Neoadjuvant Androgen Deprivation Therapy Research Articles

Surgical management of rectal cancer with synchronous treatment of prostate cancer.

To assess the safety and efficacy of synchronous treatments for rectal (RC) and prostate (PC) cancers. Single-center retrospective study (2007-2021) of patients treated with neoadjuvant radiotherapy (RT) and total mesorectal excision (TME) for RC with synchronous PC treatment. The endpoints were 30-day postoperative severe complications, R0 resection rates, 3-year disease-free survival (DFS) and 3-year overall survival (OS). Among the 16 patients, 15 (93.7%) received neoadjuvant pelvic RT (40-50.4 Gray) followed by either transperineal high dose rate prostate brachytherapy (62.5%), prostate external RT boost (25.0%), or androgen deprivation therapy (ADT) alone (6.3%). One (6.3%) patient received neoadjuvant rectal brachytherapy and ADT. Pelvic RT was combined with chemotherapy in 87.5% of cases. TME was performed in all patients with low anterior resection (87.5%) or abdominoperineal resection (12.5%), primarily using minimally invasive surgery (87.5%). The R0 resection rate was 93.8%. Six (37.5%) patients experienced 30-day Clavien-Dindo grade IIIb complications, including one (7.1%) anastomotic leak. After a median follow-up of 39.0months, 63.6% of diverting ileostomies were reversed. Three-year DFS from RC was 71.4% (CI 40.2-88.3) and 3-year OS was 84.4% (CI 95% 50.4-95.9). No PC recurrence or death occurred. Synchronous management of RC and PC with pelvic RT followed by curative prostate RT doses and TME showed acceptable morbidity and oncologic results. Prostate brachytherapy, the most commonly used treatment modality, allowed avoidance of prostatectomy and additional external RT to the rectum. PC should not limit the curative intent of RC, as all recurrences were from rectal origin.

Integration Analysis of Single-Cell Multi-Omics Reveals Prostate Cancer Heterogeneity.

Prostate cancer (PCa) is an extensive heterogeneous disease with a complex cellular ecosystem in the tumor microenvironment (TME). However, the manner in which heterogeneity is shaped by tumors and stromal cells, or vice versa, remains poorly understood. In this study, single-cell RNA sequencing, spatial transcriptomics, and bulk ATAC-sequence are integrated from a series of patients with PCa and healthy controls. A stemness subset of club cells marked with SOX9high ARlow expression is identified, which is markedly enriched after neoadjuvant androgen-deprivation therapy (ADT). Furthermore, a subset of CD8+ CXCR6+ T cells that function as effector T cells is markedly reduced in patients with malignant PCa. For spatial transcriptome analysis, machine learning and computational intelligence are comprehensively utilized to identify the cellular diversity of prostate cancer cells and cell-cell communication in situ. Macrophage and neutrophil state transitions along the trajectory of cancer progression are also examined. Finally, the immunosuppressive microenvironment in advanced PCa is found to be associated with the infiltration of regulatory T cells (Tregs), potentially induced by an FAP+ fibroblast subset. In summary, the cellular heterogeneity is delineated in the stage-specific PCa microenvironment at single-cell resolution, uncovering their reciprocal crosstalk with disease progression, which can be helpful in promoting PCa diagnosis and therapy.

Bothersome Hot Flashes Following Neoadjuvant Androgen Deprivation Therapy and Stereotactic Body Radiotherapy for Localized Prostate Cancer.

Androgen deprivation therapy (ADT) improves local cancer control in unfavorable localized prostate cancer treated with radiotherapy. ADT is known to cause hormonally related symptoms that resolve with testosterone recovery. Hot flashes are particularly burdensome. This study sought to evaluate the timeline of hot flashes following short-course ADT and stereotactic body radiotherapy (SBRT) as well as its relationship with testosterone recovery. Institutional IRB approval was obtained for this retrospective review of prospectively collected data (IRB#: 2009-510). ADT was initiated three months prior to the start of SBRT. Hot flashes were self-reported via question 13a of the Expanded Prostate Index Composite (EPIC)-26 prior to ADT initiation, the first day of robotic SBRT, and at each follow-up (one, three, six, nine, 12, 18, 24, and 36 months). The responses were grouped into three relevant categories (no problem, very small-small problem, and moderate-big problem). Scores were transformed to a 0-100 scale with higher scores reflecting less bother. Testosterone levels were measured at each follow-up. From 2007 to 2010, 122 localized prostate cancer patients (nine low-, 64 intermediate-, and 49 high-risk according to the D'Amico classification) at a median age of 72 years (range 54.5-88.3) were treated with short course ADT (three to six months) and SBRT (35-36.25 Gy) at Georgetown University Hospital. Thirty-two percent were Black and 27% were obese. Seventy-seven percent of patients received three months of ADT. At baseline, 2% of men experienced hot flashes that were a "moderate to big problem" and that proportion peaked at the start of SBRT (45%) before returning to baseline (2%) nine months post-SBRT with a cumulative incidence of 52.4%. The median baseline EPIC-26 hot flash score of 94 declined to 50 at the start of SBRT but this returned to baseline (92) by six months post SBRT. These changes were both statistically and clinically significant (MID = 9.5083, p<0.01). Testosterone recovery (> 230 ng/dL) occurred in approximately 70% of patients by 12 months post SBRT. Resolution of hot flashes correlated with testosterone recovery. Bothersome hot flashes occur in greater than 50% of men treated with neoadjuvant ADT. Resolution of hot flashes occurs in the majority of patients within one year after treatment. Reassurance of the temporary nature of hot flashes may assist in reducing patient anxiety. Measuring testosterone levels at follow-up visits may allow for anticipatory counseling that may limit the associated bother.

Neoadjuvant darolutamide plus androgen deprivation therapy for high-risk/very high-risk localized prostate cancer: A multicenter, open-labeled, single-arm phase II trial.

Neoadjuvant darolutamide plus androgen deprivation therapy for high-risk/very high-risk localized prostate cancer: A multicenter, open-labeled, single-arm phase II trial.

An objective measure of response on whole-body MRI in metastatic hormone sensitive prostate cancer treated with androgen deprivation therapy, external beam radiotherapy, and radium-223.

The aim of this study was to generate an objective method to describe MRI data to assess response in the vertebrae of patients with metastatic hormone sensitive prostate cancer (mHSPC), treated with external beam radiation therapy and systemic therapy with Radium-223 and to correlate changes with clinical outcomes. Three sets of whole-body MRI (WBMRI) images were utilized from 25 patients from the neo-adjuvant Androgen Deprivation Therapy pelvic Radiotherapy and RADium-223 (ADRRAD) clinical trial: MRI1 (up to 28 days before Radium-223), MRI2, and MRI3 (2 and 6 months post completion of Radium-223). Radiological response was assessed based on post baseline MRI images. Vertebrae were semi-automatically contoured in the sagittal T1-weighted (T1w) acquisitions, MRI intensity was measured, and spinal cord was used to normalize the measurements. The relationship between MRI intensity vs time to biochemical progression and radiology response was investigated. Survival curves were generated and splitting measures for survival and biochemical progression investigated. Using a splitting measure of 1.8, MRI1 was found to be a reliable quantitative indicator correlating with overall survival (P = 0.023) and biochemical progression (P = 0.014). MRI (3-1) and MRI (3-2) were found to be significant indicators for patients characterized by progressive/non-progressive disease (P = 0.021, P = 0.004) and biochemical progression within/after 12 months (P = 0.007, P = 0.001). We have identified a potentially useful objective measure of response on WBMRI of vertebrae containing bone metastases in mHSPC which correlates with survival/progression (prognostic) and radiology response (predictive). Measurements of T1w WBMRI normalized intensity may allow identifying potentially useful response biomarkers correlating with survival, radiological response and biochemical progression.

Early change in apparent diffusion coefficient as a predictor of response to neoadjuvant androgen deprivation and external beam radiation therapy for intermediate- to high-risk prostate cancer

To determine the role of serial apparent diffusion coefficient (ADC) as a biomarker for response to neoadjuvant androgen deprivation therapy (nADT) followed by external beam radiation therapy (EBRT) in intermediate- to high-risk prostate cancer (PCa) patients. This Health Insurance Portability and Accountability Act (HIPAA)-compliant, institutional review board (IRB)-approved prospective study included 12 patients with intermediate- to high-risk PCa patients prior to nADT and EBRT, who underwent serial serum prostate-specific antigen (PSA) and multiparametric prostate magnetic resonance imaging (mpMRI) at baseline (BL), 8-weeks after nADT initiation (time point [TP]1), 6-weeks into EBRT delivery (TP2), and 6-months after nADT initiation (TP3). Tumour volume (tVOL) and tumour and normal tissue ADC (tADC and nlADC) were determined at all TPs. tADC and nlADC dynamics were correlated with post-treatment PSA using Pearson's correlation coefficient. Paired t-tests compared pre/post-treatment ADC. There was a sequential decrease in PSA at all TPs, reaching their lowest values at TP3 post-treatment completion. Mean tADC increased significantly from baseline to TP1 (917.8±107.7×10-6 versus 1033.8±139.3×10-6 mm2/s; p<0.01), with no subsequent change at TP2 or TP3. Both percentage and absolute change in tADC from BL to TP1 correlated with post-treatment PSA (r=-0.666, r=-0.674; p=0.02). Post-treatment PSA in good responders (<0.1 ng/ml) versus poor responders (≥ 0.1 ng/ml) was associated with a greater increase in tADC from BL to TP1 (169.2±122.4×10-6 versus 22.9±75.5×10-6 mm2/s, p=0.03). This pilot study demonstrates the potential for early ADC metrics as a biomarker of response to nADT and EBRT in intermediate to high-risk PCA.

Health-Related Quality of Life Assessment in Prostate Cancer Patient Undergoing Androgen Deprivation Therapy: Real-World Experience in the READT Study.

To investigate the effect of androgen deprivation therapy (ADT) on health-related quality of life (HRQOL) in Asian men with all stages of prostate cancer. READT (real-life evaluation of the effect of ADT in prostate cancer patients in Asia) was a multi-center, prospective observational study involving six sites across four Asian populations. We enrolled eligible prostate cancer patients, who opted for ADT alone or in combination without prior neoadjuvant or adjuvant ADT within 12 months. The EuroQoL-5 dimensions, 5 level scale (EQ-5D-5L) utility index scores and visual analog scale (VAS) were evaluated at baseline, month 6 and month 12. A total of 504 patients were recruited into READT between September 2016 and May 2020 with 52.9% diagnosed with metastatic prostate cancer. The EQ-5D-5L was evaluable in 442/504 (87.7%) of patients. Overall baseline EQ-5D-5L utility index score was 0.924 (interquartile range [IQR] 0.876-1.000). We observed a statistically significant difference in baseline EQ-5D-5L utility index score among different populations with a median EQ-5D-5L utility index score of 1 for Taiwan &amp; Hong Kong, 0.897 for China and 0.838 for Malaysia. Similar trend was observed throughout multiple treatment time-points. Stage IV prostate cancer were significantly associated with a lower baseline EQ-5D-5L utility index score compared to stage I-III prostate cancer, producing a median disutility value of -0.080. Participants had a high median VAS (80, IQR 70-90), indicating good overall health on average during ADT initiation. The study highlights the differences in health state utility index scores among various Asian prostate cancer patients receiving ADT at real-world setting. Our findings will be informative and useful in cost-effectiveness evaluation and policy decision making.

Prostate-Specific Antigen Response to Androgen Deprivation Therapy in the Neoadjuvant Setting for High-Risk Prostate Adenocarcinoma (PIRANHA): Pooled Analysis of Two Randomized Clinical Trials

A suboptimal prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) among men who go on to receive definitive radiation therapy for prostate cancer might suggest the existence of castration-resistant disease or altered androgen receptor signaling. This in turn may portend worse long-term clinical outcomes, especially in men with high-risk disease. We set out to evaluate the prognostic impact of poor PSA response to neoadjuvant ADT in men with high-risk prostate cancer. This was a post hoc analysis of the multicenter TROG 03.04 RADAR and PCS IV randomized clinical trials. Inclusion criteria for this analysis were patients with high-risk prostate cancer (defined as Gleason score ≥8, initial PSA ≥20 ng/mL, or cT3a disease or higher) who received definitive radiation therapy, at least 18 months of ADT, and had a preradiation therapy PSA level drawn after at least 3 months of neoadjuvant ADT. Poor PSA response was defined as PSA >0.5 ng/mL. Cox regression and Fine-Gray models were used to test whether poor PSA response was associated with metastasis-free survival, biochemical recurrence, prostate-cancer specific mortality, and overall survival. Nine hundred thirty men met inclusion criteria for this analysis. Median follow-up was 130 months (interquartile range [IQR], 89-154 months). After a median of 3 months (IQR, 3-4.2 months) of neoadjuvant ADT, the median PSA was 0.60 ng/mL (IQR, 0.29-1.59). Overall, 535 men (57%) had a PSA >0.5 ng/mL. Poor PSA response was associated with significantly worse metastasis-free survival (hazard ratio [HR], 3.93; P=.02), worse biochemical recurrence (subdistribution HR, 2.39; P=.003), worse prostate-cancer specific mortality (subdistribution HR, 1.50; P=.005), and worse overall survival (HR, 4.51; P=.05). Patients with PSA >0.5 mg/mL after at least 3 months of neoadjuvant ADT had worse long-term clinical outcomes and should be considered for treatment intensification.

Laparoscopic total pelvic exenteration combined with transanal total mesorectal excision for locally advanced prostate cancer with rectal infiltration

IntroductionIntensive treatment is typically considered for very high‐risk patients with locally advanced prostate cancer and an expected survival time of 5 years or longer. Herein, we report a case of locally advanced prostate cancer with rectal infiltration treated with laparoscopic total pelvic exenteration combined with transanal total mesorectal excision.Case presentationA 73‐year‐old man presented with a ring‐shaped mass around the rectum. He was diagnosed with prostate cancer with rectal infiltration and underwent laparoscopic total pelvic exenteration combined with transanal total mesorectal excision following neoadjuvant androgen deprivation therapy. Twenty‐two months postoperatively during ongoing androgen deprivation therapy, no biochemical recurrence was observed.ConclusionTo our knowledge, this is the first report of a laparoscopic total pelvic exenteration combined with transanal total mesorectal excision for prostate cancer with rectal infiltration. We believe this surgery may be considered a new option for high‐risk prostate cancer patients with rectal infiltration.

FRI475 The Impact Of Suppression Of Androgen Signaling On Thyroid Hormone Homeostasis In Prostate Cancer Patients

Abstract Disclosure: K. David: None. G. Devos: None. W. Devlies: None. N. Narinx: None. L. Antonio: None. L. Deboel: None. D. Schollaert: None. D.M. Vanderschueren: None. F.A. Claessens: None. S. Joniau: None. B. Decallonne: None. Next to the classical androgen deprivation therapy (ADT) with GnRH-(ant)agonists, androgen receptor signaling inhibitors (ARSIs) such as apalutamide (APA) have become available for the treatment of prostate cancer (PC) patients in the last years. Hypothyroidism was more frequent in APA-treated patients compared to placebo in the SPARTAN trial (NCT01946204) (8.1% vs 2%). We collected serum of PC patients included in a RCT (ARNEO; NCT03080116) before and after 12 weeks of neo-adjuvant ADT (GnRH-antagonist degarelix (DGX) with APA or placebo). We aimed to explore changes in thyroid homeostasis under deep androgen suppression with combined GnRH-antagonist and ARSI. Of the 88 patients ending the trial, 1 was excluded because of history of hypothyroidism for which he received levothyroxine. 43 and 44 patients were included in the DGX+placebo and DGX+APA group, respectively. Mean age was 66.3y. Sex steroid levels measured by LC-MS/MS decreased significantly to castrate range with median testosterone 10.5 ng/dL and estradiol 3.6 ng/L. TSH levels increased in both treatment groups, but more pronounced in the DGX+APA group (DGX+placebo before: 1.18 mIU/L and after: 1.33 mIU/L, p 0.0351 vs. DGX+APA before: 1.07 mIU/L and after: 1.87 mIU/L, p &amp;lt;0.0001; difference between groups after treatment: p &amp;lt;0.0001). Free T4 and total T4 levels decreased in the DGX+APA group, but remained unaltered in the DGX+placebo group (free T4 after: 16.53 vs 13.87 pmol/L, p&amp;lt;0.0001 and total T4 after: 8.77 vs. 7.78 µg/dL, p 0.0055). Total T3 and free T3 increased in the DGX+APA group, and again did not differ after treatment in the DGX+placebo group. (free T3 after: 5.03 vs 5.41 pmol/L, p 0.0066 and total T3 after: 132.30 vs 149.50 ng/dL, p 0.0003). As a result, the total and free T3/T4 ratio increased in the DGX+APA group with 32% and 35%, respectively. Reverse T3 decreased in both treatment arms, but greater in the DGX+APA group (19.55 vs 14.20 ng/dL, p 0.0157). Thyroxine binding globulin (TBG) increased in both treatment arms, with 6.9% and 8.4%, respectively. In conclusion, interference with androgen signaling alters thyroid homeostasis in PC patients, and is most pronounced under deep androgen suppression with combined GnRH-antagonist and ARSI therapy. The increase in T3 and decrease in rT3 may indicate additional effects of ARSI on deiodinase activity. Longer follow-up trials are needed to confirm these findings and assess the clinical implications of these changes in thyroid homeostasis. Presentation: Friday, June 16, 2023

Surgery with or Without Darolutamide in High-risk and/or Locally Advanced Prostate Cancer: The SUGAR (CCAFU-PR2) Phase 2 Trial Rationale and Protocol

BackgroundHigh-risk prostate cancer (PCa) patients frequently experience recurrence and progression after radical prostatectomy (RP). Neoadjuvant androgen deprivation therapy (ADT) has not demonstrated a clear oncological benefit and is not currently recommended. ObjectiveThe SUGAR trial is the first phase 2, randomised, controlled, multicentre, noncommercial, open-label study investigating single-agent perioperative darolutamide compared with the standard of care (ie, upfront RP, without neoadjuvant ADT). Design, setting, and participantsSUGAR aims to randomise 240 men affected by nonmetastatic PCa, with the major eligibility criteria being International Society of Urological Pathology grade group ≥4, seminal vesicle invasion at magnetic resonance imaging and/or clinically node-positive disease. Patients in the experimental arm will undergo neoadjuvant darolutamide monotherapy, RP, and adjuvant darolutamide, completing 9 mo of treatment. Outcome measurements and statistical analysisThe primary endpoint is noncurable recurrence-free survival, an innovative and clinically meaningful measure; the secondary endpoints encompass safety; recurrence-free, metastasis-free, and overall survival; pathological response; and quality of life. A predictive biomarker analysis will also be performed. Results and limitationsInitial data suggest that intensified neoadjuvant treatment with androgen receptor signalling inhibitors (ARSIs) is associated with a sustained pathological response and may improve outcomes, via tumour downstaging and micrometastasis eradication. ARSI monotherapy could further enhance tolerability. ConclusionsSUGAR will provide efficacy and safety information on perioperative darolutamide monotherapy compared with upfront RP, in a contemporary high-risk PCa population undergoing surgery. Patient summaryThe on-going SUGAR clinical trial evaluates 9 mo of darolutamide treatment in addition to radical prostatectomy, in men affected by prostate cancer with specific high-risk characteristics. It investigates whether this hormonal treatment can lower the rates of noncurable recurrences, maintaining a favourable tolerability profile.

Disease and Toxicity Outcomes after Salvage Radiotherapy (SRT) for Biochemically Recurrent Prostate Cancer (PC) for Patients Enrolled in a Phase II, Open Label Trial Investigating Neoadjuvant Chemohormonal Therapy Followed by Radical Prostatectomy (RP)

Men with metastatic hormone sensitive prostate cancer have improved progression free and overall survival (PFS/OS) when treated with docetaxel and androgen deprivation therapy (ADT). Our institution conducted a phase II trial (UW17009) investigating the addition of three cycles of neoadjuvant docetaxel and ADT to RP in men with high-risk prostate cancer. Here we report toxicity and freedom from biochemical recurrence (FFBCR) for patients treated with SRT following participation in this trial. Between January 17, 2018 and August 10, 2021, 28 patients enrolled on UW17009. Patients who had a recurrence and received SRT were identified. Toxicity was assessed using modified LENT (Late Effects of Normal Tissues)/RTOG (Radiation Therapy Oncology Group) criteria, and time to recurrence following SRT was determined for each patient. Additionally, the months of ADT received by each patient was recorded. FFBCR was then determined for this cohort using the method of Kaplan and Meier. Of 28 patients enrolled on UW17009, 20 (71%) had BCR after RP. Of these, 19 received SRT, representing 68% of the patients enrolled on the trial. The rates of acute grade 1 and grade 2 GU toxicity with SRT were 37% (7) and 53% (10), respectively. The rates of acute grade 1 and grade 2 GI toxicity with SRT were 32% (6) and 37% (7), respectively. On patient experienced a grade 4 genitourinary toxicity during SRT. There were no acute grade 3 or grade 5 toxicities. The rates of late grade 1 and grade 2 GU toxicity were 16% (3) and 11% (2), respectively. The rates of late grade 1 and grade 2 GI toxicity were 11% (2) and 5% (1), respectively. There was 1 (5%) late grade 3 GU toxicity. There were no late grade 3-5 GI toxicities, or late grade 4-5 GU toxicities. The average duration of ADT after prostatectomy was 15 months (range: 0-37 months). According to the method of Kaplan and Meier, mean FFBCR after SRT was 34.0 months at a median of 37.8 months. Median FFBCR had not yet been reached. At the time of analysis, 13 patients remained free from biochemical recurrence after SRT. Rates of biochemical recurrence and SRT following neoadjuvant docetaxel and ADT and then RP were consistent with historical data, as was the rate of successful SRT. Toxicities were also consistent with historical data, though there was notably one acute grade 4 GU toxicity.

Bothersome Hot Flashes Following Neoadjuvant Androgen Deprivation Therapy and Stereotactic Body Radiotherapy for Localized Prostate Cancer

Androgen deprivation therapy (ADT) may improve cancer control in unfavorable localized prostate cancer treated with stereotactic body radiotherapy (SBRT). ADT is known to cause hormonally related symptoms that resolve with testosterone recovery. Hot flashes are particularly burdensome. This study sought to evaluate the timeline of hot flashes following short-course ADT and SBRT as well as its relationship with testosterone recovery. Institutional IRB approval was obtained for this retrospective review of prospectively collected data (IRB#: 2009-510). ADT was initiated three months prior to the start of SBRT. Hot flashes were self-reported via question 13a a healthcare software prior to ADT initiation, the first day of robotic SBRT, and at each follow-up (1, 3, 6, 9, 12, 18, 24 and 36 months). The responses were grouped into three relevant categories (no problem, very small-small problem and moderate-big problem). Scores were transformed to a 0-100 scale with higher scores reflecting less bother. Testosterone levels were measured at each follow-up. From 2007 to 2010, 122 localized prostate cancer patients (9 low-, 64 intermediate-, and 49 high-risk according to the D'Amico classification) at a median age of 72 years (range 54.5-88.3) were treated with short course ADT (3-6 months) and SBRT (35-36.25 Gy) at Georgetown University Hospital. Thirty-two percent were black and 27% were obese. 77% of patient received three months of ADT. At baseline, 2% of men experienced hot flashes that were a "moderate to big problem" and that proportion peaked at the start of SBRT (45%) before returning to baseline 9 months post-SBRT with a cumulative incidence of 52.4%. The median baseline healthcare software hot flash score of 94 declined to 50 at the start of SBRT but this returned to baseline by six months post SBRT. These changes were both statistically and clinically significant (MID = 9.5083). Testosterone recovery (> 230 ng/dL) occurred in approximately 70% of patients by 12 months post SBRT. Resolution of hot flashes correlated with testosterone recovery. Bothersome hot flashes occur in greater than 50% of men treated with neoadjuvant ADT. Resolution of hot flashes occurs in the majority of patients within one year after treatment. Reassurance of the temporary nature of hot flashes may assist in reducing patient anxiety. Measuring testosterone levels at follow-up visits may allow for anticipatory counseling that may limit the associated bother.

Bothersome Gynecomastia Following Neoadjuvant GnRH Agonists and Stereotactic Body Radiotherapy for Localized Prostate Cancer

Androgen deprivation therapy (ADT) is increasingly utilized in combination with stereotactic body radiotherapy (SBRT) for unfavorable prostate cancer. ADT such as gonadotropin releasing hormone (GnRH) agonists are known to cause hormonal-related side effects such as gynecomastia. The incidence of bothersome breast tenderness and/or enlargement following short course GnRH agonists and SBRT is unknown. This study sought to evaluate the timeline of gynecomastia as well as its relationship with testosterone recovery. Gynecomastia was self-reported via question 13b of a healthcare software prior to ADT initiation, the first day of robotic SBRT, and at each follow-up (1, 3, 6, 9, 12, 18, 24 and 36 months). The responses were grouped into three relevant categories (no problem, very small-small problem, and moderate-big problem). Scores were transformed to a 0-100 scale with higher scores reflecting less bother. Testosterone levels were measured at each follow-up. From 2007 to 2010, 122 localized prostate cancer patients (9 low-, 64 intermediate-, and 49 high-risk according to the D'Amico classification) at a median age of 72 years (range 54.5-88.3) were treated with short course ADT (3-6 months) and SBRT (35-36.25 Gy) at Georgetown University Hospital. Of the participants, 48% percent were non-white and 48% were overweight. 77% of patients received three months of ADT. At baseline, 2% of men experienced gynecomastia that was a "moderate to big problem" and that proportion peaked at 3 and 12 months post-SBRT (7%) before returning to less than baseline (0%) 24 months post-SBRT with a cumulative incidence of 14.75%. The median baseline healthcare software hot flash score of 98 declined to 90 at 3 months post-SBRT but this returned to baseline by 24 months post SBRT. These changes were both statistically and clinically significant (MID = 6.5). Testosterone recovery (> 230 ng/dL) occurred in approximately 70% of patients by 12 months post SBRT. The development and resolution of gynecomastia fluctuated at various timepoints and did not directly correlate with testosterone recovery. Bothersome gynecomastia occurs in less than 15% of men treated with neoadjuvant ADT. Resolution of gynecomastia occurs in most patients within two years after treatment. Reassurance of the temporary nature of gynecomastia may assist in reducing patient anxiety. Institutional IRB (IRB#: 2009-510) approval was obtained for retrospective review of prospectively collected data.

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.

Clinical Significance of Radical Prostatectomy in Clinical Lymph Node Metastasis in Prostate Cancer.

This study aimed to investigate the role of radical prostatectomy (RP) among clinical nodal metastasis prostate cancer and whether histological confirmation of lymph node metastasis through surgery can help with treatment. After excluding patients with distant metastatic prostate cancer or neoadjuvant androgen deprivation therapy, 42 patients with clinical nodal metastasis who underwent RP at our institution were included in the study. We classified them as having or not having pathological lymph node metastasis. Clinicopathologic data were analyzed in this retrospective chart review. Kaplan-Meier analysis was used to calculate the estimated castration-resistant prostate cancer (CRPC)-free survival, biochemical recurrence (BCR)-free survival, and cancer-specific survival (CSS). There is no significant difference in age, presence of diabetes mellitus, hypertension, BCR time, CRPC time, overall survival, salvage RT rate, and initial prostate-specific antigen level between the two groups. However, there is a significant difference in the pathology N1 group in terms of pathological T stage, pathologic Gleason score, BCR rate, CRPC rate, and CSS. A multivariate Cox proportional hazard regression analysis was used to identify predictors of CRPC-free survival. Patients with pathological lymph node metastasis had a shorter CRPC-free survival [hazard ratio (HR) 4.87; 95% confidence interval (CI) 1.25-19.00, p = 0.02]. Radical prostatectomy can confirm lymph node metastasis. Although pathologic diagnosis has no effect on time to BCR and CPRC, because it affects BCR rate, CRPC rate, and CSS, an accurate pathological diagnosis obtained through surgery is beneficial in the treatment of clinical lymph node metastasis prostate cancer.

Testosterone as a Biomarker for Quality of Life (QOL) Following Androgen Deprivation Therapy (ADT) and Stereotactic Body Radiotherapy (SBRT).

Androgen deprivation therapy (ADT) causes fatigue and sexual dysfunction. The time to testosterone recovery depends on patient and treatment-specific characteristics. The kinetics of testosterone recovery in men treated with neoadjuvant ADT and stereotactic body radiotherapy (SBRT) is not well established. This study seeks to characterize testosterone recovery and evaluate its relationship with the improvement in patient-reported hormonal and sexual function. Institutional review board (IRB) approval was obtained for retrospective review of prospectively collected data. All patients with localized prostate cancer treated with short-course ADT (3-6 months of Leuprolide) and robotic SBRT (35-36.25 Gy in five fractions) at a single institution were included in this analysis.Testosterone levels were measured at the start of radiation, every 3 months for the first year, and every 6 months thereafter. Total testosterone recovery was defined as a serum level of >230 ng/dL. Sexual and hormonal function was recorded using the Expanded Prostate Index Composite (EPIC)-26 prior to ADT initiation, the first day of SBRT, and at each follow-up. The EPIC-26 subdomain scores were transformed to a 0-100 scale with higher scores reflecting less bother. Between January 2009 and May 2018, 122 men with a median age of 72 years (range: 55-89 years) received ADT followed by SBRT. Thirty-two percent(N=39) were black and 27% [N=39 were obese (BMI > 30)]. The median pre-SBRT testosterone level was 15 ng/dL (range: 3-89 ng/dL). Around 77% (N=94) of patients received 3 months of ADT. The median pre-ADT EPIC-26 Hormone and Sexual Domain Scores were 94 and 41, respectively. At 12 months, 71% (N=87) of patients recovered to a eugonadal state with a mean recovery time of 4 months post-SBRT. Hormonal and sexual subdomain scores declined significantly following ADT but recovered to within the minimally important difference (MID) for sexual and hormonal domain scores by 12 months post-SBRT. Testosterone recovery following short-course ADTwith leuprolide and SBRT occurs rapidly in the majority of patients within one year after treatment. Quality of life domain improvements followed the testosterone recovery trend closely. Testosterone testing at follow-up appointments would allow for anticipatory counseling that may limit the bother associated with temporary quality of life decrements.

Prostate Region-Wise Imaging Biomarker Profiles for Risk Stratification and Biochemical Recurrence Prediction.

Identifying prostate cancer (PCa) patients with a worse prognosis and a higher risk of biochemical recurrence (BCR) is essential to guide treatment choices. Here, we aimed to identify possible imaging biomarker (perfusion/diffusion + radiomic features) profiles extracted from MRIs that were able to discriminate patients according to their risk or the occurrence of BCR 10 years after diagnosis, as well as to evaluate their predictive value with or without clinical data. Patients with localized PCa receiving neoadjuvant androgen deprivation therapy and radiotherapy were retrospectively evaluated. Imaging features were extracted from MRIs for each prostate region or for the whole gland. Univariate and multivariate analyses were conducted. 128 patients (mean [range] age, 71 [50-83] years) were included. Prostate region-wise imaging biomarker profiles mainly composed of radiomic features allowed discriminating risk groups and patients experiencing BCR. Heterogeneity-related radiomic features were increased in patients with worse prognosis and with BCR. Overall, imaging biomarkers profiles retained good predictive ability (AUC values superior to 0.725 in most cases), which generally improved when clinical data were included (particularly evident for the prediction of the BCR, with AUC values ranging from 0.841 to 0.877 for combined models and sensitivity values above 0.960) and when models were built per prostate region vs. the whole gland. Prostate region-aware imaging profiles enable identification of patients with worse prognosis and with a higher risk of BCR, retaining higher predictive values when combined with clinical variables.

The Association Between Low Preoperative Serum Testosterone and Post-radical Prostatectomy Urinary Function

To determine if hypogonadism leads to delayed urinary function recovery post-radical prostatectomy (RP) by studying the effect of preoperative factors including age, membranous urethral length, radiation therapy, and Body Mass Index on urinary continence in patients with or without hypogonadism. We identified 1209 patients treated by RP with both pretreatment T and post-treatment urinary outcome. We assessed whether there was an association between low preoperative T level (prenoon T≤300ng/dL) and continence (using ≤1 pad/d) at 6 and 12months post-RP. Patient-reported continence was used when available, otherwise, surgeon-assessed continence was used. Logistic regression models were used, adjusted for age at RP and nerve-sparing status. Median age at RP was 61 (Intraquatile Range (IQR) 56, 66), 92% of patients had at least one nerve spared and 99% were continent at baseline. Continence in patients with low T was nonsignificantly lower at 6months (odds ratio 0.69, 95% confidence interval 0.44, 1.06; P=.10) and nonsignificantly higher at 12months (odds ratio 1.07, 95% confidence interval 0.71, 1.58; P=.8). Sensitivity analyses excluding patients with preoperative metastasis or treated with androgen deprivation therapy (ADT) and including testosterone as a continuous predictor were consistent with the primary analysis; similarly finding no evidence of an association. Although we cannot rule out an effect on early continence, overall the evidence does not suggest that low serum testosterone adversely impacts urinary function recovery after RP. This finding can be used to counsel patients enrolled in neoadjuvant ADT trials or those patients undergoing RP who have had prior ADT, such as in the setting of oligometastatic disease.

The significance of metabolic response to neoadjuvant androgen deprivation therapy detected with [68Ga]Ga-PSMA-11-PET/CT in high-risk prostate cancer patients treated with definitive radiotherapy.

We examined the prognostic significance of early changes in primary tumor SUV measured with Gallium-68-labeled prostate-specific membrane antigen positron emission tomography ([68Ga]Ga-PSMA-11-PET/CT) and serum PSA values after neoadjuvant androgen deprivation treatment (nADT) in high-risk prostate cancer (PCa) patients treated with definitive radiotherapy (RT). The clinical data and SUV parameters of 71 PCa patients were reviewed retrospectively. The serum PSA and primary tumor SUV values were calculated before and after the start of ADT. Using univariable and multivariable analyses, the prognostic factors predicting biochemical disease free survival (bDFS) and prostate cancer specific survival (PCSS) were investigated. In addition, logistic regression analysis was used to identify predictors of biochemical failure (BF). All but one patient responded with a 98.8% reduction in serum PSA (21.8ng/mL vs. 0.3ng/mL; p < 0.001), and 64 patients (91.1%) had a median 66.6% decrease in primary tumor SUV after ADT (13.2 vs. 4.8, p < 0.001). The primary tumor SUV response rate was significantly higher in patients with Gleason score (GS) of 7 than in patients with GS > 7 (59.5% vs. 40.5%; p = 0.04), and it was significantly lower in patients with inadequate treatment response than in those with complete (CR) or partial response (PR) (1.1% vs. 66.1%; p < 0.001). There was a strong and significant correlation (Spearman = 0.41, p < 0.001) and a high concordance (91.5%) between PSA response and SUV response after ADT. With a median follow-up time of 76.1months, the 5-year bDFS and PCSS rates were 77.2% and 92.2%, respectively. Nineteen patients (26.7%) patients had recurrence at a median of 44.6months after the completion of RT. In multivariate analysis, lymph node metastasis, GS greater than 7, and SD/PD after nADT were independent predictors of worse bDFS. However, no significant factor for PCSS was identified. In the multivariable logistic regression analysis, advanced age, GS of  > 7 disease, lymph node metastasis, and SD or PD after nADT were independent predictors of BF. These results imply that the metabolic response measured with [68Ga]Ga-PSMA-11-PET/CT after nADT could be used to predict progression in high-risk PCa patients treated with definitive RT.