Adjuvant Androgen Deprivation Therapy Research Articles

Oncologic outcomes of organ-confined Gleason grade group 4-5 prostate cancer after radical prostatectomy.

Organ-confined prostate cancer (CaP) at radical prostatectomy (RP) is associated with good long-term outcomes. However, information for aggressive Gleason organ-confined CaP is scant. To investigate the impact of Gleason grade group (GG) 4-5 on long-term oncologic outcomes after RP. Within a high-volume center database we identified patients who harbored organ-confined CaP (pT2) at RP between 1992 and 2017. Only patients with negative surgical margins, without lymph node invasion and without neo- and/or adjuvant androgen deprivation therapy and/or adjuvant radiotherapy were included. Patients with GG1 were excluded. Kaplan-Meier analyses and Cox regression models tested the effect of GG4 and GG5 on biochemical recurrence-free (BFS), metastasis-free (MFS), overall survival (OS) and cancer-specific mortality (CSM) free survival. Of 10,855 identified pT2 patients, 0.1% (n=81) and 0.1% (n=114) harbored GG4 and GG5, respectively. At 10-years after RP, BFS, MFS, OS and CSM-free rates were 80.3 vs. 68.6 vs. 55.4% (P<0.001), 96.7 vs. 89.9. vs. 83.4% (P<0.001), 93.2 vs. 78.3 vs. 72.6% (P<0.001) and 99.3 vs. 98.0 vs. 82.7% (P<0.001) for GG2 and GG3 vs. GG4 vs. GG5, respectively. In multivariable Cox regression models, GG5 represented an independent predictor for biochemical recurrence (Hazard ratio [HR] 3.00, P<0.001), metastasis (HR 5.01, P<0.001), death (HR 2.72, P<0.01) and cancer-specific death (HR 30.1, P<0.001). Conversely, GG4 represented an independent predictor for death (HR 2.10, P=0.04) and cancer-specific death (HR 6.09, P=0.01) but not for biochemical recurrence and metastasis. GG4/5 in organ-confined CaP is rare. But its associated with worse oncologic outcomes after RP, namely biochemical recurrence, metastasis, death and cancer-specific death. Patients with organ-confined GG4/5 and negative margins should be closely followed and may be candidates for risk stratification by genomic markers.

Complete androgen blockade vs. medical castration alone as adjuvant androgen deprivation therapy for prostate cancer patients following radical prostatectomy: a retrospective cohort study.

Background:Till date, the optimal treatment strategy for delivering adjuvant androgen deprivation therapy (ADT) in localized and locally advanced prostate cancer (PCa), as a lower stage in PCa progression compared with metastatic PCa, is still unclear. This study compares the efficacy of castration alone with complete androgen blockade (CAB) as adjuvant ADT in patients with localized and locally advanced PCa undergoing radical prostatectomy (RP).Methods:Patients diagnosed with PCa, without lymph node or distant metastasis, who received RP in West China Hospital between January 2009 and April 2019, were enrolled in this study. We performed survival, multivariable Cox proportional hazard regression, and subgroup analyses.Results:A total of 262 patients were enrolled, including 107 patients who received castration alone and 155 patients who received CAB. The survival analysis revealed that there was no significant difference between the two groups (hazard ratios [HR] = 1.07, 95% confidence intervals [95% CI] = 0.60–1.90, P = 0.8195). Moreover, the multivariable Cox model provided similarly negative results before and after adjustment for potential covariant. Similarly, there was no significant difference in the clinical recurrence between the two groups in both non-adjusted and adjusted models. Furthermore, our subgroup analysis showed that CAB achieved better biochemical recurrence (BCR) outcomes than medical castration alone as adjuvant ADT for locally advanced PCa (P for interaction = 0.0247, HR = 0.37, 95% CI = 0.14–1.00, P = 0.0497).Conclusion:Combined androgen blockade achieved better BCR outcomes compared with medical castration alone as adjuvant ADT for locally advanced PCa without lymph node metastasis.

The 45-month therapy outcomes of permanent seed implantation and radical prostatectomy for prostate cancer patients

SummaryObjective To compare the efficacy and safety-related outcomes after radical prostatectomy (RP) and permanent seed implantation (PI) using iodine-125 seeds in patients with prostate cancer. Method A retrospective analysis of 196 patients with biopsy-confirmed prostate cancer (T2-T3) was performed in this study. Forty-five patients who underwent PI using iodine-125 seeds combined with endocrine therapy or androgen deprivation therapy (ADT) were compared with 151 patients who underwent RP combined with endocrine therapy or adjuvant ADT. The efficacy and safety outcomes were compared using Kaplan–Meier curves and t-tests. Results Between the RP and PI treatment modalities, no significant difference (P > 0.05) in biochemical recurrence-free survival (BRFS) was observed using Kaplan–Meier curves, regardless of the combination of adjuvant treatment modalities. Furthermore, no significant differences were observed (P > 0.05) with respect to PSA fluctuations, albumin, leukocyte count, urinary and rectal symptoms, erectile function or quality of life (QoL) between the two therapy methods. However, significant differences in the maximum flow rate, average length of hospital stay and indwelling catheter time were observed between the two groups (P < 0.001). Conclusion Iodine-125 seed implantation significantly shortened the average length of hospital stay and indwelling catheter time compared with RP, and the haemoglobin level was significantly higher in the PI group than in the RP group; however, the maximum urine flow rate was lower after of PI than after RP. These two methods showed similar BRFS rates among prostate cancer patients.

Post-prostatectomy adjuvant androgen deprivation therapy- Current opinions and practices of Canadian urologists.

Despite the proven benefit of adjuvant androgen deprivation therapy (ADT) for patients receiving primary radiation, there are few studies evaluating adjuvant ADT after prostatectomy. In the absence of evidence, opinions and practice patterns vary. We surveyed Canadian prostate cancer surgeons about their use of adjuvant ADT and their opinions on the design of a potential adjuvant ADT trial. An electronic survey was devised and distributed using a modified Dillman approach. The survey was sent to 38 Canadian urologists that perform radical prostatectomy and representing all 17 major academic institutions in Canada and all 10 Canadian provinces. Reminders were sent three and four weeks following the original request. In addition to demographic information, we asked surgeons about their current use of postoperative adjuvant ADT and their opinion about the need for a clinical trial. To inform trial design, we asked respondents their opinions about which patients should be eligible, what duration of ADT was most appropriate, and which outcomes are clinically meaningful. The survey was sent in February 2020 and all responses were received by March 2020. All 38 (100%) invited urologists completed the survey. Only 3 (7%) respondents currently offer postoperative adjuvant ADT as an option for patients without metastases. 35 (92%) urologists believed that a trial is needed before short-term adjuvant treatment should be offered to prevent recurrence. 15 (45%) urologists believed an adjuvant ADT trial was most appropriate for patients with an estimated PSA recurrence risk of >25% and 16 (42%) believed a recurrence risk of >50% was most appropriate. 25 (66%) respondents believed 12-month was the optimal duration of treatment with adjuvant ADT for a randomized trial. 37 (97%) respondents felt that prolonging the time to PSA recurrence and/or pelvic radiation was a clinically important outcome. The majority (20; 53%) of respondents would recommend 12 months of adjuvant ADT in their practice if a randomized trial showed a 50% relative risk reduction in PSA recurrence at 5-year postoperative. The vast majority of Canadian prostate cancer surgeons do not offer adjuvant ADT following prostatectomy in patients without metastases. Based on the results from this survey, a randomized trial was considered warranted and feasible, and would influence patient care.

Feasibility and outcome of radical prostatectomy following inductive neoadjuvant therapy in patients with suspicion of rectal infiltration.

To determine the feasibility and outcome of radical prostatectomy (RP) following neoadjuvant therapy (NAT) in patients with initial inoperable, rectum-infiltrating cT4 prostate cancer (PCa). From 01/2018 to 12/2020, 26 patients with clinical (DRE) or radiographical (mpMRI) suspicion of rectum infiltrating PCa at diagnosis and NAT prior to RP were retrospectively identified from our prospective institutional database. Two patients were still inoperable after NAT. Downsizing was administered for at least 20 weeks and RP was performed after excluding ongoing rectal infiltration. At diagnosis, median PSA was 42.5 ng/ml (IQR: 23.0-66.1). Inductive NAT consisted of androgen deprivation therapy (ADT) in combination with chemotherapy (n = 9) or without chemotherapy (n = 14). Median preoperative PSA was 0.93 ng/ml (IQR: 0.24-0.40). Median time from NAT to RP was 6 months (IQR: 5-7). Two patients were still inoperable after NAT. Of 24 patients undergoing RP, abortion of surgery due to inoperability was observed in 2 patients (8.4%), demonstrating a total failure rate of NAT in 4 out of 26 patients (15.4%). One patient suffered a rectal injury with consecutive colostomy (4.2%). No Clavien-Dindo complication Grade IV or V were observed. Urinary continence was achieved in 16 patients (84.2%). Sufficient erection for sexual intercourse was present in 2 patients (10.5%). All patients received adjuvant ADT with or without radiation therapy. Median PSA at 13 months was 0.08 ng/ml (IQR: 0.01-0.74). RP of initially rectum infiltrating PCa is feasible and safe after inductive NAT, however complications rates tend to be higher compared to standard RP.

Androgen deprivation therapy use and duration with definitive radiotherapy for localised prostate cancer: an individual patient data meta-analysis

Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups. For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3-4 months to 6-9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4-6 months to 18-36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855. Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0-15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 [95% CI 0·77-0·89], p<0·0001), as did adjuvant ADT prolongation (0·84 [0·78-0·91], p<0·0001), but neoadjuvant ADT extension did not (0·95 [0·83-1·09], p=0·50). Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group. Our findings provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended. University Hospitals Seidman Cancer Center, Prostate Cancer Foundation, and the American Society for Radiation Oncology.

Features and management of men with pN1 cM0 prostate cancer after radical prostatectomy and lymphadenectomy: a systematic review of population-based evidence.

To investigate the features and optimal management of pN+ cM0 prostate cancer (PCa) according to registry-based studies. Up to 15% of PCa patients harbor lymph node invasion (pN+) at radical prostatectomy plus lymph node dissection. Nonetheless, the optimal management strategy in this setting is not well characterized. We performed a systematic review including n = 13 studies. Management strategies comprised 13 536 men undergoing observation, 11 149 adjuvant androgen deprivation therapy (aADT), 7,075 adjuvant radiotherapy (aRT) +aADT and 705 aRT. Baseline features showed aggressive PCa in the majority of men. At a median follow-up ranging 48-134months, Cancer-related death was 5% and overall-mortality 16.6%. aADT and aRT alone had no cancer-specific survival or overall survival advantages over observation only and over not performing aRT, respectively. aADT plus aRT yielded a survival benefit compared to observation and aADT, which in one study, were limited to certain intermediate-risk categories. Age, Gleason, Charlson score, positive surgical margins, pathological stage, and positive nodes number, but not prostate specific antigen, were most relevant prognostic factors. Our work further confirmed pN+ PCa is a multifaceted disease and will help future research in defining its optimal management based on different risk categories to maximize survival and patient's quality of life.

Reduced NCOR2 expression accelerates androgen deprivation therapy failure in prostate cancer.

SUMMARYThis study addresses the roles of nuclear receptor corepressor 2 (NCOR2) in prostate cancer (PC) progression in response to androgen deprivation therapy (ADT). Reduced NCOR2 expression significantly associates with shorter disease-free survival in patients with PC receiving adjuvant ADT. Utilizing the CWR22 xenograft model, we demonstrate that stably reduced NCOR2 expression accelerates disease recurrence following ADT, associates with gene expression patterns that include neuroendocrine features, and induces DNA hypermethylation. Stably reduced NCOR2 expression in isogenic LNCaP (androgen-sensitive) and LNCaP-C4–2 (androgen-independent) cells revealed that NCOR2 reduction phenocopies the impact of androgen treatment and induces global DNA hypermethylation patterns. NCOR2 genomic binding is greatest in LNCaP-C4–2 cells and most clearly associates with forkhead box (FOX) transcription factor FOXA1 binding. NCOR2 binding significantly associates with transcriptional regulation most when in active enhancer regions. These studies reveal robust roles for NCOR2 in regulating the PC transcriptome and epigenome and underscore recent mutational studies linking NCOR2 loss of function to PC disease progression.

Association of Short-Term Patient-Reported Outcomes With Long-Term Oncologic Outcomes in Localized Prostate Cancer Patients Treated With Radiation Therapy and Androgen Deprivation Therapy in a Randomized Controlled Trial

PurposeBoth oncologic outcomes and patient-reported outcomes are pivotal in prostate cancer (PCa). However, it remains unknown if there is any association between these 2 outcomes. In this secondary analysis of a randomized controlled trial, we investigated the association of short-term changes in patient-reported outcome with long-term event-free survival (EFS) and metastasis-free survival (MFS) in localized PCa. Methods and MaterialsLocalized PCa patients with a Gleason score ≤7, clinical stage T1b to T3a, and prostate-specific antigen (PSA) <30 ng/mL were randomized to neoadjuvant and concurrent androgen deprivation therapy (ADT) for 6 months starting 4 months before prostate radiation therapy or concurrent and adjuvant ADT for 6 months starting simultaneously with radiation therapy. Patient-reported symptom burden was evaluated using the European Organisation for Research and Treatment of Cancer quality of life questionnaire (QLQ)-PR.25. Clinically meaningful deterioration (CMD) was defined as a ≥10-point worsening at any time within 10 months postrandomization regardless of subsequent improvement. Landmark analyses were performed to determine the association of CMD of urinary and bowel symptoms separately with EFS and MFS in patients who responded to the baseline questionnaire, were alive, and were event free at 10 months. ResultsOverall, 393 patients had responded to the baseline QLQ. One patient died, and 1 patient had failure within 10 months. Therefore, 391 patients were eligible for the landmark analyses. After adjusting for age, Gleason score, PSA, performance status, and treatment group, CMD of urinary symptoms was associated with worse EFS (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.21-2.65) and MFS (HR, 1.69; 95% CI, 1.11-2.57). Considering deaths as competing events, CMD of urinary symptoms was associated with a significant increase in the relative incidence of progression (subdistribution HR, 2.42; 95% CI, 1.12-5.20). However, no association was found between CMD of bowel symptoms and EFS or MFS. ConclusionsIn this study, short-term CMD of urinary symptoms was associated with significantly inferior EFS and MFS and an increase in the relative incidence of progression. Further investigations are needed to explore the biological rationale of such association in the context of ADT and radiation therapy.

Prognostic factors, efficacy, and toxicity of involved-node stereotactic body radiation therapy for lymph node oligorecurrent prostate cancer : An investigation of 117 pelvic lymph nodes.

The optimal radiotherapy regimen is not yet defined in the setting of oligorecurrent prostate cancer (oligorPC). There is evidence of high variability in treatment protocols among different centers worldwide, and no international consensus guidelines on treatment volumes, radiation schedules, and techniques. The purpose of the present retrospective study is to evaluate the efficacy and safety of involved-pelvic-node stereotactic body radiotherapy (SBRT) for oligorPC. Patients with pelvic node oligorPC following primary surgery, radical radiotherapy, or salvage radiotherapy for biochemical or local relapse of prostate cancer who underwent involved-node SBRT with biological effective dose (BED) > 100 Gy, with or without concurrent and adjuvant androgen deprivation therapy (ADT), were retrospectively evaluated. Biochemical progression-free survival (bPFS), distant progression-free survival (DPFS), overall survival (OS), possible prognostic factors, and toxicity outcomes were investigated. From November 2012 to December 2019, 74patients fitted the selection criteria. Atotal of 117 lesions were treated. Median follow-up was 31months (range 6-89). Concurrent ADT was administered in 58.1% of patients. The 1‑year, 2‑year, and 3‑year DPFS was 77%, 37%, and 19%, respectively; the 1‑year, 2‑year, and 3‑year OS was 98%, 98%, and 95%, respectively. The presence of asingle target lesion was associated with astatistically significant impact on OS. No in-field recurrence occurred. Patients who reached early prostate-specific antigen (PSA) nadir (< 3months after SBRT) had alower 3‑year survival (p = 0.004). The value of PSA nadir after SBRT and the time between primary treatment and SBRT had an impact on bPFS. Concomitant ADT was associated with improved DPFS. No acute or early late (> 6months) genitourinary and gastrointestinal adverse events of any grade were reported, albeit with relatively short median follow-up. SBRT is asafe and effective treatment for oligorPC, with a100% local control rate in our series. It is not possible to clearly assess the opportunity to postpone ADT prescription in patients with two or more nodal metastases. The number of secondary lesions, time-to-nadir PSA, PSA nadir value, and the time interval between primary treatment and SBRT were identified as prognostic factors. Future prospective randomized studies are desirable to better understand the still open questions regarding the oligorecurrent prostate cancer state.

Association of Baseline Patient-reported Health-related Quality of Life Metrics with Outcome in Localised Prostate Cancer

AimsAlthough health-related quality of life (HR-QoL) outcomes are pivotal in oncology, the prognostic significance of patient-reported HR-QoL metrics is largely undefined in localised prostate cancer. We report the association of baseline HR-QoL metrics with overall survival and toxicity in localised prostate cancer. Materials and methodsThis was a secondary analysis of a phase III randomised controlled study conducted in a single-payer health system. Patients with Gleason score ≤7, clinical stage T1b–T3a and prostate-specific antigen <30 ng/ml were randomised to neoadjuvant and concurrent androgen deprivation therapy (ADT) for 6 months starting 4 months before prostate radiotherapy or concurrent and adjuvant ADT for 6 months starting simultaneously with prostate radiotherapy. HR-QoL scores were estimated using the European Organisation for Research and Treatment of Cancer QoL questionnaire. A multistate Markov model was used to determine the association of baseline HR-QoL metrics with overall survival and a multilevel multivariable Cox regression was used to determine the association with the incidence of delayed-onset grade ≥3 radiotherapy-related toxicities. To adjust for multiple analyses, P < 0.025 was considered as statistically significant. ResultsOverall, 393 patients with baseline HR-QoL data were included in this analysis: 194 in the neoadjuvant arm and 199 in the adjuvant arm. Baseline financial difficulty (hazard ratio 1.020, 95% confidence interval 1.010–1.030, P = 0.02) and dyspnoea (hazard ratio 1.020, 95% confidence interval 1.003–1.030, P = 0.01) were associated with inferior overall survival. Baseline dyspnoea was associated with a higher incidence of grade ≥3 toxicity (hazard ratio 1.020, 95% confidence interval 1.010–1.030, P = 0.023). ConclusionIn a cohort of localised prostate cancer patients treated with radiotherapy and short-term ADT, a 10-point higher baseline financial difficulty or dyspnoea was associated with a 20% increased risk of death. With each 10-point increase in baseline dyspnoea, we noted a 20% increase in the associated risk of grade ≥3 delayed-onset radiotherapy-related toxicity.

Apoptosis and Senescence in Localized Prostate Cancer Tissues Treated With HDR-BT Boost With Radiotherapy (EBRT) and ADT

High dose rate brachytherapy HDR-BT boost with external beam radiotherapy (EBRT) and adjuvant Androgen Deprivation Therapy (ADT) is an effective treatment of localized prostate cancer (PCa). Ionizing radiation (IR) delivered by BT or by EBRT induce DNA damage leading to cell death by activation of apoptosis. On the other hand, ADT can also induce apoptosis or senescence depending on the duration of treatment. The goal of this study is to determine which signaling pathway is activated in PCa cells in response to the DNA damage induced by HDR-BT boost with EBRT and ADT.22 patients with localized PCa signed an informed consent to participate in this clinical pilot study. Ten patients were treated with only HDR-BT / EBRT alone (no ADT group) and twelve patients also received additional ADT (ADT group). The expression of Ki-67 and p53, pro-apoptotic markers Bax and PUMA and p16 as a senescence marker were analyzed by immunohistochemistry in the biopsies taken from all patients before and post-treatment.Our results show an up-regulation of pro-apoptotic markers and reduction of senescence marker expression in the tissues treated by HDR-BT/ EBRT. However, we noticed an increase expression of senescence marker p16 and no change in pro-apoptotic markers receiving additional ADT.HDR-BT/ EBRT treatment alone induces apoptosis in PCa cells while additional ADT appears to promote their senescence. This could explain the mitigated benefit of ADT to improve radiation treatment combined with BT. These results need to be validated in a larger cohort of patients.

Elective Pelvic Nodal Irradiation With A Simultaneous Hypofractionated Integrated Prostate Boost for Localized High Risk Prostate Cancer: Long Term Results From a Prospective Clinical Trial

To report on the long-term results of patients with localized high risk prostate cancer treated with elective pelvic nodal irradiation (EPNI) and a simultaneous hypofractionated prostate boost along with adjuvant androgen deprivation therapy (ADT).This was a prospective single-institution single-arm phase II study. Patients with high-risk prostate cancer (any of cT3 disease, PSA > 20 ng/mL, or Gleason score 8-10) were eligible. Patients underwent radiotherapy to a dose of 45 Gy in 25 fractions to the prostate and pelvic lymph nodes with a simultaneous image-guided (matched to prostatic fiducial markers) IMRT boost of 22.5 Gy to the prostate for a total of 67.5 Gy in 25 fractions (2.7 Gy per fraction) over 5 weeks. Patients were to receive ADT for 2-3 years. Endpoints included biochemical failure (Phoenix definition), distant radiographic failure, and overall survival. Univariate and multivariable analyses were performed to look for predictive factors. Late toxicity was assessed using CTCAE v3.0 for 5 years.Two hundred thirty patients (median age 71 years) were enrolled from 2004-2010. Median follow-up was 11.2 years (IQR 8.1-12.9). 67% of patients had Gleason score ≥ 8, 44% had PSA > 20 ng/mL, and 27% had cT3 disease. Median ADT duration was 30 months (IQR 21-33). Median PSA nadir was 0.02 ng/mL (IQR 0.02-0.02). Cumulative incidence of testosterone recovery (> 1.7 nmol/L) was 47.6% and 77.5% at 5 and 10 years, respectively. Cumulative incidence of biochemical failure was 15% and 33.4% at 5 and 10 years, respectively. At 10 years, the cumulative incidence of distant metastasis was 16.5%, and overall survival was 76.3%. On multivariable analysis, PSA nadir > 0.05 ng/mL was predictive of biochemical failure (HR 6.8, 95% CI 4-11.8, P < 0.001) and development of distant metastases (HR 7.5, 95% CI 3.9-14.5, P < 0.0001). PSA nadir > 0.1 ng/mL (HR 5.2, 95% 2.2-12, P = 0.0001) and ADT use < 12 months (versus > 24 months) (HR 2.3, 95% CI 1.3-3.9, P = 0.004) were predictive of worse survival. The 5-year cumulative incidence of any late grade ≥ 3 gastrointestinal and genitourinary toxicity was 2.3% and 7.5%, respectively.This was a large prospective study evaluating EPNI and a simultaneous hypofractionated prostate boost over 5 weeks combined with 2-3 years of ADT for localized high risk prostate cancer with very mature follow-up. Ten-year biochemical control and overall survival rates were favorable. Lower PSA nadir predicted for higher biochemical control, less distant failure, and longer overall survival. ADT duration of ≤ 12 months was associated with decreased overall survival.

Individual Patient Data Meta-Analysis of Randomized Trials in Cancer of the Prostate (MARCAP) Consortium: Impact of Androgen Deprivation Therapy Use and Duration With Definitive Radiotherapy for Localized Prostate Cancer

To conduct the first global individual patient data (IPD) meta-analysis of randomized trials to assess the impact of androgen deprivation therapy (ADT) use and duration with definitive radiotherapy (RT) in localized prostate cancer.The MARCAP Consortium was formed from international trial groups (NRG/RTOG, EORTC, TROG, DART/GICOR, and ICORG). IPD for 10,131 patients enrolled across 11 RT trials were available for three pre-specified meta-analyses: addition of ADT to RT (5 trials; n = 4736), addition of long-term adjuvant ADT (12-30 months) to short-term ADT (4 trials; n = 3674), and addition of longer neoadjuvant ADT (3-7 months) to short-term ADT (3 trials; n = 2213). The primary endpoint of all meta-analyses was overall survival (OS), with metastasis-free survival (MFS) as a secondary endpoint. Interaction tests between treatment and receipt of dose-escalated RT (≥74 Gy in 2 Gy fractions) were performed.After a median follow-up of 12.0 years, the addition of ADT to RT improved 12-year OS (absolute 7.2%, HR 0.87, 95% CI 0.8-0.95) and 12-year MFS (absolute 8.3%, HR 0.85, 95% CI 0.79-0.92). After a median follow-up of 10.9 years, prolongation of adjuvant ADT improved 12-year OS (absolute 6.3%, HR 0.86, 95% CI 0.78-0.94) and 12-year MFS (absolute 6.3%, HR 0.83, 95% CI 0.77-0.90). After a median follow-up of 10.3 years, prolongation of neoadjuvant ADT was not associated with a significant benefit in any endpoint (MFS HR 0.95, 95% CI 0.83-1.09; OS HR 0.94, 95% CI 0.82-1.09). On subgroup analysis, there was no evidence of a treatment effect interaction between RT dose and ADT use (OS P-interaction 0.59) or adjuvant ADT prolongation (OS P-interaction 0.13). In the setting of dose-escalated RT, adjuvant ADT prolongation significantly improved OS (HR 0.70, 95% CI 0.53-0.92).This study represents the strongest evidence to support ADT use and prolongation of adjuvant ADT to at least 18 months in localized prostate cancer in conjunction with definitive RT. The relative benefit of ADT use and adjuvant ADT prolongation was consistent irrespective of RT dose-escalation. In contrast, prolongation of neoadjuvant ADT beyond 2 months did not improve survival outcomes and should not routinely be employed.

A Prospective Study of MR-Guided Focal Salvage High Dose-Rate Brachytherapy for Radiorecurrent Prostate Cancer: Updated Results of 30 Patients

<h3>Purpose/Objective(s)</h3> Salvage therapies for localized radiorecurrent prostate cancer often carry significant short- and long-term morbidity. Focal salvage high dose rate (HDR) brachytherapy is an appealing treatment technique which delivers an ablative dose of radiotherapy to the portion of the prostate containing recurrent disease; however, limited prospective data is available. We sought to explore the toxicities, health related quality of life and efficacy of focal salvage HDR brachytherapy after previous definitive radiotherapy. <h3>Materials/Methods</h3> Patients with locally recurrent prostate cancer after previous external beam radiotherapy (EBRT) and/or brachytherapy were enrolled on a prospective clinical trial. Patients received MRI-guided, ultrasound-based focal HDR brachytherapy delivered over two fractions of 13.5 Gy delivered 1-2 weeks apart. Adjuvant androgen deprivation therapy (ADT) was not used. Toxicity was measured using CTCAE v4. Posttreatment response was evaluated using MRI 1-2 years after salvage. Biochemical failure was defined as PSA nadir + 2ng/mL. <h3>Results</h3> Thirty patients were treated between November 2012 and September 2019. Median follow-up was 35 months (range: 13 – 92 months). Fifteen patients were initially treated with EBRT, 3 with low dose rate (LDR) brachytherapy monotherapy, 1 with EBRT and LDR brachytherapy boost, 2 with EBRT and HDR brachytherapy boost, and 9 with HDR brachytherapy as monotherapy (all 19 Gy in a single fraction). Median clinical target volume (CTV) at time of salvage was 5.22 mL (range: 2.18 – 15.71 mL), corresponding to a median of 20.0% of the prostate volume (range: 8.8% – 39.2%). Median PSA at salvage was 4.46 ng/mL (range: 0.99 – 11.63 ng/mL). The median CTV V100 was 96.5% (range: 90.5% – 99.5%), and median CTV D90 was 15.1 Gy per fraction (range: 13.6 – 18.1 Gy). Seventeen patients experienced subsequent biochemical failure, and 9 have received ADT and/or further local salvage. No patients have died from prostate cancer. Median time to biochemical failure was 41.5 months, and median time to ADT/salvage therapy was 70.6 months. The three-year biochemical failure-free event rate was 61.8% (95% CI 44.0 – 86.6%), and three-year ADT/salvage therapy-free event rate was 86.0% (95% CI 74.1 – 99.8%). No acute grade ≥ 3 GU/GI toxicity was observed. One late grade 3 GU toxicity event occurred, cystitis at 42 months post treatment, which did not persist on follow-up. No late grade ≥ 3 GI toxicity was seen. Of the 28 patients who had a post-treatment MRI, 26 had evidence of a local treatment response. <h3>Conclusion</h3> In our updated results, we found focal salvage HDR brachytherapy is well tolerated with a favorable side effect profile and 3-year biochemical control rates in line with other salvage therapies for radiorecurrent prostate cancer. While early MRI response at the treated site is common, this does not preclude subsequent biochemical failure.

Association of Baseline Health-Related Quality of Life Metrics With Outcome in Localized Prostate Cancer

While health-related quality of life (HR-QoL) outcomes are pivotal in oncology, the prognostic significance of patient-reported HR-QoL metrics is largely undefined in localized prostate cancer (LPCa). In this exploratory analysis, we report the association of baseline HR-QoL metrics with overall survival (OS) and risk of late radiation-induced toxicity in men with LPCa treated with combination of radiotherapy (RT) and androgen deprivation therapy (ADT).This is a secondary analysis of a phase III randomized controlled study conducted in two tertiary cancer centers. LPCa patients with Gleason score ≤7, clinical stage T1b to T3a, and prostate-specific antigen < 30 ng/mL were randomized to neoadjuvant and concurrent ADT for 6 months starting 4 months before prostate RT or concurrent and adjuvant ADT for 6 months starting simultaneously with prostate RT. HR-QoL scores were estimated using European Organization for Research and Treatment of Cancer QoL questionnaire. A multi-state Markov model was used to determine the association of baseline HR-QoL metrics with OS and a multilevel multivariable Cox regression to determine the association with incidence of delayed-onset grade ≥3 radiotherapy-related toxicities. To adjust for multiple analyses, P-value < 0.025 was considered as statistically significant. Conditional approach was used to calculate 15-year adjusted OS for patients with and without financial difficulty and patients with and without dyspnea at baseline.Overall, 393 patients with baseline HR-QoL data were included in this analysis - 194 in the neoadjuvant arm and 199 in the adjuvant arm. Baseline financial difficulty (hazard ratio [HR]: 1.020, 95% confidence intervals [CI]:1.010-1.030, P = 0.02), and dyspnea (HR: 1.020, 95% CI:1.003-1.030, P = 0.01) were associated with inferior OS. Adjusted OS for patients with and without financial difficulty at baseline was 15.5% and 45.7%, respectively (P < 0.01). Adjusted OS for patients with and without baseline dyspnea was 21.2% and 46.6%, respectively. Baseline dyspnea was associated with higher incidence of grade ≥3 toxicity (HR: 1.020, 95% CI: 1.010-1.030, P = 0.023).In a cohort of LPCa patients treated with RT and short-term ADT, a 10-point increase in baseline financial difficulty or a 10-point increase in baseline dyspnea was associated with a 20% increased risk of death. With each 10-point increase in baseline dyspnea, we noted an 20% increase in the associated risk of grade ≥3 delayed-onset radiotherapy-related toxicity. These findings underscore the importance of integrating these baseline patient-reported metrics in selecting patients, making informed treatment-decisions, and optimizing overall outcome in men with localized prostate cancer.

HIGH RISK PROSTATE CANCER: COMPARISON OF RADICAL PROSTATECTOMY VERSUS RADIATION THERAPY: EXPERIENCE OF MILITARY HOSPITAL RABAT

Context: To date, there is no Level 1 evidence comparing the efficacy of radical prostatectomy and radiotherapy for patients with clinically-localized prostate cancer. Objective: to evaluate overall survival (OS) and relapse free survival of high risk prostate cancer (PCa) treated either with external beam radiotherapy (EBRT) associated with androgen deprivation therapy (ADT) or radical prostatectomy (RP) with adjuvant or salvage radiotherapy and ADT. Also, it is very interesting to compare different acute and late toxicity of the both approach. Materials and Methods: During a period of 10 years from April 2009 and December 2018, 149 patients with high-risk prostate cancer were admitted to the radiotherapy department of the Mohammed V military hospital in Rabat (HMIMV). Among these patients, 17 underwent surgery followed by EBRT and ADT: this is the experimental arm (Group I) and 34 patients who had benefited from treatment with EBRT with ADT were selected from the other patients by a 1: 2 matching method who will represent the reference group (Group II) to allow a comparison with the experimental arm with the minimum possible bias. Results: The overall survival (OS) at 5 and 10 years was 100 % in the both arms while relapse free survival at 5 years was 91,7 % and 93,1% respectively in group I and II and at 10 years 91,7% in the group multimodal approach and 88,9 % in the EBRT+ADT group without any significant difference. We note more toxicities in the surgical group with more urinary incontinence (p=0,001) and more erectile dysfunction. Conclusion: RP with adjuvant EBRT and EBRT+ADT provided similar long-term cancer control for patients with high-risk prostate cancer but with different toxicity profiles.

AUTHOR REPLY

We appreciate and fully endorse the thoughtful editorial comments. All treatments for prostate cancer balance oncological control and adverse events. Should we preserve the neurovascular bundle and maximize membranous urethral length to maximize erectile function and continence, respectively? Should we perform an extensive lymphadenectomy to maximize oncological control? What is the optimal radiation dose? Should we offer adjuvant androgen deprivation therapy and if so, for how long in candidates for radiation therapy? As highlighted in the editorial comment, focal ablation also has its risk-benefit conundrums related to extent of ablation. Should the ablation be extended beyond the capsule and risk injury to the neurovascular bundle? Should the ablation extend to the extreme apex and risk stricture formation? Should the ablation be extended to the “benign” transition zone in order to improve lower urinary tract symptoms? Finally, will extending the ablation decrease the risk of disease recurrence while rendering secondary radical prostatectomy more technically challenging? All of these treatment planning decisions are made without knowing the true extent of the index lesion and precision of energy delivery.

1632P At home androgen deprivation therapy for patients with prostate cancer during the COVID-19 pandemic. One center experience

COVID-19 pandemic created major challenges in cancer care. Studies have shown increased risk for COVID-19 infectivity, severe disease and death in patients with cancer. Cancer centers worldwide adapted by modifying and often delaying treatment to minimize contact with patients. To provide safe and uninterrupted care for patients, a home care program was created for patients with prostate cancer at Acad. F. Todua Medical center. Men with locally advanced or metastatic prostate cancer (MPC) receiving androgen deprivation therapy (ADT) were enrolled. Patients and their caretakers were instructed on gonadotropin-releasing hormone (GnRH) subcutaneous injections (SQ) for home administration. Monthly at home laboratory testing and virtual consultations with medical oncologists every 1-3 months were arranged. A total of 52 patients were enrolled during the period of March 2020 – March 2021. All men were White and had ECOG 0/1. The mean age was 71 [±6.3 y] years. Sixteen (31%) patients had stage IIIB PC and 36 (69%) patients had stage IV disease. Stage IIIB patients were receiving adjuvant ADT with SQ Goserelin Acetate 10,8mg every 8 weeks and bicalutamide 50mg daily for two weeks after definitive local treatment. Thirty-one (86%) patients had hormone sensitive metastatic PC and were receiving SQ Goserelin Acetate 10.8mg (28) every 8 weeks or SQ Leuprolide Acetate 22,5mg every 8 weeks (3) with 2 weeks of Bicalutamide 50mg daily. Five (14%) patients had castration resistant (CR) PC and were receiving SQ Goserelin Acetate 10,8mg every 8 weeks with Enzalutamide 160mg daily. Thirty-three (63%) patients had Gleason’s score of 8/9. All patients were compliant with home injections, laboratory tests and virtual physician visits. Thirty-nine (75%) patients administered injections by themselves. Forty-two (80%) patients had PSA reduction >50%. Ten (20%) patients had disease progression and required clinic visits for investigations. Median time to progression was 12 months. Only 1 (2%) patient acquired COVID-19 infection, was hospitalized and died of respiratory failure. At home ADT with appropriate patient/caregiver education and close follow up may be safe for patients with PC during the COVID-19 pandemic.

Testosterone Therapy in Men with Biochemical Recurrence and Metastatic Prostate Cancer: Initial Observations

Introduction: Although prostate cancer (PCa) has long been considered an absolute contraindication for testosterone therapy (TTh), growing literature suggests TTh may be safely offered to men with localized PCa. We here present a single-center series of men treated with TTh for relief of symptoms, despite having more advanced disease, namely biochemical recurrence (BCR) or metastatic PCa (MET). Methods: We identified men treated with TTh with BCR, MET, or adjuvant androgen deprivation therapy (ADT). Consent included risks of rapid PCa progression and death. Laboratory and clinical results were analyzed. Results: Twenty-two men received TTh: 7 with BCR, 13 with MET, and 2 with adjuvant ADT. Median age was 70.5 years (range 58–94). Median TTh duration was 12 months (range 2–84) overall, including 20 months for BCR and 9.5 months for MET. Mean serum testosterone (T) increased from 210 to 1111 ng/dL. Median PSA (interquartile range) increased from 3.1 ng/mL (0.2–4.5) to 13.3 ng/mL (3.4–22) in the BCR group, 6.3 ng/mL (1.2–31) to 17.8 ng/mL (6.2–80.1) in the MET group, and <0.1 to 0.3 ng/mL in the ADT group. All patients reported symptom relief, especially improved vigor and well-being. Overall mortality was 13.6% and PCa-specific mortality was 4.5% during the period of TTh and 6 months after discontinuation. Seven of 10 with follow-up imaging within 12 months showed no progression. Five men have died: three during TTh and two succumbed at 2 years or longer after discontinuing TTh. One of the three deaths during TTh was PCa-specific. Three men developed significant bone pain at 7–41 months; two discontinued TTh and one continued, after focal radiation. There were no cases of rapid-onset complications, vertebral collapse, or pathological fracture. Conclusions: These initial observations indicate TTh was not associated with precipitous progression of PCa in men with BCR and MET, suggesting a possible role for TTh in selected men with advanced PCa whose desire for improved quality of life is paramount.