High-risk Localized Prostate Cancer Research Articles

Neoadjuvant treatment with androgen receptor signaling inhibitors prior to radical prostatectomy: a systematic review.

There is an urgent need to develop novel treatment strategies in patients with unfavorable intermediate- and high-risk localized prostate cancer (PCa) to optimize the outcome of these patients. Androgen receptor signaling inhibitors (ARSI) have demonstrated a survival benefit in metastatic hormonesensitive and castration-resistant PCa. A similar benefit might be expected in the localized setting. To perform a systematic review about the role of neoadjuvant ARSI in unfavorable intermediate and high-risk localized PCa. We performed a systematic review of the following databases: MEDLINE (PubMed), EMBASE, Cochrane Library and Web of Science. Publications of ASCO were consulted to identify meeting abstract with early results of ongoing trials. This systematic review was performed and reported in accordance with the PRISMA guidelines. Pathological complete response (pCR) following neoadjuvant ARSI treatment was observed in 4%-13% of the patients. Minimal residual disease response ranged from 36% to 73.9% when defined as residual cancer burden < 0.25cm3 at final pathology and from 8% to 20% when defined as the diameter of the remaining tumor < 5mm. Despite intense neoadjuvant ARSI treatment, residual pT3 disease was observed in 48%-76% of the patients. In contrast, positive surgical margins (PSM) were present in only 5%-22%. Only one trial reported BCR following neoadjuvant ARSI therapy (44% BCR at a median follow-up of 4years). Despite intense neoadjuvant ARSI therapy, pCR is rarely attained and high proportions of pT3 disease are still observed at final pathology. In contrast, promising results are obtained in terms of PSMs. Long-term survival outcomes are eagerly awaited.

The role of surgery in high risk and advanced prostate cancer: A narrative review.

Patients with high-risk and advanced prostate cancer require safe and efficacious therapies likely to offer a survival advantage while minimizing the treatment-related toxicities. Improvements in the surgical technology, diagnostic modalities, radiological staging, and risk stratification have made surgery for high-risk and advanced prostate cancer a safe and feasible option. In this review, we outline the role of radical prostatectomy in high-risk localized, locally advanced, and metastatic prostate cancer. We overview available data evaluating the use of surgery in the context of a multi-modal approach and highlight ongoing trials in this area. Furthermore, the role of surgery as a non-systemic modality for metastasis-directed therapy (MDT) is also described. Emerging imaging modalities enabling more accurate staging and longer follow-up of clinical trials for prognostic endpoints are anticipated to help identify patient cohorts and treatment strategies, where the use of surgical treatments is likely to provide oncological benefits and acceptable toxicity.

Outcomes of Post-Neoadjuvant Intense Hormone Therapy and Surgery for High Risk Localized Prostate Cancer: Results of a Pooled Analysis of Contemporary Clinical Trials.

We report on the post-radical prostatectomy outcomes of patients enrolled in 3 randomized, multicenter, clinical trials of intense neoadjuvant androgen deprivation therapy prior radical prostatectomy. All patients included were enrolled in trials evaluating intense androgen deprivation therapy followed by radical prostatectomy. The primary end point was time to biochemical recurrence, defined as the time from radical prostatectomy to prostate specific antigen >0.1 ng/ml or start of first post-radical prostatectomy therapy, stratified by pathological response at radical prostatectomy (presence or absence of exceptional pathological response defined as residual tumor at radical prostatectomy measuring 0-5 mm). Secondary end points included metastasis-free survival, overall survival, and time to testosterone recovery. Overall, 117 patients were included in the analysis, of whom 78.6% (92) had high risk disease. Following neoadjuvant therapy, 21.4% (25) had 0-5 mm of residual tumor, including 9.4% (11) with a pathological complete response. Overall, 49 patients (41.9%) experienced biochemical recurrence and the 3-year biochemical recurrence-free rate was 59.1% (95% CI 49.0-67.9). Of the 25 patients with an exceptional pathological response, 2 patients (8.0%) developed biochemical recurrence while 51.1% of nonresponders (47/92) developed biochemical recurrence. Testosterone recovery was observed in 93.8% of patients (106/113). PTEN loss and intraductal carcinoma were associated with shorter time to biochemical recurrence. In this pooled analysis of prospective trials, we demonstrate that exceptional pathological response following neoadjuvant therapy is associated with a favorable impact on biochemical recurrence. PTEN loss and intraductal carcinoma were associated with biochemical recurrence. Additional followup is warranted to evaluate the impact on long-term outcomes.

Oncologic outcome of radical prostatectomy versus radiotherapy as primary treatment for high and very high risk localized prostate cancer.

To compare the oncologic outcomes of radical prostatectomy (RP) versus external beam radiotherapy (EBRT) ± androgen deprivation therapy for primary treatment of high risk localized prostate cancer (CaP). We retrospectively reviewed a prospectively-populated database for cases who underwent primary treatment for high risk localized CaP, had more than 2 years follow-up, and were treated since 2006. A total of 335 cases were studied of whom 291 underwent RP and 44 underwent EBRT. Clinical characteristics, biochemical progression-free survival (BPFS), metastasis-free survival (MFS), cancer-specific survival (CSS) and overall survival (OS) were compared. EBRT cases were older (p < .01; mean 71 years vs. 61 years) and had longer PSA doubling time (PSADT) (p = .03; median 4.8 years vs. 3.5 years) than RP. Race, pretreatment PSA and biopsy Gleason score were similar. Median follow-up was 5.1 (range: 2.3-12.8) years for RP versus 3.3 (range: 2-12.4) years for EBRT. Three- and 5-year BPFS were 42% and 36% after RP versus 86% and 75% after EBRT (p < .01). The rate of adjuvant/salvage therapy was 58% after RP versus 20% after EBRT (p < .01). Three- and 5-year MFS were 80% and 77% after RP versus 91% and 91% after EBRT (p = .11). Three-year CSS was 98% in both groups and OS was 97% after RP versus 94% after EBRT (p = .73). RP had higher rates of biochemical failure and adjuvant or salvage treatment versus EBRT in high risk localized CaP. MFS trended toward benefit after EBRT, but CSS and OS remained high in both groups.

Five-year quality of life in patients with high-risk localized prostate cancer treated with external beam radiotherapy alone versus external beam radiotherapy with high-dose-rate brachytherapy boost: a prospective multicenter study.

PurposeBrachytherapy (BT) and external beam radiation therapy (EBRT) are effective treatments for high-risk prostate cancer (PCa). However, the impact of these treatments on health-related quality of life (HRQL) remains unclear. In this study, we compared EBRT alone with EBRT plus a boost with high-dose rate (HDR)-BT to determine the impact on HRQL in patients with high-risk PCa.Material and methodsProspective, multicenter study comparing patients with high-risk PCa treated with EBRT alone or EBRT + HDR-BT from 2004 to 2006. HRQL was assessed at baseline (pre-treatment) and periodically over the 5-year follow-up, using the SF-36 (v.2), EPIC, and FACT-G and FACT-P questionnaires.ResultsA total of 129 patients were included in the study, of these, 41 received EBRT alone and 88 EBRT + HDR-BT. All patients received hormonotherapy. Baseline clinical characteristics were similar, except for a slightly higher mean number of comorbidities in the EBRT group. During follow-up, the only significant between-group difference was a greater worsening on EPIC hormonal domain in the EBRT alone group (p = 0.028). There were no significant differences in time and interaction of treatment in SF-36, and FACT-G and FACT-P questionnaires or EPIC urinary incontinence, urinary irritative-obstructive, and bowel and sexual domains over the 5-year follow-up. Oncological outcomes were similar in both groups.ConclusionsAfter five years of follow-up, EBRT alone or combined with HDR-BT boost had a similar impact on HRQL in patients with high-risk localized PCa. However, patients in the EBRT alone group experienced greater worsening of hormonal domain according to EPIC questionnaire.

Long-term results of surgical treatment in patients with high-risk localized prostate cancer

Long-term results of surgical treatment in patients with high-risk localized prostate cancer

Volumetric-Modulated Arc Radiotherapy with Daily Image-Guidance Carries Better Toxicity Profile for Higher Risk Prostate Cancer.

Purpose:To compare radiotherapy-induced toxicity for localized prostate-cancer (PCa) treated with versus without daily image-guidance. Patients and Methods:We identified consecutive intermediate and high-risk localized PCa patients treated with definitive radiotherapy using intensity-modulated radiotherapy (IMRT) with variable duration of androgen-deprivation therapy (ADT) within 2015-2016 (Arm-A) and 2005-2007 (Arm-B). Arm-A cases received daily online imaging guidance (IGRT) using cone-beam computed tomography (CBCT) unlike Arm-B candidates with no daily IGRT. After reporting demographic, clinico-pathological features and treatment details, we compared acute (within 3 months post-therapy) and late RT-induced toxicities between study groups graded by RTOG/CTCAE criteria. Uni/multivariate analyses (UVA/MVA) were performed to identify independent predictors for RT-related side-effects. Results:We were able to identify 257 cases who met our inclusion criteria. Overall, median age was 73 years (48-85), 67% had intermediate-risk and 47% received ADT. Arm-A included 72 patients who received IMRT delivered using volumetric-modulated arc therapy (VMAT), whereas, Arm-B was formed of 185 cases who utilized step-and-shoot static IMRT. Clinico-pathological features and treatment details were non-different across study arms except that Arm-A had more Grade Group 3, higher median total dose (79.2 vs. 74 Gy) and more pelvic lymph-nodes RT (P<0.05). Although acute toxicity was similar across groups, Arm-B encountered higher late toxicity score, more intense late genitourinary side-effects (P=0.008), with non-different late lower-gastrointestinal toxicities. On MVA, lack of daily CBCT, African-American race and higher comorbidities were independently predictive for late toxicities. Conclusion:IMRT with daily CBCT permitted safe delivery of dose-escalated IMRT with improved toxicity profile for higher-risk prostate cancer.

Impact of Androgen Deprivation Therapy Associated to Conformal Radiotherapy in the Treatment of D'Amico Intermediate-/High-Risk Prostate Cancer in Older Patients.

Simple SummaryAndrogen Deprivation Therapy (ADT) combined with radiotherapy is recommended for a duration of 6 months in unfavorable D’Amico intermediate-risk (IR) prostate cancer and a duration of 18 to 36 months in D’Amico high-risk (HR) prostate cancer. However, as patients ≥80 years are excluded from phase III trials combining radiotherapy and ADT, there is no consensus in this population regarding the combination of these treatments. So, we aimed to report the oncological results and morbidity radiotherapy +ADT in 101 ≥ 80 years patients with IR/HR localized prostate cancers in Marseille University Hospital. The tolerance of ADT in association to radiotherapy was acceptable in this study. There was no increase in the incidence of cardiovascular events compared to the general population, whatever the duration of ADT. The absence of significant difference in biochemical recurrence-free survival or distant metastasis-free survival between 6 and 15 months of ADT in the HR group of patients raise the question of the optimal duration of ADT in this older population. However cardio-vascular evaluation and surveillance are mandatory, especially for men over 82 years old.Purpose/objective: The association of 3D Conformal External Beam Radiotherapy (3D-CEBRT) with adjuvant Androgen Deprivation Therapy (ADT) proved to treat patients with intermediate- and high-risk localized prostate cancer (IR and HR). However, older patients were underrepresented in literature. We aimed to report the oncological results and morbidity 3D-CEBRT +ADT in ≥80 years patients. Material and Methods: From June 1998 to July 2017, 101 patients ≥80 years were included in a tertiary center. The median age was 82 years. ADT was initiated 3 months prior 3D-CEBRT in all patients, with a total duration of 6 months for IR prostate cancer (group A; n = 41) and 15 months for HR prostate cancer (group B; n = 60). Endpoints included overall survival (OS), metastasis-free survival (DMFS), biochemical recurrence-free survival (BRFS) and toxicity. Results: Five years-OS was 95% and 86.7% in groups A and B, respectively. Cardiovascular events occurred in 22.8% of ≥80 years patients with no impact on OS. In the multivariate analysis, age <82 years, Karnofsky index and normalization of testosterone levels were significantly associated with better OS. Conclusion: Age ≥80 years should not be a limitation for the treatment of IR and HR prostate cancer patients with 3D-CEBRT and ADT, but cardiovascular monitoring and prevention are mandatory.

Robot-assisted Radical Prostatectomy Using Single-port Perineal Approach: Technique and Single-surgeon Matched-paired Comparative Outcomes

BackgroundRadical perineal prostatectomy (RPP) has been revived with the advent of single-port (SP) robotic surgery. However, its interest and precise role need to be evaluated and better defined. ObjectiveTo describe in detail the technique of SP-RPP and compare initial perioperative outcomes with those of multiport robot-assisted transperitoneal radical prostatectomy (MP-RARP). Design, setting, and participantsFrom October 2018 to June 2020, perioperative data of 26 consecutive patients who underwent SP-RPP for localized prostate cancer (PCa) in a single institution were prospectively entered into an institutional review board–approved database. Data of 86 consecutive patients treated from September 2017 to September 2018 with MP-RARP by the same surgeon, before the beginning of the SP experience, were used as comparators. Surgical procedureSP-RPP was performed using the SP robotic platform (Intuitive Surgical, Sunnyvale, CA, USA) according to the technique described in the supplementary video. MeasurementsDemographics, and intra- and postoperative data were analyzed in a matched-paired design with a 1:1 ratio on the following factors: age at surgery, prostate-specific antigen level, preoperative Gleason score, and history of abdominal surgery. Results and limitationsAfter matching, baseline characteristics were comparable except for the rate of prior laparotomy, which was higher in the SP-RPP group (52% vs 8%, p < 0.001). In the SP-RPP group, 84% of the patients had a high risk and an unfavorable intermediate risk of positive surgical margins (PSMs) versus 57% in the MP-RARP group (p = 0.03). While the rate of nonlimited PSMs (ie, >3 mm) was higher in the SP-RPP group (38.5% vs 7.7%, p < 0.01), the number of patients with biochemical recurrence at 1 yr was comparable between SP-RPP and MP-RARP (1 vs 3, p = 0.3). ConclusionsSP-RPP is a complex procedure for patients with a complex surgical history and high-risk localized PCa with limited alternative therapeutic options. Patient summaryOur study suggests that patients with high-risk localized prostate cancer and limited treatment options due to a complex abdominal surgical history (ie, frozen pelvis) may be suitable candidates for single-port radical perineal prostatectomy.

Combination of Radiation Therapy and Short-Term Androgen Blockade With Abiraterone Acetate Plus Prednisone for Men With High- and Intermediate-Risk Localized Prostate Cancer

Long-term androgen-deprivation therapy (ADT) is the standard of care in combination with radiation therapy (RT) in high-risk prostate cancer (PC), despite substantial toxicity from the resulting hypogonadism. We hypothesized that a combination of more potent but shorter-term androgen inhibition in men with intermediate- or high-risk localized PC would synergize with definitive RT to provide short-term testosterone recovery and improve disease control. This prospective phase 2 single-arm trial enrolled men with low-volume unfavorable intermediate or high-risk localized PC. Treatment included 6 months of ADT concurrent with abiraterone acetate plus prednisone (AAP) once daily and RT to prostate and seminal vesicles. The primary endpoint was the proportion of men with an undetectable prostate-specific antigen (PSA) at 12-months; secondary objectives included biochemical progression-free survival (PFS), testosterone recovery, toxicity, and sexual and hormonal quality of life. We enrolled 37 men between January 2014 and August 2016, 45% of whom were high risk. All patients had T1-2 disease and PSA < 20 ng/mL. Median follow-up is 37 months (95% confidence interval [CI], 35.7-39.1). Treatment noted 32% grade 3 toxicities related to AAP, predominantly hypertension, with no toxicities ≥G4. The rate of undetectable PSA at 12 months was 55% (95% CI, 36%-72%). With 46 months of median follow-up, 2 of 37 patients developed PSA progression (36-month PFS = 96%; 95% CI, 76%-99%), and 81% of patients recovered testosterone with a median time to recovery of 9.2 months. Hormonal or sexual function declined at 6 months with subsequent improvement by 24 months. The combination of RT and 6 months of ADT and AAP demonstrated acceptable toxicity and a high rate of testosterone recovery with restoration of quality of life and excellent disease control in men with low-volume, intermediate- or high-risk localized prostate cancer. Prospective comparative studies are justified.

Can 68Ga-PSMA-11 Positron Emission Tomography/Computerized Tomography Predict Pathological Response of Primary Prostate Cancer to Neoadjuvant Androgen Deprivation Therapy? A Pilot Study.

We explored the role of 68Ga-PSMA-11 positron emission/computerized tomography as a predictor of pathological response to neoadjuvant androgen deprivation therapy combined with abiraterone for high risk prostate cancer. A total of 45 patients with localized high risk prostate cancer who had serial 68Ga-PSMA-11 positron emission tomography/computerized tomography scans before and after 6 months of androgen deprivation therapy plus abiraterone neoadjuvant treatment followed by radical prostatectomy were included in this study. Complete pathological response or minimal residual disease <5 mm on whole mount histopathology was defined as favorable pathological response. The diagnostic performance of prostate specific antigen response and positron emission tomography/computerized tomography response for favorable pathological response was calculated. Univariable and multivariable logistic regression analyses of clinical and imaging variables were also performed to identify favorable pathological response. Compared to the prostate specific antigen response, positron emission tomography/computerized tomography response had a significantly higher specificity in diagnosing favorable pathological response (89.7% vs 62.1%, p=0.043). Preoperative nadir prostate specific antigen (OR 0.121, 95% CI 0.028-0.529, p=0.005), posttreatment maximum standardized uptake value (OR 7.072, 95% CI 2.035-24.579, p=0.002) and posttreatment tumor volume (OR 7.896, 95% CI 1.415-44.054, p=0.018) measured on positron emission tomography/computerized tomography were significantly associated with favorable pathological response in univariable logistic regression analysis. On multivariable logistic regression analysis, only posttreatment maximum standardized uptake value was found to be an independent predictor of favorable pathological response (OR 9.69, 95% CI 1.439-65.242, p=0.020). 68Ga-PSMA positron emission tomography/computerized tomography has a better diagnostic performance of pathological response to neoadjuvant treatment compared with prostate specific antigen, with maximum standardized uptake value being an independent predictive factor. This pilot study suggests that prostate specific membrane antigen positron emission tomography/computerized tomography may serve as a potential predictor of pathological response to neoadjuvant treatment.

Immune profiling of the bone marrow microenvironment in patients with high-risk localized prostate cancer.

Bone marrow (BM) is a primary metastatic site in prostate cancer (PC) and bone invasion is considered incurable. T cell-mediated immune surveillance is essential in controlling both tumorigenesis and initiation of metastases. Beside tropism, dissemination of PC cells to the BM may be facilitated by defects in BM immune homeostasis predisposing this niche to colonization.To evaluate the BM immune microenvironment in locally advanced, non-metastatic PC, we performed flow cytometry analysis of myeloid and lymphoid subsets in BM aspirates and peripheral blood collected during prostatectomy. Healthy BM aspirates served to establish a reference range for comparison.We found alterations in BM immune composition of PC patients, including an increased CD4/CD8 ratio, enrichment of CD4+ T cells, increased CD56+CD3+ NKT and CD56+CD3- NK yields compared to healthy controls. The lymphoid phenotype remained comparable regarding T cell activation and chemokine receptor-based polarization patterns. Additionally, we found increased B7H3 expression in the myeloid monocyte/macrophage subset and decreased DC infiltration in BM of PC patients.These findings suggest that alterations in the immune milieu may limit immune surveillance that compromise the ability of the BM microenvironment to prevent tumor dissemination, and predispose development of bone metastases in a subset of patients with localized PC.

Cancer treatment delays caused by the COVID-19 pandemic may not hinder outcomes.

Cancer treatment delays caused by the COVID-19 pandemic may not hinder outcomes.

Erratum to: Oncological outcome of neoadjuvant low-dose estramustine plus LHRH agonist/antagonist followed by extended radical prostatectomy for Japanese patients with high-risk localized prostate cancer: a prospective single-arm study.

Background Patients with advanced high-risk prostate cancer (PCa) are prone to have worse pathological diagnoses of positive surgical margins and/or lymph node invasion, resulting in early biochemical recurrence (BCR) despite having undergone radical prostatectomy (RP). Therefore, it is controversial whether patients with high-risk PCa should undergo RP. The purpose of this study was to evaluate the efficacy of neoadjuvant chemohormonal therapy (NAC) followed by RP. Methods A total of 87 patients with high-risk PCa prospectively underwent extended RP after NAC; most of the patients underwent 6 months of estramustine phosphate (EMP) 140 mg twice daily, along with a luteinizing hormone-releasing hormone agonist/antagonist. We developed our surgical technique to reduce the rate of positive surgical margins. We aimed to approach the muscle layer of the rectum by dissecting the mesorectal fascia and continuing the dissection through the mesorectum until the muscle layer of the rectum was exposed. Results More than 1 year had elapsed after surgery in all 86 patients, with a median follow-up period of 37.7 months. The 3-year BCR-free survival was 74.9%. Multivariate Cox-regression analysis revealed that a positive core ratio of 50% or greater and pathological stage of pT3 or greater were independent predictors for BCR. About 17 of 23 cases received salvage androgen deprivation therapy and concurrent external beam radiotherapy, and showed no progression after the salvage therapies. Conclusions NAC concordant with extended RP is feasible and might provide good cancer control for patients with high-risk PCa.

PD-0058: Duration of Androgen Deprivation Therapy based on Nadir PSA in High Risk Localized Prostate Cancer

PD-0058: Duration of Androgen Deprivation Therapy based on Nadir PSA in High Risk Localized Prostate Cancer

PO-1196: long term results with moderately hypofractionated RT in high-risk localized prostate cancer.

PO-1196: long term results with moderately hypofractionated RT in high-risk localized prostate cancer.

Reduced Cardiorespiratory Fitness and Increased Cardiovascular Mortality After Prolonged Androgen Deprivation Therapy for Prostate Cancer

BackgroundProlonged androgen deprivation therapy (ADT) is favored over short-term use in patients with localized high-risk prostate cancer (PC). ObjectivesThis study sought to compare cardiorespiratory fitness (CRF) and cardiovascular (CV) mortality among patients with PC with and without ADT exposure and to explore how duration of ADT exposure influences CRF and CV mortality. MethodsRetrospective cohort study of patients referred for exercise treadmill testing (ETT) after a PC diagnosis. PC risk classification was based on Gleason score (GS): high risk if GS ≥8; intermediate risk if GS = 7; and low risk if GS <7. CRF was categorized by metabolic equivalents (METs): METs >8 defined as good CRF and METs ≤8 as reduced CRF. ADT exposure was categorized as short term (≤6 months) versus prolonged (>6 months). ResultsA total of 616 patients underwent an ETT a median of 4.8 years (interquartile range: 2.0, 7.9 years) after PC diagnosis. Of those, 150 patients (24.3%) received ADT prior to the ETT; 99 with short-term and 51 with prolonged exposure. 504 patients (81.8%) had ≥2 CV risk factors. Prolonged ADT was associated with reduced CRF (odds ratio [OR]: 2.71; 95% confidence interval [CI]: 1.31 to 5.61; p = 0.007) and increased CV mortality (hazard ratio [HR]: 3.87; 95% CI: 1.16 to 12.96; p = 0.028) in adjusted analyses. Although the association between short-term ADT exposure and reduced CRF was of borderline significance (OR: 1.71; 95% CI: 1.00 to 2.94; p = 0.052), there was no association with CV mortality (HR: 1.60; 95% CI: 0.51 to 5.01; p = 0.420) in adjusted Cox regression models. ConclusionsAmong patients with PC and high baseline CV risk, prolonged ADT exposure was associated with reduced CRF and increased CV mortality.

Outcomes Comparison Using PSA Cut-Off Values Of 0.1 Or 0.2 Ng/Ml At 6 Months In Localized High-Risk Prostate Cancer Treated With Androgen Deprivation Therapy And Radiotherapy: Prospective Data From A Phase III Trial

We evaluated if PSA response measured at 6 months after commencement of treatment predicts better clinical outcomes in patients with localized high-risk prostate cancer (HRPC) enrolled in a randomized trial (PCS4) and treated with androgen deprivation therapy (ADT) and radiotherapy (RT). A total of 547 patients with HRPC received ADT and RT. All patients received the same RT dose and were randomized to receive ADT for a total duration of either 18 or 36 months. ADT began 4 months before RT. Serum PSA was measured initially before ADT and then regularly during the follow-up period. Patients achieving a PSA level below the cut-off values of 0.1 or 0.2 ng/mL at 6 months were compared to those who did not reach these values. Clinical outcomes analyzed were biochemical failure (BF), prostate cancer progression (PCP), metastasis free survival (MFS) and overall survival (OS). BF and PCP were analyzed considering death as a competing event. Proportional sub distribution hazard models were used to estimate hazard ratios (HRs). HRs for MFS and OS were estimated with Cox models. Using the PSA cut-off of 0.1 ng/mL, 34.4% of patients achieved a PSA response of <0.1 at 6 months. At a median follow-up of 13.23 years, 17.0% of patients with PSA <0.1 developed BF compared to 35.9% for those with a PSA >0.1 [HR = 2.46 (1.68 to 3.61), p = <0.001]. Similarly, 8.5% of patients with PSA <0.1 developed PCP compared to 17.3% from the PSA >0.1 cohort [HR = 2.15 (1.24 to 3.71), p = 0.006]. Using the PSA cut-off of 0.2 ng/mL, fewer BF [HR = 3.12 (2.26 to 4.31), p = <0.001] and lower PCP [2.55 (1.61 to 4.02), p = <0,001] were also seen in the 58% of patients achieving a PSA <0.2 compared to those with a PSA >0.2. In multivariable Cox models, including treatment arm, baseline PSA and baseline Gleason score, association of PSA at 6 months for either cut-off remains significant for BF and PCP. None of the two PSA cut-off at 6 months was statistically associated with MFS or OS.MFS: HR for cut-off 0.1 was 0.92 (0.73 to 1.56), p = 0.457 while HR for cut-off 0.2 was 1.08 (0.86 to 1.36), p = 0.494 OS: HR for cut-off 0.1 was 0.85 (0.68-1.08), p = 0.181, while HR for cut-off 0.2 was 1.02 (0.81-1.28), p = 0.894. In a cohort of patients exclusively with HRPC treated with RT and ADT, a PSA response of <0.1 ng/ml or <0.2 ng/ml at 6 months post-ADT predicts fewer BF and lower PCP. These data suggest that patients remaining with a higher PSA after 6 months of ADT may harbor a more aggressive genetic phenotype and should be considered for trials testing new therapeutic strategies earlier on.

Association Between T-Stage and Cancer-Specific Mortality among Men with High-Risk Prostate Adenocarcinoma

Risk group stratification identifies men with high-risk prostate adenocarcinoma (Gleason 8-10, PSA > 20 ng/mL, or cT3-T4) who benefit from more intense treatment. However, many patients are classified as high-risk with only one high-risk feature. Although many trials that are the basis for 2-3 years of androgen deprivation therapy (ADT) studied patients with mostly cT3/T4 disease, PSA-detected, non-palpable T1c disease is currently the most commonly detected. We assessed whether within localized high-risk prostate cancer, survival differences existed based on T-stage. Data from men with high-risk N0M0 prostate adenocarcinoma from the 2004 to 2015 Surveillance, Epidemiology, and End Results database were used. Ten-year PCSM was estimated using Fine-Gray competing-risk regression. The independent variable of interest was clinical T-stage (cT1/2 vs. cT3/4); adjustments were made for PSA, Gleason score, treatment with radical prostatectomy (RP) and radiation (RT), and relevant demographic factors. A second analysis assessed PCSM only among men who received RP, with pathologic T-stage as co-variate (pT2 vs. pT3/4). The average of 12 prostate cancer prognostic signatures, including Decipher prostate cancer signature, compared genomic risk score by pT-stage. For 63,319 men included (median follow-up 6.4 years, median age 68 years), 56,322 (89.0%) had cT1/2, and 6,997 (11.1%) had cT3/4 disease. Ten-year PCSM for men with cT1/2 disease was 12.5%, and for men with cT3/4 disease was 17.5% (competing risk regression HR 0.55, 95CI 0.51—0.60, P<0.001). Greater PSA and greater Gleason score were associated with greater PCSM; receipt of RP, RT, being married, greater income, and later year of diagnosis were associated with lower PCSM. African American and Other race were also associated with lower PCSM. Of the 20,409 men who received radical prostatectomy, 9,953 (48.8%) had pT2 disease and 10,456 (51.2%) had pT3/4 disease. Ten-year PCSM for post-RP men with pT2 disease was 3.5%, and for men with pT3/4 disease was 11.9% (competing risk regression HR 0.29, 95CI 0.24—0.35, P<0.001). Greater PSA, Gleason score, receipt of radiation, and earlier year of diagnosis were associated with worse PCSM. Within a high-risk prospective RP cohort (n = 10,419) from the Decipher GRID registry (NCT02609269), patients with pT3/4 had significantly higher genomic risk scores than patients with pT2 (p<0.001). Men with cT1/2 disease had improved cancer-specific outcomes compared to men with cT3/4. Among men treated with RP, pT2 disease was associated with lower PCSM compared to pT3/4. Genomic risk scores validated these findings. Therefore, treatment paradigms given clinically relevant sub-classification of high-risk tumors based on size merit further study, with a focus on shorter-duration ADT among men with high-risk but T1/2 disease. As cT1c disease is most commonly diagnosed, more men with smaller tumors should be included in trials.

Trends And Disparities In The Diagnosis And Initial Management Of High-Risk Prostate Cancer In The United States

An increasing proportion of men are being diagnosed with high-risk prostate cancer. Standard of care for initial treatment of high-risk prostate cancer includes prostatectomy or radiotherapy with no randomized evidence comparing the modalities to guide decision-making. This study characterized US national trends associated with undergoing prostatectomy or radiotherapy for high-risk prostate cancer. This retrospective cohort study used data collected by the National Cancer Database (NCDB) to assess demographic, clinical and socioeconomic factors among 215,313 men diagnosed with high-risk prostate cancer from 2004 to 2016 and the trends in diagnosis rate and the use of prostatectomy or radiotherapy. Cochran-Armitage test was used to identify trends in prostatectomy or radiotherapy with time. Multivariable logistic regression was used to examine demographic and clinical factors associated with undergoing prostatectomy or radiotherapy. All tests were 2-sided and considered significant at an α level of .05. The rate of high-risk prostate cancer increased from 11.9% in 2004 to 20.4% in 2016. In total, 215,313 men diagnosed as having localized high-risk prostate cancer between 2004 and 2016 were identified. White men composed 81.2% of this cohort, whereas black men composed 16.1%. Government-issued insurance was used by 59.2% of men. More than 81.7% of men had a Charlson-Deyo Comorbidity Index score of 0 (range, 0 to ≥3, with lower numbers indicating fewer comorbidities). The proportion of men who underwent prostatectomy (a total of 76,606 men) compared to radiation therapy, androgen deprivation (ADT) alone, or no treatment, increased from 23.1% in 2004 to 40.9% in 2016 (p < .0001). The proportion of men who underwent radiotherapy as the first treatment (a total of 104,783 men) decreased from 59.7% in 2004 to 43.3% in 2016 (p < .0001). Men treated at an academic center, living in an urban area, or possessing higher incomes and those who were younger, healthier, white, or were diagnosed as having lower grade prostate cancer had higher odds of undergoing prostatectomy. This study found that rates of high-risk prostate cancer diagnosis have increased from 11.9% in 2004 to 20.4% in 2016. Prostatectomy rates for the initial treatment of high-risk prostate cancer increased by 17.8% from 2004 to 2016 and radiotherapy rates decreased by 16.4% in the same study period. Demographic, clinical and socioeconomic factors of high-risk cancer diagnosis and undergoing prostatectomy included age, race, income, Charlson-Deyo Comorbidity Index score, clinical stage and grade of disease, facility type and location, and year of diagnosis. These results are hypothesis generating; further studies evaluating potential disparities in the initial diagnosis and management of localized high-risk prostate cancer are warranted.