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1.  Ultra-early versus early salvage androgen deprivation therapy for post-prostatectomy biochemical recurrence in pT2-4N0M0 prostate cancer 
BMC Urology  2014;14(1):81.
The optimal timing of salvage androgen deprivation therapy (ADT) for biochemical recurrence after radical prostatectomy is controversial. We compared the outcomes of ultra-early versus early salvage ADT.
Among 855 patients undergoing radical prostatectomy at our institution between 2000 and 2012, we identified 121 with adjuvant-treatment-naïve pT2-4N0M0 prostate cancer who received salvage ADT for biochemical recurrence. These patients were divided into an ultra-early salvage ADT group (n = 51), who started salvage ADT before meeting the standardized definition of biochemical recurrence in Japan (two consecutive prostate-specific antigen [PSA] values ≥0.2 ng/ml), and an early salvage ADT group (n = 70) who started salvage ADT when they met the definition. The ultra-early ADT group consisted of those who started salvage ADT with a single PSA value ≥0.2 ng/ml (n = 30) or with two consecutive PSA values >0.1 ng/ml and rising (n = 21). The primary endpoint was biochemical recurrence after salvage ADT, defined as a single PSA value ≥0.2 ng/ml after PSA nadir following salvage ADT. Secondary endpoints were clinical metastasis and cancer-specific survival. A Cox proportional hazards model was used for multivariate analysis. The median follow-up was 65.5 months.
Biochemical recurrence occurred in one patient (2.0%) in the ultra-early group and in 12 (17.1%) in the early salvage ADT group. Multivariate analysis identified ultra-early salvage ADT and preoperative Gleason score ≤7 as independent negative predictors of biochemical recurrence after salvage ADT. Only one patient in the early salvage ADT group developed clinical metastasis to a left supraclavicular lymph node, and no patient died from prostate cancer during follow-up. The major limitations of this study were its retrospective design, selection bias, and the possibility that the ultra-early salvage ADT group may have included patients without biochemical recurrence.
Ultra-early salvage ADT was an independent negative predictor of biochemical recurrence after salvage ADT in post-prostatectomy patients. Further consideration should be given to the use of salvage ADT before meeting the current definition of biochemical recurrence.
PMCID: PMC4203971  PMID: 25323845
Androgen deprivation therapy; Biochemical recurrence; Prostate cancer; Radical prostatectomy; Salvage androgen deprivation therapy
2.  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
3.  Time to PSA nadir independently predicts overall survival in metastatic hormone sensitive prostate cancer patients treated with androgen deprivation therapy 
Cancer  2009;115(5):981-987.
The purpose of this study was to evaluate the relationship between the kinetics of PSA decline after androgen deprivation therapy (ADT) initiation and overall survival (OS) in men with metastatic hormone-sensitive prostate cancer (HSPC).
We identified a cohort of metastatic HSPC patients treated with androgen deprivation therapy (ADT) using our institutional database. Patients were included if they had at least 2 serum PSA determinations before nadir PSA and at least one serum PSA value available within 1 month of ADT initiation. Patient characteristics, PSA at ADT initiation, nadir PSA, time to PSA nadir (TTN) and PSA decline (PSAD) in relation to OS were analyzed.
179 patients were identified, with a median follow-up after ADT initiation of 4.0 years. Median OS after ADT initiation was 7.0 years. Median PSA at ADT initiation and PSA nadir were 47 and 0.28 ng/mL, respectively. On univariate analysis: TTN <6 months, a PSAD >52 ng/mL/year, PSA nadir ≥ 0.2 ng/mL, a PSA≥47.2 ng/mL at ADT initiation and Gleason score >7, were associated with a shorter OS. On multivariate analysis, TTN<6 months, Gleason score >7 and a PSA nadir ≥ 0.2 ng/mL independently predicted a shorter OS.
To our knowledge, this is the first report to show that a faster time to reach a PSA nadir post-ADT initiation is associated with shorter survival duration in men with metastatic HSPC. These results need confirmation, but may indicate that a rapid initial response to ADT indicates more aggressive disease.
PMCID: PMC2931827  PMID: 19152438
Prostate cancer; androgen deprivation therapy; hormone-sensitive metastatic prostate cancer; PSA kinetics; Time to PSA nadir
4.  Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial 
Lancet  2011;378(9809):2104-2111.
Whether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer.
Patients with: locally advanced (T3 or T4) prostate cancer (n=1057); or organ-confined disease (T2) with either a prostate-specific antigen (PSA) concentration more than 40 ng/mL (n=119) or PSA concentration more than 20 ng/mL and a Gleason score of 8 or higher (n=25), were randomly assigned (done centrally with stratification and dynamic minimisation, not masked) to receive lifelong ADT and RT (65–69 Gy to the prostate and seminal vesicles, 45 Gy to the pelvic nodes). The primary endpoint was overall survival. The results presented here are of an interim analysis planned for when two-thirds of the events for the final analysis were recorded. All efficacy analyses were done by intention to treat and were based on data from all patients. This trial is registered at as ISRCTN24991896 and as NCT00002633.
Between 1995 and 2005, 1205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6·0 years (IQR 4·4–8·0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70–78 vs 66%, 60–70; hazard ratio [HR] 0·77, 95% CI 0·61–0·98, p=0·033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0·5%) in the ADT only group, two (0·3%) in the ADT and RT group; diarrhoea grade >3, four patients (0·7%) vs eight (1·3%); urinary toxicity grade >3, 14 patients (2·3%) in both groups).
The benefits of combined modality treatment—ADT and RT—should be discussed with all patients with locally advanced prostate cancer.
Canadian Cancer Society Research Institute, US National Cancer Institute, and UK Medical Research Council.
PMCID: PMC3243932  PMID: 22056152
5.  Dose Escalation for Prostate Cancer Radiotherapy: Predictors of Long-Term Biochemical Tumor Control and Distant Metastases–Free Survival Outcomes 
European urology  2011;60(6):1133-1139.
Higher radiation dose levels have been shown to be associated with improved tumor-control outcomes in localized prostate cancer (PCa) patients.
Identify predictors of biochemical tumor control and distant metastases–free survival (DMFS) outcomes for patients with clinically localized PCa treated with conformal external-beam radiotherapy (RT) as well as present an updated nomogram predicting long-term biochemical tumor control after RT.
Design, setting, and participants
This retrospective analysis comprised 2551 patients with clinical stages T1–T3 PCa. Median follow-up was 8 yr, extending >20 yr.
Prescription doses ranged from 64.8 to 86.4 Gy. A total of 1249 patients (49%) were treated with neoadjuvant and concurrent androgen-deprivation therapy (ADT); median duration of ADT was 6 mo.
A proportional hazards regression model predicting the probability of biochemical relapse and distant metastases after RT included pretreatment prostate-specific antigen (PSA) level, clinical stage, biopsy Gleason sum, ADT use, and radiation dose. A nomogram predicting the probability of biochemical relapse after RT was developed.
Results and limitations
Radiation dose was one of the important predictors of long-term biochemical tumor control. Dose levels <70.2 Gy and 70.2–79.2 Gy were associated with 2.3-and 1.3-fold increased risks of PSA relapse compared with higher doses. Improved PSA relapse– free survival (PSA-RFS) outcomes with higher doses were observed for all risk groups. Use of ADT, especially for intermediate- and high-risk patients, was associated with significantly improved biochemical tumor-control outcomes. A nomogram predicting PSA-RFS was generated and was associated with a concordance index of 0.67. T stage, Gleason score, pretreatment PSA, ADT use, and higher radiation doses were also noted to be significant predictors of improved DMFS outcomes.
Higher radiation dose levels were consistently associated with improved biochemical control outcomes and reduction in distant metastases. The use of short-course ADT in conjunction with RT improved long-term PSA-RFS and DMFS in intermediate- and high-risk patients; however, an overall survival advantage was not observed.
PMCID: PMC4037155  PMID: 21889832
6.  Up-to-date results of carbon-ion radiotherapy for prostate cancer 
Journal of Radiation Research  2014;55(Suppl 1):i28-i29.
Carbon ion radiotherapy (C-ion RT) for prostate cancer was started in 1995 using the Heavy-Ion Medical Accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences (NIRS), Japan. After preceding phase I/II dose-escalation studies of 20 fractions over 5 weeks, a phase II study was initiated in April 2000 using the treatment techniques and the recommended dose fractionations established by the phase I/II studies. This study was also successfully completed in October 2003 when the C-ion RT for solid tumors, including the prostate cancer, was approved as ‘Advanced Medicine’ by the Ministry of Health, Labor, and Welfare. Since then, more than 1400 patients have been treated with C-ion RT as of February 2012, and advancement of hypofractionation has also been achieved. In this paper, the treatment outcomes in 1144 patients who underwent the established C-ion RT between April 2000 and July 2012 were analyzed.
Out of 1144 patients, 585 patients were categorized as high-risk group, which includes patients having at least one of the following conditions: T3 clinical stage, Gleason's score of 8 or higher and PSA of 20 or higher. One hundred and ninety-seven patients who met the conditions such as clinical stage of T2a or lower, Gleason's score of 6 or lower and PSA of <20 were categorized as low-risk group. Three hundred and sixty-two patients who were not included in either high- or low-risk group were categorized as intermediate-risk group. All patients were pathologically proven to have adenocarcinoma of the prostate, and Gleason's score was determined by the chief pathologist of our study group. Written consent was obtained from all patients included in the clinical study. Patients with the following conditions were not registered in the clinical trial: having distant metastases, having synchronous primary malignancy, not histologically proven cancer, without informed consent, post-operative/post-irradiation recurrence.
All patients were treated with three field irradiations (vertical one field and horizontal opposing two fields). The prostate and proximal part of the seminal vesicle were contoured as clinical target volume (CTV), and planning target volume (PTV) was set with 5–10 mm margins around the CTV. On the way of radiotherapy, a part of irradiation field of the posterior side was cut to reduce the rectal dose. The 197 patients in the low-risk group did not undergo androgen deprivation therapy (ADT), whereas the 947 patients of intermediate- and high-risk groups underwent ADT. The patients of intermediate-risk group underwent about 6 months of neoadjuvant ADT, and the patients of high-risk group also underwent about 6 months of neoadjuvant ADT and sequential adjuvant ADT for more than 18 months. The median age of all patients was 68 years, and the median follow-up time was 48.7 months (range: 3.6–151.1 months).
The 5-year overall survival rate and biochemical relapse-free rate of the entire groups was 95.7% and 91.0%, respectively. T-stage and Gleason's score were significant prognostic factors for both the biochemical control and patient survival and initial PSA was also a predictive factor for survival. Regarding the late radiation toxicity, the incidence of rectal toxicity of grade 2 or worse was 1.1% and that of genitourinary toxicity was 6.5%. These outcomes seemed to be better than those of the past publications [ 1– 4]. In addition, the incidence of toxicity in patients treated with more hypofractionated C-ion RT of 16 fractions over 4 weeks was lower than those of 20 fraction treatment. These favorable outcomes can be thought as apparent evidence of physical and biological advantages of the hypofractionated C-ion RT.
PMCID: PMC3941550
carbon-ion radiation therapy; prostate cancer; hypofractionation
7.  Transperineal prostate brachytherapy, using I-125 seed with or without adjuvant androgen deprivation, in patients with intermediate-risk prostate cancer: study protocol for a phase III, multicenter, randomized, controlled trial 
BMC Cancer  2010;10:572.
The optimal protocol for 125I-transperineal prostatic brachytherapy (TPPB) in intermediate-risk prostate cancer (PCa) patients remains controversial. Data on the efficacy of combining androgen-deprivation therapy (ADT) with 125I-TPPB in this group remain limited and consequently the guidelines of the American Brachytherapy Society (ABS) provide no firm recommendations.
Seed and Hormone for Intermediate-risk Prostate Cancer (SHIP) 0804 is a phase III, multicenter, randomized, controlled study that will investigate the impact of adjuvant ADT following neoadjuvant ADT and 125I-TPPB. Prior to the end of March, 2011, a total of 420 patients with intermediate-risk, localized PCa will be enrolled and randomized to one of two treatment arms. These patients will be recruited from 20 institutions, all of which have broad experience of 125I-TPPB. Pathological slides will be centrally reviewed to confirm patient eligibility. The patients will initially undergo 3-month ADT prior to 125I-TPPB. Those randomly assigned to adjuvant therapy will subsequently undergo 9 months of adjuvant ADT. All participants will be assessed at baseline and at the following intervals: every 3 months for the first 24 months following 125I-TPPB, every 6 months during the 24- to 60-month post-125I-TPPB interval, annually between 60 and 84 months post-125I-TPPB, and on the 10th anniversary of treatment.
The primary endpoint is biochemical progression-free survival (BPFS). Secondary endpoints are overall survival (OS), clinical progression-free survival, disease-specific survival, salvage therapy non-adaptive interval, acceptability (assessed using the international prostate symptom score [IPSS]), quality of life (QOL) evaluation, and adverse events. In the correlative study (SHIP36B), we also evaluate biopsy results at 36 months following treatment to examine the relationship between the results and the eventual recurrence after completion of radiotherapy.
These two multicenter trials (SHIP0804 & SHIP36B) are expected to provide crucial data regarding the efficacy, acceptability and safety of adjuvant ADT. SHIP36B will also provide important information about the prognostic implications of PSA levels in intermediate-risk PCa patients treated with 125I-TPPB.
Trial registration
NCT00664456, NCT00898326, JUSMH-BRI-GU05-01, JUSMH-TRIGU0709
PMCID: PMC2984426  PMID: 20964826
8.  Effect of dutasteride in men receiving intermittent androgen ablation therapy: The AVIAS trial 
Canadian Urological Association Journal  2014;8(11-12):E789-E794.
We studied the effect of dutasteride on the length of the off-treatment period in prostate cancer patients on intermittent androgen deprivation (IAD) therapy.
We conducted a randomized, placebo-controlled Phase II trial in men with localized prostate cancer and a rising prostate-specific antigen (PSA) level post-primary treatment. Patients were randomized to dutasteride (0.5 mg/day) or placebo. All patients received androgen deprivation therapy (ADT), which was stopped at month 9 if the PSA level was <1.0 ng/mL. ADT was resumed when PSA increased to ≥5.0 ng/mL. End points included time off treatment, PSA nadir after 9 months of ADT, serum testosterone and dihydrotestosterone levels, and time to castrate-resistant prostate cancer (rising PSA while testosterone levels remain <50 ng/mL).
There were 87 evaluable patients: 49 dutasteride, 38 placebo. In total, 80 patients completed one treatment cycle: 45 dutasteride, 35 placebo. The median time off treatment for patients reaching ≥5 ng/mL was 18.6 and 16.7 months for dutasteride and placebo, respectively (p = 0.7600). The median PSA nadir at 9 months was 0.1 and 0.075 ng/mL, respectively (p = 0.4486). There were no cases of androgen-independent prostate cancer. Our study limitations include its short duration with only one treatment cycle evaluated.
This small-scale Phase II randomized controlled trial showed no benefit to the addition of dutasteride to an IAD regimen.
PMCID: PMC4250242  PMID: 25485005
International journal of radiation oncology, biology, physics  2012;85(1):10.1016/j.ijrobp.2012.08.036.
The aim of the study was to evaluate the prognostic value of prostate specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) prior to dose-escalated radiation therapy (RT) and long-term ADT in high-risk prostate cancer.
Methods and Materials
We reviewed the charts of all patients diagnosed with high-risk prostate cancer and treated with a combination of long-term ADT (median, 24 months) and dose-escalated (median, 75.6 Gy) RT between 1990 and 2007. The association of patient, tumor and treatment characteristics with biochemical response to neoadjuvant ADT, and their effect on failure-free survival (FFS), time to distant metastasis (TDM), prostate cancer-specific mortality (PCSM) and overall survival (OS) were examined.
A total of 196 patients met the criteria for inclusion. Median follow up time for patients alive at last contact was 7.0 years (range, 0.5–18.1 years). Multivariate analysis identified the pre-radiation therapy PSA level (pre-RT PSA; <0.5 vs. ≥0.5 ng/ml) as a significant independent predictor of FFS (p=0.021), TDM (p=0.009), PCSM (p=0.039) and OS (p=0.037). On multivariate analysis, pre-treatment PSA (iPSA) and African-American race were significantly associated with failure to achieve a pre-RT PSA <0.5 ng/ml.
For high-risk prostate cancer patients treated with long-term ADT and dose-escalated RT, a pre-RT PSA level ≥0.5 ng/ml after neoadjuvant ADT predicts for worse survival measures. Both elevated iPSA and Afrian-American race are associated with increased risk of having a pre-RT PSA level ≥0.5 ng/ml. These patients should be considered for clinical trials testing newer more potent androgen depleting therapies such as abiraterone and MDV3100 in combination with radiation.
PMCID: PMC3840533  PMID: 23102837
pre-RT PSA; androgen deprivation therapy; radiation therapy; prostate cancer
10.  PSA Doubling Time Predicts for the Development of Distant Metastases for Patients Who Fail 3DCRT Or IMRT Using the Phoenix Definition 
Practical radiation oncology  2011;1(4):235-242.
PSA doubling time (PSADT) is commonly used as an indication for salvage androgen deprivation therapy (ADT) for PSA failure following RT. Previously, we had shown that PSADT of <12 months is an important predictor of distant metastasis following 3DCRT using the ASTRO definition of BF. We sought to determine if this approach is still valid using the Phoenix definition.
Eligible patients included 432 men with T1-3N0M0 prostate cancer who demonstrated PSA failure after completing definitive 3DCRT or IMRT from 1989–2005. Endpoints included freedom from distant metastasis (FDM), cause-specific survival (CSS) and overall survival (OS). PSADT was stratified by 0–6, 6–12, 12–18, 18–24, and >24 months. The median follow-up was 95 months (6–207 months).
The 7 year FDM, CSS, and OS rates for the entire group were 73%, 77% and 52%, respectively. 7 year FDM was 50% for PSADT <6 months vs. 83% for PSADT >6 months (p=0.0001). 7 year CSS was 61% for PSADT <6 and 85% for PSADT >6 (p=0.0001). 7 year OS was 47% for PSADT <6 and 53% for PSADT >6 (p=0.04). The proportion of men with BF receiving salvage ADT with a PSADT <6 months was 59%, 6–12 was 45%, 12–18 was 42%, 18–24 was 36%, >24 was 28%. ADT was associated with improved 7 year CSS (68% vs. 46%, p=0.015). Of the 314 men with PSADT >6 months, 124 received ADT and 190 were observed. With a median follow-up of 38 months from BF, there was no demonstrable benefit to ADT in the 7 year CSS (87% vs. 79%, respectively; p=0.758). Independent predictors of FDM were PSADT (p<0.0001), GS (p=0.011), and the use of initial ADT (p=0.005).
PSADT remains a significant predictor of clinical failure and CSS for men treated with 3DCRT or IMRT who fail according to the Phoenix definition. Immediate use of ADT in patients with PSADT <6 months is significantly associated with improved CSS, although the benefit is less apparent in patients with longer PSADT. These results further refine the role of PSADT in predicting which patients may benefit from salvage ADT and those who may be observed expectantly.
PMCID: PMC3197783  PMID: 22025934
Prostate Cancer; Prostate Specific Antigen; IMRT; PSA Doubling Time; Biochemical Failure; Phoenix Definition
11.  Androgen Deprivation and Thromboembolic Events in Men with Prostate Cancer 
Cancer  2011;118(13):3397-3406.
Androgen deprivation therapy (ADT) improves prostate cancer outcomes in specific clinical settings, but is associated with adverse effects, including cardiac complications and possibly thromboembolic complications. Our objective was to estimate the impact of ADT on thromboembolic events (TEs) in a population-based cohort.
In the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database, we identified men aged over 65 diagnosed with non-metastatic prostate cancer between 1999 and 2005. Medical or surgical ADT was identified by Medicare claims for gonadotropin-releasing hormone agonists or bilateral orchiectomy at any time following diagnosis. TEs included deep venous thrombosis, pulmonary embolism, and arterial embolism. We estimated ADT’s impact on the risk of any TE and on total number of events, controlling for patient and tumor characteristics.
Of 154,611 prostate cancer patients, 58,466 (38%) received ADT. During a median follow-up of 52 months, 15,950 men had at least one TE, including 8,829 (55%) who had ADT and 7,121 (45%) with no ADT. ADT was associated with increased risk of a TE (adjusted hazard ratio 1.56, 95% CI: 1.50 to 1.61, P < 0.0001), and duration of ADT was associated with the total number of events (P < 0.0001).
In this population-based cohort, ADT was associated with increased risk of a TE, and longer durations of ADT were associated with more TEs. Men with intermediate- and low-risk prostate cancer should be assessed for TE risk factors before starting ADT and counseled regarding the risks and benefits of this therapy.
PMCID: PMC3678973  PMID: 22072494
prostate cancer; deep vein thrombosis; pulmonary embolism; androgen deprivation; arterial embolism
12.  Impact of Adjuvant Androgen-Deprivation Therapy on Disease Progression in Patients with Node-Positive Prostate Cancer 
Korean Journal of Urology  2011;52(11):741-745.
The survival benefits of adjuvant androgen-deprivation therapy (ADT) in prostate cancer and lymph node metastasis remain unclear. We assessed the role of ADT in disease progression after radical prostatectomy (RP).
Materials and Methods
Of 937 patients who underwent RP, we identified 40 (4.2%) who had lymph node metastasis. A total of 18 received adjuvant ADT (ADT group) and 22 were observed (observation group). Clinical progression-free survival (PFS), cancer- specific survival (CSS), and overall survival (OS) were compared in the 2 groups. Prognostic factors for clinical progression and biochemical recurrence (BCR) were analyzed.
The 5-year PFS, CSS, and OS of the entire cohort were 75.0%, 85.0%, and 72.5%, respectively. In the ADT group, 6 patients (33.3%) showed clinical progression at a median 42.7 months. The 5-year PFS, CSS, and OS rates of this group were 72.2%, 83.3%, and 72.2%, respectively. In the observation group, 14 patients (63.6%) received salvage therapy owing to BCR. Nine patients (40.9%) with BCR in the observation group showed clinical progression at a median 43.4 months after RP. The 5-year PFS, CSS, and OS rates of this group were 77.2%, 86.4%, and 72.8%, respectively. In the observation group, the BCR rate was lower in patients with pT3a or less disease than in those with pT3b disease.
Adjuvant ADT in node-positive prostate cancer did not reduce or delay disease progression or improve survival. Because a substantial number of untreated patients with pT3a or less disease did not experience recurrence, administration of ADT should be initiated carefully. However, in patients with pT3b disease, adjuvant ADT and radiotherapy could be considered.
PMCID: PMC3242986  PMID: 22195262
Androgens; Lymph nodes; Prostatectomy
13.  Kinetics of testosterone recovery in clinically localized prostate cancer patients treated with radical prostatectomy and subsequent short-term adjuvant androgen deprivation therapy 
Asian Journal of Andrology  2013;15(4):466-470.
Androgen deprivation therapy (ADT) is a standard treatment for metastatic, recurrent and locally advanced prostate cancer (PCa). The aim of this study is to investigate the timing and extent of testosterone recovery in clinically localized PCa patients treated with radical prostatectomy (RP) and subsequent short-term adjuvant ADT. A total of 95 localized PCa patients underwent RP and 9-month adjuvant ADT were included in this prospective study. Serum testosterone level was measured before adjuvant ADT, at ADT cessation, and at 1, 3, 6, 9 and 12 months after cessation of ADT. A Cox proportional hazards model was used to assess variables associated with the time of testosterone normalization. The results showed that median patient age was 67 years and median testosterone level before adjuvant ADT was 361 (230–905) ng dl−1. All patients finished 9-month adjuvant ADT and achieved castrate testosterone level. At 3 months after ADT cessation, testosterone recovered to supracastrate level in 97.9% patients and to normal level in 36.9% patients. The percentage of patients who recovered to normal testosterone level increased to 66.3%, 86.3% and 92.6% at 6, 9 and 12 months, respectively. Cox regression model found that higher baseline testosterone level (≥300 ng dl−1) was the only variable associated with a shorter time to testosterone normalization (hazard ratio: 1.98; P = 0.012). In conclusion, in most patients, testosterone recovered to supracastrate level at 3 months and to normal level at 12 months after 9-month adjuvant ADT cessation. Patients with higher baseline testosterone level need shorter time of testosterone normalization.
PMCID: PMC3739223  PMID: 23708460
androgen deprivation therapy (ADT); luteinizing hormone-releasing hormone; prostatic neoplasms; recovery of function; testosterone
14.  Current Role of Neoadjuvant and Adjuvant Systemic Therapy for High-risk Localized Prostate Cancer 
Current opinion in urology  2013;23(4):366-371.
Purpose of review
While most men are diagnosed with readily curable localized prostate cancer, those with high risk features face a significant mortality risk. Androgen deprivation therapy (ADT) is a standard adjunct to radiotherapy for high-risk prostate cancer, but its role around prostatectomy has not been as clearly defined, and concerns over cardiovascular toxicity have led to decreasing use. The use of chemotherapy for localized disease remains experimental. We review the most recently published trials of neoadjuvant or adjuvant systemic therapy for prostate cancer.
Recent findings
The optimal duration of ADT with higher-dose modern radiation techniques is under active investigation, but current data support the use of longer duration as standard. PSA and MRI changes may be useful in future studies optimizing duration of neoadjuvant ADT. Two years of combined ADT after prostatectomy is associated with a lower risk of disease recurrence and better PCSM than predicted. Persistence of intraprostatic androgens during neoadjuvant ADT may contribute to resistance.
Androgen deprivation added to definitive radiation or surgery improves outcomes for high-risk prostate cancer, while the role of chemotherapy remains undefined. Molecular classification is needed to improve risk stratification.
PMCID: PMC4234303  PMID: 23619581
High-Risk Localized Prostate Cancer; Androgen Deprivation Therapy; Chemotherapy
15.  Role of Androgen Deprivation Therapy for Node-Positive Prostate Cancer 
Journal of Clinical Oncology  2008;27(1):100-105.
To determine the impact of adjuvant androgen deprivation therapy (ADT) for patients who have node-positive prostate cancer in the prostate-specific antigen (PSA) era.
Patients and Methods
We used linked Surveillance, Epidemiology and End Results-Medicare data to construct a cohort of men who underwent radical prostatectomy (RP) between 1991 and 1999 and who had positive regional lymph nodes. We classified men as receiving adjuvant ADT if they received ADT within 120 days of RP, and we compared them to the men who had not received adjuvant ADT. We used propensity scores to balance potential confounders of receiving adjuvant ADT (ie, tumor characteristics, extent of nodal disease, demographics, receipt of radiation therapy) and Cox proportional hazard methods to measure the impact of adjuvant ADT on overall survival (OS), stratified by propensity score quintile. We conducted a sensitivity analysis that used 90, 150, 180, and 365 days as the definition for adjuvant ADT.
A total of 731 men were identified, 209 of whom received ADT within 120 days of RP. There was no statistically significant difference in OS between the adjuvant ADT and non-ADT group (HR, 0.97; 95% CI, 0.71 to 1.27). There was no statistically significant survival difference with 90, 150, 180, and 365 days as the adjuvant ADT definition.
Deferring immediate ADT in men with positive lymph nodes after RP may not significantly compromise survival. Because observational studies should be considered hypothesis-generating studies, these results should be validated in a prospective fashion in a similar patient population.
PMCID: PMC2645095  PMID: 19047295
16.  Cognitive and Mood Changes in Men Undergoing Intermittent Combined Androgen Blockade for Non-Metastatic Prostate Cancer 
Psycho-oncology  2009;18(3):237-247.
Men with PSA-only relapse of prostate cancer after primary therapy are generally fully functional and asymptomatic with a life expectancy of up to ten or more years. Androgen deprivation therapy (ADT) is a common treatment option. This study examined mood and cognitive changes in otherwise healthy men with prostate cancer prior to, during and after ADT.
Experimental Design
Twenty hormone naïve, eugonadal prostate cancer patients without evidence of metastases and with a rising PSA were treated with intermittent ADT consisting of nine months of complete androgen blockade achieved with combined leuprolide and flutamide followed by an “off treatment” period. Cognitive function tests and mood measures were administered at baseline, after three and nine months of ADT and after three months of no treatment. Twenty healthy control patients without prostate cancer range matched for age and education were tested at the same time intervals.
ADT patients evidenced a significant decline in spatial reasoning, spatial abilities and working memory during treatment compared to baseline. No changes were noted for measures of verbal or spatial memory, selective attention or language. Significant changes in self-rated mood such as increased depression, tension, anxiety, fatigue and irritability were evident during treatment compared to baseline for ADT patients. No significant changes in either cognitive tests or mood measures were noted for the healthy control group.
These findings, suggest that nine months of combined androgen blockade may result in some adverse changes in cognition and mood. However, many but not all of these changes can return to baseline after cessation of ADT.
PMCID: PMC2853938  PMID: 18636420
Cancer; Oncology; Complete Androgen Blockade (CAB); Mood; Cognition; Memory; Prostate Cancer; Testosterone; Flutamide; Intermittent Androgen Ablation Therapy (ADT)
17.  Concurrent androgen deprivation therapy during salvage prostate radiotherapy improves treatment outcomes in high risk patients 
To determine if concurrent androgen deprivation therapy (ADT) during salvage radiotherapy (RT) improves prostate cancer treatment outcomes.
Methods & Materials
A total of 630 post prostatectomy patients were retrospectively identified that were treated with 3-D conformal RT. Of these, 441 were found to be treated for salvage indications. Biochemical Failure (BF) was defined as PSA ≥ 0.2 ng/mL above nadir with another PSA increase or the initiation of salvage ADT. Progression-free survival (PFS) was defined as the absence of: BF, continued PSA rise despite salvage therapy, initiation of systemic therapy, clinical progression or distant failure. Multivariable-adjusted Cox proportional hazards modeling was performed to determine which factors predict PFS.
Low, intermediate, and high risk patients made up 10%, 24%, and 66% of patients, respectively. Mean RT dose was 68Gy. Twenty-four percent of patients received concurrent ADT (HRT). Regional pelvic nodes were treated in 16% of patients. With a median follow-up of 3 years, the 3-yr PFS was 4.0 yrs for HRT vs. 3.4 yrs for non-HRT patients (p=0.22). Multivariable analysis demonstrated that concurrent ADT (p=0.05), Gleason score (p<0.001), and pre-RT PSA (p=0.03) were independent predictors of PFS. When stratified by risk group, the benefits of ADT (HR = 0.65, p=0.046) was significant only for high risk patients.
This retrospective study has demonstrated a PFS benefits of concurrent ADT during salvage prostate RT. This benefit was observed only in high risk patients.
PMCID: PMC3904219  PMID: 21549519
Prostatic neoplasms; prostate-specific antigen; radiotherapy; androgens, adjuvant radiotherapy; salvage therapy
18.  Salvage Pelvic Lymph Node Dissection in Recurrent Prostate Cancer: Surgical and Early Oncological Outcome 
BioMed Research International  2015;2015:198543.
Methodology. Seventeen patients with prostate-specific antigen (PSA) rise following local treatment for prostate cancer with curative intent underwent open or minimally invasive salvage pelvic lymph node dissection (SLND) for oligometastatic disease (<4 synchronous metastases) or as staging prior to salvage radiotherapy. Biochemical recurrence after complete biochemical response (cBR) was defined as 2 consecutive PSA increases >0,2 ng/mL; and after incomplete biochemical response as 2 consecutive PSA rises. Newly found metastasis on imaging defined clinical progression (CP). Palliative androgen deprivation therapy (ADT) was initiated if >3 metastases were detected or if patients became symptomatic. Kaplan-Meier statistics were applied. Results. Clavien-Dindo grade 1, 2, 3a, and 3b complications were seen in 6, 1, 1, and 2 patients, respectively. Median follow-up time was 22 months. Among 13 patients treated for oligometastatic disease, 8 (67%) had a PSA decline, with 3 patients showing cBR. Median PSA progression-free survival (FS) was 4.1 months and median CP-FS 7 months. Three patients started ADT, resulting in a 2-year ADT-FS rate of 79.5%. Conclusion. SLND is feasible, but postoperative complication rate seems higher than that for primary LND. Biochemical and clinical response duration is limited, but as part of an oligometastatic treatment regime it can defer palliative ADT.
PMCID: PMC4324111
19.  Patterns of Bone Mineral Density Testing in Men Receiving Androgen Deprivation for Prostate Cancer 
Journal of General Internal Medicine  2013;28(11):1440-1446.
Practice guidelines recommend bone mineral density (BMD) monitoring for men on androgen deprivation therapy (ADT) for prostate cancer, but single center studies suggest this is underutilized.
We examined determinants of BMD testing in men receiving ADT in a large population-based cohort of men with prostate cancer.
Retrospective cohort study.
We used the Surveillance, Epidemiology and End-Results (SEER)-Medicare database to identify 84,036 men with prostate cancer initiating ADT from 1996 through 2008.
Rates of BMD testing within the period 12 months prior to 3 months after initiation of ADT were assessed and compared to matched controls without cancer and to men with prostate cancer not receiving ADT. A logistic regression model was performed predicting use of BMD testing, adjusted for patient demographics, indications for ADT use, year of diagnosis and specialty of the physician involved in the care of the patient.
Rates of BMD testing increased steadily over time in men receiving ADT, diverging from the control groups such that by 2008, 11.5 % of men were receiving BMD testing versus 4.4 % in men with prostate cancer not on ADT and 3.8 % in the non-cancer controls. In the logistic regression model, year of diagnosis, race/ethnicity, indications for ADT use and geographic region were significant predictors of BMD testing. Patients with only a urologist involved in their care were significantly less likely to receive BMD testing as compared to those with both a urologist and a primary care physician (PCP) (odds ratio 0.71, 95 % confidence interval 0.64–0.80).
There has been a sharp increase in rates of BMD testing among men receiving ADT for prostate cancer over time, beyond rates noted in contemporaneous controls. Absolute rates of BMD testing remain low, however, but are higher in men who have a PCP involved in their care.
PMCID: PMC3797344  PMID: 23670565
prostate cancer; osteoporosis; androgen deprivation therapy; bone mineral density
20.  Contemporary Role of Androgen Deprivation Therapy for Prostate Cancer 
European urology  2011;61(1):11-25.
Androgen deprivation therapy (ADT) for prostate cancer (PCa) represents one of the most effective systemic palliative treatments known for solid tumors. Although clinical trials have assessed the role of ADT in patients with metastatic and advanced locoregional disease, the risk–benefit ratio, especially in earlier stages, remains poorly defined. Given the mounting evidence for potentially life-threatening adverse effects with short- and long-term ADT, it is important to redefine the role of ADT for this disease.
Review the published experience with currently available ADT approaches in various contemporary clinical settings of PCa and reported serious treatment-related adverse events. This review addresses the level of evidence associated with the use of ADT in PCa, focusing upon survival outcome measures. Furthermore, this paper discusses evolving approaches targeting androgen receptor signaling pathways and emerging evidence from clinical trials with newer compounds.
Evidence acquisition
A comprehensive review of the literature was performed, focusing on data from the last 10 yr (January 2000 to July 2011) and using the terms androgen deprivation, hormone treatment, prostate cancer and adverse effects. Abstracts from trials reported at international conferences held in 2010 and 2011 were also evaluated.
Evidence synthesis
Data from randomized controlled trials and population-based studies were analyzed in different clinical paradigms. Specifically, the role of ADT was evaluated in patients with nonmetastatic disease as the primary and sole treatment, in combination with radiation therapy (RT) or after surgery, and in patients with metastatic disease. The data suggest that in men with nonmetastatic disease, the use of primary ADT as monotherapy has not shown a benefit and is not recommended, while ADT combined with conventional-dose RT (<72 Gy) for patients with high-risk disease may delay progression and prolong survival. The postoperative use of ADT remains poorly evaluated in prospective studies. Likewise, there are no trials evaluating the role of ADT in patients with biochemical relapses after surgery or RT. In patients with metastatic disease, there is a clear benefit in terms of quality of life, reduction of disease-associated morbidity, and possibly survival. Treatment with bilateral orchiectomy, luteinizing hormone–releasing hormone agonist therapy, with and without antiandrogens has been associated with various serious adverse events, including cardiovascular disease, diabetes, and skeletal complications that may also affect mortality.
Although ADT is an effective treatment of PCa, consistent long-term benefits in terms of quality and quantity of life are predominantly evident in patients with advanced/metastatic disease or when ADT is used in combination with RT (<72 Gy) in patients with high-risk tumors. Implementation of ADT should be evidence based, with special consideration to adverse events and the risk–benefit ratio.
PMCID: PMC3483081  PMID: 21871711
Prostate cancer; Androgen deprivation; Hormone treatment; Adverse effects
21.  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 
Journal of Clinical Oncology  2010;28(16):2668-2673.
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.
Patients and Methods
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 ≥ 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 (≤ 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 ≤ 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.
PMCID: PMC2881848  PMID: 20421544
22.  Surveillance or metastasis-directed Therapy for OligoMetastatic Prostate cancer recurrence (STOMP): study protocol for a randomized phase II trial 
BMC Cancer  2014;14(1):671.
Metastases-directed therapy (MDT) with surgery or stereotactic body radiotherapy (SBRT) is emerging as a new treatment option for prostate cancer (PCa) patients with a limited number of metastases (≤3) at recurrence – so called “oligometastases”. One of the goals of this approach is to delay the start of palliative androgen deprivation therapy (ADT), with its negative impact on quality of life. However, the lack of a control group, selection bias and the use of adjuvant androgen deprivation therapy prevent strong conclusions from published studies.
The aim of this multicenter randomized phase II trial is to assess the impact of MTD on the start of palliative ADT compared to patients undergoing active surveillance.
Patients with an oligometastatic recurrence, diagnosed on choline PET/CT after local treatment with curative intent, will be randomised in a 1:1 ratio between arm A: active surveillance only and arm B: MTD followed by active surveillance. Patients will be stratified according to the location of metastasis (node vs. bone metastases) and PSA doubling time (≤3 vs. > 3 months). Both surgery and SBRT are allowed as MDT. Active surveillance means 3-monthly PSA testing and re-imaging at PSA progression. The primary endpoint is ADT-free survival. ADT will be started in both arms at time of polymetastatic disease (>3 metastatic lesions), local progression or symptoms. The secondary endpoints include progression-free survival, quality of life, toxicity and prostate-cancer specific survival.
This is the first randomized phase 2 trial assessing the possibility of deferring palliative ADT with MDT in oligometastatic PCa recurrence.
Trial registration identifier: NCT01558427
PMCID: PMC4175227  PMID: 25223986
Oligometastases; Prostate cancer; Salvage treatment; Stereotactic body radiotherapy; Salvage lymph node dissection; Active surveillance; Androgen deprivation therapy; Quality of life; Survival
23.  Changes in Biomarkers of Inflammation and Angiogenesis During Androgen Deprivation Therapy for Prostate Cancer 
The Oncologist  2012;17(2):212-219.
Inflammatory and angiogenic biomarkers were measured in androgen deprivation therapy–treated and control groups of men with prostate cancer. Significantly higher concentrations of some inflammatory biomarkers were found in the treatment group.
Angiogenesis and inflammation are both important to the pathogenesis of malignancies. Androgen deprivation therapy (ADT) for prostate cancer causes drastic hormonal changes that alter both disease and host factors. We measured inflammatory and angiogenic biomarkers in ADT-treated and control groups of men with prostate cancer.
Materials and Methods.
Baseline and 12-week plasma samples were collected from 37 ADT-naïve men with locally advanced or recurrent prostate cancer. Of those, 23 initiated ADT with a gonadotropin-releasing hormone (GnRH) agonist and 14 served as nontreatment controls. Samples were tested for a panel of angiogenic and inflammatory biomarkers.
The treatment group had significantly higher concentrations of the inflammatory biomarkers interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and stromal cell–derived factor (SDF)-1α. None of the angiogenic biomarkers were significantly different between the groups at baseline. Among patients with a short prostate-specific antigen (PSA) doubling time (<6 months), the proangiogenic factor basic fibroblast growth factor (bFGF) was lower at baseline. In the treatment group, plasma placental growth factor (PlGF) increased and IL-6 decreased after 12 weeks of ADT. Moreover, the treatment group continued to have significantly higher concentrations of the inflammatory biomarkers IL-1β, IL-8, and SDF-1α as well as bFGF than controls.
These men were characterized by elevations in several traditional markers of aggressive disease and also by higher levels of several inflammatory biomarkers. Although ADT decreased IL-6 levels, IL-1β, IL-8, and SDF-1α remained significantly higher than in controls. The role of these biomarkers should be further explored.
PMCID: PMC3286170  PMID: 22302227
24.  Repeated stereotactic body radiotherapy for oligometastatic prostate cancer recurrence 
To assess the outcome of prostate cancer (PCa) patients diagnosed with oligometastatic disease at recurrence and treated with stereotactic body radiotherapy (SBRT).
Non-castrate patients with up to 3 synchronous metastases (bone and/or lymph nodes) diagnosed on positron emission tomography - computed tomography, following biochemical recurrence after local curative treatment, were treated with (repeated) SBRT to a dose of 50 Gy in 10 fractions or 30 Gy in 3 fractions. Androgen deprivation therapy-free survival (ADT-FS) defined as the time interval between the first day of SBRT and the initiation of ADT was the primary endpoint. ADT was initiated if more than 3 metastases were detected during follow-up even when patients were still asymptomatic. Secondary endpoints were local control, progression free survival (PFS) and toxicity. Toxicity was scored using the Common Terminology Criteria for Adverse Events.
With a median follow-up from time of SBRT of 2 years, we treated 50 patients with 70 metastatic lesions with a local control rate of 100%. The primary involved metastatic sites were lymph nodes (54%), bone (44%), and viscera (2%). The median PFS was 19 mo (95% CI: 13–25 mo) with 75% of recurring patients having ≤3 metastases. A 2nd and 3rd course of SBRT was delivered in 19 and 6 patients respectively. This results in a median ADT-FS of 25 months (20–30 mo). On univariate analysis, only a short PSA doubling time was a significant predictor for both PFS (HR: 0.90, 95% CI: 0.82 – 0.99) and ADT-FS (HR: 0.83; 95% CI: 0.71 – 0.97). Ten patients (20%) developed toxicity following treatment, which was classified as grade I in 7 and grade II in 3 patients.
Repeated SBRT for oligometastatic prostate cancer postpones palliative androgen deprivation therapy with 2 years without grade III toxicity.
PMCID: PMC4066290  PMID: 24920079
Oligometastases; Prostate cancer; Recurrence; Salvage therapy; Stereotactic body radiotherapy
25.  Guideline-discordant androgen deprivation therapy in localized prostate cancer: patterns of use in the medicare population and cost implications 
Annals of Oncology  2012;24(5):1338-1343.
Androgen deprivation therapy (ADT) in localized prostate cancer improves overall survival and is recommended by National Comprehensive Cancer Network guidelines in certain situations. However, ADT is without benefit in other situations and can actually cause harm. This study examines recent trends in the ADT use and quantifies the cost of guideline-discordant ADT.
Patients and methods
Patients, aged 66–80 years, in the Surveillance Epidemiology and End Results-Medicare database with non-metastatic prostate cancer diagnosed between 2004 and 2007 were included for analysis. Prostate-specific antigen, Gleason score, and stage were used to define D'Amico risk categories. Logistic regression was used to examine factors associated with guideline-discordant ADT. Annual direct cost was estimated using 2011 Medicare reimbursement for ADT.
Of 28 654 men included, 12.4% received guideline-discordant ADT. In low-risk patients, 14.9% received discordant ADT, mostly due to simultaneous ADT with radiation. Discordant use was seen in 7.3% of intermediate and 14.9% of high-risk patients, mostly from ADT as primary therapy. The odds of receiving guideline-discordant ADT decreased over time (2007 versus 2004; OR 0.69; 95% CI 0.62–0.76). The estimated annual direct cost from discordant ADT is $42 000 000.
Approximately one in eight patients received ADT discordant with published guidelines. Elimination of discordant use would result in substantial savings.
PMCID: PMC3629897  PMID: 23277483
drug costs; gonadotropin-releasing hormone; health services; prostatic neoplasms; SEER program

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