Intermittent Androgen Deprivation Research Articles

EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer

ObjectivesOur aim is to present a summary of the 2010 version of the European Association of Urology (EAU) guidelines on the treatment of advanced, relapsing, and castration-resistant prostate cancer (CRPC). MethodsThe working panel performed a literature review of the new data emerging from 2007 to 2010. The guidelines were updated, and the levels of evidence (LEs) and/or grades of recommendation (GR) were added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews. ResultsLuteinising hormone-releasing hormone (LHRH) agonists are the standard of care in metastatic prostate cancer (PCa). Although LHRH antagonists decrease testosterone without any testosterone surge, their clinical benefit remains to be determined. Complete androgen blockade has a small survival benefit of about 5%. Intermittent androgen deprivation (IAD) results in equivalent oncologic efficacy when compared with continuous androgen-deprivation therapy (ADT) in well-selected populations. In locally advanced and metastatic PCa, early ADT does not result in a significant survival advantage when compared with delayed ADT. Relapse after local therapy is defined by prostate-specific antigen (PSA) values >0.2ng/ml following radical prostatectomy (RP) and >2ng/ml above the nadir after radiation therapy (RT). Therapy for PSA relapse after RP includes salvage RT at PSA levels <0.5ng/ml and salvage RP or cryosurgical ablation of the prostate in radiation failures. Endorectal magnetic resonance imaging and 11C-choline positron emission tomography/computed tomography (CT) are of limited importance if the PSA is <2.5ng/ml; bone scans and CT can be omitted unless PSA is >20ng/ml. Follow-up after ADT should include screening for the metabolic syndrome and an analysis of PSA and testosterone levels. Treatment of castration-resistant prostate cancer (CRPC) includes second-line hormonal therapy, novel agents, and chemotherapy with docetaxel at 75mg/m2 every 3wk. Cabazitaxel as a second-line therapy for relapse after docetaxel might become a future option. Zoledronic acid and denusomab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications. ConclusionThe knowledge in the field of advanced, metastatic, and CRPC is rapidly changing. These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice. A full version is available at the EAU office or online at www.uroweb.org.

Primary Intermittent Androgen Deprivation As Initial Therapy for Men with Newly Diagnosed Prostate Cancer

Background The purpose of this study was to describe the long-term incidence of cancer progression and mortality in men with localized prostate cancer treated with primary androgen deprivation (AD). Methods A retrospective chart review, from a medical oncology practice specializing in prostate cancer, was conducted of 73 men eligible for surgery or radiation treated with induction AD. Entry criteria consisted of a minimum of 9 months of induction AD, treatment initiation before 1999, clinical stage < T3, and outcome defined as the incidence of delayed local therapy, cancer progression, cancer mortality, and mortality from other causes. Results Median follow-up was 12 years. Fifteen men were at low risk, 38 were at intermediate risk, and 20 were at high risk. Three men (4%) experienced metastatic disease and died of prostate cancer after 3.5, 7.7, and 11 years, respectively. Two men were in the intermediate-risk category and 1 was high risk. Nineteen men (26%) died of non–prostate cancer causes. None had metastatic disease at the time of death. Of the remaining 51 survivors, none has experienced bone metastasis. Twenty-one men (29%) required no further therapy after the first induction course of AD. Twenty-four men (33%) maintained a prostate-specific antigen (PSA) level < 5.0 ng/mL with 2 to 5 cycles of intermittent AD. Twenty-eight men (38%) underwent delayed local therapy after a median of 5.5 years. Median follow-up after local therapy was 6.2 years. Three of these men experienced subsequent rising PSA levels but none has progressed to bone metastasis. Sixteen of 20 men (80%) in the high-risk category but only 12 of 53 men (23%) in the low- and intermediate-risk categories had delayed local therapy. Conclusions Primary intermittent AD is feasible for men with localized prostate cancer. Men who are younger and men with high-risk disease undergo delayed local therapy more frequently.

UP-02.157 The Impact of Intermittent Androgen Deprivation Therapy for Biochemical Failure After Radical Prostatectomy

UP-02.157 The Impact of Intermittent Androgen Deprivation Therapy for Biochemical Failure After Radical Prostatectomy

Control of prostate cancer associated with withdrawal of a supplement containing folic acid, L-methyltetrahydrofolate and vitamin B12: a case report

IntroductionThis is the first report of possible direct stimulation of hormone-resistant prostate cancer or interference of docetaxel cytotoxicity of prostate cancer in a patient with biochemical relapse of prostatic-specific antigen. This observation is of clinical and metabolic importance, especially at a time when more than 80 countries have fortified food supplies with folic acid and some contemplate further fortification with vitamin B12.Case presentationOur patient is a 71-year-old Caucasian man who had been diagnosed in 1997 with prostate cancer, stage T1c, and Gleason score 3+4 = 7. His primary treatment included intermittent androgen deprivation therapy including leuprolide + bicalutamide + deutasteride, ketoconazole + hydrocortisone, nilandrone and flutamide to resistance defined as biochemical relapse of PSA. While undergoing docetaxel therapy to treat a continually increasing prostate-specific antigen level, withdrawal of 10 daily doses of a supplement containing 500 μg of vitamin B12 as cyanocobalamin, as well as 400 μg of folic acid as pteroylglutamic acid and 400 μg of L-5-methyltetrahydrofolate for a combined total of 800 μg of mixed folates, was associated with a return to a normal serum prostatic-specific antigen level.ConclusionThis case report illustrates the importance of the effects of supplements containing large amounts of folic acid, L-5-methyltetrahydrofolate, and cyanocobalamin on the metabolism of prostate cancer cells directly and/or B vitamin interference with docetaxel efficacy. Physicians caring for patients with prostate cancer undergoing watchful waiting, hormone therapy, and/or chemotherapy should consider the possible acceleration of tumor growth and/or metastasis and the development of drug resistance associated with supplement ingestion. We describe several pathways of metabolic and epigenetic interactions that could affect the observed changes in serum levels of prostate-specific antigen.

Guía de la EAU sobre el cáncer de próstata. Parte II: tratamiento del cáncer de próstata avanzado, recidivante y resistente a la castración

Objectives Our aim is to present a summary of the 2010 version of the European Association of Urology (EAU) guidelines on the treatment of advanced, relapsing, and castration-resistant prostate cancer (CRPC). Methods The working panel performed a literature review of the new data emerging from 2007 to 2010. The guidelines were updated, and the levels of evidence (LEs) and/or grades of recommendation (GR) were added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews. Results Luteinising hormone-releasing hormone (LHRH) agonists are the standard of care in metastatic prostate cancer (PCa). Although LHRH antagonists decrease testosterone without any testosterone surge, their clinical benefit remains to be determined. Complete androgen blockade has a small survival benefit of about 5%. Intermittent androgen deprivation (IAD) results in equivalent oncologic efficacy when compared with continuous androgen-deprivation therapy (ADT) in well-selected populations. In locally advanced and metastatic PCa, early ADT does not result in a significant survival advantage when compared with delayed ADT. Relapse after local therapy is defined by prostate-specific antigen (PSA) values > 0.2 ng/ml following radical prostatectomy (RP) and > 2 ng/ml above the nadir after radiation therapy (RT). Therapy for PSA relapse after RP includes salvage RT at PSA levels < 0.5 ng/ml and salvage RP or cryosurgical ablation of the prostate in radiation failures. Endorectal magnetic resonance imaging and 11C-choline positron emission tomography/computed tomography (CT) are of limited importance if the PSA is < 2.5 ng/ml; bone scans and CT can be omitted unless PSA is >20 ng/ml. Follow-up after ADT should include screening for the metabolic syndrome and an analysis of PSA and testosterone levels. Treatment of castration-resistant prostate cancer (CRPC) includes second-line hormonal therapy, novel agents, and chemotherapy with docetaxel at 75 mg/m 2 every 3 wk. Cabazitaxel as a second-line therapy for relapse after docetaxel might become a future option. Zoledronic acid and denusomab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications. Conclusion The knowledge in the field of advanced, metastatic, and CRPC is rapidly changing. These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice. A full version is available at the EAU office or online at www.uroweb.org.

Predictors for response to intermittent androgen deprivation (IAD) in prostate cancer cases with biochemical progression after surgery

ObjectiveTo define characteristics of the first cycle of intermittent androgen deprivation (IAD) that would predict for outcomes in a long term follow-up. Material and methodsIn 1996 we started a prospective study of IAD for the treatment of biochemical progression (BP) after radical prostatectomy (RP) for prostate cancer (PC). The end-points of the trial were time to clinical progression (CP) and time to castration resistance PC (CRPC). Eighty-four cases were included in the study. In all cases, after an initial induction period, an acceptable nadir to switch from on-to-off-phase of IAD was considered to be a serum PSA < 1.0 ng/ml. MeasurementsAs possible predictors for time to CP and CRPC, we analyzed pretreatment parameters such as age, Gleason Score, serum PSA, testosterone, chromogranina A (CgA) levels, and characteristics from the first cycle of IAD. ResultsMean follow-up during IAD was 88.6 ± 16.7 months; 29.7% of patients developed CRPC and 14.2% of cases showed a CP with a mean time of 88.4 ± 14.3 months and 106.5 ± 20.6 months, respectively. At univariate and multivariate analysis, the PSA nadir during the first on-phase period and the first off-phase interval resulted in significant and independent predictors (P < 0.001) of the time to CRPC and CP. In particular for cases with a PSA nadir > 0.4 ng/ml and for those with an off-phase interval ≤ 24 weeks, the risk of CRPC and CP during IAD was 2.7–2.5 and 3.0–3.1 times that for patients with a PSA nadir ≤ 0.1 ng/ml and with an off-phase interval > 48 weeks, respectively. ConclusionsCases with BP after RP selected to IAD that show at the first cycle a PSA nadir ≤ 0.1 ng/ml and a off-phase interval ≥ 48 weeks may identify candidates who will experience better response to IAD treatments and delayed CP or CRPC development.

PSA doubling time (PSADT) and serum testosterone (T) during intermittent androgen deprivation (IAD) in patients with biochemically relapsed prostate cancer (BRCP; M0): Potential predictive implications.

e15006 Background: The systemic management of patients with BRPC remains controversial. IAD is commonly employed. Aims: To evaluate the PSA dynamics and serum T in pts with BRPC treated with IAD un...

Continuous vs. intermittent androgen deprivation therapy for metastatic prostate cancer

ObjectivesTo analyze the predictive value of PSA for progression and the role of testosterone for quality of life (QOL) in patients with androgen deprivation therapy (ADT) for metastatic prostate cancer. Materials and methodsPSA and testosterone data were used from a phase III trial randomizing patients without progression and PSA < 4 ng/ml (n = 193), after 6 months induction course, between continuous (CAD) (n = 96) and intermittent (IAD) (n = 97) ADT. The 2-year risk of progression was calculated for baseline PSA, ‘fast’ and ‘slow’ PSA decline to < 4 ng/ml (60 days cut-off), PSA nadir, performance status and pain. Testosterone kinetics and QOL were also evaluated. Univariate Kaplan Meier survival analysis and log rank tests were used to compare the risk of progression. ResultsFor progression analysis, 173 patients' data were available. The 2-year risk of progression for baseline PSA < 50 ng/ml, 50 to <500 ng/ml, and ≥500 ng/ml was 25%, 55%, and 76% (P = 0.03) in CAD, and 38%, 64%, and 85% (P = 0.006) in IAD, respectively. The 2-year risk of progression for PSA nadir ≤ 0.2 ng/ml, and > 0.2 to 4 ng/ml in CAD was 31% and 70% (P < 0.001), respectively. In the IAD group, a similar trend was seen. Patients with PSA nadir ≤ 0.2 ng/ml, though had significantly higher 2-year risk of progression compared to CAD (53% vs. 31% (P = 0.03), respectively. PSA decline showed no predictive value. Patients without pain had a significantly lower 2-year risk of progression in both groups. Without ADT testosterone remained at castrate level for 4 months. After the first and second IAD cycle 92% and 46%, respectively, had a normalized testosterone. No QOL difference was found, although more side effects occurred in CAD. ConclusionsMetastatic prostate cancer patients with high baseline PSA, pain, and high PSA nadir have a poor prognosis with ADT. Patients with low PSA nadir do significantly worse with IAD compared with CAD. Low testosterone after ADT and incomplete testosterone recovery may explain similar QOL. Therefore, IAD is not a good treatment option for many metastatic prostate cancer patients.

Novel agents and new therapeutics in castration-resistant prostate cancer

This review highlights recent therapeutic advances in systemic therapies for prostate cancer (PCa). Progress in PCa therapeutics has been made during the past year with the approval of a vaccine therapy, second-line chemotherapy, and reported survival advantage for a CYP (17,20) lyase inhibitor in castration-resistant prostate cancer (CRPC). This report will summarize the recently reported and expected data for PCa trials including an evaluation of intermittent vs. continuous androgen deprivation therapy. Denosumab is shown to support bone mineral density in hormonal sensitive PCa patients. Targeting of androgen-dependent pathways in CRPC postchemotherapy has been shown to improve survival with the lyase inhibitor abiraterone, and lead to prostate-specific antigen and objective responses with an androgen receptor antagonist (MDV3100). However, the addition of bevacizumab to docetaxel/prednisone in treating metastatic CRPC failed to provide a survival benefit. Cabazitaxel in metastatic CRPC postdocetaxel did demonstrate a survival benefit. Provenge, an autologous dendritic cell-based vaccine, demonstrated a reduction in the risk of death in metastatic CRPC. Other immunotherapy agents, including Prostvac and ipilimumab are under investigation. We also discuss the receptor tyrosine kinase inhibitor XL184 and poly (ADP-ribose) polymerase inhibitors which are in early clinical trials. Recent advances in androgen targeting, chemotherapy, immunotherapy, and other targeted therapies have led to significant improvements in the care of CRPC patients.

The change of PSA doubling time and its association with disease progression in patients with biochemically relapsed prostate cancer treated with intermittent androgen deprivation.

We sought to determine the change of PSA doubling time (PSADT) and its association with disease progression during intermittent androgen deprivation (IAD) therapy for prostate cancer. Data were retrospectively analyzed in 96 patients with biochemically relapsed prostate cancer (BRPC) treated with IAD since 1995. IAD consisted of LHRH-agonists ± antiandrogen given usually at PSA threshold (ng/ml) of 10-20, for 6-9 months. Cycles were repeated until the development of castration resistance. Mixed effects model was used to study PSADT change over cycles. Multivariate cox regression model was used to identify outcome-associated variables. Patients received a mean of 2.8 treatment cycles over a mean follow-up time of 71 months. Fifty-seven (59%) remain on treatment and 39 (41%) developed PSA refractoriness (n = 8) or positive scans (n = 31). First off treatment interval PSADT (median 2.3 months) was significantly shorter than the baseline (median 7.34) but remained stable in subsequent cycles. Off treatment interval PSADT adjusted for testosterone recovery (median 3.7) was significantly longer than that based on all PSA determinations (median 2). Factors associated with disease progression were pre-treatment PSADT (≥6 vs. <6), first off treatment interval PSADT (≥3 vs. <3), and PSA nadir during the first treatment interval (<0.1 vs. ≥0.1). During IAD for BRPC, PSADT becomes shorter, and is associated with testosterone recovery. PSADT before treatment and during the first off treatment interval is associated with disease progression. If prospectively validated these data may guide treatment with IAD and clinical trial design.

351 INTERMITTENT ANDROGEN DEPRIVATION AS SECONDARY THERAPY FOR BIOCHEMICAL RECURRENCE OF LOCALIZED PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Localized1 Apr 2011351 INTERMITTENT ANDROGEN DEPRIVATION AS SECONDARY THERAPY FOR BIOCHEMICAL RECURRENCE OF LOCALIZED PROSTATE CANCER Rafael Sanchez-Salas, Dominique Prapotnich, Fernando Secin, Ricardo Favaretto, Francois Rozet, Vincent Flamand, Marc Galiano, Nathalie Cathala, Annick Mombet, Eric Barret, and Xavier Cathelineau Rafael Sanchez-SalasRafael Sanchez-Salas Paris, France More articles by this author , Dominique PrapotnichDominique Prapotnich Paris, France More articles by this author , Fernando SecinFernando Secin Buenos Aires, Argentina More articles by this author , Ricardo FavarettoRicardo Favaretto Paris, France More articles by this author , Francois RozetFrancois Rozet Paris, France More articles by this author , Vincent FlamandVincent Flamand Paris, France More articles by this author , Marc GalianoMarc Galiano Paris, France More articles by this author , Nathalie CathalaNathalie Cathala Paris, France More articles by this author , Annick MombetAnnick Mombet Paris, France More articles by this author , Eric BarretEric Barret Paris, France More articles by this author , and Xavier CathelineauXavier Cathelineau Paris, France More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.436AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To present the long term oncological outcomes of patients treated with Intermittent Androgen Deprivation (IAD) after biochemical recurrence of localized prostate cancer. METHODS Between 1992 and 2010, 654 patients with prostate cancer (PC) were selected for IAD at our institution. Out of these, 263 patients (40%) had a biochemical recurrence (BCR) after local treatment and 146 patients with a minimum follow-up of 5 years were selected for the study. On-treatment period (ONTP) was gonadatropin-releasing hormone (GnRH) agonist and androgen receptor antagonist. Off-treatment period (OFTP) was indicated when PSA was < 4 ng/ml. Criteria for resumption of hormonal therapy were PSA > 20 ng/ml or clinical symptoms. Cancer specific survival curves were computed according to the Kaplan-Meier method. RESULTS Median follow-up was 93.4 months (61–219.3). Median age was 69.8 years (52.4–81.8.146 patients were primarily treated either by surgery(72) or by a physical therapy(74) like external radiation, brachytherapy or high intensity focused ultrasound (HIFU. Median PSA at initial IAD was 9.8 ng/ml (4.2–25). Median time from local treatment and IAD was 29.2 months (2–52). Cycle duration decreased progressively from 18.2 months for the 1st cycle to 11.3 months at the 5th cycle then stabilized until the 11th cycle. 55 patients (38%) became non responsive to IAD (PSA still >4 ng/ml after ONTP) and evolved towards continuous androgen deprivation(CAD), among these patients, 50(34%) became hormone resistant (PSA rising up more than + 2 ng/ml despite CAD) and underwent chemotherapy. Death occurred in 50 patients (34%) and 24(16%) was cancer related in a median time of 69 months(65–145) after the beginning of IAD. Mean cancer specific survival probability for the series is 122 months (78.6–105.1). Multivariate analysis of cancer specific survival demonstrates age, initial Gleason score and initial PSA level as significant factors affecting mortality. As IAD was given after a surgery procedure or a radiation procedure, the impact of IAD on the assessment of quality of life in term of sexual function or urinary continence by the mean of questionnaires was not reliable. Decrease of side-effects related to IAD was strongly underlined by patient during the OFTP when compared to the ONTP. CONCLUSIONS At a long term evaluation IAD after failure of primary treatment shows a good efficacy with a long term survival rate associated to a minimal amount of side-effects. Duration of cycle decreased progressively during therapy. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e142-e143 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rafael Sanchez-Salas Paris, France More articles by this author Dominique Prapotnich Paris, France More articles by this author Fernando Secin Buenos Aires, Argentina More articles by this author Ricardo Favaretto Paris, France More articles by this author Francois Rozet Paris, France More articles by this author Vincent Flamand Paris, France More articles by this author Marc Galiano Paris, France More articles by this author Nathalie Cathala Paris, France More articles by this author Annick Mombet Paris, France More articles by this author Eric Barret Paris, France More articles by this author Xavier Cathelineau Paris, France More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

887 PROGNOSTIC PREDICTORS FOR TIME TO CLINICAL PROGRESSION AND CASTRATION RESISTANCE IN

You have accessJournal of UrologyProstate Cancer: Advanced1 Apr 2011887 PROGNOSTIC PREDICTORS FOR TIME TO CLINICAL PROGRESSION AND CASTRATION RESISTANCE IN Alessandro Sciarra, Stefano Salciccia, Andrea Alfarone, Susanna Cattarino, Alessandro Gentilucci, Ulderico Parente, and Vincenzo Gentile Alessandro SciarraAlessandro Sciarra Rome, Italy More articles by this author , Stefano SalcicciaStefano Salciccia Rome, Italy More articles by this author , Andrea AlfaroneAndrea Alfarone Rome, Italy More articles by this author , Susanna CattarinoSusanna Cattarino Rome, Italy More articles by this author , Alessandro GentilucciAlessandro Gentilucci Rome, Italy More articles by this author , Ulderico ParenteUlderico Parente Rome, Italy More articles by this author , and Vincenzo GentileVincenzo Gentile Rome, Italy More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.753AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The purpose of this analysis was to define characteristics of the first cycle of intermittent androgen deprivation (IAD) that would predict for outcomes in a long term follow-up. METHODS In 1996 we started a prospective study of IAD for the treatment of biochemical progression (BP) (PSA increase > 0.2 ng/ml) after radical prostatectomy (RP) for prostate adenocarcinoma (PC). The primary end-point of the trial was time to clinical progression (CP) but also time to castration resistance PC (CRPC). Eighty-four cases fulfilled the inclusion criteria and were included in the study. In all cases, after an initial induction period, an acceptable nadir to switch from on-to-off-phase of IAD was considered to be a serum PSA of less than 1.0 ng/ml. As possible predictors for time to CP and CRPC we analyzed pretreatment parameters such as age, Gleason Score, serum PSA, testosterone and Chromogranina A (CgA) levels and also characteristics from the first cycle of IAD. RESULTS Mean follow-up during IAD was 88.69 À 16.74 months; 29.77% of patients developed CRPC and 14.28% of cases showed a CP with a mean time of 88.40 À 14.34 months and 106.50 À 20.65 months respectively. At the univariate and multivariate analysis the PSA nadir during the first on-phase period and the first off-phase interval resulted significant and independent predictors (p<0.001) of the time to CRPC and CP. In particular for cases with a PSA nadir > 0.4 ng/ml and for those with an off-phase interval Ù 24 weeks, the risk of CRPC and CP during IAD was 2.7–2.5 and 3.0–3.1 times that for patients with a PSA nadir Ù 0.1 ng/ml and with an off-phase interval > 48 weeks respectively. The predictive value of these two parameters resulted significant also after adjusting for age, stage, Gleason score and PSA at diagnosis or at BP. CONCLUSIONS Cases with BP after RP selected to IAD that show at the first cycle a PSA nadir Ù 0.1 ng/ml and a off-phase interval ¡Ý 48 weeks, are the best candidate for long IAD treatments without the development of CRPC or CP. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e355 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alessandro Sciarra Rome, Italy More articles by this author Stefano Salciccia Rome, Italy More articles by this author Andrea Alfarone Rome, Italy More articles by this author Susanna Cattarino Rome, Italy More articles by this author Alessandro Gentilucci Rome, Italy More articles by this author Ulderico Parente Rome, Italy More articles by this author Vincenzo Gentile Rome, Italy More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

PSA doubling time (PSADT) and serum testosterone (T) during intermittent androgen deprivation (IAD) in patients with biochemically relapsed prostate cancer (BRCP; M0): Potential predictive implications.

150 Background: The systemic management of patients with BRPC remains controversial. IAD is commonly employed. Aims: To evaluate the PSA dynamics and serum T in pts with BRPC treated with IAD until the development of PSA refractoriness or clinical evidence of metastatic disease. Methods: Data were retrospectively analyzed in all pts with BRCP treated with GnRH at PSA thresholds according to pre-treatment PSADT (10-15ng/mL, 15-20, and 20-30 for PSADT ≤3 mos, 3-9 mos, and ≥ 9 ms, respectively) and continued until PSA nadir. Antiandrogen (AA) was added for PSA &gt; 1.0 ng/mL after 3 mos). Follow-up (FU) consisted of PSA and T q3 mos. Cycles were repeated at the above preselected PSA thresholds and continued until lack of PSA response. Scans were obtained prior to cycles and at the time of CRPC state. Mixed effects model was used to study PSADT change over cycles. Multivariate cox regression model was used to identify prognostic variables. Results: From 1995-2010, with a mean FU of 71 mos (range 22-183 months), 96 pts received a mean of 2.8 cycles (range 1-9) of IAD; 58 (60%) remain on treatment and 38 (40%) were switched to continuous ADT due to PSA refractoriness (n=11) or positive scans (n=27). PSADT at the first off treatment (tx) interval (mean 3.1, 0.59-30.5 range, median 2.3) was significantly shorter than the baseline (p&lt;0.0001; mean 9.7, range 0.27-53.9, median 7.34) but remained relatively stable (p=0.29) in subsequent cycles. PSADT adjusted for T recovery (≥3 ms after T recovery to ≥ 150 ng/dL) was significantly longer (p=0.006) than that based only on all PSA determinations (mean 5.4, range 1.31-30.5, median 3.7 versus mean 3.1, range 0.59-30.5, median 2.3). Significant factors associated with probability of PSA refractoriness were pre-IAD PSADT (≥ 6 vs &lt;6 ms), first off tx interval PSADT (≥3 ms vs &lt;3m), the use of AA during first tx cycle, and PSA nadir during the first tx interval (&lt;0.1 vs ≥0.1 ng/mL). Conclusions: Our data suggest that PSADT becomes shorter after the initial cycle of IAD and correlate with T recovery. PSA dynamics and need for AA to enhance PSA nadir are associated with PSA refractoriness in pts BRPC treated with IAD. No significant financial relationships to disclose.

Intermittent androgen-deprivation therapy in the management of castrate-resistant prostate cancer (CRPCa): Results of a multi-institutional randomized prospective clinical trial.

131 Background: Patients who develop CRPCa typically continue on androgen deprivation therapy (ADT). Whether these patients need to remain on ADT has not been well studied. We conducted a multicenter randomized trial to compare intermittent versus continuous approach to ADT in CRPCa patients. Overall survival, health related quality of life (QOL) and cost were the main endpoints. We hypothesized that the intermittent approach would be cost-saving while maintaining similar oncologic and QOL outcomes. Methods: CRPCa patients were randomized 1:2 to continuous or intermittent luteinizing hormone releasing hormone agonists (LHRHa). Patients were followed with clinical assessments, laboratory investigations, and QOL questionnaires (EORTC QLQ-C30 or PROSQOLI) every 2 months. If the serum testosterone rose above castrate levels (1.75nmol/L), LHRHa were re-initiated. The study was designed to close if &gt;50% of patients needed to restart ADT in the intermittent arm. Results: 31 patients were followed with a median follow-up of 26.8 months; 18 in the intermittent arm and 13 in the continuous. 12/18 patients on the intermittent arm were re-initiated on LHRHa at a median time of 17.9 months. There was no difference in overall or cancer-specific survival between the two arms. There was no statistically significant difference in QOL between the two arms at 0 and 12 months. The total mean costs at 24 months were significantly lower in the intermittent arm (3135 $CAD vs 8253 $CAD, p=0.0167) compared to the continuous arm largely due to the reduced costs of the LHRHa. Conclusions: We have observed that intermittent ADT in patients with CRPCa, using a testosterone of &gt;1.75 ngmol/L as a trigger to re-initiate LHRHa, results in a substantial cost savings with no negative impact on oncologic and QOL outcomes. These findings need to be corroborated in a study with a larger sample size. [Table: see text]

Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer.

Prostate cancer is the most frequently diagnosed non-cutaneous tumor of men in Western countries. While surgery is often successful for organ-confined prostate cancer, androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. Shortening the period of androgen ablation therapy may benefit prostate cancer patients. Intermittent Androgen Deprivation therapy improves quality of life, reduces toxicity and medical costs, and delays disease progression in some patients. Cell culture and xenograft studies using androgen receptor (AR)-positive castration-resistant human prostate cancers cells (LNCaP, ARCaP, and PC-3 cells over-expressing AR) suggest that androgens may suppress the growth of AR-rich prostate cancer cells. Androgens cause growth inhibition and G1 cell cycle arrest in these cells by regulating c-Myc, Skp2, and p27Kip via AR. Higher dosages of testosterone cause greater growth inhibition of relapsed tumors. Manipulating androgen/AR signaling may therefore be a potential therapy for AR-positive advanced prostate cancer.

Inhibition of 5alpha-reductase enhances testosterone-induced expression of U19/Eaf2 tumor suppressor during the regrowth of LNCaP xenograft tumor in nude mice.

Intermittent androgen deprivation therapy (IADT) was developed to improve the quality of life and retard prostate cancer progression to castration resistance. IADT involves regrowth of the tumor during the off cycle upon testosterone recovery. Our previous studies showed that testosterone is more potent than dihydrotestosterone (DHT) in the induction of a subset of androgen-responsive genes during rat prostate regrowth. However, it is not clear if the same phenomenon would occur during androgen-induced regrowth of prostate tumors. Understanding the differences between testosterone and DHT in inducing androgen-responsive genes during prostate tumor regrowth may provide new insight for improving IADT. Nude mice bearing androgen-sensitive LNCaP xenograft were castrated and followed up for 7-10 days before being randomized into various androgen manipulations, consisting of continuous castration (C) or testosterone replacement (T) in the absence or presence of dutasteride (D), a 5alpha-reductase inhibitor that blocks the conversion of testosterone to DHT. Testes-intact animals in the absence or presence of D were used as controls. The expression of five androgen-responsive genes, including the tumor suppressor U19/Eaf2, was determined using real-time RT-PCR, 3 days after randomization. In LNCaP tumors, the expression of U19/Eaf2 was higher in the T+D group as compared with T alone (2.87-fold, P < 0.05). In contrast, dutasteride treatment in testes-intact animals inhibited the expression of U19/Eaf2. Inhibition of 5alpha-reductase during LNCaP tumor regrowth enhanced the expression of U19/Eaf2, an androgen-regulated tumor suppressor. This finding suggests that off cycle 5alpha-reductase inhibition may enhance the efficacy of IADT.

Correlation between serum PSA and testosterone (T) kinetics in patients (pts) with biochemically relapsed prostate cancer (BRPC) (M0), after local treatment (tx), treated with intermittent androgen deprivation (IAD).

4641 Background: IAD is often applied in BRPC (M0) after local tx. Criteria for initiation of androgen deprivation therapy (ADT) and evaluation based on PSA dynamics remain poorly defined. Shortening of PSA doubling time (PSADT) following repeated cycles has been reported as a common development in pts treated by IAD. Aims: To analyze the correlation between serum PSA and T dynamics following discontinuation of ADT in pts with BRPC (M0) treated with IAD. Methods: Data on pts with BRPC (M0) treated by IAD were retrospectively analyzed. Pts received 6-9 months (ms) of ADT discontinued when PSA nadired. Pts were followed with PSA, and T every 3 ms. The PSA threshold for re-tx was defined according to PSADT (PSA range of 10-15ng/ml, 15-20 ng/ml, and 20-30ng/ml for PSADT of ≤3ms, 3-9 ms, and ≥ 9 ms, respectively). IAD was continued until PSA refractoriness or development of progression of disease as evident by physical exams or scans. The correlation between the PSADT and T recovery kinetics was analyzed. Mixed effects model was used to study the dynamic change of PSADT over cycles. Results: Between 1994-2008, 76 pts received a median of 2.3 (range 1-9) cycles of IAD.The median off tx time between cycles was 17.9 mos (2-132 range). With an overall mean follow up time of 50.8 months (6-172 range), 52 pts (68%) remain on tx and 21 pts (28%) have demonstrated evidence of PSA refractoriness (n=6) or radiological progression (n=15). 3 pts (4%) were lost to followup. Evaluation of all PSA values from time of discontinuation (nadir PSA) to re-initiation of ADT (off tx period) demonstrated a progressive shortening of PSADT with each consecutive cycle (decrease of 2.11 ms per unit cycle, p<.0001). However, PSADT calculation including only PSA values obtained after a serum T >100ng/ml was reached, did not show significant shortening over time (decrease of 0.05 ms per unit cycle, p=0.2968). Conclusions: Evaluation of PSADT considering T kinetics in pts treated with IAD may provide more reliable information on PSA dynamics. This approach should be investigated prospectively and, if validated, applied in clinical practice and clinical trials. No significant financial relationships to disclose.

Dynamics of bone mineral density during intermittent androgen deprivation for men with biochemical recurrence of prostate cancer.

4558 Background: Androgen deprivation therapy (ADT) for prostate cancer leads to loss of bone mineral density (BMD) and increased fracture risk. We hypothesize that intermittent ADT (IADT) may attenuate BMD loss. Methods: Patients with rising PSA after surgery (RP) or radiation (RT) received IADT in a prospective clinical trial. After 9 months “on treatment” with leuprolide and flutamide, ADT was stopped and monthly PSA levels were measured during the “off treatment” interval until a threshold PSA (1 ng/mL for RP, 4 ng/mL for RT) was met. At that time, ADT was resumed in another cycle and patients were treated intermittently in this manner until castration resistance. Standardized average dual energy X-ray absorptiometry (DXA) scans of lumbar spine and left hip were performed at baseline and at each change in therapy. Men who completed at least one entire treatment cycle and who underwent at least 3 DXA scans were eligible for analysis. Results: Forty-eight of 100 patients met criteria. Mean spine BMD decreased 3.1% (p<0.0001) while mean hip BMD decreased 1.0% (p=0.005) during first “on treatment” interval. Significant gains were made in mean spine BMD of 1.8% (p=0.001) but not in the hip during first “off treatment” interval. Subsequent cycles of IADT also revealed attenuation of “on treatment” losses during “off treatment” intervals, though few achieved statistical significance (see table). Despite regained BMD during “off treatment” intervals, the net result for the first cycle was loss of 1.3% (p=0.08) at the spine and 1.0% (p=0.02) at the hip. Conclusions: ADT-induced loss of BMD is attenuated during the “off treatment” intervals of IADT. However, BMD does not return to baseline, sustaining only a smaller net loss. Cycle Lumbar spine Left hip N Mean BMDg/cm2 (% change) N Mean BMD g/cm2 (% change) 1 On 48 (−3.1) 48 (−1.0) Off 47 (1.8) 48 (−0.1) 2 On 38 (−0.7) 37 (0.4) Off 28 (1.2) 28 (0.2) 3 On 31 (0.1) 29 (−0.6) Off 24 (2.3) 23 (−0.1) 4 On 23 (−1.1) 20 (−0.4) Off 16 (0.4) 15 (−0.5) No significant financial relationships to disclose.

Duration of First Off-Treatment Interval Is Prognostic for Time to Castration Resistance and Death in Men With Biochemical Relapse of Prostate Cancer Treated on a Prospective Trial of Intermittent Androgen Deprivation

This was an exploratory analysis of a trial of intermittent androgen deprivation (IAD) in men with biochemical relapse (BR) to establish first cycle characteristics prognostic for progression to castration-resistant prostate cancer (CRPC) and death. Men with BR of prostate cancer after radical prostatectomy (RP) or radiation (RT) were treated with androgen deprivation therapy (ADT) comprised of leuprolide and flutamide. After 9 months on treatment, ADT was stopped, and monthly prostate-specific antigen (PSA) levels were observed during the off-treatment interval. When the PSA reached a threshold value (1 ng/mL for RP, 4 ng/mL for RT), ADT was resumed in a new cycle. Patients were treated intermittently in this manner until CRPC, which was defined as > or = two consecutive increasing PSA values while on ADT with castrate testosterone levels. Seventy-two of 100 patients enrolled onto the study met criteria for this analysis. The duration of the first off-treatment interval (< or = v > 40 weeks) was associated with shorter time to CRPC (hazard ratio = 2.9; 95% CI, 1.1 to 7.7; P = .03) and death (hazard ratio = 3.8; 95% CI, 1.1 to 13.6; P = .04) after adjusting for age, stage, grade, and PSA at diagnosis. In patients who completed the first cycle of IAD, a duration of the first off-treatment interval of < or = 40 weeks defines a subset of patients at higher risk of CRPC and death. Conversely, patients with an off-treatment interval of more than 40 weeks have a significantly better long-term prognosis.

Progression of Prostate Cancer Despite an Extremely Low Serum Level of Prostate-Specific Antigen

A 61-year-old man who had been diagnosed with prostate cancer 9 years ago and had been treated with pelvic irradiation and intermittent androgen deprivation therapy visited the emergency room because of back pain and weakness in both legs. Spine magnetic resonance imaging showed a lumbar epidural mass and spine metastasis. The whole-body workup revealed multiple metastases to the lymph nodes, bone, liver, and lung. The serum prostate-specific antigen was 0.02 ng/ml. He underwent laminectomy, posterior fixation, and epidural mass excision, and metastatic adenocarcinoma from the prostate was diagnosed. The patient underwent 1 cycle of docetaxel-based chemotherapy. More chemotherapy could not be done because of his general weakness. The patient died one month later of multiple organ failure.