Radiation Facility Volume and Survival for Men With Very High-Risk Prostate Cancer Treated with Radiation and Androgen Deprivation Therapy.

Importance: Very high-risk (VHR) prostate cancer is an aggressive substratum of high-risk prostate cancer, characterized by high prostate-specific antigen levels, high Gleason score, and/or advanced T category. Contemporary management paradigms involve advanced molecular imaging and multimodal treatment with intensified prostate-directed or systemic treatment-resources more readily available at high-volume centers. Objective: To examine radiation facility case volume and overall survival (OS) in men with VHR prostate cancer. Design, Setting, and Participants: A retrospective cohort study was performed from November 11, 2022, to March 4, 2023, analyzing data from US facilities reporting to the National Cancer Database. Patients included men diagnosed with nonmetastatic VHR prostate cancer by National Comprehensive Cancer Network criteria (clinical T3b-T4 category, primary Gleason pattern 5, >4 cores with grade group 4-5, and/or 2-3 high-risk features) and treated with curative-intent radiotherapy and androgen deprivation therapy between January 1, 2004, to December 31, 2016. Exposures: Treatment at high- vs low-average cumulative facility volume (ACFV), defined as the total number of prostate radiotherapy cases at an individual patient's treatment facility from 2004 until the year of their diagnosis. The nonlinear association between a continuous ACFV and OS was examined through a Martingale residual plot; an optimal ACFV cutoff was identified that maximized the separation between high vs low ACFV via a bias-adjusted log rank test. Main Outcomes and Measures: Overall survival was assessed between high vs low ACFV using Kaplan-Meier analysis with and without inverse probability score weighted adjustment and multivariable Cox proportional hazards. Results: A total of 25 219 men (median age, 71 [IQR, 64-76] years; 78.7% White) with VHR prostate cancer were identified, 6438 (25.5%) of whom were treated at high ACFV facilities. Median follow-up was 57.4 (95% CI, 56.7-58.1) months. Median OS for patients treated at high ACFV centers was 123.4 (95% CI, 116.6-127.4) months vs 109.0 (95% CI, 106.5-111.2) months at low ACFV centers (P < .001). On multivariable analysis, treatment at a high ACFV center was associated with lower risk of death (hazard ratio, 0.89; 95% CI, 0.84-0.95; P < .001). These results were also significant after inverse probability score weighted-based adjustment. Conclusions and Relevance: In this cohort study of patients with VHR prostate cancer who underwent definitive radiotherapy and androgen deprivation therapy, facility case volume was independently associated with longer OS. Further studies are needed to identify which factors unique to high-volume centers may be responsible for this benefit.

Dose-Escalated Radiation Alone or in Combination With Short-Term Total Androgen Suppression for Intermediate-Risk Prostate Cancer: Patient-Reported Outcomes From NRG/Radiation Therapy Oncology Group 0815 Randomized Trial.

PURPOSE: To report patient-reported outcomes (PROs) of a phase III trial evaluating total androgen suppression (TAS) combined with dose-escalated radiation therapy (RT) for patients with intermediate-risk prostate cancer. METHODS: Patients with intermediate-risk prostate cancer were randomly assigned to dose-escalated RT alone (arm 1) or RT plus TAS (arm 2) consisting of luteinizing hormone-releasing hormone agonist/antagonist with oral antiandrogen for 6 months. The primary PRO was the validated Expanded Prostate Cancer Index Composite (EPIC-50). Secondary PROs included Patient-Reported Outcome Measurement Information System (PROMIS)-fatigue and EuroQOL five-dimensions scale questionnaire (EQ-5D). PRO change scores, calculated for each patient as the follow-up score minus baseline score (at the end of RT and at 6, 12, and 60 months), were compared between treatment arms using a two-sample t test. An effect size of 0.50 standard deviation was considered clinically meaningful. RESULTS: For the primary PRO instrument (EPIC), the completion rates were ≥86% through the first year of follow-up and 70%-75% at 5 years. For the EPIC hormonal and sexual domains, there were clinically meaningful (P < .0001) deficits in the RT + TAS arm. However, there were no clinically meaningful differences by 1 year between arms. There were also no clinically meaningful differences at any time points between arms for PROMIS-fatigue, EQ-5D, and EPIC bowel/urinary scores. CONCLUSION: Compared with dose-escalated RT alone, adding TAS demonstrated clinically meaningful declines only in EPIC hormonal and sexual domains. However, even these PRO differences were transient, and there were no clinically meaningful differences between arms by 1 year.

Dose-Escalated Radiotherapy Alone or in Combination With Short-Term Androgen Deprivation for Intermediate-Risk Prostate Cancer: Results of a Phase III Multi-Institutional Trial.

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 <.001), DM (HR, 0.25; P <.001), PCSM (HR, 0.10; P = .007), and salvage therapy use (HR, 0.62; P = .025). Other-cause deaths were not significantly different (P = .56). Acute grade ≥3 adverse events (AEs) occurred in 2% of patients in arm 1 and in 12% for arm 2 (P <.001). Cumulative incidence of late grade ≥3 AEs was 14% in arm 1 and 15% in arm 2 (P = .29). 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.

Impact of 18 F-Fluciclovine PET/CT Findings on Failure-Free Survival in Biochemical Recurrence of Prostate Cancer Following Salvage Radiation Therapy.

PURPOSE: We aimed to evaluate the impact of 18 F-fluciclovine PET/CT imaging on failure-free survival (FFS) post-salvage radiotherapy (SRT) for prostate cancer (PCa) recurrence. METHODS: Seventy-nine patients were recruited in a phase 2/3 clinical trial to undergo 18 F-fluciclovine PET/CT before SRT for PCa. Four patients with extrapelvic disease were excluded. All patients were followed up at regular intervals up to 48 months. Treatment failure was defined as a serum prostate-specific antigen level of ≥0.2 ng/mL above the nadir after SRT, confirmed with an additional measurement, requiring systemic treatment or clinical progression. Failure-free survival was computed and compared between patients grouped according to 18 F-fluciclovine PET/CT imaging findings. RESULTS: Eighty percent (60/75) of patients had a positive finding on 18 F-fluciclovine PET/CT, of which 56.7% (34/60) had prostate bed-only uptake, whereas 43.3% (26/60) had pelvic nodal ± bed uptake. Following SRT, disease failure was detected in 36% (27/75) of patients. There was a significant difference in FFS between patients who had a positive versus negative scan (62.3% vs 92.9% [ P < 0.001] at 36 months and 59.4% vs 92.9% [ P < 0.001] at 48 months). Similarly, there was a significant difference in FFS between patients with uptake in pelvic nodes ± bed versus prostate bed only at 36 months (49.8% vs 70.7%; P = 0.003) and at 48 months (49.8% vs 65.6%; P = 0.040). Failure-free survival was also significantly higher in patients with either negative PET/CT or prostate bed-only disease versus those with pelvic nodal ± prostate bed disease at 36 (78% vs 49.8%, P < 0.001) and 48 months (74.4% vs 49.8%, P < 0.001). CONCLUSIONS: Findings on pre-SRT 18 F-fluciclovine PET/CT imaging, even when acted upon to optimize the treatment decisions and treatment planning, are predictive of post-SRT FFS in men who experience PCa recurrence after radical prostatectomy. A negative 18 F-fluciclovine PET/CT is most predictive of a lower risk of failure, whereas the presence of pelvic nodal recurrence portends a higher risk of SRT failure.

Differences in Failure-Free Survival After Salvage Radiotherapy Guided by Conventional Imaging Versus 18F-Fluciclovine PET/CT in Postprostatectomy Patients: A Post Hoc Substratification Analysis of the EMPIRE-1 Trial.

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 18F-fluciclovine PET/CT versus conventional imaging. We performed a post hoc analysis of the EMPIRE-1 cohort stratified by protocol-specified criteria, comparing failure-free survival (FFS) between study arms. Methods: EMPIRE-1 randomized patients to SRT planning via either conventional imaging only (bone scanning plus abdominopelvic CT or MRI) (arm A) or conventional imaging plus 18F-fluciclovine PET/CT (arm B). Randomization was stratified by prostate-specific antigen (PSA) level (<2.0 vs. ≥ 2.0 ng/mL), adverse pathology, and androgen-deprivation therapy (ADT) intent. We subdivided patients in each arm using the randomization stratification criteria and compared FFS between patient subgroups across study arms. Results: Eighty-one and 76 patients received per-protocol SRT in study arms A and B, respectively. The median follow-up was 3.5 y (95% CI, 3.0-4.0). FFS was 63.0% and 51.2% at 36 and 48 mo, respectively, in arm A and 75.5% at both 36 and 48 mo in arm B. Among patients with a PSA of less than 2 ng/mL (mean, 0.42 ± 0.42 ng/mL), significantly higher FFS was seen in arm B than arm A at 36 mo (83.2% [95% CI, 70.0-91.0] vs. 66.5% [95% CI, 51.6-77.8], P < 0.001) and 48 mo (83.2% [95% CI, 70.0-91.0] vs. 56.2% [95% CI, 40.5-69.2], P < 0.001). No significant difference in FFS between study arms in patients with a PSA of at least 2 ng/mL was observed. Among patients with adverse pathology, significantly higher FFS was seen in arm B than arm A at 48 mo (68.9% [95% CI, 52.1-80.8] vs. 42.8% [95% CI, 26.2-58.3], P < 0.001) though not at the 36-mo follow-up. FFS was higher in patients without adverse pathology in arm B versus arm A (90.2% [95% CI, 65.9-97.5] vs. 73.1% [95% CI, 42.9-89.0], P = 0.006) at both 36 and 48 mo. Patients in whom ADT was intended in arm B had higher FFS than those in arm A, with the difference reaching statistical significance at 48 mo (65.2% [95% CI, 40.3-81.7] vs. 29.1 [95% CI, 6.5-57.2], P < 0.001). Patients without ADT intent in arm B had significantly higher FFS than patients in arm A at 36 mo (80.7% [95% CI, 64.9-90.0] vs. 68.0% [95% CI, 51.1-80.2]) and 48 mo (80.7% [95% CI, 64.9-90.0] vs. 58.6% [95% CI, 41.0-72.6]). Conclusion: The survival advantage due to the addition of 18F-fluciclovine PET/CT to SRT planning is maintained regardless of the presence of adverse pathology or ADT intent. Including 18F-fluciclovine PET/CT to SRT leads to survival benefits in patients with a PSA of less than 2 ng/mL but not in patients with a PSA of 2 ng/mL or higher.

Randomized Trial of Conventional Versus Conventional Plus Fluciclovine (18F) Positron Emission Tomography/Computed Tomography-Guided Postprostatectomy Radiation Therapy for Prostate Cancer: Volumetric and Patient-Reported Analyses of Toxic Effects.

PURPOSE: Postprostatectomy radiation therapy planning with fluciclovine (18F) positron emission tomography (PET)/computed tomography has demonstrated improved disease-free survival over conventional only (computed tomography- or magnetic resonance imaging-based) treatment planning. We hypothesized that incorporating PET would result in larger clinical target volumes (CTVs) without increasing patient-reported toxic effects. METHODS AND MATERIALS: From 2012 to 2019, 165 postprostatectomy patients with detectable prostate-specific antigen 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 nodes, as well as organ-at-risk doses, were compared pre- versus post-PET (arm 2) using the paired t test and between arms using the t test. Patient-reported outcomes used International Prostate Symptom Score and Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP). Univariate and multivariable analyses were performed and linear mixed models were fitted. RESULTS: Median follow-up of the whole cohort was 3.52 years. All patients had baseline patient-reported outcomes, 1 patient in arm 1 and 3 patients in arm 2 withdrew, and 4 arm 2 patients had extrapelvic uptake on PET with radiotherapy aborted, leaving 81 (arm 1) and 76 patients (arm 2) for analysis of toxic effects. Mean CTV1 (427.6 vs 452.2 mL; P = .462, arm 1 vs arm 2) and CTV2/CTV (137.18 vs 134.2 mL; P = .669) were similar before PET incorporation. CTV1 (454.57 vs 461.33 mL; P = .003) and CTV2/CTV (134.14 vs 135.61 mL; P < .001) were modestly larger after PET incorporation. Although V40 Gy (P = .402 and P = .522 for rectum and bladder, respectively) and V65 Gy (P = .157 and P = .182 for rectum and bladder, respectively) were not significantly different pre- versus post-PET, penile bulb dose significantly increased post-PET (P < .001 for both V40 Gy and V65 Gy). On univariate and multivariable analyses, arm was not significant for any EPIC-CP subdomain. International Prostate Symptom Score and EPIC-CP linear mixed models were not significantly different between arms. CONCLUSIONS: Despite larger CTVs after incorporation of fluciclovine (18F) PET, we found no significant difference in patient-reported toxic effects with long-term follow-up.

Treatment Patterns and Overall Survival Outcomes Among Patients Aged 80 yr or Older with High-risk Prostate Cancer.

BACKGROUND: Elderly patients diagnosed with high-risk prostate cancer (PCa) present a therapeutic dilemma of balancing treatment of a potentially lethal malignancy with overtreatment of a cancer that may not threaten life expectancy. OBJECTIVE: To investigate treatment patterns and overall survival outcomes in this group of patients. DESIGN SETTING AND PARTICIPANTS: A retrospective cohort study was conducted. We queried the National Cancer Database for high-risk PCa in patients aged 80 yr or older diagnosed during 2004-2016. INTERVENTION: Eligible patients underwent no treatment following biopsy (ie, observation), androgen deprivation therapy (ADT) alone, radiation therapy (RT) alone, RT + ADT, or surgery. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier, log rank, and multivariate Cox proportional hazard regression was performed to compare overall survival (OS). RESULTS AND LIMITATIONS: A total of 19 920 men were eligible for analysis, and the most common treatment approach was RT + ADT (7401 patients; 37.2%). Observation and ADT alone declined over time (59.3% in 2004 vs 47.5% in 2016). There was no observed difference in OS between observation and ADT alone (adjusted hazard ratio [HR] 1.04, 95% confidence interval [CI], 0.99-1.09; p = 0.105). Definitive local treatment was associated with improved OS compared with ADT alone (RT alone, HR 0.54, 95% CI, 0.50-0.59, p < 0.0001; ADT + RT, HR 0.48, 95% CI, 0.46-0.50, p < 0.0001; surgery, HR 0.50, 95% CI, 0.42-0.59, p < 0.0001). CONCLUSIONS: This analysis demonstrates that the use of definitive local therapy, including surgery or RT ± ADT, is increasing and is associated with a 50% reduction in overall mortality compared with observation or ADT alone. While prospective validation is warranted, elderly men with high-risk disease eligible for definitive management should be counseled on the risks, including a possible compromise in OS, with deferring definitive management. PATIENT SUMMARY: Elderly men are more often diagnosed with higher-risk prostate cancer but are less likely to receive curative treatment options than younger men. Our analysis demonstrates that for men ≥80 yr of age with high-risk prostate cancer, definitive local therapy, including surgery or radiation therapy and/or androgen deprivation therapy, is associated with a 50% reduction in overall mortality compared with observation or androgen deprivation therapy alone. We therefore recommend that life expectancy (ie, physiologic age) be taken into account, over chronologic age, and that elderly men with good life expectancy (eg, >5 yr; minimal comorbidity) should be offered definitive, life-prolonging therapy.

Association Between Local Radiation Therapy to the Primary Bladder Tumor and Overall Survival for Patients with Metastatic Urothelial Cancer Receiving Systemic Chemotherapy.

There are limited data on the role of local therapy for metastatic urothelial carcinoma of the bladder (mUC). In this retrospective cohort analysis, we queried the National Cancer Data Base for patients with newly diagnosed mUC (cT1-4 N0-3 M1). Overall survival (OS) was compared between treatment with chemotherapy (CT) alone (n = 4122) and CT plus bladder-directed radiation therapy (CT + RT; n = 337). Multivariable Cox proportional-hazards analyses and matching and landmark analyses were performed. CT + RT was independently associated with better OS (hazard ratio 0.70, 95% confidence interval 0.62-0.79; p < 0.0001) and this result persisted in matched and landmark analyses. These findings are hypothesis-generating and limited by inherent confounding factors; however, a prospective trial evaluating the impact of bladder RT in mUC is warranted. PATIENT SUMMARY: For patients with bladder cancer that has already spread to other parts of the body, it is unclear if radiation therapy directed at the primary bladder tumor would provide any improvement in survival. In this study, we found that aggressive radiation therapy directed at the bladder combined with chemotherapy may provide a survival benefit in some patients with metastatic bladder cancer compared to chemotherapy alone.

Influence of Timing Between Androgen Deprivation Therapy and External Beam Radiation Therapy in Patients With Localized, High-Risk Prostate Cancer.

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) <8 weeks before RT. Kaplan-Meier, propensity score matching, and multivariable Cox proportional hazards were performed to evaluate overall survival (OS). RESULTS: With a median follow-up of 68.9 months, 37,606 patients with HR-PC were eligible for analysis: 13,346 (35.5%) with >11 weeks of neoadjuvant ADT, 11,456 (30.5%) with 8 to 11 weeks of neoadjuvant ADT; and 12,804 (34%) patients with <8 weeks of neoadjuvant ADT. The unadjusted 10-year OS rates for >11 weeks, 8 to 11 weeks, and <8 weeks neoadjuvant ADT groups were 49.9%, 51.2%, and 46.9%, respectively (P = .002). On multivariable and inverse probability of treatment weighting analyses, there was a significant OS advantage for patients in the 8 to 11 weeks neoadjuvant ADT group (adjusted hazard ratio 0.90; 95% confidence interval, 0.86-0.95; P < .001) but not the >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.

Patient-reported outcomes after Low-dose-rate versus High-dose-rate brachytherapy boost in combination with external beam radiation for intermediate and high risk prostate cancer.

PURPOSE: 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. METHODS: 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. RESULTS: 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; p <0.001). There were no differences between groups in incontinence, bowel function, and erectile function, or grade 2+ GI toxicity. CONCLUSION: Compared with LDR-BT, HDR-BT was associated with lower acute patient- and provider-reported GU toxicity.

18F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): a single centre, open-label, phase 2/3 randomised controlled trial.

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.

Overall Survival After Treatment of Localized Prostate Cancer With Proton Beam Therapy, External-Beam Photon Therapy, or Brachytherapy.

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.

Analysis of Radiation Facility Volume and Survival in Men With Lymph Node-Positive Prostate Cancer Treated With Radiation and Androgen Deprivation Therapy.

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.

Overall survival comparison between androgen deprivation therapy (ADT) plus external beam radiation therapy (EBRT) vs ADT plus EBRT with brachytherapy boost in clinically node-positive prostate cancer.

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.

High-dose-rate prostate brachytherapy appears safe in patients with high baseline International Prostate Symptom Scores.

PURPOSE: 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 IPSS <15. METHODS AND MATERIALS: 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. RESULTS: Median followup in the IPSS <15 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 IPSS <15 group at baseline (all p ≤ 0.05). By the >24 months time point, these scores had decreased below baseline and were not significantly different from those with a baseline IPSS <15 (all p > 0.1). 12.5% in the IPSS ≥15 group developed a new Grade 2 genitourinary toxicity requiring an alpha blocker compared with 26.5% in the IPSS <15 group (p = 0.34). No patients required emergency placement of a foley catheter within 30 days of treatment. CONCLUSIONS: Given the low rates of genitourinary toxicity, this technique appears appropriate even for those with high baseline urinary symptoms.

The effects of androgen deprivation therapy on cardiac function and heart failure: implications for management of prostate cancer.

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.