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1.  Trends of risk classification and primary therapy for Japanese patients with prostate cancer in Nara Uro-Oncological Research Group (NUORG)–a comparison between 2004-2006 and 2007-2009 
BMC Cancer  2013;13:588.
Background
To assess the trends of risk classification and primary therapy in Japanese patients who were diagnosed with prostate cancer between 2004-2006 and 2007-2009.
Methods
A total of 4752 patients who were newly diagnosed with prostate cancer at Nara Medical University and its 23 affiliated hospitals between 2004 and 2009 were enrolled. The differences in risk classification and primary therapy were compared in patients who were newly diagnosed between 2004-2006 (prior period) and 2007-2009 (latter period).
Results
The proportion of patients with a high or greater risk significantly decreased in the latter period compared to the prior period (p < 0.001). The proportion of primary androgen deprivation therapy (PADT) was 50% in the prior period, and 40% in the latter period. On the other hand, the proportion of radiation therapy was 14% in the prior period, but 24% in the latter period. The proportion of radical prostatectomy was the same in the two periods (30%). The primary therapy was significantly different between the two periods (p < 0.001).
Conclusions
Higher risk patients significantly decreased in the latter period compared to the prior period. The use of PADT also significantly decreased in the latter period. However, there were still higher risk patients in Japan, and the use of PADT was still common in patients with localized prostate cancer or locally advanced prostate cancer in Japan.
doi:10.1186/1471-2407-13-588
PMCID: PMC4028809  PMID: 24325407
Primary therapy; Primary androgen deprivation therapy; Radical prostatectomy; Radiation therapy; Risk classification; Active surveillance
2.  The Role of Primary Androgen Deprivation Therapy in Localized Prostate Cancer 
European urology  2009;56(4):609-616.
Background
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.
Objective
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).
Intervention
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.
Measurements
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.
Conclusions
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.
doi:10.1016/j.eururo.2009.03.066
PMCID: PMC2791191  PMID: 19368995
3.  Nadir PSA level and time to nadir PSA are prognostic factors in patients with metastatic prostate cancer 
BMC Urology  2014;14:33.
Background
Primary androgen deprivation therapy (PADT) is the most effective systemic therapy for patients with metastatic prostate cancer. Nevertheless, once PSA progression develops, the prognosis is serious and mortal. We sought to identify factors that predicted the prognosis in a series of patients with metastatic prostate cancer.
Methods
Two-hundred eighty-six metastatic prostate cancer patients who received PADT from 1998 to 2005 in Nara Uro-Oncology Research Group were enrolled. The log-rank test and Cox’s proportional hazards model were used to determine the predictive factors for prognosis; rate of castration-resistant prostate cancer (CRPC) and overall survival.
Results
The median age, follow-up period and PSA level at diagnosis were 73 years, 47 months and 174 ng/mL, respectively. The 5-year overall survival rate was 63.0%. The multivariable analysis showed that Gleason score (Hazard ratio [HR]:1.362; 95% confidence interval [C.I.], 1.023-1.813), nadir PSA (HR:6.332; 95% C.I., 4.006-9.861) and time from PADT to nadir (HR:4.408; 95% C.I., 3.099-6.271) were independent prognostic factors of the incidence of CRPC. The independent parameters in the multivariate analysis that predicted overall survival were nadir PSA (HR:5.221; 95% C.I., 2.757-9.889) and time from PADT to nadir (HR:4.008; 95% C.I., 2.137-7.517).
Conclusions
Nadir PSA and time from PADT to nadir were factors that affect both CRPC and overall survival in a cohort of patients with metastatic prostate cancer. Lower nadir PSA level and longer time from PADT to nadir were good for survival and progression.
doi:10.1186/1471-2490-14-33
PMCID: PMC4018264  PMID: 24773608
Prostate cancer; Metastasis; Risk factors
4.  Risk Assessment Among Prostate Cancer Patients Receiving Primary Androgen Deprivation Therapy 
Journal of Clinical Oncology  2009;27(26):4306-4313.
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1200/JCO.2008.21.5228
PMCID: PMC2744272  PMID: 19667269
5.  Survival Following Primary Androgen Deprivation Therapy among Men with Localized Prostate Cancer 
Context
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.
Objective
Evaluate the association between PADT and survival in elderly men with localized prostate cancer.
Main Outcome Measures
Cancer-specific and overall survival.
Design
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.
Setting
Medicare patients aged ≥66 years diagnosed in 1992-2002 within predefined US geographical areas.
Results
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).
Conclusions
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.
doi:10.1001/jama.300.2.173
PMCID: PMC2645653  PMID: 18612114
prostatic neoplasm; Medicare; SEER program; antineoplastic agents; hormonal
6.  Does Primary Androgen-Deprivation Therapy Delay the Receipt of Secondary Cancer Therapy for Localized Prostate Cancer? 
European urology  2012;62(6):966-972.
Background
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).
Objective
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.
Conclusions
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.
doi:10.1016/j.eururo.2012.05.003
PMCID: PMC3472155  PMID: 22608160
Prostatic neoplasm; Medicare; SEER program; Antineoplastic agents–hormonal
7.  Androgen-deprivation therapy versus radical prostatectomy as monotherapy among clinically localized prostate cancer patients 
OncoTargets and therapy  2013;6:725-732.
Background
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.
Methods
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.
Results
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).
Conclusion
With adjustment for the observed selection bias, PADT was associated with increased all-cause mortality and PC-specific mortality when compared to RP.
doi:10.2147/OTT.S44144
PMCID: PMC3699299  PMID: 23836984
prostate cancer; primary androgen-deprivation treatment; radical prostatectomy; survival
8.  National Practice Patterns and Time Trends in Androgen Ablation for Localized Prostate Cancer 
Background
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.
Methods
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.
Results
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).
Conclusions
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
9.  Primary Androgen Deprivation Therapy for Prostate Cancer in Koreans: A Retrospective Multicenter Study 
The World Journal of Men's Health  2014;32(3):159-166.
Purpose
To evaluate the characteristics of patients who received primary androgen deprivation therapy (PADT) for prostate cancer and the clinical efficacy of this treatment.
Materials and Methods
Two hundred forty patients treated by PADT were reviewed. These patients could not receive definitive therapy owing to old age, patient need, and medical comorbidity. The patients were divided into three groups according to the extent of prostate cancer: localized, locally advanced, and metastatic. Then, prostate-specific antigen (PSA) progression in these groups was analyzed.
Results
The median age of the patients was 73.0 years, and the median pretreatment PSA level was 47.0 ng/mL. Of the patients, 91.7% were treated with combined androgen blockade, and 8.3% were treated with monotherapy. Clinical factors for PSA progression were a PSA nadir and a high clinical stage. Estimated PSA recurrence-free median survival time in each group was 57, 24, and 12 months, respectively. A PSA nadir of >0.2 ng/mL and metastatic stage were independent factors for expecting a poor response to PADT (hazard ratio 4.26, p<0.001; and 2.60, p<0.001).
Conclusions
Patients with localized or locally advanced prostate cancer who did not receive definitive therapy had lower PSA progression rates than those at metastatic stage during PADT. Further, a PSA nadir of ≤0.2 ng/mL showed better progression-free survival. Therefore, PADT can be another therapeutic option in well-selected patients with localized or locally advanced prostate cancer and PSA change should be checked carefully.
doi:10.5534/wjmh.2014.32.3.159
PMCID: PMC4298819  PMID: 25606565
Androgen antagonists; Prostate; Prostate neoplasms
10.  Evaluation of primary androgen deprivation therapy in prostate cancer patients using the J-CAPRA risk score 
Prostate International  2013;1(2):81-88.
Purpose:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.12954/PI.12016
PMCID: PMC3814111  PMID: 24223407
Prostate neoplasms; Maximal androgen blockade; Overall survival; Primary androgen deprivation therapy; Risk scoring
11.  Multi-transcript profiling in archival diagnostic prostate cancer needle biopsies to evaluate biomarkers in non-surgically treated men 
BMC Cancer  2014;14(1):673.
Background
Most biomarkers in prostate cancer have only been evaluated in surgical cohorts. The value of these biomarkers in a different therapy context remains unclear. Our objective was to test a panel of surgical biomarkers for prognostic value in men treated by external beam radiotherapy (EBRT) and primary androgen deprivation therapy (PADT).
Methods
The Fluidigm® PCR array was used for multi-transcript profiling of laser microdissected tumours from archival formalin-fixed diagnostic biopsies of patients treated by EBRT or PADT. Cases were matched for disease characteristics and had known 5 year biochemical relapse outcomes (n = 60). Results were validated by immunohistochemistry in a custom needle biopsy tissue microarray. Six biomarkers previously tested only in surgical cohorts were analysed (PTEN, E-Cadherin, EGFR, EZH2, PSMA, MSMB). Transcript and protein expression was correlated with clinical outcome analysed using Kruskal Wallis, Fisher’s test and Cox proportional hazard model.
Results
Altered expression of E-Cadherin (p = 0.008) was associated with early relapse after EBRT. In PADT treated men however only altered MSMB transcript was prognostic for early relapse (p = 0.001). The remaining biomarkers however did not demonstrate prognostic ability in either cohort. In a separate tissue array we validated altered E-Cadherin protein as a predictor of early relapse after EBRT (n = 47) (HR 0.34, CI p = 0.02) but not in PADT treated men (n = 63).
Conclusion
We demonstrate proof of principle of multiple transcript profiling in archival diagnostic biopsies of non-surgically treated men for biomarker discovery. We identify a role for E-Cadherin as a novel biomarker of early relapse following EBRT.
doi:10.1186/1471-2407-14-673
PMCID: PMC4174634  PMID: 25227682
12.  Oncological results, functional outcomes and health-related quality-of-life in men who received a radical prostatectomy or external beam radiation therapy for localized prostate cancer: a study on long-term patient outcome with risk stratification 
Asian Journal of Andrology  2009;11(3):283-290.
Health-related quality-of-life (HRQOL) after a radical prostatectomy (RP) or external beam radiation therapy (EBRT) has not been studied in conjunction with oncological outcomes in relation to disease risk stratification. Moreover, the long-term outcomes of these treatment approaches have not been studied. We retrospectively analyzed oncological outcomes between consecutive patients receiving RP (n = 86) and EBRT (n = 76) for localized prostate cancer. HRQOL and functional outcomes could be assessed in 62 RP (79%) and 54 EBRT (79%) patients over a 3-year follow-up period (median: 41 months) using the Medical Outcomes Study Short Form-36 (SF-36) and the University of California Los Angeles Prostate Cancer Index (UCLA PCI). The 5-year biochemical progression-free survival did not differ between the RP and EBRT groups for low-risk (74.6% vs. 75.0%, P = 0.931) and intermediate-risk (61.3% vs. 71.1%, P = 0.691) patients. For high-risk patients, progression-free survival was lower in the RP group (45.1%) than in the EBRT group (79.7%) (P = 0.002). The general HRQOL was comparable between the two groups. Regarding functional outcomes, the RP group reported lower scores on urinary function and less urinary bother and sexual bother than the EBRT group (P < 0.001, P < 0.05 and P < 0.001, respectively). With risk stratification, the low- and intermediate-risk patients in the RP group reported poorer urinary function than patients in the EBRT group (P < 0.001 for each). The sexual function of the high-risk patients in the EBRT group was better than that of the same risk RP patients (P < 0.001). Biochemical recurrence was not associated with the UCLA PCI score in either group. In conclusion, low- to intermediate-risk patients treated with an RP may report relatively decreased urinary function during long-term follow-up. The patient's HRQOL after treatment did not depend on biochemical recurrence.
doi:10.1038/aja.2009.10
PMCID: PMC3735298  PMID: 19349948
long-term observation; quality-of-life; radiation therapy; radical prostatectomy; risk stratification
13.  Variation in Adherence to External Beam Radiotherapy Quality Measures Among Elderly Men with Localized Prostate Cancer 
Purpose
We characterized variation in adherence to quality measures of external beam radiotherapy (EBRT) for localized prostate cancer and its relation to patient and provider characteristics in a population-based, representative sample of US men.
Methods and Materials
We evaluated EBRT quality measures proposed by a RAND expert panel of physicians among men age 65 or older diagnosed from 2000 to 2002 with localized prostate cancer and treated with primary EBRT using data from the linked Surveillance, Epidemiology, and End Results (SEER) Medicare program. We assessed adherence to five EBRT quality measures that were amenable to analysis using SEER-Medicare data: 1) use of conformal radiotherapy treatment planning; 2) use of high-energy (>10MV) photons; 3) use of custom immobilization; 4) completion of two follow-up visits with a radiation oncologist in the year following therapy; and 5) radiation oncologist board certification.
Results
Of the 11,674 patients, 85% received conformal radiotherapy treatment planning, 75% received high-energy photons, and 97% received custom immobilization. One-third of patients completed two follow-up visits with a radiation oncologist, though 91% had at least one visit with a urologist or a radiation oncologist. The majority of patients (85%) were treated by a board certified radiation oncologist.
Conclusions
Overall high adherence to EBRT quality measures masked substantial variation by geography, socioeconomic status in area of residence, and teaching affiliation of the radiotherapy facility. Future research should examine reasons for variation in these measures and whether variation is associated with important clinical outcomes.
doi:10.1016/j.ijrobp.2007.05.020
PMCID: PMC2267435  PMID: 17689880
Prostate cancer; quality of care; external beam radiotherapy; SEER-Medicare; health services research
14.  Prognostic utility of CCP score in men with prostate cancer after primary external beam radiation therapy 
Purpose
The cell cycle progression (CCP) score, a prognostic RNA signature based on the average expression level of 31 CCP genes, has been shown to predict biochemical recurrence (BCR) after prostatectomy and prostate cancer specific mortality in men undergoing observation. However, the value of the CCP score in men who received primary external beam radiation therapy (EBRT) is untested.
Methods and Materials
The CCP score was derived retrospectively from diagnostic biopsy specimens of men diagnosed with prostate cancer from 1991 to 2006 (n=141). All patients were treated with definitive EBRT; approximately half of the cohort was African-American. Outcome was time from EBRT to BCR using the Phoenix definition. Median follow-up for patients without BCR was 4.8 years. Association with outcome was evaluated by CoxPH survival analysis and likelihood ratio tests.
Results
Of 141 patients, 19 (13%) had BCR. The median CCP score for patient samples was 0.12. In univariable analysis, CCP score significantly predicted BCR (p-value = 0.0017). The hazard ratio (HR) for BCR was 2.55 for a one-unit increase in CCP score (equivalent to a doubling of gene expression). In a multivariable analysis with Gleason score, PSA, percent positive cores, and androgen deprivation therapy, the HR for CCP remained significant (p-value = 0.034), indicating that CCP provides prognostic information that is not provided by standard clinical parameters. With 10-year censoring, the CCP score was associated with prostate cancer specific mortality (p-value = 0.013). There was no evidence for interaction between CCP and any clinical variable, including ethnicity.
Conclusions
Among men treated with EBRT, the CCP score significantly predicated outcome and provided greater prognostic information than was available with clinical parameters. If validated in a larger cohort, CCP score could identify high-risk men undergoing EBRT who may need more aggressive therapy.
doi:10.1016/j.ijrobp.2013.04.043
PMCID: PMC3710548  PMID: 23755923
CCP; radiation; biomarkers
15.  Salvage radiotherapy after high-intensity focused ultrasound treatment for localized prostate cancer: feasibility, tolerance and efficacy 
Background:
The objective of this study is to evaluate the feasibility, tolerance and efficacy of salvage external beam radiotherapy (EBRT) in persistent or recurrent prostate cancer after failed high intensity focused ultrasound (HIFU) therapy.
Methods:
We reviewed data on tolerance and oncologic outcomes for all patients with biopsy-proven locally recurrent or persistent prostate cancer who underwent salvage EBRT in our department between April 2004 and June 2008. Minimum follow-up for inclusion was 2 years. Failure with EBRT was defined as biochemical relapse (Phoenix definition) or introduction of androgen deprivation therapy (ADT). Gastrointestinal and urinary toxicity and urinary stress incontinence were scored at 12 and 24 months (Radiation Therapy Oncology Group and Ingelman Sundberg rating, respectively).
Results:
The mean age of the patients was 68.8 years (range: 60–79). Mean prostate-specific antigen (PSA) before EBRT was 5.57 ng/mL (range: 2.5–14.8). Median follow-up was 36.5 ± 10.9 months (range: 24–54). No patient received adjunctive ADT. The EBRT course was well-tolerated and completed by all patients. The mean PSA nadir was 0.62 ng/mL (range: 0.03–2.4) and occurred after a median of 22 months (range: 12–36). One patient experienced biochemical failure and was prescribed ADT 30 months after EBRT. The disease-free survival rate was 83.3% at 36.5 months. There was no major EBRT-related toxicity at 12 or 24 months.
Conclusions:
Our early clinical results confirm the feasibility and good tolerance of salvage radiotherapy after HIFU failure. Oncological outcomes were promising. A prospective study with longer follow-up is needed to identify factors predictive of success for salvage EBRT therapy after HIFU failure.
doi:10.5489/cuaj.10137
PMCID: PMC3478387  PMID: 21539766
16.  Long-Term Survival After Radical Prostatectomy Versus External Beam Radiotherapy for Patients with High-Risk Prostate Cancer 
Cancer  2011;117(13):2883-2891.
BACKGROUND
We compared the long-term survival of patients with high-risk prostate cancer following radical prostatectomy (RRP) and external beam radiation therapy (EBRT) with and without adjuvant androgen deprivation treatment (ADT).
METHODS
We identified 1,238 patients who underwent RRP and 609 patients treated with EBRT (344 with EBRT + ADT and 265 with EBRT alone) between 1988–2004 who had a pretreatment prostate-specific antigen level (PSA) ≥ 20 ng/mL, biopsy Gleason score 8–10, or clinical stage ≥ T3. Median follow-up was 10.2, 6.0, and 7.2 years after RRP, EBRT + ADT, and EBRT alone, respectively. The impact of treatment modality on systemic progression, cancer-specific, and overall survival was evaluated using multivariable Cox proportional hazard regression analysis and a competing risk-regression model.
RESULTS
Ten-year cancer-specific survival was 92%, 92%, and 88% following RRP, EBRT + ADT, and EBRT alone (p=0.06). After adjustment for case mix, no significant differences in the risks of systemic progression (hazard ratio, 0.78; 95% CI, 0.51 to 1.18; p=0.23) or prostate cancer death (hazard ratio 1.14; 95% CI, 0.68 to 1.91; p=0.61) were seen between patients treated with EBRT + ADT and patients who underwent RRP. The risk of all-cause mortality was, however, greater after EBRT + ADT than RRP (hazard ratio, 1.60; 95% CI, 1.25 to 2.05; p=0.0002).
CONCLUSIONS
RRP and EBRT + ADT provide similar long-term cancer control for patients with high-risk disease. Continued investigation into the differing impact of treatments on quality-of-life and non-cancer mortality are necessary to determine the optimal management approach for these patients.
doi:10.1002/cncr.25900
PMCID: PMC3139725  PMID: 21692049
prostate cancer; radical prostatectomy; radiation therapy; androgen-deprivation therapy; prostate-specific antigen
17.  3-DIMENSIONAL EXTERNAL BEAM RADIOTHERAPY FOR PROSTATE CANCER INCREASES THE RISK OF HIP FRACTURE 
Cancer  2011;117(19):4557-4565.
Background
Hip fracture is associated with high morbidity and mortality. Pelvic external beam radiotherapy (EBRT) is known to increase the risk of hip fractures in women but the effect in men is unknown.
Methods
45,662 men aged ≥66 years, diagnosed with prostate cancer in 1992–2004 were identified from the SEER-Medicare database. Using Kaplan-Meier methods and Cox proportional hazards models, the primary outcome of hip fracture risk was compared among men who received radical prostatectomy (RP), EBRT, EBRT+androgen suppression therapy (AST) or AST alone, controlling for age, osteoporosis, race and other comorbidities. A secondary outcome was distal forearm fractures as an indicator of fragility fracture risk outside the radiation field.
Results
After controlling for covariates, EBRT increased the risk of hip fractures by 76% (HR 1.76, 95% CI 1.38–2.40) without increasing the risk of distal forearm fractures (HR 0.80, 95% CI 0.56–1.14). Combination therapy with EBRT+AST increased the risk of hip fracture 145% relative to RP (HR 2.45, 95% CI 1.88–3.19) and by 40% relative to EBRT (HR 1.40, 95% CI 1.17–1.68). EBRT+AST increased the risk of distal forearm fracture by 43% relative to RP (HR 1.43, 95% CI 0.97–2.10). The number needed to treat to result in 1 hip fracture through 10 years was 51 (95% CI 31–103).
Conclusion
In men with prostate cancer, pelvic 3-D conformal EBRT is associated with a 76% increased risk of hip fracture. This risk is slightly increased further by the addition of short-course AST to EBRT. This risk associated with EBRT is site-specific as there is no increase in the risk of fall-related fractures outside the radiation field.
doi:10.1002/cncr.25994
PMCID: PMC3135749  PMID: 21412999
18.  Treatment Decisions for Localized Prostate Cancer 
OBJECTIVE
To identify what factors men consider important when choosing treatment for prostate cancer, and to assess why men reject watchful waiting as a treatment option.
PARTICIPANTS
One hundred two consecutive men with newly diagnosed localized prostate cancer identified from hospital and community-based urology practice groups.
MEASUREMENTS
Patients were asked open-ended questions about likes and dislikes of all treatments considered, how they chose their treatment, and reasons for rejecting watchful waiting. The interviews were conducted in person, after the men had made a treatment decision but before they received the treatment.
MAIN RESULTS
The most common reasons for liking a treatment were removal of tumor for radical prostatectomy (RP) (n = 15), evidence for external beam radiation (EBRT) (n = 6), and short duration of therapy for brachytherapy (seeds) (n = 25). The most frequently cited dislikes were high risk of incontinence for RP (n = 46), long duration of therapy for EBRT (n = 29), and lack of evidence for seeds (n = 16). Only 12 men chose watchful waiting. Fear of future consequences, cited by 64% (n = 90) of men, was the most common reason to reject watchful waiting.
CONCLUSION
In discussing treatment options for localized prostate cancer, clinicians, including primary care providers, should recognize that patients' decisions are often based on specific beliefs regarding each therapy's intrinsic characteristics, supporting evidence, or pattern of complications. Even if patients do not recall a physician recommendation against watchful waiting, this option may not be chosen because of fear of future consequences.
doi:10.1046/j.1525-1497.2000.90842.x
PMCID: PMC1495597  PMID: 11089712
localized prostate cancer; treatment; decision making
19.  Hypofractionated SBRT versus conventionally fractionated EBRT for prostate cancer: comparison of PSA slope and nadir 
Background
Patients with early stage prostate cancer have a variety of curative radiotherapy options, including conventionally-fractionated external beam radiotherapy (CF-EBRT) and hypofractionated stereotactic body radiotherapy (SBRT). Although results of CF-EBRT are well known, the use of SBRT for prostate cancer is a more recent development, and long-term follow-up is not yet available. However, rapid post-treatment PSA decline and low PSA nadir have been linked to improved clinical outcomes. The purpose of this study was to compare the PSA kinetics between CF-EBRT and SBRT in newly diagnosed localized prostate cancer.
Materials/methods
75 patients with low to low-intermediate risk prostate cancer (T1-T2; GS 3 + 3, PSA < 20 or 3 + 4, PSA < 15) treated without hormones with CF-EBRT (>70.2 Gy, <76 Gy) to the prostate only, were identified from a prospectively collected cohort of patients treated at the University of California, San Francisco (1997–2012). Patients were excluded if they failed therapy by the Phoenix definition or had less than 1 year of follow-up or <3 PSAs. 43 patients who were treated with SBRT to the prostate to 38 Gy in 4 daily fractions also met the same criteria. PSA nadir and rate of change in PSA over time (slope) were calculated from the completion of RT to 1, 2 and 3 years post-RT.
Results
The median PSA nadir and slope for CF-EBRT was 1.00, 0.72 and 0.60 ng/ml and -0.09, -0.04, -0.02 ng/ml/month, respectively, for durations of 1, 2 and 3 years post RT. Similarly, for SBRT, the median PSA nadirs and slopes were 0.70, 0.40, 0.24 ng and -0.09, -0.06, -0.05 ng/ml/month, respectively. The PSA slope for SBRT was greater than CF-EBRT (p < 0.05) at 2 and 3 years following RT, although similar during the first year. Similarly, PSA nadir was significantly lower for SBRT when compared to EBRT for years 2 and 3 (p < 0.005).
Conclusion
Patients treated with SBRT experienced a lower PSA nadir and greater rate of decline in PSA 2 and 3 years following completion of RT than with CF-EBRT, consistent with delivery of a higher bioequivalent dose. Although follow-up for SBRT is limited, the improved PSA kinetics over CF-EBRT are promising for improved biochemical control.
doi:10.1186/1748-717X-9-42
PMCID: PMC3923240  PMID: 24484652
SBRT; Stereotactic body radiotherapy; Prostate; External beam; Conventionally fractionated; Nadir; Kinetics; Slope
20.  Urethroplasty After Radiation Therapy for Prostate Cancer 
Urology  2012;79(6):1402-1405.
OBJECTIVE
To report urethroplasty outcomes in men who developed urethral stricture after undergoing radiation therapy for prostate cancer.
METHODS
Our urethroplasty database was reviewed for cases of urethral stricture after radiation therapy for prostate cancer between June 2004 and May 2010. Patient demographics, prostate cancer therapy type, stricture length and location, and type of urethroplasty were obtained. All patients received clinical evaluation, including imaging studies post procedure. Treatment success was defined as no need for repeat surgical intervention.
RESULTS
Twenty-nine patients underwent urethroplasty for radiation-induced stricture. Previous radiation therapy included external beam radiotherapy (EBRT), radical prostatectomy (RP)/EBRT, EBRT/brachytherapy (BT) and BT alone in 11 (38%), 7 (24%), 7 (24%), and 4 (14%) patients, respectively. Mean age was 69 (±6.9) years. Mean stricture length was 2.6 (±1.6) cm. Anastomotic urethroplasty was performed in 76% patients, buccal mucosal graft in 17%, and perineal flap repair in 7%. Stricture was localized to bulbar urethra in 12 (41%), membranous in 12 (41%), vesicourethra in 3 (10%), and pan-urethral in 2 (7%) patients. Overall success rate was 90%. Median follow-up was 40 months (range 12-83). Time to recurrence ranged from 6-16 months.
CONCLUSION
Multiple forms of urethroplasty appear to be viable options in treating radiation-induced urethral stricture. Future studies are needed to examine the durability of repairs.
doi:10.1016/j.urology.2011.11.077
PMCID: PMC3565607  PMID: 22521189
21.  Mortality After Prostate Cancer Treatment with Radical Prostatectomy, External-Beam Radiation Therapy, or Brachytherapy in Men Without Comorbidity 
European urology  2013;64(3):372-378.
Background
Medical comorbidity is a confounding factor in prostate cancer (PCa) treatment selection and mortality. Large-scale comparative evaluation of PCa mortality (PCM) and overall mortality (OM) restricted to men without comorbidity at the time of treatment has not been performed.
Objective
To evaluate PCM and OM in men with no recorded comorbidity treated with radical prostatectomy (RP), external-beam radiation therapy (EBRT), or brachytherapy (BT).
Design, setting, and participants
Data from 10 361 men with localized PCa treated from 1995 to 2007 at two academic centers in the United States were prospectively obtained at diagnosis and retrospectively reviewed. We identified 6692 men with no recorded comorbidity on a validated comorbidity index. Median follow-up after treatment was 7.2 yr.
Intervention
Treatment with RP in 4459 men, EBRT in 1261 men, or BT in 972 men.
Outcome measurements and statistical analysis
Univariate and multivariate Cox proportional hazards regression analysis, including propensity score adjustment, compared PCM and OM for EBRT and BT relative to RP as reference treatment category. PCM was also evaluated by competing risks analysis.
Results and limitations
Using Cox analysis, EBRT was associated with an increase in PCM compared with RP (hazard ratio [HR]: 1.66; 95% confidence interval [CI], 1.05–2.63), while there was no statistically significant increase with BT (HR: 1.83; 95% CI, 0.88–3.82). Using competing risks analysis, the benefit of RP remained but was no longer statistically significant for EBRT (HR: 1.55; 95% CI, 0.92–2.60) or BT (HR: 1.66; 95% CI, 0.79–3.46). In comparison with RP, both EBRT (HR: 1.71; 95% CI, 1.40–2.08) and BT (HR: 1.78; 95% CI, 1.37–2.31) were associated with increased OM.
Conclusions
In a large multicenter series of men without recorded comorbidity, both forms of radiation therapy were associated with an increase in OM compared with surgery, but there were no differences in PCM when evaluated by competing risks analysis. These findings may result from an imbalance of confounders or differences in mortality related to primary or salvage therapy.
doi:10.1016/j.eururo.2013.03.005
PMCID: PMC3930076  PMID: 23506834
Prostatic neoplasms; Prostatectomy; Radiation therapy; Comorbidity; Comparative effectiveness research
22.  Patient-reported genitourinary toxicity for long-term prostate cancer survivors treated with radiation therapy 
British Journal of Cancer  2013;108(10):1964-1970.
Background:
The objective of this study is to provide comprehensive overviews of patient-reported urinary symptoms for long-term prostate cancer survivors treated with radiation therapy and for untreated, healthy men.
Methods:
We performed a population-based cross-sectional study using a study-specific postal questionnaire assessing symptoms among 1007 men consecutively treated at the Sahlgrenska University Hospital, Göteborg, Sweden from 1993–2006 (primary or salvage external beam radiation therapy (EBRT) or EBRT and high-dose rate brachytherapy). We also randomly recruited 350 non-pelvic-irradiated matched control men from the Swedish Total Population Register. Symptom prevalence and prevalence ratios were computed.
Results:
Survey participation rate was 89% (874/985) for eligible survivors and 73% (243/332) for eligible controls. Median time from treatment to follow-up was 5 years (range, 1–14 years). Among the 21 investigated symptoms reflecting obstruction, frequency, urgency, pain and incontinence, we found significantly higher prevalence compared with controls for 9 symptoms in the EBRT group, 10 in the EBRT+brachytherapy group and 5 in the salvage EBRT group. The prevalence for a majority of the symptoms was stable over time.
Conclusion:
The presented toxicity profiles provide a thorough understanding of patient-reported urinary symptoms that can assist in developing personalised therapy for prostate cancer.
doi:10.1038/bjc.2013.180
PMCID: PMC3670502  PMID: 23632483
genitourinary toxicity; radiation therapy; prostate cancer
23.  Efficacy and Safety of High-Dose-Rate Brachytherapy of Single Implant with Two Fractions Combined with External Beam Radiotherapy for Hormone-Naïve Localized Prostate Cancer 
Cancers  2011;3(3):3585-3600.
The purpose of this study was to evaluate the efficacy and safety of high-dose-rate (HDR) brachytherapy of a single implant with two fractions plus external beam radiotherapy (EBRT) for hormone-naïve prostate cancer in comparison with radical prostatectomy. Of 150 patients with localized prostate cancer (T1c–T2c), 59 underwent HDR brachytherapy plus EBRT, and 91 received radical prostatectomy. The median follow-up of patients was 62 months for HDR brachytherapy plus EBRT, and 64 months for radical prostatectomy. In patient backgrounds between the two cohorts, the frequency of T2b plus T2c was greater in HDR brachytherapy cohort than in prostatectomy cohort (27% versus 12%, p = 0.029). Patients in HDR brachytherapy cohort first underwent 3D conformal RT with four beams to the prostate to an isocentric dose of 50 Gy in 25 fractions and then, a total of 15–18 Gy in two fractions at least 5 hours apart. We prescribed 9 Gy/fraction for target (prostate gland plus 3 mm lateral outside margin and seminal vesicle) using CT image method for radiation planning. The total biochemical failure-free control rates (BF-FCR) at 3 and 5 years for the HDR brachytherapy cohort, and for the prostatectomy cohort were 92% and 85%, and 72% and 72%, respectively (significant difference, p = 0.0012). The 3-and 5-year BF-FCR in the HDR brachytherapy cohort and in the prostatectomy cohort by risk group was 100 and 100%, and 80 and 80%, respectively, for the low-risk group (p = 0.1418); 92 and 92%, 73 and 73%, respectively, for the intermediate-risk group (p = 0.0492); and 94 and 72%, 45 and 45%, respectively, for the high-risk group (p = 0.0073). After HDR brachytherapy plus EBRT, no patient experienced Grade 2 or greater genitourinay toxicity. The rate of late Grade 1 and 2 GI toxicity was 6% (n = 4). No patient experienced Grade 3 GI toxicity. HDR brachytherapy plus EBRT is useful for treating patients with hormone-naïve localized prostate cancer, and has low GU and GI toxicities.
doi:10.3390/cancers3033585
PMCID: PMC3759211  PMID: 24212968
prostate cancer; high dose rate brachytherapy; external beam radiation therapy; radical prostatectomy
24.  P006: Peripheral and Central Markers of Fatigue in Men Receiving Localized Radiation Therapy 
Current Oncology  2012;19(5):e372.
Objective:
To explore potential markers of peripheral and central fatigue in men with localized prostate cancer receiving external-beam radiation therapy (ebrt).
Method:
Questionnaires and peripheral blood were collected at baseline (D0), midpoint (D21), and endpoint (D42) of ebrt. Fatigue was measured by the revised Piper Fatigue Scale. Aldolase and mcp-1 levels were explored as markers of peripheral and central fatigue, respectively; both were measured using elisa from serum samples. Muscle strength and cognitive function were measured by hand-grip dynamometer and stroop test, respectively. Descriptive statistics and t-tests were used to analyze the changes and differences of means between groups.
Results:
The 38 subjects enrolled were grouped into high fatigue (hf) and low fatigue (lf) based on changes in fatigue scores during ebrt, using baseline as control. Fatigue scores increased significantly from baseline to midpoint in the hf (p < 0.01) and the lf (p = 0.03) groups and remained elevated at completion of ebrt in both groups (p = 0.01). Aldolase levels significantly increased from baseline to midpoint (p = 0.05) in the lf group, but not in the hf group (p = 0.31). There were no significant changes in mcp- 1 levels over time during ebrt for both groups (p = 0.27–0.98); however, mcp-1 concentrations trended towards significance different at midpoint between the groups (p = 0.09). No significant changes in maximum voluntary contraction (mvc) and static fatigue were noted over time during ebrt compared with baseline in both groups (p = 0.30–0.82), and the number of wrong answers and reaction time from stroop test in both groups were nonsignificant (p = 0.07–0.87).
Conclusions:
Fatigue is associated with increased aldolase concentration in prostate cancer patients during ebrt. Aldolase may serve as a physical and a central marker of fatigue in this population. Further studies exploring and validating biomarkers of physical and central fatigue will be necessary to identify novel interventional targets.
PMCID: PMC3457894
25.  P005: Levels of Peripheral Blood Cells During External-Beam Radiation Therapy: Relationship with Fatigue 
Current Oncology  2012;19(5):e372.
Objectives:
To determine association between levels of peripheral blood cells and fatigue symptoms of men with nonmetastatic prostate cancer receiving external-beam radiation therapy (ebrt). ebrt is the second most common treatment modality used for treatment of nonmetastatic prostate cancer. Up to 71% of prostate cancer patients complain of fatigue during ebrt, which decreases their quality of life.
Methods:
An exploratory and longitudinal study design. Men with prostate cancer who schedule to receive ebrt were enrolled under active protocol (NCT00852111). All study participants completed the Functional Assessment of Chronic Illness Therapy–Fatigue (facit-F) and had peripheral blood drawn at 3 time points: baseline (D0), midpoint (D21), and ebrt completion (D42). One-way repeated-measures analysis of variance (ANOVA) and multivariate linear regression were used for data analysis.
Results:
The preliminary analysis included 34 prostate cancer patients. Results showed significant changes of fatigue scores, red blood cells (rbcs), hematocrit, hemoglobin, absolute basophil count, absolute lymphocyte count, and absolute reticulocyte count over time in patients during ebrt compared with baseline (p ≤ 0.05) At all 3 time points, deceasing hemoglobin (β = −2.5, p < 0.01) and increasing absolute reticulocyte count (β = 0.26, p < 0.01) and absolute basophil count (β = 233.0, p < 0.01) predict worsening fatigue.
Conclusions:
The study findings provide empirical evidence of the significant association in this population between worsening fatigue and changes in blood counts levels associated with anemia and inflammation. Interventions that address anemia and inflammation related to ebrt may reduce the fatigue symptoms experienced by these subjects.
PMCID: PMC3457893

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