Months Of Androgen Deprivation Research Articles

Radiotherapy (RT) guided by ultra‐small superparamagnetic iron oxide (USPIO)-contrast MRI staging for patients with advanced or recurrent prostate cancer.

218 Background: Aggressive treatment of oligometastatic PC may prolong survival in selected patients. USPIO-contrast MRI is potentially more sensitive in detecting early lymph node (LN) metastases than PET. Methods: This retrospective study explores the safety and utility of USPIO-guided RT in 69 patients with advanced/recurrent PC treated at 2 US institutions. All USPIO-MRIs were completed at RadboudUMC and interpreted by expert radiologists. Age, Stage, Gleason score, PSA, prior therapy, duration of androgen-deprivation (ADT), cause of death, details of RT, and adverse events (AEs) were collected by chart review. Biochemical recurrence (BCR) was defined as PSA Nadir plus 2.0 (RT) or PSA>0.2 (radical prostatectomy, RP). Patients received external beam radiation (RT) to involved nodal basins (+/-prostate/prostate bed) with either a simultaneous integrated or sequential boost to USPIO(+) nodes. All patients received >6 months of ADT. Overall (OS) and BCR free-survival (BCRFS) were calculated using Cox-PH models in R. Results: Between 2007-18, 69 patients with de novo or recurrent PC were found to have USPIO(+) LNs and received USPIO-guided RT; median age was 62. The majority of patients presented after BCR following RP (N=28), definitive RT (N=27) or RP and post-op RT (N=6). Prior to USPIO-MRI, 20/69 patients had cN1 disease based on abdominal-pelvic CT/MRI, Bone Scan, Prostascint-scan, and F18 Choline, Axumin or PSMA PET/CT. The mean(median)USPIO(+) LNs was 5.2(3) Range=[1-32]. Patients had (+)pelvic (95%), para-aortic (43%), and/or peri-rectal LNs (19%). At median follow up of 29.5(44.6) Range=[5-127] months, OS was 58/69 (84%) and 11/11 patients died of PC. At last follow up, 40 patients remained BCR-free (BCRFS not reached). The median time to BCR (N=29) was 25.9 months after USPIO-guided RT. For patients with follow-up imaging, recurrences were predominantly out-of-field (outside of elective LN fields or in osseous sites). No patients experienced >CTCAE grade 2 AEs. Conclusions: In this cohort of 69 patients with predominantly recurrent PC, USPIO-directed RT was well-tolerated, feasible and resulted in encouraging biochemical control rates.

900TiP - A phase II randomized, open-label study comparing salvage radiotherapy in combination with 6 months of androgen-deprivation therapy with LHRH agonist or antagonist versus anti-androgen therapy with apalutamide in patients with biochemical progression after radical prostatectomy

BackgroundSalvage radiotherapy (SRT) is a potentially curative option for patients with rising PSA (biochemical recurrence) after radical prostatectomy. Recently, success rates of SRT were significantly improved through the use of concomitant anti-androgen (AAT) or androgen-deprivation (ADT) therapy. In RTOG 96-01, 2 years of bicalutamide 150mg resulted in a 5% OS benefit at 12-years. In GETUG-AFU 16, 5-year progression-free survival was significantly improved when SRT was combined with 6 months of an LHRH agonist. Based on GETUG-AFU 16, most European urologists and (radiation) oncologists now combine SRT with at least 6 months of ADT. However, ADT comes with several serious side-effects, both physical (cardiovascular, metabolic, musculoskeletal) and psychological (sexual, emotional and cognitive). Considering RTOG 96-01, and in view of new AAT options, it appears worthwhile to look for alternatives. In that respect, apalutamide (ERLEADA®), a next-generation anti-androgen, is an interesting candidate. Trial designThis is a phase II randomized, open-label study comparing SRT in combination with 6 months of LHRH (ant)agonist (arm A) versus 6 cycles of apalutamide 240mg daily (each cycle is 28 +/- 2 days) (arm B) in hormone-naïve patients with biochemical recurrence (PSA > 0.1 µg/L at least 8 weeks after radical prostatectomy). Patients with severe erectile dysfunction are excluded. All subjects will receive SRT as standard of care and will be randomly assigned in a 1:1 ratio to arm A or B. Primary objective is to compare sexual function, based on the EPIC-26 sexual domain score, at 9 months (i.e. 3 months after the end of hormonal treatment). Secondary endpoints include general quality of life (EPIC-26, EORTC QLQ C30 and PR25, FACT-P), acute as well as late toxicity (CTCAE version 5.0), and PSA (complete) response rates (i.e. decline from baseline in PSA level of 80% (90%) or greater). The trial was approved by the local ethics committee on April 2nd 2019 and started recruiting immediately thereafter. Clinical trial identificationNCT03899077; 2018-004365-13. Legal entity responsible for the studyGZA Hospitals. FundingJanssen. DisclosureAll authors have declared no conflicts of interest.

Editorial Comment

Monitoring prostate-specific antigen (PSA) is the mainstay of evaluating definitive therapy in that a rising PSA is predictive of developing distant metastases and prostate cancer-specific mortality (PCSM). Recent studies have identified post treatment PSA based surrogates for PCSM which is important given that it takes 10-20years to die after unsuccessful definitive therapy. 1 Royce TJ Chen MH Wu J et al. Surrogate end point for all-cause mortality in men with localized unfavorable -risk prostate cancer treated with radiation therapy vs radiation therapy plus androgen deprivation therapy: a secondary analysis of a randomized clinical trial. JAMA Oncol. 2017; 3: 652-658 Crossref PubMed Scopus (34) Google Scholar , 2 Romesser PB Pei X Shi W et al. Prostate-Specific Antigen (PSA) bounce after dose-escalated external beam radiation therapy is an independent predictor of PSA recurrence, metastasis, and survival in prostate adenocarcinoma patients. Int J Radiat Oncol Biol Phys. 2018; 100: 59-67 Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar In this article, investigators describe an analysis of 204 men with unfavorable prostate cancer enrolled in a randomized clinical trial comparing 70.2 Gy external beam radiotherapy with or without 6 months of androgen deprivation (ADT). With a median follow-up more than 18years, men with a PSA nadir >0.2ng/mL and a time to nadir (TTN) <12 months had a statistically significant increased PCSM rate. The authors conclude that these observations infer a high likelihood of castrate resistant prostate cancer (CRPC) and propose that men with a measurable PSA nadir and a short TTN be considered for randomized trials evaluating the impact on survival of salvage ADT with or without novel agents shown to prolonged survival in men with CRPC.

Changes in cerebral metabolic activity in men undergoing androgen deprivation therapy for non-metastatic prostate cancer

ObjectiveAndrogen deprivation therapy (ADT) is a common treatment option for men with biochemical relapse from prostate cancer. ADT is associated with changes in mood, cognition, and quality of life, and most recently with increased risk for Alzheimer’s disease (AD). This study examined changes in brain metabolism using positron emission tomography (PET) in men undergoing intermittent ADT.MethodsNine men with prostate cancer and a rising PSA (biochemical recurrence) without evidence of metastases were treated with intermittent ADT consisting of 9 months of complete androgen blockade achieved with combined leuprolide acetate and flutamide. Patients underwent resting [Fuorine-18] fluorodeoxyglucose PET (18F-FDGPET) at baseline (before treatment) and again after 9 months of ADT.ResultsWhole-brain mapping analysis after 9 months of androgen deprivation compared to pretreatment baseline revealed decreased regional cerebral glucose metabolism in the cerebellum, posterior cingulate, and medial thalamus bilaterally. Associations of brain metabolism with measurements of cognition and mood while on androgen deprivation revealed positive correlations between the posterior cingulate, left inferior parietal lobule (BA40), and left mid temporal gyrus (BA39) and spatial reasoning and a negative correlation between left inferior parietal lobule and verbal memory. Several mood indices were negatively correlated with hypothalamus and brainstem.ConclusionThese findings suggest that complete androgen deprivation may result in changes in regional brain metabolism associated with variation in mood, verbal memory, and spatial performance. Brain regions that were impacted from ADT are similar and overlap with brain regions with metabolic decline found in early AD and diabetes, suggesting possible common mechanisms.

Long-Term Prostate Specific Antigen Stability and Predictive Factors of Failure after Permanent Seed Prostate Brachytherapy.

Defining biochemical failure as nadir + 2 may overestimate cure after radiotherapy. We assessed long-term prostate specific antigen stability after low dose rate prostate brachytherapy and predictors of biochemical failure when prostate specific antigen was slowly rising below the nadir + 2 ng/ml threshold. A total of 2,339 patients with low or intermediate risk prostate cancer received 125iodine brachytherapy from 1998 to 2010 with a minimum 3-year followup. In addition, 49.7% of the patients received 6 months ofandrogen deprivation. Clinical, dosimetric and prostate specific antigen data were retrieved from a prospective database. Biochemical results were classified as stable or rising prostate specific antigen (0.2 ng/ml or greater and increased 0.1 ng/ml or greater during the preceding 2 years), or biochemical failure (defined as nadir + 2). Multivariate analysis was done to identify predictors of failure used to create logistic regression models. At a median followup of 89 months (range 37 to 199) prostate specific antigen was stable (nadir 0.03 ng/ml and at 60 months 0.04 ng/ml) in 2,004 patients (86%) and rising (nadir 0.16 ng/ml and at 60 months 0.29 ng/ml) in 145 (6%) while biochemical failure (nadir 0.51 ng/ml, p <0.001) was noted in 190 (8%). When there was no prior androgen deprivation therapy, the prostate specific antigen nadir and prostate specific antigen at 60 months were the strongest predictors of failure (OR 20.6 and 18.3, respectively, each p <0.0001). The logistic regression model had 85% sensitivity and 98% specificity, and predicted failure in 8 of 82 men (9.8%). A second model was created for the group with androgen deprivation therapy and rising prostate specific antigen using the predictive factors prostate specific antigen at 60 months (OR 53.9, p <0.0001) and T stage (OR 0.25, p = 0.0008). This model predicted biochemical failure in 30 of 56 men (54%) with 85% sensitivity and 93% specificity. The 2 predictive models yield an anticipated 90% cure rate in the entire cohort. Brachytherapy is highly curative with stable prostate specific antigen at a surgical ablation level in 86% of patients. Rising prostate specific antigen is rare at a 6% incidence and often innocuous.

Surrogate End Points for All-Cause Mortality in Men With Localized Unfavorable-Risk Prostate Cancer Treated With Radiation Therapy vs Radiation Therapy Plus Androgen Deprivation Therapy

ImportanceSeveral surrogates for prostate cancer–specific mortality satisfying the Prentice criteria exist, but whether these are surrogates for all-cause mortality, and how their performance compares, is unknown.ObjectiveTo ascertain and compare the performance of 4 candidate surrogates (prostate-specific antigen [PSA] failure, PSA nadir >0.5 ng/mL, PSA doubling time <9 months, and interval to PSA failure <30 months) for all-cause mortality using the proportion of treatment-effect metric.Design, Setting, and ParticipantsFor this randomized clinical trial, 206 men with unfavorable-risk prostate cancer who were seen at a Harvard-affiliated academic hospital or an associated community hospital between December 1, 1995, to April 15, 2001, were identified, randomized to radiation therapy alone or radiation therapy followed by 6 months of androgen deprivation therapy, and followed for a median 16.62 years. This analysis looks at the subgroup of 157 men with minimal comorbidities or no comorbidity (median follow-up, 16.49 months).InterventionsPatients were previously randomized to receive radiation therapy or radiation and 6 months of androgen deprivation therapy.Main Outcomes and MeasuresRisk of all-cause mortality.ResultsOverall, a cohort of 157 men (median [interquartile range] age, 72.43 [68.75-75.53]) with unfavorable-risk prostate cancer and minimal or no comorbidities were selected for this study. Three tested metrics met all 4 Prentice criteria for surrogacy for the surrogate covariate in the adjusted model for all-cause mortality: PSA nadir greater than 0.5 ng/mL (adjusted hazard ratio [aHR], 1.72; 95% CI, 1.17-2.52; P = .01), PSA doubling time less than 9 months (aHR, 2.06; 95% CI, 1.29-3.28; P = .003), and interval to PSA failure less than 30 months (aHR, 1.76; 95% CI, 1.06-2.92; P = .03); while PSA failure did not. For the 3 successful surrogates, the proportion of treatment effect values were 103.86%, 43.09%, and 41.26%, respectively.Conclusions and RelevanceA PSA nadir value of greater than 0.5 ng/mL following radiation and androgen deprivation therapy appears to identify men prior to PSA failure who are at high-risk for death. This could be used to select men for entry at the time of PSA nadir onto randomized trials evaluating the impact on survival of salvage androgen deprivation therapy with or without agents shown to prolong survival in men with castrate-resistant metastatic prostate cancer.Trial Registrationclinicaltrials.gov Identifier: NCT00116220

Gleason score and the risk of cause-specific and all-cause mortality following radiation with or without 6 months of androgen deprivation therapy for men with unfavorable-risk prostate cancer

We evaluated whether a differential impact of adding 6 months of androgen deprivation (ADT) to radiation therapy (RT) on all-cause (ACM), prostate cancer-specific (PCSM), and other-cause mortality (OCM) in men with unfavorable-risk prostate cancer (PC) exists within Gleason score (GS) subgroups. Individual patient data from 743 men with unfavorable-risk PC from two randomized ADT trials were utilized. Competing risks and Cox regression were used to determine whether adding 6 months of ADT to RT significantly impacted PCSM, OCM, and ACM within GS subgroups. Men with GS 9/10 versus ≤8 were significantly more likely to be over 75 (23.3 versus 12.7 %; p = 0.03). At a median follow-up of 11.93 and 11.81 years in the 683 and 60 patients with GS ≤8 and GS 9/10, 315 (46.1 %) and 44 (73.1 %) died, respectively. ADT in men with GS ≤8 was associated with significantly decreased ACM (adjusted hazard ratio (AHR) 0.66; 95 % confidence interval: 0.52–0.82; p < 0.001) and PCSM (0.43; 0.28–0.66; p < 0.001) but no significant difference in OCM (0.90; 0.68–1.17; p = 0.43) Among men with GS 9/10 PC ADT significantly reduced PCSM (0.33; 0.11–0.99; p = 0.048) but not ACM (0.79; 0.38–1.61; p = 0.51) and increased OCM (2.16; 0.81–5.79; p = 0.12), resulting in opposite effects of ADT on OCM by the GS subgroup such that the relative AHR of OCM in GS 9/10 versus ≤8 was nearly significantly increased (2.42 [0.87,6.71]; p = 0.09). While ADT reduced PCSM risk overall, survival was not prolonged in men with GS 9/10 due to ADT-driven increased OCM, which supports the hypothesis that older men with significant comorbidity may not experience prolonged survival when ADT is added to RT.

Gleason score and the risk of cause-specific and overall mortality following radiation with or without 6 months of androgen deprivation therapy for men with unfavorable-risk prostate cancer.

171 Background: We evaluated whether a differential impact of adding 6 months of androgen deprivation (ADT) to radiation therapy (RT) on all-cause, prostate cancer-specific, and other-cause mortality (ACM, PCSM, OCM) in men with unfavorable-risk PC exists within Gleason score (GS) subgroups. Methods: Individual patient data from 743 men with unfavorable-risk PC from two randomized ADT trials were utilized. Competing risks and Cox regression were used to determine whether adding 6 months of ADT to RT significantly impacted PCSM, OCM and ACM within GS subgroups. Results: Men with GS 9,10 versus ≤ 8 were significantly more likely to be over 75 (23.3% versus 12.7%;p = 0.03). At a median follow-up of 11.9 and 11.8 years in the 683 and 60 patients with GS ≤ 8 and GS 9,10, 315 (46.1%) and 44 had died (73.1%), respectively. ADT in men with GS ≤ 8 was associated with significantly decreased ACM (Adjusted hazard ratio (AHR) 0.66; 95% confidence interval (CI): 0.52-0.82; p &lt; 0.001) and PCSM (0.43; 0.28-0.66; p &lt; 0.001) but was not associated with OCM (0.90; 0.68-1.17; p = 0.43). Among men with GS 9,10 PC, ADT significantly reduced PCSM (0.33; 0.11-0.99; p = 0.048) but not ACM (0.79; 0.38-1.61; p = 0.51) and increased OCM (2.16; 0.81-5.79; p = 0.12) resulting in opposite effects of ADT on OCM by GS subgroup (Table) such that the relative AHR of OCM in GS 9,10 versus ≤ 8 was nearly significantly increased (2.42; 0.87-6.71; p = 0.09). Conclusions: While ADT reduced PCSM for all men, survival was not prolonged in men with GS 9,10 due to ADT-driven increased OCM. This supports the hypothesis that older men with significant comorbidity may not experience prolonged survival when ADT is added to RT. [Table: see text]

High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial

The optimum duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains undefined. We aimed to determine whether long-term androgen deprivation was superior to short-term androgen deprivation when combined with high-dose radiotherapy. In this open-label, multicentre, phase 3 randomised controlled trial, patients were recruited from ten university hospitals throughout Spain. Eligible patients had clinical stage T1c-T3b N0M0 prostate adenocarcinoma with intermediate-risk and high-risk factors according to 2005 National Comprehensive Cancer Network criteria. Patients were randomly assigned (1:1) using a computer-generated randomisation schedule to receive either 4 months of androgen deprivation combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range 76-82 Gy; short-term androgen deprivation group) or the same treatment followed by 24 months of adjuvant androgen deprivation (long-term androgen deprivation group), stratified by prostate cancer risk group (intermediate risk vs high risk) and participating centre. Patients assigned to the short-term androgen deprivation group received 4 months of neoadjuvant and concomitant androgen deprivation with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy (flutamide 750 mg per day or bicalutamide 50 mg per day) was added during the first 2 months of treatment. Patients assigned to long-term suppression continued with the same luteinising hormone-releasing hormone analogue every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02175212. Between Nov 7, 2005, and Dec 20, 2010, 178 patients were randomly assigned to receive short-term androgen deprivation and 177 to receive long-term androgen deprivation. After a median follow-up of 63 months (IQR 50-82), 5-year biochemical disease-free survival was significantly better among patients receiving long-term androgen deprivation than among those receiving short-term treatment (90% [95% CI 87-92] vs 81% [78-85]; hazard ratio [HR] 1·88 [95% CI 1·12-3·15]; p=0·01). 5-year overall survival (95% [95% CI 93-97] vs 86% [83-89]; HR 2·48 [95% CI 1·31-4·68]; p=0·009) and 5-year metastasis-free survival (94% [95% CI 92-96] vs 83% [80-86]; HR 2·31 [95% CI 1·23-3·85]; p=0·01) were also significantly better in the long-term androgen deprivation group than in the short-term androgen deprivation group. The effect of long-term androgen deprivation on biochemical disease-free survival, metastasis-free survival, and overall survival was more evident in patients with high-risk disease than in those with low-risk disease. Grade 3 late rectal toxicity was noted in three (2%) of 177 patients in the long-term androgen deprivation group and two (1%) of 178 in the short-term androgen deprivation group; grade 3-4 late urinary toxicity was noted in five (3%) patients in each group. No deaths related to treatment were reported. Compared with short-term androgen deprivation, 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer, particularly those with high-risk disease, with no increase in late radiation toxicity. Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of androgen deprivation. Spanish National Health Investigation Fund, AstraZeneca.

Cytoreductive radical prostatectomy (CRP) in patients with prostate cancer (PCA) and low-volume osseous metastases.

272 Background: Androgen deprivation (ADT) represents the standard treatment in men with prostate cancer (PCA) and osseous metastases. Unlike therapeutic approaches in other solid tumors, RP is usually ignored due to the common view that the biology of the disease is attributed to preexisting metastases. Recently, it has been shown that potentially lethal cancers persist even after neoadjuvant ADT and chemotherapy. We explored the outcome of patients with PCA and low volume skeletal metastases who were subjected to ADT and cytoreductive radical prostatectomy (CRP). Methods: Eighteen patients with biopsy proven, completely resectable PCA, minimal osseous metastases (equal to or less than three hot spots on bone scan), absence of visceral or extensive lymph node metastases were included in the pilot study. All patients (pts) underwent neoadjuvant ADT with luteinizing hormone-releasing hormone (LHRH) analogues for 6 months. If the PSA serum level decreased to less than 0.4 ng/ml and osseous lesions disappeared on control scan, pts were considered suitable for extended RP followed by 2 years adjuvant ADT. Results: Mean age was 61 (42 to 69), the mean PSA was 96.3 (72 to 139) ng/ml and 0.29 (0 to 0.39) ng/ml at recruitment and at 6 months, respectively. Mean number of bone lesions was 1.9 (1 to 3) and all lesions disappeared after 6 months of ADT. Pathohistology revealed pT2c in 4 (22.2%), pT3a and pT3b in 3 (16.7%) and 11 (61.11%) pts, respectively. Seven (38.9%) pts and three (16.7%) pts had lymph node metastases or positive surgical margins (PSM). PSM were treated with adjuvant radiation therapy ad 66.6Gy. No Clavien grade 3 to 5 complications occurred. The mean follow-up is 29 (3 to 52) months, three (16.7%) pts relapsed. The remainder is without evidence of disease. Conclusions: CRP is feasible in well selected men with low volume osseous metastases who respond well to neoadjuvant ADT. These men have a life expectancy of around 7 years and CRP reduces the risk of locally recurrent PCA and local complications. CRP might be a new treatment option in the multimodality management of PCA and minimal metastatic disease.

ASTRO 2013

ASTRO 2013

Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Prospective evaluation of testosterone (T) recovery and PSA relapse following 18 months of androgen deprivation (ADT) after prostatectomy (RP): Results from the TAX-3501 trial.

5023 Background: Surgical adjuvant trials in men with prostate cancer (PCa) employing progression free (PFS) and overall survival (OS) endpoints require large sample sizes and long-term follow-up, challenging planned study completion. Recent adjuvant trials are designed to evaluate PSA progression as the primary study endpoint. Since PSA is T-responsive, a thorough understanding of T recovery kinetics after ADT is needed. Methods: TAX-3501 was a randomized phase III adjuvant study post-RP in men with high-risk PCa (n=228) comparing 18 months of hormonal therapy with (CHT) or without (HT) docetaxel either immediately (I) or deferred (D). We analyzed the T recovery data in 108 patients treated with HT who had at least one post-treatment T value. Results: After a median post-treatment follow-up of 676 days (d) (interquartile range 478-847 d) 90 (83%) and 64 (59%) of men had T recovery to &gt;150 ng/dL and to baseline respectively. No significant differences in T recovery between groups were observed (Table). The median time to T recovery from the last day of treatment to &gt;150 ng/dL was 306 d (95% CI, 294-345 d) and to baseline was 487 d (95% CI, 457-546 d). The baseline T recovery in the combined docetaxel [i.e. I(CHT)+D(CHT)] and HT arms [i.e. I(HT)+D(HT)] was not significantly different at 458 d (95% CI, 336-529 d) and 535 d (95% CI, 457-749 d) respectively (HR 1.4, P=0.18). After a median total follow-up of 3.4 years(IQR 2.3–3.8 years) 39/228 (17%) patients had PSA progression, metastatic progression occurred in 1 patient. Conclusions: Prospective analyses of T kinetics in TAX-3501 indicate that recovery is prolonged after 18 months of HT and PSA relapses occur late. Given that PSA is androgen responsive, concomitant post-HT T monitoring is critical for understanding PSA relapse rates after HT. Further, since the correlation of PSA relapse with PFS and OS in the adjuvant setting remains poorly defined, metastasis-free survival may be a more reliable and meaningful clinical endpoint. Clinical trial information: NCT00283062. [Table: see text]

Primary androgen deprivation (AD) followed by active surveillance (AS) for newly diagnosed prostate cancer (PC): A retrospective study

Active surveillance (AS) is only recommended for Low-Risk prostate cancer (PC) with <34% biopsies positive. Studies describing the long-term outcome of men treated with androgen deprivation (AD) followed by AS are sparse. One hundred two men were treated with 12 months of AD in a medical oncology clinic specializing in PC between 1998 and 2007 and were followed for a median of 7.25 years. The biopsy complete response rate after AD and the incidence of disease progression while on subsequent AS was assessed. Baseline age, D'Amico risk category, PSA velocity, percentage core biopsies, and prostate volume were evaluated as potential predictors of disease progression. D'Amico risk category for the 102 men: Low: n = 22, Intermediate: n = 30, and High: n = 50. Medians: Age 67.3, PSA 7.8, Gleason 3 + 4, >50% core biopsies positive, stage T1c. Seventy men had a clear biopsy and 31 of these had disease progression leading to additional treatment after a median of 52 months. D'Amico risk category of the 57 men with a positive biopsy after AD or disease progression on AS was: Low: n = 4 (18%), Intermediate: n = 16 (53%), and High: n = 37 (74%). No PC deaths occurred. Three men had clinical progression. In stepwise logistic regression analysis only higher D'Amico risk category and lower prostate volume predicted disease progression. Despite a high prevalence of ≥50% core biopsies positive at baseline, AD induces durable remissions in most men with Low-Risk and about half with Intermediate-Risk PC.

Patient-reported Quality of Life (QOL) in Unfavorable-Risk Prostate Cancer: Sexual Function Recovery after External Beam Radiation (RT) and 6 months of Androgen Deprivation

Materials/Methods: One hundred men with high-risk prostate cancer received RT to 72 Gy with rectal balloon placement for prostate immobilization. Patients received combined androgen blockade for a total of 6 months. Patients completed the validated Prostate Cancer Symptom Indices (PCSI), measuring sexual, urinary, and bowel QOL at baseline (pretreatment) and 6, 12, 18, 24, 30 and 36 months after treatment completion. Sexual Dysfunction is scored from 0 (no dysfunction) to 100 (maximum dysfunction) on the PCSI. Scores are translated into ‘normal’ (no symptoms), ‘intermediate’ (symptoms but useful function) and ‘poor’ (no useful function) levels of sexual function to facilitate interpretation of QOL results, as previously validated. Men with normal or intermediate function have ‘useful’ sexual function, while those with poor function have ‘no useful’ function.

Antivascular Effects of Neoadjuvant Androgen Deprivation for Prostate Cancer: An In Vivo Human Study Using Susceptibility and Relaxivity Dynamic MRI

The antivascular effects of androgen deprivation have been investigated in animal models; however, there has been minimal investigation in human prostate cancer. This study tested the hypothesis that androgen deprivation causes significant reductions in human prostate tumor blood flow and the induction of hypoxia at a magnitude and in a time scale relevant to the neoadjuvant setting before radiotherapy. Twenty patients were examined, each with five multi-parameter magnetic resonance imaging scans: two scans before the commencement of androgen suppression, one scan after 1 month of hormone treatment, and two further scans after 3 months of therapy. Quantitative parametric maps of the prostate informing on relative blood flow (rBF), relative blood volume (rBV), vascular permeability (transfer constant [K(trans)]), leakage space (v(e)) and blood oxygenation (intrinsic relaxivity [R(2)∗]) were calculated. Tumor blood volume and blood flow decreased by 83% and 79%, respectively, in the first month (p < 0.0001), with 74% of patients showing significant changes. The proportion of individual patients who achieved significant changes in T1 kinetic parameter values after 3 months of androgen deprivation for tumor measurements was 68% for K(trans) and 53% for v(e) By 3 months, significant increases in R(2)∗ had occurred in prostate tumor, with a rise of 41.1% (p < 0.0001). Androgen deprivation induces profound vascular collapse within 1 month of starting treatment. Increased R(2)∗ in regions of prostate cancer and a decrease in blood volume suggest a reduction in tumor oxygenation.

Androgen Deprivation Therapy in Patients Treated with External Beam Radiotherapy for High-risk Prostate Cancer in the PSA Era

Androgen Deprivation Therapy in Patients Treated with External Beam Radiotherapy for High-risk Prostate Cancer in the PSA Era

Neoadjuvant androgen deprivation for prostate volume reduction: The optimal duration in prostate cancer radiotherapy

Objectives For locally advanced prostate cancer, the results of radiotherapy are improved by combination with androgen deprivation therapy. Volume reduction achieved with neoadjuvant hormonal treatment can facilitate dose escalation without increasing the toxicity. The optimal duration of hormonal treatment, however, is unknown. The endpoint of this study is the optimal duration of androgen deprivation for prostate volume reduction in a cohort of patients scheduled for external beam radiotherapy. Patients and methods Twenty patients scheduled for external beam radiotherapy with cT2-3No/xMo prostate cancer were treated with a luteinizing hormone releasing hormone agonist (busereline) and nonsteroidal anti-androgen (nilutamide) for 9 months consecutively. Repeated CT scan examination was performed 3-monthly to measure prostate volumes until the start of radiation therapy. The analysis of volume reduction was performed with the Wilcoxon signed ranks test. Results The baseline median prostate volume for the cohort of patients was 82 cc (95% CI: 61–104 cc) with a median volume reduction of 31% (95% CI: 26%–35%) ( P < 0.0001) after 3 months of androgen deprivation. Between 3 and 6 months, a median volume reduction of 9% (95% CI: 4%–14%) ( P < 0.0001) was observed. The effect was more pronounced in large prostates (>60 cc) than in small prostates (≤60 cc). In the total cohort of patients no significant volume reduction occurred between 6 and 9 months of maximal androgen blockade (MAB). Conclusions In this study, we have shown that the most significant prostate volume reduction is achieved after 3 months of MAB with a maximum reduction after 6 months. Therefore, the optimal duration of neoadjuvant androgen deprivation to reduce prostate volume before prostate cancer radiotherapy is 6 months. In small prostates 3 months of hormonal treatment may be enough for maximal volume reduction.

Longitudinal analysis of androgen deprivation of prostate cancer cells identifies pathways to androgen independence

Following androgen ablation therapy, the majority of prostate cancer patients develop treatment resistance with a median time of 18-24 months to disease progression. To identify molecular targets that promote prostate cancer cell survival and contribute to androgen independence, we evaluated changes in LNCaP cell gene expression during 12 months of androgen deprivation. At time points reflecting critical growth and phenotypic changes, we performed Affymetrix expression array analysis to examine the effects of androgen deprivation during the acute response, during the period of apparent quiescence, and following the emergence of a highly proliferative, androgen-independent prostate cancer cell phenotype (LNCaP-AI). We discovered alterations in gene expression for molecules associated with promoting prostate cancer cell growth and survival, and regulating cell cycle progression and apoptosis. Additionally, expression of AR co-regulators, adrenal androgen metabolizing enzymes, and markers of neuroendocrine disease were significantly altered. These findings contribute greatly to our understanding of androgen-independent prostate cancer. The value of this longitudinal approach lies in the ability to examine gene expression changes throughout the adaptive response to androgen deprivation; it provides a more dynamic illustration of genes which contribute to disease progression in addition to specific genes which constitute an androgen-independent phenotype.

P68. Which IV bisphosphonates must be used after initiating androgen deprivation therapy in patients submitted to radical prostatectomy experiencing recurrence? A prospective open-label controlled study

Objectives: Androgen-deprivation therapy (ADT) may promote osteoporosis and osteopenia. Methods: 94 prostatectomized men with rising PSA were enrolled into the placebo group (31), monthly IV clodronate (39) or monthly IV zoledronic acid (24) for 36 months. Dualenergy x-ray absorptiometry measured the bone density in the lumbar (L2–L4) area. Chi-squared and ANOVA tests were used. Results: After 6 months of androgen deprivation 17 out of 31 cases of control cases developed osteopenia in the lumbar area. In 12months, 9 control cases reached osteoporosis with 13 additional cases of osteopenia. At the end of the 36months study period the untreated group showed an average BMD loss of 1.82 (±0.94) with 13 cases of osteopenia and 18 cases of osteoporosis. Clodronate group showed 2 cases of osteoporosis out of 39 after 6 months on androgen deprivation with 28 developing osteopenia and 7 cases of osteoporosis after 36 months of follow-up. Mean BMD loss in this group was 0.72 (±0.34). Zoledronic acid studied arm showed 7 cases of osteopenia after 6 months on androgen deprivation while 20 and 5 cases developed osteopenia and osteoporosis respectively after 36 months of follow-up. The former group had mean bone loss of 0.88 (±0.32). There was statistical difference for BMD loss in the treated groups starting at 6 months in comparison to the control group. Conclusions: There is impressive bone loss after androgen deprivation but it can be reverted by preventive bisphosphonates usage.