Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial

Background

The cornerstone of standard treatment for patients with primary bone metastatic prostate cancer (mPCa) is androgen deprivation therapy (ADT). Retrospective studies suggest a survival benefit for treatment of the primary prostatic tumour in mPCa, but to date, no randomised-controlled-trials (RCTs) have been published addressing this issue.

The Association Between Statin Use and Outcomes in Patients Initiating Androgen Deprivation Therapy

BackgroundStudies have conflicting results regarding the association between statin use and biochemical recurrence for prostate cancer (PCa). A limited number of studies examining statins in advanced stages report positive results, with a few specifically examining statins and androgen deprivation therapy (ADT).ObjectiveTo perform a post hoc secondary analysis of a randomised controlled trial (RCT) of men initiating ADT to examine the association between statin use and outcomes.Design, setting, and participantsPatients with prostate-specific antigen (PSA) >3 ng/ml >1 yr following primary/salvage radiotherapy were enrolled in an RCT of intermittent androgen deprivation (IAD) versus continuous ADT (NCT00003653). Baseline and on-study statin use was modelled as a time-dependent covariate.Outcome measurements and statistical analysisThe primary endpoint was overall survival. Models were adjusted for age, time from radiotherapy to ADT, baseline PSA, and prior ADT.Results and limitationsOf 1364 patients, statin users (585; 43%) were younger (72.7 vs 73.8 yr, p = 0.001) and less likely to have PSA >15 ng/ml (20% vs 25%, p = 0.04). After a median follow-up of 6.9 yr, statin use was associated with reduced overall (hazard ratio [HR]: 0.64; 95% confidence interval [CI] 0.53–0.78, p < 0.001) and PCa-specific (HR: 0.65, 95% CI 0.48–0.87, p = 0.004) mortality. Statin users had 13% longer time to castration resistance, but this did not reach statistical significance (p = 0.15). As an exploratory endpoint, in the IAD arm, statin users had longer time off treatment (median: 0.85 vs 0.64 yr, p = 0.06). Limitations include potential for residual confounding between statin users and nonusers, and confounding by indication.ConclusionsIn men treated with ADT following primary or salvage radiotherapy, statin use was associated with improved overall and PCa-specific survival. In patients treated with IAD, statin use was associated with a trend towards longer time off treatment. A prospective trial of statins in men commencing ADT is warranted.Patient summaryWe found a favourable association between statin use and survival outcomes in patients initiating androgen deprivation therapy.     

Androgen-deprivation Therapy in Treatment of Prostate Cancer and Risk of Myocardial Infarction and Stroke: A Nationwide Danish Population-based Cohort Study

BackgroundAndrogen-deprivation therapy (ADT) has been suggested to increase the risk for cardiovascular diseases, including myocardial infarction (MI) and stroke, but data are inconsistent.ObjectivesTo investigate the association between ADT and risk for MI and stroke in Danish men with prostate cancer.Design, setting, and participantsA national cohort study of all patients with incident prostate cancer registered in the Danish Cancer Registry from January 1, 2002, through 2010 was conducted.Outcome measurements and statistical analysisWe used Cox regression analysis to estimate hazard ratios (HR) of MI and stroke for ADT users versus nonusers, adjusting for age, prostate cancer stage, comorbidity, and calendar period. Additionally, we stratified the analysis on preexisting MI/stroke status.Results and limitationsOf 31 571 prostate cancer patients, 9204 (29%) received medical endocrine therapy and 2060 (7%) were orchidectomized. Patients treated with medical endocrine therapy had an increased risk for MI and stroke with adjusted HRs of 1.31 (95% confidence interval [CI], 1.16–1.49) and 1.19 (95% CI, 1.06–1.35), respectively, compared with nonusers of ADT. We found no increased risk for MI (HR: 0.90; 95% CI, 0.83–1.29) or stroke (HR: 1.11; 95% CI, 0.90–1.36) after orchiectomy. One limitation of the study is that information on prognostic lifestyle factors was not included and might have further informed our estimates.ConclusionsIn this nationwide cohort study of >30 000 prostate cancer patients, we found that endocrine hormonal therapy was associated with increased risk for MI and stroke. In contrast, we did not find this association after orchiectomy.     

Radical prostatectomy versus external beam radiation therapy for high-grade,clinically localized prostate cancer: Emulation of a target clinical trial

PurposeThe comparative effectiveness of surgery and radiation therapy for high-grade, clinically localized prostate cancer remains a seminal, open question in urologic oncology, with no randomized controlled trials to inform management. We therefore emulated a hypothetical target clinical trial of radical prostatectomy (RP) versus external beam radiotherapy (EBRT) for high-grade, clinically localized prostate cancer.Materials and MethodsWe conducted observational analyses using the National Cancer Database from 2006-2015 to emulate a target clinical trial in men 55-69 years with cT1-3cN0cM0, PSA<20 ng/mL, Gleason 8 to 10 prostate adenocarcinoma treated with RP or 75 to 81 Gy EBRT with androgen deprivation therapy (EBRT+ADT). The associations of treatment type with overall survival (OS) were estimated using Cox regression with stabilized inverse probability weights (IPW).ResultsA total of 26,806 men formed the study cohort (RP: 23,990; EBRT+ADT: 2,816). Baseline characteristics were well-balanced after IPW-adjustment. Median follow-up was 48.4 (IQR 25.5-76.2) months. After IPW-reweighting, RP was associated with improved OS compared to EBRT+ADT (HR 0.54;95% CI 0.48-0.62; P<0.001), with 5- and 10-year OS of 93% vs 87%, and 76% vs 60%, respectively. RP was associated with improved OS across all categories of Gleason score, PSA, cT stage, age, and Charlson comorbidity index examined. In sensitivity analyses adjusting for biopsy tumor volume and a biopsy-specific Gleason score, RP remained associated with improved OS compared to EBRT+ADT (HR 0.62;95% CI 0.49-0.78; P<0.001).ConclusionsIn observational analyses designed to emulate a target clinical trial of men with high-grade, clinically localized prostate cancer, RP was associated with improved OS compared with EBRT+ADT.     

Androgen deprivation therapy in men with node-positive prostate cancer treated with postoperative radiotherapy

BackgroundIn men with node-positive prostate cancer after radical prostatectomy there are limited data on the value of adding androgen deprivation therapy (ADT) to postoperative radiotherapy.ObjectiveTo determine whether there is a clear oncologic benefit to ADT in the setting of node-positive prostate cancer treated with postoperative radiotherapy.MethodsWe analyzed data for 372 prostate cancer patients treated at San Raffaele Hospital with postoperative radiotherapy for node-positive disease after radical prostatectomy, 272 received both ADT and radiotherapy. Eighty-six men were followed without an event for more than 10 years.ResultsPatients who received postoperative radiotherapy + ADT had more aggressive disease, with higher preoperative PSA level, higher rate of ISUP grade 5, pT3b-T4 tumors and ≥3 positive nodes. At multivariable Cox regression, the comparison between men treated by postoperative radiotherapy + ADT vs. radiotherapy alone did not show a significant difference for overall (hazards ratio: 0.91; 95% confidence interval: 0.45, 1.84; P = 0.8) and cancer-specific survival (hazards ratio: 5.39; 95% confidence intervalI: 0.70, 41.39; P = 0.11). These results remained consistent in a number of sensitivity analyses, including propensity score matching. Consideration of 95% CIs suggests that a clinically significant benefit of ADT in node-positive patients receiving radiotherapy after surgery is unlikely.ConclusionsWe can exclude the sort of large survival benefit that would be required to justify the risks and toxicities of ADT in men with node-positive disease receiving postoperative radiotherapy. Awaiting larger and more powered studies on this topic, men with pN+ prostate cancer treated with postoperative radiotherapy should not receive ADT outside well-controlled clinical trials.     

Outcomes with brachytherapy based dose escalation for gleason 8 versus 9-10 prostate cancer: An NCDB analysis

IntroductionThe addition of brachytherapy (BT) in high risk prostate cancer is supported by Level 1 evidence. Whether all high risk patients benefit from BT to the same extent is unknown. The National Cancer Database (NCDB) was used to investigate overall survival (OS) differences between GS 8 and 9-10 treated with external beam radiation (EBRT) only or BT +/- EBRT.Materials and MethodsWe included localized prostate adenocarcinoma definitively treated with radiation between 2004-2014. Patients were stratified into various radiation treatment groups: EBRT 7560 - 8640 cGy, EBRT 5940 - 7540 cGy, and BT +/- EBRT. All EBRT only and BT +/- EBRT patients received ADT. A multivariable Cox proportional hazard model was used to assess OS. Propensity score matching was used to account for differences between groups. Median survival was determined based on Kaplan-Meier survival curves.Results30,698 patients were included. On multivariable analysis among GS 8 patients, BT was associated with improved OS compared to 7560 - 8640 cGy (HR–0.80 (95% CI 0.70-0.92, P = 0.002). In Gleason 9-10 BT did not result in improved OS compared to 7560 – 8640 cGy (HR- 0.91 (95% CI 0.79 – 1.05, P = 0.212). Results remained significant with propensity score matching and removing patients with medical comorbidities.ConclusionBT was associated with improved OS when compared to 7560 – 8640 cGy in GS 8, but not in Gleason 9-10 disease. This hypothesis generating study suggests there may be variable benefit with BT in high risk prostate cancer patients on OS. Future prospective studies are needed to investigate whether the benefit of BT is similar across all high risk prostate cancer patients.     

Disease-specific quality of life among patients with localized prostate cancer: an Australian perspective

OBJECTIVES: To examine differences in sexual, urinary and bowel function, and bother, in patients with prostate cancer after treatment with radical prostatectomy (RP) or external beam radiation (EBRT), compared to a convenience sample of men with no diagnosis of prostate cancer, as little is known about the disease-specific health-related quality of life (HRQoL) of men in Australia after treatment for clinically localized prostate cancer. PATIENTS AND METHODS: The study was a retrospective cross-sectional survey of 95 controls, 82 men with localized prostate cancer treated with RP and 39 with EBRT at > or = 2 years before data were collected. Disease-specific HRQoL was assessed using the University of California Los Angeles Prostate Cancer Index, a validated measure that includes six subscales addressing sexual, urinary and bowel symptoms, and level of bother associated with the symptoms. Univariate analyses were conducted to ascertain differences in disease-specific HRQoL among the three groups. To minimize the influence of other factors, age and comorbid medical conditions were included as covariates. RESULTS: Men treated with RP had more sexual and urinary symptoms (both P < 0.001) than those treated with EBRT, and more sexual bother (P < 0.001). Men treated with EBRT reported significantly worse bowel function (P = 0.02) and more bother (P < 0.001) with these symptoms than those who had RP. CONCLUSIONS: Except for bowel dysfunction and the bother associated with these symptoms, disease-specific HRQoL was generally worse after RP than EBRT.     

External Beam Radiotherapy Increases the Risk of Bladder Cancer When Compared with Radical Prostatectomy in Patients Affected by Prostate Cancer: A Population-based Analysis

Background

Long-term survival can be achieved in patients affected by localized prostate cancer (PCa) treated with either radical prostatectomy (RP) or external beam radiotherapy (EBRT). However, development of a second primary tumor is still poorly investigated.

Association between pelvic nodal radiotherapy and patient-reported functional outcomes through 5 years among men undergoing external-beam radiotherapy for prostate cancer: An assessment of the comparative effectiveness analysis of surgery and radiation (CEASAR) cohort

BackgroundThe role of pelvic irradiation in men receiving external beam radiotherapy (EBRT) for prostate cancer is unclear, in part due to a lack of data on patient-reported outcomes. We sought to compare functional outcomes for men receiving prostate and pelvic versus prostate-only radiotherapy, longitudinally over 5 years.Materials and methodsWe performed a population-based, prospective cohort study of men with clinically-localized prostate cancer undergoing EBRT. We examined the effect of prostate and pelvic (n = 102) versus prostate-only (n = 485) radiotherapy on patient-reported disease-specific (using the Expanded Prostate Cancer Index Composite[EPIC]-26) and general health-related (using the SF-36) function, over 5 years. Regression models were adjusted for outcome-specific baseline function, clinicopathologic characteristics, and androgen deprivation therapy (ADT).Results587 men (median [quartiles] age 69 [64–73] years) met inclusion criteria and completed ≥1 post-treatment survey. More men treated with prostate and pelvic radiotherapy had high-risk disease (58% vs. 18%, P < 0.01) and received ADT (75% vs. 41%, P < 0.01). These men reported worse sexual (6 months–5 years), hormonal (at 6 months), and physical (6 months–5 years) function. Accounting for baseline function, patient and tumor characteristics, and use of ADT, pelvic irradiation was not associated with statistically or clinically significant differences in bowel function, urinary incontinence, irritative voiding symptoms or sexual function through 5-years (all P > 0.05). Marginally clinically important differences were noted in hormonal function at 3-years (adjusted mean difference 4.7, 95% confidence interval [1.2–8.3]; minimally clinically important difference (MCID) 4 to 6) and 5-years (4.2, [0.4–8.0]) following treatment. After adjustment, there was a transient statistically significant, but not clinically important, difference in emotional well-being at 6 months (3.0, [0.19–5.8]; MCID 6) that resolved by 1 year and no differences in physical functioning or energy and fatigue.ConclusionThis prospective, population-based cohort study of men with localized prostate cancer treated with EBRT, showed no clinically important differences in disease-specific or general health-related quality of life with the addition of pelvic irradiation to prostate radiotherapy, supporting the use of pelvic radiotherapy when it may be of clinical benefit, such as men with increased risk of nodal involvement.     

Androgen-Deprivation Therapy in Prostate Cancer: A European Expert Panel Review

ContextAndrogen-deprivation therapy (ADT) is the mainstay of treatment for metastatic prostate cancer and is also recommended in association with external-beam radiation therapy (EBRT) for patients with high-risk disease.ObjectiveOur aim was to make recommendations regarding optimal timing of ADT, target serum testosterone levels, intermittent ADT delivery, and quality of life (QoL) during ADT.Evidence acquisitionThis review contains recommendations from a European expert panel held in May 2009.Evidence synthesisThere is ongoing debate over whether ADT should be initiated at diagnosis or delayed until biochemical or symptomatic progression. Immediate ADT is recommended for metastatic disease to defer symptom development and reduce serious complications. In node-positive disease or high-risk nonmetastatic disease unfit for curative therapy, immediate ADT is also an option. Furthermore, there is a clear benefit of adjuvant ADT in association with EBRT in patients with high-risk disease. Some retrospective evidence also supports adjuvant ADT use following radical prostatectomy for high-risk localised disease. In cases of biochemical relapse after definitive local therapy, early ADT may benefit patients with poor prognostic factors. For patients on ADT, the traditional <50 ng/dl target for serum testosterone levels should be considered outdated. It is now clear that a <20 ng/dl threshold better reflects the outcome of bilateral orchidectomy, which is considered the standard of reference in ADT. Recent data demonstrate a clinical benefit of testosterone reduction to more stringent targets than the historical <50 ng/dl threshold. In addition, emerging evidence suggests that intermittent scheduling of ADT can reduce adverse events and improve QoL without compromising survival, but further data are needed to guide its clinical use. Finally, adverse events of ADT may affect QoL and must be discussed with patients.ConclusionsBased on current evidence, the panel made several recommendations for the clinical implementation of ADT.     

Risk Factors for the Development of Bone Metastases in Prostate Cancer

ObjectivesBone health of men with prostate cancer is threatened throughout the disease course. The majority of patients with advanced prostate cancer will develop bone metastases that can undermine skeletal integrity and result in skeletal complications including pathologic fractures, spinal cord compression, and palliative radiotherapy to bone. The early identification of patients who are at a high risk for bone metastases may enable earlier identification and treatment of bone lesions, thereby preserving patients’ independence throughout the disease course.MethodsCurrent guidelines for bone health maintenance were reviewed and PubMed key word searches performed to identify risk factors for the development of bone metastases in patients with prostate cancer. Additionally, guidelines and consensus recommendations were reviewed to identify bone health issues and their management in patients with early prostate cancer.ResultsCurrent prostate cancer monitoring guidelines recommend bone scans at initial diagnosis for patients with prostate-specific antigen (PSA) levels >20 ng/ml and in patients with chronic bone pain or fractures. Multiple studies have concluded that high baseline PSA levels, rising PSA despite androgen-deprivation therapy (ADT), and high PSA velocity are risk factors for the development of bone metastasis in patients with prostate cancer. In patients with early prostate cancer, bone loss is an emerging concern, and bisphosphonates have been demonstrated to prevent bone loss from ADT. Use of risk factors such as PSA kinetics may optimize screening and enable earlier identification of bone metastases.ConclusionsMonitoring bone mineral density may allow for better preservation of skeletal health in patients undergoing ADT.     

RANK Ligand-targeted Therapy: A Novel Approach to Prevent Bone Loss and Fractures in Men with Prostate Cancer

ContextThe importance of bone loss associated with both prostate cancer (PCa) and its treatment is being increasingly recognised, and new options to manage this complication are in development.ObjectiveTo assess the impact of androgen-deprivation therapy (ADT) on bone and to outline recently reported and ongoing phase 3 studies of agents designed to prevent bone loss and fractures in men with PCa.Evidence acquisitionThis article is based on a presentation at an Amgen-sponsored satellite symposium held at the European Association of Urology Congress in Stockholm, Sweden, in March 2009.Evidence synthesisADT for PCa is associated with bone loss and an increased fracture risk. Several bisphosphonates have been shown to improve bone mineral density (BMD) during ADT, but their effects on treatment-related fractures are unknown. Denosumab, a fully human monoclonal antibody to RANK Ligand, is being investigated for the management of bone loss associated with PCa. The results of a phase 3 randomised, placebo-controlled trial of denosumab to prevent bone loss and fractures during ADT in men with PCa have recently been reported. Compared with placebo, denosumab (60 mg subcutaneously every 6 mo) significantly reduced the incidence of new vertebral fractures by 62% after 3 yr. Denosumab also increased BMD significantly at various skeletal sites, including the spine, hip, and wrist.ConclusionsADT decreases BMD and increases fracture risk in men with PCa. A recent phase 3 study has demonstrated that denosumab increases BMD and significantly reduces the risk of new vertebral fractures in men with PCa. Two ongoing phase 3 studies are evaluating denosumab for the prevention and treatment of bone metastases in men with castration-resistant prostate cancer.     

Prostate-only Versus Whole-pelvis Radiation with or Without a Brachytherapy Boost for Gleason Grade Group 5 Prostate Cancer: A Retrospective Analysis

BackgroundThe role of elective whole-pelvis radiotherapy (WPRT) remains controversial. Few studies have investigated it in Gleason grade group (GG) 5 prostate cancer (PCa), known to have a high risk of nodal metastases.ObjectiveTo assess the impact of WPRT on patients with GG 5 PCa treated with external-beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT + BT).Design, setting, and participantsWe identified 1170 patients with biopsy-proven GG 5 PCa from 11 centers in the United States and one in Norway treated between 2000 and 2013 (734 with EBRT and 436 with EBRT + BT).Outcome measurements and statistical analysisBiochemical recurrence-free survival (bRFS), distant metastasis-free survival (DMFS), and prostate cancer-specific survival (PCSS) were compared using Cox proportional hazards models with propensity score adjustment.Results and limitationsA total of 299 EBRT patients (41%) and 320 EBRT + BT patients (73%) received WPRT. The adjusted 5-yr bRFS rates with WPRT in the EBRT and EBRT + BT groups were 66% and 88%, respectively. Without WPRT, these rates for the EBRT and EBRT + BT groups were 58% and 78%, respectively. The median follow-up was 5.6 yr. WPRT was associated with improved bRFS among patients treated with EBRT + BT (hazard ratio [HR] 0.5, 95% confidence interval [CI] 0.2–0.9, p = 0.02), but no evidence for improvement was found in those treated with EBRT (HR 0.8, 95% CI 0.6–1.2, p = 0.4). WPRT was not significantly associated with improved DMFS or PCSS in the EBRT group (HR 1.1, 95% CI 0.7–1.7, p = 0.8 for DMFS and HR 0.7, 95% CI 0.4–1.1, p = 0.1 for PCSS), or in the EBRT + BT group (HR 0.6, 95% CI 0.3–1.4, p = 0.2 for DMFS and HR 0.5 95% CI 0.2–1.2, p = 0.1 for PCSS).ConclusionsWPRT was not associated with improved PCSS or DMFS in patients with GG 5 PCa who received either EBRT or EBRT + BT. However, WPRT was associated with a significant improvement in bRFS among patients receiving EBRT + BT. Strategies to optimize WPRT, potentially with the use of advanced imaging techniques to identify occult nodal disease, are warranted.Patient summaryWhen men with a high Gleason grade prostate cancer receive radiation with external radiation and brachytherapy, the addition of radiation to the pelvis results in a longer duration of prostate-specific antigen control. However, we did not find a difference in their survival from prostate cancer or in their survival without metastatic disease. We also did not find a benefit for radiation to the pelvis in men who received radiation without brachytherapy.     

Androgen-deprivation Therapy and Diabetes Control Among Diabetic Men with Prostate Cancer

BackgroundAndrogen-deprivation therapy (ADT) for prostate cancer (PCa) is associated with decreased insulin sensitivity and increased diabetes risk among nondiabetic men. Few data are available about the effects of ADT on diabetes control among men with diabetes.ObjectiveWe examined care for men who had diabetes at the time of PCa diagnosis to assess the effect of ADT on diabetes control, as measured by hemoglobin A1c (HbA1c) levels and the intensification of diabetes pharmacotherapy.Design, setting, and participantsThis was an observational cohort study using US Department of Veterans Affairs registry data and administrative data to assess HbA1c levels and intensification of diabetes pharmacotherapy among 2237 pairs of propensity-matched men with PCa and diabetes who were or were not treated with ADT.Outcome measurements and statistical analysisWe calculated the difference in difference of HbA1c levels at baseline and at 1 and 2 yr in the two groups, compared using a paired Student t test. We used a Cox proportional hazards model to estimate time to intensification of diabetes pharmacotherapy.Results and limitationsThe mean HbA1c at baseline was 7.24 (standard error [SE]: 0.05) for the ADT group and 7.24 (SE: 0.04) for the no-ADT group. HbA1c increased at 1 yr for men treated with ADT to 7.38 (SE: 0.04) and decreased among men not treated with ADT to 7.14 (SE: 0.04), for a difference in differences of +0.24 (p = 0.008). Results were similar at 2 yr (p = 0.03). The worsening HbA1c control occurred despite ADT being associated with an increased hazard of addition of diabetes medication (adjusted hazard ratio: 1.20; 95% confidence interval, 1.09–1.32). The limitation of this study was that it was observational and relied on administrative data.ConclusionsADT is associated with worsening of diabetes control and increases in HbA1c levels despite the use of additional diabetes medications.     

Benefits and Risks of Primary Treatments for High-risk Localized and Locally Advanced Prostate Cancer: An International Multidisciplinary Systematic Review

ContextThe optimal treatment for men with high-risk localized or locally advanced prostate cancer (PCa) remains unknown.ObjectiveTo perform a systematic review of the existing literature on the effectiveness of the different primary treatment modalities for high-risk localized and locally advanced PCa. The primary oncological outcome is the development of distant metastases at ≥5 yr of follow-up. Secondary oncological outcomes are PCa-specific mortality, overall mortality, biochemical recurrence, and need for salvage treatment with ≥5 yr of follow-up. Nononcological outcomes are quality of life (QoL), functional outcomes, and treatment-related side effects reported.Evidence acquisitionMedline, Medline In-Process, Embase, and the Cochrane Central Register of Randomized Controlled Trials were searched. All comparative (randomized and nonrandomized) studies published between January 2000 and May 2019 with at least 50 participants in each arm were included. Studies reporting on high-risk localized PCa (International Society of Urologic Pathologists [ISUP] grade 4–5 [Gleason score {GS} 8–10] or prostate-specific antigen [PSA] >20 ng/ml or ≥ cT2c) and/or locally advanced PCa (any PSA, cT3–4 or cN+, any ISUP grade/GS) or where subanalyses were performed on either group were included. The following primary local treatments were mandated: radical prostatectomy (RP), external beam radiotherapy (EBRT) (≥64 Gy), brachytherapy (BT), or multimodality treatment combining any of the local treatments above (±any systemic treatment). Risk of bias (RoB) and confounding factors were assessed for each study. A narrative synthesis was performed.Evidence synthesisOverall, 90 studies met the inclusion criteria. RoB and confounding factors revealed high RoB for selection, performance, and detection bias, and low RoB for correction of initial PSA and biopsy GS. When comparing RP with EBRT, retrospective series suggested an advantage for RP, although with a low level of evidence. Both RT and RP should be seen as part of a multimodal treatment plan with possible addition of (postoperative) RT and/or androgen deprivation therapy (ADT), respectively. High levels of evidence exist for EBRT treatment, with several randomized clinical trials showing superior outcome for adding long-term ADT or BT to EBRT. No clear cutoff can be proposed for RT dose, but higher RT doses by means of dose escalation schemes result in an improved biochemical control. Twenty studies reported data on QoL, with RP resulting mainly in genitourinary toxicity and sexual dysfunction, and EBRT in bowel problems.ConclusionsBased on the results of this systematic review, both RP as part of multimodal treatment and EBRT + long-term ADT can be recommended as primary treatment in high-risk and locally advanced PCa. For high-risk PCa, EBRT + BT can also be offered despite more grade 3 toxicity. Interestingly, for selected patients, for example, those with higher comorbidity, a shorter duration of ADT might be an option. For locally advanced PCa, EBRT + BT shows promising result but still needs further validation. In this setting, it is important that patients are aware that the offered therapy will most likely be in the context a multimodality treatment plan. In particular, if radiation is used, the combination of local with systemic treatment provides the best outcome, provided the patient is fit enough to receive both. Until the results of the SPCG15 trial are known, the optimal local treatment remains a matter of debate. Patients should at all times be fully informed about all available options, and the likelihood of a multimodal approach including the potential side effects of both local and systemic treatment.Patient summaryWe reviewed the literature to see whether the evidence from clinical studies would tell us the best way of curing men with aggressive prostate cancer that had not spread to other parts of the body such as lymph glands or bones. Based on the results of this systematic review, there is good evidence that both surgery and radiation therapy are good treatment options, in terms of prolonging life and preserving quality of life, provided they are combined with other treatments. In the case of surgery this means including radiotherapy (RT), and in the case of RT this means either hormonal therapy or combined RT and brachytherapy.     

Survival Outcomes of Men with Lymph Node-positive Prostate Cancer After Radical Prostatectomy: A Comparative Analysis of Different Postoperative Management Strategies

Background

Optimal management of patients with lymph node metastasis (LNM) after radical prostatectomy (RP) remains undefined.

Brachytherapy monotherapy may be sufficient for a subset of patients with unfavorable intermediate risk prostate cancer

Purpose/objective(s)

Brachytherapy (BT) monotherapy is a well-established treatment modality for favorable intermediate risk (FIR) prostate cancer. However, patients with unfavorable intermediate risk (UIR) disease are often recommended trimodality therapy involving BT, androgen deprivation therapy (ADT), and external beam radiation therapy (EBRT). We sought to investigate the relative benefit of supplemental therapies (ADT and/or EBRT) for FIR and UIR prostate cancer in a large dataset.

Ductal Prostate Cancers Demonstrate Poor Outcomes with Conventional Therapies

BackgroundDuctal prostate adenocarcinoma (DAC) is a rare, aggressive, histologic variant of prostate cancer that is treated with conventional therapies, similar to high-risk prostate adenocarcinoma (PAC).ObjectiveTo assess the outcomes of men undergoing definitive therapy for DAC or high-risk PAC and to explore the effects of androgen deprivation therapy (ADT) in improving the outcomes of DAC.Design, setting, and participantsA single-center retrospective review of all patients with cT1–4/N0–1 DAC from 2005 to 2018 was performed. Those undergoing radical prostatectomy (RP) or radiotherapy (RTx) for DAC were compared with cohorts of high-risk PAC patients.Outcome measurements and statistical analysisMetastasis-free survival (MFS) and overall survival (OS) rates were analyzed using Kaplan-Meier and Cox regression models.Results and limitationsA total of 228 men with DAC were identified; 163 underwent RP, 34 underwent RTx, and 31 had neoadjuvant therapy prior to RP. In this study, 163 DAC patients and 155 PAC patients undergoing RP were compared. Similarly, 34 DAC patients and 74 PAC patients undergoing RTx were compared. DAC patients undergoing RP or RTx had worse 5-yr MFS (75% vs 95% and 62% vs 93%, respectively, p < 0.001) and 5-yr OS (88% vs 97% and 82% vs 100%, respectively, p < 0.05) compared with PAC patients. In the 76 men who received adjuvant/salvage ADT after RP, DAC also had worse MFS and OS than PAC (p < 0.01). A genomic analysis revealed that 10/11 (91%) DACs treated with ADT had intrinsic upregulation of androgen-resistant pathways. Further, none of the DAC patients (0/15) who received only neoadjuvant ADT prior to RP had any pathologic downgrading. The retrospective nature was a limitation.ConclusionsMen undergoing RP or RTx for DAC had worse outcomes than PAC patients, regardless of the treatment modality. Upregulation of several intrinsic resistance pathways in DAC rendered ADT less effective. Further evaluation of the underlying biology of DAC with clinical trials is needed.Patient summaryThis study demonstrated worse outcomes among patients with ductal adenocarcinoma of the prostate than among high-grade prostate adenocarcinoma patients, regardless of the treatment modality.     

Comparative study of surgical orchidectomy and medical castration in treatment efficacy,adverse effects and cost based on a large prospective metastatic prostate cancer registry

IntroductionAndrogen deprivation therapy (ADT) remains the mainstay of treatment for metastatic prostate cancer (mPCa) but is associated with significant morbidities. Comparisons of medical castration (MC) and surgical orchidectomy (SO) have yielded varied results. We aimed to evaluate the oncological outcomes, adverse effect (AE) profiles and costs of MC and SO in patients with mPCa.Methods and materialsWe reviewed 523 patients who presented with de novo mPCa from a prospectively maintained prostate cancer database over 15 years (2001–2015). All patients received ADT (either MC or SO) within 3 months of diagnosis. The data were analyzed with chi-square, binary and logistics regression models.ResultsOne hundred and fifty one (28.9%) patients received SO while 372 (71.1%) patients had MC. The median age of presentation was 73 [67 –79] years old. The median prostate-specific antigen (PSA) was 280ng/ml [82.4–958]. Three hundred and thirty one patients (66.3%) had high volume bone metastasis and 57 patients (10.9%) had visceral metastasis. Clinical demographics and clinicopathological were similar across both groups. Similar oncological outcomes were observed in both groups. The proportion of PSA response (PSA <1ng/ml) was 65.6% for SO and 67.2% for MC (P = 0.212). Both therapies achieve >95% of effective androgen suppression (testosterone <50ng/dL). Time to castrate-resistance was similar (18 vs 16 months, P = 0.097), with comparative overall survival (42 vs. 38.5 months, P = 0.058) and prostate cancer mortality (80.1 vs. 75.9%, P = 0.328).Similarly, no difference was observed for the 4 AE profiles between SO and MC respectively; change in Haemoglobin (-0.75 vs. -1.0g/dL, P = 0.302), newly diagnosed Diabetes mellitus (4.6 vs. 2.9%, P = 0.281), control measured by HbA1c (0.2 vs. 0.25%, P = 0.769), coronary artery disease events (9.9 vs. 12.9%, P = 0.376) and skeletal-related fractures (9.3 vs. 7.3%, P = 0.476).After adjusting for varying governmental subsidies and inflation rates, the median cost of SO was $5275, compared to MC of $9185.80.ConclusionBoth SO and MC have similar oncological outcomes and AE profiles. However, SO remains a much more cost-effective form of ADT for the long-term treatment of mPCa patients.     

Do androgen-directed therapies improve outcomes in prostate cancer patients undergoing radical prostatectomy? A systematic review and meta-analysis

IntroductionApproximately 50% of patients with non-metastatic prostate cancer are treated with radical prostatectomy (RP). While some men will be cured with surgery alone, a substantial proportion will experience cancer recurrence. Androgen-directed therapy (ADT) is an effective adjuvant therapy for patients treated with prostate radiation. Comparatively, the efficacy of ADT in surgical patients has not been well-studied.MethodsA systematic search of MEDLINE, Embase, and the Cochrane Library from inception to July 2020 was performed. Randomized trials comparing ADT with RP vs. prostatectomy alone in patients with clinically localized prostate cancer were included. Neoadjuvant ADT and adjuvant ADT interventions were assessed separately. The primary outcomes were cancer recurrence-free survival (RFS) and overall survival (OS). Pathological outcomes following neoadjuvant ADT were also evaluated.ResultsFifteen randomized trials met eligibility criteria; 11 evaluated neoadjuvant ADT (n=2322) and four evaluated adjuvant ADT (n=5205). Neoadjuvant ADT (three months of treatment) did not improve RFS (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.74–1.11) or OS (HR 1.22, 95% CI 0.62–2.41). Neoadjuvant ADT significantly decreased the risk of positive surgical margins (relative risk [RR] 0.48, 95% CI 0.41–0.56) and extraprostatic tumor extension (RR 0.75, 95% CI 0.64–0.89). Adjuvant ADT improved RFS (HR 0.65, 95% CI 0.45–0.93) but did not improve OS (HR 1.02, 95% CI 0.84–1.24).ConclusionsNeoadjuvant ADT causes a pathological downstaging of prostate tumors but has not been found to delay cancer recurrence nor extend survival. Few studies have evaluated adjuvant ADT. Trials are needed to determine the benefits and harms of intermediate- or long-term adjuvant ADT for RP patients.