Adjuvant Androgen Deprivation Research Articles

Prevalence of variant of unknown significance (VUS) in men with prostate cancer who serve as a benchmark for enhanced screening and for personalized therapy.

342 Background: Pathogenic variants (PVs) in DNA repair genes (DRG), such as in BRCA1, BRCA2, ATM, CHEK2, etc., have implications for prostate cancer (PCa) family genetic counselling, testing and risk stratification in men. However, understanding how to counsel patients with variants of unknown significance (VUS) is an unmet clinical need. On the other hand, there is the necessity to cautiously interpret VUS findings and to bolster VUS evaluations with additional evidence for pathogenicity. In this study, we aim to investigate the prevalence of germline VUS in men with PCa and their association with outcomes after robot-assisted radical prostatectomy (RARP). Methods: This is a nested cohort case study from an ongoing PCa screening, set to identify and screen men in the Italian population with a genetic predisposition (AIRC - Fondazione AIRC per la Ricerca sul Cancro project IG 2020 ID 25027). Cases for the current analysis were selected by “Adam's rib strategy” searching for germline DRG variant in men with a diagnosis of high-risk PCa who were scheduled for RARP. After informed consent was signed, a blood sample was obtained. A previously validated multigene panel test was used to assess the presence of germline variants. PVs and VUS were classified according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology consensus criteria and International Agency for Research on Cancer guidelines. The primary endpoint was to describe the prevalence of VUS and the secondary to correlate VUS with pathological outcomes after RARP. Results: A total of 118 men with diagnosis of PCa who underwent RP were enrolled. The mean age at diagnosis of PCa was 65.9 (±6.42) years; pathological grade was ISUP 1-2 in 58.0% patients and 3-5 in 42.0%. Of the 76 men evaluated, 18 (23.7%) had a VUS and 1 (1.32%) a pathogenic germline variant in BRCA1 and PALB2. Among those with VUS younger men at diagnosis were more likely to carry a VUS than older at diagnosis mean (age 64 ± 6.41 vs. 66 ± 7.20 years). Additionally, 33.3% vs 16.2 % were carrier of VUS and N+ and required adjuvant androgen deprivation therapy. No difference between ISUP at final pathology and positive margin rate were found. Conclusions: Our findings showed a high prevalence of VUS germline mutations in PCa patients undergoing RARP. These mutations seem to be associated with worse pathological outcomes. Limitations includes short follow-up and absence of non-Caucasian patients.

Final Analysis of a Phase III Controlled Randomized Study of Stereotactic Body Proton Therapy or Conventionally Fractionated Proton Therapy for Early Prostate Cancer: PCG GU002

To determine if stereotactic body proton therapy (SBPT) is non-inferior to conventionally fractionated proton therapy (CFPT) in patients with early prostate cancer. Multicenter, randomized, controlled, open-label, non-inferiority phase 3 trial that included patients with histologically confirmed low-risk prostate adenocarcinoma defined by Gleason score ≤6, PSA <10 ng/mL, and clinical stage T1-2a N0 M0 by AJCC 7th Ed. Eligible participants were randomly assigned (initially 1:1 and later 2:1 ratio) to CFPT (79.2 Gy in 44 fractions for 9 weeks) or SBPT (38 Gy in 5 fractions for 1 week). Concurrent or adjuvant androgen deprivation therapy was not allowed. The primary endpoint was freedom from failure (FFF) at 2 years, defined as the first occurrence of local, regional, or distant recurrence, biochemical failure by the Phoenix definition (increase of PSA ≥2 ng/mL over the nadir PSA), or the start of salvage therapy including ADT. Secondary endpoints included GI and GU grade ≥2 toxicity according to CTCAE v4 criteria, as well as health-related quality of life (HRQoL) metrics assessed by AUASI and EPIC scores. Non-inferiority would be declared if the 1-sided 95% confidence interval limit for the difference in 2-year FFF rate was below 4.2% between both groups by Clopper-Pearson exact method. Between November 2010 and September 2020, 133 patients were enrolled and randomly assigned to CFPT (n = 45) or SBPT (n = 88). Median follow-up was 5 years (IQ 3.9-5.2), with the last patient enrolled followed for at least 2 years. The 2-year FFF was 100% for both groups, fulfilling the pre-specified criteria for non-inferiority of SBPT compared to CFPT. By KM estimates, 5-year FFF was 97.4% and 100% (P = 0.1), and the 5-year OS was 97.1% and 95.5% (P = 0.46) for patients treated with CFPT and SBPT, respectively. The cumulative incidence of any grade ≥3 toxicities at 5 years was 0% and 5.7% (P = 0.14) for patients treated with CFPT and SBPT, respectively. The frequency of GI grade ≥2 toxicity at 6 months was of 0% and 2.3% (P = 0.55), and at 2 years was of 6.7% and 3.4% (P = 0.69) for patients treated with CFPT and SBPT, respectively. The frequency of GU grade ≥2 toxicity at 6 months was of 2.2% and 5.7% (P = 0.42), and at 2 years was of 8.9% and 5.7% (P = 0.54) for patients treated with CFPT and SBPT, respectively. Changes in HRQoL scores at 2 years were similar between groups (Table). SBPT is non-inferior to CFPT regarding FFF and associated with similar long-term toxicity rates and HRQoL metric scores.

Single Dose vs. Fractionated High-Dose Rate Brachytherapy in Localized Prostate Cancer: Long Term Results

To evaluate long-term freedom from biochemical relapse (FFbR) and overall survival (OS) after single-dose high-dose-rate brachytherapy (HDR-BT) compared with 2 or 3 fraction schedules. HDR-BT, delivering 1 × 19 Gy or 1 × 20 Gy (A = 49), 2 × 13 Gy (B = 138) or 3 × 10.5 Gy (C = 106), was given to patients with intermediate or high-risk prostate cancer as their sole treatment. Patients were staged with pelvic MRI and isotope bone scan. Transperineal transrectal ultrasound guided implantation was followed by MRI based CTV definition based on GEC ESTRO guidelines. Biochemical relapse was assessed using the Phœnix definition (PSA nadir plus 2 µg/L). Patients were evaluated prospectively from 6 months after implant and bi-annually thereafter. Estimates of freedom from biochemical relapse, and overall survival (OS) were calculated using the Kaplan-Meier (K-M) method and the log-rank test to test for significance. Univariate and multivariate hazard ratios (HR) were obtained using Cox's proportional hazard model. For multivariate modelling a stepwise reduction method was used. Median follow-up was 123, 116 and 120 months (p = 0.4), (A, B, C, respectively). Neo-adjuvant and adjuvant androgen deprivation treatment was given to 80% of all patients, median duration was 9 months for A and 6 months for B and C. K-M estimates of FFbR, at 8 and 10 years, were 67% and 64% (Group A), 78% and 72% (Group B), and 80% and 76% (Group C). Differences in FFbR between dose groups was not significant (p = 0.2). Similarly, no significant difference was seen in OS. Eight and 10-year estimates were 81% and 75% (A), 85% and 74% (B), and 90% and 83% (C); p = 0.5. Hazard Ratios for risk of biochemical recurrence were significant for ADT administration (yes/no) and overall risk category, in multivariate analyses. Only the latter was significant in univariate analysis for risk of death, Gleason risk (low, intermediate, high), MRI tumor stage risk and overall risk category were significant in univariate analyses. Only tumor stage and Gleason risk were significant in multivariate analyses. Concerns around the efficacy of 19-20 Gy single dose HDR BT as monotherapy, based on early data, may have been unfounded. Long-term outcome data up to 10 years show no significant difference in PSA control and overall survival compared to 2 and 3 fractions of HDR-BT.

Phase III Study of Hypofractionated, Dose Escalation Radiotherapy vs. Conventional Pelvic Radiation Therapy followed by High Dose Rate Brachytherapy Boost for High Risk Adenocarcinoma of the Prostate (PCS VI): Acute Toxicity Results

The low α\β ratio of 1.2-2 for prostate cancer (PCa) suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of lager fraction size. We have recently shown (PCS5) that high risk prostate cancer patients can safely and effectively be treated with moderate hypofractionated radiation therapy (HF-RT). To date there has been no phase-III randomized clinical-trial comparing moderately HF-RT with EBRT and HDR boost (HDRB). We are reporting the acute safety of EBRT+HDRB compared to moderate HF-RT in this phase III Canadian trial. From January 2015-June 2022, 308 high-risk localized PCa patients were randomized to receive either HF-RT or EBRT+HDRB. All patients received neo-adjuvant, concurrent, and long-term adjuvant androgen deprivation therapy (ADT). EBRT+HDRB consisted of 46 Gy in 2 Gy per fraction to the pelvis and a 15 Gy in one fraction HDR boost within 3 weeks of EBRT. HF-RT include concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate, and 45 Gy in 1.8 Gy per fraction to the pelvic lymph-nodes. Of the 308 patients, 148 received HF-RT and 144 EBRT+ HDRB. The remainder either withdrew from the study or were treated with standard (2 Gy per fraction) fractionation for technical reasons. In both intention to treat and as treated analysis, using log-Rank, there were more grade 1 or worse (G1+) acute GI and GU events and more G2+ acute GI events in the HF-RT than EBRT+HDRB. As treated analysis the acute G1+ and G2+ GI events were 92 vs 77 (60.1% vs. 53.5%; p < 0.017) and 21 vs 10 (13.7% vs. 6.9%; p = 0.052), respectively for HF-RT and EBRT + HDRB. Similarly, the G1+ acute GU events were 123 vs. 101 (80.4% vs.70.1%; p < 0.001) respectively for HF-RT and EBRT+HDRB. There were only four G3 GI and one G3 GU acute toxicities in both arms. No grade 4 toxicities were reported. This is the first study of EBRT+HDRB compared to moderate HF dose escalated RT in high-risk prostate cancer patients treated with long-term ADT and pelvic RT. Our results demonstrate that both treatment approaches are well-tolerated and that EBRT+HDRB carries less G2+ GI and G1+ GU acute toxicities.

Early Endpoints in High-risk Localized Prostate Cancer: Exploratory Analysis of Three Radiation Therapy Oncology Group Phase 3 Studies

BackgroundEarly endpoints in clinical trials of high-risk localized prostate cancer (HRLPC) that resemble those monitored in real-world practice could expedite clinical development. ObjectiveTo assess the association of prostate-specific antigen (PSA) recurrence (PSA-R)-based early endpoints with metastasis-free survival (MFS), overall survival (OS), and prostate cancer (PC)-specific survival (PCSS), and to identify clinically undetectable disease. Design, setting, and participantsA post hoc analysis of patients with HRLPC from Radiation Therapy Oncology Group studies 9202, 9902, and 0521 was performed. InterventionLong-term adjuvant androgen-deprivation therapy (ADT) and post-primary definitive radiotherapy. Outcome measurements and statistical analysisEvent-free survival (EFS; PSA-R, locoregional recurrence [LRR], distant metastasis [DM], or death), biochemical failure (PSA-R), general clinical failure (PSA-R, LRR, DM, ADT initiation, or death), and no evidence of disease (NED; alive patients without PSA-R, LRR, DM, and subsequent PC therapy, and with testosterone recovery) were assessed for association with MFS, OS, and PCSS using correlation and landmark analyses, Kaplan-Meier method, and Cox proportional-hazard model. PSA-R was defined as PSA nadir + 2 ng/ml; PSA nadir + 2 ng/ml and rising; PSA >5, 10, and 25 ng/ml; or PSA doubling time (PSADT) <6 mo. Results and limitationsAmong assessed early endpoints, EFS with PSA nadir + 2 ng/ml and rising, or with PSA >5 ng/ml was associated with MFS, OS, and PCSS. No development of EFS with PSADT <6 mo or ADT initiation event or achievement of NED at 3 yr was associated with prolonged OS, MFS, and PCSS (hazard ratio [95% confidence interval], 0.53 [0.45–0.64], 0.63 [0.52–0.76], and 0.26 [0.18–0.36], or 0.56 [0.48–0.66], 0.62 [0.52–0.74], and 0.26 [0.19–0.37]) after the landmark time. Older studies performed before the current guidance should be interpreted with caution. ConclusionsWe identified EFS with PSA nadir + 2 ng/ml and rising, PSA >5 ng/ml, or PSADT <6 mo ± ADT initiation and NED as potentially promising early endpoints in HRLPC that should be validated further. Patient summaryWe identified novel clinical measures that may expedite the development of new medicines for patients with localized prostate cancer at a high risk of progression. These measures, which took into account prostate-specific antigen assessments and other clinical characteristics, should be confirmed in future studies. We also defined a novel measure of no evidence of disease that can help treating physicians identify patients with clinically undetectable disease.

Extended versus standard pelvic lymph node dissection yields no difference in 3-year biochemical recurrence rates.

extended pelvic lymph node dissection (ePLND) increases the detection rate of lymph node positive prostate cancer compared to a standard pelvic lymph node dissection (sPLND). However, improvement of patient outcomes remains questionable. Here we report and compare 3-year postoperative PSA recurrence rates between patients that underwent sPLND versus ePLND at the time of prostatectomy. 162 patients received a sPLND (which involvedremoval of periprostatic, external iliac, and obturator lymph nodes bilaterally), and 142 patients received an ePLND (which involved removal of periprostatic, external iliac, obturator, hypogastric, and common iliac nodes bilaterally). Decision to undergo ePLND versus sPLND at our institution was changed in 2016 based on the National Comprehensive Cancer Network guideline. The median follow-up time was 7 and 3years for sPLND and ePLND patients, respectively. All node-positive patients were offered adjuvant radiotherapy. Kaplan-Meier analysis was carried out to assess the impact of a PLND on early postoperative PSA progression-free survival. Subgroup analyses were done for node-negative and node-positive patients, as well as Gleason score. Gleason score and T stage were not significantly different between patients who received an ePLND and sPLND. The pN1 rate for ePLND and sPLND were 20% (28/142) and 6% (10/162), respectively. There was no difference in the use of adjuvant treatments in the pN0 patients. Significantly, more ePLND pN1 patients received adjuvant androgen deprivation therapy (25/28 vs. 5/10 P=0.012) and radiation (27/28 vs. 4/10 P=0.002). Yet, no difference in biochemical recurrence between ePLND and sPLND was observed (P=0.44). This remained true in subgroup analyses of node-positive (P=0.26), node-negative (P=0.78), Gleason Score 6-7 (P=0.51), and Gleason Score 8-10 (P=0.77). PLND provided no additional therapeutic benefit, even though ePLND patients were significantly more likely to have node-positive disease and undergo adjuvant treatment, compared to a sPLND.

Hypofractionated, Dose Escalation Radiation Therapy for High-Risk Prostate Cancer: The Safety Analysis of the Prostate Cancer Study-5, a Groupe de Radio-Oncologie Génito-Urinaire de Quebec Led Phase 3 Trial

The low α\β ratio of 1.2 to 2 for prostate cancer (PCa) suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of hypofractionated (HF) radiation therapy (RT). To date, no phase 3 randomized clinical trial has compared moderately HF RT with standard fractionation (SF) exclusively in high-risk PCa patients. We are reporting the safety of moderate HF RT in high-risk PCa in an initially noninferiority-designed phase 3 clinical trial. From February 2012 to March 2015, 329 high-risk PCa patients were randomized to receive either SF or HF RT. All patients received neoadjuvant, concurrent, and long-term adjuvant androgen deprivation therapy. Standard fractionation RT consisted of 76 Gy in 2 Gy per fraction to the prostate, where 46 Gy was delivered to the pelvic lymph nodes. Hypofractionated RT included concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate and 45 Gy in 1.8 Gy per fraction to the pelvic lymph nodes. The coprimary endpoints were acute and delayed toxicity at 6 and 24 months, respectively. The trial was originally designed as a noninferiority with a 5% absolute margin. Given the lower-than-expected toxicities in both arms, the noninferiority analysis was completely dropped. Of the 329 patients, 164 were randomized to the HF and 165 to the SF arms. In total, there were more grade 1 or worse acute gastrointestinal (GI) events in the HF arm, 102 versus 83 events in the HF and SF arm, respectively (P=.016). This did not remain significant at 8 weeks of follow-up. There were no differences in grade 1 or worse acute GU events in the 2 arms, 105 versus 99 events in the HF and SF arm, respectively (P=.3). At 24 months, 12 patients in the SF arm and 15 patients in the HF arm had grade 2 or worse delayed GI-related adverse events (hazard ratio, 1.32; 95% CI, 0.62-2.83; P=.482). There were 11 patients in the SF arm and 3 patients in the HF arm with grade 2 or higher delayed genitourinary (GU) toxicities (hazard ratio, 0.26; 95% CI, 0.07-0.94; P=.037). There were 3 grade 3 GI and one grade 3 GU delayed toxicities in the HF arm and 3 grade 3 GU and no grade 3 GI toxicities in the SF arm. No grade 4-toxicities were reported. This is the first study of moderate HF dose-escalated RT in exclusively high-risk patients with prostate cancer treated with long-term androgen deprivation therapy and pelvic RT. Although our data were not analyzed as a noninferiority, our results demonstrate that moderately HF RT is well-tolerated, similar to SF RT at 2 years, and could be considered an alternative to SF RT.

Management of Pathologic Node-Positive Prostate Cancer following Radical Prostatectomy.

Approximately 15% of prostate cancer patients have lymph node metastases at the time of radical prostatectomy (RP). However, there is no universally accepted standard of care for these men. The options for treatment in this subset of patients range from observation to a combination of adjuvant androgen deprivation therapy (aADT) and radiation therapy (RT). A recent systematic review showed that there was no clear choice out of the options above to treat these patients. Studies have shown that patients treated with adjuvant radiation therapy have lower all-cause mortality when compared to patients treated with salvage radiation therapy. In this review, we summarize treatment options for pathologic node-positive (pN1) patients and discuss the urgent need for robust clinical trials that includes observation as the control group to help establish a standard of care for treating patients with node-positive prostate cancer after RP.

MP61-07 EARLY SECONDARY TREATMENT OF LYMPH NODE POSITIVE PROSTATE CANCER AFTER RADICAL PROSTATECTOMY IS ASSOCIATED WITH AGGRESSIVE TUMOR FEATURES AND DETECTABLE PROSTATE SPECIFIC ANTIGEN

You have accessJournal of UrologyCME1 Apr 2023MP61-07 EARLY SECONDARY TREATMENT OF LYMPH NODE POSITIVE PROSTATE CANCER AFTER RADICAL PROSTATECTOMY IS ASSOCIATED WITH AGGRESSIVE TUMOR FEATURES AND DETECTABLE PROSTATE SPECIFIC ANTIGEN Daniel Triner, Ji Qi, Udit Singhal, Michael Sessine, Kevin Ginsburg, Brian Lane, and Todd Morgan Daniel TrinerDaniel Triner More articles by this author , Ji QiJi Qi More articles by this author , Udit SinghalUdit Singhal More articles by this author , Michael SessineMichael Sessine More articles by this author , Kevin GinsburgKevin Ginsburg More articles by this author , Brian LaneBrian Lane More articles by this author , and Todd MorganTodd Morgan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003319.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Patients with lymph node positive (pN+) disease found at the time of radical prostatectomy (RP) and pelvic lymphadenectomy (PLND) are at high risk of disease recurrence and progression. There is ongoing debate with regards to optimal care of pN+patients. While data supports the use of adjuvant androgen deprivation therapy (ADT) with or without radiation (RT), most guidelines include observation as an alternative. We sought to understand contemporary practice patterns of patients with pN+prostate cancer (PCa) in a diverse, statewide quality collaborative. METHODS: Patients in the Michigan Urologic Surgery Improvement Collaborative (MUSIC) with PCa who underwent RP with PLND and pN+on final pathology and 12 months follow up between March 2012 and Feb 2021 were identified. Patients who received neoadjuvant therapy were excluded. The primary outcome was early post-RP treatment (ADT, RT, ADT+RT) within 12 months of diagnosis, which was categorized as either adjuvant (PSA<0.1 ng/ml) or salvage (PSA≥0.1 ng/ml). Time to any post-RP treatment and type of treatment were secondary outcomes. Multivariable logistic and Cox regression models were fit to identify factors associated with post-RP treatment. Kaplan-Meier analysis was performed to assess treatment-free survival. RESULTS: We identified 425 patients who had pN+disease at the time of RP, of which 280 (66%) underwent early post-RP treatment (86 adjuvant and 194 salvage) and 145 (34%) were observed. One year treatment-free survival for patients with first post-RP PSA≥0.1 was 18% (95% CI 14%-24%) compared to 58% (95% CI 51%-65%) for PSA<0.1 ng/ml (p<0.001). In the multivariable Cox model, pathologic grade group, tumor stage, margin status, first post-RP PSA, and race were associated with time to secondary treatment (p<0.05 for each). Of 145 patients on initial observation, 23% had post-RP PSA≥0.1. ADT was most common early adjuvant therapy (45.4%), followed by ADT+RT (36%), RT alone (17.4%), and other (1.2%) CONCLUSIONS: Most patients with pN+PCa in MUSIC received early post-RP treatment and men with a first post-RP PSA<0.1ng/mL had improved secondary treatment free survival. Early treatment, which was predominantly ADT±RT, is influenced by aggressive disease features and detectable post-RP PSA. Nearly one out of four patients with pN+cancer not receiving early post RP treatment had a detectable PSA, suggesting an opportunity for quality improvement by increasing use of postoperative therapy. Source of Funding: Blue Cross Blue Shield of Michigan © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e855 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniel Triner More articles by this author Ji Qi More articles by this author Udit Singhal More articles by this author Michael Sessine More articles by this author Kevin Ginsburg More articles by this author Brian Lane More articles by this author Todd Morgan More articles by this author Expand All Advertisement PDF downloadLoading ...

Duration of androgen deprivation with radiotherapy for high-risk or locally advanced prostate cancer: A network meta-analysis.

To evaluate various outcomes of different lengths of androgen deprivation therapy in high- and very-high-risk prostate cancer, we conducted a network meta-analysis of randomized trials. The treatment of high-risk PC comprises the use of radical radiotherapy associated with various durations of androgen deprivation therapy, with luteinizing hormone releasing hormone analogues initiated during or immediately before the beginning of radiation. This study followed the PRISMA extension statement to report network meta-analyses. We systematically searched online databases, including MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, for all randomized trials published up to April 2022. The primary outcomes were overall survival, prostate cancer-specific mortality, and metastasis-free survival. Network meta-analyses were performed under a Bayesian framework using the "gemtc" package (https://gemtc.drugis.org). The network meta-analysis included 12 studies (10 treatments) on overall survival outcomes. None of the arms showed superiority to radiotherapy alone with respect to overall deaths. Nine studies and 10 treatment arms had prostate cancer-specific mortality data. Overall, 36 months of adjuvant androgen deprivation therapy resulted in a better outcome than radiotherapy alone, three months of neoadjuvant androgen deprivation therapy, or 12 or 24 months of adjuvant androgen reprivation therapy, and it was the better treatment (73%) in terms of cancer mortality. Treatment involving luteinizing hormone releasing hormone analogues for 6 months before and during radiotherapy ranked the highest in reducing distant metastases (42%). We found that 36 months of adjuvant androgen deprivation therapy after radiotherapy was the optimal duration of endocrine treatment with regard to cancer mortality for high-risk and locally advanced prostate cancer.

Does inflammation markers or treatment type moderate exercise intensity effects on changes in muscle strength in cancer survivors participating in a 6-month combined resistance- and endurance exercise program? Results from the Phys-Can trial

BackgroundResistance exercise has a beneficial impact on physical function for patients receiving oncological treatment. However, there is an inter-individual variation in the response to exercise and the tolerability to high-intensity exercise. Identifying potential moderating factors, such as inflammation and treatment type, for changes in muscle strength is important to improve the effectiveness of exercise programs. Therefore, we aimed to investigate if inflammation and type of oncological treatment moderate the effects of exercise intensity (high vs. low-moderate) on muscular strength changes in patients with breast (BRCA) or prostate cancer (PRCA).MethodsParticipants with BRCA (n = 286) and PRCA (n = 65) from the Physical training and Cancer study (Phys-Can) were included in the present study. Participants performed a combined resistance- and endurance exercise program during six months, at either high or low-moderate intensity. Separate regression models were estimated for each cancer type, with and without interaction terms. Moderators included in the models were treatment type (i.e., neo/adjuvant chemotherapy—yes/no for BRCA, adjuvant androgen deprivation therapy (ADT)—yes/no for PRCA)), and inflammation (interleukin 6 (IL6) and tumor necrosis factor-alpha (TNFα)) at follow-up.ResultsFor BRCA, neither IL6 (b = 2.469, 95% CI [− 7.614, 12.552]) nor TNFα (b = 0.036, 95% CI [− 6.345, 6.418]) levels moderated the effect of exercise intensity on muscle strength change. The same was observed for chemotherapy treatment (b = 4.893, 95% CI [− 2.938, 12.724]). Similarly, for PRCA, the effect of exercise intensity on muscle strength change was not moderated by IL6 (b = − 1.423, 95% CI [− 17.894, 15.048]) and TNFα (b = − 1.905, 95% CI [− 8.542, 4.732]) levels, nor by ADT (b = − 0.180, 95% CI [− 11.201, 10.841]).ConclusionsThe effect of exercise intensity on muscle strength is not moderated by TNFα, IL6, neo/adjuvant chemotherapy, or ADT, and therefore cannot explain any intra-variation of training response regarding exercise intensity (e.g., strength gain) for BRCA or PRCA in this setting.Trial registration: ClinicalTrials.gov NCT02473003.

Pituitary-testis axis dysfunction following adjuvant androgen deprivation therapy.

Men with high-risk, non-metastatic prostate cancer receive adjuvant androgen deprivation therapy (ADT) for at least 2 years according to Danish guidelines. It remains unclarified if patients regain the function of the pituitary-testis axis after cessation of ADT. Thus, we aimed to investigate the function of the pituitary-testis axis following adjuvant ADT. In this study, we included men who underwent external beam radiation therapy and ADT for high-risk prostate cancer. All patients underwent assessment of testosterone deficiency (TD) symptoms, full biochemical assessment of the pituitary-testis axis, and dynamic stimulatory tests of gonadotropin (gonadotropin-releasing hormone (GnRH) test) and testosterone production (human chorionic gonadotrophin (hCG) test). Patients were diagnosed with TD based on a combination of TD symptoms and testosterone below age-specific reference ranges. TD was characterized as primary, secondary, or mixed based on serum gonadotropins and stimulatory tests. We found that among the 51 patients included in the study, the median time on ADT was 3.2 years and median time since ADT cessation was 3.8 years. Twenty-eight patients were diagnosed with TD; 10 had primary TD (testicular dysfunction), 11 secondary TD (pituitary dysfunction), and 7 mixed TD (combined pituitary and testicular dysfunction). An inadequate testosterone response to hCG stimulation was shown in 42 patients, whereas only 11 patients had a subnormal gonadotropin response to GnRH. We conclude that persistent TD is a common long-term consequence of adjuvant ADT in prostate cancer survivors, equally distributed between pituitary and testicular dysfunction. The study emphasizes the necessity for systematic follow-up of full pituitary-testis axis function in patients receiving adjuvant ADT.

Primary adenocarcinoma of the seminal vesicles in Port Harcourt, Nigeria; Our experiences: Review of current diagnosis, treatment methods and outcome

Introduction: Primary tumors of the seminal vesicles are rare. The aims of this study are to present the case of a 32-year old man with advanced primary adenocarcinoma of the left seminal vesicle (PSVCA) that simulated features of prostatic neoplasm. Challenges encountered in its diagnosis are highlighted, and the literature reviewed to compare our experiences with current views of others on precise diagnosis of the tumor, its treatment methods and outcome. Materials and Methods: Consecutive male urology patients seen at UPTH, Port Harcourt, Nigeria were evaluated clinically and with relevant investigations. Two patients who had provisional diagnosis of PSVCA had operations/ post-operative specimen histology. One had confirmed diagnosis of PSVCA, was further treated, followed up and reported. Data were collected simultaneously with patients’ services. The PubMed/Medline and PubMed Central databases were searched for articles on clinical, immune histochemical features, treatment and outcome of PSVCA. Data on these features were presented in tables. Results: Of two presumptively diagnosed patients, one (32-year-old) had histological confirmation of primary adenocarcinoma of the left seminal vesicle. Radical surgery with urinary diversion, and either neoadjuvant or adjuvant androgen deprivation therapy, or cytotoxic chemotherapy, or adjuvant radiotherapy were the common treatment options found on literature review. Conclusion: The reported patient in this study had good post-operative performance but follow-up period was short. Currently, histopathologic and radiologic diagnostic methods are reinforced with immune histochemical techniques for precise diagnosis of PSVCA. Radical surgical therapy with neoadjuvant or adjuvant therapy are currently favored. Immune histochemical facilities should be provided at our center.

Treatment Outcomes of Postoperative Ultra-Hypofractionated Stereotactic Body Radiotherapy in Prostate Cancer

<h3>Purpose/Objective(s)</h3> Prospective randomized phase 3 trials have shown that hypofractionated radiotherapy (RT) regimens are safe and effective for definitive prostate RT. There is, however, a scarcity of data describing the outcomes of ultra-hypofractionation in the postoperative setting. The purpose of this study was to assess the safety of ultra-hypofractionated RT to prostate bed using stereotactic body RT (SBRT) technique. <h3>Materials/Methods</h3> The clinical data of 69 prostate cancer patients who received postoperative prostate bed SBRT between August 2018 and September 2020 were reviewed retrospectively. All patients had had radical prostatectomy, and 44 (63.8%) had pelvic lymph node dissection, with a median of 14 (range: 2–34) lymph nodes dissected. The primary endpoints were failure from biochemical failure (FFBF) and acute and late gastrointestinal (GI) and genitourinary (GU) toxicities. Secondary endpoint was progression free survival (PFS). <h3>Results</h3> The median age was 64 years (range: 43–76 years). Thirty patients (43.5%) received adjuvant RT and 39 (56.5%) had salvage RT median 12.4 months (range: 1.5–137.6 months) after surgery. Median SBRT fraction and total doses were 7 Gy (range: 6–7.3 Gy) and 30 Gy (30–36.5 Gy), respectively delivered in 5 days. Majority of patients (82.7%) had high risk disease and only 13 patients (18.8%) had lymph node metastasis. Seminal vesicle invasion was observed in 22 patients (31.9%) and 49 patients (71%) had extracapsular invasion. Forty-eight patients (69.6%) had positive surgical margin. Pre-SBRT and post-SBRT PSA values were 0.37 ng/mL and 0.05 ng/mL, respectively. 27 patients (39.1%) also received adjuvant androgen deprivation therapy (ADT) after SBRT and post-treatment PSA nadir value was 0.01 ng/mL. Median follow-up time was 23.8 months (range: 2.8–37.2 months). The 2-year FFBF and PFS were 91.4% and 87%, respectively. Seven patients (10.1%) had BF median 18.5 months (range: 1.7–33.5 months) after completion of SBRT. Disease progression was observed in 10 patients (14.5%) median 13.9 months after treatment. Acute GI and GU system toxicities of grade 2 or greater were observed in 13% and 14.5% of patients, respectively. Late GI and GU toxicities of grade 2 or greater were observed in 4.3% and 16% of patients, respectively. <h3>Conclusion</h3> SBRT delivered to the prostate bed over a 5-day period was found to be safe, with acceptable acute and late toxicities. Longer follow-up and randomized trials with a large patient population, however, are required to validate our findings.

Outcome of Cyto Reductive Prostatectomy and ADT and Metastasis-Directed Therapy (MDT) in Patients with Oligometastatic Prostate Cancer: A Prospective Cohort

Objective: We wanted to evaluate the efficacy and safety of a new treatment of Oligosmetastatic prostate cancer (OMPC) with multimodal approach including local primary tumor therapy, in the form of Cytoreductive Prostatectomy, metastasis-directed therapy (MDT), and hormonal therapy . Methods: We reviewed data of patients with Oligometastatic Prostate Cancer(OMPC) at diagnosis treated in our institutions with ADT and followed by Cytoreductive Prostatectomy (CP) with or without metastases-directed radiotherapy. In this prospective cohort study, 19 patients underwent Cytoreductive radical Prostatectomy and routine Lymphadenectomy, ADT with Degarelix, Aberateron and Prednisolone in the form of neoadjuvant setting during the period of Jan 2016 - March 2021. Of these,05 patients (26.31%) received stereotactic body radiation therapy (SBRT) to all metastatic sites as a MDT in addition to above protocol. Results: The median follow-up period was 46.2 months. Perioperative outcomes, clinical progression, and cancer-specific mortality (CSM) were evaluated. Median age was 72 yr. Median operative time, blood loss, and length of hospitalization were 176 min, 850 ml, and 6 d, respectively. Overall, two patients (10.52%) experienced grade 3 complications in the postoperative period. All received blood transfusions. Overall, 15 (78.94%) and 8 (42.10%) patients had lymph node invasion and positive surgical margins, respectively. Adjuvant Radiation Therapy and androgen deprivation therapy was administered to all 8 patients (42.10%)who confirmed margin Positive status. Of the 19 patients, the 3-year castration-resistant prostate cancer (CRPC)-free survival and cancer-specific survival was100%. Our findings support the safety and effectiveness of Cytoreductive Prostatectomy (C P) in a highly selected cohort of PCa patients with bone metastases and long-term follow-up Conclusion: This Prospective cohort revealed the feasibility of combining ADT and Cytoreductive prostatectomy and metastasis-directed radiotherapy for newly-diagnosed Oligometastatic Prostatic Cancer. This treatment strategy has the potential to delay the progression to CRPC. Bangladesh J. Urol. 2021; 24(2): 146-154

7P HIFA1 inhibition as a therapeutic strategy for overcoming castration resistance in PTEN-deficient prostate cancer

Prostate cancer (PCa) is the second most commonly diagnosed neoplasia in men worldwide. The growth of prostate cancer cells is initially dependent of the activity of the androgen receptor (AR) and AR is the target of first-line prostate cancer systemic treatments. The benefit of adding neoadjuvant and adjuvant androgen deprivation therapy is well established for men with high-risk localized and advanced disease. However, some patients develop castration resistant prostate cancer, for which curative options are limited. PTEN is the most often tumor suppressor gene mutated in PCa patients. Hypoxic regions have been found in prostate adenocarcinoma, and elevated expression of hypoxia markers, including HIF1a (hypoxia-inducible factor 1A), have been shown to identify PCa patients with elevated risk of biochemical recurrence. Prostate tumors of sham-operated and castrated Pten(i)pe-/- mice, which have a prostatic luminal cell-specific inactivation of PTEN after puberty, were analyzed by droplet-based single cell-RNA sequencing. Moreover, the impact of genetic and pharmacological Hif1a inhibition was determined in castrated Pten(i)pe-/- mice by histological analyses. To gain insights on pathways driving androgen-independence in prostate tumor, we analyzed Pten(i)pe-/- mice which develop tumors that are resistant to castration. Droplet based single cell-RNA sequencing of 17265 cells from dissociated tumors of castrated and sham-operated Pten(i)pe-/- mice revealed that androgen deprivation enhances hypoxia signaling in luminal cells. Importantly, this is accompanied by the emergence of an immune-cell-related gene signature in luminal cells of castrated mice, indicating that activation of hypoxic signaling and induction of cellular plasticity are involved in castration resistance. Importantly, genetic ablation of Hif1a in prostatic tumors sensitizes them to castration, and pharmacological inhibition of Hif1a together with androgen deprivation leads to durable anti-tumoral response. Androgen deprivation in combination with HIF1 signaling inhibition is a promising therapeutic strategy for overcoming castration resistance in PTEN-deficient prostatic tumors.

Effect of 3-Dimensional, Virtual Reality Models for Surgical Planning of Robotic Prostatectomy on Trifecta Outcomes: A Randomized Clinical Trial.

Planning complex operations such as robotic-assisted radical prostatectomy requires surgeons to review 2-dimensional magnetic resonance imaging (MRI) cross-sectional images to understand 3-dimensional (3D), patient-specific anatomy. We sought to determine surgical outcomes for robotic-assisted radical prostatectomy when surgeons reviewed 3D, virtual reality (VR) models for operative planning. A multicenter, randomized, single-blind clinical trial was conducted from January 2019 to December 2020. Patients undergoing robotic-assisted laparoscopic radical prostatectomy were prospectively enrolled and randomized to either a control group undergoing usual preoperative planning with prostate biopsy results and MRI only or to an intervention group where MRI and biopsy results were supplemented with a 3D VR model. The primary outcome measure was margin status, and secondary outcomes were oncologic control, sexual function and urinary function. Ninety-two patients were analyzed, with trends toward lower positive margin rates (33% vs 25%) in the intervention group, no significant difference in functional outcomes and no difference in traditional operative metrics (p >0.05). Detectable postoperative prostate specific antigen was significantly lower in the intervention group (31% vs 9%, p=0.036). In 32% of intervention cases, the surgeons modified their operative plan based on the model. When this subset was compared to the control group, there was a strong trend toward increased bilateral nerve sparing (78% vs 92%), and a significantly lower rate of postoperative detectable prostate specific antigen in the intervention subset (31% vs 0%, p=0.038). This randomized clinical trial demonstrated patients whose surgical planning involved 3D VR models have better oncologic outcomes while maintaining functional outcomes.

Bone health assessment with dual energy X-ray absorptiometry in men with high-risk prostate carcinoma commencing adjuvant androgen deprivation therapy.

BackgroundAndrogen deprivation therapy (ADT) is a key component of therapy for patients with high-risk prostate carcinoma, but it may be deleterious for bone health. We sought to determine the frequency of dual energy x-ray absorptiometry (DXA) scanning in patients commencing adjuvant ADT for treatment of high-risk prostate cancer at a large integrated regional cancer centre.Material and methodsThe electronic medical records (EMR) of all patients with high-risk prostate carcinoma commenced on adjuvant ADT between January 1, 2016 and December 31, 2017 at the Mid-North Coast Cancer Institute, Coffs Harbour, Australia were reviewed. Patients commenced on neoadjuvant ADT and long-term suppressive ADT for metastatic disease were excluded. The following data were obtained: socio-demographic information, prostate cancer data, ADT details and DXA results.Results188 men (mean age ± SD, 75.4 ± 7 years) were commenced on adjuvant ADT for a total duration (mean ± SD) of 23.4 ± 7 months. Most (n = 155/188, 82%) were commenced on leuprorelin acetate. While only 26/188 (14%) had a DXA scan performed prior to ADT, another 133 (71%) had a DXA scan at a median of 20 days (interquartile range 7–98), later. Of the 159 men with DXA readings, 76 (48%) were osteopaenic and 38 (24%) were osteoporotic by DXA criteria.ConclusionA high level (85%) of DXA scanning in men commencing ADT for prostate cancer can be achieved at a regional centre. The high prevalence (72%) of low bone mass in our unselected cohort underscores the importance of routine DXA scanning to guide bone health management during ADT.

A phase III double blinded study of early intervention after radical prostatectomy with androgen deprivation therapy with darolutamide versus placebo in men at highest risk of prostate cancer metastasis by genomic stratification (ERADICATE).

TPS5114 Background: Patients with high-risk scores by Decipher molecular testing after prostatectomy have a 5-year metastasis rate of 28% (Decipher 0.6-0.7) and 38% (Decipher &gt; 0.7), likely due to micrometastatic disease. Clinical trials with intensified systemic treatment are warranted to increase cure rates and address this unmet need. Previous studies of adjuvant androgen deprivation therapy (ADT) in clinically identified high-risk disease have not demonstrated substantial benefit other than in men with lymph node positive disease. Darolutamide is a novel androgen receptor antagonist with demonstrated efficacy in improving metastasis-free survival (MFS) and overall survival (OS) in patients with non-metastatic castration-resistant prostate cancer, and OS in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Whether treatment with ADT and darolutamide can increase MFS versus ADT plus placebo in the adjuvant setting for men with molecularly identified high-risk prostate cancer is unknown. Methods: Patients with CAPRA-S scores ≥3 and a PSA &lt; 0.2 after radical prostatectomy undergo Decipher testing provided by the trial. Eligible patients with high-risk Decipher scores (&gt; 0.6) will be randomized to treatment with ADT with darolutamide or placebo for 12 months. Patients are stratified by intent to deliver adjuvant radiation and by baseline PSA (undetectable vs detectable but &lt; 0.2 ng/mL). The primary endpoint is MFS defined by novel PET or conventional imaging. With a sample size of 810 patients, the trial has 80% power with one-sided alpha = 0.025 to detect a HR of 0.60 for the experimental arm vs control arm for the primary endpoint. Secondary endpoints include recurrence-free survival, event-free survival, and quality of life (FACT-P, FACT-Cog, and FACIT-Fatigue), overall survival, and other disease-related outcomes. Trial was activated on December 9, 2020, and is currently enrolling patients. Clinical trial information: NCT04484818.

Current Status and Future Perspective on the Management of Lymph Node-Positive Prostate Cancer after Radical Prostatectomy.

Simple SummarypN1 after RP with PLND represents one of the most unfavorable prognostic factors for disease recurrence and cancer-specific mortality in prostate cancer. Treatment intensification may reduce risks of recurrence and cancer-specific mortality, but it may increase adverse events and impair quality of life. However, optimal management for pN1 patients remains unclear. Nevertheless, few randomized control trials for pN1 are under investigation, and then more research is needed to establish an optimal therapeutic strategy for patients with pN1. This review summarizes current evidence on the treatments available for men with pN1, summarizes RCTs that included pN1 prostate cancer, and also discusses future perspectives.Pathological lymph node involvement (pN1) after a pelvic lymph node dissection represents one of the most unfavorable prognostic factors for disease recurrence and cancer-specific mortality in prostate cancer. However, optimal management for pN1 patients remains unclear. Thus, the guideline from the European Association of Urology recommends discussing three following management options with pN1 patients after an extended pelvic lymph node dissection, based on nodal involvement characteristics: (i) offer adjuvant androgen-deprivation therapy, (ii) offer adjuvant androgen-deprivation therapy with additional radiotherapy and (iii) offer observation (expectant management) to a patient with ≤2 nodes and a prostate-specific antigen <0.1 ng/mL. Treatment intensification may reduce risks of recurrence and cancer-specific mortality, but it may increase adverse events and impair quality of life. Few randomized control trials for pN1 are under investigation. In addition, there are limited reports on the quality of life and patient-reported outcomes in patients with pN1. Therefore, more research is needed to establish an optimal therapeutic strategy for patients with pN1. This review summarizes current evidence on the treatments available for men with pN1, summarizes randomized control trials that included pN1 prostate cancer, and discusses future perspectives.