Dose-escalated External Beam Radiation Therapy Research Articles

Biochemical control in intermediate- and high-risk prostate cancer after EBRT with and without brachytherapy boost.

External beam radiotherapy (EBRT) with or without brachytherapy boost (BTB) has not been compared in prospective studies using guideline-recommended radiation dose and recommended androgen-deprivation therapy (ADT). In this multicenter retrospective analysis, we compared modern-day EBRT with BTB in terms of biochemical control (BC) for intermediate-risk (IR) and high-risk (HR) prostate cancer. Patients were treated for primary IR or HR prostate cancer during 1999-2019 at three high-volume centers. Inclusion criteria were prescribed ≥ 76 Gy EQD2 (α/β = 1.5 Gy) for IR and ≥ 78 Gy EQD2 (α/β = 1.5 Gy) for HR as EBRT alone or with BTB. All HR patients received ADT and pelvic irradiation, which were optional in IR cases. BC between therapies was compared in survival analyses. Of 2769 initial patients, 1176 met inclusion criteria: 468 HR (260 EBRT, 208 BTB) and 708 IR (539 EBRT, 169 BTB). Median follow-up was 49and 51months for HR and IR, respectively. BTB patients with ≥ 113 Gy EQD2Gy experienced astable, good BC outcome compared with BTB at lower doses. Patients treated with ≥ 113 Gy EQD2Gy also experienced significantly improved BC compared with EBRT (10-year BC failure rates after ≥ 113 Gy BTB and EBRT: respectively 20.4 and 41.8% for HR and 7.5and 20.8% for IR). In patients with IR and HR prostate cancer, BTB with ≥ 113 Gy EQD2Gy offered aBC advantage compared with dose-escalated EBRT and lower BTB doses.

Overall survival benefit of androgen suppression in addition to dose-escalated external beam radiotherapy for high-risk prostate cancer: Nationwide real-world data indicates a shift in men that benefit

ObjectiveTo evaluate the real-world added value of androgen deprivation therapy (ADT) in addition to external beam radiotherapy (EBRT) in men with high-risk non-metastatic prostate cancer, in view of advances in radiotherapy and diagnostics. MethodsAll Dutch men diagnosed with high-risk non-metastatic prostate cancer (defined as: ≥cT2c-T3b N0M0, PSA ≥20–50 ng/ml, and/or Gleason score ≥8 (International Society of Urological Pathology [ISUP] grade ≥4)) from 2009 through 2019 and treated with EBRT with or without ADT were identified in the population-based Netherlands Cancer Registry.Propensity scores were used to match (1:1) men that received ADT to men that did not receive ADT. Subsequently, OS was compared. Analyses were also stratified by number of high-risk features, 1 (either ≥cT2c, PSA >20 ng/ml or Gleason score ≥8) versus ≥2 (out of ≥cT2c, PSA >20 ng/ml and Gleason score ≥8). ResultsA total of 14,773 men with high-risk non-metastatic prostate cancer were identified, 3,958 (27%) of which received EBRT alone. After matching, 3,427 men remained in both groups and baseline characteristics were well-balanced. After a median follow-up of 92 months, OS was better in men treated with EBRT and ADT compared to men treated with EBRT alone (10-year OS: 66.4% versus 61.8%; HR 0.88 [95%CI: 0.80–0.96]). There was no statistically significant difference in OS in the subgroup of men with only 1 high-risk feature (10-year OS 67.7% versus 64.9%; HR 0.95 [95%CI: 0.85–1.07]). ConclusionsIn a contemporary cohort of men treated for high-risk non-metastatic prostate cancer with EBRT, an OS benefit of adding ADT was only observed in men with at least 2 high-risk features. These results suggest that improvements in diagnostics and treatment in recent decades have resulted in a stage shift of men benefiting from the addition of ADT to EBRT.

Assessment of Bioprotect's Biodegradable Balloon System as a Rectal Spacer in Radiotherapy: An Animal Study on Tissue Response and Biocompatibility.

Prostate cancer is a significant health concern for men, emphasizing the need for effective treatment strategies. Dose-escalated external beam radiotherapy shows promise in improving outcomes but presents challenges due to radiation effects on nearby structures, such as the rectum. Innovative techniques, including rectal spacers, have emerged to mitigate these effects. This study comprehensively assessed tissue responses following the implantation of the Bioprotect biodegradable fillable balloon as a rectal spacer in a rat model. Evaluation occurred at multiple time points (4, 26, and 52 weeks) post-implantation. Results revealed localized tissue responses consistent with the expected reaction to biodegradable materials, characterized by mild to moderate fibrotic reactions and encapsulation, underscoring the safety and biocompatibility of the balloon. Importantly, no other adverse events occurred, and the animals remained healthy throughout the study. These findings support its potential clinical utility in radiotherapy treatments to enhance patient outcomes and minimize long-term implant-related complications, serving as a benchmark for future similar studies and offering valuable insights for researchers in the field. In conclusion, the findings from this study highlight the safety, biocompatibility, and potential clinical applicability of the Bioprotect biodegradable fillable balloon as a promising rectal spacer in mitigating radiation-induced complications during prostate cancer radiotherapy.

Patient-Reported Urinary and Bowel Quality of Life Outcomes Following External Beam Radiotherapy with or without High-Dose-Rate Brachytherapy Boost: Post-Hoc Analyses of TROG 03.04 (RADAR)

One of the concerns with combining external beam radiotherapy (EBRT) with a high dose rate brachytherapy boost (HDRBT) for prostate cancer is increased toxicity. We aimed to evaluate long-term urinary and bowel quality of life (QoL) outcomes following EBRT vs EBRT + HDRBT using data from the TROG 03.04 trial. Men who had dose-escalated EBRT (74 Gy) or EBRT (46 Gy) + HDRBT (19.5 Gy in 3 fractions) were included in this exploratory analysis. QoL outcomes were prospectively collected using the EORTC-QLQ-PR25 at baseline, end of radiotherapy, 12, 18, 24, 36, 60 months, and annually up to 10 years. QoL score was normalized to 0-100 with higher scores representing worse symptom burden. Minimal clinically important differences (MCIDs) were defined as differences in the respective QoL scores ≥0.5 standard deviations of the baseline QoL score. Mixed models for repeated measures were used to evaluate longitudinal changes in the QoL score between EBRT and EBRT + HDRBT arms. Logistic regression was used to evaluate differences in proportion of men with 2xMCID between EBRT and EBRT + HDRBT arms at each time point. Age, baseline QoL score, ECOG performance status, and duration of androgen deprivation therapy use (6 vs. 18 months) were adjusted for in all analyses. Four hundred ninety-seven men were included in this study: 260 (52%) had EBRT and 237 (48%) had EBRT + HDRBT. The median baseline urinary QoL scores were 12.5 (IQR 4.2-19.0) and 8.3 (IQR 4.2-20.8) for men in EBRT and EBRT + HDRBT arms respectively (P = 0.5). Within the first 24 months, men in the EBRT + HDRBT arm had a slower rate of urinary QoL score resolution compared to men in the EBRT arm (P<0.001). At 12, 18, 24, and 36 months, men who had EBRT + HDRBT were 2.4 times (95% CI = 1.4-4.0; P<0.001), 3.1 times (95% CI = 1.8-5.1; P<0.001), 2.8 times (95% CI = 1.7-4.7; P<0.001), and 2.5 times (95% CI = 1.4-4.5; P = 0.002) more likely to have 2xMCID in urinary QoL scores compared to men who had EBRT alone. Beyond 24 months, there were no significant differences in the rate of urinary QoL score resolution between arms, and beyond 36 months there were no significant differences in the proportion with 2xMCID between arms. The median baseline bowel QoL score was 0 in both arms. There were no differences in the rate of bowel QoL score recovery over time between arms. Men who had EBRT + HDRBT were less likely to have 2xMCID in bowel QoL score in the immediate post-radiotherapy period (OR = 0.66; 95% CI = 0.45-0.97; P = 0.03) and at 60 months (OR = 0.51; 95% CI = 0.33-0.80; P = 0.003) compared to men who had EBRT. EBRT + HDRBT is associated with disturbances in urinary QoL that are of greater magnitude compared to EBRT alone within the first 36 months of treatment, but the differences resolved after 36 months. EBRT + HDRBT is associated with less disturbances in bowel QoL immediately after treatment and at 60 months compared to EBRT alone.

Stereotactic Body Radiation Therapy and High-Dose Rate Brachytherapy Boost in Combination with Intensity Modulated Radiation Therapy for Localized Prostate Cancer: A Single-Institution Cohort Study

The use of dose-escalated external beam radiation (EBRT) and brachytherapy (BT) boost with ADT has emerged as an option with superior biochemical control compared to dose-escalated EBRT alone. BT is traditionally delivered using low-dose rate techniques, but more recently high-dose rate (HDR) BT has also emerged as a boost option for these patients with promise of low toxicity rates. SBRT is a favorable modality for monotherapy for low and intermediate risk group patients, however its safety and efficacy as a boost in combination with EBRT is less well understood. The aim of this study is to compare SBRT boost, HDR boost and LDR boost for localized prostate cancer. A single-institution retrospective chart review was performed of men receiving EBRT delivered using intensity modulated RT and either SBRT boost (650cGy x 3), HDR-BT boost (1500cGy x 1), or LDR boost with I-125 (110Gy). Of patients treated w/ SBRT boost, 39 (80%) were treated with an SIB to the MRI-detectable lesion(s) to 700cGy x 3. Treatment characteristics for each strategy were reviewed and on-treatment toxicity outcomes for each of the cohorts were compared using Chi-square tests. From 2017-2022, 49 patients were treated with EBRT+SBRT boost, 44 patients received EBRT+ HDR-BT boost, and 46 patients received EBRT+ LDR-BT boost. The average age of patients included in the study was 71.2 years (median age 69.55 years, range 51.42-83.70 years) with average baseline PSA of 11 (median 7.6, range 3.3-64). In addition, 55% of the patients had high-risk/very high-risk disease, 39% had unfavorable intermediate disease and 6% had favorable intermediate disease. 139 patients received androgen deprivation therapy (93%). There were no differences in these baseline demographics and clinical or treatment factors between SBRT, HDR and LDR boost (p>0.05). The median dose/fx of EBRT was 4500cGy/25 fx (range 4500-5040cGy/23-28 fractions). At the end of treatment, 69% of the patients had 0-1 change in nocturia. There is an increase in nocturia episodes of 2-3 from baseline in 27% of the patients, while 4% had an increase in nocturia episodes of 4 or more from baseline with no difference between the SBRT, HDR and LDR boost. At baseline 36 patients (26%) reported urinary frequency symptoms, increasing to 80 patients (58%) by end of treatment with no difference between the SBRT, HDR and LDR boost. Similarly, there was a trend to increased use of urinary modifiers at end of treatment in patients treated with EBRT+HDR boost compared to EBRT+SBRT and EBRT+ LDR boost (89% vs. 71% v 72% respectively). There was no significant difference in acute urinary toxicity and nocturia between SBRT, HDR and LDR boost (p>0.05).

Radical prostatectomy versus external beam radiotherapy with androgen deprivation therapy for high-risk prostate cancer: a systematic review

BackgroundTo summarize recent evidence in terms of health-related quality of life (HRQoL), functional and oncological outcomes following radical prostatectomy (RP) compared to external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) for high-risk prostate cancer (PCa).MethodsWe searched Medline, Embase, Cochrane Database of Systematic Reviews, Cochrane Controlled Trial Register and the International Standard Randomized Controlled Trial Number registry on 29 march 2021. Comparative studies, published since 2016, that reported on treatment with RP versus dose-escalated EBRT and ADT for high-risk non-metastatic PCa were included. The Newcastle–Ottawa Scale was used to appraise quality and risk of bias. A qualitative synthesis was performed.ResultsNineteen studies, all non-randomized, met the inclusion criteria. Risk of bias assessment indicated low (n = 14) to moderate/high (n = 5) risk of bias. Only three studies reported functional outcomes and/or HRQoL using different measurement instruments and methods. A clinically meaningful difference in HRQoL was not observed. All studies reported oncological outcomes and survival was generally good (5-year survival rates > 90%). In the majority of studies, a statistically significant difference between both treatment groups was not observed, or only differences in biochemical recurrence-free survival were reported.ConclusionsEvidence clearly demonstrating superiority in terms of oncological outcomes of either RP or EBRT combined with ADT is lacking. Studies reporting functional outcomes and HRQoL are very scarce and the magnitude of the effect of RP versus dose-escalated EBRT with ADT on HRQoL and functional outcomes remains largely unknown.

Intensity-modulated radiation therapy for intermediate-risk prostate cancer: does ADT still have an impact in the dose-escalated external beam radiation therapy era?

This study aimed to investigate the effect of androgen deprivation therapy (ADT) on the survival of intermediate-risk prostate cancer (IR-PCA) patients treated with dose-escalated external beam radiation therapy (DE-EBRT), and to determine the group that will benefit from ADT. We analysed 620 IR-PCA patients treated with DE-EBRT at two institutions. Variables were adjusted using the stabilised inverse probability of treatment weighting method (sIPTW) between radiation therapy (RT) and RT plus ADT groups. Biochemical relapse-free survival (bRFS) rate and overall survival (OS) rate were compared using Kaplan-Meier analysis and log-rank test. Cox proportional hazard analysis (CPH) was conducted to detect unfavorable risk factors. This study included 405 patients; with 217 and 188 patients in the RT and RT plus ADT groups, respectively. The prescribed radiation dose was 78Gy in 39 fractions. The median follow-up time was 82.0months. After sIPTW-adjustment, 214.3 and 189.7 patients were assigned to the RT and RT plus ADT groups, respectively. The 7-year bRFS and OS were 89.3% and 94.6% in RT group and 92.3% and 91.0% in RT plus ADT group, respectively. Before and after sIPTW adjustment, no statistically significant differences were found in these endpoints between treatment groups. Multivariate CPH for bRFS revealed Gleason score (GS) 4+3 as an unfavorable risk factor, and ADT improved biochemical control of them. ADT may not always be effective in all Japanese IR-PCA patients treated with DE-EBRT, but it can improve biochemical control in patients with GS 4+3.

Quality rectal hydrogel placement allows for gel-enabled dose-escalated EBRT (GEDE-EBRT) without rectal interference in prostate cancer.

Multiple trials have shown that dose-escalation of radiation for prostate cancer provides a biochemical progression-free survival benefit (bPFS); however, rectal constraints are often limiting. In this dosimetric study, we hypothesized that a well-placed rectal hydrogel (RH) would permit improved dose-escalation and target coverage. We selected patients with good-quality RH and created plans with and without RH, prescribing 70 Gy in 28 fractions to the prostate and proximal seminal vesicles (PSV), and a peripheral zone (PZ) boost to 84 Gy, 98 Gy, or 112 Gy. We then compared plans with and without RH, prescribing a 112 Gy boost to 1 to 2 cm simulated dominant intraprostatic lesions (DIL). In the 18 plans created with a PZ boost, the PTV_boost D95% was higher in RH plans compared to non-RH plans (median 98.5 Gy vs 75.53 Gy, p < 0.01). The PSV planning target volume (PTV_PSV) D95% was also marginally higher with RH (71.87 Gy vs 71.04 Gy, p < 0.01). All rectal metrics were improved with RH. For the 32 plans created for simulated DILs treated to 112 Gy, the PTV_boost coverage (median D95% 112.48 Gy vs 102.63 Gy, p < 0.01) and rectal metrics were improved with RH. Four non-RH plans with at least a 4 mm rectal-PTV_boost gap achieved D95% > 98% of the prescription dose for the PTV_boost. Our study showed that placement of a high-quality RH allowed for GEDE-EBRT up to 112 Gy in 28 fractions (EQD2 160 Gy with α/β = 2.5). This concept should be tested prospectively, particularly to assess for increases in nonrectal toxicities.

P041 - Use of BioProtect balloon in patients with low- or intermediate-risk prostate cancer receiving dose-escalated EBRT: A retrospective, single institution study reporting rectal spacing and dosimetry

P041 - Use of BioProtect balloon in patients with low- or intermediate-risk prostate cancer receiving dose-escalated EBRT: A retrospective, single institution study reporting rectal spacing and dosimetry

Phase III Trial of Dose Escalated Radiation Therapy and Standard Androgen Deprivation Therapy (ADT) vs. Dose Escalated Radiation Therapy and Enhanced ADT with TAK-700 for Men with High-Risk Prostate Cancer (NRG Oncology/RTOG 1115)

<h3>Purpose/Objective(s)</h3> RTOG 1115 was a randomized phase III trial evaluating the addition of orteronel (TAK-700), a novel CYP17A1 inhibitor, to dose escalated radiation plus ADT in men with high risk, localized prostate cancer. Originally designed to evaluate overall survival, the trial was halted early due to discontinuation of orteronel development in prostate cancer. We report here the initial primary endpoint analysis. <h3>Materials/Methods</h3> The study was designed to enroll 900 men with high-risk prostate cancer (Gleason 9-10, PSA > 20, or clinical stage T2 or higher with Gleason ≥ 8). Ultimately, 238 patients were enrolled (May 2012-Sept 2014), and randomized 1:1 to receive standard therapy (Arm A), or standard therapy plus two years of twice daily orteronel (Arm B). Radiation therapy entailed dose-escalated external beam radiation (EBRT) to the prostate and pelvis to 45 Gy in 25 fractions, followed by a boost to 79.2 Gy using EBRT or either HDR or LDR. The analysis plan was reframed around detecting a reduction in rate of a composite biochemical failure endpoint (Phoenix biochemical failure, local/regional or distant disease, or salvage ADT). With 238 patients enrolled and followed, the study would have 70% power to detect a 40% decrease in the composite failure primary endpoint after 70 events had occurred. <h3>Results</h3> 231 patients were evaluable for efficacy and toxicity, 115 in Arm A and 116 in Arm B, and median follow up was 6.2 years. Grade 3 adverse events were observed in 35% and 60% of men in Arm A and B, respectively, with most common being urinary or gastrointestinal disturbance. Time to grade 3 adverse event was significantly faster in Arm B (log rank P value < 0.001). There were four deaths due to adverse events, three of which were in Arm A, and all were deemed unlikely related to treatment. Notably, only 29% of men in Arm B received 80% or more of the planned dose of orteronel due to a variety of factors that impacted drug tolerability. With respect to the primary outcome, patients did well overall with 6-year failure rates of 22.5% and 16.1%, respectively, in Arms A and B (hazard ratio [HR] 0.83, 95% CI 0.47-1.48). By Phoenix definition, PSA failure was only 18.4% and 12.1% in Arms A and B through 6 years. Distant failure occurred in 10.0% and 4.0% of patients (HR 0.71, 95% CI 0.29-1.75). Quality of life outcomes will be reported separately. While all efficacy trends favored the experimental arm, due to the small number of patients and events none of the differences between arms achieved statistical significance. <h3>Conclusion</h3> The addition of orteronel to dose escalated RT and ADT did not result in statistically significant improvement in efficacy outcomes, although results were limited by early termination of accrual and impaired drug tolerability. Intensification of hormonal therapy with better tolerated novel agents remains an appealing strategy for the treatment of high-risk localized prostate cancer.

External Beam Radiation Therapy With or Without Brachytherapy Boost in Men With Very-High-Risk Prostate Cancer: A Large Multicenter International Consortium Analysis

Very-high-risk (VHR) prostate cancer (PC) is an aggressive subgroup with high risk of distant disease progression. Systemic treatment intensification with abiraterone or docetaxel reduces PC-specific mortality (PCSM) and distant metastasis (DM) in men receiving external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT). Whether prostate-directed treatment intensification with the addition of brachytherapy (BT) boost to EBRT with ADT improves outcomes in this group is unclear. This cohort study from 16 centers across 4 countries included men with VHR PC treated with either dose-escalated EBRT with ≥24 months of ADT or EBRT+BT boost with ≥12 months of ADT. VHR was defined by National Comprehensive Cancer Network (NCCN) criteria (clinical T3b-4, primary Gleason pattern 5, or ≥2 NCCN high-risk features), and results were corroborated in a subgroup of men who met Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials inclusion criteria (≥2 of the following: clinical T3-4, Gleason 8-10, or PSA ≥40 ng/mL). PCSM and DM between EBRT and EBRT+BT were compared using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression. Among the entire cohort, 270 underwent EBRT and 101 EBRT+BT. After a median follow-up of 7.8 years, 6.7% and 5.9% of men died of PC and 16.3% and 9.9% had DM after EBRT and EBRT+BT, respectively. There was no significant difference in PCSM (sHR, 1.47 [95% CI, 0.57-3.75]; P=.42) or DM (sHR, 0.72, [95% CI, 0.30-1.71]; P=.45) between EBRT+BT and EBRT. Results were similar within the STAMPEDE-defined VHR subgroup (PCSM: sHR, 1.67 [95% CI, 0.48-5.81]; P=.42; DM: sHR, 0.56 [95% CI, 0.15-2.04]; P=.38). In this VHR PC cohort, no difference in clinically meaningful outcomes was observed between EBRT alone with ≥24 months of ADT compared with EBRT+BT with ≥12 months of ADT. Comparative analyses in men treated with intensified systemic therapy are warranted.

Propensity score-matched analysis comparing dose-escalated intensity-modulated radiation therapy versus external beam radiation therapy plus high-dose-rate brachytherapy for localized prostate cancer

PurposeDose-escalated external beam radiation therapy (EBRT) and EBRT + high-dose-rate brachytherapy (HDR-BT) boost are guideline-recommended treatment options for localized prostate cancer. The purpose of this study was to compare long-term outcome and toxicity of dose-escalated EBRT versus EBRT + HDR-BT boost.MethodsFrom 2002 to 2019, 744 consecutive patients received either EBRT or EBRT + HDR-BT boost, of whom 516 patients were propensity score matched. Median follow-up was 95.3 months. Cone beam CT image-guided EBRT consisted of 33 fractions of intensity-modulated radiation therapy with simultaneous integrated boost up to 76.23 Gy (DMean). Combined treatment was delivered as 46 Gy (DMean) EBRT, followed by two fractions HDR-BT boost with 9 Gy (D90%). Propensity score matching was applied before analysis of the primary endpoint, estimated 10-year biochemical relapse-free survival (bRFS), and the secondary endpoints metastasis-free survival (MFS) and overall survival (OS). Prognostic parameters were analyzed by Cox proportional hazard modelling. Genitourinary (GU)/gastrointestinal (GI) toxicity evaluation used the Common Toxicity Criteria for Adverse Events (v5.0).ResultsThe estimated 10-year bRFS was 82.0% vs. 76.4% (p = 0.075) for EBRT alone versus combined treatment, respectively. The estimated 10-year MFS was 82.9% vs. 87.0% (p = 0.195) and the 10-year OS was 65.7% vs. 68.9% (p = 0.303), respectively. Cumulative 5‑year late GU ≥ grade 2 toxicities were seen in 23.6% vs. 19.2% (p = 0.086) and 5‑year late GI ≥ grade 2 toxicities in 11.1% vs. 5.0% of the patients (p = 0.002); cumulative 5‑year late grade 3 GU toxicity occurred in 4.2% vs. 3.6% (p = 0.401) and GI toxicity in 1.0% vs. 0.3% (p = 0.249), respectively.ConclusionBoth treatment groups showed excellent long-term outcomes with low rates of severe toxicity.

A0958 - A nationwide study on the added value of (neo)adjuvant ADT in addition to modern dose-escalated external beam radiotherapy in men with high-risk localized prostate cancer

A0958 - A nationwide study on the added value of (neo)adjuvant ADT in addition to modern dose-escalated external beam radiotherapy in men with high-risk localized prostate cancer

Quality of Life Implications of Dose-Escalated External Beam Radiation for Localized Prostate Cancer: Results of a Prospective Randomized Phase 3 Clinical Trial, NRG/RTOG 0126

External beam radiation therapy (EBRT) dose escalation has been tested in multiple prospective trials. However, the impact on patient reported outcomes (PROs) associated with higher doses of EBRT remain poorly understood. We sought to assess the differences in PROs between men treated with a dose of 70.2 Gy versus 79.2 Gy of EBRT for prostate cancer. The phase 3 clinical trial RTOG 0126 randomized 1532 patients with prostate cancer between March 2002 and August 2008 to 79.2 Gy over 44 fractions versus 70.2 Gy over 39 fractions. Eligible patients participated in the PRO data collection. PROs completed included the International Index of Erectile Function Questionnaire (IIEF), Functional Alterations due to Changes in Elimination (FACE), and the Spitzer Quality of Life Index (SQLI). The timepoints for the IIEF were collected pre-entry and at 6, 12, and 24 months. The FACE and SQLI were collected pre-entry and at 3, 6, 12, 18, and 24 months. The impact of EBRT dose to normal structures (penile bulb, rectum, and bladder) on PROs was also examined. Mixed effects models were used to analyze trends across time. In total, 1144 patients completed baseline IIEF forms and of these, 56%, 64%, and 61% completed the IIEF at 6, 12, and 24 months, respectively; 1123 patients completed the FACE score at baseline and 50%, 61%, 73%, 61%, and 65% completed all 15 items for the FACE metric at timepoints of 3, 6, 12, 18, and 24 months, respectively. Erectile dysfunction at 12 months based on the single question was not significantly different between arms (38.1% for the standard dose radiation therapy arm vs 49.7% for the dose escalated radiation therapy arm; P=.051). Treatment arm (70.2 vs 79.2) had no significant impact on any PRO metrics measured across all collected domains. Comprehensive dosimetric analyses are presented and reveal multiple significant differences to regional organs at risk. Compliance with PRO data collection was lower than anticipated in this phase 3 trial. Examining the available data, dose escalated EBRT did not appear to be associated with any detriment to PROs across numerous prospectively collected domains. These data, notwithstanding limitations, add to our understanding of the implications of EBRT dose escalation in prostate cancer. Furthermore, these results illustrate challenges associated with PRO data collection.

Dose-Escalated External-Beam Radiation to Prostate and Pelvic Nodes in High-Risk Prostate Cancer: Long-Term Toxicities and Outcomes at a Tertiary Center

A previous prospective study of dose escalated pelvic nodal irradiation in high-risk prostate cancer patients resulted in the adoption of this strategy as a standard treatment policy at our center. Here we report the long-term outcomes and toxicities of a cohort of high-risk prostate cancer patients treated with dose escalated external-beam radiotherapy (DE-RT) to the prostate and pelvic lymph nodes with or without androgen deprivation therapy (ADT).This was a retrospective REB approved study of 189 patients with high (HRPCa) and very high risk (VHRPCa) prostate cancer, treated with DE-RT between the years 2003 to 2016. All patients receiving at least 74 Gy to the prostate and 52 Gy to the pelvic nodes were included. Acute and late toxicities were retrospectively graded and scored according to CTCAEv.4 criteria from patient charts. The cumulative incidence of endpoints including biochemical failure (BCF), local recurrence (LR), and distant metastases (DM) were estimated considering death as a competing risk. Kaplan-Meier method was used to estimate the actuarial BCF-free and DM-free survival statistics with death as composite endpoint. Univariable and multivariable Cox proportional hazard models were fitted to identify prognostic factors associated with BCF-free and DM-free survival.Median (IQR) age of patients was 69 years (62,74) and median pre-treatment PSA was 21.5 ng/ml (1.6-228). Majority had a T1-2 tumor (67%) and a Gleason Score > 8 (61%). VHRPCa was seen in 36% of the total patients. The median prostatic and pelvic node dose was 78 Gy (74-84 Gy, < 78 Gy n = 6, 84 Gy n = 1) and 54 Gy (52-60 Gy, < 54 Gy n = 17, > 55 Gy n = 6), respectively. Of the patients, 44% (83/188) had less than 24 months of ADT and 56% (105/188) had at least 24 months. At a median follow-up of 6 years (0.5-13.8) the cumulative incidence of BCF, LR and DM at 5 and 10 years are 15.8%, 1.7%, 8.8% and 39.4%, 9.8%, 24.7% respectively. Estimated BCF-free survival was 81.7% at 5 years and 54.4% at 10 years. Estimated DM-free survival was 88.7% at 5 years and 67% at 10 years. Percentage of positive cores and PSA nadir value were statistically significant prognostic factors for both BCF-free (HR 1.01 95% CI 1.01-1.04 P = 0.0011; HR 2.6 95% CI 1.79-3.77 P < 0.001 respectively) and DM-free survival (HR 1.01 95% CI 1-1.04 P = 0.019; HR 2.03 95% CI 1.21-3.41 P = 0.0076 respectively). Late GI and GU Grade 2 toxicity was 8.4% (16/189) and 2.6% (5/189) with 1.6% (3/189) Grade 3 GI toxicity and 0.5% (1/189) Grade 3 GU toxicity.A policy of moderate pelvic nodal dose escalation in HRPC patients is associated with low rates of severe late toxicity although these were possibly underestimated. Long term biochemical control and DM rates were acceptable. Increasing percentage of positive biopsy cores and higher PSA nadir values were associated with worse BCF and DM-free. Further study to determine the utility of these factors for treatment intensification in a subset of HRPC patients is needed.

Toxicity Outcomes After Low-Dose-Rate vs. High-Dose-Rate Brachytherapy Boost in Combination With External Beam Radiation for Intermediate and High-Risk Prostate Cancer

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.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.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.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.

Can EBRT Dose-Escalation Above 80 Gy Yield Comparable Survival Rates Relative to EBRT Plus Brachytherapy Boost in Men With Unfavorable Intermediate-Risk Prostate Cancer?

<h3>Purpose/Objective(s)</h3> Current recommendations regarding radiotherapy treatment for unfavorable intermediate-risk prostate cancer (UIR-PCa) include external beam radiotherapy (EBRT) ± brachytherapy boost (BT) ± androgen deprivation therapy (ADT). Dose-escalated EBRT ± ADT is associated with excellent long-term outcomes, but ERBT+BT ± ADT can achieve higher dose escalation beyond what can be achieved with EBRT alone. Prior studies have shown improved biochemical control and reduced distant metastasis with EBRT+BT vs. EBRT in men with intermediate-risk disease, but it is unclear if this translates into a survival benefit. <h3>Materials/Methods</h3> Men with UIR-PCa diagnosed between 2004 and 2015 and treated with EBRT ± ADT or EBRT+BT ± ADT were identified in the National Cancer Database (NCDB). EBRT was delivered with conventional fractionation (≥ 72 Gy in 1.8-2.0 Gy per fraction), while EBRT+BT was defined as patients receiving EBRT to a total dose of 40-50.4 Gy plus high-dose rate or low-dose rate brachytherapy. Patients with a Charlson-Deyo comorbidity index (CDCI) score > 1, who received systemic therapy other than ADT, or missing key information were excluded. Propensity-weighted multivariable analysis (MVA) using Cox regression modeling was used to compare overall survival (OS) hazard ratios. Covariables included age, race, ethnicity, year of diagnosis, CDCI score, insurance status, educational and socioeconomic metrics, treatment at an academic center, PSA at diagnosis, Gleason score, clinical T-stage, and receipt of ADT. <h3>Results</h3> The study cohort included 32,246 unfavorable intermediate-risk prostate cancer patients treated with: (<b>i</b>) EBRT (n = 13,265), (<b>ii</b>) EBRT+ADT (n = 13,123), (<b>iii</b>) EBRT+BT (n = 3,440), or (<b>iv</b>) EBRT+BT+ADT (n = 2,418). Cumulative doses of EBRT ± ADT are summarized in Table 1. The average time to follow-up was 62 months (standard deviation ± 39 months). Propensity-weighted MVA showed that EBRT+BT ± ADT was associated with improved OS relative to increasing doses of EBRT ± ADT. However, the OS benefit associated with EBRT+BT ± ADT diminished as the cumulative dose of radiation in the EBRT ± ADT cohort increased (Table 1). <h3>Conclusion</h3> The addition of brachytherapy to EBRT correlated with reduced mortality in men with UIR prostate cancer, including patients treated with EBRT ± ADT to ≥80 Gy. The relative OS benefit associated with EBRT+BT declined as the radiation dose increased in the EBRT ± ADT cohort.

Assessing ISUP prostate cancer grade groups in patients treated with definitive dose escalated external beam radiation

PurposeThe five grade group system has been validated for men treated with radical prostatectomy. However, the prognostic value for men treated with radiation therapy is uncertain, with prior studies utilising old techniques and doses. We aimed to validate the International Society of Urological Pathology (ISUP) groupings for men treated with contemporary radiation therapy. MethodsMen with localised prostate cancer treated with image-guided, dose-escalated (≥78 Gy) external beam radiation were identified across four institutions. Primary outcome was time to biochemical failure. Harrell’s C index assessed performance of the ISUP system against other grading stratifications. Results2205 men were included, withmedian follow-up of 5.6 years. Seven-year actuarial rates of biochemical failure for grade groups 1–5 were 9.3%, 10.4%, 13.2%, 12.4% and 23.4%. On multivariate analysis, hazard ratios for biochemical failure were1.19, 1.00, 1.10, 1.05 and 2.10 for grade groups 1–5, relative to 2. P values were only significant for grade group 5. Harrell’s C index favoured an alternative three group model (comprising Gleason scores [6 and 3 + 4 = 7] vs [4 + 3 = 7 and 8] vs [9 and 10]) over ISUP grade groups. ConclusionsThe ISUP grade groups were not validated in a contemporary cohort treated with dose-escalated, image-guided radiation therapy. Grade groups 1–4 were not statistically different from each other; however, grade group 5 had a significantly worse prognosis. We identified a new three group model that better predicted biochemical outcomes. Further work is requiredto validate optimal groupings for modern radiation therapy and investigate the contrasting prognostic capability of grade groups in surgical and radiation therapy patients.

The Role of Brachytherapy Boost in cN1 Prostate Cancer

With improved prostate cancer imaging modalities, the number of men with clinically node-positive (cN1) prostate cancer at diagnosis is likely to increase. However, the ideal management of these men is not clear. For high risk patients without nodal disease, the addition of brachytherapy leads to improved biochemical control. Radiation therapy with androgen deprivation therapy is considered standard of care for patients with nodal disease, but whether this population benefits from a brachytherapy boost is not known. In this study, we compared survival outcomes in cN1 prostate cancer patients undergoing dose-escalated external beam radiation therapy (DE-EBRT) versus EBRT with a brachytherapy boost (EBRT+BT). We analyzed patients from the National Cancer Database (NCDB) with non-metastatic cN1 prostate adenocarcinoma diagnosed between 2010 to 2015 who underwent DE-EBRT or EBRT+BT. DE-EBRT was defined as a dose between 75.6 to 86.4 Gy. All patients received androgen deprivation therapy. Cox regression was used to adjust survival analyses for clinical and demographic covariates. Statistical interactions between Gleason score, T stage, and the effect of brachytherapy boost on survival were assessed using tests of interaction. Overall, 1,102 patients with clinically node-positive prostate adenocarcinoma were included. 73 (7%) underwent EBRT+BT and 1,029 (93%) underwent DE-EBRT. Median follow up was 47.3 months. On multivariate analysis, there was no difference in overall survival when comparing EBRT+BT with DE-EBRT (hazard ratio [HR] = 0.98, 95% confidence interval [CI] 0.61 – 1.60, p = 0.94). This remained true on propensity-score matched analysis with 4-year overall survival being 84% with DE-EBRT and 86% with EBRT+BT (p = 0.69). No subgroup (Gleason 6-7 vs Gleason 8-10, T stage) demonstrated improved overall survival with EBRT+BT compared with DE-EBRT. In prostate cancer patients with cN1 disease, EBRT+BT did not demonstrate an improvement in overall survival compared with DE-EBRT. This study suggests that dose intensification with a brachytherapy boost to the primary site may not be beneficial in the face of clinically involved lymph nodes. Given the general limitations of NCDB studies, additional work is needed to validate these findings.

Comparing Physician-reported Toxicity in Men with Localized Prostate Cancer Undergoing External Beam, Brachytherapy, or Combination Radiation Therapy

The purpose of this study is to compare physician-reported gastrointestinal (GI), genitourinary (GU) and sexual toxicity outcomes of men with localized prostate cancer undergoing dose-escalated external beam radiation therapy (EBRT), high-dose-rate (HDR) brachytherapy or low-dose-rate (LDR) brachytherapy monotherapy (HDRm or LDRm), EBRT with HDR BT boost (HDRb), and EBRT with LDR BT boost (LDRb). We performed a retrospective cohort study of a prospectively collected database of patients with localized prostate adenocarcinoma treated with EBRT, HDRm, LDRm, HDRb, or LDRb between 2004-2019 at our institution. Hormone therapy was delivered per physician discretion. Physician-reported GI, GU, and sexual toxicity were assessed using Common Terminology Criteria for Adverse Events (CTCAE) v5.0 at time points of 3 months, 6 months, 12 months, 18 months, and 24+ months. Stratified Fisher exact tests and generalized linear mixed effects models were used to assess for differences in the physician-graded toxicity rate between radiation treatment modalities. 555 men with prostate cancer met selection criteria. 277 (49.9%) received EBRT, 76 (13.7%) received LDRm, 30 (5.4%) received LDRb, 130 (23.4%) received HDRm, and 42 (7.6%) received HDRb. Median follow-up was 33 months (interquartile range [IQR]: 15-59). 130 (23%) had low risk, 280 (50%) had intermediate risk, and 145 (26%) had high risk disease. After 24 months, Grade 3+ GI toxicity with LDRb (15%) was higher than those in the EBRT group (1.2%), and it was higher than those in the HDRb cohort (0%; p = 0.01). No other pairwise comparisons were significant. The risk of Grade 2+ GU toxicity was higher with LDRm over HDRm at months 3, 21, and 24 (p = 0.03; p = 0.02; p = 0.03). HDRm patients had higher incidence of Grade 2+ sexual toxicity than EBRT patients in the first 3 months (p = 0.02). Compared to patients receiving EBRT, patients receiving HDRb, HDRm, or LDRm had higher sexual toxicity by month 15 (p = 0.002; p < 0.001; p = 0.004). By month 21, patients receiving HDRm remained more likely than those receiving EBRT to have sexual toxicity (p = 0.01). There were no significant differences in the sexual toxicity rates between groups after 24 months. In men treated with radiation therapy for localized prostate cancer, there are differences in physician-reported toxicity across radiation treatment modalities. Our study suggests lower rates of chronic GI toxicity in patients treated with HDRb as compared to LDRb and EBRT, lower rates of acute and chronic GU toxicities in patients treated with HDRm as compared to LDRm, and similar long-term sexual toxicity among the groups. The differences in the physician-graded toxicity profiles between radiation treatment modalities can be used in shared decision-making when selecting the best radiation therapy option for each patient.