (range, 1-75) months after RT, estimated 1- and 2-year OS was 73 % and 61 %, respectively. Estimated 1-year progression-free survival was 50%. Local bladder failure was a component of progression in 17% of patients, and all local bladder failure events occurred within the first 12 months following RT. Lymph node or distant metastases occurred in 23 % of patients. Estimated 1-year OS was 83 % with pure urothelial histology but only 58 % with variant histology (P = 0.001). Late grade 3 + GU and GI toxicity occurred in 7 % and 5 % of patients, respectively. Conclusions: In this cohort with LA-MIBC treated with RT, distant failures predominate, local failures are less common, and toxicity was minimal. Survival outcomes remain encouraging for RT in this challenging patient population. Further investigation is warranted to identify biomarkers for patient selection and strategies to improve distant control.

Purpose Brachytherapy boost has been shown to improve biochemical control when added to external beam radiotherapy (EBRT) in patients with unfavorable intermediate- and high-risk prostate cancer. We report the safety and early efficacy of using proton therapy (PT) and low-dose-rate (LDR) brachytherapy boost at the University of Texas MD Anderson Cancer Center. Methods and Materials A retrospective study was conducted, including all patients with intermediate- or high-risk prostate cancer treated with a combination of PT and LDR boost with or without androgen deprivation therapy (ADT), from 2010 until 2023. Patient, initial disease, and treatment characteristics and toxicity and efficacy outcomes were collected. Biochemical failure (BF) was defined per the Phoenix definition (nadir PSA + 2). Results One hundred patients received PT and LDR boost, with median age at diagnosis of 68 (IQR 61-72). Most patients (n=78) were Caucasian, 12 were Black, 5 Asian, 3 Hispanic. Thirty-five patients had NCCN intermediate-risk (4 favorable and 31 unfavorable), 55 had high- and 10 had very high-risk disease. The median PT and LDR doses were 44 CGE (range 40-50.4) and 90 Gy (range 90-110). Pd-103 was used in 96 patients, I-125 in 4 patients, and 91 patients had MRI-assisted radiosurgery (MARS) brachytherapy. ADT was used in 92 patients. Rectal spacer was used in 22 patients. After a median follow-up of 43 months, two patients developed BF for a 5-year biochemical recurrence-free survival of 95%. Of the 2 patients with BF, one patient had a PSA 3.2 at 23 months and unknown disease site recurrence and the second developed lymph node metastasis when PSA was 5.1 at 60 months and is receiving intermittent ADT. No patients developed local recurrence or distant metastasis, and none died of prostate cancer. One patient died of other causes with PSA <0.1 at time of death. One patient has increasing PSA but has not met BF criteria. Median PSA nadir was 0.01 (range 0.0-0.4). All patients (n=30) with at least 4 years of PSA follow-up achieved a nadir PSA of 0.2 or less. Four patients had acute urinary retention. Late grade 2 GU or GI toxicity was found in 11 patients (11%) and 3 patients (3%), respectively. Only one patient had a grade 3 toxicity (urethral stricture requiring dilatation and TURP). Conclusions Acknowledging the intermediate follow-up duration, PT and LDR boost with and without ADT can achieve high control rates and low toxicity for prostate cancer patients with unfavorable intermediate and high-risk prostate cancer. MARS has enabled the use of MRI at each step of the quality assurance process.

Purpose/Objective(s) Studies have demonstrated safety and efficacy utilizing stereotactic body radiotherapy (SBRT) for definitive treatment of localized prostate cancer. Magnetic resonance (MR) guided linear accelerators leverage advanced real-time imaging to improve visualization of tumors and organs at risk with potential to improve clinical outcomes. We report genitourinary (GU) and gastrointestinal (GI) toxicities and biochemical failure for patients treated with SBRT using MR or computed tomography (CT) guidance. Materials/Methods This is a pooled analysis of 201 patients with localized prostate cancer enrolled on prospective and retrospective registries at a single institution who received SBRT with CT (n = 112) or MR guidance (n = 89) from 2015-2024. Patients were treated with androgen deprivation therapy (ADT) per physician discretion. Initial patients received 37.5-40 Gy to the planning target volume (PTV) (n = 104); subsequent patients received 36.25 Gy to the PTV with a simultaneous integrated boost (SIB) of 40 Gy to the clinical tumor volume (prostate +/- proximal seminal vesicles per physician discretion) (n = 97), all in 5 fractions every other day. Acute (≤90 days after SBRT) and late toxicities were assessed using modified RTOG criteria during treatment and at each follow-up visit. Patient characteristics were compared with Fisher’s exact test and chi-squared test. Biochemical failure (PSA nadir + 2 ng/mL) free survival was estimated by the Kaplan-Meier method. Results Median age (range) was 65 (51-81) years vs 68 (52-94) in the CT vs MR cohort. In the CT cohort, 12% were low-risk and 88% were intermediate-risk. In the MR cohort, 3% were low-risk, 90% were intermediate-risk, and 7% were high-risk. A higher percentage of patients in the MR cohort had a PSA >10 ng/mL [17% vs 4% (p = 0.003)], had a Gleason Grade Group 3+ tumor [41% vs 22% (p = 0.004)], had a rectal hydrogel spacer placed [92% vs 19% (p<0.001)], and received 1-12 months of ADT [65% vs 39% (p<0.001)]. The incidence of acute grade 2+ GI toxicity was 1% vs 0% (p = 1.0), acute grade 2+ GU toxicity was 7% vs 10% (p = 0.559), late grade 2+ GI toxicity was 19% vs 0% (p<0.001), and late grade 2+ GU toxicity was 21% vs 13% (p = 0.204) in the CT vs MR cohorts. All late grade 3+ toxicities (4% GI and 1% GU) were observed in patients treated with CT guidance to 40 Gy to the PTV without a rectal spacer. Estimated 5-year biochemical failure free survival was 100% for the CT cohort with median follow-up of 54 months (IQR 30-60). No biochemical failures were observed in the MR cohort with median follow-up of 6 months (IQR 3-60). Conclusion SBRT with ADT for definitive treatment of localized prostate cancer is safe and effective with excellent biochemical control. Increased late GI toxicities were observed in patients treated to higher doses of 40 Gy to the PTV without an SIB approach and without a rectal spacer. Additional follow-up will be reported.

Purpose MRI-assisted radiosurgery (MARS) is a novel LDR brachy technique with soft tissue delineation. We report outcomes and toxicity of salvage MARS with Pd-103 after various treatments including surgery, EBRT, and brachy. Materials & Methods We reviewed those undergoing salvage MARS for intraprostatic or prostate bed recurrences using Pd-103. Intraprostatic recurrences underwent whole or focal gland MARS based on template-guided biopsies. Preop diagnostic MR obtained 2 weeks before MARS was used to contour targets and organs-at-risk (OAR) on 3D-T2W sequence including the external urethral sphincter (EUS). Treatment sim was performed with a virtual probe and needles using MIM software. Intra-op transrectal ultrasound fused MR was verified with implantation and confirmed by postop MR on day 0. Constraints were rectum V100<1 cc and a EUS V200 <0.04 cc. Urethra was avoided with planning. No patients had metastatic disease. All patients except 1 were treated with MARS without concurrent ADT. Freedom from biochemical failure (FFbF) defined as post MARS nadir + 2 ng or initiation of ADT, hormone therapy-free survival (HFS), and overall survival (OS) were derived by Kaplan-Meier estimates. Toxicity was graded by CTCAE v5.0. Statistics performed with SAS Pro 15.0. Results 31 patients were treated between 2016-2022. Median follow up was 1.6 years. Gleason grade grouping at diagnosis was: GG1 2 patients (6%), GG2 8 (26%), GG3 10 (32%), GG4 10 (32%), and GG5 1 (3%). Median age at MARS was 71 years. 4 patients (13%) had prior prostatectomy (RP) with salvage EBRT. 24 patients (77%) underwent upfront EBRT. 3 patients had prior brachy. Median PSA at MARS was 3.3 (range, 0.01-16.3). 26 patients (84%) underwent PSMA or Fluciclovine PET before MARS. 22 patients underwent focal MARS, while 9 others had whole gland MARS. 30 patients received 100Gy, while 1 received 125Gy. Median D90 was 128 Gy, and median V200 was 54%. Median rectum V100 was 0 cc, and median EUS V200 was 0.004cc. 27 patients had SpaceOAR placement at MARS (87%). At last follow-up, 3 patients (10%) experienced bF and ADT was started, 1 additional patient started ADT before meeting bF criteria. Among 3 with bF, 2 underwent upfront RP, and 1 underwent upfront LDR. 27 patients (87%) remain bF-free and off ADT. 2 patients died from comorbidities. 2 patients had PET-avid recurrences with 1 seminal vesicle plus nodal recurrence and 1 prostate bed only. No patients died of prostate cancer. 2-year FFbF and HFS was 84.4% and 83.5%, respectively. Median PSA nadir without bF was 0.2 ng/mL. Grade 3 toxicity occurred in 5 patients (16%), including 4 patients (13%) with GU events and 1 patient (3%) with a gastrointestinal (GI) event. Grade 3+ GI involved anterior rectal wall infiltration of SpaceOAR requiring a diverting colostomy. All patients with grade 3+ GU underwent upfront EBRT. Grade 3+ GU was not associated with EUS dose, SpaceOAR usage, EBRT type, or V200 dose. Conclusions In a modern salvage MARS series with Pd-103, we observed safe and tolerable treatment with acceptable toxicity. MARS allows focal brachy of intraprostatic lesions given its reliance on MR planning, unlike ultrasound in most salvage techniques. Early data suggests promising FFbF, and broader applicability of MARS regardless of upfront treatment. MRI-assisted radiosurgery (MARS) is a novel LDR brachy technique with soft tissue delineation. We report outcomes and toxicity of salvage MARS with Pd-103 after various treatments including surgery, EBRT, and brachy. We reviewed those undergoing salvage MARS for intraprostatic or prostate bed recurrences using Pd-103. Intraprostatic recurrences underwent whole or focal gland MARS based on template-guided biopsies. Preop diagnostic MR obtained 2 weeks before MARS was used to contour targets and organs-at-risk (OAR) on 3D-T2W sequence including the external urethral sphincter (EUS). Treatment sim was performed with a virtual probe and needles using MIM software. Intra-op transrectal ultrasound fused MR was verified with implantation and confirmed by postop MR on day 0. Constraints were rectum V100<1 cc and a EUS V200 <0.04 cc. Urethra was avoided with planning. No patients had metastatic disease. All patients except 1 were treated with MARS without concurrent ADT. Freedom from biochemical failure (FFbF) defined as post MARS nadir + 2 ng or initiation of ADT, hormone therapy-free survival (HFS), and overall survival (OS) were derived by Kaplan-Meier estimates. Toxicity was graded by CTCAE v5.0. Statistics performed with SAS Pro 15.0. 31 patients were treated between 2016-2022. Median follow up was 1.6 years. Gleason grade grouping at diagnosis was: GG1 2 patients (6%), GG2 8 (26%), GG3 10 (32%), GG4 10 (32%), and GG5 1 (3%). Median age at MARS was 71 years. 4 patients (13%) had prior prostatectomy (RP) with salvage EBRT. 24 patients (77%) underwent upfront EBRT. 3 patients had prior brachy. Median PSA at MARS was 3.3 (range, 0.01-16.3). 26 patients (84%) underwent PSMA or Fluciclovine PET before MARS. 22 patients underwent focal MARS, while 9 others had whole gland MARS. 30 patients received 100Gy, while 1 received 125Gy. Median D90 was 128 Gy, and median V200 was 54%. Median rectum V100 was 0 cc, and median EUS V200 was 0.004cc. 27 patients had SpaceOAR placement at MARS (87%). At last follow-up, 3 patients (10%) experienced bF and ADT was started, 1 additional patient started ADT before meeting bF criteria. Among 3 with bF, 2 underwent upfront RP, and 1 underwent upfront LDR. 27 patients (87%) remain bF-free and off ADT. 2 patients died from comorbidities. 2 patients had PET-avid recurrences with 1 seminal vesicle plus nodal recurrence and 1 prostate bed only. No patients died of prostate cancer. 2-year FFbF and HFS was 84.4% and 83.5%, respectively. Median PSA nadir without bF was 0.2 ng/mL. Grade 3 toxicity occurred in 5 patients (16%), including 4 patients (13%) with GU events and 1 patient (3%) with a gastrointestinal (GI) event. Grade 3+ GI involved anterior rectal wall infiltration of SpaceOAR requiring a diverting colostomy. All patients with grade 3+ GU underwent upfront EBRT. Grade 3+ GU was not associated with EUS dose, SpaceOAR usage, EBRT type, or V200 dose. In a modern salvage MARS series with Pd-103, we observed safe and tolerable treatment with acceptable toxicity. MARS allows focal brachy of intraprostatic lesions given its reliance on MR planning, unlike ultrasound in most salvage techniques. Early data suggests promising FFbF, and broader applicability of MARS regardless of upfront treatment.

OBJECTIVES:To evaluate patients with clinical (c)T4 prostate cancer (PCa), which represent both a heterogenous and understudied population, who often present with locally advanced disease and obstructive symptoms causing significant morbidity and mortality. We analysed whether receiving definitive local therapy influenced symptomatic and oncological outcomes.METHODS:Retrospective analysis of 154 patients with cT4 PCa treated at a single institution in 1996-2020. Systemic therapy with or without local treatment (surgery, radiotherapy [RT], or both). Uni- and multivariate analyses of associations between clinicopathological features (including obstructive symptoms) and receipt of local therapy on overall survival (OS) and disease control were done with Cox regression.RESULTS:The median follow-up time was 5.9 years. Most patients had adenocarcinoma (88%), Gleason score 9-10 (77%), and median baseline prostate-specific antigen (PSA) of 20 ng/mL; most (54%) had metastatic cT4N0-1M1 disease; 24% regionally advanced cT4N1M0, and 22% localised cT4N0M0. Local therapies were RT (n = 44), surgery (n = 28), or both (n = nine). Local therapy was associated with improved OS (hazard ratio [HR] 0.3, P < 0.001), longer freedom from local recurrence (HR 0.39, P = 0.002), less local progression (HR 0.41, P = 0.02), fewer obstructive symptoms with progression (HR 0.31, P = 0.01), and less death from local disease (HR 0.25, P = 0.002). On multivariate, local therapy was associated with improved survival (HR 0.58, P = 0.02), and metastatic disease (HR 2.93, P < 0.001) or high-risk pathology (HR 2.05, P = 0.03) was associated with worse survival.CONCLUSION:Definitive local therapy for cT4 PCa was associated with improved symptomatic outcomes and survival even among men with metastatic disease. Pending prospective evaluation, these findings support definitive treatment with local therapy for cT4 disease in select cases.

Importance:Despite evidence demonstrating an overall survival benefit with up-front hormone therapy in addition to established synergy between hormone therapy and radiation, the addition of metastasis-directed therapy (MDT) to hormone therapy for oligometastatic prostate cancer, to date, has not been evaluated in a randomized clinical trial.Objective:To determine in men with oligometastatic prostate cancer whether the addition of MDT to intermittent hormone therapy improves oncologic outcomes and preserves time with eugonadal testosterone compared with intermittent hormone therapy alone.Design, Setting, Participants:The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a phase 2, basket randomized clinical trial for multiple solid tumors testing the addition of MDT to standard-of-care systemic therapy. Men aged 18 years or older with oligometastatic prostate cancer who had 5 or fewer metastases and were treated with hormone therapy for 2 or more months were enrolled to the prostate intermittent hormone therapy basket at multicenter tertiary cancer centers from September 2018 to November 2020. The cutoff date for the primary analysis was January 7, 2022.Interventions:Patients were randomized 1:1 to MDT, consisting of definitive radiation therapy to all sites of disease and intermittent hormone therapy (combined therapy arm; n = 43) or to hormone therapy only (n = 44). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression.Main Outcomes and Measures:The primary end point was disease progression, defined as death or radiographic, clinical, or biochemical progression. A key predefined secondary end point was eugonadal progression-free survival (PFS), defined as the time from achieving a eugonadal testosterone level (≥150 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) until progression. Exploratory measures included quality of life and systemic immune evaluation using flow cytometry and T-cell receptor sequencing.Results:The study included 87 men (median age, 67 years [IQR, 63-72 years]). Median follow-up was 22.0 months (range, 11.6-39.2 months). Progression-free survival was improved in the combined therapy arm (median not reached) compared with the hormone therapy only arm (median, 15.8 months; 95% CI, 13.6-21.2 months) (hazard ratio, 0.25; 95% CI, 0.12-0.55; P < .001). Eugonadal PFS was also improved with MDT (median not reached) compared with the hormone therapy only (6.1 months; 95% CI, 3.7 months to not estimable) (hazard ratio, 0.32; 95% CI, 0.11-0.91; P = .03). Flow cytometry and T-cell receptor sequencing demonstrated increased markers of T-cell activation, proliferation, and clonal expansion limited to the combined therapy arm.Conclusions and Relevance:In this randomized clinical trial, PFS and eugonadal PFS were significantly improved with combination treatment compared with hormone treatment only in men with oligometastatic prostate cancer. Combination of MDT with intermittent hormone therapy may allow for excellent disease control while facilitating prolonged eugonadal testosterone intervals.Trial Registration:ClinicalTrials.gov Identifier: NCT03599765.

PURPOSE:A suboptimal prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) among men who go on to receive definitive radiation therapy for prostate cancer might suggest the existence of castration-resistant disease or altered androgen receptor signaling. This in turn may portend worse long-term clinical outcomes, especially in men with high-risk disease. We set out to evaluate the prognostic impact of poor PSA response to neoadjuvant ADT in men with high-risk prostate cancer. METHODS AND MATERIALS:This was a post hoc analysis of the multicenter TROG 03.04 RADAR and PCS IV randomized clinical trials. Inclusion criteria for this analysis were patients with high-risk prostate cancer (defined as Gleason score ≥8, initial PSA ≥20 ng/mL, or cT3a disease or higher) who received definitive radiation therapy, at least 18 months of ADT, and had a preradiation therapy PSA level drawn after at least 3 months of neoadjuvant ADT. Poor PSA response was defined as PSA >0.5 ng/mL. Cox regression and Fine-Gray models were used to test whether poor PSA response was associated with metastasis-free survival, biochemical recurrence, prostate-cancer specific mortality, and overall survival. RESULTS:Nine hundred thirty men met inclusion criteria for this analysis. Median follow-up was 130 months (interquartile range [IQR], 89-154 months). After a median of 3 months (IQR, 3-4.2 months) of neoadjuvant ADT, the median PSA was 0.60 ng/mL (IQR, 0.29-1.59). Overall, 535 men (57%) had a PSA >0.5 ng/mL. Poor PSA response was associated with significantly worse metastasis-free survival (hazard ratio [HR], 3.93; P = .02), worse biochemical recurrence (subdistribution HR, 2.39; P = .003), worse prostate-cancer specific mortality (subdistribution HR, 1.50; P = .005), and worse overall survival (HR, 4.51; P = .05). CONCLUSIONS:Patients with PSA >0.5 mg/mL after at least 3 months of neoadjuvant ADT had worse long-term clinical outcomes and should be considered for treatment intensification.

Purpose/Objective(s) Patients with de novo clinical T4 (cT4) prostate cancer represent a heterogenous and understudied population. The advanced nature of their local disease often results in obstructive urinary symptoms that lead to significant morbidity and mortality. We analyzed the effects of definitive local therapy on the outcomes of patients with cT4 prostate cancer. Materials/Methods We retrospectively reviewed 155 patients with de novo cT4 prostate cancer, treated at a single institution between 1996 and 2020. Baseline obstructive symptoms were defined as lower urinary tract symptoms (LUTS, AUA_SI>20 on flomax), urinary retention requiring foley, or acute renal failure (ARF). The association between baseline and treatment characteristics with outcomes were analyzed using Cox regression univariable analysis (UVA) and multivariable analysis (MVA), p<0.05 was considered significant. Results Analysis included 155 men, with median follow-up of 71 mos. Most patients had adenocarcinoma (88%), Gleason 9-10 (77%), and median baseline PSA of 19.9ng/ml (range, 0.5-1110). The majority of patients had T4NanyM1 disease (54%), followed by T4N1M0 (24%), and T4N0M0 (22%), as defined by conventional imaging studies. All men received systemic therapy with ADT (80%), ADT+abiraterone (12%), ADT+chemo (4%) or chemotherapy alone (4%). Local therapy was delivered with radiation (RT) (n=44), surgery (n=28), or both (n=9). Median prostate RT dose was 78Gy (IQR, 70-78) in 2Gy fractions. Patients did not receive definitive RT to their metastatic disease. Seventy-two (47%) men presented with obstructive symptoms with 36 (25%) being catheter dependent. For patients with obstructive symptoms, local therapy was associated with improved overall survival (OS: HR 0.33, p=0.001), freedom from local recurrence (FFLR:HR 0.19, p=0.003), and freedom from castration resistance (FFCR:HR 0.28, p=0.002). Patients who received local therapy were less likely to have local progression (HR 0.23, p=0.01), obstructive symptoms with progression (HR 0.21, p=0.03), or die with local disease (HR 0.15, p=0.001). On MVA local therapy improved OS (HR 0.45, p=0.03). OS was also affected by Gleason 10 and M1 disease (HR 15.58, p=0.02, HR 2.99, p=0.004; respectively). Conversely, in men who did not present with obstructive symptoms (n=83), there was no improvement in OS (HR=0.63, P=0.15). Conclusion Men with cT4 prostate cancer commonly present with obstructive symptoms due to local disease burden, representing a source of significant morbidity and potential mortality. Even among patients with metastatic disease, definitive local therapy is associated with improved patient outcomes including OS. Pending prospective evaluation, these data support the use of local therapy in men with cT4 disease presenting with obstructive urinary symptoms, irrespective of the presence of metastatic disease.

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C4 Nova MRI positive-contrast fiducial markers have the least proton dose perturbation effect compared with gold and carbon MRI negative-contrast markers. These data may serve as evidence for future clinical trials to study the benefit of MRI from treatment planning to delivery using positive MRI signal C4 Nova FM in preserving tumor control while decrease radiation related toxicities in patients with prostate cancer.

Little is known about the clinical behaviors and optimal treatment of T4 prostate cancer. Previous studies on locally advanced prostate cancers have a critical lack of T4 patients to compare. In this study, we analyzed patterns of lymph node (LN) involvement and associations between treatment outcomes in a large cohort of T4 prostate cancer patients. Patients with T4 prostate cancer were identified using Natural Language Processing. Patients who had received previous treatment prior to presentation at our institution were excluded. A dedicated GU radiologist (T.B.) reviewed all existing pretreatment imaging to identify LN involvement and T4 status. Categorical variables were compared utilizing the chi-squared test while overall survival was calculated via the Kaplan Meier method with comparisons via the log rank test. Hazard ratio was calculated using Cox proportional Hazards Regression. 481 patients with T4 prostate cancer were diagnosed between 1996 and 2017; 103 met our inclusion criteria for treatment-naïve T4 condition. T4 status was identified by either clinical examination (colonoscopy, cystoscopy, and digital rectal exam; 56.3%) or imaging (43.7%); 45% of patients were M0, 55% M1, 25% N0, and 75% N1. The median age was 62 (range 44-88) and median pre-treatment PSA was 17.5 (range 0.5-900). The majority of patients presented with an adenocarcinoma histology (78.6%) followed by ductal (8.7%) and small cell (5.8%). The median follow-up time was 103.5 months (mo). Patients with any rectal involvement by the primary tumor (n = 42) exhibited significantly increased rates of perirectal and mesorectal lymph node (LN) involvements than patients without (n = 61) (45% vs 26%, p = 0.046), with no significant links with disease invasion to the bladder or pelvic side wall (p = 0.61, 0.67). Definitive local treatment (LT: surgery, definitive radiation therapy, or both) was given to 56 patients (54%). Patients who received LT demonstrated significantly higher rates of survival (median 80 vs 39 mo; HR = 0.37, p = 0.0002). Subgroup analyses revealed a trend towards improved survival with LT among N1 patients (74 vs 39 mo; p = 0.08) as well as M1 patients (74 vs 37.5 mo, p = 0.14). This analysis identified an increased frequency of perirectal and mesorectal LN involvement among patients with rectal invasion by the primary tumor. LT was associated with significantly improved overall survival, which appears to extend to patients with M1 and N1 disease. These results support the utilization of definitive local therapy among T4 prostate cancer patients with benefits that possibly extend to those with regional or metastatic disease. Further consideration should also be given to include mesorectal and perirectal LNs in pelvic radiation fields in patients with rectal involvement from the primary disease.

PURPOSE:MRI-assisted radiosurgery (MARS) is a modern technique for prostate brachytherapy that provides superior soft tissue contrast. The purpose of this analysis was to evaluate treatment planning factors associated with urinary toxicity, particularly damage to the membranous urethra (MUL) and external urethral sphincter (EUS), after MARS. MATERIAL AND METHODS:We retrospectively reviewed 227 patients treated with MARS. Comparisons were made between several factors including preimplantation length of the MUL and EUS dosimetric characteristics after implantation with longitudinal changes in American Urological Association (AUA) urinary symptom score. RESULTS:Rates of grade 3 urinary incontinence and obstructive urinary symptoms were 4% and 2%. A piecewise mixed univariate model revealed that MUL and V200, V150, V125, and D5 to the EUS were all associated with increased rates of urinary toxicity over time. On univariate logistic regression, MUL >14.2 mm (odds ratio [OR] 2.03 per cm3, 95% confidence interval [CI] 1.10-3.77, p = 0.025), V125 to the EUS (OR 3.21 cm3, 95% CI 1.18-8.71, p = 0.022), and use of the I-125 isotope (OR 3.45, 95% CI 1.55-7.70, p = 0.001) were associated with subacute urinary toxicity (i.e., that occurring at 4-8 months). Optimal dose-constraint limits to the EUS were determined to be V200 < 0.04 cm3 (p = 0.002), V150 < 0.12 cm3 (p = 0.041), V125 < 0.45 cm3 (p = 0.033), D30 < 160 Gy (p = 0.004), and D5 < 218 Gy (p = 0.016). CONCLUSIONS:MARS brachytherapy provides detailed anatomic information for treatment planning, implantation, and quality assurance. Overall rates of urinary toxicity are low; however, several dosimetric variables associated with the EUS were found to correlate with urinary toxicity.