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1.  Survival Following Primary Androgen Deprivation Therapy among Men with Localized Prostate Cancer 
Despite a lack of data, increasing numbers of patients are receiving primary androgen deprivation therapy (PADT) as an alternative to surgery, radiation or conservative management for the treatment of localized prostate cancer.
Evaluate the association between PADT and survival in elderly men with localized prostate cancer.
Main Outcome Measures
Cancer-specific and overall survival.
Population-based cohort study of 19,271 men who did not receive definitive local therapy for T1-T2 prostate cancer. Instrumental variable analysis was used to address potential biases associated with unmeasured confounding variables.
Medicare patients aged ≥66 years diagnosed in 1992-2002 within predefined US geographical areas.
Even though 41% of the population (median age 77) received PADT, PADT was associated with somewhat worse 10-year prostate cancer-specific survival (80.1% vs. 82.6%, hazard ratio [HR] 1.17; 95% CI 1.03–1.33) and no improvement in 10-year overall survival (30.2% vs. 30.3%,, HR 1.00; 95% CI 0.96–1.05) compared to conservative management. However, in a pre-specified subset analysis, PADT use in men with poorly-differentiated cancer was associated with marginally improved prostate cancer-specific survival (HR 0.84; 95% CI 0.70–1.00, P =0.05) but not overall survival (HR 0.92; 95% CI 0.84 – 1.01).
Primary androgen deprivation therapy is not associated with improved survival among the majority of elderly men with localized prostate cancer when compared with conservative management.
PMCID: PMC2645653  PMID: 18612114
prostatic neoplasm; Medicare; SEER program; antineoplastic agents; hormonal
2.  National Practice Patterns and Time Trends in Androgen Ablation for Localized Prostate Cancer 
Recent reports have suggested that growing numbers of patients with localized prostate cancer are receiving androgen deprivation therapy as primary or neoadjuvant treatment, yet sparse clinical evidence supports the use of such treatment in some contexts. We describe national trends in the use of androgen deprivation therapy for localized disease and identify sociodemographic variables that are associated with its use.
CaPSURE™ is an observational database of 7195 patients with prostate cancer. For this study, 3439 of these patients were included who were diagnosed since 1989, had clinical staging information available, and were treated with radical prostatectomy, radiation therapy, or primary androgen deprivation therapy (PADT). High-, intermediate-, or low-risk groups were defined by serum prostate-specific antigen level, Gleason sum, and clinical tumor stage. Time trends in use of PADT and neoadjuvant androgen deprivation therapy (NADT) were analyzed, and a multivariable logistic regression model was used to identify sociodemographic factors associated with various treatments. All statistical tests were two-sided.
Rates of PADT use have risen sharply from 4.6% to 14.2%, 8.9% to 19.7%, and 32.8% to 48.2% (all P<.001) in low-, intermediate-, and high-risk groups, respectively. NADT use likewise has increased in association with radical prostatectomy (2.9% to 7.8% of patients, P = .003) and external-beam radiotherapy (9.8% to 74.6%, P<.001) across all risk levels combined. Rates among patients treated with brachytherapy also have risen but the rise was not statistically significant. (7.4% to 24.6%, P = .100).
Rates of both PADT and NADT are increasing across risk groups and treatment types. Additional clinical trials must define more clearly the appropriate role of hormonal therapy in localized prostate cancer, and future results should shape updated practice guidelines.
PMCID: PMC2994265  PMID: 12837834
3.  Evaluation of primary androgen deprivation therapy in prostate cancer patients using the J-CAPRA risk score 
Prostate International  2013;1(2):81-88.
To determine the influence of maximal androgen blockade (MAB) and non-MAB hormonal therapy with an luteinizing hormone releasing hormone (LHRH) analog on overall survival of prostate cancer patients in the Japan Study Group of Prostate Cancer (J-CaP) registry according to risk, as assessed using the novel J-CAPRA risk instrument. To undertake a multivariate analysis combining J-CAPRA risk score, type of hormonal therapy and comorbidities, in order to assess their impact on overall survival.
The J-CaP database includes men in Japan diagnosed with any stage of prostate cancer between 2001 and 2003 and treated with primary androgen deprivation therapy (PADT), as monotherapy or in combination. A total of 26,272 men were enrolled and of these 19,265 were treated with PADT. This analysis was undertaken using the latest data set (30 April, 2010) including a total of 15,727 patients who received PADT and had follow-up data for periods ranging from 0 to 9.2 years.
MAB for prostate cancer patients with intermediate- or high-risk disease has a significant benefit in terms of overall survival compared with LHRH analog monotherapy or surgical castration alone. Better results may be achieved in older (≥75 years) patients. Patient comorbidities are an important factor in determining overall survival, notably in older patients, and should be considered when selecting therapy.
Based on large-scale registry data, this report is the first to analyze the outcomes of MAB therapy in patients with prostate cancer at a wide range of disease stages. MAB therapy may provide significant survival benefits in intermediate- and high-risk patients.
PMCID: PMC3814111  PMID: 24223407
Prostate neoplasms; Maximal androgen blockade; Overall survival; Primary androgen deprivation therapy; Risk scoring
4.  Risk Assessment Among Prostate Cancer Patients Receiving Primary Androgen Deprivation Therapy 
Journal of Clinical Oncology  2009;27(26):4306-4313.
Prostate cancer epidemiology has been marked overall by a downward risk migration over time. However, in some populations, both in the United States and abroad, many men are still diagnosed with high-risk and/or advanced disease. Primary androgen deprivation therapy (PADT) is frequently offered to these patients, and disease risk prediction is not well-established in this context. We compared risk features between large disease registries from the United States and Japan, and aimed to build and validate a risk prediction model applicable to PADT patients.
Data were analyzed from 13,740 men in the United States community-based Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry and 19,265 men in the Japan Study Group of Prostate Cancer (J-CaP) database, a national Japanese registry of men receiving androgen deprivation therapy. Risk distribution was compared between the two datasets using three well-described multivariable instruments. A novel instrument (Japan Cancer of the Prostate Risk Assessment [J-CAPRA]) was designed and validated to be specifically applicable to PADT patients, and more relevant to high-risk patients than existing instruments.
J-CaP patients are more likely than CaPSURE patients to be diagnosed with high-risk features; 43% of J-CaP versus 5% of CaPSURE patients had locally advanced or metastatic disease that could not be stratified with the standard risk assessment tools. J-CAPRA—scored 0 to 12 based on Gleason score, prostate-specific antigen level, and clinical stage—predicts progression-free survival among PADT patients in J-CaP with a c-index of 0.71, and cancer-specific survival among PADT patients in CaPSURE with a c-index of 0.84.
The novel J-CAPRA is the first risk instrument developed and validated for patients undergoing PADT. It is applicable to those with both localized and advanced disease, and performs well in diverse populations.
PMCID: PMC2744272  PMID: 19667269
5.  Does Primary Androgen-Deprivation Therapy Delay the Receipt of Secondary Cancer Therapy for Localized Prostate Cancer? 
European urology  2012;62(6):966-972.
Despite evidence that shows no survival advantage, many older patients receive primary androgen-deprivation therapy (PADT) shortly after the diagnosis of localized prostate cancer (PCa).
This study evaluates whether the early use of PADT affects the subsequent receipt of additional palliative cancer treatments such as chemotherapy, palliative radiation therapy, or intervention for spinal cord compression or bladder outlet obstruction.
Design, setting, and participants
This longitudinal population-based cohort study consists of Medicare patients aged ≥66 yr diagnosed with localized PCa from 1992 to 2006 in areas covered by the Surveillance Epidemiology and End Results (SEER) program. SEER-Medicare linked data through 2009 were used to identify the use of PADT and palliative cancer therapy.
Outcome measurements and statistical analysis
Instrumental variable analysis methods were used to minimize confounding effects. Confidence intervals were derived from the bootstrap estimates.
Results and limitations
This study includes 29 775 men who did not receive local therapy for T1–T2 PCa within the first year of cancer diagnosis. Among low-risk patients (Gleason score 2–7 in 1992–2002 and Gleason score 2–6 in 2003–2006) with a median age of 78 yr and a median follow-up of 10.3 yr, PADT was associated with a 25% higher use of chemotherapy (hazard ratio [HR]: 1.25; 95% confidence interval [CI], 1.08–1.44) and a borderline higher use of any palliative cancer surgery (HR: 1.07; 95% CI, 0.97– 1.19) within 10 yr of diagnosis in regions with high PADT use compared with regions with low PADT use. Because this study was limited to men >65 yr, the results may not be applicable to younger patients.
Early treatment of low-risk, localized PCa with PADT does not delay the receipt of subsequent palliative therapies and is associated with an increased use of chemotherapy.
PMCID: PMC3472155  PMID: 22608160
Prostatic neoplasm; Medicare; SEER program; Antineoplastic agents–hormonal
6.  The Role of Primary Androgen Deprivation Therapy in Localized Prostate Cancer 
European urology  2009;56(4):609-616.
Primary androgen deprivation therapy (PADT) is frequently used as a sole modality of treatment in men with localized prostate cancer, despite a lack of clinical trial data supporting its use.
To measure the impact of treatment with PADT compared to observation on overall survival in men with organ-confined prostate cancer.
Design, setting, and participants
The design was for an observational cohort from Surveillance, Epidemiology, and End Results (SEER) Medicare data. The cohort consisted of 16 535 men aged 65–80 yr at diagnosis with organ-confined well-differentiated or moderately differentiated prostate cancer who survived >1 yr past diagnosis and did not undergo treatment with prostatectomy or radiation therapy within 6 mo of diagnosis. They were diagnosed between 1991 and 1999 and followed until death or until the end of the study period (December 31, 2002).
Study subjects were selected to receive PADT alone if they received luteinizing hormone-releasing hormone agonists or bilateral orchiectomy in the first 6 mo after diagnosis, and they were selected to be observed if they did not have claims for PADT during the same interval.
Overall survival.
Results and limitations
After adjusting for potential confounders (ie, tumor characteristics, comorbidities, and demographics), patients who received ADT had a worse overall survival rate than patients who were observed (hazard ratio: 1.20; 95% confidence interval: 1.13–1.27).
In observational studies there may be unmeasured differences between the treated and untreated groups. The SEER database does not provide information on prostate-specific antigen levels.
This large, population-based study suggests that PADT did not improve survival in men with localized prostate cancer, but it suggests that PADT may instead result in worse outcomes compared with observation. Patients and physicians should be cognizant of the potential long-term side effects of ADT in a patient population for which expectant observation is an acceptable treatment strategy.
PMCID: PMC2791191  PMID: 19368995
7.  Androgen-deprivation therapy versus radical prostatectomy as monotherapy among clinically localized prostate cancer patients 
OncoTargets and therapy  2013;6:725-732.
The most recent randomized controlled trial in a predominantly prostate-specific antigen-detected prostate cancer (PC) population found a nonsignificant reduction in mortality from radical prostatectomy (RP) compared to conservative management. The optimal treatment for clinically localized prostate cancer is anything but clear. The PC-specific mortality and all-cause mortality were compared between primary androgen-deprivation treatment (PADT) and RP, both as monotherapy, among clinically localized PC patients.
A retrospective cohort study among PC patients in Surveillance, Epidemiology and End Results-Medicare data with a median follow up of 2.87 years in the PADT cohort and 2.95 years in the RP cohort. Propensity score-matching was employed to adjust for the observed selection bias. PC-specific mortality and all-cause mortality were modeled using the Fine and Gray competing risk model and Cox proportional hazards model, respectively. The independent variables in these models included age, race, Gleason score risk groups, T-score, prostate-specific antigen, Charlson comorbidity, and index year of treatment initiation.
After propensity score-matching, there were 1624 in the PADT cohort and 1624 in the RP cohort. All baseline values were comparable (all P-values >0.35). There were a total of 266 deaths (16.38%) and 60 (3.69%) PC-specific deaths among PADT recipients, while there were 56 (3.45%) deaths and four (0.25%) PC-specific deaths among RP recipients. According to the Kaplan–Meier estimation, the 8-year survival rate was 43.39% in the PADT cohort and 79.62% in the RP cohort. PADT was associated with increased risk of overall mortality (hazard ratio = 2.98, 95% confidence interval 2.35–3.79; P < 0.001) and increased risk of PC-specific mortality (hazard ratio = 12.47, 95% confidence interval 4.48–34.70; P < 0.001).
With adjustment for the observed selection bias, PADT was associated with increased all-cause mortality and PC-specific mortality when compared to RP.
PMCID: PMC3699299  PMID: 23836984
prostate cancer; primary androgen-deprivation treatment; radical prostatectomy; survival
8.  Salvage open radical prostatectomy after failed radiation therapy: a single center experience 
Currently there is no universally accepted approach for the management of radiation-recurrent prostate cancer. The aim of this study was to detail our experience performing salvage radical prostatectomy for patients who failed primary treatment of prostate cancer with radiation therapy.
Material and methods
We retrospectively queried our institutional database of radical prostatectomy cases for patients who underwent salvage surgery for radiation-recurrent prostate cancer. Patients were assessed for the risk of complications and oncologic outcomes following salvage surgery.
Twenty-four patients with a mean age of 65 years (range 51-74) underwent salvage radical prostatectomy. Fourteen of these patients (58%) received androgen deprivation therapy prior to surgery. Intraoperatively, mean blood loss was estimated at 415 mL (range 100-1000) and 19 (79%) patients received autologous blood. No patient required an allogeneic transfusion or experienced a rectal injury. Postoperative bladder neck contracture and urinary incontinence developed in 17% and 39% of men, respectively. Two (29%) of seven patients remained potent after salvage surgery. No patient developed a fistula. Overall and recurrence-free survival at 5-years was 90% and 39%, respectively. On multivariate analysis, extracapsular extension was the only significant predictor of biochemical recurrence (HR 6.9, 95% CI 1.9-25.3 p = 0.003).
In carefully selected patients, salvage radical prostatectomy for radiation-recurrent prostate cancer is a treatment option with acceptable oncologic outcomes and a moderate complication rate.
PMCID: PMC3921722  PMID: 24578882
biochemical recurrence; prostate cancer; salvage radical prostatectomy; radiation therapy
9.  Effectiveness and adverse effects of hormonal therapy for prostate cancer: Japanese experience and perspective 
Asian Journal of Andrology  2012;14(3):451-457.
Recently, novel anti-androgens and inhibitors of androgen biosynthesis have been developed through the elucidation of mechanisms of castration resistance of prostate cancer. We believe that these new developments will improve hormonal therapy. On the other hand, there has been an increase in criticism of hormonal therapy, because hormonal therapy is supposed to induce adverse effects such as cardiovascular disease. In this review, we have introduced the Japanese experience of hormonal therapy, because we believe that there may be ethnic differences between Caucasians and Asian people in the efficacy and adverse effects of hormonal therapy. First, we showed that primary hormonal therapy can achieve long-term control of localized prostate cancer in some cases and that quality of life of patients receiving hormonal therapy is rather better than previously thought. Neoadjuvant and adjuvant hormonal therapy in cases undergoing radical prostatectomy or radiotherapy are very useful for high-risk or locally advanced prostate cancer. Further clinical trials are required to confirm the efficacy of neoadjuvant or adjuvant hormonal therapy. We showed that the death from cardiovascular diseases in Japanese patients receiving hormonal therapy was not higher than that in the general population. However, efforts should be made to decrease the adverse effects of hormonal therapy, because life-style change may increase the susceptibility to adverse effects by hormonal therapy even in Japan. Managements of endocrine and metabolic dysfunction, such as diabetes mellitus, are essential. New hormonal compounds such as selective androgen receptor modulators capable of specifically targeting prostate cancer are expected to be developed.
PMCID: PMC3722884  PMID: 22447200
adverse effects; androgen deprivation therapy; hormonal therapy; prostate cancer
10.  The biochemical efficacy of primary cryoablation combined with prolonged total androgen suppression compared with radiotherapy on high-risk prostate cancer: a 3-year pilot study 
Asian Journal of Andrology  2010;12(6):827-834.
To gain beneficial effects in the management of high-risk prostate cancer, an integrated approach that combines local therapy and androgen deprivation therapy (ADT) was used. We compared biochemical responses between primary cryosurgical ablation of the prostate (CSAP) combined with prolonged ADT and radiation combined with ADT, which is the established modality in high-risk disease. A total of 33 high-risk patients received CSAP combined with ADT for 3 months before and up to 24 months after treatment. This patient group was matched with another 33 patients who had undergone three-dimensional conformal radiation therapy (3D-CRT) with the same protocol for ADT. Biochemical recurrence (BCR) was assessed by the American Society for Therapeutic Radiation Oncology (ASTRO) definition, the Phoenix definition and a prostate-specific antigen (PSA) cutoff of 0.5 ng mL−1. Median follow-up was 61.0 ± 11.9 months for the CSAP + ADT group and 86.0 ± 15.8 months for the 3D-CRT + ADT group. In the CSAP group, major complications including rectourethral fistula and incontinence were not noted. In the CSAP + ADT group, 57.0% had BCR using the ASTRO definition, 21.2% using the Phoenix definition and 54.5% using a PSA cutoff of 0.5 ng mL−1. In the 3D-CRT + ADT group, 54.5%, 21.2% and 54.5% had BCR using the ASTRO, Phoenix and PSA definition, respectively. In the CSAP + ADT group, the BCR-free survival (BRFS) was 54 ± 10 months using the ASTRO definition, 65 ± 5 months using the Phoenix definition and 51 ± 4 months using a PSA cutoff of 0.5 ng mL−1. In the 3D-CRT + ADT group, the BRFS was 68 ± 12, 93 ± 19 and 70 ± 18 months using the ASTRO, Phoenix and PSA definition, respectively. By the log-rank test, the BRFS values for each group were not statistically different. This intermediate-term result indicated that primary CSAP combined with prolonged ADT offers a parallel biochemical response compared with radiotherapy in high-risk prostate cancer.
PMCID: PMC3739070  PMID: 20711215
androgen ablation therapy; cryoablation for the prostate; radiotherapy
11.  Adjuvant Androgen Deprivation for High-Risk Prostate Cancer After Radical Prostatectomy: SWOG S9921 Study 
Journal of Clinical Oncology  2011;29(15):2040-2045.
Men with high-risk features (extraprostatic extension or high Gleason grade) face a high risk of prostate cancer recurrence after radical prostatectomy. Clinical trials of adjuvant systemic therapy for such patients have been limited.
Patients and Methods
The SWOG (Southwest Oncology Group) S9921 study randomly assigned 983 men with high-risk features at prostatectomy to receive adjuvant therapy with androgen deprivation (ADT) alone or in combination with mitoxantrone chemotherapy. ADT consisted of goserelin and bicalutamide for 2 years.
Although the final primary treatment comparison results are not ready for publication, this article reports results in the ADT-alone control arm with a median follow-up of 4.4 years. For these 481 men, the estimated 5-year biochemical failure-free survival is 92.5% (95% CI, 90 to 95), and 5-year overall survival is 95.9% (95% CI, 93.9 to 97.9).
The results of this trial, taken in context, make a compelling argument for counseling all high-risk patients with prostate cancer about adjuvant ADT. This article discusses the challenges in the design and implementation of clinical trials to take the next step forward in adjuvant therapy for prostate cancer because of the excellent survival achieved with currently available therapies and highlights the need for better molecular markers to personalize care.
PMCID: PMC3107759  PMID: 21502546
12.  Long-Term Dynamics of Bone Mineral Density During Intermittent Androgen Deprivation for Men With Nonmetastatic, Hormone-Sensitive Prostate Cancer 
Journal of Clinical Oncology  2012;30(15):1864-1870.
To investigate changes in bone mineral density (BMD) and fracture risk in men who received intermittent androgen deprivation (IAD) for nonmetastatic, hormone-sensitive prostate cancer.
Patients and Methods
Men with prostate cancer who lacked radiographically detectable metastases were treated in a prospective trial of IAD. After 9 months of treatment with leuprolide and flutamide, androgen deprivation therapy (ADT) was stopped until prostate-specific antigen reached a threshold (1 ng/mL for radical prostatectomy; 4 ng/mL for radiation or primary ADT) for a new cycle. Dual-energy x-ray absorptiometry (DXA) scans were performed before starting ADT and subsequently with each change in therapy. At least two consecutive DXA scans were required for this analysis. Computed tomography, bone scintigraphy, and lumbar spine x-rays were performed at the beginning and end of each treatment period.
Fifty-six of 100 patients met criteria for this analysis. The median age at study entry was 64.5 years (range, 49.8 to 80.9 years). The average percentage change in BMD during the first on-treatment period was −3.4% (P < .001) for the spine and −1.2% (P = .001) for the left hip. During the first off-treatment period (median, 37.4 weeks; range, 13.4 weeks to 8.7+ years), BMD recovery at the spine was significant, with an average percentage change of +1.4% (P = .002). Subsequent periods had heterogeneous changes of BMD without significant average changes. After a median of 5.5 years (range, 1.1 to 13.8+) years on trial, one patient (1.8%) had a compression fracture associated with trauma.
Patients experienced the greatest average change in BMD during early treatment periods of IAD with a smaller average change thereafter. Fractures were rare.
PMCID: PMC3383183  PMID: 22493411
13.  Biochemical Recurrence in Gleason Score 7 Prostate Cancer in Korean Men: Significance of the Primary Gleason Grade 
Korean Journal of Urology  2012;53(12):826-829.
To evaluate the impact of primary Gleason grade in Gleason score (GS) 7 prostate cancer on biochemical recurrence (BCR) after radical prostatectomy in Korean men.
Materials and Methods
We retrospectively reviewed records of 1,026 patients who underwent radical prostatectomy at Seoul National University Bundang Hospital between November 2003 and June 2009. We excluded patients who had received neoadjuvant therapy and had positive resection margins. Finally, 295 and 113 patients with GS 3+4 and GS 4+3, respectively, were included in this study. All patients were followed for at least 2 years.
Of the 408 GS 7 patients, 295 (72.3%) were 3+4 and 113 (27.7%) were 4+3. Mean serum prostate specific antigen level in primary Gleason 3 was 8.99 ng/ml and primary Gleason 4 was 11.11 ng/ml. Patients with GS 4+3 were more likely to have extracapsular extension (30.1% vs. 17.6%, p<0.010) and lymphatic invasion (16.8% vs. 7.1%, p<0.005). After 2 years follow up BCR was detected in a total of 40 patients. In GS 7 with primary Gleason 3, BCR occurred in 15 (5.08%) patients while 20 (17.70%) showed BCR in GS 7 with primary Gleason 4.
In this study of a large, single center cohort of Korean men with GS 7 prostate cancer a noticeable difference in BCR was seen. Primary Gleason grade 4 have a higher risk of BCR compared to primary Gleason grade 3. This information may be useful when counseling patients on their prognosis and further management options.
PMCID: PMC3531634  PMID: 23301125
Biopsy; Prostate; Prostatectomy
14.  The Impact of Financial Interest in Intensity-Modulated Radiation Therapy on the Utilization of Radiation Therapy for Treatment of Newly Diagnosed Prostate Cancer: A Single Center Experience 
ISRN Urology  2012;2012:759258.
Objective. As recent participants in an integrated prostate cancer (PCa) care center, we sought to evaluate whether financial investment in an intensity-modulated radiation therapy (IMRT) center resulted in an increased utilization of radiation therapy in our patients with newly diagnosed PCa. Materials & Methods. Following institutional review board approval, we retrospectively reviewed the records of all consecutive patients who were diagnosed with prostate cancer in the 12 months prior to and after investment in IMRT. Primary treatment modalities included active surveillance (AS), brachytherapy (BT), radiation therapy (XRT), radical prostatectomy (RP), and androgen deprivation therapy (ADT). Treatment data were available for all patients and were compared between the two groups. Results. A total of 344 patients with newly diagnosed PCa were evaluated over the designated time period. The pre-investment group totaled 198 patients, while 146 patients constituted the post-investment group. Among all patients evaluated, there was a similar rate in the use of XRT (20.71% versus 20.55%, P = 1.000) pre- and post-investment in IMRT. Conclusions. Financial interest in IMRT by urologists does not impact overall utilization rates among patients with newly diagnosed PCa at our center.
PMCID: PMC3329792  PMID: 22567423
15.  Reducing bias in the assessment of treatment effectiveness: androgen deprivation therapy for prostate cancer 
Medical Care  2012;50(5):374-380.
Indication bias is the major challenge in assessing treatment effectiveness in observational studies. We explored the potential advantages of using an instrumental variable approach in the context of primary androgen deprivation therapy (ADT) for prostate cancer.
We identified 31,930 men in the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database with a diagnosis of prostate cancer who were not treated definitively with radical prostatectomy or radiation in the years 1992 through 2002, with follow-up through 2005. The association between use of primary ADT and overall, prostate cancer-specific, and non-prostate cancer survival was assessed using multivariable regression and instrumental variable methods. Two instrumental variables, based on region and urologist prescribing preference, were constructed and analyzed by exogenous probit models. Pre-specified subgroup analyses in patients with lower risk and higher risk prostate tumors were also performed.
In the overall cohort, standard multivariable regression analyses showed a significantly increased risk of prostate cancer death whereas the instrumental variable approaches showed a protective effect of primary ADT, which was significant for the urologist prescribing preference instrument (HR: 0.74; 95% CI: 0.60–0.93). In the high risk subgroup, using urologist preference for primary ADT as the instrument, there was a significant reduction in overall mortality (HR: 0.75; 95% CI: 0.57–0.99), driven by a large reduction in prostate cancer-specific mortality.
Instrumental variable analysis appears to provide better control of bias when assessing the effectiveness of primary ADT for prostate cancer although the results may be more applicable to policy rather than clinical decisions.
PMCID: PMC3361681  PMID: 22635250
16.  Comparison of serum testosterone levels in prostate cancer patients receiving LHRH agonist therapy with or without the removal of the prostate 
The prostate secretes enzymes and nutrients to promote sperm motility. Recent reports suggest that the prostate may also secrete testosterone, which is believed to be a fuel for prostate tumour growth. The aim of this study was to determine if a difference in serum testosterone levels exists between men on luteinizing hormone releasing-hormone (LHRH) agonists who have undergone radical prostatectomy, radiation or hormone therapy as primary prostate cancer treatment.
Serum testosterone levels were evaluated in 165 consecutive prostate cancer patients using LHRH analogues for >3 months. We excluded patients receiving either radiation or chemotherapy at time of time of testosterone measurement. Patients were classified based on primary treatment: (1) radical prostatectomy; (2) radiation; or (3) primary hormone therapy. We used one-way ANOVA to compare testosterone levels. Pearson correlation was used to correlate testosterone with prostate-specific antigen (PSA) and time on LHRH agonists. Multivariable linear regression was used to predict serum testosterone levels.
The median (interquartile range) serum testosterone levels were 1.4 (1–1.9), 1.3 (1–1.625) and 1.25 (0.9–1.525) nmol/L for radical prostatectomy, radiation and primary hormone therapy groups, respectively. There was no statistically significant difference in testosterone levels between the groups (p = 0.3). No correlation was found between testosterone and PSA levels or time on LHRH (r = 0.02 and r = 0.01), respectively. Multivariable linear regression showed that none of the clinical variables were predictors of serum testosterone levels.
Our study suggests that primary treatment does not affect serum testosterone levels among men using LHRH analogues.
PMCID: PMC3367013  PMID: 22664629
17.  The Relationship of the Intensity of Posttreatment Prostate-Specific Antigen Surveillance and Prostate Cancer Outcomes: Results From a Population-Based Cohort 
Mayo Clinic Proceedings  2012;87(6):540-547.
To determine whether higher intensity of prostate-specific antigen (PSA) surveillance was associated with earlier detection of biochemical recurrence (BCR) or survival.
Patients and Methods
We identified a population-based cohort of 832 men diagnosed with nonmetastatic prostate cancer between January 1, 1995, and July 31, 2006. These men were treated with radical prostatectomy (RP), brachytherapy or external beam radiation therapy (RT), or primary androgen deprivation therapy or chose watchful waiting. To test the associations of intensity in PSA surveillance with study outcomes, we used a 2-year landmark analysis to assess whether the number of PSA tests during the first 2 years after treatment was associated with earlier detection of BCR, prostate cancer–related mortality, and all-cause mortality. We used landmark analysis to assess the association of PSA intensity, adjusting for clinicopathologic covariate, with outcome.
Median follow-up time for the entire cohort was 6.7 years. Higher Gleason score was the only clinicopathologic variable associated with higher PSA frequency in multivariable analysis for both the RP and RT groups (P value of .001 and .05, respectively). After adjustment for other covariates, the frequency of PSA tests during the first 2 years after RP did not increase the ability to detect BCR (hazard ratio, 1.00; 95% confidence interval, 0.84-1.19) or all-cause mortality (hazard ratio, 0.95; 95% confidence interval, 0.70-1.30) in the landmark analysis.
Higher intensity of PSA surveillance during the 2 years after RP or RT did not improve earlier detection of BCR or survival. Evidence-based guidelines for PSA surveillance after primary treatment are needed.
PMCID: PMC3498058  PMID: 22677074
ACM, all-cause mortality; ADT, androgen deprivation therapy; BCR, biochemical recurrence; HR, hazard ratio; PCSM, prostate cancer–specific mortality; PSA, prostatic-specific antigen; RP, radical prostatectomy; RT, radiation therapy; WW, watchful waiting
18.  Changes in Initial Treatment for Prostate Cancer Among Medicare Beneficiaries, 1999-2007 
In the absence of evidence from large clinical trials, optimal therapy for localized prostate cancer remains unclear; however, treatment patterns continue to change. We examined changes in the management of patients with prostate cancer in the Medicare population.
Methods and Materials
We conducted a retrospective claims-based analysis of the use of radiation therapy, surgery, and androgen deprivation therapy in the 12 months after diagnosis of prostate cancer in a nationally representative 5% sample of Medicare claims. Patients were Medicare beneficiaries 67 years or older with incident prostate cancer diagnosed between 1999 and 2007.
There were 20,918 incident cases of prostate cancer between 1999 and 2007. The proportion of patients receiving androgen deprivation therapy decreased from 55% to 36%, and the proportion of patients receiving no active therapy increased from 16% to 23%. Intensity-modulated radiation therapy replaced 3-dimensional conformal radiation therapy as the most common method of radiation therapy, accounting for 77% of external beam radiotherapy by 2007. Minimally invasive radical prostatectomy began to replace open surgical approaches, being used in 49% of radical prostatectomies by 2007.
Between 2002 and 2007, the use of androgen deprivation therapy decreased, open surgical approaches were largely replaced by minimally invasive radical prostatectomy, and intensity-modulated radiation therapy replaced 3-dimensional conformal radiation therapy as the predominant method of radiation therapy in the Medicare population. The aging of the population and the increasing use of newer, higher-cost technologies in the treatment of patients with prostate cancer may have important implications for nationwide health care costs.
PMCID: PMC3418871  PMID: 22331001
Prostatic Neoplasms; Prostatectomy; Radiotherapy; Intensity-Modulated; Androgen Antagonists; Medicare; Physician's Practice Patterns
19.  Expression of Immunosuppresive B7-H3 Ligand by Hormone-Treated Prostate Cancer Tumors and Metastases 
Prostate cancer cells uniformly express the immune cell inhibitory B7-H3 ligand. Enhanced B7-H3 expression correlates with increased disease progression and cancer-specific death after radical prostatectomy (RP).
Experimental Design
To further assess whether B7-H3 expression is hormone regulated and persists as a viable target during (or after) androgen-ablative therapy, we examined B7-H3 ligand expression within primary and metastatic cancer lesions in response to neoadjuvant hormone therapy (NHT) or palliative hormone deprivation. Tumor B7-H3 in RP specimens from men treated with ≥3 months of NHT was compared with B7-H3 in tumors from matched patients who received no therapy before RP. Hormone-treated and untreated metastatic lesions involving bone were also compared for levels of B7-H3 expression.
Of 165 consecutive RP specimens in each cohort studied, sufficient tissues were available for 148 patients (89.7%) treated with NHT versus 127 patients (77.0%) treated with surgery alone. B7-H3 was expressed in 142 (95.9%) tumors from NHT patients compared with 122 (96.0%) tumors from patients treated with surgery alone (P = 0.91). B7-H3 expression intensity in RP specimens was not affected by NHT (P = 0.12). Bone metastases from 11 (32.4%) untreated and 23 (67.6%) androgen-ablated patients revealed that B7-H3 expression increased in response to hormone therapy (P = 0.04) relative to untreated lesions.
Taken together, B7-H3 expression seems to remain stable (or may even increase) in response to hormone therapy. As such, B7-H3 may represent an attractive target to improve treatment of men with high-risk hormone-treated or refractory prostate cancer.
PMCID: PMC2676580  PMID: 19276267
20.  Locally advanced prostate cancer: a population-based study of treatment patterns 
Bju International  2011;109(9):1309-1314.
To identify treatment patterns and predictors of receiving multimodality therapy in patients with locally advanced prostate cancer (LAPC).
The cohort comprised patients ≥ 66 years with clinical stage T3 or T4 non-metastatic prostate cancer diagnosed between 1998 and 2005 identified from the Surveillance, Epidemiology and End Results (SEER) cancer registry records linked with Medicare claims.
Treatments were classified as radical prostatectomy (RP), radiation therapy (RT) and androgen deprivation therapy (ADT) received within 6 and 24 months of diagnosis.
We assessed trends over time and used multivariable logistic regression to identify predictors of multimodality treatment.
Within the first 6 months of diagnosis, 1060 of 3095 patients (34%) were treated with a combination of RT and ADT, 1486 (48%) received monotherapy (RT alone, ADT alone or RP alone), and 461 (15%) received no active treatment.
The proportion of patients who received RP increased, exceeding 10% in 2005 .
Use of combined RT and ADT and use of ADT alone fluctuated throughout the study period.
In all 6% of patients received RT alone in 2005.
Multimodality therapy was less common in patients who were older, African American, unmarried, who lived in the south, and who had co-morbidities or stage T4 disease.
Treatment of LAPC varies widely, and treatment patterns shifted during the study period.
The slightly increased use of multimodality therapy since 2003 is encouraging, but further work is needed to increase combination therapy in appropriate patients and to define the role of RP.
PMCID: PMC3311723  PMID: 22085255
prostate cancer; locally advanced; treatment; SEER; practice patterns
21.  Serum Early Prostate Cancer Antigen (EPCA) Level and Its Association with Disease Progression in Prostate Cancer in a Chinese Population 
PLoS ONE  2011;6(5):e19284.
Early prostate cancer antigen (EPCA) has been shown a prostate cancer (PCa)-associated nuclear matrix protein, however, its serum status and prognostic power in PCa are unknown. The goals of this study are to measure serum EPCA levels in a cohort of patients with PCa prior to the treatment, and to evaluate the clinical value of serum EPCA.
Pretreatment serum EPCA levels were determined with an ELISA in 77 patients with clinically localized PCa who underwent radical prostatectomy and 51 patients with locally advanced or metastatic disease who received primary androgen deprivation therapy, and were correlated with clinicopathological variables and disease progression. Serum EPCA levels were also examined in 40 healthy controls.
Pretreatment mean serum EPCA levels were significantly higher in PCa patients than in controls (16.84±7.60 ng/ml vs. 4.12±2.05 ng/ml, P<0.001). Patients with locally advanced and metastatic PCa had significantly higher serum EPCA level than those with clinically localized PCa (22.93±5.28 ng/ml and 29.41±8.47 ng/ml vs. 15.17±6.03 ng/ml, P = 0.014 and P<0.001, respectively). Significantly elevated EPCA level was also found in metastatic PCa compared with locally advanced disease (P<0.001). Increased serum EPCA levels were significantly and positively correlated with Gleason score and clinical stage, but not with PSA levels and age. On multivariate analysis, pretreatment serum EPCA level held the most significantly predictive value for the biochemical recurrence and androgen-independent progression among pretreatment variables (HR = 4.860, P<0.001 and HR = 5.418, P<0.001, respectively).
Serum EPCA level is markedly elevated in PCa. Pretreatment serum EPCA level correlates significantly with the poor prognosis, showing prediction potential for PCa progression.
PMCID: PMC3086914  PMID: 21559289
22.  Duration of androgen deprivation therapy with maximum androgen blockade for localized prostate cancer 
BMC Urology  2011;11:7.
Primary androgen deprivation therapy (ADT) is a treatment option not only for advanced but also for localized prostate cancer. However, the appropriate duration for primary ADT for localized prostate cancer has not been defined and few studies have addressed this issue. In this study, we aimed to determine the appropriate duration of ADT for localized prostate cancer.
Sixty-eight consecutive patients with localized prostate cancer who underwent a prostatectomy following neoadjuvant ADT were retrospectively reviewed. Factors associated with pT0, which is regarded as serious cancer cell damage or elimination, were investigated.
Of the 68 males, 24 (35.3%) were classified as pT0. The median duration of neoadjuvant ADT in the pT0 and non-pT0 groups was 9 months and 7.5 months, respectively (p = 0.022). The duration of neoadjuvant ADT from when PSA reached < 0.2 ng/ml to surgery was longer in the pT0 group than that in the non-pT0 group (median 5 months against 3 months, p = 0.011). pT0 was achieved in 5 of 6 patients (83.3%) who received ADT for ≥10 months after PSA reached < 0.2 ng/ml. No other clinical characteristics predicted conversion to pT0.
Continuous ADT for ≥10 months after PSA reached < 0.2 ng/ml induced serious prostate cancer cell damage in most patients (> 80%) and may be sufficient to treat localized prostate cancer.
PMCID: PMC3116482  PMID: 21569574
23.  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.
PMCID: PMC3170584  PMID: 21859492
24.  Comparative Effectiveness of Surgical Treatments for Prostate Cancer: A Population-Based Analysis of Postoperative Outcomes 
The Journal of urology  2010;183(4):1366-1372.
Enthusiasm for laparoscopic surgical approaches to prostate cancer treatment has grown, despite limited evidence of improved outcomes compared with open radical prostatectomy. We compared laparoscopic (with or without robotic assistance) versus open radical prostatectomy in terms of postoperative outcomes and subsequent cancer-directed therapy.
Materials and Methods
Using a population-based cancer registry linked with Medicare claims, we identified men age 66 or older with localized prostate cancer who received a radical prostatectomy from 2003-2005. Outcome measures were general medical/surgical complications and mortality within 90 days following surgery; genitourinary/bowel complications within 365 days; receipt of radiation therapy, androgen deprivation therapy or both within 365 days; length of hospital stay.
Of the 5,923 men,18% received a laparoscopic radical prostatectomy. Adjusting for patient and tumor characteristics, there were no differences in rates of general medical/surgical complications (OR 0.93; 95% CI: 0.77-1.14) or genitourinary/bowel complications (OR 0.96; 95% CI: 0.76-1.22) or in the use of postoperative radiation, androgen deprivation or both (OR 0.80; 95% CI: 0.60-1.08). Laparoscopic prostatectomy was associated with a 35% shorter hospital stay (p<0.0001) and a lower rate of bladder neck/urethral obstruction (OR 0.74; 95% CI 0.58-0.94). In laparoscopic patients, surgeon volume was inversely associated with length of hospital stay and the odds of any genitourinary/bowel complication.
Laparoscopic and open radical prostatectomy have similar rates of postoperative morbidity and use of additional treatment. Men considering prostate cancer surgery should understand the expected benefits and risks of each technique to facilitate decision-making and to set realistic expectations.
PMCID: PMC2866516  PMID: 20188381
prostate; prostatic neoplasms; prostatectomy; minimally invasive surgical procedures; laparoscopy
25.  Acupuncture For Hot Flashes In Prostate Cancer Patients 
Urology  2010;76(5):1182-1188.
Hot flashes are a common adverse effect of hormonal therapy for prostate cancer. We sought to determine the effect of acupuncture on hot flash frequency and intensity, quality of life, and sleep quality.
Men who had a hot flash score (HFS) > 4 while on androgen deprivation therapy for prostate cancer received acupuncture with electrostimulation biweekly for 4 weeks, then weekly for 6 weeks using a predefined treatment plan. The primary endpoint was a 50% reduction in HFS after 4 weeks of therapy, calculated from the patient daily hot flash diary. Hot flash related quality of life and sleep quality, and biomarkers potentially related to hot flashes, including serotonin, calcitonin gene-related peptide (CGRP), and urinary 5-HIAA were examined.
Twenty-five men were enrolled between 9/2003 and 4/2007; 22 were eligible and evaluable. After four weeks, 9 of 22 patients (41%, 95%CI 21 to 64%) had a > 50% reduction in HFS. Twelve of 22 patients (55%, 95%CI 32 to 76%) met this response definition at any time during the course of therapy. No patients had a significant increase in HFS on therapy. Reduced HFS was associated with improvement in hot flash related quality of life and sleep quality.
Multiple placebo-controlled trials have demonstrated a 25% response rate to placebo treatment for hot flashes. 41% of patients responded by week 4 and 55% overall in this pilot study providing evidence of a potentially meaningful benefit. Further studies of acupuncture for hot flashes in this population are warranted.
PMCID: PMC2928879  PMID: 20494414
prostate cancer; hot flashes; acupuncture; androgen deprivation therapy

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