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PURPOSE It remains unknown whether or not short-term androgen deprivation (STAD) improves survival among men with intermediate-risk prostate cancer (IRPC) treated with dose-escalated radiotherapy (RT). METHODS The NRG Oncology/Radiation Therapy Oncology Group 0815 study randomly assigned 1,492 patients with stage T2b-T2c, Gleason score 7, or prostate-specific antigen (PSA) value >10 and ≤20 ng/mL to dose-escalated RT alone (arm 1) or with STAD (arm 2). STAD was 6 months of luteinizing hormone–releasing hormone agonist/antagonist therapy plus antiandrogen. RT modalities were external-beam RT alone to 79.2 Gy or external beam (45 Gy) with brachytherapy boost. The primary end point was overall survival (OS). Secondary end points included prostate cancer–specific mortality (PCSM), non-PCSM, distant metastases (DMs), PSA failure, and rates of salvage therapy. RESULTS Median follow-up was 6.3 years. Two hundred nineteen deaths occurred, 119 in arm 1 and 100 in arm 2. Five-year OS estimates were 90% versus 91%, respectively (hazard ratio [HR], 0.85; 95% CI, 0.65 to 1.11]; P = .22). STAD resulted in reduced PSA failure (HR, 0.52; P CONCLUSION STAD did not improve OS rates for men with IRPC treated with dose-escalated RT. Improvements in metastases rates, prostate cancer deaths, and PSA failures should be weighed against the risk of adverse events and the impact of STAD on quality of life.

The EMPIRE-1 (Emory Molecular Prostate Imaging for Radiotherapy Enhancement-1) trial reported a survival advantage in recurrent prostate cancer salvage radiotherapy (SRT) guided by

Summary Background Molecular imaging is increasingly used to guide treatment decisions and planning in prostate cancer. We aimed to evaluate the role of 18F-fluciclovine-PET/CT in improving cancer control compared with conventional imaging (bone scan and either CT or MRI) alone for salvage postprostatectomy radiotherapy. Methods In EMPIRE-1, a single-centre, open-label, phase 2/3 randomised controlled trial, patients with prostate cancer with detectable PSA after prostatectomy and negative conventional imaging (no extrapelvic or bone findings) were randomly assigned in a 1:1 ratio to radiotherapy directed by conventional imaging alone or to conventional imaging plus 18F-fluciclovine-PET/CT. Computer-generated randomisation was stratified by PSA concentration, adverse pathology indicators, and androgen deprivation therapy intent. In the 18F-fluciclovine-PET/CT group, radiotherapy decisions were rigidly determined by PET findings, which were also used for target delineation. The primary endpoint was 3 year event-free survival, with events defined as biochemical or clinical recurrence or progression, or initiation of systemic therapy, using univariate and multivariable analyses in patients who received radiotherapy. This trial is registered with ClinicalTrials.gov , NCT01666808 and is closed to new participants. Findings From Sept 18, 2012, to March 4, 2019, 165 patients were randomly assigned, with median follow-up of 3·52 years (95% CI 2·98–3·95). PET findings resulted in four patients in the 18F-fluciclovine-PET/CT group having radiotherapy aborted; these patients were excluded from survival analyses. Median survival was not reached (95% CI 35·2–not reached; 33% of 81 patients had events) in the conventional imaging group compared with not reached (95% CI not reached–not reached; 20% of 76 patients) in the 18F-fluciclovine-PET/CT group, and 3 year event-free survival was 63·0% (95% CI 49·2–74·0) in the conventional imaging group versus 75·5% (95% CI 62·5–84·6) for 18F-fluciclovine-PET/CT (difference 12·5; 95% CI 4·3–20·8; p=0·0028). In adjusted analyses, study group (hazard ratio 2·04 [95% CI 1·06–3·93], p=0·0327) was significantly associated with event-free survival. Toxicity was similar in both study groups, with the most common adverse events being late urinary frequency or urgency (37 [46%] of 81 patients in the conventional imaging group and 31 [41%] of 76 in the PET group), and acute diarrhoea (11 [14%] in the conventional imaging group and 16 [21%] in the PET group). Interpretation Inclusion of 18F-fluciclovine-PET into postprostatectomy radiotherapy decision making and planning significantly improved survival free from biochemical recurrence or persistence. Integration of novel PET radiotracers into radiotherapy decisions and planning for prostate cancer patients warrants further study. Funding National Institutes of Health/National Cancer Institute, Blue Earth Diagnostics, and Winship Cancer Institute of Emory University.

The purpose of the study was to report our institutional quality of life data for those undergoing high-dose-rate brachytherapy with an International Prostate Symptom Score (IPSS) ≥15 compared with those with an IPSS15.The charts of 95 patients with localized adenocarcinoma of the prostate treated with high-dose-rate as monotherapy or as a boost after external beam radiation therapy at a single institution between 2012 and 2015 were reviewed. All patients completed the IPSS and Expanded Prostate Index for Prostate Cancer-Clinical Practice quality of life assessments before treatment and at least one followup survey. Linear mixed models were performed to test for significant changes and differences in each outcome over time.Median followup in the IPSS15 group was 23 months and 16 months in the IPSS ≥15 group. Median prostate volume was 46.3 cc and 45.4 cc, respectively (p = 0.901). IPSS, incontinence, and urinary irritation/obstruction scores were significantly higher in the IPSS ≥15 group compared with the IPSS15 group at baseline (all p ≤ 0.05). By the24 months time point, these scores had decreased below baseline and were not significantly different from those with a baseline IPSS15 (all p0.1). 12.5% in the IPSS ≥15 group developed a new Grade 2 genitourinary toxicity requiring an alpha blocker compared with 26.5% in the IPSS15 group (p = 0.34). No patients required emergency placement of a foley catheter within 30 days of treatment.Given the low rates of genitourinary toxicity, this technique appears appropriate even for those with high baseline urinary symptoms.

Addition of a brachytherapy boost to external beam radiation therapy (EBRT) reduces prostate cancer (PCa) recurrence at the expense of genitourinary (GU) toxicity. Whether brachytherapy boost technique, specifically low-dose-rate (LDR-BT) versus high-dose-rate (HDR-BT), impacts treatment-related toxicity is unclear.Between 2012-2018, 106 men with intermediate/high risk PCa underwent EBRT (37.5-45 Gy in 1.8-2.5 Gy/fraction) plus brachytherapy boost, either with LDR-BT (110 Gy I-125 or 100 Gy Pd-103; n = 51) or HDR-BT (15 Gy x1 Ir-192; n = 55). Patient-reported outcomes (PRO) were assessed by International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC-CP) surveys at 3-6-month intervals for up to three years following treatment, with higher scores indicating more severe toxicity. Provider-reported GU and gastrointestinal (GI) toxicity was graded per CTCAE v5.0 at each follow-up. Linear mixed models comparing PROs between LDR-BT versus HDR-BT were fitted. Stepwise multivariable analysis (MVA) was performed to account for age, gland size, androgen deprivation therapy use, and alpha-blocker medication use. Incidence rates of grade 2+ GU/GI toxicity was compared using Fisher's exact test.Use of LDR-BT was associated with greater change in IPSS (p=0.003) and EPIC-CP urinary irritative score (p = 0.002) compared with HDR-BT, but effect size diminished over time (LDR-BT versus HDR-BT: baseline to 6-/24-month mean IPSS change, +6.4/+1.4 versus +2.7/-3.0, respectively; mean EPIC-CP irritative/obstructive change, +2.5/+0.1 versus +0.9/+0.1, respectively). Results remained significant on MVA. Post-treatment grade 2+ GU toxicity was significantly higher in the LDR-BT group (67.5% versus 42.9% for LDR-BT and HDR-BT, respectively; p0.001). There were no differences between groups in incontinence, bowel function, and erectile function, or grade 2+ GI toxicity.Compared with LDR-BT, HDR-BT was associated with lower acute patient- and provider-reported GU toxicity.

PURPOSE/OBJECTIVE(S) In recurrent post-prostatectomy prostate cancer pts, radiotherapy (XRT) planning with fluciclovine (18F) PET/CT (PET) has demonstrated improved disease-free survival without increase in provider-reported toxicity over conventional-only [CT or MRI-based] treatment planning. We hypothesized that incorporating PET would result in larger clinical target volumes (CTV's) without increasing patient-reported toxicities. MATERIALS/METHODS From 2012-2019, 165 post-prostatectomy pts with detectable PSA were randomized (Arm 1 [no PET]: 82; Arm 2 [PET]: 83). Prostate bed target volumes with (CTV1 [45.0-50.4 Gy/1.8 Gy]) or without (CTV2/CTV [64.8-70.2 Gy/1.8 Gy]) pelvic nodal treatment, as well as organ-at-risk dose endpoints, were compared pre- v post-PET (Arm 2 only) using the paired t-test and between Arms using the t-test. V40 Gy & V65 Gy rectum, bladder(-CTV) & penile bulb constraints were identical in all cases. Patient-reported outcomes (PRO's) utilized International Prostate Symptom Score (IPSS) & Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) metrics. Linear mixed-models (LMMs) incorporating PRO changes over time were fitted comparing the Arms. Univariate & multivariable analyses (MVA) were performed including demographic, disease, and treatment factors. RESULTS Median FU of the whole cohort was 3.52 years. Though all pts had baseline PRO's, 1 pt in Arm 1 & 3 pts in Arm 2 withdrew, & 4 Arm 2 pts had extra-pelvic uptake on PET with XRT aborted, leaving 81 [Arm 1] & 76 pts [Arm 2] for toxicity analysis {1 Arm 2 pt unable to receive PET was not included in volumetric analysis but was included in toxicity analysis}. Mean CTV1 (427.63cc v 452.21cc [P = 0.462], Arm 1 v Arm 2) and CTV2/CTV (137.18cc v 134.20cc [P = 0.669]) were similar prior to PET incorporation. CTV1 (454.57cc v 461.33cc; P = 0.003) and CTV2/CTV (134.14cc v 135.61cc; P < 0.001) were significantly larger following PET incorporation. While V40 Gy (P = 0.402 & P = 0.522 for rectum & bladder, respectively) & V65 Gy (P = 0.157 & P = 0.182 for rectum & bladder, respectively) were not significantly different pre- v post-PET, penile bulb dose did significantly increase post-PET (P < 0.001 for both V40 Gy & V65 Gy). There was no significant difference in IPSS or EPIC-CP scores at baseline or beyond 18 mo between Arms. On MVA, Arm was not significant for any of the EPIC-CP subdomain scores [incontinence (P = 0.630), irritative (P = 0.076), sexual (P = 0.166), bowel (P = 0.402), vitality (P = 0.403)]. With LMMs there was no significant difference between Arms in IPSS (P = 0.276) or EPIC-CP (P = 0.209) scores over time. CONCLUSION Despite larger clinical target volumes after incorporation of fluciclovine (18F) PET into post-prostatectomy XRT treatment planning, we found no significant difference in patient-reported toxicities with long-term follow-up.

Purpose Optimal therapy for clinically node-positive, nonmetastatic (cN1) prostate cancer (PC) patients remains controversial, ranging from aggressive local therapy to palliative systematic therapy alone. Despite guideline support, it is unclear if a brachytherapy (BT) boost should be considered for cN1 patients as these patients were excluded from randomized trials establishing its benefit. Herein, we compare definitive radiation therapy (RT) with or without a BT boost in cN1 PC. Methods and materials The National Cancer Database was used to identify men with cN1 PC treated with definitive RT and concomitant androgen deprivation therapy between 2004 and 2013. Overall survival (OS) was compared between those who received external beam RT (EBRT) or combination EBRT plus BT boost (EBRT + BT) using Kaplan–Meier with propensity score matching and Cox proportional hazards. Results With a median followup of 48.5 months, 1,650 patients were eligible for this analysis, 103 (6.2%) of whom received EBRT + BT. Younger age, no medical comorbidities, and Gleason score of six were associated with higher likelihood of receiving EBRT + BT over EBRT alone. The mean (median) OS for EBRT and EBRT + BT was 99.0 (110.6) months vs 109.2 (not reached) months, respectively (p = 0.048). However, no significance difference in OS was observed between the groups after propensity score matching. On multivariable analysis, EBRT + BT was not significantly associated with improved OS (adjusted HR 0.67, 95% CI, 0.41–1.07, p = 0.098). Conclusions In this retrospective, observational study of patients with cN1 PC treated with definitive RT and concomitant androgen deprivation therapy, EBRT + BT had an unadjusted improvement in OS compared with EBRT alone that lost statistical significance after multivariable adjustment and propensity score matching.

Background: Molecular imaging is increasingly used to guide prostate cancer decisions and treatment planning. The specific aim was to evaluate the role of fluciclovine (18F) PET/CT [PET] in improving cancer control over conventional imaging for post-prostatectomy radiotherapy. Methods: Patients with prostate cancer with detectable PSA post-prostatectomy and negative conventional imaging were randomized to radiotherapy directed by conventional imaging (Arm 1) vs conventional imaging+PET (Arm 2). The treatment setting was an academic medical center with community affiliates. In Arm 2, radiotherapy decisions were rigidly determined by PET, which was also used for target delineation. Using a standard post-radiotherapy failure definition, failure rates at 3 years (primary study endpoint) were compared. Univariate and multivariable analyses were performed for demographic, disease, and treatment factors. Secondary endpoints included provider-reported gastrointestinal and genitourinary toxicities. Findings: From September 18, 2012 to March 4, 2019, 165 patients were randomized. PET findings resulted in a 35·4% rate of decision changes, including 4 patients having radiotherapy aborted. Median follow-up was 3·52 years. Three-year failure-free survival rate for Arm 1 vs Arm 2 was 63·0 vs 75·5% (difference,12·5; 95% CI:4·3-20·8; p=0·0028) and at 4-years was 51·2 vs 75·5% (difference,24·3; 95% CI:15·6-33·0; p

258 Background: Radiation dose escalation with the addition of a brachytherapy boost (BT) to external beam radiation therapy (EBRT) may be associated with improved survival in certain men with Gleason grade 5 (GG5) prostate cancer (PCa). However, low PSA, high-grade PCa has much worse outcomes, is associated with neuroendocrine genomic features, and may be more resistant to androgen suppression. It is unclear whether the addition of a BT boost in men with this disease subgroup is associated with a survival benefit and is the subject of this analysis. Methods: Men diagnosed with node-negative, non-metastatic GG5 PCa and treated with (1) EBRT plus ADT or (2) EBRT plus BT plus ADT between 2004 and 2015 were identified in the National Cancer Database (NCDB). The EBRT cohort received conventionally fractionated ≥ 74 Gy or moderately hypofractionated (2.5-3.0 Gy x 20-28 fractions) EBRT. EBRT plus BT cohort received external beam doses of conventionally fractionated ≥45 Gy or moderately hypofractionated (2.5 Gy x 15 – 18 fractions) radiation, and either LDR or HDR BT. Men receiving chemotherapy, immunotherapy, or any form of surgery were excluded. Patients were stratified into two groups based on whether the presenting PSA was above or below the normal threshold (≤4 and > 4 ng/mL). OS was compared using the Kaplan-Meier and log-rank test. Multivariable analysis (MVA) using Cox proportional hazards regression modeling was performed, accounting for age, race, year of diagnosis, Charlson-Deyo comorbidity score, insurance status, treatment facility type, Gleason Score (9 versus 10), and clinical T-stage. Results: 8,260 men met study inclusion criteria of which 658 (8%) presented with PSA ≤4. 572 (87%) patients were treated with EBRT monotherapy and 86 (13%) patients were treated with EBRT + BT. 5-year OS for EBRT versus EBRT plus BT was 79.7 +/- 2.3% versus 86.9 +/- 5.0%, respectively (P = 0.49). On MVA analysis, EBRT plus BT was not associated with improved OS versus EBRT (adjusted HR 0.90, 95% CI 0.52-1.87; P = 0.62). In comparison, for men with PSA > 4 and GG5 disease [EBRT: 6,780 patients (89.2%) & EBRT plus BT: 822 patients (10.8%)], EBRT plus BT was associated with improved OS versus EBRT (adjusted HR 0.85, 95% CI 0.66-0.99; P = 0.044). Conclusions: Receipt of dose-escalated prostate radiation by means of a BT boost was not associated with improved survival in men with PSA ≤4 ng/mL and GG5 prostate cancer. By contrast, an association with improved survival was observed in men with GG5 disease and higher initial PSA. This low PSA, high-grade subgroup may represent a unique risk tier for which current treatment paradigms need further investigation, including study of escalated systemic therapy.

PURPOSE/OBJECTIVE(S) To report the PROs of a phase III randomized trial evaluating TAS combined with dose-escalated RT for patients with intermediate risk prostate cancer. MATERIALS/METHODS Eligible patients had intermediate risk prostate cancer defined as harboring ≥ 1 of these risk factors: clinical stage T2b-T2c, Gleason score 7, or PSA > 10 to ≤ 20 ng/mL. Patients were randomized to dose-escalated RT alone (Arm 1) or RT plus TAS (Arm 2) consisting of LHRH agonist/antagonist with oral antiandrogen for 6 months. Validated PROs included the Expanded Prostate Cancer Index Composite (EPIC-50) and Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue short form. PRO change scores, calculated for each patient as the follow-up score minus baseline score (at end of RT, 6, 12, and 60 months from start of RT) were compared between treatment arms using a two-sample t test. An effect size (ES) of 0.50 SD (standard deviation) of the baseline measure was considered clinically meaningful. For the PRO sample size, 200 patients per arm would provide 90% statistical power to detect an ES < 0.50 if the completion rate was only 60%. Mixed effect regression models were also utilized. Clinical outcomes are reported in a separate abstract. RESULTS Of the 402 initial planned subset of trial patients who completed baseline PROs, PRO compliance was approximately 96%, 89%, 86% and 87% at end of RT, 6, 12 and 60 months, respectively. There were no significant differences between these 402 patients and the remaining patients on this trial with respect to age, race, performance status, # risk factors, or comorbidity score. While EPIC urinary and bowel scores decreased significantly by the end of RT in both arms, no clinically meaningful differences between arms were detected over time. For the EPIC hormonal and sexual domains, however, there were clinically meaningful differences between the two arms with greater (P < 0.0001) deficits in the RT + TAS arm. These differences improved over time, with ∼50% resolution by one year after treatment and no clinically meaningful differences by 5 years between arms. PROMIS-fatigue scores increased from baseline in both arms and were significantly higher in arm 2 at the end of RT (P = 0.016), though slightly lower at 12 and 60 months. CONCLUSION The addition of TAS to dose-escalated RT demonstrated significant clinically meaningful declines in the EPIC hormonal and sexual domains, and increases in the PROMIS-fatigue scores, compared to RT alone. These scores gradually improved over time, with no clinically meaningful differences between arms in fatigue by one year, or in hormonal and sexual domains by 5 years. Beyond the clinical outcomes, these PRO results directly from patients provide added value to help patients make informed decisions among treatment options.

Purpose: Treatment with long-term androgen deprivation therapy (ADT) and radiation therapy (RT) is the nonsurgical standard-of-care for patients with high- or very high-risk prostate cancer (HR-PC), but the optimal timing between ADT and RT initiation is unknown. We evaluate the influence of timing between ADT and RT on outcomes in patients with HR-PC using a large national cancer database. Methods and Materials: Data for patients with clinical T1-T4 N0, M0, National Cancer Comprehensive Network HR-PC who were treated with definitive external RT (≥60 Gy) and ADT starting either before or within 14 days after RT start were extracted from the National Cancer Database (2004-2015). Patients were grouped on the basis of ADT initiation: (1) >11 weeks before RT, (2) 8 to 11weeks before RT, and (3) 11 weeks of neoadjuvant ADT, 11,456 (30.5%) with 8 to 11 weeks of neoadjuvant ADT; and 12,804 (34%) patients with 11 weeks, 8 to 11 weeks, and 11 weeks group. Conclusions: Neoadjuvant ADT initiation 8 to 11 weeks before RT is associated with significantly improved OS compared with shorter neoadjuvant ADT duration. Although prospective validation is warranted, this analysis is the largest retrospective study suggesting an influence of timing between ADT and RT initiation in HR-PC.

PURPOSE/OBJECTIVE(S) The addition of a brachytherapy boost to external beam radiation therapy (EBRT) reduces prostate cancer (PCa) recurrence compared with dose-escalated EBRT alone. However, combination therapy is associated with worse genitourinary (GU) toxicity compared with EBRT monotherapy. Whether brachytherapy boost technique, specifically low-dose-rate (LDR-BT) versus high-dose-rate (HDR-BT), impacts treatment-related toxicity is unclear and the subject of this analysis. MATERIALS/METHODS This single institutional cohort study included 104 adult men with intermediate/high risk PCa treated with combination EBRT plus brachytherapy boost, with either LDR-BT or HDR-BT, between 2012 and 2018. Patient-reported outcomes (PRO) were assessed by the International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) surveys at 3-6-month intervals for up to three years following treatment, with higher scores indicating more severe toxicity. Provider-reported GU and gastrointestinal (GI) toxicities were assessed and graded per CTCAE V5.0 at each follow-up. Linear mixed models comparing PROs between LDR-BT versus HDR-BT were fitted. Stepwise multivariable analysis (MVA) was performed to account for age, gland size, androgen deprivation therapy (ADT) use, and alpha-blocker medication use. Incidence rates of grade 2+ GU/GI toxicity was compared using Chi-square test or Fisher's exact test. RESULTS The median complete follow up time for LDR-BT and HDR-BT cohorts was 17 and 18.4 months, respectively. There was no difference in alpha-blocker use at baseline between groups (P = 0.16). Median prostate gland size was larger in the HDR-BT cohort compared with the LDR-BT cohort (39.99cc vs 26.58cc for HDR-BT vs LDR-BT, respectively; P < 0.001). The use of LDR-BT was associated with a greater change in IPSS (P = 0.003) and EPIC-CP urinary irritative score (P = 0.002) compared with HDR-BT, but effect size diminished over time (LDR-BT versus HDR-BT: baseline to 6-/24-month mean IPSS change, +6.4/+1.4 versus +2.7/-3.0, respectively; mean EPIC-CP irritative/obstructive change, +2.5/+0.1 versus +0.9/+0.1, respectively). These results remained significant on MVA. Incidence of post-treatment grade 2+ GU toxicity was significantly higher in the LDR-BT group (77.5% versus 42.9% for LDR-BT and HDR-BT, respectively; P < 0.001). There were no significant differences between LDR-BT and HDR-BT in EPIC-CP (total, urinary incontinence, bowel function, sexual, vitality) or provider-reported grade 2+ GI toxicity. CONCLUSION In this single institution cohort, HDR-BT was associated with lower patient- and provider-reported GU toxicity compared with LDR-BT. However, differences in patient-reported toxicity diminished by 24 months post-treatment.

Purpose/Objective(s) Androgen suppression can improve outcomes when added to radiotherapy (RT) for intermediate risk prostate cancer, but no study to date has reported its utility in the context of contemporary, dose-escalated RT. Herein, the clinical outcomes of a phase III prospective trial evaluating the utility of total androgen suppression (TAS) combined with dose-escalated RT for patients with intermediate risk prostate cancer are reported. Materials/Methods Eligible patients had intermediate risk prostate cancer defined as harboring ≥ 1 of the following risk factors: clinical stage T2b-T2c, Gleason score 7, or PSA value > 10 and ≤ 20 ng/mL. Patients with all three risk factors and ≥ 50% of biopsy cores positive were ineligible. After stratification by number of intermediate risk factors (single vs. multiple), RT boost modality, and baseline comorbidity (ACE-27 comorbidity index ≥ vs. Results The study completed its accrual objective. Between 2009 and 2016, 1538 patients were randomized. There were 750 eligible patients on Arm 1 and 742 on Arm 2 comprising the modified intent-to-treat population. 67% had a single intermediate risk factor. 88% were treated with EBRT with the remainder receiving EBRT plus brachytherapy boost. 33% had an ACE-27 score ≥ grade 2. With a median follow up of 6.2 years, 219 deaths occurred, 119 in Arm 1 and 100 in Arm 2, yielding 5-year overall survival estimates of 90% vs. 91%, respectively [HR 0.85 (95% CI 0.65-1.11); P = 0.22]. 193 patients experienced PSA failure, 125 in Arm 1 and 68 in Arm 2 [HR 0.52 (0.39-0.70); P Conclusion While the addition of TAS to dose-escalated RT did not improve overall survival for men with intermediate risk prostate cancer, significant improvements in rates of metastases, deaths due to prostate cancer, and PSA failures support the continued use of combination dose-escalated RT and TAS. Benefits will need to be weighed against the increased risk of adverse events and the patient reported outcomes analysis.

With limited high-level evidence, we carried out a comparative effectiveness study for the effect of proton beam therapy (PBT) on overall survival compared to external-beam radiotherapy (EBRT) and brachytherapy (BT) among patients with localized prostate cancer using a national database. PBT was associated with a significant overall survival benefit compared to EBRT and had a similar performance as BT. Background: There are few comparative outcomes data regarding the therapeutic delivery of proton beam therapy (PBT) versus the more widely used photon-based external-beam radiation (EBRT) and brachytherapy (BT). We evaluated the impact of PBT on overall survival (OS) compared to EBRT or BT on patients with localized prostate cancer. Patients and Methods: The National Cancer Data Base (NCDB) was queried for 2004–2015. Men with clinical stage T1–3, N0, M0 prostate cancer treated with radiation, without surgery or chemotherapy, were included. OS, the primary clinical outcome, was fit by Cox proportional hazard model. Propensity score matching was implemented for covariate balance. Results: There were 276,880 eligible patients with a median follow-up of 80.9 months. A total of 4900 (1.8%) received PBT, while 158,111 (57.1%) received EBRT and 113,869 (41.1%) BT. Compared to EBRT and BT, PBT patients were younger and were less likely to be in the high-risk group. On multivariable analysis, compared to PBT, men had worse OS after EBRT (adjusted hazard ratio [HR] = 1.72; 95% confidence interval [CI], 1.51–1.96) or BT (adjusted HR = 1.38; 95% CI, 1.21–1.58). After propensity score matching, the OS benefit of PBT remained significant compared to EBRT (HR = 1.64; 95% CI, 1.32–2.04) but not BT (adjusted HR = 1.18; 95% CI, 0.93–1.48). The improvement in OS with PBT was most prominent in men ≤ 65 years old with low-risk disease compared to other subgroups (interaction P < .001). Conclusion: In this national data set, PBT was associated with a significant OS benefit compared to EBRT, and with outcomes similar to BT. These results remain to be validated by ongoing prospective trials.

246 Background: SBRT and HDR brachytherapy have emerged as definitive salvage re-irradiation options for men with locally recurrent prostate cancer after prior radiation therapy (RT). Toxicity with re-irradiation remains a concern in this setting, particularly for salvage of periurethral recurrences. We calculated the normal tissue complication probability (NTCP) of urethral stricture following salvage re-irradiation (HDR and SBRT) after previous definitive RT (external beam or HDR) for periurethral recurrences. Methods: Two upfront definitive treatment plans were generated for 5 men with localized prostate cancer: External Beam RT (EBRT1) to a dose of 79.2 Gy in 1.8 Gy fractions and HDR monotherapy (HDR1), 13.5 Gy x 2 implants. Periurethral recurrences were virtually created on diagnostic MRI scans for each of the five men and defined as a recurrent dominant intraprostatic lesion (DIL). Three salvage RT plans were generated for each patient (constraints in Table): HDR salvage (10 Gy whole gland; 13.5 Gy to DIL; 2 implants), SBRTr with maximal rectal sparing (constraints designed for salvage following prior EBRT; 30 Gy in 5 fractions whole gland; 40 Gy in 5 fractions to DIL), and SBRTu with maximal urethral sparing (constraints designed for patients with prior HDR monotherapy; same Rx). DVH data was collected for each plan (previous RT and each salvage approach) and the equivalent uniform dose (EUD) was calculated. NTCP for the urethral stricture in the summed plans (prior definitive treatment + each salvage plan) was calculated by the Lyman-Kutcher-Burman model using the following parameters: (α/β = 5Gy; TD50= 116.7; m = 0.23; n = 0.3). Results: Prescription coverage of 90% of the DIL volume was achieved for each plan. The mean NTCP of urethral stricture for EBRT1 + HDR salvage was 55.2% (range, 52.2-59.1%) and for HDR1 + HDR salvage was 49.2% (42.9-57.5%). For EBRT1 + SBRTr and EBRT1 + SBRTu the NTCP for urethral stricture was 54.0% (50.4-61.0%) and 43.2% (39.4-48.4%), respectively. The NTCP of urethral stricture for HDR1 + SBRTr was 48.1% (41.0-57.2%) and for HDR1 + SBRTu was 37.6% (30.9-44.6%). Conclusions: In this modeling analysis of salvage RT for periurethral recurrences following previous RT (EBRT or HDR monotherapy), the NTCP for urethral stricture was numerically lowest for salvage SBRT using maximum urethral sparing dose constraints in comparison to salvage SBRT with maximum rectal sparing constraints or salvage HDR brachytherapy. This type of analysis lends insight into personalized treatment planning based on previous RT modality and previous dose to organs at risk. Expanded analysis is underway. [Table: see text]

Key Points Question Is a cancer facility’s radiation case volume associated with long-term outcomes in men with advanced prostate cancer who were treated with primary radiation therapy? Findings In this cohort study of 1899 men from a large US cancer database, men with node-positive prostate cancer undergoing curative-intent radiation therapy with concurrent androgen deprivation therapy had significantly improved median survival rates if they were treated at facilities with a high volume of such patients, independent of academic affiliation. Meaning Node-positive prostate cancer is a complex disease entity with the potential for long-term disease control with aggressive management, and these findings suggest that treatment at a high-volume radiation center is associated with improved long-term oncologic outcomes., This cohort study evaluates the association between radiation facility case volume and overall survival among men with node-positive prostate cancer., Importance Long-term control of node-positive (N1) prostate cancer, the incidence of which is increasing, is obtainable with aggressive treatment, and definitive external beam radiation therapy (EBRT) with long-term androgen deprivation therapy (ADT) is an increasingly preferred option. Caring for these patients is complex and may require resources more readily available at high-volume centers. Objective To evaluate the association between radiation facility case volume and overall survival (OS) in men with N1 prostate cancer. Design, Setting, and Participants This cohort study included 1899 men diagnosed with T1N1M0 to T4N1M0 prostate cancer treated with curative-intent EBRT and ADT between January 2004 and December 2016 at US facilities reporting to the National Cancer Database. Data analysis was performed from March to June 2020. Exposures Treatment at a center with high vs low average cumulative facility volume (ACFV), defined as the total number of prostate radiation cases at an individual patient’s treatment facility from 2004 until the year of that patient’s diagnosis. Main Outcomes and Measures OS was assessed between high- vs low-ACFV centers using the Kaplan-Meier method with and without propensity score–based weighted adjustment and multivariable Cox proportional hazards. The nonlinear association between continuous ACFV and OS was examined through a Martingale residual plot, and the optimal ACFV cutoff point that maximized the separation between high vs low ACFV was identified via a bias adjusted log rank test. Results A total of 1899 men met inclusion criteria. The median (interquartile range) age was 66 (60-72) years, 1491 (78.5%) were White individuals, and 1145 (60.3%) were treated at nonacademic centers. The optimal ACFV cutoff point was 66.4 patients treated per year. The median OS for patients treated at high-ACFV vs low-ACFV centers was 111.1 (95% CI, 101.5-127.9) months and 92.3 (95% CI, 87.7-103.9) months, respectively (P = .01). On multivariable analysis, treatment at a low-ACFV center was associated with increased risk of death (HR, 1.22; 95% CI, 1.02-1.46, P = .03) compared with treatment at a high-ACFV center. These results persisted after propensity score–based adjustment. Conclusions and Relevance This cohort study found a significant association of facility case volume with long-term outcomes in men with N1 prostate cancer undergoing EBRT with ADT. Specifically, treatment at a facility with high radiation case volume was independently associated with longer OS. Further studies should focus on identifying which factors unique to high-volume centers may be responsible for this benefit.

Conflicting clinical evidence regarding the possible association between androgen deprivation therapy (ADT) with heart failure in men with prostate cancer is reviewed, including 2 population-based registries showing such an association, and 1 showing no association. Studies of the effects of androgens on cardiomyocyte contractility at the molecular level, the effects of testosterone on the cardiovascular system, particularly cardiac function, and the beneficial effects of testosterone therapy for patients with heart failure might help illuminate this controversy. Future studies are needed to evaluate the effect of ADT on end points of heart failure. The authors weigh the possible adverse effects of ADT on cardiac function and heart failure against its known benefits to cancer outcomes, defined according to published, randomized trials, in a discussion of the implications of the preclinical and clinical literature on the management of prostate cancer in men at risk for heart failure. In the absence of conclusive evidence that ADT causes heart failure, the authors discuss clinical situations in which ADT may be delayed, given on a short-term or intermittent basis, or withheld from treatment with the goal of reducing the risks of heart failure without compromising prostate cancer outcomes.